Walsh&Hoyt Clinical Neuro-Ophthalmology

Walsh and Hoyt’s
Clinical
Neuro-Ophthalmology
Volume One Sixth Edition
Walsh and Hoyt’s
Clinical
Neuro-Ophthalmology
Sixth Edition
Neil R. Miller, MD Nancy J. Newman, MD

Professor of Ophthalmology, Neurology, and LeoDelle Jolley Professor of Ophthalmology
Neurosurgery Professor of Ophthalmology and Neurology
Frank B. Walsh Professor of Neuro-Ophthalmology Instructor in Neurological Surgery
Director, Neuro-Ophthalmology and Orbital Units Director, Neuro-Ophthalmology Unit
Wilmer Eye Institute Emory University School of Medicine
Johns Hopkins Hospital Atlanta, Georgia
Baltimore, Maryland Lecturer in Ophthalmology
Harvard Medical School
Boston, Massachusetts
Valérie Biousse, MD John B. Kerrison, MD

Cyrus H. Stoner Professor of Ophthalmology Assistant Professor of Ophthalmology, Neurology, and
Associate Professor of Ophthalmology and Neurology Neurosurgery
Emory University School of Medicine Wilmer Eye Institute
Atlanta, Georgia Johns Hopkins Hospital
Baltimore, Maryland
Acquisitions Editor: Jonathan Pine
Developmental Editor: Grace Caputo and Stacey Sebring
Project Manager: David Murphy
Manufacturing Manager: Ben Rivera
Production Services: Maryland Composition, Inc.
Printer: Maple Press
Copyright 2005 by Lippincott Williams & Wilkins

Fifth Edition 1998 Williams & Wilkins
Fourth Edition 1982 Williams & Wilkins
Third Edition 1969
Second Edition 1957
First Edition 1947
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Library of Congress Cataloging-in-Publication Data
Walsh and Hoyt’s clinical neuro-ophthalmology.—6th ed. / [editors,

Neil R. Miller et al.]
p. cm.
Includes bibliographical references and index.
ISBN 0-7817-4811-9 (v. 1)—ISBN 0-7817-4812-7 (v. 2)—
ISBN 0-7817-4813-5 (v. 3)—ISBN 0-7817-4814-3 (set)
1. Neuroophthalmology. 2. Eye—Diseases. I. Title: Clinical
neuroophthalmology.
II. Miller, Neil R. III.Walsh, Frank Burton, 1896–
IV. Hoyt, William Fletcher, 1926–
[DNLM: 1. Eye Diseases. 2. Neurologic Manifestations.
WW 140 W223 2005]
RE725.W348 2005
617.7—dc22 2004021741
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Dedication
To Our Families
v
Preface
It goes without saying (but I will say it anyway) that times thorship. The publication of this 5-volume work occurred in
have changed since Dr. Frank B. Walsh wrote the first edi- the nearly record time of 2 years.
tion of this text in 1947. The first two editions, each a single It is now time for a 6th edition and for this, Dr. Newman
volume, were written by Dr. Walsh alone and primarily re- and I have invited two associate editors, Dr. Valérie Biousse
lated his personal experiences and those of his colleagues. In and Dr. John B. Kerrison, to assist. In addition, because of
1969, he and Dr. William F. Hoyt, wrote the third edition—a the explosion of information available on the world-wide
three-volume masterpiece of ophthalmology, neurology, web and search engines such as Pub Med and OVID, the
neurosurgery, and general medicine with extensive illustra- four of us decided to reduce the size of the text to make it
tions and references. In 1978, I was asked to write the next more manageable and more accessible for the reader, while
edition. That 4th edition consisted of five volumes and took at the same time maintaining the high quality of the previous
14 years to produce, with the volumes published sequentially editions, including an up-to-date set of references. Once
again, we called upon 60 of our trusted colleagues to help us
between 1982 and 1996. Inevitably, the material was des-
achieve this goal, and they have risen to the task. With their
tined to become outdated, even during the production of the help, we have produced a three-volume 6th edition that is
edition. Thus, for the next edition, it was clear that a single- about 2000 pages shorter than the previous edition, but main-
authored text was no longer feasible, and I asked my friend tains the high-quality illustrations, personal observations, and
and colleague, Dr. Nancy J. Newman, to co-edit a multi- both new and old references that characterized the previous
authored edition. Sixty contributors updated the material editions of this text. We hope our readers will enjoy the new
from the 4th edition and, in some cases, completely wrote edition and that it will provide them with a useful resource for
or rewrote their chapters. They brought a depth of under- teaching, research, and the best possible patient care.
standing and a wealth of knowledge to the 5th edition that
could not possibly be accomplished with single or dual au- Neil R. Miller, MD FACS
vii
Acknowledgements
The editors would first like to thank each of the authors who ton F. Goldberg, MD, for his unwavering support during the
contributed to this text. It is only through their dedication initial phases of this project, and their current chairman,
and hard work that this text could be produced. We also Peter J. McDonnell, MD, who continues the Wilmer tradi-
appreciate the hard work and expertise of the terrific staff tion of excellence. Dr. Kerrison would like to thank Neil R.
at LWW and Maryland Composition, particularly Stacey Miller, MD, Nancy J. Newman, MD, Irene H. Maumenee,
Sebring, Grace Caputo, Joyce Murphy, Jonathan Pine, Scott MD, William R. Green, MD, and Donald J. Zack, MD, PhD
Lavine, and Heidi Pongratz. They and others spent many for their continual support and encouragement. Above all,
Dr. Kerrison wishes to express his awe and gratitude to the
long hours crafting this text.
Lord, who makes all things worthwhile.
Melissa Surbaugh provided superb editorial assistance for Drs. Newman and Biousse would like to personally thank
the chapters edited by Drs. Newman and Biousse, whereas Thomas M. Aaberg, MD, for continuing to foster an unparal-
Drs. Miller and Kerrison were aided by the extraordinary leled academic environment at Emory University. A special
editorial skills of Drs. Richard Levy and Aarup Kubal. Mi- thanks also from Dr. Newman to Simmons Lessell, MD, and
chael McIlwaine and other members of the Photography de- from Dr. Biousse to her mentors Marie-Germaine Bousser,
partment of the Wilmer Eye Institute provided rapid and MD, Nancy J. Newman, MD, and Monique Schaison, MD.
superb photographic assistance for many of the chapters. Finally, Dr. Miller would like to thank Carol Miller, RD,
Drs. Miller and Kerrison thank their past chairman, Mor- MEd for 25 years of editorial and photographic assistance.
ix
Contributors
Madhu R. Agarwal, MD Valérie Biousse, MD

Assistant Professor of Ophthalmology Cyrus H. Stoner Professor of Ophthalmology
Division of Neuro-Ophthalmology and Orbital Surgery Associate Professor of Ophthalmology and Neurology
Loma Linda University Medical Center Emory University School of Medicine
Loma Linda, California Atlanta, Georgia
Clinical Instructor of Ophthalmology
Doheny Eye Institute Mark S. Borchert, MD
University of Southern California Keck School of Associate Professor of Ophthalmology and Neurology
Medicine University of Southern California Keck School of
Los Angeles, California Medicine
Division Head
Anthony C. Arnold, MD Department of Ophthalmology
Professor and Chief Childrens Hospital of Los Angeles
Neuro-Ophthalmology Division Los Angeles, California
Jules Stein Eye Institute
Department of Ophthalmology Paul W. Brazis, MD
University of California-Los Angeles Professor of Neurology
Los Angeles, California Consultant in Neurology and Neuro-ophthalmology
Mayo Clinic-Jacksonville
Laura J. Balcer, MD, MSCE Jacksonville, Florida
Associate Professor of Neurology and Ophthalmology
University of Pennsylvania Michael C. Brodsky, MD
Neuro-Ophthalmologist Professor of Ophthalmology and Pediatrics
Hospital of the University of Pennsylvania University of Arkansas for Medical Sciences
Scheie Eye Institute Chief of Pediatric Ophthalmology
Philadelphia, Pennsylvania Arkansas Childrens Hospital
Jason J. S. Barton, MD, PhD, FRCP(C) Little Rock, Arkansas
Associate Professor of Neurology
Preston C. Calvert, MD
Harvard Medical School
Assistant Professor of Neurology
Adjunct Professor of Bioengineering
Johns Hopkins University School of Medicine
Boston University
Baltimore, Maryland
Director of Neuro-Ophthalmology
Attending Physician in Neurology
Beth Israel Deaconess Medical Center
Fairfax Hospital
Boston, Massachusetts
Fairfax, Virginia
Ghassan K. Bejjani, MD
Clinical Assistant Professor of Neurosurgery David Alston Chesnutt, MD
University of Pittsburgh School of Medicine Clinical Assistant Professor of Ophthalmology
Pittsburgh, Pennsylvania Duke University Eye Center
Attending Surgeon in Ophthalmology Service
M. Tariq Bhatti, MD Durham Veterans Administration Medical Center
Assistant Professor of Ophthalmology, Neurology, and Durham, North Carolina
Neurosurgery
University of Florida College of Medicine Kimberley P. Cockerham, MD
Ophthalmology Consultant Associate Professor of Ophthalmology
Malcolm Randall Veterans Administration Medical Center University of California-San Francisco
Gainesville, Florida San Francisco, California
xi
xii CONTRIBUTORS
Wayne T. Cornblath, MD Robert A. Goldberg, MD, FACS

Clinical Professor of Ophthalmology and Visual Science Professor of Ophthalmology
and Neurology Chief, Orbital and Ophthalmic Plastic Surgeon Division
University of Michigan Jules Stein Eye Institute
Ann Arbor, Michigan University of California-Los Angeles
Los Angeles, California
Kathleen B. Digre, MD
Professor of Neurology and Ophthalmology Karl C. Golnik, MD
Moran Eye Center Associate Professor of Ophthalmology, Neurology,
University of Utah Neurosurgery
Departments of Neurology and Ophthalmology University of Cincinnati
University of Utah Hospital Cincinnati Eye Institute
Salt Lake City, Utah Cincinnati, Ohio
Robert A. Egan, MD Lynn K. Gordon, MD, PhD

Associate Professor of Ophthalmology, Neurology, and Assistant Professor of Ophthalmology
Neurosurgery Jules Stein Eye Institute
Casey Eye Institute Chief, Ophthalmology Section
Oregon Health and Science University Greater Los Angeles Veterans Affairs Health Care System
Portland, Oregon Los Angeles, California
Eric R. Eggenberger, DO Steven R. Hamilton, MD

Professor of Neurology and Ophthalmology Clinical Associate Professor of Ophthalmology and
Department of Neurology and Ophthalmology Neurology
Michigan State University University of Washington
East Lansing, Michigan Neuro-Ophthalmic Consultants Northwest
Seattle, Washington
Rod Foroozan, MD
Assistant Professor of Ophthalmology Thomas R. Hedges III, MD
Baylor College of Medicine Professor of Ophthalmology and Neurology
Houston, Texas Tufts University
Director of Neuro-Ophthalmology
Deborah I. Friedman, MD Tufts New England Medical Center
Associate Professor of Ophthalmology and Neurology Boston, Massachusetts
University of Rochester
Rochester, New York Paul N. Hoffman, MD, PhD
Research Associate of Ophthalmology and Neurology
Benjamin M. Frishberg, MD Wilmer Ophthalmological Institute
Associate Clinical Professor of Neuroscience The Johns Hopkins School of Medicine
University of California-San Diego Baltimore, Maryland
Department of Neurology
Scripps Memorial Hospital Daniel M. Jacobson
La Jolla, California deceased
Steven L. Galetta, MD Chris A. Johnson, PhD

Van Meter Professor of Neurology Director of Diagnostic Research in Ophthalmology
Professor of Neurology and Ophthalmology Devers Eye Institute
University of Pennsylvania Medical Center Legacy Health Systems
Chief, Division of Neuro-Ophthalmology Portland, Oregon
Philadelphia, Pennsylvania
Randy Kardon, MD, PhD
John W. Gittinger, Jr., MD Professor of Ophthalmology and Visual Science
Professor of Ophthalmology and Neurology University of Iowa College of Medicine
Boston University School of Medicine Director of Neuro-Ophthalmology
Residency Program Director for Ophthalmology University of Iowa Hospital and Clinics and Veterans
Boston Medical Center Administration
Boston, Massachusetts Iowa City, Iowa
CONTRIBUTORS xiii
Barrett Katz, MD, MBA Robert L. Lesser, MD

Professor of Ophthalmology, Neurology, and Clinical Professor of Ophthalmology and Visual Science,
Neurosurgery and Neurology
Weill Medical College of Cornell University and New Yale University School of Medicine
York-Presbyterian Hospital New Haven, Connecticut
Vice President for Medical Affairs Clinical Professor of Neurology and Neurosurgery
Eyetech Pharmaceuticals, Inc. University of Connecticut School of Medicine
New York, New York Farmington, Connecticut
David I. Kaufman, DO Leonard A. Levin, MD, PhD

Professor and Chair Associate Professor of Ophthalmology and Visual
Department of Neurology and Ophthalmology Sciences, Neurology, and Neurological Surgery
Michigan State University University of Wisconsin
East Lansing, Michigan Madison, Wisconsin
Director of Clinical Neurosciences
Sparrow Health Systems Grant T. Liu, MD
Lansing, Michigan Professor of Neurology and Ophthalmology
University of Pennsylvania School of Medicine
Aki Kawasaki, MD, MER Hospital of the University of Pennsylvania
Mantre d’Enseignement et de Recherche of Children’s Hospital of Philadelphia
Ophthalmology Scheie Eye Institute
University of Lausanne Philadelphia, Pennsylvania
Medecin Associee in Neuro-Ophthalmology
Hopital Ophtalmique Jules Gonin Joseph C. Maroon
Lausanne, Switzerland Professor of Neurosurgery
Heindl Scholar
Christopher Kennard, PhD, FRCP, FMedSci Tristate Neurosurgical Associates
Head, Department of Visual Neuroscience University of Pittsburgh Medical Center
Faculty of Medicine Pittsburgh, Pennsylvania
Imperial College London
Charing Cross Hospital Neil R. Miller
London, United Kingdom Professor of Ophthalmology, Neurology, and
John S. Kennerdell, MD Neurosurgery
Professor of Ophthalmology Frank B. Walsh Professor of Neuro-Ophthalmology
Drexel University College of Medicine Director, Neuro-Ophthalmology and Orbit Units
Philadelphia, Pennsylvania Wilmer Eye Institute
Chairman of Ophthalmology Johns Hopkins Hospital
Allegheny General Hospital Baltimore, Maryland
Pittsburgh, Pennsylvania
Mark L. Moster, MD
John B. Kerrison, MD Professor of Neurology
Assistant Professor of Ophthalmology, Neurology, and Thomas Jefferson School of Medicine
Neurosurgery Chairman, Division of Neuro-Ophthalmology
Wilmer Eye Institute Albert Einstein Medical Center
Johns Hopkins Hospital Instructor, Neuro-Ophthalmology
Baltimore, Maryland Wills Eye Institute
Philadelphia, Pennsylvania
Andrew G. Lee, MD
Professor of Ophthalmology, Neurology, and Golnaz Moazami
Neurosurgery Assistant Clinical Professor of Ophthalmology
University of Iowa Hospitals and Clinics Edward S. Harkness Eye Institute
Iowa City, Iowa Columbia University
New York, New York
R. John Leigh, MD
Blair-Daroff Professor of Neurology Parashkev Nachev, MRCP
Case Western Reserve University Clinical Research Fellow of Visual Neuroscience
Staff Neurologist Faculty of Medicine
Louis Stokes Veterans Affairs Medical Center Imperial College London
Cleveland, Ohio London, United Kingdom
xiv CONTRIBUTORS
Nancy J. Newman, MD Matthew Rizzo, MD

LeoDelle Jolley Professor of Ophthalmology Professor of Neurology, Engineering, and Public Policy
Professor of Ophthalmology and Neurology Director, Division of Neuroergonomics
Instructor in Neurological Surgery Carver College of Medicine
Director, Neuro-Ophthalmology Unit University of Iowa
Emory University School of Medicine Iowa City, Iowa
Atlanta, Georgia
Lecturer in Ophthalmology Janet C. Rucker, MD
Harvard Medical School Assistant Professor of Neurology
Boston, Massachusetts Case Western Reserve University
Staff Neurologist
Steven A. Newman, MD University Hospitals
Professor of Ophthalmology Cleveland, Ohio
University of Virginia
Director, Neuro-Ophthalmology Alfredo A. Sadun, MD, PhD
University of Virginia Thornton Chair
Charlottesville, Virginia Professor of Ophthalmology and Neurological Surgery
David E. Newman-Toker, MD Doheny Eye Institute
Assistant Professor of Neurology and Ophthalmology University of Southern California Keck School of
The Johns Hopkins University School of Medicine Medicine
Active Staff in Neurology Los Angeles, California
Johns Hopkins Hospital
Baltimore, Maryland Jane C. Sargent, MD
Professor of Clinical Neurology and Clinical Surgery
Paul H. Phillips, MD University of Massachusetts Medical School
Associate Professor of Ophthalmology Department of Neurology
University of Arkansas for Medical Sciences University of Massachusetts Memorial Medical Center
Department of Ophthalmology Worcester, Massachusetts
Arkansas Childrens Hospital
Little Rock, Arkansas James A. Sharpe, MD, FRCP(C)
Professor of Neurology
Howard D. Pomeranz, MD, PhD University of Toronto
Associate Professor of Ophthalmology, Neurology, and Director of Neuro-Ophthalmology and Neuro-Otology
Neurosurgery Center
University of Minnesota Medical School University Health Network
Minneapolis, Minnesota Toronto, Ontario, Canada
Valerie Purvin, MD Barry Skarf, MD, PhD
Clinical Professor of Ophthalmology and Neurology Adjunct Associate Professor of Ophthalmology
Indiana University Medical Center University of Toronto
Chief, Neuro-Ophthalmology Service Toronto, Ontario, Canada
Midwest Eye Institute Director of Neuro-ophthalmology service
Methodist Hospital Henry Ford Hospital
Indianapolis, Indiana Detroit, Michigan
Michael X. Repka, MD
Professor of Ophthalmology and Pediatrics Craig H. Smith, MD
The Johns Hopkins School of Medicine Clinical Professor of Neurology, Medicine, and
Department of Ophthalmology Ophthalmology
The Johns Hopkins Hospital University of Washington
Baltimore, Maryland President, MS Hub Medical Group
Seattle, Washington
Joseph F. Rizzo III, MD
Associate Professor of Ophthalmology Kenneth David Steinsapir, MD
The Massachusetts Eye and Ear Infirmary Assistant Clinical Professor of Ophthalmology
Harvard Medical School Jules Stein Eye Institute
Director, Center for Innovative Visual Rehabilitation David Geffen School of Medicine at the University of
Boston Veterans Administration Hospital California-Los Angeles
Boston, Massachusetts Los Angeles, California
CONTRIBUTORS xv
Prem S. Subramanian, MD, PhD Joel M. Weinstein, MD

Assistant Professor of Surgery Clinical Associate Professor of Ophthalmology & Visual
Division of Ophthalmology Sciences and Neurology
Uniformed Services University of the Health Sciences University of Wisconsin
Bethesda, Maryland University of Wisconsin Hospital
Director, Neuro-Ophthalmology Madison, Wisconsin
Walter Reed Army Medical Center
Washington, District of Columbia Jacqueline M. S. Winterkorn, MD, PhD
Clinical Professor of Ophthalmology and Neurology &
Gregory P. Van Stavern, MD Neuroscience
Assistant Professor of Ophthalmology and Weill Medical College of Cornell University
Neurology Attending in Ophthalmology and Neurology
Wayne State University The New York Presbyterian Hospital
Director of Neuro-Ophthalmology New York, New York
Kresge Eye Institute
Detroit, Michigan Agnes M. F. Wong, MD, PhD, FRCSC
Assistant Professor of Ophthalmology and Neurology
University of Toronto
Michael S. Vaphiades, DO
UHN-Toronto Western Hospital, and The Hospital for
Associate Professor of Ophthalmology, Neurology, and
Sick Children
Neurosurgery
Toronto, Ontario, Canada
University of Alabama at Birmingham
Assistant Professor (adjunct) of Ophthalmology and
Birmingham, Alabama
Visual Sciences
Washington University
Nicholas J. Volpe, MD St. Louis, Missouri
Adele Niessen Associate Professor of Ophthalmology
and Neurology Rochelle S. Zak, MD
University of Pennsylvania School of Medicine Clinical Instructor
Vice Chairman, Residency Program Director Department of Neurology in Psychiatry
Scheie Eye Institute Weill Cornell Medical College
Philadelphia, Pennsylvania New York-Presbyterian Hospital
New York, New York
Michael Wall, MD
Professor of Neurology & Ophthalmology David S. Zee, MD
University of Iowa College of Medicine Professor of Neurology and Ophthalmology
Veterans Administration Hospital The Johns Hopkins University School of Medicine
Iowa City, Iowa Baltimore, Maryland
Contents
Volume I
Preface ............................................................................................................................................................................. vii
Acknowledgments ........................................................................................................................................................... ix
Section I: The Visual Sensory System

Chapter 1: Embryology, Anatomy, and Physiology of the Afferent Visual Pathway ......................................... 3
Joseph F. Rizzo III
Chapter 2: Principles and Techniques of the Examination of the Visual Sensory System ................................ 83
Michael Wall and Chris A. Johnson
Chapter 3: Congenital Anomalies of the Optic Disc ............................................................................................... 151

Michael C. Brodsky
Chapter 4: Topical Diagnosis of Acquired Optic Nerve Disorders ....................................................................... 197

Alfredo A. Sadun and Madhu R. Agarwal
Chapter 5: Papilledema ............................................................................................................................................... 237

Deborah I. Friedman
Chapter 6: Optic Neuritis ........................................................................................................................................... 293

Craig H. Smith
Chapter 7: Ischemic Optic Neuropathy .................................................................................................................... 349

Anthony C. Arnold
Chapter 8: Compressive and Infiltrative Optic Neuropathies ............................................................................... 385

Nicholas J. Volpe
Chapter 9: Traumatic Optic Neuropathy ................................................................................................................. 431

Kenneth D. Steinsapir and Robert A. Goldberg
Chapter 10: Toxic and Deficiency Optic Neuropathies ............................................................................................ 447

Paul H. Phillips
Chapter 11: Hereditary Optic Neuropathies .............................................................................................................. 465

Nancy J. Newman
Chapter 12: Topical Diagnosis of Chiasmal and Retrochiasmal Disorders ........................................................... 503
Leonard A. Levin
Chapter 13: Central Disorders of Visual Function ................................................................................................... 575

Matthew Rizzo and Jason J.S. Barton
xvii
xviii CONTENTS
Section II: The Autonomic Nervous System

Chapter 14: Anatomy and Physiology of the Autonomic Nervous System ............................................................ 649
Randy Kardon
Chapter 15: Principles and Techniques of Examination of the Pupils, Accommodation, and Lacrimation ..... 715
Kathleen B. Digre
Chapter 16: Disorders of Pupillary Function, Accommodation, and Lacrimation ............................................... 739
Aki Kawasaki
Section III: The Ocular Motor System

Chapter 17: Anatomy and Physiology of Ocular Motor Systems ........................................................................... 809
James A. Sharpe and Agnes M.F. Wong
Chapter 18: Principles and Techniques of the Examination of Ocular Motility and Alignment ........................ 887
Mark S. Borchert
Chapter 19: Supranuclear and Internuclear Ocular Motility Disorders ................................................................ 907
David S. Zee and David E. Newman-Toker
Chapter 20: Nuclear and Infranuclear Ocular Motility Disorders ......................................................................... 969
Jane C. Sargent
Chapter 21: Disorders of Neuromuscular Transmission .......................................................................................... 1041

Preston C. Calvert
Chapter 22: Myopathies Affecting the Extraocular Muscles ................................................................................... 1085

Paul N. Hoffman
Chapter 23: Nystagmus and Related Ocular Motility Disorders ............................................................................. 1133
R. John Leigh and Janet C. Rucker
Section IV: The Eyelid

Chapter 24: Normal and Abnormal Eyelid Function ............................................................................................... 1177
Barry Skarf
Section V: Facial Pain and Headache

Chapter 25: The Trigeminal Nerve and Its Central Connections ........................................................................... 1233
Grant T. Liu
Chapter 26: Headache and Facial Pain ...................................................................................................................... 1275

Gregory P. Van Stavern
Section VI: Nonorganic Disease

Chapter 27: Neuro-Ophthalmologic Manifestations of Nonorganic Disease .......................................................... 1315
Neil R. Miller
CONTENTS xix
Volume II
Section VII: Tumors
Chapter 28: Topical Diagnosis of Tumors .................................................................................................................. 1337
Nancy J. Newman
Chapter 29: Tumors of Neuroectodermal Origin ...................................................................................................... 1413
Thomas R. Hedges III
Chapter 30: Tumors of the Meninges and Related Tissues: Meningiomas and Sarcomas .................................. 1483
Kimberly P. Cockerham, John S. Kennerdell, Joseph C. Maroon, and Ghassan K. Bejjani
Chapter 31: Tumors of the Pituitary Gland .............................................................................................................. 1531
John W. Gittinger, Jr
Chapter 32: Tumors of Maldevelopmental Origin and Related Lesions ................................................................ 1547
Karl C. Golnik
Chapter 33: Tumors of the Cranial and Peripheral Nerves .................................................................................... 1587
David A. Chesnutt
Chapter 34: Tumors Derived from Hematopoietic Cells and Tissue ...................................................................... 1607
John B. Kerrison
Chapter 35: Miscellaneous Tumors of Neuro-Ophthalmologic Interest ................................................................. 1679
Benjamin M. Frishberg
Chapter 36: Paraneoplastic Diseases of Neuro-Ophthalmologic Interest ............................................................... 1715
Daniel M. Jacobson and Howard D. Pomeranz
Chapter 37: Complications of Cancer Therapy ......................................................................................................... 1759
Mark L. Moster and Rod Foroozan
Section VIII: The Phacomatoses

Chapter 38: Phacomatoses ............................................................................................................................................ 1823
John B. Kerrison
Section IX: Vascular Disease

Chapter 39: Anatomy and Physiology of the Cerebrovascular System .................................................................. 1901
Robert A. Egan
Chapter 40: Cerebrovascular Disease ......................................................................................................................... 1967
Valérie Biousse
Chapter 41: Aneurysms ................................................................................................................................................ 2169
Steven A. Newman
Chapter 42: Carotid-Cavernous Sinus Fistulas ......................................................................................................... 2263
Neil R. Miller
Chapter 43: Vascular Malformations and Tumors of Blood Vessels ...................................................................... 2297
Andrew G. Lee
Chapter 44: Vasculitis ................................................................................................................................................... 2333
Steven L. Galetta
Chapter 45: Venous Occlusive Disease ....................................................................................................................... 2427
Valerie Purvin
xx CONTENTS
Volume III
Section X: Degenerative and Metabolic Diseases
Chapter 46: Degenerative and Metabolic Diseases in Infants and Children ......................................................... 2469
Michael X. Repka
Chapter 47: Degenerative and Metabolic Diseases in Adults ................................................................................... 2513
Parashkev Nachev and Christopher Kennard
Section XI: Infectious, Inflammatory, and Demyelinating Diseases

Chapter 48: Lesions Produced by Infections and Inflammations of the Central Nervous System ..................... 2551
Barrett Katz
Chapter 49: Bacteria and Bacterial Diseases ............................................................................................................. 2647
Prem S. Subramanian
Chapter 50: Fungi and Mycotic Diseases .................................................................................................................... 2775
Joel M. Weinstein
Chapter 51: Diseases Caused by Helminths ............................................................................................................... 2853
Golnaz Moazami
Chapter 52: Mycoplasmal Diseases ............................................................................................................................. 2917
M. Tariq Bhatti
Chapter 53: Prions and Prion Diseases ....................................................................................................................... 2933
Eric R. Eggenberger
Chapter 54: Protozoa and Protozoal Diseases ............................................................................................................ 2957
Wayne T. Cornblath
Chapter 55: Rickettsiae, Rickettsial-Like Organisms and the Diseases They Produce ........................................ 3049
Michael S. Vaphiades
Chapter 56: Spirochetal Diseases ................................................................................................................................. 3077
Robert L. Lesser
Chapter 57: Viruses (Except Retroviruses) and Viral Diseases ............................................................................... 3115
Paul W. Brazis and Neil R. Miller
Chapter 58: Retroviruses and Retroviral Diseases .................................................................................................... 3323
Lynn K. Gordon
Chapter 59: Sarcoidosis ................................................................................................................................................ 3369
Steven R. Hamilton
Chapter 60: Multiple Sclerosis and Related Demyelinating Diseases ..................................................................... 3469
Laura J. Balcer
Chapter 61: Peripheral Demyelinating and Axonal Disorders ................................................................................ 3527
David I. Kaufman
Chapter 62: Miscellaneous Diseases of Presumed Infectious Etiology .................................................................... 3555
Jacqueline M.S. Winterkorn and Rochelle S. Zak
Index ................................................................................................................................................................................ I-1
SECTION I:
The Visual Sensory System
Nancy J. Newman, section editor
Each human optic nerve contains about 1.2 million axons, the optic disc and their distinction from congenital disc
representing about 40% of all fibers entering or leaving the anomalies are of fundamental importance not only to the
central nervous system (CNS). When the rods and cones are ophthalmologist but also to the neurologist, neurosurgeon,
added to this number, the total number of sensory units that and other physicians. Chapters 3–11 are devoted to the
forward visual information to the brain is increased by a symptoms, signs, pathogenesis, and various etiologies of
factor of 80. That number is increased further when one both anterior (with optic disc swelling) and retrobulbar (with
considers the millions of axons that transmit information an initially normal disc) optic neuropathies and optic atrophy
from the lateral geniculate body to the striate cortex and and to their differentiation from congenital disc anomalies.
from the striate cortex to other parts of the CNS. Thus, any Knowledge of the various disorders that affect the optic chi-
physician who evaluates patients with disorders of vision asm, tracts, radiations, and striate cortex are also important
must have knowledge of the embryology, anatomy, and to the physician dealing with patients complaining of visual
physiology of the visual sensory system. This information dysfunction, as is an understanding of the so-called ‘‘cen-
is covered in the first chapter of this section. The second tral’’ (also called ‘‘higher’’) disorders of visual function.
chapter describes the principles and techniques of examina- The last two chapters of this section deal with the features
tion of the visual sensory system. The ophthalmoscopic rec- of such disorders.
ognition and differential diagnosis of swelling or pallor of
CHAPTER 1
Embryology, Anatomy, and Physiology
of the Afferent Visual Pathway
Joseph F. Rizzo III
RETINA Physiology
Embryology of the Eye and Retina Blood Supply
Basic Anatomy and Physiology POSTGENICULATE VISUAL SENSORY PATHWAYS
Overview of Retinal Outflow: Parallel Pathways Embryology
OPTIC NERVE Anatomy of the Optic Radiations
Embryology Blood Supply
General Anatomy CORTICAL VISUAL AREAS
Optic Nerve Blood Supply Cortical Area V1
Optic Nerve Sheaths Cortical Area V2
Optic Nerve Axons Cortical Areas V3 and V3A
OPTIC CHIASM Dorsal and Ventral Visual Streams
Embryology Cortical Area V5
Gross Anatomy of the Chiasm and Perichiasmal Region Cortical Area V4
Organization of Nerve Fibers within the Optic Chiasm Area TE
Blood Supply Cortical Area V6
OPTIC TRACT OTHER CEREBRAL AREAS CONTRIBUTING TO VISUAL
LATERAL GENICULATE NUCLEUS PERCEPTION
Anatomic and Functional Organization
The brain devotes more cells and connections to vision lular, magnocellular, and koniocellular pathways—each of
than any other sense or motor function. This chapter presents which contributes to visual processing at the primary visual
an overview of the development, anatomy, and physiology cortex. Beyond the primary visual cortex, two streams of
of this extremely complex but fascinating system. Of neces- information flow develop: the dorsal stream, primarily for
sity, the subject matter is greatly abridged, although special detection of where objects are and for motion perception,
attention is given to principles that relate to clinical neuro- and the ventral stream, primarily for detection of what
ophthalmology. objects are (including their color, depth, and form). At
Light initiates a cascade of cellular responses in the retina every level of the visual system, however, information
that begins as a slow, graded response of the photoreceptors among these ‘‘parallel’’ pathways is shared by intercellular,
and transforms into a volley of coordinated action potentials thalamic-cortical, and intercortical connections. The mech-
at the level of the retinal ganglion cells (RGCs), the axons anisms by which the visual system uses these data streams
of which form the optic nerve. The outflow of visual signals to create vision remain mysterious and are beyond the
from photoreceptors is parsed into parallel pathways that are current grasp of technology, although recent multichannel
distributed to the diencephalon, midbrain, lateral geniculate recordings within associative visual cortices are providing
body, primary visual cortex, and beyond. These pathways insights into how complex visual scenes are assembled
are broadly divided into three major streams—the parvocel- by the brain.
3
4 CLINICAL NEURO-OPHTHALMOLOGY
RETINA
EMBRYOLOGY OF THE EYE AND RETINA Müller cells differentiate. Cones, which appear before rods,
develop around the same time as the horizontal cells, but
The sensory retina is a part of the central nervous system
both cones and rods do not mature until after connections
(CNS). The retina develops from the optic cup, a structure
within the inner retina begin to form. Maturation of the pho-
formed by the invagination of the lateral walls of the optic
toreceptors leads to formation of the outer plexiform layer
vesicles, which emerge as outpouchings of the prosencepha-
lon during the third week of gestation (1–3) (Fig. 1.1). The (OPL), which establishes connections among photoreceptors
invagination is dependent upon a temporally specific associ- and horizontal and bipolar cells (Fig. 1.2). Each Müller cell
ation of the developing optic vesicle with the overlying pre- may be the kernel of a functionally intertwined ‘‘columnar
lens ectoderm (4). The outer wall of the optic cup becomes unit’’—each Müller cell (in the rabbit) ensheathes a collec-
the retinal pigment epithelium (RPE), while the inner wall tion of rods, bipolar cells, and amacrine cells, with each
mostly develops into the sensory retina (3). cell class having a precisely maintained ratio to Müller cells
Several highly conserved genes contribute to the forma- across the retina (9).
tion of the eye and retina (5). The optic cup and optic stalk Generation of cells from the neuroepithelial (or neuro-
express Pax-2 and Pax-6, which belong to a family of tran- blastic) layers is followed by their differentiation, and most
scription factors involved in the regulation of early develop- differentiated cells then migrate through the developing ret-
ment. Pax-2 expression occurs in cells that will form the ina. RGCs migrate inward, leaving in their wake an acellular
optic fissure (which develops at the future site of the optic region that is developing into an expanded inner plexiform
nerve head) and the optic stalk (which becomes the optic layer (IPL) (Fig. 1.3). Simultaneously, horizontal cells mi-
nerve) (6). Pax-6 expression occurs in cells that will become grate inward and combine with cells of the inner neuroblastic
the neural retina (and most of the eye except the cornea and layer to form the INL. Photoreceptors remain stationary. De-
lens) (7). termination of cell number for each cell class is controlled
The general principles of retinal development are as fol- by expression of the homeodomain protein Prox 1, which
lows (2,8). Ganglion cells develop first, at the seventh week regulates the timing at which dividing cells become quies-
of gestation. Amacrine and horizontal cells develop next. cent (10). Fibroblastic growth factors and hedgehog (Hh)
Connections among amacrine cells and RGCs create a nas- proteins also are important for retinal development and RGC
cent inner nuclear layer (INL), at which time bipolar and axon guidance (11). N-cadherin plays a crucial role in the
Figure 1.1. The formation of the optic

vesicle and cup in a 7.5-mm (5-week)
human embryo. Note that the stalk has
two separate regions, a distal invaginated,
crescent-shaped segment and a proximal
noninvaginated circular segment. The
lens vesicle is formed by an invagination
of the pre-lens ectoderm, which in turn
prompts the invagination of the optic cup.
(Redrawn from Hamilton WJ, Boyd JD,
Mossman HW. Human Embryology. Bal-
timore, Williams & Wilkins, 1962.)
EMBRYOLOGY, ANATOMY, AND PHYSIOLOGY OF THE AFFERENT VISUAL PATHWAY 5
Figure 1.2. Basic structure and temporal order of cell differentiation of the vertebrate retina. A, The neural retina begins as
a sheet of neuroepithelial cells (NBL, neuroblastic layer) with processes that contact the internal (ILM) and external (ELM)
limiting membranes. B, Ganglion cells (G) are the first cell type to differentiate and migrate toward the ILM to form the
ganglion cell layer (GCL). C, Amacrine cells (A) and horizontal cells (H) differentiate next. Cone photoreceptors are born at
this stage but do not differentiate until later. The first network of connections, between amacrine cells and ganglion cells, is
established as a continuous inner plexiform layer (IPL) across the retina. D, In the inner nuclear layer (INL), bipolar cells (B)
and Müller cells (M) are generated and differentiate. At this stage, both cone (C) and rod (R) photoreceptors composing the
outer nuclear layer (ONL) begin to mature, bearing few outer segments or discs. The outer plexiform layer (OPL) emerges,
and connections between photoreceptors, horizontal cells, and bipolar cells are formed. Cell genesis (mainly rods) continues
at this stage but to a greatly reduced degree. E, At maturity, all cell types are present, connections in both plexiform layers
are established, and photoreceptor outer segments are well developed. (From Chalupa LM, Werner JS, eds. The Visual Neurosci-
ences. Cambridge, MA, MIT Press, 2004⬊78.)
development of lamination within the retina (12). RGCs may tivity, influences a competitive selection process that deter-
regulate the ultimate number of amacrine cells by secreting mines the final number of RGCs and their pattern of synaptic
brain-derived neurotrophic factor (13). arrangement at their termination sites (20). Apoptosis elim-
RGC axonal guidance is partially directed by EphA recep- inates noncompetitive RGCs (21).
tor tyrosine kinases (14). EphA receptors are expressed on
all RGC axons, but only temporal axons have receptors with BASIC ANATOMY AND PHYSIOLOGY
high ligand sensitivity. The differential (i.e., temporal versus
Retinal Pigment Epithelium
nasal) sensitivity is determined by varying degrees of phos-
phorylation of the EphA receptor, which (in the chick) is The RPE is a monolayer of cells whose development in
controlled by relatively greater expression of ephrin-A6 in lower vertebrates involves expression of Hh proteins (Fig.
the nasal retina (15). The relatively low state of phosphoryla- 1.3). Peripherally, in the homologous zone of the pigmented
tion of EphA receptors on temporal axons increases their ciliary epithelium in mammals, expression of Hh proteins is
sensitivity, which allows them to respond to low concentra- associated with the presence of retinal stem cells that retain
tions of ephrin-A ligands at the tectal termination zone. a capacity to differentiate into any type of retinal neuron,
Proper topography at the tectum is also at least partially which has therapeutic implications (22).
controlled by variable expression of ephrin-A at that location The RPE has several functions. It (a) regenerates chromo-
(16). Neuronal activity (via N-methyl-D-aspartate [NMDA] phore; (b) provides trophic support for photoreceptors; (c)
receptors) and expression of nitric oxide also contribute to is a transport barrier between the choriocapillaris and the
topographic precision (17–19). Embryonic spontaneous ac- sensory retina; (d) participates in ocular immune responses;
tivity of RGCs, which is regulated by ␥-aminobutyric acid (e) binds reactive oxygen species; and (f) absorbs excess
(GABA) receptor activity, specifically GABA, receptorac- radiation with their melanin granules. These granules can
Figure 1.3. Cellular components of the fully developed primate retina, showing cellular relationships and major synaptic
interactions. OPL, outer plexiform layer; ONL, outer nuclear layer; ELM, external limiting membrane; OS, outer segment; As,
astrocyte; G, ganglion cell; Am, amacrine cell; I, interplexiform cell; H, horizontal cell; B, bipolar cell; c, cone; R, rod; M,
Müller cell. The photoreceptor nuclei lie in the ONL, and a large stretch of the photoreceptors consists of their outer segments,
which lie proximal (i.e., nearer to the retinal pigment epithelium) to their nuclei. The outer segments contain chromophore,
which captures the energy from incoming light and initiates the ionic exchange that hyperpolarizes the photoreceptors. The
inner segments of photoreceptors (not labeled) are the segments between the outer segments and the nucleus that contain a
high concentration of mitochondria and endoplasmic reticulum.
bind photosensitizing drugs, like hydroxychloroquine, and rosis (LCA), the most common inherited form of childhood
cause blindness by interfering with the ability of the RPE blindness. Gene therapy in the RPE65 null mutation dog
to support the photoreceptors (23). RGCs are also damaged model has produced some recovery of vision, which is the
by hydroxychloroquine, although presumably by some other first molecular genetic therapeutic success for blindness
mechanism. (28). In total, six genes preferentially expressed in the retina
Eyes of almost any species detect light in basically the or RPE account for half of all LCA cases (29). The metabolic
same manner. The process begins when rhodopsin molecules strategies used to regenerate 11-cis chromophore are remark-
located on the horizontal discs of the outer segment of photo- ably conserved across species, but only for rods. Cones re-
receptors (Fig. 1.4) capture photons, which causes isomer- generate their respective photopigments by interactions with
ization of 11-cis-retinal to all-trans-retinal (24,25). This re- Müller (not RPE) cells (30). However photopigment regen-
action initiates the phototransduction cascade that ultimately eration is achieved, sluggishness in doing so interferes with
influences the propagation of nerve impulses through the vision by causing an abnormally prolonged recovery of cen-
retina. Regeneration of 11-cis-retinal, which is necessary to tral vision following exposure to bright light, as is often
maintain the responsiveness of photoreceptors to light, is reported by patients with a maculopathy.
performed by the RPE (Fig. 1.5). Interphotoreceptor retinol
binding protein (IRBP) contributes to this process by binding Sensory Retina and Glial Cells
retinols and retinals (which alone are highly insoluble) and
escorting them to and from the RPE (26,27). Generation of The human retina contains over 110 million neurons,
the 11-cis chromophore in vertebrates requires the enzyme among which are approximately 55 cell types that use at
RPE65. Mutations in RPE65 cause Leber congenital amau- least 10 neurotransmitters (31–33). The functions of about
A B
Figure 1.4. A, Electron micrograph of a rod, showing the outer segment (OS) connected to the ellipsoid (E). Note the horizontal
disc membranes, which represent the bulk of the outer segment, and the numerous mitochondria within the ellipsoid portion
of the inner segment. B, A portion of amphibian rod outer segment showing a stack of disc membranes. The segment was
treated with low salt to strip away the plasma membrane, rapidly frozen, etched to expose the disc surfaces, and unidirectionally
shadowed with a mixture of platinum and carbon. The small bumps scattered across the cytoplasmic surface of each membrane
are transducin molecules. Bar ⳱ 0.1 ␮m. (A, From Hogan MJ, Alvarado JA, Weddell JC. Histology of the Human Eye: An
Atlas and Textbook. Philadelphia, WB Saunders, 1971. B, From Roof D, Heuser J. Surfaces of rod photoreceptor disk membranes:
integral membrane components. J Cell Biol 1982;95⬊487–500.)
Figure 1.5. Phototransduction cascade.

Junction of rod, retinal pigment epithelium,
and choroid shows the interrelationship
among those structures required to regener-
ate photopigment. Trans-retinol is carried
by the blood to the choriocapillaris, where
it can then enter the retinal pigment epithe-
lium and contribute to the cycle.
22 of these cells are known or reasonably well appreciated. function of other retinal neurons will be recognized in the
This base of knowledge makes the retina the best-understood future.
area of the more complex regions of the brain (34). The retina contains six classes of neurons that are arranged
Most architectural schemas fail to represent the intricacy into three parallel layers (Table 1.1), except in the perifovea,
of the retina because retinal function depends on a variety where the retina thins to a single layer. The retina also con-
of factors, including the region of the retina being illumi- tains three types of glial cells—astrocytes and Müller cells,
nated, the characteristics of the light stimulus, and the state and a smaller number of microglia.
of light adaptation. For instance, colors of short wavelength
are relatively more apparent when viewed under dim rather Photoreceptors
than bright light because of the shift toward rod function in The photoreceptors are the primary sensory transducers
the scotopic state (i.e., the Purkinje shift). Given this com- of the visual system. Photoreceptor pigments respond to
plexity, one might imagine that a large number of symptoms wavelengths of light (400–700 nm) that are not absorbed by
would result from dysfunction of these many cell types. On the optical media and hence reach the retina. Most vertebrate
the contrary, most clinically recognized diseases of the retina eyes contain two types of photoreceptors, rods and cones.
are limited to dysfunction of either photoreceptors or RGCs. A small number of RGCs also contain an opsin and are
Undoubtedly, new patterns of visual loss secondary to mal- capable of responding to light (discussed later).
Table 1.1 rods are predominately affected in vitamin A deficiency reti-

Cellular Organization of the Retina nopathy, nyctalopia is usually the initial visual symptom.
Cell Layer Neuronal and Glial Nuclei
The retinopathy of vitamin A deficiency is reversible if treat-
ment is prompt enough. Hypovitaminosis A is a leading
Outer nuclear layer Photoreceptors cause of blindness in developing countries, but it also occurs
Inner nuclear layer Horizontal cells in developed countries in patients with malabsorption syn-
Bipolar cells dromes, liver disease, or restrictive diets (42–44). A wide
Interplexiform cells range of genetic mutations that interfere with vitamin A (i.e.,
Amacrine cells all-trans retinol) metabolism may cause blindness (45).
Müller cells
Cones also contain 11-cis-retinal but have different apo-
Ganglion cell layer Ganglion cells
Displaced amacrine cells
proteins than rods. Variation of the opsin moiety produces
Astrocytes three spectral response curves that correspond to the blue,
green, and red cones, which are more appropriately called
short (S-), medium (M-), and long (L-) wavelength cones to
emphasize that their responsiveness spans across a portion
Rods contain rhodopsin, a molecule that is composed of of the visible spectrum. The amino acid sequences of rho-
the apoprotein, opsin, and 11-cis-retinal (35). A rod (and dopsin and the three cone pigments have been characterized
cone) ‘‘Rim’’ protein, which is encoded by the ABCA4 gene, (46). Antibodies to the three cone pigments have revealed
is the transmembrane transporter of vitamin A intermediates mosaics for each photoreceptor class in the primate retina.
needed for the visual cycle. Mutations in this gene produce Human cone mosaics can be noninvasively visualized in a
Stargardt macular dystrophy and fundus flavimaculatus (36). living eye (47).
Once in the extracellular space, vitamin A intermediates are Congenital dyschromatopsia is usually caused by loss or
shuttled by the IRBP to the RPE (discussed previously). significant alteration in the red or green photopigment
Rhodopsin is present in very high concentrations within gene(s), which are located on the X chromosome and which
the membranes of the outer segment discs (Fig. 1.4), which are 98% homologous with one another (46). Anomalous
are oriented vertically to maximize capture of incident pho- trichromacy, a more minor defect, is caused by gene hybridi-
tons. The efficiency of this system is so great that single zation. Among individuals with ‘‘normal’’ color vision,
photons can initiate the phototransduction cascade (37), al- there is a surprisingly large variation in performance (7–8
though in the dark-adapted (i.e., the most sensitive) state, nm range in peak spectral responsiveness), presumably due
about five photons are needed to induce light perception. to polymorphic variations in human M- and L-cone pigments
Photon capture causes phosphorylation of rhodopsin. This (48) and variation in the relative number of M- and L-cones
step, which initiates the phototransduction cascade, can be (49).
modulated by recoverin, a 23-kD intracellular protein that Humans have a cone-to-rod ratio of approximately 1⬊20,
inhibits rhodopsin kinase, which in turn inhibits the phos- with each retina containing 92 million rods and 4.6 million
phorylation of rhodopsin. Antibodies to recoverin, which cones, on average. Rods are absent or only rarely present in
may push the photoreceptors into a persistent state of hyper- the fovea (Fig. 1.7) and are in highest density in an elliptical
polarization (because of prolonged phosphorylation of rho- ring that passes through the optic nerve. Fifty percent of
dopsin), may be found in association with apoptosis-induced cones in the human retina are located within the central 30
photoreceptor death in patients with small cell carcinoma degrees of the visual field (50), an area that roughly corre-
who develop cancer-associated retinopathy (38,39). sponds to the size of the macula. There is an age-related
Activation of the phototransduction cascade causes an in- decline in the number of rods in human retina, with an annual
tracellular decline in the guanosine cyclic monophosphate loss of about 0.2–0.4% (51). The age effect upon cones is
(cGMP) concentration within rod outer segments, followed less clear (52).
by closure of the cGMP-gated cation channel and cessation The human fovea matures anatomically just prior to 4
of inflow of the extracellular cations that generate the ‘‘dark years of age (53). By this time, the outer segments of the
current.’’ The resultant hyperpolarization decreases neuro- foveal cones attain a width of only 1.0 ␮m, which permits
transmitter (i.e., glutamate) release at the synaptic terminal very high spatial resolution (i.e., acuity). The high density
(Fig. 1.6). The decline in cGMP after light exposure is of foveal cones poses a structural problem because the cone
caused by activation of rod outer segment phosphodiesterase synaptic terminals, known as pedicles, and the RGCs to
(PDE), specifically PDE-6. Inhibition of PDE, as occurs which they connect have larger diameters than the cone inner
with sildenafil (which mainly inhibits PDE-5, but also segments. Thus, each foveal ganglion cell soma is displaced
weakly inhibits PDE-6), increases the cGMP concentration, from the cone that provides its input. This resulting horizon-
which opens sodium channels and depolarizes the rods. This tal displacement occurs via the nerve fiber layer of Henle,
effect may account for the transient disturbance of color an elongation of photoreceptors between their nuclei and
(typically blue-yellow) vision reported by some users of sil- their synaptic terminals (Fig. 1.7). Deposition of hard exu-
denafil (40,41). dates within the Henle layer produces the clinical sign of a
Vitamin A is used in phototransduction and photopigment ‘‘macular star.’’
regeneration. Vitamin A must be replenished from the circu- As described previously, retinal neurons mature at differ-
lation, and failure to do so can result in retinopathy. Since ent times, influencing the timing of their respective synaptic
Figure 1.6. Neurotransmitters used by retinal neurons of the rod and cone pathways. The neurotransmitters are released
within the outer and inner plexiform layers. The mGluR6 and AMPA receptors (see text) of the bipolar cells are also depicted.
The former uses a G protein to control the intracellular concentration of cGMP that, in turn, regulates the NaⳭ-Ca2Ⳮ-cGMP-
gated ion channel.
connections. There is a prodigious expansion of synapses nal and central factors (59). An abnormal delay in achieving
for several years after birth, which doubles the width of the normal vision occurs in patients with delayed maturation
IPL between birth and adulthood. The human foveal outflow of the visual system, which results from excessively slow
pathway (cones to ganglion cells) develops more quickly, myelination along the afferent visual pathway (60).
with synapses being established possibly as early as mid- The synaptic terminals of photoreceptors contain ribbon
gestation (54). During the period of synaptogenesis, wide- synapses, which are specialized synaptic features found only
spread neuronal death can occur if there is significant expo- in the retina and pineal gland. Ribbon synapses guide synap-
sure to ethanol because of disruption of glutamate and tic vesicles to preferred sites on the presynaptic membrane in
GABA neurotransmitter systems (55). The complex process preparation for their release. Photoreceptor synapses usually
of retinal development does not occur without flaws, in that exist as a triad, which comprises one bipolar and two hori-
seemingly misplaced cones and cone bipolar and horizontal zontal cells. Gap junctions are ion channels through which
cells are not infrequently observed in the retina (56,57). pass ions and molecules without typical synaptic specializa-
The normal delay in achieving adult visual performance tions. Gap junctions, which are formed by alignment of two
for spatial resolution and various other tasks may extend to connexin hexamers, create a cellular syncytium. Gap junc-
3 years postpartum (58) and is probably related to both reti- tions normally exist between adjacent photoreceptors and are
Figure 1.7. Section through center of fovea. Nuclei of rod receptor cells are indicated by arrows. Remaining receptor cells
are foveal cone cells. Os, outer nuclear layer; of, outer cone fiber; oh, outer fiber layer of Henle; in, inner nuclear layer; ip,
inner plexiform layer; g, ganglion cell; cp, capillary; im, internal limiting membrane; is, inner segment; om, outer limiting
membrane; on, outer nuclear layer (reduced from ⳯400). (From Yamada E. Some structural features of the fovea centralis in
the human retina. Arch Ophthalmol 1969;82⬊151–159.)
typically present near their synaptic terminals. Gap junctions tion), through which electrical current alters the release of
also occur between horizontal cells, between amacrine cells, glutamate by modulating the calcium channels of cones (65).
and between bipolar and amacrine cells. Given the length and small diameter of the HII axon, it
Photoreceptor terminals contain dystrophin, the cyto- is unlikely that the cell body and axon terminal of the same
skeletal protein that is a product of the Duchenne muscular cell influence one another electrically (66). On the other
dystrophy (DMD) gene. Patients with DMD can have an hand, the axon of the HII cell can extend several millimeters,
abnormal electroretinogram (ERG) that reveals abnormal which presumably allows this cell to influence signal trans-
transmission between photoreceptors and ON-bipolar cells. mission over a very wide area. The presence of gap junc-
The role of dystrophin in the retina is not known, although tions, which permit electrical potentials to spread among
there are three isoforms distributed widely on neurons, blood cells, probably further extends the effective reach of horizon-
vessels and Müller cell end-feet, where dystrophin influ- tal cells. An increase in extracellular dopamine or nitric
ences the formation of potassium channels (61,62). oxide, as occurs in the light-adapted state, closes gap junc-
tions between horizontal cells. Constraining the horizontal
Horizontal Cells spread of electrical signals between horizontal cells may be
one mechanism by which central acuity is enhanced under
Photoreceptors and horizontal and bipolar (discussed photopic conditions. The interplexiform cell (discussed
later) cells synapse in the OPL (Fig. 1.8). Humans have two later) may be the source of dopamine in the OPL.
types of horizontal cells, both of which have axons. The HI Horizontal cells may provide the anatomic substrate for
cell, the smaller of the two, makes dendritic contact with the concentric, circular, antagonistic, center-surround re-
cones and axonal contact with rods, whereas both ends of sponse characteristics of RGCs and bipolar cells. Specifi-
the HII cell synapse with cones. Both horizontal cell types cally, the response of RGC to light that falls within the
appear to contact all three types of cones, which suggests center of its receptive field (which matches the dendritic
that color input to horizontal cells is not spectrally selective arbor of the cell) is opposite to that which occurs if the same
(63), although in macaque monkeys specific contact occurs light stimulus falls within its ‘‘surround’’ (i.e., that portion
between horizontal cells and blue cones (64). Horizontal of the receptive field concentric to but beyond the center).
cells provide an inhibitory feedback to cones via hemi-chan- The antagonistic center-surround response property empha-
nels (i.e., one part of a normally dual component gap junc- sizes contrast within the visual scene by generating marked
Figure 1.8. Rod and cone through pathways to the retinal ganglion cells. The photoreceptor synaptic terminals (i.e., the cone
pedicles and rod spherules) have flat and invaginating surfaces upon which bipolar and horizontal cells make contact within
the outer plexiform layer. AII amacrine cells and bipolar cells contact one another within the inner plexiform layer, which is
subdivided into zones that contain synapses of either ON center or OFF center cells. In particular, the OFF zone, which is
closer to the photoreceptors, is known as sublamina a, and the ON zone, which is nearer to the vitreous, is known as sublamina
b. Sites of chemical (i.e., ribbon) synapses and gap junctions between cells are labeled or indicated by symbols (⳱, gap
junction; four small circles, two on each side of a small line, chemical synapse); AII, AII amacrine cell.
differences in the responsiveness of cells at precise points extends to sublamina b of the IPL to synapse exclusively
across the retina (Fig. 1.9). Enhanced contrast improves spa- with an AII amacrine cell (discussed later) (Fig. 1.8). The
tial resolution, which underlies the routine use of high-con- rod pathway, therefore, is formed by sequential connections
trast charts to measure the best-corrected acuity of patients. from rods to rod bipolar cells to AII amacrine cells to RGCs.
In the macaque, the HI cell, which is not highly electrically Two main types of cone bipolar cells can be distinguished
coupled to other HI cells, has a relatively small receptive by whether they make an invaginating or a flat synapse at
field that may form the ‘‘surround’’ of foveal midget cell the photoreceptor terminal. These synaptic structures corre-
outflow (67), which provides the greatest spatial resolution spond to the IPL termination site of the cells’ dendrites.
in the retina. The center-surround profile is maintained, al- Invaginating cone bipolar cells terminate more vitreally in
though altered somewhat, at the dorsal lateral geniculate nu- the IPL within sublamina b, whereas flat cone bipolar cells
cleus (dLGN) (discussed later). terminate more proximally in sublamina a. This anatomic
segregation is of fundamental importance in that bipolar cells
Bipolar Cells whose processes ramify in sublamina b produce more action
potentials when their receptive field centers are stimulated
Bipolar cells receive input from photoreceptors and pro- with light (i.e., ON cells). Conversely, bipolar cells whose
vide output to amacrine and RGCs. There are roughly 17 dendrites ramify in sublamina a become more quiet when
types of bipolar cells, which can be broadly divided into ON their receptive field centers are covered with light (i.e., OFF
and OFF cells, midget cells, and diffuse cells. Some receive cells) (Fig. 1.8).
input solely from rods (i.e., rod bipolar cells), whereas others The midget outflow pathway provides the most spatially
receive input solely from cones (i.e., cone bipolar cells). detailed visual profile. Midget cells dominate the center of
There is only one type of rod bipolar cell, which begins at the retina but are also present peripherally (68,69). Centrally,
invaginations of the rod synaptic terminal (i.e., spherule) and the midget system is organized such that each M or L cone
Figure 1.9. Center-surround organization of retinal ganglion cell receptive fields, and the resultant output of a ganglion cell
in response to a light-dark border falling within its receptive field. Depicted is an OFF center ganglion cell, which responds
most vigorously when a dark spot precisely fills its receptive field center. The responsiveness of the cell is diminished by
darkness that covers its surround. The output in (a) is the resting, basal level of spontaneous action potentials, which are a
characteristic feature of all retinal ganglion cells. In (b), the output is decreased because the darkness falls only across the
inhibitory surround. In (c), the responsiveness is greatly enhanced because darkness fills the excitatory center of this OFF cell.
In (d), the cellular output is above the basal level of activity because the receptive field center is filled by darkness, despite
the fact that the entire surround is also covered by darkness. (From Bear MF, Connors BW, Paradiso MA. Neuroscience.
Exploring the Brain. 2nd ed. Baltimore, Lippincott Williams & Wilkins, 2001⬊306.)
contacts one ON and one OFF center bipolar cell, and each centration of cGMP; this, in turn, opens cation channels that
bipolar cell contacts only one cone. In the fovea, OFF RGCs depolarize the cell. As such, release of glutamate by photore-
receive input from only one (OFF) bipolar cell, whereas ON ceptors initiates two opposing but parallel signals to the inner
RGCs may receive input from up to three (ON) bipolar cells, retina (72). These ON and OFF bipolar responses are
although at the synaptic level only one bipolar cell domi- matched to two RGCs of the same physiologic type. Rod
nates. This organizational pattern shifts across the retina. In bipolar cells also have a metabotropic receptor; hence, they
the parafovea, all midget RGCs receive input from only one become depolarized when rods are activated by light.
midget bipolar cell, although more peripherally they receive Bipolar cells may be the target of a paraneoplastic immune
input from up to four bipolar cells (69). In the periphery, attack in some patients with cutaneous malignant melanoma
midget bipolar cells can receive input from up to 12 cones. (73). The primary physiologic impact is loss of the scotopic
In contrast, in the peripheral retina one RGC may receive b-wave of the ERG, similar to that seen in patients with
input from up to 1,500 rods through bipolar cells (70). congenital stationary night blindness (74). The persistence
The ON signal in the blue (i.e., short wavelength) pathway of the scotopic a-wave in eyes in this melanoma-associated
does not pass through a midget bipolar cell; rather, a special retinopathy (MAR) indicates that the rods are responsive to
S-cone ON bipolar cell receives ON input from S-cones. In light, whereas loss of the b-wave is evidence of a blocked
the fovea, the dendritic arbor of this bipolar cell is so small transmission distal to the rod synapses. Selective immuno-
that it receives input from only one S-cone. Each S-cone histochemical staining suggests that the signal blockage is
also contacts an OFF midget bipolar cell (71). The blue path- caused by dysfunction of rod bipolar cells. MAR patients
way also uses a special RGC—the small, bistratified cell also exhibit abnormal ERG cone ‘‘ON’’ responses, which
(discussed later). suggests that the primary deficit may be generalized dys-
The major excitatory neurotransmitter in the retina is glu- function of depolarizing (‘‘ON’’) bipolar cells (75,76). Anti-
tamate. Photoreceptors are hyperpolarized by light, which bipolar cell antibodies have also been found in a patient with
decreases their release of glutamate. Reduced glutamate con- a paraneoplastic retinopathy secondary to colon cancer (77).
centration within the OPL causes two opposing effects on
bipolar cells (Fig. 1.6). For OFF center bipolar cells, de- Amacrine Cells
creased glutamate at their ionotrophic (i.e., ion-exchanging)
alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionic Amacrine cells were named in the belief that they lacked
acid (AMPA) glutamate receptors hyperpolarizes the cell, axons, which is now recognized not to be universally true.
thus conserving the sign of the response with respect to the Unlike axons of RGCs, amacrine cell axons, when present,
photoreceptor. ON center bipolar cells, however, possess a do not enter the optic nerve. There are 26–40 types of ama-
different receptor, a metabotropic glutamate receptor crine cells (71,78), most of which have somas that lie at the
(mGluR6) that drives ion exchange via a second messenger inner border of the INL, although some somas are ‘‘dis-
system. The metabotropic receptor becomes active by chang- placed’’ into the ganglion cell layer. In the peripheral retina,
ing its conformation after binding to glutamate. Decreased the spatial density of amacrine cells within the ganglion cell
glutamate concentration, therefore, reduces the activity of layer can exceed that of RGCs. Some amacrine cells are
the mGluR6 receptor, which increases the intracellular con- interneurons between bipolar and RGCs. Others connect to
fellow amacrine cells, forming a lateral pathway within the

IPL reminiscent of horizontal cells that ramify within the
OPL. These different subtypes can be differentiated accord-
ing to various criteria, including the shape of the cell, the
zone or zones in which their dendrites ramify within the IPL,
and their neurotransmitter(s) (Fig. 1.10).
The most numerous amacrine cell is the AII cell, which
is an integral part of the rod pathway. Outflow of rod bipolar
cells is entirely to sublamina b of the IPL, which indicates
that rod outflow is entirely ON in nature. The AII cell re-
ceives and then transmits this ON rod signal to one cone
ON and one cone OFF center bipolar cell. Both cone bipolar
cells transmit their signals to RGCs of the same physiologic
type (Fig. 1.8). Rods, therefore, influence both ON and OFF
pathways, despite having only one of the two bipolar cell
types found in the cone pathway. This architecture is an
apparent conservation of resources for the highly preponder-
ant rod pathway that contains roughly 92 million rods (versus
5 million cones) in humans.
‘‘Starburst’’ amacrine cells exist as equal populations of
ON and OFF varieties (79). These cells have several interest-
ing features. Starburst cells release acetylcholine in response
to light stimulation and also have the capacity to generate
GABA, although they do not release GABA in response
to light (80). Acetylcholine also ‘‘leaks’’ out of the cell in
darkness, a phenomenon of unknown significance that is
similar to the leakage of acetylcholine that occurs at the
neuromuscular junction (81). Starburst cells are presynaptic
to three cell types: amacrine cells, bipolar cells, and dendrites
of ‘‘direction-selective’’ RGCs (82). The role of starburst
cells in motion detection is revealed by the fact that they do
not develop in mouse embryos that are genetically modified
so as not to develop extraocular muscles (83).
An odd-shaped, polyaxonal amacrine cell (with a small
dendritic field but many widely ramifying axons) has re-
cently been recognized as playing an important role in distin-
guishing movement of an image against a stationary back-
ground. It is biologically important to distinguish such
relative movement from the type of global movement of the
visual scene that occurs during saccades and microsaccades.
The ‘‘suppression’’ of vision during a saccade was believed
to be a cortical phenomenon. However, the discovery of the
polyaxonal amacrine cell indicates that visual suppression Figure 1.10. Mosaics of various anatomically distinct amacrine cells
during some eye movements begins in the retina. This func- showing their different dendritic patterns. Three cell types are shown, all
tion is accomplished with a specialized RGC that responds in flat view. Individual cells are at the left; the drawings at the right were
only when movement has a different trajectory across the synthesized on the basis of average cell shape and density and show an
center versus surround of its receptive field (i.e., relative approximation of the mosaic that would result if all the cells of that particu-
lar class were seen simultaneously. Top, Cholinergic amacrine cells are
movement) (84,85).
numerous, and their branching dendrites form an almost uninterrupted
Nitric oxide synthase (NOS) is found in some amacrine meshwork. Center, the mosaic of AII amacrine cells is sparser, and there
cells, but its function is unknown. It has been observed that is more space among their dendrites. Bottom, Dopaminergic amacrine cells
release of nitric oxide is associated with neuronal injury (via are sparser still. (From Masland RH. The functional architecture of the
a second messenger) and that upregulation of NOS-contain- retina. Sci Am 1986;255⬊102–111.)
ing retinal cells occurs following reperfusion of the retina
after a period of induced ischemia (86), perhaps because
of excessive glutamate stimulation caused by the ischemia. A dopaminergic amacrine cell has been identified in the
Further, degeneration of RGCs following axotomy may be retinas of all species that have been appropriately examined
secondary to upregulation of NOS (87). Generation of nitric (88). Dopaminergic amacrine cells have far-reaching den-
oxide, however, does not necessarily injure neurons; for in- drites that contact cone bipolar cells (Fig. 1.10); however,
stance, the endothelial isoform of nitric oxide is protective. they also synapse with AII and other amacrine cells that are
part of the rod pathway. Thus, the dopaminergic amacrine during retinal development for migrating neurons and forma-
cell contributes to both rod and cone outflow pathways. Reti- tion of interneuronal connections (104). The ability of
nal dopamine also plays a role in light adaptation. Dopamine, Müller cells to generate adenosine triphosphate (ATP) from
which is released during light exposure, uncouples gap junc- glycolysis frees them from the need to generate energy from
tions in horizontal cells. In this way, dopamine acts as a oxygen, which is thus spared for use by neurons (105).
neuromodulator in that it can affect the function of nearby Müller cells have high-affinity potassium channels, per-
neurons in the absence of synaptic connections to those neu- mitting low-resistance entry of extracellular potassium even
rons. Dopamine also can be neuroprotective, given its ability at the normally high resting electrical potential of the cell.
to inhibit NOS-induced glutamate toxicity (89). Dopami- These channels allow Müller cells to serve as a sink for the
nergic amacrine cells spontaneously generate action poten- elevated levels of extracellular potassium that arise follow-
tials in a rhythmic fashion, at least in vitro (90,91). These ing activation of ON bipolar cells in response to light. The
rhythmic potentials emanate specifically from interplexi- Müller cells then release the absorbed potassium at their end-
form neurons, which have their cell bodies in the IPL and feet. This cycling of potassium generates an electrical current
extend their axons to the OPL, and thus convey information that is the substrate of the ERG b-wave (Fig. 1.11). Oguchi’s
opposite to the direction of normal retinal outflow (92–96). disease, a form of congenital stationary night blindness, is
Dopaminergic neurons in the midbrain also show sponta- one of a small number of diseases that manifest the Mizuo
neous action potentials. phenomenon, in which the retina develops a golden metallic
A clinical form of amacrine cell blindness may occur fol- sheen when light-adapted. Although the mechanism of this
lowing endoscopic surgery of the prostate gland. This condi- phenomenon is not known, one hypothesis asserts that the
tion apparently occurs from the toxic effects of the irrigating sheen relates to an abnormally high extracellular potassium
solution—usually isotonic glycine—on the visual sensory concentration that is a consequence of decreased absorption
pathway. The finding of an abnormal ERG (i.e., large ampli- by Müller cells (106). Müller cells are also thought to be
tude a-wave; reduced amplitude and loss of oscillatory po- the source of the negative component and proximal slow
tentials of the b-wave) coupled with the fact that glycine is component of the ERG c-wave (107).
an inhibitory neurotransmitter normally present in the inner Blindness may result from a (35-kD) antibody directed
retina suggests that amacrine cells are the likely targets of against Müller cells. In the one reported case, which occurred
this toxicity (97,98). in the absence of a known malignancy, slowly progressive
blindness developed over several years. The ERG showed
Glial Cells greatly reduced b-wave amplitudes (photopic greater than
Müller Cell scotopic), perhaps from deficient uptake of potassium by
Müller cells (108).
The primary glial cell of the retina is the Müller cell. Most remarkably, there is growing evidence that glial cells
Somas of Müller cells are located in the IPL, but their pro- can be progenitors for neurons (109). At least in the chick
cesses extend throughout the retina (Fig. 1.3). The apical retina, fully developed and functional Müller cells can be-
processes form the outer limiting membrane by making junc- come neurons (110). A similar phenomenon has not yet been
tional complexes with one another and with photoreceptors. identified in non-avian retina.
On the vitreal side, apposed Müller cell end-feet form the
inner limiting membrane. Lateral extensions from Müller Astrocytes and Oligodendrocytes
cells (a) contact neurons, (b) form synapses with dendrites Astrocytes are found only on the vitreal side of the retina,
within the plexiform layers and with axons within the nerve within the nerve fiber and ganglion cell layers, but only in
fiber layer (NFL), and (c) contribute to the blood–retinal species that have a retinal vasculature (111). Two types of
barrier by their contact with blood vessels. Müller cells also retinal astrocytes develop from stem cells in the optic nerve,
provide trophic support for blood vessels within the inner and each type preferentially contacts either nerve fiber bun-
retina through release of vascular endothelial growth factor dles or blood vessels (112). These astrocytes migrate from
(VEGF) (99). the optic nerve and serve as a retinal angiogenic factor by
Müller cells metabolize glucose to lactate, which is re- secreting VEGF adjacent to developing blood vessels. VEGF
leased and used by photoreceptors for oxidative phosphory- production is induced by hypoxia (secondary to neuronal
lation. The need for energy is signaled by neuronal (i.e., metabolism), which entices growth of the blood vessels. The
photoreceptor and bipolar) release of glutamate, which is newly formed blood vessels release oxygen, which encour-
aggressively taken up by Müller cells (100). Once absorbed, ages the astrocytes to remain mobile and stay just ahead of
glutamate is detoxified by conversion to glutamine, which is the wave of the developing vasculature (113).
then recycled by photoreceptors to glutamate for subsequent During retinal development, astrocyte precursor cells
release (101). Müller cells provide nourishment to neurons around the optic nerve head express the Pax2 gene. A Pax2
while protecting them by absorbing excess glutamate and gene defect is found in some patients with optic nerve colo-
nitric oxide (102,103). The ability of Müller cells to uptake bomas, which suggests that abnormal development of the
glutamate (and GABA) rapidly also probably reduces the lineage or function of astrocytes may be responsible (114).
synaptic noise that would otherwise be present with any lin- Astrocytes also are a controlling influence for synapse for-
gering concentrations of these neurotransmitters. mation. In fact, few neuronal synapses form in the absence
The radial architecture of Müller cells provides guidance of glia. The astrocyte mediator of synapse formation appears
Figure 1.11. Müller cell regulation of potassium ions and

generation of the ERG b-wave in the amphibian retina. De-
polarizing neurons within the retina release potassium ions
(KⳭ) upon stimulation with light, resulting in an increase
in potassium [KⳭ]o in the inner (IPL) and outer (OPL) plexi-
form layers. The increase in [KⳭ]o causes an influx of KⳭ
into Müller cells (M) and a simultaneous efflux of KⳭ from
their end-feet (white arrows). These KⳭ fluxes establish a
radially oriented flow of current within the retina (solid lines)
that results in the transfer of KⳭ from the retina to the vitre-
ous. The flow of current generates a vitreous-positive poten-
tial, the ERG b-wave. (From Albert DM, Jakobiec FA. Prin-
ciples and Practice of Ophthalmology. Philadelphia, WB
Saunders, 1994⬊406.)
to be cholesterol, which is transported by apolipoprotein E. sels (122). Retinal microglia become activated after section
Neurons take up apolipoprotein E molecules, which is asso- of the optic nerve (123) and in association with a variety of
ciated with expanded synaptogenesis (115,116). retinal degenerations (124). Activated microglia may secrete
Astrocytes, like Müller cells, also may protect neurons molecules that kill retinal neurons (124). In glaucoma, mi-
by taking up glutamate. In certain circumstances, however, croglia in the optic nerve head become activated and migrate
astrocytes may mediate neuronal injury by release of stored into the peripapillary chorioretinal region, which becomes
glutamate via hemi-channels. The ability of astrocytes to increasingly atrophic as the disease progresses (125).
release glutamate has the potential to affect synaptic trans-
mission (117). Astrocytes also communicate among them- Retinal Ganglion Cells
selves, even at extended distances, via release of ATP, which
causes an increase in calcium in neighboring glia that Adult humans have, on average, 1.2 million RGCs
prompts ATP release from those cells, and so on. Astrocytes (126,127). This is the residual number following loss of
also have the ability to modulate neuronal synapses (118). 50–90% of the population originally present early in devel-
Oligodendrocytes migrate into the optic nerve from the opment (128,129). RGC attrition is effected by apoptosis.
brain during embryonic development and usually do not ex- A similar, massive loss of neurons occurs throughout the
tend past the lamina cribrosa in primates (119). However, brain during early development. Across individuals there is
the presence of myelinated nerve fibers in the retinas of marked variability in the final RGC number (127,130).
about 0.5% of normal persons indicates that migration across Whatever that final number, roughly 70% of RGCs will sub-
the lamina cribrosa does occasionally occur. Rarely, espe- serve the central 30 degrees of the visual field. Some RGCs
cially in patients with neurofibromatosis, myelination in the are ‘‘displaced’’ into the INL, and the RGC layer contains
retina may appear to increase during childhood (120). ‘‘displaced’’ amacrine cells. In fact, displaced amacrine cells
A new class of glial cells, called synantocytes, have been account for 3–80% of neurons in the RGC layer, depending
discovered. These cells, which are ubiquitous, specifically upon eccentricity (127). Astrocytes, endothelial cells, and
contact neurons at their synapses and at nodes of Ranvier pericytes are also found in the ganglion cell layer. The distri-
(121). The role of these cells is not well understood, but bution of RGCs with respect to the Goldmann visual field
they are in an advantageous position to monitor neuronal map is shown in Fig. 1.12.
activity and potentially detect altered function. The fate determination that leads to creation of an RGC
is not sufficient for axonal generation. Axons are generated
Retinal Microglia only after exposure to glial cells and neurotrophic factors. A
complex orchestration of molecular factors and physiologic
Microglial cells enter the retina from the bloodstream as activity is also required to ensure proper growth and direc-
macrophages during mid-embryogenesis. In human retinas, tion of RGC axons to their targets. There is also evidence
quiescent microglia exist throughout much of the retina, al- that RGCs secrete their own neurotrophic factors to help
though they are more common near inner retinal blood ves- sustain themselves, perhaps even bolstering their ability to
Figure 1.12. Visual field overlay for the distribution of the human retinal ganglion cells for perimetry using a Goldmann
perimeter. Each sector of the map equals 1% of the total number of cells. An inset (left) has been provided to assist in counting
of boxes when a field defect involves the central region. The blind spot is included for orientation only and should not influence
the counting of boxes when field defects involve the peripapillary region. The hatched lines extending from the meridia in the
nasal quadrants are a reminder that a relatively small number of ganglion cells (less than 1%) are present beyond the superior,
inferior, and nasal borders of the map. (Map constructed by Rizzo JF and Castelbuono AC using original data from Curcio
CA, Allen KA. Topography of ganglion cells in human retina. J Comp Neurol 1990;300⬊5–25.)
withstand axonal injury (126). The possible clinical signifi- based on cell size (71) (Table 1.2). Of these, the most numer-
cance of neurotrophic factors on RGC survival is revealed ous are small cells known as ‘‘beta’’ or ‘‘P’’ (for parvocellu-
by the report of a deficiency in retrograde transport of brain- lar) cells, which as their name implies, synapse in the parvo-
derived neurotrophic factor (BDNF) and upregulation of the cellular layers of the dLGN. A much smaller population,
BDNF receptor (TrkB) at the optic nerve head in a glaucoma perhaps 5–10% of primate RGCs, are large cells known
model (131,132). as ‘‘alpha,’’ ‘‘parasol,’’ or ‘‘M’’ (for magnocellular) cells,
Dendrites of RGCs branch in well-defined strata within which synapse in the magnocellular layers of the dLGN.
the IPL, and the specific region of stratification varies with These cell types, which are divided equally between ON and
the particular cell type. As noted above, ON center and OFF OFF varieties, are the best-studied RGCs. It has generally
center ganglion cells have dendrites that terminate in either been assumed that collectively these populations represent
the b or a sublamina of the IPL, respectively (Fig. 1.8). 85–90% of all primate RGCs. Recently it has been reported
Axons of RGCs terminate in the dLGN, hypothalamus, pre- that a small cell type (i.e., a ‘‘local edge detector’’ cell) may
tectum, or midbrain. In the primate, there may be 15–20 be the most common RGC in the rabbit (133), although it
more subpopulations of RGCs (71,133,134). Each RGC type is not yet known whether this finding will hold for primates.
has a specific anatomy (Fig. 1.13), and for many a specific The smallest RGCs are the ␬, koniocellular, or K cells,
physiology (i.e., ‘‘form matches function’’) has been identi- so named because the cell bodies are small enough to resem-
fied (Fig. 1.14). ble small particles of dust (from the Greek word konis) (135)
RGCs have traditionally been divided into two main types (Table 1.2). These cells are a mixed population with the
Figure 1.13. The branching and level of stratification for 11 types of ganglion cells identified in rabbit retina. Several labeling
methods were used to identify these cell types, and it is likely that these representations constitute most ganglion cell types
in the rabbit retina. The cell types with a known physiologic response profile are as follows: G1, local edge detector; G4, either
an ON or OFF brisk sustained; G6, uniformity detector; G7, ON-OFF direction selective; G10, ON direction selective; G11,
either an ON or OFF brisk transient. Cells with both ON and OFF varieties (i.e., G4 and G11) ramify in one of two sublaminae
within the inner plexiform layer. Ramification nearer the ganglion cell layer (i.e., in sublamina b) is associated with ON
responsiveness. INL, inner nuclear layer; GCL, ganglion cell layer. Numbers to the right indicate depth within the inner
plexiform layer. Scale bar ⳱ 100 ␮m. (From Rockhill RL, et al. The diversity of ganglion cells in a mammalian retina. J
Neurosci 2002;22⬊3831–3843.)
common features of a small cell body and wide, diffusely complete loss of conscious vision (140). The majority of
branching dendrites (136), although some have a larger soma cells in the retinohypothalamic pathway begin not at the
(137). These diverse anatomic traits suggest that the ␬ cell level of photoreceptors, but rather with a small population
class includes more than one physiologic type of cell. of RGCs that respond to light (Fig. 1.15). This light-respon-
A few RGCs exit the afferent visual pathway via the poste- siveness is conferred by melanopsin, a recently described,
rior aspect of the optic chiasm and terminate in one of several novel opsin-like protein (141–145). Roughly 30% of the
areas of the hypothalamus, one of which is the suprachias- melanopsin-containing RGCs receive input from rods and
matic nucleus that regulates circadian rhythms (138,139). cones, and thus presumably are activated directly (via their
Retinohypothalamic cells can survive and regulate circadian own melanopsin) and indirectly (via synaptic input from bi-
rhythms even when retinal or optic nerve disease causes polar cells) by light (146).
Table 1.2
Equivalent Anatomic Nomenclature and Associated Physiologic Properties of Some Retinal Ganglion Cell Types
Cell Size/Dendritic Concentric Linear/ Sustained/

Anatomic Referencea Field Size Physiologic Reference Center/Surround Nonlinear Transient
Beta; P␤; P; Parvo- Medium/narrow and dense X ⫹ Linear Sustained

Alpha; P␣; M-; Magno Large/wide and dense Y ⫹ Non-linear Transient
Gamma; koniocellular; Most have small somas and/wide Mixed types/some W Most Either Either
K- but sparse dendrites. Some have
larger somas.
Delta Medium/wide, moderately dense Mixed types/some W Most Either Either
a
The nomenclature can be confusing since multiple names are used to define the same cell types. For instance, The P in the P␤ or P␣ nomenclature is
a reference to primate. The P- and M-cell nomenclature refers to whether the cell terminates in the parvocellular or magnocellular region of the dorsal
lateral geniculate nucleus.
Figure 1.14. Correlation between morphology of photostained retinal ganglion cells and their light response properties when
recorded in vitro. A and B, Aspects of the spatial and temporal response properties of an OFF-center parasol ganglion cell
photostained prior to intracellular penetration and voltage recording. A, In vitro photomicrograph of recorded cell taken after
recording was complete and electrode was withdrawn from cell. Dendritic field diameter equals 240 ␮m. Scale bar ⳱ 50 ␮m.
B, Intracellular recording in response to a spot or annulus centered on receptive field shows OFF-center (left trace), ON surround
(right trace) light response; square wave below voltage trace shows time course of 2-Hz modulated stimulus; icons situated
below trace illustrate spatial configuration of stimulus. When the light stimulus is turned on (indicated by the upward direction
of the square wave trace shown below the physiologic recording), the bright spot of light placed in the center of the receptive
field of this OFF cell (left) results in dramatic reduction of recorded activity. By comparison, stimulating this same cell with
a bright annulus in the surround of its receptive field (right) produces a dramatic increase in firing rate. This response profile
reveals the antagonistic, center-surround organization that is characteristic of most retinal ganglion cells. C and D, Morphology
and light response of a large field bistratified cell. C, Photomicrograph of a darkly stained cell that was retrogradely labeled
by tracer injections placed in the lateral geniculate nucleus and then processed for histochemistry after labeling with horseradish
peroxidase immunoreaction. On the left, the soma (arrow) and inner dendrites are shown; on the right, a slightly different
focal plane shows the outer dendrites (arrow) of the same cell. Dendritic field diameter equals 415 ␮m. Scale bar ⳱ 50 ␮m.
D, The cell shown in C gave an ON response to 1-Hz square wave chromatic stimuli modulated to isolate S cones (left trace)
and an OFF response to stimuli modulated to isolate L and M cones (right trace). A difference of Gaussian model fit to spatial
frequency response data (not shown) was used to construct the one-dimensional center and surround receptive field profiles
shown in the middle insert. The model gives a Gaussian receptive field diameter of 510 ␮m. (Modified from Dacey DM, et
al. Fireworks in the primate retina: In vitro photodynamics reveals diverse LGN-projecting ganglion cell types. Neuron 2003;
37⬊15–27.)
Most RGCs that contain melanopsin mRNA project to viously identified biplexiform (or interplexiform) RGCs,
each suprachiasmatic nucleus and to the contralateral pretec- which stretch into the OPL and receive input directly from
tal area via collaterals, which allow one cell to provide input rods, is not known (71). However, the fact that biplexiform
to two locations (142,147). Roughly 20% of these special cells bypass the middle retinal circuitry suggests they influ-
RGCs innervate the intergeniculate leaflet (see dLGN, ence functions that depend upon ambient light intensity, like
below). The olivary pretectal nuclei and superior colliculi circadian rhythms and pupillary light reflexes.
also receive input from melanopsin-containing RGCs. These A subset of motion-detecting cells known as object motion
latter inputs to noncircadian centers suggest that these cells cells respond differently depending on whether object mo-
serve broader roles (145), perhaps by providing information tion is similar to or different from the background (84). In
about the mean retinal illumination that may contribute to other words, these cells are quiet if an object moves ‘‘in
control of sleep–wake cycles and influence pupillary light sync’’ with the background but fire when ‘‘local’’ motion
reflexes (147,148). The relationship of these cells to the pre- differs from the background (also see polyaxonal amacrine
their development (153), is not one of symmetric opposition.

ON pathways introduce a tonic inhibition of OFF cells at
mean luminances and a phasic inhibition of the OFF pathway
in response to increases of incident light (154). As such, the
pathways are not truly ‘‘parallel’’ in that there are significant
asymmetries, with a unidirectional inhibition of the ON sys-
tem onto the OFF system.
Third, the responses to light of most RGCs are either sus-
tained or transient (155,156). Transient responses are be-
lieved to result from feedback synapses within the IPL that
alter the sustained responses typical of the outer retina. Cells
with sustained responses also show linearity of spatial sum-
mation (i.e., the response magnitude is proportional to the
area of illumination within the receptive field center). Gener-
ally, cells classified anatomically as P cells have a sustained
(i.e., X-cell) response profile, whereas M cells have a tran-
sient (i.e., Y-cell) response profile (Table 1.2). Lastly, RGCs
maintain a continuous spontaneous discharge, which re-
Figure 1.15. Melanopsin immunoreactivity is found in a subset of retinal quires considerable energy but provides a dynamic range of
ganglion cells constituting the retinohypothalamic tract. This is a photomi- response for either increases or decreases in the level of
crograph of a flat-mounted rat retina that reveals a subpopulation of retinal illumination for each cell type. In other words, even an ON
ganglion cells that contain melanopsin immunoreactivity in the plasma RGC can signal a response to decreased light in the center
membrane of the soma and dendritic processes, which forms an extensive of its receptive field by reducing its spontaneous firing rate.
photoreceptive network. Scale bar ⳱ 100 ␮m. (From Hannibal J, Fahrenk- However, the dynamic range of its response to lowered illu-
rug J. Melanopsin: a novel photopigment involved in the photoentrainment
mination is substantially less than it can achieve to increased
of the brain’s biological clock? Ann Med 2002;34⬊401–407.)
illumination, for which its dynamic range of response is
vastly greater. OFF RGCs have a higher spontaneous firing
rate than ON cells, which may contribute to the physiologic
cell, above). This response property may form (or contribute segregation of these cell types at the dLGN (discussed later).
to) cognitive inattention to visual input during saccadic or P cells are color-opponent (i.e., the center of the receptive
microsaccadic eye movements. These cells have been identi- field is maximally responsive to either red or green light,
fied in a mammalian retina but not yet in primates, although whereas the inverse is true for the surround), have small
the requisite neuronal architecture is present in primates. receptive fields, and have low sensitivity to contrast in the
Some RGCs respond preferentially to short wavelengths. visual scene (155,157). Color-opponency is generated by
One such cell (i.e., ‘‘small, bistratified’’ cell) has a small connections at both the OPL and IPL (158). P cells are proba-
soma with (relatively wide, similar to parasol cells) dendritic bly the major afferent input to the brain for central (e.g.,
arbors that ramify in both the ON and OFF sublaminae of Snellen) acuity, color vision, and fine stereopsis (159).
the IPL. The ON input derives from ‘‘blue’’ cones (via 2 or M cells are spectrally ‘‘broad-band.’’ In other words, their
3 S-cone bipolar cells); the OFF input derives from M- and peak responsiveness at a given intensity of light is not deter-
L-cones. These cells are therefore sensitive to blue and yel- mined by the wavelength, a property that derives from the
low colors. Collectively these cells constitute perhaps 10% combined input from all three cone types. M cells also have
of the color-sensitive RGCs. much larger receptive fields and are more responsive to lumi-
nance contrast than P cells (152,157). Most M cells respond
Retinal Ganglion Cell Physiology nonlinearly to light. In other words, their activity increases
in response to changes in the visual scene, rather than re-
Most RGCs share some fundamental physiologic proper- sponding proportionately to the intensity and duration of the
ties (149,150) (Table 1.2). First, RGCs have a concentric stimulating light.
and antagonistic center-surround organization, a property Lesions of the ‘‘M’’ retinogeniculate pathway in monkeys
that probably derives from lateral inhibition of horizontal impair high-temporal-frequency flicker and motion percep-
and, possibly, amacrine cells (151). Second, most RGCs re- tion (159). It might therefore be assumed that the increased
spond in an ON or OFF manner to change in luminosity sensitivity of M cells to luminance contrast would permit
or spectral distribution of light within their receptive field selective testing of these cells in patients with optic neuropa-
centers, which correspond to a particular depth of the den- thies. Selective lesions to the M-cell pathway in monkeys,
dritic arbor that ramifies in either sublamina a (i.e., OFF) however, do not degrade performance on tests of contrast
or sublamina b (i.e., ON) of the IPL (152). The precise depth sensitivity (160). This apparent paradox can be explained
within the IPL differs for the major RGC classes (e.g., M by the preponderance of P cells. Although P cells are individ-
versus P cells). This physiologic dichotomy of ON and OFF ually less responsive to contrast than M cells, their total
pathways, which requires postnatal visual stimulation for number is much greater than M cells (perhaps an 8⬊1 ratio).
Thus, patients with a neurologic decrement in contrast sensi- within this quadrant can take advantage of cues from the
tivity probably have P- and M-cell dysfunction. previously established axons for guidance toward the optic
As suggested above, cells that conform to the ␬ morphol- nerve head. Epithelial cells in the optic stalk give rise to
ogy (i.e., K cells) are physiologically diverse. These cells glial cells in the optic nerve and other cells that line the
may or may not have concentric center-surround receptive fissure (Fig. 1.1). The latter cells express the transcription
field organization, may have sustained or transient changes factor Pax-2. Failure to express Pax-2 prevents closure of
in firing rate, and may be ON center or OFF center respon- the optic nerve fissure and causes failure of axons to leave
sive (161). Some ␬ cells are part of a third physiologic class the retina (6). Pax-2 deficiency is a cause of optic nerve
of RGCs called W cells, which have large receptive fields, head coloboma and optic nerve hypoplasia in humans (166).
slow onset latency, and slow axonal conduction velocity. At RGCs have relatively long axons, which are entirely de-
the level of the dLGN, K cells receive direct input from the pendent upon their soma for tropic support. An axon is a
superficial layers of the superior colliculus, which is not dynamic structure that requires nearly constant repair of its
provided to M or P cells. In addition, many K cells project membranes, a process that includes bidirectional transport
indirectly to the dorsal visual pathway (discussed later). of proteins, enzymes, and subcellular components (including
These features suggest that some K cells contribute informa- mitochondria) to, and detritus from, sites up to the synapse.
tion about eye movements, since both the superior colliculus Axonal velocities are somewhat bimodal and range from fast
and dorsal median visual area are preferentially driven by (i.e., hundreds of millimeters per day) to slow (less than
motion. 10 mm/day) speeds. At least five classes of proteins are
Some W cells are direction-selective cells. One such cell transported at different velocities within RGCs, and these
type is the ON center direction selective cell, which tran- relationships vary during development (167).
siently increases its firing rate when a stimulus enters its Slow anterograde transport, which largely carries compo-
receptive field from a specific direction. These cells receive nents like cytoskeletal proteins that remain within the cell,
their primary input from ‘‘starburst’’ cholinergic amacrine constitutes the bulk (about 85%) of all transport. Fast antero-
cells (discussed previously). Another type of direction-selec- grade transport is used to carry neurotransmitter-containing
tive W cell responds when a stimulus enters (ON) or leaves vesicles. Molecular transport is aided by repetitive to-and-
(OFF) its receptive field. As might be expected (Figs. 1.8 fro realignment of kinesin, a protein ‘‘molecular motor’’
and 1.13), such cells have bistratified dendritic arborization with a globular head that reacts with microtubules, structures
within the IPL. that serve as internal guidewires for transport within the
axon. Transport speed for neurofilaments, the most signifi-
Retinal Ganglion Cell Axons cant cytoskeletal protein, is slowed by increased C-terminal
phosphorylation, which may dissociate neurofilament mole-
As mentioned above, RGCs are the first retinal neurons cules from kinesin. Rapid axonal transport may be predomi-
to develop. The extension and guidance of their axons are nately impaired in axons that project to the magnocellular
complex phenomena directed by growth factors. Both attrac- layers of the dLGN in instances of chronic (but not acute)
tive and repulsive molecules are present in the developing elevation of intraocular pressure (168). Retrograde transport,
retina and optic nerve head, and RGC axons express recep- which is less well understood, proceeds at roughly half the
tors for those molecules that participate in the growth process maximum velocity of anterograde transport. Axonal trans-
(162). port, whether anterograde or retrograde, is highly energy
RGC axonal sprouts are repulsed from penetrating into dependent. The ATP needed to sustain transport is supplied
the retina, perhaps by Müller cell somata (which conversely by mitochondria that are distributed along the axon.
encourage growth of RGC dendrites). Axonal repulsion may The common defect in pathologic swelling of the optic
be performed by ephrin-A5, one of many ligands for receptor disc from almost any etiology is disruption of anterograde
tyrosine kinases of the ‘‘Eph’’ family (163). (Other ligands axonal transport of RGCs at the lamina cribrosa. Experimen-
of this family are involved in axonal termination in the mid- tally induced ischemia of the anterior optic nerve of monkeys
brain; discussed later.) With molecular guidance, the axons disrupts both fast and slow anterograde axonal transport
move toward the vitreal surface and then bend toward the (169,170). Slow anterograde transport can be selectively dis-
optic nerve when they contact the end-feet of the developing rupted in experimental optic nerve crush injury (171). An-
Müller cells (164). The axons travel within fascicles toward terograde axonal transport also can be disrupted by increased
the optic nerve head with remarkable, although not perfect, or decreased intraocular pressure, increased intracranial
precision. Their journey across the retina is probably influ- pressure (172–175), and possibly decreased energy reserves
enced by several factors, although laminin (especially lami- secondary to mitochondrial dysfunction (176). Disruption
nin-1) may be particularly instrumental. RGC axons express of axonal transport may contribute to the death of RGCs.
integrins, which are the receptors for laminin. At the optic Following severe injury, some RGCs can regenerate, but the
nerve head, the guidance molecule netrin-1 influences axo- potential is quite limited (177,178). Generally, the larger
nal bending into the optic nerve head (ONH) (165). Defi- RGCs are more capable of surviving axotomy and regenerat-
ciency of netrin-1 is a cause of optic nerve hypoplasia in ing their axons (179).
humans. Membranes of RGC axons contain many ionic channels.
The first RGCs develop in the dorsotemporal quadrant, The voltage-dependent sodium channel (Nav) is the most
near the optic nerve stalk. The axons that sprout thereafter important channel with respect to generation of action poten-
tials. Nav channels exist in very high density at the axonal

hillock and nodes of Ranvier. The normal complement and
localization of channel isoforms along axons are altered with
demyelination, which presumably accounts for some of the
disability that occurs in multiple sclerosis (180,181).
Bifurcation of RGC axons has been well documented,
especially for cells that terminate in the hypothalamus and
that also may send an axonal branch to the intergeniculate
leaflet of the thalamus (145,147,182). In the cat, axonal bi-
furcation occurs for all three major physiologic classes of
RGCs (i.e., X, Y, and W cells). Such bifurcations have not
been documented in humans but have been discovered in
many areas of the monkey brain (183).
A superficial plexiform layer located between the gan-
glion cell layer and the traditional nerve fiber layer is present
in some mammalian retinas. The layer is composed of pro-
cesses of M RGCs and some amacrine cells. This arrange-
ment provides the potential for local feedback loops (184).
Nerve Fiber Layer

The NFL is composed of RGC axons, astrocytes, compo-
nents of Müller cells, and rare efferent fibers to the retina
whose function is unknown (185,186). The NFL is thinnest
in the peripheral retina and thickest adjacent to the superior Figure 1.16. Retinal nerve axons as they extend from the ganglion cells
and inferior margins of the optic disc, where it measures to the disc. The axons arising from ganglion cells in the nasal macula project
about 200 ␮m in humans. The temporal and nasal NFL adja- directly toward the optic disc (OD) and compose part of the papillomacular
bundle (P). Axons from ganglion cells of the temporal macula have a slight
cent to the optic disc is about one-tenth as thick (187). NFL arching pattern around the nasal macular axons. They form the remainder
thickness declines with age, which can be demonstrated non- of the papillomacular bundle. Axons from nonmacular ganglion cells that
invasively with optical coherence tomography (188). are nasal to the fovea (F) have a straight or gently curved course to the
The gross organization of the NFL bears several distinc- optic disc, whereas axons from ganglion cells temporal to the fovea must
tive features. First, peripheral RGC axons from the temporal arch around the papillomacular bundle and enter the disc at its superior
retina arch around the papillomacular bundle, which contains and inferior poles. The superior and inferior portions of the temporal retina
nerve fibers originating from RGCs in the foveal area. This are delineated by an anatomic landmark, the temporal raphe (R). The dotted
pattern is dictated by the relatively early formation of the lines delineate the nasal (N), temporal (T), superior, and inferior portions
central retina. Second, a demarcation on the temporal side of the retina. Consider that the temporal and nasal parts of the retina are
defined by a vertical line through the fovea, not the OD. (Redrawn from
of the fovea called the temporal raphe separates superior and
Hogan MJ, Alvarado JA, Weddell JE. Histology of the Human Eye. An
inferior axons out to the far periphery of the retina (189). Atlas and Textbook. Philadelphia, WB Saunders, 1971.)
This raphe therefore creates a physiologic separation be-
tween the superior and inferior regions of the nasal visual
field (which is monitored by the retina temporal to the
fovea). Third, fibers from the nasal aspect of the optic disc nerve fiber layer of Henle (discussed previously). This lat-
are organized radially as they approach the optic nerve head eral shifting could theoretically connect photoreceptors on
(Fig. 1.16). one side of the vertical meridian to RGCs on the opposite
The demarcation between temporal and nasal retina (and side (195). This seemingly awry anatomy would not neces-
thus the visual field) is a vertical line that passes through sarily disrupt visual field topography, since the determinant
the fovea—not the optic disc. Generally, RGC axons nasal to for visuospatial localization is based upon the position of
the fovea decussate within the optic chiasm, whereas axons the photoreceptor and not the RGC soma. Nonetheless, some
temporal to the fovea remain ipsilateral. However, at a cellu- degree of imprecision between nasal and temporal hemi-
lar level in monkeys, some RGC axons temporal to the fovea fields can be observed by visual field testing, especially more
cross within the chiasm, whereas some nasal axons remain peripherally (196), even when the scanning laser ophthalmo-
uncrossed (190–194). This overlap, which is more signifi- scope is used to precisely control the position of the stimulus
cant in the peripheral retina (192,193), if present in humans on the retina.
would not necessarily disrupt the demarcation between nasal Within the NFL, axons from central RGCs are more super-
and temporal hemifields. A RGC located on one side of the ficial than those from more peripheral RGCs. To achieve
fovea does not necessarily receive input from a photorecep- this arrangement, fibers from central RGCs extend upward
tor located on the same side of the fovea. The relatively between fibers of more peripheral RGCs (197) (Fig. 1.17).
larger width of the cone pedicle compared to the foveal cone Near the disc margin, most axons from peripheral RGCs are
soma forces a lateral displacement of cone pedicles via the relatively deep within the NFL and more peripheral at the
and possibly the presence of xanthophyll within the macula,

which absorbs shorter wavelengths of light and thus reduces
chromatic aberration, also contribute to the high spatial reso-
lution provided by the central retina.
Retinal Blood Vessels

The human retina receives its essential nutrients, oxygen
and glucose, from both the retinal and the choroidal circula-
tions. The border between these circulations is near the OPL
(200). The choroidal circulation supplies the photoreceptors,
whereas the retinal arteries supply the inner retina, except
within the foveal avascular zone. The degree to which the
inner retina is vascularized appears to correlate best with the
degree of oxidative metabolic demand rather than with the
thickness of the retina (201). Astrocytes in the developing
retina are extremely sensitive to hypoxia, which prompts
release of VEGF. The release of VEGF just ahead of the
advancing edge of the developing retinal vasculature pro-
motes further extension of the vasculature into the more pe-
ripheral retina (202). Amacrine cells and RGCs synthesize
and express VEGF, which presumably helps to secure a via-
ble blood supply. Müller cells also provide a similar trophic
support via VEGF (99).
Retinal blood vessels are barrier vessels, analogous to the
blood–brain barrier elsewhere in the CNS. These vessels are
Figure 1.17. The three-dimensional organization of the nerve fiber layer
impermeable to particles larger than 20 Å (203). Astrocytes
in the primate retina and optic disc. A, Anterior-posterior organization of
axons projecting from ganglion cells (G) located in peripheral, middle, and
and pericytes almost certainly play a role in maintaining low
peripapillary retina (R) into the optic nerve (ON). Lamination of axons capillary permeability within the NFL, whereas Müller cells
within retina is speculative. Only half of retina and optic nerve are repre- probably play a similar role more deeply within the retina.
sented, as if displayed in standard horizontal section. B, Horizontal topogra- The blood–retinal barrier is also maintained by chemical
phy of axon bundles from the arcuate fibers (i.e., those that course around factors (204).
the papillomacular bundle) as they project into the anterior portion of the Autoregulation of retinal (and choroidal) blood vessels
optic nerve head. Peripherally located ganglion cells project to the periph- may be at least partially controlled chemically by hormonal
eral aspect of the optic nerve (triangles), centrally located ganglion cells products of the local vascular endothelium, including vasodi-
to the midperipheral aspect of the optic nerve (circles), and peripapillary lators such as nitric oxide and prostaglandins, and vasocon-
ganglion cells to the center of the nerve (squares). (From Minkler DS. The
strictors, particularly endothelin and the products of the
organization of nerve fiber bundles in the primate optic nerve head. Arch
Ophthalmol 1980;98⬊1630–1636.)
renin-angiotensin system that are produced and released via
angiotensin-converting enzyme located on the endothelial
cell membrane (205). Additionally, adenosine and ␣1-adren-
ergic receptors mediate vasodilation and vasoconstriction,
optic nerve head (197). Despite this general plan, near the respectively. Amacrine cells contact retinal vessels and may
optic disc there is significant intermingling of fibers (198). also influence autoregulation.
Retinal blood vessels impede light transmission through
Macula the retina and produce ‘‘angioscotomas.’’ This highly local-
Numerous anatomic specializations contribute to the
higher spatial resolution afforded by the macula. The most
significant factor is the especially high density of photore- Table 1.3
ceptors, particularly cones (50). At the fovea, cones have a Retinal Neurons and Some of Their Associated Neurotransmitters
center-to-center separation of only 2 ␮m. The foveal pit (Fig. Cell Type Neurotransmitter
1.7) enhances spatial fidelity by reducing the amount of tis-
sue through which light must pass to reach the cones. The Photoreceptors Glutamate
relatively high density of centrally placed rods (but not Horizontal cells GABA
cones) and RGCs is related to the greater density of ocular Bipolar cells
ON-center (depolarizing) Glutamate
melanin, although not in a dose-dependent fashion (199).
OFF-center (hyperpolarizing) Glutamate
This observation provides a theoretical basis for the poor
Interplexiform cells Dopamine, GABA
vision of albinos. Melanin also plays a critical role in axonal Amacrine cells Acetylcholine glycine, GABA
direction at the chiasm (discussed later). The lack of blood peptides, dopamine
vessels in the central macula (i.e., the foveal avascular zone)
Table 1.4
Primary Projection Pathways from the Retina
Retinal Outflow Site of Termination Function
Parvocellular Layers 3–6 of dLGN Fine spatial detail

Color vision
Magnocellular Layers 1–2 of dLGN Contrast sensitivity
Motion detection
Koniocellular Intercalated layers of dLGN Contribute information about eye motion
Pregeniculate complex Manifests saccade-related activity and influences activity in the 6 primary
laminae, especially for the M-pathway
Gamma cell Pre-tectal nuclei Pupillomotor function

Melanopsin-containing retinal Intergeniculate leaflet “Phase shifting” of circadian cycle
ganglion cells Hypothalamus Regulation of circadian cycle
This table is meant to convey only general patterns of information flow and function. This list of retinal outflow cell types descriptions of function are not complete .
ized visual depravation causes a rewiring of connections be- scotopic conditions, rod signals are transmitted to the rod
tween the dLGN and the primary visual cortex. The corre- bipolar cells via a sign-inverting signal that depolarizes the
sponding areas of the visual cortex are relatively less active, bipolar cells. The signal is then carried via rod bipolar cell
as revealed by ‘‘shadows’’ in the cytochrome oxidase stain- to sublamina b of the IPL, where there is a sign-conserving
ing pattern (206). synapse onto AII amacrine cells. (Rod bipolar cells do not
make direct contact with RGCs.) AII amacrine cells have
Retinal Neurotransmitters gap junctions with depolarizing cone bipolar cells and also
make a sign-inverting glycinergic synapse onto hyperpolar-
A review of neurotransmitters in the retina is beyond the
izing cone bipolar cells, which terminate in sublamina a of
scope of this chapter. Table 1.3 provides a list of known
the IPL, where they contact OFF center RGCs.
neurotransmitters for the major classes of retinal cells, and
Cone output in the central retina uses the ‘‘midget’’ sys-
Figure 1.6 shows some of the neurotransmitters used by the
tem. A sign-conserving synapse using the AMPA glutamate
intraretinal cone and rod through pathways.
receptor is made on a cone-hyperpolarizing (OFF center)
OVERVIEW OF RETINAL OUTFLOW: PARALLEL bipolar cell, and a sign-conserving synapse that uses the
PATHWAYS mGluR6 receptor is made with a cone-depolarizing (ON cen-
ter) bipolar cell. The two bipolar cells terminate in sublamina
There is a complex orchestration of neuronal responses a and sublamina b of the IPL, respectively, where they con-
evoked by light stimulation of the retina. Light causes the tact OFF center (sublamina a) or ON center (sublamina b)
photoreceptors to hyperpolarize, which decreases the release RGCs. Amacrine cells have a complex influence on RGCs,
of glutamate from both rod and cone synaptic terminals. with both diffuse and highly local control and both excitatory
Horizontal cells then become hyperpolarized, which sup- and inhibitory effects. Various qualitative aspects of vision
presses the light response of the photoreceptors. Rod and (e.g., spatial detail, color, contrast, motion detection) pro-
cone out flows generally diverge, although gap junctions ceed to the brain through the optic nerve in parallel (Table
between them are believed to provide a signal path from 1.4), although there are physiologic interactions across the
rods to cones under mesopic or photopic conditions. Under ‘‘parallel’’ pathways at the retina, dLGN, and cortex.
OPTIC NERVE
EMBRYOLOGY comes atrophic as its blood supply withers when the hyaloid
The optic nerve develops in the substance of the optic artery involutes. The degree of atrophy determines the size
stalk (1,2,207,208). This stalk, which becomes apparent at of the optic nerve head cup: more complete atrophy produces
the fourth week of gestation, has a wide circular lumen that a deeper cup. With minimal atrophy, glial remnants remain
is continuous with the cavity of the forebrain at one end and on the surface of the optic disc. A Bergmeister papilla can
the optic vesicle at the other (Fig. 1.1). Its walls are com- persist as glial sheaths of the proximal segments of retinal
posed of a single layer of undifferentiated epithelial cells. arteries.
The optic stalk and vesicle both invaginate; in the stalk this At 8 weeks, two glial cell populations develop from two
produces a shallow depression ventrally. The lumen of the cell lines of the primitive neuroepithelium of the optic stalk
stalk shrinks as the stalk lengthens. and ventral forebrain. One cell line produces type 1 astro-
A proliferation of glial cells on the developing optic disc cytes. The second cell line originates from the oligodendro-
produces the Bergmeister papilla. This structure later be- cyte type 2 astrocyte (also known as the oligodendrocyte
precursor cell), which produces both oligodendrocytes and of the variation occurring intracranially. A discussion of
type 2 astrocytes. The size of the astrocytic populations de- optic nerve axon number is provided above.
pends upon signaling from RGCs, which express Hh protein,
which in turn induces expression of the Pax2 gene, which GENERAL ANATOMY
is expressed in the neuroepithelial precursor cells (114,209).
Mutations of the Pax2 gene are associated with optic nerve The optic nerve can be separated into four sections: the
coloboma, which suggests that disordered astrocytic devel- intraocular, intraorbital, intraosseous, and intracranial por-
opment may cause this defect. Partitioning of the glial popu- tions (Fig. 1.18). The intraocular segment of the optic nerve
lations is influenced by local biochemical cues. For instance, (i.e., the ONH) is primarily formed by coalescence of RGC
astrocytes within the optic nerve avoid the chiasm because axons, with the addition of three nonneural elements: astro-
of the presence of netrin-1 and semaphorin 3a (210,211). cytes, capillary-associated cells, and fibroblasts. The ONH
The functions of astrocytes are described above. Within the is a major zone of transition because the nerve fibers (a)
optic nerve, astrocytes also participate in the formation of pass from an area of relatively high intraocular pressure to
connective tissue septae (see later). the lower-pressure zone of the retro-orbital segment of the
Neuroepithelial cells within the ventral forebrain, also re- optic nerve, which is (usually) equivalent to the intracranial
sponding to an Hh protein, migrate into the developing optic pressure; (b) leave the blood supply of the central retinal
nerve and express different genes that direct neuroepithelial artery to receive blood from branches of the posterior ciliary
cells to become oligodendrocytes, which is the first step and ophthalmic arteries; (c) make a 90-degree turn and enter
toward the myelination of axons (210). Migration to distant the tight confines of the lamina cribrosa; and (d) become
targets (i.e., here, into the optic nerve) is characteristic of myelinated just behind the lamina cribrosa (Fig. 1.19).
The lamina cribrosa is a specialized arrangement of glial
the development of oligodendrocyte populations elsewhere
columns and connective tissue plates that form 200–300
in the CNS. The differentiation of glial cell populations also
holes through which all optic nerve axons pass (225,226)
is influenced by exposure to extrinsic factors that influence
(Figs. 1.20 and 1.21). The fenestrations of the lamina cri-
the redox state of the precursor cells. In general, greater
brosa form a tight seal that shields the relatively high intraoc-
oxidation encourages differentiation (212).
ular pressure from the retrolaminar tissues (227,228). Cells
Myelination, which begins centrally during embryogene- within the lamina cribrosa and the ONH astrocytes secrete
sis, gradually extends up to the lamina cribrosa and invests neurotrophin and glial cell-line–derived neurotrophic factor
almost all optic nerve fibers at or shortly after birth, and (GDNF), which suggests they may be important in maintain-
then ceases. In about 1% of patients, however, oligodendro- ing the health of the nearby axons, although it is not yet
cytes enter or are already present within the eye during em- known whether RGC axons express GDNF receptors
bryogenesis and produce intraocular myelination that usu- (229,230). However, alterations in the structure of the lamina
ally affects the NFL adjacent to the optic disc (213). The cribrosa may damage neurons. For instance, elevated intra-
‘‘stop’’ signal that (typically) prevents migration of oligode- ocular pressure induces (a) changes in the extracellular ma-
ndrocytes into the retina may be related to transient expres- trix that cause posterior displacement of the lamina cribrosa;
sion of netrin-1 and increased concentration of tenascin-C (b) changes in the pore size of the lamina cribrosa; (c) a
(214). higher translaminar pressure gradient; and (d) astrocytes to
Myelination is also dependent upon connexins, which pro- elaborate nitric oxide, which kills neurons (231–236). Simi-
mote gap junction formation (215). Both astrocytic and oli- larly, elevated intracranial pressure, which is transmitted
godendrocytic populations are linked by gap junctions, along the perineural subarachnoid space to the ONH (237),
which create a functional syncytium (216,217). Abnormal can displace the lamina cribrosa anteriorly, which also can
connexin protein can cause peripheral nervous system dys- damage axons (238).
myelination, as is seen in Charcot-Marie-Tooth disease. The
role that connexins might play with respect to RGC axons
is not known. Myelin speeds the transmission of impulses
but is not essential for some visual system functions, as is
evident in newborns, in whom myelination may not be com-
pleted for 2–4 years after birth (120,218,219). In general,
the thickest myelin sheaths are found around the thickest
axons (i.e., those of ‘‘M’’ RGCs), endowing them with the
fastest conduction velocities of 1.3–20 m/sec (220).
The optic nerve increases both in diameter and length
during gestation and through early adolescence (221–223).
By the beginning of the second decade, the diameter of the
intraocular portion of the optic nerve is 2 mm, while that of Figure 1.18. Histologic section showing the four topographic divisions
the extraocular portion of the nerve is 3–4 mm, the differ- of the normal optic nerve (1, intraocular; 2, intraorbital; 3, intracanalicular;
ence resulting largely from the formation of myelin sheaths. 4, intracranial) and optic chiasm (OC). (From Hogan MJ, Zimmerman LE.
The optic nerve diameter increases even beyond this time Ophthalmic Pathology. An Atlas and Textbook. Philadelphia, WB Saun-
(224). The adult length of the nerve is 40–50 mm, with most ders, 1962.)
Figure 1.19. Light photomicrograph showing architectural arrangement of the

prelaminar (P), laminar (L), and retrolaminar (R) portions of the optic nerve.
The retrolaminar segment of the optic nerve is darker because of the presence
of myelin. Note the abrupt transition between myelinated and unmyelinated seg-
ments of the optic nerve, which occurs just posterior to the lamina cribrosa.
(Courtesy of Dr. H. A. Quigley.)
Figure 1.20. Scanning electron micrograph of the lamina cribrosa, viewed from the vitreous cavity.
A B
Figure 1.21. Histology of the optic nerve head at the laminar cribrosa. A, Longitudinal section of the optic nerve head and
adjacent retrolaminar segment of the optic nerve in rhesus monkeys. LC, lamina cribrosa; PL, prelaminar region; RL, retrolaminar
region. B, Transmission electron micrograph of optic nerve axons (lighter cells) of lamina choroidalis. Axons make intimate
contact with astrocytic processes (As), which are the dark cells that are filled with intermediate filaments and interconnect
with each other. Magnification ⳯13,000. (A, Hayreh SS. From Anterior Ischemic Optic Neuropathy. New York, Springer-
Verlag, 1975⬊4. B, From Kline LD, ed. Optic Nerve Disorders. American Academy of Ophthalmology Monograph, 1996⬊5.)
The extracellular space is relatively small compared to the ual field. Alternatively, visual field defects may result from
total tissue volume of the ONH (173). However, diffusion of neural and not optical factors, owing to a partially hypoplas-
ions, molecules, or fluid within the extracellular space may tic nerve as an associated finding of the titled disc syndrome
alter axonal function (239). Normally, free diffusion of mol- (248).
ecules within the intravascular spaces of the ONH is limited The orbital segment of the optic nerve is about 25 mm
by tight junctions between capillary endothelial cells. Fur- long and is lax in its course, which allows the eye to move
ther, free diffusion of molecules to the subretinal space is fully without creating tension on the optic nerve (249) (Fig.
constrained by tight junctions between specialized cells lo- 1.22). This redundancy also provides an allowance of up
cated at the point of contact between the medial edge of the
retina and the perineural RPE (240). However, there is no
impediment to intercellular molecular diffusion at the ONH
surface, and thus fluid can move from choroid to the optic
nerve extracellular space or between the vitreous and the
cerebrospinal fluid (CSF) through the ONH.
The clinical appearance of the ONH varies with the size
of the scleral canal and the angle at which the optic nerve
exits the eye. A larger scleral canal is associated with a larger
physiologic cup size (241). A relatively small optic nerve
cup is generally associated with a smaller scleral canal. Pa-
tients with a small cup-to-disc ratio are prone to develop
nonarteritic, anterior ischemic optic neuropathy (242–244).
There is a positive correlation between the size of the ONH
and the number of photoreceptors, RGC axons, and retinal
surface area (245–247).
A tilted ONH is a common feature of myopia. In this
condition, the optic nerve fibers exit the sclera at an acute
angle temporally and a turn of more than 90 degrees nasally.
This anomaly is also associated with a slightly recessed tem- Figure 1.22. Sagittal section through a normal orbit showing the optic
poral, perineural border of the RPE, which produces a tem- nerve (N). The length of the nerve within the orbit appears to exceed the
distance from the posterior aspect of the globe to the apex of the orbit.
poral crescent. Also, there is ectasia of the inferonasal fun-
The intraorbital and intracanalicular portions of the nerve are covered by
dus, which often accounts for the relative depression of leptomeninges, the dural sheath of which is continuous with the periorbita
superotemporal isopters on visual field testing of myopic lining the inner surface of the orbital walls and the dura lining the base
patients. Stimuli presented superotemporally may fall short of the skull. (From Unsöld R, DeGroot J, Newton TH. Images of the
of the retinal focal plane in myopic eyes, which retards their optic nerve: anatomic-CT correlation. AJR Am J Roentgenol 1980;
recognition and produces an apparent depression of the vis- 135⬊767–773.)
Figure 1.23. Cross-section of human optic

nerve. Bundles of nerve fibers are divided into
bundles by connective tissue septa that are con-
tinuous with both the connective tissue of the
pia mater and the adventitia of the central retinal
vessels. Small, penetrating blood vessels and cap-
illaries within the connective tissue septae are
the dominant source of nourishment to the axons
along the orbital segment of the optic nerve.
to 9 mm of proptosis before the optic nerve becomes fully nerve exits the orbit through the optic foramen, which is the
stretched. The orbital segment of the optic nerve expands to anterior opening of the optic canal in the orbital apex. The
⬃4.5 mm from 3 mm because of the addition of myelin to 10-mm-long canal, which widens toward the intracranial
most axons (225) (Fig. 1.20). Bundles of nerve fibers are end, is formed by the union of the lesser wings of the sphe-
surrounded by connective tissue septa containing small arte- noid bone (250–252) (Fig. 1.25). The thickness of the bony
rioles, venules, and capillaries (Fig. 1.23). With the excep- optic canal wall varies from medial to lateral, and anterior
tion of the central retinal artery (CRA), there are few vessels to posterior. The medial wall, which is thinnest in the mid-
larger than capillaries within this portion of the optic nerve. canal, separates the optic nerve from the sphenoid and poste-
At the orbital apex, the ophthalmic artery lies below and rior ethmoid sinuses. Inferolaterally, the optic canal is sepa-
lateral to the optic nerve. The inferior division of the oculo- rated from the superior orbital fissure by a bony ridge, the
motor nerve, the abducens nerve, and the ciliary ganglion optic strut. Anomalies of the optic canals may occur, includ-
are all located lateral to the optic nerve (Fig. 1.24). ing its absence (253,254).
The intracanalicular (intraosseous) segment of the optic Each optic canal runs posteriorly and medially at an angle
Figure 1.24. View of the posterior orbit showing the relationship of the optic nerve to the ocular motor nerves and extraocular
muscles. The ophthalmic artery lies immediately below the optic nerve. (Redrawn from Wolff E. Anatomy of the Eye and
Orbit. 6th ed. Philadelphia, WB Saunders, 1968.)
Figure 1.25. Horizontally sectioned sphenoid bone demonstrates tapering of optic canals as they approach the orbit (best
seen on the right). The optic ring is formed by dense bone that surrounds the distal segment of the optic canal. The roof of
both optic canals has been removed. (From Maniscalco JE, Habal MB. Microanatomy of the optic canal. J Neurosurg 1978;
48⬊402–406.)
of about 35 degrees with the midsagittal plane (Fig. 1.26).

The intracanalicular optic nerve is tightly fixed within the
optic canal, which is lined with dura mater (Fig. 1.27). This
tight packing of the nerve within the canal may predispose
the optic nerve to percussive trauma from a blow to the
frontotemporal region of the skull (i.e., indirect traumatic
optic neuropathy), even sometimes following seemingly in-
significant trauma. Each canal transmits the optic nerve, the
ophthalmic artery, some filaments of the sympathetic carotid
plexus, and the orbital extension of the cranial leptomenin-
ges. Above each optic canal is a plate of bone that separates
it from the frontal lobe of the brain. Medially, the sphenoid
sinus and the posterior ethmoidal air cells border the canal.
Anatomic variations of the canalicular region include ab-
sence of bone (255), protrusion of the optic canal into the
sphenoid sinus (256), and pneumosinus dilatans, which is
an expansion of the paranasal sinuses without erosion of
adjacent bone. Development of pneumosinus dilatans may
be associated with an adjacent optic nerve sheath meningi-
oma (257–260). Lack of a bony partition from the sinuses
Figure 1.26. Axial section of normal optic nerves (N) showing relation-
can permit spread of sinus infection to the optic nerve ships to other orbital and intracranial structures. The intraorbital and intra-
(256,261). canalicular portions of the nerve are covered by a dural sheath that is contin-
The intracranial segment of the optic nerve exits under a uous with the periorbita lining the inner surface of the orbital walls and
firm fold of dura mater. The optic nerves, which are some- the dura lining the base of the skull. C, optic chiasm. (From Unsöld R,
what flattened immediately after emerging from the canal, DeGroot J, Newton TH. Images of the optic nerve: anatomic-CT correlation.
extend posteriorly, superiorly, and medially to join at the AJR Am J Roentgenol 1980;135⬊767–773.)
optic chiasm. The length of the intracranial optic nerve varies

considerably, from 3 to 16 mm (262). Proximally, the gyrus
recti of the frontal lobes lie above the optic nerves. The
olfactory tract is separated from the optic nerve by the ante-
rior cerebral and anterior communicating arteries. The in-
ternal carotid arteries lie lateral to the optic nerves
(255,263–266).
OPTIC NERVE BLOOD SUPPLY

Most of the optic nerve receives its blood from branches
of the ophthalmic artery (OA), which is the first major
branch of the internal carotid artery (ICA). The OA arises
typically just above the exit of the ICA from the cavernous
sinus (265,267). The OA then passes through the optic canal
below the optic nerve (Fig. 1.24), although the artery is sepa-
rated from the nerve by a dural sheath. Within the orbit, the
ophthalmic artery gives rise to two or three posterior ciliary
arteries (PCAs) and the CRA, which pierces the optic nerve
approximately 12 mm behind the globe and then runs anteri-
orly within the optic nerve (Fig. 1.28).
The blood supply to the optic nerve differs significantly
Figure 1.27. Optic nerve sheaths, showing their relationship to the optic depending upon which segment is considered. Although
nerve (ON) and to the surrounding sphenoid bone. The dura is tightly adher- there is considerable variability in the pattern of blood supply
ent to the bone within the optic canal. Within the orbit it divides into two to the optic nerve, the following generalizations follow from
layers: one remains as the outer sheath of the optic nerve, and the other studies of large numbers of humans (268). The blood supply
becomes the orbital periosteum (periorbita). Intracranially, the dura leaves to the most superficial aspect of the ONH is from branches
the optic nerve to become the periosteum of the sphenoid bone. of the CRA (Fig. 1.29). The blood supply to the region
around the lamina cribrosa derives from the short PCAs or
Figure 1.28. The internal carotid artery blood supply to the orbit and eye, with emphasis on the ophthalmic artery and its
major branches. Key for arteries: 16, frontal branch; 17, internal carotid; 18, ophthalmic; 20, posterior ethmoidal branch of
the ophthalmic; 25, superior peripheral arcade; 27, lacrimal; 28, recurrent meningeal; 35, central retinal; 37, muscular branches
for the superior rectus, superior oblique, and levator palpebrae muscles; 38, medial posterior ciliary; 39, short ciliary; 40, long
ciliary; 41, anterior ciliary; 42, greater circle of the iris; 43, lesser circle of the iris; 44, episcleral; 45, subconjunctival; 46,
conjunctival; 47, marginal arcade; 49, medial palpebral; 48, vortex vein. (From BM Zide, GW Jelks. Surgical Anatomy of the
Orbit. New York: Raven Press, 1985.)
plete ring, which should not necessarily imply there is an

incomplete functional anastomosis. The radial branches
from the circle of Zinn-Haller that supply the laminar optic
disc are autoregulated (275,280). The venous drainage of
the ONH is primarily via the central retinal venous system.
The blood supply to the orbital segment of the optic nerve
is almost entirely from PCAs via the pial network (Fig. 1.30).
The plethora of pial vessels that surround and enter the optic
nerve proper within the septae (Fig. 1.23) presumably ex-
plains the relative resilience of the intraorbital segment of
the optic nerve to ischemia. Branches of the internalized
CRA also may contribute to the optic nerve blood supply
(115,267,269–276,281). At the orbital apex, collateral circu-
lation from the external carotid artery via the middle menin-
geal artery may contribute substantially to the optic nerve
blood supply (269,270). Orbital vessels can be seen with
magnetic resonance imaging (MRI) (282).
Figure 1.29. Scanning electron micrograph showing intraocular vascula- The blood supply to the intracanalicular segment of the
ture of the optic disc. Note central retinal artery, central retinal vein, and optic nerve lies within a watershed zone. Here there are
numerous capillary-sized vessels. (Courtesy of Dr. H. A. Quigley.) contributions anteriorly from collateral branches of the oph-
thalmic artery and posteriorly from pial vessels arising from
the ICA and superior hypophyseal arteries (269,270,283).
circle of Zinn-Haller. More specifically, the prelaminar re- The blood supply to the intracranial segment of the optic
gion is derived mostly from the peripapillary, short PCAs nerve derives from several sources, including the ICA, the
via the choroid (Figs. 1.30 to 1.32). The laminar supply is superior hypophyseal arteries, the A1 segment of the anterior
usually more directly from the short posterior ciliary arteries cerebral artery, and the anterior communicating artery
or the circle of Zinn-Haller (265,267,269–276). This circle, (263–265,283,284) (Fig. 1.33).
when present, lies within the sclera and surrounds the optic The blood vessels of the optic nerve generally have been
nerve at the neuro-ocular junction. It receives blood from believed to have a blood–brain barrier. Recently, however,
four to eight PCAs, choroidal feeder vessels, and the perineu- human prelaminar microvessels have been shown to lack a
ral, pial arterial network (272,273,277–279). The vessels characteristic biochemical marker of a blood–brain barrier.
entering the circle of Zinn-Haller do not always form a com- Despite the presence of tight junctions, these vessels are
Figure 1.30. The blood supply to the

proximal optic nerve and choroid arises
from the branches of the medial (MPCA)
and lateral (LPCA) posterior ciliary arter-
ies, the incomplete circle of Zinn-Haller,
the pial network, and recurrent choroidal
arteries. The posterior ciliary arteries send
branches to the circle of Zinn-Haller and
the pial network. The central retinal artery
(CRA) provides minute branches to the
optic nerve capillaries as it passes anteriorly
to supply the retina. The central retinal
vein (CRV) parallels the course of the
CRA. (From Kupersmith MJ. Neuro-
vascular Neuro-Ophthalmology. New
York, Springer-Verlag, 1993.)
Figure 1.32. High-power scanning electron micrograph showing a poste-

rior ciliary artery (PCA) with separate branches to the choroid (C) and to
the optic nerve head (B). ONH, optic nerve head. (Courtesy of Dr. H. A.
Quigley.)
Figure 1.31. Low-power scanning electron micrograph showing the vas-
culature of the posterior aspect of the globe as viewed from behind the
globe. The posterior ciliary arteries (long and short) are visualized, as are
their branches to the choroid and optic nerve head. (From Risco JM, Grim-
son BS, Johnson PT. Angioarchitecture of the ciliary artery circulation of
the posterior pole. Arch Ophthalmol 1981;99⬊864–868.)
Figure 1.33. Blood supply to the dorsal aspect of the optic chiasm and intracranial optic nerves. ON, optic nerve; OT, optic
tract. (From Wollschlaeger P, Wollschlaeger G, Ide C, et al. Arterial blood supply of the human optic chiasm and surrounding
structures. Ann Ophthalmol 1971;3:862–869.)
abnormally permeable, perhaps because of active transendo- The pia mater is a very thin and delicate membrane that
thelial, pinocytotic vesicular transport (285). This perme- adheres to the surface of the optic nerve. The pia, which is
ability may explain the very early hyperfluorescence of the the most vascular sheath covering the optic nerve, invests
ONH seen in fluorescein angiography, a finding previously capillaries as they enter the substance of the nerve to create
ascribed to diffusion of dye from the adjacent choroid. fibrovascular septa within the optic nerve (Fig. 1.23).
OPTIC NERVE SHEATHS OPTIC NERVE AXONS

The leptomeninges that surround the optic nerve—the Nerve fibers represent roughly 90% of the tissue of the
dura mater, arachnoid, and pia mater—are continuous with ONH (173). The topography of the fibers at the ONH is
the leptomeninges of the brain (Figs. 1.27 and 1.34). Em- described above (Fig. 1.17). The right-angle turn of the
bryologically, the meninges develop from different sources: axons at the ONH is associated with an increased concentra-
the dura from mesenchyme, and the arachnoid and pia tion of mitochondria in the prelaminar region (227,289). This
largely from ectoderm. The dura mater near the globe splays accumulation of mitochondria, which had been thought to
out slightly and fuses with the sclera surrounding the optic result from mechanical stricture of axons as they pass
nerve. At the apex of the orbit, the dura fuses with the perios- through the lamina cribrosa, may more likely reflect meta-
teum and annulus of Zinn, then passes through the foramen, bolic differences between unmyelinated and myelinated seg-
where it merges with the intracranial dura that lines the base ments of the optic nerve (290). Unmyelinated nerves require
of the skull. Thus, the intracranial portion of the optic nerve more energy to conduct impulses than myelinated axons,
is surrounded only by pia mater. Normal human optic nerves which (mostly) only need to employ energy demanding volt-
have a sparse population of mast cells in their dura mater age-gated channels at the nodes of Ranvier. Mitochondrial
(much less so in the arachnoid). These cells become more accumulation at the ONH can be induced by elevated intra-
numerous and can be found in the optic nerve parenchyma ocular pressure, which decreases the expression of microtu-
in injured eyes, although it is not known whether they can bule-associated protein 1, which disrupts axonal ultrastruc-
incite injury to the optic nerve or are merely epiphenomenal ture and transport (289).
to the primary disease (286). RGC axons express numerous types of ionic channels.
The arachnoid that surrounds the optic nerve consists of Voltage-gated sodium channels are located at nodes of Ran-
a trabeculum of collagenous and elastic fibers that is identi- vier at 25 times the concentration found along myelin-cov-
cal with arachnoid tissue elsewhere in the CNS. Delicate ered axonal segments. The high density of sodium channels
trabeculae connect the arachnoid with the dura and underly- at the nodes is guided by a protein secreted by oligodendro-
ing pia. Mesothelial cells line the subarachnoid and subdural cytes. The voltage-gated sodium channels permit the rapid
spaces and can give rise to laminated and often calcified influx of sodium ions that depolarizes the cell, which can
psammoma bodies. Arachnoidal villi are present in the optic lead to generation of an action potential. By contrast, volt-
nerve sheaths (287). The perineural subarachnoid space is age-gated potassium channels (of which there are at least
quite small, holding approximately 0.1 mL of fluid. This four types) permit the efflux of potassium ions to repolarize
space is continuous with the intracranial subarachnoid space, a cell after an action potential has been generated. The potas-
and there is a rough equivalence between subarachnoid and sium channels are located mainly at juxtaparanodal regions
CSF pressure (237). Variations in partitioning of the perineu- where the axon is covered by compact myelin sheaths, which
ral subarachnoid space may explain the variable presence produce tight axoglial contact. A molecular cue for potas-
of papilledema among patients with increased intracranial sium channel development has not been identified (291).
pressure (288). Voltage-gated sodium and voltage-gated potassium chan-
nels, therefore, are segregated along an axon. Their respec-
tive distributions change after a demyelinating injury.
The axons within the optic nerve are extensions from a
diverse collection of RGC types. As such, the optic nerve
is a conduit for parallel paths that transmit visual information
to the brain. A review of afferent pathway physiology is
presented above and below.
Adult humans have, on average, 1.2 million RGCs
(126,127,246,292–297). The axonal diameters have two
peaks (0.7 and 1.5 ␮m), which presumably correlate with
the large (i.e., M-) and small (i.e., P-) RGC classes
Figure 1.34. Transverse section through the optic nerves of a patient with (246,292,297). A few centrifugal fibers that originate in the
optic atrophy. The dura mater (D) and arachnoid of the left optic nerve are
brain are present in the optic nerve, even in humans
distended and show the delicate subarachnoid trabeculae stretched between
the arachnoid and the pia (arrowheads). SA, distended subarachnoid space.
(298–301). In the rat, cell bodies of origin for these efferent
The sheaths of the right optic nerve are folded around the nerve so that fibers have been identified in the suprachiasmatic nucleus,
neither the arachnoid trabeculae nor the pia are visible. (From Lindenberg which suggests they might participate in circadian rhythm
R, Walsh FB, Sacks JG. Neuropathology of Vision: An Atlas. Philadelphia, physiology (302).
Lea & Febiger, 1973.) The arrangement of fibers in the ONH and distal optic
Figure 1.35. Cross-section of the anterior optic nerve

in a patient with atrophy of the papillomacular bundle
from toxic optic neuropathy. The atrophy is confined to a
wedge-shaped sector in the temporal portion of the nerve.
Figure 1.36. Light-field (A) and dark-field (B) autoradiographs of a horizontal section through the optic chiasm of a macaque
monkey. The right eye was enucleated 4 years earlier, at which time the left eye was injected with [H3]proline. A, Under
lightfield illumination, the labeled left optic nerve appears dark. Label extends into the distal portion of the atrophic right optic
nerve (arrow), producing Wilbrand’s knee. B, Under dark-field illumination, the radioactive label from the left eye appears
bright. Note the extension of label representing Wilbrand’s knee into the distal aspect of the atrophic right optic nerve. (Courtesy
of Dr. Jonathan Horton.)
A B
Figure 1.37. Wilbrand’s knee in human tissue. A, Woelcke myelin stain of a horizontal section through the optic chiasm
from a patient whose left eye was enucleated 5 months before death. There is reduced myelin staining in the left optic nerve
(arrow), but there is no evidence of Wilbrand’s knee. B, Woelcke myelin stain of a horizontal section through the optic chiasm
from a patient whose right eye was enucleated 2 years before death. There is more pronounced atrophy of the right optic nerve,
and a small Wilbrand’s knee is evident (arrow). (Courtesy of Dr. Jonathan Horton.)
nerve corresponds generally to their distribution in the retina. millimeters, then turn back posteriorly to enter the chiasm
The outflow from the papillomacular bundle is positioned (308,309). The ‘‘knee’’ is now believed to be an artifact
temporally within the anterior optic nerve (Fig. 1.35), then (310). A ‘‘knee’’ can be created by removal of one eye (310).
gradually moves centrally in the more posterior optic nerve Apparently, the gliotic reaction secondary to optic nerve at-
(303–305). Intracranially, the axons partially lose their reti- rophy over a period of years distorts the anterior chiasm,
notopy because of the decussation of some axons (306). The pulling some axons into an aberrant location (Figs 1.36 and
macular projection does not have a precise localization in 1.37). Thus, a ‘‘knee’’ is not present normally. A paradox
the posterior nerve (307). therefore exists, given that visual field defects produced by
Historically, a Wilbrand’s knee was believed to exist at compressive lesions at the anterior chiasm often include a
the junction of the optic nerve and chiasm, where a small contralateral, superotemporal field depression (i.e., junc-
number of inferonasal retinal axons were believed to cross tional scotoma), which heretofore was explained by the pres-
into the opposite optic nerve and pass anteriorly for a few ence of a ‘‘knee.’’
OPTIC CHIASM
EMBRYOLOGY chiasm. The differential spatial and temporal expression of
The optic chiasm is a commissure formed by converging the Pax2 gene by the growing axons and the sonic Hh gene
optic nerves anteriorly and diverging optic tracts posteriorly at the developing chiasm are also likely relevant to the for-
(Fig. 1.38). During development, the chiasmal anlage sepa- mation of the decussation (319). Specialized glial cells in
rates from the floor of the third ventricle, maintaining contact the developing diencephalon extend their radial processes,
only at the boundary between its posterior aspect and the which physically interact with the incoming axons (306).
anterior-inferior wall of the third ventricle (Fig. 1.39). These glial cells express Eph/ephrinA molecules, which in-
The location of the chiasm is established by the first RGC fluence the growth of axons within the chiasm (see also the
fibers that arrive, which occurs between the fourth and sixth section on the retina). Metalloproteases, which modulate the
week of development. The next fundamental step is the interaction of local environmental cues with growth cones
proper routing of the incoming axons. Numerous factors extending from the distal axons, also seem to be relevant
contribute to the directional preferences of the arriving axons for proper wiring (320). Axons that remain uncrossed tend
(311,312) (Fig. 1.40). Glia within the optic nerve and some to reach the chiasm before those that will cross, which might
highly conserved molecules are believed to be instrumental expose the different populations to time-varying changes in
to the process (306,313–318). For instance, Zic2 is ex- the local environment (321,322).
pressed early in retinal development in the cells that will The decision point is apparently not binary for these in-
project ipsilaterally, and thus Zic2 may endow these cells coming axons. Real-time video microscopy has revealed that
with response properties that influence their trajectory at the axons move through the chiasm in a pulsed, saltatory fash-
Figure 1.38. The optic chiasm viewed from

below. Note relationships of the mammillary bod-
ies, oculomotor nerves (III nerve), and cerebral
peduncles to the chiasm. (Redrawn from Pernkopf
E. In: Ferner HA, ed. Atlas of Topographical and
Applied Human Anatomy. Vol 1. Philadelphia,
WB Saunders, 1963.)
ion. All axons that approach the chiasmal midline display of the fovea and chiasm occurs in patients with albinism.
especially long pauses in activity, with ameboid movements Deficient melanin production leads to an abnormally small
of their growth cones, which assume a more complex mor- uncrossed projection, perhaps because of the timing of RGC
phology than is typical of advancing axons (323,324). Fol- development (discussed previously) rather than to some in-
lowing this complex orchestration near the end of 3 months fluence at the chiasm per se (312). In particular, albino mice
of gestation, an adult-like hemidecussation is established. have fewer Zic2-positive retinal neurons than their pig-
The shape of the developing optic chiasm differs from mented counterparts, which (given the putative role of Zic2
that of the mature chiasm. The evolution in shape partly described above) may explain the diminished ipsilateral pro-
relates to the shift from a lateral to eventually a frontal posi- jection (327). The disordered chiasmal projection in albinos
tion of the eyes in the head. In the second half of gestation the can be recognized by MRI, which can reveal a smaller chias-
gross anatomic changes include (a) progressive narrowing of mal width and a relatively wide angle between the optic
the angle between the two optic nerves to about 45 degrees, nerves and the optic tracts (328).
without a corresponding change in the angle formed by the
optic tracts; (b) separation of the chiasm from the dia- GROSS ANATOMY OF THE CHIASM AND
phragma sellae and pituitary gland with development of the PERICHIASMAL REGION
chiasmatic cistern; (c) progressive elevation of the chiasm
above the optic foramina; and (d) thinning of attachments The optic chiasm has a transverse diameter of 10–20 mm,
of the chiasm to the floor of the third ventricle. an anteroposterior width of 4–13 mm, and thickness of 3–5
Rarely, a chiasm does not form, and this can occur despite mm (262,329). The optic chiasm is covered, except where
normal development of the fovea (325,326). Malformation attached to the brain, by arachnoid and pia mater, the latter
Figure 1.39. Midsagittal section through the cerebral hemispheres, showing the position of the optic chiasm relative to the
third ventricle and basal cisterns. (Redrawn from Pernkopf E. In: Ferner HA, ed. Atlas of Topographical and Applied Human
Anatomy. Vol 1. Philadelphia, WB Saunders, 1963.)
being continuous with the pia of the optic nerves and part angle of 15–45 degrees (331). The chiasm lies above the
of the optic tracts. The optic chiasm is in direct contact with diaphragma sellae, the dural covering of the sella turcica, by
CSF anteriorly within the subarachnoid space, and poste- approximately 10 mm (332–335) (Fig. 1.43). The sphenoid
riorly within the third ventricle (Fig. 1.39 and 1.41), features sinuses lie under the chiasm only when they extend far back
easily visualized with MRI (Fig. 1.42). into the body of the sphenoid bone. In one third of adults,
Inferiorly, the optic chiasm lies over the body of the sphe- an arachnoid membrane extends outward from the infundib-
noid bone, typically above the diaphragma sellae and (para- ulum to fuse with arachnoid around the carotid arteries and
doxically) only rarely within the sulcus chiasmatis (330) the inferior surface of the chiasm (336).
(Fig. 1.25). The relative position of the chiasm over the sella The shape of the pituitary gland varies considerably
turcica is variable. The chiasm is (a) above the tuberculum among individuals. The width of the gland is typically
sellae (i.e., ‘‘prefixed’’) in 12%; (b) above the diaphragma greater than or equal to its depth or length. The lateral and
sellae in 79%; and (c) above the dorsum sellae (i.e., ‘‘post- superior margins of the gland are more variable in shape
fixed’’) in 4% of cases (264,330) (Fig. 1.41). In patients because they are not confined within bone. Rarely, the pitui-
with brachycephaly, the chiasm typically is more rostral and tary gland protrudes inferiorly into the sphenoid sinus (264).
dorsal than in dolichocephaly. This variability of position Superiorly, the lamina terminalis, which defines the ante-
partially accounts for the variable patterns of visual field rior end of the diencephalon, extends upward from the chi-
defects seen in patients with upwardly expanding pituitary asm to the anterior commissure. The A2 segments of the
adenomas. anterior cerebral arteries pass medially and upward above
The intracranial optic nerves do not lie on a horizontal the optic chiasm. The anterior cerebral and anterior commu-
plane; rather, they rise upward from the optic canals at an nicating arteries may be situated above the chiasm or the
Figure 1.40. Trajectory of retinal ganglion cell axons during early and late phase of chiasm formation. Horizontal view of
axon growth and cells of the ventral diencephalon during the early (E12–E13) and later (E15–E16) phases of axon growth.
Specialized radial glia (small dots) form palisades on either side of the midline and express RC2 as well as Slit2 (rostrally),
EphA and EphB receptors, and NrCAM. The early-born neurons (large dots) express CD44 and SSEA-1 as well as ephrinAs,
Slit 1, Robo1 and Robo2, and disulfated proteoglycans. Slit1 is expressed dorsal to and around the optic nerve as it enters the
brain and more weakly by the CD44/SSEA neurons. Slit2 is strongly expressed in the preoptic region directly dorsal and
anterior to the chiasm. A, At E15–E16, during the major phase of retinal axon divergence, growth cones have different forms
depending on their locale and behavior. Crossing (thick line) and uncrossed (thin line) fibers have slender streamlined growth
cones in the optic nerve and optic tract. Near the midline, all axons pause and have more spread forms. Uncrossed growth
cones extend along the midline in highly complex shapes before turning back to the ipsilateral optic tract. B, In the early phase
of retinal axon growth, the first-born uncrossed retinal axons from the dorsocentral retina (DC) enter the ipsilateral optic tract
directly, quite far from the midline. In contrast, in the later period, uncrossed axons travel toward the midline and diverge from
crossing axons within the radial glial palisade. Crossed axons at both ages traverse the midline close to the rostral tip of the
early-born neurons. All retinal axons at both ages grow around the contours of the early-born neurons. C, Maneuvers of retina
axons with respect to the resident cells of the optic chiasm. DC, dorsocentral; D, dorsal; V, ventral; N, nasal; T, temporal.
(From Mason C, Erskine L. The development of retinal decussations. In: Chalupa LM, Werner JS, eds. The Visual Neurosciences.
Cambridge, MA, MIT Press, 2004⬊97.)
optic nerves, or they may rest directly on these structures the vulnerability of the chiasm to compression or infiltration
(Fig. 1.44). The junction of the anterior communicating ar- by lesions within the ventricle or even an expanded ventricle.
tery with the A1 segments usually occurs above the chiasm
rather than the optic nerves (263). Laterally, the ICAs ORGANIZATION OF NERVE FIBERS WITHIN THE
emerge from the cavernous sinuses and approach the poste- OPTIC CHIASM
rior optic nerves and sides of the chiasm. Occasionally, the Several generalizations can be made about the topography
ICAs contact and compress these structures. Posteriorly, the of fibers passing through the chiasm, although much of our
chiasm is bounded by the third ventricle, which explains knowledge in this regard derives from nonhuman primates.
Figure 1.41. Three sagittal sections of the optic chiasm and sellar region showing the positions of a prefixed chiasm above
the tuberculum sellae (left), a normal chiasm above the diaphragma sellae (center), and a postfixed chiasm above the dorsum
sellae (right). The W-shaped clear zone behind the chiasm is the anterior aspect of the third ventricle. (Redrawn from Rhoton
AL Jr, Harris FS, Renn WH. Microsurgical anatomy of the sellar region and cavernous sinus. In: Glaser JS, ed. Neuro-
Ophthalmology Symposium of the University of Miami and the Bascom Palmer Eye Institute. St Louis, CV Mosby,
1977⬊75–105.)
Figure 1.42. MRIs of the normal optic chiasm. A, Noncontrast T1-weighted image shows position of the optic chiasm in sagittal
section. Note the angle made by the incline of the intracranial portion of the optic nerve as it approaches the chiasm (arrowhead).
B, T1-weighted image after contrast administration shows the position of the body of the chiasm in coronal section.
Figure 1.43. Relationships of the optic nerves and

optic chiasm to the sellar structures and 3rd ventricle
(III); C, anterior clinoid; and D, dorsum sellae. (Redrawn
from Glaser JS. Neuro-ophthalmology. Hagerstown,
MD, Harper & Row, 1978.)
39
Figure 1.44. Anterior views of the A1 and proxi-

mal A2 segments of the anterior cerebral arteries,
anterior communicating arteries, and recurrent ar-
teries, showing variations in their relationship to
the intracranial optic nerves and optic chiasm. Gyri
recti and olfactory nerves are located superiorly.
(From Perlmutter D, Rhoton AL Jr. Microsurgi-
cal anterior cerebral–anterior communicating–
recurrent artery complex. J Neurosurg 1976;
45⬊259–272.)
First, the proportion of crossed fibers is always greater than from the dorsal retina project more caudally in the chiasm
the uncrossed population, typically with a ratio of roughly than crossed fibers of the ventral retina. An exception to
53⬊47 in humans (293). Second, retinal fibers projecting to these principles occurs for fibers that project to the superior
the ipsilateral dLGN come only from the temporal retina, colliculi, which project from throughout the retinae (337).
whereas fibers projecting to the contralateral dLGN come Third, macular projections are both crossed and uncrossed
only from the nasal retina. The separation between crossed and constitute a large percentage of the chiasmal fibers. Mac-
and uncrossed fibers begins just as the fibers reach the chi- ular fibers are more concentrated dorsally and centrally and
asm. Uncrossed fibers, both dorsal and ventral, maintain are generally not present in the inferior rostral and caudal
their relative position through the lateral chiasm and pass regions of the chiasm (68,307,329,338). Fourth, retinohypo-
directly into the ipsilateral optic tract (310). Crossed fibers thalamic axons exit the chiasm posteriorly (without entering
the tracts) to reach the hypothalamus. Finally, some retinal the chiasmal blood supply comes from a dorsal and ventral
fibers, especially those of melanopsin-containing RGCs (dis- group of feeder vessels. The dorsal supply derives from
cussed previously), bifurcate and project to two central sites branches of the ICA, usually via superior hypophyseal arter-
after they emerge from the chiasm. ies, the A1 and occasionally the A2 segments of the anterior
cerebral artery, and the anterior communicating artery.
BLOOD SUPPLY Branches from more distal stretches of the anterior cerebral
The distal optic nerves, optic chiasm, and proximal optic artery typically supply some of the dorsal chiasm (265,340).
tracts pass below the anterior communicating artery and an- The ventral supply derives from branches of the posterior
terior cerebral arteries and above the posterior communicat- communicating artery, PCA, and basilar artery (339). The
ing arteries, PCAs, and basilar artery (339) (Figs. 1.33 and superior hypophyseal artery, a branch of the ICA, often pro-
1.44). The chiasm obtains blood from branches of all of these vides blood to the ventral chiasm (284). There is often signif-
surrounding vessels. There is considerable interindividual icant collateralization among these vessels (341), which ex-
variation in the blood supply of the chiasm (329). In general, plains the utter rarity of chiasmal infarction.
OPTIC TRACT
The optic tract, which is fully formed by the 13th week sule to reach the dLGN (Figs. 1.38, 1.45, and 1.46). Unlike
of gestation, is the segment of the afferent visual pathway the intracranial optic nerves, the optic tracts are firmly at-
between the chiasm and dLGN. From their origin, the optic tached to the brain throughout their course by glial cells.
tracts diverge in front of the interpeduncular space and wind Each tract contains crossed and uncrossed fibers, most of
laterally above the uncus and then around the internal cap- which synapse in the dLGN. A few tract fibers turn medially
Figure 1.45. The optic tracts and lateral geniculate body viewed in sagittal section. Note the relationship of the optic tract
to the internal capsule and corticospinal tract. The pulvinar is just medial to the lateral geniculate body. (Redrawn from Pernkopf
E. Atlas of Topographical and Applied Human Anatomy. Vol 1. Philadelphia, WB Saunders, 1963.)
Figure 1.46. Anatomy of the optic tracts and optic radiations. Appearance
of the visual sensory pathway in axial section, viewed from below. Note the
position of the optic tracts as they originate from the optic chiasm and diverge
to end at the lateral geniculate nuclei. The optic radiations extend as fan-shaped
structures from the lateral geniculate nuclei to the visual cortices. A large
proportion of fibers in the radiations are feedback fibers projecting from the
visual cortices to the lateral geniculate nuclei and other deep structures. (From
Ghuhbegovic N, Williams TH. The Human Brain: A Photographic Guide.
Hagerstown, MD, Harper & Row, 1980.)
before reaching the dLGN to terminate in the pretectal nuclei tracts, there is a partial rearrangement of fibers based upon
of the rostral midbrain, where they influence the pupillomo- the functional class of cells. The larger axons of the M-
tor light reflex. A few of these fibers, whose function is not RGCs (discussed previously) are generally more superficial,
known, enter the medial geniculate body. and the smaller fibers of the P-RGCs are nearest to the pia
The optic tract fibers rotate their topographic axes with mater (343,344).
respect to the fibers that enter the tracts. The superior retinal The major blood supply to the optic tract comes from the
fibers rotate laterally in the tract, and the ventral fibers rotate anterior choroidal artery, a branch of the ICA (345,346).
to a medial position (342,343). The macular fibers shift Other arteries often contribute to the blood supply. A dorsal
slightly to the dorsolateral position, whereas the peripheral and a ventral ‘‘artery of the optic tract’’ may arise directly
fibers from the upper and lower retinas are situated dor- from the internal carotid artery (341). The posterior commu-
somedially and ventrolaterally, respectively. Within the nicating artery may also supply branches to the tract (347).
LATERAL GENICULATE NUCLEUS

The lateral geniculate nucleus (LGN) develops from the extent V2. Each LGN is an oval structure situated in the
lateral wall of the diencephalon, which gives rise to the thala- posterior thalamus, below and lateral to the pulvinar (Fig.
mic, hypothalamic, and habenular nuclei. The LGN is the 1.45). There is considerable variability in the structure of
first of the habenular nuclei to appear, which occurs at the the LGN (352,353), which is also true for the striate cortex
eighth week of gestation as RGC axons arrive (348–351). (354).
Myelination of the optic tract begins only after the axonal Dorsal to the LGN are the white matter tracts of the acous-
connections to the LGN have been established. Myelination tic radiations that connect the medial geniculate nucleus to
of the pregeniculate visual pathway begins at the LGN at the the transverse convolution of Heschl, which is the primary
fifth month of gestation, then moves rostrally. Lamination of hearing cortex. Dorsolateral to the LGN are the fibers of the
the LGN does not develop until the following month. optic radiations (Figs. 1.46 and 1.47). Optic and acoustic
radiations both pass through the temporal isthmus, the nar-
ANATOMIC AND FUNCTIONAL ORGANIZATION row bridge that connects the deep nuclei of the brain to the
The LGN is the principal thalamic visual center linking temporal lobe. The LGN can be visualized by MRI (355).
the retina and the visual cortical areas V1 and to a lesser The LGN contains three substructures: the dorsal nucleus
Heschl's transverse
convolution—hearing cortex Fornix
First temporal convolution Thalamus

Ventrolateral nuclei
Temporal isthmus
Medical geniculate body
Optic radiation
Lateral geniculate body
Inferior ventricular horn Cisterna ambiens
Ammon's horn
Figure 1.47. Axial section of brain demonstrating lateral geniculate body and surrounding structures. (From Lindenberg R,
Walsh FB, Sacks JG. Neuropathology of Vision: An Atlas. Philadelphia, Lea & Febiger, 1973.)
(dLGN), the pregeniculate complex, and the intergeniculate

leaflet (IGL). Development of the dLGN occurs in three
phases: (a) initial segregation of eye-specific laminae, (b)
initial segregation of cell-specific (P- versus M-RGCs) and
ON and OFF laminae, and (c) refinement of the receptive
fields for all cells that synapse in the dLGN (Fig. 1.48). The
first two processes are completed prior to visual experience,
whereas the latter is completed with the addition of visual
experience (356). How are some of these primary anatomic
characteristics established without visual experience?
The dLGN, which is the largest of the three subunits,
receives the great majority of retinothalamic and corticotha-
lamic input and is the interconnection for the conscious (i.e.,
retinocalcarine) pathway. The dLGB has six laminae, with
laminae 2, 3, and 5 (with numbering beginning ventrally)
receiving input solely from the ipsilateral eye and laminae
1, 4, and 6 receiving input solely from the contralateral eye.
This laminar segregation evolves from an earlier develop-
mental stage in which projections from both eyes completely
overlap. Refinement of this laminar organization, which re-
quires at least weeks of visual experience after birth to de-
velop (357), is created by comparison of the relative activity
among axonal terminals arriving at the dLGN (358).
Relative synchrony among axons increases the probability
those synapses will strengthen and be retained. The discov-
ery of spontaneous, slow (i.e., one or two times per minute)
‘‘waves’’ of retinal activity that are present only during early
development have been considered the likely force that
drives eye-specific lamination in the dLGN. These waves,
initiated by the ‘‘starburst’’ amacrine cells (359) (discussed
previously), are synchronized within each retina but desyn-
chronized between the two retinas. Incoming retinogenicu- Figure 1.48. A coronal section through the lateral geniculate nucleus of
late fibers are therefore divided into those with one or the a macaque monkey showing the parvocellular (P), magnocellular (M), and
other firing pattern. Adjacent fibers with more similar wave koniocellular (K) layers. At this plane there are four P layers, two M layers,
and six K layers. Laminae 1, 4, and 6 receive input from the contralateral
patterns are more likely to be retained, while those with more
eye; laminae 2, 3, and 5 receive input from the ipsilateral eye. The thin
dissimilar patterns are more likely to be eliminated. These layers ventral to each of the six primary lamina to which the K-retinal
waves persist through the development of eye-specific lami- ganglion cells project are known as ‘‘intercalated’’ or interlaminar layers.
nae and then segregation of ON and OFF laminae (360), Scale bar ⳱ 500 ␮m. (From VA Casagrande, JM Ichida. The lateral genicu-
and may participate in constructing the retinotopic maps to late nucleus. In: Kaufman PL, Alm A, eds. Adler’s Physiology of the Eye.
various brain termination sites (361). More recent and some- 10th ed. St Louis, Mosby, 2003⬊657.)
what contradictory evidence regarding the developmental

role of the spontaneous waves derives from experimental
ablation selectively of the starburst amacrine cells, which
eliminates retinal waves but does not disrupt eye-specific
lamination of the dLGN, although elimination of all activity
certainly does (362).
Laminar segregation extends beyond eye-specific input.
Layers 1 and 2 receive input exclusively from M-RGCs and
contain relatively large somas, and are therefore referred to
as magnocellular layers. Layers 3–6 receive input exclu-
sively from P-RGCs and contain relatively small somas, and
are therefore referred to as parvocellular layers (363). Each
M cell innervates many more relay cells in the dLGN than
do P cells, such that the total number of relay cells in the
dLGN devoted to M- or P-cell input is roughly equal, even
though there are roughly eight times as many incoming P-
RGCs. There is also a small input from K-RGCs, which
synapse in thin intercalated laminae that lie ventral to each
of the primary lamina (Figs. 1.48 to 1.50).
Following the eye-specific and M- versus P-specific orga-
nization, there is a further separation of each lamina into
ON and OFF sublaminae (364). This separation also appears
Figure 1.50. Examples of the morphology of some of the common retinal

ganglion cell types in the primate retina, together with their projection
targets in the lateral geniculate nucleus and some of their physiological
properties. (From DM Dacey. Parallel pathways for spectral coding in the
primate retina. Annu Rev Neurosci 2000;23⬊743–755.)
to be related to a competitive process. OFF cells have signifi-

cantly higher spontaneous mean firing rates than ON cells,
and thus these cell types can be distinguished by comparison
of their relative activities during development (365).
The pregeniculate nucleus, which is part of the ventral
thalamus, is actually a collection of nuclei known as the
pregeniculate complex (PrGC). The PrGC is a relatively thin
(partially) multilayered structure that extends over the me-
dial and lateral aspects of the dLGN. The PrGC receives
input from the retina, striate, and extrastriate cortices and
has extensive connections with the superior colliculus (SC)
Figure 1.49. Eye-specific and functional-specific laminar organization of
the lateral geniculate nucleus in the macaque monkey. Projections from
and pretectal nucleus of the optic tract (NOT) (366) (Fig
the contralateral and ipsilateral eyes are shown with respect to parvo (P),
1.51). Neurons of the PrGC in primates manifest saccade-
magnocellular (M), and koniocellular (K) retinal ganglion cell axons. The related activity, which can be modulated by visual input
abbreviations W, X, and Y refer to physiologic criteria, and the abbrevia- (367). This visuosensory input alters the firing rate and sensi-
tions K, P, and M refer to morphologic criteria, used to classify retinal tivity of neurons in the six primary laminae, especially for
ganglion cells (see text for details). (From Sherman SM, Guillery RW. The the M-pathway (368,369). This saccadic influence presum-
visual relays in the thalamus. In: Chalupa LM, Werner JS, eds. The Visual ably contributes to the ‘‘suppression’’ of visual awareness
Neurosciences. Cambridge, MA, MIT Press, 2004⬊567.) during saccades.
sent that location. This spatial fidelity is maintained for the

physiologically distinct classes of parvocellular and magno-
cellular LGN layers, which may be independently modulated
by separate populations of cortical layer 6 neurons
(373,374).
Other afferent input comes from the brain stem, including
the SC, the parabigeminal nucleus (at least in the cat), several
pretectal nuclei, and caudal midbrain and rostral pontine re-
gions. Inputs from the SC and parabigeminal nucleus are
concentrated within the interlaminar zones (375). The para-
brachial nucleus, locus ceruleus, and dorsal raphe nucleus
send cholinergic, noradrenergic, and serotonergic projec-
tions, respectively, to the dLGN (376). These projections
modulate function in different ways. For example, serotoner-
gic axons appear to have a diffuse neuromodulatory role in
dLGN transmission, whereas cholinergic connections from
the parabrachial region provide selective synaptic input to
specific postsynaptic elements.
Organization of Efferent Output

Dorsal LGN cells send their main axons almost exclu-
sively to the striate cortex, where they terminate primarily
Figure 1.51. The afferent and efferent connections of the pregeniculate within granular layer 4 (discussed later). Geniculocalcarine
nuclear complex (PrGC) subnuclei. The restriction of retinal input to a projections from the parvocellular layers of the dLGN termi-
single subnucleus is evident. Neurons in the retinorecipient sublayer and nate mainly within the lower portion of layer 4 (i.e., layer
the lateral subdivision of the ventral lamina project to the superior colliculus 4C), with some terminating higher in layer 4A (discussed
(SC) and pretectal nucleus of the optic tract (NOT). The superior sublayer previously) (374,377,378). The projections from magnocel-
and the medial division of the PrGC are reciprocally connected with the SC/ lular cells also terminate in layer 4C (379,380). The magno-
NOT. (From Livingston CA, Mustari MJ. Brain Res 2000;876⬊166–179.) cellular and parvocellular pathways also send collaterals to
layer 4A, which sends retinotopic collaterals back to the
dLGN. The koniocellular laminae send afferents to layers
The IGL is a relatively thin cellular layer that separates 1 and 3 of the striate cortex (135,380–382). The efferent
the dLGN from the PrGC. In rats, the majority of input to projections from the dLGN are far more limited than the
the IGL is from melanopsin-containing RGCs, 20% of which afferent (retinogeniculate and corticogeniculate) input.
send axons to the IGL (147). The IGL is believed to control
circadian ‘‘phase-shifting’’ but may influence other aspects PHYSIOLOGY
of photoperiodic control (i.e., regulation of circadian period
and phase angle) via its photic and nonphotic output through Relay Neurons
the geniculohypothalamic tract (370). Dorsal LGN relay neurons are those that receive input
from RGCs and project to the visual cortices, almost exclu-
Organization of Afferent Input
sively to area V1. The receptive field properties of these
Each dLGN receives a precise retinotopic map from the relay neurons are similar to those of the RGCs that supply
contralateral visual hemifield. The macular fibers terminate their afferent input, although the surround properties of
within the center region over the caudal three quarters of dLGN relay neurons are generally stronger (383) (Table 1.5).
the nucleus that includes all six laminae (371,372) (Fig. Early in development, there are imprecisions in the anatomic
1.52). There is a 90-degree counterclockwise rotation (as if and physiologic matching of retinal inputs and geniculate
viewed from the incoming side) of the retinotopic orienta- relay neurons. The establishment of proper interconnections
tion, such that the axons from the superior retina lie laterally is then molded by Hebbian influences, which is to say that
and those from the inferior retina lie medially (Fig. 1.53). synapses with coordinated activity are more likely to sur-
All fibers rotate to the position they had assumed in the vive. Visual experience after birth contributes to a pruning
proximal optic tract as they exit the dLGN along its supero- of the input pathways and their alignment with the relay
posterior margin. The mature dLGN usually has a monocular neurons. Eventually, Hebbian principles create a spatially
segment, a small ventral region with one M- and one P-cell and physiologically precise arrangement of retinothalamic
layer, and a segment with four layers (371). connections. Merger of this neuronal substrate with other
The corticothalamic pathway is the major source of non- afferent inputs, mostly from area V1, yields the mature pro-
retinal input. This pathway is oriented topographically such file of thalamacortical response properties.
that regions in the striate cortex representing a particular Dorsal LGN relay cells have (a) circular receptive-field
retinal location project to cells in the dLGN that also repre- centers with an antagonistic surround; (b) receptive-field
Figure 1.52. The macular representation in the

human lateral geniculate nucleus indicated by
transsynaptic degeneration in the right (R) and
left (L) lateral geniculate nuclei following a mac-
ular lesion in the right retina. The column on the
left (A) shows the extent of the macular represen-
tation for both eyes. The levels shown are approx-
imately 218, 316, 414, 512, and 516 mm, respec-
tively, from the rostral pole of the lateral
geniculate nucleus. (From Kupfer C. The pro-
jection of the macula in the lateral geniculate
nucleus of man. Am J Ophthalmol 1962;
54⬊597–609.)
centers that enlarge with increasing eccentricity within the sponsiveness to visual contrast. RGCs respond to increasing
visual field; and (c) the same ON and OFF dichotomy found stimulus intensity (or contrast) with a monotonic increase
in RGCs (discussed previously) (383). Dorsal dLGN neu- in their firing rate. Thus, the frequency of a RGC response
rons also display orientation selectivity, which is not found codes the stimulus intensity. However, dLGN relay cells
in RGCs. This orientation selectivity, a fundamental prop- respond less vigorously than RGCs for the same intensity
erty of area V1 neurons, might be related to the shapes of stimulus (391), which reduces the likelihood of signal trans-
the dendritic arbors of dLGN relay cells (384,385). mission to the visual cortex. This ‘‘nonlinear gain control’’
The surround antagonism of dLGN relay neurons is may protect cells in the striate cortex from response satura-
stronger than that of the RGCs that synapse with these neu- tion. This response attenuation may relate to the organization
rons. This enhanced surround response is believed to result of having several dLGN relay cells provide input to one
from (feedforward and feedback) inhibition upon the dLGN, striate cortical cell: any decrease in individual cell respon-
primarily from the visual cortex (386,387). The corticogeni- siveness can be balanced by the influence of a local popula-
culate pathways that influence the spatial, temporal, and gat- tion of neurons that collectively exert a stronger input to the
ing responses of dLGN neurons are both excitatory and in- cortex.
hibitory (388–390). Many dLGN cells exhibit responses to more complex
Another distinction of dLGN physiology is reduced re- stimuli than RGCs. Roughly 40% of dLGN cells are sensi-
Figure 1.53. Representation of the visual field in the lateral geniculate nu-
cleus (LGN) in humans. Top, The right LGN in coronal section from behind.
Bottom, The left homonymous hemifield separated into specific sectors desig-
nated by numbers (top) and letters (bottom). The numbers and letters on the
LGN correspond to the projection of the similarly numbered and lettered sectors
of the visual hemifield. Central vision is represented by cells located superiorly
in the LGN, peripheral vision by cells located inferiorly. The upper quadrant
of the visual field is represented in the lateral portion of the LGN, the lower
portion of the visual field in the medial portion of the LGN. The horizontal
meridian is roughly a vertical curved line through the midportion of the LGN.
A consecutive series of numbers or letters (i.e., i, ii, iii; 1, 2, 3; or A, B, C)
indicates a sector of the visual field; corresponding symbols from adjoining
series of numbers or letters (e.g., ii, II, 2 or y, B, b) indicate an arc in the visual
field. (From Shacklett DE, O’Connor PS, Dorwart H, et al. Am J Ophthalmol
1984;98⬊283–290.)
Table 1.5
Overview of Physiological Response Properties Along the Afferent Visual Pathway
Outer Retinal Dorsal Lateral

Response Properties Retina Ganglion Cells Geniculate Nucleus Primary Visual Cortex
Graded responses ⫹
Sustained responses ⫹ ⫹ ⫹ (simple and complex cells)
Transient responses ⫹ ⫹ ⫹ (simple and complex cells)
Circular receptive fields ⫹ ⫹
Linear receptive fields ⫹ (much larger surround zone compared to
RGCs or dLGN cells)
Antagonistic surround responses ⫹ Stronger than retinal Substantially larger
ganglion cells
On vs off ⫹ ⫹ ⫹
Binocular response cells ⫹ (the majority of cells in layers 2, 3, 5, and 6)
Responses to horizontal and ⫹
vertical disparity
Orientation selectivity ⫹ ⫹
Motion sensitive responses Relatively small population(s) Complex cells (relatively large population)
Sensitive to direction of moving Small number 20%
stimulus
Response to contrast Strong Weaker
Responses influenced by eye ⫹
movement; auditory and
tactile stimuli
dLGN, dorsal lateral geniculate nucleus; RGCs, retinal ganglion cells.

tive to orientation, and 20% are sensitive to the direction which release GABA and inhibit the relay neurons. The inhi-
of a moving stimulus (392). Auditory and tactile stimuli, bition of relay neurons decreases their transmission ratio of
stretching of eye muscles (393), and saccadic eye move- visual signals from the retina to the visual cortex (Fig. 1.54).
ments also influence dLGN responses (394). Afferent input from area V1 of the visual cortex is retino-
There are different types of relay neurons for both of the topically organized with respect to the dLGN cells. This
major retinal outflow pathways. For the M-cell pathway, corticogeniculate feedback pathway, which is substantially
there are two types of relay neurons and one type of in- larger than the geniculate-cortical pathway, utilizes gluta-
terneuron. For the P-cell pathway, there is one type of relay mate and aspartate as neurotransmitters, thus imparting an
neuron and one type of interneuron (395). excitatory influence onto the dLGN (400). This excitation
increases the firing rate and transmission efficiency of dLGN
Information Transfer neurons (401). The same corticogeniculate pathway passes
Perception and visual behavior do not result from activa- through the perigeniculate nucleus and synapses onto neu-
tion of single neurons. Rather, the brain receives input from rons that send inhibitory input via the same neurons within
populations of afferent neurons, which must then be ‘‘pro- the dLGN (Figs. 1.55 and 1.56). This feedforward influence
cessed’’ to create vision as we experience it. Visual signals is thought to account for the bias for dLGN neurons to trans-
leaving the eye are the primary input to the visual brain, but mit impulses generated by relatively long lines that exceed
action potentials from RGCs do not necessarily reach the a critical threshold for length. This response property, which
visual cortex. The dLGN imposes significant influences on is quite different from the preferred circular response proper-
what information is transmitted to the striate visual cortex. ties of the RGCs that provide input to the dLGN, is shaped
by feedback connections from the primary visual cortex,
This influence on information transfer at the dLGN is
which responds very strongly to linear stimuli and only
dependent upon at least three factors: retinal input, local
weakly to circular stimuli. Other elements of the cortical-
interneurons, and subcortical and cortical afferent input. The geniculate feedback pathway are inhibitory. In general, the
relative dominance of these factors is revealed by the fact magnocellular pathway is more significantly affected by cor-
that more than 80% of synapses within the dLGN are not tical influences than is the parvocellular pathway (390).
from the retina, but from local interneurons and other affer- Some brain stem pathways globally influence dLGN re-
ent sources. All of these afferent inputs converge upon the sponses through sparse but diffuse connections. One path-
dLGN relay neurons. way is a serotonergic, primarily inhibitory connection from
The retinogeniculate pathway is excitatory to dLGN relay the raphe nucleus (402). Another is a noradrenergic, excita-
neurons, which substantially outnumber the incoming RGC tory influence from the locus ceruleus (403). There are also
axons (396). The retinal input is spatially divergent in that cholinergic inputs from several brain stem afferent pathways
most relay neurons receive strong input from one or two that provide a relatively strong excitation directly onto
RGCs, with additional weaker input from several other dLGN relay cells (404), although this same pathway inhibits
RGCs (397). The input from the dLGN to the primary visual
cortex, however, is convergent. This architecture allows a
cluster of RGCs to strongly influence a small number of
dLGN relay neurons, which strongly influence the responses
of the smaller number of cortical neurons upon which they
converge.
Any visual stimulus alters activity among a population of
RGCs. The incoming signals from these cells will more
likely effect transmission through the dLGN if the afferent
signals come from cells with substantial receptive field over-
lap and similar physiology (397). Nearly coincident firing
of adjacent retinogeniculate neurons strongly increases
transmission efficiency through the dLGN (398). Higher-
frequency action potentials have a greater chance of exciting
dLGN relay neurons and thus are more likely to influence
the signals sent to the visual cortex.
As stated above, dLGN relay neurons have relatively
strong, antagonistic surround responses. More diffuse retinal
illumination is more likely to activate these receptive field
surrounds, which decreases transmission efficiency to the Figure 1.54. Synaptic contacts within the lateral geniculate nucleus
cortex. Viewed in another way, the dLGN sharpens the spa- (LGN) between retinal afferents and LGN relay cells (R), feedforward in-
terneurons (I), and feedback cells in the reticular nucleus of the thalamus
tial detail of percepts by increasing the likelihood that
(RNT). GABA-ergic inhibitory neurons are indicated in black. The dashed
smaller attributes of a stimulus will reach the cortex. line making a synapse onto the RNT cell represents collateral inputs from
The influence of local interneurons within the dLGN on other relay cells (R′) that is adjacent to the LGN relay cell in the center of
information transfer is especially strong. Interneurons repre- the diagram. (From Casagrande VA, Norton TT. Lateral geniculate nucleus:
sent a substantial proportion (25–35%) of all dLGN neurons a review of its physiology and function. In: Leventhal AG, ed. The Neural
(399). Incoming RGC axons synapse on the interneurons, Basis of Visual Function. Boca Raton, CRC Press, 1991⬊46.)
Figure 1.55. Geniculate-cortical loop. Shaded ovals denote the typical retinotopic extent (at 5 degrees of eccentricity from
the area centralis) of the axonal arborizations of X and Y retinal ganglion cell axons and corticofugal axons. Two dimensions
are given for feedback axons: the smaller dimension depicts the typical spread for the dense central core projection, while the
larger dimension depicts the overall coverage of the axonal arborization. Percentages to the right of the drawing summarize
the contribution of synaptic contacts from retinal axons, corticofugal feedback axons, and inhibitory interneurons that synapse
on lateral geniculate nucleus relay cells, as well as the contributions from geniculate axons, layer 6 collaterals, and layer 4
connections that synapse on spiny stellate cells in layer 4 of the cortex. (From Sillito AM, Jones HE. Feedback systems in
visual processing. In: Chalupa LM, Werner JS, eds. The Visual Neurosciences. Cambridge, MA, MIT Press, 2004⬊610.)
dLGN interneurons (405). Afferents from the SC and pretec- BLOOD SUPPLY
tal nuclei provide excitatory input, enhancing information
transfer through the dLGN (400,401). The dLGN has a dual blood supply. The anterior hilus,
Collectively, the gating of activity at the dLGN presum- together with the anterior and lateral aspects of the nucleus,
ably influences the level of cognitive attention to visual stim- is usually supplied by branches of the anterior choroidal
uli, which varies greatly with the level of alertness. Apropos artery, which arises from the ICA. The remainder of the
to this role in attention, en route to the dLGN the corticofugal dLGN receives blood from the lateral choroidal ar-
pathway passes through and provides input to the thalamic tery, which arises from the posterior cerebral artery
reticular nucleus, which drapes the lateral aspect of the (346,406–409). Both arteries probably supply the area of
dLGN. The thalamic nucleus contains GABA-ergic neurons, the macular representation. Distinct visual field defects
from which enlarge strong reciprocal connections with the occur with compromise of either of these vascular distribu-
dLGN. tions (410) (see Chapter 12).
Figure 1.56. Schematic organization that summarizes the notion that feedback-linked surround antagonism leads to greater
synchronization of firing of relay cells in the lateral geniculate nucleus to coherent contours, which thus increases the probability
of transmission of this visual input arriving at the lateral geniculate nucleus to layer 4 neurons in the striate cortex. (From
Sillito AM, Jones HE. Corticothalamic interactions in the transfer of visual information. Philosophical Trans R Soc Lond B
2002;357⬊1739–1752.)
POSTGENICULATE VISUAL SENSORY PATHWAYS

EMBRYOLOGY ANATOMY OF THE OPTIC RADIATIONS
The telencephalon develops at about 6 weeks of gestation The optic radiations, also called the geniculocalcarine
from the most anterior aspect of the prosencephalon as bilat- tract, extend from the dLGN to the primary visual cortex
eral evaginations, the walls of which develop into the cere- (V1, striate cortex, Brodmann area 17) in the occipital lobe
bral hemispheres. The superior portions of the walls develop (Fig. 1.46). The optic radiations are separated into three bun-
into the pallium, or primordium of the cerebral cortex. In dles that occupy the external sagittal stratum: the upper,
humans, the largest portion of the pallium is the neopallium, lower, and central bundles (413). The upper and central bun-
from which arise the visual cortices. dles pass posteriorly through the temporal and parietal lobes
Cortical differentiation begins as a migration of cells from to reach the occipital lobes. The lower bundle (i.e., Meyer’s
the mantle zone into the marginal zone to form a superficial loop) initially courses anteriorly, superior to and around the
cortical layer, which begins at 8 weeks of gestation. This
migration, which is complete shortly thereafter, occurs first
in the olfactory cortex, then the somatic sensory cortex, and
lastly in the frontal and visual cortices. Programmed cell
death occurs in the human cerebral cortex, just as it does
in the optic nerve (discussed earlier) (411). The number of
neurons initially increases, peaking at about 28 weeks of
gestation, and then progressively declines by about 70%
around the time of birth (412).
Myelination of the visual pathways does not begin until
the entire pathway has developed. Myelination of the postge-
niculate visual sensory pathway begins at birth and generally
is complete by the fourth month of life, although the occipital
poles may not be fully myelinated until the twelfth month
(218,219). Myelination begins at the occipital poles and pro-
gresses anteriorly.
Figure 1.58. The representation of the inferior retinal quadrants in the

temporal lobe portion of the optic radiation in humans, based on studies
of patients who have undergone temporal lobectomy. The tip of the temporal
horn is not surrounded by the optic radiation. Further, although the distribu-
Figure 1.57. The optic radiations, redrawn from Max Brodel’s interpretation from each retina extends anteriorly to an equal degree, the representa-
tion of the geniculocalcarine radiation in humans. Meyer’s loop is that tion of the ipsilateral retina lies lateral to that from the contralateral retina.
portion of the optic radiation that projects anteriorly (arrows) before then The macular fibers at all levels are considered to lie mesial to the fibers
turning back to extend toward the primary visual cortex. (From Cushing representing the peripheral retina. (Redrawn from Van Buren JM, Baldwin
H. Distortions of the visual fields in cases of brain tumor: the field defects M. The architecture of the optic radiation in the temporal lobe of man.
produced by temporal lobe lesions. Brain 1922;44⬊341–396.) Brain 1958;81⬊15–40.)
temporal horn of the lateral ventricle (414) (Figs. 1.57 and ymous quadrantanopia. There is conflicting evidence re-
1.58). This bundle then turns laterally and posteriorly to garding the congruity of such field defects, with numerous
reach the striate cortex. The central bundle, which is the opinions for both incongruity (415,416) and congruity
largest, transmits the macular projection in a base-out wedge (417–421). Variable anatomy may account for some of the
configuration (Fig. 1.59). The upper and lower bundles trans- discrepancy of visual field findings. There is some consensus
mit information about the lower and upper regions of the that (a) projections of central vision are positioned laterally
visual field, respectively. at the anterior aspect of the radiations and then move to a
Damage to Meyer’s loop causes a partial, superior homon- more intermediate zone, and (b) fibers subserving peripheral
vision initially are medial and then extend posteriorly to the
upper and lower edges of the radiations (353,418,422,423)
(Fig. 1.58). MRI can reveal the topographic pattern of fiber
degeneration following cortical injury (424).
The location of optic radiation fibers subserving the tem-
poral crescent, the unpaired nasal fibers (discussed later), is
uncertain. In general, however, the projection from the infe-
rior visual field of the monocular crescent travels in the
upper quadrant of the superior radiation, and vice versa
(425). These fibers converge in the most anterior part of the
striate cortex to occupy less than 10% of the total surface
of the striate cortex (426). The counterclockwise rotation
of fibers that occurs in the dLGN (discussed previously) is
rectified within the 2–3 mm anterior to the visual cortex.
The medial dLGN fibers pass downward to reach the inferior
bank of the occipital cortex to serve the superior visual field,
while the lateral dLGN fibers pass upward (353,422). There
is no interhemispheric crossing of the optic radiations (338,
427,428).
BLOOD SUPPLY
The superior portion of the optic radiation is supplied pri-
marily by branches from the inferior division of the middle
cerebral artery. The inferior portion of the radiation receives
blood mainly from the PCA. The PCA dominates the blood
Figure 1.59. The representation of the visual field in the lateral geniculate supply to the optic radiation more posteriorly (Fig. 1.60).
body and the optic radiations. In the representation of the visual field (A),
the different parts of the upper quadrant are indicated by numbers and the
lower by letters. In both quadrants, each series runs from center to periphery,
so that any one series (e.g., i, ii, iii) indicates a sector, whereas the corre-
sponding symbols from adjoining series (e.g., i, 1, I) indicate an arc of the
visual field. Radii dividing the visual field are represented by dotted lines
and linear arcs by dashed lines. In the lateral geniculate body (B), central
vision is represented in cells lying superiorly and peripheral vision in cells
lying inferiorly. The upper quadrant of the visual field is represented lat-
erally, the lower medially, and the horizontal meridian approximately verti-
cally. In the anterior radiation (C), the orientation of fibers has turned coun-
terclockwise through almost a right angle. The fibers representing central
vision are now spread out over a large part of the lateral aspect of the visual
radiation, although they tend to concentrate on its intermediate part. In
contrast, the fibers of peripheral vision are spread out over the medial aspect
of the visual radiation and tend to concentrate at the upper and lower margins
and to thin out over the intermediate part. The horizontal meridian, there-
fore, is represented more or less horizontally in the intermediate part of the
radiation at this point. In the posterior radiation (D), the fibers of central
vision have come to occupy the whole of the intermediate part of the radia-
tion and lie lateral to the posterior horn of the lateral ventricle as they pass
back to the posterior pole of the occipital lobe. The fibers of peripheral
vision have become concentrated at the margins of the radiation, at the two
ends of the horseshoe-shaped structure. At this location the fibers are enter-
ing the anterior part of the striate cortex. (Redrawn from JMK Spalding.
Wounds of the visual pathway: I. The visual radiation. J Neurol Neurosurg Figure 1.60. Blood supply of the visual sensory system. (From Walsh
Psychiatry 1952;15⬊99–107.) FB, Smith GW. J Neurosurg 1952;9:517–537.)
CORTICAL VISUAL AREAS

CORTICAL AREA V1 occipital pole, and the calcarine fissure is sometimes crossed
by other gyri (430). An average neuron in macaque striate
Anatomy cortex receives approximately 2,300 synapses (1,400 in layer
In the human, the primary visual cortex is situated along 4C␤ and 2,800 in layers 2 and 3; discussed later) (434).
the superior and inferior banks of the calcarine fissure, corre- There are approximately 150,000 cells/mm3 in visual cortex.
sponding to area 17 of Brodmann (Fig. 1.61). This area often Visual cortical neurons are separated into two main mor-
is called the striate cortex because of a prominent white band phologies (pyramidal and nonpyramidal), which forms the
of myelinated fibers known as the stria of Gennari, which basis for the histologic segregation of the visual cortex into
forms horizontal connections within the cortex. The striate six laminae (435,436) (Fig. 1.62). Layer 1, the most superfi-
cortex envelops the posterior pole of the hemisphere, extend- cial layer, contains few neurons and is composed mostly of
ing laterally about 1.5 cm. Rostrally and medially, V1 ex- fibrillary astrocytes with some microglia and oligodendro-
tends anteriorly beyond the juncture of the parieto-occipital cytes. Layer 2 contains small pyramidal cells, many with
and calcarine fissures, especially ventrally (427,429,430). short axons or axons that ascend and split within layer 1
The optic radiations from the dLGN provide the main affer- (437).
ent connections to area V1. The three main outflow pathways Layer 3, which is indistinctly separated from layer 2, is
from the retina—parvocellular, magnocellular, and konio- traditionally defined as containing mostly medium-sized and
cellular (discussed previously)—remain distinct at the small pyramidal cells, with granule cells more deeply. A
dLGN, but there is some convergence of these outflow in more recent interpretation further divides layer 3 into four
area V1 (431,432). There are also inputs to area V1 from subregions: 3A, 3B␣, 3B␤, and 3C (438,439) (Fig. 1.62).
the pulvinar and other cortical regions. Large pyramidal cells of 3A project to V2 in the monkey
V1 represents about 3.5% of the cortical area of the brain. (437) (Fig. 1.63). Cells in 3B␤ project to area V2, while
There is considerable variability in the configuration of the those in 3C project both to V2 and MT (discussed later). An
calcarine fissure and the distribution of the striate cortex, appealing feature to this newer schema (which has not yet
even within an individual. The surface covered by the visual been widely adopted) is that layer 3 is the primary projection
projection area varies among individuals 2.5–3-fold, with a layer from area V1 to the associative visual cortices. In the
range of 15–45 cm2. There is even considerable variability macaque, layer 3 receives input from the intercalated layers
of the area of exposed striate cortex (3.6–13 cm2) of the dLGN (135) (Figs. 1.48 and 1.50). Projections from
(427,430,433). These estimates indicate that on average 67% layer 3 of area V1 to cortical area V2 arise from ‘‘inter-
of the striate cortex is buried in the calcarine fissure or its patches,’’ whereas projections to area MT arise from both
accessory sulci. The striate cortex does not always reach the interpatches and patches (i.e., more darkly staining cyto-
Figure 1.61. The areas occupied by the primary visual cortex and the extrastriate areas, according to Brodmann’s classification.
A, Lateral surface; B, Mesial surface. (From Lindenberg R, Walsh FB, Sacks JG. Neuropathology of Vision: An Atlas. Philadel-
phia, Lea & Febiger, 1973.)
Figure 1.62. Nissl-stained section through

area V1 of macaque monkey. The layers are
numbered according to a recent modification of
Hässler’s nomenclature. The more traditional
Brodmann’s nomenclature is shown in paren-
theses. As indicated by the brackets, layer IV
receives the main input from the lateral genicu-
late nucleus, the layers above IV send projec-
tions to other cortical areas, and the layers
below IV send projections to subcortical areas.
A subdivision of layer 4 known as layer 4ctr
(i.e., center) which lies between layers 4␣ and
4␤ is not shown. WM, white mater. (From Ca-
sagrande VA, Ichida JM. The primary visual
cortex. In: Kaufman PL, Alm A, eds. Adler’s
Physiology of the Eye. 10th ed. St Louis,
Mosby, 2003⬊672.)
chrome oxidase regions). Layer 3 can be considered the point Layer 5 contains pyramidal cells of various sizes, includ-
at which the dorsal and ventral steams of information begin ing the giant pyramidal cells of Meynert. Layer 5 (in the
to diverge to different cortical regions (discussed later). monkey) projects to the SC and pulvinar nucleus (444).
Layer 4 is a relatively large lamina that is the primary Layer 6 contains medium-sized neurons (450–452), most of
recipient area of the geniculate-calcarine projection, which which project as a feedback pathway to the dLGN (discussed
mostly synapses on stellate cells that have a uniform, radial previously) (444,453,454). Layer 6 of macaque consists of
topography. A recent revision of visual cortical architecture three sublayers, only two of which project to the dLGN. The
divides layer 4 into three zones: 4␣, 4ctr, and 4␤ (438,439) upper tier projects exclusively to parvocellular layers, while
(Figs. 1.62 and 1.63). Using this new schema, layer 4 does the lower tier projects to parvocellular and magnocellular
not send axons outside of area V1; rather, layer 4 forms a layers of the dLGN (454).
host of intracortical connections to areas, like layer 3, which The majority of striate cortical cells receive their (supra-
then project to associative visual cortices. The traditionally threshold) excitatory input from either the ‘‘P’’ or ‘‘M’’
described layer 4A, which contains large stellate cells with pathway via the dLGN. This description of parallel inputs,
axons that descend to deeper laminae or enter the subcortical however, too greatly simplifies the reality. In macaque mon-
white matter, expresses in humans monoclonal staining pat- keys, a substantial proportion (at least 25%) of area V1 neu-
terns not found in nonhuman primates, which suggests evo- rons receive convergent input from two dLGN outflow path-
lution of an enhanced interneuronal population (440). ways, usually the ‘‘M’’ and ‘‘P’’ pathways, and possibly
The traditional layer 4B, recently considered to be 3C, from the koniocellular projections as well (431). This type
contains mostly granule cells and has the stria of Gennari. of area V1 neuron, which responds to both color and lumi-
The neurons of layer 4B, which predominantly receive input nance (i.e., black-white, contrast-sensitive cells), may pro-
from the ‘‘M’’ pathway via layer 4␣ (new classification), vide boundary cues between differently colored regions.
are mostly tuned for orientation, although a smaller popula- Other neurons in V1 that respond purely to color are not very
tion of cells are direction-selective (377,441–443). These sensitive to spatial localization and therefore may provide
cells project mostly to area MT. Pyramidal cells in layer 3C information about fluctuation of color within a particular
receive M- and P-cell input and project mainly to area V2 region (455).
(444,445); (446–448). Parvocellular input from the dLGN The primary projections of area V1 are to areas V2 or
is to layers 4␤ and 4ctr (449). MT. Uncommonly but notably, some V1 ‘‘manifold’’neu-
Most cortical outputs from other brain regions project to

the superficial layers of the striate cortex, which then connect
to (traditional) layer 4. Feedback projections, on the other
hand, emerge more deeply within the striate cortex and ex-
tend to either layers 1 or 6 (457). Feedback projections are
typically more divergent, partly because of their use of mani-
fold neurons (discussed previously) that project to two sites,
and they arise from widespread areas, including limbic-asso-
ciated cortices. Thus, the patterns of interconnections are
complex and not well appreciated (458,459). Nonetheless,
the sheer number and extent of feedback connections indi-
cate their probable importance in the process of creating
vision. For example, feedback connections may enhance at-
tention or synchronize responses that bind different features
of an image (460–462).
Physiology
The physiology of the striate cortex initially was defined
in the cat, which led to the recognition of distinctive response
properties of simple and complex cells (383,463–465). Sub-
sequent work in monkeys revealed significant differences
from the cat (379,465–474), including identification of a
third cortical neuron, the end-stopped cell. In general, the
receptive field properties of cortical neurons are quite differ-
ent and more complicated than the circular receptive field
properties found in the retina and dLGN (Table 1.5). This
might seem counterintuitive, given that there is a monosyn-
Figure 1.63. Some of the main intrinsic and extrinsic connections of V1 aptic connection between the geniculate afferent and layer
in primates. No effort is made to define the strength of connections or to 4 neurons with area V1. This intricacy of feedforward and
indicate true axon collaterals or species-unique features. Feedback connec- intracortical and intercortical connections to area V1 pre-
tions to V1 and the lateral geniculate nucleus (LGN), as well as connections
sumably accounts for this more intricate physiology (475).
between extrastriate areas, are not shown. The major input to V1 is from
the dorsal LGN, which arrives via three pathways: the koniocellular (K),
Comparisons of some response properties across the various
magnocellular (M), and parvocellular (P) pathways. The retina also projects visual cortical areas are shown in Table 1.6.
to other targets, one of which, the superior colliculus (SC), is shown. Within The receptive fields of simple cells, like retinal and dLGN
V1, cell layers are heavily interconnected, not only by some of the axonal cells, show either ON or OFF responses, each with an antag-
pathways shown but also by dendritic arbors (not shown). The main ipsi- onistic surround. Unlike RGCs, however, receptive field
lateral connections to extrastriate cortex exit from layer III. In layer IIIA, centers of simple cells are linear rather than circular, which
the cells within cytochrome oxidase (CO)–rich blobs (indicated by dotted explains the high sensitivity of these cells to long, narrow
ovals; see text), and CO-poor interblobs send information to different target slits of light. Simple cells also are orientation-selec-
cells within bands of V2. In layer IIIB, cells within CO blobs send projec- tive—that is, they respond best to a line oriented at a particu-
tions to the dorsomedial area (DM) of the cortex. Cells that lie under the
lar angle (Fig. 1.64). The response of simple cells increases
CO blobs in layer IIIC send information to the middle temporal area (MT),
also called cortical area V5. Although connections between V1 and V3
in proportion to the stimulus length, up to the limit of the
have been documented, it is not known from which layer/module these receptive field. Adjacent columns of simple cells show a
connections arise. A subdivision of layer 4 known as layer 4ctr (i.e., center) progressive shift in their preferred orientation. In the mon-
which lies between layers 4␣ and 4␤, is not shown. DLc (V4), dorsolateral key, simple cells are almost entirely in (traditional) layer 4,
caudal (cortical area V4). (From Casagrande VA, Ichida JM. The primary with a few cells in layer 6.
visual cortex. In: Kaufman PL, Alm A eds. Adler’s Physiology of the Eye. Complex cells are orientation-selective and motion-sensi-
10th ed. St Louis, Mosby, 2003⬊675.) tive. Complex cells respond inconsistently to stationary stim-
uli but fire vigorously to a moving stimulus oriented at pre-
ferred angles. The responses are direction-specific and are
rons project to both sites (448). The MT projecting axons also influenced by the stimulus speed (Fig. 1.65). Like sim-
come from ‘‘patch’’ areas, which provide koniocellular sys- ple cells, the response of complex cells is proportionate to
tem input to area MT (448). In general, the receptive field stimulus size up to the limit of the receptive field. Like RGCs
widths of outwardly projecting cells from the striate cortex and dLGN cells, both simple and complex cells have spatial
are smaller than those of cells that project to the striate and temporal responses that can be either sustained or tran-
cortex (456). This observation suggests that the striate cor- sient (476–478). Complex cells, which greatly outnumber
tex is organized partly to enhance detection of fine spatial simple cells, are found above and below (traditional) layer
detail. 4, but only rarely in layer 4.
Table 1.6
General Summation of Certain Features of Visual Cortical Areas
Cortical
Area Some Specialized Response Properties or Cell Types General Comments
V1 • Simple cells • Receives almost all of the cortical afferent input from the dLGN
• Complex cells • “Cortical magnification” of dLGN input is substantial
• End-stopped cells • Some convergence of the P-, M- and K-cell input
• Response properties in general are more complicated than dLGN relay
neurons
• Primary projections are to V2 and MT
• Some cells respond to first order motion
V2 • Most neurons are orientation selective • Largest extrastriate visual cortical area
• Half of the neurons are color selective • First location along visual pathway at which there is a convergence of
• “Depth cells” respond to retinal disparity input from retina and pulvinar
• Many neurons respond to more than one visual feature, • Most of the V1 afferent input is sent to V2 before being distributed
which suggests convergence of input elsewhere
• Directionally selective cells are sparse (motion • Further increase in cortical magnification from V1 to V2
information may largely bypass V2) • Receptive fields are larger than V1
• Assessment of retinal disparity may be an important feature
• Some cells respond to first order motion
• Projects to V3 (mainly), V4 and V5 ipsilaterally; V2 contralaterally
V3/V3A • 76% of neurons are strongly orientation selective • Area 3d has more connections with V1 than any other area, but these are
• 40% of neurons are strongly direction selective less numerous than V1 to V2 connections
• Most neurons are optimized for stimulus speed direction • Relatively small area
• 50% of neurons are color sensitive • Likely receives nonretino-calcarine input from pulvinar
• Most neurons are binocularly driven • Receptive fields larger than V2
• 33% of V3A neurons may respond to light even with • V3d and V3v respond to second order motion
complete ablation of V1 • Projects primarily to pulvinar and midbrain
• Anatomical subdivisions are controversial
V4 • Neurons respond primarily to shape, color, and texture • Receptive fields are larger than V3, which are larger than more proximal
of visual stimulus visual cortices
• Most neurons show preference for near objects • Major projection to IT, but significant projection to posterior parietal
• 50% of neurons are color opponent cortex
• Few neurons are orientation or direction selective • Neurons code shape in reference to boundary features of objects
• May play a role in visual discrimination tasks
TE • 33% of neurons selectively respond to 3D object shape • Lies at end of ventral stream of visual information
• May play a role in identification of visually complex objects
• Strong output to medial temporal region, perhaps important to establish
visual memory
V5 (MT) • 90% of neurons are direction selective • Smallest of the named visual areas
• 33% of neurons are direction selective for patterns of • Receives direct but sparse, high velocity input from V1; also receives
movement input from V2, V3d, V3v, MST
• Area MST contains neurons that specialize in processing • Dense intracortical branching may amplify incoming signals
“motion in depth,” which may permit estimation of • Ablation of V1 does not eliminate activity, even direction selectivity
one’s direction of movement in an environment • May be primary cortical area for motion processing, especially of
motion patterns; also responds to first and second order motion
V6 • Cells respond nearly identically to those of V6A to • Poorly understood
orientation and direction of movement of visual stimuli • Receives input from V2
• Like neurons of V6A, the response of neurons is affected • Has large receptive fields
by eye movements • May function in mapping of relative spatial relationships
• Responds strongly to motion
• Does not contain a conventional retinotopic map
• Strongly interconnected to V6A
V6A • Contains cells that do not respond to visual stimuli but • Much larger receptive fields than V6
respond to intentional arm movements • Retinotopy is relatively coarse
• “Real-position” cells that represent orientation with • May function to help guide skeletomotor activity into extrapersonal
respect to craniotopic receptive fields space
• Response of neurons is affected by eye movements
The descriptions in this table are meant to serve as a superficial overview of the purported function of these areas. Any notion that specific visual cortical areas perform only cer-
tain highly specific tasks should be carefully scrutinized.
Figure 1.65. Receptive field of a complex cell from the monkey striate
Figure 1.64. Simple cortical cell with preferred axis of orientation. Stimu- cortex. Outline of receptive field is shown by the dashed lines. Orientations
lus is white bar of varying orientation shown on representation of receptive of black bar stimulus are shown on the left, and responses to that partic-
field at left. A horizontal stimulus (top) falls on excitatory and inhibitory ular orientation are shown on the right. Arrows indicate direction of bar
regions, and therefore no response is evident in the recording from the cell movement. (From DH Hubel, TN Wiesel. Receptive fields and functional
(shown on right). A stimulus that is tilted slightly off vertical (middle row) architecture of monkey striate cortex. J Physiol [Lond] 1968;195⬊215–
produces a weak response. When stimulus is vertical (bottom), however, 243.)
the stimulus is entirely in the excitatory region of field and the response
is vigorous. (From D Hubel. The visual cortex of the brain. Sci Am 1963;
209⬊54–62.)
End-stopped cells (once called hypercomplex cells) also

respond proportionately to the length of a stimulus, but they
are novel in that their response decreases when the stimulus
length reaches the boundary of the activating portion of the
receptive field (Figs. 1.66). This effect results from an inhibi-
tory surround. Unlike the simple and complex cells, stimula-
tion exclusively within the antagonistic zone of an end-
stopped cell does not alter the cell’s responsiveness. End-
stopped cells are located above and below (traditional) layer
4. In the cat, these cells are also found in areas V2 and V3.
The antagonistic surrounds of these cortical cells are sub-
stantially larger than those of RGCs or dLGN neurons. These
relatively large surrounds are thought to result from feedback
from other cortical areas, especially from V2, V3, and V5
(475). Figure 1.66. End-stopped cell recorded in area 17 of the monkey. Activat-
Each of these striate cells is arranged in columns, within ing region of receptive field is outlined by the broken line on the left.
which the cells show a consistent preference for stimu- Stimulus, in this instance a moving slit of white light, is represented by
the solid rectangles, and responses to movements in directions indicated
lus orientation and have very similar receptive fields
by arrows are shown on the right. A, The stimulus is contained within the
(379,468–470,479,480) (Fig. 1.67). Adjacent columns, sep- activating region. B, The stimulus extends into antagonistic regions on either
arated by about 50 ␮m in the monkey, contain cells with side. In the latter case the response is substantially reduced because the
sequential shifts of about 10 degrees in the preferred orienta- stimulus exceeded a critical length and entered an antagonistic sur-
tions. Therefore, approximately 1 mm in linear dimension round region. (From DH Hubel, TN Wiesel. Receptive fields and functional
contains 18 orientation columns and subserves all possible architecture of monkey striate cortex. J Physiol [Lond] 1968;195⬊215–
linear orientations. In a rare opportunity to correlate neuronal 243.)
Figure 1.67. Modular organization of the primary visual cortex

(area V1). Each module (or hypercolumn) consists of two ocular
dominance columns (representing right [R] and left [L] eyes), a
series of orientation columns (representing 180 degrees of rota-
tion), and cytochrome oxidase blobs (dotted columns; representing
color information). This schematic uses the traditional designation
for the cortical layers. (From Livingstone MS, Hubel DH. Anat-
omy and physiology of a color system in the primate visual cortex.
J Neurosci 1984;4:309.)
activity and perceptual behavior, improved performance on the parafoveal representations of V1 and V2 in monkeys.
psychophysical tests of orientation selection in monkeys has Within this parafoveal response zone, roughly 20% of the
been correlated with training-induced refinement of orienta- cells respond solely to vertical disparity, and they do so
tion tuning of individual striate neurons (481). with a higher spatial resolution than cells that respond to
A full set of orientation columns defines the spatial extent horizontal disparity (482). This tighter monitoring of vertical
of a pixel for one eye, which is referred to as an ocular interocular disparity might account for the relatively uncom-
dominance column (discussed later). An immediately adja- mon occurrence of congenital vertical strabismus in the pri-
cent ocular dominance column is present for the fellow eye. mary position.
A hypercolumn is a pair of ocular dominance columns, each Adjacent columns of eye-specific input form the ocular
with its full set of orientation columns and cytochrome oxi- dominance columns (468,472,483–485) (Fig. 1.68). These
dase blobs (379) (Fig. 1.67). There are several hundred hy- columns are roughly 0.4 mm wide in the macaque monkey
percolumns throughout the striate cortex. (379,486–488). The columns can be visualized with cyto-
chrome oxidase (CO), a marker for areas of high metabolic
Binocularity and Ocular Dominance Columns activity within mitochondria and the neuropil in general. By
The primary visual cortex integrates visual information removing visual input from one eye, obvious differences can
from both eyes. Although the ‘‘simple’’ cells of the striate be seen in CO staining among adjacent ocular dominance
cortex can receive input from either one eye or both, the columns. The positive staining regions contain blobs, oval-
complex and end-stopped cells receive only binocular input, shaped regions of greater staining, organized in rows aligned
which is nearly identical from each eye. Given the respective within ocular dominance columns (Figs. 1.69 and 1.70).
locations of these cells (discussed previously), almost all Ocular dominance columns are found mostly in primates,
cells in layer 4C are monocular, whereas over half of the including humans (483,489,490). The blobs are most evident
cells in layers 2, 3, 5, and 6 are binocular. Specialized cells in (traditional) layers 4A, 4C, and 6, which are those that
that respond to horizontal disparity of a visual stimulus are receive ‘‘M’’ and ‘‘P’’ afferent input from the dLGN (Fig.
present within the foveal representation of V1, and within 1.70).
Ocular dominance columns begin to form in the monkey

in the last month of gestation, prior to visual experience,
and they are nearly developed at birth (491,492). Deprivation
amblyopia (created by closing the palpebral fissure of one
eye) in cats and monkeys causes shrinkage of ocular domi-
nance columns from that eye (493,494). In humans, how-
ever, neither anisometropic nor strabismic amblyopia alters
the width of ocular dominance columns (495,496), which
suggests that deprivation amblyopia is caused by a different
mechanism. In fact, the molecular basis for deprivation am-
blyopia has recently been shown to result from changes in
the postsynaptic NMDA glutamate receptor. The retinal ac-
tivity from the ‘‘weak’’ eye does not drive the visual cortex A
as strongly as the normally sighted eye. This imbalance initi-
ates a cascade of biochemical changes, beginning with al-
tered phosphorylation of specific AMPA receptors, which
leads to a decrease in the surface expression of the synaptic
B
A Figure 1.69. Distribution of the enzyme cytochrome oxidase in the cells
of the striate cortex. A, The organization of cytochrome oxidase blobs in
striate cortex of a macaque monkey. B, A photograph of a histologic section
of layer III, stained for cytochrome oxidase and viewed from above. (From
Bear MF, Connors BW, Paradiso MA. Neuroscience: Exploring the Brain.
Philadelphia, Lippincott Williams & Wilkins, 2001⬊330.)
glutamate receptor and therefore to decreased transmission

across the synapse (497). By this same mechanism, monocu-
lar deprivation can alter the relative sizes of ocular domi-
nance columns, even in adult mice (498). Of further clinical
significance is the observation that decreases in CO activity
within the striate columns are induced by panretinal laser
photocoagulation in monkeys (499).
B Some Psychophysical Aspects

Figure 1.68. Ocular dominance columns in striate cortex. A, Organization The majority of the human striate cortex represents only
of ocular dominance columns in layer IV of the striate cortex of a macaque the central portion of the visual field. In fact, the central 10
monkey. The distribution of lateral geniculate nucleus (LGN) axons serving degrees of the visual field is subserved by at least 50–60%
one eye is darkly shaded. In cross-section, these eye-specific zones appear of the striate cortex, and the central 30 degrees is represented
as patches, each about 0.5 mm wide, in layer IV. When the superficial by about 80% of the cortex (Fig. 170a) (426,500). The large
layers are peeled back, allowing a view of the ocular dominance columns area that is devoted to central vision explains the fact that
in layer IV from above, these zones take on the appearance of zebra stripes.
the pattern-reversal visual evoked potential is essentially a
B, An autoradiograph of a histologic section of layer IV viewed from above.
Two weeks prior to the experiment, one eye of this monkey was injected reflection of macular activity (501). In the striate cortex, the
with radioactive praline. In the autoradiograph, the radioactive LGN termi- area devoted to a square degree of the fovea is almost 1,000
nals appear bright on a dark background. (From LeVay S, Wiesel TN, times greater than that devoted to the same amount of area
Hubel DH. The development of ocular dominance columns in normal and from the far peripheral (60 degrees from fixation) retina.
visually deprived monkeys. J Comp Neurol 1980;191⬊1–51.) The cortical representation of the macula is large enough to
Figure 1.70. Magnocellular (originating from large dots) and parvocellular (originating from small dots) pathways from the
lateral geniculate body extending through areas V1 and V2 to eventually reach areas V4 and V5. Each module of striate cortex
contains a few complete sets of ocular dominance columns (R and L), orientation columns, and about a dozen cytochrome
oxidase-positive blobs (stippled cylinders). The orientation columns, depicted with hashmarks on the cortical surface, extend
through all layers except 4C␤. Their borders are not discrete. The magnocellular stream courses through layer 4C to layer 4B
and then to dark thick stripes in area V2 and to area V5. The parvocellular stream courses through layer 4C␤ to layers 2 and
3. Cells within the cytochrome oxidase blobs project to dark thin stripes in area V2, whereas cells within interblob regions
project to pale thin stripes in V2. Both dark and pale thin stripes in area V2 probably project to area V4 and other regions.
Layers 5 and 6 in area V1 send projections to the superior colliculus and the lateral geniculate body, respectively. The koniocellu-
lar pathway is not shown. (From JC Horton. The Central Visual Pathways. In: Hart WM Jr. Adler’s Physiology of the Eye.
9th ed. St Louis, CV Mosby, 1992⬊751.)
straddle the vascular territories of the PCA and middle cere- afferent channels terminate exclusively in layers 3B and 4A.
bral artery (MCA), which might explain the phenomenon of The ‘‘blue OFF’’ cells terminate in layer 4A, while the ‘‘blue
macular sparing that may occur in patients with visual field ON’’ cells terminate in layers 4A and lower layer 2/3 (502).
defects secondary to occipital lobe injury. Color-selective cells in the striate cortex have been believed
Color information is transmitted to the primary visual cor- to terminate mostly within the CO blobs (503–507) (Fig.
tex along parallel pathways. In macaque monkeys, red-green 1.70). Although not yet resolved, recent data reveal that color
afferent channels terminate in layer 4C␤ and blue/yellow patches in striate cortex only loosely correlate with the loca-
Figure 1.70a The representation of the visual field in the human striate cortex. A, Left occipital lobe showing location of
striate cortex within the calcarine fissure (between arrows). The boundary (dashed line)between the striate cortex (area V1)
and the extrastriate cortex contains the representation of the vertical meridian. B, View of the striate cortex after opening the
lips of the calcarine fissure. The dashed lines indicate the coordinates of the visual field map. The representation of the horizontal
meridian runs approximately along the base of the calcarine fissure. The vertical dashed lines mark the isoeccentricity contours
from 2.5 to 4.0. Striate cortex wraps around the occipital pole to extend about 1 cm onto the lateral convexity where the fovea
is represented. C, Schematic map showing the projection of the right visual hemifield upon the left visual cortex by transposing
the map illustrated in B onto a flat surface. The row of dots indicates approximately where striate cortex folds around the tip
of the occipital lobe. The black oval marks the region of the striate cortex corresponding to the blind spot of the contralateral
eye. HM, horizontal meridian. D, Right visual hemifield plotted with a Goldman perimeter. The strippled region corresponds
to the monocular temporal crescent, which is mapped within the most anterior 8–10% of the striate cortex. (From Horton JC,
Hoyt WF. The representation of the visual field in human striate cortex. A revision of the classic Holmes map. Arch Ophthalmol
1991;109:816–824.)
tion or size of CO blobs. Further, color-selective patches in the striate cortex, the extrastriate cortex (discussed later)
may be poorly correlated with the location of ocular domi- is a more color-dominant area. There are light-driven cells
nance and orientation columns. Further, in squirrel monkeys within CO blobs that are neither orientation- nor wavelength-
at least, there is a tremendous variability in the expression selective but that respond to high-spatial-frequency contrast
of ocular dominance columns (206). These observations call gratings (510).
into question the validity or consistency of the ocular domi-
nance and hypercolumn organizational schema (508). Blood Supply
Nonetheless, color cells that do terminate within CO blobs
are grouped together by wavelength sensitivity, such that The striate cortex benefits from a rich anastomotic net-
individual blobs appear to process only one class of color work between terminal branches of the MCA and PCA, par-
opponency (509). Although color-sensitive cells are present ticularly at the occipital pole. The primary branches of the
Figure 1.71. The posterior cerebral artery and its branches that supply the striate cortex. (From Lindenberg R, Walsh FB,
Sacks JG. Neuropathology of Vision. Philadelphia, Lea & Febiger, 1973.)
MCA that serve the primary visual cortex are the occipital calcarine input to area V1 passes to area V2 before being
branches. The primary branches of the PCA that serve the distributed elsewhere (520,521). There is a further increase
visual cortex are the parieto-occipital (superiorly), calcarine in ‘‘cortical magnification’’ from V1 to V2 (522,523).
(centrally), and posterior temporal (inferiorly) branches As described above, area V1 shows two distinct modules:
(511–517) (Figs. 1.60 and 1.71). blobs and orientation columns (Fig. 1.70). The output from
area V1 to V2 is primarily via two paths—either from the
CORTICAL AREA V2 patch or interpatch areas related to CO staining (524). Within
area V2, most neurons are orientation-selective, and half are
In the human, area V2 (corresponding to area 18 of Brod- color-selective (525,526). Information from the two eyes has
mann) is within the occipital lobe, adjacent to area V1 converged by the time it reaches area V2, and ‘‘depth cells’’
(518,519) (Figs. 1.72 and 1.73). Area V2, the largest of the within the thick stripe regions respond to retinal spatial dis-
extrastriate visual areas, is the first region along the afferent parity (522,527,528). In fact, assessment of retinal disparity
visual pathway at which there is a convergence of input from may be one of the more significant roles of area V2. These
the retina and pulvinar (Fig. 1.74). Although these inputs various functions are segregated in three distinct area V2
terminate in different areas, the dense network of local inter- modules: pale, thin, and thick CO-staining regions (Figs.
connections in layer 2/3 may integrate them. Most retino- 1.63, 1.70, and 1.75). Cells within cytochrome ‘‘patches’’
Figure 1.72. Arrangement of V1, V2, and V3 along the

medial and posterior occipital surface. Most of V1 is buried
within the calcarine fissure. Considerable variation occurs
among individuals in the relative position and size of dif-
ferent cortical visual areas. (From Horton JC, Hoyt WF.
Quadrantic visual field defects. A hallmark of lesions in
extrastriate [V2/V3] cortex. Brain 1991;114⬊1703–1718.)
Figure 1.74. How projections from primary visual cortex (V1) and the
pulvinar converge in the cortical visual area V2. As indicated by black
arrows, the projections from V1 to V2 are richest to pale stripes, whereas
those from the pulvinar are strongest to thick and thin stripes. This segrega-
tion is far from absolute, as shown by gray arrows indicating weaker projec-
tions. The strongest projections from V1 and the pulvinar are interdigitated
in V2. LGN, lateral geniculate nucleus. (From Sincich LC, Horton JC.
Pale cytochrome oxidase stripes in V2 receive the richest projection from
macaque striate cortex. J Comp Neurol 2002;447⬊18–33.)
plex responses (e.g., binocular color cells with orientation

selectivity) are found in area V2 (523,531,532). There are
also cells with mixed color and disparity functions. The two
‘‘interpatch’’ projections (one from layer 4B and one from
layer 2/3 of area V1) are composed primarily of M- and P-
cell input, respectively, from area V1. But some interpatch
afferents project to the same V2 stripes. This suggests that
M and P outflow is merged at V2 and then distributed to both
dorsal and ventral streams via V3 (discussed later) (524).
Compared to V1, receptive fields are larger in V2, and
Figure 1.73. Identified visual areas on the Human.colin surface-based cells can respond to lower spatial frequencies. However, di-
atlas. The boundary of MTⳭ on the atlas map was estimated by projecting rectionally selective cells are sparse in area V2, which sug-
the motion-related activation foci tabulated by Van Essen and Drury (1997) gests that motion information bypasses V2 en route to area
onto the atlas surface. The visuotopic map from Figure 5A of Tootel and V5 (discussed later). Some cell columns are arranged in a
Hadjikhani (2001) was then registered to the atlas using the V1/V2 boundary
highly ordered fashion, with the orientation of cells in adja-
and the posterior boundary of MTⳭ as landmarks. Additional areas LO
and V7 were drawn manually onto the atlas, based respectively on the
cent columns differing by small but constant amounts. Occa-
studies of Tootel and Hadjikhani (2001) and Press et al. (2001). A, Lateral sionally, the shift in orientation between neighboring col-
view. B, Medial view. C, Inflated (i.e., the cortex is shown as a flat surface umns is abrupt and appears random in direction and variable
without the normal indentations of the sulci) lateral view. D, Inflated medial in size (523).
view. E, Flat magnified view. The red dotted contour represents the main Area V2 is intimately related with area V3 on the same
cluster activation focus center involved in face and place analysis. The side of the brain, and also projects ipsilaterally to V4 and
abbreviations indicate areas of striate and extrastriate cortex: FF, fusiform V5. Area V2 projects contralaterally via the corpus callosum
face area; LOP, lateral occipital parietal; PH, parahippocampal place area; to the fellow area V2. This callosal connection integrates
VP, ventral posterior area. (From Van Essen DC. Organization of visual roughly half of V2 from each side and connects topographi-
areas in macaque and human cerebral cortex. In: Chalupa LM, Werner JS,
cally opposite halves of the homonymous visual field be-
eds. The Visual Neurosciences. Cambridge, MA, MIT Press, 2004⬊610.)
tween the vertical meridian and the 45-degrees isopolar line
(533) (Fig. 1.76). The connections between areas V1 and
V2 occur between cells at the same cortical depth (with the
of V1 send their axons to thin V2 stripes; cells between greatest input coming from layer 4) and are retinotopically
cytochrome V1 patches (‘‘interpatches’’) send their axons organized (Fig. 1.77). Area V2 projects to and receives input
to pale and thick stripes of area V2 (524). In area V2, the from prefrontal, sensory, motor, and auditory association
thin, pale, and thick CO bands are primarily responsive to areas; the insula; and, by multisynaptic pathways, the ante-
color, orientation, and retinal disparity, respectively (529) rior temporal lobe. Area V2 contributes corticotectal and
(Fig. 1.70). Each of these zones contains smaller compart- corticomesencephalic fibers to the superior colliculi that may
ments, each with functional distinctions (523). The dark (thin function in initiation of slow vertical or oblique eye move-
and thick) zones receive significant input from the pulvinar ments.
(530). The clinical consequences of lesions restricted to area V2
Many area V2 cells respond to more than one visual fea- in humans is unclear. In monkey, cell body-specific (i.e.,
ture, which suggests that some degree of visual integration axonal sparing) lesions of V2 produce no decrement in visual
occurs in V2 (Table 1.6). For instance, color cells with com- acuity or contrast sensitivity, although complex spatial func-
Figure 1.75. A simplified connectivity

diagram of the magnocellular (M), parvo-
cellular (P), and koniocellular (K) pathways
in the primate visual system. The magno-
dominant (‘‘where’’) stream is marked in
dashed lines and bold italics; the ventral
(‘‘what’’) stream is indicated by solid lines
and faint stripes. (From Kaplan E. The M,
P, and K pathways of the primate visual
system. In: Chalupa LM, Werner JS eds.
The Visual Neurosciences. Cambridge,
MA, MIT Press, 2004⬊486.)
Figure 1.76. Correlating the callosal pattern and the visual field map in area V2. The left panel shows the overall pattern of
callosal connections (in gray) in dorsal and ventral halves of right area V2 superimposed to mapping data of V2 taken from
Gattass et al. (1981), Van Essen et al. (1986), and Rosa et al. (1988). Posterior is to the left. The symbols in the topographic
map correspond with those in the left visual hemifield represented in the right panel. The arrows between left and right panels
indicate that dorsal and ventral V2 represent lower and upper visual field quadrants, respectively. The posterior border of V2
represents the vertical meridian (black squares); the striate cortex would then be to the left of the black squares. The anterior
border represents the horizontal meridian (large dots), the uppermost and lowermost regions of V2 represent peripheral fields
(triangles), and the fovea representation is in the middle of V2 (star). Isoeccentricity lines are represented with small dots,
isopolar contours with thin lines. The shaded area in the hemifield corresponds approximately to the extent of the visual field
represented in the callosally connected region in V2. (From Abel PL et al. Organization of callosal linkages in visual area V2
of macaque monkey. J Comp Neurol 2000;428⬊278–293.)
to area V2 (including area V3) is highly controversial (Fig.

1.79). One current opinion is that macaque and owl monkeys
have both a dorsal and ventral area V3 (i.e., area V3d and
V3v) that are physically discontinuous (536). This view con-
trasts with the view that the absence of connections between
V1 and a ventral V3 area indicates that there is no V3v (537).
With this interpretation, the ventral area of V3 is referred
to as VP (i.e., ventroposterior) (538). A third opinion is that
there is little or no area V3 in macaque monkeys, but rather
an area V6 (discussed later) that abuts the rostral border
of area V2 (539). However they are referred to, the area
contiguous but peripheral to V2 is heavily myelinated, and
there is strong immunoreactivity for the antibody CAT-301
within the area referred to as V3d. Functional MRI data
from humans, however, suggest that there is one functionally
similar although physically discontinuous area V3 (540).
Nonetheless, the weight of evidence from animal experimen-
tation favors the notion that V3d and V3v are functionally
distinct (discussed later).
Figure 1.77. Schematic coronal section through right occipital lobe show- A definite retinotopy exists for area V3, with the border
ing connections from V1 (stippled area) to V2/V3 (small triangles and between areas V2 and V3 sharing the representation of the
hatched lines, respectively). Projections pass between common retinotopic horizontal meridian of the visual field (541–543) (Figs. 1.78
coordinates. In V1, the horizontal meridian is represented along the base and 1.80). Topographically, areas V2 and V3 are mirror im-
of the calcarine sulcus. Fibers coursing in the white matter of the upper ages of one another (536). The fovea is represented where
and lower calcarine banks serve the lower and upper visual quadrants, the upper and lower fields of areas V2 and V3 are juxtaposed
respectively. For simplicity, feedback pathways from V2/V3 to V1 and the
(544). Area V3 projects primarily to the pulvinar and the
projection between V2 and V3 are omitted. The ventral V1 to V3 pathway
is doubtful (Van Esen et al. [1986]). (From Horton JC, Hoyt WF. Quadrantic
midbrain. Area V3 also has CO staining patterns, but these
visual field defects. A hallmark of lesions in extrastriate [V2/V3] cortex. are relatively weak and variable.
Brain 1991;114⬊1703–1718.) Within area V3, 76% of neurons are strongly orientation-
selective, whereas 40% are strongly direction-selective.
Most V3 neurons are optimized for stimulus speed discrimi-
tions (e.g., orientation of lines or detection of texture) are nation, with half of the cells being optimized for stimulus
abolished. In humans, lesions of V2 and V3 produce homon- movement of 16 degrees per second, which gives this area
ymous quadrantanopias (534). Loss of visual field along the a strong sensitivity for motion detection, like area V5 (dis-
horizontal meridian is explained by the mutual alignment of cussed later) (526,545,546). Functional MRI in humans re-
the representation of the horizontal visual field meridian at veals that the V3 complex is activated strongly by second-
the intersection of V2 and V3 (Fig. 1.78). Human lesions of order motion (i.e., contrast or frequency modulation, not lu-
V2 may cause selective impairment of the perception of the minance modulation) (540). Additionally, roughly half of
direction of first-order motion (i.e., spatial and temporal area V3d neurons are color-sensitive (546), which is similar
variation of luminance in a scene), even with an intact area to area V3v (alternatively referred to as VP) (547). Most
MT (discussed later) (535). area V3 neurons are binocularly driven.
One interpretation of the anatomy of area V3 is that its
CORTICAL AREAS V3 AND V3A two divisions—V3d and V3v or VP—are differentially in-
volved in partitioning visual information. Area V3d may be
The most detailed information regarding the organization part of the dorsal stream that specializes in motion detection.
of the visual cortices comes from monkeys, and this body Area V3d may be part of the ventral stream that specializes
of information provides moderate detail on only three areas: in form recognition (discussed later). Neurons in both V3d
V1, V2, and MT (discussed later). The current frontier of and V3v have response properties similar to those found in
study is of area V3, for which there are good anatomic data V2 (i.e., they respond to color, object, motion, and space),
of its interconnections but only recently a compelling picture although V3v neurons are more wavelength-selective and
of its retinotopy. Area V3d (i.e., dorsal) has more connec- less directionally selective than those in V3d. Interestingly,
tions with V1 than any other area, although these are less the representation of each V3 area is only for one quadrant
numerous than the connections between areas V1 and V2. of the visual field (e.g., V3d represents only the contralateral,
Area V3, which is relatively small (i.e., roughly half the inferior visual field) (537,538).
width of V2) is located adjacent to the boundary between Complete damage to V1 quiets all V2 and nearly V3 neu-
areas 18 and 19 of Brodmann (area V3 is not synonymous ronal responses to visual stimuli. However, roughly one
with area 19 of Brodmann, which occupies a large area lat- third of the area V3A (i.e., the adjoining cortex just rostral
erally where it surrounds area V2). to V3) neurons may respond to photic stimuli even with
The anatomy of the visual cortices just lateral and rostral complete ablation of V1 or V2 (548,549). Area V5 also re-
Figure 1.78. Maps of the posterior cortex of three subjects obtained by simulating a flattening of the gray matter. The left
hemisphere is shown in all cases; similar results were obtained in the right hemispheres. Overlaid on the map is a pseudocolor
representation of the phase of the fundamental component of the activation time course elicited by a rotating, flickering
checkerboard (inset, upper left). The variations in gray reflect visual field position (key in a) and show a smooth progression
through the visual field within each visual area, with a reversal of the direction of change at each cortical boundary. Estimates
of the locations of various boundaries are indicated. The dotted white line shows the approximate location of the fundus of
the calcarine sulcus. The approximate position of the occipital pole is marked with a star. (From Smith AT, et al. The processing
of first- and second-order motion in human visual cortex by functional magnetic resonance imaging [fMRI]. J Neurosci 1998;
18⬊3816–3830.)
Figure 1.79. Three views of the organization of dorsal extrastriate cortex in the macaque. Each diagram is an unfolded view
of the cortex of the left hemisphere. A, An early opinion of the organization (e.g., Van Essen and Zeki [1978]), which proposed
that a striplike V3, containing a representation of the lower quadrant (ⳮ), formed the rostral border of dorsal V2. B, Revised
view based on the studies of Gattass et al. (Colby et al. [1988]; Gattass et al. [1988]; Neuenschewander et al. [1994]). In this
construct, the lower-quadrant representation in area V3 is discontinuous. Moreover, V3 does not extend as far medially as
shown in A. Instead, another area (PO), which represents the periphery of both quadrants, is present medial to V3. C, A more
current interpretation based on the results of Galletti et al. (1999) in the macaque, and Rosa and Schmid (1995) in the marmoset.
Area PO, together with the medial island of V3 and an adjacent part of V3A, forms a complete representation of the visual
field, named V6 or DM. This area contains a continuous representation of the lower quadrant and a split representation of the
upper quadrant (Ⳮ). Area V3 does not extend medially as far as proposed by earlier studies. (From Rosa MGP, Tweedale
R. The dorsomedial visual areas in New World and Old World monkeys: homology and function. Eur J Neurosci 2001;
13⬊421–427.)
Figure 1.80. A, Artificially flattened map showing retinotopic organization of V1 (stippled area), V2 (small triangles), and
V3 (hatched lines) in the left occipital lobe. B, Right visual field coordinates corresponding to map in A. The monocular
temporal crescent (stippled area) is represented within a small area at the rostral end of striate cortex (border between binocular
and monocular field runs between arrows in A). V2 and V3 are split along the representation of the horizontal meridian into
separate dorsal and ventral halves. More than half of visual cortex is devoted to processing the central 10 degrees of vision.
(From Horton JC, Hoyt WF. Quadrantic visual field defects: a hallmark of lesions in extrastriate [V2/V3] cortex. Brain 1991;
114⬊1703–1718.)
mains visually responsive without input from V1, although a term used in New World monkeys). Area 6, as it will be
more weakly than V3A. The retained responsiveness of these called here, is located between areas V3 and V4, in the lunate
extrastriate cortices even without input from area V1 is evi- and parieto-occipital sulci (Fig. 1.73). Area 6 has reciprocal
dence that they receive input from other than the retinocalca- connections with areas V1, V2, V3, MT, MST, and other
rine pathway. The most likely alternative pathway is proba- sensorimotor areas (551). As such, area V6 is in a position
bly dominated by input from the pulvinar. Any such non- to distribute visual information from area V1 throughout the
retinocalcarine pathway provides a neuroanatomic basis for sensorimotor cortices of the parietal lobe, and thus assist in
the (admittedly controversial) clinical phenomenon of coordination of visuomotor tasks (Fig. 1.82). Area V6 has
‘‘blindsight’’ (see Chapter 13). a retinotopy that is distinct among visual cortices—there is
a physical discontinuity between central and peripheral vi-
DORSAL AND VENTRAL VISUAL STREAMS sion for the upper quadrant only (539). Most cells in V3 and
Two major streams of information flow are believed to V6 are binocularly driven. The receptive fields of cells are
exist from the V1 and V2 areas to other visual association larger in areas V3 and V6 than in area V2. There is a simi-
cortices in primates: the dorsal and ventral pathways (Fig. larity of responses among cells within V6 and the medial
1.81). The dorsal pathway, which is divided into dorsomed- part of V3, which has contributed to the controversy over
ial and dorsolateral sectors, is believed to be primarily con- regional boundaries (539) (Fig. 1.79). The medial extrastri-
cerned with where objects are and how they could be manip- ate cortex in and around the V6 area is one of the major
ulated. The ventral pathway is believed to be primarily afferent inputs from the cortex to the pontine nuclei (552).
concerned with form (i.e., ‘‘what’’) detection, although de- Area V6 is heavily myelinated, as is area 5 (discussed later).
tection of ‘‘second-order’’ motion (i.e., spatiotemporal scene The area just dorsal to V6 in macaque is known as V6A.
variation of contrast, depth, etc., but not luminance) or ‘‘bio- Area V6 and V6A are strongly interconnected (553), al-
logic motion’’ (discussed later) may be impaired with lesions though their physiologic properties are quite different. Most
to this pathway (550). The dorsal and ventral information significantly, V6A contains some cells that do not respond
streams do not have precise anatomic boundaries. to visual stimuli; ‘‘real-position’’ cells that represent orienta-
The area of visual cortex just rostral to V3 has been variation with respect to craniotopic receptive fields; and cells
bly referred to as area V3A, V6, or DM (i.e., dorsal median, with much larger receptive fields than area V6, among other
A B
Figure 1.81. Beyond striate cortex in the macaque brain. A,

Dorsal and ventral visual processing streams. B, Extrastriate vis-
ual areas. C, Flow of information in the dorsal and ventral
streams. (From Bear MF, Connors BW, Paradiso MA. Neurosci-
ence: Exploring the Brain. 2nd ed. Philadelphia, Lippincott Wil-
liams & Wilkins, 2001⬊338.)
C
properties. The nonvisual neurons are activated by inten- (544,558–560) and from area V2 (specifically to layers 1,
tional arm movements into peripersonal space, even in the 2, and 4) (561). The sparseness of input from these areas
dark (554). There are some physiologic similarities between does not necessarily imply that V5 has any less significant
V6 and V6A in that these two areas respond nearly identi- functional impact. Consider the following: The area V1 neu-
cally to orientation and direction of movement of visual rons that project to MT have very large receptive fields and
stimuli, and their cells are similarly affected by eye move- the highest velocity compared to other paths of outflow from
ment (i.e., gaze activity). The retinotopy in area V6A is V1. Area MT also receives input from V3d, V3v, MST, and
coarser than the more proximal visual cortical areas. the pulvinar. There may also be considerable amplification
Area 6A receives input from both of the better-character- of incoming signals in area V5 because of very dense intra-
ized motion-sensitive areas V6 and MT (discussed later). cortical branching and the relatively large, excitatory postsy-
Given this input, the function of area V6A is believed to naptic densities that are present in this area (562). Blocking
help guide skeletomotor activity into extrapersonal space input from area V1 impairs but does not eliminate activity
(555). Lesions of area V6A in monkeys cause specific defi- in MT, and in this situation even direction selectivity of the
cits in reaching, wrist orientation, and grasping and a reluc- neurons is retained (although it is more crude than normal)
tance to move (556). Disruption of V6A or nearby areas (549,563). Activity in MT is abolished when both the SC
may explain the inability of patients with Balint syndrome (with input via the pulvinar) and area V1 are damaged (563).
to accurately reach out to objects that they can see and de- Positron emission tomography (PET) and functional MRI
scribe (557) (see Chapter 13). have demonstrated the presumptive location of area V5 in
humans by having subjects view an array of moving stimuli
CORTICAL AREA V5 (564–567). The location of area V5 varies by as much as
27 mm in the left hemisphere and 18 mm in the right but
Area V5 is also referred to as MT because of its location is consistently located ventrolaterally, just posterior to the
in the caudal third of the middle temporal gyrus of the owl junction of the ascending limb of the inferior temporal sulcus
monkey (558). Area 5 is the smallest of the named visual and the lateral occipital sulcus. Area V5 has a columnar
areas. V5 in humans is an oval area, located 5–6 cm anterior organization for direction specificity similar to area V1
and dorsal to the foveal V1–V2 border, at the junction of (568).
Brodmann areas 19 and 37 (Fig. 1.73). Area V5 receives Ninety percent of neurons within area V5 are direction-
direct but relatively sparse inputs from striate cortex (specifi- selective (526,569,570). Although this property is common
cally from layers 4B and 6 to layers 3, 4, and 6) among complex cells of the magnocellular pathway in area
data in humans (discussed later). PET scanning, however,

has shown that many areas in the human brain, including
bilateral foci at the border between Brodmann areas 19 and
37, a V1/V2 focus, and foci in the cuneus, cerebellum, and
cortical vestibular areas, are also involved with visual mo-
tion perception (573). In fact, motion perception can occur
even with disruption of the magnocellular system (i.e., the
retinal outflow pathway concerned with motion detection)
at the level of the dLGN (574).
Nonetheless, it is generally considered that the magnocel-
lular pathway is the primary conduit for motion processing.
The heavily myelinated outflow from area V1 to area V5
within the dorsal stream delivers very rapid visual input to
the parietal lobe, even before an object is precisely fixated.
This extraordinary response time may be important for gen-
erating visual attention to a visual stimulus (575). The clini-
cal relevance of area MT neurons is revealed by the ex-
tremely close match between the response rates of
directionally selective neurons in MT to the psychophysical
response rates of monkeys when they discriminate the direc-
tion of moving visual stimuli (576). This direction response
property is fairly modest for most individual area MT neu-
rons, but it seems likely that information from many neurons
is pooled, given that so many of the neurons respond simi-
larly. Area MST lies close to area V5, from which it receives
significant input. Area MST contains neurons that behave
indistinguishably from those in area V5 (577), but also may
specialize in processing ‘‘motion in depth,’’ which permits
an estimation of one’s direction of movement within an envi-
ronment (578). Lesions of area V1 produce the same effect
Figure 1.82. Functional magnetic resonance imaging (fMRI) representa-
upon areas MT and MST (579). In one human, blindness
tions of the proximity of various sensory and motor cortices in the human caused by a (subtotal) lesion of the primary visual cortex
brain. The visual cortex and other functional modalities are mapped onto was associated with functional MRI activity within the blind
a surface-based atlas of human cerebral cortex. The atlas was generated visual field that was confined to the dorsal pathway, which
from a high-resolution structural MRI volume provided by A. Toga (Case reveals the presence of an alternative path to the dorsal
Human.colin) using SureFit and Caret software. A, Modality assignments stream from areas other than area V1 (580).
were based on (A) stereotactic mapping of fMRI volume data on the atlas Functional MRI studies have revealed significant insights
surface from the studies of Corbetta et al. (1998), Lewis and DeYoe (2000), into the motion processing streams in humans. For instance,
and Lewis et al. (2001); (B) stereotactic projection of published Talairach areas V1 and V2 respond well to all motion stimuli. Areas
coordinates of activation focus centers (Ishai et al. [1999]; Kanwisher et
3d and 3v show much greater responsiveness for second-
al. [1997]; Van Essen and Drury [1997]); and (C) manually transposed
boundaries related to local geographic and/or functional landmarks from
order (contrast or flicker modulation, with luminance held
surface maps published by Burton and Sinclair (2000), Press et al. (2001), constant) versus first-order (spatiotemporal changes in lumi-
and Tootel and Hadjikhani (2001). (From Van Essen DC. Organization of nance) motion than is found in areas V1 or V2. Area V5
visual areas in macaque and human cerebral cortex. In: Chalupa LM, Wer- participates in both types of motion processing (540). An-
ner JS, eds. The Visual Neurosciences. Cambridge, MA, MIT Press, 2004.) other newly recognized area for motion processing is known
as area V3B (referred to previously as KO, for kinetic occip-
ital).
V1 and in some cells in areas V2, V3, V3A, and V4 Damage to area V5 in monkeys produces deficits for ocu-
(526,571), area V5 appears to be the primary cortical region lar pursuit of moving targets and for adjusting the amplitude
for processing the direction of stimulus movement. The input of a saccadic eye movement in response to target motion,
to MT from area V1 is directionally selective and appears although saccades to stationary targets are unaffected (581).
to convey motion of individual regions within a visual scene The threshold for direction discrimination also increases
rather than motion of the entire scene (i.e., ‘‘global motion’’) (582). The significance of area V5 for motion detection in
(572). Area MT may perform a higher-order analysis of mo- humans has been revealed with transcranial magnetic stimu-
tion by extracting patterns of movement from the specific lation, which was to reversibly inactivate areas V1 and V5
data that it receives from each pixel of visual space. Approxi- (583). The speed of a moving object had been reported to
mately one third of MT neurons are directionally selective influence the patterns of induced cortical activity in that rela-
for patterns of movement. To a lesser extent, area V3 may tively fast visual motion would activate area V5 before area
perform similar tasks, as is suggested by the functional MRI V1 (584), although this finding was not corroborated by a
more recent study in monkeys with unilateral area V1 lesions scene that encompass the object of regard. The visual inte-
(579). gration to determine ‘‘form’’ seems to occur within the ven-
The ability of humans to detect visual motion even in areas tral visual pathway, which derives from input primarily from
rendered ‘‘blind’’ by a lesion of area V1 (i.e., blindsight) is areas V1 and V2. An intermediate step along the ventral
consistent with the presence of parallel pathways for motion pathway occurs at area V4, which in humans is located in
detection (585–591). The availability of more than one path- the lingual and fusiform gyri, with a caudal region that ex-
way for motion detection makes it challenging to find pa- tends into area 18 of Brodmann (602) (Figs. 1.73, 1.75, and
tients with complete blindness to moving visual stimuli (i.e., 1.80). Area V4 receives projections from the CO-rich thin
cerebral akinetopsia) (592). Extensive bilateral lesions of the stripes and the CO-poor interstripe regions of V2 (537). Area
dorsolateral visual association cortices that spare areas area V4 contains a complete topographic representation of the
V1 can produce severe deficits in motion detection (593), contralateral visual field (542,603). The receptive fields of
although by more sophisticated testing such a patient may V4 are larger than those of V3 (542), which are in turn larger
be shown to retain the ability to perceive global coherent than the more proximal visual cortices. The major projection
motion and discriminate motion direction, although with less of V4 is to IT (i.e., inferotemporal cortex, discussed later),
sensitivity than normal when there is background noise in the but there is also a significant projection to the posterior pari-
visual scene (594). These motion deficits, however, almost etal cortex.
never occur in pure isolation. Deficits in speed and motion Area V4 neurons respond primarily to the shape, color,
direction discrimination have also been reported in humans and texture of a visual stimulus (Fig. 1.83). Area V4 neurons
with more restricted lesions involving the lateral occipital receive input from both P- and M-retinofugal pathways
areas, possibly more specifically at area V5 (595,596). (604), perhaps via a subset of area V1 neurons that receive
There is evidence for two dorsal pathways for motion convergent input from these pathways (431). Inactivation of
processing: a medial and lateral pathway. The dorsomedial either the P or M pathway moderately but equivalently re-
pathway includes area V6; the dorsolateral pathway includes duces the responsiveness of V4 neurons (604). A prevalence
area MT as well as the parietal-insular vestibular cortex. of area V4 neurons show preferences for objects that are
This distinction has been demonstrated by functional MRI relatively near (605). Few V4 neurons are orientation- or
studies in humans in which area V6 is activated mostly by direction-sensitive (526).
wide-field coherent motion, while area MT is activated pri- In monkeys, half of area V4 neurons have color-opponent
marily by movement within a limited area of the visual field properties (570,602,606–608). Cerebral dyschromatopsia
or by differential movement in different areas of the visual may occur in humans following damage to an area of visual
field (597). These two pathways may provide information cortex anterior and inferior to the primary visual cortex,
about self-motion through the dorsomedial pathway and ob- which has been presumed to be the homolog of area V4 in
ject motion through the dorsolateral pathway (598). This monkeys (609) (see Chapter 13). Bilateral removal of area
distinction is reminiscent of the newly described RGC type V4 in monkeys, however, does not disrupt the ability to
known as the object motion cell, which responds differently discriminate between rows of colored or gray stimuli. Al-
depending on whether object motion is similar to or different though in this experimental paradigm there are deficiencies
from the background (discussed previously) (84). in color performance, the color impairment is no more severe
Clinical manifestations related to these two dorsal path- than for discrimination of gray tones (610). This seeming
ways have been defined. Humans with lesions of area V6 inconsistency is probably explained by the fact that human
experience difficulty with postural adjustments and walking diseases that affect area V4 (mainly strokes and tumors)
(599), possibly because V6 may be important in determining produce less specific cortical injury and tend to include un-
the direction and speed of one’s own body motion through derlying white matter. The human case with perhaps the
an environment. In distinction, perception of ‘‘biologic mo- most selective, bilateral lesions of area V4 had severe color
tion’’ (i.e., perception of motion created by lights to the blindness and pattern perception loss with prosopagnosia,
major joints and head of a human who is walking but whose although there was normal luminance detection thresholds,
form is otherwise not evident) has been shown by functional spatial contrast sensitivity, stereopsis, motion processing,
MRI to activate both dorsal and ventral streams of visual and flicker perception (611).
outflow. Perception of biologic motion may depend upon Area V4 neurons code shape in reference to the boundary
information processing in both dorsal pathways, the conflu- features of objects. Their responses vary with respect to the
ence of which is at the superior temporal sulcus (STS) (600). location and angulation of contour features within the image
Patients with bilateral lesions of the ventral visual pathways of the object. Recent experimentation has provided a com-
can see and describe motion, which distinguishes them from pelling insight into how an image might be created. The
patients with cerebral akinetopsia, but they have difficulty shape of an object can be predicted by assimilating the peaks
recognizing moving (even very familiar) faces, persons, or of activity across a population of area V4 neurons, each of
objects. These patients report no difficulty with stationary which responds maximally to specific structural elements of
visual stimuli (601). the object (612). These results suggest that the brain uses a
‘‘parts-based’’ representation method, rather than the alter-
CORTICAL AREA V4 native notion of a ‘‘holistic’’ representation, where neurons
Visual detection of the shape of an object requires the would be most responsive to the form of the entire object.
integration of neuronal responses from pixels of the visual Area V4 neurons are not only tuned to one particular geome-
Figure 1.83. Functional magnetic resonance imaging (fMRI)

maps that reveal activation of specific cortical regions in re-
sponse to a variety of visual stimuli in humans. The images are
‘‘inflated’’ (i.e., the cortical sulci are eliminated by digitally
expanding the sulci to present a flattened cortical surface). The
large cortical map (left) is a flattened, lateral and ventral view
of the upper and lower visual cortical pathways of the right
hemisphere. The two smaller cortical maps on the right are the
inflated (but not flattened) views of the lateral (top right) and
ventral (bottom right) posterior right hemisphere that were com-
bined to form the larger flattened map. Certain cortical regions
are more strongly activated by either images of objects, faces,
or places. (From Grill-Spector K. The neural basis of object
perception. Curr Opin Neurobiol 2003;13⬊159–166.)
try but rather respond to a wide variety of shapes, although ously learned). Area V4, therefore, may play a generic role
their strongest response is for a particular boundary shape in visual discrimination tasks including color, pattern, lumi-
located at a specific position within the object (613). In addi- nance, texture, rate of movement, and size when many rela-
tion to this presumed capability to extract object shape, area tively similar objects are viewed. Chronic lesions of area
V4 neurons may also convey information about the location V4 in monkeys, however, produce relatively little or no defi-
of the object in visual field space. cit for motion-, color-, or luminance-defined contours, al-
Area V4 may also be important for responding to targets though there are significant deficits for contours defined by
within a field of similar stimuli that have relatively low con- texture and for illusory contours. Perhaps area V4 plays only
trast, smaller size, or slower motion (614). Preliminary infer- a minor role in color and luminance perception and motion
ences about the role of area V4 for these types of functional detection, or perhaps there is sufficient plasticity following
tasks come from single cell recordings that have shown in- a chronic injury to area V4 that these visual functions can
creased activity of V4 neurons when unique features of stim- be subserved in other ways (618).
ulus embedded within other similar stimuli were being dis- The effect of disrupting the major retinocalcarine path-
criminated (615,616). The evidence of impaired clinical ways differs for various extrastriate cortices. For area V4,
function comes from ablation studies in monkeys. In rhesus inactivation of either the parvocellular or magnocellular lay-
monkeys, V4 ablation creates significant visual deficits ers causes a moderate reduction of visual responses (604).
when multiple stimuli are presented but permits normal per- For area V5, inactivation of the magnocellular area of the
formance when the same stimuli are presented individually dLGN produces greatly reduced responses, whereas few
(617). In macaque monkeys, ablation of V4 produces se- neurons are affected by parvocellular blockade (619). Pre-
verely disrupted form and shape discrimination, mildly re- sumably area V4, but not V5, receives strong input from
duced luminance and red-green contrast sensitivity, and an both the magnocellular and parvocellular subdivisions of the
inability to learn hue and luminance matching (although the dLGN.
monkeys retained the matching skills if they had been previ- Perceptual learning has been shown to modify the re-
Figure 1.84. Demonstration from the inferotemporal cortex of a macaque monkey that a spatially complex visual stimulus
(like the fire extinguisher shown in e) activates combinations of discontinuous, cellular modules. Each module responds to
specific visual features of the stimulus, and in combination, the perception of the object is created. This experiment used an
intrinsic signal imaging technique to detect local modulation of light absorption changes in area TE. a, Surface view of the
exposed portion of dorsal area TE. b–d, Active regions, elicited by the visual stimulus shown in e, in which the reflection
change elicited by the stimulus was significantly greater than that elicited by the control. f, A filtered differential image showing
local increase in absorption. g, Extracted active spots outlined by connecting pixels with half the peak absorption value. h,
Active spots outlined by different thresholds, one third, one half, and two thirds of the peak absorption value. Scale bars ⳱
1.0 mm (a–d, f–h); 10 degrees (e). These results argue against the concept that object recognition results from activation of
a combination of cells specific for each type of stimulus. (From Tsunoda K et al. Complex objects are represented in macaque
inferotemporal cortex by the combination of feature columns. Nature Neurosci 2001;4:832–838.)
sponse properties of neurons in area V4. In macaque mon- tion, visual stimuli elicit responses within area TE from sev-
keys, the process of learning to discriminate the orientation eral clusters of neurons that are not physically contiguous.
of a visual stimulus has been correlated with the develop- Recognition of an object may derive from activation of spe-
ment of stronger and more narrowly tuned responses of area cific combinations of cortical columns, each of which re-
V4 neurons. This is the first demonstration that training to sponds to different spatial aspects of the object shape; they
perform a complex task modifies neuronal responses related tend to respond best to less spatially complicated objects
to that task (620). (621) (Fig. 1.84). The complexity of the object shape may
be derived by assessing the combinations of activated and
AREA TE nonactivated neuronal regions. For instance, some objects
The end of the ventral pathway for form recognition oc- with relatively simple geometries activate a larger number
curs at the anterior region of the inferotemporal cortex, area of cortical columns within area TE than some more complex
TE, which is the last area that is exclusively visual along visual stimuli. There are other less common neurons in area
this pathway. Area TE may play a role in the visual identifi- TE that respond more specifically to objects of a particular
cation of complex objects. Unlike almost all other visual shape or object class. For instance, some area TE cells are
cortical areas that maintain a precise retinotopic organiza- especially well tuned for faces or hands, while others are
Figure 1.85. The location of area V6 in the macaque

monkey brain, seen on horizontal section. Area V6 (dark-
ened region) is located on the medial aspect of the visual
cortex, somewhat remote from the other extrastriate
areas important for visual function. (From Zeki S. A
Vision of the Brain. Cambridge, MA, Blackwell Scien-
tific Publishers, 1993⬊105.)
tuned for more general images of the human body (622,623) CORTICAL AREA V6
(Fig. 1.83). Generally, however, object recognition in area Area V6, which is located medially in the parietal cortex
TE probably relates to the patterns of activity of multiple adjacent to area V3A (Fig. 1.85), is poorly understood (see
columns of cells, rather than the responses of individual the previous section on Area V3 for discussion of contro-
cells. Recognition of complex object shape may be facili- versy in naming this and related areas). Area V6 receives
tated in area TE by a substantial population of neurons input from V2, has large receptive fields, and is thought to
(roughly one third of the total number) that selectively re- function in the mapping of relative spatial relationships
spond to three-dimensional object shapes (624). Area TE (626). Adjacent cells within area V6 respond to stimuli that
has strong connections to the medial temporal region, which are located in a similar area of the visual field, although V6
may provide a substrate to form visual memories (625). does not have a conventional retinotopic map.
OTHER CEREBRAL AREAS CONTRIBUTING TO VISUAL PERCEPTION

Many areas of the brain other than those listed in Table Neuronal responses to visual stimuli are typically en-
1.6 contribute to the analysis of vision. Neurons in the SC hanced by visual attention to the object. Effects of attention
are special in their ability to respond to stimuli from different may be mediated partly by widespread influences on neu-
sensory inputs (627). These multisensory neurons have over- ronal activity. For instance, activation of the frontal eye
lapping receptive fields for input from, for instance, simul- fields increases the gain of neuronal responses in area V4
taneous visual and auditory input. The SC in the monkey (634). Activation of the occipital cortex results in distribu-
contains cells in its superficial layers that fire in response tion of visual information widely over temporal, parietal,
to visual stimulation and may play a role in localization of and frontal lobes. Excitatory activity can spread from the
targets in space (628–632). The SC contains fixation, burst, occipital cortex to the frontal lobes in just over 20 msec
and build-up cells. Monkeys can quickly learn to make accu- (635).
rate saccades into a hemifield made ‘‘blind’’ by ablation of Extensive interconnections exist among cortical areas and
area V1, but lose the ability to do so if their SC is then from cortical areas to deeper structures. In humans there
destroyed (590). The SC projects to pulvinar, which projects are 25 neocortical areas that predominantly or exclusively
to area MT and to all other visual cortical regions (633) (Fig. subserve vision, and 7 other areas have some visual function
1.86). Isolated SC lesions in humans do not cause lasting (636). All corticocortical connections among visual areas
visual deficits. appear to be reciprocal and are linked retinotopically (637).
Figure 1.86. Main efferent and afferent connections of the primate pulvinar. PM, medial pulvinar; PL, lateral pulvinar; PI,
inferior pulvinar; PO, oral (i.e., anterior) pulvinar; SC, superior colliculus. (From Casanova C. The visual functions of the
pulvinar. In: Chalupa LM, Werner JS, eds. The Visual Neurosciences. Cambridge, MA, MIT Press, 2004⬊594.)
Cortical feedback to deeper centers is essential for their 32. Vaney DI. Retinal neurons: cell types and coupled networks. Prog Brain Res
2002;136:239–254.
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11:431–436.
form properly, which does not occur until some months after 35. Stryer L. The molecules of visual excitation. Sci Am 1987;257:42–50.
birth, at least in monkeys (627). The extensive cortical feed- 36. Koenekoop RK. The gene for Stargardt disease, ABCA4, is a major retinal gene:
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37. Baylor DA. Photoreceptor signals and vision. Proctor lecture. Invest Ophthalmol
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CHAPTER 2
Principles and Techniques of the
Examination of the Visual
Sensory System
Michael Wall and Chris A. Johnson
HISTORY PSYCHOPHYSICAL TESTS

CLINICAL EXAMINATION Visual Acuity
Refraction and Visual Acuity Contrast Sensitivity
Stereoacuity Perimetry and Visual Field Testing
Color Vision and Brightness Comparison Color Vision
Visual Field Examination Dark Adaptation
Photo Stress Test ELECTROPHYSIOLOGIC TESTS
Pulfrich Phenomenon Electroretinogram (ERG)
Pupillary Examination Electro-Oculogram (EOG)
Fundus Examination Other Retinal Potentials
Other Procedures Visual-Evoked Potential
Despite advances in neurodiagnostic imaging and other Examples of the various concepts and test procedures are
techniques, examination of the afferent visual sensory sys- presented, where appropriate. Electrophysiologic tests (i.e.,
tem is still the core of the neuro-ophthalmologic examina- electroretinography, electrooculography, visual-evoked po-
tion. This chapter describes the most common subjective and tentials) that may be helpful in assessing the afferent system
objective tests used in the afferent visual system examina- are also described.
tion. In addition, recent developments in perimetry, clinical Evaluation of the afferent system begins with a thorough
psychophysics, and electrophysiology are discussed. medical history, followed by an ophthalmologic examina-
We begin with an overview of the basic neuro-ophthalmo- tion, evaluation of selected psychophysical visual functions
logic examination of the afferent visual sensory system. (acuity, stereoacuity, color vision, visual fields, contrast sen-
Next, key visual functions (visual acuity, contrast sensitivity, sitivity, etc.) and relevant ancillary test procedures. Once
perimetry, new visual field tests, color vision, and dark adap- the examiner has performed these functions, it should be
tation) associated with the afferent system are discussed possible to provide a diagnosis, or at least a differential diag-
along with their physiologic and psychophysical principles. nosis, for the etiology of an afferent visual system deficit.
HISTORY
An examination of patients experiencing dysfunction of altitudinal, or hemianopic, and if the onset of the loss is
the afferent visual system begins with a history of the details gradual, sudden, or intermittent along with any associated
of the visual loss. This thorough history is often the most symptoms.
important part of the evaluation, because it determines the It is also important to ask about photopsias (visual phe-
initial strategy for differential diagnostic evaluation and ex- nomena such as flashing black squares, flashes of lights, or
amination. It is essential to establish if the visual loss is showers of sparks), distortions in vision (metamorphopsia
monocular or binocular, if its location is central, peripheral, or micropsia), and positive scotomas. A positive scotoma is
83
one that is seen by the patient, like the purple spot that is in patients with maculopathies, whereas photopsias may be
often seen after a flash bulb goes off, whereas a negative present in patients with retinal disease, optic nerve dysfunc-
scotoma refers to a non-seeing area of the visual field. Meta- tion, or cerebral dysfunction from migraine and other vascu-
morphopsia, micropsia, and positive scotomas often occur lar disorders.
CLINICAL EXAMINATION
Clinical evaluation of the afferent visual system for each aminer can frequently make a determination as to the ana-
eye incorporates the items in Table 2.1, which can be per- tomic site of the afferent system abnormality and the most
formed in the office. This section presents a brief discussion probable cause or causes.
of each component, with a more detailed discussion of sev-
eral visual function tests (visual acuity, contrast sensitivity, REFRACTION AND VISUAL ACUITY
color vision, perimetry, and visual field testing) and ancillary A thorough refraction is an essential part of all clinical
procedures (dark adaptation and clinical electrophysiology) neuro-ophthalmologic examinations. Identification of a pre-
presented later in this chapter. Other aspects of the clinical viously undetermined refractive error, corneal pathology, or
examination are covered in subsequent chapters of this book. a subtle lens problem can prevent initiation of an expensive
The first goal for the neuro-ophthalmology examination and time-consuming evaluation. It is essential to have the
is to determine if the visual loss is caused by a disorder best refraction possible when measuring visual acuity to dis-
anterior to the retina (ocular media), in the retina, in the optic tinguish whether visual acuity loss is caused by optical fac-
nerve, in the optic chiasm, in the retrochiasmal pathways, or tors or damage to neural elements in the visual system. Re-
is nonorganic (i.e., hysteria or malingering). The second goal fractive problems can not only cause loss of visual acuity
is to establish a differential and working diagnosis. By exam- but may also produce symptoms such as monocular diplopia.
ining various parameters of afferent visual function, the ex- A cycloplegic refraction is important, not only to obtain the
correct refraction, but also to observe the red reflex through
the retinoscope as a means of identifying corneal irregulari-
Table 2.1
ties and lens opacities that may not be as apparent with a
Components of the Clinical Neuro-Ophthalmologic Examination slit lamp examination. Visual acuity measurements obtained
with the patient viewing through a pinhole can also help
I. REFRACTION identify problems with the optics of the eye. In many in-
Retinoscopy stances, it is useful to dilate the patient in conjunction with
Keratometry the use of a pinhole to maximize the likelihood of finding
Manifest refraction a clear pinhole region around an opacity. Improvement of
Cycloplegic refraction visual acuity with the use of a pinhole indicates that the
II. VISUAL FUNCTION cause of the visual loss is optical in nature.
Visual acuity (distance and near)
Small degrees of visual acuity loss can be due to large
Stereoacuity
Color vision, color comparison
losses in neuronal function. Frisén and Frisén (1) estimated
Brightness comparison that 20/20 visual acuity requires no more than 44% of the
Photo stress test normal quantity of foveolar, neuro-retinal channels. Since
Pulfrich phenomenon 20/15 acuity is the population norm up to age 50, asymmetry
Visual fields of best corrected visual acuity of 20/20 to 20/15 can indicate
Confrontation fields substantial damage to the prechiasmal afferent system.
Amsler grid The Potential Acuity Meter (PAM), which utilizes the
Tangent screen pinhole principle, can be helpful (2). Keratoconus and sur-
Manual kinetic perimetry (Goldmann perimeter) face irregularities of the cornea can be diagnosed by im-
Automated static perimetry
provement in visual acuity with the use of a hard contact
III. PUPILS
Size
lens. A Placido’s disk, keratometry readings, or corneal to-
Direct and consensual response pography maps can also help to identify corneal surface ir-
Accommodation response regularities and associated problems.
Afferent pupillary defect Subtle central vision loss can often be identified by the
IV. CRANIAL NERVES I, III, IV, V, VI, VII, VIII use of low contrast visual acuity charts or contrast sensitivity
V. EXOPHTHALMOMETRY measurements. In addition, low luminance visual acuity can
VI. EXTERNAL AND ANTERIOR SEGMENT be compared with similar measures made under standard
External examination lighting conditions. von Noorden and Burian (3) and Glaser
Slit lamp examination and Goodwin (4) reported that placing a 2.0 log unit neutral
Applanation tonometry density filter before the eye (i.e., producing a 100-fold reduc-
VII. FUNDUS
tion in the luminance of the visual acuity chart) causes a
Optic nerve head and nerve fiber layer appearance
Macula and retinal vessels
normal eye to be reduced from 20/20 to 20/40 visual acuity
Peripheral retina (a factor of 2 or 0.3 logMAR). Patients with optic nerve
conduction abnormalities, such as optic neuritis or multiple
PRINCIPLES AND TECHNIQUES OF THE EXAMINATION OF THE VISUAL SENSORY SYSTEM 85
sclerosis with optic atrophy, have a disproportionately that is possible. Near visual acuity measurements can be
greater reduction in visual acuity (e.g., from 20/30 down to performed with any of the standard near acuity cards, which
20/200) when the neutral density filter is placed before the are held at 13–14 inches from the eyes with the patient wear-
affected eye. Other anomalies such as amblyopia do not ing an appropriate near refractive correction. In patients with
demonstrate this disproportionate drop in visual acuity with normal visual function, there is little or no difference be-
the neutral density filter. tween distance and near visual acuity. A discrepancy be-
Another low-contrast visual acuity test that also uses low tween near and distance visual acuity suggests several possi-
background luminance levels is the SKILL (Smith-Ket- ble etiologies. Patients with cataracts often perform better
tlewell Institute Low Luminance) test, which has been used on near acuity than distance acuity. Young patients with
to evaluate patients with optic neuritis, children with ambly- head trauma may complain of reading problems from loss of
opia, and the reading abilities of younger and older individu- accommodation, resulting in poorer near acuity than distance
als (5–9). acuity. Patients with nonorganic loss of vision may not un-
Measuring visual acuity in children requires skill, pa- derstand the relationship between near and distance acuity
tience, and an enthusiastic attitude. By creating a friendly, and may provide inconsistent responses with the two mea-
relaxed environment for the child in which vision testing is surements (11). One must be careful, however, to ensure
presented as a game, the chances of success will be greater. that optical factors (e.g., cataract, accommodation loss) are
A system of positive rewards, ranging from a verbal ‘‘Hoo- not responsible for the differences.
ray!’’ or ‘‘That’s Terrific!’’ to the use of mechanical animal
toys and projected cartoons, is essential (Fig. 2.1). A video STEREOACUITY
demonstration of many techniques for evaluating children
Stereoacuity requires good visual acuity in both eyes and
and infants is available from the American Academy of Oph-
normal cortical development. As such, stereoacuity can be
thalmology (10).
helpful in establishing if a patient has visual loss from con-
During any neuro-ophthalmologic examination, it is es-
genital amblyopia or monofixation syndrome, as well as ver-
sential to measure not only distance visual acuity but also
ifying the extent of any monocular visual acuity loss. Using
near visual acuity. In some instances (e.g., an in-hospital
the Titmus Stereo Tester, Donzis and coworkers (12) mea-
consultation on a patient who is unable to come to the exami-
sured stereoacuity in 30 normal observers with good binocu-
nation room), near visual acuity is the only measurement
lar function and visual acuity. Stereoacuity was 40 seconds
of arc or better when both eyes had 20/20 visual acuity.
They then placed plus lenses before one eye and published
a nomogram that relates visual acuity to stereoacuity. This
provides a useful reference for cross-checking mild losses
of monocular visual acuity, especially when nonorganic vis-
ual loss is suspected (11) (see Chapter 27). Random dot
stereogram tests can also be helpful in identifying patients
with good binocular visual acuity.
COLOR VISION AND BRIGHTNESS COMPARISON

Color vision testing, using pseudoisochromatic plates, the
Farnsworth 100 Hue and D-15 tests, or the Lanthony 15
Desaturated D-15 panel can be helpful in detecting subtle
signs of optic neuropathy or macular disease. While it has
been proposed that acquired color vision loss respects color
vision axes, more often than not, this does not hold. On the
other hand, congenital loss respects these axes with red/
green deficits occurring in approximately 8% of the male
population and in 0.4% of females (13) (Table 2.2). Congeni-
tal blue/yellow deficits are much less common, occurring
in 0.005% of the population. Nevertheless, both types of
congenital color vision deficits need to be distinguished from
acquired color vision loss. A comparison of color vision
between the two eyes can be helpful, because both the type
and severity of congenital color vision deficits are the same
for each eye, a situation that is often not true for acquired
color vision loss. In addition, congenital color vision deficits
are stable over time and are almost always red/green deficits.
Figure 2.1. Wall-mounted mechanical animals and video projection sys- A comparison of the saturation of colors, between eyes
tem for providing fixation targets and ‘‘rewards’’ for pediatric patients and across the vertical midline, can sometimes identify sub-
during the examination. tle optic nerve dysfunction or chiasmal lesions. The same is
Table 2.2 30⬚ radius of the visual field. A 1-meter tangent screen can
Approximate Incidence of Congenital Color Vision Deficiencies be placed on the wall of an examining room for easy use.
Type Incidence (%)
It can provide more detailed, quantitative visual field infor-
mation than that afforded by confrontation field testing. In
Red-green (females) 0.4% the hands of a skilled perimetrist, the tangent screen exami-
Red-green (males) 8% nation may provide information that is equal to or better
Anomalous trichromacy than that obtained with automated perimetric test procedures.
Protanomalous (red) 1% Sophisticated, quantitative evaluations can be achieved
Deuteranomalous (green) 5% with kinetic testing on the Goldmann perimeter, which pro-
Dichromacy
vides greater flexibility through close interaction between
Protanopia (red) 1%
Deuteranopia 1%
the patient and the perimetrist to obtain the most accurate
Blue-yellow (tritan) 0.005% responses from the patient. In children, the elderly, or pa-
Monochromacy (achromats) 0.003% tients with dementia, this may be the only form of quantita-
tive visual field test that can be performed. The Goldmann
Adapted from Pokomy et al., 1979, Table 7.1. perimeter also makes it possible to evaluate efficiently the
far peripheral visual field beyond a radius of 30⬚. In some
instances, this information can be useful in determining the
extent of visual field loss and in establishing a differential
true for brightness comparisons between the two eyes and
diagnosis. The major disadvantages of this form of perimetry
across the vertical midline. Glaser and Goodwin (4) empha-
include the lack of standards and normative values and the
sized the use of subjective color and brightness comparisons
high dependence on the skills of the perimetrist.
in the assessment of presumed unilateral or asymmetric optic
Automated perimetry is the most popular form of visual
neuropathy. Although such tests can be used to corroborate
field testing. The major advantages of automated perimetry
other evidence of optic neuropathy, subjective brightness
include standardized test procedures, age-related normal
differences between the two eyes as an isolated finding with
population values, and statistical analysis procedures for
an otherwise normal examination should be treated with cau-
evaluating the data. Its major disadvantages include long
tion.
testing times, high variability in areas of visual loss, inflexi-
VISUAL FIELD EXAMINATION bility, and learning and fatigue effects.
Examination of the visual field is one of the fundamental PHOTO STRESS TEST
portions of the afferent system evaluation. A variety of visual
field test procedures can be employed, including confronta- The differentiation between unilateral retinal disease and
tion fields, the Amsler grid, the tangent (Bjerrum) screen, retrobulbar optic neuropathy may be aided using the photo
manual kinetic testing using a Goldmann perimeter, and au- stress recovery test described by Glaser et al. (15). This test
tomated static perimetry. When evaluating a patient with an is based on the principle that visual pigments bleach when
afferent system deficit, it is important to keep in mind the exposed to an intense light source, resulting in a transient
advantages and disadvantages of the various procedures. state of sensitivity loss and reduced central visual acuity.
Confrontation visual fields should be part of every afferent Recovery of retinal sensitivity is dependent upon regenera-
system examination. Although testing by confrontation may tion of visual pigments, which is determined by the anatomic
lack the sophistication of modern techniques, it is the most and physiologic apposition of the photoreceptors and retinal
flexible form of visual field testing, can be performed almost pigment epithelium. It is independent of neural mechanisms
anywhere, and may be the only form of visual field testing (16). Diseases that produce visual loss by damaging the pho-
that is possible. In skilled hands, confrontation testing can toreceptors or the adjacent retinal pigment epithelium cause
provide information equivalent to that obtained with more a lag in regeneration of pigment, resulting in a delay in visual
extensive forms of visual field testing, although only 1/3 of recovery following light stress.
optic nerve-related defects are detected by this method (14). The photo stress test is performed by determining best-
The Amsler grid can be useful in identifying patients with corrected visual acuity, shielding one eye, and then asking
retinal pathology. Amsler grid testing is performed at 30 cm, the patient to look directly at a bright focal light held 2 to
where each 5-mm square subtends 1⬚ of visual angle (total 3 cm from the eye for about 10 seconds. The time needed
extent is 20⬚ diameter, or 10⬚ radius). The patient is shown to return to within one line of best-corrected visual acuity
the Amsler grid with a black background and is told to look level is called the photo stress recovery time (PSRT). In the
at the center spot and report if there is absence or distortion study by Glaser et al. (15), PSRT in 179 normal eyes aver-
of the central fixation spot, if any portions of the Amsler aged 27 seconds with a standard deviation of 11 seconds.
grid are missing, and if any of the lines are wavy or bent Ninety-nine percent of the normal eyes had a PSRT of 50
(metamorphopsia). This type of image distortion is usually seconds or less. In 63 eyes with macular disease, PSRT was
indicative of macular disease (Fig. 2.2A), whereas inability significantly prolonged, even when the retina appeared to
to see the central fixation point may indicate a central sco- be relatively normal. PSRT was relatively normal in 20 eyes
toma (Fig. 2.2B). with optic neuropathies. The photo stress test is especially
Tangent screen testing permits evaluation of the central useful in the differential diagnosis of subtle macular disease
Figure 2.2. Amsler grid defects. A, Metamorphopsia and paracentral scotomas in a patient with a maculopathy. B, A small
central scotoma in a patient with optic neuritis.
from subtle optic neuropathies. It may also be abnormal with mobility over uneven terrain, or with recreational activities
severe carotid stenosis and borderline ocular perfusion. such as tennis, volleyball, and baseball. The Pulfrich phe-
nomenon has a similar clinical implication as a relative affer-
PULFRICH PHENOMENON ent pupillary defect.
In 1922, Pulfrich reported that when a small target oscil- PUPILLARY EXAMINATION
lating in a frontal plane is viewed binocularly with one eye
covered with a filter to reduce light intensity, the target ap- Examination of the pupils is an essential part of the affer-
pears to move in an elliptic path, rather than a to-and-fro ent system evaluation. Pupil size for each eye should be
path (17). When the filter is placed over the right eye, the noted, as should the magnitude and latency of the direct
rotation appears counterclockwise; if it is placed over the and consensual responses to light and near stimulation. The
left eye, the rotation appears clockwise. The explanation for presence of a relative afferent pupil defect (RAPD) is the
this stereo phenomenon is that the covered eye is more hallmark of a unilateral afferent sensory abnormality or bilat-
weakly stimulated than the uncovered eye, resulting in a eral asymmetric visual loss (24–26). The etiology is usually
delay in the transmission of visual signals to the striate cor- an optic neuropathy, but other abnormalities such as a central
tex. This disparity in latency between eyes results in a differ- retinal artery occlusion, retinal detachment, or a large macu-
ence in the apparent position of the target in the two eyes, lar scar may be responsible (24–27). In the case of a retrobul-
thereby producing a retinal disparity cue underlying the ste- bar optic neuropathy with a relatively normal-appearing fun-
reoscopic effect. The magnitude of the effect is determined dus examination, the RAPD may be the only objective sign
by the velocity of the target, the difference in retinal illumi- of anterior visual pathway dysfunction. Cataracts, refractive
nation between the two eyes, the level of retinal illumination, errors, and nonorganic visual loss do not cause a RAPD. A
and the distance of the observer from the target (18). patient with a dense strabismic or anisometropic amblyopia
Because optic nerve damage results in delayed transmis- (visual acuity of 20/200 or worse) may demonstrate a mild
sion of impulses to the occipital cortex, patients with unilat- RAPD, but the clinical history will be of a long-standing
eral or markedly asymmetric optic neuropathy sometimes visual deficit rather than a progressive or sudden onset of
observe the Pulfrich phenomenon under natural viewing visual loss (28,29). Fineberg and Thompson (30) recom-
conditions without a filter in front of one eye (19–23). This mended quantifying the RAPD by placing graded neutral
can present difficulties for the patient driving an automobile, density filters over the normal or lesser affected eye until
the RAPD can no longer be appreciated. The amount of should perform a dilated fundus examination using both a
neutral density filter needed is proportional to the amount handheld direct ophthalmoscope and a 20-diopter lens in
of visual field loss present. conjunction with an indirect ophthalmoscope, using a low
level of illumination for both assessments. A lid speculum
FUNDUS EXAMINATION is not necessary for most pediatric neuro-ophthalmologic
examinations, because the macula and optic disc are the pri-
A fundus examination is essential for evaluating the mac- mary areas of interest. If a child becomes uncooperative, it
ula, retina, nerve fiber layer, and optic nerve. This can be may be necessary for the parents to hold the child in a ‘‘lock-
performed by several methods, including direct ophthalmos- down’’ position (one parent holding the arms outstretched
copy and indirect ophthalmoscopy with a 20-diopter hand- over the ears with the other parent holding the feet) to com-
held lens. Examination of the macula with a 78- or 90-diopter plete the examination. This is a stressful and difficult situa-
handheld lens or a corneal contact lens viewed through a tion for all concerned, and all rapport with the child is gone
slit lamp may identify the cause of visual loss as being from when this occurs. If it is not possible to perform an adequate
retinal dysfunction rather than neuro-ophthalmologic dis- dilated examination of the infant or child, it may be neces-
ease. sary to conduct an evaluation with light sedation.
Performing a fundus examination on infants and young
children can be a challenge. In preparation for the examina- OTHER PROCEDURES
tion, the parents should bring an assortment of treats for Other tests beyond a conventional office examination may
young children and plenty of feeding bottles for infants. It be needed to establish the site of the pathology in the afferent
is best to leave the room after performing the afferent system visual system. Fluorescein angiography and indocyanine
and motility evaluations, allowing a nurse or technician to green angiography (ICG) may be necessary to identify reti-
administer dilating drops to preserve your rapport with the nal pathology. An electroretinogram (ERG), focal or macu-
child. In the case of infants, it is best to ask the parents to loscope ERG, pattern ERG (PERG), dark adaptation, visual-
withhold a feeding bottle until you return to the room. Most evoked potential (VEP), multifocal ERG, multifocal VEP,
infants will readily accept a bottle at this point and will or a combination of these tests may be needed to establish
be cooperative during a cycloplegic refraction and dilated the locus of the afferent system disorder. Finally, neuroimag-
fundus examination. The soporific effect of the cycloplegic ing with magnetic resonance (MR) imaging or computed
drops may also cause them to fall asleep. tomographic (CT) scanning may be needed to establish the
After completing the cycloplegic refraction, the physician anatomic site of the afferent system abnormality.
PSYCHOPHYSICAL TESTS
Light represents a very small portion of the electromag- pathway appears to be primarily involved in the processing
netic spectrum (wavelengths between 400 and 700 nm), is of color, form, acuity, and related functions (31–34).
emitted by natural and artificial sources, and is reflected by Ganglion cells that project to the magnocellular layers of
objects in the environment, thereby serving as the stimulus the lateral geniculate nucleus (M-cells) are distributed rather
for vision. Light entering the eye is first refracted by the uniformly throughout the visual field, tend to have larger-
tear film, cornea, and lens to form an inverted image on the diameter axons and higher conduction velocities, and are
retina. Photoreceptors convert this light energy into electric most effectively stimulated by high temporal frequencies
signals that are subsequently processed by neural elements and low spatial frequencies (31–34). The M-cell pathway
in the retina, optic nerve, and higher visual centers of the appears to be primarily involved in the processing of motion,
brain. The relationship between the physical properties of high-frequency flicker, and related functions. These major
light and perceptual and behavioral responses is known as pathways can be further divided into more specific sub-
visual psychophysics, which serves as the foundation for groups with distinct response properties. The M-cell and
the clinical assessment of visual function. P-cell dichotomy carries through to higher visual centers,
A variety of specialized neural mechanisms are responsi- with specific projections to a large number of cortical sites
ble for encoding motion, form, color, depth and other funda- that have highly specialized functions (35), although there
mental properties of the visual image (31–36), with new is considerable overlap of these pathways at the cortical level
information about neural processing of visual information (see Chapter 1). A third group of ganglion cells (37) project
accumulating rapidly. Beginning at the ganglion cell level, to the koniocellular (K-cell) intralaminer layers of the lateral
there are three major visual processing streams whose path- geniculate nucleus and are believed to be involved in the
ways run in parallel. Ganglion cells that project to the parvo- processing of blue-yellow opponent color information.
cellular layers of the lateral geniculate nucleus (P-cells) are Because these subpopulations of neural elements have
most prevalent in central vision, tend to have smaller diame- such distinct response characteristics to particular visual at-
ter axons with lower conduction velocities, and are most tributes, it is possible to design psychophysical tests that
effectively stimulated by low temporal frequencies and high isolate (or at least are dominated by) the activity of specific
spatial frequencies (31–34). Some P-cells respond most ef- visual mechanisms. These psychophysical tests can thus
fectively to chromatic information whereas others have ach- serve as probes to evaluate different neural populations
romatic responses to luminance and contrast. The P-cell throughout the visual pathways. Early detection of eye dis-
ease, differential diagnosis of various ocular and neurologic order to recognize objects (e.g., letters of the alphabet). It
disorders, and monitoring the efficacy of therapeutic regi- is specified in terms of the Minimum Angle of Resolution
mens are just a few of the purposes that psychophysical tests (MAR), logMAR, or values such as Snellen notation or met-
can subserve in a clinical setting. This section provides a ric equivalents based on MAR. Table 2.3 presents a compari-
brief overview of some of the more common psychophysical son of the various methods of designating visual acuity. For
test procedures that can be used in the clinical evaluation of clinical visual acuity charts, the MAR is the angle subtended
patients. by the thickness or stroke of a letter, with the overall height
and width of the letter typically being five times larger than
VISUAL ACUITY the thickness. Figure 2.3 presents an example of a typical
The most common measurement of visual function in a

clinical setting is visual acuity. It is the primary method of
assessing the integrity of the optics of the eye and the neural
mechanisms subserving the fovea. Visual acuity is used to
monitor central visual function in patients, is an essential
part of clinical refraction procedures, and is important to the
patient for reading (38,39), face recognition (40), and other
tasks involving fine visual detail. Visual acuity is specified
in terms of the visual angle subtended by the finest spatial
detail that can be identified by the observer. The physical
size of an object and its distance from the observer deter-
mines its visual angle.
There are three basic types of visual acuity measurements:
detection acuity, resolution acuity, and identification acuity.
Detection acuity is the smallest stimulus object or pattern
of elements (the minimum angle of detection) that can be
distinguished from a uniform field and it is primarily limited
by stimulus contrast. The optics of the eye are the main
factors limiting detection acuity for normal human foveal
vision, producing an attenuation of contrast for small stimuli
imaged on the retina (41). Resolution acuity is the smallest
spatial detail that can be discriminated to permit one stimulus
pattern to be distinguished from another (e.g., distinguishing
horizontal from vertical stripes), and it is usually measured
by grating patterns of alternating light and dark lines of vary-
ing widths. Resolution acuity also is limited by contrast.
Identification acuity, the measure used for clinical pur-
poses, is the smallest spatial detail that can be resolved in
Table 2.3
Visual Acuity Notation Systems
Distance Ditance MAR Cycles/

(feet) Snellen (meters) Metric (minutes) LogMAR Degree
10 20/10 3.0 6/3 0.50 ⫺0.3 60.0

12 20/12 3.6 6/3.8 0.60 ⫺0.2 50.0
16 20/16 4.8 6/4.8 0.80 ⫺0.1 38.0
20 20/20 6.0 6/6 1.00 0.0 30.0
25 20/25 7.5 6/7.5 1.25 0.1 24.0
30 20/30 9.0 6/9 1.50 0.2 20.0
40 20/40 12.0 6/12 2.00 0.3 15.0
50 20/50 15.0 6/15 2.50 0.4 12.0
60 20/60 18.0 6/18 3.00 0.5 10.0
80 20/80 24.0 6/24 4.00 0.6 7.5
100 20/100 60.0 6/60 5.00 0.7 6.0
200 20/200 120.0 6/120 10.0 1.0 3.0
400 20/400 240.0 6/240 20.0 1.3 1.5
MAR ⫽ minimum angle of resolution. Figure 2.3. An example of a standard eye chart for visual acuity testing.
eye chart used for clinical evaluation of visual acuity. This central visual function of infants begins with an assessment
design is essentially the same as that introduced by Snellen of how well the infant fixes and follows the examiner’s face,
in 1862, and the most common form of reporting visual a small toy, or other objects of interest. For older children,
acuity is still in terms of ‘‘Snellen notation,’’ consisting of the ‘‘Tumbling E Cube’’ can be used for visual acuity test-
a fraction in which the numerator is the testing distance (20 ing. This cube is a white block with black E letters of differ-
feet or 6 meters) and the denominator is the distance at which ent sizes on each of its sides. By rotating the cube, an individ-
a ‘‘normal’’ observer is able to read the letter (42). By defini- ual E can be presented in four different orientations to test
tion, a visual acuity of 20/20 (6/6) refers to a MAR of one the patient’s ability to distinguish the direction of the E. The
minute of arc letter thickness. A 20/60 (6/18) visual acuity cube can be placed at various distances from the patient,
letter therefore has a thickness corresponding to 3 minutes and different-sized E targets can be evaluated to make a
of arc and is 15 minutes of arc high and wide. The standard determination of visual acuity. The Tumbling E Cube thus
of 20/20 for ‘‘normal’’ vision was developed more than 100 relies on a child’s ability to orient the hand according to the
years ago, and with today’s high contrast eye charts and direction of the E. For older children the ‘‘E game’’ can
better light sources, normal best-corrected visual acuity for be performed using a projected ‘‘E’’ acuity chart. The
persons under the age of 50 is 20/16 or better (43) (Fig. 2.4). ‘‘HOTV’’ test, a simplification of the older Sheridan-Gardi-
Another type of visual acuity chart is known by various ner test (48), involves matching each test letter to one of
names, including the Early Treatment for Diabetic Retinopa- four letters (H, O, T, or V) printed on a card held by the
thy Study (ETDRS) chart, the Bailey-Lovie chart, and the child. Some visual acuity tests use pictures or symbols (49).
logMAR chart (44,45) (Fig. 2.5). This chart has several ad- These may be more reliable than the HOTV test. The most
vantages over the standard Snellen chart. First, the letters popular of the picture visual acuity tests are the Allen Cards
used are equally detectable for normal observers. Second, (50). Projector slides with the familiar cake, bird, telephone,
each line has an equal number of letters. Third, the spacing and other pictures are also available. Other devices like the
between letters is proportional to the letter size. Fourth, the B-VAT vision tester can generate many random sequences
change in visual acuity from one line to another is in equal of characters and figures to avoid memorization by the child.
logarithmic steps. Fifth, better specification of visual acuity ‘‘Preferential-looking’’ techniques, oculomotor responses
with either Snellen notation, MAR or logMAR values can such as optokinetic nystagmus, and electrophysiologic mea-
be achieved. Also, new methods of scoring responses can be sures such as the VEP can also be used to estimate visual
implemented that produce greater sensitivity and reliability acuity (51–54). In addition, a number of eye charts and be-
(46,47). havior test procedures can be used to assess visual acuity in
The measurement of visual acuity in special populations nonverbal or physically challenged patients (55). These tests
(e.g., young children and physically challenged persons) is utilize patterned stimuli and caricatures of faces (e.g., Mr.
not always possible with a standard letter chart. Testing of Happy Face) or common objects with ‘‘critical detail’’ (e.g.,
Figure 2.4. Population normal scores for vi-

sual acuity across ages (43). Note that normal
visual acuity is 20/16 or better up to age 50.
Figure 2.5. An example of the Bailey-Lovie logMAR visual acuity chart.

Cheerios) that can be used to obtain an indication of the should be able to see an E that is five times smaller at a
individual’s level of visual acuity. distance of 4 feet, because they subtend the same visual
Visual acuity measurements in children present special angle). By moving the cube from one distance to another,
problems, in part because the child wants to do well and the consistency of visual acuity responses can be ascertained.
please the examiner. It is therefore important for the exam- If this is done quickly, it is extremely difficult for a patient
iner to ensure that the non-tested eye is properly occluded with nonorganic visual loss to maintain consistent responses
to avoid peeking (Fig. 2.6). The examiner must work (i.e., select appropriate target sizes for different distances to
quickly, may need to use more than one procedure to estab- maintain a constant visual angle). Often the patient will pick
lish visual acuity capabilities, and should continually provide the same physical target size, irrespective of the distance at
positive feedback to the child to maintain cooperation. which it is presented (11).
In patients suspected of having nonorganic visual loss, A helpful device that can be used to test patients with
several additional methods of assessing visual acuity may suspected nonorganic monocular visual acuity loss is a cross-
be useful (11). The Tumbling E cube can be used as a cross- Polaroid projection chart (the American Optical Vectograph
check of the eye chart visual acuity determination (e.g., a Project-O-Chart slide). This consists of a projector eye chart
patient that can see the 20/200 E on the eye chart at 20 feet that is combined with polarizing material. The left or right
Figure 2.6. Peeking techniques that may be used by children whose visual acuity is being tested and techniques to avoid
this problem. Top left, the examiner is attempting to test vision in the left eye. The child is supposed to be covering the right
eye with her fingers, but the fingers are spread, allowing her to view with the right eye. Top right, the examiner is attempting
to test vision in the left eye. The child is supposed to be covering the right eye with an occluder but is holding the occluder
to one side, allowing her to view with the right eye. Middle, the examiner is attempting to test vision in the right eye. The
child is supposed to be covering the left eye with the palm of her hand but is holding the hand to one side, allowing her to
view with the right eye. Bottom left, the examiner uses his or her own hand to occlude one of the child’s eyes. In this way,
the examiner can be certain that the child is viewing with only one eye. Bottom right, using a patch to occlude one eye is the
optimum technique for testing monocular visual function.
half of the eye chart is projected through horizontally polar-

ized material, and the other half is projected through verti-
cally polarized material. The patient views the chart wearing
a pair of glasses with polarized material that has different
orientations over the two eyes (e.g., horizontal left eye polar-
ization, vertical right eye polarization). Thus, one eye sees
only the left half of the eye chart, and the other eye sees
only the right half. The chart is viewed by the patient with
both the ‘‘good’’ eye and the ‘‘bad’’ eye open. Patients with
nonorganic visual loss in one eye will often read all of the
eye chart, even though the ‘‘good’’ eye can only see half of
the chart. Another portion of the American Optical Vecto-
graph slide has randomly arranged visual acuity letters (rang-
ing from 20/20 to 20/40) that can be seen with the left eye
only, the right eye only, or with both eyes. This is especially
useful in patients with nonorganic monocular visual acuity
loss.
In normal observers, visual acuity is highest for the foveal
region and decreases rapidly with increasing visual field ec-
centricity (Fig. 2.7). Randall et al. (56) evaluated visual acu-
ity from the fovea out to 20⬚ along the horizontal meridian
of 27 normal subjects and compared their results with data
Figure 2.8. The relationship of visual acuity and visual field in patients
obtained from 30 subjects with central scotomas of varying
with experimental (x) and actual (o) central scotomas. (From Randall HG,
sizes. The results from the patients with central scotomas Brown J, Sloan LL. Peripheral visual acuity. Arch Ophthalmol 1966;
were similar to those of normal observers viewing the stimuli 75⬊500–504.)
at an eccentricity corresponding to the edge of a patient’s
scotoma. For example, visual acuity dropped from approxi-
mately 20/20 to 20/40 at an eccentricity of 2.5⬚ nasal to the
may be at or near normal sensitivity, but visual acuity may
fovea and was reduced to 20/120 for an eccentricity of 10⬚
be dramatically reduced. These conditions include refractive
from the fovea (Fig. 2.8).
errors, corneal surface irregularities, cataract, retinal edema
In many instances, central visual field loss and reduced
or serous detachment, and amblyopia. Frisén (57) noted that
visual acuity appear to be closely related. However, visual
patients with a ‘‘median chiasmal syndrome’’ have subnor-
acuity can also be reduced when there is generalized depres-
mal visual acuity despite perimetric evidence of disturbed
sion of the central visual field and no scotoma is apparent.
conduction only in crossing fibers (temporal field defects).
There are also several conditions for which the visual field
The explanation for these findings is unclear but probably
emphasizes the relative insensitivity of conventional visual
field testing for some forms of damage to the visual system.
CONTRAST SENSITIVITY
Visual acuity defines the smallest spatial detail that can
be resolved for high-contrast stimuli, but it does not specify
the responses of the visual system to objects of different sizes
and contrasts. Measurement of the spatial contrast sensitivity
function (CSF) is necessary to obtain this information. The
CSF is most commonly determined by measuring contrast
thresholds for sinusoidal gratings, an alternating pattern of
light and dark bars with luminance that varies sinusoidally
in a direction perpendicular to orientation of the grating. The
size of the grating is specified according to spatial frequency,
which is the number of cycles (pairs of light and dark bars)
of the grating pattern per degree of visual angle. Typically,
between 3 and 10 spatial frequencies from 0.5 to 30 cycles
per degree are measured for the CSF. Contrast is defined by
the luminance of the peaks (Lmax) and troughs (Lmin) of
Figure 2.7. Reduction in visual acuity with visual field eccentricity. The the sinusoidal grating, according to the equation:
graph presents a composite of results obtained by various investigators.
(From Randall HG, Brown J, Sloan LL. Peripheral visual acuity. Arch Lmax ⳮ Lmin
Contrast ⳱
Ophthalmol 1966;75⬊500–504.) Lmax Ⳮ Lmin
Contrast can vary from a minimum of 0 for a uniform specific combination of sinusoidal distributions of light of
field (Lmax ⳱ Lmin) to a maximum of 1 (Lmin ⳱ 0). A different spatial frequencies, amplitudes, and phases in the
contrast threshold is the minimum amount of contrast needed vertical and horizontal dimensions. It should be emphasized,
to detect the presence of the grating, and contrast sensitivity however, that the CSF describes the behavior of the visual
is the reciprocal of the contrast threshold (sensitivity ⳱ 1/ system at threshold contrast levels, which is not completely
threshold). representative of the visual system’s characteristics for pro-
There are several advantages of using sinusoidal gratings cessing suprathreshold contrast information (60).
to evaluate the CSF. First, blur does not change the shape A number of factors influence the measurement of the
or appearance of sinusoidal gratings, other than to reduce normal CSF, including background adaptation luminance
contrast. Second, the CSF provides a means of characterizing (61–63), stimulus size (64,65), visual field eccentricity
the overall response properties of the visual system to a wide (66–68), pupil size (69,70), temporal characteristics (62,71),
variety of visual images. The CSF may be considered the stimulus orientation (72,73), and various optical factors such
visual counterpart of an audiogram (58). The audiogram as defocus, dioptric blur, diffusive blur, and astigmatism
specifies the minimum amount of sound energy necessary (70,71). The CSF can be used to evaluate optical properties
to detect pure tones (temporal sinusoidal waveforms) for of the human eye, including refractive error and defocus
various frequencies of pitch. This information can then be (70,71), corneal disease (74), cataract (75), refractive sur-
used to determine an individual’s ability to hear complex gery (76), intraocular lenses (77), and the normal aging prop-
sounds. In a similar fashion, the spatial CSF for vision makes erties of the optics of the eye (78,79). Contrast sensitivity
it possible to determine an individual’s ability to process deficits sometimes occur in patients with normal visual acu-
spatial information from complex visual scenes. Fourier ity and optical conditions that produce subtle changes in the
analysis demonstrates that any complex waveform can be quality of their vision.
decomposed into a series of sine waves of various frequen- CSF losses occur in patients with retinal conditions such
cies, amplitudes, and phase (position) relationships (59). as diabetic retinopathy (80), age-related macular degenera-
Thus, any complex visual scene can be broken down into a tion (81), and a variety of other disorders. Foveal contrast
Figure 2.9. Examples of the various types of contrast sensitivity loss: generalized depression (A); high spatial frequency loss
(B); low spatial frequency loss (C); middle spatial frequency loss (D).
sensitivity deficits also occur in patients with glaucoma a test procedure that is highly familiar to most patients and
(82–84). clinicians.
From a neuro-ophthalmologic standpoint, measurement A third method of testing contrast sensitivity using a chart
of the CSF can reveal subtle deficits in patients with optic was introduced by Pelli et al. (101) and is called the Pelli-
neuritis and multiple sclerosis (85,86) as well as in patients Robson chart (Fig. 2.10). The Pelli-Robson chart consists
with a variety of other optic neuropathies and cerebral abnor- of letters of a fixed size that vary in contrast. Each line
malities (86–89), amblyopia (90), and other conditions such consists of six letters, with the three left-most and three right-
as Alzheimer’s disease (91) and Parkinson’s disease (86). most letters having the same amount of contrast. The patient
In general, the CSF is clinically useful for detecting early reads the chart in a manner similar to a standard visual acuity
or subtle visual loss (especially when visual acuity is nor- chart, and the minimum contrast at which the letters can be
mal), making comparisons between the two eyes, or for mon- detected is recorded. This method of testing contrast sensi-
itoring the progression or improvement of visual function. tivity is highly reproducible (102) and is capable of detecting
One of the shortcomings of the CSF, however, is that sensi- disturbances in visual function that are not evident with stan-
tivity losses have little specificity for differential diagnostic dard visual acuity testing. The Optic Neuritis Treatment
purposes. The main patterns of contrast sensitivity loss are Trial (103) used the Pelli-Robson charts for evaluation of
(a) generalized contrast sensitivity loss at all spatial frequen- contrast sensitivity as an outcome measure for comparison
cies; (b) greater high spatial frequency contrast sensitivity of treatment groups.
loss; (c) greater low spatial frequency contrast sensitivity The use of sinusoidal gratings versus low contrast letters
loss; and (d) a ‘‘notch’’ produced by contrast sensitivity for the measurement of contrast sensitivity is controversial.
loss for a particular group of spatial frequencies (Fig. 2.9). A number of arguments support each approach (104–106). It
is also important to note that different results are sometimes
Generalized and high-frequency contrast sensitivity deficits
obtained by the two procedures. Under certain stimulus con-
are by far the most common patterns of loss across a wide
ditions, normal observers can demonstrate different contrast
variety of pathologic ocular conditions.
sensitivity characteristics for gratings versus letters (107),
The CSF can be measured in infants and young children and patients with certain visual disorders can also produce
using either electrophysiologic or behavior techniques (92) different contrast sensitivity values for gratings versus letters
and can provide valuable clinical information about the func- under standard clinical testing conditions (108).
tional visual status in such individuals. The CSF also may
be helpful in predicting the performance for various daily
tasks, such as the identification of distant objects (93), read-
ing highway signs (94) and books (95), recognizing faces
(96), and mobility (97). Thus, the CSF is not only useful
for revealing subtle visual deficits associated with ocular
disorders but is also helpful in identifying problems that a
patient is likely to encounter during daily activities.
Contrast sensitivity may be measured with wall charts in a
manner similar to the way in which visual acuity is typically
measured. One of these methods uses the Vistech chart (98).
This chart has a series of five rows (A–E), each with a
different spatial frequency. Each row consists of a group of
nine circular targets containing a sinusoidal grating that is
either vertical, tilted to the left, or tilted to the right. From
the left side of the chart to the right, there is a successive
reduction in the contrast of the grating. Patients are posi-
tioned 10 feet from the chart and are asked to read each row
from left to right by indicating the orientation of the grating.
A second method of testing contrast sensitivity utilizes
the typical letter charts for testing visual acuity, but there is
a low contrast between the letters and the background. Regan
and Neima (99,100) developed a series of visual acuity
charts at several different contrast levels. Although normal
observers show a small reduction in visual acuity for low
contrast targets (about two lines), patients with early or sub-
tle abnormalities sometimes demonstrate quite profound re-
ductions in visual acuity for low contrast targets compared
with high contrast letters. Thus, this approach to contrast
sensitivity testing can reveal mild disturbances of visual sen-
sory function not detectable by standard visual acuity testing.
The advantage of a low contrast acuity chart is that it uses Figure 2.10. The Pelli-Robson contrast sensitivity chart.
PERIMETRY AND VISUAL FIELD TESTING be detected by either a history or other parts of a standard
eye examination.
General Principles In this section, we present a brief description of the psy-
chophysical basis for perimetry, the various methods for per-
Perimetry and visual field testing have been clinical diag-
forming visual field testing, and some helpful guidelines for
nostic test procedures for more than 150 years. Although
interpreting test results. It is not intended to be a comprehen-
instrumentation and testing strategies have changed dramati-
sive treatment of perimetry, however, and the interested
cally over this time, the basic principle underlying conven-
reader is directed to several excellent sources for a more
tional perimetry has remained the same. Detection sensitivity
detailed account of perimetric techniques and other related
is determined for a number of locations throughout the visual
topics (113–124).
field using a small target presented against a uniform back-
Some form of visual field testing should be performed on
ground. The loss of sensitivity at various visual field loca-
all patients, particularly those at greater risk of having visual
tions serves as a noninvasive marker for identifying pathol-
field loss: (a) patients over the age of 60; (b) individuals
ogy or dysfunction of the visual pathways. The ability of
with high myopia, elevated intraocular pressure, diabetes,
perimetry to provide helpful clinical information has been
vascular disease, systemic disease, family history of glau-
responsible for its long-term use as a diagnostic procedure.
coma or other eye disease, or other risk factors for develop-
Because perimetry can provide information about both the
ment of ocular or neurologic disorders; (c) individuals with
likely anatomic locus and disease process or processes for
visual symptoms or complaints, but minimal findings on
afferent system abnormalities, it remains a vital part of the
their eye examination; and (d) individuals with significant
neuro-ophthalmologic evaluation.
problems involving orientation and mobility, balance, driv-
Perimetry and visual field testing fulfill several important
ing, night vision and related activities. It is not feasible or
diagnostic functions:
necessary to perform a long quantitative visual field exami-
nation on all patients. However, a confrontation visual field
1. Early detection of abnormalities. Because many ocular or brief tangent screen evaluation should be performed as
and neurologic disorders are initially expressed as sensi- part of a standard neuro-ophthalmologic examination. When
tivity loss in the peripheral visual field, perimetry is an more sensitive measurements of the visual field are needed,
important factor in identifying early signs of afferent sys- automated static perimetry or manual kinetic perimetry can
tem dysfunction. Perimetry is typically the only clinical be performed.
procedure that evaluates the status of the afferent visual Manual perimetry with the Goldmann perimeter has many
pathways for locations outside the macular region. advantages. Since the perimetric stimulus presentation is
2. Differential diagnosis. The spatial pattern of visual field done by a human, subjects can be cheered on or cajoled into
deficits and comparison of patterns of visual field loss performing. When the perimetrist senses subject fatigue, a
between the two eyes also provide valuable differential rest break is given. Unlike the fixed, 6⬚ spaced grid of con-
diagnostic information. Not only can this information be ventional automated perimetry, Goldmann perimetry has
helpful in defining the location of damage along the vis- custom test point locations along with improvisation of
ual pathways, it can also assist in identifying the specific strategies based on coexisting findings. Specific exploration
type of disease that has caused the damage. strategies can be used for individual concerns. This allows
3. Monitoring progression and remission. The ability to for much more accurate mapping of defect shape. This can
monitor a patient’s visual field over time is important be invaluable for the topographic localization of visual field
for verifying a working diagnosis, establishing whether defects. However, manual perimetry is less sensitive than
a condition is stable or progressive, and evaluating the conventional automated perimetry and it may be more time-
effectiveness of therapeutic interventions. consuming. Its most severe limitation, though, is that many
4. Revealing hidden visual loss. Perhaps the most impor- perimetrists are not adequately trained (125). This may be
tant role subserved by perimetry is the ability to find worse than no perimetry at all.
afferent visual pathway loss that may not be apparent to Automated perimetry has had a dramatic impact on im-
the patient. Changes in foveal visual function are typi- proving the quality of care for patients with ocular disorders.
cally symptomatic. Peripheral vision loss, on the other Automatic calibration of instruments, standardized test pro-
hand, can often go unnoticed, especially if it is gradual cedures, high sensitivity and specificity, reliability checks
and monocular. Visual field screening of 10,000 Califor- (‘‘catch trials’’), and quantitative statistical analysis proce-
nia driver’s license applicants was performed, and nearly dures are some of the many advantages of this method of
60% of individuals with peripheral visual field loss were perimetry; however, there are also disadvantages of auto-
unaware that they had any vision problem (109). Paradox- mated perimetry, including prolonged test time, increased
ically, even though a patient may be unaware of periph- cognitive demands, fatigue, and lack of flexibility for evalu-
eral visual field loss, it can significantly affect the perforating difficult patient populations. We believe that there is
mance of daily activities such as driving (109–112), no single method of visual field testing that is best for all
orientation, and mobility (97). circumstances and all patients. Automated perimetry is but
one of many tools that the clinician can use to evaluate pe-
Perimetry and visual field testing are therefore important ripheral visual function, and the various forms of visual field
in identifying visual abnormalities that might not otherwise testing should be regarded as complementary techniques,
the utility and appropriateness of which are determined by usually represented in terms of sensitivity, the reciprocal of
the clinical circumstances and the question that is being ad- threshold (sensitivity ⳱ 1/threshold). At the 31.5 asb back-
dressed. There is no single method of data representation, ground luminance, the fovea has the highest sensitivity and
analysis procedure, visual field index, or other method of is able to detect both the dimmest and the smallest targets.
evaluating visual field data that provides all of the essential Sensitivity drops rapidly between the fovea and 3⬚ decreases
clinical information. It is important to consider all of the gradually out to 30⬚, and then drops off more rapidly again
information available, including reliability characteristics beyond 50⬚ (Fig. 2.11). The characteristic three-dimensional
and the subjective clinical interpretation of the visual field. representation of the visual field sensitivity profile is often
In addition, it should be kept in mind that although the test called the ‘‘hill of vision’’ or an ‘‘island of vision in a sea
may be automated, the patient is not. It is unreasonable to of blindness.’’ In addition to eccentricity-dependent changes
begin an automated visual field test, leave a patient alone in in the slope of the visual field profile, the temporal visual
a dark room, and expect the patient to remain alert, energetic, field (to the right of the foveal peak) extends farther than
attentive, interested, and to maintain proper alignment and the nasal visual field, and the inferior visual field extends
fixation throughout the test procedure. Some patients require farther than the superior visual field. The location of the
periodic rest breaks, encouragement, and personal contact blind spot, approximately 15⬚ temporal to the foveal peak,
to perform visual field examinations in a reliable manner. It is indicated in most representations by a darkened vertically
is also important to insure that proper test conditions, refrac- oval area.
tive characteristics, and other factors have been properly Visual field sensitivity can be affected by many differ-
established before initiating the examination. Visual field ent stimulus attributes, including background luminance
testing can be a powerful clinical diagnostic tool when these
factors are kept in mind.
Psychophysical Basis For Perimetry and Visual Field

Testing
The primary psychophysical concept underlying perime-
try and visual field testing is the increment or differential
light threshold. The increment threshold (Weberian contrast)
is the minimum amount of light that must be added to a
stimulus (gd L) to make it just detectable from the back-
ground (L). At very low background luminances, the amount
of light needed to detect a stimulus is constant. At higher
background luminances, the increment threshold increases
in direct proportion to the background luminance, e.g., a
doubling of the background luminance requires a doubling
of the stimulus luminance for detection. This relationship,
which holds over a large range of background luminance
levels, is known as Weber’s law, in honor of the German
scientist who initially described it (126).
The standard background luminance used by most perime-
tric devices is 31.5 apostilbs (asb), or 10 cd/m2. This is in
the range of background luminance levels for which Weber’s
law is valid. There are several advantages to the use of this
background luminance level: (a) it is close to the ambient
lighting conditions found in offices and waiting rooms, re-
quiring a minimal amount of adaptation time; (b) the back-
ground luminance is one that is comfortable for most pa-
tients; (c) patients have the least amount of response
variability at this background luminance; and (d) factors af-
fecting the amount of light reaching the retina (pupil size
changes, ocular media transmission loss, etc.) have an equal
effect on the background and stimulus luminance. Thus, over
the range of background illuminances for which Weber’s law
holds, these changes in retinal illumination will not affect the
increment threshold measure.
Increment threshold determinations are usually made at a
number of visual field locations during quantitative perime- Figure 2.11. Three-dimensional representation of the normal visual field
try. For a normal visual field, the increment threshold varies represented as a hill of vision. Sensitivity is plotted as a function of visual
as a function of visual field location. Visual field results are field eccentricity.
(113,115,127), stimulus size (113,115,128–130), stimulus Most examiners test patients monocularly using double si-
duration (113,115,131), chromaticity (132–136), and other multaneous finger counting to survey the visual field for any
factors (113,115). Of these parameters, stimulus size is the dense quadrantic defect. Finger counting is followed by a
most important for clinical perimetry. Next to stimulus lumi- test of the central visual field to evaluate for the presence
nance, it is the most common method of adjusting the detect- of relative visual field defects. One such test is to have the
ability of perimetric stimuli. Not only does a change in stim- subject look at the examiner’s face and report any difference
ulus size affect the overall sensitivity to light, but the slope from the expected. Another is to use two red objects and
of the sensitivity profile is also changed (113,115). Small compare perception of the two eyes or parts of the visual
targets produce steeper sensitivity profiles, and larger targets field. Unfortunately, for optic nerve-related visual field de-
result in a flatter sensitivity profile, especially for the central fects, finger confrontation identifies only about 10% of de-
30–40⬚ eccentricity. Response variability is also reduced as fects while bedside color techniques yield defects in about
stimulus size is increased (130). one-third of patients with abnormalities on formal perimetry
Certain patient characteristics that are not associated with (157). Color confrontation techniques fare better with chias-
ocular or neurologic pathology can also influence the incre- mal defects, detecting about three-quarters of patients (157).
ment or differential light threshold. Blur and refractive error Even by combining seven confrontation visual field tests,
(137), media opacities such as cataract (138), ptosis (139), only about half of perimetrically identified defects are found
and pupil size (140,141) can affect visual field sensitivity (158). Therefore, formal perimetry is usually necessary
characteristics. In addition, procedural circumstances related when the patient has visual loss not explained by a general
to trial lens rim obstructions (142), fixation instability (143), ophthalmologic examination.
response errors (144–146), and other artifacts of testing can Confrontation visual field techniques for infants and chil-
produce the appearance of visual field loss or can obscure dren can be quite challenging (Fig. 2.12). Because of their
visual field deficits that are actually present. adaptive abilities, children may demonstrate good mobility
Cognition, attention, and other higher-order functions in skills and fool the examiner as to the extent of visual field
patients undergoing visual field testing can influence visual loss. For infants and young children, a visually mediated
field sensitivity, as well as attention, practice, and learning startle response can be used to detect hemianopic defects
(147–151). Fatigue effects can reduce visual field sensitivity and other substantial defects in the peripheral field. A child
(152–154), particularly after the test procedure has taken who sees a startle stimulus will look in that direction. For
more than 5–7 minutes of testing. Patients with visual field older children, finger mimicking or a ‘‘Simon says’’ game
loss typically demonstrate greater fatigue effects than those can be used to evaluate the peripheral visual field. The child
with normal perimetric function, and this may be especially mimics the examiner by holding up the same number of
true for some conditions such as optic neuritis (155,156). fingers he or she observes. ‘‘Finger puppet perimetry’’ can
be performed, with one puppet used to direct central fixation
Techniques For Perimetry and Visual Field Testing and the other puppet used as a peripheral stimulus for sac-
Visual field examinations have been conducted for over cadic eye movements. A story with dialogue between the
150 years and, as a consequence, a variety of procedures puppets is used to redirect attention from one puppet to the
and techniques have been developed. Perimetry and visual other.
field test procedures may be categorized in several different In many instances, simultaneous comparison of color satu-
ways: (a) the amount of information obtained by the test, ration or brightness of stimuli between hemifields or be-
i.e., screening versus quantitative; (b) the type of stimulus tween the two eyes is useful in distinguishing subtle anoma-
used to perform the test (kinetic, static, or suprathreshold lies. When the stimuli are presented in a double simultaneous
static); and (c) the manner in which the test is administered fashion to the right and left of fixation, it is possible to detect
(manually vs. computer-driven). There are both advantages homonymous defects. Subtle deficits across the vertical mid-
and disadvantages for each method. Automated perimetry, line can be detected by asking the patient to indicate which
for example, provides greater standardization, calibration, of the two test objects is clearer or brighter. In addition,
and statistical analysis of results than manual visual field double simultaneous presentation can be used to detect the
testing, but it is less efficient, less flexible, and too demand- phenomenon of visual extinction—the lack of awareness of
ing for some patients. Kinetic perimetry, when performed an object in a seeing area of the visual field when other
appropriately, is a more efficient method of performing an seeing areas of the visual field are stimulated simultane-
evaluation of the full visual field than static perimetry and ously. Confrontation visual field testing is also useful in
the technique can yield exquisite information about defect evaluating patients suspected of having nonorganic visual
shape, but the technique varies from one test to another. field loss (11).
Quantitative procedures provide a better ability to detect sub- The obvious advantages of confrontation visual field test-
tle anomalies and monitor changes over time, but they are ing include its simplicity, flexibility, speed of administra-
more time-consuming than screening procedures and may tion, and ability to be performed in any setting, including at
cause fatigue in some patients. the bedside. The disadvantages of confrontation visual field
testing include the lack of standardization, the qualitative
Confrontation Visual Fields nature of the results, and the limited ability to detect subtle
Confrontation visual field examination is rapid, reliable, deficits and monitor progression or remission of visual loss.
and easy to perform. It is tailored to the clinical situation. Because it is quick and easy to perform, confrontation visual
This technique is well known to ophthalmologists who

routinely examine patients with known or suspected macular
disease, because Amsler grids can be used to identify and
plot small scotomas and other visual field defects that occur
with macular scars, mild macular degeneration, central ser-
ous chorioretinopathy, and related disorders. It is perhaps
less well recognized that small central or paracentral scoto-
mas that occur with optic nerve disease can also be identified
with these plates. The Amsler grid (Fig. 2.2) is particularly
useful for identifying small central scotomas and other subtle
central visual disturbances that are difficult to detect with
more sophisticated automated and manual perimeters. Here,
patients report missing areas rather than metamorphopsia.
The grid can be dimmed in various ways to increase the
sensitivity of detection of these small scotomas (160). The
Amsler grid is very quick and easy to administer. Its main
disadvantages are related to the qualitative, subjective nature
of the information derived from the test.
Tangent (Bjerrum) Screen

The central visual field can be studied in detail using a
tangent or Bjerrum screen. The screen is made of black felt
or other black matte material and can be mounted on the wall
or hung from the ceiling. The screen has several concentric
circles and radial lines imprinted on it to provide a reference
for the examiner. A dark wand with circular targets of var-
ious sizes and colors mounted on the end is used to examine
the central visual field, usually within 30⬚ of fixation. In its
most common application, testing is performed at a distance
of 1 meter, and a light source is employed to provide a
relatively uniform illumination of 7 foot-candles on the
screen. Targets are specified in terms of their diameter, their
color, and the testing distance in millimeters. For example,
a 1-mm-diameter white target used with the patient located
1 meter from the tangent screen would be designated as 1/
Figure 2.12. Examples of confrontation visual field testing in children 1000W, and a 5-mm red target used with the patient located
using the startle response (a); finger counting (b); and finger puppets (c). 2 meters from the screen would be designated as 5/2000R.
A kinetic technique is usually performed to test the visual
field during a tangent screen examination. The patient fixates
field should be performed on all patients, regardless of their a central target, and a stimulus is slowly moved from the
visual complaints. periphery towards the center of the screen along a particular
meridian until the patient reports detection of the stimulus.
Amsler Grid By repeating this procedure along different meridians, a con-
tour of equal sensitivity—an isopter—can be plotted (Fig.
Mark Amsler developed a series of charts, specifically 2.13). The use of several different target sizes generates sev-
designed to qualitatively analyze the disturbances of visual eral different isopters and creates a map of visual field sensi-
function which accompany the beginning and evolution of tivity. Scotomas, areas of low sensitivity or non-seeing areas
maculopathies. The charts are a series of lined and patterned surrounded by normal visual field regions, are also plotted.
grids that test the central visual field within 10⬚ of fixation A well-performed kinetic tangent screen examination can
when the plates are held at 1/3 of a meter from the eyes detect subtle defects and provide quantitative information
(159). Each square of the grid subtends 1⬚ of visual angle, for the central visual field that is comparable to that obtained
making the ability to define the location of small defects by more sophisticated automated procedures.
rather easy. The patient is asked to fixate a central spot on Suprathreshold static visual field screening can also be
the grid, using one eye at a time, and is asked if he or she accomplished with the tangent screen. Using targets that are
can see the spot. If not, the patient’s finger can be placed white on one side and black on the other, the wand can be
on the center to help fixation. The patient is then asked to rotated to present and then extinguish the stimulus at key
point out any regions in which the lines are missing, blurred, locations throughout the visual field. The target size em-
distorted, bent, or irregular. ployed is typically one that can be readily detected by per-
objects, single versus multiple stimuli used simultaneously),

speed, and ease of use. Varying the distance of the patient
from the screen can be helpful in differentiating organic from
nonorganic constriction of the visual field (Fig. 2.14). The
main disadvantages are the strong dependence of results on
the skill and technique of the perimetrist, the lack of stand-
ardization, difficulty in monitoring the patient’s fixation
while performing the visual field examination, and the need
to establish age-related population norms.
Goldmann Manual Projection Perimeter

The Goldmann perimeter is a white hemispheric bowl of
uniform luminance (31.5 asb) onto which a small bright
stimulus is projected. It is generally used to perform kinetic
perimetry, although static and suprathreshold static perime-
try can also be tested with this perimeter. Unlike the Amsler
grid and tangent screen, the Goldmann perimeter can be used
to evaluate the entire visual field. With one eye occluded,
the patient fixates a small target in the center of the bowl,
and the perimetrist monitors eye position by means of a
Figure 2.13. An example of an isopter generated by kinetic perimetric telescope. A particular stimulus size and luminance is
testing. (From Johnson CA. Perimetry and visual field testing. In Zadnik projected onto the bowl, the target is moved from the far
K, ed. The Ocular Examination. Philadelphia, WB Saunders, 1996.)
periphery toward fixation at a constant rate of speed, typi-
sons with normal visual fields. In this manner, it is possible

to quickly determine whether or not visual field abnormali-
ties are present.
The main advantages of the tangent screen are its flexibil-
ity (i.e., variable distance from the patient, different colored
Figure 2.14. A demonstration of physiologically invalid tunnel vision

(‘‘tubular vision’’) associated with nonorganic visual field loss, and the Figure 2.15. Representation of kinetic perimetry results (below) com-
normal cone-shaped expansion of the normal visual field as testing distance pared with three-dimensional hill of vision (above). (From Johnson CA.
is increased. (From Beck RW, Smith CH. The neuro-ophthalmologic exami- Perimetry and visual field testing. In Zadnik K, ed. The Ocular Examination.
nation. Neurol Clin 1983;1⬊807–830.) Philadelphia, WB Saunders, 1996.)
cally 4–5⬚ per second (161), and the patient is instructed to perimeters, it is most often performed with an automated
press a response button when he or she first detects the stimu- perimeter such as the Humphrey Field Analyzer or the Octo-
lus. The location of target detection is noted on a chart, and pus perimeter. Measurements of the increment threshold are
the process is repeated for different meridians around the obtained at a variety of visual field locations that are usually
visual field. Isopters and scotomas are plotted in a manner arranged in a grid pattern or along meridians. A bracket-
similar to that described for the tangent screen examination, ing or staircase procedure may be used to measure thresh-
except that both the target size and luminance can be ad- old sensitivity, although new techniques such as SITA
justed to vary stimulus detectability. This process produces (162–164) and ZEST (165–167) use Bayesian forecasting
a two-dimensional representation of the hill of vision that methods.
is basically a topographical contour map of the eye’s sensi- The SITA method uses two maximum likelihood visual
tivity to light (Fig. 2.15). Kinetic testing (at least 1 or 2 field models: normal and glaucoma. The likelihood of a set
isopters) on the Goldmann perimeter can be performed in of data is the probability of obtaining that set of data, given
cooperative children as young as 5 or 6 years of age. the chosen probability distribution model (in this case either
a normal or glaucoma model). The models are based on the
Static Perimetry
fact that the slope of the frequency-of-seeing curves (vari-
Static perimetry uses a stationary target, the luminance of ability) increases with threshold. Figure 2.16 shows the two
which is adjusted to vary its visibility. Although it can be models. Log likelihood is on the y-axis and threshold (inten-
performed manually using either the Goldmann or Tübinger sity) on the x-axis. At the beginning of the test, there is a
Figure 2.16. Visual field models for normal

and glaucoma test results and their change dur-
ing the perimetry test using SITA. As the test
continues, the maximum likelihood model is
updated based on the results at the tested loca-
tion and surrounding correlated locations. In
this example, the glaucoma model gradually
becomes the most likely model at the end of
the test.
likelihood that the test location results are either normal or along meridians are usually represented by a sensitivity pro-
abnormal. As the test continues, the model is updated until file plot (Fig. 2.17B).
the threshold is estimated with the given level of confidence. The major advantages of automated static perimetry are
To reduce test time, the SITA-FAST algorithms interrupt standardization of test conditions, quantitative visual field
the threshold even earlier. However, this reduction in test measurements, a normative database, statistical analysis pro-
time is at the expense of accuracy and variability. cedures, and automatic calibration. The major disadvantages
Introduction of the SITA algorithm resulted in a 50% re- include a lengthy amount of time required for testing, limited
duction in test time. Thresholds are 1 to 2 db higher than flexibility, the need for additional testing space, and a high
with the use of the full staircase (full threshold) method. The variability in areas of visual field damage.
shortening of test time is likely the result of a combination Both static and kinetic perimetry are quantitative proce-
of less patient fatigue and interruption of the staircase procedures that require a considerable amount of testing time.
dure before threshold is reached. The algorithm has been so Suprathreshold static perimetry is a procedure that is
successful in cutting down test time that full threshold testing faster than quantitative techniques and is typically used for
has largely been replaced. However, the efficacy of SITA screening purposes. There are a number of variations in test
for serial examinations to detect change has not yet been procedures, strategies, and theoretical bases for suprathresh-
validated. old static perimetry (113,123,168). The basic technique,
The presentation of visual field sensitivity for grid patterns however, is that stimuli that can be easily detected by persons
is typically a gray scale representation (Fig. 2.17A), rather with normal peripheral vision are presented at specific loca-
than the three-dimensional ‘‘hill of vision’’ that is produced tions throughout the visual field. These locations are selected
during kinetic perimetry. Areas of high sensitivity near the to evaluate areas that are frequently affected by various ocu-
peak of the hill of vision are denoted by lighter shading lar or neurologic disorders that damage the visual pathways
and areas of low sensitivity by dark shading. Determinations (e.g., glaucoma, chiasmal tumors). Locations at which the
target is seen are denoted by one symbol and locations where
the target is not seen are denoted by another.
Interpretation of Visual Field Information
A large amount of visual field information is derived from
perimetric testing, especially from automated perimetry.
Test conditions and stimulus parameters used, indicators of
patient reliability and cooperation, physiologic factors (pupil
size, refractive state, visual acuity, etc.), summary statistics
and visual field indices, and other items are presented in
conjunction with sensitivity values for various locations in
the patient’s visual field. Visual field sensitivity can also
be represented in many different forms (numerical values,
deviations from normal, gray scale representations, probabil-
ity plots, etc.). The following discussion presents a brief
overview of the various types of information provided on
the final printed outputs. Because of its current popularity
and widespread use, this discussion and most of the exam-
ples are derived from automated static perimetry. However,
some examples of kinetic testing using the Goldmann perim-
eter are presented for certain clinical cases, especially for
situations in which kinetic testing provides more information
about visual field status.
There is no single type of data representation or item of
visual field information that provides a sufficient or com-
plete description of visual field properties. All of the avail-
able information from the output needs to be evaluated in
order to properly interpret the results. Just as the results from
individual components of a standard eye exam need to be
combined to render an appropriate impression and diagnosis,
consideration of all of the individual components of perime-
try must be considered in order to properly appreciate the
findings.
Graphic Representation of Visual Field Data
Figure 2.17. Representation of static perimetry results according to gray In most instances, the numeric representation of visual
scale (A) and profile sensitivity plots (B). field information, whether by means of summary values such
as visual field indices or by sensitivity values for individual to use a soft contact lens correction that is appropriate for
visual field locations, is difficult to interpret. A graphic rep- the testing distance to avoid lens rim artifacts. Proper near
resentation of visual field data makes it easier to evaluate, refractive corrections that are appropriate for the near testing
particularly for detecting specific patterns of visual field loss distance of the perimeter bowl and the patient’s age must
or for assessing progression or other visual field changes be used to minimize the likelihood of refraction scotomas
over time. There are three primary methods of graphically and sensitivity reductions from blur (Fig. 2.19C). Small pu-
representing visual field data: isopter/scotoma plots, profile pils (less than 2 mm diameter) can produce spurious test
plots, and gray scale plots (Fig. 2.18). results, especially in older persons who may have early len-
ticular changes. If pupil size is small, the patient should be
Ancillary dilated to 3 mm or greater (Fig. 2.19D). Finally, the patient’s
visual acuity can also provide useful information when as-
Several important pieces of information that should be sessing generalized visual field sensitivity loss and the po-
checked on each visual field examination are the position tential sources responsible for the loss.
of the eyelids, the refractive correction used for testing, pupil
size, and visual acuity. Ptosis can produce a superior visual Reliability Indices
field defect that may be minimal or significant (Fig. 2.19A).
High refractive corrections (greater than 6-diopter spherical The quality of information obtained from perimetry and
equivalent) can sometimes produce trial lens rim artifacts visual field testing depends on a patient’s cooperation, will-
(Fig. 2.19B). When a patient’s spherical equivalent correc- ingness, and ability to respond in a reliable fashion and main-
tion for perimetric testing exceeds 6 diopters, it is advisable tain a consistent response criterion. It is important to have
Figure 2.18. A comparison of the various graphic methods of representing visual field data: profile plot (A); gray scale plot
(B); isopter/scotoma plot (C).
Figure 2.19. Influences on visual field test results. A, An example of visual field results for ptosis before (left) and after
(right) taping up the upper lid and brow. B, Example of trial lens rim artifact (left) and its disappearance (right) after realigning
the patient. C, Refractive error introduced by improper lens correction (left) and results after proper lens was employed (right).
D, Visual field results obtained in the same eye with a 1 mm (left) and a 3 mm (right) pupil diameter.
an assessment of patient reliability and consistency in order Octopus perimeters refer to the average deviation of sensitiv-
to properly evaluate the significance of visual field informa- ity at each test location from age-adjusted normal population
tion. With manual perimetry, it is possible to monitor the values. They provide an indication of the degree of general-
patient’s fixation behavior directly by means of a telescopic ized or widespread loss in the visual field. The Pattern Stan-
viewer. The use of ‘‘catch’’ trials has been as an index of dard Deviation (PSD) on the Humphrey Field Analyzer and
patient response reliability. False-positive errors (responses the Loss Variance (LV) on the Octopus perimeter present a
when no stimulus is presented) and false-negative errors summary measure of the average deviation of individual vis-
(failure to respond to a stimulus presented in a region previ- ual field sensitivity values from the normal slope after cor-
ously determined to be able to detect equal or less detectable recting for any overall sensitivity differences, i.e., MD. They
targets) can be monitored throughout the test procedure. represent the degree of irregularity of visual field sensitivity
Automated test procedures not only have the capability about the normal slope and therefore indicate the amount of
of monitoring false-positive errors, false-negative errors, and localized visual field loss, because scotomas produce signifi-
fixation behavior in the same manner as described above, cant departures from the normal slope of the visual field.
but also can obtain an assessment of response fluctuation by Corrected Pattern Standard Deviation (CPSD) and Corrected
retesting a sample of visual field locations. Also, indirect Loss Variance (CLV) take into account the patient’s short-
indicators of fixation accuracy (e.g., whether or not a patient term fluctuation (STF) during testing. STF is derived by
responds to a target presented to the physiologic blind spot) testing a sample of ten locations twice to determine the aver-
can be monitored. An additional advantage of automated test age deviation of repeated measures. This correction mini-
procedures is that these reliability indices (false positives, mizes the influence of patient variability on the local devia-
false negatives, fixation losses, short-term fluctuations) can tion measures. Note that CPSD and STF are not evaluated
be immediately compared with those of age-adjusted normal by the SITA test algorithm.
control subjects, thereby providing an indication as to
whether or not the patient’s reliability parameters are within Probability Plots
normal population characteristics.
Some of the reliability indices for automated perimetry Another advantage of automated static perimetry is that a
are not always accurate indicators of a patient’s true perfor- patient’s test results are compared with age-adjusted normal
mance. For example, false-negative rates are correlated with population values. Thus, it is possible to determine the
visual field deficits, i.e., there is an increase in false-negative amount of deviation from normal population sensitivity val-
responses with increased field loss (144). Thus, high false- ues on a point by point basis for all visual field locations
negative rates may be more indicative of disease severity tested. A useful means of expressing this information is by
than of unreliable patient responses. Excessive fixation means of probability plots. The Humphrey Field Analyzer
losses can be caused by factors such as mislocalization of has two methods of presenting this type of information. One
the blind spot during the initial phases of testing, misalign- is called the ‘‘Total Deviation Plot’’ and the other is called
ment or head tilt of the patient midway through testing, or the ‘‘Pattern Deviation Plot.’’ For the Total Deviation Plot,
inattention on the part of the technician administering the each visual field location has one of a group of different
visual field examination. Also, one should be careful not to symbols indicating whether the sensitivity is within normal
consider reliability indices as a replacement for technician limits, or is below the 5, 2, 1, or 0.5% of normal limits,
interaction and monitoring of patients. Some patients are respectively. In other words, visual field locations or in-
uncomfortable when left alone in a darkened room during dices that have a probability corresponding to p less than
automated perimetry testing. In addition, misalignment of 1% mean that this value is observed less than 1% of the
the patient, drowsiness, and related factors can occur during time in a normal population of the same age. This provides
testing and go undetected if the patient is not adequately an immediate graphic representation of the locations that
monitored. It is important to remember that it is the test are abnormal and the degree to which they vary from
procedure that is automated, not the patient. normal levels.
Although reliability indices are helpful in determining if The Pattern Deviation Plot is similar to the Total Devia-
the visual field is accurate, they are not sufficient to eliminate tion Plot, except that the determinations are performed after
the possibility that a visual field defect is nonorganic in na- the average or overall sensitivity loss has been subtracted,
ture. It has been shown that both patients and otherwise thereby revealing specific locations with localized devia-
normal subjects can ‘‘fool’’ the automated perimeter, pro- tions from normal sensitivity values. The value of these rep-
ducing a variety of abnormal fields despite maintaining relia- resentations is twofold. First, they provide an immediate in-
bility indices that are within normal limits (169–171). dication of the locations with sensitivity loss. Second, the
comparison of the Total and Pattern Deviation Plots provides
Visual Field Indices a clear indication of the degree to which the loss is diffuse or
localized. If the loss is predominantly diffuse, the abnormal
A distinct advantage afforded by automated perimeters is locations will appear on the Total Deviation Plot, but all or
the ability to provide summary statistics, usually called vis- most of these locations will be within normal limits on the
ual field indices. The Mean Deviation (MD) on the Hum- Pattern Deviation Plot (Fig. 2.20A. If the deficit is predomi-
phrey Field Analyzer and the Mean Defect (MD) on the nantly localized, the Total and Pattern Deviation Plots will
complete acceptance by the clinical ophthalmic community

(172). Nevertheless, the use of quantitative statistical analy-
sis procedures may be helpful in monitoring a patient’s vi-
sual field status.
There are several important factors to consider when eval-
uating a patient’s visual field status over time. First, it is
necessary to examine the test conditions that were present
for each visual field examination. If different test strategies,
target sizes or other test conditions are different from one
examination to another, it is difficult to compare the results,
because the type of test procedure and the stimulus size (and
characteristics) can significantly alter the appearance of the
visual field (Figs. 2.22 and 2.23). Second, it is important to
determine if there are any differences in patient conditions
from one visual field to another. If there are meaningful
differences in pupil size, refractive corrections, visual acuity,
time of day, or other factors (e.g., upper lid taped on one
occasion and not on another occasion), this can have a dra-
matic effect on the visual field results obtained on different
visits (Fig. 2.19). Third, unless the visual field changes are
dramatic, it is important to base judgments of visual field
progression or stability on the basis of the entire series of
visual fields that are available. It is not possible to distinguish
subtle visual field changes from long-term variation on the
basis of two visual fields (e.g., comparing the current visual
field to the previous visual field). In particular, patients with
moderate to advanced visual field loss can sometimes exhibit
considerable variations from one visual field to another.
Also, factors such as fatigue and experience can pro-
duce significant differences in visual field characteristics
(147–154). If it is suspected that a change in visual field
loss has occurred, it is best to repeat the examination on a
separate visit to confirm the suspected change. Depending
on which part of the sequence and which eye is examined,
any two successive visual fields can reflect apparent im-
provement, progression, or stability of the visual field.
Figure 2.20. Examples of diffuse loss (A), localized loss (B), and ‘‘trigger
happy’’ (C) patient results as they are depicted on the Total Deviation and
Five-Step Approach to Visual Field Interpretation
Pattern Deviation probability plots for the Humphrey Field Analyzer.
One of the common errors that occur in visual field inter-
pretation is the lack of attention to details and specific pat-
look almost identical (Fig. 2.20B). The degree of similarity terns of visual field loss before obtaining a global evaluation
between the Total and Pattern Deviation Plots thus gives an of the visual field. To avoid this tendency, we suggest a
indication of the proportion of loss that is diffuse and local- simple five-step approach to visual field interpretation:
ized. In a few instances, the Total Deviation Plot may appear
to be normal, but the Pattern Deviation Plot reveals a number 1. Determine if the visual field is normal or abnormal for
of abnormal locations (Figs. 2.20C and 2.21). This occurs each eye separately. Automated perimetry results provide
when the patient’s measured sensitivity is significantly better assistance with this task, because they show both point-
than normal, and it is most often caused by a patient who by-point and summary comparisons of the patient’s test
presses the response button too often (‘‘trigger happy’’). results with age-matched normal population values. If
both eyes are normal, both in terms of statistical compari-
Progression of Visual Field Loss son and clinical assessment, then further evaluation is not
necessary. However, subtle visual field loss can some-
The determination of whether a patient’s visual field im- times be present despite visual field indices that are
proves, worsens, or remains stable over time is the most within normal limits. Perhaps the most common of these
difficult aspect of visual field interpretation. Although there occurrences are the subtle vertical steps in the superior
are several quantitative analysis procedures available for visual field that may reflect an early bitemporal chiasmal
evaluating visual field progression, none of them enjoys lesion.
Figure 2.21. An example of automated static perimetry results from a ‘‘trigger happy’’ patient who presses the response
button too often and inappropriately.
Figure 2.22. Examples of different fields obtained when pa-

tients with a field defect are tested with different strategies
on an automated perimeter or with different perimeters. A, A
patient with an optic neuropathy who was tested on two differ-
ent automated perimeters. Note marked difference in results.
(Figure continues.)
Figure 2.22. Continued. B, A macular scotoma using a
central 30⬚ test (left) and central 10⬚ test (right). Note appear-
ance of scotoma when 10⬚ test is performed. C, Advanced
glaucoma using a central 30⬚ test (left) and a central 10⬚ test
(right).
Figure 2.23. Appearance of visual fields ob-

tained by different techniques in a patient with
retinitis pigmentosa. A, Visual field defects with
static perimetry using a Humphrey 30-2 test with
a size III target for the left and right eyes shows
diffuse reduction in sensitivity in each eye with
a small area of central sparing. B, Results using
a size V target for the central 30⬚. Note expansion
of the clear central area. C, Results obtained by
full field kinetic perimetry using a Goldmann pe-
rimeter. Note that with static perimetry the true
extent of the field defects cannot be appreciated.
With kinetic perimetry the scotomatous nature of
the defects can be appreciated.
108
2. If one or both visual fields are abnormal, examine the

ancillary information to determine if proper test condi-
tions were employed, the appropriate near correction was
used (based on the patients’ age, distance refraction, and
whether or not they were cyclopleged), and the pupil size
was sufficiently large. Also, check for patterns of visual
field loss that are indicative of a trial lens rim artifact, a
droopy upper eyelid, or other nonpathologic conditions
that may account for the visual field loss. Fatigue, drowsi-
ness, and related conditions can also produce apparent
visual field loss. It is crucial that the person who performs
the perimetric testing, especially with automated perime-
tric tests, be attentive to these factors. A surprising num-
ber of visual field deficits can be attributed to nonpatho-
logic influences.
3. Determine if the visual field is abnormal in both eyes or
Figure 2.25. Humphrey visual field (top) and corresponding fundus photo
(bottom) from a patient with low tension glaucoma in the right eye. Note
moderate cupping (large arrow), small peripapillary nerve fiber layer hem-
orrhage (medium arrow), and wedge-shape nerve fiber layer defect (thin
arrows) that corresponds to the superior arcuate field defect detected by
perimetry.
in only one eye. If the visual field is abnormal in only

one eye, the defect is almost always caused by a disorder
anterior to the optic chiasm (Figs. 2.24–2.27). If the vi-
sual field of both eyes is abnormal, it means that the defi-
cit is at or posterior to the optic chiasm (Figs. 2.28–2.30)
or that the patient has bilateral intraocular or optic nerve
disease (Figs. 2.31–2.33).
4. Determine the general location of the visual field loss
for each eye independently. Specifically, determine if the
visual field loss is in the superior or inferior hemifield,
the nasal or temporal hemifield, or the central portion of
the field. This is especially important for the nasal and
Figure 2.24. Monocular field loss in a patient with myelinated nerve temporal hemifield assessment. If the loss is extensive,
fibers in the right eye. Kinetic visual field testing, performed on the Tüb- determine where the greatest amount of visual field loss
inger perimeter (top), shows an inferior arcuate scotoma that corresponds is present. If the visual field loss is bitemporal and re-
to the area of myelinated nerve fibers in the superior arcuate region (bottom). spects the vertical midline, then a chiasmal locus should
Figure 2.26. Unilateral visual field defect in the left eye of a patient with a peripapillary staphyloma. Top, Visual field of
the left eye shows marked enlargement of the physiologic blind spot. Bottom left, Appearance of left ocular fundus. Bottom
right, Axial computed tomographic scan shows ovoid enlargement of posterior aspect of the left globe (arrow). The patient’s
visual acuity in this eye was 20/20.
Figure 2.27. Unilateral visual field defect in a patient with segmental hypoplasia of the right optic nerve. Visual acuity was
20/20 in the eye. Left, Kinetic perimetry using a Goldmann perimeter shows marked inferior altitudinal defect that does not
obey the horizontal midline. Note preservation of the central field to small isopters. Right, Fundus photograph shows absence
of the upper part of the disc substance. The thin arrow indicates the location of the optic disc and the thick arrow indicates
the scleral crescent.
Figure 2.28. Bilateral visual field defect in a

patient with a tumor in the region of the optic
chiasm. Top, Static perimetry reveals a bilateral
temporal hemianopia, worse in the right eye
(right). Bottom, Sagittal (left) and coronal
(right) T1-weighted magnetic resonance im-
ages show a large mass in the sella turcica with
suprasellar extension (large arrows). The mass
compresses and elevates the optic chiasm
(small arrows).
Figure 2.29. Preoperative and postoperative visual fields in a patient with a craniopharyngioma. A and B, Kinetic perimetry
reveals an incomplete incongruous left homonymous hemianopia. C, Axial computed tomographic scan shows an enhancing
lesion in the suprasellar region. D and E, Marked improvement in visual fields following removal of the tumor. The homonymous
field defect resulted from compression of the right optic tract by the mass.
Figure 2.30. Bilateral visual field defects in a patient with an occipital lobe infarct. Top, Static perimetry using a Humphrey
visual field analyzer shows a left homonymous field defect with macular sparing. Middle, T2-weighted axial magnetic resonance
image shows a hyperintense region consistent with an infarct (medium arrow) in the right occipital lobe. Note normal appearance
of the posterior aspect of the right occipital lobe (thick arrow), corresponding to the macular sparing. In addition, the deep
portion of the calcarine fissure (thin arrow), which has only monocular representation and is responsible for the temporal
crescent, also appears normal. Bottom, Kinetic perimetry confirms a left homonymous hemianopia with macular sparing and
sparing of the temporal crescent of the visual field of the left eye.
Figure 2.31. Bilateral visual field defects in a patient with a progressive retinal cone dystrophy. Top, Static perimetry shows
dense central field defects with extension toward the periphery. Bottom, Kinetic perimetry demonstrates dense central scotomas
with sparing of the peripheral visual field of both eyes.
Figure 2.32. Bilateral visual field defects in a patient with pseudotumor cerebri. Kinetic perimetry demonstrates complete
loss of the nasal visual field of both eyes, with involvement of the temporal fields as well. (Figure continues.)
Figure 2.32. Continued. Fundus pho-

tographs show bilateral chronic papil-
ledema with early atrophy.
Figure 2.33. Bilateral visual field defects in a patient with bilateral optic disc drusen. A and B, Static perimetry reveals
significant nasal field loss in both eyes. C, Axial computed tomographic scan set at bone window density shows calcified
drusen. D and E, Fundus photographs show extensive optic disc drusen. Note absence of visible nerve fiber layer and constriction
of retinal arteries.
be strongly suspected, especially if the deficit is in the 5. Look at the specific shapes, patterns, and features of the
superior temporal quadrant in each eye (Fig. 2.34). If the visual field loss (Figs. 2.40–2.43 and Table 2.4). Does the
visual field loss is nasal in one eye and temporal in the defect respect either the horizontal or vertical meridians?
other eye (i.e., homonymous), then a retrochiasmal loca- What is the shape of the deficit (arcuate, oval, circular,
tion should be suspected (Fig. 2.35). Binasal defects or pie-shaped, irregular)? Does the deficit ‘‘point’’ to the
a nasal deficit in only one eye should generate a suspicion blind spot or to fixation? If there is visual field loss in
of glaucoma, various nonglaucomatous optic neuropa- both eyes, is it congruous or incongruous, symmetric be-
thies, or certain types of retinal disorders (Figs. 2.36 and tween the two eyes, or asymmetric? Do the edges of the
2.37). A central deficit in one or both eyes may indicate defect have a steep or a gradual sloping profile? These
a macular disorder (especially if the visual field defect and other specific features of the visual field should pro-
does not connect to the blind spot) or an optic neuropathy vide confirmatory information for the location of the
(Figs. 2.38 and 2.39). With this simple step, a global view damage determined by Step 4 or allow one to differentiate
of visual field properties is generated, and a hierarchy of among several possible alternative locations. However,
potential locations of damage along the visual pathway it should not be used as the initial basis for generating a
and probable disease entities is hypothesized. hypothesis about location of damage. Attention to
Figure 2.34. Mild superior bitemporal field defect in a patient with 20/20 vision in both eyes. The gray scale representation
demonstrates the superior temporal deficit respecting the vertical meridian in both eyes, although the probability plots do not
show the deficit in the right eye. The patient was found to have a pituitary adenoma.
Figure 2.35. Left homonymous hemianopia with macular sparing in a patient with a right occipital lobe infarct. Top, Static
perimetry demonstrates a dense left homonymous hemianopia with about 5⬚ of inferior macular sparing. Note marked congruity
of the field defects in the two eyes. Bottom, Kinetic perimetry reveals that the homonymous field defect has both absolute and
relative features. The congruous nature of the defects is apparent, at least with small isopters. Middle, Axial T1-weighted
magnetic resonance shows hyperintensity in right occipital lobe, consistent with the congruous homonymous visual field defect.
Figure 2.36. Bilateral visual field defects in a patient with bilateral optic nerve pits and focal loss of the nerve fiber layer.
A, Kinetic perimetry in left eye shows small superior arcuate defect encroaching on fixation. B, Kinetic perimetry in right eye
shows large superior nasal/arcuate defect. C, Fundus photograph of left eye shows a small inferotemporal optic pit (large
arrow) and loss of nerve fiber layer in the inferior arcuate region (small arrows). D, Fundus photograph of the right eye shows
an inferior pit (large arrow) associated with a broad region of nerve fiber loss in the inferior and inferotemporal region (small
arrows).
A B
Figure 2.37. Bilateral visual field defects in a patient with postpapilledema optic atrophy. A and B, Kinetic perimetry shows
mild loss of the nasal visual field in the left (A) and right (B) eyes. Note that most of the field loss is relative. (Figure continues.)
C D
Figure 2.37. Continued. C and D, Fundus photographs show moderate postpapilledema optic atrophy.
Figure 2.38. Bilateral visual field de-

fects in a patient with bilateral central se-
rous chorioretinopathy. A and B, Kinetic
perimetry reveals bilateral central defects
with normal peripheral fields. C and D,
Early (C) and late (D) fluorescein angiog-
raphy shows leakage of dye consistent
with central serous chorioretinopathy in
the posterior pole of the left eye (arrows).
Figure 2.39. Improvement in a visual field defect as detected by static perimetry in a patient with optic neuritis over a 15-
day period. Note marked clearing of the defect. (From Keltner JL, Johnson CA, Spurr JO, et al. Visual field profile of optic
neuritis: One year followup in the Optic Neuritis Treatment Trial. Arch Ophthalmol 1994;112⬊946–953.)
Figure 2.40. Visual field defects indicating an anterior chiasmal mass in a 7-year-old child with decreased vision in the left
eye. A, Kinetic perimetry in the left eye reveals a dense central scotoma with constriction of the peripheral field. B, Kinetic
perimetry in the right eye reveals a supertemporal field defect (junctional scotoma of Traquair). C, Axial computed tomographic
scan shows a large circular lesion in the suprasellar region (arrows). At surgery, a craniopharyngioma was found and removed.
D, After surgery, kinetic perimetry shows substantial improvement in the visual field of the left eye. E, Kinetic perimetry in
the right eye reveals a normal visual field.
Figure 2.41. Two examples of visual field deficits produced by lesions of the lateral geniculate body (LGB). Top, Kinetic
perimetry from a patient who experienced a stroke reveal a left quadruple sectoranopia from damage to the LGB in the territory
of the distal anterior choroidal artery. Bottom, Right homonymous horizontal sectoranopia with metastatic cancer to the LGB
in the region supplied by the lateral choroidal artery. (Courtesy of Dr. William T. Shults.)
specific features of the visual field before getting a global New Perimetry Tests
view of the visual field from Step 4 may lead to misinter-
pretation of visual field information. Automated perimetry has enhanced the clinical utility of
visual field testing by providing standardized procedures,
quantitative measures, normative population characteristics,
The approach to visual field interpretation outlined above immediate statistical analyses, new graphic representations
is not intended to cover all possible scenarios but is rather of data, and many other desirable features. However, the
meant as a guide to identify most kinds of visual field deficits basic test procedures have essentially remained the same
and to avoid many of the common pitfalls. Once the pattern for more than 150 years. Usually, a small white stimulus is
and degree of visual field loss has been established, a differ- presented on a uniformly illuminated adapting background,
ential diagnosis needs to be determined. If there is doubt and the detection threshold of the stimulus is determined at
about the validity of visual field results, the test should be various locations throughout the visual field.
repeated when the patient is well-rested. Pathologic visual In order to improve sensitivity of visual field testing, sev-
field changes usually are replicable, whereas nonpathologic eral test procedures have been modified for use in perimetry.
visual field changes typically are not. If there is concern Although the tests vary widely in terms of the visual func-
about fatigue affecting visual field results, a shorter test pro- tions that they measure, they have a common objective: by
cedure should be employed. creating a unique stimulus display, these tests attempt to
Table 2.4
Differential Diagnosis of Visual Field Deficits
I. GENERAL DEPRESSION
A. Cataract (diffuse depression from cataracts may improve with
dilation)
B. Corneal disease (shows no improvement with dilation)
C. Other media opacities
D. Some optic neuropathies
II. ENLARGED BLIND SPOT
A. Optic nerve disease
1. Papilledema and big blind spot syndrome
2. Drusen of the optic nerve head
3. Congenital optic nerve lesion (coloboma, staphyloma)
4. Optic neuritis
B. Retinal disease
1. Multiple evanescent white dot syndrome (MEWDS)
2. Acute zonal occult outer retinopathy (AZOOR)
C. High myopia
III. ARCUATE, ALTITUDINAL, NASAL STEP, NASAL DEPRESSION
A. Optic nerve disease
1. Glaucoma
2. Papilledema
3. Drusen of the optic nerve head
4. Other optic neuropathies (AION, optic neuritis, etc.)
B. Branch artery occlusion
IV. CROSSES THE VERTICAL AND HORIZONTAL MERIDIANS
A. Retinal disease
1. Ring scotomas, peripheral depression, “scalloped” field loss
B. Optic neuropathy
1. Generalized depression, sparing of central vision
C. Fatigue, poor testing ability
1. Fatigue in conjunction with visual pathology
D. Malingering
1. Peripheral depression, square visual fields, spiraling or crossed
isopters, inconsistent patterns of loss
V. CENTRAL OR CENTROCECAL DEFECTS
A. Maculopathy (visual acuity often more affected than visual field)
B. Optic neuropathies of all types
VI. BITEMPORAL DEFECTS
A. Superior bitemporal defects (pituitary adenoma)
Figure 2.42. Visual field defects caused by postgeniculate lesions in the B. Inferior bitemporal defects (craniopharyngioma, hypothalamic
temporal (top), parietal (middle), and occipital (bottom) lobes as defined tumor)
by static perimetry. Top, Right incomplete incongruous homonymous hemi- VII. HOMONYMOUS HEMIANOPSIA
anopia, denser above, from left temporal lobe lesion. Middle, Left incom- A. Complete homonymous hemianopsia
plete incongruous homonymous hemianopia, denser below, from lesion of 1. Retrochiasmal defect with no further localizing value
the right parietal lobe. Top, Right congruous superior quadrantanopia from B. Tongue- or keyhole-shaped homonymous defect, or remaining
lesion of the inferior aspect of the left occipital lobe. visual field
1. Lateral geniculate lesion
C. Incongruous homonymous hemianopsia (anterior optic tract,
radiations)
isolate (or strongly bias) threshold responses to be mediated 1. Optic tract
by a specific subpopulation of neural mechanisms, instead 2. Temporal lobe (“pie in the sky” defect)
of the wide range of neural mechanisms stimulated by con- 3. Parietal lobe (“pie on the floor” defect)
ventional perimetry. D. Highly congruous homonymous hemianopsia
These test procedures have several theoretical advantages. 1. Occipital lobe lesion
First, because these tests are designed to target specific vis- a. “Cookie cutter” punched-out lesion
ual mechanisms, their response properties bear a strong link- b. Macular sparing
age to the underlying physiology and anatomy of the visual c. Temperal crescent
pathways. Second, if certain diseases cause selectively d. Statokinetic dissociation
greater amounts of damage to some visual mechanisms than
others, these new test procedures may be able to detect early
losses or changes in visual function that may not otherwise
be noticed with conventional perimetry. Finally, because
L R
Figure 2.43. Complete homonymous hemianopia with macular sparing from an occipital lobe lesion. A and B, Kinetic
perimetry shows a complete left homonymous hemianopia with about 5⬚ of macular sparing. C, Axial computed tomographic
scan shows a small low-density area, consistent with an infarct, in the right occipital lobe (arrow), with sparing of the occipital
tip.
these test procedures are designed to isolate specific subpop- (‘‘blue’’) stimulus to isolate and measure the sensitivity of
ulations of neural mechanisms, they eliminate much of the short-wavelength chromatic mechanisms. The bright yellow
redundancy and overlap that is normally present in the visual background depresses the sensitivity of middle (‘‘green’’)
pathways. By reducing this redundancy, it becomes easier and long (‘‘red’’) wavelength mechanisms, thereby allowing
to detect early, subtle losses or changes in visual function, the sensitivity of the short-wavelength system to be mea-
even if these losses are not selective (173). sured using a large blue target. The test is available on sev-
In this section, we briefly describe five perimetry tests eral automated projection perimeters and can utilize the same
that appear to have the greatest potential for clinical utility test strategies, target presentation patterns, and other param-
in neuro-ophthalmologic diagnosis: Short Wavelength Auto- eters that are employed in conventional automated perimetry
mated Perimetry [SWAP], High-Pass Resolution Perimetry (174–177). The test procedure is commercially available for
(HRP), Flicker Perimetry, Motion and Displacement Perim- the Humphrey Field Analyzer, which provides a statistical
etry, and Frequency Doubling Perimetry. analysis procedure and age-related normative database for
interpreting results. The SITA strategy is also available for
Short Wavelength Automated Perimetry (SWAP) SWAP (178).
Short Wavelength Automated Perimetry [SWAP] utilizes A number of longitudinal and cross-sectional investiga-
a bright yellow background and a large short-wavelength tions have established that SWAP is not only an early indica-
tor of damage from glaucoma but that it also detects visual try. In cases in which visual field loss was evident for con-
field defects that are not determined by conventional auto- ventional automated perimetry, the SWAP deficit was more
mated perimetry (174–177). About 5–20% of glaucoma sus- extensive (Figs. 2.45 and 2.46).
pects with normal visual fields when tested by conventional
automated perimetry have localized deficits when testing High-Pass Resolution Perimetry (HRP)
with SWAP. In addition, SWAP deficits are present in
35–40% of high-risk glaucoma suspects compared with High-pass resolution perimetry (HRP) was developed by
about 8% of low-risk glaucoma suspects. Longitudinal in- Frisén (180,181) and consists of a series of ‘‘ring’’ targets
vestigations demonstrate that SWAP is able to predict the of varying size that are generated on a video monitor by
onset and location of subsequent glaucomatous visual field performing a ‘‘high pass’’ spatial frequency filtering of a
loss by conventional perimetry 3–5 years before its occur- target incorporating a light circular center and a dark annular
rence. SWAP is also able to predict subsequent progression surround (Fig. 2.47). The average luminance of the ring stim-
of glaucomatous visual field loss (Fig. 2.44). However, its ulus is equal to the background. This combination creates
high variability limits its ability to detect progression (176). a vanishing optotype. The special property of a vanishing
SWAP is also useful for patients with neuro-ophthalmo- optotype is that detection and resolution occur at approxi-
logic disorders. Keltner and Johnson (179) studied 40 pa- mately the same threshold. The ring test is believed to pre-
tients with various neuro-ophthalmologic disorders. In some dominantly test the function of parvocellular mechanisms
instances, SWAP deficits were present in eyes with normal that are responsible for the processing of fine detail, form
visual fields obtained with conventional automated perime- vision, and related spatial vision functions (181).
Sample et al. (182) reported a 67% agreement between
HRP and the Humphrey Field Analyzer in a group of normal
persons, ocular hypertensives, and patients with primary
open-angle glaucoma. In patients with visual field defects
detected with both tests, there was a 92% agreement in the
location of the deficit. Lachenmayr et al. (183,184) reported
that HRP was significantly less sensitive in detecting early
glaucomatous visual field loss than either conventional auto-
mated perimetry or flicker perimetry (see later).
Evaluations of HRP in patients with neuro-ophthalmo-
logic disorders are encouraging (180–182,185–192). For ex-
ample, Wall et al. (188) found that in patients with pseudotu-
mor cerebri, HRP had slightly lower sensitivity and slightly
higher specificity than automated perimetric testing using a
Humphrey Field Analyzer, although the differences were not
statistically significant. Wall (187) also reported that HRP
was useful for evaluating patients with optic neuritis and
was especially sensitive in revealing subtle deficits in the
fellow ‘‘uninvolved’’ eyes of optic neuritis patients.
Most importantly, the ring test has been shown to have low
retest variability (188,193). Chauhan and coworkers have
shown that the ring test can detect visual field progression in
glaucoma significantly earlier than conventional automated
perimetry.
The main advantages of HRP are its relatively quick ex-
amination time, the interactive feedback the test procedure
provides to patients, excellent patient ergonomics, low retest
variability, and the high degree of patient preference for HRP
over conventional perimetric techniques. The main disad-
vantages are its greater susceptibility to blur, and alignment
problems (e.g., lens rim artifacts).
Figure 2.44. Results of a 5-year longitudinal comparison of standard

Flicker Perimetry
white-on-white perimetry (left) and short wavelength automated perimetry
[SWAP] (right) in an ocular hypertensive patient who converted to glau-
Another psychophysical procedure that shows promising
coma. Note that the SWAP deficit was present before the standard visual initial results for detecting and evaluating subtle visual loss
field loss, and predicted its development and location several years later. is the detection of flicker. The rationale underlying flicker
(From Johnson CA, Adams AJ, Casson EJ, et al. Blue-on-yellow perimetry perimetry testing is that high temporal frequencies of flicker
can predict the development of glaucomatous visual field loss. Arch Oph- preferentially stimulate ganglion cells that project to the
thalmol 1993;111⬊645–650.) magnocellular layers of the lateral geniculate body. M-cell
Figure 2.45. Gray scale and total deviation plots for standard automated perimetry (top) and short wavelength automated
perimetry [SWAP] (bottom) for an asymptomatic patient with multiple white matter abnormalities on magnetic resonance
imaging (thick and thin arrows). The standard visual fields are normal, whereas SWAP reveals a right homonymous hemianopia,
probably related to the white matter lesions in the left occipital lobe (large arrow). (From Keltner JL, Johnson CA. Short
wavelength automated perimetry [SWAP] in neuro-ophthalmologic disorders. Arch Ophthalmol 1995;113⬊475–481.)
fibers primarily consist of large-diameter ganglion cell axons distinguishing which ocular hypertensives with normal vis-
that may be preferentially damaged in glaucoma. Thus, by ual fields will develop glaucomatous visual field loss within
presenting a stimulus that preferentially stimulates this group several years (194). Thus, flicker perimetry seems to be a
of nerve fibers, mild glaucomatous deficits may be more useful adjunct to conventional automated perimetry, espe-
readily detected. Flicker perimetry is effective in detecting cially for detecting early glaucomatous losses.
mild glaucomatous visual field loss. Indeed, in some ocular Flicker sensitivity has several desirable features as a clini-
hypertensives, flicker deficits are found in locations within cal diagnostic test procedure. Unlike many psychophysical
the visual field in which there were normal responses when tests, flicker detection thresholds are relatively unaffected
tested using conventional automated perimetry. In addition, by moderate amounts of blur, light scatter, and other forms
this form of perimetry seems to have predictive value in of image degradation (195). Thus, optical factors such as
Figure 2.46. Pretreatment (top) and posttreatment (bottom) standard visual fields (left) and Short Wavelength Automated
Perimetry [SWAP] fields (right) in a patient with a right optic nerve sheath meningioma. Standard perimetry shows a minimal
inferonasal defect in the visual field of the right eye (top left), whereas SWAP shows an extensive reduction in sensitivity (top
right). Middle, T1-weighted axial MR image after intravenous injection of paramagnetic contrast material shows enlargement
and enhancement of the posterior portion of the right optic nerve (arrow). Following radiation treatment, standard automated
perimetry is normal (bottom left), but SWAP shows a persistent nasal step (bottom right). (From Keltner JL, Johnson CA.
Short wavelength automated perimetry [SWAP] in neuro-ophthalmologic disorders. Arch Ophthalmol 1995;113⬊475–481.)
cataract, refractive error, and media opacities do not influ- adapted for use as a perimetric test procedure. As with high
ence flicker sensitivity as much as they affect visual acuity temporal frequency flicker, the rationale underlying this test
and related psychophysical tests. The primary disadvantage procedure is that motion is preferentially detected by M-cell
of flicker sensitivity is that specialized equipment must be mechanisms, which may be more susceptible to glaucoma-
used. Most automated projection perimeters and other clini- tous damage. Thresholds for detection of motion may there-
cal instruments are not easily modified to perform this type fore reveal early glaucomatous defects in localized visual
of visual field testing. field locations.
Two different approaches have been used to evaluate mo-
Motion Perimetry tion sensitivity of the visual field. The first method measures
The ability to detect motion or small displacements of a the minimum displacement of a small target superimposed
stimulus at various locations in the visual field can be on a uniform background that can be detected as movement
Figure 2.48. An example of the video stimuli used to determine motion

and coherence thresholds for motion perimetry. (From Wall M, Ketoff KM.
Random dot motion perimetry in patients with glaucoma and in normal
subjects. Am J Ophthalmol 1995;120⬊587–596.)
Longitudinal studies are needed to verify the clinical signifi-

cance of these findings and those of Wall and Montgomery
(203) that motion perimetry is able to detect localized visual
field defects in patients with idiopathic intracranial hyperten-
sion (see Chapter 5).
Motion and displacement perimetry have several desirable
characteristics as clinical diagnostic test procedures. Motion
detection is a very robust visual function, being only mod-
Figure 2.47. High-pass resolution perimetry targets. (From Frisén L. High
estly affected by such factors as contrast, luminance, adapta-
pass resolution perimetry: Recent developments. In Heijl A, ed. Perimetry tion level, and target size (207). In addition, motion detec-
Update 1988/1989. Amsterdam, Kugler and Ghedini, 1989⬊383–392.) tion, like flicker sensitivity, is very resistant to the effects
of cataract, refractive error, and other forms of image degra-
dation (199). The dynamic stimulus range for motion is also
very large, especially for displacement of a single small
(196–199). Motion displacement thresholds are then deter- target.
mined for a number of visual field locations in a manner
similar to traditional static perimetry. In this way, motion Frequency Doubling Perimetry
sensitivity can be determined for small localized regions of
the visual field. The second method presents a large display When a low spatial frequency sinusoidal grating (less than
of small dots that are moving in random directions (Brown- 1 cycle/degree) undergoes high temporal frequency coun-
ian-like motion). A stimulus is produced by briefly moving terphase flicker (greater than 15 Hz), the grating appears to
a small group of dots in the same direction (coherence). have twice its real spatial frequency (i.e., there appear to be
The patient’s task is to detect this coherent direction of dot twice as many light and dark bars in the grating) (Fig. 2.49).
motion. A ‘‘motion coherence’’ threshold is determined by This phenomenon, called the frequency doubling effect,
varying the percentage of dots within the small group that was first described by Kelly (208,209). Because the fre-
are moving in the same direction (200,201), or by keeping quency doubling stimulus incorporates a low spatial fre-
coherence constant and changing the size of the patch of quency and a high temporal frequency, it is ideally suited
coherent motion (202–204) (Fig. 2.48). This test evaluates for stimulation of M-cell mechanisms and has been adapted
large visual field regions but requires the combined input for use as a screening test for glaucoma by Maddess and
from a population of cells to be able to detect motion. Other Henry (210). Johnson and Samuels (211) modified the origi-
versions of this test limit the size of the stimulus so that nal test procedure to perform frequency doubling perimetry
more localized regions of the visual field can be tested of localized visual field regions. In its initial form, frequency
(202,203,205). doubling perimetry evaluated 17 visual field locations (four
Studies of motion and displacement threshold perimetry per visual field quadrant, each 10⬚ in diameter, plus a stimu-
indicate that motion sensitivity is abnormal in glaucoma pa- lus presented to the central 5⬚ of the visual field) throughout
tients, and that motion thresholds are sometimes able to de- the central 20⬚ radius of the visual field. In its current form
tect subtle glaucomatous losses that are not evident with (the Humphrey Matrix FDT perimeter), 54 and 72 test loca-
conventional automated perimetry (196–199,202,204,206). tions matching the 24–2 and 30–2 grids of conventional
greater than 15 Hz patients prefer the test to conventional automated perimetry.

counterphase flicker Third, it has low test-retest variability. Fourth, the equipment
is small and portable and does not require a special room
with controlled lighting. Fifth, it is unaffected by blur of up
to 3 diopters for FDT using the 24–2 pattern and 6–7 diop-
ters for the initial version with larger stimuli. Finally, pa-
tients can wear their normal spectacle correction to take the
test, even if they have a bifocal added. The primary disadvan-
tage of frequency doubling perimetry is that it is affected
by cataract, as are all tests of contrast sensitivity.
} COLOR VISION
A comprehensive discussion of color vision is beyond the
1 cycle/ degree or less scope of this chapter. Instead, we will limit our discussion
of this subject to an overview of normal color vision and its
Figure 2.49. Schematic representation of the stimulus used in frequency underlying physiologic mechanisms, congenital and ac-
doubling perimetry.
quired color vision deficiencies, the use and interpretation
of common clinical color vision tests, and the diagnostic
value of color vision testing in ophthalmic and neurologic
automated perimetry are utilized. A contrast threshold is ob- disorders. Several excellent sources are available (13,
tained for detection of the frequency-doubled stimuli at each 215,216) for those interested in a more thorough discussion
visual field location. The sensitivity and specificity of fre- of color vision, the history of color vision research, and a
quency doubling perimetry are similar to those of conven- detailed account of color vision deficiencies in specific ocu-
tional automated perimetry for detection of glaucomatous lar disorders. In particular, the book by Kaiser and Boynton
visual field loss (sensitivity and specificity of 95% or better) (216) contains an especially interesting chapter pertaining
(211–213) (Fig. 2.50). In addition, results obtained in pa- to the history of color vision.
tients with nonglaucomatous optic neuropathies suggest that
frequency doubling perimetry is also useful for evaluation General Principles of Color Testing
of such patients (213, 214). Commercial versions of the fre-
quency doubling perimetry test developed by Welch Allyn, From a clinical diagnostic standpoint, it is important to
Inc. (Skaneateles, NY) is available from Carl Zeiss Meditec distinguish whether a color vision deficiency is congenital
(Dublin, CA). or acquired (Table 2.5). Congenital color vision deficits are
Frequency doubling perimetry has several advantages as usually easy to classify using standard clinical color vision
a clinical diagnostic tool. First, it is a rapid test. Second, tests because color discrimination is usually impaired for a
Figure 2.50. Comparison of results obtained for the Humphrey Field Analyzer and frequency doubling perimetry in a patient
with glaucomatous visual field loss.
Table 2.5
Differences Between Congenital and Acquired Color Defects
Cogenital Acquired
Usually color vision loss in specific spectral regions. Often no specific spectral region of color discrimination loss.
Less marked dependence of color vision on target size and illuminance. Marked dependence of color vision on target size and illuminance.
Characteristic results obtained on various clinical color vision tests. Conflicting or variable results may be obtained on various clinical color
vision tests.
Many object colors are named correctly, or predictable errors are made. Some object colors are named incorrectly.
Both eyes are usually affected to the same degree. The two eyes are often affected to different degrees.
Usually there is no other visual complaint or problems. Often there are additional visual complaints, reduced visual acuity or visual
field loss.
The deficit does not change appreciably over time. The defect may show clear progression or remission of color discrimination
loss.
Are almost always red/green deficits and are mostly found in males. Are often blue or blue-yellow deficits.
Adapted from Pokorny J, Smith VC, Verriest G, et al., eds. Congenital and Acquired Color Vision Defects. New York, Grune & Stratton, 1979, Table 4.1.
specific region of the visual spectrum, and the deficits are optic nerve disease, using specialized laboratory techniques,
long-standing, stable, symmetric in the two eyes, and unas- suggest that although many optic nerve and retinal diseases
sociated with other visual symptoms or complaints. In pa- affect more than just a single opponent pathway, the magni-
tients with acquired color vision loss, however, color dis- tude of loss in such disorders is often greater in one of the
crimination may be impaired throughout the visual spectrum opponent channels than in any of the others (224–227). Ce-
or along a specific axis, and the deficits may be mild or rebral dyschromatopsias are uncommon, but result in severe
severe, of sudden onset, asymmetric, and often associated color vision loss, sometimes producing a total achromatopsia
with other visual symptoms or complaints. (vision in black and white only) (228).
Table 2.6 presents a list of color vision deficits associated It should be emphasized that color comparison tests, al-
with various ocular and neurologic disorders. Additional in- though only qualitative in nature, can provide valuable infor-
formation may be found in Pokorny et al. (13). mation concerning subtle visual anomalies. Using pages
Investigations of acquired color vision losses in retinal and from the pseudoisochromatic plates, colored bottle caps, or
other brightly colored objects, comparisons of color appear-
ance can be very effective in detecting subtle differences
Table 2.6 between the two eyes. The brightness or saturation of the
Acquired Color Vision Deficits Associated with Eye Disease colored objects may be less in one eye, making the object’s
color appear to be dim or washed out. Similarly, comparisons
Condition Color Vision Defect
within the same eye across the vertical and horizontal mid-
Glaucoma B-Y line, or between central vision and the mid-periphery can
Retinal detachment B-Y detect subtle differences in color appearance that are indica-
Pigmentary degeneration of retina (including RP) B-Y tive of an early visual disturbance.
Age-related macular degeneration B-Y
Myopic retinal degeneration B-Y Normal Color Vision Mechanisms
Chorioretinitis B-Y
Retinal vascular occlusion B-Y Beginning approximately 200 years ago, a controversy
Diabetic retinopathy B-Y existed concerning the mechanisms underlying normal color
Hypertensive retinopathy B-Y vision. The trichromatic theory of color vision, usually at-
Papilledema B-Y tributed to Young (217) and Helmholtz (218), was that there
Methyl alcohol poisoning B-Y
were three different receptors that were maximally sensitive
Dominant hereditary optic atrophy B-Y
Central serous retinopathy B-Y
to wavelengths in different regions of the visual spectrum,
Optic neuritis R-G with sensitivity peaks at short (blue), middle (green), and
Tobacco-alcohol (ETOH) or toxic amblyopia R-G long (red) wavelengths, respectively. Although maximally
Leber’s optic atrophy R-G sensitive to a specific part of the spectrum, each of these
Lesions of the optic nerve and posterior pathways R-G receptor types has some degree of sensitivity to wavelengths
Papillitis R-G throughout most of the visual spectrum. An efficient means
Stargardt’s disease R-G of uniquely signaling thousands of different colors is
Best’s disease R-G achieved by examining the ratio of excitation of the three
Juvenile macular degeneration R-G or B-Y receptors. A large amount of psychophysical evidence was
Adapted from Adams AJ, Verdon WA, Spivey BE. Color vision. In: Tasman W,
accumulated in support of the trichromatic theory of color
Jaeger EA, eds. Duane’s Foundations of Clinical Ophthalmology. Vol 1, Chap 52, vision.
pp 1–43, Philadelphia, JB Lippincott, 1996. An alternate view of color vision, the opponent-process
Figure 2.51. Schematic representation of the ab-

sorption spectra of the three major cone types as-
sociated with human color vision. S, short wave-
length (blue) cone; M, middle wavelength (green)
cone; L, long wavelength (red) cone. (From Kaiser
PK, Boynton RM. Human Color Vision. Washing-
ton DC, Optical Society of America, 1996.)
theory was proposed by Hering (219), who believed that

there were two chromatic mechanisms (red-green and blue-
yellow) and one achromatic mechanism (black-white) that
paired sensations in an opposing or antagonistic manner.
Much of the evidence he provided to support this theory was
observational. For example, after prolonged viewing of a
bright red stimulus, a neutral color would appear to be green.
Surrounding a neutral color with a large blue annulus would
cause it to appear yellow. In addition, some color combina-
tions would give rise to the appearance of both components
(e.g., blue-green or red-yellow), but there was never the ap-
pearance of yellow-blue or red-green. The opponent process
theory was proposed as a means of accounting for the six
distinct color sensations (blue, green, yellow, red, black, and
white) proposed by Hering (219).
There is abundant psychophysical and physiologic evi-
dence supporting both theories (13,215,216). Initially, vi-
sual stimuli are processed by three types of cone photorecep-
tors, one with peak sensitivity in the short wavelength region
(approximately 440 nm), one with peak sensitivity in the
middle wavelength region (approximately 530–540 nm),
and one with peak sensitivity in the long wavelength region
(approximately 560–580 nm) (Fig. 2.51). The output from
the three cone photoreceptors is then transmitted to neurons
in the inner retina that process information according to two
opponent chromatic mechanisms (yellow-blue and red-
green) and one achromatic mechanism (black-white), in ac-
cordance with the opponent process theory (Fig. 2.52). Al-
though there is additional spatial and temporal processing
of this information at different levels of the visual pathways,
this opponent coding of chromatic information is carried
through to the higher visual centers.
Clinical Tests of Color Vision

A wide variety of color vision tests are available clinically.
Because most of them were designed to evaluate congenital
red-green color vision deficiencies, many do not permit ade- Figure 2.52. An illustration of a simple model for obtaining opponent
quate testing of blue-yellow deficits or optimal characteriza- process responses from the three cone types. Interactions within the inner
tion of acquired color vision losses. A number of techniques retina transform trichromatic photoreceptor responses into center-surround
can be used to evaluate acquired color vision deficiencies opponent responses at the retinal ganglion cell level. An achromatic (black-
white) luminance channel is activated by the summed input from middle
(220–222), but most of them are not available for routine
(M) and long (L) wavelength cones. The red-green (r-g) spectrally opponent
clinical use. pathway is activated by the difference in output by the M and L cones.
As with any test of visual function, it is important that The yellow-blue (y-b) spectrally opponent pathway by the difference in
the testing conditions are standardized and are performed in output by the short wavelength (S) cones and by the summed output
the proper manner. Each of the clinically available color of the M and L cones (the luminance channel). (From Kaiser PK,
vision tests comes with a set of detailed instructions for ad- Boynton RM. Human Color Vision. Washington, DC, Optical Society
ministering the test and interpreting the results. These in- of America, 1996.)
structions should be judiciously followed, because erroneous tion of figures is made on the basis of color discrimination
results can sometimes be obtained if the tests are not properly and not other cues.
administered. The main advantages of color vision tests using pseudo-
An important factor for all clinical color vision test proce- isochromatic plates are that they are quick and easy to per-
dures is the use of proper lighting, both in terms of having form and therefore are an excellent screening procedure for
an adequate amount of light for the test and having a light distinguishing between normal color vision and any type of
source with the proper spectral distribution. Most color vi- color vision abnormality. The disadvantages of pseudoiso-
sion tests specify that testing should be performed under chromatic plate tests are that they have rather limited ability
daylight illumination. Because natural daylight varies in to classify color vision deficits and determine their severity,
spectral distribution and intensity, it is not a reliable source. and they have little or no ability (depending on the particular
Instead, a standardized daylight lighting source (Illuminant test) to test for blue-yellow color vision deficits.
C) is preferred. This is usually provided by a Macbeth Easel
Lamp, which consists of a tungsten filament bulb that is
Farnsworth Panel D-15 Test
located behind a light blue glass filter. The filtered light
provides an appropriate source of Illuminant C for color The Farnsworth Panel D-15 test is a color arrangement
vision testing. Because of the high cost of the Macbeth Easel test consisting of 15 caps that form a color circle covering
Lamp, an alternative approach consists of using a specialized the visual spectrum. A reference cap is permanently fixed
fluorescent bulb such as the Verilux daylight F15 T8 VLX in the arrangement tray; the other 15 caps are placed in a
(or an equivalent fluorescent tube with a high color rendering scrambled order in front of the patient. The patient’s task is
index) placed in a desk lamp (13). to select the cap that is closest in hue to the reference cap
and place it next to the reference cap in the tray. The patient
Pseudoisochromatic Plates is then asked to continue to place the caps in the tray, one
Pseudoisochromatic plates are the most common color at a time, so that they are arranged in an orderly transition
vision tests employed clinically. A number of pseudoiso- of hue. Once all the caps are in the tray, the patient has an
chromatic plate tests are available, although the Ishihara and opportunity to make any final changes in the order of caps.
Hardy-Rand-Rittler are the most commonly used versions The caps are designed so that persons with normal color
in a clinical setting. Each of these tests consists of a series vision or very mild color vision deficits (e.g., mild anoma-
of plates that contain colored dots of varying size and bright- lous trichromacy) will arrange the caps in a perfect color
ness. The tests are designed so that humans with normal circle. Patients with moderate to severe protan (red), deutan
color vision will see numbers, shapes, or letters as a conse- (green), or tritan (blue) color vision deficits will confuse
quence of grouping certain colored dots together to form a colors across the color circle, so that the arrangement con-
figure. Depending on how the particular test is designed, tains misplaced caps. The specific arrangement indicates the
those with color deficiencies will either be unable to see the type of color deficiency (Fig. 2.53). The Panel D-15 test
figure because the figure dots are confused with the back- does not indicate the degree of color deficiency, other than
ground dots, or they will see a figure different from that to separate color normals and mild anomalous trichromats
seen by persons with normal color vision. The variation in from those with moderate to severe color vision deficiencies.
size and brightness of the dots is used to ensure that recogni- A desaturated D-15 test has been developed and validated
Figure 2.53. Examples of tritan (blue), protan (red), and deutan (green) color vision deficiencies as determined by the
Farnsworth Panel D-15 Test. (From Elliott DB. Supplementary clinical tests of visual function. In Zadnik K, ed. The Ocular
Examination. Philadelphia, WB Saunders, 1996.)
Figure 2.54. Examples of tritan (blue), protan

(red), and deutan (green) color vision deficiencies
as determined by the Farnsworth-Munsell 100 Hues
Test. The figures on the left depict the results scored
according to the method originally described by
Farnsworth, whereas the figures on the right depict
a modified scoring system. (From Kinnear PR. Pro-
posals for scoring and assessing the 100-Hue test.
Vision Res 1970;10⬊423–433.)
by Lanthony (13), and it detects milder color vision deficien- numbered on the back, and scoring is determined by the
cies. arrangement of the caps in the box. Depending on the
type of color deficiency, specific caps across the color
Farnsworth-Munsell 100 Hues Test circle will be confused, resulting in greater arrangement
errors in those locations. In this manner, the type of color
The Farnsworth-Munsell 100 Hues test permits both clas- vision deficit can be classified (Fig. 2.54). In addition to
sification of the type of color vision deficiency and its sever- classification of the color deficiency, its severity can be
ity. Since Farnsworth determined that 15 of the original caps quantified by determining an overall error score for ar-
were too difficult for most normals the test now consists of rangement errors. Thus, it is possible to quantify the degree
85 colored caps that are arranged in roughly equal small
of color vision deficiency and monitor progression and
steps around the color circle. Interestingly, Nichols and co-
remission of acquired color losses. Normative values for
workers (223) have shown that at least two more caps in the
different age groups are also available for the Farnsworth-
blue range are too difficult for many normals.
The caps are divided into four boxes, and arrangements Munsell 100 Hues test (13). There is evidence that certain
of caps are performed one box at a time. In each box, there types of optic neuropathies, including optic neuritis, can
are two reference caps, one at each end, that are permanently be diagnosed reliably using only 21 of the 85 chips (chips
attached to the box. The other caps are taken out of the box, 22–42) in the set (223).
scrambled, and placed before the patient. The patient is then
asked to arrange the caps so that there is an orderly transition Other Color Vision Test Procedures
in hue from one reference cap to another. As with the Panel
D-15 test, the Farnsworth-Munsell 100 Hues test is designed A number of instruments can be used to test color vision
so that certain caps will be confused by persons with both tests other than those described above, including the Nagel
congenital and acquired color deficiencies. The caps are anomaloscope, the Pickford-Nicholson anomaloscope, lan-
tern tests, the Lovibond Color Vision Analyzer, and the is limited. The reader interested in these additional color
Chromagraph (13, 215). However, because these devices are vision tests is directed to the aforementioned reference
not often used for routine clinical testing, their availability sources.
ELECTROPHYSIOLOGIC TESTS
Frequently, the physician is confronted with a patient who (Fig. 2.55). Granit (236) identified three fundamental pro-
has unexplained loss of vision and an apparently normal cesses that he called P-I, P-II, and P-III from the ERG of a
fundus examination. Because electrophysiologic testing cat. He proposed that these components interact to produce
often provides diagnostic clues as to the etiology of the unex- the ERG waveform, with the P-II giving rise to the leading
plained visual loss, it should be part of the neuro-ophthalmo- edge of the a-wave, P-II and P-III interacting to produce the
logic examination in selected patients. Electrophysiology b-wave, and the interaction of P-I and P-III producing the
provides an objective method for evaluating the function of c-wave.
the visual system from the retina to the visual cortex. Several The consequence of the pioneering work of Granit (236)
electrodiagnostic methods can be used to evaluate the status was a continuing search for the retinal generators that are
of individual components of the afferent visual pathways responsible for the P-I, P-II, and P-III. Tomita (237,238)
(Table 2.7). The reader interested in a more detailed account reported that the ERG components of the frog could be local-
of retinal and optic nerve electrophysiology is directed to ized in the retina by depth recording with microelectrodes,
the excellent chapter by Berson in Adler’s Physiology of the and that the retinal components corresponded to those wave-
Eye (229), as well as to several additional resource texts forms that were recorded at the cornea. Brown and Wiesel
(229–233). This section is largely based on material from (239) demonstrated that part of the a-wave was generated
in a layer external to that responsible for the b-wave, and
Berson (229) and Fishman and Sokol (232).
these investigators also found that maximum responses for
the a-, b-, and c-waves occurred in different retinal layers.
ELECTRORETINOGRAM (ERG) Subsequently, Brown and Watanabe (240) recorded a large
a-wave in the fovea of the monkey; in the periphery, the a-
Historical Overview wave was much smaller and the b-wave was relatively larger.
Their findings provided evidence that the photoreceptor
The Swedish physiologist Holmgren reported in 1865 that layer was responsible for the a-wave. Murakami and Kaneko
in vertebrates and higher invertebrates, an alteration in the (241) divided the P-III into a distal component in the receptor
electric potential occurred when light fell on the retina. layer that correlated with the onset of the a-wave (242) and
Dewar (234) subsequently recorded this electric response a proximal component generated by the inner nuclear layer.
and called it the electroretinogram. Einthoven and Jolly Armington et al. (243) identified two components of the a-
(235) identified three main components of the ERG: (a) an wave recorded under dark-adapted (scotopic) conditions.
early cornea-negative ‘‘a-wave’’; (b) a cornea-positive ‘‘b- The as component had the spectral sensitivity of the rod
wave’’; and (c) a slower, usually cornea-positive ‘‘c-wave’’ system and was depressed by light adaptation, whereas the
ap component had the spectral sensitivity of the cone system
and was relatively unaffected by light adaptation. It is now
Table 2.7
generally accepted that the leading edge of the a-wave of
Isolation of Components of the Afferent Visual Pathways Using the human ERG is generated by the rods and cones in the
Electrophysiology
Anatomical Structure Technique
Retinal pigment epithelium Electro-oculogram

Electroretinogram (flash ERG)
c-wave
Photoreceptors
Rods Rod-flash ERG (scotopic) a-wave
Cones Cone-flash ERG (photopic) a-wave
30 Hz flicker ERG
Middle retinal layers Scotopic threshold response
Flash ERG b-wave
Oscillatory potentials
Pattern ERG (P50)
Ganglion cell layer Pattern ERG (N95)
Macula or other local region Focal ERG
30 Hz flicker ERG
Optic tract, radiations, and cortex VEP
Figure 2.55. Einthoven and Jolly’s separation of retinal responses into
From Weisinger HS, Vingrys AJ, Sinclair AJ, 1996c, Table 1. three components or processes. (Courtesy of Adrian and Mathews, 1927.)
photoreceptor layer of the retina and that this can be modeled

by the photochemical events involved in the process of pho-
totransduction (243, 244).
The cellular origin of the b-wave is less clear. Henkes
(245) and Gouras and Carr (246) studied the ERG following
central retinal artery occlusion, which leaves the photorecep-
tor response intact because this layer receives its blood sup-
ply from the choroidal vasculature, not the retinal vessels.
Under these conditions, the b-wave was eliminated, whereas
a modified a-wave was preserved. Hashimoto et al. (247)
showed that responses similar in waveform to the b-wave
were present when microelectrodes were placed on opposite
sides of the inner nuclear layer. Subsequent studies by Miller
and Dowling (248) showed that the b-wave potential and
the potential recorded from Müller cells are similar across
5–6 log units of intensity, suggesting that Müller cell cur-
rents subserve the b-wave. Stockton and Slaughter (249)
showed that the ON-bipolar cells are the source of the potas-
sium ion fluxes that create the Müller cell currents and are
therefore the generators of the P-II portion of the ERG.
Rod and cone contributions to the ERG response were
initially reported by Adrian (250, 251). Photopic (cone) stim-
ulus conditions resulted in small b-waves with short latency,
whereas stimulation using scotopic (rod) conditions pro-
duced relatively large b-waves with longer latency (Fig.
2.56). The peak sensitivity of the ERG b-wave under com-
plete dark adaptation conditions is approximately 504 nm,
and the spectral sensitivity approximates the rhodopsin ab-
sorption spectrum. Under conditions of steady white light
adaptation sufficient to eliminate rod contribution to the
ERG, the peak sensitivity of the ERG b-wave shifts from
504 nm to approximately 555 nm, consistent with the
photopic (cone) system (252). The photopic b-wave can
be further separated into three distinct responses, depending
on the wavelength of the light stimulus (253,254). The
spectral sensitivity curves of these three ERG-derived
mechanisms approximate the cone pigment absorption data
from microspectrophotometric measurements of individual
cones (255,256). Thus, it would appear that ERG b-waves
provide some measure of cone and rod system activity in
primates. Figure 2.56. Normal electroretinographic response under photopic and
Microelectrode studies, as well as observations of the ef- scotopic conditions. Cone responses are generally isolated using photopic
fects of various retinotoxic agents, have helped define the adaptation conditions and 30-Hz flicker. Rod responses are isolated after 30
minutes of dark adaptation with a low luminance short-wavelength stimulus
cellular origin of the c-wave. In the cat, c-wave polarity
either as a single flash or with 10-Hz flicker. A dark-adapted scotopic white
becomes reversed when a microelectrode penetrates the ‘‘R flash measures a combined rod-cone response. (From Fishman GA, Sokol
membrane’’ of the retinal pigment epithelium (238). A mod- S. Electrophysiologic Testing in Disorders of the Retina, Optic Nerve, and
ified c-wave was also recorded intracellularly from retinal Visual Pathway. San Francisco, American Academy of Ophthalmology,
pigment epithelium by Steinberg et al. (257). These findings 1990.)
indicate that the retinal pigment epithelium must be present
to generate the c-wave. However, because the spectral sensi-
tivity of the dark-adapted c-wave corresponds to the absorp-
tion spectrum of rhodopsin and not to that of melanin con- altering the retinal state of adaptation or by using different
tained in the retinal pigment epithelium, the photoreceptors flicker rates for the stimulus. Although the rods are more
must also contribute to this response (258, 259). sensitive than the cones across most of the visible spectrum,
this difference decreases with increasing wavelength so that
Separation of Rod and Cone ERG Components it is possible to isolate a cone response if the stimulus wave-
length is greater than 680 nm. The rod contribution to the
The rod and cone components of the ERG may be sepa- ERG can be separated by recording from a dark-adapted
rated on the basis of their respective spectral sensitivities by subject and stimulating with a short wavelength or long
wavelength light that has been scotopically matched for their stimuli result in faster and larger responses. Flickering stim-
luminances. uli presented at 25 to 30 flashes per second (25–30 Hz)
ERGs are often described as having photopic (light- isolate cone responses, because the rod system is unable to
adapted) and scotopic (dark-adapted) responses. ERG wave- follow a flickering stimulus above 20 Hz (265–268). The
forms obtained from relatively intense white stimuli usually ERG elicited with a white stimulus of high luminance after
represent contributions from both the rod and cone systems 30 minutes of dark adaptation has both rod and cone compo-
(mixed response), whereas scotopic ERGs to relatively dim nents. The major contributor to both the increased amplitude
blue light can be generated by the rods alone. Photopic ERGs and implicit time is the rod component. However, an isolated
obtained on an adapting background represent responses rod response can be evoked by a low-intensity short wave-
from the cone system. The wavelength, intensity, and tem- length (blue) stimulus (232).
poral properties of the stimulus, as well as the state of retinal
adaptation are all important in separating rod and cone sys- Oscillatory Potentials
tem contributions (229,261). To successfully separate rod
In normal persons, low-amplitude rapid oscillations are
and cone responses, it is important to carefully control the
superimposed on the ascending limb of the b-wave (269).
stimulus conditions used to obtain these measures in order
These are called the oscillatory potentials (OPs). Special
to ensure that rod and cone responses have been adequately
recording procedures are required to isolate the OPs (229).
isolated. International standards for ERG testing are avail-
Bandpass filtering over 70–300 Hz will extract these oscilla-
able (262). These standards should be considered to be a
tions from the underlying a- and b-waves (Fig. 2.57), and
minimum clinical protocol, and some physicians may wish
they can then be quantified by giving their summed and
to perform more extensive evaluations by determining a
rectified amplitudes. OPs are thought to reflect activity in
complete intensity–response relationship to achieve greater
the inner retinal layers. They are of clinical importance be-
information about the nature of the retinal response (263).
cause they are often absent in patients with diabetic retinopa-
By stimulating the eye in the presence of a background
thy and other diseases that are associated with ischemia of
light sufficient to eliminate the rod response, it is possible
the inner retina (229,270).
to obtain a reasonably isolated cone response (264) (Fig.
2.57). The cone and rod ERG responses have temporal as- Testing Conditions and Interpretation
pects that are dependent on stimulus intensity and state of
retinal adaptation. Dim, short wavelength light elicits slow, One of the major advances in ERG technology was the
small responses from the rod system, and more intense light development of low impedance, user-friendly electrodes.
Figure 2.57. Rod (top left) and cone (top right) electroretinographic waveforms and corresponding oscillatory potentials
(bottom) extracted from the ascending limb of the b-wave. (From Fishman GA, Sokol S. Electrophysiologic Testing in Disorders
of the Retina, Optic Nerve, and Visual Pathway. San Francisco, American Academy of Ophthalmology, 1990.)
poral aspects of the waveform can be described by the la-

tency and implicit times. Latency refers to the time between
stimulus onset and response onset, whereas implicit time
refers to the time needed for the response to reach maximum
amplitude. Waveform amplitudes are measured from the
baseline (which is usual for the a-wave) or as a peak-to-peak
comparison (which is usual for the b-wave). The b-wave/
a-wave ratio can be used as an index of inner to outer retinal
function.
The ERG can be affected by a number of additional fac-
tors. The implicit time of the waveform does not mature
until 4–6 months of age (273), and the amplitude may be
reduced until 1 year of age (274). The ERG may be greater
in women than in men (274,275) and may be reduced in
Figure 2.58. Amplitude, latency, and implicit time measurements for the myopes with more than 6 D of refractive error (275,276).
standard single flash electroretinogram. (From Weisinger HS, Vingrys AJ, There may be as much as a 13% reduction in ERG amplitude
Sinclair AJ, et al. Electrodiagnostic methods in vision. I. Clinical application
in the morning, which corresponds to the time of the maxi-
and measurement. Clin Exp Optom 1996;79⬊50–61.)
mal photoreceptor disk shedding (277). Systemic drugs and
anesthetics may also alter the ERG (278–280).
Riggs (271) discovered that a stable electric connection with
the cornea could be achieved with a silver disc electrode Use of the Electroretinogram
mounted in a scleral contact lens. The electrode made contact An ERG can provide important information about a num-
with a physiologic saline solution between it and the cornea ber of retinal disorders that may simulate neuro-ophthalmo-
when the contact lens was placed on the cornea. A modified logic problems. A number of different conditions can affect
version of the Riggs scleral electrode is the Burian-Allen retinal function and produce an abnormal ERG; however,
electrode, which contains a silver annulus implanted into there are a limited number of patterns that the ERG wave-
a plastic (hard) contact lens that is placed on a topically form can exhibit in normal and diseased retinas (Fig. 2.59).
anesthetized cornea. The contact lens is insulated and kept Nevertheless, ERG can be used to diagnose such disorders
separate from a lid speculum that is used to keep the eyelids as congenital stationary night blindness, congenital achro-
open during testing. Physiologic saline solution is necessary matopsia, retinitis pigmentosa (rod-cone dystrophy), reti-
to improve electrical contact and minimize impedance. If the nitis pigmentosa sine pigmenta, cone-rod dystrophy, cone
speculum is impregnated with silver granules, it can serve as dystrophy, cancer-associated retinopathy (CAR syndrome)
an inactive electrode, permitting a difference potential to be (281–283), and melanoma-associated retinopathy (MAR
measured. This is called a bipolar electrode (272). Difference syndrome) (284,285) (Figs. 2.60–2.63). An ERG is also use-
potentials have the benefit of affording better signals by re- ful for diagnosis of toxic retinopathies (232).
moving noise common to both the active and inactive elec- The pattern electroretinogram (PERG) is produced by a
trodes by means of a differencing process. Bipolar electrodes phase-reversing patterned stimulus (checkerboard or grat-
produce high-quality signals, because the active and inactive ing) that maintains a constant average luminance. When the
electrodes are close to each other. pattern reverses once or twice per second, an isolated re-
sponse is obtained, whereas a steady-state signal is generated
ERG Waveform and Factors Affecting It when faster reversal rates (greater than 9 Hz) are used. Signal
The ERG is described by the temporal characteristics and averaging techniques are employed to record the small sig-
amplitudes of the recorded waveform (Fig. 2.58). The tem- nals. The isolated PERG has three components: (a) a nega-
Figure 2.59. Examples of the different patterns of normal and abnormal photopic and scotopic electroretinographic responses
that can be obtained in patients with retinal diseases. (From Fishman GA, Sokol S. Electrophysiologic testing in Disorders of
the Retina, Optic Nerve, and Visual Pathway. San Francisco, American Academy of Ophthalmology, 1990.)
Figure 2.62. Electroretinogram (ERG) from a patient with congenital sta-

tionary night blindness (left) compared with normal ERG (right). Note
enhanced a-wave. (From Fishman GA, Sokol S. Electrophysiologic Testing
in Disorders of the Retina, Optic Nerve, and Visual Pathway. San Francisco,
American Academy of Ophthalmology, 1990.)
Figure 2.60. An example of electroretinogram (ERG) recordings from a
patient with autosomal-dominant retinitis pigmentosa (left) compared with
normal ERG responses (right). (From Fishman GA, Sokol S. Electrophysio-
logic Testing in Disorders of the Retina, Optic Nerve, and Visual Pathway. tive lobe at about 30 msec called N1 or N30; (b) a positive
San Francisco, American Academy of Ophthalmology, 1990.) lobe at about 50 msec called P1 or P50; and (c) a second
negative lobe at about 95 msec called N2 or N95. In normal
observers, the PERG waveforms are symmetric between
eyes and have an amplitude ratio of about 0.8–0.9. It is
believed that the N2 reflects ganglion cell activity and the
P1 reflects outer retinal function. The PERG is abnormal in
a variety of retinal and optic nerve diseases (261,278–280).
Multifocal ERG Mapping Techniques

(Topographical ERG)
Sutter and colleagues (286,287) developed a method of
simultaneously recording ERG signals from a large (up to
256) number of retinal locations. These investigators used
a binary m-sequence procedure that simultaneously tests a
large number of small retinal areas by multiplexing their
responses onto a single signal derived from the cornea. After
processing of the signal, the net result is an ERG map of
the central visual field (Fig. 2.64). This topographical ERG
is able to detect localized abnormalities in a variety of retinal
diseases, including age-related macular degeneration, macu-
lar holes, retinitis pigmentosa, branch retinal artery occlu-
sion, and other retinal conditions (287,288). The test has
great utility for evaluation of patients with disease of the
retina and a normal or near normal retinal examination. It
may also be useful in optic neuropathies. A commercial sys-
tem is available for clinical use.
Figure 2.61. Electroretinographic (ERG) recordings from a patient with ELECTRO-OCULOGRAM (EOG)
congenital achromatopsia (left) compared with normal ERG responses
(right). (From Fishman GA, Sokol S. Electrophysiologic Testing in Disor- In 1848, Dubois-Reymond reported that a difference in
ders of the Retina, Optic Nerve, and Visual Pathway. San Francisco, Ameri- electric potential of about 6 microvolts was present between
can Academy of Ophthalmology, 1990.) the cornea and the back of the eye (229). It was subsequently
Figure 2.63. Findings in cancer-associated retinopathy (CAR) syndrome. Top, Electroretinogram findings over 6 months.
Note progressive loss of both photopic and scotopic responses in both eyes. Bottom, Fluorescein angiograms of the right (left)
and left (right) fundi show mottling of the retinal pigment epithelium in both eyes and a macular hole in the right eye. Middle,
Histopathology reveals the macular hole in the right eye and almost complete absence of photoreceptors. (Adapted from Thirkill
CE, Roth AM, Keltner JL. Cancer-associated retinopathy. Arch Ophthalmol 1987;105⬊372–375.)
appreciated that the human eye acts as a dipole, with the Under typical recording conditions, the EOG is measured
cornea positive with respect to the retina. If two electrodes under conditions of dark adaptation after prior exposure to
are placed near the inner and outer canthi respectively, a pre-adapting illumination (289). The patient is asked to
movement of the eye will produce a change in the potential make saccades every second between two stimuli (usually
measured between the two electrodes, with the electrode LEDs) spaced approximately 30⬚ apart that are alternately
closest to the cornea being more positive. A recording of illuminated (Fig. 2.65). These saccadic eye movements pro-
this potential change produced by movement of the eye is duce the change in potential that comprises the EOG signal,
called the electro-oculogram (289). The EOG consists of with the average of several saccades being taken as the po-
two different potentials, one that is sensitive to light, and tential at that time. The light-insensitive potential (also
the other that is insensitive to light (Fig. 2.65). called the standing potential) decreases slightly over a period
of 8 or 9 minutes, at which time the lowest potential recorded

in the dark-adapted state can be measured (the dark trough).
Following reexposure to light, the potential gradually in-
creases and reaches its peak in another 10 to 15 minutes (the
light peak). The amplitude of the light peak is approximately
twice that of the dark trough (light rise of the EOG) in normal
persons. Because the standing potential can vary consider-
ably, in part related to the placement of the electrodes, the
EOG is most appropriately represented as a ratio of the light
peak to the dark trough. This ratio is called the Arden ratio
and is typically greater than 1.8 in normal persons. The Inter-
national Society for Clinical Electrophysiology of Vision
(ISCEV) standards have been established for EOG testing
(290).
Clinical studies suggest that the retinal pigment epithe-
lium is probably responsible for generating the EOG. Micro-
electrode investigations revealed a large direct current (DC)
Figure 2.64. Example of a topographic electroretinogram obtained at 255 component of the EOG just distal to the outer margin of the
locations throughout the central 30⬚ of the visual field. (From Sutter EE, outer nuclear layer of the retina (239). The light-sensitive,
Tran D. The field topography of ERG components in man. I. The photopic large, slow, cornea-positive component must depend upon
luminance response. Vision Res 1992;32⬊433–446.)
the activity of the photoreceptors and on cells in the inner
nuclear layers of the retina, because it is induced by light
Figure 2.65. The electro-oculogram (EOG). Top, Method of obtaining the EOG. The patient looks from right to left, and
the movement produces an electric potential. Bottom, The EOG signal with dark and light adaptation. Dt, dark trough; Lp,
light peak. (Courtesy of Dr. G.A. Fishman, 1982.)
and can be eliminated by central retinal artery occlusion electric activity of the human cortex. It was subsequently
(247). determined that if the spontaneous occipital EEG was
Based on studies of the action spectrum of the EOG in recorded while brief flashes of light were presented to an
both dark-adapted and light-adapted states, as well as the eye, changes would result in the occipital potential. These
observation that human subjects without rod function may changes were called the visual-evoked potential, visual-
have a large, light rise response, this response is thought to evoked response (VER), or the visual-evoked cortical poten-
represent both rod and cone activity. The light-insensitive tial (VECP). The VEP is simply a gross electric potential
potential of the EOG provides a way to measure the function of the visual cortex in response to visual stimulation. Unlike
of the pigment epithelium without having to stimulate the the alpha rhythm that can be recorded from most regions
photoreceptors (291). The EOG probably should not be used of the cortex, the VEP is limited mainly to the occipital
in patients with poor fixation because their poor ability to region of the brain. In addition, although the EEG contains
make accurate saccades can affect the outcomes. In the early signals with amplitudes generally between 20 and 100 mi-
stages of retinitis pigmentosa, the light rise of the EOG is crovolts and occasionally larger, the amplitude of VEP is
reduced, but the standing potential is normal even at a time between 1 and 20 microvolts. Because the VEP amplitude
when the ERG is abnormal or even nondetectable (229). In is considerably smaller than the EEG, a major problem that
advanced retinitis pigmentosa, the standing potential of the existed for many years was that of extracting the VEP from
EOG becomes reduced. the background EEG. Initially, van Balen and Henkes (305)
The EOG has limited usefulness in the diagnosis of visual used time-locked signal averaging techniques to separate
dysfunction. It can help to distinguish the dominant type of light-evoked responses, based on the assumption that by re-
stationary night blindness from the recessive type (229) as petitively stimulating the occipital cortex, one can produce
well as from Stargardt’s disease and Best’s disease (see a consistent wave form that can be distinguished from the
below). In chloroquine retinopathy, the EOG is abnormal nonspecific EEG wave produced by the rest of the brain.
in the advanced stages when large areas of retinal pigment Another technique involved obtaining a difference potential
epithelium are abnormal, but in the very early stage, the between two cortical locations—one in which the signal in-
EOG is normal (292,293). cluded both the VEP and the EEG (active electrode: occipital
When the EOG is abnormal, the ERG is also usually ab- lobe) and the other in which the signal had only the EEG
normal. There are four exceptions, however, in which pa- and no or very little VEP (inactive electrode: EEG only).
tients may have a normal or nearly normal ERG with an This technique allowed extraction of the VEP even when
abnormal EOG light-rise to dark-trough ratio. The condi- there was a substantial EEG component.
tions are (a) butterfly-shaped pigment dystrophy of the fovea Although the VEP can easily be measured, the portion or
(294); (b) Stargardt’s disease (fundus flavimaculatus) (294); portions of the brain responsible for its generation are un-
clear. Jeffreys and Axford (306,307) studied the first two
(c) advanced drusen (295); and (d) vitelliform dystrophy or
components of the human VEP (which they called C.I and
Best’s disease (296,297). The EOG is probably most useful
C.II). These investigators concluded that the first component
in vitelliform macular dystrophy because the EOG is abnor-
originated in striate cortex from surface negative cortical
mal even in the presence of a normal ERG. In addition,
activity, whereas the second component originated from ex-
abnormal EOGs may be found in asymptomatic ‘‘carriers’’ trastriate cortex on the outer surface of the occipital lobes.
who have no abnormalities visible in the fundus (289,298). Streletz et al. (308) emphasized a positive correlation of
Thus, the EOG can serve as a genetic marker to identify unilateral occipital lobe lesions, homonymous visual field
this autosomal-dominant disease in families with skipped loss, and VEP abnormalities, but Cohn (309) reported that
generations (229). From a neuro-ophthalmologic standpoint, the VEP to light stimulation in monkeys was initially attenu-
the EOG is more important for the recording and analysis ated after ablation of the occipital cortex and then returned
of ocular motor function than in diagnosing causes of visual to normal 3 weeks later despite persistence of visual deficits.
loss. Bodis-Wollner et al. (310) described normal VEPs to both
flash and pattern stimuli in a patient in whom CT scanning
OTHER RETINAL POTENTIALS suggested bilateral destruction of areas 18 and 19 with pres-
There are several retinal potentials other than the ERG ervation of area 17. Clearly, the VEP is dependent on the
and EOG (e.g., early receptor potentials, oscillatory poten- integrity of the entire visual pathway, although it remains
tials, the scotopic threshold response) that can be measured to be seen whether or not its components can truly be sepa-
under specific test conditions, but they are more commonly rated into anatomic correlates (311). The precise origin and
used for clinical research studies than for routine clinical pathways through which the VEP is mediated are still in
evaluation of patients and are therefore not discussed further question. Nevertheless, the clinical importance of the VEP
in this chapter. The interested reader is directed to several rests on its usefulness as a relatively objective determinant
excellent sources (229,299–304) for descriptions of these of the integrity of the visual pathways. Numerous reviews
techniques and the waveforms generated. of the VEP are available and should be consulted by the
interested reader (312–318).
VISUAL-EVOKED POTENTIAL (VEP) Methodology
Until the early 1960s, the electroencephalogram (EEG) The VEP is measured by placing scalp electrodes over
was the main technique available for clinical evaluation of the occipital region (Oz) of both hemispheres, with reference
Figure 2.66. Method for generating and recording the visual-evoked potential (VEP). (From Fishman GA, Sokol S. Electro-
physiologic Testing in Disorders of the Retina, Optic Nerve, and Visual Pathway. San Francisco, American Academy of
Ophthalmology, 1990.)
electrodes attached to the ear (Fig. 2.66). The patient then affect the amplitude of the VEP signal (Fig. 2.68), as can
views the display; typically a xenon-arc photostimulator for the rate of alternation of the pattern. At low rates of alterna-
flash VEPs and a television screen or computer video display tion (1–2 reversals per second), the waveform typically con-
with checkerboard patterned stimuli for pattern VEPs. Re- tains two negative (N1, N2) and two positive (P1, P2) poten-
cordings of the VEP may be made from either hemisphere tials. This is called the ‘‘transient’’ pattern VEP and is the
with one or both eyes fixating. Typically, 100 to 150 stimu- most commonly used procedure for routine clinical pur-
lus presentations are generated, and time-locked signal aver- poses. As the rate of alternation is increased (more than six
aging procedures are used to extract the VEP waveform from
the spontaneous EEG activity. The amplitude and latency of
the waveform are then measured. A flash stimulus is gener-
ally used only when no response is produced using a pattern
stimulus. Thus, patients with extremely poor acuity, dense
media opacities, poor fixation and infants are most com-
monly tested with flash VEP. In most patients, however, a
pattern stimulus is preferred for obtaining the VEP, because
of the greater clinical utility and more reliable waveform
generated with this stimulus. Rather than bright flashes of
light, a repetitive pattern of light and dark areas (checker-
boards, bar gratings) are phase-reversed every 1 or 2 sec-
onds. The pattern VEP is primarily generated from the cen-
tral 5⬚ of the visual field. Indeed, when the central 3⬚ is
occluded (Fig. 2.67, middle), there is a dramatic reduction in
the amplitude of the pattern VEP, and the waveform almost
completely disappears when the central 9⬚ is occluded (Fig.
2.67, bottom). These findings are consistent with the findings
of Horton and Hoyt (319), who estimated that the central
10⬚ of the visual field are represented by at least 50–60%
of the posterior striate cortex and that the central 30⬚ is repre-
sented by about 80% of the cortex (see Chapters 1 and 12).
The VEP appears different for stimuli that reverse contrast
(ON-OFF-ON) compared with those that abruptly come on Figure 2.67. Visual-evoked potential waveforms. Top, From stimulation
(onset) and then go off (offset). Why these differences occur of the central 30⬚ visual field. Middle, With the central 3⬚ occluded. Bottom,
is not clear, but they may reflect the fact that these different With the central 9⬚ occluded. Note that the majority of the waveform is
subserved by the central 9⬚ of the visual field. This is consistent with the
onset modalities tap discrete cortical processes (i.e., contrast observations of Horton and Hoyt (319) that the central 10⬚ of the visual
versus luminance). Most clinical laboratories use contrast- field are represented by at least 50–60% of the posterior striate cortex.
reversal patterns. (From Fishman GA, Sokol S. Electrophysiologic Testing in Disorders of
The amplitude of the pattern VEP is affected by a number the Retina, Optic Nerve, and Visual Pathway. San Francisco, American
of different factors. The size of the stimulus pattern can Academy of Ophthalmology, 1990.)
Figure 2.68. Transient visual-evoked response waveforms for small (12 minutes of arc) (A) and large (48 minutes of arc)
(B) checkerboard stimuli. Note difference in size of waveforms. (From Fishman GA, Sokol S. Electrophysiologic Testing in
Disorders of the Retina, Optic Nerve, and Visual Pathway. San Francisco, American Academy of Ophthalmology, 1990.)
reversals per second), the response is not able to fully recover although the amplitudes vary considerably from one person
between presentations, and only the initial portions of the to another. The most useful clinical features of the VEP are
waveform are observed, similar to the waveforms obtained therefore the latency of its major components and a compari-
for ERG with rapidly flickering stimuli. This is called the son of the symmetry of the amplitudes between eyes and
‘‘steady-state’’ VEP. In addition, Celesia and Daly (320) between hemispheres in the same person. van Dijk (326)
found that the latencies of the first major positive and nega- presented an excellent discussion of the pitfalls associated
tive components of the VEP become increasingly delayed with VEP testing, and many other authors have emphasized
with increasing age in adults. Latency of the response is the importance of optimized and standardized test conditions
indirectly related to stimulus intensity, but amplitude tends (327–329).
to reach maximum at only moderate stimulus intensities and
varies with electrode placement, scalp thickness, etc. Infants Visual-Evoked Potential in Clinical Ophthalmology
and young children have quite variable waveforms and pro- and Neuro-Ophthalmology
longed latencies (52,321–323). The VEP also varies with
stimulus size and frequency, attention, mental activity, pupil The VEP represents sensory activity in the visual path-
size, fatigue, state of dark adaptation, color of the stimulus, ways, beginning at the retina and ending at the occipital
background illumination, and the emotional content of the cortex. A summary of the changes observed in VEP record-
stimulus (313–315,318,324,325). All of these factors em- ings from different visual disorders was published by Sokol
phasize the importance of using standardized and optimized and Fishman (330) and are reproduced in Table 2.8. As can
test conditions (including the best refractive correction) for be seen from the table, the VEP can be useful in differentiat-
clinical VEP testing, as well as establishing age-related nor- ing among retinal, optic nerve, and cortical diseases
mative standards for the procedures employed for each labo- (331–335). It may also be helpful in determining if an infant
ratory. or young child has intact vision (336) and if a patient has
Analysis of the VEP waveform is rather complex. For nonorganic visual loss (337). In general, the VEP should be
transient pattern VEPs, the amplitude and latency of the N1, evaluated for latency, amplitude, waveform, and morphol-
P1, and N2 components are typically measured (Figs. 2.67 ogy. The latency and amplitude can be quantified, but wave-
and 2.68). For steady-state VEPs, the amplitude and phase form morphology is more of a subjective interpretation.
of the waveform are measured. The latencies of the pattern Although the clinical utility and differential diagnostic
VEP are quite consistent both within and among observers, capabilities of the VEP are limited, there are numerous set-
Table 2.8 breakthrough occurred when Sutter and coworkers used a

Visual-Evoked Potential Abnormalities 60–sector scaled checkerboard set of patches that subserves
Disorder Amplitude Latency Morphology
the central 22⬚. The stimuli are presented in a pseudo-random
m-sequence (340,341). Using these sequences with cross-
Optic nerve and visual pathway correlation techniques, electrical responses to pattern rever-
Optic neuritis A/N ⫹⫹⫹ N sal stimuli can be extracted from occipital scalp recordings.
Ischemic optic neuropathy ⫺⫺ ⫹ A In 30 patients with established glaucoma, Klistorner and
Toxic amblyopia ⫺ N A Graham demonstrated a good concordance of visual field
Dominant optic atrophy ⫺ N/⫹ ? defects found by conventional automated perimetry and with
Leber’s optic atrophy ⫺⫺ ⫹ A
mfVEP (342). Both the number and location of the defects
Optic nerve hypoplasia ⫺⫺ ⫹ A
Glaucoma N/⫺ N/⫺ N
were highly correlated between the two tests. An excellent
Optic disc drusen ⫺ ⫹ A general review of this technique is provided by Hood (343).
Papilledema N/⫺ N/⫹ N/A Wall and colleagues (344) tested normals and patients
Tumors (anterior pathway) ⫺ ⫹ A with three types of neuro-ophthalmologic disease: demyelin-
Neurologic disorders ating optic neuropathies, nondemyelinating optic neuropa-
Multiple sclerosis N/⫺ ⫹⫹⫹ N/A thies, and homonymous hemianopias. They found that in
Vitamin B12 deficiency N ⫹ N nondemyelinating optic neuropathies mfVEP results corre-
Congenital nystagmus ⫺ ⫹ A late very well with perimetry. In demyelinating optic neurop-
Parkinson’s disease N/⫺ N/⫹⫹ N athies, the mfVEP showed defects when conventional auto-
Migraine N ⫹ N/A
mated perimetry was normal. The mfVEP failed to detect
Down syndrome ⫺ N ?
Cortical blindness N/⫺ N N
perimetrically obvious homonymous hemianopia in three of
Occipital lobe lesion ⫺ ⫹ A five subjects tested. The test does perform well in patients
Huntington’s chorea ⫺ N A with nonorganic visual loss as long as they look at the stimu-
Friedreich’s ataxia ⫺ ⫹⫹ A lus display. This new technique is early in its development.
Hereditary spastic ataxia N N/⫹ N It may become a more clinically useful test in time.
Nonspecific rec. ataxia N N N
Charcot-Marie-Tooth ? ⫹ N Simultaneous Recording of the Visual-Evoked
Phenylketonuria N ⫹ N Potential and PERG
N ⫽ normal, A ⫽ abnormal, ? ⫽ information not available, ⫹(⫺) ⫽ mild increase Simultaneous recording of PERG and VEP was found by
(decrease), ⫹⫹(⫺⫺) ⫽ moderate increase (decrease), ⫹⫹⫹(⫺⫺⫺) ⫽ severe
increase (decrease). Kaufman and Celesia (345) to be helpful in the diagnosis
From Sokol and Fishman, 1990, Table 3.1. of neuro-ophthalmologic disorders (Fig. 2.69). The PERG
and pattern VEP can be used to assess the onset of the electri-
cal activity traveling from the retina to the visual cortex to
tings in which the VEP can be quite helpful (see above and determine retino-cortical transit time (RCT). RCT is defined
Table 2.8). In conjunction with retinal electrophysiologic as the time between the peak latency of the b-wave of the
responses, the status of visual function from retina to cortex PERG and either the N1 or P1 potential of the pattern VEP.
can be evaluated. The VEP and ERG are usually performed Kaufman and Celesia (345) investigated simultaneous
separately; however, Hirose et al. (338) developed a system
that allows simultaneous recording of both the ERG and
VEP with focal photic stimulation of the retina under direct
observation of the fundus.
Celesia and Daly (339) used computer analysis to evaluate
several parameters of the visual-evoked response generated
by both flash and pattern-reversal stimulation. These investi-
gators selected for analysis: (a) peak latency of the first nega-
tive wave; (b) interocular difference of peak latency for the
first negative wave; (c) peak latency of the first positive
wave; (d) interocular difference of peak latency for the first
positive wave; and (e) critical frequency of photic driving.
They studied 194 subjects and concluded that measurement
and computer analysis of these five parameters, which they
called ‘‘visual electroencephalographic computer analysis’’
or ‘‘VECA,’’ was a more reliable and sensitive method of
detecting both clinical and subclinical optic neuropathies
than routine evaluation of the VEP.
Figure 2.69. Simultaneous recordings of pattern electroretinogram (P-
Multifocal VEP
ERG) and pattern visual-evoked potential (P-VEP) in a patient with a left
Many attempts have been made to investigate visual field optic nerve lesion and a normal right eye. Note abnormalities in both studies.
function using evoked potentials to visual stimuli. A major (Courtesy of Dr. David I. Kaufman.)
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CHAPTER 3
Congenital Anomalies of the
Optic Disc
Michael C. Brodsky
OPTIC NERVE HYPOPLASIA CONGENITAL OPTIC DISC PIGMENTATION

EXCAVATED OPTIC DISC ANOMALIES AICARDI SYNDROME
Morning Glory Disc Anomaly DOUBLING OF THE OPTIC DISC
Optic Disc Coloboma OPTIC NERVE APLASIA
Peripapillary Staphyloma MYELINATED (MEDULLATED) NERVE FIBERS
Megalopapilla PSEUDOPAPILLEDEMA
Optic Pit Pseudopapilledema Associated with Optic Disc Drusen
Papillorenal Syndrome (the ‘‘Uncoloboma’’) Anomalous Disc Elevation without Either Visible or Buried
CONGENITAL TILTED DISC SYNDROME Drusen
OPTIC DISC DYSPLASIA
Certain general principles are particularly useful in the of the morning glory configuration are associated with
evaluation and management of patients with anomalous the transsphenoidal form of basal encephalocele, whereas
optic discs. colobomatous optic discs may be associated with a sys-
temic anomalies and a variety of syndromes.
1. Children with bilateral optic disc anomalies generally 3. Any structural ocular abnormality that reduces visual acu-
present in infancy with poor vision and nystagmus; those ity in infancy may lead to superimposed amblyopia (1).
with unilateral optic disc anomalies generally present dur- A trial of occlusion therapy may be warranted in young
ing their preschool years with sensory esotropia. children with unilateral optic disc anomalies and de-
2. CNS malformations are common in patients with mal- creased vision (2).
formed optic discs. Small discs are associated with a vari- 4. Anomalous optic discs (particularly excavated optic disc
ety of malformations of the cerebral hemispheres, pitui- anomalies and pseudopapilledema with or without optic
tary infundibulum, and midline intracranial structures disc drusen) may produce episodes of transient visual loss
(septum pellucidum, corpus callosum). Large optic discs (3–6).
OPTIC NERVE HYPOPLASIA

Optic nerve hypoplasia is an anomaly that, until recently, construed as congenital optic atrophy are now correctly diag-
escaped the scrutiny of even the most meticulous observers nosed. In addition, some investigators believe that parenteral
(7). It was not until the late 1960s that its clinical description drug and alcohol abuse, which have become more wide-
became commonplace. Optic nerve hypoplasia is now un- spread in recent years, may also be contributing to an in-
questionably the most common optic disc anomaly encoun- creasing prevalence of optic nerve hypoplasia (8,9).
tered in ophthalmologic practice. The dramatic increase in Ophthalmoscopically, the hypoplastic disc appears as an
prevalence of optic nerve hypoplasia primarily reflects its abnormally small optic nerve head (10–14) (Fig. 3.1A). It
greater recognition by clinicians. Many cases of optic nerve may appear gray or pale in color and is often surrounded by
hypoplasia that previously went unrecognized or were mis- a yellowish mottled peripapillary halo, bordered by a ring of
151
Figure 3.1. Optic nerve hypoplasia. A, The disc is small and pale but the retinal vessels are of normal size. B, The disc is
small and surrounded by a rim of variably pigmented tissue.
increased or decreased pigmentation (dubbed the ‘‘double- hyperopia or anisometropia could be causative (29). Lempert
ring’’ sign), which facilitates recognition of the anomaly addressed this issue in a subsequent study which showed
(15) (Fig. 3.1B). Optic nerve hypoplasia is often associated that, even when axial length was factored into the calcula-
with selective tortuosity of the retinal veins. This finding tion, the optic disc areas of eyes with hyperopic strabismus
can be particularly helpful in establishing the diagnosis in with and without amblyopia were disproportionately and
infants with nystagmus (16). markedly reduced when compared with hyperopic eyes with-
Optic nerve hypoplasia is characterized histopathologi- out amblyopia or esotropia (29).
cally by a subnormal number of optic nerve axons with nor-
mal mesodermal elements and glial supporting tissue
(17,18). The double-ring sign correlates to a normal junction
between the sclera and lamina cribrosa, which corresponds
to the outer ring, and the termination of an abnormal exten-
sion of retina and pigment epithelium over the lamina cri-
brosa, which corresponds to the inner ring (17,18) (Fig. 3.2).
Visual acuity in optic nerve hypoplasia ranges from 20/
20 to no light perception, and affected eyes show localized
visual field defects, often combined with generalized con-
striction (19–25). Because visual acuity is determined pri-
marily by the integrity of the papillomacular nerve fiber bun-
dle, it does not necessarily correlate with the overall size of
the disc. The strong association of astigmatism with optic
nerve hypoplasia warrants careful attention to correction of
refractive errors (26).
Unilateral optic nerve hypoplasia has recently been impli-
cated in the pathogenesis of amblyopia (27). Using optic
disc photographs corrected for magnification, Lempert
found smaller optic discs and smaller axial lengths in ambly-
opic eyes compared to their fellow eyes and suggested that
vision impairment in presumed amblyopia may be caused
Figure 3.2. Pathology of optic nerve hypoplasia. Section through center of
by optic nerve hypoplasia with relative microphthalmos (27).
optic disc shows junction of sclera and lamina cribrosa (large arrowheads)
Archer noted that a small optic disc area could be associated delineating outer ring and extension of retina and retinal pigment epithelium
with amblyopia by being correlated with hyperopia and an- overlying the lamina cribrosa on both sides. Termination of retina and
isometropia rather than being the cause of the decreased retinal pigment epithelium (short arrowheads) marks inner ring or hypo-
vision (28). Archer stated that small eyes may have small plastic nerve head. (From Mosier MA, Lieberman MF, Green WR, et al.
optic discs, and either the small optic nerves or the associated Hypoplasia of the optic nerve. Arch Ophthalmol 1978;96⬊1437–1442.)
CONGENITAL ANOMALIES OF THE OPTIC DISC 153
Except when amblyopia develops in one eye, visual acuity with optic nerve hypoplasia (38). However, a subgroup have
usually remains stable throughout life. However, Taylor (30) decreased amplitudes, suggesting coexistent retinal dysgene-
has documented mild optic nerve hypoplasia in patients with sis (39,40). Visual-evoked responses (VER) vary from nor-
congenital suprasellar tumors. Such tumors can slowly en- mal to extinguished (38,39). Some patients with poor vision
large to produce acquired visual loss. Spandau et al. (31) have normal flash VEP latencies, probably resulting from
recently reported bilateral visual loss in an elderly patient the normal transmission speed of residual axons (32).
with severe optic nerve hypoplasia in both eyes. The authors Optic nerve hypoplasia is frequently associated with other
attributed this phenomenon to normal axonal loss superim- CNS anomalies. Septo-optic dysplasia (de Morsier syn-
posed upon a critically low retinal nerve fiber count with no drome) refers to the constellation of small anterior visual
compensatory reserve. pathways, absence of the septum pellucidum, and thinning
Although moderate or severe optic nerve hypoplasia can or agenesis of the corpus callosum (41). The clinical associa-
be recognized ophthalmoscopically, the diagnosis of mild tion of septo-optic dysplasia and pituitary dwarfism was doc-
hypoplasia is problematic in infants and small children umented by Hoyt et al. in 1970 (42). Subsequent studies
whose visual acuity cannot be quantified with accuracy (32). demonstrated deficiencies of other anterior pituitary hor-
Several techniques have been devised to measure fundus mones as well as diabetes insipidus in patients with septo-
photographs of the optic disc directly in an attempt to apply optic dysplasia (43–57). Growth hormone deficiency is the
quantitative criteria to the diagnosis of optic nerve hypopla- most common endocrinologic deficiency associated with
sia. Jonas et al. (33) defined ‘‘microdiscs’’ statistically as optic nerve hypoplasia, but hypothyroidism, hypocorti-
the mean disc area minus two standard deviations (33). In solism, diabetes insipidus, and hyperprolactinemia may also
their study of 88 patients, the mean optic disc area measured occur (58–63). Children with an intact septum pellucidum
2.89 mm2 and the diagnosis of a microdisc corresponded to and optic nerve hypoplasia may still have endocrinologic
a disc area smaller than 1.4 mm2. Romano et al. (34) advo- deficiency (64). Parents should be asked about previous epi-
cated the simple method of directly measuring the optic disc sodes of hypoglycemia in the neonatal period or during pe-
diameter using a hand ruler and a 30⬚ transparency (both riods of illness (which suggest hypocortisolism), and neo-
under magnification) and concluded that a horizontal disc natal jaundice (which suggests hypothyroidism) (8,65,66).
diameter of less than 3.4 mm constitutes optic nerve hypo- Conversely, newborn infants with hypoglycemia and chole-
plasia. This quick and simple technique is limited to eyes stasis should probably be screened for optic nerve hypoplasia
with minimal spherical refractive error. Zeki et al. (35) calcu- (67). Growth hormone deficiency may not be clinically ap-
lated the disc-to-macula/disc diameter ratio and found, in parent within the first 3–4 years of life because high prolac-
95% of normals, that the ratio was greater than 2.94, in tin levels can stimulate normal growth over this period (68).
contrast to an average of 2.62 for the group with optic nerve Puberty may be precocious or delayed in children with hypo-
hypoplasia. Calculation of this ratio has the important advan- pituitarism (49,69). Anterior pituitary hormone deficiencies
tage of eliminating the magnification effect of high refractive may evolve over time in some patients; thus, longitudinal
errors (myopic refractive errors can make a hypoplastic disc reevaluation and periodic monitoring of anterior pituitary
appear normal in size, whereas hyperopic refractive errors hormone function are indicated in children with posterior
can make a normal disc appear abnormally small). Borchert pituitary ectopia (66,70). Estimates of the prevalence of pi-
et al. (32) found a bimodal distribution in the ratio of the tuitary hormone deficiency in children with septo-optic dys-
horizontal disc diameter to the disc-macula distance, with a plasia are as high as 62% (56), but these clinical reports are
ratio of greater than 0.3 separating eyes with good acuity strongly skewed toward cases with endocrinologic manifes-
from those with poor acuity. tations, and the true prevalence is probably closer to 15%
Although the technique described by Zeki et al. (35) is (64,71).
especially useful in patients with high refractive errors, the Children with septo-optic dysplasia and corticotropin de-
notion that one can establish an unequivocal dividing line ficiency are at risk for sudden death during febrile illness
between the normal and hypoplastic disc is inherently flawed (72). This clinical deterioration appears to be caused by an
(36), because large optic discs can be axonally deficient impaired ability to increase corticotropin secretion to main-
(14,37), and small optic discs do not preclude normal visual tain blood pressure and blood sugar in response to the physi-
function. Theoretically an extremely small disc is associated cal stress of infection. These children may have coexistent
with a diminution in axons, but this reasoning has limited diabetes insipidus that contributes to dehydration during ill-
applications with regard to mild or borderline cases. Other ness and hastens the development of shock. Some also have
variables must be considered, including the size of the cen- hypothalamic thermoregulatory disturbances signaled by ep-
tral cup, the percentage of the nerve occupied by axons (as isodes of hypothermia during well periods and high fevers
opposed to glial tissue and blood vessels), and the cross- during illnesses, which may predispose to life-threatening
sectional area and density of axons. Furthermore, segmental hyperthermia. Children with septo-optic dysplasia who are
forms of optic nerve hypoplasia (see below) may affect a at risk for sudden death usually have had multiple hospital
sector of the disc without producing a diffuse diminution in admissions for viral illnesses. These viral infections can pre-
size. As such, it would seem prudent to reserve the diagnosis cipitate hypoglycemia, dehydration, hypotension, or fever
of optic nerve hypoplasia for patients with small optic discs of unknown origin (72). Because corticotropin deficiency
who have reduced vision or visual field loss with correspond- represents the preeminent threat to life in children with
ing nerve fiber bundle defects. septo-optic dysplasia, a complete anterior pituitary hormone
Electroretinography is normal in the majority of patients evaluation, including provocative serum cortisol testing and
assessment for diabetes insipidus, should be performed in quently demonstrated structural abnormalities involving the
children who have clinical symptoms (history of hypoglyce- cerebral hemispheres and the pituitary infundibulum (9,64).
mia, dehydration, or hypothermia) or neuroimaging signs Cerebral hemispheric abnormalities, which are evident on
(absent pituitary infundibulum with or without posterior pi- MR imaging in approximately 45% of patients with optic
tuitary ectopia) of pituitary hormone deficiency. Sherlock nerve hypoplasia, may consist of hemispheric migration
and McNicol (73) noted that subclinical hypopituitarism can anomalies (Fig. 3.4) such as schizencephaly, cortical hetero-
manifest as acute adrenal insufficiency following surgery topia, polymicrogyria, as well as evidence of intrauterine or
under general anesthesia and suggested that it may be pru- perinatal hemispheric injury such as periventricular leuko-
dent to empirically treat children who have optic nerve hypo- malacia, encephalomalacia, or porencephaly (75–83). Mid-
plasia with perioperative intravenous corticosteroids. line fusion of the cerebral hemispheres (holoprosencephaly)
Magnetic resonance imaging is the optimal noninvasive (84) and cerebellar hemispheres (85) is also occasionally
neuroimaging modality for delineating associated CNS mal- seen. Barkovich (86) questioned whether those forms of
formations in patients with optic nerve hypoplasia (74). MR septo-optic dysplasias with central holoventricles and no
imaging provides high-contrast resolution and multiplanar hemispheric malformations represent the mildest end of the
imaging capability, allowing the anterior visual pathways to spectrum of holoprosencephaly. Optic nerve hypoplasia may
be visualized as distinct, well-defined structures (74). In also accompany other intracranial anomalies including anen-
optic nerve hypoplasia, coronal and sagittal T1-weighted cephaly (87,88), hydranencephaly (89–91), and transsphe-
MR images consistently demonstrate thinning and attenua- noidal encephalocele (92). The association of optic nerve
tion of hypoplastic prechiasmatic intracranial optic nerves hypoplasia with periventricular leukomalacia presents an in-
(Fig. 3.3). Coronal T1-weighted MR imaging in bilateral teresting diagnostic challenge. In 1995, Jacobson et al. rec-
optic nerve hypoplasia shows diffuse thinning of the optic ognized that periventricular leukomalacia produces a unique
chiasm (Fig. 3.3B) in patients with bilateral optic nerve hy- form of bilateral optic nerve hypoplasia characterized by
poplasia, and focal thinning or absence of the side of the an abnormally large optic cup and a thin neuroretinal rim
chiasm corresponding to the hypoplastic nerve in unilateral contained within a normal-sized optic disc (Fig. 3.5) (93).
optic nerve hypoplasia. When MR imaging shows a decrease They attributed this morphologic characteristic to intrauter-
in intracranial optic nerve size accompanied by other fea- ine injury to the optic radiations with retrograde transsynap-
tures of septo-optic dysplasia, a presumptive diagnosis of tic degeneration of retinogeniculate axons after the scleral
optic nerve hypoplasia can be made (74). canals had established normal diameters. Unlike other forms
The notion of septo-optic dysplasia as a distinct nosologic of optic nerve hypoplasia, the pseudoglaucomatous optic hy-
entity has been overturned because MR imaging has fre- poplasia of periventricular leukomalacia is not associated
Figure 3.3. Magnetic resonance imaging in optic nerve hypoplasia. A, Left optic nerve hypoplasia. Thick arrow denotes
normal right optic nerve. Thin arrow denotes hypoplastic intracranial prechiasmatic optic nerve. B, Bilateral optic nerve hypopla-
sia. Arrow denotes hypoplastic chiasm. (From Brodsky MC, Glasier CM, Pollock SC, et al. Optic nerve hypoplasia: Identification
by magnetic resonance imaging. Arch Ophthalmol 1990;108⬊562–567.)
Figure 3.4. Cerebral hemispheric abnormalities commonly associated with optic nerve hypoplasia. A, Schizencephaly. The
schizencephalic cleft (arrows) consists of an abnormal band of dysmorphic gray matter in the left cerebral hemisphere extending
from the cortical surface to the lateral ventricle. B, Cortical heterotopia. An abnormal area of gray matter (black arrows) in
the deep white matter, indents the ventricular lumen. (From Brodsky MC, Glasier CM, Pollock SC, et al. Optic nerve hypoplasia:
Identification by magnetic resonance imaging. Arch Ophthalmol 1990;108⬊562–567.)
with endocrinologic deficiency. The large optic cups can thalamic dysgenesis, including absence of hypothalamic
simulate glaucoma, but the history of prematurity, normal nuclei, neuronal loss, and gliosis have also been found
intraocular pressure, and characteristic symmetrical inferior at necropsy in children with septo-optic dysplasia and
visual field defects all serve to distinguish periventricular hypopituitarism. These findings suggest that a central hypo-
leukomalacia from glaucomatous optic atrophy (94). thalamic insufficiency may coexist in some cases (48,49,52,
Whether this anomaly warrants classification as a prenatal 83,99).
form of optic atrophy because of its normal optic disc diame- In a child with optic nerve hypoplasia, posterior pituitary
ter remains controversial (94). ectopia is virtually pathognomonic of anterior pituitary hor-
Evidence of perinatal injury to the pituitary infundibulum mone deficiency with normal posterior pituitary function,
(seen on MR imaging as posterior pituitary ectopia) is found while absence of a normal or ectopic posterior pituitary
in approximately 15% of patients with optic nerve hypopla- bright spot predicts coexistent antidiuretic hormone defi-
sia (64). Normally, the posterior pituitary gland appears ciency (i.e., diabetes insipidus) (57,66). Cerebral hemi-
bright on T1-weighted images (Fig. 3.6A), probably because spheric abnormalities are highly predictive of neurodevelop-
of the phospholipid membrane component of its hormone- mental deficits (64). Absence of the septum pellucidum
containing vesicles (95). In posterior pituitary ectopia, MR alone does not portend neurodevelopmental deficits or pitui-
imaging demonstrates absence of the normal posterior pituitary hormone deficiency (100). Thinning or agenesis of the
tary bright spot, absence or attenuation of the pituitary infun- corpus callosum is predictive of neurodevelopmental prob-
dibulum, and an ectopic posterior pituitary bright spot where lems only by virtue of its frequent association with cerebral
the upper infundibulum is normally located (Fig. 3.6B) hemispheric abnormalities. The finding of unilateral optic
(9,64,66). It is unknown whether posterior pituitary ectopia nerve hypoplasia does not preclude coexistent intracranial
results from defective neuronal migration during embryo- malformations (64). MR imaging thus provides critical prog-
genesis (66), or from a perinatal injury to the hypophyseal- nostic information regarding the likelihood of neurodevelop-
portal system, which causes necrosis of the infundibulum mental deficits and pituitary hormone deficiency in the infant
(96,97). In a retrospective study, Phillips et al. found poste- or young child with unilateral or bilateral optic nerve hypo-
rior pituitary ectopia and/or absence of the pituitary infun- plasia (64).
dibulum in 23 of 26 cases of optic nerve hypoplasia and Numerous environmental factors that are detrimental to
congenital hypopituitarism, versus none of the 41 cases with the fetus are sporadically associated with optic nerve hypo-
normal endocrinologic function (97). The finding of poste- plasia. These include maternal insulin-dependent diabetes
rior pituitary ectopia implicates the pituitary infundibulum mellitus (23,101–104), fetal alcohol syndrome (107), mater-
as one site of structural derangement in children with septo- nal ingestion of quinine (105), anticonvulsants (106), illicit
optic dysplasia and panhypopituitarism (98). Signs of hypo- drugs (61,62,107), and fetal or neonatal infection with cyto-
Figure 3.5. Pseudoglaucomatous optic nerve hypoplasia

associated with periventricular leukomalacia. Top, Both
optic discs are normal in size with large cups. Middle, Vi-
sual fields show bilateral constriction with symmetrical in-
ferior depression that spares fixation. Bottom, Magnetic res-
onance imaging shows high signal intensity in the optic
radiations and contiguous enlargement of the posterior ven-
tricles.
megalovirus (108,109) or hepatitis B virus (109). Optic penia (139), and bilateral microphthalmos (140). A pur-
nerve hypoplasia occurs with increased frequency in first- ported association between optic nerve hypoplasia and albi-
born children of young mothers (110–113). The majority of nism (141) is controversial because high-resolution MR
cases are sporadic, although a handful of familial cases have imaging of the intracranial optic nerves in human albinos
been reported in siblings (21,114–116). The growing list of shows no diminution in size (36). Kottow (142) described
systemic and ocular disorders associated with optic nerve unilateral optic nerve hypoplasia in three patients with ipsi-
hypoplasia includes frontonasal dysplasia (92,117), aniridia lateral congenital retinal arteriovenous malformations and
(118), fetal alcohol syndrome (107), Dandy-Walker syn- no evidence of cutaneous or intracranial involvement.
drome (116), Kallmann syndrome (119), Delleman syn- Some forms of optic nerve hypoplasia are segmental. A
drome (120), Duane syndrome (121), Klippel-Trenaunay- superior segmental optic hypoplasia with an inferior visual
Weber syndrome (122,123), Goldenhar syndrome (124), lin- field defect occurs in children of insulin-dependent diabetic
ear nevus sebaceous syndrome (125), Meckel syndrome mothers (Fig. 3.7) (23,102–104). In a prospective study of
(126), hemifacial atrophy (13), blepharophimosis (127), os- children of diabetic mothers, Landau et al. (143) found an
teogenesis imperfecta (128), chondrodysplasia punctata 8.8% prevalence of superior segmental optic hypoplasia. De-
(129–131), Aicardi syndrome (82,132–134), Apert syn- spite the multiple teratologic effects of maternal diabetes
drome (135), Potter syndrome (136), chromosome 13qⳮ early in the first trimester (144), superior segmental hypopla-
(137), trisomy 18 (138), neonatal isoimmune thrombocyto- sia is usually diagnosed in patients with no other systemic
Figure 3.6. Posterior pituitary ectopia. A, MR image demonstrating the normal hyperintense signal of the posterior pituitary
gland (lower arrow), normal pituitary infundibulum (open arrow), optic chiasm (upper arrow). B, MR image demonstrating
posterior pituitary ectopia that appears as an abnormal focal area of increased signal intensity at the tuber cinereum (upper
arrow). Note absence of the pituitary infundibulum and absence of the normal posterior pituitary bright spot (lower arrow).
(From Brodsky MC, Glasier CM, Pollock SC, et al. Optic nerve hypoplasia: Identification by magnetic resonance imaging.
Arch Ophthalmol 1990;108⬊562–567.)
Figure 3.7. Superior segmental optic hypoplasia in a child whose mother had adult-onset diabetes mellitus. A, Right optic
disc demonstrating an abnormal superior entrance of the central retinal artery, relative pallor of the superior disc, and a superior
peripapillary halo. The superior nerve fiber layer is absent, while the inferior nerve fiber layer is clearly seen. B, Humphrey
visual field in superior segmental hypoplasia showing a nonaltitudinal inferior visual field defect with milder superior depression.
(From Brodsky MC, Schroeder GT, Ford R. Superior segmental optic hypoplasia in identical twins. J Clin Neuroophthalmol
1993;13⬊152–154.)
anomalies (145). Kim et al. (104) noted that the inferior across the disc. The ipsilateral optic disc may range from
visual field defects in superior segmental optic hypoplasia normal in size to frankly hypoplastic (149). Homonymous
differ from typical nerve fiber bundle defects, and suggested hemioptic hypoplasia in retrogeniculate lesions results from
that a regional impairment in retinal development could play transsynaptic degeneration of the optic tract (78,149,151).
a role in the pathogenesis. Hashimoto et al. (146) docu- The term ‘‘optic nerve hypoplasia’’ implies that the nerve
mented superior segmental optic hypoplasia in four Japanese is deficient in axons because of a primary failure of these
patients whose mothers were not diabetic, demonstrating that axons to develop. Initial investigators understandably attrib-
this anomaly is not pathognomonic for maternal diabetes. uted optic nerve hypoplasia to a primary failure of retinal
The teratologic mechanism by which insulin-dependent ganglion cell differentiation at the 13- to 15-mm stage of
diabetes mellitus selectively interferes with the early gesta- embryonic life (4–6 weeks’ gestation) (11). However, Mo-
tional development of superior retinal ganglion cells or their sier et al. (17) noted that third-order retinal neurons (i.e.,
axons is unknown (147). Mice lacking EphB receptor guid- ganglion cells) arise from the same precursor cells as ama-
ance proteins exhibit specific guidance defects in axons orig- crine and horizontal cells, and injury to the stem cells would
inating from the dorsal or superior part of the retina (148).
be unlikely to affect only one of the differentiated cell types.
Developmental mechanisms that control the expression of
At least two distinct mechanisms appear to be operative
axon guidance molecules along the dorsal-ventral axis of the
in the embryogenesis of optic nerve hypoplasia. Recent ex-
retina may eventually explain this segmental optic hypopla-
sia (148). periments have shown that a deficiency of axon guidance
Congenital lesions of the retina, optic nerve, chiasm, tract, molecules at the optic disc can lead to optic nerve hypopla-
or retrogeniculate pathways are associated with segmental sia. Netrin-1 is an axon guidance molecule that is involved
hypoplasia of the corresponding portions of each optic nerve in the development of spinal commissural axons and is ex-
(149,150). Hoyt et al. (151) coined the term ‘‘homonymous pressed by neuroepithelial cells at the developing optic nerve
hemioptic hypoplasia’’ to describe the asymmetric form of head. Retinal ganglion cells in vitro respond to netrin-1 as
segmental optic nerve hypoplasia seen in patients with uni- a guidance molecule. Mice with a targeted deletion of the
lateral congenital hemispheric lesions affecting the postchi- netrin-1 gene exhibit pathfinding errors at the optic disc,
asmal afferent visual pathways. In this setting, the nasal and where retinal ganglion cells fail to exit into the optic nerve
temporal aspects of the optic disc contralateral to the hemi- and instead grow inappropriately into the other side of the
spheric lesion show segmental hypoplasia and loss of the retina. As a result of this aberrant pathfinding, these mice
corresponding nerve fiber layers (Fig. 3.8). This anomaly exhibit optic nerve hypoplasia (152,153). In addition to de-
may be accompanied by a central band of horizontal pallor fects in optic nerve formation, the lack of netrin-1 function
Figure 3.8. Homonymous hemioptic hypoplasia in a patient with a right occipital porencephalic cyst. Both optic discs are
hypoplastic (A and B). The left optic disc shows some loss of disc substance and peripapillary nerve fiber layer nasally and
temporally. (From Novakovic P, Taylor DSI, Hoyt WF. Localizing patterns of optic nerve hypoplasia-retina to occipital lobe.
Br J Ophthalmol 1988;72⬊176–182.)
during development also results in abnormalities in other injuries or malformations that injure the optic radiations can
parts of the CNS, such as agenesis of the corpus callosum, lead to retrograde transsynaptic degeneration and segmental
and cell migration and axonal guidance defects in the hypo- hypoplasia of both optic nerves (64,81,149,151). These latter
thalamus (154). Thus, elimination of specific axon guidance lesions clearly cannot be reconciled with a deficiency of
molecules during development of the mouse nervous system axon guidance molecules at the optic disc (64,93,94,156,
results in a phenotype that bears striking resemblance to 158,159).
septo-optic dysplasia (153). Reported cases of optic nerve hypoplasia in siblings
The timing of coexistent CNS injuries would suggest that (115,160) are sufficiently rare that parents of a child with
some cases of optic nerve hypoplasia result from intrauterine optic nerve hypoplasia can reasonably be assured that subse-
destruction of a normally developed structure (i.e., an en- quent siblings are at little or no additional risk. While genetic
cephaloclastic event), whereas others represent a primary mutations in the human netrin-1 and DCC genes have not
failure of axons to develop (8,55,155,156). In human fetuses, been described, homozygous mutations in the Hesx1 gene
Provis et al. (157) found a peak of 3.7 million axons at 16–17 have been identified in two siblings with optic nerve hypo-
weeks of gestation, with a subsequent decline to 1.1 million
plasia, absence of the corpus callosum, and hypoplasia of
axons by the 31st gestational week (see Chapter 1). This
the pituitary gland (161). Five additional mutations in Hesx1
massive degeneration of supernumerary axons, termed
‘‘apoptosis,’’ occurs as part of the normal development of have recently been observed in children with sporadic pitui-
the visual pathways and may serve to establish the correct tary disease and septo-optic dysplasia (162). Mutations have
topography of the visual pathways (8). Toxins or associated clustered in the DNA-binding region of the protein consis-
CNS malformations could augment the usual processes by tent with a presumed loss in protein function. Formal exami-
which superfluous axons are eliminated from the developing nation of homeobox genes with expression patterns similar
visual pathways (8,9,55,64,149). Taylor (30) documented to Hesx1, such as Six3 and Six6, may yield additional genes
mild optic nerve hypoplasia in patients with congenital su- responsible for both sporadic and familial septo-optic dys-
prasellar tumors, suggesting that the space-occupying effects plasia (163). Optic nerve hypoplasia may accompany other
of these lesions can directly interfere with the normal migra- ocular malformations in patients with mutations in the PAX6
tion of optic axons to their target sites. Prenatal hemispheric gene (164).
EXCAVATED OPTIC DISC ANOMALIES

Excavated optic disc anomalies include optic disc colo- excavation (167–173) (Fig. 3.9). A wide annulus of
boma, morning glory disc anomaly, peripapillary staphy- chorioretinal pigmentary disturbance surrounds the disc
loma, megalopapilla, and optic pit. Recently, two new exca- within the excavation. A white tuft of glial tissue overlies
vated optic disc anomalies have been associated with the central portion of the disc. The blood vessels appear
periventricular leukomalacia (see above) and the ‘‘vacant increased in number and often arise from the periphery of
optic disc’’ associated with papillorenal syndrome. In the the disc (165). They often curve abruptly as they emanate
morning glory disc anomaly and peripapillary staphyloma, from the disc, then run an abnormally straight course over
an excavation of the posterior globe surrounds and incorpo- the peripapillary retina. It is often difficult to distinguish
rates the optic disc, while in the other conditions, the excava- arterioles from venules. Close inspection may reveal the
tion is contained within the optic disc. Pollock (165) has presence of peripapillary or arteriovenous communications
detailed the clinical features that distinguish the excavated that can be confirmed by fluorescein angiography (174,175).
optic disc anomalies. He emphasized that the terms ‘‘morn- The macula may be incorporated into the excavation
ing glory disc,’’ ‘‘optic disc coloboma,’’ and ‘‘peripapillary (165,174). Computed tomographic (CT) scanning shows a
staphyloma’’ are often transposed in the literature, causing funnel-shaped enlargement of the distal optic nerve at its
tremendous confusion regarding their diagnostic criteria, as- junction with the globe (Fig. 3.10) (176–178). Additional
sociated systemic findings, and pathogenesis. From his anal- findings may include diffuse thickening with increased or
ysis, it is clear that optic disc colobomas, morning glory optic decreased radiodensity of the orbital optic nerve, cavum ver-
discs, and peripapillary staphylomas are distinct anomalies, gae, and, most notably, transsphenoidal encephalocele (179).
each with its own specific embryologic origin, and not sim- The morning glory disc anomaly usually occurs as a uni-
ply clinical variants along a broad phenotypic spectrum. lateral condition, but several bilateral cases have been re-
ported (174). Visual acuity usually ranges from 20/200 to
MORNING GLORY DISC ANOMALY finger counting, but cases with 20/20 vision as well as no
light perception have been reported. Unlike optic disc colo-
The morning glory disc anomaly is a congenital, funnel- bomas, which have no racial or gender predilection, morning
shaped excavation of the posterior fundus that incorporates glory discs are more common in females and rare in African
the optic disc (165). It was so-named by Kindler (166) be- Americans (165,172,180). With rare exceptions (164,181),
cause of its resemblance to the morning glory flower. Oph- the morning glory disc anomaly is not part of a genetic disor-
thalmoscopically, the disc is markedly enlarged, orange or der (165). However, Holmström and Taylor (182) docu-
pink in color, and may appear to be recessed or elevated mented the association of morning glory disc anomaly with
centrally within the confines of a funnel-shaped peripapillary ipsilateral orofacial hemangioma. Metry et al. (183) sug-
A B
Figure 3.9. Morning glory disc anomaly. A, The optic disc shows the classic features of the morning glory syndrome: An
enlarged, funnel-shaped, excavated and distorted optic disc that is surrounded by an elevated annulus of chorioretinal pigmentary
disturbance. B, In another case of morning glory syndrome, a large optic disc is surrounded by an annular zone of pigmentary
disturbance and a V-shaped zone of infrapapillary depigmentation. The retinal vessels appear increased in number, appear to
emerge from the disc periphery, and have an abnormally straight radial configuration. A tuft of white glial overlies the center
of both optic discs.
gested that this association falls within the spectrum of the

PHACE syndrome (posterior fossa malformations, large fa-
cial hemangiomas, arterial anomalies, cardiac anomalies and
aortic coarcation, and eye anomalies), which occurs only
in girls. Recent findings of ipsilateral intracranial vascular
dysgenesis in such patients support this contention (184).
Atypical morning glory disc anomalies have also rarely been
reported in patients with neurofibromatosis 2 (185).
The association of morning glory disc anomaly with the
transsphenoidal form of basal encephalocele is well estab-
lished (174,177,186–191). The finding of V- or tongue-
shaped infrapapillary depigmentation adjacent to a morning
glory disc anomaly or other optic disc malformation (Fig.
3.9B) is highly associated with transsphenoidal encephalo-
cele (92), although transsphenoidal encephalocele is also
well-documented in the absence of this unique infraperipapil-
lary retinal malformation (117). Transsphenoidal encephalo-
cele is a rare midline congenital malformation in which a
meningeal pouch, often containing the chiasm and adjacent
hypothalamus, protrudes inferiorly through a large, round
defect in the sphenoid bone (Fig. 3.11). Patients with this
occult basal meningocele have a wide head, flat nose, mild
hypertelorism, a midline notch in the upper lip, and some-
times a midline cleft in the soft palate (Fig. 3.12A). The
meningocele protrudes into the nasopharynx, where it may
Figure 3.10. CT scan of morning glory disc anomaly. Note calcified fun- obstruct the airway. Symptoms of transsphenoidal encepha-
nel-shaped enlargement of the distal optic nerve at its junction with the locele in infancy include rhinorrhea, nasal obstruction,
globe. (From Brodsky MC. Congenital optic disk anomalies. Surv Ophthal- mouth-breathing, or snoring (186,192,193). These symp-
mol 1994;39⬊89–112.) toms may be overlooked unless the associated morning glory
Figure 3.11. MR imaging in transsphenoidal encephalocele. A, Sagittal MR image shows an encephalocele (delimited by
open arrows) extending down through the sphenoid bone into the nasopharynx with impression on the hard palate (white
arrow). B, Coronal MR image shows the third ventricle and hypothalamus (white arrowheads) extending inferiorly into the
encephalocele (delimited inferiorly by open arrow). (From Brodsky MC. Congenital optic disk anomalies. Surv Ophthalmol
1994;39⬊89–112. Courtesy of A. James Barkovich, MD.)
A B
Figure 3.12. A, Photograph of a child with transsphenoidal encephalocele. Note hypertelorism, depressed nasal bridge, and
subtle midline upper lip defect. B, MR angiography in a different patient with a morning glory disc anomaly. Note decrease
in caliber of the left internal carotid artery with focal narrowing of the distal portion (long arrow), and narrowing of the
bifurcation into middle and anterior cerebral arteries. The increased size of the lenticulostriate arteries (short arrow) produce
a moyamoya appearance. (A, From Brodsky MC, Hoyt WF, Hoyt CS, et al. Atypical retinochoroidal coloboma in patients with
dysplastic optic discs and transsphenoidal encephalocele. Arch Ophthalmol 1995;113⬊624–628. B, From Wisotsky BJ, Magat-
Gordon CB, Puklin JE. Vitreopapillary traction as a cause of elevated optic nerve head. Am J Ophthalmol 1998;126⬊137–139.)
disc anomaly or the characteristic facial configuration are space, which may have resulted from surgical removal of
recognized. A transsphenoidal encephalocele may appear tractional glial tissue overlying the disc. Spontaneous resolu-
clinically as a pulsatile posterior nasal mass or as a ‘‘nasal tion of morning glory-associated retinal detachments have
polyp’’ high in the nose, and surgical biopsy or excision of also been reported (180).
the lesion can have severe and even lethal consequences Several authors have documented contractile movements
(186). Associated brain malformations include agenesis of in a morning glory optic disc (165,210–212). Pollock (165)
the corpus callosum and posterior dilatation of the lateral attributed the contractile movements in his case to fluctua-
ventricles. Absence of the chiasm is seen in approximately tions in subretinal fluid volume, altering the degree of retinal
one-third of patients at surgery or autopsy. Most of the af- separation within the confines of the excavation. Graether
fected children have no overt intellectual or neurologic defi- (3) described a patient with a morning glory disc anomaly in
cits, but hypopituitarism is common (186,192,194,195). Sur- whom episodes of amaurosis were accompanied by transient
gery is contraindicated for transsphenoidal encephalocele dilation of the retinal veins in an eye with a morning glory
because herniated brain tissue may include vital structures disc. Subretinal neovascularization may occasionally de-
such as the hypothalamic-pituitary system, optic nerves and velop within the circumferential zone of pigmentary disturb-
chiasm, and anterior cerebral arteries, and because of the ance adjacent to a morning glory disc (213,214).
high postoperative mortality, particularly in infants. The embryologic defect leading to the morning glory disc
In 1985, Hansen et al. documented the association of anomaly is widely disputed (177). Histopathologic reports
morning glory disc anomaly with hypoplasia of the ipsi- have, unfortunately, lacked clinical confirmation (215–218).
lateral intracranial vasculature (196). With the advent of MR Some authors hypothesized that the morning glory disc
angiography, numerous reports have found ipsilateral intra- anomaly results from defective closure of the embryonic
cranial vascular dysgenesis (hypoplasia of the carotid arter- fissure and is but one phenotypic form of a colobomatous
ies and major cerebral arteries with or without Moyamoya (i.e., embryonic fissure-related) defect (176,219). Others in-
syndrome), in patients with morning glory disc anomaly (Fig terpreted the clinical findings of a central glial tuft, vascular
3.12B). These reports underscore the need for MR angiogra- anomalies, and a scleral defect, together with the histologic
phy in the neurodiagnostic evaluation of patients with morn- findings of adipose tissue and smooth muscle within the
ing glory disc anomaly (197–199). The coexistence of these peripapillary sclera in presumed cases of the morning glory
intracranial vascular anomalies supports the Dempster hy- disc to signify a primary mesenchymal abnormality. These
pothesis that the morning glory disc anomaly results from researchers suggested that the associated midfacial anoma-
a primary vascular dysgenesis that occurs in the context of lies in some patients further support the concept of a primary
a regional mesodermal dysgenesis (200). mesenchymal defect, since most of the cranial structures are
Patients with a morning glory disc anomaly may experi- derived from mesenchyme (177). Dempster (200) has at-
ence both transient visual loss (3) and permanent visual loss tempted to reconcile these two views by proposing that the
later in life. Serous retinal detachments occur in 26–38% of basic defect is mesodermal but that some clinical features
eyes with morning glory optic discs (172,180,201). These of the defect result from a dynamic disturbance between the
detachments typically originate in the peripapillary area and relative growth of mesoderm and ectoderm. Pollock (165)
extend through the posterior pole, occasionally progressing has argued that the fundamental symmetry of the fundus
to total detachments (202). Although retinal tears are rarely excavation with respect to the disc implicates an anomalous
evident, several reports identified small retinal tears adjacent funnel-shaped enlargement of the distal optic stalk at its
to or overlying the optic nerve in patients with morning glory junction with the primitive optic vesicle, as the primary em-
disc-associated retinal detachments (202–205). In other bryologic defect.
cases with acquired visual loss, there is nonattachment and
radial folding of the retina within the excavated zone (165). OPTIC DISC COLOBOMA
The sources of subretinal fluid may be multiple (206). Brown
and Brown (207) reported successful retinal reattachment The term ‘‘coloboma,’’ of Greek derivation, means cur-
with pars plana vitrectomy, laser photocoagulation, and in- tailed or mutilated (220,221). It is used only with reference
travitreal gas injection. Irvine et al. (206) reported a patient to the eye. According to Mann (220), colobomas of the optic
with a morning glory disc-associated retinal detachment, disc result from incomplete or abnormal coaptation of the
who was treated with optic nerve sheath fenestration fol- proximal end of the embryonic fissure. Liebrich (222) is
lowed by gas injection into the vitreous cavity. Following credited with the first ophthalmoscopic description of an
the procedure, gas bubbled out through the dural window, isolated optic disc coloboma, and Coats discussed the subject
suggesting a connection between the vitreous cavity and the in detail in 1908, adding clinical and pathologic data on
subarachnoid space through the anomalous disc. Chang et al. cases from his own experience to the three cases already in
(208) also reported resolution of a morning glory-associated the literature at that time. Subsequent reports presented simi-
serous retinal detachment following optic nerve sheath fen- lar examples of isolated optic disc coloboma (223–226).
estration. Bartz-Schmidt and Hermann (209) noted subreti- Optic disc coloboma is characterized by a sharply delim-
nal leakage of gas injected into the vitreous following vitrec- ited, glistening white, bowl-shaped excavation that occupies
tomy for a complete retinal detachment in as eye with a an enlarged optic disc (Fig. 3.13). The excavation is decen-
morning glory anomaly, thereby demonstrating a direct com- tered inferiorly, reflecting the position of the embryonic fis-
munication between the vitreous cavity and the subretinal sure relative to the primitive epithelial papilla (165). The
Goldenhar sequence (245,246), and linear sebaceous nevus

syndrome (240,244). Optic disc coloboma has recently been
linked to a mutation of the PAX6 (164).
Optic disc coloboma may be accompanied by other ocular
malformations. For example, large orbital cysts can commu-
nicate with atypical dark excavations of the disc that may
be colobomatous in nature (151,223,229,247). Villalonga
Gornés et al. (247) photographically documented an eye with
an orbital cyst in which spontaneous closure of a large infe-
rior papillary excavation transformed the colobomatous disc
into a morning glory anomaly! Theodossiadis et al. (248)
described a unique case of an optic disc coloboma that was
associated with a small disc and numerous retinal venous
malformations. Biedner et al. (249) found a macular hole in
a myopic patient with an optic disc coloboma. Although
peripapillary subretinal neovascularization, which may com-
plicate chorioretinal colobomas, has been reported in two
patients with optic disc colobomas (214,250), these optic
Figure 3.13. Coloboma of the optic disc in an eye with an old serous disc anomalies were, in fact, a morning glory anomaly and
macular detachment. The disc is enlarged. A deep white excavation occu- an optic pit.
pies most of the disc but spares its superior aspect. Note absence of inferior Histopathologic examination in optic disc coloboma dem-
retinal nerve fiber layer and pigment epithelial disturbance in the macula. onstrates intrascleral smooth muscle strands oriented con-
The patient had a large superior, altitudinal visual field defect.
centrically around the distal optic nerve (251,252). Presum-
ably, this pathologic finding accounts for the contractility
of the optic disc seen in rare cases of optic disc coloboma
inferior neuroretinal rim is thin or absent, while the superior (253). Heterotopic adipose tissue is also present within and
neuroretinal rim is relatively spared. Rarely, the entire disc adjacent to some optic disc colobomas (251,252). Eyes with
appears excavated; however, the colobomatous nature of the an isolated optic disc coloboma can develop a serous macular
defect can still be appreciated ophthalmoscopically because detachment (Fig. 3.13) (in contrast to the rhegmatogenous
the excavation is deeper inferiorly (165). The defect may retinal detachments that complicate retinochoroidal colobo-
extend further inferiorly to include the adjacent choroid and mas) (254,255). In a clinicopathologic study of an optic disc
retina, in which case microphthalmia is frequently present coloboma and associated macular detachment in a rhesus
(227). Iris and ciliary colobomas often coexist. Axial CT monkey, Lin et al. (254) noted disruption of the intermediary
scanning shows a crater-like excavation of the posterior tissue of Kuhnt with diffusion of retrobulbar fluid from the
globe at its junction with the optic nerve (176,219). Colobo- orbit into the subretinal space. The nonrhegmatogenous de-
matous malformations of the optic disc produce an inferior tachment can be treated in a variety of ways, including oc-
segmental hypoplasia of the optic nerve, with a C-shaped or clusion of the affected eye, bed rest, corticosteroids, vitrec-
quarter-moon-shaped neuroretinal rim confined to the supe- tomy, scleral buckling procedures, gas-fluid exchange, and
rior aspect of the optic disc (Fig. 3.13) (228). Colobomas photocoagulation (207,255,256). Schatz and McDonald
constitute the most common segmental form of optic nerve (255) advocated waiting 3 months before treating coloboma-
hypoplasia encountered in clinical practice (228). Coronal associated macular detachments because spontaneous reat-
T1-weighted MR imaging confirms that the intracranial por- tachment may occur (256).
tion of the optic nerve is reduced in size (228). The nosologi- Unfortunately, many uncategorizable dysplastic optic
cal overlap between colobomatous derangement of the optic discs (discussed later) are indiscriminately labeled as optic
nerve and segmental hypoplasia reflects the early timing of disc colobomas. This practice complicates the nosology of
colobomatous dysembryogenesis which results in primary coloboma-associated genetic disorders. It is therefore crucial
failure of inferior retinal ganglion cells to develop. that the diagnosis of optic disc coloboma be reserved for
Visual acuity, which depends primarily upon the integrity discs that show an inferiorly decentered, white-colored exca-
of the papillomacular bundle, may be mildly to severely vation, with minimal peripapillary pigmentary changes. For
decreased and is difficult to predict from the appearance of example, the purported association between optic disc colo-
the disc. Unlike the morning glory disc anomaly, which is boma and basal encephalocele (186,257,258) is deeply en-
usually unilateral, optic disc colobomas occur unilaterally trenched in the literature; however, a critical review reveals
or bilaterally with approximately equal frequency (165). As only two photographically documented cases (258,259). In
with uveal colobomas, isolated optic disc colobomas may striking contrast to the numerous well-documented reports
be sporadic or inherited (230–235). Ocular colobomas may of morning glory optic discs occurring in conjunction with
be accompanied by other systemic anomalies (236–239), in basal encephaloceles, cases of optic disc coloboma with
genetic disorders such as the CHARGE association basal encephalocele are actually conspicuous by their ab-
(240–243), Walker-Warburg syndrome (240), Goltz focal sence.
dermal hypoplasia (240,244), Aicardi syndrome (82,106), Early in the century, von Szily, in his monumental study
Table 3.1
Ophthalmoscopic Findings That Distinguish the Morning Glory Disc
Anomaly from Optic Disc Coloboma
Morning Glory Disc Optic Disc Coloboma
Optic disc lies within the excavation Excavation lies within the optic
disc
Symmetrical defect (disc lies Asymmetrical defect (excavation
centrally within the excavation lies inferiorly within the disc)
Central glial tuft No central glial tuft
Severe peripapillary Minimal peripapillary
pigmentary disturbance pigmentary disturbance
Anomalous retinal vasculature Normal retinal vasculature
of colobomas, stated ‘‘with certainty’’ that ‘‘all the true mor-

phological malformations of the optic disc, including true
colobomas . . . are only different manifestations of the same
developmental anomaly, namely a different form and degree
of malformation of the primitive or epithelial optic papilla’’ Figure 3.14. Peripapillary staphyloma. The optic disc is situated within
(187,260). However, the ophthalmoscopic features of optic a bowl-shaped excavation.
disc coloboma are most consistent with a primary structural
dysgenesis of the proximal embryonic fissure, as opposed
to an anomalous dilation confined to the distal optic stalk rounds the optic disc (Fig. 3.14) (263,264). In this condition,
in the morning glory disc anomaly (Table 3.1) (165,261). the disc is seen at the bottom of the excavated defect and
The profound differences in associated ocular and systemic may appear normal or show temporal pallor (165,265). The
findings between the two anomalies (Table 3.2) lend further walls and margin of the defect may show atrophic changes
credence to this hypothesis. Anomalous optic discs with in the retinal pigment epithelium (RPE) and choroid (265).
overlapping features of the morning glory disc anomaly and Unlike the morning glory disc anomaly, there is no central
optic disc coloboma are occasionally seen (235,262). These glial tuft overlying the disc, and the retinal vascular pattern
‘‘hybrid’’ anomalies could easily represent instances of early remains normal, apart from reflecting the essential contour
embryonic injury affecting both the proximal embryonic fis- of the lesion (165). The staphylomatous excavation in peri-
sure and the distal optic stalk. Their existence should not papillary staphyloma is also notably deeper than that seen in
obscure the fact that colobomatous and morning glory optic the morning glory disc anomaly. Several cases of contractile
discs appear as clinically distinct anomalies in most cases. peripapillary staphyloma have been documented (265–268).
The concept of ‘‘an optic disc coloboma with a morning Seybold and Rosen (269) described a patient who had tran-
glory configuration’’ should be abandoned. sient visual obscurations in an eye with an atypical peripapil-
lary staphyloma.
Visual acuity is usually markedly reduced in eyes with a
PERIPAPILLARY STAPHYLOMA peripapillary staphyloma, but cases with nearly normal acu-
Peripapillary staphyloma is an extremely rare, usually uni- ity have also been reported (270). Affected eyes are usually
lateral anomaly, in which a deep fundus excavation sur- emmetropic or slightly myopic, and eyes with decreased vi-
sion frequently have centrocecal scotomas (264). Although
peripapillary staphyloma is clinically and embryologically
distinct from morning glory optic disc, these conditions are
Table 3.2 frequently transposed in the literature (3,210,271). Table 3.3
Associated Ocular and Systemic Findings That Distinguish the
Morning Glory Disc from Isolated Optic Disc Coloboma
Table 3.3
Morning Glory Disc Optic Disc Coloboma Ophthalmoscopic Findings That Distinguish Peripapillary
Staphyloma from the Morning Glory Disc Anomaly
More common in females; rare in No sex or racial predilection
blacks Peripapillary Staphyloma Morning Glory Disc
Rarely familial Often familial
Rarely bilateral Often bilateral Deep, cup-shaped excavation Less depth, funnel-shaped
No iris, ciliary, or retinal Iris, ciliary, and retinal excavation
colobomas colobomas common Relatively normal, well-defined Grossly anomalous, poorly
Rarely associated with multisystem Often associated with optic disc defined optic disc
genetic disorders multisystem genetic disorders Absence of glial and vascular Central glial bonquet, anomalous
Basal encephalocele common Basal encephalocele rare anomalies vascular pattern
contrasts the ophthalmoscopic features that distinguish these and is often associated with a large cup-to-disc ratio, which
two anomalies. almost invariably raises the diagnostic consideration of nor-
Although peripapillary staphyloma is usually unasso- mal-tension glaucoma (Fig. 3.15A). However, the optic cup
ciated with systemic or intracranial disease, it has been reis usually round or horizontally oval with no vertical notch-
ported in association with transsphenoidal encephalocele ing or encroachment, so that the quotient of horizontal to
(272), PHACE syndrome (184,273), linear nevus sebaceous vertical cup-to-disc ratio remains normal, in contradistinc-
syndrome (274), and 18qⳮ (de Grouchy) syndrome (275). tion to the decreased quotient that characterizes glaucoma-
The fairly normal appearance of the optic disc and retinal tous optic atrophy (33). Because the axons are spread over
vessels in eyes with a peripapillary staphyloma suggests that a larger surface area, the neuroretinal rim may also appear
the development of these structures is complete before the pale, mimicking optic atrophy (286). Less commonly, the
staphylomatous process begins (165). Pollock (165) has ar- normal optic cup is replaced by a grossly anomalous noninfe-
gued that the clinical features of peripapillary staphyloma rior excavation that obliterates the adjacent neuroretinal rim
are most consistent with diminished peripapillary structural (Fig. 3.15B), as described in a large autosomal-dominant
support, perhaps resulting from incomplete differentiation pedigree by Slusher et al. (287). The inclusion of this rare
of sclera from posterior neural crest cells in the 5th month variant under the rubric of megalopapilla serves the nosolog-
of gestation. ically useful function of distinguishing it from a coloboma-
tous defect with the latter’s attendant systemic implications.
MEGALOPAPILLA Cilioretinal arteries are common in eyes with megalopapilla
(33). A high prevalence of megalopapilla was observed in
This congenital anomaly was first described by Kraupa natives of the Marshall Islands (288).
(276) and has since been reported in numerous other individ- Two reports documented large optic discs in patients with
uals (187,277–286). In 1950, Franceschetti and Bock origi- optic nerve hypoplasia associated with a congenital homony-
nally applied the term megalopapilla to signify enlargement mous hemianopia (37,289). This rare combination of find-
of the optic disc without additional structural abnormalities. ings suggests that a prenatal loss of optic nerve axons leading
Since that time, megalopapilla has become a generic term to optic nerve hypoplasia does not always alter the geneti-
that connotes an abnormally large, excavated optic disc that cally predetermined size of the scleral canals (37).
lacks the numerous anomalous features of the morning glory Visual acuity is usually normal with megalopapilla, but
disc anomaly, the inferior displacement of a coloboma, or the it may be mildly decreased. The visual field is also usually
striking cilioretinal circulation of the papillorenal syndrome normal, except for an enlarged blind spot, allowing the ex-
(see below). In its current usage, megalopapilla comprises aminer to rule out normal-tension glaucoma or compressive
two phenotypic variants. The first is a common variant in optic atrophy. Colobomatous discs are distinguished from
which an abnormally large optic disc (greater than 2.1 mm megalopapilla by their predominant excavation of the infe-
in diameter) retains an otherwise normal configuration rior optic disc. Aside from glaucoma and optic disc colo-
(264,278). This form of megalopapilla is usually bilateral boma, the differential diagnosis of megalopapilla includes
A B
Figure 3.15. Megalopapilla. A, A common variant of megalopapilla in which an abnormally large optic disc contains a large
central cup. Unlike glaucomatous optic atrophy, the cup is horizontally oval with an intact neuroretinal rim, and there is no
nasalization of vessels at the point of origin. B, An uncommon variant of megalopapilla in which an anomalous superior
excavation obliterates much of the temporal neuroretinal rim. (From Brodsky MC. Congenital optic disk anomalies. Surv
Ophthalmol 1994;39⬊89–112.)
orbital optic glioma, which in children can cause progressive unless there is fluid within or beneath the macula (see
enlargement of a previously normal-sized optic disc (290). below). Although visual field defects are variable and often
Pathogenetically, most cases of megalopapilla may simply correlate poorly with the location of the pit, the most com-
represent a statistical variant of normal. However, it is likely mon defect appears to be a paracentral arcuate scotoma con-
that megalopapilla occasionally results from altered migra- nected to an enlarged blind spot (293,295). Optic pits do
tion of optic axons early in embryogenesis, as evidenced not portend additional CNS malformations, although rare
by two reports of megalopapilla in patients with anterior exceptions exist (300). Acquired depressions in the optic
encephaloceles (187,291). Nevertheless, the rarity of an as- disc that are indistinguishable from optic pits are said to
sociation between megalopapilla and CNS abnormalities occur in normal-tension glaucoma (301).
suggests that neuroimaging is unwarranted in a patient with Serous macular elevations develop in 25–75% of eyes
megalopapilla, unless midline facial anomalies (e.g., hyper- with optic pits (Fig. 3.16B) (293,295,302,303). Optic pit-
telorism, cleft palate, cleft lip, depressed nasal bridge) co- associated maculopathy generally becomes symptomatic in
exist. the third and fourth decades of life. Vitreous traction on the
margins of the pit and tractional changes in the roof of the
OPTIC PIT pit may be the inciting events that ultimately lead to late-
An optic pit is a round or oval, gray, white, or yellowish onset macular detachment (299,303,304).
depression in the optic disc (Fig. 3.16A). Wiethe (292) first All optic pit-associated macular elevations were once
described two black depressions with an olive-gray tint thought to be caused by serous detachments. Lincoff et al.
within the optic disc of a 62-year-old woman. Early investi- (305), however, proposed that careful stereoscopic examina-
gators labeled these depressions as colobomas, crater-like tion of the macula in conjunction with kinetic perimetry
holes, congenital holes, and congenital pits (293). Reis (294) demonstrates the following progression of events:
estimated the frequency of optic pits to be approximately 1
in 11,000—a figure later confirmed by Kranenburg (295). 1. A schisis-like inner layer retinal separation initially forms
Numerous reports of familial optic pits suggest an autoso- in direct communication with the optic pit, producing a
mal-dominant mode of transmission (296–298). mild, relative, centrocecal scotoma.
Optic pits commonly affected the temporal portion of the 2. An outer layer macular hole develops beneath the bound-
optic disc but may be situated in any sector (207). Such aries of the inner layer separation and produces a dense
temporally located pits are often accompanied by adjacent central scotoma.
peripapillary pigment epithelial changes. One or two ciliore- 3. An outer layer retinal detachment develops around the
tinal arteries emerge from the bottom or the margin of the macular hole, presumably from influx of fluid from the
pit in more than 50% of cases (264,299). Although optic inner layer separation. This outer layer detachment oph-
pits are typically unilateral, bilateral pits are seen in 15% of thalmoscopically resembles an RPE detachment but fails
cases (264). In unilateral cases, the affected disc is slightly to hyperfluoresce on fluorescein angiography.
larger than the normal disc. Visual acuity is typically normal 4. The outer layer detachment may eventually enlarge and
Figure 3.16. Optic pit. A, Oval white excavation occupies the temporal portion of the disc. B, Grayish temporal optic disc
with adjacent retinoschisis cavity (large arrows), serous macular detachment (small arrows) and outer layer hole (open arrow).
obliterate the inner layer separation. At this stage, it is

no longer ophthalmoscopically or histopathologically
distinguishable from a primary serous macular detach-
ment.
Optical coherence tomography confirms the presence of

an inner layer retinal separation in communication with
the optic pit in eyes with serous macular detachments
(306–308). Figure 3.16B depicts the retinal findings that
can be observed in the evolution of an optic pit-associated
macular detachment. The finding of a sensory macular de-
tachment in histopathologically studied eyes with optic pits
presumably represents the end stage of this sequence of
events. Whether or not this sequence of events leads to all
optic pit-associated macular detachments is unclear.
The risk of optic pit-associated macular detachment is
greater in eyes with large optic pits and in eyes with tempo- Figure 3.17. Histologic appearance of optic pit.
rally located pits (293). Spontaneous reattachment occurs in
approximately 25% of cases (213,293). Sugar’s (302) early
report of spontaneous resolution of most optic pit-associated copy often reveals a thin membrane overlying the pit (293)
macular detachments with good visual recovery differs from or a persistent Cloquet’s canal, terminating at the margin of
the experience of most subsequent investigators, who re- the pit (322). Brown et al. (323) documented active flow of
ported permanent visual loss in untreated patients, even fluid from the vitreous cavity through the pit to the subretinal
when spontaneous reattachment occurred (213,309). Bed space in collie dogs, but this mechanism has never been
rest and bilateral patching have led to retinal reattachment conclusively demonstrated in humans.
in some patients, presumably by decreasing vitreous traction Histologically, optic pits consist of herniations of dysplas-
(255,310). Laser photocoagulation to block the flow of fluid tic retina into a collagen-lined pocket extending posteriorly,
from the pit to the macula is usually unsuccessful, perhaps often into the subarachnoid space, through a defect in the
because of the inability of laser photocoagulation to seal a lamina cribrosa (Fig. 3.17) (264,304). Friberg and McLellan
retinoschisis cavity (255,303,305,309–312). Vitrectomy (324) demonstrated a pulsatile communication of fluid be-
with internal gas tamponade and laser photocoagulation tween the vitreous cavity and a retrobulbar cyst through an
were shown to produce long-term improvement in acuity optic pit. Rarely, macular holes can develop in eyes with
in several independent studies (207,255,305,310,311, optic pits or optic disc colobomas and lead to rhegmatogen-
313–315). The initial intent of this treatment was to com- ous retinal detachment (249,325).
press the retina at the edge of the disc to enhance the effect Although most researchers view optic pits as the mildest
of laser treatment (316). However, Lincoff et al. (316) have variant in the spectrum of optic disc colobomas (179,
postulated that internal gas tamponade functions to mechani- 206,254,255,293,295,301,309,319,321,326,327), this widely
cally displace subretinal fluid away from the macula, allow- accepted hypothesis is probably untenable for the following
ing a shallow, inner-layer separation to persist, which is asso- reasons:
ciated with a mild scotoma and relatively good visual acuity.
Based upon clinical and perimetric observations following 1. Optic pits are usually unilateral, sporadic, and unasso-
treatment, Lincoff et al. (316) concluded that laser photoco- ciated with systemic anomalies. Colobomas are bilateral
agulation probably does not contribute to the success of this as often as unilateral, commonly autosomal dominant,
procedure. Perhaps because of age-related differences in vi- and may be associated with a variety of multisystem dis-
treopapillary traction, optic pit-associated serous maculopa- orders.
thy in children may have a tendency toward spontaneous 2. It is rare for optic pits to coexist with iris or retinochoroi-
resolution (317,318). dal colobomas.
The source of intraretinal fluid in eyes with optic pits 3. Optic pits usually occur in locations unrelated to the em-
is controversial. Possible sources include vitreous cavity bryonic fissure.
via the pit, the subarachnoid space, blood vessels at the
base of the pit, and the orbital space surrounding the
dura (254,264,303,319). Although fluorescein angiography PAPILLORENAL SYNDROME
shows early hypofluorescence of the pit, followed in many (THE ‘‘UNCOLOBOMA’’)
cases by late hyperfluorescent staining (293,303,311,320),
optic pits do not generally leak fluorescein and there is no The papillorenal syndrome, also previously known as
extension of fluorescein into the subretinal space toward the renal-coloboma syndrome, was first described by Rieger in
macula (319,321). The finding of late hyperfluorescent stain- 1977 (328). This syndrome was initially considered to be a
ing correlates strongly with the presence of cilioretinal arter- rare autosomal-dominant disorder consisting of bilateral
ies emerging from the pit (299). Careful slit-lamp biomicros- optic disc anomalies associated with hypoplastic kidneys
A B
Figure 3.18. Papillorenal syndrome. Both optic discs show a central excavation with multiple cilioretinal arteries in place
of the normal central retinal circulation. This 9-year-old girl with chronic renal failure had 20/20 acuity in each eye. Renal
biopsy showed interstitial fibrosis. (Photographs courtesy of Erika M. Levin, M.D.)
(329). Associated retinal detachments were described, as nal hypoplasia and, in some cases, to later-onset serous
was eventual renal failure. In 1995, Sanyanusin et al. discov- retinal detachments. Peripheral visual field defects corre-
ered mutations in the developmental gene PAX2, the human sponding to areas of retinal hypoplasia are often present.
homologue of the mouse gene Pax2 in two affected families The central optic disc excavation and peripheral field defects
(330). Schimmenti et al. (331) identified three additional can simulate coloboma as well as normal tension glaucoma.
families with PAX2 mutations with similar ophthalmologic Follow-up examination has shown renal disease in some pa-
features and a wider spectrum of renal abnormalities, which tients who were originally reported as having isolated famil-
may include hypoplasia, variable proteinuria, vesiculoure- ial autosomal dominant ‘‘coloboma.’’ (333).
teral reflux, recurrent pyelonephritis, microhematuria, echo- Parsa et al. have attributed this malformation to a primary
genicity on ultrasound, or high resistance to blood flow on deficiency in angiogenesis involved in vascular development
Doppler ultrasound (331). (329). In these patients, there is a failure of the hyaloid sys-
Parsa et al. have since determined that the papillorenal tem to convert to normal central retinal vessels. The absence
syndrome is characterized by a distinct optic disc malforma- of a well-defined central retinal artery or vein in several adult
tion that bears no relationship to coloboma (329,332,333).
mammalian species including lemurs and cats, suggests that
In this syndrome, the excavated optic disc is normal in size,
this malformation could be considered analogous to an evo-
and may be surrounded by variable pigmentary disturbance.
Unlike in colobomatous defects, the excavation is centrally lutionary regression to a feline pattern of circulation (329).
positioned. According to Parsa et al., the defining feature is Since ocular tissues and renal cortex are the most highly
the presence of multiple cilioretinal vessels which emanate perfused tissues of the body, both develop a significant por-
from the periphery of the disc, and variable attenuation or tion of their vasculature by means of angiogenesis (budding)
atrophy of the central retinal vessels (Fig. 3.18) (329). Color in addition to vasculogenesis (329). These tissues may thus
Doppler imaging has confirmed the absence of central retinal be particularly susceptible to anomalies in vascular develop-
circulation in patients with papillorenal syndrome (329). ment resulting in hypoplasia or anomalies of associated
Visual acuity is usually 20/20 but may occasionally be se- structures (329). Many patients with papillorenal syndrome
verely diminished (329,334) secondary to choroidal and reti- have no detectable mutations in the PAX2 gene (329,334).
CONGENITAL TILTED DISC SYNDROME

The tilted disc syndrome is a nonhereditary, usually bilat- inferonasal conus, thinning of the inferonasal RPE and cho-
eral condition in which the superotemporal optic disc is ele- roid, and bitemporal hemianopia that does not respect the
vated and the inferonasal disc is posteriorly displaced, result- vertical midline (335). Histopathologically, the optic nerve
ing in an oval-appearing optic disc, with its long axis enters at an extremely oblique angle, the superior or supero-
obliquely oriented (Fig. 3.19). This configuration is accom- temporal portion of the disc is elevated, and there is posterior
panied by situs inversus of the retinal vessels, congenital ectasia of the inferior or inferonasal fundus and optic disc
Figure 3.19. Congenital tilted disc syndrome. Both optic discs are oval with relative elevation of the superior-temporal portion
compared to the inferior-nasal portion. This elevation is often mistaken for true disc swelling. Note situs inversus of the vessels
and inferior retinochoroidal hypopigmentation.
(Figs. 3.20 and 3.21). Affected patients often have myopic and ‘‘Fuchs coloboma’’ probably are descriptions of this
astigmatism, with the plus-axis oriented parallel to the ecta- condition in its full or partial form. The inferior crescent is
sia. The ocular imagery resulting from a tilted retina creates created by a disparity between the size of the retinal and
a type of curvature of field that may subjectively simulate scleral openings. According to Dorrell (340), the retinal
astigmatic blur (336). Flüeler and Guyton (336) demon- opening is usually circular in shape, whereas the outline of
strated that the astigmatic retinoscopic reflex in the tilted the scleral canal is contracted across one segment, so that it
disc syndrome cannot result from the retinal tilt, since only conforms to a stirrup or D-shape. In some eyes, the entire
a minute area of the tilted retina is viewed during retinos- disc assumes a D-shape. The congenital tilted disc syndrome
copy. The tilted disc syndrome has been described in detail is bilateral in about 80% of cases (343). The cause of the
as such by several authors (335,337–342). In retrospect, tilted disc syndrome is unknown, but the inferonasal or infe-
however, early descriptions of congenital crescent, congeni- rior location of the excavation suggests a pathogenetic rela-
tal conus, situs inversion of the disc, optic disc dysversion, tionship to retinochoroidal coloboma (319).
Familiarity with the tilted disc syndrome is crucial for the
ophthalmologist, since affected patients may present with
bitemporal hemianopia, suggesting a chiasmal syndrome
(335,337–339,344,345). The bitemporal hemianopia in pa-
tients with tilted discs, however, is typically incomplete and
confined primarily to the superior quadrants. It is, in fact, a
refractive scotoma, secondary to regional myopia localized
to the inferonasal retina (Fig. 3.22) Unlike the visual field
loss that results from damage to the optic chiasm, the field
defects seen in the tilted disc syndrome fail to respect the
vertical meridian on both kinetic and static perimetry. Fur-
thermore, the superotemporal depression on Goldmann per-
imetry is selectively detected with mid-sized isopters,
whereas the large and small isopters give fairly normal re-
sults because the ectasia that occurs in such cases is confined
to the midperipheral fundus (Fig. 3.22) Despite the regional
retinal ectasia, recent topography studies have suggested that
Figure 3.20. Histologic appearance of a tilted optic disc. The nerve enters
an irregular corneal curvature underlies the associated astig-
the eye at an extremely oblique angle. Also note elevation of the superior matism (346,347). Repeat perimetry with a spectacle lens
(left) portion of the disc as compared with the inferior (right) portion of in place to correct myopic astigmatism may reduce or elimi-
the disc. A small area of optic nerve infarction is present just posterior to nate the superotemporal defect, confirming its refractive na-
the lamina cribrosa (arrowhead). ture (348). In some cases, retinal sensitivity may be de-
or optic nerve hypoplasia. In some cases, elevation of the

superior-temporal portion of the disc mimics optic disc
swelling (319,340,351).
The congenital retinal malformation in tilted disc syn-
drome may influence the development of acquired reti-
nal diseases. For example, the chorioretinal degenerative
changes within the ectatic inferonasal sector of retina
may predispose to macular subretinal neovascularization
(352,353). Numerous reports suggest that associated anoma-
lies at the junction of the staphyloma (354) or at the junction
of between peripapillary retina and the altered disc margin
(355,356) may play a role in the pathogenesis of serous mac-
ular detachments (354–356). Central serous papillopathy oc-
curs in eyes with tilted discs or the full tilted disc syndrome.
On the other hand, the inferonasal ectasia may also exert a
regional protective effect against background diabetic reti-
nopathy because of increased oxygenation from the choroid
to the thin ectatic retina (357).
It should be emphasized that a true bitemporal hemianopia
may occur in patients with the tilted disc syndrome who also
harbor a congenital suprasellar tumor (30). As with optic
Figure 3.21. CT scan showing ectasia of the lower nasal aspect of globes nerve hypoplasia, these two seemingly disparate lesions may
in a patient with the congenital tilted disc syndrome. The nasal aspects of reflect the disruptive effect of a suprasellar lesion on the
both globes protrude posteriorly. (From Brodsky MC. Congenital optic disk migration of optic axons during embryogenesis (30,
anomalies. Surv Ophthalmol 1994;39⬊89–112.) 358,359). This sinister association mandates neuroimaging
in any patient with a tilted disc syndrome whose bitemporal
hemianopia either respects the vertical meridian or fails to
creased in the area of the ectasia, and the defect thus persists preferentially involve the midperipheral isopter on kinetic
to some degree despite appropriate refractive correction perimetry. Margolis and Siegel (291) also documented the
(335,340,342,349). Brazitikos et al. (350) demonstrated that tilted disc syndrome in patients with craniofacial anomalies,
other quadrants also show mildly decreased sensitivities on including Crouzon’s disease and Apert’s disease.
threshold perimetry and suggested that the tilted disc syn- Tilted discs without retinal ectasia occur in patients with
drome may actually include some degree of diffuse retinal transsphenoidal encephalocele (92,272), congenital tumors
Figure 3.22. Kinetic perimetry demonstrates a supertemporal visual field defect in both left (A) and right (B) eyes. Note that
the defect is confined to the midperipheral isopter that does not respect the horizontal meridian.
of the anterior visual pathways (30), X-linked congenital and Biedner (363) reported a patient who had bilaterally
stationary night blindness (360,361), Ehlers-Danlos syn- tilted discs, facial hemiatrophy, and congenital horizontal
drome (type III), and familial dextrocardia (362). Rothkoff gaze paralysis.
OPTIC DISC DYSPLASIA

Optic disc dysplasia is a term that connotes a markedly
deformed optic disc that fails to conform to any recognizable
diagnostic category (Fig. 3.23). The distinction between an
nonspecifically ‘‘anomalous’’ disc and a ‘‘dysplastic’’ disc
is somewhat arbitrary and based primarily upon the severity
of the lesion. For instance, in the past, the term ‘‘optic disc
dysplasia’’ was applied to cases that are now identified as
the morning glory disc anomaly or papillorenal syndrome
(187,364). Conversely, many dysplastic optic discs have
been indiscriminately labeled as optic disc colobomas. New
variants of optic disc dysplasia continue to be recognized
(365,366).
Dysplastic optic discs in patients with transsphenoidal en-
cephalocele (188,367) tend to be associated with a discrete
infrapapillary zone of V- or tongue-shaped retinochoroidal
depigmentation (Figs. 3.9 and 3.24) (92). These juxtapapil-
lary defects differ from typical retinochoroidal colobomas,
which widen inferiorly and are not associated with basal
encephalocele. Unlike the typical retinochoroidal coloboma,
this distinct juxtapapillary defect is associated with minimal
scleral excavation and no visible disruption in the integrity of
the overlying retina. In patients with anomalous or dysplastic
optic discs, the finding of a V- or tongue-shaped retinocho-
roidal defect should prompt neuroimaging to look for trans-
sphenoidal encephalocele (92).
Figure 3.24. Optic disc dysplasia and transsphenoidal encephalocele. A,

Enlarged dysplastic optic disc with peripapillary pigmentary disturbance
Figure 3.23. Optic disc dysplasia. The optic disc is grossly malformed, and tongue-shaped area of inferior depigmentation. Optic disc dysplasia
and the retinal vessels emerge from the region of the disc in an anomalous with peripapillary pigmentary disturbance. B, Computed tomographic scan
pattern. shows transsphenoidal encephalocele.
CONGENITAL OPTIC DISC PIGMENTATION

Congenital optic disc pigmentation is a condition in which
melanin deposition anterior to or within the lamina cribrosa
imparts a slate-gray appearance to the entire optic disc. True
congenital optic disc pigmentation is extremely rare, but it
has been described in a child with an interstitial deletion of
chromosome 17 (368), in Aicardi syndrome (244), and in
optic nerve hypoplasia (Fig. 3.25) (368,369). Congenital
optic disc pigmentation is compatible with good visual acu-
ity but may be associated with coexistent optic disc anoma-
lies that decrease vision (368). Silver and Sapiro (370) dem-
onstrated that, in developing mice and rats, a transient zone
of melanin in the distal developing optic stalk influences
migration of the earliest optic nerve axons. The effects of
abnormal pigment deposition on optic nerve embryogenesis
could explain the frequent coexistence of congenital optic
disc pigmentation with other anomalies, particularly optic
nerve hypoplasia.
The majority of patients with gray optic discs do not have
congenital optic disc pigmentation. For reasons that are
poorly understood, optic discs of infants with delayed visual
maturation and albinism often have a diffuse gray tint when
viewed ophthalmoscopically. In these conditions, the gray
Figure 3.25. Congenital optic disc pigmentation. Entire disc is gray, and
tint usually disappears within the first year of life without the disc is hypoplastic with a surrounding zone of depigmentation, suggest-
visible pigment migration (371). Beauvieux (372,373) ob- ing migration of peripapillary pigment onto the disc.
served gray optic discs in premature infants and in albinotic
infants who were apparently blind but who later developed
good vision as the gray color disappeared. He attributed the
gray appearance of these neonatal discs to delayed optic mentation can usually be distinguished ophthalmoscop-
nerve myelination with preservation of the ‘‘embryonic ically, because melanin deposition in true congenital optic
tint.’’ It should be noted, however, that gray optic discs may disc pigmentation is often discrete, irregular, and granular
also be seen in normal neonates and are usually a nonspecific in appearance (368). True optic disc pigmentation may also
finding of little diagnostic value, except when accompanied be acquired, as in cases of melanocytoma or malignant mela-
by other clinical signs of delayed visual maturation or albi- noma of the optic nerve head. Sobanski (379) documented
nism. Myelinated peripapillary nerve fibers may impart a acquired pigmentation of the optic disc following a scleral
gray cast to the optic disc (374), as may pseudopapilledema buckling procedure. Hoyt and Beeston (374) photographed
associated with buried drusen (368,375). A grayish cast to acquired pigmentation of the optic disc following retrobulbar
the optic discs was described in three patients with Pelizaeus- amputation for optic glioma. Taylor and Ffytche (380) de-
Merzbacher disease (376), in an infant with maple syrup scribed a patient who developed an area of optic disc pig-
urine disease (377), and in a child with partial trisomy 10q mentation associated with a visual field defect following an
syndrome (378). episode of presumed optic neuritis associated with chick-
Optically gray optic discs and congenital optic disc pig- enpox.
AICARDI SYNDROME
Aicardi syndrome is a congenital cerebroretinal disorder Other ocular abnormalities include microphthalmos, ret-
of unknown etiology. Its salient clinical features are infantile robulbar cyst, pseudoglioma, retinal detachment, macular
spasms, agenesis of the corpus callosum, a modified form of scar, cataract, pupillary membrane, iris synechiae, iris colo-
the electroencephalographic pattern termed hypsarrhythmia, boma, and persistent hyperplastic primary vitreous
and a pathognomonic optic disc appearance consisting of (106,134). The most common systemic findings associated
multiple depigmented ‘‘chorioretinal lacunae’’ clustered with Aicardi syndrome are vertebral malformations (fused
around the disc (82,106) (Fig. 3.26). Histologically, vertebrae, scoliosis, spina bifida) and costal malformations
chorioretinal lacunae consist of well-circumscribed, full- (absent ribs, fused or bifurcated ribs) (106,134,381). Other
thickness defects limited to the retinal pigment epithelium systemic findings in Aicardi syndrome include muscular
and choroid. The overlying retina remains intact but is often hypotonia, microcephaly, dysmorphic facies, cleft lip and
histologically abnormal (82). palate, auditory disturbances, and auricular anomalies
Congenital optic disc anomalies, including optic disc colo- (134,382,383). Aicardi syndrome has also been associated
boma, optic nerve hypoplasia, and congenital optic disc pig- with choroid plexus papilloma (382,384).
mentation, may accompany chorioretinal lacunae (82,134). Severe mental retardation is present in almost all cases
Figure 3.26. Aicardi syndrome. A, An enlarged, malformed optic disc is surrounded by numerous, well-circumscribed,
chorioretinal lacunae. B, Sagittal MR image demonstrating agenesis of the corpus callosum (upper solid arrow denotes normal
position of the corpus callosum), an arachnoid cyst in the region of the quadrigeminal cistern (open arrows) and hypoplasia
of the cerebellar vermis with cystic dilatation of the 4th ventricle (Dandy-Walker variant). (A, From Carney SH, Brodsky MC,
Good WV, et al. Aicardi syndrome: More than meets the eye. Surv Ophthalmol 1993;37⬊419–424.)
(82,134). Aicardi syndrome is associated with decreased life Neuropathologic specimens show a characteristic profile,
expectancy, but some patients survive into their teenage consisting of unlayered polymicrogyria, subcortical or peri-
years. Menezes et al. (385–387) retrospectively reviewed ventricular heterotopias, and agenesis of the corpus callosum
ocular and neurologic findings in 14 girls with Aicardi syn- (394–396). This complex cerebral malformation suggests a
drome and found that the size of the largest chorioretinal problem in nerve cell proliferation and migration (396). An
lacuna correlated significantly with neurologic outcome, overlap between Aicardi syndrome and septo-optic dysplasia
whereas age at presentation, type, and severity of seizures has been recognized in several patients (82,134).
did not. Rosser et al. (388) found the neurodevelopmental Aicardi syndrome is thought to result from an X-linked
prognosis of Aicardi syndrome to be extremely poor, with mutational event that is lethal in males (134,397). Parents
most children having seizures that are intractable despite should therefore be asked about a previous history of miscar-
therapy, and 91% attaining milestones no higher than 12 riages. In 1986, Chevrie and Aicardi suggested that all cases
months. Ganesh et al. (389) have proposed that a persistence of Aicardi syndrome represent fresh gene mutations because
of fetal vasculature between gestational weeks 9 and 12 may no cases of affected siblings had been reported (134), how-
provide a unifying hypothesis for the embryogenesis of Ai- ever, a report of Aicardi syndrome in two sisters challenges
cardi syndrome, based on the presence of associated intraoc- this notion that Aicardi syndrome always results from a de
novo mutation in the affected infant and suggests that paren-
ular malformations such as microphthalmos, persistent pu-
tal gonadal mosaicism for the mutation may be an additional
pillary membrane, persistent hyperplastic primary vitreous,
mechanism of inheritance (398). With rare exceptions
vascular loops on the optic disc, and epiretinal glial tissue. (399,400), cytogenetic testing with special attention to the
Since callosal development and neuronal migration occur X chromosome gives normal results in Aicardi syndrome
concurrently during this period of gestation, this mechanism (401). One girl reported as having Aicardi syndrome with a
would also explain the associated callosal agenesis and neu- balanced X/3 translocation had no chorioretinal lacunae
ronal migration defects within the brain. (402). Although early infectious CNS insults could lead to
Central nervous system anomalies in Aicardi syndrome severe CNS anomalies, tests for infective agents are consis-
include agenesis of the corpus callosum, cortical migration tently negative. No teratogenic drug or other toxin has yet
anomalies (pachygyria, polymicrogyria, cortical heteroto- been associated with Aicardi syndrome. Based on the pattern
pias), and multiple structural CNS malformations (cerebral of cerebroretinal malformations in Aicardi syndrome, it is
hemispheric asymmetry, Dandy-Walker variant, colpo- speculated that an insult to the CNS must occur between the
cephaly, midline arachnoid cysts) (Fig. 3.26) (390–393). 4th and 8th week of gestation (134).
DOUBLING OF THE OPTIC DISC

Doubling of the optic discs is a rare anomaly in which aration of various portions of an intracranial or orbital optic
two optic discs are seen ophthalmoscopically and presumed nerve into two strands as an incidental finding (412–416).
to be associated with a duplication or separation of the distal This anomaly was also visualized by Sourdille during an
optic nerve into two fasciculi (403). Collier (404) described enucleation (407). The majority of clinical reports antedate
a case and reviewed eight such reports in the literature. Al- the use of high-resolution neuroimaging and have relied
though these anomalies varied considerably, most had a upon the roentgenographic demonstration of two optic
‘‘main’’ disc and a ‘‘satellite’’ disc, each with its own vascu- nerves in the same orbit, the results of fluorescein angiogra-
lar system (Fig. 3.27). Most cases occur unilaterally and are phy, synchronous pulsations of each major disc artery, dual
associated with decreased acuity in the affected eye (403). blind spots, and angioscotomas to provide indirect evidence
Since Collier’s report, several other cases have been reported of double optic nerves (403). More commonly, an apparent
which appear to represent ‘‘pseudodoubling’’ of the optic doubling of the optic disc results from focal juxtapapillary
disc (403,405–411). retinochoroidal colobomas, which may display abnormal
Documented separation of the optic nerve into two or vascular anastomoses with the optic disc (403). Neuroimag-
more strands is rare in humans but common in some lower ing should allow in vivo confirmation of true optic nerve
vertebrates (403). A handful of autopsy cases document sep- diastasis.
OPTIC NERVE APLASIA

Optic nerve aplasia is a rare nonhereditary malformation, Ophthalmoscopically, optic nerve aplasia may take on any
that is seen most often in a unilaterally malformed eye of of the following appearances (7):
an otherwise healthy person (18,417–425). In its current
usage, the term implies complete absence of the optic nerve 1. Absence of a normally defined optic nerve head or papilla
(including the optic disc), retinal ganglion and nerve fiber in the ocular fundus, without central blood vessels and
layers, and optic nerve vessels (426). Histopathologic exami- with an absence of macular differentiation;
nation usually demonstrates a vestigial dural sheath entering 2. A whitish area corresponding to the optic disc, without
the sclera in its normal position, as well as retinal dysplasia central vessels or macular differentiation;
with rosette formation (Fig. 3.28) (423). Some early reports 3. A deep avascular cavity in the site corresponding to the
of optic nerve aplasia actually described patients with severe
optic disc, surrounded by a whitish annulus.
hypoplasia at a time when the latter entity was not clearly
recognized (422).
Visual fields are normal in the unaffected eye (427). Fluo-
rescein angiography shows absent retinal blood vessels in
the affected eye and normal retinal circulation in the opposite
eye (7,422,427). The electroretinographic waveform (ERG)
may be flat; if present, the a- and b-waves are diminished
(7,422,427). CT scanning may show the globe and bony
orbit to be smaller than normal (426). In addition, MR imag-
ing may show isolated absence of the optic nerve on the
affected side (426,427). The cause of optic nerve aplasia
is unknown. Chromosome studies were normal in all cases
studied by Howard et al. (427).
Optic nerve aplasia seems to fall within a malformation
complex that is fundamentally distinct from that seen with
optic nerve hypoplasia, as evidenced by the proclivity of
optic nerve aplasia to occur unilaterally and its frequent asso-
ciation with malformations that are otherwise confined to the
affected eye (microphthalmia, malformations in the anterior
chamber angle, hypoplasia or segmental aplasia of the iris,
cataracts, persistent hyperplastic primary vitreous, anterior
colobomas, macular staphyloma, retinal dysplasia, or pig-
mentary disturbance) (7,425,427,428). However, when optic
nerve aplasia occurs bilaterally, it is usually associated with
severe and widespread congenital CNS malformations
Figure 3.27. Doubling of the optic disc. Note ‘‘main’’ disc and ‘‘satel- (426,427,429,430). An animal model of unilateral optic
lite’’ disc. (From Donoso LA, Magaragal LE, Eiferman RA. Ocular anoma- nerve aplasia was induced in rat fetuses by folic acid defi-
lies simulating double optic discs. Can J Ophthalmol 1981;16⬊84–87. Pho- ciency, in rat offspring by x-ray irradiation, and in rabbit
tograph courtesy of Larry A. Donoso.) fetuses by actinomycin D treatment (431).
Figure 3.28. Optic nerve aplasia. A, Note absence of optic disc and retinal vessels. B, Histologic appearance of optic nerve
aplasia. The edge of the choroid and retinal pigment epithelium is marked by an arrowhead. Fibroglial tissue (asterisk) occupies
the colobomatous area. A ciliary vessel (C) traverses the sclera, but optic nerve tissue is absent. (A, From Little LE, Whitmore
PV, Wells TW Jr. Aplasia of the optic nerve. J Pediatr Ophthalmol 1976;13:84–88. B, From Hotchkiss ML, Green WR. Optic
nerve aplasia and hypoplasia. J Pediatr Ophthalmol Strabismus 1979;16:225–240.)
In patients with unilateral optic nerve aplasia, the intracra- appeared grossly normal bilaterally, even though the optic
nial course of the ‘‘intact’’ optic nerve may vary. Hoff et chiasm was formed from a single optic nerve on the right
al. (432) reported on a patient with unilateral anophthalmos side. Margo et al. (426) described a patient with unilateral
with optic nerve aplasia associated with a congenital giant optic nerve aplasia and microphthalmos in whom MR imag-
suprasellar aneurysm. The remaining optic nerve was identi- ing demonstrated true unilateral optic nerve aplasia, hemi-
fied at craniotomy as passing posteriorly as a single cord to chiasmal hypoplasia on the affected side, but bilateral optic
form an optic tract with no adjoining chiasm. Hotchkiss and tracts. VEPs were increased over the occipital lobe contralat-
Green (18) provided necropsy findings from a patient with eral to the intact optic nerve, suggesting chiasmal misdirec-
a Hallerman-Streiff-like syndrome and left optic nerve tion of axons from the temporal retina of the normal eye, as
aplasia in whom the lateral geniculate bodies and optic tracts seen in albinos.
MYELINATED (MEDULLATED) NERVE FIBERS

Myelination of the anterior visual system begins centrally ence in some areas of myelinated nerve fibers, and their
at the lateral geniculate body at 5 months of gestation. It absence in other areas (434).
proceeds distally and reaches the chiasm by 6–7 months of Ophthalmoscopically, myelinated nerve fibers usually ap-
gestation, the retrobulbar optic nerve by 8 months, and the pear as white striated patches at the upper and lower poles
lamina cribrosa at term; although in some cases myelination of the optic disc (Fig. 3.29). In these locations, they may
may continue for a short time after birth. Normally, myelin impart a gray appearance to the optic disc, and they may
does not extend intraocularly; however, intraocular myelina- also simulate papilledema, both by elevating the adjacent
tion of retinal nerve fibers occurs in 0.3–0.6% of the popula- portions of the disc and by obscuring the disc margin and
tion by ophthalmoscopy and in 1% by postmortem examina- underlying retinal vessels (436). Distally, they have an irreg-
tions (433). Straatsma et al. (434) studied both eyes from ular fan-shaped appearance that facilitates their recognition.
3,968 consecutive autopsy cases and found 37 eyes from 32 Small slits or patches of normal-appearing fundus color are
patients with myelinated retinal nerve fibers. In this series, occasionally visible within areas of myelination. Myelinated
males and females were equally affected, and in most eyes nerve fibers are bilateral in 17–20% of cases and, clinically,
(81%), myelination was continuous with the optic disc. The they are discontinuous with the optic nerve head in 19%.
majority of the patients had normal visual acuity, although Isolated patches of myelinated nerve fibers are occasionally
four patients with unilateral myelinated nerve fibers had ipsi- found in the peripheral retina (Fig. 3.29).
lateral anisometropic myopia, strabismus, and amblyopia Leys et al. (437) described seven patients who had retinal
(435). The explanation for the occurrence of intraocular my- vascular abnormalities within areas of myelinated nerve fi-
elination is unknown. Oligodendrocytes, which are responsi- bers. These abnormalities ranged from mild telangiectasis
ble for myelination of the CNS, are not normally present in to frank neovascularization, with or without obstruction of
the human retina, but histologic studies confirm their pres- the capillary network and signs of branch artery and vein
Figure 3.29. Myelinated nerve fibers. A, The optic disc is surrounded by myelinated, feathery nerve fibers. B, Myelinated
nerve fibers extend superiorly and inferiorly from the optic disc along the arcuate nerve fiber bundles.
occlusion. Vitreous hemorrhage occurred in the four youn- Extensive unilateral (or rarely bilateral) myelination of
gest patients. This report, together with a similar one by nerve fibers can be associated with high myopia and severe
Tabassian et al. (438) would suggest that the retinal vessels amblyopia. Unlike other forms of unilateral high myopia
within patches of myelinated nerve fibers should be carefully that characteristically respond well to occlusion therapy, the
examined for occult microvascular abnormalities. amblyopia that occurs in children with myelinated nerve fi-
Myelinated retinal nerve fibers do not usually reduce vis- bers is notoriously refractory to this treatment (440). In such
ual acuity; however, relative scotomas may be charted if patients, myelination surrounds most or all of the circumfer-
a sufficient number of myelinated fibers are present. The ence of the disc. Additionally, the macular region (although
scotomas are invariably smaller than the size of the myelin- unmyelinated) usually appears abnormal, showing a dulled
ated patch would suggest. Because myelinated fibers are reflex or pigment dispersion (441). Hittner et al. (441) found
usually adjacent to the optic disc, the blind spot is often the appearance of the macula to be the best direct correlate
enlarged in such patients. When the nerve fibers surround the of response to occlusion therapy.
macula, there may be a ring scotoma, and isolated patches in Myelinated nerve fibers occur in association with the Gor-
the retinal periphery may produce isolated peripheral scoto- lin syndrome (multiple basal cell nevi) (442). This autoso-
mas. If the macula is affected, there may be a central sco- mal-dominant disorder can often be recognized by the find-
toma, but this is exceedingly rare. In a single instance, Walsh ing of numerous tiny pits in the hands and feet, which
and Hoyt (439) observed a pronounced defect in visual acu- produce a ‘‘sandpaper’’ irregularity. Multiple cutaneous tu-
ity as a result of myelinated fibers. In that case, the entire
mors develop in the second to third decades, but they may
fundus except for a small area temporal to the disc contained
occasionally develop in the first few years of life. When
myelinated nerve fibers.
present in childhood, these lesions remain quiescent until
The pathogenesis of myelinated nerve fibers remains
largely speculative, but Williams (436) questioned whether puberty, when they increase in number and demonstrate a
a defect in the lamina cribrosa may allow oligodendrocytes more rapid and invasive growth pattern (443). Additional
to gain access to the retina and produce myelin there. It is features include jaw cysts (which are found in approximately
known that animals with little or no evidence of lamina cri- 70% of patients and often appear in the first decade of life),
brosa tend to have deep physiologic cups and extensive my- and mild mental retardation (443). Rib anomalies (bifid ribs,
elination of retinal nerve fibers, whereas animals with a well- splaying, synostoses, and partial agenesis) are found in ap-
developed lamina cribrosa tend to show fairly flat nerve proximately 50% of patients. Facial abnormalities include
heads and no myelination of retinal nerve fibers. In eyes hypertelorism, prominent supraorbital ridges, frontoparietal
with remote, isolated peripheral patches of myelinated nerve bossing, a broad nasal root, and mild mandibular progna-
fibers, an anomaly in the formation or timing of formation thism (443). Ectopic calcification, especially of the falx
of the lamina cribrosa could permit access of oligodendro- cerebri, is an almost constant finding (442). Medulloblasto-
cytes to the retina. These cells may then migrate through the mas develop in some patients. Gorlin syndrome should be
nerve fiber layer until they find a region of lower nerve fiber considered in children with myelinated nerve fibers and cuta-
layer density, where they proceed to myelinate some axons neous lesions because small lesions can be treated with curet-
(436). tage, electrophotocoagulation, cryosurgery, and topical
Figure 3.30. Disappearance of myelinated nerve fibers following an acute optic neuropathy. A, Prior to visual symptoms,
patient has 20/25 visual acuity with an enlarged blind spot. Myelinated nerve fibers completely surround the disc. B, Seven
years later, after an acute optic neuropathy, there is marked disappearance of intraocular myelin. Visual acuity is 20/300 and
there are superior and inferior arcuate defects. (From Schachat AP, Miller NR. Atrophy of myelinated nerve fibers after acute
optic neuropathy. Am J Ophthalmol 1981;92⬊854–856.)
chemotherapy to forestall the development of more aggres- nerve fiber layer, severe degeneration of the vitreous, high
sive and invasive lesions (443). myopia, a retinal dystrophy with night blindness, reduction
Myelinated nerve fibers may be familial, in which case the of the electroretinographic responses, and limb deformities.
trait is usually inherited in an autosomal-dominant fashion Rarely, areas of myelinated nerve fibers may be acquired
(220,444). Isolated cases of myelinated nerve fibers may after infancy and even in adulthood (1). Trauma to the eye
also occur in association with abnormal length of the optic (a blow to the eye in one patient and an optic nerve sheath
nerve (oxycephaly) (445), defects in the lamina cribrosa fenestration in the other) seems to be a common denominator
(tilted disc) (446), anterior segment dysgenesis (436,441), in these cases (449,450). Williams (436) suggested that suffi-
cient damage to the lamina cribrosa may permit oligodendro-
and neurofibromatosis type 2 (447). Although myelinated
cytes to enter the retina, whereupon they move to the nearest
nerve fibers are purported to be associated with neurofibro- area of fairly loose nerve fibers and myelinate them. Aaby
matosis, many authorities believe that this association is for- and Kushner (451) photographically documented progres-
tuitous, and we agree. sion of myelinated nerve fibers in children. Conversely, my-
Traboulsi et al. (448) described an autosomal-dominant elinated nerve fibers disappear as a result of tabetic optic
vitreoretinopathy associated with myelination of the nerve atrophy (452), pituitary tumor (453), glaucoma (454), central
fiber layer. The condition is characterized by congenitally retinal artery occlusion (455), branch retinal artery occlusion
poor vision, bilateral extensive myelination of the retinal (456), and various optic neuropathies (Fig. 3.30) (457,458).
PSEUDOPAPILLEDEMA
Anomalous optic disc elevation (pseudopapilledema) may be distinguished from other local causes of pseudopapille-
bear a striking resemblance to true optic disc swelling and dema, such as hyaloid traction on the optic disc (459), epi-
therefore represents a primary diagnostic consideration in papillary glial tissue, myelinated nerve fibers, scleral in-
the patient referred for papilledema (374). In most instances, filtration, vitreopapillary traction (6), and high hyperopia
a patient is noted to have elevated optic discs or blurred disc (244,375,460). In the patient with additional systemic disor-
margins during the course of a routine examination. The ders, consideration must be given to the possibility that pseu-
diagnostic uncertainty and alarm created by this finding ov- dopapilledema may be related to an underlying genetic disor-
ershadows the fact that the patient has no other signs or der. Systemic disorders that include pseudopapilledema are
symptoms of increased intracranial pressure. Many patients Down syndrome (461), Alagille syndrome (arteriohepatic
with pseudopapilledema are referred for neuro-ophthalmo- dysplasia) (462), Kenny syndrome (hypocalcemic dwarfism)
logic evaluation only after being subjected to neuroimaging, (410), linear nevus sebaceous syndrome (463), and Leber’s
lumbar puncture, and extensive laboratory studies. hereditary optic neuropathy. Awan (464) described an asso-
Once the diagnosis of pseudopapilledema is established, ciation between orbital hypotelorism and pseudopapilledema
pseudopapilledema associated with optic disc drusen must with situs inversus of the vessels.
PSEUDOPAPILLEDEMA ASSOCIATED WITH OPTIC that familial drusen are transmitted as an autosomal-domi-
DISC DRUSEN nant trait, and subsequent studies have confirmed the famil-
ial nature of this anomaly (475,480,481). The low prevalence
The word drusen, of Germanic origin, originally meant of disc drusen in African Americans (470,475) may be attrib-
tumor, swelling, or tumescence (4). According to Lorentzen utable to racial variation in optic disc size (482).
(4), the word was used in the mining industry approximately
500 years ago to indicate a crystal-filled space in a rock. Natural History
Drusen of the optic disc were first described clinically by
Liebreich in 1868. Other terms for these lesions include hya- The evolution of disc drusen is a dynamic process that
line bodies and colloid bodies of the optic disc (465–467). continues throughout life. It is rare to see visible drusen or
significant optic disc elevation in an infant. During child-
Epidemiology hood, the affected optic disc begins to appear ‘‘full’’ and
acquires a tan, yellow, or straw color (483,484). In a retro-
Lorentzen (4) reported a prevalence of optic drusen of spective study of 40 children, Hoover et al. (484) first noted
3.4 per 1,000 in a clinical study of 3,200 individuals. This drusen at a mean age of 12.1 years and found that visual
prevalence increased by a factor of 10 in family members field defects are commonly detectable in the second decade
of patients with disc drusen. The prevalence of drusen in of life. Gradually, buried drusen impart a scalloped appear-
autopsy series varies between 0.41% (468) and 2.0% (469). ance to the margin of the disc and produce subtle excres-
Rosenberg et al. (470) examined 98 patients with disc eleva- cences on the disc surface that tend to predominate nasally
tion and ophthalmoscopic evidence of buried drusen. Their (4,204). They later enlarge and calcify, and become more
ages ranged from 7 to 73 years, with a mean age of 22 years. visible on the disc surface (485–487). As they enlarge they
Males and females were equally affected. Visible drusen sometimes deflect retinal vessels overlying the disc (486).
were bilateral in approximately two-thirds of cases, whereas In adulthood, the optic disc elevation diminishes, the disc
pseudopapilledema associated with buried drusen was bilat- gradually becomes pale, the nerve fiber layer thins, and dis-
eral in 86% of cases. These findings were in accordance crete slits appear (483,488). This evolution reflects a slow
with previous clinical studies (4,471,472). Erkkila (473,474) attrition of optic axons over decades. Despite this progres-
found a high prevalence of clumsiness, learning disabilities, sion, most patients remain asymptomatic and retain normal
and neurologic problems in a Finnish population of children acuity. The finding of disc elevation without visible drusen
with drusen, but subsequent studies have not substantiated in children of parents with florid drusen attests both to the
these findings. The early notion that pseudopapilledema as- dynamic nature of this anomaly and to its heredofamilial
sociated with disc drusen tend to develop primarily in hyper- character.
opic eyes has also been dispelled; Hoyt and Pont (475) found
an equal number of hyperopes and myopes in their study of Ophthalmoscopic Appearance of Visible Drusen
28 patients with pseudopapilledema, and Rosenberg et al.
(470) found a distribution of refractive error among their When a beam of light from a direct or scanning laser
pseudopapilledema patients (both with and without visible ophthalmoscope or a slit lamp is directed on a portion of
drusen) identical with that present in the general population; the elevated disc, drusen appear as round, slightly irregular
François (476–478), and later Lorentzen (479), determined excrescences that are present within and occasionally around
Figure 3.31. Visible disc drusen. Note multiple white nodules lining the periphery of the discs and abnormal branching of
retinal vessels.
the disc (Fig. 3.31) (479,489). Surface drusen may be scat- and venous branchings, increased tortuosity, vascular
tered or form conglomerates that cover part or all of the disc. loops, and cilioretinal arteries (4,474,476,477,492,493).
Surface drusen affecting only a portion of the disc are usually 7. Elevation is confined to the optic disc and does not extend
concentrated nasally and are most conspicuous at the periph- to the peripapillary nerve fiber layer, which may retain
ery of the disc. Superficial drusen reflect whitish yellow its normal linear pattern of light reflexes (494) or show
light, are globular, and vary in size from minute dots to abnormalities indicative of nerve fiber atrophy (349,495).
granules 2 or 3 times the diameter of a retinal vessel. When 8. The anomalously elevated disc usually has an irregular
illuminated directly drusen glow brightly at their edges, and border with pigment epithelial defects being present, giv-
uniformly but less intensely at their center. In indirect light, ing the border a ‘‘moth-eaten’’ appearance.
the side of a drusen that is away from the light appears as
a dark crescent in contrast to its glowing central region.
Deeply situated drusen lack sharp margins, but they may Distinguishing Pseudopapilledema Associated with
still be illuminated when indirect lighting is used. Buried Drusen from Papilledema
Ophthalmoscopic Appearance of Buried Disc Drusen The distinction between pseudopapilledema associated
with buried drusen and papilledema (or other forms of optic
Drusen buried within the tissue of the disc produce moder- disc swelling) can be difficult (Fig. 3.33), but several clinical
ate elevation of the surface of the disc, as well as blurring signs are particularly helpful (Table 3.4). In papilledema,
of its margins with the following features (Fig. 3.32): the disc swelling extends into the peripapillary retina and
obscures the peripapillary retinal vasculature. In pseudopap-
1. The anomalously elevated disc is not hyperemic, and illedema, there is a discrete, sometimes grayish or straw-
there are no dilated capillaries on its surface. colored elevation of the disc without obscuration of vessels
2. Despite extreme elevation of the disc, the surface arteries or opacification of peripapillary retina. Hoyt and Knight
are not obscured. (494) emphasized the graying or muddying of the peripapil-
3. The physiologic cup is absent in the anomalously ele- lary nerve fiber layer that occurs with swelling of the optic
vated disc. disc from papilledema or other causes. In pseudopapilledema
4. Anomalously elevated discs are smaller than normal associated with buried drusen, light reflexes of the peripapil-
(490,491). lary nerve fiber layer appear sharp, and the elevated disc is
5. The most elevated portion of the disc is usually the central often haloed by a crescentic peripapillary ring of light that
area from which the vessels emerge. reflects from the concave internal limiting membrane sur-
6. In a large percentage of cases, there are anomalous vascu- rounding the elevation (Fig. 3.32). This crescentic light re-
lar patterns on the disc surface, including an increased flex is absent in papilledema, because of diffraction of light
number of otherwise normal vessels, abnormal arterial from distended peripapillary axons (494,496–498). Individ-
Figure 3.32. Buried disc drusen. Both optic discs have a similar appearance, with absence of the central cup, and an increased
number of retinal vessels with an anomalous branching pattern. The disc elevation does not obscure the overlying vessels.
Although no discrete drusen are seen, there is a subtle nodularity of the disc margin.
Figure 3.33. Comparison of papilledema and pseudopapilledema with buried drusen. A, Papilledema. The disc is elevated
and hyperemic. There is distortion of the normal linear light reflexes from the peripapillary nerve fiber layer and obscuration
of large vessels as they cross the disc surface. B, Pseudopapilledema. The disc is elevated but shows no hyperemia, disruption
of the nerve fiber layer reflexes, or obscuration of vessels.
ual flame-shaped, subretinal, or sub-RPE hemorrhages are lary studies. It is common for children who carry the diagno-
occasionally seen in the peripapillery region in eyes with sis of papilledema to arrive for consultation with their
optic disc drusen, but exudates, cotton wool spots, hyper- ‘‘negative’’ CT scan in hand, only to observe calcification
emia of the disc, and venous congestion are conspicuously of the optic discs upon review of the scan. Both CT scanning
absent (4,493,497). and ultrasonography readily demonstrate such calcification
within the elevated optic disc (Figs. 3.34 and 3.35). Opinions
Ancillary Studies
The differentiation between papilledema and pseudopapil-
ledema caused by buried drusen is frequently aided by ancil-
Table 3.4
Ophthalmoscopic Features Useful in Differentiating Optic Disc
Edema from Pseudopapilledema Associated with Buried Drusen
Optic Disc Edema Pseudopapilledema with Buried Drusen
Disc vasculature obscured at Disc vasculature remains visible

disc margins at disc margins
Elevation extends into Elevation confined to optic
peripapillary retina disc
Graying and muddying of Sharp peripapillary nerve fiber
peripapillary nerve fiber
layer
Venous congestion No venous congestion
⫾ exudates No exudates
Loss of optic cup only in Small cupless disc
moderate to severe disc
edema
Normal configuration of disc Increased major retinal vessels
vasculature despite venous with early branching
congestion
No circumpapillary light Crescentic circumpapillary light
reflex reflex Figure 3.34. ‘‘Normal’’ CT scan showing posterior scleral calcification
Absence of spontaneous venous Spontaneous venous pulsations corresponding to optic disc drusen. (From Brodsky MC, Baker RS, Hamed
pulsations may be present or absent LM. Pediatric Neuroophthalmology. New York, Springer-Verlag, 1996.
Photograph courtesy of Stephan C. Pollock, MD.)
Figure 3.35. Ultrasonography in a patient with deep (buried) optic disc drusen. A, Appearance of the right optic disc. B, B-
scan ultrasonography, high gain, shows that the area of disc elevation is clearly seen as a focal area of brightness that persists
when reflections from the remainder of the posterior segment of the eye are no longer visible (arrow). This finding is consistent
with the appearance of calcified drusen. (Courtesy of Cathy DiBernardo, RN, RMDS.)
differ as to which imaging modality is preferable and 1 patient had pseudotumor cerebri. Not surprisingly,
(25,499–505). Kurz-Levin and Landau (506) found B-scan patients with optic disc drusen and progressive visual loss
ultrasonography to be superior to either CT scanning or pho- can also have pituitary tumors (515–519), meningiomas
tography to look for autofluorescence in the detection of disc (349,520–523), craniopharyngiomas (524), ophthalmic ar-
drusen. tery aneurysms (525), cerebral abscesses (526), and other
Special photographic techniques may also be useful in intracranial masses (262,519,527,528), but no significant re-
identifying superficial or buried optic disc drusen. Mono- lationship between drusen and any of these lesions has ever
chromatic (red-free) photography may highlight the glisten- been established.
ing drusen against the intact or atrophic nerve fiber layer. There is absolutely no evidence that patients with optic
Photographs taken with the filters normally used for fluores- disc drusen are at increased risk to develop an intracranial
cein photography in place, but without injection of fluores- mass later in life. Recognition of papilledema in eyes with
cein show that superficial disc drusen often demonstrate the disc drusen is confounded by the fact that globular intrapapil-
phenomenon of autofluorescence (Fig. 3.36) (349,507,508). lary masses that are indistinguishable from hyaline bodies
Fluorescein angiography can also facilitate the differentia- can develop in patients with chronic papilledema (522). Un-
tion between true papilledema and pseudopapilledema. After like disc drusen, however, these lesions disappear following
intravenous fluorescein injection, drusen exhibit a true nodu- regression of papilledema (522,529).
lar hyperfluorescence corresponding to the location of the
visible drusen (467,508). The late phases may be character- Complications Associated With Pseudopapilledema
ized by minimal blurring of the drusen that either fade or and Disc Drusen
maintain fluorescence (i.e., stain) (467,508). Unlike in papil- Visual Field Defects
ledema, however, there is no visible leakage along the major
vessels (476,480,509). Fluorescein angiography may also Peripheral visual field defects develop in 71–75% of eyes
disclose venous anomalies (venous stasis, venous convolu- with disc drusen (460,471,476,477,495,530). In most cases,
tions, and retinociliary venous communications) and staining the asymptomatic nature of the defects reflects the insidious
of the peripapillary vein walls in eyes with optic disc drusen attrition of optic nerve fibers over decades. Nevertheless, a
(508,510). Electrophysiologic studies may show abnormali- minority of patients experience episodes of sudden, step-like
ties but add little to the diagnostic evaluation of pseudopapil- visual field loss (77,460,476,477). Mustonen (477) found
ledema (495,511–513). visual field defects in 38.9% of eyes with pseudopapilledema
Patients with pseudopapilledema are not immune to the and 73.4% of eyes with visible drusen. Savino et al. (460)
neurologic and ophthalmologic disorders of the general pop- found visual field defects in 21% of eyes with pseudopapille-
ulation (125,514). We have observed concomitant papilledema without visible drusen, and 71% of eyes with visible
dema, anterior optic neuritis, and anterior ischemic optic drusen. These visual field defects fall into three general cate-
neuropathy in patients with anomalously elevated discs. In gories: (a) nerve fiber bundle defects; (b) enlargement of
all cases, however, the history was typical of either increased the blind spot; and (c) concentric visual field constriction.
intracranial pressure or an optic neuropathy, and obvious Several studies using kinetic perimetry described inferonasal
disc swelling was present. Of the 142 patients with pseudo- steps as the most common nerve fiber bundle defect, but both
papilledema studied by Rosenberg et al. (470), 2 patients had arcuate defects and sector defects may also occur (4,460,465,
concomitant papillitis, 2 patients had intracranial neoplasms, 479,495,530,531). Lansche and Rucker (530) and François
Figure 3.36. Fluorescent characteristics of drusen. A, Fundus photograph

of optic disc drusen. B, Autofluorescence of drusen observed through a
fluorescein filter but without injection of fluorescein dye. C, Late staining
of drusen after fluorescein angiogram.
and Verriest (471) emphasized the slowly progressive nature 2. Direct compression of prelaminar nerve fibers by drusen;
of many of the defects. Although concentric constriction of and/or;
the visual field is usually a chronic process, some patients 3. Ischemia within the optic nerve head (77).
experience sudden severe visual field constriction with and
without preservation of central vision (532–534). These pa-
At the heart of the controversy is whether drusen produce
tients often have no disc swelling or retinal edema to suggest
damage to nerve fibers through direct axonal or vascular
an ischemic process. A relative afferent pupillary defect may
compression, or whether they are merely an epiphenomenon
result from unilateral or asymmetric visual field loss in the
absence of central acuity loss (477,535). of a chronic low-grade axonal stasis that produces a slowly
The pathogenesis of visual field loss in patients with disc progressive diminution in optic axons (375). Several studies
drusen could involve one or more of the following mecha- have been unable to correlate the location of visible disc
nisms: drusen with the location of field defects (4,537). Stevens
and Newman (495) found no correlation between the degree
1. Impaired axonal transport in an eye with a small scleral of nerve fiber layer damage and the degree of visual field
canal leading to gradual attrition of optic nerve fibers; abnormality in eyes with disc drusen. These results do not
(483,536); rule out the possibility that axonal compression could result
from drusen that lie just above the lamina cribrosa rather frequent in patients with optic disc drusen than are superfi-
than those that are superficial and easily seen. cial (flame-shaped), subhyaloid, or vitreous hemorrhages.
Splinter hemorrhages associated with optic disc drusen tend
Central Visual Loss to be single and prepapillary in location, in contrast to the
multiple nerve fiber layer hemorrhages that characterize pap-
Idiopathic central visual loss is a rare but well-docu- illedema (497). Deep peripapillary hemorrhages may be sub-
mented complication of disc drusen (77,496,538–540) that retinal or subpigment epithelial and are typically circumfer-
should be considered only when no other causes can be iden- entially oriented around the disc (470,474,538,548).
tified (521). In such cases, central visual loss usually follows Even in severe cases, most patients with optic disc drusen
a series of episodic, step-like events that progressively di- and hemorrhages recover normal or near-normal vision.
minish the peripheral visual field. Beck et al. (77) described Whether or not these hemorrhages can be caused by
four patients with reduced central acuity resulting from optic compression of thin-walled veins by conglomerates of dru-
disc drusen. The authors emphasized that this rare phenome- sen or by erosion of the vessel wall by the sharp edge of the
non remains a diagnosis of exclusion that should be consid- drusen (510) remains unsettled. Wise et al. (549) postulated
ered when visual loss is acute and nonprogressive, stepwise that enlarging disc drusen could result in circulatory compro-
in a nerve fiber bundle distribution, or not produced until mise and local hypoxia, which might stimulate the growth
visual field constriction is severe. of new vessels between the RPE and Bruch’s membrane.
Peripapillary pigmentary disruption may remain following
Prepapillary or Peripapillary Hemorrhages resolution of subretinal hemorrhage. Subretinal hemorrhage
Prepapillary or peripapillary hemorrhages may develop may also occur in severe papilledema, but its occurrence in
in eyes with disc drusen (497,519,531,538,541–548). Sand- mild papilledema is rare and should suggest the possibility
ers et al. (538) divided hemorrhages associated with optic of disc drusen (497). A subgroup of patients can develop a
drusen into three groups: serous maculopathy without hemorrhage, which can tent the
temporal peripapillary retina into striate folds (548).
1. Small superficial hemorrhages on the optic disc;
2. Large hemorrhages on the disc, extending into the vitre- Ischemic Optic Neuropathy
ous; and Ischemic optic neuropathy may occur as a single episode
3. Deep peripapillary hemorrhages extending from the optic or as successive episodes of discrete visual loss over years
disc under the peripapillary retina (Fig. 3.37). (374,550,551). Karel et al. (510) reported ischemic optic
neuropathy associated with the abrupt onset of arcuate field
Large superficial hemorrhages may rarely extend into the defects and segmental disc pallor in three young patients
vitreous. In our experience, subretinal and subpigment epi- with optic disc drusen. Michaelson et al. (552) described
thelial hemorrhages, although uncommon, are much more bilateral visual loss that was precipitated by systemic hypo-
tension from peritoneal dialysis in a patient with disc drusen.
Newman and Dorrell (553) described anterior ischemic optic
neuropathy in a 13-year-old boy with disc drusen.
Retinal Vascular Occlusions

Retinal vascular occlusions occur in patients with optic
disc drusen (554–559). Drusen-associated retinal arterial
and venous occlusions tend to occur in young adults (5)
but may rarely be seen in children (560). Retinal vascular
occlusions that occur in eyes with disc drusen could result
from:
1. Vascular crowding secondary to the small scleral canal

size in eyes with drusen;
2. Anomalous optic disc vasculature that may make it more
susceptible to the effects of disrupted hemodynamics; or
3. Mechanical displacement of the prelaminar vasculature
by hard, unyielding drusen (5,561).
Transient Visual Loss

Transient visual loss occurred in 8.6% of the patients with
Figure 3.37. Peripapillary subretinal hemorrhage in a patient with intra- disc drusen in Lorentzen’s study (5). Sadun et al. (562) pro-
papillary drusen. Note the difference between this type of hemorrhage and posed that such visual loss occurs because both papilledema
the superficial nerve fiber layer hemorrhages seen with optic disc swelling. and anomalous elevation of the optic discs produce increased
interstitial pressure and decreased perfusion pressure in the hemorrhages from subretinal neovascularization (Fig. 3.38).
intraocular portion of the optic nerve. Thus, minor fluctua- In severe cases, this complication may simulate a juxtapapil-
tions in arterial, venous, or cerebrospinal fluid pressure result lary mass lesion or a neuroretinitis (375,547,564). Harris et
in brief but critical decrements in perfusion, leading to tran- al. (547) found subretinal neovascularization in seven eyes
sient obscurations of vision. Katz and Hoyt (6) attributed of 57 patients with optic disc drusen. These investigators
mild visual disturbances to vitreopapillary traction in a group emphasized that hemorrhages occurring in the absence of
of young myopic Asians whose optic discs were mildly dys- choroidal vascularization produced no symptoms and re-
plastic and slightly elevated. These patients manifested intra- solved without sequelae, whereas hemorrhages arising from
papillary and subretinal peripapillary hemorrhages, with in- choroidal neovascularization commonly produced visual
complete posterior vitreous detachment. Rarely, transient symptoms. Six of the seven eyes with neovascularization
visual loss may be a harbinger of retinal vascular occlusion retained visual acuities of 20/40 or better. Based upon these
in patients with disc drusen (5). findings, Harris et al. (547) recommended observation rather
than laser photocoagulation for peripapillary choroidal neo-
Peripapillary Subretinal Neovascularization vascularization associated with disc drusen. Saudax et al.
(565) reported an 8-year-old girl with a peripapillary subreti-
Peripapillary subretinal neovascularization is a rare but nal membrane that extended from the inferotemporal disc
well-documented complication in eyes with disc drusen. to the macula and produced a serous hemorrhagic maculopa-
Henkind et al. (563) and Wise et al. (549) emphasized that thy. In one case, surgical excision of a peripapillary subreti-
temporary or permanent visual loss can occur in patients nal neovascular membrane produced marked improvement
with optic disc drusen who develop subpigment epithelial in vision (566).
Figure 3.38. Subretinal neovascularization in a patient with intrapapillary

drusen. A, The left optic disc is moderately elevated and has blurred disc
margins. Several small drusen were identified in the center of the disc.
Temporal to the disc there is a crescent-shaped hyperpigmented area of
subretinal neovascularization. B, Arterial phase of the fluorescein angio-
gram shows extensive subretinal and retinal vascular leakage from abnormal
vessels. Note that there is no leakage from the disc vessels. C, In the arterio-
venous phase of the fluorescein angiogram, there is diffuse staining of the
optic disc and there is both staining of and leakage of dye from the area
of subretinal neovascularization.
Peripapillary Central Serous Choroidopathy chloric acid, nitric acid, sulfuric acid, potassium hydroxide,
and sodium hydroxide.
Peripapillary central serous choroidopathy was docu-
mented in an eye with disc drusen (567). Fluorescein angiog- Pathogenesis of Optic Disc Drusen
raphy showed a bright hyperfluorescent spot superonasal to
the disc. The detachment resolved following focal laser pho- The primary pathology of optic disc drusen may be an
tocoagulation of the RPE defect. inherited dysplasia of the optic canal, or the optic disc and
its vasculature, which predisposes to the formation of optic
Histology of Optic Disc Drusen disc drusen (572). Mullie and Sanders (490) suggested that
the primary developmental expression of the genetic trait
Drusen of the optic disc were first described histologically for drusen may be a smaller-than-normal scleral canal (482).
by Müller (568). Several investigators subsequently per- After formation of the optic stalk is complete, mesenchymal
formed histopathologic examinations on optic disc drusen elements from the sclera invade the glial framework of the
and found that they consist of homogenous, globular concre- primitive lamina, reinforcing it with collagen (490). An ab-
tions, often collected in larger, multilobulated agglomera- normal encroachment of sclera, Bruch’s membrane, or both,
tions (Fig. 3.39) (467–469,561,569–571). Individual druse upon the developing optic stalk would narrow the exit space
usually exhibit a concentrically laminated structure, that is of optic axons from the eye (490,561). The small optic disc
not encapsulated and contains no cells or cellular debris (4). size and absence of a central cup in affected eyes are consis-
Drusen are often most concentrated within the nasal portion tent with the mechanism of axonal crowding. The clinical
of the disc. The common finding of prelaminar spongiotic and histopathologic observation that drusen are often first
edema may contribute to the optic disc elevation seen clini- detected at the margins of the optic disc suggests that the
cally (561). Optic disc axons are atrophic adjacent to large rigid edge of the scleral canal may be an aggravating factor
accumulations of drusen, whereas axons that are not adjacent in producing a relative mechanical interruption of axonal
to the drusen are normal (4,467–469). Drusen take up cal- transport (490). The lower prevalence of optic disc drusen
cium salts and must be decalcified before being cut into in African Americans, who have a larger disc area with less
sections for histopathologic study. According to most inves- potential for axonal crowding, is also consistent with the
tigators, drusen are composed predominantly of a mucopro- notion that axonal crowding is a fundamental anatomic sub-
tein matrix with significant quantities of acid mucopoly- strate for disc drusen (482).
saccharides, small quantities of ribonucleic acid and, In 1962, Seitz and Kersting first proposed that drusen
occasionally, iron. In addition, Friedman et al. (467,469) may be the product of long-term pathologic alterations in
found that drusen stain positively for amino acids and cal- the retinal nerve fibers. In 1968, Seitz again proposed this
cium but negatively for amyloid. Boyce et al. (468) found idea and concluded from a series of histochemical studies
Bodian’s stain for the presence of nerve fibers to be positive that drusen originate from axoplasmic derivatives of disinte-
in the two cases that they studied in this fashion; however, grating nerve fibers. Seitz (573) also suggested that drusen
specific stains, including the Nauta-Gygax stain for degener- form by a slow degenerative process rather than by a rapid
ating axon terminals and Guillery’s stain for degenerating one. Sacks et al. (574) advanced an alternative hypothesis
nerve fibers were negative in the same cases. Drusen are that the tendency to develop optic nerve drusen results, at
insoluble in most of the common solvents, including abso- least in part, from a congenitally abnormal disc vasculature
lute ethanol, ether, chloroform, xylene, acetic acid, hydro- that allows transudation of plasma proteins which in turn
Figure 3.39. Histopathology of drusen. Intrapapillary drusen are seen as irregular dark masses within the substance of the
prelaminar optic nerve head. Note the diffuse elevation of the optic disc.
serve as a nidus for the deposition of extracellular materials. Systematic Associations With Optic
The axonal degeneration theory of Seitz and Kersting (571) Disc Drusen
is supported by the findings of Spencer (483,575) and Tso
Retinitis Pigmentosa
(536). Spencer (483,575) has proposed that alteration in axo-
nal transport might be the basic pathogenetic mechanism for Retinitis pigmentosa—globular excrescences of the optic
formation of drusen in the optic nerve. Tso (536) studied 18 nerve head—are occasionally seen in patients with this condi-
cases of optic disc drusen ultrastructurally and proposed that tion (576–579). Spencer (483) emphasized that although the
abnormal axonal metabolism leads to intracellular mitochon- drusen associated with retinitis pigmentosa may arise within
drial calcification. Some axons then rupture; mitochondria the optic disc, they more often lie just off the disc margin
are extruded into the extracellular space; and calcium contin- in the superficial retina (Fig. 3.40). In such cases, the disc
ues to be deposited in the extracellular mitochondria. Small is not elevated or anomalous but appears waxy yellow. These
calcified microbodies are then produced, and calcium contin- drusen increase in size, leading some authors to conjecture
ues to deposit on the surface of these nidi to form drusen. that they may be hamartomas rather than drusen (367,580);
Figure 3.40. Development of drusen in a patient with retinitis pigmentosa. A, The right optic disc is fairly normal. Small
drusen bodies can be appreciated at 2 and 5 o’clock at the disc margin. B, The left optic disc showed drusen only at 10 o’clock
at the disc margin when the patient was first examined. C and D, Four years later, the entire nasal margin of the disc is
surrounded by drusen and the left disc shows marked drusen formation from 7 to 11 o’clock.
however, histopathologic examination indicates that the with pseudopapilledema and cautioned that such children
globular excrescences of the optic nerve in retinitis pig- can be misdiagnosed as having hydrocephalus.
mentosa are drusen and not astrocytic hamartomas (581).
Patients with syndromes that include pigmentary retinopathy Migraine Headaches
may also have optic disc drusen. Shiono et al. (582) de-
scribed optic disc ‘‘mulberry’’ tumors that were presumed Migraine headaches are said to occur with increased fre-
to be drusen in two children with Usher syndrome, and Ed- quency in patients with disc drusen (202,596). Newman et
wards et al. (583) reported photographically apparent optic al. (5) pointed out that the concurrence of migraine and optic
disc and peripapillary drusen in 24 of 151 patients (16%) disc drusen probably reflects the frequent and often expe-
with Usher syndrome. Sebag et al. (584) documented histo- dited referral of patients with headache and elevated discs
pathologically giant intrapapillary drusen in a patient with for specialty evaluation.
Alström syndrome. Young and Small (585) noted disc dru-
sen in a patient with pigmented paravenous retinochoroidal ANOMALOUS DISC ELEVATION WITHOUT EITHER
atrophy. VISIBLE OR BURIED DRUSEN
Children with retinitis pigmentosa and buried drusen may Not all anomalously elevated optic discs develop drusen.
present with optic disc elevation and be thought to have As noted above, the morning glory syndrome is associated
neurologic disease (586). The combination of vitreous cells with disc elevation; the superotemporal portion of a tilted
with optic disc elevation may mimic uveitis in children with optic disc is usually elevated; and dysplastic discs may show
early retinitis pigmentosa. In this setting, the finding of atten- some degree of elevation. In addition, hypoplastic discs may
uated retinal arterioles provides an important (and easily have some elevation that seems out of proportion to the size
overlooked) clue to the diagnosis, which can be established of the disc. Such discs are often described as ‘‘crowded’’
by electroretinography (586). to distinguish them from discs that are truly swollen. In addi-
tion, vitreopapillary traction can produce optic disc elevation
Angioid Streaks (6,597). B-scan ultrasonography and optical coherence to-
Initial observations suggested that the association of disc mography allow confirmation of vitreopapillary traction
drusen with angioid streaks was unique to patients with pseu- (597).
doxanthoma elasticum (587–590). Subsequent studies indi-
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CHAPTER 4
Topical Diagnosis of Acquired Optic
Nerve Disorders
Alfredo A. Sadun and Madhu R. Agarwal
DISTINGUISHING AN OPTIC NEUROPATHY FROM Pathogenesis of Acquired Optic Disc Pallor

RETINAL DISEASE Ophthalmoscopic Features of Optic Atrophy
Differentiation by History Differential Diagnosis of Optic Atrophy
Differentiation by Physical Examination TOPICAL DIAGNOSIS OF OPTIC NERVE LESIONS
Differentiation by Visual Field Optic Disc Swelling
OPTIC ATROPHY Syndromes of Unilateral Optic Nerve Dysfunction
Nonpathologic Pallor of the Optic Disc Bilateral Lesions of the Optic Nerves
Pathology of Optic Atrophy
DISTINGUISHING AN OPTIC NEUROPATHY FROM RETINAL DISEASE

Severe optic neuropathies associated with syndromes and Retinal diseases may be divided into two main groups:
producing profound losses of optic nerve functions may be (a) those affecting the detecting apparatus, i.e., the receptor
obvious. However, mild optic neuropathies may only pro- cells and their synapses; and (b) those affecting the conduct-
duce subtle impairments of visual function and be difficult ing apparatus, i.e., the ganglion cell and nerve fiber layer.
to diagnose. When the optic discs appear normal and the In many cases, the diagnosis is obvious from the appearance
visual field defects do not have a classical pattern, distin- of the affected region of the retina. In other cases, however,
guishing such a mild optic neuropathy from retinal disease it may be possible to diagnose retinal dysfunction from other
may be difficult. For example, optic neuritis can be an easy aspects of the clinical examination. Patients with ‘‘unex-
diagnosis, but when it produces very mild loss of vision, it plained visual loss’’ may, in fact, have a disorder of the
may be easily confused with central serous retinopathy. Both retina that may not be obvious during a clinical examination.
occur in young adults and can present as acute, painless, Indeed, even when the examination of the ocular fundus is
mild monocular visual loss. The relative absence of fundus performed with a 90-diopter hand-held lens, or direct oph-
findings in such patients further challenges the clinician in thalmoscope, a retinal disorder may be missed.
sorting out the differential diagnosis. However, since optic
nerve disease may be the harbinger of intracranial pathology, DIFFERENTIATION BY HISTORY
and both optic nerve and retinal diseases are often amenable
to a variety of therapeutic modalities, it is important for the It is important to elicit from the patient the timing (tempo)
clinician to make the early and accurate distinction between of the visual loss, including the onset and course of each of
an optic neuropathy and macular or other retinal disease. the symptoms. For example, optic neuritis often develops
The most common optic neuropathies in adults are optic over a few days, stabilizes and then shows improvement
neuritis and nonarteritic anterior ischemic optic neuropathy. over a period of weeks. Anterior ischemic optic neuropathy
The cell that is injured in these disorders, or in any optic begins suddenly with little by way of progression or resolu-
neuropathy, is the retinal ganglion cell. Often, its axon tion thereafter (1). Central serous retinopathy, by compari-
undergoes degeneration and then anterograde degeneration son, often comes on more insidiously.
results in optic atrophy. Retinal diseases may arise from a The nature of the visual loss needs to be characterized in
variety of lesions of the outer or inner retina or choroid and the history as well. Loss of visual acuity from optic nerve
significant improvement in visual function is often possible. disease is usually perceived as a darkening. Patients may
197
Table 4.1
Distinguishing Optic Neuropathies and Maculopathies
Features Optic Nerve Macula
Presenting deficit Central dark cloud Distortions

Pain (rarely) Sometimes with eye movement Rarely
Refractive error Unchanged Sometimes hyperopia
Visual acuity Variable Markedly impaired
Afferent pupillary defect Present Absent
Color vision Very reduced Slightly reduced
Brightness sense Very reduced Variable
Amsler grid Scotoma Metamorphopsia
describe this as a black, gray, or brown patch or more gener- thies (Table 4.1). By comparison, patients with retinal
ally as a generalized dimness across portions of the visual disease, especially maculopathies, most often note metamor-
field (1). There is darkening, or desaturation of colors and phopsia in the central visual field (2). Objects look distorted
a loss of color contrast. Patients may see worse when the and straight lines become irregularly curved. Micropsia
lighting is hazy. Some optic neuropathies produce phos- (seeing everything slightly minimized) is more common than
phenes (positive visual phenomenon, often in the form of macropsia. Patients with retinal disease that involves the
bright spots or sparkles). Pain, especially with eye move- macula also complain of mild photophobia or glare. Instead
ments, is part of the presentation of several optic neuropa- of seeing a central patch that is too dim, as in optic neuropa-
Figure 4.1. Subtle macular lesions causing visual loss. A, Pigment

changes in right macula of a patient with ‘‘unexplained’’ central visual
loss. B, Epiretinal membrane in the left macula of a patient complain-
ing of blurred vision in the eye. C, Changes in the right macula of a
patient who complained of decreased central vision in the eye after
blunt ocular trauma. It was initially suspected that he had a traumatic
optic neuropathy or was malingering.
TOPICAL DIAGNOSIS OF ACQUIRED OPTIC NERVE DISORDERS 199
thies, such patients often note a zone that appears as too

bright (3).
DIFFERENTIATION BY PHYSICAL EXAMINATION

Visual acuity is nearly always impaired in macular disease
and often in optic neuropathies. The issue often comes to the
extent of loss of vision in comparison to the three common
measures of optic nerve function. This optic nerve triad con-
sists of the relative afferent pupillary defect (APD), color
vision and brightness sense (4–6). An APD is seen when
the consensual pupillary response is greater than the direct
pupillary response. This is noted qualitatively, or it can be
quantitated with the use of neutral density filters (5). Color
vision is best assessed with a Farnsworth-Munsell 100-hue
(FM-100) test (6). However, shorter and more convenient
tests are often performed, such as the D-15 which is the
desaturated form of the FM-100, or the use of pseudoiso-
chromatic plates of the A-O or Ishihara type. A third sensi-
tive measure of optic nerve function is noting the change in
brightness sense. This can be performed subjectively or with
some quantitative objectivity through the use of a device that
uses cross-polarizing filters to diminish light transmission as Figure 4.2. Distortion of lines on Amsler grid in a patient with unilateral
a match of the perceived brightness-sense disparity (3). In visual loss. The patient had central serous chorioretinopathy.
optic neuropathies, these three measures of optic nerve func-
tion are usually greatly diminished in proportion to the loss
of visual acuity. While there might be some slight loss of (Fig. 4.2). The results of a photostress test usually are abnor-
these functions in retinal disease as well, this is usually in mal in such patients (13–15), as are the results of fluorescein
the setting of a profound loss of visual acuity (Table 4.1). angiography, focal electroretinography (16–19), or both.
Visual Acuity Color Vision
Central vision may or may not be affected by disease that Color vision is often but not always abnormal in patients
damages the retina. Disorders that cause dysfunction only with retinal disease. For instance, patients with central serous
of extramacular retina typically are unassociated with a re- chorioretinopathy and epiretinal membrane formation rarely
duction in central acuity, whereas macular disorders and dis- have any significant dyschromatopsia, whereas patients with
orders that damage the entire retina invariably reduce central macular cone or cone-rod dystrophies usually do (20); such
vision. Most disorders that affect the macula are easily de- patients may even develop difficulties with color vision as
tected by a careful funduscopic examination, particularly the initial sign of the disease (21). In such cases, the correct
when the macula is examined with a slit lamp biomicroscope diagnosis is not made until other studies such as photostress
using a corneal contact lens, a 78- or 90-diopter handheld testing, fluorescein angiography, or electroretinography are
lens. Nevertheless, some disorders, such as central serous performed. Retinal disorders are more likely to produce
chorioretinopathy, cystoid macular edema, and epiretinal either generalized loss of color vision or a blue-yellow
membrane formation (surface wrinkling retinopathy, cello- dyschromatopsia (22–24), but there are sufficient exceptions
phane maculopathy) can easily be overlooked (Fig. 4.1). In that make the pattern of color vision loss an unreliable diag-
other diseases that affect the macula, such as macular cone nostic criterion.
dystrophy, there are often no changes that can be observed
Afferent Pupillary Defect
in the macula, even though the patient has decreased central
vision and a visual field defect. In such cases, the diagnosis A relative afferent pupillary defect can be detected clini-
of retinal disease may be suspected if there is associated cally as well as with neutral density filters in patients with
metamorphopsia (an irregularity or distortion in the appear- unilateral or asymmetric retinal disease. In most cases, the
ance of viewed objects), photophobia, nyctalopia (night retinal disease is severe, affects most of the retina or the
blindness), or hemeralopia (the inability to see as distinctly entire macula, and is obvious during a funduscopic examina-
in a bright light as in a dim one). These symptoms occur tion (25–27). If a relative afferent pupillary defect is ob-
much more often in patients with ocular disease than in pa- served in a patient with decreased visual acuity associated
tients with neurologic disease (7–12). Photophobia should with some macular drusen, central serous chorioretinopathy,
be obvious during the examination. Evidence of metamor- cystoid macular edema, an epiretinal membrane, or a nor-
phopsia may be detected in patients with and without the mal-appearing fundus, a lesion affecting the optic nerve
complaint of distortion of objects by using an Amsler grid should be suspected.
Figure 4.3. Variation in visual fields caused by posterior pole lesions. A, Small chorioretinal scar in the papillomacular bundle
adjacent to right fovea. Because this lesion is located in the deep retina at the level of the photoreceptors and retinal pigment
epithelium, it produces only a small central scotoma (B).
DIFFERENTIATION BY VISUAL FIELD

Peripheral Retina
When the photoreceptors are affected, the defect in the
visual field corresponds to the retinal defect in position,
shape, extent, and intensity (28). When the ganglion cell or
nerve fiber layer is damaged, however, the field defect does
not conform to the size and shape of the lesion but rather
to the field represented by the ganglion cells whose fibers
are damaged. Thus, a small lesion situated close to the optic
disc that damages only photoreceptors usually causes a small
scotoma, whereas a lesion of the same size that damages the
ganglion cells and nerve fibers in the same area may result
in an extensive defect in the visual field (Fig. 4.3). Con-
versely, a small lesion in the periphery that damages only
a few fibers transmitting impulses from widely separated
ganglion cells may produce such a small field defect that it
may be difficult or even impossible to detect.
Diseases that cause photoreceptor damage usually pro-
duce a greater loss of the visual field when it is tested with
blue stimuli than when it is tested with red stimuli (28). This
observation is useful because the situation is reversed in
disorders that damage the conducting apparatus of the retina. Figure 4.4. Anatomy of the retinal nerve fiber layer and retinal origin of
In lesions of the ganglion cells, retinal nerve fiber layer, and arcuate visual field defect produced by a chorioretinal scar. A, Drawing of
optic nerve, there usually is a more pronounced loss of the the normal pathway of retinal nerve fiber layer axons. The axons that origi-
visual field for red than for blue. nate from ganglion cells superior, inferior, and nasal to the optic disc (OD)
take a fairly straight course to the disc, as do the axons in the papillomacular
If a lesion superotemporal or inferotemporal to the optic
bundle (P) that originate from ganglion cells nasal to the fovea (F) but
disc damages peripheral visual fibers, the field defect is arcu- temporal to the disc. The courses of axons from peripheral ganglion cells
ate in shape because the fibers from peripheral ganglion cells temporal to the disc are arched. N, nasal retina; R, horizontal raphe; T,
arch around the papillomacular bundle (Fig. 4.4). The field temporal retina. The dotted lines delineate the nasal, temporal, superior,
defect is, of course, situated nasal to the blind spot. If the and inferior portions of the retina. (Redrawn from Hogan MJ, Alvarado
lesion is nasal to the optic disc, it damages a nasal bundle. JA, Weddell JE. Histology of the Human Eye: An Atlas and Textbook.
The resultant field defect is temporal and fan-shaped, be- Philadelphia, WB Saunders, 1971.)
cause fibers from ganglion cells located nasal to the optic of the scotoma and the functioning upper or lower field. This
disc take a direct path to the disc. is particularly evident in large arcuate scotomas, so much
An arcuate defect in the visual field may indicate a defect so that visual fields performed on tangent screen or by auto-
in the nerve fiber layer. When such a retinal lesion is present, mated static perimetry may suggest complete loss of the
it usually can be identified by ophthalmoscopic examination. superior or inferior hemifield unless the entire field is tested
Because of the anatomy of the temporal raphe that separates (Fig. 4.5).
fibers from ganglion cells located above the horizontal mid- Retinal photoreceptors (by way of intermediaries) project
line from those from ganglion cells below the horizontal to ganglion cells, and the axons of the ganglion cells com-
midline, there is often a sharp dividing line between the area prise the nerve fiber layer which, in turn, makes up the optic
Figure 4.5. Arcuate visual field defect that

appears altitudinal when only the central field
is tested. The patient was a 74-year-old man
who experienced an attack of nonarteritic ante-
rior ischemic optic neuropathy. Visual acuity
was 20/30 in the affected right eye. A, Static
perimetry demonstrates a ‘‘complete’’ inferior
altitudinal defect. B, Kinetic perimetry shows
that the defect identified on static perimetry is
actually a scotoma. The actual field defect is
arcuate in nature, and the remaining field is
larger than might have been expected from the
results of static perimetry.
nerve. Clearly, then, any visual field defect that can be pro- ganic disease can produce spurious central, paracentral, and
duced by a retinal lesion can also be produced by a lesion even quadrantanopic and hemianopic field defects, regard-
of the optic nerve (29). Ophthalmoscopic evidence pointing less of whether they are tested with kinetic or static perime-
to the retina as the site of the lesion is conclusive, but, as tric techniques (35–41). It should also be emphasized that
noted in the section below, lack of an ophthalmoscopically a spurious central or paracentral scotoma may be charted if
visible retinal abnormality does not necessarily indicate that the central field of an eye with a high refractive error or
the retina is not the site of the lesion. under a cycloplegic is plotted without correction for the re-
fractive error (42).
Central Retina Symptoms of metamorphopsia or micropsia are caused
Most visual field defects in the central fields that are by distortion or displacement of the retinal photoreceptors.
caused by retinal lesions are associated with ophthalmoscop- Metamorphopsia is usually caused by a distortion of the nor-
ically visible changes. In patients with macular lesions, the mal alignment of the photoreceptors. When there is in-
field defects are those already described as resulting from creased separation among cones (and among rods to a lesser
lesions of the receptor cells; that is, the field defect occupies extent because of the central position of the lesion), there is
an area consistent with the size of the lesion. However, some an apparent decrease in the size of objects (micropsia). The
macular lesions that produce a central scotoma cannot be foveal cones are already so close to each other that it is
easily detected by ophthalmoscopy. In most of these cases, unlikely that an apparent increase in the size of objects (ma-
small lesions of the retina or retinal pigment epithelium may cropsia) can occur from further crowding together of these
be diagnosed using red-free ophthalmoscopy, slit lamp bio- cells.
microscopy with a contact lens or a 90- or 78-diopter hand- Changes in the apparent size of viewed objects usually
held lens, fluorescein angiography, or a combination of these result from primary retinal damage. Such symptoms may
techniques. In other cases, the diagnosis cannot be made also be described by patients with acquired cerebral disor-
without a focal electroretinogram (ERG). ders that affect perception (e.g., migraine) (43–45), although
Multifocal ERG (mfERG) relies on multiple samples of the phenomenon should occur in both eyes simultaneously
ERG responses from different parts of the retina. Computed in that setting. One case of micropsia associated with myas-
localization is made by Fourier transform analysis (30–32). thenia gravis has been reported in which the authors postu-
Like a visual field, this technology can map out retinal im- lated that the symptom was caused by overconvergence
pairments (33). Furthermore, an optic nerve head component (46,47).
(ONHC) can be dissected out through an algorithm that takes
into account the distance from the optic disc (34). This new Cecocentral Scotomas
methodology has much promise in the diagnosis of regional Damage to the papillomacular area of the retina results in
retinal diseases. a central scotoma that connects to the physiologic blind spot;
Of course, not all monocular field defects are caused by this is a cecocentral scotoma (Fig. 4.6). A cecocentral sco-
organic retinal or optic nerve lesions. Patients with nonor- toma may result from damage to the papillomacular bundle
Figure 4.6. Cecocentral scotoma caused by a lesion in the papillomacular bundle. A, The patient has a small cecocentral
scotoma in the visual field of the left eye. B, There is a serous detachment of the retina in the papillomacular bundle of the
left eye, associated with a temporal optic pit.
alone or may occur in conjunction with peripheral contrac- scotoma, when unilateral, always indicates damage to the
tion of the visual field (48). macula. When bilateral pericentral scotomas are present,
there is usually bilateral macular disease; however, bilateral
Arcuate (Nonglaucomatous) Defects ‘‘pericentral’’ scotomas can develop from lesions that dam-
age the posterior aspects of both occipital poles. When such
An arcuate visual field defect usually results from damage lesions occur bilaterally at the occipital tips, bilateral ‘‘cen-
to retinal nerve fibers or ganglion cells in the superior or tral’’ scotomas occur. Actually, these visual field defects
inferior arcuate nerve fiber bundles. In such cases, there is are bilateral homonymous scotomas, and kinetic or static
a central field defect that is not circular but instead is limited perimetry will generally disclose a vertical step between the
above or below by the horizontal meridian. This visual field two hemianopic scotomas, indicating their true nature (50)
defect may occur in patients with occlusion of the blood (Fig. 4.7).
supply of the superior or inferior portion of the macula or Annular or ring scotomas occur in a variety of conditions,
in patients with glaucoma (49). In both settings, the scotoma most notably in patients with various pigmentary retinopa-
is associated with normal visual acuity, since it does not thies. Ring scotomas may also occur in patients with open
completely affect the macula. Virtually any lesion, whether angle glaucoma, but in such cases, the ring is actually caused
ischemic, inflammatory, infiltrative, or compressive, can by the coalescence of upper and lower arcuate scotomas
cause an arcuate field defect and, as noted above, may be originating from the physiologic blind spot and extending
located in either the retina or the optic nerve. across the vertical midline into the nasal visual field (51).
A roughly circular pericentral scotoma may be observed Rarer causes of annular or ring scotomas include retinitis,
in patients with macular or papillomacular disease. Such a choroiditis, blinding by diffuse light, retinal migraine, mal-
Figure 4.7. Bilateral hemianopic scotomas simulating central scotomas in a patient with reduced central vision after simultane-
ous bilateral occipital lobe infarctions.
A B
Figure 4.8. Optic atrophy in unilateral retinitis pigmentosa. A, The right optic disc is normal. Note healthy color of the disc
and normal-appearing peripapillary retinal nerve fiber layer. B, The left optic disc is pale. Note marked pigmentary change in
the posterior pole, as well as marked narrowing of the retinal arteries. (Courtesy of Dr. Daniel Finkelstein.)
nutrition, and myopia (52). Similar defects may be seen in eral field is so contracted and central vision so reduced that
various optic neuropathies, particularly those caused by is- the ring scotoma may not be detected even when careful
chemia, compression, and inflammation. The width of such perimetry is performed. A ring scotoma may also persist
scotomas varies within wide limits, but the ring is rarely less after incomplete resolution of a preexisting central scotoma
than 5–6⬚ in width, and may be much wider. Occasionally, in patients with retinal or optic nerve disease.
ring or annular scotomas are found in patients with nonor- In general, a unilateral temporal or nasal hemianopia that
ganic visual loss. In such patients, the scotomas are typically respects the vertical midline is either nonorganic or caused
very narrow. by dysfunction of the optic nerve (see below). Nevertheless,
A ring scotoma can be detected in most types of pigmen- a unilateral temporal hemianopia rarely can be caused by
tary retinopathy (e.g., retinitis pigmentosa) if the visual field sectoral retinitis pigmentosa (53).
is carefully examined. In some cases, however, the periph- The optic nerve is composed primarily of axons whose
Figure 4.9. Arcuate visual field in a 68-year-old woman

with open-angle glaucoma. Static perimetry, using a Hum-
phrey perimeter to perform a 24-2 Threshold Test, reveals
a superior arcuate defect located within the central 30⬚
from fixation.
cell bodies are the ganglion cells of the retina. Any retinal paracentral scotomas that occur in patients with chronic open
disorder that directly or indirectly damages the ganglion cells angle glaucoma have no associated nasal step and, even less
or their axons in the retinal nerve fiber layer will produce frequently, a nasal step is present without a paracentral sco-
optic atrophy. Loss of the nerve fiber layer and optic atrophy toma. As damage proceeds, the paracentral scotoma be-
are not uncommon in patients with various photoreceptor comes deeper, wider, or both, and new scotomas may de-
dystrophies and degenerations, particularly those affecting velop in the same arcuate region. As these defects coalesce,
the cones (20,54–60) (Fig. 4.8). they take on an arching shape between the nasal horizontal
meridian and the blind spot. Isolated enlargement or elonga-
Glaucomatous Optic Neuropathy tion of the blind spot is a relatively nonspecific finding and
The visual field defects in chronic open angle glaucoma is not considered diagnostic for glaucomatous damage, al-
occur from damage to nerve fiber bundles at the level of the though it may indicate a general depression in visual sensi-
lamina within the optic nerve head (61). This damage seems tivity. Defects in the field temporal to the blind spot occur
to occur focally in its initial stages and is thus expressed in in early glaucomatous damage, but are much less frequent
the visual field as isolated scotomas appearing between 5⬚ (66). As arcuate scotomas enlarge and affect both the upper
and 30⬚ from fixation in the arcuate or Bjerrum area and lower regions, they may meet at the horizontal meridian
(51,62–64) (Fig. 4.9). About two-thirds of these isolated and produce a ring-shaped scotoma, as noted above. Further
paracentral or arcuate scotomas are accompanied by a damage results in the breaking out of the scotoma to the
depression in sensitivity in the upper or lower half of the peripheral field, so-called ‘‘baring’’ to the periphery. Thus,
field. This loss of sensitivity appears initially as a step in a patients with advanced glaucoma may retain only the central
plotted isopter, usually at the nasal, horizontal meridian (the 5⬚ and a temporal island of vision.
nasal step of Rönne) (28,65) (Fig. 4.10). One-third of early Although the visual field defects that occur in chronic
A B
Figure 4.10. Field changes in various patients with glaucomatous optic neuropathy. A, Superior nasal step in right eye. B,
Inferior arcuate field defect in right eye. (Figure continues.)
C D
Figure 4.10. Continued. C, Progression of inferior and superior arcuate defects in left eye. D, Central field loss in left eye.
In the cases in which central field loss is seen in glaucoma, the horizontal meridian is usually respected, as in this case.
open angle glaucoma may be identical with defects that re- (Fig. 4.11C), diffusely or sectorally pale without enlarge-
sult from various types of nonglaucomatous optic neuropa- ment in the size of the cup (Fig. 4.11D), or pale with substan-
thy, the differentiation between glaucoma and nonglaucoma- tial cupping but also with pallor of the remaining neuroreti-
tous optic neuropathy is made by history and examination. nal rim (Fig. 4.11E) (87–91). Thus, when the optic disc and
Most patients with chronic open angle glaucoma develop retinal nerve fiber layer findings are considered in a patient
loss of visual field long before they experience loss of central with various visual field defects, it is rarely difficult to differ-
vision, although exceptions indeed occur. Color vision defi- entiate glaucoma from other diseases producing such de-
cits are typically of the blue-yellow type (67–80) but again, fects.
exceptions regularly occur, and red-green deficits are not
uncommon (81). A relative afferent pupillary defect is not The Blind Spot
uncommon in cases of unilateral or asymmetric glaucoma
(82–86). The blind spot also plays a role in the interpretation of
Patients with glaucoma develop visual field defects only the visual field. It represents the negative scotoma that is
after there is extensive damage to the optic disc. The ophthal- the projection of the optic disc. The optic disc is located
moscopic appearance of such a disc is typical: in nearly nasal to the fovea, and its center is slightly above it. Thus,
every such case, there is substantial cupping of the disc with the blind spot is temporal to the point of fixation, and its
the remaining neuroretinal rim appearing relatively normal, center is slightly below it.
without evidence of pallor, and with diffuse thinning of the The dimensions of the blind spot have already been noted;
retinal nerve fiber layer (Fig. 4.11A and B). This is in contrast however, it is important to be aware that the blind spot has
to other types of optic nerve diseases producing similar vis- both an absolute and a relative portion. The relative portion
ual field defects, in which the optic disc may appear normal is a band, about 1⬚ in width, that surrounds the absolute
Figure 4.11. Appearance of optic disc in patient with glaucomatous field

loss, compared with varied appearances of optic discs with nonglaucoma-
tous field loss. A, Right optic disc in an eye with glaucomatous field loss.
Note moderate cupping with preservation of normal color of remaining
neuroretinal rim. B, In another patient with glaucoma, the right optic disc
is markedly cupped, but the remaining neuroretinal rim (from about 12 to
7 o’clock) retains its normal color. C, In a patient with 20/20 visual acuity
and visual field loss similar to that seen in glaucoma, the right optic disc is
normal in appearance. The patient had experienced an attack of retrobulbar
neuritis several days earlier. D, Appearance of left optic disc in a patient
with good visual acuity but significant visual field loss in the left eye after
an attack of optic neuritis. Note diffuse pallor of the disc without obvious
cupping. E, Appearance of the left optic disc after an attack of anterior
ischemic optic neuropathy in the setting of temporal arteritis. The disc
is diffusely pale and cupped. Note that the remaining neuroretinal rim,
particularly temporally, is as pale as the cupped portion of the disc.
A
Figure 4.12. A, Enlargement of the blind spot in a 30-year-old obese woman with headaches. B, Appearance of left optic
disc, showing chronic swelling. An evaluation revealed increased intracranial pressure.
scotoma. In this band, white objects of l–2 mm can be seen nal dysfunction. This dysfunction can occur because the
when a subject is tested at 2 meters (28). This zone of relative peripapillary retina is diseased, as occurs in patients with
scotoma is caused by the gradual rather than abrupt termina- the so-called ‘‘big blind spot syndrome’’ (94) and related
tion of the retina at the edge of the optic disc (28), and in disorders such as acute zonal occult outer retinopathy
it metamorphopsia can often be demonstrated (92). (AZOOR) and the multiple evanescent white dot syndrome
Undoubtedly, then, the blind spot becomes larger when (MEWDS) (95–99), or because expansion of the optic disc
small or less bright test objects are used to test the visual tissue encroaches on the peripapillary retina, as occurs in
field. It has also been demonstrated that the size of the blind optic disc swelling and in pseudopapilledema (Fig. 4.12).
spot depends in part on the surrounding illumination. It is Because both true optic disc swelling and pseudopapille-
smaller when the visual field is tested with high degrees of dema are often associated with a variable degree of enlarge-
illumination than when testing is performed in dim light. ment of the blind spot, the size of the blind spot is rarely a
Finally, the size of the blind spot is smaller when it is tested crucial factor in determining the presence or absence of disc
centripetally than when it is tested centrifugally (93). swelling or in differentiating acquired disc swelling from
The blind spot becomes enlarged from peripapillary reti- congenital elevation of the optic disc.
OPTIC ATROPHY
Optic atrophy is not a disease. It is a nonspecific morpho- causes of optic atrophy is not attempted. These disorders are
logic end point of disease—any disease—that causes dam- discussed in detail elsewhere in this text.
age to ganglion cells and axons of the optic nerve. The term
‘‘optic atrophy’’ is, therefore, a pathologic generalization NONPATHOLOGIC PALLOR OF THE OPTIC DISC
applied to an appearance due to degeneration of axons in
The determination of disc pallor requires familiarity with
the anterior visual system. Although the pathologist can de- normal disc color. The temporal side of the normal disc
termine optic atrophy by direct observation of histopatho- usually has less color than its nasal side. The degree of this
logic changes in the optic nerve, the clinical diagnosis of temporal pallor is primarily related to the size of the physio-
atrophy is usually based on ophthalmoscopic abnormalities logic cup, and to the thin translucent character of the tem-
of color and structure of the optic disc with associated poral nerve fiber layer.
changes in the retinal vessels and nerve fiber layer, and de- The normal physiologic cup may vary in size. When it
fective visual function that can be localized to the optic extends almost to the temporal edge of the disc, the temporal
nerve. side of the disc is pale. Sometimes the temporal margins of
Both the pathologic and ophthalmoscopic features of optic large physiologic cups are steep-walled. When the margins
atrophy are discussed in this section, but a listing of all slope gradually downward from the margin of the disc, the
crescent of sclera adjacent to the temporal, and occasionally A brighter, whiter ophthalmoscope bulb may give the illu-
to the inferior margin of the disc, is visible and appears sory impression of disc whiteness. Similarly, true pallor of
mottled grayish white. This crescent, known as a temporal an optic disc may be overlooked when the light source has
or sometimes inferior conus, is exposed by retraction of the become weak and yellow. The color of the disc changes with
dark retinal pigment epithelium from the disc margin and the color temperature of the light source (100) and the age
enhances the whitish appearance of such a disc. of the lens (101,102). Sorensen (103) examined the color of
Marked recession or excavation of a physiologic cup cre- the optic discs of 200 normal subjects using a slit lamp and
ates a central area of pallor. The retinal vessels are partially contact lens. His findings are in agreement with those of
obscured as they ascend through a thin rim of neural tissue others (102,104,105) that optic disc color depends on the
that borders the excavation. It is difficult to distinguish this incident light on the disc.
cup from a glaucomatous cup. The pallor of the floor of a
physiologic cup comes from the glistening whiteness of the PATHOLOGY OF OPTIC ATROPHY
lamina cribrosa, a connective and elastic tissue structure with
small sieve-like openings through which axonal bundles The optic nerve axons arise from the ganglion cells located
pass. Because the openings are irregular, direct light entering in the retina. Hence damage to such axons may occur at
them is reflected in many directions, and the holes appear several locations: (a) from disease within the eye that dam-
as yellow/white ovals or dots. When this dotting is seen, it ages the ganglion cells, the retinal nerve fiber layer, or the
signifies that there is no abnormal opaque connective tissue optic disc; (b) from disease within or surrounding the intraor-
present over the surface of the cribriform plate. bital, intracanalicular, or intracranial portions of the optic
A white-appearing disc is common in an eye with axial nerve; (c) from intracranial diseases of the optic chiasm,
myopia. Because the optic nerve enters the globe obliquely, optic tracts, or lateral geniculate body (LGB); and (4) from
the contents of the disc, including the nerve fibers and the diseases of the retrogeniculate pathways that produce trans-
retinal vessels, are displaced nasally. The physiologic cup synaptic (transneuronal) degeneration. Such precesses may
is shallow, and its extension to the temporal margin produces be focal, multifocal, or diffuse. They may destroy axons di-
relative temporal pallor that is often exaggerated by a tem- rectly or by effects on the blood supply. Focal disruption at
poral conus. any place along an axon causes degeneration of the entire axon
In infants, ophthalmoscopic examinations are more diffi- and its cell body, the retinal ganglion cell. When large num-
cult. Opening the lids against squeezing may increase the bers of axons undergo such degeneration, gross shrinkage or
intraocular pressure and that may artifactually add to the atrophy of the optic nerve becomes evident (Fig. 4.13).
appearance of optic disc pallor. When an axon is irreversibly damaged, it undergoes either
Figure 4.13. Histopathologic appearance of optic atrophy. A, Cross section of normal optic nerve stained with myelin. B,
Cross section of atrophic optic nerve photographed at same magnification to show extensive shrinkage. This nerve is about
one-third the diameter of the specimen seen in A. (Courtesy of Dr. Harry A. Quigley.)
anterograde or retrograde degeneration. Anterograde degen- Retrograde degeneration is relatively independent of the
eration proceeds posteriorly along the axon that has been distance of the injury from the ganglion cell body. Damage
separated from its cell body, whereas retrograde degenera- to the retrobulbar portion of the optic nerve, the optic chiasm,
tion occurs in the proximal segment of the axon that remains and the optic tract all cause pathologic and visible degenera-
in contact with the cell body. tion of the ganglion cell bodies at about the same time
(116–118).
Anterograde (Wallerian) Ascending Degeneration After an optic nerve is severed, bulbous axonal swellings
of Axons (Cajal end bulbs) can be seen at the anterior cut ends of the
fibers. A few additional swellings on the posterior end of
When an axon of the central nervous system is severed,
the severed nerve provide evidence of centrifugal axons in
its distal (ascending) segment, being separated from its cell
the optic nerve (119,120). This has been confirmed by ultra-
body, quickly degenerates and disappears, and its investing
structured analysis of optic nerves in humans with complete
myelin sheath undergoes a slower breakdown into simpler
loss of retinal ganglion cell bodies due to Leber’s hereditary
lipids that are eventually catabolized. This process is called
optic neuropathy (121). These fibers, about 1,000 in number,
anterograde or Wallerian degeneration (106).
may have a vasomotor function and may represent melato-
Axons in the optic nerve undergo Wallerian degeneration
nin-containing cells that subserve circadian rhythm (122).
at a rate proportional to their thickness. Large axons show
Regeneration of axons in the optic nerve in human and
varicosities as early as 30 hours from the time of severance
nonhuman primates is quite limited and abortive. By about
from the cell body. Within 4–8 days, they break up into
2 months, all sectional optic nerve fibers degenerate
shorter oval or spherical fragments that progressively disin-
(123,124). Various purported neurotrophic factors can ex-
tegrate and disappear. In medium-sized myelinated fibers,
tend but not preserve indefinitely retinal ganglion cells from
the axon is still in the varicose or beaded stage at the end
retrograde degeneration (125–128).
of a week and it finally breaks up from the second week
Remyelination does occur after injury to the optic nerve.
onward. In small-caliber fibers, the process is slower, with
Bunge et al. (129) and Bornstein et al. (130) first showed
many axons showing little change during the first 10 days.
that CNS tissue in various species, including primates, has
Changes in their myelin sheaths correspond to the changes
the capacity to reform myelin following experimental pri-
in the axon. Breakdown of myelin into simpler lipids occurs
mary demyelination as long as the axon itself is intact. Other
over the subsequent weeks and spherules of myelin may be
investigators subsequently confirmed these initial observa-
present indefinitely (107,108). By the end of the fourth
tions (131–140). This remyelination results from the activity
month, most or all of the broken down myelin has been
of uninjured, injured but surviving, and newly generated oli-
engulfed and removed by phagocytic microglia. These mi-
godendroglia (141). This has also been demonstrated in optic
croglia appear around degenerating fibers by the fourth day
neuropathies such as Leber’s hereditary optic neuropathy
and increase in numbers during the next two weeks, with
(142–144).
their cytoplasm filling with fine fatty droplets. These phago-
In multiple sclerosis (MS) and other immune-mediated
cytes absorb the large amount of lipid that is produced as
disorders, remyelination occurs both in and at the edges of
myelin breakdown occurs. The lipid-laden microglia (Gitter-
plaques (137,138,140,145). Restoration of conduction by re-
zells) migrate to blood vessel walls where, from the third
myelination may thus play a role in the characteristic remis-
month onward, they crowd the adventitial spaces. Leuko-
sions of MS.
cytes are rarely present in Wallerian degeneration.
Remyelination probably plays a larger role in the recovery
An essential feature of Wallerian degeneration is the
from acute and chronic compressive lesions of the CNS than
swelling and degeneration of the axon terminals in the lateral
it does in the recovery from primary demyelinating disease
geniculate bodies. This consists of globular thickening or
(138,139). Acute experimental compression of the spinal
swelling of the terminals of visual axons that can be identi-
cord is accompanied by secondary demyelination that is fol-
fied within layers of the geniculate body as early as 24 hours
lowed almost immediately by remyelination that occurs even
after a lesion of the axon (109). Wallerian degeneration and
though the nerve is still compressed (132–136,146). Thus,
the optic pallor it produces can only be observed clinically
even nerves within the CNS that have been chronically com-
when this dying-back reaches the axons within the eye
pressed have the potential to begin conducting impulses as
(110–115).
soon as the compression is relieved, as long as there has not
Retrograde (Descending) Degeneration of Axons been severe irreversible damage to the axons themselves.
This phenomenon may explain the progressive improvement
Anterograde degeneration begins and becomes virtually in vision that is often seen after removal of compressive
complete within 7 days after injury; however, the portion of lesions of the optic nerves and chiasm that have produced
the axon still connected to the cell body, and the cell body profound visual loss. Likewise, it may explain why the de-
itself, can remain normal in appearance for up to 3–4 weeks. gree of visual recovery depends to a large extent on the
During this time, orthograde axonal transport continues. duration of visual symptoms, the severity of preoperative
Eventually, however, the entire remaining structure (the cell visual loss, and the presence or absence of optic atrophy
body and axon from the point of injury) degenerates by retro- (147–150).
grade degeneration so that by about 6–8 weeks after severe Primate retinal ganglion cells show no detectable regener-
optic nerve injury, no affected ganglion cells remain viable. ation after injury. These cells are capable of developing an
axon in embryologic life; but it remains hotly debated as to containing capillaries. They postulated that the transparent
whether the adult primate ganglion cell fails to receive a nerve fibers act as fiberoptic pathways in conducting light.
signal for regeneration, is actively inhibited from regenera- The light diffuses among adjacent columns of glial cells and
tion, or has lost this ability. capillaries and acquires the pink color of the capillaries. The
Transsynaptic (transneuronal) degeneration is a phenome- axon bundles of an atrophic optic disc have been destroyed,
non by which a neuron on one side of a synapse degenerates and the remaining astrocytes are arranged at angles to the
as a consequence of the loss of a neuron on the other side. entering light. Thus, little light passes into the disc substance
This is more likely to occur in the anterograde direction to traverse the capillaries The light reflected from opaque
and when the lesion occurs in the immature brain (151). glial cells does not pass through capillaries, remains white,
Transneuronal degeneration is a well-established phenome- and the optic disc appears pale. In some areas, loss of tissue
non in the cells of the LGB following destruction of parts also allows light to pass directly to the opaque scleral lamina,
of the retina or the optic nerve (152–157). Van Buren (158) and this adds to the white color of the disc.
performed a right-sided occipital lobectomy on an adoles- Other explanations for optic disc pallor include the paucity
cent macaque monkey and examined the eyes 4 years later. of capillaries and astroglial proliferation. However, Henkind
He found a striking loss of ganglion cells in the correspond- et al. (167) as well as Quigley and Anderson (166) observed
ing right halves of the retinas and also noted subtle changes that despite optic atrophy, disc capillaries are still present
in the bipolar cells of the retina. These observations were and appear to be functional. In addition, Hayreh (168)
subsequently confirmed by other investigators working with showed that small blood vessels can be demonstrated in pale
developing monkeys (159,160). Wilbrand and Saenger (161) discs by fluorescein angiography.
thought that retrograde transsynaptic degeneration occurred
most often in patients with occipital lobe damage in utero OPHTHALMOSCOPIC FEATURES OF
or during early infancy, and this has been confirmed patho- OPTIC ATROPHY
logically (156).
The evaluation of optic disc color is a routine but often
It has been suggested that transsynaptic degeneration may
challenging problem. This seemingly simple task has many
occur in mature adult primate visual systems if enough time
pitfalls. Estimating the lack of color in an optic disc is diffi-
has elapsed. Weller and Kaas (160) reported loss of retinal
cult to assess, record, compare, and describe. The normal
ganglion cells in adult monkeys with striate cortex lesions,
color of the optic disc is dependent upon its composition
but the changes were less severe than in developing mon-
and the relationship of the components to each other and to
keys. Weller et al. (162) were unable to produce similar
the light that is reflected or refracted from the disc surface.
changes in the adult prosimian primate, Galago, so there
Because the neural elements are gray, the pink color of the
appears to be major species differences. Retrograde trans-
disc is also related to its blood vessels .
synaptic degeneration probably is not clinically significant
Pallor of the optic disc has often been graded as mild,
in human adults. (163). However, histological evidence of
moderate, or severe; however, such distinctions are subjec-
retrograde degeneration in the human visual system exists.
tive and unreliable. More objective evaluation of the pale
Van Buren (164) described three cases of metastatic cancer
optic disc can be obtained by detailed observation of its
affecting the occipital lobes in which histopathological evi-
configuration and neural tissue; its veins, arteries, and capil-
dence of degeneration was found in the lateral geniculate
laries; and the peripapillary retinal nerve fiber layer that sur-
nuclei and retinas in all three cases. In addition, Beatty et
rounds it.
al. (165) used paraphenylene diamine to stain degenerated
Schwartz et al. (169) suggested that pallor of the optic
optic nerve axons and axon terminals in a patient who had
disc be assessed with color fundus photographs from which
unilateral removal of the striate cortex 40 years before ne-
enlarged, high-contrast black and white prints are made. The
cropsy and showed histologic evidence of retrograde trans-
measure of color contrast for estimating the degree of optic
synaptic degeneration of retinal ganglion cells in both eyes.
disc pallor was studied by other investigators (170–174).
Sorensen (175) estimated the degree of optic atrophy by
PATHOGENESIS OF ACQUIRED OPTIC color contrast and quantitated the degree of atrophy by mi-
DISC PALLOR crodensitometry in the blue (470 nm) and in the red (640
nm) regions. This technique has proven to be of limited value
Loss of function within the CNS is consistently associated
to most clinicians. Red-free nerve fiber layer photography
with a reduction of blood supply to the affected tissue, re-
is both useful as well as practical. Newer technologies such
gardless of the primary pathogenetic process. When the optic
as Optical Cohenence Tomography (OCT) or Gdx, which
nerve degenerates, its blood supply is reduced, and smaller
measure the polarization of light produced by nerve fiber
vessels that have been recognizable in the normal nerve are
layer microtubuoles, have also proven useful.
no longer visible. Optic atrophy reflects this reduction of
blood supply and also the formation of reactive glial tissue. Appearance of the Atrophic Optic Disc with Special
Quigley and Anderson (166) performed histopathologic Reference to Vasculature
studies on monkey eyes with descending optic atrophy and
suggested that the factors important for the normal pink ap- Pallor of the optic disc may be diffuse or confined to one
pearance of the optic disc were its thickness and the cytoar- sector (Fig. 4.14). Kestenbaum (176) introduced a ‘‘capillary
chitecture of fiber bundles passing between glial columns number test’’ in which the small vessels at the margins of
Figure 4.14. Pallor of the optic disc. A, Mild temporal pallor in a patient with multiple sclerosis but who denied acute optic
neuritis. B, Temporal pallor in a patient with toxic amblyopia. C, Pallor with glaucomatous cupping. Note preservation of small
nasal neuroretinal rim. D, Diffuse pallor in a patient with retrograde (descending) optic atrophy from the effects of an intracranial
mass. (From Hoyt WF, Beeston D. The Ocular Fundus in Neurologic Disease. St Louis, CV Mosby, 1966.)
an optic disc are observed and counted using an ophthalmo- the changes that develop during the progression to atrophy
scope. There are usually about 10 such vessels, but Kesten- do not result in a significant change in the central cup of the
baum (176) found that the number of visible vessels was optic disc. In some cases, however, pathologic optic disc
decreased in patients with diffuse optic atrophy. Kant (177) cupping develops in patients with normal intraocular pres-
performed the capillary number test on the optic discs of sures and optic atrophy from various causes, including is-
125 eyes. Forty-nine of the optic discs were said to have chemia, compression, inflammation, hereditary disorders,
had normal optic discs by other criteria, whereas the remain- and trauma (87,91,178–183). There has been significant
ing 76 eyes had atrophic discs. The Kestenbaum count can controversy as to whether the cupping in such cases is equiv-
also be used to measure hyperemia of the optic disc when alent to that seen with glaucoma. Both Quigley and Ander-
the number of visible vessels exceeds 12. son (182) and Radius and Maumenee (183) concluded that
the cupping seen in nonglaucomatous optic neuropathies,
Appearance of the Atrophic Optic Disc with Respect such as the arteritic variety of anterior ischemic optic neurop-
to Cupping athy, was quite distinct from that seen in glaucoma. Trobe
In the early stages of atrophy, the optic disc loses its red- et al. (87) asked three ophthalmologists experienced in as-
dish hue, and the substance of the disc slowly disappears, sessing optic discs to evaluate stereo fundus photographs of
leaving a pale, shallow concave meniscus, the exposed lam- 29 eyes with nonglaucomatous optic atrophy associated with
ina cribrosa (Fig. 4.15). In the end stages of the atrophic cupping. Thirteen of the discs (44%) were misdiagnosed as
process, retinal vessels of normal caliber still emerge cen- showing glaucomatous cupping by at least one observer.
trally through the otherwise avascular disc. In many cases, Trobe et al. (87) also analyzed various morphologic features
Figure 4.15. Development of pallor of the optic disc in a patient with retrograde (descending) optic atrophy. A, The optic
disc is normal in the early stage of the process. B, With time, the optic disc loses its reddish hue, and the substance of the
disc slowly disappears, leaving a pale, shallow concave meniscus, the exposed lamina cribrosa. As these changes occur, the
peripapillary retinal nerve fiber layer begins to show defects that appear as dark linear striations (arrowheads). C, With more
time, the disc becomes more diffusely pale, and the peripapillary nerve fiber layer becomes less visible. D, In the end stage
of the atrophic process, retinal vessels of normal caliber still emerge centrally through the otherwise avascular-appearing disc,
and the peripapillary retinal nerve fiber layer is no longer visible. (From Miller NR, Fine SL. The Ocular Fundus in Neuro-
Ophthalmologic Diagnosis: Sights and Sounds in Ophthalmology. Vol 3. St Louis, CV Mosby, 1977.)
of the optic disc in patients with both glaucomatous and and any remaining rim tissue has a normal color (Fig. 4.16).
nonglaucomatous cupping and concluded that pallor of the In nonglaucomatous optic neuropathies, significant loss of
neuroretinal rim was 94% specific for nonglaucomatous at- visual acuity, color vision, and field often occurs in combina-
rophy and cupping, whereas focal or diffuse obliteration of tion with little or only mild cupping. In addition, the optic
the neuroretinal rim with preservation of color of any re- discs in such cases rarely have any areas in which the neuro-
maining rim tissue was 87% specific for glaucoma. Thinning retinal rim is completely absent, and the remaining rim is
of the neuroretinal rim was more common in glaucomatous often pale (87). The appearance of the neuroretinal rim is a
cupping than in nonglaucomatous cupping, but not signifi- crucial factor in determining whether cupping is caused by
cantly. glaucomatous or nonglaucomatous optic nerve damage.
There is occasional confusion between glaucomatous and
nonglaucomatous optic neuropathy that occurs in patients Evaluation of the Peripapillary Retinal Nerve Fiber
with pathologic cupping and pallor of the optic disc (88–90). Layer in the Diagnosis of Optic Atrophy
However careful clinical examination invariably results in Focal destruction of nerve fiber bundles occur in diseases
the correct diagnosis. Glaucomatous visual field defects that affect the inner retinal layers, optic disc, retrobulbar
occur only after extensive cupping is present, and visual optic nerve, or a combination of these structures. Hoyt et al.
acuity loss usually occurs even later. In such cases, there is (184) first called attention to the ophthalmoscopic appear-
usually absence of at least a portion of the neuroretinal rim, ance of such defects. These authors emphasized that the nor-
Figure 4.16. Optic disc cupping in glaucomatous and nonglaucomatous optic atrophy. A, Glaucomatous cupping. Note pallor
and thinning of the neuroretinal rim. B, Nonglaucomatous cupping. This patient had sudden loss of the inferior visual field
associated with optic disc swelling. When the swelling subsided, the superior-temporal portion of the disc was pale and deeply
cupped. Note thinning and pallor of the neuroretinal rim.
mal appearance of the peripapillary retinal nerve fiber layer Diffuse thinning of the nerve fiber layer around the optic
consists of fine curvilinear striations that overlie the retinal disc is difficult to recognize in the early stages. In more
vessels, causing them to be seen slightly out of focus (Fig. advanced stages, signs of atrophy include decreased opacity
4.17). of the arcuate fiber bundles, enhanced linear highlights on
Early focal loss of axons is represented by the develop- large and small retinal blood vessels, reduced caliber of
ment of dark slits or wedges in the peripapillary retinal nerve blood vessels, and pallor of the optic disc with fewer detecta-
fiber layer (184,185). These slits or bands appear darker or ble disc capillaries (Fig. 4.18F). Diffuse thinning of the
redder than the adjacent normal tissue in which the normal nerve fiber layer may accompany focal atrophy (slit defects).
linear or curvilinear nerve fiber layer striations can easily To view such abnormalities the illumination of the oph-
be seen (186) (Figs. 4.18A and B). The slit defects are most thalmoscope must be sufficiently bright. In addition, Hoyt
easily identified in the superior and inferior arcuate regions (187,188) and others (100,189–205) have stressed the ad-
where the nerve fiber layer is particularly thick. With in- vantage in visualization of the nerve fiber layer provided by
creasing distance from the disc, the defects gradually lose red-free light. Lundstrom and Frisén (117) and Lundstrom
contrast and cannot be identified. When only a few nerve
(206) assessed atrophy of the nerve fiber layer in the manner
fiber bundle defects are present, they can be identified only
described above and found a fairly high degree of correlation
by the appearance of a dark, linear, arching region among the
lighter, linear nerve fiber reflexes; however, when multiple among observers. In addition, Quigley and Addicks (207)
nerve fiber bundle defects are present they impart a ‘‘raked’’ demonstrated that clinical detection of nerve fiber layer atro-
appearance to the nerve fiber layer. phy is possible in nonhuman primates, but only after loss of
Multiple nerve fiber bundle defects may coalesce to pro- 50% of the neural tissue in a given area. The detectability
duce a large wedge pattern (Fig. 4.18C–E). This pattern of nerve fiber layer atrophy is directly affected both by the
may also occur when a large region of nerve fiber layer is pattern of nerve fiber loss as well as by the zone of the retina
simultaneously damaged (e.g., after ischemic optic neuropa- in which the loss has occurred. Computer densitometry has
thy). Within the wedge, the entire retina takes on a flat granu- been used Lundstrom and Eklundh (208) to evaluate progres-
lar appearance with no striations (Figs. 4.18E and F). In sive nerve fiber layer atrophy, as have other methods of
addition, vessels in this area, being denuded of their sur- assessing the thickness of the retinal nerve fiber layer
rounding nerve fiber covering, appear darker than normal (197,205,209–215). None of these methods of analysis has
and stand out sharply in relief. yet been shown as practical for the clinician (216).
Figure 4.17. Appearance of the normal peripapillary retinal nerve fiber

layer. A, Normal nerve fiber layer in the right ocular fundus of a patient
with no visual complaints and a normal ocular examination. Note fine, linear,
and curvilinear striations emanating from all parts of the optic disc and
representing light reflexes from bundles of nerve fibers. B, Normal nerve
fiber layer in the inferior arcuate region of the right eye from another patient.
Again, note fine curvilinear striations. Both photographs were obtained using
a monochromatic red-free (540 nm) filter. C, Artist’s drawing of normal
peripapillary retinal nerve fiber layer (Schematic illustrations from Miller
NR, Fine SL. The Ocular Fundus in Neuro-Ophthalmologic Diagnosis:
Sights and Sounds in Ophthalmology. Vol 3. St Louis, CV Mosby, 1977.)
Figure 4.18. Appearance of atrophy of the peripapillary retinal nerve fiber layer. A, Monochromatic red-free photograph
shows mild nerve fiber bundle defects in the inferior arcuate fiber bundle. They are seen as thin dark streaks interrupting the
normal linear light reflexes. B, Artist’s drawing of the thin defects in the peripapillary retinal nerve fiber layer that occur in
patients with mild optic neuropathies. (Figure continues.)
Figure 4.18. Continued. C, Monochromatic red-free photograph shows two large defects in the peripapillary retinal nerve
fiber layer in the inferior arcuate region of the left eye in a patient with radiation-induced optic neuropathy. Compared with
A, the defects in this photograph are darker, wider, and more distinct from the surrounding nerve fiber layer. D, Artist’s drawing
of moderate defects in the peripapillary retinal nerve fiber layer. Note that the darker appearance results both from widening
and deepening of the defects. E, Monochromatic red-free photograph shows a single broad defect in the peripapillary retinal
nerve fiber layer in the inferior arcuate region of the right eye in a patient with early glaucoma and inferior extension of the
optic cup. The defect is dark and quite distinct from the otherwise normal peripapillary nerve fiber layer. Note the granular
appearance of the fundus within the defect caused by loss of the axons. The vessels crossing the defect are seen more clearly
than are other vessels for the same reason. F, Complete loss of the peripapillary retinal nerve fiber layer in a patient with
severe glaucoma. No linear striations can be seen; the peripapillary region has a distinct granular appearance; and the retinal
vessels are seen clearly because of absence of overlying nerve fibers. G, Artist’s drawing of complete loss of the nerve fiber
layer in a large sector. Note draping of the inner limiting membrane over the retinal vessels.
Retinal Vascular Changes Associated with

Optic Atrophy
In most cases of optic atrophy, the retinal arteries are
narrowed or attenuated (217,218). In some instances, the
narrowing is minor in nature; however, in others, such as in
severe nonarteritic anterior ischemic optic neuropathy, the
vessels may be focally narrowed or completely obliterated
(217). Not all cases of optic atrophy are associated with
retinal vascular changes, however. Henkind et al. (219)
found normal-sized vessels in a trypsin digest of the retina
of an eye that had been blind for 4 months following arteritic
anterior ischemic optic neuropathy (AION). This finding is
consistent with the finding of Rader et al. (217) that eyes
with arteritic AION are least likely to have significant nar-
rowing of retinal arteries, compared with eyes with most
other types of optic neuropathies. Kurz et al. (220) reported
the case of a 33-year-old man with a gunshot injury to the
head, resulting in no light perception, absence of pupillary
reactions to direct light, and diffuse, severe optic atrophy.
Remarkably, on postmortem examination, the retinal vascu- Figure 4.19. Temporal pallor in optic atrophy. The patient had previously
lar pattern in both eyes was completely normal. experienced an attack of acute retrobulbar optic neuritis in the right eye.
Landers et al. (221) studied five patients with unilateral She initially had visual acuity of 20/200 in the eye, but the vision improved
optic atrophy. Two of these patients had experienced orbital over several months to 20/25. The fundus photograph shows temporal pallor
trauma; one had an orbital granuloma and two had intracra- of the right optic disc.
nial lesions in the region of the optic chiasm. None of these
patients had any changes in the retinal vasculature of the
affected eye when compared with the vasculature of the un- mental optic atrophy (Fig. 4.19). The white area, which gen-
affected eye by clinical observation, color fundus photogra- erally extends from the temporal edge of the disc to the
phy, and fluorescein angiography. Henkind et al. (222), per- central vessels, may appear totally devoid of capillaries.
formed unilateral optic nerve transection without damage to Margins of this white area tend to blend gradually with the
the intraocular circulation in 13 cats. These investigators reddish-yellow color of the surrounding disc tissue. How-
performed fluorescein angiography, trypsin digestion, and ever, sharply demarcated wedge-shaped temporal pallor is a
histologic preparation of the retinas of all animals and found consequence of specific lesions to the papillomacular bundle
no changes in the retinal circulation or angioarchitecture. that usually occur in the retina between the macula and the
Apparently, if optic atrophy is from damage to the retrolami- disc. Temporal pallor is usually caused by optic neuropathies
nar optic nerve, the retinal vessels are often unaffected. Eyes that selectively affect central vision and field, sparing the
with retinal vascular changes associated with optic atrophy peripheral field. Such optic neuropathies include toxic and
presumably have suffered an additional insult in addition to nutritional optic neuropathies, hereditary optic neuropathies,
loss of the retinal ganglion cells. and optic neuritis. When superior or inferior disc pallor is
present, an ischemic etiology is more likely.
DIFFERENTIAL DIAGNOSIS OF OPTIC ATROPHY The specific organization of the retinal nerve fiber layer
results in specific patterns of nerve fiber layer and optic
When optic atrophy is complete, it is often impossible to atrophy in patients with visual loss from optic chiasmal and
determine its etiology solely from its appearance. Trobe et retrochiasmal-pregeniculate lesions. In patients with chias-
al. (223) viewed 163 color fundus stereophotographs of nine mal lesions, for example, temporal field defects are mirrored
disease entities: glaucoma, central retinal artery occlusion, by loss of fibers from ganglion cells nasal to the fovea. The
ischemic optic neuropathy, anterior and retrobulbar optic atrophy is most impressive directly nasal and temporal to
neuritis, compressive optic neuropathy, traumatic optic neu- the disc, since the superior and inferior arcuate nerve fiber
ropathy, Leber’s hereditary optic neuropathy, and autosomal bundles are composed of fibers from ganglion cells both
dominant optic neuropathy. The atrophy caused by glau- temporal and nasal to the fovea. Thus, the arcuate bundles
coma, central retinal artery occlusion, and ischemic optic are relatively spared compared with other areas. The optic
neuropathy was diagnosed by at least one of five observers pallor is thus primarily nasal and temporal with sparing supe-
with an accuracy above 80%; however, the other conditions riorly and inferiorly. This ‘‘band’’ or ‘‘bow tie’’ atrophy
were correctly identified with less than 50% accuracy. Reti- is characteristic of temporal field loss (Fig. 4.20). Patients
nal arteriolar attenuation and sheathing were most helpful in with optic chiasmal syndromes and bitemporal hemianopic
differentiating central retinal artery occlusion and ischemic field defects develop ‘‘band’’ optic atrophy (187,188,191,
optic neuropathy from other entities. 224–226) (see Chapter 12).
Temporal pallor is the most common expression of seg- In patients with congenital or neonatally acquired homon-
Figure 4.20. ‘‘Band’’ or ‘‘bowtie’’ atrophy of the

right optic disc in a patient with a temporal hemianopia
caused by a pituitary adenoma. Note horizontal band
of atrophy across the right disc, with preservation of
the superior and inferior portions of the disc.
ymous hemianopia, or in patients with pregeniculate homon- more, judgment of optic disc atrophy must be made in the
ymous hemianopias, the eye contralateral to the lesion shows context of optic nerve function. Careful testing of visual
the pattern of nerve fiber and optic nerve atrophy described acuity, contrast sensitivity, and color vision, as well as quan-
above with temporal field loss. The eye ipsilateral to the titative perimetry, examination of the pupils, and electro-
lesion has a complete nasal field loss with loss of ganglion physiologic studies must be taken into consideration. In the
cells temporal to the fovea. Because the nerve fibers from absence of visual impairment, an optic disc that appears to
these ganglion cells primarily comprise the superior and in- be pale is most likely reflecting physiologic rather than
ferior arcuate bundles, these regions show extensive loss of pathologic changes. Conversely, an optic disc occasionally
appears normal despite severe and even long-standing visual
nerve fibers; nonetheless the disc atrophy is generalized. The
acuity or field loss caused by optic nerve dysfunction. In
characteristic features of the fundi of such individuals are most of these cases, careful evaluation of the optic disc as
thus a ‘‘bow tie’’ or ‘‘band’’ atrophy in the contralateral eye well as the peripapillary retinal nerve fiber layer will provide
and a relative absence of the superior and inferior arcuate evidence of retinal nerve fiber atrophy, either too focal or
nerve fiber bundles in the ipsilateral eye (187,188,191,225, too mild and diffuse to produce obvious optic pallor. Never-
227,228). theless, there are rare patients with clinical and electrophysi-
In conclusion, the extent of pathologic pallor of the optic ologic evidence of chronic optic nerve dysfunction who ex-
disc cannot be directly equated with visual function. Further- hibit a normal-appearing optic disc and nerve fiber layer.
TOPICAL DIAGNOSIS OF OPTIC NERVE LESIONS

The diagnosis of an optic neuropathy depends upon the may result from compression, ischemia, inflammation, meta-
constellation of signs and symptoms including history of bolic, or toxic disturbances. In some cases, infiltration of the
visual loss (rapid vs. slow onset, progressive vs. stable), the proximal portion of the disc by inflammatory or malignant
presence or absence of other neurologic or ocular signs (rela- processes causes an appearance that is indistinguishable
tive afferent pupillary defect, acquired color deficit, visual from true swelling. In other cases, congenital anomalies of
field loss, ocular motor paresis, proptosis, optociliary shunt the optic disc produce an appearance that mimics swelling
veins, optic disc swelling, optic pallor), and, occasionally, of the optic disc.
the results of electrophysiologic testing (187,188,229–233).
Indeed, the optic disc has only two main ways to respond True Optic Disc Swelling
to the many pathologic processes that may affect the optic
nerve. It can swell, or it can remain normal in appearance. Papilledema
If the pathologic process causes irreversible damage to the Patients with increased intracranial pressure may develop
optic nerve, the disc will eventually become pale (see above). optic disc swelling. This condition is called papilledema.
The symptoms and signs in patients with papilledema gener-
OPTIC DISC SWELLING
ally are those typically associated with raised intracranial
Swelling of the optic disc occurs when there is obstruction pressure, including headache, nausea, vomiting, and pulsa-
of axonal transport at the level of the lamina cribrosa. This tile tinnitus. Visual symptoms in such patients include tran-
sient obscurations of vision and diplopia. Loss of central the appearance of the optic disc, patients with a typical
vision, dyschromatopsia, a relative afferent pupillary defect, ‘‘choked disc’’ suggestive of papilledema may, in fact, have
and visual field defects other than enlargement of the blind inflammatory or ischemic disc swelling (Fig 4.22).
spot caused by the swollen disc are uncommon in patients There are ten cardinal signs of papilledema. The five me-
with acute papilledema unless the lesion causing the in- chanical signs are (a) anterior extension of the optic nerve
creased intracranial pressure also directly damages the visual head; (b) blurring of the disc margins; (c) loss of the physio-
sensory system in some way or there are hemorrhages or logic cup; (d) edema of the nerve fiber layer; and (e) retinal
exudates in the macula. or choroidal folds. The five vascular signs are (a) hyperemia
The optic disc swelling in papilledema is usually bilateral of the optic disc; (b) venous dilation and tortuousity; (c)
and symmetric, but it may be asymmetric or even unilateral. peripapillary flame-shaped hemorrhages; (d) peripapillary
It may be very mild or extremely severe (Fig. 4.21) Although exudates; and (e) nerve fiber layer infarcts. Papilledema is
some physicians believe they can diagnose papilledema from further discussed in Chapter 5.
Figure 4.21. Variability in severity of papilledema. A and B, Mild papilledema in a 14-year-old boy with hydrocephalus
caused by congenital aqueductal stenosis. The right disc (A) is somewhat more hyperemic and swollen than the left (B). C and
D, Severe papilledema in a 32-year-old woman with pseudotumor cerebri. Note numerous hemorrhages and nerve fiber layer
infarcts surrounding the markedly swollen right (C) and left (D) optic discs as well as other cardinal signs. Also note hard
exudates (lipid) in both maculae.
A B
Figure 4.22. The appearance of a ‘‘choked disc’’ caused by papilledema compared with a ‘‘choked disc’’ in a patient with
anterior optic neuritis. A, Right optic disc in a young woman with papilledema. There is moderate swelling of the disc, which
is surrounded by several intraretinal hemorrhages and soft exudates. B, Left optic disc in a patient with anterior optic neuritis.
The disc is moderately swollen, and there are mild circumferential retinal folds temporal to the disc. Note that both optic discs
appear similar in appearance. It is impossible to determine the cause of optic disc swelling in most cases withhout clinical
correlation.
Ischemic Optic Neuropathy Optic Neuritis

Ischemia that affects the prelaminar portion of the optic Inflammation of the proximal portion of the optic nerve
nerve will produce swelling of the optic disc. This condition, will produce swelling of the optic disc. This condition, called
called anterior ischemic optic neuropathy (AION), is char- anterior optic neuritis or papillitis, is characterized by the
acterized by the sudden, monocular, and usually painless sudden occurrence of visual loss, usually in one eye and
occurrence of visual loss associated with a relative afferent usually associated with pain around or behind the eye. The
pupillary defect and the development of a visual field defect pain is often exacerbated by eye movement. The appearance
that is most often altitudinal or arcuate in nature. The loss of the optic disc ranges from very mild to severe swelling
(Fig. 4.25). Vitreous cells may be present, particularly over-
of vision usually occurs over several hours to several days.
lying the swollen disc, but peripapillary hemorrhages are
It then stabilizes and remains stable in most cases; however,
rarely seen.
about 40% of patients with the nonarteritic form of the condi-
In most cases of anterior optic neuritis, vision continues
tion who have worse than 20/60 vision will improve sponta-
to decline for several hours to several days. It then stabilizes
neously within 6 months. AION occurs most often in patients
and, after several days to several weeks, begins to improve.
over 50 years of age, many of whom have underlying sys- Anterior optic neuritis typically occurs in young adults
temic vasculopathies, such as systemic hypertension, diabe- and is most often caused by demyelination, although it may
tes mellitus, and giant cell arteritis. The optic disc swelling also develop in patients with a variety of systemic disorders,
that occurs in AION may be hyperemic or pallid and is usu- such as Lyme disease, sarcoidosis, and syphilis. In demyelin-
ally accompanied by one or more flame-shaped hemorrhages ating optic neuritis, vitreous cells are almost always absent,
near the margins of the swollen disc (Fig. 4.23). When the whereas they are more likely to be present and significant
swelling is pallid, visual loss is usually very severe and inca- in patients with underlying systemic inflammatory or infec-
pable of improving. Patients with nonarteritic AION invari- tious disease. Patients who develop optic neuritis that is
ably have a congenitally small optic disc with an absent or unassociated with a systemic inflammatory or infectious dis-
small central cup (Fig. 4.24), and this congenital abnormality order have an increased risk of having white matter lesions
is thought to be a major risk factor for the development of on MR imaging and of developing clinical evidence of multi-
the disorder. Patients with arteritic AION, on the other hand, ple sclerosis (MS).
may have congenitally small or normally developed optic Neuroretinitis, is characterized ophthalmoscopically by
discs. Thus, if a patient with AION has a normal optic disc optic disc swelling associated with a macular star figure
in the opposite eye, one should be suspicious the AION composed of lipid exudates in Henle’s nerve fiber layer
is arteritic in origin. Further discussion of ischemic optic (234,235) (Fig. 4.26). This form of optic neuritis is almost
neuropathy is in Chapter 7. never caused by demyelination and occurs most often in the
Figure 4.23. Optic disc swelling in anterior ischemic optic neuropathy. A, Hyperemic swelling. B, Pallid swelling. Eyes with
pallid disc swelling usually have worse visual function than eyes with hyperemic disc swelling.
setting of cat scratch disease or in association with other mally in the orbit, such as the extraocular muscles in dysthy-
systemic infectious diseases, such as Lyme disease, sarcoid- roid ophthalmopathy, causes optic nerve compression. Pa-
osis, syphilis, toxoplasmosis, and tuberculosis. Optic neuritis tients in whom such compression occurs initially may have
is further discussed in Chapter 6. no visual complaints and may have few signs of optic nerve
dysfunction. Alternatively, they may complain of insidious
Compressive Optic Neuropathy and slowly progressive visual loss. In such cases, there is
invariably some degree of dyschromatopsia, a relative affer-
Compression of the proximal portion of the optic nerve ent pupillary defect, and a defect in the visual field of the
may produce optic disc swelling. The compression may be affected eye. The optic disc is generally only mildly to mod-
caused by a tumor, such as a glioma, meningioma, or erately swollen and hyperemic (Fig. 4.27). Peripapillary
schwannoma. In other cases, enlargement of structures nor- hemorrhages are usually absent, but chorioretinal striae are
Figure 4.24. The ‘‘disc at risk’’ in nonarteritic anterior ischemic optic neuropathy (NAION). A, Small left optic disc with
no cup in a patient who had experienced an attack of NAION in the right eye several months earlier. B, NAION characterized
by hyperemic disc swelling and peripapillary hemorrhages in the same eye several months later.
Figure 4.25. Variability in appearance of the optic disc in patients with

anterior optic neuritis. A, Mild swelling of right optic disc in a 13-year-old
girl with acute loss of vision in the right eye, a central visual field defect, and
an ipsilateral relative afferent pupillary defect. B, Moderate swelling of the
left optic disc in a 20-year-old woman with a similar history. C, Severe swelling
with exudates and sheathing in a 25-year-old man with syphilis.
Figure 4.26. Neuroretinitis. The patient was a

young woman who developed acute visual loss in
the right eye while visiting Connecticut. The right
optic disc is swollen, and there is a star figure
composed of lipid (hard exudate) in the macula.
An evaluation revealed serologic evidence of
Lyme disease. Neuroretinitis is not associated
with the subsequent development of MS, but is
most often caused by an underlying systemic in-
fection, such as cat-scratch disease, Lyme disease,
syphilis, or sarcoidosis.
Figure 4.27. Optic disc swelling from compression of

the anterior portion of the orbital optic nerve. A, Right
optic disc of a 25-year-old man who noted mildly de-
creased vision in the right eye. Visual acuity was 20/
25 and there was an ipsilateral relative afferent pupillary
defect. The optic disc is moderately swollen. B, Noncon-
trast CT scan, coronal view, shows that the mass com-
presses the nasal and superior portions of the optic nerve,
displacing it downward. C, Noncontrast CT scan, axial
view, shows a well-circumscribed orbital mass compress-
ing the optic nerve. Note distortion and irregularity of the
nerve. The patient’s vision returned to normal, and the
optic disc swelling resolved after the mass was removed.
present in some cases, particularly when the compressive reversing the metabolic abnormality is associated with some
lesion is adjacent to the globe (Fig. 4.28). The diagnosis of degree of recovery of visual function. Chapter 10 further
anterior compressive optic neuropathy is usually made by details toxic optic neuropathies.
ultrasonography or neuroimaging of the orbit. More discus-
sion of compressive optic neuropathies is in Chapter 8. Hypotony
Toxic and Metabolic Optic Neuropathies Intraocular hypotony may induce optic disc swelling. It
is well known that following a penetrating wound of the eye
Toxic and metabolic disorders rarely cause swelling of or following an operation in which the wound is not tightly
the optic disc. In such cases, the swelling is usually bilateral closed, there may be development of disc swelling. In addi-
and mild (Fig. 4.29). Central vision is often reduced, with tion, blunt trauma to the eye may result in damage to the
visual loss progressing slowly over several weeks to months, ciliary body and reduction of aqueous humor formation with
and color vision is almost always markedly abnormal, re- subsequent development of hypotony and disc swelling de-
gardless of the level of central vision. Bilateral symmetry spite the absence of globe rupture (236) (Fig. 4.30). In such
of visual impairment reflects the symmetry of the systemic cases, the hypotony resolves spontaneously as does the disc
metabolic process. Bilateral central or cecocentral scotomas swelling. Although visual acuity is impaired in such cases,
are the rule, in some cases being associated with mild to the visual disturbance appears to be related primarily to in-
severe constriction of the peripheral visual field. In many creased corneal thickness from the hypotony rather than to
but not all cases, eliminating the source of the toxicity or a true optic neuropathy.
Figure 4.28. Chorioretinal striae associated with optic disc swelling in a patient with a left orbital hemangioma. A, Left optic
disc is swollen and hyperemic. Note curvilinear chorioretinal striae radiating from the temporal and superior aspects of the
disc. B, Noncontrast computed tomographic scan, axial view, shows a well-circumscribed mass compressing the posterior
aspect of the left globe.
Figure 4.29. Optic disc swelling in nutritional optic neuropathy. The patient was a 34-year-old alcoholic man who had a
poor diet and who developed progressive loss of vision in both eyes. Visual acuity was 20/200 OU, and there were bilateral
cecocentral scotomas. The concentration of folic acid in the patient’s red blood cells was low. A, The right optic disc is pale
temporally and hyperemic nasally. There is atrophy of the papillomacular bundle. B, The left optic disc is hyperemic and mildly
swollen. An assay of the patient’s blood for mitochondrial mutations of Leber’s optic neuropathy was negative. The patient’s
vision improved and the disc swelling resolved after he reduced his alcohol intake, improved his diet, and was treated with
vitamin supplements that included folic acid.
As with other forms of disc swelling, the pathophysiology

of disc swelling in patients with ocular hypotony appears
to be blockage of axonal transport at the lamina cribrosa
(237,238,239).
Infiltrative Optic Neuropathy

Infiltration of the proximal portion of the optic nerve
by tumor or inflammatory cells can produce an appearance
similar to true swelling of the optic disc (Fig. 4.31). The
disc changes may be asymptomatic or associated with vari-
able visual loss, dyschromatopsia, and a visual field defect.
The infiltration may be unilateral or bilateral, and a relative
afferent pupillary defect may be present if the infiltration is
unilateral or bilateral but asymmetric. Infiltration of the optic
nerve occurs most frequently in patients with malignant tu-
mors, such as leukemia, lymphoma, and various carcinomas
that spread to the central nervous system (CNS), but it may
also occur in patients with systemic inflammatory disorders,
including sarcoidosis, tuberculosis, and syphilis. Further dis-
cussion of infiltrative optic neuropathy is in Chapter 8.
Figure 4.30. Optic disc swelling in hypotony. The patient was a 43-year-
Anomalous Elevation of the Optic Disc
old woman who developed hypotony in the right eye after a glaucoma
filtering operation. Note moderate swelling and hyperemic of the right optic Anomalous elevation of the optic disc (pseudopapille-
disc. The appearance of this disc is similar to that which may occur in dema) may bear a striking resemblance to true optic disc
papilledema, anterior optic neuritis, and other conditions that produce optic swelling and thus represents a major pitfall in neuro-ophthal-
disc swelling. mologic diagnosis. Congenital elevation of the optic disc
may be caused by drusen that are visible with an ophthalmo-
scope, by drusen that are invisible by ophthalmoscopic ex-
amination (‘‘buried’’ drusen), by an oblique entrance of the
optic disc into the eye (the ‘‘tilted’’ optic disc), or simply by
abnormal development of tissue without any other associated
abnormalities.
Optic disc drusen are structures that may occur within
the substance of the optic nerve anterior to the lamina cri-
brosa. They probably result from abnormal axon metabolism
that leads to calcification of intracellular mitochondria
(240–243). Superficial drusen reflect whitish-yellow light,
are globular, and vary in size from minute dots to granules
2–3 times the diameter of a retinal vessel. Although they
may be scattered, they tend to form conglomerates that may
fill the entire disc. When the drusen are visible over only a
portion of the disc, they are most often concentrated nasally
and are usually most conspicuous at the periphery of the
disc. Visual field defects may occur and are often peripheral
in nature. Photographs taken with the filters normally used
for fluorescein photography, but without injection of fluores-
cein (hence blocking the blue light used for illumination)
have shown that superficial disc drusen often demonstrate
the phenomenon of autofluorescence (225,244). The auto-
fluorescence is at a longer wavelength which can get through
the barrier filter. Diagnosis can be confirmed by ultrasonog-
raphy and computed tomographic (CT) scanning. Optic disc
Figure 4.31. Optic disc swelling from infiltration of the orbital portion of drusen are further discussed in Chapter 3.
the optic nerve. The patient was an 11-year-old boy with acute lymphocytic
leukemia that was thought to be in remission when he developed mild Tilted Optic Disc
blurred vision in the right eye. Note moderate swelling of the right optic
disc, associated with dilation of small disc vessels. Malignant cells were In eyes with a congenitally tilted optic disc, the optic
detected in the patient’s cerebrospinal fluid. The disc swelling resolved and nerve enters the eye at an extremely oblique angle. This
visual acuity improved after radiation therapy. oblique entrance produces a unique ophthalmoscopic ap-
Figure 4.32. Acquired optociliary (retinochoroidal) shunt veins. A–D, Four fundus photographs showing optociliary shunt
veins in patients with optic atrophy from chronic compression of the optic nerves. Note varying size of the vessels, which are
shunting venous blood from the retinal to the choroidal circulation so that it can exit the eye via the vortex veins to the superior
and inferior ophthalmic veins rather than via the central retinal vein. E, Artist’s drawing of retinochoroidal shunt veins that
enlarge in the setting of chronic compression of the optic nerve. F, Computed tomographic scan, axial view, shows the appearance
of a left optic nerve sheath meningioma in the patient whose fundus appearance is shown in A. Note that the nerve is thickened
and brighter than the opposite optic nerve. (Schematic drawing from Miller NR, Fine SL. The Ocular Fundus in Neuro-
Ophthalmologic Diagnosis: Sights and Sounds in Ophthalmology. Vol 3. St Louis, CV Mosby, 1977.)
pearance characterized by (a) an oval disc with a depression disc swelling that is accompanied by optic atrophy, and the
on one side, usually inferiorly, and an elevation on the other, appearance of dilated venous channels called optociliary
usually superiorly; (b) a peripapillary crescent, usually infe- shunt veins. These shunt veins are new potential connections
rior; and (c) an oblique direction of retinal vessels, usually between the retinal and choroidal venous circulations.
emerging from the superior–temporal portion of the disc and Chronic compression of the optic nerve, particularly when
sweeping nasally across the disc before turning temporally. the lesion is within the orbit, causes these veins to enlarge
In extreme cases, all of these features are obvious; however, and shunt blood from the retinal to the choroidal venous
in milder cases, only one or two of the features are apparent. circulation, thus allowing the retinal venous blood to bypass
Patients with congenitally tilted optic discs usually have the obstructed central retinal vein and exit the orbit via the
normal visual acuity, although they often have myopic astig- choroidal circulation, vortex veins, and ophthalmic veins
matism, and normal color vision. Visual field testing, on (245) (Fig. 4.32). Sphenorbital meningiomas most com-
the other hand, may reveal an asymptomatic temporal field monly cause this syndrome, although it may also be caused
defect that either crosses or does not reach the vertical mid- by chronic papilledema (246–249), arachnoid cysts of the
line. Further discussion of tilted discs can be found in Chap- optic nerve (250), craniopharyngioma (251), and probably
ter 3. any cause of chronic congestion of the anterior optic nerve.
Acquired optociliary shunt veins also develop in patients
SYNDROMES OF UNILATERAL OPTIC NERVE after central retinal vein occlusion and in patients with orbital
DYSFUNCTION vascular malformations (252).
Although the appearance of the optic disc alone is usually
insufficient to permit an accurate diagnosis of the cause of Prechiasmal Optic Nerve Compression Syndrome
an optic neuropathy, the consideration of a complete history
and a meticulous examination can often provide an accurate This syndrome is characterized by slowly progressive
diagnosis of an acquired optic neuropathy. monocular dimming of vision with near-normal acuity (ini-
tially), poor color vision, a relative afferent pupillary defect,
Optociliary Shunts and the Syndrome of Chronic and a normal-appearing optic disc (253). In such patients,
Optic Nerve Compression there are generally subtle central or arcuate visual field de-
Chronic optic nerve compression may cause a specific fects that can be detected by careful tangent screen examina-
syndrome characterized by progressive loss of vision, optic tion and that are themselves slowly progressive. Neuroimag-
Figure 4.33. Two examples of the syndrome of the

distal optic nerve (anterior chiasmal syndrome). A, Ki-
netic perimetry in a patient with a decreased vision in
the right eye from a pituitary adenoma shows a dense
temporal defect with a central scotoma in that eye. In
addition, however, there is a superior temporal defect
in the visual field of the contralateral eye. B, Static
perimetry in another patient with loss of vision in the
left eye from a pituitary adenoma shows almost com-
plete loss of the central field in that eye as well as a
small superior temporal defect in the visual field of the
right eye.
ing in such patients almost always detects a compressive

lesion.
Distal Optic Nerve Syndrome (Distal Optic

Neuropathy; Anterior Optic Chiasm Syndrome)
The particular fiber anatomy at the optic nerve/chiasm
junction provides another opportunity for anatomic diagno-
sis. Traquair (28) termed this region the anterior angle of
the optic chiasm. The crossed and uncrossed fibers are sepa-
rated at this level but are quite compact, and a small lesion
affecting either the crossed or the uncrossed fibers can pro-
duce a unilateral hemianopic defect. Traquair (28) called
such a defect a ‘‘junctional scotoma.’’ In such cases, it is
not uncommon to find an asymptomatic scotoma in the upper
temporal field of the opposite eye (Fig. 4.33). This scotoma
results from damage to ventrally located fibers originating
from ganglion cells located inferior and nasal to the fovea
that, upon reaching the distal end of the optic nerve, are
thought to loop anteriorly as much as 4mm, but more proba-
bly only about 1–2 mm into the contralateral optic nerve
(Fig. 4.34). This loop, called Wilbrand’s knee is vulnerable
to damage from lesions that damage the distal aspect of an
optic nerve (254) (Fig. 4.35). Horton (255) has argued that
Wilbrand’s knee is not a true anatomic structure under nor-
mal circumstances; rather, it is an artifact that develops when
there is distortion from chronic atrophy of the ipsilateral
optic nerve. This may well be the case, but Wilbrand’s knee
exists from a clinical standpoint, and the concept of an optic
neuropathy in one eye with a superior temporal defect in the
visual field of the opposite eye remains important in the
topical diagnosis of unilateral optic neuropathy.
As mentioned, Traquair (28) used the term ‘‘junctional
scotoma’’ to refer to the temporal hemianopic scotoma pro-
duced by damage to nasal fibers of the intracranial optic
nerve at its junction with the optic chiasm. Thus, the term
was used when a strictly unilateral visual field defect was Figure 4.34. Traditional anatomy of Wilbrand’s knee. Artist’s drawing
present, and the assumption was made that the lesion was shows visual fiber projections from the upper and lower nasal quadrants
near the optic chiasm. However, it has become common of the retina of the left eye. Note that the fibers from the superior quadrant
practice to use the term ‘‘junctional scotoma’’ to refer not pass directly into the contralateral (right) optic tract (arrows), whereas fibers
to the field defect in the affected eye but rather to the superior from the inferior quadrant pass for a short distance into the distal portion
temporal field defect seen in the opposite or unaffected eye. of the contralateral optic nerve (short arrowhead) before proceeding into
In this setting, the location of the lesion is definite rather the optic tract. (Redrawn from Hoyt WF, Luis O. Visual fiber anatomize
than assumed. in the infrageniculate pathways of the primate; uncrossed and crossed retinal
quadrant fiber projections studied with Nauta silver stain. Arch Ophthalmol
Most monocular temporal field defects, whether quad-
1962;68⬊94–106.)
rantanopic or hemianopic, are caused by damage to the distal
optic nerve near the optic chiasm. However, such defects
can also be produced voluntarily by normal subjects and
phic, the increased intracranial pressure produces papille-
by malingerers with no organic disease (35,37,38,41). The
dema only in the contralateral eye (dead axons do not swell).
detection of a monocular defect in the temporal visual field
Ipsilateral optic atrophy and contralateral papilledema, often
that respects the vertical midline should establish that a le-
associated with anosmia, are the hallmarks of the so-called
sion of the distal optic nerve is present and the patient needs
Foster Kennedy syndrome (256). This is seen with frontal
neuroimaging; however, such a lesion is not always present.
lobe tumors and olfactory groove meningiomas; however,
Foster Kennedy Syndrome François and Neetens (257) have also described the syn-
drome in patients with optochiasmatic arachnoiditis and ath-
Intracranial lesions that exert direct pressure on one optic erosclerosis of an internal carotid artery. Huber (7) reported
nerve often lead to unilateral optic atrophy. As these lesions that in his series, 68% of cases of Foster Kennedy syndrome
enlarge, they may eventually produce increased intracranial were caused by tumor, whereas 32% were caused by other
pressure. Because the compressed optic nerve is already atro- disorders.
Figure 4.35. Traditional anatomy of Wil-

brand’s knee. A section through the optic
nerves, optic chiasm, and optic tracts of a 43-
year-old man who died after coronary bypass
surgery, and who had loss of vision in the right
eye shortly after birth, reveals a loop or ‘‘knee’’
of stained fibers (small arrowhead) in the
otherwise unstained right optic nerve (R) at its
junction with the optic chiasm. There is also
mild pallor in the corresponding area of the
normal left optic nerve (large arrowhead).
(Section stained with Luxol fast blue.) Note al-
ternative explanation in text. (From Breen LA,
Quaglieri FC, Schochet SS Jr. J Clin Neurooph-
thalmol 1983;3:283–284.)
This syndrome of optic atrophy in one eye and papille- caused by a lesion of the retina or optic nerve. Similarly,
dema in the other eye has been shown to be falsely localizing bilateral visual field defects of this type usually represent
in some cases, with the optic atrophy on the side contralateral bilateral lesions damaging the retinas or optic nerves. In
to the tumor (258). Indeed, a true Foster Kennedy syndrome many of these cases, one eye is affected before the other. In
is rare (7). Optic atrophy on one side and optic disc swelling such cases, the pathology is typically ischemia, and most
on the other may result from asymmetric optic nerve patients have an underlying systemic vasculopathy, such as
compression from an intracranial mass in the absence of giant cell arteritis, diabetes mellitus, or systemic hyperten-
increased intracranial pressure (259). Furthermore, it is sion that has caused nonsimultaneous bilateral ischemic
much more common to see optic atrophy on one side with optic neuropathy (260). In other cases, acute hemorrhage
optic disc swelling on the opposite side in cases of bilateral with resultant anemia; acute intraoperative, postoperative,
nonsimultaneous anterior ischemic optic neuropathy or ante- or spontaneous hypotension; or a combination of these phe-
rior optic neuritis (pseudo-Foster Kennedy syndrome). In nomena may cause a simultaneous bilateral ischemic optic
such cases, the symptoms and signs are profoundly different neuropathy (261–263).
and should cause no difficulty in diagnosis. Rarely, a large prechiasmal lesion compresses both optic
nerves, producing bilateral altitudinal field defects. Schmidt
BILATERAL LESIONS OF THE OPTIC NERVES and Buhrmann (264) reviewed their experience with intra-
The visual fields of both eyes may be altered by a single cranial mass lesions in the chiasmal region that produced
lesion posterior to the optic chiasm, by a single lesion affect- such defects. In most cases, the etiology was a pituitary ade-
ing the chiasm itself, or by bilateral optic nerve lesions. In noma that compressed the inferior aspects of both optic
the majority of cases, the distinction between a single chias- nerves, producing bilateral superior altitudinal defects. In
mal or retrochiasmal lesion and lesions of both optic nerves other cases, however, compression of the optic nerves from
is not difficult. Bilateral central, cecocentral, and arcuate below elevates them against the dural shelves extending out
defects all suggest dysfunction of both optic nerves. Ring from the intracranial end of the optic canals (Fig. 4.36).
scotomas do the same when there is no visible retinal abnor- Pressure from the dura against the superior aspects of the
mality to account for them. Bitemporal visual field defects nerves subsequently produces bilateral inferior altitudinal
are usually produced by a single lesion affecting the optic defects.
chiasm, whereas homonymous visual field defects are invari- Bilateral altitudinal visual field defects may also result
ably produced by a single lesion affecting the visual sensory from bilateral symmetric damage to the postchiasmal visual
pathway posterior to the optic chiasm. Bilateral altitudinal pathways. Bilateral occipital lesions (usually traumatic or
field defects usually are caused by bilateral retinal or optic ischemic, but occasionally inflammatory) may produce bilat-
nerve lesions, although, rarely, they may be caused by bilateral inferior or, somewhat less frequently, superior hemia-
eral postgeniculate lesions as well (see Chapter 12). nopias (265–268) (see Chapter 12).
Some patients with bilateral optic neuropathies, particu-
Bilateral Superior or Inferior (Altitudinal) Hemianopia larly those who develop bilateral simultaneous or nonsimul-
A unilateral visual field defect in which all or most of the taneous anterior ischemic optic neuropathy, develop a supe-
upper or lower portion of the field is abnormal is always rior altitudinal defect in one eye and an inferior altitudinal
Figure 4.36. Upward displacement of the intracranial portions of the optic nerves from below, causing compression of the
superior aspects of the nerves against the dural folds at the intracranial ends of the optic canals. Such compression explains
how intracranial lesions that compress the optic nerves from below can nevertheless produce inferior visual field defects. A,
Inferior altitudinal defect in the visual field of the left eye of a 66-year-old man with progressive visual loss in the eye.
Arteriography demonstrated dolichoectasia of the supraclinoid portion of the left internal carotid artery. The patient underwent
an exploratory craniotomy. B, Artist’s drawing of intraoperative findings. Left optic nerve is pushed upward by the dolichoectatic
atheromatous artery. The superior aspect of the optic nerve is compressed against the dural shelf of the optic canal, causing a
horizontal band of subpial hemorrhage. C, Artist’s drawing shows relationship of left optic nerve and carotid artery before and
after unroofing of optic canal. Before unroofing (left), there is compression and upward displacement of the optic nerve against
the dural shelf, producing subpial hemorrhage. After unroofing (right), the nerve is no longer compressed. The area of hemorrhage
on the superior aspect of the nerve, corresponding to the inferior visual field defect, can be clearly seen. (Courtesy of Dr. Joel
G. Sacks.)
defect in the other, the so-called bilateral ‘‘checker board’’ aspects of the optic chiasm. Rather, they result from damage
altitudinal hemianopia. Such patients may experience, in to the temporal aspects of one or both optic nerves (28).
addition to the loss of visual acuity, color vision, and visual A unilateral nasal hemianopia has been reported by sev-
field, binocular diplopia caused by decompensation of a eral investigators (275,276). Amyot (277) and Cox et al.
preexisting vertical or horizontal phoria. The problems en- (278) described cases with unilateral nasal hemianopia from
countered by these patients result from loss of the normal suprasellar aneurysms, whereas Meadows (279) described a
partial overlap of the superior or inferior fields of the two patient with a unilateral nasal hemianopia from a pituitary
eyes. This overlap normally permits fusion of images and adenoma compressing the lateral aspect of one optic nerve.
helps to stabilize ocular alignment in patients with vertical Two other cases of unilateral nasal hemianopia were re-
or horizontal phorias. Because their remaining visual fields ported by Schlossberg (280) and Huber (7), but neither of
do not overlap, patients with a superior hemianopia in one these authors reported the complete ophthalmologic findings
eye and an inferior hemianopia in the other do not have a in their patients.
physiologic linkage between the two remaining altitudinal Binasal hemianopia is an exceedingly infrequent visual
hemifields. In such patients, a preexisting minor phoria be- field defect that can be explained only by damage to the
comes a tropia because of vertical or horizontal separation or temporal fibers of the two optic nerves. A clear-cut bilateral
overlap of the two nonoverlapping hemifields (269). These nasal hemianopia with the vertical meridians passing
patients complain of diplopia and may have difficulty read- through the points of fixation is infrequent (281). O’Connell
ing because of doubling or inability to see printed letters or and Du Boulay (282) described three patients with ‘‘binasal
words. This condition, called the ‘‘hemifield slide phenome- hemianopia,’’ each of whom had an intracranial tumor that
non’’ (270) (Fig. 4.37), was initially described in patients had grown between the intracranial optic nerves, pushing
with bitemporal hemianopic field defects (271–274), and it them laterally against the anterior cerebral or internal carotid
is in such patients that it most often occurs (see Chapter 12). arteries. However, the field defects described in these pa-
tients (282) were, in fact, arcuate in nature and did not re-
Unilateral and Bilateral Nasal Hemianopia spect the vertical midline.
As mentioned above, most organic nasal visual field de- Numerous authors have described bilateral nasal field de-
fects are actually arcuate in nature. In some cases, however, fects in patients with a variety of intracranial lesions, includ-
a true unilateral hemianopia or bilateral nasal hemianopias ing pituitary tumors (283,284), meningiomas (284), doli-
may develop, with the defects having no connection to the choectatic internal carotid arteries (284), optochiasmatic
blind spot and respecting the vertical meridian. Such field arachnoiditis (284–287), and primary empty sella syndrome
defects are rarely caused by direct damage to the lateral (288) (Fig. 4.38).
Figure 4.37. Hemifield slide phenomenon from bilateral optic neuropathy. Artist’s drawing shows that such defects can
produce a vertical or horizontal hemifield slide phenomenon from loss of overlapping portions of the visual fields. Affected
patients may complain of vertical, horizontal, or diagonal diplopia.
Figure 4.38. Bilateral complete nasal hemianopia in a 34-year-old woman with a suprasellar aneurysm that displaced both
optic nerves laterally against the supraclinoid portion of the internal carotid arteries. The field defect resolved after clipping
of the aneurysm. A, Visual field of the left eye. B, Visual field of the right eye.
Bilateral nasal field defects also occur in patients with 9. Cummings JL, Gittinger JW Jr. Central dazzle: A thalamic syndrome? Arch
Neurol 1981;38:372–374.
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by intracranial tumors. In such cases, enlargement of the 3rd blindness after a posterior fossa tumor. Neurosurgery 1986;19:263–266.
11. Young WB, Heros DO, Ehrenberg BL, et al. Metamorphopsia and palinopsia:
ventricle pushes the optic chiasm forward, causing lateral Association with periodic lateralized epileptiform discharges in a patient with
displacement of the chiasm and optic nerves against the su- malignant astrocytoma. Arch Neurol 1989;46:820–822.
praclinoid portion of the internal carotid arteries (285,287). 12. Seron X, Matagine F, Coyette F, et al. Étude d’un cas de métamorphopsie limitée
aux visages et à certains objects familiers. Rev Neurol 1995;151:691–698.
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CHAPTER 5
Papilledema
Deborah I. Friedman
TERMINOLOGY ETIOLOGY
MEASUREMENTS OF INTRACRANIAL PRESSURE General Considerations
OPHTHALMOSCOPIC APPEARANCE Conditions Associated with Papilledema
Stages of Papilledema PSEUDOTUMOR CEREBRI (IDIOPATHIC INTRACRANIAL
Other Signs of Papilledema HYPERTENSION)
Chronic Papilledema Definition
Postpapilledema Atrophy Epidemiology
Unilateral or Asymmetric Papilledema Diagnosis
DIAGNOSIS Secondary Causes
Differential Diagnosis Complications
COURSE Pathophysiology
Visual Prognosis Monitoring
Papilledema and Age Treatment
PATHOLOGY Special Circumstances
Pathogenesis REFERENCES
SYMPTOMS AND SIGNS
Nonvisual Manifestations
Visual Manifestations
TERMINOLOGY
Papilledema is one of the most alarming signs in clinical ated with increased ICP, few authors followed his lead (3).
medicine. Papilledema specifically refers to swelling of the For instance, Foster Kennedy’s classic monograph regarding
optic disc resulting from increased intracranial pressure frontal lobe tumors that cause optic atrophy in one eye from
(ICP). The term ‘‘papilledema’’ is often loosely applied to compression by the tumor and optic disc swelling in the
any type of swelling of the optic disc regardless of the etiol- other from increased ICP is entitled ‘‘Retrobulbar neuritis
ogy (1). Although the literal interpretation of ‘‘papilledema’’ as an exact diagnostic sign of certain tumors and abscesses
encompasses optic nerve head swelling from any cause, the in the frontal lobe’’ (4).
term has evolved to connote a particular, ingrained mean- The first detailed morphologic studies of optic disc
ing to ophthalmologists, neurologists, and neurosurgeons. swelling performed in 1911 provided definitive descrip-
Therefore, other forms of disc swelling caused by local or tions of the noninflammatory ‘‘passive edema’’ associated
systemic processes should be designated in general terms as with normal visual acuity that was encountered in patients
‘‘optic disc edema’’ and referenced to the presumed etiology with increased ICP (5). The term ‘‘papilledema’’ distin-
(i.e., anterior ischemic optic neuropathy, optic nerve menin- guished these cases from those with ‘‘optic neuritis,’’
gioma, etc.). the optic disc swelling associated with visual loss and
Confusion in the English terminology dates back to the presumably caused by local or systemic inflammation.
1800s, when Hughlings Jackson and others of his time called Other nomenclature has been used over time, including
all cases of optic disc swelling ‘‘optic neuritis,’’ even though ‘‘noninflammatory papilledema’’ for optic disc swelling
they were aware that not all cases of ‘‘optic neuritis’’ were from increased ICP, ocular hypotony, orbital masses, and
inflammatory (2). Although Parsons first used the term ischemia, as well as ‘‘inflammatory papilledema’’ for optic
‘‘papilledema’’ in 1908 to refer to optic disc swelling associ- disc swelling from demyelination, infection, and inflamma-
237
tion. These obsolete terms are not clinically useful. When and for others to diagnose papilledema on insufficient
reviewing the medical literature one should be aware that grounds. In this chapter, the term ‘‘papilledema’’ refers
there is a tendency for some authors to call all cases of to optic disc swelling associated with and caused by proven
optic disc swelling, regardless of the etiology, papilledema, increased ICP.
MEASUREMENTS OF INTRACRANIAL PRESSURE

Normal cerebrospinal fluid (CSF) pressure in adults, mea- Murphy in 1939 that ‘‘one determination of intracranial pres-
sured by lumbar puncture with the patient in the lateral de- sure in a case of disease of the central nervous system (CNS)
cubitus position, varies between 80 and 200 mm of water. is no more instructive than one determination of a patient’s
Contrary to popular belief, CSF pressure is not dependent temperature during the course of a fever’’ (9).
on weight or height (6) (Figure 5.1), although pressure read- In addition to situational and and temporal variations in
ings may be spuriously elevated when the patient coughs, ICP, one must be aware of other factors in the assessment
strains, or holds his or her breath during the procedure. Mea- of ICP. Lumbar CSF pressure is often lower than the true
surements between 201 and 249 mm water are not diagnostic ICP in patients with infratentorial tumors that block commu-
and those greater than 250 mm water are elevated. Normal nication between the ventricular system and the spinal sub-
values have not been well established in children but are arachnoid space (10). However, papilledema is occasionally
generally accepted to be 200 mm water or less. Additionally, found with low intrathecal pressure, regardless of the tumor
ICP in normal persons and in patients with increased ICP location (11,12).
can vary widely from one moment to the next (Fig. 5.2). Lumbar puncture (LP) is generally a safe procedure, but
Adson and Lillie (7) introduced a needle into the lateral in certain situations it carries significant risk. Except under
ventricle of a patient with a glioma of the frontal lobe and extraordinary circumstances, a neuroimaging study (com-
made continuous readings of the ICP at hourly intervals for puted tomography or magnetic resonance imaging) should
4 days and recorded variations in pressure that ranged from always be performed prior to the LP to make sure there is
130 to 980 mm of water! Fifty years later, Gucer and no mass effect in the brain. Removal of fluid from the spinal
Viernstein (8) implanted a small epidural pressure sensor in canal may allow the compressed brain to shift downward
four patients with pseudotumor cerebri (PTC) and continu- and to impact at the tentorial incisura or the foramen mag-
ously monitored the patients before and after medical and num, often with fatal results. LP occasionally induces an
surgical treatment. ICP before treatment showed irregular acquired Chiari malformation that may be reversible (13,14).
variations ranging from 50 to 500 mm of water over a 24- Post-LP headaches may occur in up to 40% of patients after
hour period. Their findings support the claim of Ford and a lumbar tap. The symptoms of having low CSF pressure
mimic those of increased ICP with visual disturbances and
diplopia from VI, III, or IV nerve paresis (15). Despite the
devastating consequences of brain herniation, the incidence
is actually quite low, even when a mass lesion is present. A
large series of diagnostic LP in 129 patients with unequivo-
cal papilledema or intracranial hypertension from a variety
Figure 5.1. Range of normal cerebrospinal fluid pressure in nonobese Figure 5.2. Intracranial pressure (ICP) recorded by epidural sensor over
and obese adults. Note that normal intracranial pressure does not exceed 24 hours. The intracranial pressure shows great variability ranging from
250 mm of water. (From Corbett JJ, Mehta MP. Cerebrospinal fluid pressure 50 to 400 mm of water. (Redrawn from Gucer G, Viernstein L. Long-term
in normal obese subjects and patients with pseudotumor cerebri. Neurology intracranial pressure recording in the management of pseudotumor cerebri.
1983;33⬊1386-1388, ) J Neurosurg 1978;49⬊256-263.)
PAPILLEDEMA 239
of causes had only one complication (16). A review by the (see Chapter 3), computed tomography (CT) scanning or
same authors of 418 additional cases of papilledema from magnetic resonance imaging (MRI) can be obtained immedi-
mass lesions and increased ICP verified by lumbar puncture ately to determine if an intracranial mass is present or the
found only five complications (1.2%) (16). ventricles are enlarged. The LP may then be performed if
In cases where the physician cannot decide if the elevation needed, and a decision can be made regarding the need for
of the optic disc is true papilledema or pseudopapilledema further diagnostic testing.
OPHTHALMOSCOPIC APPEARANCE
There are several classification systems for papilledema. STAGES OF PAPILLEDEMA
One system describes the disc appearance according to the
duration of papilledema: (a) early; (b) fully developed; Normal Optic Disc (Frisén Stage 0)
(c) chronic; and (d) atrophic (17,18). However, for medical Stereoscopic viewing of a normal optic disc often reveals
decision making, the Frisén grading system (Table 5.1) is mild nasal elevation of the nerve fiber layer, owing to the
most useful as it classifies the papilledema grade by severity increased density of nerve fibers representing the temporal
(19). visual field. With the direct ophthalmoscope the nasal disc
margin may appear indistinct compared to the temporal disc
rim. The vessels are generally seen coursing across the optic
nerve head, although, rarely, a portion of a major vessel may
Table 5.1
be obscured in the upper pole.
Papilledema Grading System (Frisén Scale)
Stage 0 – Normal Optic Disc Very Early Papilledema (Frisén Stage 1)

Blurring of nasal, superior and inferior poles in inverse proportion to
disc diameter The early phase of papilledema consists of the incipient
Radial nerve fiber layer (NFL) without NFL tortuosity disc changes that occur before the development of obvious
Rare obscuration of a major blood vessel, usually on the upper pole disc swelling. Papilledema may be difficult to detect at this
Stage 1 – Very Early Papilledema stage. Several features have been described, including hyper-
Obscuration of the nasal border of the disc emia of the optic disc, blurring of the peripapillary retinal
No elevation of the disc borders nerve fiber layer, swelling of the optic disc, blurring of the
Disruption of the normal radial NFL arrangement with grayish opacity disc margins, peripapillary flame-shaped hemorrhages, and
accentuating nerve fiber layer bundles absent spontaneous venous pulsations (20) (Fig. 5.3A). None
Normal temporal disc margin of these features are reliable indicators of very early papille-
Subtle grayish halo with temporal gap (best seen with indirect
dema.
ophthalmoscopy)
Concentric or radial retrochoroidal folds
The term ‘‘hyperemia’’ has been used to indicate a reddish
Stage 2 – Early Papilledema discoloration of the optic nerve head as well as increased
Obscuration of all borders vascularity of the optic disc. As the natural disc color is
Elevation of the nasal border quite variable, reliance on this sign is often misleading. True
Complete peripapillary halo ‘‘hyperemia,’’ or increased vascularity, develops as a result
Stage 3 – Moderate Papilledema of dilation of capillaries on the surface of the disc in early
Obscurations of all borders papilledema; however, it is unclear whether the hyperemia
Increased diameter of optic nerve head always precedes actual disc swelling (21,22). Stereoscopic
Obscuration of one or more segments of major blood vessels leaving color photography and fluorescein angiography of experi-
the disc
mentally produced papilledema in monkeys showed that hy-
Peripapillary halo–irregular outer fringe with finger-like extensions
Stage 4 – Marked Papilledema
peremia of the disc as well as capillary dilatation and devel-
Elevation of the entire nerve head opment of microaneurysms on the disc surface appear after
Obscuration of all borders disc swelling and blurring of the peripapillary retinal nerve
Peripapillary halo fiber layer (22).
Total obscuration on the disc of a segment of a major blood vessel The detection of early papilledema is enhanced by bright
Stage 5 – Severe Papilledema direct ophthalmoscopes and handheld 90- or 78-diopter
Dome-shaped protrusions representing anterior expansion of the optic lenses using slit lamp biomicroscopy. Incorporating a red-
nerve head free filter accentuates subtle changes in the peripapillary reti-
Peripapillary halo is narrow and smoothly demarcated nal nerve fiber layer that may be observed in early papille-
Total obscuration of a segment of a major blood vessel may or may not
dema. During this stage, there may be disruption of the nor-
be present
Obliteration of the optic cup
mal radial nerve fiber layer arrangement with grayish opacity
accentuating nerve fiber bundles. A subtle grayish halo may
(Frisén L. Swelling of the optic nerve head: A staging scheme. J Neurol Neurosurg be visible with the indirect ophthalmoscope (19). In eyes
Psychiatry 1982;45 :13–18.) with early papilledema, the peripapillary retina loses its su-
Figure 5.3. A, Very early papilledema (Frisén stage 1). The disc shows slight hyperemia and blurring of the peripapillary
nerve fiber layer at the superior and inferior poles of the disc. B, Early papilledema (Frisén stage 2). This disc is hyperemic
and mildly swollen. Note the inferior peripapillary nerve fiber hemorrhages. C, The disc is moderately swollen (Frisén stage
3) with obscuration of all borders, a peripapillary halo, and several small ‘‘splinter’’ hemorrhages adjacent to the disc margins
at 7 and 10 o’clock.
perficial linear and curvilinear light reflexes and appears subjects (8,29,30). Thus, 20% of patients with normal ICP
deep red and without luster (23) (Fig. 5.4A). also lack spontaneous venous pulsations. For these reasons,
The absence of spontaneous retinal venous pulsations is the absence of spontaneous venous pulsations does not al-
thought by some investigators to be an early sign of papille- ways support a diagnosis of papilledema. The observation
dema. According to several authors, pulsations cease when of spontaneous venous pulsations suggests only that the ICP
ICP exceeds about 200 mm of water (24–26). Thus, if spon- is probably below 200–250 mm of water at that moment.
taneous venous pulsations are present, ICP should be below
this figure. However, as noted above, marked fluctuations Early Papilledema (Frisén Stage 2)
in ICP can occur in patients with increased ICP (8,27,28),
and in such patients, the ICP may occasionally drop into the Early papilledema is characterized by obscuration of the
normal range. A patient could therefore have increased ICP optic disc borders, elevation of the nasal border and a com-
but be examined at a time when ICP was transiently reduced plete peripapillary halo (Figs. 5.3B and 5.5). Using stereo-
at the trough of a pressure wave, at which time spontaneous scopic color photography and fluorescein angiography,
venous pulsations might be observed. In addition, sponta- Hayreh and Hayreh concluded that the first sign of raised
neous venous pulsations occur in only about 80% of normal ICP is swelling of the optic disc (21,22). In 32 animals with
PAPILLEDEMA 241
Figure 5.4. Red-free photographs showing nerve fiber layer in papilledema and in pseudopapilledema. A, Moderate papille-
dema (Frisén stage 3). The nerve fiber layer has mild distortion of light reflexes and a ‘‘muddy’’ appearance obscuring small
vessels traversing the disc margin. B, Marked papilledema (Frisén stage 4). The reflexes from the peripapillary retinal nerve
fiber layer are completely distorted and blurred. Note the dilated disc capillaries. C, Pseudopapilledema. Although the disc is
moderately elevated, the surface vessels appear normal and the nerve fiber layer reflexes are sharply defined. Superficial drusen
are visible between 3 and 4 o’clock.
papilledema produced by a balloon introduced into the sub- there is lingering uncertainty of the diagnosis. If clinically
arachnoid space, the swelling did not affect the entire disc prudent, serial observations may be made in order to estab-
simultaneously or to an equal degree. Instead, it appeared lish a diagnosis. In the setting of a potentially serious con-
first at the lower pole, then at the upper pole, and later at dition the diagnosis must be established by other means,
the nasal and temporal portions of the disc. The investigators including ultrasonography, fluorescein angiography, CT
could visualize this early swelling only with stereoscopic scanning, MR imaging, or lumbar puncture (see below).
photography and not by direct ophthalmoscopy (21,22). Slit
lamp biomicroscopy is especially helpful in this circum- Moderate Papilledema (Frisén Stage 3)
stance.
‘‘Blurring of the disc margins’’ is a nebulous description As the severity of papilledema increases, the margins of
that is neither specific nor helpful. Numerous congenital the optic disc become obscured and elevated. The diameter
anomalies of the optic disc are associated with indistinct of the optic nerve head increases, often resulting in enlarge-
disc margins. Moreover, interpretation of a ‘‘blurred’’ disc ment of the physiologic blind spot. The optic cup may still
margin is often impossible using the direct ophthalmoscope. be preserved at this stage. An important finding is that the
Unless it is accompanied by other more definitive signs of edematous, opaque nerve fiber layer obscures one or more
papilledema, this sign has limited clinical utility. segments of major blood vessels leaving the disc (19). The
In summary, the diagnosis of early papilledema cannot gray peripapillary halo becomes more apparent and may
and should not be made on the basis of a single finding. have an irregular outer fringe with finger-like extensions
Often, the disc appearance is suggestive of papilledema but conforming to the nerve fiber layer (Fig. 5.3C).
Figure 5.5. Moderate papilledema. Two splinter hemorrhages can be seen in the nerve fiber layer adjacent to the disc margin
at 9 o’clock and 12 o’clock. Gray edema surrounds the disc, and the optic cup is partially obliterated by hyperemic disc tissue.
Both veins and venules are engorged. (From Hoyt WF, Beeston D. The Ocular Fundus in Neurologic Disease. St Louis, CV
Mosby, 1966.)
Marked Papilledema (Frisén Stage 4) figuration. The optic cup is obliterated and the peripapillary
Marked papilledema is characterized by elevation of the halo is narrow and smoothly demarcated. Often, there are
entire optic nerve head. The optic cup is often obliterated. no appreciable landmarks to distinguish the optic nerve head
There is obscuration of all the borders of the nerve with a from the surrounding retina. Obscuration of segments of
prominent peripapillary halo. Edema and infarction of the major blood vessels may or may not be present (Figs.
nerve fiber layer cause total obscuration on the disc of a 5.7–5.9).
segment of a major blood vessel. The retinal veins are often OTHER SIGNS OF PAPILLEDEMA
engorged and tortuous (Fig. 5.6A and B).
Other signs of papilledema may contribute to visual im-
Severe Papilledema (Frisén Stage 5) pairment but are often not helpful in determining the severity
Severe, acute or subacute, papilledema is present when of papilledema. One may observe flame-shaped, nerve fiber
the optic nerve protrudes anteriorly with a dome-shaped con- layer hemorrhages, that may increase in number as the ICP
PAPILLEDEMA 243
Figure 5.6. Progression from fully developed papilledema to postpapilledema optic atrophy. A and B, Right and left fundi
showing severe papilledema. Note the obscuration of major vessels traversing the disc margin, and the extensive peripapillary
hemorrhages and exudates, including star figure of lipid in the maculae. C and D, Two weeks later, both optic discs are less
swollen but pale. The hemorrhages and exudates are resolving but the vessels crossing the disc are still partially obscured by
the edematous nerve fiber layer. E and F, Four months later, both optic discs are diffusely pale; the retinal vessels are sheathed;
and the nerve fiber layer is absent.
Figure 5.7. Severe papilledema (Frisén stage 5). There is complete elevation of the optic disc with obliteration of the optic
cup. The major vessels are obscured as they cross the disc margin. There are white ‘‘fleck’’ exudates (small infarcts) among
the nerve fibers, retinal wrinkling, and intraretinal exudates in the macular area (on the left). Note the corkscrew-like venules
on the surface of the swollen tissue. (From Hoyt WF, Beeston D. The Ocular Fundus in Neurologic Disease. St Louis, CV
Mosby, 1966.)
PAPILLEDEMA 245
Figure 5.9. Macular star figure in fully developed papilledema. The in-
complete star in the papillomacular bundle is characteristic but occasionally
a complete star figure is seen.
papillary region may be an extremely important sign of early

papilledema. Such a hemorrhage appears as a thin, radial
streak on the disc or near its margins and is presumably
caused by rupture of a distended capillary within or sur-
rounding the disc (Fig. 5.5). Although peripapillary nerve
fiber layer hemorrhages can be detected by routine direct
Figure 5.8. Severe papilledema (Frisén stage 5) with marked dilation of ophthalmoscopy, they are often more apparent with the mag-
disc vessels and formation of microaneurysms. This nerve is the same Frisén
nification provided by slit lamp biomicroscopy using a hand-
stage as the optic disc in Figure 5.7 as hemorrhages and exudates are not
used in the Frisén classification scheme. A, Fundus photograph; B, Red-
held or contact lens.
free photograph.
When the increase in ICP is rapid, subhyaloid hemor-
rhages may be present in addition to the more common intra-
retinal hemorrhages (Fig. 5.12). These hemorrhages may
break into the vitreous in some cases (37). Among 402 pa-
increases. There may also be cotton wool spots (focal retinal tients with papilledema from various causes, 14 (4%) had
infarcts) and tortuous vessels on or surrounding the disc (Fig. severe posterior pole hemorrhages or prominent subhyaloid
5.7). In severe cases, circumferential retinal folds (Paton’s and vitreous bleeding (38). In these patients, the subhyaloid
lines) often develop; linear or curvilinear choroidal folds and vitreous hemorrhages were thought to have resulted
may be observed (31–34) (Fig. 5.10). Choroidal folds from from forward dissection of severe peripapillary hemorrhage,
increased intracranial pressure often result in acquired, pro- whereas scattered posterior pole hemorrhages were believed
gressive hyperopia (32–34). Hard exudates and hemorrhages to represent central retinal vein compromise from optic disc
may occur in the peripapillary region and in the macula, swelling (38). Rarely patients with papilledema develop
producing decreased central vision (35,36) (Figs. 5.9 and macular and peripapillary subretinal neovascularization, es-
5.11C). Because nerve fibers in the macula have a radial pecially when the papilledema is chronic (39–41) (Fig.
orientation, hemorrhages and exudates in this region can 5.11). The presence of peripheral retinal hemorrhages in ad-
assume a fan or star shape. Since vascular compromise on dition to hemorrhages in the posterior pole suggests exten-
and around the optic disc is responsible for these macular sive retinal venous congestion produced by significantly ele-
changes, the star figure in such cases is usually asymmetric, vated ICP (42). In moderate to severe papilledema, the
being more prominent on the nasal side of the fovea toward retinal veins are frequently engorged and tortuous. This fea-
the disc. ture is often helpful in distinguishing papilledema from local
Hemorrhages are frequently present with papilledema, al- causes of optic disc edema.
though they are not incorporated into the Frisén staging sys-
tem. Nerve fiber layer hemorrhages are the most common CHRONIC PAPILLEDEMA
and indicate that the edema is acute to subacute (Figs. 5.8 When papilledema persists, hemorrhages and exudates
and 5.9). A small nerve fiber layer hemorrhage in the peri- slowly resolve, and the disc develops a rounded appearance
Figure 5.10. Persistent choroidal striae associated with resolving papilledema. A, The right optic disc is mildly pale and
minimally swollen. Curvilinear striae extend toward the macula. B, Striae extend into the right macula. C, The left optic disc
is also mildly pale and minimally swollen. Striae are present in the papillomacular region. D, The striae extend into the left
macula.
PAPILLEDEMA 247
Figure 5.11. Subretinal neovascularization in chronic papilledema. A, Right eye shows a marked subretinal neovascular
membrane superotemporal to the optic disc with subretinal hemorrhage, serous subretinal fluid, and retinal striae. B, Late stage
fluorescein angiogram of right eye reveals marked staining of subretinal neovascular membrane and hyperfluorescence of the
disc. C, Left eye with elevated disc and an inferior-temporal subretinal neovascular membrane with surrounding hemorrhage,
hard exudate, and retinal striae. D, Fluorescein angiogram of the left eye shows the residual subretinal neovascular membrane
with a surrounding area of mottled disruption of the retinal pigment epithelium. (From Morse PH, Leveille AS, Antel JP,
et al. Bilateral juxtapapillary subretinal neovascularization associated with pseudotumor cerebri. Am J Ophthalmol 1981;
91⬊312–317.)
Figure 5.12. Subhyaloid hemorrhage with papilledema. The patient had

a severe, subarachnoid hemorrhage from an intracranial aneurysm.
Figure 5.14. Drusen-like bodies (arrows) in chronic atrophic papille-
dema. (From Hoyt WF, Beeston D. The Ocular Fundus in Neurologic Dis-
(20) (Fig. 5.13). The central cup, which may be retained in ease. St Louis, CV Mosby, 1966.)
the acute phase of papilledema, ultimately becomes obliter-
ated. Over a period of months, the initial disc hyperemia
changes to a milky gray appearance, with hard exudates be- occurs primarily in patients with pseudotumor cerebri (PTC)
coming apparent in the superficial disc substance. These ex- but may also be observed in patients with intracranial tu-
udates resemble optic disc drusen (Fig. 5.14) and may result mors.
in a misdiagnosis of pseudopapilledema (43,44) (Fig. 5.4C).
Most patients with chronic papilledema have evidence of POSTPAPILLEDEMA ATROPHY
nerve fiber layer atrophy (45). The appearance of the atrophy
With time, untreated papilledema subsides, the disc be-
ranges from slit-like defects to diffuse loss. Nerve fiber layer
comes atrophic, and the retinal vessels become narrow and
atrophy can be best appreciated by viewing through the red-
sheathed (20). In such cases, the nerve fiber layer can no
free filter of a direct ophthalmoscope or slit lamp biomicro-
longer be visualized by either direct ophthalmoscopy or slit
scope.
lamp biomicroscopy (45). Some patients have persistent
Occasionally, papilledema persists for a long period of
pigmentary changes or choroidal folds in the maculae
time without significant visual symptoms (46). This situation
(20,47,48) (Fig. 5.15). If the papilledema has been particu-
larly severe, these changes may resemble those caused by a
hamartoma of the pigment epithelium (49).
The time required for papilledema to evolve into optic
atrophy depends upon many factors, including the severity
and constancy of the increased intracranial pressure (ICP).
Atrophic changes can appear within weeks or days following
the initial observation of acute papilledema in some cases,
particularly if the rise in ICP is rapid, severe, and sustained.
In such cases, the disc appearance may rapidly progress to
fully developed papilledema and then to postpapilledema
optic atrophy without ever having gone through a stage of
chronic papilledema. In still other cases, many months or
even years may elapse before atrophy develops. In such
cases, the appearance of the fundus is typically that of
chronic papilledema that gradually melts away into atrophy.
Finally, there are patients who appear to have stable chronic
papilledema for many months to years until, for unclear rea-
sons, they rapidly develop optic atrophy.
In some cases, as papilledema evolves from the fully de-
veloped stage to the chronic stage and then to the atrophic
Figure 5.13. Chronic, severe papilledema. Note round compact appear- stage, optociliary shunt veins develop and then disappear
ance of the optic disc and lack of hemorrhages. (50–53). These vessels, which are pre-existing veins that
PAPILLEDEMA 249
Figure 5.15. Postpapilledema optic atrophy and pigmentary changes in

the macula in a patient who previously had severe papilledema. The gliotic
changes of the nerve fiber layer give the disc margin a ‘‘dirty’’ appearance.
Note pallor of left optic disc, narrowed sheathed retinal vessels, and exten-
sive pigmentary changes in left macula.
connect the retinal and choroidal venous circulations (53),

enlarge because the increased ICP either directly compresses
the central retinal vein or indirectly compresses it by com-
pressing the optic nerve (Fig. 5.16). In either case, the vessels
shunt venous blood from the retinal to the choroidal venous
circulations. Therefore, blood exits the eye and orbit via the
vortex veins to the superior and inferior ophthalmic veins,
bypassing the obstructed central retinal vein. At this stage,
patients usually have significant visual field defects, dimin-
ished color vision, and variably reduced visual acuity (see
below). Optociliary shunt veins may disappear after the ICP
is surgically lowered or following optic nerve sheath de-
compression surgery (54,55) (Fig. 5.17).
Optic atrophy that results from chronic papilledema has
a specific pattern of axonal loss. Loss of peripheral axons
with sparing of central axons has been demonstrated in sev-
eral postmortem studies (56,57). Good central visual acuity
despite severe papilledema and optic atrophy is found in
most patients with chronic papilledema.
Figure 5.16. Development of optociliary shunt veins in a patient with
UNILATERAL OR ASYMMETRIC PAPILLEDEMA chronic papilledema from pseudotumor cerebri. A, Marked (Frisén stage
4) papilledema. Note the small vessel located on the surface of the disc at
Papilledema is usually bilateral and relatively symmetric 8 o’clock (arrowhead). B, As disc swelling resolves, the previously noted
in the two eyes. In some instances, it is strictly unilateral or vessel becomes more apparent (arrowhead). C, Disc swelling has almost
at least much more pronounced in one eye than in the other completely resolved. The vessel at 8 o’clock appears larger than previously,
(58–60) (Figs. 5.18 and 5.19). Some patients may have had and clearly represents a retinal-choroidal shunt (arrowhead).
preexisting atrophy before the development of increased ICP
(the pseudo-Foster Kennedy syndrome; see below and in
Chapter 4). If there are not enough viable nerve fibers, papil-
ledema cannot occur (‘‘dead axons don’t swell’’). However,
Figure 5.17. Disappearance of optociliary shunt veins in a patient with postpapilledema optic atrophy after intracranial
decompression for sclerosteosis. A, Preoperative appearance of left optic disc shows shunt vessels at 10 and 12 o’clock (arrow-
heads). B, Postoperative photograph of left disc shows disappearance of shunt veins. (From Stein SA, Witkop C, Hill S, et al.
Sclerosteosis: Neurogenetic and pathophysiologic analysis of an American kinship. Neurology 1983;33⬊267–277.)
Figure 5.18. Unilateral papilledema in a 34-year-old woman with pseudotumor cerebri. A, The right optic disc shows fully
developed papilledema. B, The left optic disc is normal.
Figure 5.19. Asymmetric papilledema in a 35-year-old man with pseudotumor cerebri. A, The right optic disc is minimally
hyperemic and swollen (Frisén stage 1). B, Frisén stage 3 papilledema of the left optic disc.
PAPILLEDEMA 251
if sufficient nerve fibers remain, papilledema may develop eye with a nasal hemianopia, atrophy of temporal fibers has
even though the optic disc is pale. A particularly interesting occurred, and most of the swelling is confined to the nasal
pattern of papilledema can occur in patients with optic atro- portion of the disc (61). This specific pattern of papilledema
phy from previous damage to the optic chiasm or optic tract. also occurs in patients with congenital hemioptic hypoplasia
In such patients, an eye with a temporal hemianopia and who develop increased ICP (62).
atrophy of nasal fibers has band atrophy with preservation In the Foster Kennedy syndrome (see Chapter 4) patients
of the majority of the upper and lower (temporal) arcuate with frontal lobe or olfactory groove tumors develop the
fibers. When papilledema develops, the swelling is thus con- triad of (a) optic atrophy in one eye; (b) papilledema in
fined to the superior and inferior poles of the disc. In an the other eye; and (c) anosmia (Fig. 5.20). The optic nerve
Figure 5.20. Foster Kennedy syndrome. A, The right optic disc shows mild papilledema. Visual acuity in this eye is 20/20.
There is slight enlargement of the blind spot on visual field testing. B, The left disc is pale with vision of hand motions. C
and D, Computed tomographic scan in axial (C) and coronal (D) planes shows large right sphenoid ridge meningioma.
Figure 5.21. Unilateral papilledema with contralateral optic disc dysplasia. This 25-year-old woman had pseudotumor cerebri.
A, The right optic disc shows marked (Frisén stage 4) papilledema. B, The left optic disc is markedly dysplastic and definite
papilledema cannot be identified.
ipsilateral to the tumor is generally atrophic because of 5.22), suggesting that pressure is transmitted at least to the
compression. A rise in CSF pressure in the optic nerve sheath globe. The anatomic arrangement of the venous sinuses may
is a prerequisite condition for development of papilledema contribute to unequal or unilateral papilledema in patients
(63,64). Optic nerve compression prevents elevated in- with previously normal optic discs, particularly in the setting
trasheath pressure and produces ipsilateral atrophy of optic of venous sinus thrombosis (67,68). Lastly, a difference in
nerve fibers. Similarly, patients with unilateral optic disc the lamina cribrosa between the two optic discs producing
dysplasia may develop papilledema only on the side of the reduced transmission of the ICP to the optic nerve in the
previously normal disc (Fig. 5.21). scleral canal has been postulated (60). If congenital anoma-
When unilateral papilledema occurs in a patient with an lies of the optic nerve sheaths or venous sinuses cause ab-
apparently normal optic disc on the opposite side, it often sence of ipsilateral papilledema, they may also explain the
results from some congenital anomaly of the optic nerve absence, asymmetry or unilaterality of papilledema in at
sheath that prevents transmission of pressure to the optic least some patients with significantly elevated ICP (69).
nerve head on the side where the papilledema is absent (65). In most patients with apparent unilateral papilledema,
Neuroimaging and ultrasonography in such patients reveal careful observation of the ‘‘normal’’ optic disc often dis-
bilateral dilation of the optic nerve sheaths (59,66) (Fig. closes minimal hyperemia, a blurred nerve fiber layer, or disc
Figure 5.22. Bilaterally enlarged optic nerve sheaths in a patient with unilateral papilledema. The patient was a 32-year-old
woman with pseudotumor cerebri. A, The right optic disc is moderately swollen (Frisén stage 3) with a well-developed peripapil-
lary halo. B, The left optic disc is normal. C, Computed tomographic scan, axial view, after intravenous injection of contrast
material, shows bilateral symmetric dilation of the optic nerve sheaths. (From Strominger MB, Weiss GB, Mehler MF. Asymp-
tomatic unilateral papilledema in pseudotumor cerebri. J Clin Neuroophthalmol 1992;12⬊238–241.)
PAPILLEDEMA 253
swelling that is easily overlooked in the face of significant Papilledema that is unilateral, or at least more pronounced
papilledema on the opposite side (70) (Fig. 5.19). Careful on one side, may be of significance in many cases of intracra-
stereoscopic ophthalmoscopy and fluorescein angiography nial mass lesions, particularly abscesses, where the papille-
may be necessary to detect subtle papilledema. Nevertheless, dema is usually ipsilateral to the lesion (72).
purely unilateral papilledema has been described with PTC, In summary, unilateral optic disc swelling is unlikely to
cerebral tumors, abscesses, intracranial hemorrhage caused be true papilledema. More frequently, it is caused by local
by aneurysm, aqueductal stenosis, and traumatic brain injury pathology (e.g., inflammation, ischemia, or compression of
(58,71–74). In a series of 1,346 neurosurgical patients with the optic nerve within the orbit). When an optic disc is signif-
papilledema admitted to the State Hospital of Copenhagen icantly atrophic or anomalous, it may not develop papille-
over a 15-year period, 25 cases (1.8%) revealed unilateral dema, or papilledema will develop only in the regions of
papilledema with a normal contralateral optic disc (72); 17 functioning axons. Most patients with ‘‘unilateral’’ optic
patients had papilledema ipsilateral to the lesion; 7 patients disc swelling in the setting of increased ICP actually have
had contralateral papilledema; and 1 patient had a midline bilateral asymmetric papilledema, but truly unilateral edema
tumor. does infrequently occur.
DIAGNOSIS
The most important method of diagnosing papilledema is that may be resolved with ultrasonography. CT scanning can
careful ophthalmoscopic examination, assessing the features be used to determine if there are buried drusen causing an
described above. An examination that includes red-free oph- appearance mimicking papilledema, and both CT scanning
thalmoscopy (23) and slit lamp biomicroscopy with a hand- and MR imaging can be used to detect evidence of an intra-
held or contact lens is usually sufficient to determine whether cranial mass or hydrocephalus.
papilledema is present. If the diagnosis remains uncertain High resolution MRI of the orbits shows characteristic
several options are available. Fluorescein angiography is changes of the optic nerves and posterior globe in papille-
often used to confirm early papilledema (50,75–82). The dema. In papilledema, the subarachnoid space becomes dis-
test itself is easily performed in an outpatient setting: 5 ml tended, the nerve sheath widens and there is flattening of
of 10% fluorescein sodium are rapidly injected into a superfi- the posterior sclera (88,89) . The prelaminar optic nerve may
cial arm vein. Alternatively fluorescein can be given orally enhance and protrude anteriorly (88).
(83). The passage of dye through retinal vessels is then ob- Confocal scanning laser tomography (CSLT; Heidelberg
served and photographed at rapid intervals, with a cobalt Retinal Tomography) of normal optic nerves demonstrates
blue filter interposed in front of the light source to visualize gradually increasing retinal surface elevation from the center
the fluorescence of the dye. Even if photographic facilities of the disc to the disc margin, with a steeper contour nasally
are lacking, the examiner can observe the ocular fundus than temporally (90). The retinal surface area over the optic
using an indirect ophthalmoscope or a slit lamp with a hand- disc is diffusely displaced anteriorly in patients with active
held or contact lens with the correct filter in place. papilledema from PTC, and significantly different from con-
According to most investigators, the earliest frames of trol optic nerves in all locations. Compared to controls, pa-
the fluorescein angiogram in patients with early papilledema tients with clinically resolved papilledema show anterior dis-
show disc capillary dilation, dye leakage, and microaneu- placement of the optic nerve head in all areas except nasally.
rysm formation, whereas later frames show leakage of dye Another study comparing B-scan ultrasonography to CSLT
beyond the disc margins (Fig. 5.23). Unfortunately, the found a positive correlation (R ⳱ .62) between the two mo-
above findings do not always correctly identify true papille- dalities in papilledema from idiopathic intracranial hyperten-
dema (50,79). Some authors claim that fluorescein angiogra- sion, although there was much higher agreement (R ⳱ .84)
phy may not show any abnormalities until optic disc swelling for optic nerve cupping (85). This may be attributable to a
is of a ‘‘mild to moderate degree’’ (22). Nevertheless, one difference in reference planes used in each method. Ultra-
study reviewed the fluorescein angiograms of 100 patients sound measures the maximum elevation from the optic disc
with possible papilledema and found that in all cases of true to the lamina cribrosa; since the lamina is not recognizable
papilledema, the retinal angiograms showed a combination with papilledema, the distance is measured from the disc to
of either excess early and late disc fluorescence or excess the retinal surface. Multiple measurements may be required
disc vascularity with late fluorescence (81). to achieve optimal accuracy with CLST in edematous optic
If it is available, orbital echography is extremely useful nerves (91), but this new modality is promising for quantita-
in cases of questionable papilledema. This sensitive test reli- tive evaluation of papilledema (90). In clinical practice, the
ably determines if the diameter of the optic nerve is increased diagnosis of papilledema may elude even the most experi-
and, if so, whether or not the increase is caused by CSF enced examiners. One study assessed the ability of various
surrounding the nerve. It can also easily detect buried optic medical specialists to identify papilledema and pseudopapil-
disc drusen. Thus, by performing A- and B-scan ultrasonog- ledema using stereophotographic slides (92). Under such
raphy with a 30⬚ test when indicated, the examiner can deter- ideal circumstances, even the neuro-ophthalmologic ‘‘ex-
mine not only if an optic disc is truly swollen but if there perts’’ who pre-screened the study slides did not achieve a
is increased ICP (84,85). Coexisting optic disc drusen and perfect score! However, neuro-ophthalmologists and oph-
papilledema from PTC (86,87) create diagnostic confusion thalmologists were more accurate than family physicians,
Figure 5.23. Fluorescein angiogram of mild papilledema (A–C) and pseudopapilledema (D–F). A, Reproduction of color
photograph of the left fundus showing indistinct disc margins and an incomplete peripapillary halo (Frisén stage 2). No
hemorrhages are visible. B, In arteriovenous phase, fluorescein angiogram shows early leakage of dye into peripapillary region.
C, Ten minutes after fluorescein injection, angiogram shows residual hyperfluorescence of disc and surrounding region. D,
Optic disc shows tortuous vessels, indistinct disc margins and mild elevation. E, Fluorescein angiogram in early arteriovenous
phase shows no disc fluorescence or leakage into the peripapillary region. F, Eight minutes after fluorescein injection shows
no evidence of disc leakage or hyperfluorescence. (Courtesy of Dr. Michael Sanders.)
neurologists, and neurosurgeons in identifying papilledema such as headaches, however, the differentiation of papille-
and pseudopapilledema (92). Family physicians were as dema from other causes of optic disc elevation becomes
good as or better than neurologists and neurosurgeons in more complex.
identifying acute and chronic papilledema, but had difficulty Anomalous elevation of the optic discs is probably caused
distinguishing between papilledema and pseudopapille- most often by buried optic disc drusen; however, hypoplastic
dema. One would expect that the detection rate among all discs may be anomalously elevated, and tilted optic discs
specialists would decline under many less ideal circum- often show elevation of their superior and nasal portions. In
stances, e.g., using direct ophthalmoscopy through an undi- addition, some optic discs are anomalously elevated but do
lated pupil. not contain drusen, nor are they small or tilted. In all cases,
Finally, if the diagnosis of papilledema remains uncertain,
the ICP can be measured directly by lumbar puncture. This
procedure should only be performed after neuroimaging has Table 5.2
been performed to determine that no intracranial mass is Differential Diagnosis of Papilledema
present.
Anomalously elevated optic disc
DIFFERENTIAL DIAGNOSIS With and without buried drusen
Tilted optic disc
The differential diagnosis of papilledema (with normal Hypoplastic optic disc
visual acuity and bilaterality) includes anomalous elevation Intraocular inflammation
of one or both optic discs and true optic disc swelling caused Asymptomatic nonarteritic anterior ischemic optic neuropathy (e.g.,
by some etiologies other than increased ICP (Table 5.2). diabetic “papillopathy”)
Hypertensive disc edema
In most cases, the patients have no neurologic or systemic
Optic neuritis, optic perineuritis (perioptic neuritis)
symptoms or signs referable to increased ICP, and this lack
Infiltrative optic neuropathy (e.g., from leukemia)
of manifestations should help the physician focus on other Compressive optic neuropathy (e.g., from optic nerve sheath meningioma)
possibilities. When the patient does have other complaints,
PAPILLEDEMA 255
a careful ophthalmoscopic examination combined with ultra- Nonarteritic anterior ischemic optic neuropathy (NAION)
sonography should differentiate anomalously elevated optic can mimic papilledema, particularly when it is asymptom-
discs from true optic disc swelling. Anomalous optic discs atic. The sectoral nature of the disc swelling, and the pattern
are discussed in Chapter 3 of this text. of visual field loss in NAION generally distinguish it from
True optic disc swelling that mimics papilledema may true papilledema. Rare patients with anterior optic neuritis
be caused by inflammatory, vascular or infiltrative disease. have normal central visual acuity; however, such patients
Inflammatory conditions are generally accompanied by invariably complain of pain on eye movement and decreased
vision, and other tests of visual function in such patients
other evidence of inflammation such as aqueous or vitreous
(e.g., contrast sensitivity, color vision, visual fields) usually
cells, and sheathing of retinal vessels. Retinal vascular dis- reveal an abnormality inconsistent with papilledema (93).
turbances can also produce optic disc swelling. In this cir- Unlike papilledema and NAION, nerve fiber layer hemor-
cumstance, correct diagnosis may not be possible without rhages are very uncommon in optic neuritis (94). Finally,
performing appropriate neuroimaging and a lumbar punc- optic discs infiltrated by inflammatory or neoplastic cells
ture. Patients with optic perineuritis (perioptic neuritis) have may appear similar to papilledema. The diagnosis in such
optic disc swelling that is also indistinguishable from papil- cases can usually be made by neuroimaging, with or without
ledema unless there is associated intraocular inflammation. a lumbar puncture.
COURSE
The rapidity of developing papilledema depends to a large superior poles of the optic disc prior to the nasal and tem-
extent on the etiology and degree of the increased ICP. Ex- poral poles (21). Blurring of the disc margins by direct oph-
perimental models using inflatable balloons in the subarach- thalmoscopy is only apparent after optic disc elevation oc-
noid space of monkeys showed papilledema in 30% of the curs (21).
animals in 24 hours, in 50% after 2 days, and in 90% after Fully developed papilledema may resolve completely
5 days when papilledema was assessed using direct ophthal- within hours, days, or weeks, depending on the way in which
moscopy, stereoscopic photography, and fluorescein angiog- ICP is lowered (Fig. 5.24). In monkeys with experimental
raphy (21,22). Most of the animals developed papilledema intracranial hypertension produced by an inflatable balloon,
from the surgery even prior to the balloon being inflated papilledema disappeared within 2 weeks after the intracra-
(21) and papilledema took 1 to 3 weeks to re-develop after nial pressure was abruptly normalized (21). In humans, pap-
the postoperative edema resolved and the balloon was in- illedema can resolve 6-8 weeks after a successful craniotomy
flated (21). Clinical experience with humans suggests that to remove a brain tumor or after subtemporal decompression
the development of optic disc edema may be protracted. The for PTC (101). Optic disc edema may improve in less than
largest study investigating this process was performed in 37 a week following optic nerve sheath decompression surgery
patients with acutely elevated ICP from cerebral hemorrhage (102), but the time course to complete resolution is uncer-
or trauma receiving continuous ICP monitoring (95). Using tain. Papilledema from PTC generally takes two or more
both direct and indirect ophthalmoscopy, no papilledema months to resolve (103).
was observed in the 13 patients with mildly elevated ICP In most cases, retinal venous as well as disc capillary
(20–30 mm Hg) and only two patients had venous congestion dilations begin to regress as soon as ICP is lowered to a
by day six. In seven patients with ICP ranging from 30–70 normal level. During the next few days to weeks, presumably
mm Hg, papilledema developed in one patient with a sub- because of the change in hemodynamics at the disc, new
arachnoid hemorrhage who developed fatal cerebral edema hemorrhages may appear; however, these are of no signifi-
and carotid artery distribution infarction postoperatively. No cance and they disappear within a short time. Gradually, disc
optic disc or fundus abnormalities were seen in the other six hyperemia and elevation resolve. The last abnormalities to
patients. Within the first three days of developing transient disappear are blurring of the disc margins and abnormalities
of the peripapillary retinal nerve fiber layer. In some cases,
increased ICP (prior to successful treatment), none of 17 pa-
as noted above, papilledema resolves into optic atrophy.
tients had papilledema. This experience suggests that clini-
Optic atrophy following papilledema is sometimes referred
cally detectable papilledema is not usually present with acute
to as ‘‘secondary’’ or ‘‘dirty’’ optic atrophy. Unlike the crisp
elevations of ICP, and may take over a week to develop. optic disc margin seen in optic atrophy following other types
Cases have been reported of papilledema within 2 to 4 of optic neuropathy, there may be extensive sheathing of
hours after intracranial hemorrhage (96). Fulminant, hemor- vessels and gliosis following papilledema, suggesting that
rhagic papilledema was also seen within 5 to 8 hours in the the optic nerve axons died ‘‘after a struggle.’’ However, in
context of other conditions (metastatic frontal lobe tumor, many cases, the atrophy is indistinguishable from that caused
epidural hematoma) (97). In addition, minimal papilledema by inflammation, vascular disease, or trauma (104). In other
may exist and suddenly become fully developed in several cases, the papilledema never completely resolves despite
hours in certain settings, such as encephalitis in the setting normalization of the ICP.
of a cerebral abscess (98,99). Occasionally, a paradoxic de-
velopment or progression of papilledema several days to a VISUAL PROGNOSIS
week after normalization of increased ICP may occur (100). Establishing the visual prognosis in a patient with papille-
Papilledema usually produces swelling of the inferior and dema is often impossible. Generally, the more severe the
Figure 5.24. Resolution of papilledema in a patient with pseudotumor cerebri. A and B, Right and left optic discs prior to
treatment. C and D, One month after beginning treatment with dehydrating agents, much of the disc swelling has resolved in
both eyes, and no hemorrhages are evident. E and F, Three months after beginning treatment, both discs show complete
resolution of swelling and now appear normal.
PAPILLEDEMA 257
papilledema, the worse the visual prognosis (105). An omi- PAPILLEDEMA AND AGE
nous sign is narrowing of the retinal arteries, which often
Papilledema may be observed at any age. Not only is
occurs with sheathing. In this setting, irreversible damage
there no upper age limit, but there is abundant evidence that
to the optic nerve tissue has already occurred, as is the case
papilledema also occurs frequently in infants and children.
when there is loss of the peripapillary retinal nerve fiber This phenomenon is remarkable because we explain the ab-
layer. Disc pallor that becomes evident while papilledema sence of papilledema in most cases of congenital hydroceph-
is still present is also an indication of poor visual prognosis alus on the basis of expansibility of the skull. If this were
(105), even if ICP is lowered immediately, because the pallor true, one would expect a lower prevalence of papilledema in
is caused by loss of axons. Most patients with these infants and children with intracranial tumors. Nevertheless,
changes have clinical evidence of visual dysfunction, in- there are many reports of papilledema or post-papilledema
cluding decreased color vision, visual field defects, and optic atrophy in children and in infants under two years of
abnormal contrast sensitivity. Loss of visual acuity may age (9,106–108). Walsh reviewed the case records of the
be the last visual parameter to be affected, much as in pediatrics department of the Johns Hopkins Hospital from
patients with chronic open angle glaucoma. It is our experi- 1928 to 1944 and found 18 cases of cerebral tumor in chil-
ence that once there is visual acuity decline or significant dren 3 years of age or younger (26); 13 patients (72%) had
visual field deficits the visual prognosis is extremely ten- papilledema. The youngest patient was 3 months old and
uous. On the other hand, severe venous engorgement, had a cerebellar medulloblastoma. Thus, the distensibility
retinal hemorrhages, and hard and soft exudates have no of an infant’s skull may not prevent an increase in pressure
prognostic significance. within the optic nerve sheaths.
PATHOLOGY
The essential histological features of papilledema are secondary optic atrophy has occurred. The perineuronal
optic disc edema, neuronal swelling, venous and capillary spaces are often distended, with stretching of the delicate
dilatation, an abnormal protrusion of the optic nerve head arachnoidal strands that bridge the subarachnoid space (Fig.
toward the vitreous, lateral displacement of the adjacent ret- 5.26).
ina, and folds of the posterior retinal layers (Fig. 5.25) Electron microscopic studies indicate that most of the in-
(5,109). The physiologic optic cup is generally preserved crease in tissue elevation that occurs in papilledema results
(109). The separation of the swollen optic disc from the from intra-axonal swelling and not from extracellular edema
adjacent retina is typically sharp and has the form of an S- (114). The swelling is most marked in the superficial optic
shaped curve. nerve head, where some of the axons increase to 10 to 20
Compression, detachment, and lateral displacement of the times their normal diameter (21,115). The intra-axonal
peripapillary retina appear to be the major reasons that the swelling is accompanied by an increase in mitochondria,
blind spot increases in size in patients with papilledema disorganization of neurofilaments, and the accumulation of
(110,111); however, the blind spot may be enlarged even dense intracellular membrane-enclosed bodies. With severe
when there is no obvious retinal displacement or detachment. papilledema, cytoid bodies are especially apt to occur in
In this setting, the enlarged blind spot represents a refractive those portions of the optic disc that bulge laterally toward the
scotoma caused by acquired peripapillary hyperopia from adjacent retina. These cytoid bodies and resultant necroses
elevation of the retina by peripapillary subretinal fluid (112). appear to result from strangulation of the angulated nerve
A blind spot that is enlarged by this mechanism can be re- fibers. Although interstitial fluid is present in the region of
duced to near normal size by the use of progressively degenerating fibers (116,117), it is insufficient to account
stronger plus lenses (112). The neuronal swelling in papille- for the large increase in the mass of the optic disc that occurs
dema is more extensive peripherally, accounting for the vis- in fully developed papilledema. Electron microscopy dem-
ual field constriction. Vascular interruption at the annulus onstrates that what appear to be free intra-axonal spaces by
of Zinn produces the typical arcuate and inferonasal visual light microscopy are actually swollen axons (Fig. 5.27). The
field defects (111,113). findings noted above in humans also occur in rhesus mon-
Hemorrhages may overlie and obscure the optic disc and keys with experimentally produced papilledema (21,118).
may occur in all layers of the peripapillary retina, occasion-
ally extending into the vitreous or into the adjacent subretinal PATHOGENESIS
space. Focal necroses of nerve fibers are frequent, most often Any unifying mechanism for papilledema must account
occurring in the lateral outpouchings of the nerve substance for (a) transient unilateral or bilateral visual obscurations;
adjacent to the retina. The small vessels of the optic disc (b) edema localized to the optic nerve head; (c) flattening
often appear prominent with abnormally plump and prolifer- of the posterior sclera as demonstrated by neuroimaging
ative endothelial cells (1). The substance of the prelaminar techniques, and (d) venous distension and cessation of ve-
portion of the optic nerve is clearly swollen, but does not nous pulsations (111). Various hypotheses have been pro-
ordinarily show any increase in cellularity until secondary posed over the years, including direct infiltration of the optic
gliosis occurs. By light microscopy, the swelling takes the nerve head by CSF (119,120), obstruction of posterior flow
form of vacuoles (21). The swelling does not extend to the of intraocular fluid (121), inherent turgescence of prelaminar
postlaminar optic nerve which usually appears normal unless nerve substance (122), swelling of glia (123), absence of the
Figure 5.25. Histological appearance of papille-

dema by light microscopy. A and B, Both photo-
graphs show axonal swelling limited to the prelam-
inar portion of the optic nerve. The peripapillary
retina is pushed laterally. Note small collection of
subretinal fluid in the peripapillary region.
Figure 5.26. Gross pathologic appearance of orbital

optic nerves, subarachnoid space, and optic nerve
sheaths in chronic papilledema. Note marked disten-
tion and stretching of the delicate arachnoid trabecu-
lations that bridge the subarachnoid space around the
nerves. (From Cogan DG. Neurology of the Visual
System, Ed 6. Springfield, IL, Charles C Thomas,
1966.)
PAPILLEDEMA 259
Figure 5.27. Ultrastructural appearance of papilledema. A, Most of the axons in the immediately prelaminar portion of the
optic nerve are swollen (A) and show disruption of their neurotubules and swelling of the mitochondria. Some of the axons
remain normal in size and structure. Glial elements (G) in this region are not swollen. B, Another section of the prelaminar
portion of the optic nerve head demonstrates axonal swellings of varying severity. Some axons are mildly swollen, whereas
others show hydropic degeneration (A). One axon contains giant mitochondria (M), whereas in other axons, the mitochondria
are normal in size (m). A dense body (D) is present in the cytoplasm of a perivascular glial cell (G). L, lumen of a blood
vessel. (From Tso MOM, Hayreh SS. Optic disc edema in raised intracranial pressure. III. A pathologic study of experimental
papilledema. Arch Ophthalmol 1977;95⬊1448–1457.)
restraining influence of Müller cells in the peripapillary ret-

ina (124), disequilibrium of hydrostatic pressure in the tissue
and bloodstream (125), and compression of the central reti-
nal vein as it traverses the subarachnoid space (125) or cav-
ernous sinus (126) with elevated central venous pressure
(111).
An animal model of experimental papilledema, developed
in the 1960s, provided a means to test most of the theories
regarding the pathogenesis of papilledema. Increased ICP
has been produced in monkeys by cranial irradiation (127)
and by the introduction of an inflatable balloon into the sub-
arachnoid space (63,128,129). Using these models, there are
some general points of agreement regarding the pathogenesis
of papilledema. First, papilledema occurs only when there
is patency of the subarachnoid space surrounding the optic
nerve and intracranial structures (116,130,131). Blockage of
these spaces by adhesions or tumor prevents papilledema
from occurring on the side of the obstruction. Second, papil-
ledema does not occur when antecedent optic atrophy has
Figure 5.28. Blockage of axon transport in papilledema. Phase contrast
destroyed most or all of the nerve fibers. Finally, and most
photomicrograph shows accumulation of axonal products (seen as white
important, axonal transport is clearly abnormal in patients material) in the region of the lamina cribrosa.
with papilledema as well as in patients with disc swelling
from all other causes (e.g., ischemia, inflammation, hypot-
ony).
Orthograde transport is studied using autoradiography by of choroidal folds, acquired hypermetropia, shortening of the
injecting labeled amino acids (usually leucine or proline) globe on MRI scanning, and forward bowing of the lamina
into the vitreous cavity. Both the fast (Ⳳ400 mm/day) and cribrosa (111). However, experimental compression of the
slow (Ⳳ1 mm/day) components of axon transport accumu- central retinal vein at its site of exit from the optic nerve
late in the regions of the lamina cribrosa of monkeys with does not produce optic disc edema (137). Similarly, monkeys
experimentally produced increased ICP and papilledema exposed to raised CSF pressure for up to 2 hours showed
(132,133) (Fig. 5.28). The stagnant axoplasmic flow results increased ophthalmic vein pressure but not disc edema (138).
in the swelling of axons seen by electron microscopy (118). Concurrent impaired perfusion of the neurons traversing the
Several studies confirm that eyes with optic disc swelling lamina cribrosa (the arteriolar branches of the circle of Zinn)
from increased ICP as well as other causes have stasis of
may be the final critical factor required to produce the vascu-
both fast and slow axonal transport (115,133–136).
The role of central retinal venous pressure in papilledema lar changes at the optic disc and impaired axoplasmic flow
is controversial. If the CSF pressure in the optic nerve sheath in papilledema (111,139).
constantly fluctuates, as it does in the brain, the sheath, like Research to date suggests that there are three components
the spinal dural sac, could function as an expansion vessel required for the development of papilledema: increased and
(111). Unlike the extradural veins of the spinal sac, the cen- fluctuating pressure in the distal optic nerve sheath; elevated
tral retinal vein is located within the subarachnoid space. central retinal venous pressure; and impaired perfusion of
With markedly elevated ICP, the venous pressure in the optic the nerve fibers traversing the lamina cribrosa (111). Despite
nerve sheath could be double that of the eye, accounting for the findings described above, numerous questions still exist
the loss of spontaneous venous pulsations and the presence regarding the pathogenesis of papilledema (140).
SYMPTOMS AND SIGNS

Both nonvisual and visual symptoms occur in patients ICP are nonspecific. They are usually global and aching
with papilledema. As a general rule, the nonvisual symptoms (‘‘tension type’’), but may be unilateral and throbbing (‘‘mi-
are more severe and bothersome to the patient, although grainous’’). The headache may be constant or intermittent.
visual symptoms can be both distressing and indicative of Neither the severity of the headache nor its location has any
impending permanent visual dysfunction. value in determining whether an intracranial mass is present
and, if so, its location. The typical ‘‘brain tumor headache’’
NONVISUAL MANIFESTATIONS that is worst upon awakening is only present in about one-
third of patients with tumors and does not correlate with the
Headache presence of increased ICP (141). Headaches associated with
increased ICP often worsen during a Valsalva maneuver
Headache is often the first symptom of increased ICP, (coughing, straining, etc.). The headache associated with in-
although there may be a considerable increase in ICP without creased ICP may be caused by stretching of the meninges
headache. The characteristics of headaches with increased or from distention of cerebral veins.
PAPILLEDEMA 261
Nausea, Vomiting, and Photophobia part of the pathway via a secondary effect on surrounding
brain (e.g., gyrus rectus compression of the optic nerves
Nausea and vomiting are frequently associated with sig- producing a bilateral optic neuropathy in a patient with a
nificantly increased ICP. Photophobia is commonly present frontal lobe tumor), and infiltration of a part of the pathway
and is occasionally the presenting symptom of intracranial (e.g., infiltration of the optic chiasm by a germinoma, pro-
hypertension. ducing a bitemporal hemianopia).
CSF Rhinorrhea Transient Visual Obscurations
Spontaneous CSF rhinorrhea is most commonly seen in As papilledema worsens, patients may experience brief,
patients with a mass lesion, congenital anomaly or previous transient obscurations of vision. During these episodes, vi-
trauma (142). This phenomenon has also been reported with sion may vary from mild blurring to complete blindness.
PTC and in patients with a CSF fistula that is usually located Some patients describe a rapid gray-out of vision, whereas
in the region of the cribriform plate (143). others experience positive visual phenomena, such as pho-
topsias and phosphenes that obscure their vision. In all cases,
VISUAL MANIFESTATIONS however, recovery of vision is invariably rapid and complete
(17,145). The obscurations may affect either eye or both
Early papilledema is usually asymptomatic. Even well- eyes simultaneously (146). They usually last only a few sec-
developed papilledema may produce minimal or no symp- onds, although attacks lasting several hours rarely occur
toms. Sometimes the only abnormality found on careful test- (17,145,147–149). The episodes may occur up to 20–30
ing is mild to moderate enlargement of the physiologic blind times a day, and are often precipitated by changes in posture,
spot. Other patients may be aware of their physiologic blind particularly from a bent-over position (146). There may be
spot, and describe a negative scotoma in the temporal field gaze-evoked amaurosis, a phenomenon that is also observed
of vision of one or both eyes. Still other patients have vari- by patients with orbital lesions that compress the optic nerve
able loss of visual acuity, visual field, or both. (150) (see Chapter 4). Transient obscurations of vision are
Coexisting retinal or vitreous hemorrhages or exudates often worrisome to the patient but they do not predict visual
may reduce central acuity (37) (Fig. 5.29). For example, outcome (105,151).
sudden monocular blindness from a subretinal neovascular Although transient obscurations were once thought to
membrane has been reported as the first symptom of PTC occur most frequently with lesions in the posterior fossa,
(144). When papilledema is caused by an intracranial mass, particularly cerebellar tumors (145,148), they occur more in
decreased acuity or a visual field defect in one or both eyes patients with PTC than in patients with intracranial mass
may occur by several mechanisms, including direct compres- lesions. They are most likely attributable to transient
sion of a portion of the visual sensory pathway (e.g., compression or ischemia of the optic nerve, as they are iden-
compression of the occipital lobe by a meningioma, produc- tical to those that occur in patients with unilateral meningio-
ing a homonymous field defect), indirect compression of mas of the optic nerve sheath (see Chapter 8).
Figure 5.29. Papilledema associated with bilateral visual loss related to macular hard exudate. The patient was a 35-year-
old woman with headaches and decreased vision in both eyes. Visual acuity was 20/50 OU. Visual fields showed marked
enlargement of the blind spots. Both optic discs are severely swollen (Frisén stage 5). A and B. There are numerous hemorrhages
and soft exudates on and surrounding the discs, and there is a star figure composed of hard exudate (lipid) in the maculae.
Visual Field Defects in patients with papilledema (110); however, the blind spot
may be enlarged even when there is no obvious retinal dis-
Concentric enlargement of the blind spot is the most com- placement or detachment. In this setting, the enlarged blind
mon—and frequently the only—visual field defect in pa- spot represents a refractive scotoma caused by acquired peri-
tients with papilledema (152). Compression, detachment, papillary hyperopia that, in turn, results from elevation of
and lateral displacement of the peripapillary retina appear the retina by peripapillary subretinal fluid (153).
to be the major reasons that the blind spot increases in size Uhthoff (154) described the various types of visual field
Figure 5.30. Progression of visual field defect in a patient with chronic papilledema. A–C, Progression of chronic papilledema
to optic atrophy. D–F, Progression of the visual field defects. Note progressive loss of nasal and superotemporal fields and
associated constriction with preservation of visual acuity.
PAPILLEDEMA 263
Figure 5.31. Difference in sensitivity of kinetic versus static perimetry in chronic papilledema. A and B, Right and left optic
discs show chronic papilledema. C and D, Kinetic perimetry shows no abnormalities except for mildly enlarged blind spots.
E and F, Static perimetry in the same patient shows nasal steps, inferior arcuate defects, and reduction in sensitivity in both
eyes.
defects in papilledema, including enlargement of the blind weeks in cases with markedly increased ICP (161). When
spot (30%), concentric constriction (29%), and complete acute loss of vision occurs in patients with papilledema, local
blindness (25%), with the rest of the defects divided among causes are generally responsible (161,162). Central vision
homonymous hemianopia and central and arcuate scotomas. loss may be produced by hemorrhages or exudates in the
In chronic papilledema, the inferior nasal quadrant is most maculae. Ischemic optic neuropathy or retinal vascular oc-
often affected (155). Dense paracentral scotomas may be clusions may be related to the underlying process (e.g., a
found in the Bjerrum area, and may progress to form ring coagulopathy) or to the rapid rate at which the ICP has risen
scotomas (155). Visual acuity usually deteriorates late in the (163–167). Rare patients, many of them children, seem to
course of the disease. The defects can be reversed if ICP is have a fulminant course characterized by a rapid progression
lowered before chronic papilledema develops (156). As with from normal vision to profound and permanent visual loss
loss of visual acuity, loss of visual field is usually slow and (162,168,169).
progressive. Sudden loss of visual field suggests a superim-
posed local cause, such as ischemia (113). Other Abnormalities in Visual Sensory Function
Automated static perimetry confirms that early visual field As in other optic neuropathies, papilledema may be asso-
defects in eyes with papilledema are not uncommon and are ciated with nonspecific abnormalities of visual sensation that
often present when standard kinetic perimetry gives normal can be detected when specific tests are performed. For exam-
results (157–159). These early defects are generally arcuate ple, patients with visual acuity of 20/20, a full visual field,
scotomas or nasal steps. Constriction of the visual fields and normal color perception may nevertheless have abnor-
may occur with high-grade papilledema or as a late sign of mal contrast sensitivity (170–174). Visual evoked potentials
papilledema during the chronic stage as it progresses to optic do not become abnormal until marked visual loss has oc-
atrophy. The field defects are usually worse nasally than curred and have no role in the diagnosis or monitoring of
temporally (160) (Figs. 5.30 and 5.31). Thus, in advanced visual function with papilledema (171,175).
papilledema, only a temporal island of vision may remain
before progressing to complete blindness. The slowly pro- Diplopia
gressive visual field defects in chronic papilledema are simi-
lar to those seen in glaucoma, suggesting that there may be The most common cause of diplopia from increased ICP
a common pathogenetic mechanism in the two conditions is a lateral rectus palsy, as one or both abducens nerves are
(155), or a similar vulnerability of specific nerve fibers to compressed against one of the transverse branches of the
different insults. basilar artery at the base of the skull (176,177). Infrequently,
trochlear nerve palsies occur in patients with increased ICP,
Loss of Central Vision presumably from compression of either the dorsal midbrain
or the nerves themselves, by a ballooned suprapineal recess
Patients with papilledema caused by intracranial mass le- (178,179). Trochlear nerve palsies may be mistaken for a
sions or meningitis (septic, aseptic, carcinomatous, and lym- ‘‘skew deviation’’ if quantitative testing of eye movements
phomatous) can lose central vision acutely or progressively or a Bielschowsky head tilt test is not performed, although
from the effects of the underlying process on the optic true skew deviation can also occur in patients with increased
nerves. In other cases, permanent loss of central vision re- ICP (168,180,181). Oculomotor nerve palsy is distinctly un-
sults from the nonspecific effects of increased ICP on the common as a non-localizing sign of increased ICP (168,182).
optic nerve and begins with visual field constriction that is Intracranial hypertension occasionally presents with global
slowly progressive. In this setting, loss of central acuity usu- ophthalmoparesis that resolves as the ICP is normalized
ally is a late phenomenon, although it may occur over several (183).
ETIOLOGY
GENERAL CONSIDERATIONS the cerebral aqueduct (of Sylvius) into the 4th ventricle, and
out into the subarachnoid space through the foramina of
The craniospinal cavity is an almost rigid bony enclosure Luschka and Magendie. In the subarachnoid space, CSF
completely filled by tissue, CSF, and circulating blood. flows rostrally from the posterior fossa through the lower
Within this enclosure, CSF is constantly produced at the ventral basal cisterns and tentorial notch to reach the interpe-
rate 500 ml/day, or 0.35 ml/minute (184). Almost all of the duncular and chiasmatic cisterns. The CSF then flows dor-
production is by the choroid plexus within the lateral ventri- sally through the communicating cisterns to reach the dorsal
cles, although the choroid plexuses of the 3rd and 4th ventri- cisterns, and lateral and superiorly from the chiasmatic cis-
cles and the ependymal lining of the ventricular system also tern into the cisterns of the Sylvian fissure. From the cisterns
contribute a small amount. The secretion of CSF is related and Sylvian fissures, CSF moves outward and superiorly
to sodium transport in the brush border of the choroid plexus over the cerebral convexities where it is absorbed.
epithelium, and is dependent on sodium-potassium-activated The chief route of absorption of CSF in the brain is pas-
ATPase as well as the enzyme carbonic anhydrase (184). sively through the arachnoid granulations that protrude into
CSF flows from the lateral ventricles through the interven- the venous sinuses and diploic veins. These vessels drain to
tricular foramina into the 3rd ventricle and mixes with the the internal jugular vein and other extracranial veins. CSF
CSF produced in that ventricle. The CSF then flows through is also absorbed in the spinal sac.
PAPILLEDEMA 265
Many factors influence CSF formation, including toxins, of Sylvius, but may produce papilledema by deflection of
medications, and neurotransmitters. Cholera toxin increases the falx and pressure upon the great vein of Galen (199).
CSF production (185,186), while serotonin, sympathomi- Tumors below the tentorium usually produce papilledema
metic drugs, acetazolamide, furosemide, vasopression, dopa- by obstruction of the aqueduct. Nevertheless, some infraten-
mine D1 receptor antagonists, atrial naturetic hormone, hy- torial masses do not obstruct the aqueduct but still produce
perosmolar agents and hypothermia decrease CSF formation papilledema, perhaps related to elevation of the tentorium
(184,187). Corticosteroids seem to have no effect on CSF with pressure on the vein of Galen or on other cerebral ve-
production but lower intracranial pressure by a different nous sinuses (165,197–200). Both central and transtentorial
mechanism (184). There is likely a feedback mechanism of herniation syndromes may cause papilledema.
increased ICP on CSF production but it is not well elucidated Brain tumors in certain locations may produce papille-
(188). dema without lateralizing or localizing signs, particularly if
The Monro-Kellie hypothesis (189,190), states that the they are supratentorial and situated within the nondominant
volume of blood, brain and CSF within the cranial cavity hemisphere or within one of the lateral ventricles (201).
must be in equilibrium, and a change in the volume of one Moreover, not all intracranial tumors cause a pressure rise
component must be offset by a reciprocal change in another. sufficient to produce papilledema (202).
However, within this rigid system, there is an elastic element Papilledema may be dependent not only on tumor location
of the spinal dural sac and the vascular channels (191). Under but also on the type and growth rate of the tumor. For exam-
appropriate circumstances, as little as 80 cc of rapidly added ple, gliomas may produce papilledema in three-quarters of
volume (CSF, blood, edema, tissue, etc.) will raise ICP to cases, whereas meningiomas produce papilledema in less
a level incompatible with life (189). Given the intracranial than half (203). Papilledema was observed in 50% of patients
compartmental equilibrium, increased ICP occurs by several with rapidly growing glioblastomas, while 65% of those pa-
mechanisms: tients with slowly progressive benign astrocytomas and me-
ningiomas demonstrated papilledema (204). Papilledema
An increase in the total amount of intracranial tissue by a was present in 61% of patients with cerebral metastases
space-occupying lesion; (204). These data raise the possibility that papilledema may
An increase in intracranial tissue volume by focal or diffuse develop more frequently in those patients with slowly pro-
cerebral edema; gressive tumors rather than those with malignant and rapidly
A decrease in total volume within the cranial vault by thick- growing masses (204).
ening of the skull; Papilledema may occur with other intracranial masses,
Blockage of the flow of CSF within the ventricular system such as hamartomas (205), teratomas, parasitic lesions such
(obstructive or noncommunicating hydrocephalus) or as cysticercus cysts (206), abscesses, hematomas, aneu-
within the arachnoid granulations (nonobstructive or com- rysms, and granulomas, usually in association with sarcoido-
municating hydrocephalus); sis, tuberculosis, or syphilis.
Reduced absorption of CSF from obstruction or compromise
of venous outflow both intracranially and extracranially; Arteriovenous Malformation (AVM)
and/or AVMs need not rupture to produce papilledema
Increased production of CSF by an intracranial tumor at a (176,207–213). The mechanism producing increased ICP is
rate that precludes adequate absorption for maintenance likely from direct shunting of arterial blood from AVMs into
of normal ICP (192,193). the cerebral venous system, elevating the cerebral venous
pressure and decreasing CSF resorption (209,214–217). Ad-
CONDITIONS ASSOCIATED WITH PAPILLEDEMA ditionally, there may be venous sinus thrombosis or direct
venous sinus compression from the AVM causing increased
Tumors ICP (209). Both intracerebral and dural-based AVMs involv-
Intracranial masses such as tumors produce increased ICP ing the transverse sinus are associated with papilledema
through most of the mechanisms mentioned above. They (218). Treatment may include surgery, embolization or shunt
may act solely as space-occupying lesions; they may produce placement to lower the intracranial pressure (209,217).
focal or diffuse cerebral edema, and they may block the
outflow of CSF by direct compression of CSF drainage path- Aqueductal Stenosis
ways or by infiltration of the arachnoid villi or the cerebral Aqueductal stenosis often presents in childhood. It may
venous sinuses. Other potential mechanisms are the produc- be congenital, in which case it may or may not be associated
tion of increased protein or blood products that secondarily with a Chiari malformation, or it may be acquired from intra-
block the arachnoid villi, and by directly producing CSF. cranial infections such as toxoplasmosis or mumps epen-
Papilledema does not develop in every patient with a cere- dymitis (219). Presentation in infancy is accompanied by
bral tumor. Several large studies found papilledema in macrocephaly. Adults may have headaches, dorsal midbrain
60–80% of patients with cerebral tumors (194–198). Tu- syndrome, meningitis, hemorrhage, endocrine disturbances
mors that are situated below the tentorium (infratentorial) from compression of the pituitary gland, seizures, gait distur-
are more likely to produce papilledema than those situated bances, and CSF rhinorrhea (220,221). Occasionally aque-
above it (supratentorial). Supratentorial tumors rarely cause ductal stenosis produces unilateral ocular symptoms and
primary obstruction to the flow of CSF through the aqueduct optic disc edema (58).
Intracranial Hemorrhage suggesting that the disc swelling was caused by inflamma-
tion rather than increased ICP.
Papilledema occurs in patients with both acute and chronic
Papilledema may occur with any form of meningoenceph-
subdural hematoma but is more commonly observed in the
alitis. Many viral encephalidites are associated with papille-
acute phase (204,222,223). The converse is true with epi-
dema (239,240), including herpes simplex and herpes zoster
dural hematoma, when the papilledema may develop many
encephalitis (241,242), measles encephalitis (243), Califor-
weeks after the injury, particularly when the hematoma is
nia encephalitis (244), lymphocytic choriomeningitis (245),
located at the vertex causing compression of the superior
infectious mononucleosis (246), and coxsackie B2, B4, and
sagittal sinus (224–226).
B5 meningoencephalitis (247,248). However, papilledema
In almost all cases, subarachnoid hemorrhage produces
uncommonly occurs with encephalitis caused by rubella,
papilledema either by blocking CSF flow within the ventric-
mumps and varicella (249). Patients with poliomyelitis may
ular system or by blocking CSF absorption at the arachnoid
develop increased ICP during both the acute and convales-
granulations. The site of the hemorrhage may be intracranial
cent phases of the disease, and papilledema may develop in
or spinal (227). In one series of 192 patients with ruptured
such cases (250–253). Generally, there is an elevated CSF
intracranial aneurysms, papilledema was found in 16%
protein with a moderate lymphocytic or mixed pleocytosis.
(228). The presence of papilledema was not related to gen-
Papilledema is rare in subacute sclerosing panencephalitis
der, age, or site of the aneurysm. In seven cases, the papille-
as the disease is slowly progressive and not generally associ-
dema was unilateral, and it was ipsilateral to the lesion in
ated with increased ICP (254,255). Papilledema in syphilis
six of these cases. Other investigators report the incidence
and tuberculosis may result from meningoencephalitis, ob-
of papilledema in patients with aneurysmal subarachnoid
struction of CSF flow or mass effect.
hemorrhage as 10–24% (229,230). It may be present within
Psittacosis presented with increased ICP and papilledema
several hours after the hemorrhage (154,231), or develop
in a 46-year-old man who developed headache, malaise,
only after several weeks of increased ICP (232).
weight loss, sweats, and anorexia (256). Central nervous
Infections system involvement of Whipple’s disease has also been asso-
ciated with papilledema and increased ICP (257,258).
Although papilledema is uncommon in patients with a Papilledema occurs occasionally in Reye syndrome, an
cerebral hemispheric abscess, abscesses in the occipital lobe encephalopathy that follows a viral illness and occurs in
frequently produce pronounced papilledema (204), and children between ages 1 and 15 years (259,260), associated
chronic brain abscesses are associated with papilledema with fever and vomiting followed by convulsions and coma.
more frequently than acute abscesses (99,233). There is no Fatty infiltration and inflammation of the liver, kidney, and
definite relationship between the size of the abscess and the pancreas occur, and the mortality rate is 10% (259). In all
severity of the papilledema. Unilateral papilledema caused patients, acute noninflammatory encephalopathy is con-
by a brain abscess may have localizing value. Cerebellar firmed by increased ICP, normocellular CSF, and diffuse
abscesses are not likely to produce papilledema, perhaps cerebral edema. Although the fundi are normal in most cases,
because of more rapid surgical intervention or hastened mor- papilledema has been reported in rare instances (259,260).
tality compared to supratentorial hemispheric lesions (98).
The etiology of ICP in patients with meningitis or en- Noninfectious Inflammatory Disorders
cephalitis is usually diffuse cerebral edema. However, the
reported frequency of papilledema with meningitis is fairly Sarcoidosis affecting the CNS occurs in about 5% of
small, and the papilledema tends to be mild and transient. cases, mimicking practically any intracranial mass lesion
Only 2.5% of patients had papilledema in one study of 2,178 (261,262); see (Chapter 59). Granulomas may develop in
cases of meningitis (234) and other large series of syphi- the meninges, causing nodular masses or, more commonly,
litic meningitis showed a similar incidence of papilledema an adhesive meningitis, or they may develop within brain
(235,236). Papilledema was more likely to occur in patients parenchyma. The papilledema that occurs in sarcoidosis is
with tuberculous meningitis (25% of cases) than in any other usually associated with an aseptic meningitis, obstructed
type of bacterial meningitis (234). CSF flow or mass effect (263). Occasionally, however, sar-
Among 80 patients with clinical signs of aseptic meningi- coidosis is associated with a true PTC syndrome; i.e., there
tis, 17 had optic disc swelling (237). The disc swelling was is no evidence of a mass lesion, the ventricles are normal in
associated with moderate elevation of the discs, minimal size, the ICP is elevated, and the CSF contains no cells and
venous congestion, and small peripapillary hemorrhages. In has a normal concentration of glucose and protein. Some of
slightly more than half of the patients, there was confirmed these cases may be caused by dural venous sinus thrombosis
increased ICP. In the others, it is likely that the disc swelling (264). In other cases, the etiology is unclear. PTC associated
was caused by an optic perineuritis (see Chapter 6). All pa- with sarcoidosis often responds to treatment with systemic
tients recovered completely in 6–12 months. A retrospective corticosteroids.
review of 100 patients hospitalized with a definite or proba- Behçet’s disease is a multisystemic, recurrent, inflamma-
ble diagnosis of viral meningitis, encephalitis, or meningo- tory disorder affecting the eyes, skin, mucosa, joints, vascu-
encephalitis found six patients with disc swelling, two of lar system, gastrointestinal tract, and nervous system (265).
whom had increased ICP (238). In the four other patients, the The disc swelling often seen in patients with Behçet’s dis-
CSF was under normal pressure but pleocytosis was present, ease is usually associated with intraocular inflammation.
PAPILLEDEMA 267
However, Behçet’s syndrome has been associated with pap- Trauma

illedema from dural venous sinus thrombosis and thrombo-
phlebitis (266–270). The PTC syndrome with papilledema Papilledema occurs in 20–30% of persons who have suf-
is the most common presentation of dural venous sinus fered severe cranial injuries, both with and without an associ-
thrombosis in Behçet’s disease (265,270,271) and is an im- ated skull fracture (280). In most of these cases, the increased
portant diagnostic consideration in atypical patients with ICP is caused by a severe subarachnoid hemorrhage or a
PTC. The MRI scan is abnormal in almost all cases of Beh- significant intracerebral, subdural, or epidural hematoma. In
çet’s disease affecting the brain, revealing contrast-enhanc- other cases, however, the increased ICP is caused by diffuse
ing lesions in the basal ganglia or diencephalon, small scat- or localized cerebral edema (280). Papilledema that develops
tered periventricular or white matter lesions, or dural sinus in patients after head trauma is usually mild and may develop
occlusion (265). immediately, several days after the injury, or up to 2 weeks
Papilledema and the PTC-like syndrome was reported in later (281). Among 15 patients evaluated by a neuro-ophthal-
a patient with familial Mediterranean fever, an inherited in- mologist after blunt head trauma, papilledema was recog-
flammatory disease of unknown cause (272). nized immediately in 1 patient, during the first week in 10
In almost all CNS infections and inflammations, swelling patients, and not until the second week in 4 patients (282).
of the optic disc may occur without elevated ICP, presum- A sudden, severe, but transient increase in ICP is postulated
ably from inflammation of the optic nerve. Many times the to be responsible for the immediate development of papille-
disc swelling is termed ‘‘papilledema’’ (240) even though dema, whereas sustained but mild to moderately elevated
the ICP is normal, because the discs are swollen and the ICP accounts for papilledema that appears during the first
patients have normal visual function. In other cases, the diag- week after injury (282). Papilledema during the second week
nosis of papilledema is made on clinical grounds alone, with- or later results from impaired CSF absorption and conse-
out measurement of ICP. However, some patients have both quent communicating hydrocephalus or delayed focal or dif-
increased ICP and a substantial inflammatory reaction in the fuse cerebral swelling.
CSF. In this situation, differentiating between papilledema Just as not all patients with increased ICP from an intracra-
and optic perineuritis is impossible because, in both condi- nial mass develop papilledema, not all patients with in-
tions, there is normal visual function. Only when a lumbar creased ICP after head trauma develop papilledema, espe-
puncture is performed in a patient with a CNS infection and cially in the acute period (95). Thus, the absence of
disc swelling, and the CSF is found to be under normal papilledema in a patient with head trauma does not exclude
pressure with an increased protein and a pleocytosis, can the the presence of increased ICP.
true inflammatory etiology of the disc swelling be ascer-
Spinal Cord Lesions
tained.
The association of increased ICP and papilledema with
Neoplastic Infiltrating Disorders tumors in the spinal canal is an unusual but well-documented
Increased ICP, often associated with papilledema, occurs phenomenon (283–287). Most of these tumors are intra-
in patients with diffuse spread of tumors throughout the dural; however, extradural spinal tumors can also cause in-
CNS. These tumors include carcinomas, lymphomas, and creased ICP associated with papilledema (288,289). In some
leukemias (273,274). The increased pressure is usually cases, the tumors are located in the high cervical region, and
caused by tumor cells that either obstruct CSF outflow across the explanation for the increased ICP is thought to be upward
the arachnoid villi or CSF flow in the basal cisterns. swelling of the tumor with compression of the cerebellum
While most intracranial gliomas occur as solid mass le- and obstruction of CSF flow through the foramen magnum
sions within the brain, in rare cases, the entire brain is infil- (106,290). This mechanism seems unlikely in the majority
trated by a glioma—gliomatosis cerebri. The MRI usually of cases, however, because over 50% of spinal cord lesions
shows multifocal lesions (275), but occasionally the dif- associated with papilledema are ependymomas or neurofi-
fusely infiltrated brain may present with normal neuroimag- bromas, usually in the thoracic and lumbar regions (291).
ing and normal CSF contents (276). The most common pre- These tumors can produce extremely high concentrations of
senting symptoms are headaches, seizures, mental status and protein in the CSF, and therefore the likely cause of in-
cognitive changes, and hemiparesis (275). Papilledema may creased ICP and papilledema is via defective CSF absorption
be present in one-third of patients at diagnosis (275). Such that results from blockage of the arachnoid granulations by
patients may initially be thought to have PTC, until further protein. In other cases, recurrent subarachnoid hemorrhage,
growth of tumor cells occurs, and the true diagnosis becomes which occurs commonly from bleeding from the surface of
evident. ependymomas, may also cause lowered CSF absorption from
Leptomeningeal gliomatosis affecting the spinal cord blockage of the arachnoid villi by blood or blood products.
can also cause increased ICP and papilledema (277,278). Other mechanisms for the production of increased ICP in
Patients with this condition have a diffuse CNS glioma that is patients with spinal cord tumors are probable but have yet
confined to the leptomeninges and that is thought to originate to be elucidated.
from a heterotopic glial nest in the subarachnoid space (279). Papilledema may occasionally be present in patients with
The initial manifestations are headache, papilledema, and spinal cord pathology other than malignancy, presumably
evidence of aseptic meningitis. Tumor cells are almost al- by a similar mechanism. It has been reported in a patient
ways found in the CSF. with a herniated thoracic disc, resolving postoperatively
(292). The authors postulated that the papilledema in this cating axonal loss; and (f) a frequent association with sys-
patient was caused either by chronic epidural venous conges- temic diseases such as systemic lupus erythematosus and
tion from pressure of the extradural herniated disc producing Hodgkin’s disease (300,302).
a partial subarachnoid block, or by an associated aseptic Increased ICP, often associated with papilledema, occurs
meningitis and an elevated CSF protein. more often in patients with CIDP than in patients with acute
GBS, and appears to result from the markedly increased
Demyelinating Disorders protein concentration that is one of the laboratory hallmarks
Papilledema is an uncommon complication of the Guil- of the disease (303) (Fig. 5.32).
lain-Barré syndrome (GBS) and its pathogenesis remains Papilledema occurs in a small percentage of patients with
uncertain (293–295). Denny-Brown postulated that papille- myelinoclastic diffuse sclerosis (Schilder disease). Cerebral
dema was a consequence of abnormal protein that interfered edema from the numerous acute demyelinating brain lesions
with the absorption of CSF (296). Six years later, Joynt de- may mimic the clinical presentation of a neoplasm, abscess
scribed cerebral edema with normal CSF absorption in pa- or PTC (304). In the majority of cases, optic neuritis is also
tients with GBS (297). Subsequently, evidence was submit- present from demyelination of the optic nerves (see Chapter
ted supporting both theories, as well as invoking a partial 60). Disc edema in multiple sclerosis most commonly re-
venous sinus thrombosis (298–300); the mechanism may be flects optic nerve demyelination and inflammation, rather
multifactorial. than increased intracranial hypertension. Bilateral, simul-
GBS usually is a monophasic illness, with a rapid initial taneous anterior optic neuritis may be difficult to distinguish
onset, progressive weakness and other neurologic manifesta- clinically from acutely elevated ICP (305). The reported as-
tions over 1–4 weeks, and partial or complete recovery over sociation between papilledema and increased intracranial
subsequent months. However, a small percentage of patients pressure in a few patients with multiple sclerosis may be
with an otherwise typical episode of acute GBS subsequently coincidental (306).
relapse, have a protracted onset, or slowly improve and then
Inborn Errors of Metabolism
worsen over weeks to months. The chronic and relapsing
form of GBS was first defined largely by its responsiveness Hydrocephalus is a known complication of the inherited
to systemic corticosteroids (301). This disorder, now known disorders of lysosomal multienzymes called the mucopoly-
as chronic inflammatory demyelinating polyneuropathy saccharidoses (MPS) (307) and papilledema occurs in some
(CIDP), is distinguished from acute GBS by: (a) a longer of these cases (308–311). Increased ICP in patients with the
progression (2–3 months) before plateau; (b) a tendency for systemic mucopolysaccharidoses probably results from an
the illness to be less severe than the typical acute disease; obstruction to the distal circulation of CSF over the cerebral
(c) fluctuations in the severity of symptoms over many years; convexities, in the arachnoid villi, or both, by the deposition
(d) greater elevations in CSF protein concentration; (e) more of mucopolysaccharide in the meninges, leading to delayed
profoundly slowed motor nerve conduction velocities indi- CSF absorption.
Figure 5.32. Papilledema in chronic inflammatory demyelinating polyneuropathy (CIDP). The patient was a 44-year-old man
with well-documented CIDP who was being treated with low-dose systemic corticosteroids when he developed mild headaches
but no visual symptoms. Visual acuity was 20/20 OU; color vision was normal; and visual fields were full. A, The right optic
disc is mildly hyperemic and swollen (Frisén stage 2). B, The left optic disc is mildly hyperemic and swollen (Frisén stage
2). Brain neuroimaging was normal. A lumbar puncture showed increased intracranial pressure with a moderately increased
concentration of protein. No specific treatment was given, and the papilledema gradually resolved over about 6 months.
PAPILLEDEMA 269
Citrullinemia is caused by deficient activity of arginino- pophosphatasia (323), sclerosteosis (324), progressive dia-
succinate synthetase, a urea-cycle enzyme. Hyperammo- physeal dysplasia (324) and idiopathic acroosteolyses
nemia is usually present in this disorder (312,313). Citrulli- (Hedju-Cheney syndrome) (325).
nemia may present acutely in neonates, subacutely in
children, or as a late-onset condition in young adults. The Plasma Cell Dyscrasias
late-onset type (Type II) may be associated with increased
ICP and papilledema (314). Affected patients experience POEMS syndrome (Crow-Fukase syndrome) is an unu-
lethargy or recurrent episodes of syncope. Neuroimaging sual multisystem disorder that is characterized by polyneu-
shows small ventricles and changes consistent with cerebral ropathy (P), organomegaly (O), endocrinopathy (E), mono-
edema (312). CSF pressure is elevated, but the CSF contains clonal gammopathy (M), and skin changes (S) (326–328).
no cells and normal concentrations of protein and glucose. Polyneuropathy is frequently the initial and most disabling
Most patients in whom late-onset citrullinemia occurs have problem. It is usually associated with electrophysiological
a peculiar fondness for beans, peanuts, and meat. Although and histological evidence of mixed demyelination and axon
the findings in late-onset citrullinemia associated with papil- degeneration (328). Enlarged organs include the liver,
ledema suggest a diagnosis of pseudotumor cerebri, i.e., no spleen, and kidneys (328). Common endocrine abnormalities
intracranial mass lesion, small ventricles, increased ICP, nor- are diabetes mellitus, hypothyroidism, hypogonadism, hypo-
mal CSF content (see below), affected patients have evi- cortisolism, and gynecomastia in men (328). Polycythemia
dence of an encephalopathy and thus do not strictly meet is often present. Common skin findings include diffuse
the diagnostic criteria for PTC (315). hyperpigmentation, peripheral edema, hypertrichosis, skin
thickening similar to that observed in scleroderma, hyper-
Anomalies of the Cranium hidrosis, and clubbing of the fingers (328,329). Additional
systemic features include osteosclerotic bone lesions, lym-
The intracranial vault may become smaller in certain types phadenopathy, and peripheral edema.
of craniosynostoses. Of 171 patients with premature synos- Over 50% of patients with the POEMS syndrome develop
tosis of the cranial sutures, the vast majority (91%) had sim- papilledema (327,328,330) that may occur with or without
ple cranial synostosis (oxycephaly, scaphocephaly, trigono- increased ICP (331,332). The disc swelling in most of these
cephaly, or plagiocephaly), whereas the remainder had cases results from altered capillary permeability in the optic
dysostosis craniofacialis (Crouzon’s syndrome) or acroceph- disc or from the effects of an associated infiltrative orbi-
alosyndactyly (Apert’s syndrome) (316). Twenty-six of topathy.
these patients (15%) had papilledema (316). When patients The POEMS syndrome is usually associated with a plasma
with simple cranial stenosis, which is almost never associ- cell dyscrasia, such as myeloma, plasmacytoma, or mono-
ated with papilledema, were excluded, however, the inci- clonal gammopathy of undetermined significance. A mono-
dence of papilledema increased to 40%. In another large case clonal immunoglobulin, inflammatory cytokines, vascular
series, ophthalmoscopic evaluations were performed in 122 endothelial growth factor and human herpes virus-8 are im-
children with craniosynostoses who then underwent moni- plicated in its pathogenesis (333). The monoclonal protein
toring of ICP revealing 15 patients (12%) with papilledema component, present in most cases, may be IgG gamma, IgM
and 4 patients with optic atrophy (317). The patients with gamma, gamma light chain, or others (328). Clinical im-
papilledema had higher ICP, were older, and were more provement following treatment of the plasmacytoma or soli-
likely to have craniofacial syndromes than patients without tary bone lesion associated with an M component suggests
papilledema (317). The authors concluded that the presence that a tumor product may be the cause of the condition (328).
of papilledema in a young child with craniosynostosis reli- Patients with multiple myeloma can develop increased
ably indicates increased ICP, but its absence does not ex- intracranial pressure and papilledema from CNS involve-
clude increased ICP. ment (334,335). The PTC syndrome was described in pa-
Papilledema that occurs in patients with craniosynostoses tients with multiple myeloma who had no other features of
is often chronic by the time it is detected, possibly because the POEMS syndrome (see above) or generalized hypervis-
such patients may not undergo a careful examination of the cosity (336). The mechanism of the raised ICP in these pa-
ocular fundi unless they complain of visual disturbances tients is unclear.
(154,316,318). Almost 50% of patients with craniosynosto-
sis and papilledema eventually develop severe reduction of Toxins
vision or blindness in both eyes (195). In one study of 31
patients with postpapilledema optic atrophy, 52% had visual Lead has both direct and indirect effects on the nervous
acuity of 20/60 or better in both eyes, 29% had acuity of system. At levels above 4 ␮M the blood brain barrier is
20/60 or better in one eye, and only 19% had visual acuity damaged, leading to severe cerebral edema and increased
less than 20/60 in both eyes (316). ICP (337,338). Lead encephalopathy in children is character-
Papilledema in craniosynostosis usually develops before ized by lethargy, anorexia and irritability, progressing over
the age of 10 years (317,319) but a patient with oxycephaly weeks to clumsiness, ataxia then stupor, coma, and seizures
was observed to developed papilledema at 53 years of age (338). Lead toxicity continues to be a public health problem,
(317,320,321). Papilledema occurs not only in patients with particular in the inner city, from the ingestion of lead-based
primary craniosynostosis (322) but also in patients with hy- paint chips (pica). Exposure to lead dust during the renova-
tion or restoration of older homes is another source of tox- cur in association with hyperthyroidism without dysthyroid
icity. orbitopathy (339–341). One patient had communicating hy-
drocephalus and papilledema associated with severe thyro-
Hyperthyroidism toxicosis; the ICP and papilledema fluctuated proportionate
Optic disc swelling in hyperthyroidism is usually due to to her serum thyroid hormone levels (340). Increased cere-
compression or ischemia of the optic nerves caused by dys- bral blood volume during thyrotoxicosis was proposed as
thyroid orbitopathy. Nevertheless, true papilledema can oc- the cause of the hydrocephalus (340).
PSEUDOTUMOR CEREBRI (IDIOPATHIC INTRACRANIAL HYPERTENSION)

DEFINITION studies; and (e) no other etiology of intracranial hypertension
identified (315,362). Each of these criteria are discussed
The pseudotumor cerebri syndrome was first described by below.
Quincke in 1897 (342). The terminology used historically
in the literature gives a sense of the various conditions asso-
ciated with pseudotumor cerebri (PTC): toxic hydrocephalus Symptoms and Signs
(343), otitic hydrocephalus (344), hypertensive meningeal
Occasionally, PTC is asymptomatic and discovered dur-
hydrops (345), pseudoabscess (7), ICP without brain tumor
(27), brain swelling of unknown cause (346,347), and papil- ing a routine ophthalmic examination when papilledema
ledema of indeterminate etiology (348). The most popular is found (363). However, the most common symptom is
and enduring term ‘‘pseudotumor cerebri’’ was first used in headaches, occurring in approximately 90% of cases
1914 (349). Noting that the condition was not caused by a (362,364–366). The character of the headache is not specific
tumor or malignancy, Foley introduced the term ‘‘benign but it is usually different from previous headaches and is
intracranial hypertension’’ in 1955 (350). However, the term severe (367). It most commonly is bifrontal or generalized,
‘‘benign’’ also implies a favorable process or the absence pressure-like, and often associated with neck pain (367). The
of harm. As significant visual morbidity may result from headache is usually daily but may be intermittent. Many
PTC, the use of the prefix ‘‘benign’’ was challenged (351) patients have migrainous features including unilateral pain,
and is no longer considered acceptable terminology. The nausea, vomiting, photophobia and phonophobia. It may
disorder is most correctly termed idiopathic intracranial hy- awaken the patient from sleep or resemble a ‘‘brain tumor
pertension (IIH) or intracranial hypertension from a second- headache’’ that is worse in the morning, and aggravated
ary cause, depending upon whether or not an etiology is when cerebral venous pressure is increased by Valsalva ma-
identified. The older term, PTC, describes the clinical syn- neuvers (coughing, sneezing, etc.).
drome without reference to the underlying cause. The second most common symptom of PTC is transient
visual loss. Typical transient obscurations of vision (TOV)
EPIDEMIOLOGY are reported by approximately 70% of patients (367). They
may be unilateral or bilateral, usually last less than a minute,
PTC affects infants, children and young adults but rarely and are often precipitated by a change in posture (e.g., bend-
has onset over age 45 years (161,169,352–357). The idio- ing over, arising from a stooped position) or rolling the eyes.
pathic form (IIH) is typically a disorder of obese females of In some patients TOVs occur 20 to 30 times daily. The visual
childbearing age. The incidence of PTC varies throughout loss may be partial or complete. TOVs indicate the presence
the world. Two studies in the United States estimated the of optic disc edema and are not, in isolation, an ominous
incidence at approximately 0.9 per 100,000 in the general symptom if the vision returns to normal interictally. They
population with a female⬊male ratio of 8⬊1 (358,359). The likely reflect transient ischemia to the optic nerve head
incidence rises to 3.5 per 100,000 in women aged 20 to 44 caused by papilledema.
years, and further increases to 13 per 100,000 in women While TOV are common and generally not worrisome, a
who are 10% over ideal weight, and 19 per 100,000 in smaller percentage of patients will complain of visual loss.
women who are 20% over ideal weight (358). The incidence They may notice an enlarged physiologic blind spot, describ-
in Benghazi, Libya was 2.2 per 100,000 in the general popu- ing a dark spot in the temporal visual field. Tunnel vision
lation, 4.3 per 100,000 in women, and 21.4 per 100,000 in
and central visual loss may occur (362,367). With severe
women aged 15-44 years who were 20% over ideal weight
disease, ischemic optic neuropathy ensues, producing rapid,
(360). In Israel, whose population is a mixture of people
severe and often irreversible visual loss (113). Visual loss
originating from various Eastern and Western countries, the
in PTC may also arise from macular hemorrhages, exudates,
incidence was similar to that in western populations with a
pigment epithelial changes, retina striae, choroidal folds,
preponderance of obese women (361).
subretinal neovascularization or retinal artery occlusion
(41,48,144,166,368).
DIAGNOSIS
Diplopia, observed by approximately 40% of patients, is
The diagnostic criteria for IIH are: (a) symptoms and signs usually horizontal resulting from unilateral or bilateral abdu-
solely attributable to increased ICP; (b) elevated CSF pres- cens nerve paresis, a nonlocalizing feature of increased intra-
sure; (c) normal CSF composition; (d) normal neuroimaging cranial pressure (362,367). Rarely, there is vertical diplopia
PAPILLEDEMA 271
from trochlear nerve paresis, oculomotor nerve paresis, or clude inferonasal loss (nasal step) and generalized constric-
skew deviation (168,179–181,369). tion of the visual field. Central, paracentral, arcuate and alti-
Intracranial noises (pulsatile tinnitus) are also common tudinal scotomas may occur (158,367). Abnormalities of
but must be queried for as patients seldom volunteer this ocular motility include unilateral or bilateral abducens pa-
symptom. Often described as a whooshing sound, ‘‘hearing resis (362,367) or, uncommonly, trochlear nerve paresis,
my heartbeat in my head’’ or high-pitched noises, they are oculomotor nerve paresis or skew deviation (168,179–
thought to reflect flow disturbances within the cerebral ve- 181,369). Global ophthalmoparesis or ophthalmoplegia may
nous system (366,367,370). They may be unilateral or bilat- be present, and resolves as the intracranial pressure normal-
eral and are often more prominent at night. izes (183).
Focal neurologic deficits in patients with PTC are ex-
tremely uncommon, and their occurrence should make one Cerebrospinal Fluid Examination
consider alternative diagnoses (371). Nevertheless, isolated
A CSF examination is required for the diagnosis of PTC
unilateral and bilateral facial paresis (171,372–376), hemifa-
to confirm an elevated opening pressure and exclude a malig-
cial spasm (377,378), trigeminal sensory neuropathy (379),
nant, infectious or inflammatory process that might simulate
hearing loss (380), hemiparesis, ataxia, paresthesias, mono-
PTC. Normal lumbar CSF pressure in adults is 200 mm
neuropathy multiplex (381), arthralgias, and both spinal and
water or less. For the diagnosis of PTC, the CSF opening
radicular pain (382) have been reported in patients with PTC
pressure should be 250 mm of water or greater. Values be-
(383,384). Patients with chronic PTC are more likely to be
tween 201–249 are not diagnostic (6). In prepubertal chil-
anxious or depressed than age- and weight-matched control
dren, a value over 200 mm water is likely abnormal. Because
subjects (385). Cognitive deficits are less well substantiated
CSF pressure normally fluctuates, multiple CSF pressure
and may be a manifestation of headache-related concentra-
measurements or prolonged CSF pressure monitoring is
tion difficulties, depression, or anxiety (386,387).
sometimes required, depending on the clinical circumstance
Papilledema is the diagnostic hallmark of PTC and is pres-
(395). In obese patients, the LP may be technically challeng-
ent in almost all patients (362,366,367). The papilledema of
ing to perform. To ensure accuracy, the lumbar CSF pressure
PTC is identical with that which occurs in patients with other
must be measured with the patient in the lateral decubitus
causes of increased ICP and may be asymmetrical or, occa-
position, relaxed with the legs partially extended. The pres-
sionally, unilateral (60). PTC without papilledema has been
sure may be artifactually elevated if the patient is crying,
reported but it is uncommon and the diagnosis should be
performing a Valsalva maneuver or is in severe pain (396).
made with caution (69,388–390). Occasionally, continuous
It is recommended that the CSF from the initial LP be ana-
CSF pressure monitoring may be needed to confirm the diag-
lyzed for glucose, protein, cell count, cytology, and atypical
nosis (391). Although there is a correlation between visual
infections (e.g., syphilis, Cryptococcus, fungus). The CSF
loss and high-grade papilledema, the appearance of the optic
contents should be normal in PTC; the protein is generally
disc does not predict visual loss (105,392). There is no corre-
in the normal to low-normal range (397,398).
lation between severity of optic disc swelling and age, race,
or body weight in patients with PTC (393).
Neuroimaging Studies
As with papilledema from other causes, loss of central
visual acuity is uncommon in PTC. One prospective study The rationale for neuroimaging studies in patients with
showed Snellen visual acuity worse than 20/20 in approxi- suspected PTC is twofold:
mately 15% of patients at presentation (367). Visual acuity
is relatively insensitive to visual loss in PTC and should not 1. Prior to obtaining the cerebrospinal fluid, a brain imaging
be relied upon as the sole indicator of visual function (158). study is required to exclude a condition that would put
Color vision testing and visual evoked potentials are simi- the patient at risk of herniation, such as a tumor producing
larly insensitive (171). In general, early central acuity loss, hydrocephalus or mass effect; and
particularly if it is rapidly progressing, is a worrisome sign. 2. To assure that there is no secondary cause of increased
Postpapilledema optic atrophy occurs in untreated or inad- ICP.
equately treated patients after a variable period of time, usu-
ally over several months, but occasionally within weeks of The recommended type of study has been modified with
the onset of symptoms. Some patients have persistent advances in neuroimaging technology. While a plain CT
chronic papilledema without visual deterioration or optic at- scan is generally adequate to ensure that the patient is not
rophy. Postpapilledema optic atrophy in patients with PTC at risk for having a lumbar puncture, the resolution of this
usually develops symmetrically, but just as papilledema may study is insufficient to exclude posterior fossa abnormalities,
be asymmetric, so postpapilledema optic atrophy can be isodense lesions not associated with ventriculomegaly, glio-
asymmetric. Some patients develop a pseudo-Foster Ken- matosis cerebri, meningeal abnormalities or venous sinus
nedy syndrome characterized by postpapilledema optic atro- thrombosis. Thus, MRI is recommended for most patients.
phy in one eye and papilledema in the other (394). For those patients who are not ‘‘typical,’’ such as slim indi-
Visual field testing, by either automated static or manual viduals, children and men, contrast-enhancement and MR
(Goldmann) perimetry, reveals enlargement of the physio- venography should also be considered (315). If the patient’s
logic blind spot in virtually all patients with PTC who have body habitus exceeds the capacity of the MR gantry, a CT
papilledema (158). Other common visual field defects in- scan with contrast should be obtained; catheter angiography
with venous phase sequences may also be needed in such Table 5.3
patients if venous sinus thrombosis is suspected. Etiologies of Obstruction/Impairment of Cerebral Venous
The brain MRI is normal in PTC. The ventricular size Drainage Associated with Pseudotumor Cerebri
should be normal for the patient’s age (399). An asymptom-
Obstruction of superior sagittal sinus
atic empty sella which results from chronically increased Primary hematologic
ICP may be present in over half of cases (400–403). Other Activated protein C deficiency (427,438)
radiographic evidence of increased ICP, best visualized on Essential thrombocythemia (434,436)
orbital images, includes dilation of the perineuronal sub- Factor V Leiden mutation (424)
arachnoid space surrounding the optic nerves, protrusion of Idiopathic thrombocytopenic purpura (430)
the optic papilla into the posterior aspect of the globe and Paroxysmal nocturnal hemoglobinuria (683,684)
flattening of the posterior sclerae (88,404–406). A small Prothrombin gene 20210GA transition (425,426)
percentage of patients of patients have a Chiari type 1 mal- Thrombocytopenic purpura (430)
formation. In addition, orbital echography may be useful Systemic conditions associated with coagulopathy
Behçet’s disease (266–268,271,685)
to differentiate pseudopapilledema from optic nerve head
Cancer (439,686)
drusen and to identify the edematous optic nerve sheath Neurosarcoidosis (264)
using a 30⬚ test (see above) (84,85,407). Pregnancy (433)
Renal disease (495,687)
Secondary Causes Systemic lupus erythematosus (101,435,573–576,688,689)
Trichinosis (690)
IIH is a diagnosis of exclusion that occurs primarily in Surgical/traumatic (440)
young obese women, and occasionally obese men, with no Tumors
evidence of any underlying disease (362,366,408,409). The Extravascular
PTC syndrome may be associated with a number of different Intravascular (418)
conditions. The suspicion of a secondary cause is heightened Obstruction of transverse sinus
Dural arteriovenous fistula (165,210,211,215)
in prepubertal children, men, nonobese women and other-
Hematologic (see above)
wise typical patients with rapidly progressive visual loss that Infection (mastoiditis) (412,420)
does not respond to treatment. The secondary causes of PTC Tumors (extravascular) (419)
include: (a) obstruction or impairment of cerebral venous Occlusion of internal jugular vein (441–444,686)
drainage; (b) endocrine and metabolic dysfunction; (c) expo- Iatrogenic
sure to exogenous drugs and other substances; (d) with- Indwelling catheter (416)
drawal of certain drugs; and (e) systemic illnesses (351, Surgery/traumatic (441–444)
357,409,410). It is important to realize that, although many Tumors
conditions have been reported with PTC, relatively few are Intravascular
likely to be true associations. Tables 5.3–5.6 list associated Extravascular
conditions; the best-substantiated and most frequently ob-
served ones are discussed in the text.
Obstruction or Impairment of Intracranial may also be associated with papilledema, although the disc
Venous Drainage swelling develops late.
Aseptic thrombosis usually occurs in the nonpaired si-
Uncompensated obstruction of cerebral venous drainage nuses of both adults and children, with the superior sagittal
may result in increased ICP and papilledema without en- sinus most frequently affected (422,423). It is sometimes
largement of the ventricles and with otherwise normal CSF accompanied by pronounced engorgement of the vessels of
(68,411–417) (Table 5.3). The obstruction is most often the scalp, retina, and conjunctiva in addition to papilledema.
caused by compression or thrombosis, with the superior sag- Many of these patients have a coagulopathy from a primary
ittal and transverse (lateral) sinuses most often affected (see hematologic disorder such as factor V Leiden mutation
Chapter 45). As previously discussed, tumors that obstruct (424), prothrombin gene 20210GA transition (424–426), ac-
the superior sagittal sinus are usually extra-axial masses, tivated protein C resistance (427), essential thrombocy-
such as meningiomas and vascular lesions (165,418). The themia (428) or, rarely, anti-anticardiolipin antibodies (429)
transverse sinus may be occluded by acoustic neuromas, me- and thrombocytopenic purpura (430). Venous sinus throm-
ningiomas, and metastatic tumors (165,419). bosis is also associated with systemic conditions (e.g., renal
Septic thrombosis of the transverse sinus tends to occur disease, pregnancy, cancer), medication (oral contracep-
in the setting of acute or chronic otitis media, with extension tives), or systemic inflammatory or infectious diseases (e.g.,
of the infection to the mastoid air cells and then to the adja- systemic lupus erythematosus, Behçet’s disease, trichinosis,
cent lateral sinus (412,420). In such cases, papilledema usu- sarcoidosis) (264,268,269,430–439).
ally occurs early and tends to be bilateral and symmetric PTC was reported in a patient after surgical ligation of
(421). A similar appearance occurs in patients with septic the dominant sigmoid sinus to treat long-standing pulsatile
thrombosis of the superior sagittal sinus, a much less com- tinnitus (440). Ligation of one jugular vein (if it is the princi-
mon condition. Septic thrombosis of the cavernous sinus pal vein draining the intracranial area) or both jugular veins
PAPILLEDEMA 273
may produce papilledema. In most instances, occlusion of ning demonstrated a marked reduction of CSF absorption in
the jugular veins occurs during radical neck dissection for a patient with primary hypoparathyroidism, papilledema and
regional tumors (441–444); in other cases, the veins become seizures that returned to normal after correction of the pa-
thrombosed from the effects of indwelling catheters (416). tient’s hypocalcemia (467). It is possible that hypocalcemia
The papilledema in such cases usually does not appear for in patients with hypoparathyroidism leads to an increase in
a week or two. It is virtually always bilateral and severe; intracellular sodium and water that, in turn, interferes with
however, it typically resolves in 2–3 months as collateral transport of CSF through the arachnoid granulations (468).
venous drainage from the head develops to meet the demands
of cerebral blood flow. Medications and Other Exogenous Agents
Patients who are exposed to, or ingest, a variety of sub-
Endocrinologic and Metabolic Conditions stances can develop PTC (Table 5.5). For some of these
Obesity is the most common finding in patients with PTC substances, the association between exposure or ingestion
(362,445–448); one case-control study found obesity and and the development of PTC is well documented in numer-
recent weight gain significantly more prevalent in PTC pa- ous reports and investigations; for others, however, a causa-
tients compared to control subjects (449). Many of these tive relationship is supported by only a single case report
patients also have irregular menses, likely a co-morbidity of and is tenuous at best (409).
obesity rather than an effect of increased ICP (450). The Even when a patient is taking a drug that is known or
female gender predilection in adolescents and adults with suspected to cause PTC, one should not necessarily assume
PTC also suggests a hormonal component. PTC in children that the drug is the sole cause of the condition. For example,
affects prepubertal boys and girls equally and without regard patients may have idiopathic PTC or a real tumor (276) that
to body habitus (103,451,452). After puberty, the female is brought to medical attention or worsens when a particular
predominance and association with obesity emerge as factors medication is used.
for idiopathic PTC (451,453,454). Several antibiotics have been associated with the develop-
PTC has been associated with numerous forms of endo- ment of PTC. The most well-known of these drugs are the
crine and metabolic dysfunction (Table 5.4) but no specific tetracyclines. Tetracycline can produce the syndrome in in-
endocrinologic disturbances are evident (447). Plasma and fants (469,470), children (471,472), and young and older
urinary levels of adrenal steroids in females and urinary go- adults (473–477). PTC has also been infrequently associated
nadotrophins in males are normal (362,364). Plasma renin with minocycline (478–482) and, rarely, with doxycycline
activity and aldosterone levels at baseline, following plasma (483–485). In infants, the condition manifests itself as bulg-
volume contraction by furosemide, and after dexamethasone ing of the fontanelles and occasionally by spreading of su-
therapy in six women with PTC were within normal range tures. Irritability, drowsiness, feeding disturbances, and
(455). In women, PTC is associated with idiopathic ortho-
static edema, a condition characterized by abnormal reten-
tion of sodium, water or both (456). Such patients have Table 5.5
Exogenous Substances Whose Exposure or Ingestion Has Been
symptoms and signs of peripheral edema that may worsen
Associated with Pseudotumor Cerebri
during menses, when fluid retention is most common
(456,457). Amiodarone (524–527)
Although there is no increased incidence of PTC during Antibiotics
pregnancy compared to nongravid young women of similar Tetracycline (469–471,475)
ages (433), PTC may occur or recur during pregnancy Minocycline (478,479,481,482,693)
(458–462). The risk of visual loss in pregnant women with Doxycycline (483–485)
PTC is no greater than in those who are not pregnant (433). Nalidixic acid (486–488)
There is no contraindication to pregnancy among women Beta-human chorionic gonadotropin hormone withdrawal (536,537)
with PTC; the management of PTC during pregnancy is dis- Chlordecone (Kepone) (539)
Corticosteroids withdrawal (355,490–496)
cussed below.
Danazol administration (528,529) or withdrawal (530)
Papilledema occurs in patients with both primary and sec- Growth hormone (516–520)
ondary hypoparathyroidism (354,463–466). 131I-RISA scan- Isotretinoin (509,510)
Lead (338)
Leuprolide acetate (Lupron) (531,532)
Table 5.4 Levonorgesterol implants (Norplant) (521–523)
Endocrine and Metabolic Disturbances Lithium carbonate (533,534)
Associated with Pseudotumor Cerebri Oxytocin (intranasal)
Quinagolide (535)
Addison’s disease (691) Retinoids
Hypoparathyroidism (354,464,466,467) Vitamin A (501–504,506–508,694–705)
Obesity (idiopathic) (447,449) Isotretinoin (509,538,706,707)
Orthostatic edema (456) All-trans-retinoic acid (511–514)
Turner’s syndrome (585,692) Thyroid hormone (708,709)
vomiting are common, although some infants are asymptom- associated with resolution of all symptoms and signs, al-
atic. There is no correlation between the onset of the syn- though Morrice et al. emphasized that resolution of disc
drome and either the dosage of the drug or the length of swelling may take 4 to 6 months (508). Other systemic reti-
therapy, and the reaction has been observed within weeks noids may produce PTC, such as isotretinoin (509,510) and
of starting the medication (481). Older children and adults all-trans retinoic acid (511–514). Rarely, PTC is caused by
have manifestations more consistent with typical PTC. Tet- vitamin A deficiency (515).
racycline is no longer recommended for use in young chil- Other substances associated with the development of
dren because of permanent tooth discoloration, so tetra- PTC include supplemental growth hormone (516–520),
cycline-induced PTC is most frequently encountered in ado- levon-orgestrel implants (Norplant) (521–523), amio-
lescents and young adults who are treated for acne. Cessation darone (524–527), danazol administration and withdrawal
of tetracycline administration causes regression of symp- (528–530), leuprolide acetate (Lupron—a gonadotropin-
toms, although intracranial pressure-lowering therapies may releasing hormone) (531,532), lithium carbonate (533,534),
be needed in the short term, as permanent visual deficits and quinagolide (a nonergot-derived dopamine agonist)
may occur. Although no longer used, nalidixic acid has also (535). It has also been reported following treatment with
been associated with PTC (486–488). declining levels of exogenous beta human chorionic gonado-
Corticosteroids are frequently used to treat increased ICP tropin (536,537).
in patients with brain tumors and may be given acutely to Patients who develop drug-induced PTC are not necessar-
lower the ICP in patients with PTC. Thus, it seems contradic- ily susceptible to PTC when they take another drug that is
tory that corticosteroids may be associated with the develop- known to induce the condition. On the other hand, some
ment of PTC. Nonetheless, chronic functional suppression patients develop PTC when they are taking more than one
of the adrenal cortex with systemic corticosteroid therapy implicated medication, most commonly for the treatment of
has been recognized as a cause of PTC since the late 1950s acne vulgaris (538). Therefore, appropriate caution and mon-
(489). Subsequently, it was recognized that regardless of itoring is advised if attempting to administer another poten-
their underlying condition, patients with steroid-induced tially causative agent in a patient who has a history of drug-
PTC had certain features of Cushing’s syndrome (490). induced PTC.
Within days or weeks after a change in the dosage or type Chlordecone (Kepone) is an organochlorine insecticide
of steroid, and sometimes associated with an intercurrent associated with PTC (539). The capacity for CSF absorption
infection, the patients complained of headache, often accom- as assessed by graded saline infusions into the subarachnoid
panied by nausea and vomiting, less commonly by diplopia, space was found to be impaired in three patients with ele-
and occasionally drowsiness or stupor. Examination of the vated blood, serum and adipose levels of chlordecone (539).
fundi revealed bilateral papilledema, usually low-grade and One effect of chlordecone in experimental animals is inhibi-
often without hemorrhage (490–492). Whereas corticoste- tion of Na-K-ATPase, a major component of the cellular
roids initially lower ICP, their withdrawal may prompt sodium transport system (540). Because inhibition of this
a rebound increase in the ICP and produce PTC system may cause cellular edema, interference with this en-
(355,493–495). There is only one report of papilledema as- zyme may contribute to edema within subarachnoid villi in
sociated with topical steroid treatment in a child being patients intoxicated with chlordecone.
treated for severe eczema (496).
Although there are isolated reports of PTC in patients Systemic Illnesses
taking oral contraceptives (497–499) or estrogen replace-
Vitamin D deficiency produces nutritional rickets and can
ment after hysterectomy (500), this association is likely coin-
be associated with PTC in infants and young children
cidental. One would imagine an epidemic of PTC if this
(541,542). In developed countries, the child at special risk
relationship was causal, given the number of women world-
is an exclusively breast-fed child of a strict vegan mother
wide using these medications.
(357). This form of PTC resolves slowly.
Hypervitaminosis A is another well-recognized cause of
Many systemic disorders have been reported in associated
PTC. Daily ingestion of 100,000 or more units of vitamin
with PTC but most of them do not cause a true PTC syn-
A may, within a few months, produce increased intracranial
drome (Table 5.6). Although they produce papilledema
pressure. In infants and small children, the condition is char-
with normal ventricular size and increased intracranial pres-
acterized by anorexia, lethargy, and an increasing head cir-
sure, they are generally associated with fever, other neuro-
cumference (501–503). Older children and adults develop
logic deficits, altered mental status, seizures or abnormal
PTC (504–506). Other manifestations of hypervitaminosis
cerebrospinal fluid.
A may be present, such as fissuring of the angles of the lips,
loss of hair, migratory bone pain, hypomenorrhea, hepato- Hematologic Disorders
splenomegaly, and dryness, roughness, and desquamation of
the skin. The association of PTC with anemia is tenuous as some
The diagnosis of PTC caused by hypervitaminosis A is of the reported cases had other co-morbid conditions, such
usually straightforward, providing the physician knows that as obesity. Anemia was not shown to be a risk factor for
the patient is ingesting excessive amounts of vitamin A, PTC in case-control studies (366,449). Papilledema is a rare
either as the vitamin itself or in calf, bear, chicken or shark finding in patients with anemia from iron deficiency or,
liver (507). Reduction of the excessive vitamin intake is rarely, vitamin B12 deficiency, hemolytic anemia, megalo-
PAPILLEDEMA 275
Table 5.6 thies, and obstructive sleep apnea (556,557). Studies of the
Systemic Illnesses Associated with Pseudotumor Cerebri pH and pCO2 levels in arterial blood gases and CSF were
performed over a 3-month period in a patient with chronic
Anemia (543–545)
respiratory insufficiency and optic disc swelling (558). The
Chronic respiratory insufficiency (551)
Pickwickian syndrome (562,564)
authors concluded that respiratory acidosis causes an accu-
Obstructive sleep apnea (561,563,565) mulation of CO2 in brain tissue, reflected by inversion of
Hyperthyroidism (339,341) the normal CO2 tension ratio between CSF and arterial
Polyangiitis overlap syndrome (578) blood. This, in turn, causes dilation of cerebral capillaries
Psittacosis (256) and increases intracranial blood volume.
Renal disease (495,687) The Pickwickian syndrome develops when extreme obe-
Sarcoidosis (263,710) sity produces hypoventilation and a typical cardiopulmonary
Systemic lupus erythematosus (101,573,574,576,689,711) syndrome (559). The obesity causes diminished vital capac-
Thrombocytopenic purpura ity, polycythemia, and cyanosis. Severe drowsiness is com-
Vitamin D deficiency (541,542)
mon, and many patients have obstructive sleep apnea (OSA)
(560–562). OSA may be underrecognized in obese patients
with PTC and is diagnosed using overnight polysomnogra-
blastic anemia, or aplastic anemia (543–546). Almost all of phy. Continuous ICP monitoring in an obese man with OSA
the patients are women under age 45, and most have systemic and papilledema showed increased ICP during sleep only,
manifestations of anemia, including fatigue and dyspnea with normal CSF values recorded while he was awake (563).
(543). The presenting symptoms of PTC are headaches, with The nocturnal rise in ICP correlated with a 20–52% drop in
or without or diplopia, and the exam reveals optic disc and oxygen saturation. This finding suggests that increased ICP
retinal hemorrhages. The mechanism may be a related to a may be missed in patients with OSA if the LP is performed
hypercoagulable state in cases of iron defiency anemia, ve- during the daytime. Clinical and necropsy findings were de-
nous sinus thrombosis, or increased blood volume (543). scribed in another patient who weighed 330 pounds (564).
Most patients reported to date have recovered promptly after The patient had marked bilateral optic disc swelling; the
treatment of their anemia. retinal veins were dilated, tortuous, and had a blue-black
PTC occurs in association with two forms of thrombocyto- appearance. A lumbar puncture revealed an opening pressure
penic purpura, both of which are associated with decreased of 480 mm of water with normal CSF contents. Pulmonary
platelet survival: immune idiopathic thrombocytopenic pur- function studies showed a combination of hypoxemia and
pura (ITP) and nonimmune thrombotic thrombocytopenic hypercapnia. At autopsy, the cerebral vessels were dilated,
purpura (TTP). ITP may be acute or chronic. Acute ITP but the dural sinuses were patent. Cut sections of the brain
occurs most often in children, usually after an upper respira- showed diffuse congestion and vascular engorgement with
tory tract infection, whereas chronic ITP occurs most often small ventricles.
in women between 20 and 45 years of age. The etiology of The optic disc swelling that is seen in patients with chronic
this condition is a spontaneously appearing antibody that respiratory disease is likely true papilledema associated with
damages the platelets, causing them to be removed from the cerebral edema and increased ICP. In some patients, how-
circulation by the reticuloendothelial system. PTC in this ever, disc swelling occurs in the absence of increased ICP,
setting may be associated with cerebral venous sinus throm- presumably from a local tissue response to changes in blood
bosis (430). TTP occurs abruptly in previously healthy peo- viscosity and venous pressure (565). When disc swelling is
ple (547). It is characterized by severe thrombocytopenia, secondary to local causes, it is usually not severe (566). The
hemolytic anemia, fever, renal dysfunction, and CNS distur- most prominent features are dilation and tortuosity of retinal
bances. Papilledema and increased ICP occur rarely in TTP vessels, with the fundus having a cyanotic appearance. When
(548,549). increased ICP is present, papilledema may be minimal or
severe. The disc swelling and fundus abnormalities usually
Chronic Respiratory Insufficiency and Hypercapnia resolve rapidly once respiratory acidosis and hypoxia are
treated (563,566).
Chronic respiratory insufficiency of various etiologies Other neurologic manifestations of respiratory failure in-
may produce the PTC syndrome. Affected patients have clude somnolence, asterixis, other movement disorders, and
chronic hypercapnia, with retention of carbon dioxide (CO2), in severe cases, coma (567). Supportive respiratory therapy
reduced blood oxygen (O2) levels, polycythemia, increased and prompt treatment of the acute physiologic, metabolic,
venous pressure, and increased ICP (550). In most cases of and electrolyte abnormalities can significantly prolong sur-
increased ICP related to pulmonary insufficiency, the pulmo- vival and improve the quality of survival time in patients
nary dysfunction is caused by primary pulmonary disease with respiratory failure who have papilledema or other neu-
(551–554). One of the earliest reports in 1933 described a rologic complications (551,568).
34-year-old miner with severe pulmonary emphysema who
initially developed bilateral disc swelling and venous Hypertension
congestion and who eventually became blind from optic at-
rophy (555). Increased ICP was subsequently described with Optic disc swelling occurs in some patients with severe
emphysema, the Pickwickian syndrome, systemic myopa- hypertension (569). Some of these patients have neurologic
symptoms of an encephalopathy; others do not. Among the vated for many years, even if systemic and visual symptoms
patients with evidence of an encephalopathy, almost all have resolve. The feared complication of PTC is permanent visual
increased ICP caused by cerebral edema. In addition, some loss. In one long-term study performed prior to the era of
patients without symptoms of encephalopathy have evidence modern neuroimaging, 57 patients with a diagnosis of PTC
of cerebral edema by neuroimaging and increased ICP on were followed for 5–41 years (572). Severe visual impair-
lumbar puncture. In patients with optic disc swelling associ- ment occurred in one or both eyes in 14 patients (26%), and
ated with normal ICP, the swelling may be caused by break- in 7 patients the visual loss occurred months to years after
down of the blood-retinal barrier, or it may represent hyper- initial symptoms appeared. In over 80% of the patients in
tensive retinopathy or an anterior ischemic optic neuropathy this study, CSF pressure remained elevated, regardless of
(570,571). Coexisting systemic hypertension confers a poor the treatment the patients had received. PTC may recur years
visual prognosis in patients with PTC (105,572). after successful treatment, sometimes resulting in visual loss
(165,167). The effects of even self-limited PTC on the visual
Vasculitis system may be catastrophic. PTC produces significant visual
The PTC syndrome may occur in patients with systemic impairment in approximately 25% of patients (151,350,357,
lupus erythematosus (101,573,574). In some of these cases, 581,582) and permanent visual field abnormalities in most
the pathogenesis is occlusion of one of the dural venous patients (156,158,367).
sinuses, usually the superior sagittal sinus (435,575). In other
cases, the pathogenesis is unclear (576). The condition usu- PATHOPHYSIOLOGY
ally resolves with corticosteroid treatment suggesting that
inflammation and tissue necrosis in the region of the arach- The etiology of increased ICP in patients with idiopathic
noid villi interferes with CSF absorption, raising the ICP. PTC is uncertain (583,584). A unifying theory must explain
In other patients, fluctuating corticosteroid dosage and the several features of IIH: (a) the predilection for obese women
weight gain associated with corticosteroid use may be con- of childbearing age; (b) lack of ventriculomegaly; and (c)
tributory. clinically identical syndrome produced by other etiologies,
PTC was described as the presenting sign of the polyangi- such as cerebral venous sinus thrombosis and medications.
itis overlap syndrome, a disorder with a conglomerate of Several mechanisms are postulated to account for the disrup-
features that intersect several vasculitic syndromes, particu- tion in CSF homeostasis, including increased CSF produc-
larly Churg-Strauss syndrome and polyarteritis nodosa tion and decreased CSF absorption.
(577). A 9-year-old girl presenting with PTC as the cardinal Why is the disorder more common in overweight women?
manifestation of the polyangiitis overlap syndrome has been Some authors have suggested that extraovarian estrogen may
reported. The child died despite treatment with high-dose produce the menstrual irregularities in some of the obese
systemic corticosteroids (578). At postmortem examination, young women with PTC (585). After finding that the concen-
cerebral edema was present, but the dural sinuses were pat- tration of estrone in the CSF of obese women was higher
ent. Two primary mechanisms by which vasculitis causes than normal, it was postulated that estrone stimulates the
PTC were postulated: (a) the vasculitis may affect the cere- secretory cells of the choroid plexus to produce more CSF
bral venous sinuses and produce thrombosis; or (b) inflam- than can be absorbed at normal CSF pressures (586). How-
mation and tissue necrosis in the region of the arachnoid ever, others could not confirm this finding and indeed found
villi could interfere with CSF absorption (578). that the concentration of estrogen in the CSF of 15 patients
with PTC, 8 of whom were obese women, was undetectable
Renal Failure (587).
What is the primary pathology of PTC? Most evidence
Renal failure is uncommonly associated with PTC. Re-
points to decreased absorption of CSF (362,588,589) with
ports suggest that coexisting renal failure may be associated
increased cerebral blood volume (590). ICP is normally
with more aggressive intracranial hypertension that causes
maintained by a compliance factor arising from distention of
visual loss and is often refractory to treatment (293,572,579).
meningeal membranes and compression of vascular volume,
The cause of PTC in patients with renal failure is probably
and a resistance factor that modulates CSF volume by vent-
multifactorial. Some patients are obese, an important associ-
ing CSF through the arachnoid granulations into the cerebral
ation in PTC. Fluid overload, increased cerebral blood flow
venous system (591). Fifty percent of CSF is below the fora-
and hypervitaminosis A may also be contributory.
men magnum and almost half is absorbed in the spinal sac
Familial Pseudotumor Cerebri (111,590). In the intracranial compartment, infusion studies
indicate that resistance factors are quickly exceeded (591).
The occurrence of PTC in multiple family members is With increased CSF volumes, a point is eventually reached
well recognized (351,476,580) (Fig. 5.33). In some families, where compliance mechanisms fail and a small increase in
the affected members are all obese but no definitive common volume results in a large increased in ICP (592,593).
metabolic or endocrinologic abnormalities have been found. Some authors speculate that within the cranium, there may
be increased cerebral venous pressure, reversing the normal
COMPLICATIONS
gradient between sinus and subarachnoid space, or an in-
The natural history of PTC is unknown. In some cases it crease in the resistance to flow of CSF across the arachnoid
is a self-limited condition; in others, the ICP remains ele- villi (362,364). Others postulate that an abnormality in the
PAPILLEDEMA 277
Figure 5.33. Familial pseudotumor cerebri. A and B, Right and left optic discs, respectively, in a 45-year-old man with
pseudotumor cerebri. C and D, Right and left optic discs, respectively, in his 18-year-old daughter who also had pseudotumor
cerebri.
cerebral microvasculature is responsible for an elevated ce- It is possible that the increased pressure and cerebral blood
rebral blood volume and that the intracranial hypertension volume is reflected primarily within the venous system, as
in patients with IIH can be explained only by tissue swelling it is distensible, rather than the ventricles. Venous hyperten-
from an increase in total water content (590). sion has been proposed as a unifying hypothesis to explain
Why is there no ventricular enlargement? Measurements PTC syndromes (599,600). Manometry has shown elevated
of ICP, conductance to CSF outflow, and cerebral blood cerebral venous pressure in patients with PTC (599). Cere-
flow in 14 patients with PTC suggest that patients with PTC bral venography and manometry demonstrated venous hy-
have both a defect in CSF absorption and an increased cere- pertension in the superior sagittal sinus and proximal trans-
bral volume associated with a noncompliant ventricular sys- verse sinus, but not in the distal transverse sinus, of all
tem that resists dilation (594). The presence of cerebral patients with idiopathic PTC but not in the patients with
edema could also account for the lack of ventriculomegaly. minocycline-induced PTC (601). The possibility of focal ste-
Some MRI studies have shown white matter signal changes nosis or thrombosis of the venous sinuses was raised. Subse-
consistent with increased water content in patients with PTC quent studies showed a reciprocal relationship between CSF
(595,596) while others have not (400,597). An initial report pressure and pressure in the superior sagittal sinus and trans-
of a pathology specimen examined from subtemporal de- verse sinuses in patients with IIH (600). That is, removal of
compression suggested that edema might be present (347) CSF from the cervical region resulted in a decline of venous
but reexamination of the pathologic material and evidence pressure. The investigators postulated that the increased ve-
from two other cases refuted the presence of interstitial nous pressure was a result of compression from raised ICP
edema (598). rather than a primary venous occlusive process. Lateral sinus
stenting in 12 patients produced a reduction in torcular and and transudation (614). Urinary excretion of vasopressin
jugular bulb pressure in all cases that was not necessarily (AVP) is excessive in patients with orthostatic edema in the
accompanied by clinical improvement (602). upright posture (614). High levels of vasopressin are found
The association between venous hypertension and PTC in the CSF of patients with PTC (587,615–617). The role
syndrome seen with venous sinus thrombosis has prompted of AVP in the CSF is to regulate brain water content and it
investigations looking for a hypercoaguable state in patients raises intracranial pressure by increasing water transudation
with idiopathic and secondary PTC. Initial studies suggested from cerebral capillaries in the choroid plexus epithelium
that anticardiolipin antibodies were more common in pa- and the arachnoid villi (618). Although there does not seem
tients with PTC than would be expected in the general popu- to be a significant component of cerebral edema in PTC,
lation (603,604). Subsequently, a prospective case-control the excessive fluid may be absorbed by the venous system,
study evaluated subjects for the factor V Leiden mutation, accounting for the venous hypertension described above.
the prothrombin G20210A allele, homocysteine, antithrom- The high association of anxiety and depression in PTC
bin III, protein C, activated protein C resistance, protein S, patients compared to age- and weight-matched control sub-
lupus anticoagulant, anticardiolipin antibodies, liver and thy- jects (385) raises the possibility of a common neurotransmit-
roid functions, urea, glucose, electrolytes, lipid levels, pro- ter derangement. Serotonin and norepinephrine are associ-
thrombin time, activated partial thromboplastin time, and ated with these mood disorders and CSF homeostasis.
derived fibrinogen (605). There was no evidence of familial Serotonin, implicated in depression and anxiety, is found in
thrombophilia in patients with IIH. the highest concentrations within the brain in the choroid
Can the conditions known to produce the PTC syndrome plexus, and serotonin receptors play a role in CSF production
provide any clues to the pathogenesis of the disorder? Hyper- (619). Administration of 5-hydroxytryptamine intrathecally,
vitaminosis A is perhaps the best studied of these associa- or intraventricular or intravenous infusion of norpinephrine,
tions, as PTC may develop with the use of vitamin A and produce a dose-related decrease CSF production of 30–50%
other retinoids. Vitamin A, in the form of retinol, is carried in rabbits (186,187). Neurotransmitter levels in PTC patients
in the serum by retinol-binding protein (RBP) (606). This have not been studied.
protein is normally excreted by the kidney; however, in the Despite the progress in our understanding of IIH, Fish-
setting of renal failure, or when the capacity for hepatic man’s comment that there are ‘‘more speculations than data
storage or binding to RBP is exceeded, the concentration of available’’ remains applicable (584).
the protein in the serum rises, as do the concentrations of
both bound and unbound vitamin A (579,606,607). Although
bound retinol is nontoxic, unbound retinyl esters cause hy- MONITORING
pervitaminosis A (607,608). Excessive retinol and retinyl
Since the major morbidities of PTC are visual loss and
esters disrupt the integrity of cell membranes. Retinol is
headaches, a team approach to management is necessary.
actively transported across the blood-brain barrier by trans-
thyretin (previously called prealbumin) in a complex with The tempo of visual loss in patients with PTC may be rapid
RBP and is found in human choroid plexus epithelium. It is or slowly progressive. Most visual defects associated with
also transported to endothelial cells in the microvasculature papilledema are reversible if ICP is lowered before there is
of the brain (609,610). The effect on choroid plexus transport severe visual loss or optic nerve ischemia (105,156). Thus,
may be impairing CSF outflow or producing a toxic effect it is imperative that patients be monitored by an ophthalmol-
on CSF absorption (607,610,611). ogist who can assess the best corrected visual acuity, optic
One study demonstrated that serum retinol levels were nerve functions, visual fields by quantitative static or kinetic
higher in IIH patients than in control subjects, and were perimetry, and the severity of papilledema (157,367). Pa-
not correlated to body mass index, diet, or age (612). No tients with papilledema most often develop progressive loss
difference was found in retinyl ester concentration or retinyl of visual function in a manner similar to that which occurs
ester levels. Another study found no significant difference in chronic open angle glaucoma. Loss of central vision is
in serum retinol and RBP levels between IIH patients and usually a late phenomenon, whereas visual field defects, usu-
controls subjects overall (613). However, some of the IIH ally arcuate scotomas and nasal steps, are an early finding
patients had markedly elevated RBP levels whereas none of (157).
the control subjects did (613). Examination of vitamin A Although all patients with papilledema should be tested
in the cerebrospinal fluid showed significantly higher CSF to determine if there is a relative afferent pupillary defect
vitamin A levels in some IIH patients that were not associ- (RAPD), papilledema tends to be a bilateral and fairly sym-
ated with increased ICP, body mass index, age, or gender metric in this condition (see above). Thus, when present in
(609). a patient with papilledema, a RAPD is a cause for concern
IIH in women is associated with idiopathic orthostatic as it indicates more damage to the retina or optic nerve of
edema, a condition characterized by excessive sodium and/ the affected eye with the RAPD. The absence of a RAPD,
or water retention, particularly in the upright posture (456). however, cannot be taken as evidence that there is no optic
The pathogenesis of both disorders has been linked to a vas- nerve damage from increased ICP (620). In addition to stan-
cular etiology and abnormal vasopressin regulation. Ortho- dard clinical testing, stereo color photographs of the optic
static edema is generally attributed to an incompetent pre- discs obtained on a regular basis are helpful to provide the
capillary sphincter causing increased vascular permeability examiner with objective evidence of the appearance of the
PAPILLEDEMA 279
optic discs. Alternatively, scanning laser tomography of the though treating the underlying condition usually produces
discs can be performed (90,621). improvement, it may also be necessary to employ other med-
The intervals between clinical assessments of patients ical and surgical treatments specifically directed at control-
with papilledema must be individualized. At disease onset, ling ICP (417).
some patients will require an evaluation every 1–2 weeks
until a pattern of progression or stability is established. Other Treatment Related to Obesity
patients are examined every 1–3 months, and patients with
Weight loss is advised for obese patients based on retro-
stable vision from papilledema may only be examined every
spective analyses indicating that a modest degree of weight
4–12 months. Most patients may be monitored clinically by
loss (approximately 6% of body weight) correlates with a
following their visual status. Monitoring the status of the
reduction in papilledema (623–625). Weight reduction
ICP by lumbar puncture is not necessary on a routine basis.
should be considered a long-term management solution and
Once it is established that the neuroimaging studies are nor-
is not useful as a sole treatment modality for patients with
mal, subsequent scans are not helpful to assess the patient’s
acute visual loss. When possible, the weight loss should be
progress unless another condition, such as venous sinus
achieved through a combination of diet and exercise pre-
thrombosis, is suspected.
scribed by a registered dietician or nutritionist setting realis-
tic goals. Many women with idiopathic PTC also have ortho-
TREATMENT static edema and have excessive sodium or water retention
Most patients with PTC will require co-management from (456). In such patients, decreasing the food intake while
more than one physician. A neurologist, ophthalmologist, increasing water consumption, as is commonly employed
primary care physician and neurosurgeon may be involved in weight reduction plans, may be counterproductive, and
in the patient’s care. The primary responsibility for coordi- sodium restriction is often helpful (456). When weight loss
nating the patient’s treatment is generally relegated to the efforts fail, bariatric surgery may be considered. Such sur-
neurologist or neuro-ophthalmologist; good communication gery is generally successful in producing weight reduction
between providers is crucial for a successful outcome. The (626), although significant complications exist, including
approach to treatment depends on several factors: anastomotic leaks, small bowel obstruction, malabsorption
syndromes and gastrointestinal bleeding. Normalization of
ICP and resolution of papilledema have been reported after
The presence and degree of symptoms such as headache;
bariatric surgery in retrospective case series (626,627).
The degree of visual loss at presentation;
Obese patients with PTC from hypoxia and hypercapnia
The rate of progression of visual loss;
(i.e., the Pickwickian syndrome, obstructive sleep apnea)
The presence of an identifiable underlying etiology (e.g.,
may respond not only to weight loss but also to low flow
medication induced PTC);
oxygen and positive airway ventilation using either continu-
The detection of factors known to be associated with a poorer
ous positive airway pressure (CPAP) or bilevel positive air-
visual prognosis (e.g., high-grade papilledema with macu-
way pressure (bi-PAP) (568,628). Often there is a rapid im-
lar edema, venous sinus thrombosis, systemic hyperten-
provement in headaches once CPAP or bi-PAP is initiated.
sion);
Pregnancy. Medications to Lower the Intracranial Pressure
Regardless of the etiology, the primary goals of treatment Carbonic anhydrase, present in the choroid plexus, has
are to preserve vision and alleviate symptoms. The treatment a major role in the secretion of CSF. Carbonic anhydrase
of PTC in adults and children is similar. Both medical and inhibitors decrease production of CSF, resulting in decreased
surgical treatments are used, often in combination. No single sodium ion transport across the choroidal epithelium
treatment is completely effective in this regard (151, (184,629,630). They also have a mild diuretic effect. The
388,622). Current practice patterns regarding the manage- most commonly used agent is acetazolamide (Diamox)
ment of PTC are based largely on case series and clinical (631–633). Reduced ICP may be observed in patients with
experience; there are no randomized trials prospectively as- idiopathic PTC treated with intravenous acetazolamide
sessing the effectiveness of treatment in this disorder. Addi- within several hours (8). In adults, acetazolamide is started
tionally, PTC is considered an ‘‘off label’’ usage for all at a dose of 1 gm per day, given in divided doses of either
medications currently prescribed to treat the disorder. 250 mg qid or 500 mg SequelsTM bid. Theoretically, the
dose can be increased up to a maximum of 4 gm per day.
Medical Treatment The effective dose is 1–4 grams daily, but maximum dose
is often limited by side effects, which include paresthesias of
Medical therapy is most appropriate when the primary the extremities, lethargy, and altered taste sensation (8,631).
problem is headache in the setting of good vision. In asymp- These side effects can be reduced but not eliminated by using
tomatic patients with papilledema, close observation of vi- Sequels, if available (634). Alternatively, methazolamide
sual function without specific therapy may be employed (Neptazane) may be used and is sometimes better tolerated
once an underlying etiology is excluded. If a secondary cause than acetazolamide.
is identified, it should be treated appropriately. For example, Other diuretics are used to treat PTC (635), including furo-
implicated exogenous agents should be discontinued. Al- semide and chlorthalidone (456,579,632). Spironolactone
and triamterene may be considered in patients who are aller- mary pathology, the risks and benefits to each procedure
gic to carbonic anhydrase inhibitors and other sulfonamide must be considered for each patient. Sometimes more than
containing diuretics. Combining diuretics, or using them one type of surgical procedure is necessary (167,639). Nei-
with carbonic anhydrase inhibitors, may produce hypoka- ther procedure is generally employed until there is convinc-
lemia and should be done with extreme caution. ing evidence of an optic neuropathy that accounts for the
Although systemic corticosteroids are clearly beneficial lack of improvement or continued visual deterioration in
in the treatment of PTC associated with various systemic some patients undergoing technically ‘‘successful’’ surgery.
inflammatory disorders, such as sarcoidosis and systemic There are no studies comparing ONSD and shunting. Meta-
lupus erythematosus, they are not generally recommended analysis of either condition is confounded by differences in
for routine use in PTC. Corticosteroids lower the ICP acutely surgical technique and outcomes assessment, the retrospec-
but their withdrawal leads to a rebound increase in ICP. tive nature of the data, and underreporting of adverse events.
Moreover, their long-term side effects (weight gain, fluid
retention) are undesirable in the population most affected by Cerebrospinal Fluid Diversion Procedures
PTC. Corticosteroids are reserved for the urgent treatment
Ventriculoperitoneal shunting is quite effective in lower-
patients with impending or progressive visual loss while ar-
ing intracranial pressure in patients with PTC but this proce-
ranging a definitive surgical procedure (410,636).
dure can be difficult unless a stereotactic method is used,
because the ventricles in patients with PTC are normal in
Headache Management
size, not enlarged (640–642). Thus, most neurosurgeons pre-
For patients in whom headache is the main problem, tech- fer the lumboperitoneal shunt, in which a silicone tube is
niques of headache management are employed as in patients placed percutaneously between the lumbar subarachnoid
with frequent migraines or tension-type headaches. There space and the peritoneal cavity (643). Most patients treated
are many prophylactic medications that may be helpful, al- with a shunt experience rapid normalization of ICP and reso-
though some of them have the potential to cause weight gain lution of papilledema, often with improvement in visual
(e.g., sodium valproate, tricyclic antidepressants), or fluid function after shunting (644–648). However, the shunts tend
retention (e.g., calcium channel blockers). Early experience to obstruct over time, and over half of patients ultimately
with topiramate has been promising; it effectively prevents require one or more shunt revisions, often within months
headaches, has mild carbonic anhydrase activity and com- after their initial insertion (647–649). Complications of the
monly produces weight loss (637). Many patients with PTC shunt procedure include spontaneous obstruction of the
experience other types of headaches unrelated to their intra- shunt, usually at the peritoneal end, excessively low pres-
cranial pressure (638). The frequent use of analgesics is dis- sure, infection, radiculopathy, and migration of the tube, re-
couraged, as analgesic induced headaches may develop. sulting in abdominal pain (645,649–652). Some patients also
develop a Chiari malformation after lumboperitoneal
Repeated Lumbar Punctures shunting that may or may not be symptomatic (647). Al-
though the risks of shunting are generally minor, fatal tonsil-
Lumbar punctures are sometimes useful to relieve the in- lar herniation after shunting in PTC has been reported (13).
creased ICP of idiopathic PTC. The rationale behind the Many of the complications from lumboperitoneal shunts can
procedure is uncertain. Repeated LPs are traumatic for the be avoided by using a programmable valve. Alternatively,
patient and often technically difficult to perform but they ventriculoperitoneal shunting or cisterna magna shunting
are useful in selected individuals with intermittent symptom (589), can be performed, but those procedures are technically
exacerbations. They are also one of the preferred treatments more difficult.
of PTC during pregnancy. Some clinicians favor a ‘‘high
volume’’ LP, removing 20 ml or CSF or more, but patients Optic Nerve Sheath Decompression
may develop low pressure headaches after this procedure.
Another approach is to lower the pressure into the normal Optic nerve sheath decompression (ONSD) was first used
range (target range for closing pressure 140–180 mm water), to treat papilledema in increased ICP in 1872 (653). Subse-
which generally affords relief while lessening the likelihood quent investigators employed modifications of de Wecker’s
of post-LP headache. technique and found it to be at least transiently effective
(654,655). In 1964, Hayreh employed the technique on mon-
Surgical Procedures keys to demonstrate that papilledema could be relieved by
reducing the CSF pressure within the subarachnoid space
Surgery is employed when patients initially present with of the optic nerve (63). Both lateral (656–658) and medial
severe optic neuropathy or when other forms of treatment (64,659) approaches are used, incorporating the operating
have failed to prevent visual loss. It is not recommended for microscope.
the treatment of headaches alone. Historically, subtemporal A successful optic nerve sheath fenestration results in res-
decompression was performed but it has been replaced by olution of papilledema on the operated side and, occasion-
a shunting procedure or optic nerve sheath decompression ally, on the other, with bilateral improvement in visual func-
(ONSD). The decision of whether to proceed with a shunt tion in many cases (392,622,660–669). The procedure
versus ONSD depends largely on the local resources avail- immediately reduces pressure on the nerve by creating a
able. Although one may argue that shunting treats the pri- filtration apparatus that controls the intradural pressure sur-
PAPILLEDEMA 281
rounding the orbital segment of the optic nerve (102). Al- REFERENCES
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ing ONSD and concluded that the decrease in papilledema 4. Kennedy F. Retrobulbar neuritis as an exact diagnostic sign of certain tumors
and the visual improvement occurred from a local decrease and abscesses in the frontal lobe. Am J Med Sci 1911;142:355.
5. Paton L, Holmes G. The pathology of papilloedema. A histological study of 60
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CHAPTER 6
Optic Neuritis
Craig H. Smith
IDIOPATHIC AND PRIMARY DEMYELINATING OPTIC Optic Neuritis After Vaccination

NEURITIS Optic Neuritis in Sarcoidosis
Acute Idiopathic Demyelinating Optic Neuritis Syphilis
Chronic Demyelinating Optic Neuritis Optic Neuritis in HIV-Positive Patients and Patients with Aids
Asymptomatic (Subclinical) Demyelinating Optic Neuritis Optic Neuritis in Systemic Lupus Erythematosus and Other
Neuromyelitis Optica (Devic’s Disease) Vasculitides
Optic Neuritis in Myelinoclastic Diffuse Sclerosis (Encephalitis Lyme Disease
Periaxialis Diffusa, Schilder’s Disease) Sinus Disease
Encephalitis Periaxialis Concentrica (Concentric Sclerosis of Miscellaneous Causes of Optic Neuritis
Baló) BILATERAL OPTIC NEURITIS
CAUSES OF OPTIC NEURITIS OTHER THAN PRIMARY OPTIC NEURITIS IN CHILDREN
DEMYELINATION NEURORETINITIS
Optic Neuritis from Viral and Bacterial Diseases OPTIC PERINEURITIS (PERIOPTIC NEURITIS)
Optic neuritis is a term used to refer to inflammation of ocular optic nerve and the peripapillary retina. In addition to
the optic nerve. When it is associated with a swollen optic optic disc swelling, eyes with neuroretinitis show extensive
disc, it is called papillitis or anterior optic neuritis. When retinal edema, vitreal inflammatory changes, hemorrhages,
the optic disc appears normal, the term retrobulbar optic and hard exudates (lipid) in the macula in a star-shaped pat-
neuritis or retrobulbar neuritis is used. In the absence of tern. Optic perineuritis, also called perioptic neuritis, de-
signs of multiple sclerosis (MS) or other systemic disease, scribes inflammatory involvement of the optic nerve sheath
the optic neuritis is referred to as monosymptomatic or idio- without inflammation of the nerve itself. Patients with this
pathic, or as a clinically isolated syndrome. The pathogenesis condition have optic disc swelling that may be unassociated
of isolated optic neuritis is presumed to be demyelination with any visual complaints. In such cases, visual acuity is
of the optic nerve, similar to that seen in MS. It is likely normal in the affected eye, and there is no visual field defect
that most cases of isolated acute optic neuritis are a forme except for an enlarged blind spot. The disc swelling thus
fruste of MS. Optic neuritis, as a harbinger of a more diffuse may be difficult to differentiate from papilledema, particu-
demyelinating process, merits careful attention to an exact larly when it is bilateral, without performing neuroimaging
diagnosis and a thorough consideration of treatment para-
studies and lumbar puncture (discussed later).
digms.
Most of this chapter deals with acute demyelinating optic
Optic neuritis does not always present as acute loss of
vision. It may develop as insidious progressive or nonpro- neuritis, occurring in isolation, in association with MS, or
gressive visual dysfunction, and it may even be asymptom- in association with other demyelinating diseases. The later
atic. Patients with asymptomatic optic neuritis have electro- sections of the chapter discuss other forms of demyelinating
physiologic evidence of optic nerve dysfunction and may optic neuritis, optic neuritis caused by processes other than
also have subtle clinical evidence of optic nerve damage if MS and related disorders, and the variants of optic neuritis:
appropriate clinical studies are performed. neuroretinitis and perioptic neuritis. Our knowledge of the
Optic neuritis can be caused by disorders other than MS immunopathogenesis and clinical aspects of optic neuritis
and related demyelinating diseases. In addition, two unusual has taken huge steps with the information provided by the
variants of optic neuritis can occur. Neuroretinitis is a term Optic Neuritis Treatment Trial (ONTT) and ancillary devel-
used to describe inflammatory involvement of both the intra- opment of the genetic and neuroimmunologic basis of MS.
293
IDIOPATHIC AND PRIMARY DEMYELINATING OPTIC NEURITIS

Despite remarkable advances in neuroimaging and elec- (1 mg/kg/d) for 11 days; or (c) oral placebo for 14 days.
trophysiologic testing, the diagnosis of optic neuritis remains Each regimen was followed by a short oral taper.
basically a clinical one. Nettleship (1) first described a syn- Measurement of visual function was made at study entry,
drome characterized by ‘‘failure of sight limited to one eye, at seven follow-up visits during the first 6 months, yearly
often accompanied by neuralgic pain about the temple and for 4 years, then at 5 and 10 years (as the Longitudinal
orbit and by pain in moving the eye; many recover but per- Optic Neuritis Study [LONS]). Data collected at the 6-month
manent damage and even total blindness may ensue; there follow-up visit served as the primary measure of visual out-
is at first little, sometimes no, ophthalmoscopic change, but come. Both the rate of visual recovery and long-term visual
the disc often becomes more or less atrophic in a few outcome were assessed by four measures:
weeks.’’ Nettleship (1) also emphasized the tendency for the
orbital pain to antedate the loss of vision and for the maxi- 1. Snellen acuity with a retroilluminated Bailey-Lovie chart
mum visual field defect to be central in nature. Subsequently, at 4 meters
Parinaud (2), Uhthoff (3), Buzzard (4), and Gunn (5) de- 2. Color vision with the Farnsworth-Munsell 100-hue test
scribed similar patients. 3. Contrast sensitivity with the Pelli-Robson chart
Optic neuritis usually is a primary demyelinating process. 4. Perimetry with the Humphrey Field Analyzer (program
It almost always occurs as an isolated phenomenon or in 30-2) and Goldmann perimeter
patients who either have, or will develop, MS. Patients in
whom optic neuritis occurs as an isolated phenomenon have A standardized detailed neurologic examination was per-
a higher risk of developing MS at some later date than the formed at study entry, after 6 months, after 1 year, yearly for
normal population. Optic neuritis is also part of the de- 4 years, and then at 5 and 10 years (in the LONS). Additional
myelinating syndrome called ‘‘neuromyelitis optica’’ or examinations were performed when patients developed new
‘‘Devic’s disease,’’ and it occasionally occurs in two other neurologic symptoms during the first 5 years, and brain mag-
primary demyelinating diseases: myelinoclastic diffuse scle- netic resonance imaging (MRI) was obtained on all patients
rosis (encephalitis periaxialis diffusa, Schilder’s disease) and at 10 years who had initially had a normal brain MRI. Clini-
encephalitis periaxialis concentrica (concentric sclerosis of cally definite multiple sclerosis (CDMS) was diagnosed
Baló). There are three forms of primary demyelinating optic when a patient developed new neurologic symptoms attribut-
neuritis: acute, chronic, and subclinical. able to demyelination in one or more regions of the central
nervous system (CNS), other than new optic neuritis in either
ACUTE IDIOPATHIC DEMYELINATING OPTIC eye, occurring at least 4 weeks after the optic neuritis at study
NEURITIS entry and lasting more than 24 hours, with abnormalities
Acute demyelinating optic neuritis is by far the most com- documented on neurologic examination.
mon type of optic neuritis throughout the world. It is also
the type that is best known and understood. Although the Demographics
clinical syndrome of acute optic neuritis has been well recog- Much of the following information on demographics,
nized for many years, much information about optic neuritis long-term risk of MS development, and visual outcome in
was obtained from the ONTT (6–26), a multicenter con- optic neuritis comes from the ONTT/LONS. The annual in-
trolled clinical trial funded by the National Eye Institute of cidence of acute optic neuritis has been estimated in popula-
the National Institutes of Health in the United States. This tion-based studies to be 1–5 per 100,000 (27–33). In Olm-
trial was the first in the field of MS research to look rigor- stead County, Minnesota, where the Mayo Clinic is located
ously at a treatment outcome as well as to define metrics and where extensive and accurate studies of the incidence
of outcome. The ONTT enrolled 455 patients with acute of various diseases have been performed, the incidence rate
unilateral optic neuritis. Although the primary objective of is estimated to be 5.1 per 100,000 person-years and the prev-
the trial was to assess the efficacy of corticosteroids in the alence rate 115 per 100,000 (33).
treatment of optic neuritis, the trial also provided invaluable Most patients with acute optic neuritis are between the
information about the clinical profile of optic neuritis, its ages of 20 and 50 years, with a mean age of 30–35 years.
natural history, and its relationship to MS. Females are affected more commonly than males. In the
Entry criteria in the ONTT included a clinical syndrome ONTT, 77% of the patients were female, 85% were Cauca-
consistent with unilateral optic neuritis (including a relative sian, and the mean age was 32 Ⳳ 7 years. Nevertheless,
afferent pupillary defect and a visual field defect in the af- optic neuritis can occur at any age. It is well described in
fected eye), visual symptoms of 8 days or less, no previous children in the first and second decades of life (34–38), and
episodes of optic neuritis in the affected eye, no previous it can occur in adults in the sixth and seventh decades (39).
corticosteroid treatment for optic neuritis or MS, and no
evidence of a systemic disease other than MS as a cause for Symptoms
the optic neuritis. Patients were randomly assigned to one
of three treatment groups: (a) oral prednisone (1 mg/kg/d) The two major symptoms in patients with acute optic neu-
for 14 days; (b) intravenous methylprednisolone sodium suc- ritis are loss of central vision and pain in and around the
cinate (250 mg QID for 3 days) followed by oral prednisone affected eye. Other symptoms are much less common.
OPTIC NEURITIS 295
Loss of Central Vision blurring, both at the onset of their visual symptoms and dur-
Loss of central visual acuity is the major symptom in most ing the course of the disorder. These phenomena are sponta-
cases of acute optic neuritis, being reported by over 90% of neous flashing black squares, flashes of light, or showers of
patients (7). Loss of vision is usually abrupt, occurring over sparks (39,49,50). These visual phenomena may be precipi-
several hours to several days. Progression for a longer period tated by eye movement (44,50) or certain sounds (51,52).
of time can occur but should make the clinician suspicious Positive visual phenomena were reported by 30% of the pa-
of an alternative disorder. The degree of visual loss varies tients in the ONTT.
widely. In some cases visual acuity is minimally reduced;
in others there is complete blindness with no perception of Signs
light. Most patients describe diffuse blurred vision, although Examination of a patient with acute optic neuritis reveals
some state that blurring is predominantly central. The visual evidence of optic nerve dysfunction. Visual acuity is reduced
loss is monocular in most cases, but in a few patients, partic- in most cases. Contrast sensitivity and color vision are im-
ularly in children, both eyes are simultaneously affected. paired in almost all cases. The reduction in contrast sensitiv-
ity often parallels the reduction in visual acuity (53), al-
Loss of Visual Field
though in some cases it is much worse (7). The reduction
Not all patients with acute optic neuritis complain of loss in color vision is often much worse than would be expected
of central vision. Some complain of loss of peripheral vision, from the level of visual acuity (54,55). Visual field loss can
usually in a particular area of the visual field, such as the vary from mild to severe. A relative afferent pupillary defect
inferior or superior region, often to one side. Such patients is present and detectable with a swinging flashlight test in
may deny loss of central acuity and may be found to have almost all unilateral cases. When such a defect is not present,
20/20 or better vision in the affected eye (40). either there is a coexisting optic neuropathy in the fellow
eye or the visual loss in the affected eye is not caused by
Ocular or Orbital Pain optic neuritis or any other form of optic neuropathy. Patients
Pain in or around the eye is present in more than 90% of with optic neuritis also can be shown to have a reduced
patients with acute optic neuritis. It is usually mild, but it sensation of brightness in the affected eye simply by asking
may be extremely severe and may even be more debilitating them to compare the brightness of a light shined in one eye
to the patient than the loss of vision. It may precede or occur and then another or by performing more complex testing
concurrently with visual loss; usually is exacerbated by eye with a flickering light, the frequency of which can be varied
movement; and generally lasts no more than a few days between 50 and 0 Hz (56–58).
(7,39,41–44). In the ONTT, pain was reported by 92% of Slit-lamp biomicroscopy in eyes with demyelinating optic
patients, of whom 87% indicated that it was worsened by neuritis is almost always normal. There may be a few cells
eye movement. Rose (45) theorized that the pain is caused in the vitreous overlying the optic disc, but there is rarely
by inflammation or swelling in the optic nerve sheaths that any significant cellular reaction. In eyes with anterior optic
are innervated by small branches of the trigeminal nerve; neuritis (papillitis) from causes other than demyelination,
however, Swartz et al. (46) hypothesized that the pain is such as sarcoidosis, tuberculosis, syphilis, or Lyme disease,
initiated by inflammation of the optic nerve in the apex of a significant vitritis may be present (discussed later). The
the orbit, where the extraocular muscles are firmly attached optic disc in optic neuritis may appear normal (retrobulbar
to the sheaths of the nerve. In support of this hypothesis, neuritis) or swollen (papillitis), and if the patient has experi-
Lepore (47) reported that among 101 eyes with optic neuritis, enced a previous clinical or subclinical attack of optic neuri-
pain was more commonly present with retrobulbar neuritis tis in the eye, the disc may appear pale. Both the swelling
than with papillitis; however, in the ONTT, pain was present and the pallor are nonspecific findings in optic neuritis, and
in 93% of the 295 eyes with retrobulbar neuritis and in 90% neither is useful in distinguishing demyelinating optic neuri-
of the 162 eyes with papillitis. The presence of pain is a tis from the optic neuritis that may accompany other inflam-
helpful feature to differentiate it from nonarteritic anterior matory or infectious diseases.
ischemic optic neuropathy (AION), particularly when it is
severe and when it occurs or worsens during movement of Visual Acuity
the eyes. Swartz et al. (46) reported that the incidence of
The severity of visual acuity loss varies from a mild reduc-
pain in patients with AION was only 12%, compared with
tion to no light perception. In the ONTT, baseline visual
a frequency of pain of 92% in the patients enrolled in the
acuity was ⱖ 20/20 in 11%, 20/25 to 20/40 in 25%, 20/50
ONTT. Gerling et al. (48) reported a similar figure and also
to 20/190 in 29%, 20/200 to 20/800 in 20%, finger counting
found that pain tended to be described as much more severe
in 4%, hand motion in 6%, light perception in 3%, and no
by patients with optic neuritis compared with patients with
light perception in 3% (7).
AION, and that patients with AION rarely experienced pain
on movement of the eyes.
Color Vision
Positive Visual Phenomena Color vision is almost always abnormal in patients with
Patients with optic neuritis may experience positive visual optic neuritis and is usually more severely affected than vis-
phenomena, called photopsias, in addition to pain and visual ual acuity itself. Thus, testing of color vision may be particu-
OPTIC NEURITIS 297
larly helpful in diagnosing optic neuritis in patients with clear, however, that virtually any type of field defect can
minor visual loss. occur in an eye with optic neuritis, including an arcuate
Ishihara pseudoisochromatic color plates can detect color defect, a cecocentral scotoma, a superior or inferior altitudi-
vision defects in eyes with retrobulbar optic neuritis and nal defect, and a temporal or nasal hemianopic defect.
normal-appearing optic discs and can detect evidence of Among 100 patients with optic neuritis, Chamlin (71) found
optic nerve dysfunction in the eyes of patients with MS in 44 patients with arcuate defects and 4 patients with periph-
whom retrobulbar neuritis is suspected. Another type of eral defects. Perkin and Rose (39) found only 31% of their
color plates, the Hardy-Rand-Rittler (HRR) pseudoisochro- patients to have pure central defects alone. Vighetto et al.
matic plates, was first printed in 1954 and was used by (72) reported similar results. Patients with optic neuritis may
Steinmetz and Kearns (59) at the Mayo Clinic to detect ac- also simply have diffuse loss of sensitivity throughout the
quired color vision defects in patients with presumed ret- visual field. Among 415 patients in the ONTT with baseline
robulbar optic neuritis. Rosen (60) published the results of visual acuity of hand motions or better, the predominant
a study of 272 patients with MS tested with HRR plates and pattern of visual field loss was found to be focal in 52% and
found that 100% of eyes with ophthalmoscopic evidence of diffuse in 48% (73). Focal nerve fiber bundle type defects
definite optic disc pallor (n ⳱ 24) and 46% of eyes with (altitudinal, arcuate, and nasal step) were present more fre-
possible pallor (n ⳱ 39) had abnormal color vision when quently (20%) than pure central or cecocentral defects (8%).
tested with these plates. Based on these findings, he empha- Other types of defects were present in 24% of patients, in-
sized the usefulness of HRR plates in the early diagnosis of cluding hemianopic defects in 5% (73) (Fig. 6.1).
demyelinating optic neuritis and in the diagnosis of MS it-
self. Some patients with optic neuritis can see none or only Pupillary Reaction
some of the figures with the affected eye but all of the figures Despite reports to the contrary (74), a relative afferent
with the fellow eye. Other patients may see all of the figures pupillary defect is almost always present in patients with
correctly with each eye; however, when the patient is asked acute optic neuritis, whether anterior or retrobulbar (75–78).
to look at a single plate, first with one eye and then with The only exception to this rule is the patient who has suffered
the other, he or she will note a striking difference in color a previous attack of optic neuritis in the fellow eye or who
and brightness between the two eyes. Although patients may has subclinical (asymptomatic) optic neuritis in the fellow
have congenitally defective color vision, the pattern of color eye (discussed later). In such a case, damage to the optic
defects found in patients with congenital color blindness is nerve in the fellow eye may offset the damage from acute
much different from that of acquired color defects from optic optic neuritis in the affected eye (even when there is asym-
neuropathy (60). metry of visual function by clinical testing), and there will
A more sensitive test of color vision, the Farnsworth- be no evidence of a relative afferent pupillary defect. In
Munsell 100-Hue test, has been recommended for detection cases of apparent acute optic neuritis in which no relative
of various optic neuropathies, including optic neuritis afferent pupillary defect is detected by a swinging flashlight
(61–63). In the ONTT, Ishihara color plates were abnormal test, the use of neutral density filters may uncover such a
in the affected eye in 88%, whereas the Farnsworth-Munsell defect (see Chapter 15).
100-Hue test was abnormal in 94% (7).
Ophthalmoscopic Appearance
Visual Field
In most series, about 20–40% of patients with acute optic
Griffith (64) and Gunn (65) considered the central field neuritis have some degree of disc swelling (3,39,68,69,74,
to be always affected in patients with optic neuritis, and both 79–83). In the ONTT, optic disc swelling was observed in
Berliner (66) and Carroll (67) recorded typical central and 35% of the patients (7). The optic disc may be slightly or
paracentral defects in their patients, although Carroll (67) markedly blurred (Fig. 6.2). At times, the disc swelling is
recorded a few cases with an associated peripheral constric- so severe that it mimics the ‘‘choked disc’’ seen in patients
tion or with extensions of a central defect to the periphery. with papilledema (Fig. 6.3). The degree of disc swelling
Central or paracentral scotomas, with and without peripheral does not correlate with the severity of either visual acuity
extension, represented over 90% of field defects in the cases or visual field loss (39). Disc or peripapillary hemorrhages
reported by Marshall (68), and Hyllested and Moller (69) are uncommon in eyes with acute optic neuritis, as opposed
found such defects in 98.5% of their cases. Thus, the typical to AION, in which they more frequently accompany disc
visual field defect in optic neuritis has always been thought swelling. In the ONTT, disc or peripapillary hemorrhages
to be a central scotoma (70). It has subsequently become were present in 6% of patients (7).
䉳
Figure 6.1. Visual field defects in acute optic neuritis. Fourteen types of localized monocular visual field defects that may
occur in acute optic neuritis, as defined by static perimetry as performed with a Humphrey automated perimeter using a
30-2 program incorporating the full-threshold test strategy, a 31.5-apostilb background, and size III targets for the test and
blind spot checks. The foveal threshold and fluctuation tests were turned on. Central, cecocentral, arcuate, altitudinal, quadrantic,
and even hemianopic defects may develop. VA, visual acuity. (From Keltner JL, Johnson CA, Spurr JO, et al. Baseline visual
field profile of optic neuritis. The experience of the optic neuritis treatment trial. Optic Neuritis Study Group. Arch Ophthalmol
1993;111⬊231–234.)
Figure 6.2. Anterior optic neuritis. There is significant swelling and hy- Figure 6.4. Anterior optic neuritis with venous sheathing. The patient
peremia of the disc with dilated surface capillaries. was a 45-year-old man with sudden onset of reduced central vision in his
left eye. Visual acuity was 8/200 with a large central scotoma.
In some patients with anterior optic neuritis, a few vitreous

cells may be observed, particularly in the vitreous overlying have an ongoing chronic optic neuritis. With time, the optic
the optic disc. When the cellular reaction is extensive, etiolo- disc becomes pale, even as the visual acuity and other param-
gies other than MS should be considered (discussed later). eters of vision improve (Fig. 6.5). The pallor may be diffuse
Similarly, when macular or peripapillary hard exudates ac- or localized to a particular portion of the disc, most often
company the disk swelling, other conditions such as neuro- the temporal region.
retinitis should be considered (discussed later). Sheathing of
retinal veins may occur in acute optic neuritis caused by Other Tests of Optic Nerve Function
certain conditions, including MS and sarcoidosis (84,85) The results of other tests of optic nerve function, including
(Fig. 6.4). contrast sensitivity (86), visual evoked potential (VEP), and
Most patients with idiopathic or demyelinating acute optic other psychophysical tests, are almost always abnormal in
neuritis have a normal optic disc in the affected eye, unless patients with acute optic neuritis. For example, contrast sen-
they have had a previous attack of acute optic neuritis or sitivity was abnormal in the affected eye at baseline in 98%
of patients in the ONTT. Nevertheless, these tests rarely need
be performed for diagnosis if other parameters are carefully
evaluated. On the other hand, Froehlich and Kaufman (87)
found that pattern electroretinography was useful in distin-
guishing anterior optic neuritis from AION. These authors
reported that the amplitude of the N95 peak was abnormally
reduced for every eye affected with AION, whereas it re-
mained normal in eyes with acute anterior optic neuritis.
Visual Function in the Fellow Eye
Numerous studies have reported that asymptomatic visual
dysfunction may be detected in the fellow eyes of a patient
with acute unilateral optic neuritis (86–90). In the ONTT,
abnormalities in the fellow eye were found on measurement
of visual acuity in 13.8%, contrast sensitivity in 15.4%, color
vision in 21.7%, and visual field in 48.0% of patients (7,11).
Most of the fellow eye deficits resolved over several months,
suggesting that such abnormalities may be caused by sub-
clinical acute demyelination in the fellow optic nerve.
Diagnostic, Etiologic, and Prognostic Studies
Figure 6.3. Severe optic disc swelling mimicking papilledema. Note hy-
peremia and elevation of the disc and several peripapillary retinal hemor- Studies in patients with presumed acute optic neuritis are
rhages. usually performed for one of three reasons:
OPTIC NEURITIS 299
Figure 6.5. Optic atrophy after acute, retrobulbar optic neuritis. A, In acute phase, visual acuity in the left eye is 20/300 with
a central scotoma, but the optic disc is normal. B, Three months later, visual acuity has returned to 20/30 but the optic disc
is pale, particularly temporally, and there is mild nerve fiber layer atrophy.
1. To determine whether the cause of the acute optic neurop- ing lesions that compress the optic nerve in patients with
athy is something other than inflammation, particularly presumed optic neuritis; however, the usefulness of MR im-
a compressive lesion aging in detecting such lesions in patients with presumed
2. To determine whether a cause other than demyelination acute optic neuritis is minimal. Among 455 patients enrolled
is responsible for the optic neuritis in the ONTT with a presumptive diagnosis of acute optic
3. To determine the visual and subsequent neurologic prog- neuritis, only 2 patients (0.4%) were found to have a com-
nosis of optic neuritis; whether the patient will develop pressive lesion that was responsible for the acute visual loss
a more generalized demyelinating process. (7). One patient had an intracranial aneurysm that was not
identified at the time of the initial MR imaging but that
subsequently produced visual loss in the opposite eye. This,
Diagnostic Studies as well as worsening of the patient’s visual acuity in the
initially affected eye, led to a second MR study that identi-
The major concern of the physician who is evaluating a
fied the aneurysm (92). In the second patient, a pituitary
patient with acute visual loss and evidence of a unilateral
adenoma was detected by initial MR imaging; however, it
optic neuropathy is whether the optic neuropathy truly is
may be assumed that this lesion would have been diagnosed
optic neuritis or is an acute manifestation of compression of
within several weeks by neuroimaging had such imaging not
the optic nerve by an intraorbital, intracanalicular, or intra-
cranial mass. To eliminate this possibility, physicians typi- been performed initially, since it is likely that the patient’s
cally perform neuroimaging studies, both computed tomo- vision would not have improved over several weeks, as
graphic (CT) scanning and magnetic resonance (MR) would be expected in a patient with true acute optic neuritis
imaging, in such patients. In fact, neither study is probably (discussed previously).
warranted in patients with a typical history and findings sug- MR imaging can also detect demyelinating lesions of the
gesting optic neuritis. optic nerve in patients with optic neuritis. Such lesions are
With the widespread availability of MR imaging, CT seen as foci, sometimes quite extensive, of enhancement in
scanning has little or no role in the evaluation of patients various locations along the nerve (Fig. 6.6). Unfortunately,
with presumed optic neuritis. Before MR imaging was avail- the appearance of these lesions is nonspecific, and a similar
able, CT scanning was used to detect causes of optic neurop- appearance can be observed in patients with infectious optic
athy other than inflammation, with positive results only oc- neuritis and radiation-induced optic neuropathy.
casionally. CT scanning reveals diffuse enlargement of the Although it would seem that the use of CT scanning or
optic nerve in some cases of typical optic neuritis (91). The MR imaging to detect either a demyelinating optic nerve
finding of an enlarged optic nerve by CT scanning in a pa- lesion or a compressive lesion causing acute visual loss in
tient with symptoms and signs most consistent with optic a patient whose symptoms suggest optic neuritis is unwar-
neuritis should not deter the physician from making that ranted from the standpoint of both yield and cost effective-
diagnosis. ness, there are more compelling reasons to obtain neuroim-
MR imaging is more sensitive than CT scanning in detect- aging in this patient population. MR imaging should, as
Figure 6.6. MR imaging of the optic nerve in acute demyelinating optic neuritis. A, Unenhanced proton density-weighted
axial MR image in a 24-year-old man with right optic neuritis shows diffuse hyperintensity of the right optic nerve. B, T1-
weighted axial MR image after intravenous injection of paramagnetic contrast material in a 25-year-old woman with right optic
neuritis shows marked thickening and enhancement of the orbital portion of the right optic nerve.
noted below, be carried out primarily to look at the potential We believe that neither serologic nor CSF studies are war-
for future development of a more widespread demyelinating ranted in a patient with presumed acute optic neuritis, unless
process in patients with a typical demyelinating optic neuri- the history or examination suggests that the patient has an
tis; doing so assists clinicians in deciding on the potential underlying systemic or local infection or inflammation or
use of immunomodulatory therapy. the patient’s course does not follow that of typical optic
neuritis (7).
Etiologic Studies For many years it has been postulated that a virus may
play a role in the pathogenesis of MS. Numerous studies
Although systemic and local infectious and inflammatory have also addressed this issue in patients with optic neuritis.
disorders can cause acute optic neuritis, the vast majority of Link et al. (94) found a marked increase in hemolysis-inhib-
patients with optic neuritis caused by such disorders can iting measles virus antibody titers in the serum of patients
be identified simply by performing a thorough history. In with optic neuritis and oligoclonal immunoglobulin IgG,
patients without a history of (or consistent with) syphilis, whereas Arnason et al. (95) were unable to find any differ-
sarcoidosis, Lyme disease, systemic lupus erythematosus, ence in titers of hemagglutination-inhibiting measles virus
and so forth, the likelihood of such a condition being respon- antibody in patients with optic neuritis, compared with a
sible for optic neuritis is low. In the ONTT, a comprehensive normal population. Nikoskelainen et al. (74) studied both
medical history was obtained from all patients, who then types of antibody in 33 patients with isolated optic neuritis
underwent blood testing for connective tissue disease (anti- and found elevated titers of both.
nuclear antibody assay [ANA]) and syphilis (fluorescent Antibodies against viruses other than measles have been
treponemal antibody adsorbent test for syphilis [FTA- studied in patients with optic neuritis. Nikoskelainen et al.
ABS]), and a chest radiograph to evaluate for sarcoidosis or (74) studied varicella-zoster, mumps, Coxsackie A3 and B5,
tuberculosis (7). A lumbar puncture was optional. The key polio 3, ECHO 6, cytomegalovirus, parainfluenza 1, Epstein-
findings from this testing were as follows: Barr virus, influenza A and B viruses, adenovirus, and herpes
simplex antibody levels. No significant difference in viral
1. The ANA was positive in a titer less than 1⬊320 in 13% titers was found among patients with optic neuritis, a control
and 1⬊320 or more in 3%. Only one patient developed a population, and a population with other neurologic disorders.
diagnosable connective tissue disease in the first 2 years These investigators performed serial estimations of titers in
of follow-up. Visual and neurologic outcomes were no 17 patients over a period of several months and failed to
different in this subgroup. find any changes in the levels. The role of a virus in the
2. The FTA-ABS was positive in six patients (1.3%), but development of optic neuritis remains uncertain.
none had active syphilis. MR imaging can identify areas of inflammation within
3. The chest radiograph did not reveal evidence of sarcoido- the optic nerve, thus supporting a diagnosis of optic neuritis
sis or tuberculosis in any patient (8). (96–99). The most important application of MR imaging in
4. Analysis of cerebrospinal fluid (CSF) did not yield any patients with optic neuritis, however, is the identification of
unsuspected information in the 131 patients in whom it signal abnormalities in the white matter of the brain, usually
was performed (93). in the periventricular region, consistent with demyelination.
OPTIC NEURITIS 301
Numerous studies have reported the prevalence of such ab- In the ONTT, 131 patients underwent a lumbar puncture.
normalities in patients with clinically isolated optic neuritis. Eighty-three of the patients had no clinical signs of MS at
Two or more lesions on brain MR imaging of patients with the time of optic neuritis and underwent the lumbar puncture
isolated optic neuritis were reported by Miller et al. (96) in within 24 hours of study entry (93). A pleocytosis of more
64% of 53 patients less than 50 years old who were scanned than six white blood cells was present in 36% of patients;
1–40 weeks after onset. Frederiksen et al. (100) reported elevated levels of myelin basic protein (MBP) were present
abnormal MR imaging in 62% of 50 patients aged 12–53 in 18%; the IgG ratio was increased in 22%; IgG synthesis
years scanned after 3–49 days, and Jacobs et al. (101) ob- was increased in 44%; oligoclonal bands were present in
served such abnormalities in 40% of 48 patients aged 12–61 50%; and kappa-light chains were present in 27%.
years scanned between 3 weeks and 7 years after the onset The predictive value of CSF oligoclonal banding for the
of acute visual loss. In the ONTT, only 27% of patients had development of CDMS within 5 years after optic neuritis
two or more signal abnormalities at least 3 mm in size (7,12), was assessed in 76 patients enrolled in the ONTT (93). The
a lower percentage than reported in most other studies. The presence of oligoclonal bands was associated with the devel-
presence of multiple lesions on MR imaging in the periven- opment of CDMS (P ⳱ 0.02). However, the results suggest
tricular or other white matter in the brain of a patient with that CSF analysis is useful in the risk assessment of optic
presumed acute optic neuritis suggests that not only is the neuritis patients only when brain MR imaging is normal; it
diagnosis of optic neuritis correct but also that the cause of is not of predictive value when brain MR imaging lesions
the optic neuritis is demyelination. are present at the time of optic neuritis.
Of the 131 patients who had CSF testing in the ONTT
Prognostic Studies cohort, 76 patients without a clinical diagnosis of probable
or definite MS at trial entry who had a lumbar puncture and
A substantial percentage of patients with isolated optic
nonenhanced brain MR imaging performed within 24 hours
neuritis develop MS within months to years after the onset
of enrollment were then evaluated at 5 years into the study.
of the optic neuritis (discussed later). It would be helpful if
The demographic characteristics of the 76 patients in this
there were certain studies that could be performed in a pa-
cohort were similar to the remaining ONTT patients: average
tient with isolated optic neuritis, as with any clinically iso-
age was 33 Ⳳ 7 years, 80% were female, and 91% were
lated syndrome, that would allow the physician to accurately
Caucasian. Oligoclonal band testing was performed at a local
predict the chance of the patient developing MS. To this
clinic laboratory for 26 of the patients and at a central labora-
end, many investigators have performed serologic, CSF, and
tory for 50 (111). Brain MR imaging scans were graded by
neuroimaging studies in an attempt to detect a correlation
a previously published protocol (12). Neurologic examina-
between the results of such studies and the eventual develop-
tions were performed at baseline, after 6 months, at 1 year,
ment of MS in patients with isolated optic neuritis. We will
and yearly thereafter for 5 years. A demyelinating attack
now explore that relevant information, much of which has
was defined as a patient-reported episode of symptoms at-
come from the ONTT.
tributable to acute demyelination in one or more regions of
CSF STUDIES
the CNS lasting more than 24 hours and separated from
a previous attack by at least 4 weeks (112). Patients were
The role of CSF analysis in the evaluation of patients with diagnosed as having CDMS when a second attack (in addi-
monosymptomatic optic neuritis is not clear. Although the tion to the optic neuritis at the time of study entry) was
presence of oligoclonal banding in the CSF is associated confirmed by an examination that detected a new neurologic
with the development of CDMS (102–104), the powerful abnormality. Recurrent episodes of optic neuritis in either
predictive value of brain MR imaging for MS has reduced eye were not considered in the diagnostic criteria for MS.
the role of lumbar puncture in the evaluation of a patient CDMS developed within 5 years in 22 (29%) of the 76
with optic neuritis. Whether CSF analysis can add to the patients: in 16 (42%) of the 38 patients with oligoclonal
predictive ability of brain MR imaging has not been defini- bands present and in 6 (16%) of the 38 patients without
tively determined; however, results of the ONTT have bands (odds ratio [OR] ⳱ 3.88; 95% confidence interval
helped elucidate this issue (discussed later). [CI] ⳱ 1.18, 13.86; P ⳱ 0.02). Among the 54 patients not
Immunologic abnormalities in the CSF are common in classified as having CDMS, 5-year follow-up was complete
patients with optic neuritis. Frederiksen et al. (103) reported for 50 (93%).
that CSF abnormalities were present in 79% of 45 patients The predictive value of CSF oligoclonal band assessment
with isolated optic neuritis. A pleocytosis was present in for the development of CDMS over and above that of brain
38%, increased IgG index in 36%, and oligoclonal bands in MR imaging was apparent only among patients with no brain
69%. Söderström (105) reported that oligoclonal IgG bands MR imaging lesions at study entry. Among the 39 patients
were present in 69% of patients with optic neuritis. Other with normal brain MR imaging, CDMS developed in 3 of
studies have reported similar results, with cell counts exceed- 11 (27%) patients with oligoclonal bands present but in only
ing 4–5/mm3 in 15–51%, elevated protein concentration in 1 of 28 (4%) without oligoclonal bands. In contrast, among
12–49%, elevated globulin in 18–40%, and oligoclonal the 37 patients with abnormal brain MR imaging, CDMS
bands in 17–51% (39,94,106–109). Rudick et al. (110) re- developed in 13 of 27 (48%) with oligoclonal bands and in
ported that free kappa-light chains in the CSF may be present 5 of 10 (50%) without oligoclonal bands.
in patients with optic neuritis. Brain MR imaging has been demonstrated to be a strong
predictor of CDMS among patients with monosymptomatic ström et al. (114) of anti-MBP and anti-MBP peptide anti-
optic neuritis. In the ONTT, there was a 51% 5-year inci- body-secreting cells in the CSF of patients with both acute
dence of CDMS in patients who had abnormal brain MR optic neuritis and MS. The presence of multiple oligoclonal
imaging at the time of optic neuritis compared with a 16% bands in the CSF of a patient with isolated optic neuritis
incidence in those with normal brain MR imaging (22). also seems to be highly predictive of the future development
These results indicated that performing a lumbar puncture of MS (94,115–118). Finally, Deckert-Schlüter et al. (119)
to detect oligoclonal bands is not of added value for predict- detected increased concentrations of several different cyto-
ing the 5-year risk of CDMS in patients who have abnormal kines in the serum, CSF, or both of 20 patients with isolated
brain MR imaging at the time of development of monosymp- optic neuritis who eventually developed MS, and Link et al.
tomatic optic neuritis. However, the results suggested that (120) reported similar results. The presence of these sub-
oligoclonal band testing may be helpful in the risk assess- stances suggests an activation of the T lymphocytes of the
ment of optic neuritis patients with normal brain MR im- immune system both within and outside the CNS and sug-
aging. gests that either their presence alone or their particular con-
That the value of CSF analysis would depend on the brain centration may be used to predict the ultimate development
MR imaging findings is not surprising. Patients with abnor- of MS in these patients.
mal brain MR imaging already have morphologic evidence
of disseminated disease, and as such it is expected that most GENETIC STUDIES
of these patients will eventually develop additional neuro-
logic events sufficient for a diagnosis of CDMS. Therefore, There is considerable evidence that genetic factors play
there is no reason to expect that a CSF analysis would be a role in the development of MS (121). This is based on the
predictive of MS among these patients. The group of patients familial incidence of the disease (122), twin studies (123),
with optic neuritis and normal brain MR imaging likely in- and HLA typing patterns (108,124–127). Because T cells
cludes a subset of those destined to have MS and a subset bind antigen only in association with a cell surface molecule
of those who may have optic neuritis unassociated with MS. encoded by the major histocompatibility complex (MHC),
Among these patients, the finding of oligoclonal bands in genes encoded by the MHC, and class II MHC genes in
the CSF does appear to increase the likelihood that CDMS particular, have long been considered as candidate suscepti-
ultimately will be diagnosed. Additionally and perhaps more bility loci in MS (128,129). Although an overrepresentation
importantly, the absence of oligoclonal bands in the CSF of A3, B7, and DR2 alleles is common in MS patients of
makes the development of CDMS within 5 years unlikely. Northern European ancestry (124,130), other MHC alleles
Although the number of patients whose CSF was studied may be present in other ethnic groups with MS. Indeed,
in the ONTT was too small for definitive conclusions to be association studies suggest that specific DR- or DQ-related
made with regard to the role of CSF analysis in the evalua- restriction fragment length polymorphisms (RFLP) influ-
tion of patients with optic neuritis, the results suggest that ence susceptibility in some patients (131–133).
a lumbar puncture has limited value in patients with typical Having stated that various HLA haplotypes are found with
monosymptomatic optic neuritis who have demyelinative increased frequency in patients with MS compared with con-
changes on brain MR imaging. However, CSF analysis may trols, we must also state that HLA type does not seem to
help predict the development of CDMS when such MR im- strongly influence the risk of MS in patients with isolated
aging changes are not present. With longer follow-up of this optic neuritis (134). Hely et al. (135) reported that the rela-
cohort, a more definitive statement on the value of CSF tive risk for MS in patients with optic neuritis was 2.7 for
analysis in the MR-normal patients will be possible. those with the DR2 haplotype, 4.8 for those with the B7/
DR2 type, 1.4 for those with DR3, and 0.2 for patients with
IMMUNOLOGIC STUDIES the DR4 haplotype. Francis et al. (130) compared the fre-
quency of HLA types in optic neuritis patients who devel-
Nyland et al. (109) studied T and B lymphocytes in the oped MS compared with those who did not. HLA DR2 was
blood and CSF of 10 patients with acute optic neuritis (3 with present in 57% of the 58 patients who developed MS com-
anterior optic neuritis and 7 with retrobulbar optic neuritis). pared with 44% of those who did not. DR3 was present in
These investigators found that although the percentage of T 36% and 16% of the two groups, respectively (P ⬍ 0.05).
lymphocytes in the patients’ blood was significantly de- DR2 and DR3 together were present in 14% of the MS group
creased compared with controls, absolute numbers of T lym- and 2% of the non-MS group (relative risk ⳱ 6.7; P ⬍ 0.05).
phocytes, and both relative and absolute B-lymphocyte con- Sandberg-Wollheim et al. (102) found that MS developed
centrations, were not significantly different from controls. in 42% of 45 patients with optic neuritis who had the HLA
However, the percentage of T lymphocytes in the CSF of DR2 haplotype and in 34% of 41 patients without this haplo-
the 10 patients was significantly elevated compared with type.
control subjects. Among 33 patients with optic neuritis, 23 with isolated
Frick and Stickl (113) reported that the presence of MBP spinal cord syndromes, and 14 with an isolated brain stem
in the CSF of a patient with otherwise isolated optic neuritis disturbance, Kelly et al. (127) reported that clinical MS de-
and no history of previous neurologic symptoms or signs veloped within a mean follow-up period of 5.3 years in 67%
nevertheless is highly predictive of the development of MS of 30 DRB1*1501-positive patients compared with 38% of
in the future, a conclusion supported by the findings of Söder- 40 negative patients; 62% of DQA1*0102-positive patients
OPTIC NEURITIS 303
compared with 32% of negative patients; and 67% of Disease heterogeneity is an important emerging concept
DQB1*0602-positive patients compared with 35% of nega- in MS. Neuropathologic studies support the concept that
tive patients. Patients who did not progress to MS appeared more than one form of MS exists, defined by whether the
to be similar to the controls. The predictive value of HLA oligodendrocyte or the myelin sheath is the initial target of
typing in relation to brain MR imaging also was evaluated injury, and by whether evidence of antibody-mediated tissue
in this study. MR imaging was found to be a much stronger damage is present (142,143). One clinical example of a re-
indicator of risk than HLA, but the combination of MR imag- stricted variant of MS is primary progressive MS, which in
ing and HLA haplotype DRB1*1501 increased the predic- Caucasians is characterized by common occurrence in men,
tive ability. Compston et al. (125) found that positive typing little inflammation, few cerebral lesions, frequent spinal cord
for the HLA BT101, winter onset of the initial attack of optic disease, and a prominent axonal pathology (144). In another
neuritis in BT101-positive patients, and recurrent attacks of example, two clinical forms of MS have been described in
optic neuritis were associated with an increased incidence Japan. The first, a disseminated disorder with widespread
of MS. brain lesions detected by MR imaging, resembles MS in
A substantial body of data indicates that MS is a complex Caucasians and is associated with DR2. The second, a relaps-
genetic disorder (136). This complexity may reflect poly- ing-remitting or progressive disorder with predominant
genic inheritance (e.g., multiple susceptibility genes in a spinal cord and optic nerve involvement, is not DR2 associ-
given individual), locus heterogeneity (e.g., different genes ated (137). Thus, at least in some situations, DR2-negative
in different patients), and possibly etiologic heterogeneity individuals may have a propensity to develop topographi-
as well (e.g., more than one underlying cause). To date, the cally restricted forms of demyelinating disease.
most consistently observed genetic influence on MS arises A better understanding of the predictive value of these
from a gene or genes linked to the MHC at chromosome and other serum and CSF findings for the development of
6p21 and associated with haplotypes of DR2 (molecular des- MS awaits further development in the arenas of neuroimmu-
ignation DRB1*1501, DQA1*0102, DQB1*0602) (136). nology and the genetics of demyelinating disease. Neverthe-
Several exceptions exist to the general finding of the DR2 less, there appear to be certain serologic and CSF risk factors
association with MS, most notably MS in Asians (137) and that increase the likelihood that a patient with isolated optic
MS in Sardinians (138). A recent genetic analysis of the neuritis will eventually develop MS.
MHC in an American MS population reported that linkage
was confined to DR2-positive multiplex families; thus, locus MR IMAGING
heterogeneity exists in MS, with one DR2-associated form
and one or several others unassociated with DR2 (139). In the previous sections, we emphasized that MR imaging
The association of the HLA-DR2 allele with brain MR in patients with presumed acute optic neuritis is probably
imaging signal abnormalities and with the development of not warranted with respect to the identification of a lesion
MS was assessed in 178 patients enrolled in the ONTT. HLA that is compressing the optic nerve and producing a compres-
haplotype DR2 was present in 85 (48%) of the 178 patients. sive optic neuropathy that is mimicking optic neuritis. Simi-
Its presence was associated with increased odds of probable larly, one does not necessarily need to perform MR imaging
or definite MS at 5 years (OR ⳱ 1.92, 95% CI 1.01–3.67, to confirm a diagnosis of optic neuritis. On the other hand,
P ⳱ 0.04). The association was most apparent among pa- it is certainly clear that the results of MR imaging correlate
tients with signal abnormalities on baseline brain MR imag- with the eventual development of MS.
ing (140). The presence of multiple lesions in the periventricular and
A high prevalence of DR2 was present in the ONTT co- other white matter on MR imaging, a phenomenon noted in
hort of patients with acute unilateral optic neuritis. This find- 30–70% of patients with isolated optic neuritis (7,12,145,
ing is consistent with earlier studies of HLA genes in which 146), appears to be the most significant risk factor associated
the DR2 association was nearly as strong for optic neuritis with an increased likelihood of developing MS (13,103,147,
as for MS (141). The ONTT also confirmed that DR2 is 148). MS was reported by Jacobs et al. (101) to have devel-
associated with evolution of optic neuritis to MS, as reported oped in 6 of 23 patients (26%) with abnormal brain MR
in some but not all earlier reports (141). The predictive imaging, compared with only 3 of 25 patients (12%) with a
power of HLA typing in optic neuritis was weak compared normal scan within a mean follow-up of 4 years. Martinelli
with abnormal MR imaging, an expected observation consid- et al. (149) diagnosed MS in 7 of 21 patients (33%) with
ering the relatively high prevalence of DR2 in healthy Cau- isolated optic neuritis and an abnormal MR scan compared
casians, and the specificity of MR imaging abnormalities with none of 16 patients with optic neuritis and a normal
for MS. Unexpected was the strong association observed scan within a mean follow-up of 2.7 years. Frederiksen et
between DR2 and MS among optic neuritis patients with al. (100) diagnosed MS in 7 of 30 (23%) patients with optic
abnormal baseline MR imaging, and the absence of this asso- neuritis and an abnormal MR scan compared with none of
ciation in patients whose MR imaging was normal. Although 20 patients with optic neuritis and a normal scan within mean
derived from a relatively small number of observations, follow-up of 0.9 years. Finally, Morrisey et al. (150) reported
which limits the statistical power, this nevertheless suggests the development of MS in 23 of 28 (82%) optic neuritis
that multifocal disease at onset may be influenced by the patients with an abnormal scan compared with only 1 of 16
HLA status of the individual, specifically by DR2 itself or (6%) patients with a normal scan over a mean follow-up of
by another gene in linkage disequilibrium with DR2. 5.5 years. The study by Morrisey et al. (150) is particularly
important because it suggested that with sufficiently long were present at the time of the initial scan but were not
follow-up, most, if not all, patients with acute optic neuritis detected due to the scan technique. On the other hand, the
who have silent brain MR imaging signal abnormalities ulti- fact that 34 patients (56%) did not develop clinical signs or
mately develop additional clinical manifestations sufficient MR evidence of demyelination after 10 years suggests that
for a diagnosis of definite MS. Among patients with isolated there are many cases of optic neuritis that may be unrelated
optic neuritis in the ONTT, the cumulative percentage devel- to MS.
oping MS within 4 years of the onset of the optic neuritis Among the 35 patients whose baseline MR scan showed
was about 13% in patients with normal MR imaging, 35% at least one T2 lesion measuring at least 3 mm, 26 (74%)
in patients with only one or two lesions, and 50% in patients developed at least one new lesion larger than 3 mm on fol-
with more than two lesions (20). By 10 years, patients who low-up imaging in the absence of a clinical diagnosis of MS
had one or more typical MR lesions had a 56% risk and (26). This phenomenon merely underscores the well-known
those with no baseline lesions had a 22% risk (23) (Fig. 6.7). dissociation between MR findings and clinical expression
Higher numbers of lesions did not increase the risk of MS. of MS. The fact that an abnormal baseline MR scan was
MR imaging has taken on an increasingly important role more likely to show additional lesions than a normal baseline
in the diagnosis and monitoring of patients with MS (151). MR scan emphasizes the predictive value of the initial scan.
Current MS diagnostic criteria following a monosymptom- The presence of even a single lesion predicted the develop-
atic presentation incorporate changes in serial MR findings ment of further lesions. However, the development of new
as documentation of dissemination in time (152). Accord- lesions does not necessarily indicate that the patient will
ingly, the long-term MR characteristics of monosymptom- develop clinical signs of MS even after 10 years.
atic optic neuritis patients not developing MS on clinical Among the 12 patients with only punctate T2 hyperinten-
grounds are of great interest. Continued follow-up of the sities on baseline imaging, 9 (75%) exhibited changes on
cohort of participants enrolled in the ONTT has provided long-term MR scanning, a frequency similar to that in the
the opportunity to evaluate brain MR scans 10 to 14 years patients with at least one lesion measuring more than 3 mm
after optic neuritis in patients who have not developed on the baseline MR scan (26). This finding suggests that a
CDMS. The objective of this study was to determine the focal signal abnormality of any size may predict that addi-
proportion of such patients who manifest new brain MR tional signal abnormalities will occur in this population.
lesions on follow-up scans (26). The data from the ONTT follow-up patients have several
In the ONTT, among 61 patients with normal baseline limitations. MR technology continues to advance, and multi-
MR scan who had not developed clinical evidence of MS center, serial MRI studies are often forced to compare im-
ages obtained with different magnets, field strengths, and
after 10 years, 27 (44%) exhibited at least one new lesion
protocols. Repositioning error on serial imaging is also a
of more than 3 mm on follow-up brain MR scans (23,26).
source of potential difference between baseline and follow-
Subclinical demyelination is the most logical explanation for
up MR scans. The use of magnets with higher field strength
the new MR findings within this relatively young population,
and smaller slice thickness scans at follow-up may have
although for some of the patients it is possible that the lesions overestimated MR changes over time. However, changes in
these parameters appear to affect the assessment of lesion
volume more than lesion numbers. The addition of good-
quality spinal cord imaging may also increase the percentage
of patients with asymptomatic demyelinating lesions. Imag-
ing confined to the brain would, therefore, underestimate the
total burden of T2 changes over time. It is possible that
not all the T2 MR changes over time were the result of
demyelination. Vasculopathic risk factors such as advanced
age, diabetes, and hypertension may contribute to T2 MR
lesions, but this seems unlikely to explain a significant por-
tion of the change observed in this relatively young cohort.
Despite the limitations on interpretation of the results im-
posed by the differences in MR technique from baseline to
follow-up scans in the ONTT cohort studied, it is important
to recognize that these differences affect only the incidence
of new lesions and not the observed proportion of patients
who have remained lesion-free after 10 years.
Figure 6.7. The cumulative probability of multiple sclerosis was statisti-
The ONTT experience is unique in reporting the long-term
cally significantly higher in patients with one or more lesions seen on the
baseline MR scan of the brain than in patients with no brain lesions (P ⬍
MR changes following monosymptomatic optic neuritis in
0.001, log rank test) but was not significantly different between patients
the absence of the development of clinical signs of MS. The
with a single brain lesion and patients with multiple lesions (P ⳱ 0.22, results support the notion that not all cases of monosymp-
log-rank test). (From Optic Neuritis Study Group. High- and low-risk pro- tomatic optic neuritis are related to MS, since a subset of
files for the development of multiple sclerosis within 10 years after optic patients manifested neither clinical signs nor MR evidence
neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol of demyelination after more than 10 years of follow-up
2003;121⬊944–949.) (23,26). In addition, the results indicate that MR signal ab-
OPTIC NEURITIS 305
normalities may accumulate without causing any clinical difference in vision between groups at 12 months. In the
manifestations of MS, even when the patient is followed for meantime, Spoor (161) and Spoor and Rockwell (162) de-
over a decade. Although treatment decisions should take this scribed rapid recovery of vision in two small series of pa-
fact into account, it should be emphasized that MS is a life- tients with optic neuritis treated with intravenous methyl-
long disease, and the majority of disability is encountered prednisolone.
following 10–15 years of disease involvement. As noted previously, patients with acute optic neuritis who
enrolled in the ONTT were randomized to one of three treat-
VITREOUS FLUOROPHOTOMETRY ment groups: (a) oral prednisone (1 mg/kg/day) for 14 days;
(b) intravenous methylprednisolone sodium succinate (250
Braude et al. (153) evaluated vitreous fluorophotometry
mg qid for 3 days followed by an oral prednisone 1 mg/kg/
in six patients with acute retrobulbar optic neuritis. These
day) for 11 days; and (c) oral placebo for 14 days. Each
investigators found an acute increase in posterior vitreous
regimen was followed by a short oral taper (6,8). Most pa-
fluorophotometric readings in one or both eyes of all six
tients in all three treatment groups had a good recovery of
patients. They speculated that the abnormally high vitreous
vision (8). After 6 months of follow-up, the median visual
fluorophotometric findings in the patients are caused by an
acuity in each group was 20/16, and less than 10% of the
increased permeability of the blood–ocular barrier, presum-
patients in each group had visual acuity of 20/50 or worse.
ably the result of inflammation in the retrolaminar portion
One year after the onset of visual symptoms, there was no
of the optic nerve and possibly in the posterior pole vascula-
significant difference in mean visual acuity, color vision,
ture. As with other tests that have been suggested as aids in
contrast sensitivity, or visual field (by mean deviation)
the diagnosis of optic neuritis, further testing is necessary
among the three groups (14,15). On the other hand, patients
to determine the accuracy and clinical usefulness of this pro-
treated with the regimen of intravenous methylprednisolone
cedure.
followed by oral prednisone recovered vision considerably
Treatment faster than patients treated with oral placebo (8) (Fig. 6.8).
The benefit of this treatment regimen was greatest in the
In 1949, Hench et al. (154) described the beneficial effects first 15 days of follow-up and decreased subsequently.
of systemic corticosteroids in the treatment of rheumatoid Patients treated with oral prednisone alone did not recover
arthritis. Following this report, physicians began to consider vision any faster and had no better vision at the end of a 6-
other disorders, including optic neuritis, that might respond month follow-up period than patients treated with oral pla-
to similar treatment or to treatment with adrenocortico- cebo (8). Unexpectedly, patients treated with oral prednisone
trophic hormone (ACTH). The first systematic attempt to alone had an increased rate of recurrent attacks of optic neu-
address this issue was a double-blind prospective study of ritis in the previously affected eye and an increased rate of
the treatment of 50 patients with acute retrobulbar neuritis new attacks of optic neuritis in the fellow eye compared with
with either ACTH or placebo (155,156). The study showed patients in the other two groups (8) (Fig. 6.9). Thus, oral
that the group treated with ACTH recovered vision faster, prednisone in a dose of 1 mg/kg/day did not speed recovery
but at 1 year the mean visual acuities in the two groups were of vision compared with no treatment, did not improve ulti-
not significantly different from each other. mate visual acuity compared with no treatment, and pro-
In the Cooperative Multiple Sclerosis Study (157), there duced a higher rate of recurrent and new attacks of optic
were 41 cases in which optic neuritis was the primary mani- neuritis than no treatment.
festation of MS for which patients were entered into the The ONTT also evaluated the rate of development of clini-
study. The 22 patients treated with ACTH improved faster cal MS in the three treatment groups and found that the
than the 19 patients treated with placebo, but there was no patients treated with the intravenous followed by oral corti-
long-term follow-up. Bowden et al. (158) performed a pro- costeroid regimen had a reduced rate of development of
spective clinical trial in 54 patients with acute optic neuritis. clinically definite MS during the first 2 years (13,19). The
The study showed no benefit on visual acuity of ACTH com- benefit of treatment was seen only in patients who had signif-
pared with placebo in these patients. icantly abnormal brain MR imaging at the onset of the optic
Gould et al. (159) performed a prospective single-blind neuritis. The 2-year risk of MS was too low in those with
controlled clinical trial in which 74 patients with optic neuri- normal brain MR imaging to assess the value of treatment
tis either received a retrobulbar injection of triamcinolone in such patients. The clinical benefit of the intravenous treat-
or were randomized to a control group that received no treatment lessened over time, such that at 3 years of follow-up
ment. Visual acuity in the affected eyes of the treated patients there was no significant difference in the rate of development
improved faster than did visual acuity in the affected eyes of MS among treatment groups.
of patients who received no treatment, but there was no dif- In the acute phase of optic neuritis, no treatment other
ference in mean visual acuity between the two groups after than corticosteroids or related agents such as ACTH have
6 months. Trauzettel-Klosinski et al. (160) subsequently per- been shown to be efficacious; however, intravenous immu-
formed a study in which 50 patients with acute optic neuritis noglobulin (IVIg) has been demonstrated in animals to pro-
were randomized to receive either oral corticosteroids or mote remyelination of the CNS in experimental allergic en-
placebo. There was a suggestion of a slightly more rapid cephalomyelitis (163–165) and in Theiler’s virus model of
recovery of vision in the patients treated with steroids com- MS (166–169).
pared with patients in the placebo group, but there was no In a small pilot study, it was suggested that IVIg may
Figure 6.9. Incidence of recurrent attacks of optic neuritis in the previ-

ously affected eye and new attacks of optic neuritis in the fellow eye of
patients enrolled in the Optic Neuritis Treatment Trial and Longitudinal
Optic Neuritis Study by treatment groups. Patients treated with oral predni-
sone alone, in a dose of 1 mg/kg/day for 14 days, had a much higher
incidence of such attacks than patients given oral placebo or patients treated
with intravenous methylprednisolone in a dose of 250 mg q6h for 3 days,
followed by an 11-day course of oral prednisone in a dose of 1 mg/kg/day.
ized to receive either IVIg 0.4 g/kg daily for 5 days followed
by three single infusions monthly for 3 months, or placebo.
The trial was terminated by the National Eye Institute be-
cause of negative results when 55 of the planned 60 patients
had been enrolled. Fifty-two patients completed the sched-
uled infusions, and 53 patients completed 12 months of fol-
low-up. Analysis of these data indicated that a difference
between treatment groups was not observed for the primary
outcome measure, improvement in logMAR visual scores
at 6 months (P ⳱ 0.766). Exploratory secondary analyses
suggested that IVIg treatment was associated with improve-
ment in visual function (including logMAR visual scores at
6 months and visual fields at 6 and 12 months) in patients
with clinically stable MS during the trial. It was the conclu-
sion of the investigators that IVIg administration does not
reverse persistent visual loss from optic neuritis to a degree
Figure 6.8. Speed of visual recovery in patients with acute optic neuritis that merits general use.
treated with intravenous high-dose methylprednisolone (1 g/day for 3 days), On the basis of the above data, we believe there is no
followed by a 2-week course of oral prednisone (1 mg/kg/day) (solid line), treatment for acute demyelinating optic neuritis that can im-
compared with patients treated with oral prednisone alone (dotted line) prove the ultimate visual prognosis compared with the natu-
and untreated patients (given placebo) (dashed line) in the Optic Neuritis ral history of the disorder (9,10,20,21). A short course of
Treatment Trial. Improvement in visual acuity (A), contrast sensitivity (B), intravenous methylprednisolone (250 mg every 6 hours for
and visual field (C) occurred more rapidly in patients treated with the intra- 72 hours) followed by a 2-week course of oral prednisone
venous regimen than in patients given either low-dose oral prednisone or
given orally (11 days of 1 mg/kg/day followed by a 3-day
in untreated patients. (From Beck RW, Cleary PA, Anderson MM Jr, et al.
A randomized, controlled trial of corticosteroids in the treatment of acute
taper) may result in an increase in the speed of recovery of
optic neuritis. The Optic Neuritis Study Group. N Engl J Med 1992; vision by 2–3 weeks compared with no treatment when the
326⬊581–588.) steroids are begun within 1–2 weeks of the onset of visual
loss (8,172), but the ultimate visual function at 1 year will
be the same as it would have been if no treatment were given
(14). The use of oral corticosteroids alone, when given to
have some benefit in patients with resolved optic neuritis patients with acute optic neuritis at a dosage of 1 mg/kg/
who have significant residual visual deficits (170). Nosewor- day, not only does not improve visual outcome or speed
thy et al. (171) looked at whether IVIg reverses chronic recovery but is also associated with a significantly higher
visual impairment in MS patients with optic neuritis. In a incidence of recurrent attacks of optic neuritis in the same
double-blind, placebo-controlled phase II trial, 55 patients eye and new attacks in the contralateral eye than in patients
with persistent acuity loss after optic neuritis were random- who either are not treated or receive intravenous corticoste-
OPTIC NEURITIS 307
roids before a short oral course of steroids (8). In view of after the onset of visual symptoms (14,18,39,41,82) (Fig.
these findings, we and others believe it is inappropriate to 6.10). Among patients enrolled in the ONTT who received
treat any patient with acute demyelinating optic neuritis with placebo, visual acuity began to improve within 3 weeks of
oral corticosteroids alone at this dosage (8–10,20,21). It is onset in 79% and within 5 weeks in 93%. For most patients
possible that a high dose of prednisone, given orally, might in this study, recovery of visual acuity was nearly complete
have the same effect as intravenously administered methyl- by 5 weeks after onset (8,14). The mean visual acuity 12
prednisolone. months after an attack of otherwise uncomplicated optic neu-
ritis is 20/15, and less than 10% of patients have permanent
Visual Prognosis visual acuity less than 20/40 (14). Other parameters of visual
function, including contrast sensitivity, color perception, and
The natural history of acute demyelinating optic neuritis visual field, improve in conjunction with improvement in
is to worsen over several days to 2 weeks, and then to im- visual acuity (16,41,55,173–175).
prove. The improvement initially is fairly rapid. It then levels The visual improvement that occurs in patients with acute
off, but further improvement can continue to occur 1 year optic neuritis tends to do so regardless of the degree of visual
Figure 6.10. Time course of improvement in visual function after an attack of acute demyelinating optic neuritis in two
different patients, neither of whom was treated with systemic corticosteroids. Note the rapid drop in visual function over several
days followed shortly thereafter by concomitant improvement in visual acuity, contrast sensitivity, and visual field. Improvement
in visual function initially was rapid but then leveled off.
loss, although there is some correlation between the severity acuity of 20/40 or more (24) is comparable to that of Bradley
of visual loss and the degree of eventual recovery. Factors and Whitty (82), who reported that 86% of 66 patients were
such as age, gender, optic disc appearance, and pattern of 20/25 or more (mean follow-up after episode of optic neuritis
the initial visual field defect do not appear to have any appre- of 10.2 years, range 6 months to 20 years), and Cohen (51),
ciable effect on the visual outcome (18,39,82,176). Bradley who reported that 82% of 60 patients had visual acuity of
and Whitty (82) evaluated 73 patients with acute optic neuri- 20/40 or more (mean follow-up 7.1 years after optic neuritis,
tis and found that among patients with initial visual acuity range 5–12 years). The 10-year ONTT recurrence rate of
of 20/200 or worse, about 60% had acuity of 20/30 or better 35% is similar to that reported by Cohen (42%) (51) but
at 6 months compared with about 70% in patients whose higher than that reported in other studies with extended fol-
initial visual acuity was better than 20/200. Cohen et al. (51) low-up such as those by Bradley and Whitty (18%) (82),
found that in 24 patients with acute unilateral optic neuritis Hutchinson (24%) (83), and Rodriguez (16%) (33).
and initial visual acuity worse than 20/200, the visual acuity Over time, some attrition of the original ONTT cohort
remained at that level in only 9 eyes. Slamovits et al. (177) has occurred. This has more impact on the vision assessment
reported that of 12 patients with acute optic neuritis whose than it does on the neurologic assessment, since for the latter
vision became reduced to no light perception, all 12 showed the investigators were able in many cases to determine
some improvement; indeed, visual acuity improved to 20/ whether MS had developed through either phone contact
40 or better in 8 and 20/20 or better in 5. Of 167 eyes of with the patient or medical records, whereas the former re-
patients enrolled in the ONTT in which the baseline visual quires the completion of specific visual function tests. Pa-
acuity was 20/200 or worse, only 10 (6%) had this level of tients who were no longer being followed in the cohort had
vision or worse 6 months later (8,15). Of 28 patients whose slightly worse baseline acuity in the affected eye both at
initial visual acuity in the affected eye was light perception baseline and at the time of the last completed visit. The
or no light perception, 18 (64%) recovered to 20/40 or better ONTT reported vision results for the patients completing the
(8,15). examination are likely to be slightly biased toward those
Even though the overall prognosis for visual acuity after with better vision. The results of the ONTT can be used by
an attack of acute optic neuritis is extremely good, some clinicians to advise patients that the long-term visual prog-
patients have persistent severe visual loss after a single epi- nosis is good following an episode of optic neuritis. Follow-
sode of optic neuritis (8,14,15,41,178,179). Even those pa- up of this cohort will continue with the support of the Na-
tients with improvement in visual function to ‘‘normal’’ may tional Eye Institute, and patients will be examined again in
complain of movement-induced photopsias and may have 2006 (24).
persistent visual deficits when tested using more sensitive
clinical, electrophysiologic, or psychophysical tests (58,60, Residual Visual Deficits After Resolution of Optic
180–194). Neuritis
Continued follow-up of the cohort of patients who were
Following an attack of acute optic neuritis, disturbances
enrolled in the ONTT has provided a unique opportunity to
in visual acuity (15–30%), contrast sensitivity (63–100%),
assess the long-term course of vision following an episode
color vision (33–100%), visual field (62–100%), stereopsis
of acute optic neuritis. In most patients, once visual acuity
(89%), light brightness sense (89–100%), pupillary reaction
stabilized after the initial episode of optic neuritis (as deter-
to light (55–92%), optic disc appearance (60–80%), and the
mined from the acuity measurement 1 year after the episode),
VEP (63–100%) may all persist. Kirkham and Coupland
it remained remarkably stable for more than 10 years (24).
(195) examined 93 patients with previously diagnosed optic
After 10 years, 69% of patients had acuity of 20/20 or better
neuritis and submitted the results of several diagnostic tests
in each eye, whereas 1% were worse than 20/200 in both
in these patients to linear stepwise multiple regression analy-
eyes. As was reported after 5 years of follow-up, visual func-
sis. The analysis indicated that the most common findings
tion was worse in those patients with MS than in those with-
after an attack of acute optic neuritis were optic atrophy,
out MS (22,24). Further attacks of optic neuritis in either
defective color vision, and a prolonged pupil cycle time.
eye occurred in 35% of all patients and were twice as com-
Other findings in these patients included a relative afferent
mon among patients diagnosed with MS at baseline or who
pupillary defect, an abnormal response to the Pulfrich test,
developed MS during the follow-up period. As a group, the
and an abnormal VEP.
ONTT patients had lower (worse) quality of life scores as
measured on the National Eye Institute Visual Function Visual Acuity
Questionnaire (NEI-VFQ) compared with a reference group
(24). A reduction in NEI-VFQ scores was strongly related Most patients recover to normal or near-normal visual
to a measured reduction in visual acuity and to the presence acuity. Bradley and Whitty (82) found that 50% of patients
of MS. Among patients with acuity in each eye of 20/20 or recovered vision to 20/30 or better within 1 month of initial
better and among patients who did not have MS, the scores visual loss, and 75% recovered to 20/30 or better within 6
were quite similar to the reference group. months. In the series reported by Perkin and Rose (39), 87%
There are few long-term follow-up data in the literature of patients with optic neuritis recovered vision better than
for comparison with the results of the ONTT. The finding 20/40, and only 8% had vision worse than 20/200 after a
that after more than 10 years of follow-up 86% of the af- minimum follow-up period of 6 months. In the ONTT, after
fected eyes had visual acuity of 20/25 or more and 91% had 12 months of follow-up visual acuity was more than 20/20
OPTIC NEURITIS 309
in 69%, 20/40 or more in 93%, and 20/200 or less in only ods of measuring contrast sensitivity have shown that con-
3%. The results in each treatment group were similar (14). trast sensitivity remains abnormal regardless of the degree
of visual recovery in most eyes after resolution of acute
Color Vision optic neuritis. Arden and Gucukoglu (86) reported abnormal
contrast sensitivity using hand-held grating plates in 70% of
Persistent disturbances of color vision are present in a 57 eyes with resolved optic neuritis, and both Zimmern et
high percentage of eyes with otherwise resolved optic neuri- al. (199) and Sjöstrand and Abrahamsson (200) reported ab-
tis. Wybar (196), for instance, found disturbances of color normal contrast sensitivity in 100% of eyes with 20/20 visual
vision in 56% of 25 cases of resolved optic neuritis using acuity after an attack of acute optic neuritis. Using an auto-
Ishihara pseudoisochromatic plates, whereas Lynn (197) re- mated system, Sanders et al. (53) found abnormal contrast
ported a figure of 84% among 143 cases. Burde and Gallin sensitivity over a wide range of spatial frequencies in 63%
(181) reported an abnormal Farnsworth-Munsell 100-Hue of 64 eyes with resolved optic neuritis. In this study, the
color test in three of nine eyes in which visual acuity had subjective visual complaints of the patients correlated better
recovered to normal after an attack of retrobulbar neuritis. with impaired contrast sensitivity than with any other mea-
Griffin and Wray (63) tested 30 eyes with resolved retrobul- sure of visual function, including visual acuity, color vision,
bar neuritis that recovered visual acuity to 20/40 or better. and visual field. Beck et al. (88) reported abnormal contrast
Color vision testing using Ishihara pseudoisochromatic sensitivity in 78% of 51 eyes with recovered optic neuritis.
plates was abnormal in 15 of 22 patients tested, and assess- Among 33 of these eyes with visual acuity of 20/25 or better,
ment of color vision using the Farnsworth-Munsell 100-Hue contrast sensitivity was still abnormal in 67%. Fleishman et
test revealed abnormalities in all 30 patients. Perkin and al. (90) found abnormalities in contrast sensitivity in 75%
Rose (39) reported finding defects in color vision in 50% of 27 eyes with recovered optic neuritis and good visual
of 112 eyes with resolved optic neuritis. Kirkland and Coup- acuity. Drucker et al. (201) tested 25 eyes with good visual
land (195) found that defective color vision was one of the acuity (20/30 or better) following optic neuritis with the
most common findings in eyes with a history of well-docu- Regan Low Contrast Letter Chart. Contrast sensitivity was
mented acute optic neuritis. Fleishman et al. (90) tested 27 abnormal (defined as two standard deviations below the nor-
patients with resolved optic neuritis and found abnormalities mal group mean determined as part of the study) in 84% of
in 34% of eyes tested with Ishihara color plates and 63% of the affected eyes. In the ONTT, contrast sensitivity measured
eyes tested with the Farnsworth-Munsell 100-Hue test. In with the Pelli-Robson chart was abnormal at 6 months in
the ONTT, color vision measured by the Farnsworth- 56% (8).
Munsell 100-Hue test was normal within 6 months in only Contrast sensitivity is often abnormal in cases of MS in
60% of patients (8). In our experience, the percentage of which there has not been overt acute optic neuritis (202,203)
eyes with color vision disturbances is related in large part and in some fellow eyes in cases of apparent unilateral optic
to the sensitivity of the test that is used to detect such defects. neuritis (53,86,88). These findings suggest that these eyes
have subclinical optic nerve demyelination that was not nec-
Visual Field essarily detected by testing of other types of visual function.
Residual visual field defects are usually present in eyes
after resolution of acute optic neuritis, even when visual Stereopsis
acuity has returned to 20/20 or better. Using a Friedman Stereopsis is a binocular function that is defined as the
Visual Field Analyzer, Bowden et al. (158) found defects in ability to discern a separation in the distance of two static
67% of 35 eyes tested; Van Dalen and Greve (198) in 86% objects. Patients with reduced stereopsis often complain of
of 14 eyes; and Perkin and Rose (39) in 72% of 120 eyes. a loss of depth perception. Friedman et al. (204) tested stere-
Nikoskelainen (107) performed kinetic perimetry using a opsis using the Titmus test in patients with various optic
Goldmann perimeter and found abnormalities in the visual neuropathies and found that it was worse relative to the re-
field in 62% of 167 eyes that had experienced an attack of duction in visual acuity in most of these patients. In the 13
acute optic neuritis. Burde and Gallin (181) reported normal patients they tested with visual acuity of 20/40 or better, 11
kinetic perimetry but abnormal static perimetry in each of had stereopsis worse than predicted by the level of acuity.
nine eyes with a good recovery of visual acuity following Fleishman et al. (90) found stereopsis to be reduced in 89%
an attack of acute retrobulbar optic neuritis. Fleishman et of 19 patients with a history of unilateral optic neuritis and
al. (90) reported visual field defects in 26% of eyes that had in 75% of 8 patients with a history of bilateral optic neuritis.
normal visual acuity after an attack of acute optic neuritis.
Among patients enrolled in the ONTT, the mean deviation Light-Brightness Sense
of the visual field performed using a Humphrey Field Ana-
lyzer was abnormal at 6 months in 32% (8). Patients often complain that vision appears dimmer in one
eye compared with the other after resolution of optic neuritis.
Contrast Sensitivity Sadun and Lessell (205) developed an instrument that could
quantify this reduction in brightness. Among 15 patients
Contrast sensitivity provides a measure of the ability of with acute unilateral optic neuritis of less than 3 months’
an eye to detect a difference in luminosity between an object duration, 12 of whom had recovered visual acuity to 20/20
and its background. Numerous studies using various meth- in the affected eye, all noted a reduction in perceived light
brightness in the previously affected eye compared with the in 60% of 167 eyes, Burde and Gallin (181) in 5 of 9 eyes,
unaffected eye. Fleishman et al. (90) found light brightness and Perkin and Rose (39) in 62% of 165 eyes. In the ONTT,
to be reduced in a high percentage (89%) of patients with 63% of patients had evidence of optic disc pallor at 6 months
resolved unilateral optic neuritis. (8).
Perhaps more common than optic atrophy is the develop-
Pupillary Reaction ment of defects in the retinal nerve fiber layer after an attack
of acute optic neuritis (207). Most patients develop such
Many patients with unilateral acute optic neuritis have a defects, which may be diffuse, localized to the papillomacu-
persistent relative afferent pupillary defect on the affected lar bundle, or isolated defects in the arcuate regions.
side, even when excellent recovery of vision has occurred.
In the ONTT, 54% of the patients without a past history of Visual Evoked Potentials (VEPs)
optic neuritis in the fellow eye had a relative afferent pupil-
The VEP is an electroencephalographic recording over
lary defect 6 months after the onset of visual symptoms (8).
the occipital lobe in response to visual stimulation. It is occa-
Burde and Gallin (181) detected a relative afferent pupil-
sionally used as an objective measure of conduction in the
lary defect in five of nine eyes following a good recovery
afferent visual system (see Chapter 2). After resolution of
from acute unilateral optic neuritis. Using pupillometry, Ellis
acute optic neuritis, most patients have a prolonged latency,
(77) found a relative afferent pupillary defect in each of 13
indicating impaired optic nerve conduction. Shahrokhi et al.
patients with resolved optic neuritis. All of the 13 eyes also
(208) reported an abnormal VEP in 95% of 58 eyes with
had a persistent reduction in the amplitude of the VEP. Per-
resolved optic neuritis, Bynke et al. (206) in 71% of 42 cases,
kin and Rose (39) noted a relative afferent pupillary defect
and Wutz et al. (209) in each of 19 patients. In cases of optic
in 55% of 139 eyes after acute optic neuritis, Bynke et al.
neuritis with visual recovery to 20/40 or better, Griffin and
(206) in 41% of 31 patients. Cox et al. (78) detected a relative
Wray (63) reported an abnormal VEP in 93% of 30 eyes,
afferent pupillary defect by the swinging flashlight test in
Arden and Gucukoglu (86) in 63% of 24 eyes. Halliday et
92% of 50 patients with resolved optic neuritis.
al. (210) and Asselman et al. (211) found abnormal visual
evoked potentials in all 24 and 15 cases, respectively, of
Optic Disc Appearance resolved optic neuritis occurring in patients with MS. Halli-
Optic disc pallor is almost always present when visual day et al. (212) reported that when visual acuity returned to
recovery has been incomplete and is often present even when 20/20, the amplitude of the VEP often was normal, but the
recovery has been excellent (Figs. 6.5 and 6.11). The pallor latency was virtually always still abnormal.
is usually temporal, but it may be generalized. Wybar (196)
Subjective Visual Complaints
noted optic disc pallor in 67% of 33 eyes with resolved optic
neuritis, whereas Lynn (197) reported it in 80% of 160 eyes, Despite the often-excellent measured recovery of visual
Bowden et al. (158) in 70% of 54 eyes, Nikoskelainen (107) function after an attack of acute optic neuritis, many patients
Figure 6.11. Optic atrophy after acute, anterior optic neuritis. A, Mild optic disc swelling. Visual acuity is 20/400, and there
is a central scotoma in the right eye. B, Two months after initial visual loss, disc swelling has resolved. Visual acuity has
returned to 20/20, but the optic disc now shows temporal pallor, and there are defects in the peripapillary retinal nerve fiber
layer (arrowheads).
OPTIC NEURITIS 311
still complain of difficulties with vision. As noted above, it (216) developed visual blurring during exercise despite a
is important to realize that many patients with optic neuritis stable body temperature, most investigators agree that Uht-
whose visual acuity returns to normal (20/20 or better) never- hoff’s symptom is most often associated with an elevation
theless have clinical and laboratory evidence of significant of body temperature (220). Two major hypotheses regarding
optic nerve dysfunction (89,90,135), particularly when using this phenomenon are that elevation of body temperature in-
tests of color vision (60,107,197) or measuring the VEP terferes directly with axon conduction and that a rise in body
(206,208,211,212). Such patients will state that their vision temperature releases a chemical substance that interferes
is ‘‘not right’’ or that it remains ‘‘fuzzy.’’ This difficulty with conduction. Although several studies appear to demon-
with fine visual function may cause disability in some pa- strate humoral factors capable of blocking nerve conduction
tients with resolution of optic neuritis who try to return to (221–224), Zweifach (225) examined three patients with
vocations requiring detailed visual function. Uhthoff’s symptom and found that blood removed from the
In the ONTT, a questionnaire was completed after 6 patients at the time of maximal visual loss and readminis-
months by 382 of the patients (213). Persistent visual symp- tered in the normothermic state did not reproduce the symp-
toms were reported by 56% of the patients. Among the 215 tom. Tasaki (226) postulated a safety factor for nerves that
patients who perceived their vision in the eye affected by he defined as the ratio of the action current generated by the
optic neuritis to be somewhat or much worse than before nerve impulse to the minimum amount of current needed to
optic neuritis, visual acuity was nevertheless normal in 66%, maintain conduction; if the safety factor is decreased by in-
contrast sensitivity in 30%, color vision in 55%, and the jury, disease, or pharmacologic insult, a small additional
mean deviation of the visual field in 58%. insult could be sufficient to block conduction. Davis (227)
One cause of symptoms in these patients is probably re- and Rasminsky (228), using severely demyelinated periph-
lated to subtle abnormalities in the visual field that may be eral nerve fibers, found that reversible conduction block can
difficult to detect with standard static perimetry in which be induced by increasing the temperature as little as 0.5⬚C.
patients experience abnormally rapid disappearance of focal Increased temperature increases the threshold for excitation
visual stimuli and abnormally rapid fatigue in sensitivity. for a nerve and also decreases the duration of the action,
Patients in whom such abnormalities are present typically presumably reducing the safety factor in the nerve. It is likely
complain that when they look at something, it appears as if that this direct temperature effect explains Uhthoff’s symp-
they have ‘‘holes’’ in their field of vision. If they continue tom in most cases (229); however, although temperature ele-
concentrating on the object, some holes fill in, whereas new vation may be the primary factor responsible for Uhthoff’s
holes appear elsewhere in the field. Ellenberger and Ziegler symptom, it may not be the only factor. Persson and Sachs
(183) called this phenomenon the ‘‘Swiss cheese’’ visual (230) studied the effects of physical exercise on the pattern-
field. It occurs not only in optic neuritis but also in other reversal VEP in patients with MS, with and without a history
types of optic neuropathy. of Uhthoff’s symptom, and in normal subjects. These inves-
tigators found that physical effort produced a short-lasting
Uhthoff’s Symptom reduction in the amplitude of the VEP and in the visual acuity
of patients with MS with a history of Uhthoff’s symptom;
Following an episode of optic neuritis, some patients de- however, there was no significant change observed in the
scribe transient visual blurring during exercise, during a hot already prolonged latency of VEP. In patients with MS with-
bath, or during emotional stress (3,214–216). This phenome- out a history of Uhthoff’s symptom, and in normal subjects,
non, called Uhthoff’s symptom, is most common in patients neither visual acuity nor any aspect of the VEP was affected.
with other evidence of MS but is also experienced by other- The authors interpreted their results as an indication that
wise healthy patients after optic neuritis, by patients with Uhthoff’s symptom results from a reversible conduction
Leber’s optic neuropathy (217), and by patients with optic block in impulse transmission by demyelinated nerve fibers,
neuropathies from other causes (218). Some patients with supporting the work of Davis (227) and of Rasminsky (228);
Uhthoff’s symptom note that their visual symptoms improve however, changes in oral temperature were very slight or nil
in colder temperatures or when drinking cold beverages. In- in these patients. Selhorst et al. (231) studied the monocular
deed, we have a patient who reported that she kept ice and pattern-reversal VEP in four patients with MS, well-compen-
ice water at her bedside at all times. Whenever she wanted sated optic neuritis, and Uhthoff’s symptom during and after
to read something or see clearly at distance, she would place peddling a lightly loaded ergometer bicycle. These investiga-
an ice cube in her mouth or drink the ice water. She would tors found no change in either oral or tympanic membrane
then see clearly for several minutes or longer. On examina- temperature at a time when visual acuity became reduced
tion, her visual acuity improved from 20/400 to 20/40 in and the VEP showed absence or reduction in amplitude of
both eyes about 2 minutes after she placed an ice cube in the P2 wave. Because all patients studied showed a slight
her mouth. Scholl et al. (219) reported that when Uhthoff’s decline in venous pH and a rise in lactic acid, Selhorst et
symptom was present following optic neuritis, MR imaging al. (231) postulated that the demyelinated nerves may be
of the brain was more likely to be abnormal and MS was susceptible not only to temperature changes but also to meta-
more likely to develop. Uhthoff’s symptom was reported bolic changes in the environment. Uhthoff’s symptom can
after 6 months by about 10% of patients enrolled in the occur not only in patients who have experienced an attack
ONTT (213). of acute optic neuritis but also in patients who have chronic
Although the patient studied by Goldstein and Cogan or subclinical optic neuritis (discussed later).
Neurologic Prognosis optic neuritis in the fellow eye increased the risk of the devel-
opment of MS; however, at least one lesion in the periven-
Both retrospective and prospective studies have been per- tricular white matter on MR imaging, a phenomenon noted
formed in an effort to determine the prognosis for the devel- in 30–70% of patients with isolated optic neuritis (7,12,145,
opment of MS in patients who experience an attack of acute 146), was the most significant risk factor associated with an
optic neuritis (232). Retrospective studies provide figures increased likelihood of developing MS (13,23).
ranging from 11.5% to 85% in both adults (28,32,82,83,118, Deckert-Schlüter et al. (119) detected increased concen-
197,315) and children (35,233–235). The marked discrep- trations of several different cytokines in the serum, CSF, or
ancy in these figures may result from biases common to both of 20 patients with isolated optic neuritis who eventu-
almost all retrospective studies, including criteria for diagno- ally developed MS, and Link et al. (120) reported similar
sis of MS and optic neuritis, the nature and length of follow- results. The presence of these substances suggests an activa-
up, and the care with which neurologic and visual testing tion of the T lymphocytes of the immune system both within
was performed. Most prospective studies seem to support and outside the CNS, and suggests that either their presence
higher figures, indicating that the risk of developing MS in alone or their particular concentration may be used to predict
patients who experience an attack of acute optic neuritis is the eventual development of MS in these patients.
only about 30% in patients followed 5–7 years after the Some authors believe that patients in whom optic neuritis
attack of optic neuritis (51,135) but eventually increases to
is the initial manifestation of MS tend to have a more benign
about 75% in women and 34% in men with longer follow-
course than patients in whom MS presents with no visual
up (102,130,236). Rodriguez et al. (33) reported that among
symptoms and signs (51,82,244–247). Other investigators,
95 incident cases of optic neuritis occurring in Olmstead
however, have found no difference in the eventual outcome
County, the estimated risk of MS was 39% by 10 years, 49%
of the disease (248–251).
by 20 years, 54% by 30 years, and 60% by 40 years. Again,
the risk of MS was higher in women than in men in this In the ONTT (23), the 10-year risk of MS was 38%. Pa-
study. The reason for the apparent difference in neurologic tients (n ⳱ 160) with one or more typical lesions on the
prognosis between women and men is unclear, particularly baseline brain MR scan had a risk of 56%; those with no
since there seems to be no difference in the clinical disease lesions (n ⳱ 191) had a risk of 22% (P ⬍ 0.001). The
or its course between the two sexes (10). The average time presence of more than one lesion did not appreciably in-
interval from an initial attack of optic neuritis until other crease that risk (23–26). Even when brain MR lesions were
symptoms and signs of MS develop varies considerably; present, over 40% of patients did not develop clinical MS
however, most authors find that the majority of persons who after 10 years. The 10-year risk of development of MS, based
develop MS after an attack of optic neuritis do so within 7 strictly on conventional clinical criteria, was 38%, compared
years of the onset of visual symptoms (32,96,102,236). Even with a 5-year risk of 30% (22–26). Thus, although these
patients who live in tropical and subtropical regions of the patients continued to develop MS with each passing year,
world have a substantial risk of developing MS after an at- most did so within the first 5 years after the initial episode
tack of isolated optic neuritis (237), although this risk may of optic neuritis. These results have applicability not only
be lower in Japan (238) and in some Latin American coun- to optic neuritis but also to patients presenting with a first
tries (239). It therefore seems appropriate to consider most demyelinating event of the brain stem or spinal cord because
cases of optic neuritis a limited form of MS (240) and to the three presentations share a common pathogenesis and
counsel patients appropriately (147,241–243). have been reported to have similar risks for MS (83). The
As noted above, there appear to be certain risk factors finding, in the ONTT cohort of patients, of a 38% 10-year
that increase the likelihood that a patient with isolated optic risk of MS after optic neuritis is similar to that of several
neuritis will eventually develop MS. Compston et al. (125) prior reports (33,102,236) and lower than that of other re-
found that positive typing for HLA BT101, winter onset of ports (83,130,252), all of which had smaller sample sizes.
the initial attack of optic neuritis in BT101-positive patients, Differences in risk estimates across studies can also be attrib-
and recurrent attacks of optic neuritis were associated with uted to differences in patient inclusion criteria, retention
an increased incidence of MS. Frick and Stickl (113) re- rates, and diagnostic criteria for MS.
ported that the presence of MBP in the CSF of a patient with The most potent predictor of MS in the ONTT was the
otherwise isolated optic neuritis and no history of previous presence of white matter lesions on the baseline brain MR
neurologic symptoms or signs nevertheless is highly predic- scan (23). The presence of one such lesion at least 3 mm in
tive of the development of MS in the future, a conclusion diameter more than doubled the 10-year risk of MS (from
supported by the findings of Söderström et al. (114) of anti- 22% to 56%). However, the presence of one or more lesions
MBP and anti-MBP peptide antibody-secreting cells in the did not signify that the patient was destined to develop MS.
CSF of patients with both acute optic neuritis and MS. Multi- Among patients with brain MR lesions, the 10-year probabil-
ple oligoclonal bands in the CSF of a patient with isolated ity of remaining free of MS was 44%. Conversely, the ab-
optic neuritis also seems to be highly predictive of the future sence of brain MR lesions did not eliminate the risk of devel-
development of MS (94,115–118). oping MS; in the absence of any lesions, the 10-year
Among patients with isolated optic neuritis enrolled in the probability of MS was 22%.
ONTT, a positive family history of MS, a history of previous There are certain gender and optic disc appearance charac-
neurologic symptoms, and a history of a previous attack of teristics that help predict whether a patient with optic neuritis
OPTIC NEURITIS 313
Table 6.1 in 72 (55%). After 10 years, MS was present in 83% of those

Gender and Optic Disc Appearance Combined as Predictors of with entry MR lesions and in 11% of those without entry
Multiple Sclerosis in Patients with No Brain Lesions on MR Imaging MR lesions. Differences between these results and the
at Study Entry
ONTT may be related to the former study’s smaller sample
Number size and lower follow-up rate. That study found, as the
Developing 10-Year Risk ONTT/LONS did, that once there is at least one MR lesion,
Multiple of Multiple Hazard Ratio an increasing number of lesions does not appreciably am-
N Sclerosis Sclerosis a (95% CI)b
plify the long-term risk of MS.
Female The eligibility criteria of the ONTT/LONS were suffi-
Disc normal 85 26 31% 1.0 ciently broad that the results should be applicable to most
Disc edema 57 9 16% 0.42 (0.20–0.89) patients presenting with optic neuritis as a first demyelinat-
Male ing event. Having incomplete data for 13% of the original
Disc normal 25 3 15% 0.36 (0.11–1.19) cohort was unlikely to be a source of appreciable bias. How-
Disc edema 24 1 5% 0.14 (0.02–1.00) ever, because the patients with incomplete follow-up had a
a
lower prevalence of brain MR scans with one or more lesions
Kaplan-Meier estimate of cumulative probability.
b
From proportional hazards model. than did the patients with complete follow-up, the computed
(From Optic Neuritis Study Group. Long-term brain MRI changes after optic neuritis in 10-year risk of MS could be a slight overestimate.
patients without clinically definite multiple sclerosis. Arch Neurol 2004 [in press].) The results of the ONTT/LONS long-term follow-up are
important to the clinician in several respects (23,650). First,
they reaffirm the prognostic value of a brain MR scan per-
will subsequently develop MS (Table 6.1) (26). In the formed at the time of a first episode of optic neuritis. The
ONTT, among patients with one or more brain MR lesions, presence of a single brain MR white matter lesion of at least
no demographic characteristics or clinical features of the 3 mm in diameter markedly increases the risk of developing
optic neuritis were useful in further defining the risk MS; higher numbers of lesions do not appreciably increase
(23–26). But among patients without brain MR lesions, the that risk. Second, they establish that even when MR lesions
risk was three times lower in males than in females, consis- are present, clinically defined MS does not develop within
tent with the well-documented lower prevalence of MS in 10 years in over 40% of patients. Third, the results highlight
males than in females and consistent with studies conducted the importance of an ophthalmologic examination for pa-
prior to the availability of brain MR imaging. The risk was tients whose brain MR scan is normal, because ophthalmos-
also lower when the optic neuritis was associated with a copy can identify features (severe optic disc swelling, hem-
swollen rather than a normal optic disc. Among females with orrhages, and exudates) associated with a very low risk of
no brain MR lesions, those with optic disc edema had a risk developing MS. This natural history information is a critical
of MS that was half as great as those without optic disc input for estimating a patient’s 10-year MS risk and for
edema. The risk of MS when no baseline brain MR lesions weighing the benefit of initiating prophylactic treatment at
were present was zero among the small group of patients the time of optic neuritis or other first demyelinating events
who had any one of the following findings: no light percep- in the CNS.
tion vision in the affected eye, optic fundus findings includ- Recurrent Optic Neuritis
ing severe optic disc edema, peripapillary hemorrhages, reti-
Patients in whom idiopathic acute optic neuritis occurs,
nal exudates, or the absence of periocular pain (24–26).
whether anterior or retrobulbar, may experience a recurrence
Thus, when there are no brain MR lesions, the presence of
in the eye at a later date or may experience a similar attack
any of these clinical features appears to predict a very low
in the fellow eye. Recurrent attacks occurred in 11.3% of
risk of MS. In patients who bear these atypical features, the
the patients reported by Marshall (68), in 14% of the patients
optic neuritis may not be part of a multifocal demyelinating studied by Classman and Phillips (254), in 20.6% of the
CNS illness. patients in the series reported by Lynn (197), in 24% of
The difference in the risk profile between patients with Hutchinson’s patients (83), and in 16.7% of the patients stud-
and without brain MR lesions is not surprising (24–26). Pa- ied by Perkin and Rose (39). The 10-year ONTT recurrence
tients with MR lesions already have imaging evidence of rate of 35% was similar to that reported by Cohen (42%)
disseminated disease, the pathogenesis of which is almost but higher than that reported in other studies with extended
certainly related to MS. Therefore, there is no reason to ex- follow-up such as those by Bradley and Whitty (18%),
pect to be able to identify true risk factors for future develop- Hutchinson (24%), and Rodriguez (16%). Although it has
ment of MS. On the other hand, the group of patients with been believed that the likelihood of visual acuity returning
optic neuritis and a normal brain MR scan likely includes a to normal decreases with each recurrence (83,197), the expe-
subgroup destined to have MS and another subgroup not rience of the ONTT has shown that long-term visual function
destined to have MS. is generally good despite this recurrence rate.
With regard to the predictive role of MR lesions, the only
study comparable to the ONTT (252,253) enrolled 131 pa- Management Recommendations for Patients with
tients with an acute demyelinating event in which optic neu- Presumed Acute Optic Neuritis
ritis constituted half of the cohort. Ten-year follow-up was In a patient with typical features of optic neuritis, a clinical
achieved in 81 (62%) patients and 12- to 16-year follow-up diagnosis can be made with a high degree of certainty with-
out the need for ancillary testing. Brain MR imaging is a complete demyelination, and the naked axons contained
powerful predictor of the long-term probability of MS (for swollen, vacuolated mitochondria in these areas. There were
at least the first 10 years); this information, as outlined some oligodendrocytes in areas of partial demyelination, and
above, when coupled with clinical trial outcomes suggesting axon architecture was maintained in these regions. In all
significant efficacy of early immunomodulatory therapy in areas, there was an excess of fibrous astrocytes.
patients with clinically isolated demyelinating syndromes Several experimental animal models of demyelinating
and abnormal MR scans, should be helpful to clinicians in optic neuritis can be produced for study of pathologic
planning long-term therapy as prophylaxis. changes and other features of the condition. Rao et al. (261)
Based on the results of the ONTT, it is reasonable to produced experimental allergic optic neuritis in guinea pigs
consider treatment with intravenous methylprednisolone, by sensitization with isogenic spinal cord emulsion in com-
250 mg q6h for 3 days or 1 g/day in a single dose ⳯ 3 days, plete Freund’s adjuvant. The optic neuritis produced in this
followed by a 2-week course of oral prednisone, 1 mg/kg/ manner has two major forms: (a) a ‘‘retrobulbar’’ form, with
day, with a rapid taper for patients with acute optic neuritis, a diminished pupillary response to light despite a normal-
particularly if brain MR imaging demonstrates multiple sig- appearing retina and optic disc, and (b) a ‘‘neuroretinitis,’’
nal abnormalities in the periventricular white matter consis- with a diminished pupillary response associated with hyper-
tent with MS, or if a patient needs to recover vision faster emia and swelling of the optic disc and edema of the peripap-
than the natural history of the condition. Since the potential illary retina. Histopathologic study of animals with retrobul-
beneficial effects on the visual and neurologic courses are bar neuritis reveals a mononuclear cell infiltrate localized to
short term and not lasting, prescribing no treatment is also the retrobulbar portion of the optic nerve and chiasm with
a reasonable approach. However, oral prednisone alone in multiple foci of axial and periaxial demyelination. Similar
standard dosages (e.g., less than 1 mg/kg/day) should be pathologic changes are present in animals with experimental
avoided. As noted above, the visual recovery is excellent neuroretinitis, but in these animals, the lesions are located
without treatment and the long-term vision is not any better just behind the lamina cribrosa, with marked swelling of
when corticosteroids are prescribed. axons in the prelaminar portion of the optic nerve, identical
with that seen in human disc swelling. In addition, Hayreh
Pathology et al. (262) observed acute optic neuritis with variable de-
grees of optic disc swelling in adult rhesus monkeys with
There is little material available regarding the pathologic experimental allergic encephalomyelitis. Histopathologic
findings in the optic nerves of patients with acute isolated examination of the optic nerves of these animals revealed
optic neuritis. What pathology exists has been in optic nerves inflammatory infiltrates, extensive demyelination, and axon
from patients with acute MS and shows active demyelinating degeneration, without inflammation in the retina or optic
plaques similar to those in the brain (255–258). In such nerve head. Okamoto (263) observed macrophages in the
plaques, the inflammatory response is marked by perivascu- subarachnoid space in rabbits with experimental allergic
lar cuffing, T cells, and plasma cells. Initially there is swell- optic neuritis. He suggested that these macrophages may
ing of nerve tissue in the area of demyelination, following digest the myelin debris in the subpial spaces of the affected
which the myelin sheaths begin to break down into fat drop- optic nerves. It is likely that these models will facilitate fu-
lets. As degeneration proceeds, the nerve fibers themselves ture studies of pathogenetic mechanisms of demyelinating
are destroyed, with the degeneration occurring in both the diseases of the human optic nerve (264).
proximal and distal segments. As the inflammatory reaction Sergott et al. (265) injected the serum from 17 patients
subsides, fat-laden macrophages become numerous, and with MS and 3 patients with isolated optic neuritis into the
there is glial proliferation. Gartner (259) examined 14 eyes optic nerves of guinea pigs. These investigators then sacri-
from 10 patients in whom a diagnosis of MS had been made ficed the animals and examined the optic nerves. They found
clinically and confirmed at postmortem examination. An at- demyelination in the optic nerves injected with the serum
tack of optic neuritis had been diagnosed during life in only from 12 of the 17 MS patients and in the optic nerves injected
two of the cases, and all cases were in an advanced state of with serum from all 3 of the optic neuritis patients. There
the disease by the time of their death. Gartner (259) found were areas in which axons were relatively spared within the
only optic atrophy, predominantly in the temporal portion of areas of demyelination, similar to those seen in the brains
the nerve. Although the papillomacular bundle was primarily of patients with MS.
affected, the peripheral fibers were also damaged. There was It is believed that demyelination of nerve fibers leads to
an increase in cellularity of the nerve, especially with respect complete conduction block, slowing of conduction, or a fail-
to glial cells. The surface of the optic discs showed extensive ure to transmit a rapid train of impulses (256,266,369).
gliosis, and the blood vessels on and near the disc were
thickened and sclerosed. The retina showed atrophy of the Relationship of Optic Neuritis to MS
nerve fibers and ganglion cells, most readily observed at the
macula. de Preux and Mair (260) described the ultrastructure Optic neuritis occurs in about 50% of patients with MS
of the optic nerves of a patient who developed Schilder’s and in about 20% it is the presenting sign (39). Available
disease and bilateral demyelinating optic neuritis. Both evidence suggests that the pathogenesis of isolated optic neu-
nerves contained areas of complete, as well as partial, demy- ritis is no different than that of MS in general. In fact, a
elination. No oligodendrocytes were present in the areas of strong case can be made for optic neuritis being a forme
OPTIC NEURITIS 315
fruste of MS, based on similarities between the two in inci- that 46% of 54 females and 28% of 32 men developed MS
dence, CSF findings, histocompatibility data, results of MR within a mean of 12.9 years after their attack. In the ONTT
imaging, and family history as well as other features (240). with 10 years of follow-up, no gender difference in risk for
For instance, both isolated optic neuritis and MS are more development of MS was observed (23) when the presenting
common in northern latitudes and in females compared with MR scan was found to be abnormal. In contrast, among the
males. Immunologic changes in the CSF similar to those in 191 patients without MR lesions, certain features did alter
MS may also occur in optic neuritis (267) (discussed previ- the risk of MS (Table 6.1), with the risk of MS lower in
ously). Feasby and Ebers (115) found that 75% of 36 patients males than in females.
with isolated optic neuritis had abnormalities on somatosen- Kurland et al. (269) found no difference between whites
sory evoked potentials, brain stem evoked potentials, or CSF and nonwhites in his comparison of United States service-
protein electrophoresis, and Sanders et al. (251) found that men, but this study had low power to observe such a differ-
67% of 30 patients had similar abnormalities. As noted ence if, indeed, one existed. Alter et al. (271) compared the
above, 25–60% of patients with isolated optic neuritis have Asian and Caucasian populations in Hawaii and found no
changes in the brain on MR imaging consistent with areas significant differences in the rate of development of MS after
of demyelination. Ebers et al. (268) described 10 patients optic neuritis between the two races. Although the 2-year
with isolated optic neuritis who had a family member with data from the ONTT suggested that Caucasians are at higher
MS, which also suggests an etiologic association between risk than African-Americans (13), results from this study at
the two, and similar HLA types (108,125) are also present 10 years had insufficient statistical significance to comment
in both optic neuritis and MS. on this variable. Among Caucasians in the study, 14% of
Although Kurland et al. (269) did not find age at onset 331 developed MS within 2 years compared with 5% of
of optic neuritis to be a risk factor in the eventual develop- 58 non-Caucasians, most of whom were African-American.
ment of MS, and Hely et al. (135) reported that there was This difference was still present at 4-year follow-up (20).
no difference in the age range of those patients with optic Kurland et al. (269) found neither birthplace nor residence
neuritis who developed MS compared with those who did to be a risk factor for MS in a study of U.S. veterans with
not, most studies indicate that the younger the age at which optic neuritis, but the study by Kahana et al. (30) of optic
optic neuritis develops, the greater the risk for the develop- neuritis in Israel found that MS developed in 23% of 35
ment of MS. Bradley and Whitty (82) first suggested that patients born in Europe, 32% of 25 patients born in Asia
the risk of MS increased with increasing age, but they did or Africa, and 44% of 25 patients born in Israel. There is
not provide any supportive data. Kahana et al. (30), however, increasing epidemiologic evidence suggesting that the place
reported that 39% of patients who were less than 39 years old of residence in regard to distance from the equator during
when they had an initial attack of optic neuritis eventually the first 15 years of life is a major risk factor for the develop-
developed MS, compared with 21% of patients who eventu- ment of MS after optic neuritis. Indeed, it seems clear that
ally developed MS after they developed optic neuritis when persons who migrate from one country or region to another
they were older than 40. Mapelli et al. (270) reported similar during childhood (i.e., under 15 years of age) take on the
findings. These investigators reported that 31% of 26 pa- risk of the country of destination (272–274). It is less clear
tients who were less than 40 years of age when they experi- whether persons who migrate later in life retain the risk of
enced a first attack of optic neuritis eventually developed their country of origin or take on the risk of their new place
MS, compared with only 14% of 14 patients who were older of residence.
than 40 years of age when they experienced their first attack. Kurland et al. (266) and Bradley and Whitty (82) reported
Rizzo and Lessell (236) reported that the relative risk for that season of onset of optic neuritis was not a risk factor
MS increased by 1.7 for each decade less than 54 years. for the subsequent development of MS but provided no data.
Like Bradley and Whitty (82), Sandberg-Wollheim et al. Sandberg-Wollheim et al. (102), however, reported that MS
(102) suggested that younger age at onset of optic neuritis developed in 43% of 42 patients with onset of optic neuritis
was a risk factor in the development of MS but provided no between October and March, compared with 29% of 44 pa-
supportive data. Age at onset was not found to be statistically tients with onset of optic neuritis between April and Sep-
related to ultimate development of MS in the ONTT/LONS tember.
(24–26). There are few data available on the features of optic neuri-
There is some controversy as to whether gender is a risk tis that relate to the subsequent risk of MS. Kurland et al.
factor for the development of MS after optic neuritis. Some (266) did not find any aspects of optic neuritis to be risk
investigators report no difference in the incidence of MS factors; however, Bradley and Whitty (82), without any sup-
after optic neuritis (30,82,237,270). Rodriguez et al. (33) porting data, reported that optic disc appearance and severity
also found no gender differences in their study: 38% of 26 of visual loss were not risk factors for MS but that the pres-
men and 40% of 66 women developed MS at 10 years after ence of pain and a typical visual field defect were risk fac-
onset of optic neuritis. On the other hand, Hely et al. (135) tors. Kahana et al. (30) found that MS developed in only
reported that the relative risk of MS was almost three times 13% of 45 patients with anterior optic neuritis, compared
greater in women compared with men. Rizzo and Lessell with 60% of 30 patients with retrobulbar optic neuritis.
(236) reported that MS developed in 69% of 47 women and Data from the ONTT confirm the findings of Kahana et
33% of 20 men within 14.9 years of their initial attack of al. (30) that the presence of severe disc swelling reduces the
optic neuritis, and Sandberg-Wollheim et al. (102) reported likelihood that MS will develop, particularly when the pa-
tient also has normal brain MR imaging (13,23–26). In the MS. Anmarkrud and Slettnes (118) reported that 15 of 19
ONTT, among the 22 patients with severe disc swelling and (78.9%) patients with optic neuritis who had abnormal CSF
normal brain MR imaging at baseline, none developed clini- but only 1 of 10 (10%) patients with optic neuritis and nor-
cal signs of MS in 10 years of follow-up. In patients of both mal CSF developed MS within a mean follow-up of 5.8
genders without brain MR lesions, MS did not develop in years. Sandberg-Wollheim et al. (102) reported that 26 of
any patients whose visual loss was painless (n ⳱ 18) or total 55 (47.3%) patients with optic neuritis who had abnormal
(no light perception, n ⳱ 6) or in those who had ophthalmo- CSF and 7 of 31 (22.6%) patients with normal CSF devel-
scopic findings of severe disc swelling (n ⳱ 22), hemor- oped MS over a mean follow-up of 12.9 years. These studies
rhage of the optic disc or surrounding retina (n ⳱ 16), or indicate that 25–50% of patients with isolated acute optic
retinal exudates (n ⳱ 8) (Table 6.1). In the 191 patients neuritis and abnormal CSF remain free of neurologic mani-
without MR lesions, the risk of MS was lower when the festations of MS for many years (if not for life), whereas
optic disc was swollen (anterior optic neuritis, papillitis) than 10–50% of patients with optic neuritis and normal CSF
when it was not swollen (retrobulbar neuritis). Among fe- nevertheless develop other manifestations of MS during the
males, the risk of MS was halved when optic disc swelling same period. In view of these findings, it seems likely that
was present. Among males, only 1 of 24 patients with optic CSF abnormalities alone are not a primary risk factor in
disc swelling developed MS. One hundred seventy-nine of determining whether a patient with acute optic neuritis even-
the 191 patients with no brain MR lesions had no prior his- tually develops clinical evidence of disseminated demyelin-
tory of neurologic symptoms or optic neuritis in the fellow ation.
eye and would be considered to have monofocal optic neuri- No long-term study has evaluated the added value of the
tis; their 10-year risk of MS was 20%. detection of CSF abnormalities in conjunction with MR im-
In most series, adult patients with bilateral simultaneous aging of the brain; however, data from the ONTT suggest
optic neuritis are said to have the same risk of developing that the presence of CSF abnormalities has little predictive
MS as patients with unilateral optic neuritis (82,269,275); value for the development of MS over and above the power-
however, Hutchinson (83) found an increased incidence of ful predictive value of MR imaging (discussed previously)
MS in patients who developed bilateral optic neuritis either (13,93,276,277).
simultaneously or whose second eye became affected within The predictive value of CSF oligoclonal banding for the
2 weeks of the first eye. In the ONTT/LONS, when the development of CDMS within 5 years after optic neuritis
criteria for MS were expanded to include the occurrence of was assessed in 76 patients enrolled in the ONTT. In the
optic neuritis in the fellow eye, the 10-year risk of MS was patients followed in the ONTT for 5 years, the following
45%: 31% in patients with no baseline brain MR lesions and findings were noted:
60% in patients with one or more lesions (23). Most authors
believe that ultimate visual acuity after optic neuritis has no 1. Oligoclonal bands were present in 50% of the patients
bearing on the subsequent development of MS (23–26, (73% of the 37 patients with abnormal brain MR and
39,82). 28% of the 39 patients with normal brain MR).
Although it might be expected that recurrent optic neuritis 2. CDMS developed within 2 years in 29% of the 38 with
would increase the risk for MS, the reports on this provide oligoclonal bands and in 5% of the 38 patients without
mixed results, with some authors reporting an increased risk oligoclonal bands (P ⳱ 0.015).
(33,83,102,267) and others not (130,236). Data from the 3. The association of oligoclonal bands and the develop-
ONTT data do not show a strong relationship between recur- ment of CDMS was attenuated when adjusted for brain
rent optic neuritis and the early development of MS MRI (P [adjusted for MRI] ⳱ 0.09).
(13,20,23–26). 4. There were 11 patients with normal brain MR scans who
Evidence of immunologic dysfunction (e.g., oligoclonal had oligoclonal bands, two of whom had developed
banding) in the CSF is common in patients with MS. CDMS by 2 years (93).
Whether the presence of these abnormalities in patients with
clinically isolated optic neuritis increases the risk that such CDMS developed within 5 years in 22 (29%) of the 76
patients will develop MS in the future is controversial (dis- patients: in 16 (42%) of the 38 patients with oligoclonal
cussed previously). Nikoskelainen et al. (267) studied 48 bands present and in 6 (16%) of the 38 patients without
patients with isolated optic neuritis, 27 (56.3%) of whom bands (OR ⳱ 3.88; 95% CI ⳱ 1.18, 13.86; P ⳱ 0.02).
developed probable MS during a 7- to 10-year follow-up. Among the 54 patients not classified as CDMS, 5-year fol-
Although increased relative IgG, abnormal electrophoresis, low-up was complete for 50 (93%). The predictive value of
or an abnormal ratio of measles antibody titer in the serum CSF oligoclonal band assessment for the development of
compared with the CSF at the time of presentation correlated CDMS over and above that of brain MR imaging was appar-
with the development of clinical signs of disseminated dis- ent only among patients with no brain MR lesions at study
ease, 6 of 11 (54.5%) patients with normal CSF values on entry. Among the 39 patients with normal brain MR imag-
every laboratory study developed MS. Stendahl-Brodin and ing, CDMS developed in 3 of 11 (27%) patients with oli-
Link (117) reported that 9 of 11 (81.8%) patients with iso- goclonal bands present but in only 1 of 28 (4%) without
lated optic neuritis but with abnormal CSF developed MS oligoclonal bands (P ⳱ 0.06). In contrast, among the 37
within a mean follow-up of 11 years. During this period only patients with abnormal brain MR imaging, CDMS devel-
1 of 19 (5.3%) similar patients with normal CSF developed oped in 13 of 27 (48%) with oligoclonal bands and in 5 of
OPTIC NEURITIS 317
10 (50%) without oligoclonal bands (P ⳱ 1.00). The positive numerous patients who have no history of acute visual loss
predictive value of oligoclonal bands was 42% and the nega- (painful or otherwise) but who nevertheless complain that
tive predictive value was 84%. Among the 39 patients with the vision in one or both eyes is not normal and who have
normal brain MR imaging, the positive and negative predic- evidence of unilateral or bilateral optic nerve dysfunction
tive values were 27% and 96%, respectively, whereas among (198,254,278–285). Such patients may complain of a static
the 37 patients with abnormal brain MR imaging, the values disturbance of vision, a slowly progressive loss of vision in
were 48% and 50%, respectively. one or both eyes, or, occasionally, a stepwise loss of vision
Brain MR imaging has been demonstrated to be a strong unassociated with periods of recovery.
predictor of CDMS among patients with monosymptomatic Some patients with MS complain of blurred or distorted
optic neuritis. In the ONTT there was a 51% 5-year incidence vision even though visual acuity is 20/20 or better in both
of CDMS in patients who had abnormal brain MR imaging eyes. Such patients often are found to have evidence of
at the time of optic neuritis compared with a 16% incidence chronic optic neuritis by clinical testing (e.g., color vision,
in those with normal brain MR scans (22). These results visual fields, ophthalmoscopy) (Fig. 6.12), electrophysio-
indicate that performing a lumbar puncture to detect oli- logic testing (visual evoked responses), psychophysical test-
goclonal bands is not of added value for predicting the five- ing (e.g., contrast sensitivity), or a combination of these
year risk of CDMS in patients who have abnormal brain MR methods (202,286–289). Regan et al. (202), for example,
scans at the time of development of monosymptomatic optic used sine wave gratings to test contrast sensitivity for nar-
neuritis. However, the results suggest that oligoclonal band row, broad, and intermediate-width bars in a group of 48
testing may be helpful in the risk assessment of optic neuritis patients with MS and resolved optic neuritis. These investi-
patients with normal brain MR scans. gators found that in 20 of the 48 patients with MS in whom
That the value of CSF analysis would depend on the brain Snellen acuity fell within normal limits, contrast sensitivity
MR findings was not felt to be surprising (277). Patients to gratings of broad and/or intermediate bar width was abnor-
with abnormal brain MR scans already have morphologic mally low, whereas sensitivity to narrow bars was normal.
evidence of disseminated disease, and as such it is expected Most patients with chronic unilateral or bilateral demye-
that most of these patients will eventually develop additional linating optic neuritis develop visual symptoms after other
neurologic events sufficient for a diagnosis of CDMS. There- signs and symptoms of MS have developed, and this is why
fore, there is no reason to expect that a CSF analysis would the percentage of patients with MS and evidence of chronic
be predictive of MS among these patients. The group of progressive optic neuritis increases the longer the patients
patients with optic neuritis and normal brain MR imaging are followed (278,281). Nevertheless, slowly progressive
likely includes a subset of those destined to have MS and a visual loss or complaints of blurred or distorted vision are
subset of those who may have optic neuritis unassociated the first symptoms of the underlying neurologic disease in
with MS. Among these patients, the finding of oligoclonal some patients (278,281). We are unaware of any treatment
bands in the CSF does appear to increase the likelihood that for chronic progressive demyelinating optic neuritis.
CDMS ultimately will be diagnosed. Additionally and per-
haps more importantly, the absence of oligoclonal bands in
the CSF makes the development of CDMS within 5 years
unlikely. Although the number of patients in the ONTT was
too small for definitive conclusions with regard to the role of
CSF analysis in the evaluation of patients with optic neuritis,
according to the authors the results suggested that a lumbar
puncture has limited value in patients with typical mono-
symptomatic optic neuritis who have demyelinative changes
on brain MR imaging (277).
CHRONIC DEMYELINATING OPTIC NEURITIS

It was once stated that for all intents and purposes chronic
optic neuritis does not occur. The reason for this dogmatic
statement was that too many patients with mass lesions com-
pressing the intracranial portion of the optic nerve were
being diagnosed as having chronic optic neuritis, leading to
delayed treatment of the underlying lesion with resultant Figure 6.12. Retinal nerve fiber bundle defects in the right eye of a patient
with bilateral chronic optic neuritis in the setting of multiple sclerosis. The
permanent visual loss. Thus, the statement that chronic optic
patient had never experienced any episodes of acute loss of vision. Instead,
neuritis was never a tenable diagnosis was made in an effort she stated that her vision was slightly blurred and had been slowly worsen-
to raise the consciousness of the majority of physicians to ing for the past 6–8 months. Visual acuity was 20/20 OU; however, color
look for another, potentially treatable, cause of unilateral vision was slightly diminished in both eyes when tested using Hardy-Rand-
progressive optic neuropathy. Rittler pseudoisochromatic plates. Visual fields were normal by kinetic
In fact, chronic optic neuritis not only occurs but is not perimetry. There was no relative afferent pupillary defect. Both optic discs
uncommon. In any group of patients with MS, one can find were mildly pale.
ASYMPTOMATIC (SUBCLINICAL) had no evidence of MS, this case emphasizes that patients
DEMYELINATING OPTIC NEURITIS with and without evidence of MS may experience an attack
of subclinical optic neuritis.
A substantial percentage of patients with MS have clinical Evidence for optic neuritis in a patient who is visually
or laboratory evidence of optic nerve dysfunction even asymptomatic may be clinical, electrophysiologic, psycho-
though they have no visual complaints and believe their vi- physical, or a combination of these (40,188,291,292). A
sion to be normal (194,198,282,283,285,290–292). The careful clinical examination may reveal that despite having
Optic Neuritis Study Group (7,11) found that 48% of patients visual acuity of 20/20 or better, the patient has a subtle dis-
with apparently unilateral optic neuritis and no history of turbance of color perception when tested with color plates,
previous optic neuritis in the contralateral eye nevertheless the Farnsworth-Munsell 100-Hue test, or some other method
had an abnormal visual field unexplained by intraocular pa- (8,60,126,187,188,190,295,296). There may be subtle visual
thology in their asymptomatic, fellow eye. A substantial per-
field defects in one or both eyes detected using automated
centage of these eyes also had disturbances of visual acuity,
perimetry (194,297,298). A relative afferent pupillary defect
color vision, and contrast sensitivity. These findings are con-
may be present (299), or the patient may have subtle optic
sistent with the pathologic finding of demyelination in the
nerve or nerve fiber layer atrophy (191,286,300–302) (Fig.
optic nerves in patients who never had visual complaints
during life (293). Miller (294) reported having evaluated a 6.14). In some cases, MR imaging shows enhancement of
21-year-old woman who came to the Wilmer Eye Institute the optic nerve in question (Fig. 6.15).
for a routine examination. Visual acuity was correctable to Visually asymptomatic patients suspected of having or
20/15 OU, color vision was normal, and kinetic perimetry known to have MS may be shown to have disturbances of
was normal in both eyes using both a tangent (Bjerrum) the visual sensory pathways by electrophysiologic testing.
screen and a Goldmann perimeter. Ophthalmoscopy re- VEPs seem to be a particularly sensitive indicator of optic
vealed normal-appearing optic discs and peripapillary nerve nerve and other visual sensory pathway disturbances in such
fiber layer with no evidence of atrophy; however, the patient patients (40,188,190,191,210,289,291,292,296,303–305).
had a definite right relative afferent pupillary defect. It was Psychophysical tests of visual function, such as contrast
decided to perform a CT scan. Shortly after the patient re- sensitivity using a Pelli-Robson chart, Arden gratings, oscil-
ceived an intravenous injection of contrast, she experienced loscope screen projections, or similar techniques, may reveal
a seizure and then had cardiorespiratory arrest from which abnormalities in patients with MS and other disorders who
she could not be resuscitated. Postmortem examination re- are visually asymptomatic (40,58,189,192,202,283,287,289,
vealed no brain neuropathologic findings; however, the right 291,292,306,307). Some psychophysical tests, such as mea-
optic nerve showed several small areas of demyelination surements of sustained visual resolution (308) and assess-
and secondary atrophy consistent with a previous attack of ment of chromatic, luminance, spatial, and temporal sensi-
subclinical optic neuritis (Fig. 6.13). Although this patient tivity (309–313), give similar results but are too complex
Figure 6.13. Pathology of probable subclinical optic neuritis. The patient was a 21-year-old woman with no previous history
of systemic disease, neurologic disease, ocular disease, or trauma who was noted during a routine eye examination to have a
right relative afferent pupillary defect. The patient had no visual complaints once her refractive error was corrected, and she
had visual acuity of 20/15 OU, normal color perception in both eyes, using Hardy-Rand-Rittler pseudoisochromatic plates, and
normal visual fields by kinetic perimetry. The patient subsequently suffered a fatal cardiac arrest during CT scanning, possibly
related to a toxic reaction to contrast material. A, Section through the right optic disc and anterior portion of the right optic
nerve shows segmental optic atrophy. Masson trichrome. B, Higher-power view of the right optic nerve shows the atrophic
area (A) adjacent to normal nerve fiber bundles (N). Masson trichrome.
OPTIC NEURITIS 319
ease’’ through the efforts of his pupil, Gault (322), who

devoted his thesis to the subject.
Devic’s disease (neuromyelitis optica [NMO]) is an idio-
pathic inflammatory demyelinating disease of the CNS,
characterized by attacks of optic neuritis and myelitis. The
co-occurrence of optic neuritis and myelitis is seen in pa-
tients with MS, acute disseminated encephalomyelitis, sys-
temic lupus erythematosus (SLE), and Sjögren’s syndrome;
it can also occur in association with viral and bacterial infec-
tions (Table 6.2). Often, however, no underlying cause can
be found. NMO may occur as a monophasic illness that is
either fulminant and fatal or associated with varying degrees
of recovery. A polyphasic course, characterized by relapses
and remissions, also occurs (323).
Although Devic’s disease has been acknowledged as a
unique type of optic neuritis for over 130 years, only recently
Figure 6.14. Retinal nerve fiber bundle defects in the asymptomatic eye has the pathologic appearance of this unique form of demye-
of a patient with multiple sclerosis. Note numerous curvilinear dark streaks linating process been more clearly elucidated. Much debate
in the inferior arcuate nerve fiber bundle of the left eye. has revolved around whether NMO is a distinct disease, and
what its relationship is to MS and other autoimmune disor-
ders.
and time-consuming to be of use in screening patients in
clinical practice. Other tests, such as assessing the presence Epidemiology
or absence of the Pulfrich phenomenon (314), and the ‘‘flight NMO constitutes less than 1% of demyelinating disease
of colors’’ test (316–319), give little more information than in Western countries (324,325) and may be more prevalent
one can obtain by an otherwise complete clinical and electro- than typical MS in Japan (326–329). NMO occurs primarily
physiologic examination. in children and young adults (330–336), but all ages may
be affected, and the condition has been described in patients
NEUROMYELITIS OPTICA (DEVIC’S DISEASE)
over 60 years of age (331,337,338). Both sexes are equally
The association of acute or subacute loss of vision in one affected. It does not seem to be inherited, although McAlpine
or both eyes caused by acute optic neuropathy preceded or (339) reported its occurrence in monozygotic twins. Al-
followed within days to weeks by a transverse or ascending though most patients who develop this condition are other-
myelitis was initially described by Allbutt (320) and later wise healthy, NMO has been reported in patients with SLE
by Devic (321). Devic called the condition neuromyelitis (340,341), pulmonary tuberculosis (342–344), and after
optica, but it subsequently became known as ‘‘Devic’s dis- chickenpox (345,346). Hainfellner et al. (347) reported the
case of a previously healthy 40-year-old woman who devel-
oped both NMO and myelinoclastic diffuse sclerosis
(Schilder’s disease; discussed later). This case gives some
credence to those who believe that both disorders are variants
of MS.
Table 6.2
Neuromyelitis Optica and Associated
Systemic Diseases
Autoimmune disorders
Systemic lupus erythematosus (340,341,526–530,635)
Sjögren’s syndrome (636–639)
P-ANCA (640,641)
Anticardiolipin antibody syndrome (642,643)
Mixed connective tissue disease (644,645)
Infectious disease
Tuberculosis (343,344,646)
Viral
HIV (511)
Figure 6.15. MR imaging in subclinical optic neuritis. T1-weighted coro- Varicella-zoster virus (345,346,369,647)
nal MR image after intravenous injection of paramagnetic contrast material Epstein-Barr virus (370)
in a 29-year-old woman with a history of left optic neuritis but no visual Toxins
symptoms or signs of optic neuropathy in the right eye shows enhancement Clioquinol (648–650)
of the orbital portion of the right optic nerve (arrowhead).
Pathology Although serologic and clinical evidence of B-cell auto-

immunity has been observed in a high proportion of patients
The brain, optic nerves, and spinal cord are affected by with NMO, the mechanisms that result in selective localiza-
scattered lesions of demyelination that principally affect the tion of inflammatory demyelinating lesions to the optic
white matter but may also affect the gray matter (348). In nerves and spinal cord are unknown. Lucchinetti et al. (360)
some cases, the cerebral cortex is only slightly affected or provided detailed molecular studies on 82 lesions from nine
completely spared (349); however, the optic nerves and the autopsy cases of NMO using a similar classification, patho-
spinal cord are invariably damaged (350). Both optic nerves logically, as in their paper on the classification of MS lesions
are affected, although the degree of demyelination may be (359). Demyelinating activity in the lesions was immunocy-
symmetric or asymmetric. Mandler et al. (349) described the tochemically classified as early active (21 lesions), late ac-
pathologic findings in five cases of ‘‘neuromyelitis optica’’ tive (18 lesions), inactive (35 lesions), or remyelinating (8
and found unilateral demyelination in three of the five cases. lesions) by examining the antigenic profile of MDPs with
All of these cases also showed evidence of a severe necrotiz- macrophages. The pathology of the lesions was analyzed
ing myelopathy with thickening of blood vessel walls and using a broad spectrum of immunologic and neurobiologic
absence of lymphocytic infiltration or demyelination in the markers, and lesions were defined on the basis of myelin
spinal cord. In view of these unusual findings, we would protein loss, the geography and extension of plaques, the
question the diagnosis of NMO in these patients.
patterns of oligodendrocyte destruction, and the immuno-
The spinal cord is extensively affected in all cases of
pathologic evidence of complement activation. The pathol-
NMO (350). Liquefaction and formation of cavities are com-
ogy was identical in all nine patients. Extensive demyelin-
mon. There is widespread destruction of myelin sheaths, and
ation was present across multiple spinal cord levels,
axis cylinders may also be destroyed. There may be small
associated with cavitation, necrosis, and acute axonal pathol-
areas of perivascular lymphocytes in both brain and spinal
cord. Formation of glial tissue occurs in mild or moderately ogy (spheroids), in both gray and white matter. They found
severe cases; however, it is not present or is minimal in a pronounced loss of oligodendrocytes within the lesions.
fulminating, rapidly fatal cases. The inflammatory infiltrates in active lesions were character-
Walsh (351) studied a patient with presumed NMO in ized by extensive macrophage infiltration associated with
whom scattered areas of destroyed tissue were present large numbers of perivascular granulocytes and eosinophils
throughout the subcortex with more pronounced lesions in and rare CD3Ⳮ and CD8Ⳮ T cells. A pronounced perivas-
the occipital lobes, particularly in the region of the calcarine cular deposition of immunoglobulins (mainly IgM) and com-
fissure. Small areas of demyelination were present in the plement C9 neo-antigen in active lesions was associated with
basal ganglia, in the region of the red nucleus, and in perivas- prominent vascular fibrosis and hyalinization in both active
cular locations throughout the mesencephalon. The optic and inactive lesions. Lucchinetti et al. concluded that the
nerves showed extensive demyelination, as did the optic chi- extent of complement activation, eosinophilic infiltration,
asm. The spinal cord was most severely affected, with the and vascular fibrosis observed in these Devic NMO cases
lesions increasing in severity as they passed down the cord was more prominent compared with that in prototypic MS,
(352). Rare patients with NMO have pathologic evidence of and that this supported a role for humoral immunity in the
a demyelinating peripheral neuropathy (353). pathogenesis of NMO. Further, they felt that therapeutic
Although some investigators believe that NMO is simply strategies designed to limit the deleterious effects of comple-
a rare and aggressive variant of MS (329,347,354–356), ment activation, eosinophil degranulation, and neutrophil/
there are several important differences in the pathologic find- macrophage/microglial activation were worthy of further in-
ings in the two conditions (357,358). First, the cerebellum vestigation.
is almost never affected in patients with NMO, whereas it The animal model for MS, experimental autoimmune en-
is frequently affected in MS. Second, excavation of affected cephalomyelitis (EAE), may be of help in understanding
tissue with formation of cavities is rare in MS but common which immunologic effector mechanisms, in particular auto-
in NMO, where there is often liquefaction of tissue. Third, antibodies, contribute to the pathogenesis of NMO. Aug-
gliosis is characteristic of MS but is almost always absent mentation of demyelination in EAE in the Lewis rat by circu-
or minimal in NMO. Fourth, the arcuate fibers located in lating antibodies directed toward myelin oligodendrocyte
the cerebral subcortex are relatively unaffected in patients glycoprotein (MOG) was described in the late 1980s (361).
with NMO but are severely damaged in most patients with Since then a wide array of experimental models have focused
MS. on MOG as autoantigen and generated variants of EAE in
Lassmann et al. (359) proposed a classification for MS rats and mice that more closely mimic the complex of pathol-
lesions based on molecular histopathologic findings from ogies seen in MS (362).
diagnostic biopsies and autopsies. The patterns I–IV of de- All the salient immunopathologic features of NMO are
myelination and inflammation are not closely linked to spe- reproduced in Brown Norway (BN) rats immunized with
cific relapsing-remitting or progressive disease courses but MOG (363). MOG-induced EAE in this strain follows a
may help us to understand the underlying immunologic and fulminant clinical course associated with widespread demye-
neurodegenerative mechanisms involved in lesion forma- lination and axonal injury. The lesion distribution also ex-
tion. These patterns may also be defining in the pathophysio- hibits a preference for the optic tract and spinal cord similar
logic process underlying NMO. to that seen in NMO. More importantly, the inflammatory
OPTIC NEURITIS 321
infiltrate contains large numbers of eosinophils and demye- variant of acute disseminating encephalomyelitis due to the
lination is associated with complement deposition. Recruit- association with preceding infection, monophasic course,
ment of eosinophils into the CNS was not seen in demyelin- and generally good outcome in children (336,372).
ating lesions induced by the cotransfer of MOG-specific
antisera and encephalitogenic Th-1 MOG-specific T cells in Loss of Vision
BN rats, suggesting that eosinophil recruitment was depen-
dent on a MOG-specific Th-2 T-cell response. However, it Visual loss in patients with neuromyelitis optica almost
was not possible to identify a clear highly polarized MOG- always is bilateral (323,330,331,336), although unilateral
specific Th-2 T-cell response. In particular, no enhanced cases have been reported (323,336,349). One eye usually is
secretion of the classical Th-2–associated cytokine IL-4 was affected first, but the second eye typically is affected within
observed and the MOG-specific antibody response included hours, days, or rarely weeks after onset (364). The loss of
both Th-1–associated (IgG2b) and Th-2–associated (IgG1 vision is typically rapid and usually severe. It is not uncom-
and IgE) isotypes. mon for complete blindness to develop. The rapid, bilateral
These findings demonstrate that even in inbred strains loss of vision that occurs in patients with NMO is in sharp
with a high susceptibility for Th-2–driven autoimmune re- contrast to the loss of vision in optic neuritis, which tends
sponses, it is difficult to disentangle the effector pathways to be unilateral and not as severe, and to the loss of vision
involved in lesion formation and ultimately tissue destruc- in Leber’s hereditary optic neuropathy, which tends to be
tion. Cree (323) suggested that all we know about the molec- more slowly progressive. Pain in or about the eye precedes
ular basis for the induction of this NMO disease model is the loss of vision in a few cases, again distinguishing the
that while the eosinophilic component is controlled by non- condition from optic neuritis, in which pain is an almost
MHC genes, the intensity and pathogenicity of the antigen- universal feature (discussed previously). It is not currently
specific autoimmune response is determined by multiple possible to predict whether a patient presenting with optic
genes within the MHC. Cree further queried whether the neuritis or myelitis will develop NMO. However, the abrupt
susceptibility to NMO in humans is determined by a similar onset of a severe bilateral optic neuritis alerts one to the
interplay between ‘‘background’’ and MHC loci. Just why possible development of subsequent myelitis.
the immune system in NMO selectively attacks the optic Since the foci of demyelination that affect the optic nerves
tract and spinal cord while sparing the brain remains specula- are irregular and occur in a variety of different locations,
tive. Because these regions of the CNS are not thought to the visual field defects that occur are similarly variable. In
possess a different repertoire of glial cells or myelin proteins, many instances, vision is so poor when the patient is first
the selective attack may be the result of differences in the examined that it is impossible to plot the field defect. Never-
structure/stability of the blood–brain barrier or subtle re- theless, central scotomas seem to be the most common defect
gional differences in the ability of the CNS to process and observed, with some patients developing concentric contrac-
present antigen to T cells (323,360,363). tion of one or both fields.
The ophthalmoscopic appearance of the optic discs varies
Clinical Manifestations considerably in patients with NMO. Most patients have mild
swelling of both optic discs (330,336,365). Some patients,
The primary features of NMO are visual loss caused by however, have substantial disc swelling that may be associ-
damage to the anterior visual sensory pathways and paraple- ated with dilation of retinal veins and extensive peripapillary
gia caused by damage to the spinal cord. Other visual and exudates, and others have normal-appearing optic discs.
neurologic manifestations are much less common. With time, many patients develop pallor of the discs regard-
less of their initial appearance (Fig. 6.16). In some of these
Prodrome cases, there is slight narrowing of retinal vessels.
Some recovery of vision usually occurs in patients with
Approximately one third of NMO patients develop a mild NMO (323,331,332). Walsh stated that he had observed only
febrile illness several days or weeks before the onset of one case of total permanent blindness among 12–15 cases
visual or neurologic manifestations of the disease (323, (373), and Jeffery and Buncic (336) reported return of visual
336,364). Typical manifestations of this prodrome include acuity to 20/20 in all 17 affected eyes of nine patients whom
sore throat, headache, and fever (365–367). In rare cases, they studied. Visual acuity usually begins to improve within
there is a clear history of an antecedent viral illness, such as 1 week after visual symptoms begin, with maximum im-
mumps (368), varicella (369), or infectious mononucleosis provement occurring within several weeks to months. The
(370). The patient reported by Ko et al. (366) had high titers peripheral fields usually begin to recover before there is no-
of antibodies against Epstein-Barr virus in her serum. A pa- ticeable improvement in the central-field defects. Neverthe-
tient reported by Kline et al. (371) developed typical neuro- less, some patients have severe and permanent visual loss
myelitis optica 11 days after receiving a vaccination with in both eyes. Khan et al. (367), for example, reported the
attenuated live rubella virus. case of a 27-year-old pregnant woman who developed bilat-
In children, NMO is frequently preceded by infection eral optic neuritis first in the right eye and 2 months later
(72%); these cases typically have a monophasic course and in the left eye. The visual function remained stable over the
many have a complete recovery (336). Speculation exists next several months. The patient then developed an acute
regarding whether pediatric NMO should be considered a transverse myelitis. On examination, she had no light percep-
Figure 6.16. Ophthalmoscopic appearance in neuromyelitis optica (Devic’s disease). The patient was a 13-year-old girl who
developed transverse myelitis, followed several months later by bilateral visual loss. Visual acuity decreased to 20/400 OD
and hand motions at 2 feet OS over 72 hours. The pupils were sluggishly reactive to light, and both optic discs appeared
normal. The patient was treated with intravenous corticosteroids and gradually recovered both neurologic and visual function.
Visual acuity eventually stabilized at 20/40 OD and 20/70 OS associated with small cecocentral scotomas. The ophthalmoscopic
appearance of the right and left ocular fundi, A and B respectively, shows symmetric pallor of the optic discs associated with
atrophy of the retinal nerve fiber layer, especially in the papillomacular bundles.
tion in the right eye and only bare light perception in the The onset of paraplegia, like that of visual loss, usually
left eye. There was no improvement in visual acuity over is sudden and severe, and it may be associated with a mild
the subsequent 3 months. fever. Some patients develop an ascending paralysis that
There is some controversy about the relationship of visual simulates the Guillain-Barré syndrome; however, the pres-
loss to the onset of paraplegia. Most authors have reported ence of associated sensory symptoms should be sufficient to
that loss of vision precedes the onset of paraplegia in most eliminate Guillain-Barré syndrome from consideration (see
cases (374); however, others have found that paraplegia usu- Chapter 61). The paraplegia of NMO varies in different
ally precedes loss of vision (375). A similar controversy cases. Paraplegia in flexion, paraplegia in extension, and
relates to whether one can diagnose NMO in a patient with paraplegia with loss of all deep tendon (muscle stretch) re-
bilateral severe optic neuritis without clinical evidence of flexes may occur. There may be severe root pains, and uri-
spinal cord dysfunction. Although we agree that spinal cord nary retention may be present or develop shortly after the
damage in such cases could be minimal and subclinical, we onset of motor weakness. Ascending paralysis may paralyze
would be averse to diagnosing ‘‘neuromyelitis optica sine respiration and cause death at an early stage of the disease.
myelitis’’ unless other studies such as MR imaging showed Most patients with NMO recover to some extent but have
clear evidence of demyelinating lesions of the spinal cord. some residual paraparesis, and some have persistent and
complete paralysis. The subsequent recovery of neurologic
Paraplegia function, particularly in children suspected of having De-
Paraparesis, which rapidly progresses to paraplegia, may vic’s syndrome, should alert the clinician regarding the diag-
precede or follow the loss of vision in patients with NMO nosis of possible acute disseminated encephalomyelitis.
(330). As noted above, the experience of some authors is
Laboratory Studies and Neuroimaging
that the visual loss occurs first (373,374), whereas that of
other authors is that paraplegia occurs initially (375) and During the active stage of NMO, the CSF usually shows
may be mistakenly assumed to be caused by an infarct or evidence of an inflammatory process. There often is a mild
tumor of the spinal cord (376) until appropriate neuroimag- lymphocytic pleocytosis (323,332,338,364,366,378), al-
ing studies are performed. Regardless of which manifesta- though Walsh (351) reported a case in which there were
tion develops first, the interval between manifestations may 1,000 white blood cells/mm3. The concentration of protein
be days, weeks, or months (349). In some cases, the blind- in the CSF may be increased, but intrathecal synthesis of
ness and paraplegia occur simultaneously. Hershewe et al. IgG is not increased, and oligoclonal bands are rarely de-
(332) suggested that a diagnosis of NMO should not be made tected (378). The glucose concentration in the CSF invari-
unless the interval between the onset of visual loss and para- ably is normal. Rare cases have been recorded in which there
plegia is 2 months or less. has been evidence of increased intracranial pressure (379).
OPTIC NEURITIS 323
Chou et al. (380) reported a patient with NMO whose CSF IgG had recurrent, longitudinally extensive myelitis and sub-
contained antibody to glial fibrillary acidic protein (GFAP). sequently developed clinically definite NMO. It was their
The patient’s serum did not contain this antibody, and it was feeling that the autoantibody NMO-IgG represents a poten-
therefore postulated by these authors that the antibody was tial biologic marker of NMO, and the presence or absence
being synthesized in the CNS. of this marker might help distinguish clinically defined
Neuroimaging rarely shows intracranial lesions in patients NMO from typical MS. Their finding that seropositive high-
with NMO (323). The spinal cord, however, may show risk patients later developed clinically definite NMO was
changes consistent with demyelination (323,332,338,349, quite striking. When positive, this autoantibody might allow
381), typically with areas of increased signal intensity span- early diagnosis and initiation of treatment in cases of definite
ning several sections of the spinal cord on T2-weighted im- NMO and in patients at high risk to convert to NMO. These
ages and with gadolinium enhancement (382). Cord swell- findings may extend the spectrum of NMO to include some
ing, in our experience, has been significant enough to be patients with recurrent optic neuritis or longitudinally exten-
mistaken for an intrinsic cord tumor. Orbital MR imaging sive transverse myelitis.
may demonstrate enlarged optic nerves with abnormal signal Lennon (384) looked at sera from patients with definite
(Fig. 6.17) (381). NMO (48), MS (20), and numerous control disorders, in-
Recent interest has centered on serologic markers with cluding paraneoplastic vision loss (16), Sjögren’s syndrome
myelin-specific antigens, which might identify patients with (10), vasculitides (10), and myasthenia gravis (10). The
NMO. Weinshenker (383) analyzed sera from 101 patients assay was indirect immunofluorescence with a standard
with potential NMO on clinical grounds. The detection rate composite substrate of mouse brain, gut, and kidney; sera
of NMO-IgG was 26/48 (54.2%) for patients with definite or were preabsorbed with liver extract. IgG in 26 (54%) of
probable NMO (using the most stringent clinical diagnostic 48 patients with NMO yielded a distinctive staining pattern
criteria that require longitudinally extensive cord lesions), (NMO-IgG) associated with capillaries throughout the cere-
13/33 (39.4%) for high-risk patients, and 0/20 (0%) for those bellar cortex and midbrain, and with pia and a subpial mesh
with MS. Three high-risk patients seropositive for NMO- (prominent in midbrain). The capillary pattern was not seen
Figure 6.17. Neuroimaging in neuromyelitis optica (Devic’s disease). The patient was a 39-year-old man who developed
loss of vision in the left eye 4 days after developing paraparesis. A, Unenhanced proton density-weighted coronal MR image
performed several hours after the onset of visual symptoms shows enlargement of the left optic nerve. B, Unenhanced proton
density-weighted coronal MR image at a slightly different setting shows marked hyperintensity of the left optic nerve. (From
Barkhof F, Scheltens P, Valk J, et al. Serial quantitative MR assessment of optic neuritis in a case of neuromyelitis optica,
using Gadolinium-‘‘enhanced’’ STIR imaging. Neuroradiology 1991;33⬊70–71.)
in gut mucosa, kidney, or liver, and NMO-IgG was not noted disorders. First, NMO is not uncommon in the first decade
in any other study group, but it was identified incidentally of life, whereas MS rarely occurs in patients under 10 years
in seven patients among thousands whose sera were submit- of age. Second, the occurrence of bilateral optic neuritis as-
ted to Mayo Clinics Neuroimmunology Laboratory for para- sociated with myelitis is rarely recorded in cases of patholog-
neoplastic Ab service testing. Their histories revealed that ically proven MS. Third, bilateral blindness is extremely
one had definite NMO, three were at high risk for NMO unusual in MS but is the rule in NMO. Also, and as reviewed
(i.e., compatible findings but not fulfilling stringent criteria above, the neurogenetic, serologic, and neuroimaging find-
for definite NMO classification), one had new-onset myelop- ings specific to NMO will likely allow better determination
athy, one had unclassified steroid-responsive CNS inflam- of this condition in the future as these modalities of testing
matory disorder, and one had gastroesophageal cancer and become more widely available.
akathisia.
Lennon et al. (384) believed that the novel autoantibody Treatment
NMO-IgG appears to bind selectively to an element associ-
ated with CNS capillaries, pia, and subpia. They felt that it There is no specific treatment for NMO, although as noted
held promise as a tool for serologic diagnosis of NMO at above one should consider the implications of the immuno-
an early stage and for advancing the classification and ther- pathophysiology in rendering early and perhaps selective
apy of related disorders. Given the above discussions, this treatment based on considerations of the uniqueness of this
autoantibody merits investigation as a candidate effector of disease process. Supportive care is crucial to ensure survival
NMO, which recent immunohistochemical studies suggest in patients with severe myelitis. The use of intravenous corti-
has a humoral and complement-mediated basis targeting costeroids may lessen the severity of the attack and increase
CNS perivascular regions. the speed of recovery of both visual and motor function
Genetics (323,332,366). Frohman et al. (390) reported the case of a
15-year-old boy who developed typical NMO when he was
Kuroiwa et al. (385) found several patterns that distin- 12 years old. His vision recovered, but he experienced recur-
guish MS in Asia from MS in Western countries. Visual rent attacks of bilateral, simultaneous optic neuritis over the
impairment, often accompanied by other manifestations of next 3 years and became steroid dependent. Administration
NMO, was more frequently seen in Asian populations. Shi- of IVIg allowed discontinuation of steroids without further
basaki et al. (386) found that visual loss at the onset of ophthalmologic or neurologic deterioration or recurrent dis-
neurologic symptoms and severe visual deficits were more ease.
frequent in Japanese patients. These clinical differences be- Despite our limitations in understanding the genetics, im-
tween Eastern and Western cases of MS have led to a hypoth- munology, and cellular biology of NMO, the findings of
esis that clinical phenotypes of Asian-type MS may be due Lucchinetti et al. are of substantial therapeutic importance
to immunogenetic variation. Kira et al. (137) studied the
(362). As noted above, NMO is associated with clearly de-
HLA locus in a series of Japanese patients with MS and
fined MR and CSF abnormalities that should allow us to
found that, unlike in Western MS, the DR2-associated
identify these patients rapidly. With the recent knowledge
DRB1*1501 and DRB5*0101 alleles were not associated
that humoral effector mechanisms have a central role in
with NMO; rather, DPA1*0202 and DPB1*0501 alleles
NMO, acute therapeutic interventions may focus on inter-
were associated with the NMO phenotype in Japanese pa-
tients but not with healthy control subjects or Japanese pa- rupting antibody/complement-dependent effector mecha-
tients with typical MS (387). The HLA alleles with the nisms. This could include plasmapheresis in cases where
strongest association with Western-type MS in Japanese pa- glucocorticosteroids are ineffective (391), IVIg, or comple-
tients were found to be DRB1*1501 and DRP1*0301 (323). ment inhibitors such as soluble CR-1. Long-term immuno-
Of interest, the clinical course of MS in Japan may be therapy of NMO may be more problematic as drugs such as
changing: fewer patients present with Asian-type (opticos- glatiramer acetate have the potential to augment Th-2-type
pinal) MS and relatively more present with Western-type responses (392). In patients with NMO, it may be worthwhile
MS (388). This may, however, be due to an increased aware- to consider treatment with highly active immunosuppres-
ness of Asian cultures to the more subtle forms of Western- sants such as mitoxantrone early in disease, reducing the
type MS. immunotherapeutic regimen as soon as the patient has
achieved stabilization or remission.
Diagnosis
It may be impossible to differentiate between NMO and Prognosis
MS on clinical grounds alone, and some authors believe, as
noted above, that they are simply variants of the same disease The mortality rate in patients with NMO was reported in
(323,329,337,354–356,573). Indeed, review of the literature the past to be as high as 50% (374,393); however, improve-
suggests that some cases diagnosed as NMO are, in fact, ments in supportive care have greatly reduced this rate, and
MS (323,389). Nevertheless, not only are there important we would estimate that death occurs in less than 10% of
pathologic differences and differences in the CSF findings cases (323,364).
between the two diseases (discussed previously), but also As noted above, most patients experience some degree of
there are important clinical differences between these two recovery of both visual and motor function (323,332,364,
OPTIC NEURITIS 325
366). The recovery is rarely complete but may be substantial, (350,402–406). There is typically extension across the cor-
particularly as regards vision (333). Visual recovery usually pus callosum and damage to the opposite hemisphere. Both
occurs within several weeks to months after the onset of hemispheres are symmetrically affected in some cases. Care-
visual loss; however, Walsh and Hoyt (377) evaluated a pa- ful examination of the optic nerves, brain stem, cerebellum,
tient whose visual acuity decreased to 20/400 OU and re- and spinal cord often discloses typical discrete lesions con-
mained at this level for 2 years. Four years later, vision in sistent with MS, and histopathologic examination of both
the right eye was still 20/400, but vision in the left eye had large and small foci reveals the characteristic features remi-
improved to 20/30. We wonder if this was a true case of niscent of MS, including fibrillary gliosis with formation of
NMO or perhaps could have been a case of Leber’s optic giant multinucleated or swollen astrocytes and perivascular
neuropathy with other neurologic manifestations and late cuffing with inflammatory infiltrates containing plasma
recovery, as has been reported in patients with the some cells. The axons themselves may show little damage.
of the mitochondrial mutations (394). Some patients who Both the clinical and histopathologic features of myelino-
experience an attack of NMO, however, never recover visual clastic diffuse sclerosis disease suggest that it is closely re-
function and are left with severe bilateral visual loss. lated to MS and probably is a variant of it, as Schilder origi-
NMO tends to occur as a single episode without recur- nally proposed (407). The occurrence of myelinoclastic dif-
rences, unlike MS. Nevertheless, occasional recurrences of fuse sclerosis in a patient who also had neuromyelitis optica
both visual loss and paraplegia, both separate and simultane- (Devic’s disease; discussed previously) lends credence to
ous, have been documented (323,330,364,390). this philosophy (347).
Myelinoclastic diffuse sclerosis occurs most often in chil-
OPTIC NEURITIS IN MYELINOCLASTIC DIFFUSE dren and young adults (400,402,405,408,409,651), but it oc-
SCLEROSIS (ENCEPHALITIS PERIAXIALIS casionally occurs in older persons (404,410). It is character-
DIFFUSA, SCHILDER’S DISEASE) ized by a progressive course that may be steady and
unremitting or punctuated by a series of episodes of rapid
In 1912, Schilder reported the case of a 12-year-old girl worsening (398).
who experienced rapidly progressive mental deterioration A change in personality may be the first evidence of the
associated with signs of increased intracranial pressure and disease. Irritability, peevishness, unprovoked laughter or
death within 19 weeks. Postmortem examination disclosed crying, and general apathy may also be present. Cortical
large, well-demarcated areas of demyelination in the white blindness may also be an early feature of the disease, particu-
matter of both cerebral hemispheres and a number of smaller larly in adults. Central deafness may also occur. Other mani-
demyelinating foci that resembled the typical plaques of MS. festations include dementia, homonymous visual field de-
There was a prominent inflammatory reaction in both types fects, varying degrees of hemiparesis or quadriparesis often
of lesions with relative sparing of axon cylinders. Because culminating in plegia, and pseudobulbar palsy. The brain
of the similarities of the pathologic changes in this case to stem and cerebellum are affected in some cases, and in such
those of MS, Schilder called this disease ‘‘encephalitis peri- cases, nystagmus, intention tremor, scanning speech, and
axialis diffusa’’ to contrast it with the term ‘‘encephalitis spastic paraplegia of spinal origin may develop.
periaxialis scleroticans’’ that had previously been used by The ocular symptoms that develop in patients with my-
Marburg (395) to describe a case of acute MS. Unfortu- elinoclastic diffuse sclerosis depend on the location of the
nately, Schilder subsequently used the same term for two lesions. As noted above, they may occur early in the course
other completely different conditions (396,397). One seems of the disease or later. Berliner (66) reviewed 35 cases of
to have been a case of adrenoleukodystrophy and the other this disorder and found evidence of visual loss in 21 (60%).
a case of subacute sclerosing panencephalitis (398). These In 16 of the 21 cases (75%), visual loss occurred late in the
later reports seriously confused the subject for many years, disease.
and cases of adrenoleukodystrophy are still often called Most patients who develop visual loss in this condition
‘‘Schilder’s disease’’ (399). Nevertheless, if one separates do so from damage to the postchiasmal visual pathways,
the hereditary metabolic dystrophies and the various child- producing homonymous hemianopic or quadrantic visual
hood disorders of cerebral white matter that have been called field defects or cortical blindness (402,411). Occasional pa-
‘‘Schilder’s disease,’’ there remains a characteristic group tients develop demyelination in the optic chiasm, producing
of cases that do indeed correspond to Schilder’s original bitemporal field defects. Other causes of visual difficulties
description (400,401). These latter cases, often referred to in patients with myelinoclastic diffuse sclerosis include pap-
as myelinoclastic diffuse sclerosis, are nonfamilial, do not illedema (412,413), damage to association areas of the cere-
follow an obviously viral exanthem, and are not character- bral cortex, and optic neuritis.
ized pathologically by inclusion bodies or viral particles in The frequency with which optic neuritis occurs in patients
the CNS. Throughout the remainder of this section, we will with myelinoclastic diffuse sclerosis is unclear, but it seems
call this condition ‘‘myelinoclastic diffuse sclerosis.’’ to be less frequent than in patients with MS. Berliner (66)
The characteristic lesion in patients with myelinoclastic was able to document only two cases, although Ford (413)
diffuse sclerosis is a large, sharply outlined, asymmetric remarked that he had observed examples of both anterior
focus of demyelination with severe, selective myelinoclasia and retrobulbar optic neuritis in the condition. Such patients
that often affects an entire lobe or cerebral hemisphere invariably develop optic atrophy if they survive long enough.
Nover (414) described a case of myelinoclastic diffuse scle- Encephalitis periaxialis concentrica usually is character-
rosis in which the ophthalmoscopic appearance of the fundus ized clinically by a relatively rapid course during which pa-
resembled retinitis punctata albescens. Accumulations of ab- tients develop a variety of neurologic symptoms and signs
normal material were present on the inner aspect of the inter- separated in both space and time, including visual loss and
nal limiting membrane. It is unclear to us whether this was diplopia. As in encephalitis periaxialis diffusa, the visual
a true case of encephalitis periaxialis diffusa and whether loss that occurs in most patients with encephalitis periaxialis
the retinal findings were truly related to the underlying neu- concentrica is usually caused by damage to postgeniculate
rologic disease. visual pathways and is characterized by homonymous field
The CSF may show changes similar to those seen in typi- defects or cortical blindness; however, a patient reported by
cal MS (discussed previously). The intracranial pressure usu- Currie et al. (430), who initially had a left homonymous
ally is normal, but in some patients the CSF is under in- hemianopsia, eventually developed complete blindness asso-
creased pressure. The protein content of the CSF is usually ciated with pupils that were nonreactive to light and optic
slightly increased, and there may be a mild lymphocytic discs that were markedly pale.
pleocytosis. The IgG content is often increased, as is the The pathologic changes in the disease described by Baló
CSF IgG index (411). Oligoclonal bands may be present, consist of alternating bands of demyelination and preserved
and MBP is not only present but also extremely elevated myelin in a series of concentric rings in the cerebral white
(411). Neuroimaging studies show large, multifocal areas of matter (348,350,406,424,430,431). The occurrence of le-
extensive demyelination (404,405,409,415–419). In some sions in this pattern has suggested to some investigators that
cases, these lesions are similar in appearance to tumors or there is centrifugal diffusion of some factor that is damaging
abscesses (411,417–419). to myelin (427); however, Moore et al. (429) performed a
The diagnosis of myelinoclastic diffuse sclerosis may be complete histologic and ultrastructural examination of neu-
suspected when a child or young adult develops evidence ral tissue obtained from a 54-year-old woman with the dis-
of a subacute or chronic progressive neurologic disease with ease and concluded that the predominant feature of the bands
neuroimaging and laboratory evidence of focal hemispheric of myelin is remyelination. These authors suggest that the
demyelinating disease but without adrenal dysfunction or lesion originates as a small focus of acute demyelination
abnormal long chain fatty-acid components of serum choles- around a perivascular inflammatory cuff and that the concen-
terol esters (409). Most patients do not have evidence of tric bands are actually alternating areas of demyelination and
peripheral nerve damage; however, Szabo and Hegedus remyelination. The remyelination occurs at the outer rim
(420) described a case of otherwise typical myelinoclastic of the initial demyelinated area. Further demyelination then
diffuse sclerosis in which there was evidence of a mild pe- occurs external to the area of remyelination, and remyelina-
ripheral neuropathy. The diagnosis may be confirmed by tion then occurs along the outer rim of this second area of
brain biopsy (402,404,405,410,411,417,419). demyelination. In this way, successive concentric rings of
Most patients with myelinoclastic diffuse sclerosis follow demyelination and remyelination are produced. The findings
a progressive unremitting course that ends in death within of Moore et al. (429) have not been corroborated by other
a few months or years. A few cases have been reported investigators (431). Some patients with otherwise typical en-
in which there was temporary or permanent spontaneous cephalitis periaxialis concentrica have not only pathologic
improvement (413,418), and rare patients have been reported changes consistent with the disease but also lesions typical
to survive for a decade or longer (420). Some patients have of acute MS (429,431), suggesting that the former disease
improved after being treated with systemic corticosteroids may actually be a variant of the latter.
administered orally or intravenously (404,405,409,411,421). Neuroimaging studies initially may be normal in patients
The patient reported by Lana-Peixoto and dos Santos experi- with encephalitis periaxialis concentrica; however, eventu-
enced improvement in vision from hand motions in each eye ally both CT scanning and MR imaging show multiple le-
to 20/20. Konkol et al. (422) reported improvement in an 8- sions consistent with demyelination (432,433). Similarly,
year-old boy after intravenous administration of ACTH and analysis of the CSF at an early stage of the disease may
cyclophosphamide. Patients who improve clinically gener- reveal normal findings, but later analysis may show mild to
ally show disappearance or shrinkage of the lesions seen on moderate pleocytosis, increased protein, an increased IgG
neuroimaging studies. index, and multiple oligoclonal bands (430). The diagnosis
can be made with certainty only by a stereotactic biopsy of
ENCEPHALITIS PERIAXIALIS CONCENTRICA affected brain (432,433).
(CONCENTRIC SCLEROSIS OF BALÓ) Without treatment, encephalitis periaxialis concentrica
usually progresses inexorably and is invariably fatal within
Encephalitis periaxialis concentrica was first described by a few weeks to a year. Treatment with systemic corticoste-
Marburg (395) in 1906 and later by Baló (423,424) in 1927 roids, however, may result in both immediate and long-term
and 1928. Since then, more than 40 case reports have ap- improvement in neurologic symptoms and signs. Early diag-
peared in the literature (425–429). The disease clinically nosis thus is extremely important, and stereotactic biopsy
resembles myelinoclastic diffuse sclerosis but differs from seems to be an acceptable method of achieving this goal
it pathologically. (432,433).
OPTIC NEURITIS 327
CAUSES OF OPTIC NEURITIS OTHER THAN PRIMARY DEMYELINATION

In a few cases, a primary demyelinating process in the cance of these and other bacteria is discussed in detail in
optic nerve or the CNS is not the cause of unilateral or Chapter 49.
bilateral anterior or retrobulbar optic neuritis. Instead, the
condition develops in the setting of, or as the presenting OPTIC NEURITIS AFTER VACCINATION
manifestation of, an underlying systemic infection. Although there is extensive anecdotal evidence of optic
neuritis occurring following vaccinations, the actual evi-
OPTIC NEURITIS FROM VIRAL AND BACTERIAL dence of a demyelinating event following vaccination is lim-
DISEASES ited. In this section we first review the anecdotal information
regarding optic neuritis and vaccinations; we then will ex-
Parainfectious optic neuritis typically follows the onset of plore the evidence-based medicine surrounding the relation-
a viral or, less often, a bacterial infection by 1 to 3 weeks ship of vaccinations to demyelinating events in general.
(37,434,435). It is more common in children than in adults Optic neuritis has been reported to occur after vaccina-
and is thought to occur on an immunologic basis, producing tions against both bacterial and virus infections (38). Most
demyelination of the optic nerve. The optic neuritis may be cases are bilateral, and both anterior and retrobulbar forms
unilateral, but it is often bilateral. The optic discs may appear of optic neuritis may occur. Optic neuritis may develop after
normal or swollen. Swelling of the peripapillary retina may vaccinations with bacillus Calmette Guérin (BCG) (481),
be observed in patients with anterior optic neuritis. If a star hepatitis B virus (482,483), rabies virus (484–486), tetanus
figure composed of lipid exudates develops in the macula toxoid (487), and variola virus (488). The use of a combined
of the affected eye, the condition is called ‘‘neuroretinitis’’ smallpox, tetanus, and diphtheria vaccine was associated
(discussed later). If there is evidence of optic disc swelling with a bilateral anterior optic neuritis in a 7-year-old child
but no evidence of optic nerve dysfunction, and the intracra- who eventually recovered completely (489), and a similar
nial pressure is normal, the inflammation is assumed to be case was reported in association with combined measles,
affecting the periphery of the nerve and is called ‘‘perioptic mumps, and rubella vaccination (490). Influenza vaccine is
neuritis’’ or ‘‘optic perineuritis’’ (discussed later). commonly associated with the development of optic neuritis.
Parainfectious optic neuritis, whether viral or bacterial, Perry et al. (491) reported a patient with bilateral anterior
may occur in patients with no evidence of neurologic dys- optic neuritis that occurred 6 days following vaccination
function or in association with a meningitis, meningoenceph- with bivalent influenza vaccine. Ray and Dreizen (492) de-
alitis, or encephalomyelitis. When neurologic manifestations scribed a similar case. Cangemi and Bergen (493) reported
are present, patients have typical abnormalities in the CSF. a previously healthy man who developed a unilateral optic
Patients with encephalitis usually have disturbances on elec- neuritis with disc swelling, 3 weeks after inoculation with
troencephalography and also may have changes in the brain 200 units of A-New Jersey swine influenza and 200 units
seen by neuroimaging, whereas patients with encephalomy- of A-Victoria influenza whole-virus vaccine. Although most
elitis may show such changes in both the brain and the spinal cases of postvaccination optic neuritis appear to be of the
cord. anterior variety, unilateral retrobulbar neuritis has been re-
Visual recovery following parainfectious optic neuritis is ported 3 weeks following a swine influenza vaccination
usually excellent without treatment. Whether corticosteroids (494).
hasten recovery in patients with postviral optic neuritis is Despite the previous anecdotal reports, the evidence-
unknown, but this treatment is reasonable to consider, partic- based medicine that vaccination may precipitate the onset
ularly if visual loss is bilateral and severe. of MS or lead to relapses is simply not present. Confavreux
Optic neuritis may occur in association with infections by et al. (495) conducted a case-crossover study to assess
a large number of both DNA and RNA viruses, including whether vaccinations increase the risk of relapse in MS. The
adenovirus (436,437), Coxsackie virus (438,439), cytomega- subjects included 643 patients included in the European Da-
lovirus (440), hepatitis A (441), hepatitis B (442,443), tabase for Multiple Sclerosis who had a relapse between
human herpesvirus type 4 (Epstein-Barr virus) (444–448), 1993 and 1997. The index relapse was the first relapse con-
human immunodeficiency virus (HIV) type 1 (449,450), firmed by a visit to a neurologist and preceded by a relapse-
measles (451–455), mumps (456–458), rubeola, rubella free period of at least 12 months. Information on vaccina-
(459), and varicella zoster (in chicken pox [460,461] and in tions was obtained in a standardized telephone interview and
herpes zoster [462,463]). The neuro-ophthalmologic signifi- confirmed by medical records. Exposure to vaccination in
cance of these and other viruses is discussed in detail in the 2-month risk period immediately preceding the relapse
Chapters 57 and 58. was compared with that in the four previous 2-month control
Bacterial infections can produce optic neuritis. Some bac- periods for the calculation of relative risks, which were esti-
terial infections in which anterior or retrobulbar optic neuri- mated with the use of conditional logistic regression. Of
tis may occur include anthrax (464), ␤-hemolytic streptococ- these patients with relapses of MS, 15% reported having
cal infection (465), brucellosis (466,467), cat scratch disease been vaccinated during the preceding 12 months. The reports
(39,468,469,470), meningococcal infection (471), pertussis of 94% of these vaccinations were confirmed. Of all the
(472), tuberculosis (473–477), typhoid fever (478,479), and patients, 2.3% had been vaccinated during the preceding 2-
Whipple’s disease (480). The neuro-ophthalmologic signifi- month risk period, compared with 2.8–4.0% who were vac-
cinated during one or more of the four control periods. The relationship between the vaccine and the central demyelinat-
relative risk of relapse associated with exposure to any vacci- ing events. The results of these studies failed to establish
nation during the previous 2 months was 0.71 (95% CI, the causality of the HB vaccine. Nevertheless, molecular
0.40–1.26). There was no increase in the specific risk of mimicry between HB antigen(s) and one or more myelin
relapse associated with tetanus, hepatitis B, or influenza vac- proteins, or a nonspecific activation of autoreactive lympho-
cination (range of relative risks, 0.22–1.08). Analyses based cytes, could constitute possible pathogenetic mechanisms for
on risk periods of 1 and 3 months yielded similar results. these adverse neurologic events.
These authors concluded that vaccination does not appear Although demyelinating events might in fact be precipi-
to increase the short-term risk of relapse in MS. tated by vaccinations, the chance of this occurring is low,
To further evaluate the association between vaccination and the risk to the patient with MS is minimal compared
and onset of MS or optic neuritis, DeStefano et al. (496) with the potential risk to the MS patient of disease state
looked at a case-control study involving cases of MS or worsening due to an infectious disease.
optic neuritis among adults 18–49 years of age. Data on
vaccinations and other risk factors were obtained from com- OPTIC NEURITIS IN SARCOIDOSIS
puterized and paper medical records and from telephone in-
Granulomatous inflammation of the optic nerve may
terviews in three health maintenance organizations. Four
occur in sarcoidosis, producing a typical anterior or retrobul-
hundred forty case subjects and 950 control subjects matched
bar optic neuritis (498–502). In some cases, the optic neuritis
on health maintenance organization, sex, and date of birth
occurs during the disease; in others, it is the presenting mani-
were assessed. They noted the onset of first symptoms of
festation. Clinical findings may be indistinguishable from
demyelinating disease at any time after vaccination and dur-
those of demyelinating optic neuritis. However, the optic
ing specified intervals after vaccination (less than year, 1–5
disc may have a characteristic lumpy, white appearance,
years, and more than 5 years). Cases and controls had similar
which suggests a granulomatous etiology, and there may be
vaccination histories. The odds ratios (95% CI), adjusted for
an inflammatory reaction in the vitreous. Pain, common in
potential confounding variables, of the associations between
a demyelinating optic neuritis, is often absent in the optic
ever having been vaccinated and risk of demyelinating dis-
neuropathy of sarcoidosis.
ease (MS and optic neuritis combined) were 0.9 (0.6–1.5)
Unlike primary demyelinating optic neuritis, which does
for hepatitis B vaccine; 0.6 (0.4–0.8) for tetanus vaccination;
not respond dramatically to systemic corticosteroids (dis-
0.8 (0.6–1.2) for influenza vaccine; 0.8 (0.5–1.5) for mea-
cussed previously), the optic neuritis associated with sar-
sles, mumps, rubella vaccine; 0.9 (0.5–1.4) for measles vac-
coidosis is usually extremely sensitive to steroids. In most
cine; and 0.7 (0.4–1.0) for rubella vaccine. The results were
cases, recovery of vision is rapid after treatment is instituted,
similar when MS and optic neuritis were analyzed sepa-
although vision may decline again once steroids are tapered
rately. There was no increased risk according to timing of
or stopped. Indeed, it must be emphasized that rapid recovery
vaccination. It was the conclusion in this case-control study
of vision with corticosteroid treatment and subsequent wors-
that vaccination against hepatitis B, influenza, tetanus, mea-
ening when the steroids are tapered is atypical for demyelin-
sles, or rubella is not associated with an increased risk of
ating optic neuritis and suggests an infiltrative or nondemye-
MS or optic neuritis.
linating inflammatory process, such as sarcoidosis.
It would appear that there are two primary issues regarding
Patients with possible sarcoid optic neuritis should
the relationship between vaccinations and MS: Does the vac-
undergo an evaluation that includes a careful history and
cination precipitate the first attack of MS? Does it increase
physical examination, a chest radiograph, serum chemistries,
the short- or long-term risk in patients with known disease?
an assay for angiotensin converting enzyme (ACE) in the
It would appear from the preceding studies that vaccinations
serum and CSF, a gallium scan, and in some cases broncho-
do not precipitate the seminal event in MS. The second ques-
scopic lavage or biopsy of skin, conjunctiva, lung, liver, or
tion is more difficult to answer. Acute disseminated encepha-
other organs looking for noncaseating granulomas. Sarcoid-
lomyelitis (ADEM), a monophasic and multifocal illness of
osis and related conditions are discussed in detail in Chapter
the white and gray matter, has been observed following var-
59.
ious viral or bacterial infections as well as vaccine injections
for diseases such as pertussis, tetanus, and yellow fever. The SYPHILIS
similarities between ADEM and EAE are suggestive of an
immunologic process. In addition to the dramatic presenta- Optic neuritis from syphilis is not rare (503–505), but it
tion of ADEM, more limited white matter involvement, such is particularly common in patients also infected with HIV
as optic neuritis or myelitis, has been reported following (506–509) (see Chapters 56 and 58). The optic neuritis of
vaccine injections and has occasionally been counted as the syphilis can be unilateral or bilateral and anterior or retrobul-
first attack of MS. In France, 25 million inhabitants, almost bar. When the condition is anterior, there is usually some
half of the population, were vaccinated against hepatitis B cellular reaction in the vitreous, which serves to distinguish
(HB) between 1991 and 1999 (497). Several hundred cases it (and other systemic inflammatory diseases that cause ante-
of an acute central demyelinating event following HB vacci- rior optic neuritis) from demyelinating optic neuritis, in
nation were reported to the pharmacovigilance unit, leading which the vitreous usually is clear (discussed previously).
to a modification of vaccination policy in the schools and the The diagnosis of syphilis is established using a variety
initiation of several studies designed to examine the possible of serologic and CSF assays. Treatment with intravenous
OPTIC NEURITIS 329
penicillin produces visual recovery in many cases; however, tapered) (531,532,532a). It is interesting that among patients
the disease may be difficult to cure, particularly in patients enrolled in the ONTT, 3% had a positive ANA titer greater
who are HIV positive or who have the acquired immune than 1⬊320 (7). Only one of these patients developed other
deficiency syndrome (AIDS). evidence of connective tissue disease during the first 2 years
Syphilis can cause both neuroretinitis and optic perineuri- of follow-up. In addition, patients with a positive ANA (re-
tis (discussed later). Syphilis is discussed in detail in Chapter gardless of the titer) who were treated with placebo had
56. the same visual outcome as those treated with intravenous
methylprednisolone (8). SLE and other vasculitides that pro-
OPTIC NEURITIS IN HIV-POSITIVE PATIENTS AND duce neuro-ophthalmologic manifestations are discussed in
PATIENTS WITH AIDS detail in Chapter 44.
Many infectious agents that do not normally cause optic
neuritis can do so in patients who are immunocompromised LYME DISEASE
from drugs or disease. Such optic neuritis is particularly Optic neuritis can occur in patients with Lyme borreliosis
common in patients who are infected with HIV and in pa- (Lyme disease) (533–536). This disorder is a spirochetal
tients with AIDS (510,511). infection that is transmitted through the bite of an infected
Optic neuritis, both anterior and retrobulbar, is an occa- tick. It can produce a multitude of ocular and neurologic
sional finding in HIV-infected patients with cryptococcal findings, including both anterior and retrobulbar optic neuri-
meningitis, cytomegalovirus infection, herpesvirus infec- tis. The diagnosis of Lyme disease is made by serologic
tions, syphilis, tuberculous meningitis, and a variety of fun- detection of infection or by finding the organism or its nu-
gal infections (440,507,510,511–517). Rare patients with cleic acid in the serum or CSF. Treatment with antibiotics
toxoplasmosis may also develop optic neuritis (518,519). In is usually effective, particularly in the early stages of the
some cases, such infections cause neuroretinitis, whereas in disease. As with other systemic infectious processes that can
others, optic perineuritis occurs. cause optic neuritis, Lyme disease can also cause neuroreti-
Some patients with AIDS develop optic neuritis that is nitis (discussed later). Lyme disease is discussed in detail
probably caused by infection of the optic nerve by HIV itself in Chapter 56.
(449). Infection with HIV and AIDS are discussed in detail
in Chapter 58. SINUS DISEASE
OPTIC NEURITIS IN SYSTEMIC LUPUS ERYTHE- In the pre-antibiotic era, spread of infection from the para-
MATOSUS (SLE) AND OTHER VASCULITIDES nasal sinuses to the optic nerve was not unusual. However,
this is a rare occurrence now, and most cases of sinusitis in
Patients with SLE, polyarteritis nodosa, and other vasculi- patients with optic neuritis are fortuitous. Nevertheless,
tides can experience an attack of what seems clinically to some patients with acute severe sinusitis develop a second-
be typical acute optic neuritis (520). This phenomenon oc- ary optic neuritis from spread of infection. When the infec-
curs in about 1% of patients with SLE (521–531). In rare tion originates from the ethmoid or maxillary sinuses, there
cases, the optic neuropathy is the presenting sign of the dis- generally are obvious signs of orbital inflammation; how-
ease. The pathogenesis is not a true infection or inflamma- ever, spread of infection from the sphenoid sinus to the pos-
tion of the nerve tissue itself but is related to ischemia, which terior optic nerve in the apex of the orbit or within the optic
may produce demyelination alone, axonal necrosis, or a canal can be silent except for the loss of vision. Aspergillosis
combination of the two. and other fungal infections are considerations in this clinical
The clinical profile of optic neuropathy in SLE and other setting (537,538). Neuroimaging techniques, particularly CT
vasculitides actually can take several forms in addition to scanning and MR imaging, generally can be used to diagnose
an acute anterior or retrobulbar optic neuropathy associated paranasal sinus disease.
with pain. Patients may present with symptoms and signs Even when sinus disease is present in the setting of optic
that suggest a retrobulbar or anterior ischemic optic neuropa- neuritis, one must be wary of attributing the optic neuritis
thy, or they may have slowly progressive loss of vision that to this cause. Obviously, those patients with retrobulbar neu-
suggests a compressive lesion. ritis and supportive sinusitis with signs of orbital inflamma-
The diagnosis of SLE or other vasculitides as a cause of tion should be actively treated not only to eradicate the infec-
optic neuropathy is established by identification of systemic tion but also for the possible beneficial effects of treatment
symptoms and signs of the disease as well as by serologic on the optic neuritis; however, in our opinion, operative in-
testing. Treatment with either intravenous or oral corticoste- tervention in patients with radiologic evidence of sinus dis-
roids may be indicated in this condition. ease that normally would not call for medical or surgical
The term ‘‘autoimmune optic neuritis’’ has been sug- therapy is unwarranted.
gested for cases of optic neuritis in which there is both sero-
logic evidence of vasculitis, such as a positive ANA, but no MISCELLANEOUS CAUSES OF OPTIC NEURITIS
signs of systemic involvement other than the optic neuropa-
thy; and progressive visual loss that tends to be responsive Optic neuritis has been reported to occur rarely in many
to treatment with systemic corticosteroids and that is often conditions other than bacterial or viral infections, including
steroid dependent (i.e., vision worsens when steroids are acute posterior multifocal placoid pigment epitheliopathy
Figure 6.18. Optic disc swelling in a patient with pars planitis (chronic cyclitis). The patient was initially believed to have
papilledema. A, The left optic disc is hyperemic and slightly swollen. The hazy appearance is due to the presence of vitreous
cells. B, Fluorescein angiogram of the left macula shows cystoid macular edema, characteristic of this disorder. The opposite
eye had a similar ophthalmoscopic appearance.
(504,539), after a bee sting (540–543), Behçet’s disease secondary changes that occur in the macula (e.g., cystoid
(544), birdshot retinochoroidopathy (545), Creutzfeldt- edema). Perhaps the most common form of disc swelling
Jakob disease (546,547), cysticercosis (548), familial Medi- that occurs as part of an ocular inflammatory syndrome is
terranean fever (549), Guillain-Barré syndrome (550–553), that which occurs after cataract extraction and is associated
inflammatory bowel disease (554–559), intraocular nema- with moderately decreased visual acuity and cystoid macular
tode infection (504,560,561), presumed histoplasmosis edema: the Irvine-Gass syndrome (576–578).
(562,563), Reiter’s syndrome (564,565), toxocariasis As mentioned above, the presence of uveitis and other
(566), toxoplasmosis associated with or unassociated with symptoms of intraocular inflammation in a patient with acute
AIDS (567,568), and Mycoplasma pneumoniae infection anterior optic neuritis should alert the examiner to search
for an associated intraocular or systemic disease.
(569–572). As is true for optic neuritis associated with bacte-
Hanna and Girgis (579) found a 1.5% prevalence of optic
rial or viral infections, some of these cases are isolated, atrophy in 2,178 patients after meningitis. Although postpap-
whereas others are associated with other evidence of CNS illedema optic atrophy accounted for some of these cases,
dysfunction. primary optic atrophy, presumably the result of an associated
Intraocular inflammation alone may cause optic disc optic neuritis, was much more frequent. In this study, optic
swelling; however, in such cases, visual acuity is usually atrophy occurred more frequently after tuberculous meningi-
not significantly affected from damage to the optic nerve tis than after bacterial meningitis, including meningococcal,
(504,573–575) (Fig. 6.18). In such patients, visual acuity is pneumococcal, and purulent meningitis of unknown eti-
limited only by the degree of vitreous inflammation or by ology.
BILATERAL OPTIC NEURITIS

In adults, bilateral simultaneous acute optic neuritis, par- their cases into those that were unilateral (71%), those that
ticularly that associated with MS, is uncommon but well were bilateral and simultaneous (7%), those that were bilat-
described. Adie (80) found only one case of bilateral optic eral and nonsimultaneous but occurred within 3 months of
neuritis in his series of 70 adult patients, and other authors each other (12%), and those that occurred more than 3
(66,580) agreed with him that both simultaneous and early months apart (12%). These authors found no significant dif-
consecutive cases were exceedingly rare (Fig. 6.19). How- ferences in rate and degree of recovery between bilateral
ever, reports indicate that the incidence of bilateral simul- and unilateral cases, regardless of the time interval between
taneous acute optic neuritis in patients with MS is 10–75% the attacks. The studies of Rischbieth (582) and of Hutchin-
(68,82,83,197,581). Morrissey et al. (275) performed a retro- son (83) seem to support this view.
spective analysis of the causes of bilateral simultaneous In the ONTT, approximately 48% of patients with in-
acute optic neuritis in 23 adults and found that 5 of the volvement of one eye had some other definable visual field
patients (22%) had developed clinical evidence of MS. In involvement of the contralateral eye, suggesting that optic
many of these series, the time interval between attacks in neuritis is quite frequently present bilaterally from the onset
the two eyes is not stated. Bradley and Whitty (82) separated (11).
OPTIC NEURITIS 331
Figure 6.19. Bilateral anterior optic neuritis. The patient is a 19-year-old girl who suffered bilateral visual loss 2 weeks
following a flulike illness. Both optic discs show moderate swelling without hemorrhages. Visual acuity is 20/400 in the right
eye and 20/300 in the left eye, and there are bilateral central scotomas. Visual acuity returned to normal within 6 weeks, and
disc swelling completely resolved.
In contrast to adults, acute optic neuritis is quite often often presumed to be related to a viral infection (discussed
bilateral and simultaneous in children. In such cases, it is later).
OPTIC NEURITIS IN CHILDREN

Optic neuritis in children has several unique characteris- tients. Eight of the patients with idiopathic optic neuritis in
tics that distinguish it from optic neuritis in adults. First, it this study developed MS over a mean follow-up period of
is more often anterior. Second, it is more often a bilateral 8 years.
simultaneous condition. Third, it often seems to occur within Kriss et al. (37) studied 39 children with optic neuritis.
1–2 weeks after a known or presumed viral infection. Fourth, After a mean follow-up of 8.8 years (range 3 months to 29
it is less often associated with the development of MS. Fi- years), MS had developed in six (15%). The visual prognosis
nally, it is often steroid sensitive and steroid dependent. was reported to be excellent. Riikonen (38) reported on 18
Kennedy and Carroll (35) examined 30 children with idio- children with optic neuritis. A vaccination preceded the de-
pathic optic neuritis. The youngest child was 4 years old, and velopment of optic neuritis in 6 of the 18 (33%) and a bacte-
the mean age of the group was 9.5 years. These investigators rial or viral infection preceded it in 10 (55.6%). Eight of the
found disc swelling in more than 70% of children (as op- 18 (44.4%) children developed MS during the study.
posed to a prevalence of 20–40% in adults). In addition, Nakao et al. (583) found 9 cases of optic neuritis in chil-
over 50% of the children whom Kennedy and Carroll (35) dren among 201 cases (5%) of optic neuritis evaluated at
studied had bilateral disease, a significantly higher frequency Osaka University Medical School in Japan. In all nine cases,
than in adults. Most of the patients in this series had central the optic neuritis was bilateral and associated with severe
scotomas and visual acuity less than 20/200, with only one visual loss. Optic disc swelling was present in most of the
patient having visual acuity better than 20/50. Despite the children, several of whom had associated upper respiratory
poor initial visual acuity in these patients, the visual prog- tract infections, meningitis, or encephalitis. All were treated
nosis in children with optic neuritis appears to be quite good. with systemic corticosteroids, and all experienced improve-
Kennedy and Carroll (35) performed follow-up examina- ment in vision.
tions on 19 of their 22 children with idiopathic anterior optic Hierons and Lyle (34) collected data on 13 cases of bilat-
neuritis. Fifteen of the children recovered completely, two eral optic neuritis in children under the age of 13, 10 of
had moderate return of vision, and only two children had whom were girls. Five of the patients had a history of specific
no significant improvement. Of three children with acute exanthem or an indeterminate febrile illness before visual
retrobulbar optic neuritis and normal optic discs at the time symptoms began, and all but one patient made a good visual
of visual loss, two had a complete recovery, although the recovery. Only one patient developed MS over a mean fol-
third child had only a moderate return of vision and suffered low-up period of 4 years.
a second attack of visual loss 4 years later from which she Meadows (36) reviewed 35 cases of bilateral optic neuritis
never recovered. No further information was given by these in children, most between the ages of 5 and 12. Over a fol-
authors regarding final visual acuity or fields in these pa- low-up period of 3–18 years, 12 of the patients were lost to
examination, but of the remaining 21, none developed MS. disease were reviewed. MR images and CSF findings were
Although Meadows (36) referred to his cases as examples also analyzed. Twenty-five patients (39 eyes) 21 months of
of ‘‘retro-bulbar neuritis,’’ he stated that in the ‘‘vast major- age to 18 years of age were included in the study, with a
ity of cases seen during the early acute phase, the optic discs mean follow-up of 11 months. Fourteen patients (56%) had
were abnormal,’’ with the abnormality varying from mild bilateral optic neuritis, and 11 patients (44%) had unilateral
blurring of the disc margins to marked swelling of the disc disease. Thirty-three of 39 eyes (84%) had visual acuity of
with peripapillary hemorrhages. 20/200 or less at presentation. Twenty-one of 25 patients
Keast-Butler and Taylor (584) described four cases, and (84%) were given intravenous methylprednisolone (10–30
Cohen et al. (585) and Rollinson (586) reported isolated mg/kg/day). Thirty of 39 eyes (76%) recovered 20/40 visual
cases, of bilateral optic neuritis with disc swelling in chil- acuity or better. Three of 39 eyes (7%) recovered vision in
dren. None of the children experienced any preceding exan- the 20/50 to 20/100 range. Six of 39 eyes (15%) recovered
thema, and all patients recovered excellent vision, even vision of 20/200 or less. Twenty-three of 25 patients (92%)
though the patient reported by Cohen et al. (585) had no underwent MR imaging of the brain. A normal MR image
perception of light in either eye at one point during her hospi- of the brain was associated with recovery of 20/40 or better
tal course. visual acuity in six of six affected eyes (100%). Seven pa-
Farris and Pickard (435) described six children who devel- tients were 6 years of age or younger at presentation. Six of
oped acute simultaneous bilateral optic neuritis. Five of the these seven (85%) had bilateral disease, and 12 of 13 (92%)
six children had recently experienced a brief upper respira- affected eyes recovered 20/40 visual acuity or better. Eigh-
tory or gastrointestinal illness, presumed to be viral in nature. teen patients were 7 years of age or older at presentation.
Five of the six patients also demonstrated marked neurologic Eight of these 18 (44%) had bilateral disease, and 10 of 18
deficits, including seizures and cerebellar dysfunction. Lum- patients (56%) had unilateral disease. Eighteen of 26 af-
bar puncture was abnormal in three of the six patients. All fected eyes (50%) recovered 20/40 visual acuity or better.
patients were treated with a course of intravenous methyl- These authors concluded that pediatric optic neuritis is usu-
prednisolone, ranging from 1–2 mg/kg/day, and each patient ally associated with visual recovery; however, a significant
experienced a rapid and nearly complete recovery of vision number (22%) remain visually disabled. A normal MR
during treatment. image of the brain may be associated with a better outcome.
Koraszewska-Matuszewska et al. (587) reported a large Younger patients were more likely to have bilateral disease
series of optic neuritis in childhood. These investigators re- and a better visual prognosis.
viewed the records from 110 children, aged 2–18 years Morales et al. (590) reviewed all charts of patients less
(mean 13 years) with optic neuritis. Sixty percent of the than 15 years of age who presented with optic neuritis to
children had bilateral simultaneous optic neuritis. Children the Bascom Palmer Eye Institute or the Miami Children’s
younger than 14 years of age tended to have anterior optic Hospital between 1986 and 1998. Fifteen patients were iden-
neuritis, whereas retrobulbar neuritis was more common in tified. There was a slight female predilection in the study
children over 14 years old. In younger patients, the cause of group (60%), with a mean age of 9.8 years at presentation.
the inflammation seemed to be viral infections or chronic A preceding febrile illness within 2 weeks of visual symp-
focal infection. Older children often had underlying neuro- toms was reported in 66% of patients. Initial visual acuity
logic disease. The use of systemic steroids resulted in im- ranged from 20/15 to no light perception. Involvement was
provement of visual acuity in about 75% of cases and im- bilateral in 66% of patients, and disc swelling was present
provement or normalization of the visual field in over 50% in 64% of involved eyes. Of the patients who underwent
of cases, regardless of whether the optic neuritis was of the MR imaging, 33% had focal demyelinating lesions in the
anterior or retrobulbar variety. Normal visual function was brain, and 63% of affected nerves were enlarged or enhanced
regained in about 50% of the children during a follow-up with gadolinium. Eleven patients were treated with intrave-
period of 3 years. These children tended to be those with nous steroids. Final visual acuity was 20/40 or more in
the least severe visual loss during the acute phase of the 58.3% of eyes. Thirty percent of the patients had vision of
optic neuritis. finger counting or worse. Four (26%) patients developed
Good et al. (588) reviewed the records of 10 children MS. The mean age of patients with MS was 12 years, com-
with optic neuritis in whom recovery of vision was poor or pared with 9 years in children who did not develop MS.
incomplete. These investigators found that in all cases, the Patients with unilateral involvement had an excellent visual
condition had been bilateral. Optic disc swelling had been prognosis (100% more than 20/40) but a higher rate of devel-
present in 7 of the 10 cases (70%), and 70% of the cases opment of MS (75%). Two patients had positive serology
had been preceded by a viral illness. Five of the 10 children for Lyme disease. It was their conclusion that optic neuritis
(50%) had developed evidence of MS. presents differently in children than in adults. Children typi-
Brady et al. (589) evaluated the presenting features, neu- cally have bilateral involvement with papillitis following an
roimaging findings, CSF abnormalities, associated systemic antecedent viral illness. Although visual prognosis is poorer
disease, and visual outcome in children with optic neuritis. in children than adults, the development of MS is less com-
A retrospective analysis was performed on all patients who mon in children. Children who present with unilateral in-
were seen at Baylor College of Medicine with optic neuritis volvement have a better visual prognosis; however, they also
during a 6-year period from 1991 to 1997. The degree of develop MS at a greater frequency than children with bilat-
initial visual loss, subsequent visual recovery, and associated eral involvement. Patients who developed MS were, on aver-
OPTIC NEURITIS 333
Figure 6.20. Neuroretinitis. A, The right optic disc is swollen; there is peripapillary edema; and there is a star figure composed
of hard exudate in the macula. This is a form of optic neuritis that is not associated with multiple sclerosis. B, In another case,
the star figure is incomplete and located nasal but not temporal to the fovea. Note the extensive transudate surrounding the
swollen optic disc. (Courtesy of Dr. J.M. Christiansen.)
age, older at presentation with optic neuritis than those who is a contraindication to doing so, we then treat these children
did not develop MS. with intravenous methylprednisolone 1–2 mg/kg/day for
We have been impressed with the tendency for optic neuri- 3–5 days. We do not use an oral corticosteroid taper in these
tis in children, whether unilateral or bilateral, to be quite patients.
responsive to treatment with systemic corticosteroids and, Gass (469) and Rush (591) emphasized that both chil-
more importantly, to be quite steroid sensitive. We have seen dren and adults can develop acute, usually unilateral, visual
several children, primarily those with anterior optic neuritis, loss associated with an ophthalmoscopic picture of disc
experience relapses of their condition, some of them quite swelling, peripapillary exudative retinal detachment, and
severe, when steroids were rapidly tapered. It is our policy a macular star figure (Fig. 6.20). This type of ophthalmo-
to evaluate all patients with optic neuritis less than 15 years scopic appearance has been called neuroretinitis (discussed
of age with MR imaging and a lumbar puncture. Unless there later).
NEURORETINITIS
In 1916, Theodore Leber described a condition character- of whom had an antecedent viral illness, usually affecting
ized by acute unilateral visual loss associated with an exuda- the respiratory tract, a few weeks before the onset of visual
tive maculopathy consisting of hard exudates arranged in a symptoms. It has subsequently become clear that some cases
star figure around the fovea. Leber (592) believed that the of neuroretinitis are associated with particular infectious dis-
condition was a primary retinal process and called it a ‘‘stel- eases, whereas others occur as apparently isolated phenom-
late maculopathy.’’ The condition subsequently became ena (594,595). In the latter setting, the condition is called
known as Leber’s stellate maculopathy (593) until 1977, Leber’s idiopathic stellate neuroretinitis (594,596–599).
when Gass (469) reported that patients with the condition Neuroretinitis affects persons of all ages, although it oc-
showed swelling of the optic disc before and often concur- curs most often in the third and fourth decades of life. There
rent with the appearance of the star figure. The optic disc is no sex predilection. The condition usually is painless, but
swelling then resolved, leaving the maculopathy as the pri- some patients complain of an aching sensation behind the
mary or sole ophthalmoscopic abnormality. Gass (469) per- affected eye or eyes, and the discomfort occasionally wors-
formed fluorescein angiography in several of the patients ens with eye movements. Affected patients complain of vis-
with this condition and showed that there was no leakage ual blurring that progresses as the maculopathy evolves. Vis-
from retinal vessels surrounding the macula. He thus con- ual acuity at the time of initial examination may range from
cluded that the condition was not a primary maculopathy, 20/20 to light perception. We have never seen a patient who
but rather a form of optic neuritis. Because the condition lost all perception of light during this condition. Color vision
affected both the optic nerve and the retina, he called it is variably affected, and we have the impression that the
neuroretinitis. Gass (469) emphasized that the condition oc- degree of color deficit is usually significantly worse than
curred commonly in children and young adults, up to 50% the degree of visual loss would suggest. The most common
field defect is a cecocentral scotoma, but central scotomas, Small, discrete chorioretinal lesions may occur in idio-
arcuate defects, and even altitudinal defects may be present, pathic cases in both symptomatic and asymptomatic eyes
and the peripheral field may be nonspecifically constricted. (594–596,600). Posterior inflammatory signs consisting of
A relative afferent pupillary defect is present in most pa- vitreous cells and venous sheathing, as well as occasional
tients, unless the condition is bilateral, in which case even anterior chamber cell and flare, may occur in patients with
patients with clinically asymmetric visual loss may have no neuroretinitis. Fluorescein angiography in patients with
evidence of a relative afferent pupillary defect. The degree acute neuroretinitis demonstrates diffuse disc swelling and
of disc swelling ranges from mild to severe, depending in leakage of dye from vessels on the surface of the discs (469).
part on the point in time at which the patient is first exam- The retinal vessels may show slight staining in the peripapil-
ined. In severe cases, splinter hemorrhages may be present. lary region; however, the macular vasculature is entirely nor-
Segmental disc swelling has been reported but is uncommon. mal. Chorioretinal lesions, when present, show late hyperflu-
A macular star figure composed of lipid (hard exudates) may orescence and exhibit progressive scarring on follow-up
not be present when the patient is examined soon after visual examinations (594,595).
symptoms begin, but it becomes apparent within days to Neuroretinitis is a self-limited disorder. With time, usually
weeks and tends to become more prominent even as the optic over 6–8 weeks, the optic disc swelling resolves, and the
disc swelling is resolving (469,504,594,595) (Fig. 6.21). appearance of the disc becomes normal or nearly so
Figure 6.21. Neuroretinitis. A, The right optic disc is moderately swol-

len, and there is a star figure just temporal to the disc. B, The macula
shows a star figure that is primarily nasal to the fovea. C, Fluorescein
angiogram in the mid-arteriovenous phase shows extensive leakage from
the optic disc but no retinal vascular abnormality in the macula or papillo-
macular bundle.
OPTIC NEURITIS 335
(469,504,594,595). The macular exudates progress over delineated; unusual manifestations include conjunctival and
about 7–10 days. They then remain stable for several weeks retinal bacillary angiomatosis.
before gradual resolution occurs. Resolution may take 6–12 Other common infections that cause neuroretinitis are the
months, but the lipid eventually completely disappears. Most spirochetes. Neuroretinitis frequently occurs in patients with
patients ultimately recover good visual acuity, although secondary and tertiary (late) syphilis. It may develop in pa-
some complain of persistent metamorphopsia or nonspecific tients with secondary syphilis as part of the syndrome of
blurred vision from mild disruption of the macular architec- syphilitic meningitis (607). In such cases, it is usually bilat-
ture despite disappearance of the macular exudates. Ophthal- eral and associated with evidence of meningeal irritation and
moscopy and fluorescein angiography usually reveal defects multiple cranial neuropathies. It may also occur as an iso-
in the retinal pigment epithelium of the macula in such cases. lated phenomenon in patients with secondary syphilis, in
Rare patients develop moderate to severe visual loss, and which case it is often associated with uveitis and may be
we have seen one patient who had bilateral loss of vision either unilateral or bilateral (607–614). Neuroretinitis occa-
down to 20/400 OU. Such patients invariably have evidence sionally occurs in patients with late syphilis, usually in pa-
of optic atrophy. tients with meningovascular neurosyphilis (607). The condi-
Most patients who develop neuroretinitis do not experi- tion is indistinguishable from that which occurs in patients
ence a subsequent attack in the same eye, and only a few with secondary syphilis.
patients who have experienced an attack in one eye subse- Lyme disease is another spirochete that is associated with
quently develop a similar attack in the fellow eye. Neverthe- neuroretinitis. Almost all cases occur in patients with stage
less, we have examined several patients who had recurrent II Lyme disease (534,617). Like the neuroretinitis that occurs
episodes of neuroretinitis in one or both eyes. Such patients in syphilis, the neuroretinitis of Lyme disease may be unilat-
almost always suffer significant visual loss associated with eral or bilateral; when bilateral, it is usually simultaneous
optic atrophy and permanent macular pigmentary distur- and symmetric. Also like the neuroretinitis of syphilis, the
bances. neuroretinitis that occurs in Lyme disease may recover spon-
Neuroretinitis is thought to be an infectious or immune- taneously but also resolves rapidly once the patient is treated
mediated process that may be precipitated by a number of with appropriate antibiotics (607).
different agents. A common association is with an anteced- Leptospira were identified in the CSF in one of three pa-
ent viral syndrome, suggesting a possible viral etiology for tients with neuroretinitis who all had unilateral visual loss
and bilateral small, deep, intraretinal lesions consistent with
up to 50% of cases; however, viruses are rarely cultured
septic retinitis (594). The patient in whom the leptospira
from the CSF of such patients, and serologic evidence of a
were detected had no evidence of leptospirosis. No infec-
concomitant viral infection is usually lacking (469,594,595).
tious agent was identified in blood or CSF in the remaining
One case of neuroretinitis associated with herpes simplex
two patients.
encephalitis was reported by Johnson and Wisetzley (601),
Patients with toxoplasmosis, toxocariasis, and histoplas-
as was a case of bilateral neuroretinitis associated with mosis may develop an acute anterior optic neuritis that, in
serologic evidence of hepatitis B virus infection (602). rare cases, may be associated with a macular star figure
Foster et al. (311) reported a case of neuroretinitis that (560,566,568,618–621). Whether such conditions are truly
occurred in association with mumps in a young man, and examples of neuroretinitis is unclear. We believe that any
Margolis et al. (603) reported the occurrence of an ‘‘arcuate presumed or known inflammatory or infectious optic neu-
neuroretinitis’’ associated with optic disc swelling in a ropathy that is characterized by optic disc swelling and the
patient with the acute retinal necrosis syndrome, a condi- eventual development of a macular star figure should be
tion thought to be caused by one or more of the herpes defined as neuroretinitis; thus, these cases would fit that
viruses (see Chapter 57). description. On the other hand, there are noninfectious and
Neuroretinitis may occur in patients with evidence of in- noninflammatory conditions that should not be called neuro-
fectious disease caused by organisms other than viruses. retinitis even though they are characterized by optic disc
Gass (469) described neuroretinitis associated with cat- swelling that may on occasion be associated with the devel-
scratch disease, a systemic infection caused by the bacterium opment of a macular star figure. These mimicking conditions
Bartonella henselae (see Chapter 49). Since then, numerous include papilledema, anterior ischemic optic neuropathy,
similar cases of neuroretinitis have been described in patients and infiltration of the optic disc by tumor. Systemic hyper-
with clinical manifestations consistent with cat scratch distension may cause both optic disc swelling and a macular
ease (470,594,600,604), some of whom have had positive star figure, but fluorescein angiography in such cases shows
cat scratch antigen and antibody testing (604–606). In our leakage from macular vessels. A similar phenomenon may
experience, cat scratch disease is the most common infec- occur in the condition called diffuse unilateral subacute neu-
tious process associated with neuroretinitis. The vitreoretinal roretinitis, thought to be caused by one or more types of
manifestations include anterior uveitis, vitritis, pars planitis, helminths (see Chapter 51).
focal retinal vasculitis, a characteristic retinal white spot syn- One condition that is not associated with neuroretinitis is
drome, Bartonella retinitis, branch retinal arteriolar or venu- MS. One might assume that since neuroretinitis is a form of
lar occlusions, focal choroiditis, serous retinal detachments, optic neuritis, the likelihood of developing MS after an at-
and peripapillary angiomatous lesions. The pattern of ocular tack of neuroretinitis would be as high as it seems to be after
disease in AIDS-associated B. henselae infections is poorly an attack of straightforward optic neuritis. In fact, although
the rate of development of MS after an attack of anterior or may eventually result in identification of specific viruses
retrobulbar optic neuritis is substantial (discussed previ- that cause the condition in otherwise normal persons or in
ously), there is no increased tendency for patients who expe- persons who have recently suffered what seems to be a viral
rience an attack of neuroretinitis to develop MS (622), and illness. At this time, however, we cannot recommend that
the rate of development of MS in such patients is the same such techniques be used on a regular basis, since they are
as that in the normal population, about 6–80 per 100,000. both time-consuming and expensive and the therapeutic im-
Thus, the designation of an attack of acute optic neuropathy plications may be nil. Patients in whom neuroretinitis is ac-
as an episode of neuroretinitis rather than anterior optic neu- companied by diffuse retinal or choroidal lesions suggesting
ritis substantially alters the systemic prognosis in the patient septic retinitis or choroiditis may require a complete evalua-
being evaluated. tion for systemic infection (600).
Investigation into the etiology of neuroretinitis should be Treatment of neuroretinitis depends on whether there is
done systematically. A careful history is crucial and should an underlying infectious or inflammatory condition that re-
include questioning regarding sexually transmitted diseases, quires therapy. B. henselae is the principal cause of cat
skin rashes, and viral exanthema. Complete physical and scratch disease (623,624). The availability of specific sero-
ocular examinations are also essential, and a neurologic ex- logic investigations has allowed the recognition of a spec-
amination may be required. trum of ocular cat scratch disease syndromes that previously
Patients with cat scratch fever usually have a history of were ill defined and considered idiopathic. The benefit of
contact with a cat. They complain of malaise, fever, muscle antimicrobial therapy for cat scratch disease in immunocom-
aches, and headache. Examination typically reveals local petent individuals has been difficult to establish, partly be-
lymphadenopathy. Rare patients also have symptoms of ar- cause most infections are self-limited. Empirically, azithro-
thritis, hepatitis, meningitis, or encephalitis. mycin, ciprofloxacin, rifampin, parenteral gentamicin, and
Patients with secondary or tertiary syphilis usually pro- trimethoprim-sulfamethoxazole are the best therapeutic
vide a history of previous sexual contact, and they may have choices to minimize damage to the eye. Such treatment is
had a chancre in the past. They may also complain of arthral- almost always associated with improvement of the associ-
gias and myalgias, and some have symptoms of meningitis ated neuroretinitis, although whether the neuroretinitis
or encephalopathy. Many of these patients have been treated would resolve spontaneously without treatment is unknown
for syphilis or some other sexually transmitted disease in (470,600,623,624). Patients with neuroretinitis who are
the past.
found to have secondary or late syphilis should be treated
Patients with stage II Lyme disease usually live or work
with intravenous penicillin as recommended by the Centers
in an endemic area and may even give a history of a tick
for Disease Control and Prevention (625), and patients with
bite within the last 6 months. They often have cutaneous,
neuroretinitis that occurs in the setting of Lyme disease
cardiac, or neurologic manifestations in addition to visual
should also be treated with appropriate antibiotics, such as
complaints. The most common cutaneous manifestation is
a solitary red or violaceous abnormality that ranges in size ceftriaxime, amoxicillin, or tetracycline (534). Patients in
from a small nodule to a plaque several centimeters in diame- whom neuroretinitis is found to be associated with evidence
ter. The lesion is called a ‘‘lymphocytoma’’ or ‘‘lymphaden- of toxoplasmosis, toxocariasis, or histoplasmosis should
osis benigna cutis.’’ It may appear at the site of the tick bite likewise undergo treatment specific for their underlying sys-
or remote from it. Typical remote sites are the earlobe in temic disease.
children and the nipple in adults. Cardiac manifestations Patients with presumed viral or idiopathic neuroretinitis
occur in about 5–8% of patients with stage II Lyme disease. may or may not require treatment. Some authors advocate
Neurologic manifestations occur in 10–15% of cases of the use of systemic corticosteroids or ACTH to treat isolated
stage II Lyme disease and include meningitis, myelitis, en- neuroretinitis, but there is no definite evidence that such
cephalitis, cranial neuropathies, meningoradiculitis, and pe- treatment alters either the speed of recovery of the condition
ripheral neuropathies. Some patients with neuroretinitis or the ultimate outcome. Interestingly, Weiss and Beck (600)
caused by Lyme disease have other ocular disturbances, in- reported a case of idiopathic neuroretinitis that did not re-
cluding unilateral or bilateral granulomatous iridocyclitis, spond to treatment with oral prednisone but that improved
choroiditis, pars planitis, vitritis, and panophthalmitis. Intra- rapidly and dramatically when intravenous corticosteroids
ocular vascular disturbances, such as retinal perivasculitis, were given.
branch retinal artery occlusion, recurrent vitreous hemor- As noted above, the ultimate prognosis for most cases of
rhage, sheathing of retinal vessels, and intraretinal hemor- Leber’s idiopathic neuroretinitis is excellent. Most patients
rhages, are also common in such patients. Fluorescein angi- achieve good visual recovery, although a subgroup of pa-
ography may reveal areas of nonperfusion in one or both tients develop optic atrophy and poor vision. These patients
eyes in such patients. typically have very poor visual acuity from the beginning
Specific patients may require lumbar puncture, MR imag- of the process, significant visual field loss at presentation,
ing or CT scanning, and serologic tests for syphilis, Lyme and a marked, relative afferent pupillary defect if the condi-
disease, toxoplasmosis, histoplasmosis, or toxocariasis, tion is unilateral or asymmetric (595). Nevertheless, even
whereas others should undergo antibody testing for cat patients who present with profound loss of visual function
scratch disease. The use of molecular biologic techniques to may recover normal or near-normal vision over time. Recur-
identify viral nucleic acids in various body tissues and fluids rent neuroretinitis may occur in rare cases (626).
OPTIC NEURITIS 337
OPTIC PERINEURITIS (PERIOPTIC NEURITIS)

Perioptic neuritis is a condition in which only the periph- sarcoidosis, and viral encephalitides (628–632). The puru-
ery of the optic nerve is inflamed. Edmunds and Lawford lent form, actually a leptomeningitis, arises as an extension
(627) initially described optic perineuritis as occurring in from the cerebral meninges. Pathologically, the pia and
two forms: exudative and purulent. The exudative form, rep- arachnoid are infiltrated by polymorphonuclear leukocytes
resenting a localized, nonsuppurative pachymeningitis, oc- that are also found free in the subarachnoid space surround-
curs infrequently, most often in association with syphilis, ing the optic nerve (Fig. 6.22). From the leptomeninges, the
Figure 6.22. Optic perineuritis. A, The optic disc is hyperemic and swollen (as was the left disc). The patient was a 15-year-
old boy complaining of a headache and stiff neck. He had a moderate fever. Visual acuity was 20/15 in both eyes, color vision
was normal, and visual fields were full. The patient was believed to have papilledema. A lumbar puncture, however, revealed
normal intracranial pressure, an increased concentration of protein in the CSF, and a significant CSF lymphocytosis. B, Histologic
appearance of optic perineuritis in a case of fatal meningitis. Polymorphonuclear leukocytes (PMNs) are infiltrating the leptomen-
inges surrounding the optic nerve and are present in the subarachnoid space. C, Magnified view of affected area of peripheral
optic nerve. PMNs extend from the pia in the septal system deep into the nerve. There is no invasion of the nerve tissue,
however. (Specimen courtesy of Dr. S.T. Orion.)
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data for young adults. Clin Vis Sci 1993;8:207–210.
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Purvin et al. (633) reviewed the medical records of 14 the Optic Neuritis Treatment Trial. Control Clin Trials 1993;14:123–142.
18. Beck RW, Cleary PA, Backlund JC, et al. The course of visual recovery after
patients with optic perineuritis who were seen in two neuro- optic neuritis: experience of the Optic Neuritis Treatment Trial. Ophthalmology
ophthalmology clinics. The patients ranged in age from 24 1994;101:1771–1778.
to 60 years; 5 were older than 50 years. All patients had 19. Beck RW. The Optic Neuritis Treatment Trial: three-year follow-up results.
visual loss, eye pain, or both. The visual acuity was 20/20 20. Beck RW, Trobe JD, Optic Neuritis Study Group. What have we learned from
or better in 8 of the 15 eyes. The results of visual field testing the Optic Neuritis Treatment Trial? Ophthalmology 1995;102:1504–1508.
were normal in two eyes, and a paracentral scotoma or an 21. Beck RW, Trobe JD, Optic Neuritis Study Group. The Optic Neuritis Treatment
Trial: putting the results in perspective. J Neuroophthalmol 1995;15:131–135.
arcuate defect was seen in seven. MR imaging demonstrated 22. Optic Neuritis Study Group. The five-year risk of multiple sclerosis after optic
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23. Optic Neuritis Study Group. High- and low-risk profiles for the development
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CHAPTER 7
Ischemic Optic Neuropathy
Anthony C. Arnold
ANTERIOR ISCHEMIC OPTIC NEUROPATHY (AION) Perioperative

Arteritic Anterior Ischemic Optic Neuropathy (AAION) Hypotension
Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) RADIATION OPTIC NEUROPATHY
POSTERIOR ISCHEMIC OPTIC NEUROPATHY ISCHEMIC OPTIC DISC EDEMA WITH MINIMAL
ISCHEMIC OPTIC NEUROPATHY IN SETTINGS OF DYSFUNCTION
HEMODYNAMIC COMPROMISE Pre-AION Optic Disc Edema
Spontaneous or Traumatic Hemorrhage Diabetic Papillopathy
Ischemic syndromes of the optic nerve (ischemic optic ment is the vasculitis of giant cell, or temporal, arteritis
neuropathy [ION]) are classified according to (a) the loca- (GCA); therefore, ION is typically classified as either arteri-
tion of the ischemic damage of the nerve and (b) the etiologic tic (usually due to GCA) or nonarteritic. Nonarteritic ION
factor, if known, for the ischemia. Anterior ischemic optic is most often idiopathic, but specific etiologies such as sys-
neuropathy (AION) includes syndromes involving the optic temic hypotension and radiation injury have been identified.
nerve head, with visible optic disc edema. Posterior is- Finally, several syndromes of optic disc edema with rela-
chemic optic neuropathy (PION) incorporates those condi- tively mild dysfunction, including preinfarct optic disc
tions involving the intraorbital, intracanalicular, or intracra- edema and diabetic papillopathy, are presumed to represent
nial portions of the optic nerve, with no visible edema of optic nerve ischemic edema with dysfunction that is not de-
the optic disc. While several specific etiologic factors have tectable, mild, or reversible.
been identified in ION, the most critical for initial manage-
ANTERIOR ISCHEMIC OPTIC NEUROPATHY (AION)

AION typically presents with the rapid onset of painless (Fig. 7.5). Retinal arteriolar emboli are only rarely associ-
unilateral visual loss developing over hours to days. An alti- ated.
tudinal visual field defect (typically inferior) is the most
common pattern of loss (Fig. 7.1 but arcuate scotomas, ceco- ARTERITIC ANTERIOR ISCHEMIC OPTIC
central defects, and generalized depression are also fre- NEUROPATHY (AAION)
quently seen (Fig. 7.2). Visual acuity is decreased if the field
Demographics
defect involves fixation but may be normal if an arcuate
pattern spares the central region. The pupil in the affected Although it often produces a severe and devastating optic
eye is sluggishly reactive, with a relative afferent pupillary neuropathy, GCA is the cause for AION in a relatively small
defect present unless pre-existing or concurrent optic neu- minority (5.7%) (1) of cases, with an estimated annual inci-
ropathy in the fellow eye makes its pupillary response dence in the United States of 0.57 per 100,000 over age 60
equally sluggish. The optic disc is edematous at onset; the (2). AION is, however, the most common cause of visual
edema may be pallid, but it is not uncommon to see disc loss in GCA (3–5), accounting for 71–83% of cases (6,7),
hyperemia, particularly in the nonarteritic form (Fig. 7.3). with retinal artery occlusion, choroidal ischemia, and PION
The disc most often is diffusely swollen, but a segment of less common. The mean age of onset for AAION is 70 years
more prominent edema is frequently present (Fig. 7.4). (1), with only rare occurrence under age 60. GCA occurs
Flame hemorrhages are commonly located adjacent to the more frequently in women and with increasing age (8,9). It
disc, and peripapillary retinal arteriolar narrowing may occur is most common in Caucasians and is unusual in African-
349
Figure 7.1. Automated quantitative perimetry in AION. Broad arcuate (altitudinal) defect (A) is most common, with central
(B) and less severe arcuate (C) defects also frequently noted.
ISCHEMIC OPTIC NEUROPATHY 351
Figure 7.2. Goldmann perimetry, showing common visual field defects in anterior ischemic optic neuropathy. A, Altitudinal
defect. B, Broad arcuate defect.
American and Hispanic patients (2). Liu et al. reviewed 121 constant, and disabling. True jaw claudication, with muscu-
consecutive temporal artery biopsies, assessing the rate of lar cramping and fatigue progressing with continued chew-
positive biopsies by ethnic background: 19/66 (29%) of Cau- ing activity, has high specificity for temporal arteritis, al-
casian patients had positive biopsies, compared with 0/40 though it has also been reported in amyloidosis (14).
Hispanic patients and 0/6 African-Americans (10). Claudication may also occur in muscles of the neck or
tongue. The syndrome of polymyalgia rheumatica (PMR),
Clinical Manifestations including malaise, anorexia, weight loss, fever, proximal
joint arthralgia and myalgia, is frequently reported. PMR
AAION usually occurs in association with other systemic with hematologic inflammatory markers, but without tem-
symptoms of the disease. Headache is the most common poral artery or ocular involvement, may lead to arteritis in
symptom, while jaw claudication and temporal artery or some cases. One series indicated that 15.8% of PMR patients
scalp tenderness are the most specific for the disorder eventually developed GCA with visual loss (15). In contrast,
(11–13) (see also Chapter 44). The headache is often severe, so-called occult GCA, without overt systemic symptoms and
Figure 7.3. Ophthalmoscopic appearance of nonarteritic anterior ischemic optic neuropathy. A, Pallid swelling of the optic
disc associated with a few small flame-shaped hemorrhages at the disc margin. B, Hyperemic swelling of the optic disc associated
with numerous hemorrhages and a few soft exudates.
Figure 7.4. Segmental optic disc edema in AION. The optic disc is edem-
atous, with more prominent involvement inferiorly.
Figure 7.5. Parapapillary retinal arteriolar narrowing in AION. The ves-

sometimes without abnormal blood testing, may occur sels are focally attenuated overlying the disc, widening as they course to-
ward the retinal periphery.
(16,17). In Hayreh’s recent report, 21.2% of patients with
GCA and visual loss had no systemic symptoms of the dis-
ease (17).
In addition to systemic symptoms, certain associated local
signs may aid in the diagnosis of AAION. Induration of the over hours to days (Table 7.1). Twenty-one percent of cases
temporal region, decreased or absent temporal artery pulse, in one series had no light perception (6). While the initial
and cordlike firmness or nodularity of the temporal artery presentation is often unilateral, bilateral simultaneous AION
all may be seen. Ischemic scalp necrosis has been docu- is more commonly arteritic than nonarteritic, and its occur-
mented in GCA, and it may masquerade as herpes zoster rence raises suspicion for GCA. The persistent visual loss
dermatitis, with facial pain and even a vesicular reaction of of AAION is preceded in 7–18% (6,7,20,23) of cases by
the affected skin (18). A wide variety of additional signs transient visual loss similar to that of carotid artery disease,
relating to vasculitic ischemia of the central nervous system although the episodes may be of shorter duration; these are
have been reported; these include mental status alterations only rarely associated with the nonarteritic form of AION
(19), brain stem and cerebellar syndromes (20), and damage and are highly suggestive of arteritis. The pallid type of optic
to the retrochiasmal afferent visual pathways, with corre- disc edema (Fig. 7.6) is seen more frequently in the arteritic
sponding visual field defects (20). than in the nonarteritic form (24,25); chalk-white pallor with
AAION typically presents with severe visual loss (visual edema is seen in severe cases and is highly unusual in nonart-
acuity less than 20/200 in 57.8% to 76.5% of cases [6,7, eritic ION (NAION). Cotton-wool patches (Fig. 7.7) indica-
21,22], frequently hand motion or worse) developing rapidly tive of concurrent retinal ischemia may be seen (26). Retinal
Table 7.1
Ischemic Optic Neuropathies
Arteritic Nonarteritic Diabetic Papillopathy Posterior
Age Mean 70 yr Mean 60 yr Variable (⬍50) Variable

Gender F⬎M F⫽M F⫽M F⫽M
Associated symptoms Headache, jaw claudication, transient Usually none Usually none None unless arteritic or
visual loss postoperative
Visual acuity ⬍20/200 in ⬎60% ⬎20/60 in ⬎50% ⬎20/40 in ⬎75% Usually poor
Disc Pale swelling common Pale or hyperemic Hyperemia, telangiectasia Normal
Cup normal ⫹ choroid ischemia Cup small Cup small Variable
ESR Mean 70 mm/hr Usually normal Usually normal Elevated if arteritic
FA Disc delay Disc delay Disc delay Not studied
Choroid delay
Natural history Rarely improve 16–42.7% improve Resolves 2–10 mo Rarely improves
Fellow eye 54–95% Fellow eye 12–19% Bilateral 40% Bilateral ⬎60%
Treatment Systemic steroids None proven None proven Steroids if arteritic
Figure 7.6. Bilateral simultaneous anterior ischemic optic neuropathy in a patient with GCA and no light perception in either
eye. The right and left optic discs show markedly pale swelling.
Figure 7.7. Progressive optic atrophy and pseudoglaucomatous cupping

after an attack of AAION. A, Right optic disc at the time of initial visual
loss. Note pale optic disc swelling, peripapillary hemorrhage, and cotton-
wool spot. B, Eight weeks after visual loss, the optic disc swelling has
resolved, and both the hemorrhage and the cotton-wool spot are resolving.
Note narrowing of retinal vessels. C, Four months after visual loss, the
optic disc is pale and now has a large cup. The retinal vessels, especially
the arteries, are markedly narrowed.
a normal physiologic cup (30,31), as opposed to that in

NAION, which tends to be small in diameter, with little or
no physiologic cup (31) (see below).
Pathophysiology
Histopathologic studies in AAION demonstrate vasculitis
of the short posterior ciliary vessels supplying the optic nerve
head, in addition to variable involvement of the superficial
temporal, ophthalmic, choroidal, and central retinal arteries
(32–37). Infiltration of the short posterior ciliary arteries
by chronic inflammatory cells, with segmental occlusion of
multiple vessels by inflammatory thickening and thrombus
(Fig. 7.9), has been documented (32,33,37). Autopsy studies
have demonstrated ischemic necrosis predominantly involv-
ing the laminar and retrolaminar portions of the optic nerve
supplied by these vessels and their distal tributaries (32,
34,35).
Fluorescein angiographic data support involvement of the
Figure 7.8. AAION with associated cilioretinal artery occlusion. In addi- short posterior ciliary arteries in AAION. Delayed filling of
tion to the optic disc edema, there is a focus of retinal edema in the distribu- the optic disc and adjacent choroid (Fig. 7.10) is consistently
tion of the cilioretinal artery. noted (24,28,38–41). Extremely poor or absent filling of the
choroid has been suggested as one useful factor in distin-
guishing arteritic from nonarteritic AION. Mack et al. (29)
arterial occlusion may occur simultaneously with the optic reported mean choroid perfusion time (from first appearance
neuropathy (6). In Hayreh’s series (23), cilioretinal artery to filling) of 69 seconds in patients with AAION, compared
occlusion occurred in 21.2%; this is a very unusual occur- with 5.5 seconds in NAION; Siatkowski et al. (25) confirmed
rence in NAION and is highly suggestive of GCA (Fig. 7.8). this finding with slightly different parameters, mean time
Peripapillary choroidal ischemia may be associated with the from injection to choroid filling measuring 29.7 seconds in
optic neuropathy, producing edema deep to the retina adja- AAION compared with 12.9 seconds in NAION.
cent to the optic disc and exacerbating the visual loss (27,28).
It may also occur in a more widespread area, with or without Differential Diagnosis
optic disc involvement (27,29). The optic disc of the fellow The acute onset of severe visual loss in the setting of
eye in AAION most frequently is of normal diameter, with headache and optic disc edema, particularly when bilateral,
Figure 7.9. Pathophysiology of AION in GCA. A, The right optic disc shows pale swelling with extension of edema into
the peripapillary retina. B, Section through several short posterior ciliary arteries shows that they contain a granulomatous
inflammation in their walls with fragmentation of the internal elastic lamina and subendothelial aggregation of giant cells. The
lumens are markedly narrowed or occluded. (Courtesy Dr. I. H. L. Wallow.)
diagnosis may be made on the basis of advanced age and

typical clinical symptoms in conjunction with elevation of
the erythrocyte sedimentation rate (ESR). Most cases of ac-
tive GCA show markedly elevated ESRs (mean 70 mm/hr,
often above 100 mm/hr). When the level is not extremely
high, however, interpretation of the value becomes more
difficult, as normative data are imprecise. As a rule, we rec-
ommend the clinically useful guideline that the upper level
of normal, in mm/hr, is calculated by dividing patient age
by 2 in males and patient age plus 10 by 2 in females (50).
However, by these criteria, the level may be normal in up
to 22% of patients with GCA (5,51). Conversely, the ESR
rises with age, and levels above the listed upper limit of
normal for the laboratory are common (up to 40% over 60
mm/hr) in patients over 70 without arteritis (52). In the Is-
chemic Optic Neuropathy Decompression Trial (IONDT),
9% of patients with NAION had ESR levels over 40 mm/hr,
with a range of 0–115 (53). Moreover, the test is nonspecific,
elevation confirming only the presence of any active inflam-
matory process or other disorder affecting red cell aggrega-
tion. In studies of temporal artery biopsy-negative cases with
Figure 7.10. Fluorescein angiography in AAION. The optic disc and adja- such elevation, the most common associated diseases have
cent choroid show marked filling delay. been occult malignancy (most frequently lymphoma) in
18–22%, other inflammatory disease in 17–21%, and diabe-
tes in 15–20% (54,55). In these cases initially suspected of
requires consideration of alternate diagnoses, including being GCA, internal medicine consultation to rule out other
acute optic neuropathy secondary to chronic papilledema systemic diseases is essential.
(with or without intracranial mass), infiltrative optic neurop- Additional blood abnormalities are common in GCA and
athy, and meningeal carcinomatosis involving the optic may have prognostic value. Measurement of C-reactive pro-
nerves. In cases of suspected AAION with negative workup tein, levels of which do not rise with age or anemia, may
or atypical course, neuroimaging should be performed to increase diagnostic accuracy and are currently recommended
evaluate for intracranial mass or visible meningeal thicken- in conjunction with the ESR (56). Hayreh et al. (69) reported
ing and enhancement, and lumbar puncture should be con- that a specificity of 97% for GCA was attained for AION
sidered to assess for evidence of elevated intracranial pres- patients with ESR levels above 47 mm/hr and C-reactive
sure or malignant cells. protein above 2.45 mg/dL (normal less than 0.5) from their
Clinical Course laboratory. We currently recommend simultaneous measure-
ment of both parameters in suspected cases of AAION. Fi-
If untreated, AAION results in severe damage of the af-
brinogen is commonly elevated and may supplement C-reac-
fected optic nerve. Recovery of useful vision after initial
tive protein levels in increasing accuracy over the use of
involvement is unusual, even with prompt therapy. In cases
ESR alone (57,58). Thrombocytosis is seen in up to 50% of
with unilateral presentation, estimates for development of
patients with GCA; its presence has been shown to be a
AAION in the fellow eye without therapy range from 54%
to 95% (6,42–44). Time to second eye involvement varies marker for positive temporal artery biopsy (59) and may be
greatly, but it may occur within hours to days. The optic a predictor of visual loss (60,61). Liozon et al. (61) assessed
disc edema typically resolves over 4–8 weeks, with resultant 174 patients with GCA, correlating thrombocytosis with the
optic atrophy and generalized attenuation of retinal arteri- development of permanent visual loss. Of 20 patients with
oles. Excavation of the optic disc (Fig. 7.7) occurs frequently permanent visual loss due to AAION, 13 (65%) had throm-
after AAION (40,45–49) but is unusual in NAION. Danesh- bocytosis. This feature may have implications for therapy
Meyer et al. (48) reported optic disc cupping in 92% of 92 (see below).
patients with AAION versus 2% of 102 patients with Giant cell arteritis is confirmed by a positive temporal
NAION. The excavation may be severe, mimicking glauco- artery biopsy, which is strongly recommended in any case
matous damage. Hayreh and Jonas (49) noted lack of in- of suspected arteritic AION. The certainty of biopsy-proven
crease in peripapillary atrophy associated with the cupping GCA provides support for long-term systemic corticosteroid
after AAION, in contrast to glaucoma. The severity of the therapy, which often is required for up to a year and may
optic atrophy seen after AAION also differentiates it from be associated with severe systemic complications. It also
glaucomatous excavation. makes later decisions regarding the risk/benefit ratio of pro-
longed therapy more clearcut. A negative biopsy, however,
Diagnostic Confirmation does not rule out GCA. A false-negative biopsy may result
The most important initial step in the management of from (a) discontinuous arterial involvement (‘‘skip le-
AION is the assessment for evidence of GCA. A tentative sions’’) (62–65), undetected in 4–5% due to insufficient
length (minimum 3–6 cm recommended) of specimen or temic corticosteroid therapy has been reported to reduce pos-
insufficiently detailed step-sectioning; (b) unilateral involve- itive biopsy results in GCA from 60% to 20% (74), delay
ment with biopsy of the uninvolved temporal artery; (c) im- of 7–10 days has no significant effect on the results, and in
proper handling of specimens; or (d) review by a pathologist some cases active inflammation may be detected after longer
inexperienced in the diagnosis of acute and healed arteritis. therapy (75). High-dose intravenous methylprednisolone at
The false-negative error rate for unilateral temporal artery 1 g/day for the first 3–5 days is most often recommended,
biopsy has previously been estimated at 5–11% (66–68). particularly when the patient is seen in the acute phase, since
Hayreh et al. (69) more recently prospectively studied 76 this mode of therapy produces higher blood levels of medica-
patients who underwent contralateral biopsy due to high clin- tion more rapidly than oral therapy (76,77). As these patients
ical suspicion after initially negative biopsy; 7 (9.2%) had are often elderly with multiple and complex medical prob-
evidence of active inflammation in the second biopsy. Boyev lems, we routinely provide inpatient therapy under the super-
et al. (70) reviewed bilateral biopsy results for concordance vision of an internist.
in 186 cases of suspected GCA. Identical diagnoses were Liu et al. (6) reported improvement of visual loss in
obtained in 176, an overall concordance rate of 97%. Six of AAION in 39% of those treated initially with intravenous
the remaining 10 cases had useful biopsy results from each therapy, compared with 28% in those treated orally alone.
side, all demonstrating discordance (3%); 5 of the 6 were Hayreh et al. (78) similarly suggested a better visual outcome
eventually diagnosed with GCA based on clinical evidence. with intravenous administration, although Cornblath et al.
Most (150) of the cases involved bilateral simultaneous biop- (79) have raised questions regarding the advantages of this
sies, but 36 were sequential, more directly addressing the mode of therapy. Oral prednisone at doses of at least 1 mg/
issue of the value of a second (contralateral) biopsy after kg/day is recommended after intravenous therapy (or ini-
an initially negative one; of these, only 1 (2.8%) showed tially if the intravenous route is not used) and is tapered
discordance. Danesh-Meyer et al. (71) performed a similar slowly, monitoring for control of systemic symptoms and
retrospective study of 91 bilateral biopsies, the majority si- ESR level; therapy is usually maintained for at least 4–6
multaneous, finding concordance in 90 (99%); it is unclear months, often up to a year. Systemic symptoms typically
whether the discordant case involved sequential biopsies. subside within a week, a response so characteristic that if it
They performed a meta-analysis of previous reports that is absent, an alternate disease process should be strongly
yielded an overall discordance rate of 4%. Pless et al. (72) considered. Alternate-day corticosteroid therapy is inade-
reviewed 60 bilateral biopsies, 31 of which were simultane- quate for GCA. Hunder et al. (66) compared alternate-day
ous, finding discordance in 13.4% overall but only 5% in to daily therapy in GCA, finding that both systemic symp-
toms and ESR were incompletely suppressed on alternate-
sequential cases in which the initial result was negative. Hall
day therapy; one patient in this treatment group suffered
et al. (73) found a similar rate.
recurrent transient visual loss, while none in the daily groups
While the overall discordance rate for bilateral biopsies
had similar symptoms.
is low (1–3% in the largest series), there is substantial varia-
Some degree of visual recovery in the affected eye may
tion, even in major academic institutions with experienced be obtained on therapy but is not generally anticipated. Re-
pathologists, with rates as high as 13.4%. In the critical sub- ports of visual improvement on corticosteroids vary widely
set of patients who undergo contralateral biopsy after an with regard to delay to therapy, dosage, and parameters for
initially negative result (a sample biased toward the positive visual recovery. Aiello et al. (7) reported improvement of
based on clinical parameters raising suspicion for GCA), vision in 5 of 34 patients (15%), while Liu et al. (6) noted
studies with the greatest number of patients suggest a slightly it in 14 of 41 (34%). Foroozan et al. (80) reported improve-
higher discordance (2.8–9.2%), but the difference is small. ment in visual acuity in 5 of 39 eyes (13%), although visual
The data all suggest some degree of increased accuracy from fields remained severely constricted. Hayreh et al. (78) stud-
bilateral biopsies, and considering the severe consequences ied 114 eyes in 84 patients for evidence of visual improve-
of missed diagnosis, the relatively low risk of procedural ment, finding only 5 eyes (4%) with both improved visual
complications, and the benefit of biopsy proof in the long- acuity and central visual field after therapy.
term management of these patients, we consider bilateral The major goal of therapy, other than prevention of sys-
biopsy in all cases. Expert opinion varies, however, as to temic vascular complications, is to prevent contralateral vis-
preference for bilateral simultaneous biopsies versus imme- ual loss. Untreated, fellow eye involvement occurs in
diate sequential biopsies (with negative initial frozen-section 50–95% (42,81), often within weeks. With therapy, Aiello
analysis) versus delayed sequential biopsies (with negative et al. (7) found that 2/24 (6.3%) patients with AAION devel-
initial permanent section analysis) if clinical suspicion for oped such involvement, at 4 days and 1 month after initiation
GCA is high. of therapy; Liu et al. (6) detected fellow-eye AAION on
therapy in 3 cases. While corticosteroid therapy reduces the
Therapy
risk of further visual loss, it is not uniformly effective (82);
If GCA is suspected, therapy should be instituted immedi- breakthrough involvement of an affected eye while on ther-
ately, as patients are at high risk for further visual loss in apy occurred in 9–17% (6,7). Liu et al. (6) found six cases
the affected eye, involvement of the fellow eye, and systemic developing AAION while on systemic corticosteroid therapy
complications of vasculitis, including stroke and myocardial for systemic symptoms alone, without previous visual loss.
infarction. Initial treatment should not await diagnostic con- The risk of recurrent or contralateral optic nerve involvement
firmation by temporal artery biopsy. Although chronic sys- with tapering of medications has been reported at 7% (6).
Thrombocytosis in GCA and its possible predisposition 50 years of age, with an estimated annual incidence in the
to visual loss suggests the possibility that antiplatelet therapy United States of 2.3–10.2 per 100,000 population (2,100),
may be of benefit in conjunction with corticosteroids. Nesher accounting for at least 6,000 new cases annually. The preva-
et al. (83) reviewed 175 cases with GCA for evidence of lence of NAION in the Medicare Database has been reported
cranial ischemic complications (predominantly AION and at 0.30% (101). The disease occurs with significantly higher
stroke), comparing those with and without low-dose aspirin frequency in the white population than in black or Hispanic
therapy for other conditions. At presentation, 3 (8%) of the individuals (2). There is no gender predisposition (1,21,22,
aspirin-treated cases had cranial ischemic complications, 53,102). The mean age at onset in most studies ranges from
compared with 40 (29%) of the non-aspirin-treated cases (P 57–65 years (1,21,22,102). In the IONDT, mean age was
⳱ 0.01). During follow-up of at least 3 months on steroid 66 years, probably somewhat biased by the exclusion crite-
therapy, cranial ischemic complications developed in 3% of rion for patients under 50 (53).
the aspirin-treated cases versus 13% on steroids alone (P
⳱ 0.02). Further study may confirm a benefit for low-dose Clinical Presentation
aspirin or other antiplatelet therapy in GCA.
NAION presents with loss of vision occurring over hours
Other Vasculitides to days, often described as blurring, dimness, or cloudiness
Arteritic conditions other than GCA may cause AION, in the affected region of the visual field, most often inferi-
including herpes zoster (84,85), relapsing polychondritis orly. Although Hayreh et al. (103) reported that visual loss
(86,87), rheumatoid arthritis (88,89), Takayasu’s arteritis was most frequently reported upon awakening, this feature
(90), and connective tissue disorders such as periarteritis was not confirmed in the IONDT (53). NAION typically
nodosa, systemic lupus erythematosus (91,92), and allergic presents without pain, although some form of periocular dis-
granulomatosis (Churg-Strauss angiitis) (93,94). The clini- comfort has been reported in 8–12% (21,104,105); in the
cal picture is typically that of sudden unilateral or bilateral IONDT, 10% reported minor ocular discomfort (53). In con-
visual loss, often central, and sometimes accompanied by trast to patients with optic neuritis, those with NAION usu-
pain, with minimal recovery. Fibrinoid necrosis of the arteri- ally do not report pain with eye movement. Headache and
oles and secondary myelin and axonal loss has been demon- other symptoms associated with GCA are absent. Episodes
strated in multiple cases (91). Crompton et al. (89) docu- of transient visual loss as seen in GCA are rare, but vague
mented necrotizing lymphocytic vasculitis and perivasculitis intermittent symptoms of blurring, shadows, or spots were
affecting the posterior ciliary arteries, in a case of AION in reported in 5% of patients in the IONDT (53). The initial
rheumatoid arthritis. course may be static, with little or no fluctuation of visual
Goldstein and Wexler (95) reported the histopathologic level after initial loss, or progressive, with either episodic,
findings in a patient with periarteritis nodosa who had sud- stepwise decrements or steady decline of vision over weeks
den bilateral visual loss and pale optic discs. They described prior to eventual stabilization. The progressive form has
mononuclear cell infiltration of the posterior ciliary arteries, been reported in 22–37% of nonarteritic cases (21,104,106,
necrosis and infiltration of some choroidal arteries, and infil- 107), 29% in a limited group of patients with visual acuity
tration and atrophy of the optic nerves. Although the patient better than 20/64 in the IONDT (53).
was not examined at the time of visual loss, it is likely that NAION usually presents with less severe visual loss than
the process was a bilateral simultaneous AION. AION has AAION, with visual acuity better than 20/200 in 58–61.2%
also been described in two patients with Behçet’s disease of patients (21,22,104) (Table 7.1). In the IONDT, 49% had
(96) and in a patient with Crohn’s disease (97), presumably initial visual acuity of at least 20/64, 66% better than 20/
from posterior ciliary arteritis. 200 (53). Color vision loss in NAION tends to parallel visual
The term ‘‘autoimmune optic neuropathy’’ (98,99) has acuity loss, as opposed to that in optic neuritis, in which
been used to describe patients with nonspecific symptoms color loss is often disproportionately greater than visual acu-
of connective tissue disease, frequently insufficient to con- ity loss. Visual field defects in NAION may follow any pat-
firm a specific diagnosis such as lupus, who develop acute tern related to optic nerve damage, but altitudinal loss, usu-
optic neuropathy, either anterior or posterior (retrobulbar). ally inferior, occurs in the majority, ranging from 55–80%
The syndrome is atypical for optic neuritis in that pain is not of reported cases (21,22,104,108,109).
a consistent feature, and visual recovery is variable. Steroid The optic disc edema in NAION may be diffuse or seg-
dependence, with improvement on therapy but recurrence mental, hyperemic or pale, but pallor occurs less frequently
on tapering, is common. Immunosuppressive therapy may than in the arteritic form. A focal region of more severe
be required. Histopathologic studies have not been docu- swelling is often seen and may display an altitudinal distribu-
mented, but it has been postulated that vasculitis of the cili- tion, but it does not consistently correlate with the sector
ary arteries results in optic nerve ischemia in these cases. of visual field loss (110). In the IONDT, 25% of patients
NONARTERITIC ANTERIOR ISCHEMIC OPTIC demonstrated sectoral disc edema (53). Diffuse or focal tel-
NEUROPATHY (NAION) angiectasia of the edematous disc (Fig. 7.11) may be present,
occasionally prominent enough to resemble a vascular mass
Demographics (pseudohemangioma) (111). Peripapillary retinal hemor-
Most (94.7%) cases of AION are nonarteritic (1) NAION rhages are common, seen in 72% in the IONDT (53). Retinal
is the most common acute optic neuropathy in patients over exudates are unusual, but both soft and hard exudates may
of the vasculopathy and its pathogenetic mechanism remain

unproven.
Location of Vasculopathy
There has been no definite histopathologic documentation
of the vasculopathy resulting in NAION. Implication of both
the posterior ciliary arteries and the choroid has been based
on indirect evidence. Recent data suggest that vasculopathy
within the paraoptic branches of the short posterior ciliary
arteries may play a major role.
There are few histopathologically studied cases of typical
NAION. Eight cases of nonarteritic optic nerve head infarc-
tion have been reported. Three of these cases were atypical
forms, associated with internal carotid occlusion, multiple
embolic lesions, and severe acute blood loss, rather than
Figure 7.11. Focal optic disc surface vascular telangiectasia in NAION. classic idiopathic NAION (36,119–124). The short posterior
ciliary arteries were described only in an atypical case in
occur (7% in the IONDT) (53). A partial or complete macu- which emboli within them produced optic disc infarction,
lar star pattern of exudate, as seen in neuroretinitis, is occa- and in which the central retinal and pial arteries were also
sionally seen (Fig. 7.12). The retinal arterioles are focally involved with emboli (121). Tesser et al. indicated that the
narrowed in the peripapillary region (Fig. 7.5) in up to 68% optic disc infarct studied in their case did not follow a spe-
of cases (112). The optic disc in the contralateral eye is cific vascular territory (124). Knox et al. (125) reported a
typically small in diameter (113,114) and demonstrates a series of 193 eyes with a histopathologic diagnosis of is-
small or absent physiologic cup (31,115–117) (Fig. 7.13A). chemic optic neuropathy, but those with typical NAION
The disc appearance in such fellow eyes has been described were not identifiable due to lack of clinical information. No
as the ‘‘disc at risk,’’ referring to structural crowding of the confirmation of lipohyalinosis or other occlusive process or
axons at the level of the cribriform plate, associated mild inflammation within the optic disc vascular supply was doc-
disc elevation, and disc margin blurring without overt edema umented in these or other cases. The available evidence does,
(118). however, highlight one important fact: the infarctions were
predominantly located in the retrolaminar region of the optic
Histopathology and Pathophysiology nerve head (Fig. 7.14), with extension to the lamina and
NAION is presumed to result from circulatory insuffi- prelaminar layer in some. This pattern suggests that the vas-
ciency within the optic nerve head, but the specific location culopathy responsible for NAION does not lie within the
Figure 7.12. AION with partial macular star formation in the papillomacular nerve fiber layer.
Figure 7.13. Development of optic atrophy after AION. A, Appearance of the left optic disc before visual symptoms in the
left eye. The patient subsequently developed decreased vision in the left eye associated with an inferior altitudinal field defect.
B, The left optic disc is swollen and hyperemic. There are numerous flame-shaped, peripapillary, intraretinal hemorrhages. C,
Two months later, the left optic disc is diffusely pale, the retinal arteries are narrowed, and the nerve fiber layer is no longer
visible.
choroidal circulation, since the contribution of the choroid formed specifically in cases of NAION, these data also speak
to the optic nerve head vascular supply is to the more anterior against a substantial role of the choroid in NAION pathogen-
laminar and prelaminar layers. esis.
Olver et al. (126) and Onda et al. (127) have demonstrated In the acute phase of NAION, fluorescein angiography
in autopsy eyes that the optic disc is supplied by a partial shows delayed filling of the prelaminar layers of the edema-
or complete vascular circle (corresponding to prior descrip- tous optic disc. This is the most compelling in vivo evidence
tions of the circle of Zinn-Haller) derived from the short of optic disc circulatory impairment in NAION (38–40,110).
posterior ciliary arteries (Fig. 7.15). This vascular supply In studies by Arnold and Hepler (110), delayed prelaminar
may demonstrate distinct upper and lower halves consistent optic disc filling (more than 5 seconds later than choroid
with the altitudinal damage of the nerve head commonly and retinal vasculature) was demonstrable in 76% of subjects
seen in NAION. These studies also demonstrated the separa- with acute NAION (Fig. 7.16). This feature was seen in
tion of the paraoptic branches of the short posterior ciliary no normal controls or subjects with nonischemic optic disc
arteries (optic nerve head supply) from the choroidal edema (128), suggesting that the delayed filling represents
branches. Both studies concluded that the choroidal circula- a primary ischemic process rather than a mechanical process
tion provides only a minor contribution to the optic nerve secondary to obstruction from the disc edema itself. The
head blood supply. Although no such studies have been per- overlying disc surface vasculature, derived from the retinal
Figure 7.16. Fluorescein angiography in NAION. Optic disc filling is

delayed.
Figure 7.14. Histopathology of AION. Infarct is located in the retrolami-
nar portion of the optic nerve. (Courtesy of David L. Knox, MD)
be a manifestation of shunting to relatively spared regions
of the disc in NAION (110,118,129).
arterial circulation, showed sectoral dilation and early fluo- Arnold and Hepler (110) and Siatkowski et al. (25) both
rescein filling (Fig. 7.17) in 54% of cases (110). It has been found that segmental parapapillary choroidal filling delay
postulated that this focal vascular dilation, may be analogous (more than 5 seconds) was not a consistent feature in NAION
to the ‘‘luxury perfusion’’ seen at the junction of perfused (Fig. 7.18) (46%, versus 58% in normal controls). Addition-
and nonperfused regions in cerebral infarctions and could ally, segments of disc and adjacent choroidal filling were
poorly correlated; disc filling delay was commonly seen ad-
jacent to normally filling choroidal segments, and vice versa.
Similar findings have been reported with indocyanine green
Figure 7.15. Scanning electron photomicrograph of the vasculature of

the posterior globe. Superior and inferior anastomoses from the medial and
lateral short posterior ciliary arteries suggest a possible anatomic correlation
for the altitudinal pattern of optic nerve damage in NAION. (From Olver Figure 7.17. Segmental early hyperfluorescence in NAION, correlating
JM, Spalton DJ, McCartney ACE. Microvascular study of the retrolaminar with focal disc surface telangiectasia. (From Arnold AC, Hepler RS. Flu-
optic nerve in man: the possible significance in anterior ischemic optic orescein angiography in acute anterior ischemic optic neuropathy. Am J
neuropathy. Eye 1990;4:7–24.) Ophthalmol 1994;177:222–230.)
monocular blindness (TMB), and 30 age-matched controls.

Mean stenosis was not significantly worse in NAION pa-
tients (19%) than controls (9%), while those with TMB dem-
onstrated a significantly worse mean of 77%. Two of 15
patients with NAION had stenosis of more than 30%, com-
pared with 5 of 30 controls and 10 of 11 with TMB. Muller
et al. (138) did not find hemodynamically significant steno-
sis in any of 17 subjects with NAION.
Pathogenetic Mechanism
The mechanisms involved in the development of optic
disc ischemia in NAION similarly remain unclear. Whether
ischemia results from local arteriosclerosis with or without
thrombosis, embolization from a remote source, generalized
hypoperfusion, vasospasm, failure of autoregulation, or
some combination of these processes is not known. While
structurally small, ‘‘crowded’’ optic discs are associated
Figure 7.18. Normal parapapillary choroidal filling in NAION. Optic disc with NAION, the mechanism by which this contributes to
filling is delayed. (From Arnold AC, Hepler RS. Fluorescein angiography ischemia has not been elucidated. The role of additional fac-
in acute anterior ischemic optic neuropathy. Am J Ophthalmol 1994;177: tors such as nocturnal hypotension and sleep apnea is un-
222–230.)
proven. Multiple risk factors for vasculopathy and coagulo-
pathy have been associated with NAION, but conclusive
large-scale epidemiologic studies have not been performed.
(ICG) studies of the choroidal flow, which show substantial No studies have documented features of the optic disc
slowing in AAION but not in NAION (130,131). These data vasculature in NAION in a systematic way. As noted above,
speak against a proximal vascular occlusion in the short pos- isolated histopathologic studies have commented on the lack
terior ciliary arteries, which would produce delay in both of inflammation within the visible vessels within the disc.
optic disc and choroidal filling, and against a choroidal ori- Emboli have rarely been documented. No studies of the short
gin, which would produce consistently delayed choroidal posterior ciliary vessels have been performed to assess for
filling. They are consistent with flow impairment at the level arteriosclerotic change or thrombosis.
of the paraoptic branches of the short posterior ciliary arter-
ies described by Olver et al. (126) and Onda et al. (127). VASOSPASM AND IMPAIRED AUTOREGULATION
The significance of the location of the optic disc within
the choroidal watershed zone between territories supplied by Whatever the cause for impaired blood flow in the optic
the posterior ciliary artery branches has been controversial nerve vasculature, persistent hypoperfusion may require im-
(110,132–136). Hayreh (135,136) reported its presence in a pairment in the normal autoregulatory mechanisms of the
substantial number of patients with NAION; he suggested optic nerve head. Flow is normally maintained constant with
that with impaired perfusion pressure within the distribution variations in perfusion pressure, intraocular pressure, and
of a posterior ciliary artery, such a disc is at risk for infarc- metabolic conditions (including tissue oxygen and CO2 lev-
tion. Arnold and Hepler (110), however, reported significant els) by factors that vary resistance to flow. Autonomic input
(more than 5 seconds) delayed filling of a vertical watershed to vessels and vasoactive substances (e.g., vasoconstrictor,
zone encompassing at least a quadrant of the optic disc in endothelins [ET], and vasodilator, nitric oxide) released in
42% of normal controls versus 27% of patients with NAION. response to metabolic influences or mechanical deformation
Filling of the optic disc located within these zones, either of vascular smooth muscle contribute to the regulation of
in normals or in NAION, did not correlate with adjacent blood flow in response to these external influences. These
choroidal filling, again consistent with a separate source of autoregulatory mechanisms may be reduced by arteriosclero-
flow to the optic disc (i.e., the paraoptic branches of the sis, vasospasm, or medications, including beta-blockers and
short posterior ciliary arteries). While impaired flow within other antihypertensive medications. Intravenous and intravi-
the posterior ciliary artery system might produce hypoperfu- treal infusions of ET-1 in rabbits have resulted in decreased
sion of the disc, the data suggest that distal flow impairment optic nerve head blood flow. Strenn et al. (139) showed a
within the paraoptic branches is the critical feature, rather decrease in blood flow measured by laser Doppler flowmetry
than disc location within a watershed zone. (LDF) after ET-1 administration, reversed by the calcium
Although carotid occlusive disease occasionally results in channel blocker nifedipine. Oku et al. (140) produced
optic nerve ischemia, most often in the setting of more gen- chronic optic disc ischemia in rabbits by repeated intravitreal
eral ocular ischemia and occasionally with associated cere- injections of ET-1.
bral ischemia, the vast majority of cases of NAION are unre- Hayreh (141,142) has postulated that endogenous seroto-
lated to carotid disease. Fry et al. (137) performed carotid nin, released with platelet aggregation stimulated at athero-
duplex scans in 15 patients with NAION, 11 with transient sclerotic plaque, may play a role in the development of is-
chemic optic nerve damage via its role in vasoconstriction

of arterioles and resultant impaired autoregulation, possibly
mediated by endothelial-derived vasoactive agents, includ-
ing endothelins. He has reported serotonin-induced vasocon-
striction in the central retinal artery and posterior cerebral
arteries in atherosclerotic monkeys, reversed by discontinu-
ing the atherogenic diet (141).
DISC STRUCTURE
The optic discs in patients with NAION are typically small

in diameter, with small or absent cups, suggesting that
‘‘crowding’’ plays a role in pathogenesis, although the pre-
cise mechanism remains unclear (113–117). The discs in
AAION are usually normal in diameter and cup size (113);
more severe vasculopathy in GCA probably is responsible
for the development of ischemia without the contribution of Figure 7.19. Cavernous degeneration in infarct of the optic nerve in
disc crowding. Possible contributory mechanical effects of NAION. Note the distortion of the adjacent axons. (From Knox DL, Kerri-
structural crowding in NAION include: son JB, Green WR. Histopathologic studies of ischemic optic neuropathy.
Trans Am Ophth Soc 2000;98⬊203–222.)
1. Chronic mechanical obstruction to axoplasmic flow, with
resultant intracellular axonal swelling, particularly at the
most crowded region, the cribriform plate
regulatory mechanisms are impaired (103,143). This effect
2. Secondary compression and further microcirculatory
might be worsened with aggressive antihypertensive ther-
compromise in the laminar region due to additional axo-
apy, particularly if administered at night, by exacerbating
plasmic stasis from subclinical ischemia created by basic
the nocturnal pressure drop. Hayreh et al. (103) performed
vasculopathy
24-hour ambulatory blood pressure monitoring in 52 sub-
3. Decreased return of neurotrophins due to mechanical axo-
jects with NAION, compared with 19 cases of primary open
plasmic flow obstruction after ischemia, with resultant
angle glaucoma (POAG) and 65 cases of normal tension
additional ganglion cell death
glaucoma (NTG). Mean decreases in systolic and diastolic
4. Abnormally stiff (less compliant) cribriform plate in addi-
blood pressure of 25.3% and 31.2%, respectively, were noted
tion to small size, and exaggerating factors 1–3
in NAION. As no controls were monitored, it remains un-
clear whether this represents an exaggerated nocturnal drop
The structure of the optic disc as a relatively inflexible
in pressure. In general, no significant differences in pressure
region encompassing the axons of the optic nerve has been
decrease were observed among NAION, NTG, and POAG;
implicated in two histopathologic studies. Tesser et al. (124)
however, the 31.2% diastolic decrease in NAION was signif-
reported that the infarct documented in their case did not
icantly less (P ⳱ 0.004) than the 36.0% figure for NTG. In
follow a specific vascular territory, suggesting a compart-
patients with NAION with systemic hypertension on medi-
ment syndrome as a mechanism. Knox et al. (125) reviewed
cation, nighttime blood pressure figures were significantly
the histopathologic features in 193 eyes classified as having
lower in those with visual field deterioration (progressive
optic nerve ischemia (without clinical correlation) in the Eye
NAION, 25 of 42 patients). A subsequent report (143) from
Pathology Laboratory of the Wilmer Eye Institute and acces-
these authors included a total of 114 NAION, 131 NTG,
sioned from 1951–1998. Sixty-nine eyes (36%) demon-
and 30 POAG subjects, presumably incorporating the prior
strated cavernous degeneration within the laminar region.
study. From the total data, the authors implied that nocturnal
Those cases in which there was substantial compression of
systemic hypotension played a significant role in the devel-
the adjacent axons by the expanding mucopolysaccharide
opment of NAION in certain susceptible subjects.
cavern (Fig. 7.19) lend support to the compartment syn-
In contrast, Landau et al. (144) performed 24-hour ambu-
drome as a mechanism in at least a portion of NAION cases.
latory blood pressure monitoring in 24 subjects with NAION
NOCTURNAL HYPOTENSION
and 24 age-, disease-, and medication-matched controls.
Mean decreases of 11% systolic and 18% diastolic were
It is clear that acute severe systemic hypotension, particu- measured in NAION, compared with 13% and 18%, respec-
larly associated with anemia, can produce optic nerve is- tively, in controls, showing no significant difference. They
chemia (see below). Hayreh has proposed that less severe did, however, see mildly lower mean daytime pressures in
nocturnal systemic hypotension may play a role in the devel- NAION than controls, averaging 5–7 mm Hg; the largest
opment of NAION, stating that the relative hypotension that difference was noted in the morning, indicating a slower
normally occurs with sleep may chronically compromise morning rise in pressure in NAION subjects when compared
optic disc circulation, particularly in patients with an exag- with normal controls. The conflicting data from these two
gerated nocturnal ‘‘dip’’ or in patients, such as those with groups leave the role of nocturnal hypotension in NAION
systemic hypertension, in whom optic disc circulation auto- unresolved (145,146). We do, however, discuss with our
patients and their physicians the possible accentuation of of such lesions, which are believed to represent focal peri-
nocturnal hypotension by nighttime use of antihypertension vascular ischemic demyelination and gliosis (153,154). Jay
medications; consideration of dosing other than at bedtime and Williamson (155) found no such association in 9 patients
is recommended. with NAION compared with 11 controls, but Arnold et al.
(156) reported a significant increased number of lesions in
SLEEP APNEA SYNDROME 13 NAION patients compared with 16 controls. Both studies
suffered from small sample size and questionable statistical
The sleep apnea syndrome (SAS) has been associated in
analyses, and no firm conclusions regarding this possible
some cases with optic disc edema, presumably the result of
association can be drawn.
occult elevations in intracranial pressure. Occasional optic
Recent studies have addressed additional vasculopathic
nerve damage was documented, but whether it resulted from
risk factors. Jacobson et al. (157) performed a case-control
chronic papilledema, the hypoxemia of SAS, or both was
study in NAION, addressing hypertension and diabetes
unclear. In 1998, Mojon et al. (147) reported seven patients
along with smoking and hypercholesterolemia in 51 patients
with SAS evaluated for visual field loss, finding four with
compared with two separate control groups. While hyperten-
arcuate defects; all patients had normal optic disc appear-
sion was found in 57% of patients, it was not found to be
ance. In 2002, these authors compared 17 consecutively seen
significantly more prevalent than controls in any age group;
NAION patients to 17 age- and sex-matched controls for
however, diabetes, found in 34%, was a significant risk fac-
evidence of SAS (148). Diagnostic criteria for SAS were
tor in all age groups. Neither hypercholesterolemia nor
met in 71% of the NAION patients versus 18% of controls.
smoking demonstrated significant risk. The 61-patient case-
Additionally, elevation of C-reactive protein, increasingly
control study of Salomon et al. (158) also confirmed diabetes
implicated as a predictor for cardiovascular disease, has been
but not hypertension as a risk factor; hypercholesterolemia
associated with SAS. Shamsuzzaman et al. (149) suggested
was found to be significant, while smoking was not. Two
that the chronic hypoxia occurring with repeated apneic epi-
other case-control studies of risk factors (159,160) have ad-
sodes stimulates C-reactive protein. These studies are pre-
dressed the issues of hyperlipidemia and smoking; hypercho-
liminary and involve small patient numbers, with insufficient
lesterolemia was a significant risk in both, while hypertri-
data from which to draw conclusions.
glyceridemia and smoking were linked in a limited number
VASCULOPATHIC AND COAGULOPATHIC RISK FACTORS
studied. A large-scale (137 cases) but uncontrolled study by
Chung et al. (161) concluded that smoking was a significant
NAION has been reported in association with many condi- risk factor on the basis that smokers developed NAION at
tions that may predispose to decreased optic nerve head per- a significantly younger age than nonsmokers. Deramo et al.
fusion via microvascular occlusion. Several cross-sectional (162) recently reported a series of 37 patients with NAION
case series have estimated the prevalence of systemic dis- presenting before the age of 50, in which mean serum choles-
eases that might predispose to vasculopathy in patients with terol level was significantly elevated when compared with
NAION (1,21,22,53,102,150–152). Systemic hypertension age- and gender-matched controls (235.4 versus 204.0 mg/
was documented in 34–49.4% of patients (47% in the dL).
IONDT) (53); however, in several of the studies that com- Elevated plasma homocysteine levels have been associ-
pared these figures to matched population data from the Na- ated with an increased risk of premature ischemic events
tional Health Survey, statistical significance was reached (peripheral vascular disease, stroke, myocardial infarction)
only in the younger age group, 45–64 years (1,22). Hayreh in patients younger than 50. The prevalence of hyperhomo-
et al. (102), in contrast, found a significantly increased prev- cysteinemia in the general population is estimated at 5%, a
alence in all age groups. Diabetes was reported in 5–25.3% figure that increases to 20–30% in nondiabetic stroke or
(24% in the IONDT) (53), with statistically significant in- myocardial infarction patients younger than 55. The mecha-
creased prevalence in all ages in all but one study. Diabetes nism of vasculopathy related to hyperhomocysteinemia
was associated with the development of NAION at a younger is unclear. While some severe cases are related to an in-
age in most series as well. In these series, the association of herited deficiency of methylenetetrahydrofolate reductase
NAION with other cardiovascular events such as stroke and (MTHFR), resulting in decreased conversion of homocyste-
myocardial infarction was inconsistent. While the incidence ine to methionine, in others, poor intake or absorption of
of prior or subsequent cerebrovascular or cardiovascular common vitamins B6, B12, and folic acid may impair the
events was not increased in the reports of Boghen and Glaser breakdown of homocysteine.
(21) or Repka et al. (22), Guyer et al. (1) found both events Reports have linked central retinal artery and vein occlu-
were more common than in the normal population, and in sion in younger patients to elevated blood levels of homocys-
the studies of Hayreh et al. (102) and Sawle et al. (152), late teine, but the relation to NAION remains unclear. Kawasaki
cerebrovascular disease was increased. et al. (163) reported hyperhomocysteinemia in 2/17 cases of
Some investigators have identified an association between NAION under age 50, while Biousse et al. (164) reported
subcortical and periventricular white matter lesions observed normal values in 14/14 patients with a mean age of 43 years.
with magnetic resonance (MR) imaging (as a marker for Pianka et al. (165) reported elevated levels in 45% of 40
small vessel cerebrovascular disease) and NAION. Patients NAION patients (mean age 66 years) versus 9.8% of con-
with hypertension, diabetes mellitus, cardiovascular disease, trols, and Weger et al. (166) also reported mean elevation
and cerebrovascular disease have an increased prevalence (11.8 versus 9.8 ␮mol/L) in 59 NAION patients versus con-
trols. The clinical significance of these statistically signifi- ence in IOP between 45 NAION patients and 45 controls.
cant findings is uncertain, limited by small patient numbers Hayreh et al. (143) performed IOP diurnal curves on patients
and widely varying results (0/14 in Biousse et al. [164] to with open angle glaucoma, normal tension glaucoma, and
45% in Pianka et al. [165]). NAION and found no IOP elevation in the NAION patients
Isolated reports have documented prothrombotic risk fac- compared with the other two groups. Chung et al. (161)
tors in patients with NAION, but a larger-scale recent study found a mean IOP of 16.2 mm Hg in 137 patients with
by Salomon et al. (158) has not confirmed an association. NAION, a value no higher than that expected in the general
They evaluated risk factors for thrombosis, including lupus population; only 11 (8%) patients had a documented IOP
anticoagulants, anticardiolipin antibodies, prothrombotic above 21 mm Hg. The role of chronically elevated IOP in
polymorphisms (factor V Leiden), and deficiencies of pro- the pathogenesis of NAION hence remains unclear.
tein C and S and antithrombin III in a series of 61 patients The role of acute elevation of IOP has also been consid-
with NAION versus 90 controls. No correlation with any of ered. Slavin and Margulis (180) described a case of NAION
these factors was detected. Similarly, Salomon et al. (167) 2.5 weeks following angle closure attacks in each eye. Ar-
found no association of angiotensin-converting enzyme and nold et al. (181) reported a case of NAION 1 week following
angiotensin II type 1 receptor polymorphisms with NAION. ocular pneumoplethysmography, in which IOP is transiently
Salomon et al. (168) recently compared 92 consecutive pa- elevated to levels near 130 mm Hg. Lee et al. (182) reported
tients with NAION to 145 controls for evidence of platelet four cases of optic neuropathy associated with laser in situ
glycoprotein polymorphisms. They found a statistically sig- keratomileusis (LASIK), in which IOP may be elevated up
nificant association with the VNTR B allele in NAION ver- to 230 mm Hg during the vacuum phase. Two showed optic
sus controls; second eye involvement was more frequent and disc edema and two did not; all noted visual loss within
earlier in onset in those with the polymorphism. These data hours to 3 days after the procedure and developed subsequent
suggest that previously undetected prothrombotic conditions optic atrophy without visual recovery. The patients were
may be linked to the development of NAION; further investi- presumed to have suffered ischemic optic neuropathy. Cam-
gation is required to definitively establish these and other eron et al. (183) described a patient who developed bilateral
associations. optic neuropathy after LASIK, although the clinical features
may have represented a glaucomatous process. These cases
OTHER ASSOCIATIONS are few in number, particularly in view of the large volume
of LASIK procedures performed, and a definite causal asso-
NAION has been associated infrequently with a multitude ciation has not been established.
of additional factors and disorders that may be causative, Two patients described by Gartner (184) developed an
either due to optic disc structure or other features that might anterior optic neuropathy within 2 weeks of cataract surgery.
affect optic disc perfusion pressure. These include hyper- Hayreh (185) described 11 patients who developed anterior
opia, optic disc drusen, elevated intraocular pressure, cata- optic neuropathy within 1–3 weeks after uncomplicated cat-
ract surgery, migraine, embolism, and medications. aract extraction. Hayreh suggested that the condition may
NAION in patients with optic disc drusen has been de- occur from a rise in IOP in the immediate postoperative
scribed in anecdotal reports (169–173). Purvin et al. (174) period, but this concept was challenged by Serrano et al.
recently reviewed the clinical presentation in 24 eyes of 20 (186), who reported several cases in which there was no
patients with NAION occurring in the presence of optic disc evidence of increased IOP during or after surgery. A case
drusen. No unusual features were present aside from the of NAION developing after secondary intraocular lens im-
substantially lower age group involved (mean 49.4 years, plant has also been reported (187). McCulley et al. (188)
range 18–69). Vasculopathic risk factors were present in reviewed 5,787 cases of cataract extraction over a 5-year
50%. While it is reasonable to attribute early development period, finding 3 cases of NAION occurring within 1 year
of NAION in this patient group to an exaggerated contribu- of the procedure (29, 36, and 117 days), an estimated 6-
tion of optic disc ‘‘crowding’’ due to the drusen, it remains month incidence of 51.8/100,000, significantly higher than
unclear as to why it remains a relatively rare occurrence. the reported overall incidence. Two of the three patients had
Some investigators have reported an association of ele- prior NAION in the fellow eye, and as did Hayreh, the au-
vated intraocular pressure (IOP) and glaucoma with NAION thors suggested that there may be an increased risk for
(175–178). Tomsak and Remler (176) described five pa- NAION after cataract surgery in the second eye. The associa-
tients with ‘‘discs at risk’’ who had mild elevations of IOP tion of NAION and cataract extraction was supported by a
at the time they developed NAION. Katz et al. (177) deter- subsequent study by McCulley et al. (189), in which the
mined that the mean peak diurnal IOP was greater in a group temporal association of 18 cases of NAION occurring within
of 16 NAION patients compared with 15 controls. These 1 year following cataract surgery was compared with a uni-
authors suggested that since perfusion pressure in the optic form distribution; the finding that all 18 cases occurred
nerve is a balance between systemic blood pressure and IOP, within 6 months after surgery was statistically significant
a transient rise in IOP could result in ischemia to the optic for an association.
nerve head from a fall in perfusion pressure below some NAION occurs in patients with migraine and, as in those
critical level. with optic disc drusen, tends to develop at an earlier age.
More recent and larger-scale investigations have not con- No systematic study has been performed, but reported pa-
firmed this association. Kalenak et al. (179) found no differ- tients were predominantly below age 50 at onset, many in
their 20s (190–193). Visual loss occurred during or immedi- mic agent and has been associated with the development of
ately following an episode of cephalgia. The mechanism of optic neuropathy (207–213). Macaluso et al. (214) summa-
vasculopathy has been postulated to be vasospasm. Katz and rized the data from 73 patients, including 16 published case
Bamford (192) and Kupersmith et al. (194) suggested that reports and 57 patients with information recorded in the Na-
beta-blocking agents may potentiate this vasospastic effect tional Registry of Drug-Induced Ocular Side Effects, with
in patients with complicated migraine, recommending avoid- optic neuropathy associated with amiodarone use. They em-
ance of this class of drugs in this patient group. phasized that these patients with significant cardiovascular
Embolism to the optic disc blood supply is felt to contrib- disease have risk factors for NAION and that many cases
ute only rarely to the development of NAION. As the micro- of optic neuropathy with amiodarone use may be typical
vasculature of this region is supplied by both the short poste- NAION unrelated to the drug. A syndrome more consistent
rior ciliary artery and choroidal systems and is not primarily with medication toxicity, including insidious bilateral onset,
an end-arterial circulation, as is the retinal vasculature, it generalized rather than altitudinal visual field loss, and
is likely that extensive embolization would be required for chronic optic disc edema persisting months after onset of
significant optic nerve damage. Confirmation of embolic visual loss, was suggested as more likely to represent the
NAION is dependent upon histopathologic study or evidence optic neuropathy related to amiodarone use. Limited visual
of simultaneous retinal embolization and NAION. A small recovery occurred in most cases after discontinuance of med-
number of case reports have confirmed its rare occurrence ication. Ultrastructural study of the optic nerves after amio-
(121,195–197). darone use has shown evidence of impaired axoplasmic
Two medications have been associated with the develop- flow, possibly responsible for chronic metabolic optic disc
ment of NAION (interferon-alpha and sildenafil), although dysfunction and swelling (215). Nagra et al. (216) reported
the number of cases is insufficient to confirm a definite caus- three cases in which optic disc edema persisted more than 4
ative effect. A third, amiodarone, has been linked to NAION months after discontinuing the medication, with slow, partial
but probably produces a toxic optic neuropathy that mimics recovery of visual field loss. The small number of cases
it. precludes definitive conclusions; it remains to be seen
Interferon-alpha is a glycoprotein with antiviral, antitu- whether, as in the case of certain antineoplastic agents such
mor, and antiangiogenic effects used as adjuvant therapy for as cisplatinum and BCNU, there may be a medication-in-
malignancies, including melanoma, leukemia, and lym- duced microvasculopathy—hence an amiodarone-induced
phoma, and for chronic hepatitis C. Ischemic retinopathy has NAION.
been described with its use (198). Several reports (199–203)
confirm the development of NAION, usually bilateral, se- CELLULAR MECHANISMS
quential, and temporally associated with the institution of
interferon therapy; recurrences with restarting the medica- Recent advances in the understanding of ischemic central
tion have also been described. The clinical course is variable, nervous system damage have raised new questions regarding
with some patients showing improvement with discontinu- the pathogenesis of neuronal damage in both the arteritic
ance of therapy. Possible pathogenetic mechanisms include and nonarteritic forms of AION (217). Neurotrophin depri-
interferon-induced systemic hypotension or immune com- vation in retinal ganglion cells after ischemic insult may play
plex deposition within the optic disc circulation. a significant role in cell death (218,219). Secondary neuronal
Sildenafil is a commonly used therapy for erectile dys- degeneration in cells adjacent to infarcted tissue may de-
function that may produce systemic hypotension; the thera- velop as a result of a toxic environment produced by the
peutic dose may reduce systemic blood pressure by at least dying cells (220). Such deterioration may be mediated by
10 mm Hg. Pomeranz et al. (204) reviewed the five cases processes including excitatory amino acid (especially gluta-
of NAION reported in association with the use of sildenafil mate) toxicity, bursts of reactive oxygen species (includ-
through 2002 (205,206). The patients ranged in age from ing lipid peroxidation), intracellular calcium influx, and
42–69, and four had no known vasculopathic risk factors. apoptosis (221–223). Experimental models of optic nerve
The optic discs in each case showed the typical ‘‘crowded’’ injury have been shown to be associated with elevated levels
configuration commonly seen in NAION; one patient had of glutamate in the overlying vitreous (224). Levin et al.
prior NAION in the fellow eye. The onset of visual loss (123) have shown evidence of apoptosis in the ganglion cells
was within 3 hours of medication use in three cases. The in a case of NAION. Thus, ischemia-induced cell death may
postulated mechanism in these cases has been systemic hy- result in release of glutamate, with further cell damage and
potension in patients with structurally predisposed optic death by excitotoxic induction of apoptosis. The specific role
discs, possibly complicated by an exaggerated nocturnal dip each of these mechanisms may play in the development and
in blood pressure. While the number of cases is extremely clinical course of AION, however, remains unproven.
small, particularly considering the widespread use of the A unique animal model for optic nerve ischemia, which
drug, the authors suggest that the drug may be contraindi- may provide a means to further study these aspects, has
cated in patients with prior NAION, and that this group of recently been developed in rodents. Bernstein et al. (225)
patients should be counseled regarding the risk of developing selectively thrombosed the surface microvascular supply of
NAION with further use. Additional data are required for the optic nerve, using a photoablative technique. After intra-
definitive recommendations in this regard. venous infusion of the photosensitizing agent rose bengal,
Amiodarone is in widespread use as a cardiac antiarrhyth- the optic nerve was exposed to a laser source, producing
photoactivation of the intravascular agent, with selective

damage of the endothelium by the superoxide radicals cre-
ated in the exposed region, with resultant thrombosis. Cellu-
lar responses, including alterations in ganglion cell histopa-
thology, retinal gene and protein expression, were studied
and are consistent with other models of ischemic neuronal
injury. While the mechanism of production of ischemic in-
jury in this model differs from typical NAION, it neverthe-
less provides insight into the cellular mechanisms involved
with ischemic damage to ganglion cells and may be instru-
mental in testing future hypotheses for neuroprotective ther-
apy in NAION.
Clinical Course
Untreated, NAION generally remains stable, most cases
showing no significant improvement or deterioration over Figure 7.20. Sectoral optic atrophy after NAION.
time (21,22,104,106–108,152,226,227). Even in the so-
called progressive form, further deterioration after reaching
the low point of visual function within 1–2 months is rare dian follow-up of 5 years was 14.7%. A history of diabetes
(21,228–230). Recent studies, however, indicate that sponta- and baseline visual acuity of 20/200 or worse in the study
neous improvement of visual acuity is not unusual. Recov- eye, but not age, sex, aspirin use, or smoking were signifi-
ery of at least 3 Snellen acuity lines has been reported in cantly associated with new NAION in the fellow eye.
13% (152) to 42.7% (in the IONDT [231]) of patients Comparisons of the degree of optic nerve dysfunction and
(104,106,107,152), including up to 30.3% of those consid- visual loss between the two involved eyes in bilateral cases
ered progressive (107,229,232). Visual acuity at 6 months have been inconclusive. Boone et al. (233) found similar
was 20/200 or worse in 52% of the randomized (initial visual degrees of loss, while WuDunn et al. (237) did not. The
acuity 20/64 or worse) patients in the IONDT (231). Other IONDT found second-eye visual acuity within three lines of
studies, which include patients with better initial acuity, have the first in approximately half of patients (239). Final fellow-
reported 31–41% of patients with final visual acuity 20/200 eye visual acuity was significantly worse in those patients
or worse and 21–53% of patients having vision 20/200 or with new fellow-eye NAION whose baseline study eye vi-
better (21,22,106,108,109,233). Limited quantitative visual sual acuity was 20/200 or worse.
field studies regarding the natural history of NAION are Occurrence in the second eye produces the clinical appear-
available. Arnold and Hepler (106) confirmed a 24% rate of ance of the ‘‘pseudo-Foster Kennedy syndrome,’’ in which
improvement in mean sensitivity by at least 2 dB; perimetric the previously affected disc is atrophic and the currently
data from the IONDT are under analysis. involved nerve head is edematous (Fig. 7.22). Significantly
After stabilization of vision, usually within 2 months, re- impaired visual function in the eye with disc edema distin-
current or progressive visual loss in an affected eye is ex- guishes this condition from the true Foster Kennedy syn-
tremely unusual and should prompt evaluation for another drome, in which disc edema is due to elevated intracranial
cause of optic neuropathy. Repka et al. (22) reported recur- pressure and therefore does not produce visual loss acutely
rent episodes in only 3 of 83 (3.6%) patients. Hayreh (234) in the edematous eye.
reviewed 829 eyes in 594 consecutive patients with NAION
for evidence of recurrent events in the same eye occurring Differential Diagnosis
at least 2 months after initial onset. Recurrence was docu-
mented in only 53 eyes (6.4%). A syndrome of recurrent NAION must be differentiated from idiopathic optic neu-
episodes in young patients, often below age 35, has been ritis, syphilitic or sarcoid-related optic nerve inflammation,
described by several authors (232,235,236). In the study by particularly in patients under 50 years of age; infiltrative
Hayreh et al. (234), however, the greatest number of patients optic neuropathies, anterior orbital lesions producing optic
with recurrence were 45–64 years of age. nerve compression; and idiopathic forms of optic disc
The optic disc becomes visibly atrophic, either in a sec- edema, including diabetic papillopathy. Optic neuritis may
toral (Fig. 7.20) or diffuse pattern (Fig. 7.21), usually within resemble ischemia with regard to rate of onset, pattern of
4–6 weeks. Persistence of edema past this point should visual field loss, and optic disc appearance; however, in most
prompt consideration of an alternate diagnosis. Eventual in- cases, the patient’s younger age, pain with eye movement,
volvement of the contralateral eye has been reported in 24% and character of the disc edema (diffuse and hyperemic with-
(24) to 39% (237), with varying follow-up (22,42,233). Beck out hemorrhages, rather than pale or segmental) make dis-
et al. (238), however, systematically reviewed 431 patients tinction clear. Occasionally, ancillary testing such as fluores-
with NAION, finding a substantially lower 5-year risk of cein angiography, ultrasonography, or MR imaging of the
12–19%. Similarly, in the IONDT (239), the only large study optic nerve may be helpful in differentiation. Fluorescein
with prospective follow-up, fellow-eye involvement at a me- angiography often shows delayed optic disc filling in optic
Figure 7.21. Resolution of anterior ischemic optic neuropathy. A, In the

acute phase of visual loss, the left optic disc is hyperemic and swollen.
B, Two weeks after the onset of visual loss, the temporal portion of the
disc has become pale. The nasal disc is still slightly swollen, and there are
a few small, nerve fiber layer hemorrhages. Note the apparent narrowing of
retinal arteries and arterioles. C, Two months after visual loss, the disc is
generally pale, with loss of the nerve fiber layer and apparent narrowing
of retinal arteries and arterioles.
disc ischemia, whereas filling is normal in papillitis (240). Diagnostic Testing

Ultrasonography and MR imaging are typically normal in
In patients with a typical presentation of NAION, without
NAION. Intraorbital optic nerve swelling and enhancement
symptoms or signs to suggest GCA, and with normal ESR
are frequently seen on MR with inflammation and infiltra-
tion. Increased optic nerve diameter and a positive 30-degree and C-reactive protein levels, we do not routinely perform
test for perineural fluid may be seen on ultrasound in optic additional testing. Evaluation by a primary care physician
nerve inflammation. Optic nerve inflammation associated for evidence and control of risk factors such as hypertension,
with syphilis or sarcoidosis often is associated with other diabetes, and hyperlipidemia is essential. Neuroimaging is
intraocular inflammatory signs, which should prompt further not performed unless the patient presents with substantial
testing. Orbital lesions producing disc edema usually are pain or follows an atypical course, such as prolonged optic
associated with gradually progressive visual loss, but occa- disc edema or continued progressive or recurrent visual loss
sionally onset is more rapid. The detection of subtle signs more than 2 months after initial presentation. The value of
of orbital disease, including mild proptosis, lid or eye move- additional testing for vasculopathic and prothrombotic risk
ment abnormalities, or the persistence of optic disc edema factors remains unclear. Carotid studies are not routinely
past the usual 4–6 weeks in NAION, may indicate the need performed unless prominent pain or other signs of orbital
to perform neuroimaging to detect orbital inflammation or ischemia are present (see above). For NAION in the typical
tumor (such as optic nerve sheath meningioma). In the great age group, we do not routinely assess homocysteine levels,
majority of cases, however, such testing is not required. but in patients under 50, we proceed with this testing since
Diabetic papillopathy typically does not produce a signifi- elevated levels are amenable to therapy. We do not test for
cant afferent pupillary defect or visual field loss (discussed prothrombotic risk factors unless there is other evidence of
later). personal or familial thrombosis, and we do not screen for
Figure 7.22. Pseudo-Foster Kennedy syndrome in a patient with bilateral, nonsimultaneous AION. A, The right optic disc
is pale, and the arteries are narrowed. B, The right visual field shows a relative, superior altitudinal defect with a central
scotoma. C, The left optic disc is hyperemic and swollen with numerous superficial retinal hemorrhages and several soft
exudates. D, The left visual field shows a complete, inferior arcuate defect. The patient gave a history of sudden visual loss
in the right eye followed 3 months later by sudden visual loss in the left eye. Visual acuity was 20/400 in the right eye and
20/50 in the left eye.
vasculitides other than GCA unless there is clinical evidence Therapy

for them. In patients with substantial hyperhomocysteine- There is no proven effective therapy for NAION. Early
mia, we recommend vitamin supplementation (B6, B12, medical therapies attempted included anticoagulants
folic acid) and continued monitoring for evidence of sys- (242,243), diphenylhydantoin for its effect in improving
temic vasculopathy by an internist, although the value of conduction in hypoxic neurons (244–246), sub-Tenon injec-
lowering homocysteine levels for reduction of vascular tions of vasodilators (243,247–249), intravenous IOP-lower-
events is unproven. A large-scale international study (Vita- ing agents and vasopressor agents (norepinephrine) to im-
mins to Prevent Stroke [VITATOPS] [241]) is in progress prove the gradient of nerve head perfusion pressure to IOP
to evaluate the effect of such multivitamin therapy in reduc- (250,251), thrombolytic agents and stellate ganglion block
ing the risk of stroke and other serious vascular events in (252), oral corticosteroids in an attempt to decrease neuronal
hyperhomocysteinemic patients at risk. edema and any secondary damage related to it (38–40,
145,108,249), aspirin (253), and heparin-induced low- experimental nature of this procedure and recommended a
density lipoprotein/fibrinogen precipitation or hemodilution randomized clinical trial prior to considering this approach.
(254). None has been proved effective. Advances in the understanding of cellular mechanisms
More recently applied nonsurgical modalities include hy- of retinal ganglion cell and optic nerve axonal damage in
perbaric oxygen and levodopa/carbidopa. Arnold et al. (255) ischemic injury may point to new directions in therapy (267).
treated 22 eyes in 20 patients with acute NAION using hy- Studies in traumatic optic neuropathy postulate an ischemic
perbaric oxygen at 2.0 atmospheres twice a day for 10 days, component, with secondary effects such as lipid peroxidation
comparing visual outcome to 27 untreated controls; no bene- resulting in excess free radical production and further tissue
ficial effect was found. Johnson et al. (256) reported 18 pa- damage (220–223,268). Very high doses of intravenous
tients with NAION treated with a 3-week course of levo- methylprednisolone have been shown to be beneficial for
dopa/carbidopa within 45 days of visual loss, compared with acute spinal cord injury and may be beneficial in optic neu-
19 historical untreated controls. At 6 months, 10 of 13 ropathy as well, based on an antioxidant effect rather than
(76.9%) treated versus 3 of 10 (30%) controls improved at direct anti-inflammatory activity (269). The beneficial ef-
least 3 lines in Snellen visual acuity testing. The study was fects of neuroprotective agents in animal models of retinal
limited by small numbers and possible confounding factors, ganglion cell damage and optic neuropathy have recently
and results have not been corroborated by other investigators been reported (221,223). By intervening in such processes
(257–259). This therapeutic modality remains unproven. as excitatory amino acid toxicity, intracellular calcium ion
The IONDT studying optic nerve sheath decompression influx, reactive oxygen species bursts, and apoptosis (222),
surgery for NAION was based on the beneficial effect of these agents may have future applicability to the treatment
the surgery in the optic neuropathy of elevated intracranial of AION. A trial of megadose intravenous corticosteroids,
pressure (260–262) and the postulate that reduction of peri- at the level used in the NASCIS Trials (269) for presumed
neural subarachnoid cerebrospinal fluid pressure could im- oxygen free radical scavenging neuroprotective effect, has
prove local vascular flow or axoplasmic transport within the been considered.
optic nerve head, thus reducing tissue injury in reversibly Yoles et al. (223) reported a beneficial effect of the alpha-
damaged axons. Several earlier studies had suggested a bene- adrenergic agonist brimonidine in the rat crush model of
ficial effect in the progressive form of NAION optic neuropathy, with an effective time window of 24–48
(230,263,264). Recruitment for the IONDT was ceased after hours after injury. Kent et al. (270) studied the intravitreal
levels attained after topical administration of brimonidine,
2 years, with 119 treated and 125 untreated patients, when
finding adequate levels to activate peripapillary retinal gan-
data analysis revealed no significant benefit for treatment
glion cell adrenergic receptors. Based on this and other data,
(improvement in visual acuity by at least 3 lines was 32.6%
a national multicenter clinical trial of topical brimonidine
in treated patients versus 42.7% in untreated patients) (231).
for NAION administered during the 48 hours following
Moreover, the treatment group showed a statistically signifi-
acute visual loss (NPION Trial) was begun in 2000. Recruit-
cantly greater risk for worsening by 3 lines or more (23.9% ment difficulties with the required 48-hour time window to
among treated patients versus 12.4% in untreated patients) therapy prevented completion of the trial. A similar study
(231). By the criteria used in the trial for progressive with a 7-day window (BRAION Trial) was performed in
NAION, there was no beneficial effect in this subgroup. The Europe (271). Fazzone and Kupersmith (272) treated 14 pa-
24-month follow-up data from the study confirmed the initial tients with NAION, using topical brimonidine one drop two
6-month report (227). This technique is not currently recom- to four times/day, comparing visual outcome to 17 historical
mended for the treatment of NAION. controls. They found a trend to worse visual outcome with
Transvitreal optic neurotomy has been proposed as a ther- treatment at 8–12 weeks. The study was limited by small
apy for both central retinal vein occlusion (265) and NAION patient numbers, low doses, and delay to treatment but raised
(266). The procedure involves a pars plana vitrectomy and questions as to effectiveness of this mode of therapy. This
induced posterior vitreous detachment, associated with a stab prompted early termination of the BRAION trial.
incision at the nasal margin of the optic disc, with the pur-
pose of opening the scleral canal and relieving compression
Prevention
of an edematous optic nerve. If a compartment syndrome is
at least a component of the pathophysiology of NAION, then There is no proven prophylactic measure for NAION. Al-
such a procedure in theory could break the cycle of edema though aspirin has a proven effect in reducing stroke and
and vascular compression. Soheilian et al. (266) reported the myocardial infarction in patients at risk, published data re-
results of transvitreal neurotomy performed in seven cases of garding its role in decreasing the severity of optic neuropathy
NAION with severe visual loss (visual acuity range counting (253) and the incidence of fellow-eye involvement after the
fingers to 20/800) and onset prior to surgery ranging from initial episode have been controversial. Kupersmith et al.
15–90 days. Improvement of visual acuity was noted in six (273) retrospectively reviewed a series of 131 patients with
patients with a final range of counting fingers to 20/60. This NAION for the effect of aspirin use (65–1,300 mg more
study was limited by several factors, including small patient than twice a week) on the development of fellow-eye in-
numbers, sample bias (i.e., severe visual loss with difficulty volvement. They found an incidence of 17.5% in treated
accurately measuring pre- and postoperative visual levels), patients versus 53.5% in untreated patients, 68.8% of which
and delayed onset of therapy. The authors emphasized the occurred during the first year. Minimum follow-up was 2
years. In a similar retrospective study of 52 patients by Salo- experts recommend the use of aspirin after an initial episode,
mon et al. (274), fellow-eye involvement was detected in 8 if only for its role in decreasing risk for stroke and myocar-
of 16 (50%) untreated patients versus 3 of 8 (38%) patients dial infarction in this vasculopathic population group.
treated with an aspirin dosage of 100 mg/day and 5 of 28 The risk for subsequent stroke, myocardial infarction, and
(18%) treated with 325 mg/day. In contrast, a larger retro- death in patients with NAION has been incompletely stud-
spective review by Beck et al. (238) studied 431 patients ied. Early studies indicated no statistically significant in-
with NAION for second-eye involvement with and without crease in cerebrovascular events (21,22,150), but later stud-
aspirin use. The 5-year risk for fellow-eye involvement was ies by Guyer et al. (1), Sawle et al. (152), and Hayreh et al.
calculated at 12–19%, depending on the analysis method, (102) indicated an increased risk (only for patients with both
and no long-term benefit for aspirin use was found hypertension and diabetes in the series of Hayreh et al).
(238,275). The 5-year cumulative probability risk for fellow- Guyer et al. (1) and Sawle at al. (152) also reported an in-
eye NAION after the initial episode was 17% among treated crease in frequency of myocardial infarction in patients with
patients versus 20% among untreated patients. NAION, not confirmed by other studies. Sawle et al. (152)
In consideration of a national multicenter clinical trial of
reported increased mortality. These issues remain unclear,
aspirin for NAION prophylaxis, plans for the trial were aban-
requiring a large-scale population study for answers.
doned because the rate of second-eye involvement was too
low to make development of a controlled study practical. Based on the postulated role of crowding of optic nerve
Criticisms of the studies that show beneficial prophylactic head axons in the development of NAION, peripheral retinal
effects focus on the unusually high rates of untreated fellow- laser photocoagulation has been suggested in an attempt to
eye involvement of 50–53.5%, compared with the rates of ‘‘decompress’’ the nerve by producing a controlled degree
12–19% at 5 years found by Beck et al. and confirmed at of axonal dropout and optic atrophy (118,276). This action
14.7% in the follow-up phase of the IONDT (239). Aspirin theoretically could prevent or delay the occurrence of an
was not found to be beneficial in the IONDT, but the study acute ischemic event that would create more severe visual
design was not optimal for this evaluation. Although benefi- loss. No controlled studies of this technique have been per-
cial long-term effects remain unproven for NAION, many formed.
POSTERIOR ISCHEMIC OPTIC NEUROPATHY

Although the anterior form of ION is far more common 3. Related to surgery (coronary artery bypass and lumbar
than the posterior variety, ischemia of the retrobulbar por- spine procedures most frequently reported), or severe
tions of the optic nerve occurs in many settings, both arteritic bleeding, or hypotension (as seen in cases of gastrointesti-
and nonarteritic. Ischemia can independently affect the pos- nal hemorrhage or trauma; see below)
terior portion of the optic nerve because of the distinct and
separate arterial supplies of the anterior and posterior por- The differential diagnosis includes compressive and infil-
tions of the optic nerve. The anterior optic nerve is supplied trative optic neuropathies, although the onset in PION is
by the short posterior ciliary artery and choroidal circula- typically more abrupt. In most cases, neuroimaging is indi-
tions, while the retrobulbar optic nerve is supplied intraorbit- cated to rule out these possibilities. NAION typically shows
ally by a pial plexus arising from the ophthalmic artery, and no enhancement of the optic nerves on MR, presumably due
intracranially by branches of the ipsilateral internal carotid, to limitation to the optic nerve head. PION also typically
anterior cerebral, and anterior communicating arteries. shows no abnormalities of the optic nerve, except in cases
Posterior ischemic optic neuropathy (PION) is a syndrome of GCA PION in which enhancement has been demonstrated
of acute visual loss with characteristics of optic neuropathy and must be differentiated from other causes, such as inflam-
without initial disc edema and marked by the subsequent mation and infiltration (279,280).
development of optic atrophy. Occasionally, a small amount Recently, Sadda et al. (277) reported a multicenter, retro-
of disc edema appears within the first week or so after acute spective review covering 22 years, revealing 72 patients with
visual loss, presumably as a result of propagation of swelling PION, classifying them into the three groups: perioperative
forward along the course of the optic nerve from the point PION, arteritic PION, and nonarteritic PION. The nonarter-
of original ischemia. The diagnosis of PION is most often itic group accounted for 38 of the 72 patients, exhibited
made in one of the following settings (277): similar risk factors, and followed a clinical course precisely
1. GCA (Fig. 7.23) (3,32,278) or rarely other vasculitides like that of NAION. In contrast to perioperative and arteritic
such as herpes zoster, polyarteritis nodosa, or lupus ery- PION, which were characterized by severe visual loss with
thematosus. Indeed, evaluation for GCA is essential in little or no recovery, nonarteritic PION was less severe and
cases without other apparent cause and should be the showed improvement in 34% of patients. It is important to
primary consideration with this presentation in the el- recognize this nonarteritic form in patients with acute optic
derly, with urgent ancillary testing as described earlier neuropathy but no optic disc edema, a scenario that may be
for AION (see above). mistaken for optic neuritis. Such patients, as in some patients
2. Nonarteritic PION in a population of patients with similar with AION and disc edema, particularly those with ischemic
demographics to those patients with NAION (277) white matter lesions on MR imaging, might be incorrectly
Figure 7.23. Pathology of PION in a patient with GCA. A, The right ophthalmic artery near its origin from the internal
carotid artery shows intimal thickening with narrowing of the lumen. Numerous chronic inflammatory cells, including giant
cells, surround the artery and infiltrate its wall. B, A short posterior ciliary artery is occluded by a marked granulomatous
inflammation. Note numerous multinucleated giant cells. Many short posterior ciliary arteries in both orbits were occluded or
narrowed by granulomatous inflammation. C, Longitudinal section through the proximal portion of the right optic nerve shows
a well-defined zone of ischemic necrosis (N) immediately behind the lamina cribrosa (L). D, Cross-section through the ischemic
zone shows complete destruction of the nerve fiber and glial elements with preservation of the fibrovascular pial septae. (From
Spencer WH, Hoyt WF. A fatal case of giant cell arteritis (temporal or cranial arteritis) with ocular involvement. Arch Ophthalmol
1960;64⬊862–867.)
started on immunomodulatory therapy to reduce the risk of its occurrence in older age groups and its lack of pain on
multiple sclerosis (281). PION differs from optic neuritis by eye movements.
ISCHEMIC OPTIC NEUROPATHY IN SETTINGS OF HEMODYNAMIC COMPROMISE

Systemic hypotension, blood loss, and anemia may pro- (284) has postulated that delayed visual loss is caused by
duce optic nerve ischemia (36,282–285). The most com- vasoconstriction in the ciliary artery system secondary to
monly reported causes of blood loss associated with ION activation of the renin-angiotensin pathway as a late re-
are (a) spontaneous gastrointestinal or uterine bleeding and sponse to blood loss.
(b) surgically induced hemorrhage, related most frequently
to cardiac bypass or lumbar spine procedures. Less often, SPONTANEOUS OR TRAUMATIC HEMORRHAGE
hypotensive episodes in the setting of chronic anemia with-
out blood loss (as in chronic hemodialysis) may result in Patients in whom visual loss occurs after spontaneous
ION. hemorrhage are usually 40–60 years old and debilitated.
The optic neuropathy that occurs in these settings is typi- Most of these patients have experienced repeated episodes
cally bilateral, although unilateral cases occur. Visual loss of bleeding, but cases following a single episode of massive
is often severe. AION (with optic disc edema) accounts for hemorrhage with secondary hypotension have been reported
the majority of cases (286), although PION is not infrequent. (285). The visual loss is usually bilateral, but it may affect
Visual loss may occur immediately after the episode or may both eyes asymmetrically or be unilateral (282–285). The
be delayed as much as 2–3 weeks in cases of AION. Hayreh severity of visual loss ranges from mild or transient blurred
vision in one eye to irreversible total blindness in both eyes patients had hemoglobin counts less than 8.0 g/dL over pe-
(285). Both AION and PION have been reported in this riods of time ranging from 30 minutes to 72 hours, and all
setting, although AION is more common (284,285). experienced episodes of decreased mean blood pressure
About 50% of patients who experience ION after an acute ranging from 24–46% of preoperative levels over 15- to
spontaneous hemorrhage experience some recovery of vi- 120-minute periods. Based on these cases, the authors con-
sion, but only 10–15% recover completely (282–287). The cluded that although severe anemia alone may not cause
source of bleeding seems to be irrelevant, although the most ION, even a short episode of hypotension in an already ane-
frequent sites are the gastrointestinal tract in men and the mic patient may predispose to ION-induced vision loss.
uterus in women. Presencia et al. (288) reported that in most Brown et al. (304) and Lee (298) emphasized that the
documented cases of bilateral blindness related to systemic acquired immunodeficiency syndrome (AIDS) epidemic has
blood loss, the hemoglobin measures less than 5.0 g/dL at resulted in the establishment of low absolute thresholds for
the time of visual loss. Other authors have reported higher blood transfusion in the perioperative period. These authors
hemoglobin levels and emphasize the importance of both point out that patients who are not transfused until their he-
anemia and hypotension in the pathogenesis of optic nerve moglobin reaches very low levels may be at risk for develop-
infarction (285). Hayreh (284) speculated that blood loss ing both AION and PION related to a combination of anemia
alone, with or without arterial hypotension, can cause an and hypotension intraoperatively or during the immediate
increase in the release of endogenous vasoconstrictor agents postoperative period.
that can lead to direct vasoconstriction and occlusion of optic Nuttall et al. (305) assessed risk factors for ION after
nerve head capillaries, resulting in AION. cardiopulmonary bypass, identifying 17 cases in 27,915 sur-
gical procedures (0.06%). Involvement was bilateral in 53%,
PERIOPERATIVE anterior in 71%. The presence of atherosclerotic vascular
disease and a minimum postoperative hemoglobin were sig-
ION occurs in the setting of various surgical interventions, nificantly associated with postoperative ION, although not
most commonly cardiopulmonary bypass (176,289–297), uniformly present. Minimum hemoglobin of 8.5 g/dL was
and lumbar spine surgery (286,298–,303). Other cases in- present in 76.5% of ION patients versus 41.2% of controls.
clude abdominal procedures (282–284,287,288), hip inci- Lumbar spine surgery may carry an increased risk for
sion and drainage (295), cholecystectomy (282), and para- postoperative ION, usually PION, compared with other sur-
thyroidectomy (291). geries. In 1997, Myers et al. (301) reviewed 37 cases of
In 1994, Katz et al. (286) reviewed the literature to date visual loss following spinal surgery, finding 8 with AION
on perioperative ION and found 30 well-documented cases, and 14 with PION. Average operative time was 410 minutes,
most of which were of the anterior variety. Most cases oc- with blood loss of 3,500 mL and a mean drop in systolic
curred after coronary bypass surgery, but several occurred blood pressure from 130 to 77 mm Hg; none of these figures
after back surgery in which there was no evidence of orbital differed significantly from a matched group of operated pa-
or ocular compression. All were associated with hypoten- tients without visual loss. Of the 28 patients with postopera-
sion, anemia, or both, although control values corresponding tive PION in Sadda et al.’s (277) series, 14 (50%) followed
to similar procedures in patients who did not suffer ION were spinal surgery. Dunker et al. (306) examined seven cases of
not provided. Among the four patients whose hemogram was postoperative PION, five of which followed lumbar spine
reported, the mean hemoglobin level decreased from 14.3 surgery. Contributing factors were thought to include pro-
to 8.3 g/dL (a 42% decrease) in the perioperative period. longed intraoperative hypotension (diastolic range 40–60
The distinguishing feature of the reviewed cases of ION mm Hg), blood loss (1.2–16 L) with anemia and hypovo-
associated with back surgery was the deliberate reduction lemia, and prolonged prone, face-dependent positioning with
of intraoperative blood pressure to reduce bleeding. All but subsequent orbitofacial vascular congestion and edema.
two of the patients were over 40 years of age, and most had It is important to distinguish visual loss from postopera-
typical vascular risk factors for ION, including hypertension, tive ION with associated facial edema from the prolonged
coronary artery disease, diabetes mellitus, and a history of prone position from those cases of visual loss secondary to
smoking. In 18 of 30 cases, both eyes were affected. Visual direct compression of the eye from malpositioning. In the
acuities were worse than 20/100 in over 50%, and substantial latter cases (307–309), which have been termed the ‘‘head-
recovery of vision was unusual. Optic disc swelling was rest syndrome,’’ direct compression results in orbital is-
present at the time of initial visual loss in most cases, but chemia, with severe orbital congestion, ecchymoses, and
it was delayed in appearance by several days in others. In most often central retinal artery occlusion.
most cases, the optic nerve was the only site of infarction by The purposeful maintenance of relative systemic hypoten-
both clinical and imaging criteria, underscoring the apparent sion to control intraoperative hemorrhage and the prolonged
selective vulnerability of the optic nerve in this setting. prone position may be significant features in the develop-
Brown et al. (304) reported on six patients who developed ment of some cases of perioperative ION, although it re-
ION in the postoperative period as a result of anemia and mains a rare occurrence in a common surgical procedure.
hypotension, three of whom had AION. The condition was Lee (310) summarized the multiple possible contributing
bilateral in two of the AION patients and unilateral in one. features and the complex nature of adjusting operative proce-
All of the AION patients had features consistent with the dures to prevent ION. While aggressive fluid replacement
‘‘disc at risk’’ seen in cases of typical NAION. All three and transfusion of blood products seem appropriate in cases
where deficiencies are detected, there are no controlled stud- found 4 cases of AION in a series of 60 patients undergoing
ies of these interventions, and no therapy has been proven dialysis over a 2-year follow-up. The hypotension may be
to significantly improve visual outcome in perioperative acute, temporally associated with the dialysis procedure, or
ION. To help understand the multiple and likely complicated it may be chronic. Most patients also are chronically anemic.
interacting factors underlying perioperative ION, the Ameri- The accelerated diffuse vasculopathy that occurs in this dis-
can Society of Anesthesiologists (ASA) established the in- ease may predispose to the development of ION, as may
ternational ASA Postoperative Visual Loss (POVL) Registry previous chronic hypertension, with possible arteriosclerosis
in 1999 with the goal of acquiring a large database with and impaired autoregulation of the optic disc vascular
detailed information on patient characteristics and periopera- supply.
tive conditions (311–313). Preliminary results confirm that The term ‘‘uremic optic neuropathy’’ has been applied to
at least two thirds of cases are associated with spine surgery cases of acute optic nerve dysfunction and disc edema in
and that ION can occur even with the head suspended in patients with renal failure. Knox et al. (315) reported sub-
Mayfield tongs with no external compression of the eyes stantial visual improvement in five of six patients who under-
and face. Indeed, perioperative ION can occur in young pa- went immediate dialysis and corticosteroid therapy, postulat-
tients, with relatively short prone durations, with little blood ing that correction of the uremia reversed a metabolic optic
loss, a normal hematocrit, and without hypotension. Clearly neuropathy. Saini et al. (316) reported a similar case of im-
there is more we need to learn regarding the cause of this provement on dialysis. However, Hamed et al. (317) re-
potentially devastating disorder. ported three cases of optic neuropathy in patients with ure-
mia, two of which did not improve on dialysis; one of these
HYPOTENSION was severely hypertensive with elevated intracranial pres-
ION related to hypotension most often presents in patients sure, and the other showed more typical features of AION.
with chronic renal failure and dialysis. Haider et al. (314) The third patient was presumed to suffer desferrioxamine
Figure 7.24. Histopathologic appearance of the optic nerves in PION. A, Cross-section of the right optic nerve about 2 cm
posterior to the globe shows complete infarction. B, Cross-section of the right optic nerve about 3 cm posterior to the globe
shows only a few isolated infarcted nerve fiber bundles. C, Cross-section of the left optic nerve about 3 cm posterior to the
globe shows complete infarction. D, Cross-section of the left optic nerve about 3.5 cm posterior to the globe shows only a
few individual infarcted nerve fiber bundles. (From Johnson MW, Kincaid MC, Trobe JD. Bilateral retrobulbar optic nerve
infarctions after blood loss and hypotension. Ophthalmology 1987;94⬊1577–1584.)
toxicity and recovered vision after discontinuing the therapy. rotic risk factors is mild enough to spare the hemispheric
The authors stressed the heterogeneity of optic neuropathy watershed regions but severe enough to cause juxtalami-
in this patient group. Servilla et al. (318) reported a case of nar optic nerve infarction that produces a clinical (and
typical AION in a uremic patient, which occurred following pathologic) picture consistent with NAION.
an acute hypotensive episode (blood pressure 40/0 mm Hg) 3. Hypotension in an anemic patient without arteriosclerotic
during hemodialysis. Jackson et al. (319), Michaelson et al. risk factors predisposes the patient to PION that is caused
(320), and Basile et al. (321) also reported cases believed by infarction in the posterior orbital portion of the optic
secondary to hypotensive episodes. Connolly et al. (322) nerve (Fig. 7.24), where pial end vessels are subject to
described three patients with presumed AION in patients compression from hypoxic edema.
with chronic renal failure, hypotension, and anemia, aged
25, 26, and 39 years. Acute hypotension was a precipitating Although in theory this ischemia helps sort through the
factor in all cases; volume replacement was associated with various proposed pathogenetic mechanisms, there is great
improvement of vision, in one eye from no light perception overlap among cases of ION related to hemodynamic com-
to 20/40. The authors emphasized that visual loss from hypo- promise, with multiple potential factors, some yet to be eluci-
tension-induced ischemia in this setting may respond to rapid dated. Several cases of AION resulting from rapid correction
volume replacement and restoration of normotension. Fur- of malignant hypertension have been reported (322–325).
ther study is required to corroborate these findings. Two of the four children reported by Taylor et al. (325)
Johnson et al. (285) concluded that visual loss from hypo- experienced limited recovery of vision following the devel-
tension may be of three types: opment of AION during treatment of accelerated hyperten-
sion, but it is unclear whether this improvement was related
1. Sustained and profound hypotension in a nonanemic pa- to any specific therapy that the children received. The patho-
tient without arteriolar sclerosis causes watershed white genesis of AION that occurs in this setting is likely related
and gray matter infarction in parietal and occipital lobes. to impaired autoregulation of the nutrient vessels supplying
The optic nerves tend to be spared. the optic nerve head and to reduction in perfusion pressure,
2. Brief hypotension in an anemic patient with arterioscle- leading to ischemia.
RADIATION OPTIC NEUROPATHY

Radiation optic neuropathy (RON) is thought to be an eration prior to the development of any vascular changes
ischemic disorder of the optic nerve that usually results in (334). Pathologic specimens of optic nerves with RON show
irreversible severe visual loss months to years after radiation ischemic demyelination, reactive astrocytosis, endothelial
therapy to the brain and orbit. It is most often a retrobulbar hyperplasia, obliterative endarteritis, and fibrinoid necrosis
process. RON occurs most frequently after irradiation of (326,335–339).
paranasal sinus and other skull base malignancies, but it may Both the total dose of radiation given and the daily frac-
develop after radiation treatment for pituitary adenomas, par- tionation size are important factors in determining the risk
asellar meningiomas, craniopharyngiomas, frontal and tem- of delayed radiation necrosis in the central nervous system.
poral gliomas, and intraocular tumors (326–330). In a series Most investigators agree that a maximum total dose of 5,000
of 219 patients (328) treated for nasal and paranasal malig- centigray (cGy) in fractions under 200 cGy provides an ac-
nancies between 1969 and 1985, 19 patients with optic nerve ceptable low risk (340–343), except perhaps in patients with
or chiasmal radionecrosis were identified. It has also been diabetes mellitus and in patients receiving chemotherapy
reported after low-dose radiation therapy for dysthyroid or- (341,344). The cumulative doses of radiation therapy re-
bitopathy, although only in patients with diabetes mellitus. ported in patients with RON range from 2,400 cGy (345) to
The pathogenesis of delayed radionecrosis in the central 12,500 cGy (346); however, over 75% of the reported cases
nervous system is not fully understood. At one time it was of RON have received a total dose of more than 5,000 cGy
thought to be primarily vascular damage with subsequent (329). The risk of RON thus appears to increase significantly
neuronal injury (331); however, it may be that both direct at doses over 50 Gy. Jiang et al. (328), in a retrospective
effects to replicating glial tissue and secondary effects from study of 219 patients receiving radiation therapy for cancers
damage to vascular endothelial cells are important in the of the paranasal sinuses and nasal cavity, found no cases of
pathogenesis of this condition (332,333). Somatic mutations RON when the dose was under 50 Gy. In contrast, the 10-
in the glial cells induced by ionizing radiation are thought to year actuarial risk for RON after doses of 50–60 Gy and
result in genetically incompetent cells that are metabolically 61–78 Gy was 5% and 30%, respectively. Parsons et al.
deficient. Over time, these cells gradually increase, produc- (347) demonstrated no risk of RON in doses of 59 Gy or
ing demyelination and neuronal degeneration. A similar pro- less. However, among nerves that received doses of 60 Gy
cess may occur in vascular endothelial cells, eventually re- or greater, the dose per fraction was more important than
sulting in vascular occlusion and necrosis. This model is the total dose in producing RON. The 15-year actuarial risk
consistent with the observed long latent period of delayed of RON was 11% when fraction size was less than 1.9 Gy,
radionecrosis, because both the glial and endothelial cells compared with 47% when fraction size was 1.9 Gy or more.
have a slow cellular turnover rate. It is also consistent with The data obtained by Parsons et al. (347) also suggested an
the observation of direct neuronal demyelination and degen- increased risk of RON with increasing age. Goldsmith et al.
(348) found that a cumulative dose of 54 Gy delivered at imaging is the diagnostic procedure of choice to distinguish
18 Gy/day carried a very low risk of RON. Young et al. tumor recurrence from RON (349,354,357,358,363,364).
(349), by correlating dosimetric measurements with gadolin- The development of the fat-saturation techniques and the use
ium-enhanced MR images, concluded that the tolerance level of paramagnetic contrast solutions allow detailed imaging of
of the optic nerve is 50–55 Gy. the chiasm and the intracranial and orbital portions of the
Both Jiang et al. (328) and Parsons et al. (347) noted that optic nerves. In RON, the unenhanced T1- and T2-weighted
in contrast to patients irradiated for paranasal and oral cavity images may show no abnormality, but on T1-weighted en-
tumors, patients irradiated for pituitary tumors can develop hanced images, there is marked enhancement of the optic
RON after doses ranging from 42 to 50 Gy (338,340,350). nerves, optic chiasm, and even the optic tracts in some cases
They theorized that optic nerve compression and vascular (Fig. 7.25). The enhancement usually resolves in several
compromise lower the optic nerve threshold to injury from months, at which time visual function usually stabilizes. Oc-
radiation. Similarly, patients who have received chemother- casionally, enhancement may even precede visual loss.
apy in conjunction with radiation therapy and those with Treatment for RON is controversial. Although delayed
growth hormone-secreting pituitary adenomas are also re- radionecrosis in the central nervous system can be treated
portedly at higher risk for RON, even at lower cumulative with some success with systemic corticosteroids, which are
doses (345,350–354). In some cases, the dose actually deliv- effective in reducing tissue edema and may have some bene-
ered to the optic nerves is higher than desired because of ficial effect on demyelination (365), their use in RON, in
improper calibration or equipment malfunction. Conse- oral or intravenous form, has produced disappointing results.
quently, RON should be considered even in situations where Among 16 reported cases treated with steroids alone, only
‘‘safe’’ doses of radiation therapy have supposedly been ad- 2 improved (326,347,352,355,357,363,366,367). Similarly,
ministered. the use of anticoagulation to reverse or stabilize central ner-
The syndrome typically presents with acute, painless vis- vous system radionecrosis (368) does not appear to provide
ual loss in one or both eyes. Visual loss in one eye may be significant benefit in patients with RON (369,370).
rapidly followed by visual loss in the fellow eye. Episodes Hyperbaric oxygen therapy is used in the treatment of
of transient visual loss may precede the onset of RON by radionecrosis of bone and following irradiation in poorly
several weeks (355). The onset of visual symptoms associ- healing wounds in oral and maxillofacial surgery (358,
ated with RON may be as short as 3 months or as long as 371,372). At 2.0 atmospheres, the level of dissolved oxy-
8 years after radiation therapy, but most cases occur within gen in blood may be raised 14-fold, thus extending the oxy-
3 years after radiation, with a peak at 1.5 years (326,327,354, gen diffusion distance in ischemic tissue and enabling lim-
356,357). Visual acuity loss ranges widely (329), and pro- ited correction of local hypoxia (371). Hyperbaric oxygen
gression of visual loss over weeks to months is common. therapy enhances fibroblastic activity, collagen synthesis,
Spontaneous visual recovery is unusual. Final vision is no and neovascularization in irradiated tissues (372). To the
light perception in 45%, with a total of 85% of reported eyes extent that RON is an ischemic process, hyperbaric oxygen
with RON having final visual acuity of 20/200 or worse therapy has a theoretical basis for effectiveness, but clinical
(329). results are not uniform (373).
The affected optic disc is often pale initially, related to Guy and Schatz (355) first reported visual improvement
prior damage from tumor with possible superimposed radia- in RON in two patients whose treatment with hyperbaric
tion injury; less frequently it is edematous. Cases with disc oxygen was initiated within 72 hours of onset of visual
edema at onset often have associated radiation retinopathy, symptoms. The treatment protocol consisted of 14 daily 2-
with cotton-wool patches, hard exudates, and retinal hemor- hour sessions at 2.8 atmospheres. In one patient, visual acu-
rhages, secondary to irradiation of intraocular or orbital ity improved from 20/50 to 20/20; the improvement was
structures. The visual field may show altitudinal loss or a maintained over a 9-month follow-up period. Visual acuity
central scotoma. A junctional syndrome with an optic neu- in the second patient initially improved from counting fin-
ropathy and contralateral temporal hemianopia may occur gers to 20/40 after 2 days of treatment, but it then deterio-
in patients with damage to the distal optic nerve (358). Pa- rated to 20/300 over 2 weeks and did not improve despite
tients with radionecrosis of the optic chiasm typically de- continued hyperbaric oxygen therapy. Two other patients
velop a bitemporal hemianopia that initially may suggest treated more than 2 weeks after the onset of visual loss
recurrence of the tumor for which the patient was initially showed no response. Roden et al. (327) reported no improve-
irradiated (355,357), but superimposed optic neuropathy ment in 13 patients with RON treated with hyperbaric oxy-
may involve the nasal visual fields as well. gen, 11 of whom were also given systemic corticosteroids;
The differential diagnosis of RON includes recurrence of however, treatment was initiated in these patients no earlier
the primary tumor, secondary empty sella syndrome with than 2 weeks and as late as 12 weeks after the onset of visual
optic nerve and chiasmal prolapse (359), arachnoiditis loss. Hyperbaric oxygen therapy at 2.0 atmospheres was ad-
(360,361), and radiation-induced parasellar tumor (326,362). ministered daily, ranging from a total of 18–160 hours per
These conditions typically present with slowly progressive patient. Subsequent reports showed no significant improve-
visual loss rather than the rapid onset of RON. ment in visual function in patients with RON (374) until
The diagnosis of RON is generally suspected from the Borruat et al. (358) reported the case of a patient who initially
clinical setting and may be confirmed in most cases with lost vision to 20/70 in the left eye, associated with an inferior
neuroimaging. CT scanning is typically normal (326). MR nasal field defect. The fellow eye was initially normal; how-
Figure 7.25. Radiation optic neuropathy in a 65-year-old woman who

had undergone transsphenoidal resection of a nonsecreting pituitary ma-
croadenoma followed by radiation therapy totalling 5,500 cGy 18 months
earlier. A, T1-weighted MR image, coronal view, shows enlargement of
the left side of the optic chiasm. B, T1-weighted MR image, coronal
view, after intravenous injection of paramagnetic contrast material, shows
enhancement of the enlarged region. C, T1-weighted MR image, axial
view, after intravenous injection of paramagnetic contrast material, shows
enhancement and enlargement of the distal portion of the left optic nerve
and the left side of the optic chiasm. (Courtesy of Dr. Neil R. Miller.)
ever, 15 days later, vision in the left eye declined to no light gen. These investigators concluded that hyperbaric oxygen
perception, and the right eye developed marked temporal should be started as early as possible after the onset of visual
field loss. Hyperbaric oxygen therapy was initiated along loss, even if there is a possibility that the visual loss is caused
with intravenous steroid therapy. Two weeks later, the visual by some other process, such as recurrent tumor. From avail-
field loss in the left eye had significantly improved, although able data, visual improvement has been documented with
vision in the right eye was light perception. therapy only in those treated within 72 hours. There are no
Borruat et al. (373) subsequently reviewed the rationale good data for therapy begun 4–14 days after visual loss;
for, and results of, treatment of RON with hyperbaric oxy- after 2 weeks, therapy is most likely ineffective.
ISCHEMIC OPTIC DISC EDEMA WITH MINIMAL DYSFUNCTION

PRE-AION OPTIC DISC EDEMA pressive optic neuropathy from an orbital mass. Often, how-
ever, the asymptomatic disc swelling is noted in the fellow
Patients may develop disc swelling from NAION before eye of a patient with a history of a previous attack of NAION,
they have any visual symptoms (38,375,376). In such cases, and the diagnosis is less confusing. Boghen and Glaser (21)
the patient may be thought to have papilledema or a com- reported one patient who at the time of presentation with
NAION had disc swelling in the asymptomatic contralateral 1. Presence of diabetes (approximately 70% type I, 30%
eye, which lost vision 2 weeks later. Likewise, Hayreh (377) type II).
described four patients with bilateral NAION, all of whom 2. Optic disc edema (unilateral in roughly 60%, bilateral in
initially had visual loss in one eye and asymptomatic optic 40%).
disc swelling in the fellow eye. Several weeks later, the pa- 3. Absence of substantial optic nerve dysfunction (at most
tients developed visual symptoms in the second eye. Others a minor relative afferent pupillary defect; no more than
have described similar patients (232,378). Almog and Gold- mild generalized depression or enlarged blind spot on
stein (379) reviewed a series of 23 cases of asymptomatic visual fields, specifically no central, cecocentral, or altitu-
optic disc edema in vasculopathic patients (19 patients were dinal visual field defect). Visual acuity levels may vary,
diabetic). In 9 eyes, overt AION developed, within a mean since coexisting maculopathy is a common confounding
interval of 16.8 weeks, while in 25 eyes, disc edema resolved feature, but over 75% of reported cases measured 20/40
over a mean of 15.5 weeks. On the basis of vasculopathic or better at onset.
risk factors, lack of evidence for other causes of disc edema, 4. Lack of evidence for ocular inflammation or elevated
evidence of AION in the fellow eye, and the later develop- intracranial pressure.
ment in some patients of AION in the asymptomatically
edematous eye, the disc edema has been presumed ischemic Although younger patients predominate (most of those
in origin. reported have been under age 50), patients with diabetic
papillopathy may be of any age and typically present either
DIABETIC PAPILLOPATHY with no visual complaints or with vague, nonspecific visual
disturbance such as mild blurring or distortion; transient vis-
Clinical Presentation ual obscurations have rarely been reported. Pain is absent,
as are other ocular or neurologic symptoms.
Early reports of diabetic papillopathy described the acute The involved optic disc(s) may demonstrate either non-
onset of unilateral or bilateral optic disc edema in young, specific hyperemic edema or, in about half of cases, marked
type I diabetics, without the usual defects in visual field and dilation of the inner optic disc surface microvasculature (Fig.
pupillary function associated with NAION or optic neuritis 7.26). Pale swelling has typically been a criterion for exclu-
(380–384). Disc edema was prolonged in these cases, but sion, because it suggested AION. The surface telangiectasia
vision generally was preserved. A recent report added a sub- is prominent enough in some cases to be mistaken for optic
stantial number of older patients with type II diabetes (385). disc neovascularization (NVD). The dilated optic nerve sur-
Overall, fewer than 100 total cases have been reported, and face vasculature of diabetic papillopathy may be distin-
the specific criteria for diagnosis have been vague, especially guished from NVD by the following characteristics:
regarding the allowable degree of optic nerve dysfunction
and the corresponding differentiation from mild NAION. 1. Generally radial distribution of the dilated vessels in dia-
The currently accepted criteria for the diagnosis of diabetic papillopathy, as opposed to the random branching
betic papillopathy include: pattern of neovascularization.
Figure 7.26. Appearance of diabetic papillopathy. The patient was an 18-year-old man with juvenile diabetes mellitus who
was noted to have optic disc swelling during a routine eye examination. He had no visual complaints. Note dilated telangiectatic
vessels mimicking neovascularization on the surface of both the right (A) and left (B) optic discs. (Courtesy of Dr. Neil R.
Miller.)
Figure 7.27. Fluorescein angiography in diabetic papillopathy (left) versus optic disc neovascularization (right). Leakage
overlying the disc and vessels occurs primarily in neovascularization.
2. Limitation of the telangiectatic vessels to the disc surface about 25% of cases. The fellow eye frequently demonstrates
in diabetic papillopathy, as opposed to proliferation into a ‘‘crowded’’ optic disc with a small cup/disc ratio similar
the vitreous cavity with neovascular fronds. to the configuration seen in patients with NAION (385).
3. Limitation of fluorescein dye leakage to the disc sub- The pathogenesis of diabetic papillopathy is unproven.
stance and peripapillary retina, demonstrating late ‘‘shad- Early investigators postulated either a toxic effect on the
owing’’ of the retinal vessels in diabetic papillopathy, optic nerve secondary to abnormal glucose metabolism or
as opposed to leakage anteriorly into the vitreous from an inner disc surface vascular disturbance, with resultant
neovascular tissue, with obscuration of the retinal vessels microvascular leakage into the disc (380,381). The most
(Fig. 7.27). commonly proposed theory suggests it to be a mild form of
NAION, with reversible ischemia of both the prelaminar and
True disc neovascularization is occasionally superim- inner surface layers of the optic nerve head (383). Ischemic
posed on the edema of diabetic papillopathy (Fig. 7.28). optic disc edema may occur with irreversible dysfunction
Diabetic retinopathy is usually (more than 80% of re- (infarction in NAION), with no dysfunction (pre-NAION
ported cases) present at the time of onset of papillopathy, optic disc edema without visual loss), or with varying de-
varying in severity and associated with macular edema in grees of reversible dysfunction (spontaneous recovery in
NAION [377]). Diabetic papillopathy fits this category as
well. The prominent surface telangiectasia seen in many
cases is reminiscent of a similar phenomenon seen focally
on the disc in NAION (110,111) and may represent vascular
shunting from prelaminar ischemic vascular beds. The fre-
quent occurrence of a ‘‘crowded’’ optic disc in the fellow
eye (385), as in NAION, supports an ischemic mechanism
as well. Fluorescein angiographic sequences of optic disc
filling are similar to those in NAION (386), suggestive of
impaired optic disc perfusion. Hayreh (387) has recently
summarized his data corroborating an ischemic etiology for
diabetic papillopathy and suggesting that it is indeed the
same entity as NAION. We believe that it is most likely an
ischemic syndrome, although the clinical course is often
quite distinct from typical NAION.
Conditions that may simulate diabetic papillopathy in-
clude papilledema (elevated intracranial pressure), optic disc
Figure 7.28. Diabetic papillopathy (left) with superimposed optic disc neovascularization, malignant hypertension, papillitis, and
neovascularization (right). Note the random branching pattern of the neo- NAION. Symptoms of elevated intracranial pressure usually
vascular vessels. distinguish papilledema, but in patients with suspected bilat-
eral diabetic papillopathy, even without such symptoms, 21. Boghen DR, Glaser JS. Ischaemic optic neuropathy: the clinical profile and
natural history. Brain 1975;98:689–708.
neuroimaging and lumbar puncture must be considered. Disc 22. Repka MX, Savino PJ, Schatz NJ, Sergott RC. Clinical profile and long-term
edema related to systemic hypertension does not typically implications of anterior ischemic optic neuropathy. Am J Ophthalmol 1983;96:
478–483.
demonstrate prominent telangiectasia and is usually associ- 23. Hayreh SS, Podhajsky PA, Zimmerman B. Ocular manifestations of giant cell
ated with hypertensive retinopathy; blood pressure measure- arteritis. Am J Ophthalmol 1998;125:509–520.
ment is important in suspected cases. Papillitis and NAION 24. Hayreh SS. Anterior ischemic optic neuropathy: differentiation of arteritic from
non-arteritic type and its management. Eye 1990;4:25–41.
both demonstrate significant optic nerve dysfunction, as evi- 25. Siatkowski RM, Gass JDM, Glaser JS, et al. Fluorescein angiography in the
denced by a relative afferent pupillary defect, visual acuity, diagnosis of giant cell arteritis. Am J Ophthalmol 1993;115:57–63.
and visual field loss. 26. Melberg NS, Grand MG, Dieckert JP, et al. Cotton-wool spots and the early
diagnosis of giant cell arteritis. Ophthalmology 1995;102:1611–1614.
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CHAPTER 8
Compressive and Infiltrative
Optic Neuropathies
Nicholas J. Volpe
COMPRESSIVE OPTIC NEUROPATHIES WITH OPTIC DISC COMPRESSIVE OPTIC NEUROPATHIES WITHOUT OPTIC
SWELLING (ANTERIOR COMPRESSIVE OPTIC DISC SWELLING (RETROBULBAR COMPRESSIVE OPTIC
NEUROPATHIES) NEUROPATHIES)
Orbital Inflammatory Syndrome VISUAL RECOVERY FOLLOWING DECOMPRESSION
Thyroid Eye Disease INFILTRATIVE OPTIC NEUROPATHIES
Meningiomas Tumors
Inflammatory and Infectious Infiltrative Optic Neuropathies
COMPRESSIVE OPTIC NEUROPATHIES WITH OPTIC DISC SWELLING

(ANTERIOR COMPRESSIVE OPTIC NEUROPATHIES)
Compressive lesions within the orbit, the optic canal and, This clinical picture is particularly common in patients with
rarely, intracranially, may result in disc swelling (Fig. 8.1). orbital hemangiomas adjacent to the optic nerve and in pa-
Most compressive optic neuropathies, whether they result tients with primary optic nerve meningiomas (4,7,11,
from orbital or intracranial lesions, are not associated with 13–18). In such patients, careful testing of color vision may
optic disc swelling. However tumors, infections, and inflam- reveal subtle defects. Computerized perimetry may show en-
mations, and even adnexal structures that have become swol- larged blind spot or reduction of the mean deviation and
len or enlarged by disease, can all cause an optic neuropathy there may occasionally be a relative afferent pupillary defect.
associated with optic disc swelling. When other signs of orbital disease are not present (e.g.,
Within the orbit, mass lesions that compress the proximal proptosis, limitation of ocular motility, orbital congestion)
optic nerve and produce optic disc swelling include optic these patients may be thought to have unilateral papilledema
gliomas (1–8), meningiomas (4,7,9–18), hamartomas (e.g., from increased intracranial pressure. Although it is obvious
hemangiomas, lymphangiomas), choristomas (e.g., dermoid that patients with slowly progressive, unilateral visual loss
cysts), malignancies (e.g., carcinoma, lymphoma, sarcoma, and proptosis associated with disc swelling should undergo
multiple myeloma) (19–22) and arachnoid cysts of the optic evaluation for a possible orbital lesion, patients with unilat-
nerve sheath (23,24) (although some of these cysts may be eral optic disc swelling without signs of intraocular inflam-
associated with optic nerve sheath menigiomas at the orbital mation and without visual loss should also undergo such
apex (25,26). Additionally, inflammatory disorders such as an evaluation, particularly when there are no systemic or
idiopathic orbital inflammatory syndrome and thyroid oph- neurologic symptoms or signs of increased intracranial pres-
thalmopathy can result in compressive optic neuropathies sure. Orbital disease is the most common cause of unilateral
with disc edema. disc swelling without visual loss since truly unilateral papil-
In most cases of anterior compressive optic neuropathy, ledema is rare (27).
there is progressive visual loss associated with proptosis; In addition to proptosis, congestion, and limitation of ocu-
however, in many patients, visual acuity remains near nor- lar motility, patients with orbital disease may develop var-
mal, visual field loss is mild (blind spot enlargement and ious folds or striae that occur either at the posterior pole,
mild generalized constriction) and there is virtually no exter- adjacent to the optic disc (Fig. 8.2), or elsewhere in the
nal evidence of orbital disease despite obvious disc swelling. fundus if the orbital compressive lesion contacts the globe.
385
Figure 8.1. Disc swelling and optociliary shunt veins in a patient with optic nerve sheath meningioma. A–D, Progressive
development of optociliary shunt veins (arrows) from the stage of chronic disc swelling (A), through intermediate stages of
shunt vein formation (B and C), to the final stage of optic atrophy with fully formed optociliary shunts (D). Neuroimaging with
computed tomographic (CT) scanning and magnetic resonance (MR) imaging provides complementary information. Calcified
psammoma bodies in the tumor produce a well-delineated ‘‘tram-track’’ sign in the contrast-enhanced, reconstructed CT images
(E), whereas MR imaging with surface coil (T1-weighted, without fat suppression or enhancement) (F) clearly defines the
nerve surrounded by tumor (arrows).
These folds may be horizontal or vertical and generally result evoked amaurosis has also been reported to occur in associa-
from indentation of the globe by the lesion itself or secondar- tion with secondary lesions invading the orbit (38). Body
ily by the optic nerve (28–30). position associated transient visual obscurations as occur in
Transient monocular visual loss occurs commonly in pa- patients with papilledema also may occur in patients with
tients with orbital lesions(4,13,31–38). The visual loss oc- unilateral disc swelling from a compressive lesion.
curs only in certain positions of gaze, and vision immediately Computed tomographic (CT) scanning (40–53), magnetic
clears when the direction of gaze is changed. It has been resonance (MR) imaging (54–59), and ultrasonography
assumed that either gaze dependency, direct pressure on the (60–69) have revolutionized the diagnosis of orbital lesions.
optic nerve, or interruption of the blood supply is the expla- CT scanning, MR imaging, and ultrasonography are rapid,
nation for this phenomenon. Knapp et al. (39) demonstrated safe, and accurate methods of determining the presence of
the latter with color Doppler imaging in a 13-year-old girl an orbital lesion, its location, and occasionally, its identity
with a left intraconal mass. Abduction of the affected eye (66,70–73). CT scanning and MR imaging offer superior
was associated with gaze-evoked amaurosis and a dramatic topographic depiction (size, shape, and location) of lesions
reduction in central retinal artery blood flow that returned (74), whereas standardized echography provides supplemen-
to normal two months after removal of the lesion (an orbital tary information that often helps in refinement of the differ-
varix), by which time the girl was asymptomatic. Gaze ential diagnosis (66,69). CT scanning is particularly useful
COMPRESSIVE AND INFILTRATIVE OPTIC NEUROPATHIES 387
Figure 8.2. Optic disc swelling and choroidal folds in thyroid eye disease. A, The left optic disc shows mild hyperemia,
swelling, and blurring of the peripapillary retinal nerve fiber layer at the upper and lower poles. Horizontal chorioretinal folds
extend across the posterior pole toward the macula. B, Coronal and off-axis sagittal reconstructed computed tomographic scans
show greatly enlarged extraocular muscles surrounding the optic nerve within the orbit. Note that the muscles actually appear
to be in contact with the nerve. C, Coronal T1-weighted, enhanced MRI scan showing enlarged extraocular muscles (black
arrows) crowding the optic nerve (white arrow).
for imaging bone, calcium, and metallic foreign bodies (75) quently, meningiomas of the orbital apex produce a similar
(suspicion of the last being a contraindication for the use clinical picture (80). CT scanning and MR scanning usually
of MR imaging), whereas MR imaging excels at defining show thickening and enhancement of normal tissues or a
inflammatory and intrinsic disease of the visual pathway and mass lesion. Ultrasound can be very helpful in the identifica-
parasellar area. MR imaging is particularly suited to imaging tion of posterior scleritis and thickening of Tenon’s capsule
the intracanalicular optic nerve, as it is not affected by partial and the sclera. The pain and rapid evolution of symptoms
volume averaging from adjacent bone as is CT scanning generally distinguish orbital inflammatory disease from the
(76). With the use of fat-saturation techniques and intrave- more indolent course characteristic of most orbital tumors.
nous injection of paramagnetic substances such as gado- Most of these patients respond rapidly to systemic steroid
linium-diethylene-triamine-pentaacetic acid (gadolinium- treatment.
DTPA), demarcation of optic nerve sheath meningiomas can
be optimized (54,55). Plain skull radiographs should no THYROID EYE DISEASE
longer play a role in the evaluation of patients with unex-
plained visual loss (77). Approximately 6% of patients with thyroid eye disease
develop evidence of a compressive optic neuropathy, some
ORBITAL INFLAMMATORY SYNDROME associated with optic disc swelling (Fig. 8.2) (81). Dysthyr-
oid optic neuropathy is a compressive optic neuropathy
Inflammatory conditions involving the orbit, including ab- caused by pressure on the optic nerve by enlarged extraocu-
scesses and the nonspecific condition called idiopathic in- lar muscles. In such patients, congestive symptoms almost
flammatory pseudotumor or idiopathic orbital inflammatory always precede visual loss, which is usually bilateral, sym-
syndrome, may also cause anterior compression of the proxi- metric, and gradual in onset. Of the 36 eyes of 21 patients
mal optic nerve and secondary disc swelling that can be with dysthyroid optic neuropathy examined by Trobe et al.
confused with primary optic nerve tumors (78,79). Associ- (82), 12 (33%) had mild to marked disc swelling. Presenting
ated posterior scleritis may also cause disc swelling. Af- visual acuities were 20/60 or worse in these patients, who
fected patients usually experience acute or subacute visual usually had central scotomas, often combined with arcuate
loss, pain, proptosis, and congestion associated with the defects. Kennerdell et al. (83) emphasized the compressive
optic disc swelling, possibly with retinal vein occlusion. The etiology of the optic neuropathy in their report of the CT
presence of an orbital process is rarely in question. Infre- findings in seven patients with dysthyroid optic neuropathy,
four of whom had evidence of optic disc swelling. In all

cases, there was moderate to severe enlargement of the extra-
ocular muscles at the orbital apex (Fig. 8.2). Direct measure-
ment of orbital pressure and tissue compliance through ma-
nometry demonstrates higher orbital tissue tension and lower
orbital compliance in patients with thyroid eye disease (84).
Optic neuropathy can even occur as a late complication sev-
eral years after initial presentation without evidence of pro-
gressive orbitopathy or recurrent inflammation (85). A
Treatment options for thyroid-associated compressive
optic neuropathy include intravenous or oral steroids and
orbital decompression which can be accomplished success-
fully via a transantral (86), endoscopic (87), or transcaruncu-
lar approach (88). Combined approaches allowing endo-
scopic decompression of the medial wall and orbital apex
and subciliary approaches to the orbital floor may be most
effective (89–92). Radiation therapy may also be effective
(93), but its effects are often delayed and therefore more
acutely effective treatments with steroids or surgery should
be given in conjunction with radiation. Visual evoked poten-
tials have also been shown to be abnormal in patients with B
thyroid eye disease without symptoms or measurable optic
nerve dysfunction and useful in monitoring and detecting
treatment effects in thyroid patients (94–97). Most patients
(90%) improve and maintain excellent vision. A subset of
patients require additional interventions including repeat
orbital surgery, steroid treatment or radiation, and a small
percentage (5%) develop permanent visual disability
(86,98,99).
MENINGIOMAS
Anterior compressive optic neuropathy may result from
primary optic nerve sheath meningiomas (ONSM) (see C
Chapter 30). The tumors arise from meningiothelial cells in
Figure 8.3. Neuroimaging in optic nerve sheath meningioma. A, Coronal
the arachnoid villi. Optic nerve sheath meningiomas sur- T1-weighted, enhanced orbital image with fat saturation demonstrating en-
round the optic nerve and result in impaired axonal transport larged and enhancing optic nerve sheath (arrow). B, Axial T1-weighted,
(leading to disc swelling) and also interfere with the pial enhanced, fat-saturated image demonstrating a left optic nerve sheath me-
blood supply to the optic nerve. The tumor occurs most com- ningioma with linear enhancment (arrows) along the optic nerve sheath.
monly in middle-aged women and is usually unilateral (100). C, Axial orbital CT scan demonstrating calcification (arrow) of an optic
Patients present with slowly progressive vision loss, mild nerve sheath meningioma.
proptosis, double vision, transient visual obscurations, and
gaze-evoked amaurosis (13,15,16,100). Examination reveals
a color vision defect, afferent pupillary defect, and visual gadolinium. The imaging appearance of fusiform enlarge-
field defects including central scotomas, enlarged blind ment can be similar to that of optic nerve glioma but ‘‘kink-
spots, and generalized constriction. The optic nerve appears ing’’ (see later) is not seen with meningiomas. On CT, calci-
abnormal with either optic atrophy and or with disc edema fication (Fig. 8.3) can be seen in one third of patients as
(13,15,16,100). Optociliary collateral vessels (see below) linear bright lines extending over the length of the optic
may be present and are seen in both swollen and atrophic nerve (tram track sign) (4,13,14,100). Clinical findings and
nerves (101). neuroimaging generally establish the diagnosis and biopsy
Neuroimaging (CT or MRI) demonstrates focal or diffuse, is almost never needed. However, the radiographic appear-
tubular or fusiform, optic nerve enlargement (Fig. 8.1) (100). ance of diffuse optic nerve enlargement or sheath thickening
MRI is often diagnostic, showing the tumor to be separate is also seen in patients with optic neuritis (103), optic peri-
from the optic nerve proper on coronal views, allowing dis- neuritis(104), sarcoidosis involving the meninges (105), or-
tinction from gliomas (Fig. 8.3). MRI is particularly good bital inflammatory syndrome (particularly the sclerosing va-
at imaging the intracanalicular optic nerve, and delineating riety) (79), metastases (106–108), and lymphomatous and
the extent of intracranial extension of the ONSM carcinomatous meningitis. Clinically these conditions can
(54,55,102). This kind of tumor is typically isointense with usually be distinguished by a much more rapid presentation
brain on T1 and T2 images and smoothly enhances with and associated pain as well as associated systemic symp-
toms. In the rare equivocal case, biopsy is only recom- ported that none of the patients developed other neurologic
mended in an eye with poor vision, after a systemic work sequelae of their tumor, four patients remained stable, and
up and serial lumbar punctures exclude inflammatory disor- three actually improved based on visual acuity and visual
ders and neoplasms, and after steroids fail to improve vision. field criteria.
Growth of ONSM is usually indolent over many years. Radiation therapy (50–55 Gy) is the best treatment avail-
Growth rate may increase with pregnancy (109). Intracranial able for patients with optic nerve sheath meningioma
extension of optic nerve sheath meningioma with involve- (11,112–120). In the largest series to date, Andrews and
ment of the chiasm and adjacent structures is quite rare. associates reported the results of fractionated stereotactic
Bilateral cases occur in neurofibromatosis type II (110). Pro- radiotherapy in 30 patients with ONSM (113). Vision was
spective clinical trial data are not available for comparison preserved in 92% of patients and improved visual acuity or
of available treatments. Natural history data suggest that pa- visual fields were noted in 42%, compared to only 16% of
tients can remain stable or improve over several years (100). patients with preserved vision in an historical control group
In a series of 16 patients followed for a mean time of 6 years (Fig. 8.4). Becker and associates (114) and Pitz and associ-
(2–18 years) without treatment, Egan and Lessell (111) re- ates (120) reported similar results in two different studies
A B
C D
E F
Figure 8.4. Successful treatment of optic nerve sheath meningioma with radiation treatment. The patient presented at age
39 with transient visual obscurations and blurred vision in the left eye and had optic disc swelling (A), reduced acuity to
20/60, and significant visual field loss including blind spot enlargement and constriction (C). She was found on MRI scan (E)
to have an optic nerve sheath meningioma. Nine years after radiation therapy the visual acuity improved and remained at 20/
25, the optic disc was mildly pale (B), the visual field (D) improved, and the MRI scan (F) showed a stable appearance.
of 15 ONSM patients. Stable visual acuity and fieldswere disc swelling (112). The mechanism by which disc swelling
noted for 3 years in 29 of 30 patients treated with stereotactic occurs in such cases is not clear, but it presumably results
radiotherapy. Narayan and associates (121) reported stability from direct compression of the optic nerve with blockage
or improvement over an average of about a 4-year follow-up of axonal transport. Less common than optic disc swelling
in 12 of 14 patients treated with three-dimensional conformal from an intracanalicular lesion is optic disc swelling from
radiation. Turbin and associates (122) reviewed their series compression of the intracranial portion of the optic nerve.
of 64 patients with ONSM who were either observed or Tomsak et al. (124) reported a patient who developed blurred
treated with radiation and/or surgery and found that radiation vision in the left eye associated with an inferior-temporal
alone was superior, had the least complications, best visual visual field defect, an ipsilateral relative afferent pupillary
outcome, and least progression on MRI. defect, and a mildly swollen, hyperemic optic disc associated
Alternatively, if visual function is excellent then observa- with peripapillary exudates and choroidal folds. The patient
tion alone is reasonable, and radiation therapy is initiated was ultimately found to harbor a carotid ophthalmic aneu-
when progression is documented (100,111). Surgical exci- rysm that compressed the intracranial portion of the left optic
sion of these lesions to improve vision is usually not possible nerve superior-medially against the intracranial aspect of the
because of the tumor involvement of the pial blood supply optic canal.
to the optic nerve. Portions of the tumor are occasionally Intracranial lesions, particularly sphenoid wing meningio-
removed to treat blind or uncomfortable eyes (proptosis), to mas, not infrequently extend through the optic canal, com-
decompress associated mass effect, or reduce the risk of pressing the intracranial, intracanalicular, and intraorbital
intracranial extension. In patients with intracranial exten- optic nerve in the process. Optic disc changes, from swelling
sion, surgery and radiation have been tried. Surgical results to pallor, may be minimal in such cases, even when the
are poor, although radiation has been shown to be of some lesion is quite large (Fig. 8.5).
benefit (123). In many patients with chronic compression of the intra-
Patients with meningiomas confined entirely to the optic canalicular or intraorbital optic nerve, a specific clinical triad
canal may occasionally present with blurred vision and optic develops. This triad consists of visual loss, optic disc swell-
A B
Figure 8.5. Optic disc swelling in a patient with a large meningioma with intraorbital, intracanalicular, and intracranial
components. The patient was a 21-year-old woman who experienced reduced vision in the left eye during pregnancy. A, Normal
right optic disc. B, Mild swelling of left optic disc. C, T1-weighted axial magnetic resonance image obtained after intravenous
injection with gadolinium-DTPA shows large mass involving the left sphenoid wing and posterior orbit. Although both coronal
(D) and sagittal (E) images clearly show compression of the optic chiasm by the tumor (arrow), the resulting visual field defect
was purely unilateral, affecting only the left eye.
A B
Figure 8.6. Left optic disc swelling in a patient with an orbital meningioma. A, Disc swelling is associated with the development
of an optociliary shunt or collateral vessel seen at 1 o’clock position. B, Axial enhanced CT scan showing the large lesion
compressing and surrounding the optic nerve.
ing that evolves into optic atrophy, and the appearance of Chronic obstruction of the central retinal vein presumably
optociliary (retinochoroidal) shunt veins (Figs. 8.1 and 8.6). results in dilation of a previously existing system that shunts
The optociliary veins overlie the optic disc and peripapillary blood to the choroid, allowing it to leave the eye via the
region and shunt venous blood between the retinal and cho- vortex veins (132–134). These veins drain directly into the
roidal venous circulations (125–130). The vessels may occur superior and inferior ophthalmic veins that anastomose with
as congenital anomalies, in which case they are associated the facial and angular veins and with the pterygoid venous
with normal visual acuity and shunt blood from the choroid plexus. Thus, an outlet is provided for retinal venous blood
to the retina (128–131). When they occur with chronic optic other than via the central retinal vein to the cavernous sinus.
nerve compression, however, they are generally associated This clinical picture has been described most frequently in
with severe visual loss and disc swelling or optic atrophy patients with spheno-orbital meningiomas (12,135–138),
and they shunt blood from the retina to the choroid. The but it also occurs in patients with optic nerve gliomas
common denominator in such cases appears to be prolonged (139,140), chronic papilledema (141–144), craniopharyngi-
compression of the optic nerve with gradual compression oma (145), sarcoidosis (146), and other rare causes of optic
and obstruction of the central retinal vein. nerve compression (23,147).
The normal route of retinal venous blood flow is through However, the most common cause of retinochoroidal
the central retinal vein directly to the cavernous sinus. shunt vessels is central retinal vein occlusion.
COMPRESSIVE OPTIC NEUROPATHIES WITHOUT OPTIC DISC SWELLING

(RETROBULBAR COMPRESSIVE OPTIC NEUROPATHIES)
The importance of early diagnosis of compressive lesions tory and early findings in patients with a retrobulbar com-
that affect the retrobulbar portions of the optic nerve and do pressive optic neuropathy.
not cause optic disc swelling cannot be overemphasized. In most cases of prechiasmal optic nerve compression,
Early decompression of the optic nerves or chiasm may re- progressive dimming of vision is noted at an early stage.
sult in significant return of visual function (148,149), Painless, slowly progressive visual dimming should be the
whereas misdiagnosis may result in progressive visual fail- first warning that a compressive lesion of the optic nerve or
ure and irreversible visual loss, neurologic dysfunction, or chiasm is present. Such patients may have normal or near
death. Unfortunately, intracranial, intracanalicular, and oc- normal visual acuity, but they complain of ‘‘foggy,’’ ‘‘dim,’’
casionally, posterior orbital compressive lesions, usually do or ‘‘blurred’’ vision. Although these patients may read the
not produce disc swelling or significant neurologic or sys- 20/25 or the 20/20 Snellen letters with the affected eye, they
temic manifestations. Thus, by the time such lesions cause do so slowly and with great difficulty compared with the
visible optic pallor, significant damage to the optic nerve opposite eye. Patients with aneurysms, mucoceles, pituitary
has often already occurred, preventing return of visual func- apoplexy, and fibrous dysplasia may have a more rapidly
tion even with otherwise successful decompression. The progressive and painful course that can initially be confused
physician managing a patient with unexplained unilateral with optic neuritis (discussed later).
visual loss therefore must be aware of the characteristic his- Patients with unilateral visual complaints from compres-
sion of the optic nerve usually have some type of visual field neurosurgical intervention is more apt to serve the patient’s
defect, particularly when tested with automated perimetry, best interests. Reports supporting the concept of optic nerve
but the nature of the defect does not, in itself, suggest the compression by adjacent doliochoectatic internal carotid ar-
etiology of the visual loss. Compression of the optic nerve teries add weight to such an approach (159,163–165). Rarely
may produce any type of field defect, including an altitudi- does a patient require exploratory craniotomy to define the
nal, arcuate, hemianopic, central, or cecocentral scotoma. cause of compressive optic neuropathy, although decom-
These same defects can be caused not only by other types pression of the optic canal may be therapeutic in selected
of optic neuropathies but also by intraocular disorders, in- cases (166).
cluding cataract and macular disease. Despite the almost universal availability of CT scanning
By far, the two most striking abnormalities that are present and MR imaging, it is astonishing that patients with progres-
in a patient with a retrobulbar compressive optic neuropathy sive visual loss continue to be diagnosed as having macular
are unilateral dyschromatopsia (as detected using pseudoiso- degeneration, cataract, or ‘‘chronic optic neuritis.’’ Cer-
chromatic color plates or simple red objects) and an ipsi- tainly, chronic optic neuritis occurs and may produce slowly
lateral relative afferent pupillary defect. The afferent defect progressive visual loss in one or both eyes; however, chronic
is obvious even when visual acuity is minimally reduced optic neuritis is a diagnosis of exclusion. This diagnosis
and provides the observer with absolute evidence that the should not be made in any patient until neuroimaging studies
visual difficulty is caused by something other than a simple have been performed and have failed to detect a compressive
refractive error, incipient cataract, or minimum macular dis- lesion of the optic nerve. Even then, the diagnosis of chronic
ease. Once a relative afferent pupillary defect is detected in optic neuritis must be made with caution and follow-up im-
a patient with an apparently normal fundus who is complain- aging studies must be obtained and rigorously interpreted
ing of progressive dimming of vision, compression must be (167). Most cases of delayed diagnosis of compression of
ruled out by whatever neuroimaging studies are available the anterior visual system are caused by failure to perform
and is best suited to the task. CT scanning and MR imaging color vision or visual field testing, a less than careful exami-
have dramatically improved the potential to diagnose ret- nation of the opposite ‘‘normal’’ eye, failure to test for a
robulbar compressive optic neuropathies and, when used in relative afferent pupillary defect, and the necessity to obtain
the appropriate manner, are the best screening tests to use adequate and appropriate neuroimaging studies which are
in this setting (74,150–159) (Fig. 8.7). accurately interpreted (75,168).
Prior to the era of modern neuroimaging, many authors The optic disc of a patient with a compressive optic neu-
concluded that even if neuroradiologic diagnostic proce- ropathy may appear normal or show a variable degree of
dures fail to demonstrate a lesion, neurosurgical exploration pallor. Asymmetric cupping of the optic disc is not usually
is advisable in patients with unilateral progressive vision a prominent feature, but it may occur and be quite prominent
loss (160–162). However, with continuing advances in neu- in some patients (Fig. 8.8) (49,169–171). In such cases, the
roimaging, including the use of paramagnetic substances visual loss may be thought to have resulted from glaucoma,
such as gadolinium-DTPA, orbital fat suppression, MR angi- particularly when there is an arcuate defect (171).
ography, and thin section CT scanning, it is a rare lesion that Bianchi-Marzoli et al. (170) analyzed the occurrence of
escapes detection. When modern neuroimaging techniques optic disc cupping (as measured by cup⬊disc areas) in eyes
have been carefully tailored to the clinical problem at hand, with compressive optic neuropathy. They used highly repro-
have been properly performed, and are correctly interpreted, ducible planimetric measurement techniques applied to ste-
but are nevertheless unrevealing, observation rather than reoscopic disc photographs. These investigators found con-
A B
Figure 8.7. MRI scanning in the diagnosis of retrobulbar compressive optic neuropathies. Both patients presented with slowly
progressive vision loss over months with normal appearing optic nerves. A, Axial T1-weighted, enhanced, fat-saturated MRI
scan demonstrating a subtle (arrows) meningioma at the orbital apex compressing the optic nerve. B, Coronal T1-weighted,
enhanced MRI scan of a different patient demonstrating contact between meningioma (white arrow) and optic nerve (black
arrow).
C D
Figure 8.8. Optic disc cupping in a patient with aneurysmal compression. The patient was a 55-year-old woman who suddenly
lost the inferior field in the right eye after suffering mild head trauma in a motor vehicle accident 8 days earlier. A, Cupped
and pale right optic disc. B, Normal left optic disc. C and D, Magnetic resonance images, axial C and coronal D views, revealing
flow void (arrows) in a carotid-ophthalmic aneurysm that is compressing the right optic nerve.
vincing evidence of acquired enlargement of the ipsilateral field defect, a central scotoma that breaks out into the
cup in patients with unilateral optic nerve compression. periphery, or a ‘‘junctional’’ scotoma in the superior tem-
Compressive lesions of the anterior visual pathways are poral field of the opposite eye strongly suggest a compres-
important in the differential diagnosis in patients with ‘‘nor- sive lesion, it is the insidious, progressive nature of the
mal tension glaucoma,’’ particularly if there is pallor beyond symptoms that is most often the critical feature of the
cupping, atypical rate of progression, or atypical visual field compressive process.
defects. Ahmed et al. (172) found compressive lesions in 4 Treatment of retrobulbar optic nerve compressive lesions
(6.5%) of 62 consecutive patients thought to have normal must be tailored to the specific disease process and patient.
pressure glaucoma. Portney and Roth (173) performed a Generally compression of the optic nerve must be relieved
pathologic examination of the optic nerve from a patient either by removal of the lesion surgically or by reducing its
with progressive cupping of the optic disc caused by aneu- size with medical therapy. In addition, both intracranial and
rysmal optic nerve compression. The specimen demon- extrancranial optic canal decompression may also be neces-
strated loss of axons and glial tissue in the nerve head. It is sary and additive for lesions affecting the optic canal
unclear how neural compression results in loss of glial tissue (166,189). Spontaneous improvement in visual acuity and
in the disc of some patients and why significant cupping is visual field defects have been reported in patients with or-
such an uncommon accompaniment of compressive optic bital apex lesions (190).
neuropathy. Optic atrophy in one eye and disc swelling in Causes of retrobulbar optic nerve compression include
the other (Foster Kennedy syndrome) may result from asym- intraorbital and intracranial benign and malignant tumors
metric optic nerve compression (174) or from the more tradi- (148,191–204), aneurysms (205–221) (Figs. 8.8 and 8.9),
tional explanation of tumor-induced direct optic nerve inflammatory lesions, particularly of the paranasal sinuses
compression in one eye and papilledema from increased in- (222–235), primary bone disease (e.g., osteopetrosis, fibrous
tracranial pressure in the other (see Chapter 4). dysplasia, craniometaphyseal dysplasia, Paget’s disease)
As noted above, virtually any field defect may be present (236–247), orbital fractures (248,249), optic canal invasion
in patients with a compressive optic neuropathy. Central, by rhabdomyosarcoma (250), dolichoectatic intracranial
paracentral, cecocentral, arcuate, altitudinal, nasal, or tem- vessels (165,251–254), congenital and acquired hydroceph-
poral hemianopic defects, as well as diffuse depression of alus (255–259), thyroid eye disease (82,260–263), and or-
the visual field, have all been described in patients with bital hemorrhage, whether spontaneous (264–266), trau-
compressive lesions (175–188). Although a hemianopic matic (267–270), iatrogenic (271–274), or associated with
A B
Figure 8.9. Bilateral carotid-ophthalmic aneurysms producing bilateral retrobulbar compressive optic neuropathies. Axial (A)
and coronal (B) magnetic resonance images show bilateral giant carotid-ophthalmic aneurysms that produced slowly progressive
visual loss in both eyes. An ophthalmologist, internist, and psychiatrist had all ascribed the loss of vision to conversion-hysteria.
orbital, paranasal sinus, or systemic diseases (275,276). An- mild to moderate symptoms who are not good surgical candi-
terior visual system compression has also been reported from dates can be observed with serial visual fields and MRI
such disparate causes as intranasal balloon catheters placed scans. Treatment generally includes surgery and radiation
for treatment of severe epistaxis (277), errant placement of therapy when vision loss is significant (see above).
intraventricular catheters (278,279), downward displace- The intracranial optic nerve is near the anterior cerebral
ment of gyrus rectus in patients with meningiomas of the artery, the anterior communicating artery, the ophthalmic
anterior falx cerebri (280), basal encephalocele (281), hyper- artery, and the supraclinoid portion of the internal carotid
trophic cranial pachymeningitis (282), renal osteodystrophy artery. Aneurysms arising from the carotid ophthalmic junc-
leading to calvarial hypertrophy (283), and fat packing after tion, ophthalmic artery, and the supraclinoid carotid artery
transsphenoidal hypophysectomy (284,285). can all present with unilateral retrobulbar compressive optic
Meningiomas, pituitary tumors, and aneurysms are the neuropathy or chiasmal syndrome. Patients often have fluc-
most commonly identified lesions causing retrobulbar com- tuating visual symptoms, perhaps related to aneurysm size
pressive optic neuropathy without disc swelling. Often there and flow changes. Aneurysms in the supraclinoid region
is associated chiasmal visual dysfunction. These lesions are classically present with a nasal scotoma which can be bilat-
discussed more extensively elsewhere in this text (see Chap- eral if there is sufficient compression of the optic nerves and
ters 28, 30, 31, and 41) but certain features of their presenta- chiasm shifting them toward the other carotid artery. The
tion are worth mentioning in this discussion. diagnosis is usually easily made with MRI and MRA, but
Meningiomas arising from the planum sphenoidale or ol- conventional angiography remains the gold standard. The
factory groove may involve the intraorbital or intracanalicu- natural history of these lesions is generally unfavorable and
lar optic nerve. Tumors in this area can grow to a large size therefore treatment is generally recommended with endovas-
without causing any other neurologic symptoms. Patients cular or neurosurgical intervention (see Chapter 41).
with olfactory groove meningiomas may present with papil- Rarely fusiform aneurysms or ectatic dilation of the ca-
ledema from mass effect or retrobulbar compressive optic rotid artery may also compress the intracranial optic nerve
neuropathy and further review may reveal anosmia from or chiasm (see above). This has been suggested as a possible
compression of the olfactory nerve and abnormal behavior cause of optic neuropathy in elderly patients and is thought
associated with frontal lobe dysfunction. To compress the to possibly have a role in the pathogenesis of some cases
superior aspect of the intracranial optic nerve these tumors of low tension glaucoma (163,171). Jacobson et al. (286)
must grow posteriorly over the planum sphenoidale. This demonstrated that contact between the carotid artery and
results in compression of one optic nerve leading to unilat- optic nerve or chiasm is seen in 70% of asymptomatic pa-
eral optic atrophy as well as intracranial pressure elevation tients suggesting that this may be a coincidental finding in
leading to contralateral papilledema (Foster Kennedy syn- patients with unexplained optic neuropathy.
drome). Suprasellar and tuberculum sellae meningiomas The sudden onset of unilateral visual loss, combined
more commonly cause chiasmal syndromes but can cause with signs of retrobulbar optic nerve dysfunction, usually
isolated involvement of the prechiasmatic intracranial optic suggests a diagnosis of optic neuritis or ischemic optic neu-
nerve. Parasellar, and sphenoid wing meningiomas can also ropathy. In rare instances, however, compressive lesions
cause optic neuropathy, but because of a more lateral loca- may produce acute monocular visual loss, presumably from
tion generally present with cranial nerve palsies and eye hemorrhage or from sudden interruption of the vascular sup-
movement abnormalities. Neuroimaging of patients with ply to the optic nerve, and thereby mimic optic neuritis or
menigiomas reveals a lesion which is isointense with brain, ischemic optic neuropathy (167,287). This phenomenon
smoothly enhancing, often with a dural tail (Fig. 8.5), and probably occurs most frequently in patients with pituitary
is usually sufficient to make the diagnosis of skull-based apoplexy (288), but it has also been reported in patients with
meningiomas, obviating the need for biopsy. The clinical pituitary tumors and meningiomas during pregnancy (289)
course is usually one of insidious progression, although oc- and in otherwise healthy patients upon awakening (290).
casional patients remain stable for years. Patients with only Stern and Ernest (291) reported the sudden onset of monocu-
A B
Figure 8.10. Clinical photograph (A) and MRI scan in patient that presented with sudden vision loss secondary to a hemorrhage
in a preexisting lymphangioma. The axial T1–weighted, enhanced image (B) demonstrates a large tumor (white arrows) with
heterogeneous signal that can be seen to stretch and compress the optic nerve (black arrow).
lar visual loss in a patient with a ruptured ophthalmic artery (297), and in patients with mucoceles or pyoceles of the
aneurysm and Melen et al. (292) reported sudden monocular paranasal sinuses, particularly the sphenoid sinus (229,235).
visual loss in a 13-year-old boy with fibrous dysplasia. Dol- In other cases, patients with sudden retrobulbar optic neurop-
man et al. (270) reported five patients who experienced rap- athies from compressive lesions have initially improved
idly evolving visual loss in the setting of rapidly progressive when treated with systemic corticosteroids. In such cases,
proptosis from such disparate causes as orbital hemorrhage, visual function invariably worsens as soon as steroids are
subperiosteal abscess, and orbital cellulitis. In all cases, there tapered. Lesions that have caused this syndrome include pi-
was optic nerve traction with dramatic tenting of the poste- tuitary adenoma, craniopharyngioma, plasmacytoma, and
rior globe that was demonstrated by orbital neuroimaging medulloblastoma (168,298–300).
studies (Fig. 8.10). The current practice of obtaining MR imaging in patients
The combination of ocular pain and unilateral visual loss, with suspected optic neuritis as a means of determining
simulating retrobulbar neuritis, has been observed in cases which patients are at high risk for developing multiple scle-
of anterior communicating artery aneurysms, pituitary ade- rosis should lessen the frequency of such delays in diagnosis
noma (293,294), aneurysm (295,296), craniopharyngioma of these optic neuritis imposters.
VISUAL RECOVERY FOLLOWING DECOMPRESSION

In 1915, Cushing and Walker (301) analyzed 81 cases of ways may experience sudden and severe vision loss pre-
chiasmal compression and showed that restoration of visual sumed secondary to either optic nerve manipulation or
function was not only possible following surgical de- ischemia (305,306).
compression but it began within days after surgery. Pen- Although it is not surprising that prompt decompression
nybacker (302) also described a dramatic response to surgi- may restore visual function in patients rendered suddenly
cal treatment in patients with loss of vision from pituitary blind by pituitary apoplexy (307,308), it is not intuitively
adenoma and commented on the possibility of full recovery obvious that patients who have lost all light perception for
within a few days postoperatively. In a recent series of 27 days or weeks can occasionally experience dramatic visual
patients undergoing decompression of the optic nerve, 47% recovery following decompression surgery (309,310).
showed improvement which, in two-thirds of the patients Kayan and Earl (311) examined 11 patients with compres-
happened almost immediately (303). Zevgaridis and associ- sive lesions of the intracranial optic nerves and chiasm, 7
ates reported on 65 patients with meningiomas in the sellar of whom had complete or nearly complete visual recovery
region, and found that 39 (65%) of patients had improved with decompression. All of these patients experienced their
vision after surgery on long-term follow-up (average 5 years) recovery within 15 days, with 5 patients recovering within
(204). Favorable prognostic indicators included younger 5 days. One patient had no change in visual acuity or visual
age, shorter duration of symptoms and an intact arachnoid fields following surgery. Subsequent authors reported simi-
membrane around the lesion. Li et al. (189) reported on 30 lar results in patients with both pituitary adenomas and me-
patients with biopsy proven tumors and optic nerve compres- ningiomas (148,149). With increasing use of the transsphe-
sion that underwent optic canal decompression via an exter- noidal technique for removal of pituitary tumors and
nal ethmoidectomy approach, with 20 (67%) demonstrating improvements in anesthesia for patients undergoing neuro-
improved visual function. ‘‘Medical decompression’’ of the surgical procedures, it has become possible to evaluate pa-
optic nerve with bromocriptine in patients with prolactin- tients several hours after they have undergone decompres-
secreting pituitary tumors has yielded similar improvements sion of the intracranial optic nerves or optic chiasm. Miller
in visual function (304). On the other hand, patients undergo- (312) found that patients with pituitary adenomas who have
ing surgery for aneurysms involving the anterior visual path- normal fundi (as well as many who have mild disc pallor
and loss of the nerve fiber layer) invariably experience im- duction in demyelinated axons is likely to contribute to the
pressive return of visual acuity and visual field that can be visual loss commonly produced by tumors compressing the
detected almost immediately after they awaken from anes- anterior visual system, the observation of Clifford-Jones et
thesia. In most other cases of optic nerve compression in al. (321) that remyelination occurs in the anterior visual sys-
which adequate decompression has been obtained, patients tem (at least in cats) is of extreme importance.
are aware of improvement within several days. Many pa- McDonald (297) provided a lucid summary of this work
tients achieve maximum recovery by the time they are dis- and described the neurophysiology underlying the visual
charged from the hospital 5–10 days after surgery; others symptoms of anterior visual pathway compression. Accord-
experience improvement during this period but continue to ing to McDonald (297), there are three stages of visual recov-
improve over the subsequent weeks to months (303). Other ery after decompression of the anterior visual pathway. Re-
investigators have reported similar findings (313–315). Al- lief of visual pathway compression is initially followed by
though there are patients who do not improve dramatically rapid recovery of some vision within minutes to hours. Mc-
immediately after decompression surgery but do improve Donald likened this recovery to the relief of conduction
gradually several months following surgery, such patients block after an arm or leg ‘‘goes to sleep.’’ This initial recov-
are increasingly rare and are primarily those with preopera- ery is followed by delayed recovery of additional function
tive hydrocephalus or postoperative cerebral edema. As in over weeks to months. This improvement may be related to
the cases reported by Kayan and Earl (311), Miller (312) progressive remyelination of previously compressed demye-
found no correlation between the rapidity of visual loss and linated axons. Finally, there is an even longer period of im-
the rapidity of visual return. Tumor volume has also proved provement, taking many months to years. The mechanism
to be a poor predictor of the extent of visual recovery, both by which this late recovery occurs is unknown.
for pituitary adenomas and suprasellar meningiomas Several authors have suggested that measurement of vis-
(316,317). ual evoked potentials in patients undergoing neurosurgical
Visual loss in patients with compressive optic neuropa- decompression of the anterior visual system may be advanta-
thies is unlikely to be caused by vascular insufficiency, as geous not only in assessing the adequacy of the procedure
has been postulated in the past (318), but by demyelination but also in aiding the surgeon with respect to the extent of
insufficient to cause cell death. Gledhill and McDonald surgery and in warning of excessive manipulation of the
(319), as well as Harrison and McDonald (320), demon- optic nerve (324–328). Other investigators, however, have
strated remyelination following the demyelination that oc- found the results to be unreliable because the latency and
curs with acute compression of the cat spinal cord. Clifford- configuration of the visual evoked potential wave forms are
Jones et al. (321) described remyelination of demyelinated adversely affected by direct pharmacologic effects of the
fibers of the cat optic nerve after chronic compression. Since anesthetics, and intraoperative changes in latency and ampli-
remyelination is capable of restoring the ability of previously tude have shown little correlation with postoperative visual
demyelinated central fibers to conduct trains of impulses at function change (329–332). These drawbacks have pre-
physiologic frequencies (322,323), and since impaired con- vented the technique from being widely used.
INFILTRATIVE OPTIC NEUROPATHIES

The optic nerve can become infiltrated by tumors and by can be of any type, and a relative afferent pupillary defect
various inflammatory processes (Table 8.1). Such processes when the infiltration is unilateral or asymmetric. In other
typically produce one of three clinical pictures: (a) optic disc cases, however, the disc elevation is asymptomatic, and there
elevation or swelling with evidence of an optic neuropathy; is no clinical evidence of an optic neuropathy, although elec-
(b) optic disc elevation or swelling with no evidence of optic trophysiologic testing, such as visual evoked responses, may
nerve dysfunction; and (c) a normal-appearing optic disc be abnormal. The more distal (posterior) the infiltrative pro-
associated with evidence of an optic neuropathy. cess, the less likely it is that any change will be noted in the
Infiltration of the proximal portion of the optic nerve, optic disc. In such cases, the optic nerve initially appears
either anterior or just posterior to the lamina cribrosa, pro- normal, and the clinical picture is that of a retrobulbar optic
duces elevation and swelling of the optic disc. When the neuropathy.
prelaminar portion of the nerve is infiltrated, the elevation Table 8.1 lists both common and uncommon processes that
of the disc is caused by the infiltrative process and is not true infiltrate the optic nerve. The most common lesions that infil-
disc swelling. When the retrolaminar portion of the nerve is trate the optic nerve are tumors and inflammatory/infectious
infiltrated, the disc elevation is caused by true swelling of processes. Tumors may be primary or secondary. Primary
the disc, and the appearance is indistinguishable from the tumors are far more common than are secondary ones. The
disc swelling caused by such diverse entities as increased most common inflammatory disorder is sarcoidosis; the most
intracranial pressure, ischemia, and inflammation. common infectious agents are opportunistic fungi.
The disc elevation observed in patients with infiltrative TUMORS
processes of the optic nerve, whether true swelling or an
infiltrative process, may be associated with other signs of Primary Tumors
optic nerve dysfunction. In such cases, there is variable loss Primary tumors that infiltrate the nerve include optic glio-
of visual acuity and color vision, a visual field defect that mas, astrocytic hamartomas, gangliogliomas, capillary and
Table 8.1 70% of patients with optic pathway gliomas develop visual
Lesions that Infiltrate the Optic Nerve symptoms or signs, and 90% of the lesions are detected by
the second decade (338–342). Some studies suggest no par-
Primary Tumors ticular sex predilection for these tumors (333,343) and others
Optic glioma
point to a slight female predilection (338).
Benign/malignant ganglioglioma
Malignant teratoid medulloepithelioma
Patients with gliomas confined to the optic nerve have
Capillary hemangioma three clinical presentations that are determined in part by
Cavernous hemangioblastoma the location, size, and extent of the tumor (344). When the
Other glioma is confined to the orbital portion of the nerve or the
Secondary Tumors bulk of the lesion is within the orbit, the patient typically
Metastatic carcinoma develops proptosis associated with evidence of an anterior
Nasopharyngeal carcinoma and other contiguous tumors optic neuropathy (loss of visual acuity and color vision, a
Lymphoreticular tumors visual field defect, a relative afferent defect, and a swollen
Lymphoma optic disc) (2,345). Whether the optic disc swelling that is
Leukemia
observed in such patients results from infiltration alone, vas-
Other
Infections and Inflammation
cular insufficiency, or compression by the arachnoidal pro-
Sarcoidosis liferation or extension of the tumor outside the pia-arachnoid
Idiopathic perioptic neuritis of the nerve that may accompany such lesions is unclear
Bacteria (346).
Virus Another mechanism that may be responsible for disc
Fungi swelling in such patients is secondary obstruction of the cere-
brospinal fluid (CSF) space surrounding the orbital portion
of the optic nerve by the tumor (333). Patients with gliomas
that both infiltrate and compress the optic nerve can eventu-
cavernous hemangiomas, hemangioblastomas, and melano- ally develop optociliary shunt vessels–congenital venous
cytomas. channels that enlarge in the setting of chronic compression
of the optic nerve and that shunt blood from the retinal to the
Optic Nerve Glioma choroidal circulations (see above) (Fig. 8.12). The increased
volume of the optic nerve pressing on the globe and shorten-
The most common lesion that infiltrates the optic nerve ing it may induce hyperopia. In such a case, retinal striae
is the optic glioma (1,333,334), although the most common may be seen (342) (Fig. 8.13A and B). In rare cases the
tumors to affect the pediatric orbit are vascular tumors (335) tumor directly infiltrates the optic disc and swelling and in-
(Fig. 8.11) (see Chapter 28). Optic pathway gliomas repre- filtration of the surrounding retina is seen ophthalmoscop-
sent 1% of all intracranial tumors, 1.5–3.5% of all orbital ically (Fig. 8.13C).
tumors, and 65% of all intrinsic optic nerve tumors When the tumor is located posteriorly in the orbit, and
(336,337). Gliomas confined to the optic nerve constitute especially when the process begins in, or is limited to the
about 25% of all optic pathway gliomas, with the remainder intracanalicular or intracranial portions of the nerve, the pre-
infiltrating the optic chiasm and optic tracts in addition to sentation is that of a slowly progressive or relatively stable
one or both optic nerves (333). In the first decade of life retrobulbar optic neuropathy (347–352). In most of these
cases, the optic disc on the affected side is pale when the
patient is first assessed, and the disc does not appear to have
been previously swollen. Such patients do not typically have
proptosis; if they do, it is usually less than 3 mm. Pain is not
a feature of the clinical presentation of optic nerve gliomas,
unless they suddenly hemorrhage (342,353).
With the widespread availability of neuroimaging, partic-
ularly MR imaging, and the increasing tendency of physi-
cians to screen patients with neurofibromatosis type 1 (NF-1)
radiologically, more patients with asymptomatic, presumed
optic gliomas are being identified. Such patients have no
visual complaints and may or may not have evidence of
visual dysfunction (e.g., an asymptomatic visual field defect
or a relative afferent pupillary defect) on careful testing,
although most have abnormal visual evoked responses to
pattern stimuli. Many patients first come to medical attention
because they develop a sensory strabismus (2,333). In other
patients, the tumor displaces the globe, producing a primary
Figure 8.11. Optic nerve glioma. The optic nerve is diffusely enlarged. strabismus. Such patients may have variable visual loss that
(Courtesy of Dr. William R. Green.) is caused not by the tumor per se but by strabismic ambly-
A B
Figure 8.12. Optociliary shunt vessels in a patient with an optic nerve glioma. A, The left optic disc is pale and mildly
swollen. There are optociliary shunt vessels on its surface. B, T2-weighted MR image, axial view, shows diffuse enlargement
of the orbital portion of the left optic nerve. The patient was initially thought to have an optic nerve sheath meningioma. Note
the ‘‘pseudo-CSF sign’’ caused by extension of the tumor into the subdural space around the intraorbital optic nerve.
opia. The diagnosis in such cases may be suspected when decreased vision with evidence of an anterior or retrobulbar
color vision is less severely affected than is visual acuity. optic neuropathy or who has asymptomatic optic disc swell-
Patients with optic nerve gliomas may have stable and ing or pallor, particularly if the child has the stigmata of NF-
even normal visual acuity for many years (354–356). In 1. Both CT scanning and MR imaging can be used to identify
some cases, however, there is slowly progressive visual loss, the lesion, which typically appears as a fusiform enlargement
and in rare cases there is sudden and profound visual loss that of the orbital portion of the optic nerve, with or without
simulates that of acute optic neuritis (357). Overall, when concomitant enlargement of the optic canal (358,359) (Figs.
initially confined to the optic nerve, gliomas are associated 8.12B and 8.14). In other cases, the nerve is diffusely en-
with a 5% mortality rate, although with hypothalamic in- larged, thus mimicking a meningioma (360).
volvement mortality increases to 50% (333). MR imaging is generally better at defining the extent of
The diagnosis of an optic nerve glioma should be sus- an optic nerve glioma than is CT scanning (361). On MR
pected in any young child who develops or is found to have imaging, optic gliomas typically have normal to slightly pro-
Figure 8.13. Optic nerve glioma producing proptosis, optic disc

swelling, and chorioretinal striae. A, The left eye is proptotic
and displaced inferiorly. B, The left optic disc is swollen, and
chorioretinal striae are present. C, In a different patient the tumor
can be seen to invade the optic nerve head and surrounding retina.
(Courtesy of Dr. Grant T. Liu.)
B C
A C
B
Figure 8.14. Neuroimaging in three patients with optic nerve gliomas. A, CT scan, axial view, shows fusiform enlargement
of the orbital portion of the left optic nerve. The enlargement begins at the globe and continues for about three fourths the
length of the nerve. Note normal size nerve at orbital apex. B, CT scan, axial view, after intravenous injection of contrast
material in another patient shows fusiform enlargement and enhancement of the entire optic nerve within the right orbit. C,
CT scan, axial view, in a third patient shows fusiform enlargement of the right optic nerve within the orbit, with extension of
the enlarged nerve through an enlarged optic canal and intracranially.
longed T1 relaxation times and are isointense or hypointense A review of 2,186 published cases reveals that approxi-
to normal brain on T1-weighted images. Many of these tu- mately 29% of optic pathway gliomas occur in the setting
mors also have a prolongation of the T2 relaxation times. of NF-1 (333). Therefore, any patient found to harbor an
The T2-weighted images are better at assessing the extent optic pathway glioma should be assessed for evidence of
of the tumor than are T1-weighted images (361). Although NF-1, and patients with cutaneous lesions consistent with
gliomas of the optic nerve may show minimal enhancement NF-1 should be screened for optic pathway gliomas and
after intravenous injection of a paramagnetic contrast mate- other intracranial lesions that occur in patients with neurofi-
rial, the enhancement is not nearly as pronounced as is typi- bromatosis. Indeed, Listernick et al. (366) performed neu-
cally seen with a meningioma (362). roimaging on 176 children with NF-1 and found that 15%
Two important signs help differentiate optic nerve glio- of those who were visually asymptomatic harbored an optic
mas from other lesions. One is an unusual ‘‘kinking’’ of the pathway glioma. Creange et al. (367) found 20 (13%) of 158
optic nerve within the orbit (Fig. 8.15). This is seen almost patients with NF-1 to have an optic pathway tumor. The
exclusively in patients with neurofibromatosis type 1. The sporadic, non-NF-1-associated form of the tumor tends to
other is a double-intensity tubular thickening of the nerve, present at an earlier age, more often involves and or spreads
best seen on MR images. This sign is called the ‘‘pseudo- to the chiasm with associated hydrocephalus, and may be-
CSF’’ signal because the increase in T2 signal surrounding have more aggressively (338,359,368,369).
the nerve may be misinterpreted as a CSF signal (363) (Fig. Gliomas that affect the optic nerve may occasionally be
8.16). The genesis of this signal is perineural arachnoidal confined to the optic disc. Most of these rare lesions occur
gliomatosis that occurs in optic nerve gliomas in patients in patients with NF-1. They may cause a change in the ap-
with NF-1 (364,365). Cystic components to the tumor are pearance of the optic disc that simulates true swelling
more common in non-NF-1-associated glioma (359). Kink- (370,371). In most cases, however, the normal features of
ing of the nerve and the pseudo-CSF signal are often seen the optic disc are obscured by a mass of whitish, gray, or
together. yellow tissue that projects from and above the disc surface
A B
Figure 8.15. Kinking of the optic nerves in patients with neurofibromatosis type 1 and an optic nerve glioma. A, Axial CT
scan shows ‘‘kinking’’ (arrow) of an enlarged optic nerve within the right orbit. B, Axial T1 weighted MRI scan demonstrating
kinking of the left optic nerve. This sign is pathognomonic of an optic nerve glioma. (B, Courtesy of Dr. Grant T. Liu.)
(Fig. 8.17A). Visual acuity in patients with gliomas of the Less common features include capillary proliferation, tissue
optic disc is variably affected. necrosis with hemorrhage, glial giant cells, and even mitotic
Optic nerve gliomas are not hamartomas but are, in fact, figures (342,353,375). A reactive leptomeningeal hyperpla-
true neoplasms (372,373) with a potential for significant vis- sia occurs around some of these lesions, both within the orbit
ual morbidity and a small but significant mortality (5,374). and within the optic canal. This can lead to the erroneous
Most of these tumors, regardless of their localization or ex- diagnosis of optic nerve meningioma if only the superficial
tent within the nerve, are of the juvenile pilocytic variety aspect of the nerve is biopsied (376). In one series, certain
and have a benign appearance on microscopy (Fig. 8.17). immunohistologic features were found to predict aggressive
A B
Figure 8.16. The pseudo-CSF sign in a patient with neurofibromatosis type 1 and bilateral optic nerve gliomas. A, T1-
weighted MR image, axial view, shows that the orbital portion of the left optic nerve consists of a fusiform area of low intensity
(closed arrow) surrounding a core of high signal intensity. An arachnoid cyst (open arrow) occupies the left anterior cranial
fossa. Note that the peripheral (outer) tumor signal is isointense to the CSF in the cyst. The tumor is kinked posteriorly. The
right optic nerve glioma cannot be seen on this image. B, T2-weighted MR image, axial view, shows a donut-shaped signal
of high intensity (dark arrow) surrounding an inner circle of low signal intensity in the left orbit. This image represents a
tangential cut through the superior aspect of the upwardly kinked tumor. In the right orbit, a linear area of high signal intensity
surrounds a central core of low signal intensity. Note that the outer signal within both tumors is isointense to CSF within the
arachnoid cyst (open arrow). (From Brodsky MC. The ‘‘pseudo-CSF’’ signal of orbital optic glioma on magnetic resonance
imaging: A signature of neurofibromatosis. Surv Ophthalmol 1993;36⬊213–218.)
Figure 8.17. Histologic appearance of an optic disc

glioma. A, At lower power, the disc is elevated and
infiltrated with numerous astrocytes. B, At higher mag-
nification optic nerve gliomas can be seen to be com-
posed of large, benign-appearing astrocytes. (A, Cour-
B tesy of Dr. William R. Green.)
behavior (373). Gliomas that occur in patients with NF-1 and chiasmal gliomas (380–383). The natural history and
show the unique feature of extension of tumor into the sub- prognosis may be better in patients with NF-1-associated
arachnoid and dural spaces surrounding the nerve, whereas tumors (338,359,369,383).
gliomas that occur in patients without neurofibromatosis In younger children, an optic nerve tumor can be amblyo-
produce diffuse enlargement of the nerve without extension genic. In young children with monocular vision loss from
into the subdural or subarachnoid space (364,377) (Fig. an optic pathway tumor, part-time occlusion therapy (patch-
8.18). ing) of the unaffected eye is recommended (384). Some glio-
The treatment of optic nerve gliomas is controversial. mas, however, enlarge and cause progressive visual loss in
These tumors when confined to the optic nerve generally one or both eyes. Lesions may even extend into the hypothal-
have a more favorable prognosis than tumors presenting with amus and 3rd ventricle and lesions that involve the postchias-
or ultimately involving the chiasm, hypothalamus, and retro- mal visual pathways often have a greater effect on vision
chiasmal visual pathways (352,368). The natural history of (352,385,386). There has been only one well-documented
these benign lesions is generally good, with long-term useful case of an optic nerve glioma presenting without radio-
visual function and few, if any, neurologic complications graphic demonstration of chiasmal or hypothalamic involve-
(369,378). Most optic nerve gliomas do not change substan- ment which subsequently extended posteriorly (379); how-
tially in size or shape over many years (366). Some, however this case was evaluated only with CT scanning. Patients
ever, rapidly enlarge and extend along the nerve to the chi- with optic nerve glioma with unequivocal sparing of the
asm and even into the 3rd ventricle (379) (see below). Others chiasm at presentation (evaluated with modern gadolinium-
suddenly expand from intraneural hemorrhage. Conversely, enhanced MRI, with thin, high resolution sections) who later
rare lesions exhibit spontaneous regression (380–382). develop chiasmal involvement are exceedingly unusual.
Spontaneous and significant improvement of vision and re- However, in a study of 106 patients with unilateral gliomas
duction of lesion size has been reported in patients with optic initially confined to the orbit at study entry, local progression
Figure 8.18. Difference in appearance of optic nerve gliomas in patients with and without neurofibromatosis type 1 (NF-1).
A, In a patient without NF-1, gross appearance of an optic nerve glioma in cross section shows that the nerve is diffusely
enlarged. There is no extension of tumor into the subarachnoid or subdural spaces. B, Longitudinal histologic section through
an optic nerve glioma in another patient without NF-1 also shows diffuse enlargement of the nerve without extension of tumor
into the subarachnoid or subdural space. C, In a patient with NF-1 and an optic nerve glioma, gross appearance of the affected
nerve in cross section shows that the nerve is infiltrated and enlarged by tumor. Note, however, that the tumor also extends
into the subdural and subarachnoid spaces, where it appears necrotic and hemorrhagic. D, Histologic cross sections comparing
a normal optic nerve (left) with an optic nerve glioma in another patient with NF-1 (right) show marked enlargement of the
affected nerve as well as extension of tumor into the subarachnoid and subdural spaces.
occurred in 20% of untreated patients, 29% following in- line treatment in a child under age six, while radiation of
complete surgical resection, and 2.3% following apparent the optic nerve tumor would be the primary option in an
complete excision (387). The possibility of intracranial ex- older child.
tension exists in any given patient and for this reason patients It must be remembered that radiation therapy can have
are followed with serial neuro-ophthalmic examinations and significant side effects, particularly in children. These in-
MRI scanning. clude developmental delay, vasculitis, moya-moya disease,
Patients with optic nerve gliomas are generally not treated leukoencephalopathy, radionecrosis of the temporal lobes,
with either chemotherapy or radiation therapy unless there endocrinopathies, behavior disturbances, and the induction
is clear evidence of progression with the lesion extending of secondary malignancies (391–393). Fractionated stereo-
into the optic chiasm, opposite optic nerve, or hypothalamus tactic radiotherapy is effective and may be associated with
(2,349,369,388,389). Radiation therapy is probably effective less morbidity and pituitary gland dysfunction (394). Surgi-
in improving vision and disease-specific survival probability cal resection is generally reserved for those patients who
in gliomas of the anterior visual pathway that are clearly are already blind when first seen; for patients with severe
progressing clinically (368,390). Because of the risk of ra- proptosis; and for patients whose lesions seem to be threaten-
diation to the developing brain, chemotherapy is the first- ing the optic chiasm but that have not yet reached it
(333,358,383,395–397) (Fig. 8.19). No clinical trials have Other Primary Tumors

been performed to indicate if removal of an apparently uni-
lateral optic nerve glioma is associated with a better visual Tumors primarily composed of mature ganglion cells may
and neurologic prognosis than no treatment at all. occur in both the peripheral nervous system and the central
The efficacy of chemotherapeutic agents in the treatment nervous system (CNS). Ganglion cell tumors of the CNS
of optic nerve gliomas is unclear. Most investigators agree are less common than their peripheral counterparts and there
that the drugs are never curative; however, they may stabilize are two main types. Ganglioneuromas (also called ganglio-
or reduce the growth rate and progression of visual manifes- cytomas) are composed predominantly of mature ganglion
tations of the tumor and thus delay the need for radiation cells supported by a stroma of spindle cells and containing
therapy, particularly in young children (374,398). calcospherites, whereas gangliogliomas are composed of a
Most gliomas that infiltrate the optic nerve or chiasm are, mixture of mature ganglion cells and mature glial cells and
as noted above, benign juvenile pilocytic astrocytomas; how- are thus true mixed neurogliogenic tumors (406–409). These
ever, some are malignant (399–403). Malignant optic glio- two types of tumor represent extremes of the spectrum of
mas almost always occur in adults and produce one of two tumors containing mature ganglion cells, and there are many
clinical pictures. When the tumor initially affects the intra- tumors that must be considered transition forms between
cranial optic nerves or chiasm, there is rapidly progressive them. Ganglion cell tumors occur most frequently in children
visual loss associated with optic discs that initially appear and young adults (409,410). Nevertheless, the age range is
normal but that rapidly become atrophic (404,405). The vis- broad—from several months (337,410,411) to 80 years of
ual loss in these cases is often bilateral and simultaneous, age (412). They occur with equal frequency in males and
but it may initially begin in one eye and may be mistaken females.
for retrobulbar optic neuritis, particularly when there is asso- The most common location of ganglion cell tumors is the
ciated pain (402). When the malignant glioma initially af- floor of the 3rd ventricle, where they produce symptoms and
fects the proximal portion of the intraorbital optic nerve, signs related to dysfunction of the hypothalamus or pituitary
there is acute loss of vision associated with optic disc swell- gland, including precocious puberty, diabetes insipidus, ac-
ing and the ophthalmoscopic appearance of a central retinal romegaly, and panhypopituitarism. In rare instances, the
vein occlusion (402). The prognosis in almost all cases of gangliogliomas originate within the substance of the optic
malignant optic glioma is poor, regardless of treatment with chiasm or intracranial portion of the optic nerves, and thus
radiotherapy or chemotherapy. Most patients become com- may be mistaken for a typical ‘‘optic glioma’’ (413). Cases
pletely blind within several months after the onset of symp- of gangliogliomas infiltrating one or both optic nerves and
toms, and most die within 6–12 months. the anterior visual pathways have been reported (414–419).
Figure 8.19. Left optic glioma near the optic chiasm in

a 6-year-old boy without neurofibromatosis type 1. A, T1-
weighted MR image, axial view after intravenous injection
of paramagnetic contrast material shows that the glioma
extends through the optic canal up to the optic chiasm. B,
T1-weighted enhanced MR image, coronal view, shows en-
largement and enhancement of the intracranial portion of
the left optic nerve. C, T1-weighted enhanced MR image,
coronal view, 3 mm posterior to the view seen in B shows
that the left optic nerve just anterior to the optic chiasm is
normal in size and does not enhance, suggesting that the
tumor has not yet reached this site. This is the type of patient
who might be considered a candidate for excision of the
A tumor.
B C
Lu et al. (420) and Shuangshoti et al. (417) reported the MR nant elements are usually glial rather than neuronal
characteristics of a ganglioglioma which had no distinguish- (423,424), and metastases may occur (337,425).
ing features and simply appeared as a fusiform dilation of Astrocytic hamartomas can infiltrate the optic disc. In
the right optic nerve with enhancement in one patient and a most cases, they protrude above or overlie the surface of the
circumscribed cystic lesion with an enhancing mural nodule affected disc. They initially have a grayish or grayish-pink
in another. The lesion has been identified in a patient with appearance, but they later develop a glistening, yellow, mul-
NF-1 (416). berry appearance (Fig. 8.20). Although this latter appearance
Liu et al. (421) described chiasmatic infiltration by a gan- is similar to that of optic disc drusen, drusen are located
glioglioma in three patients. In one of the patients, the tumor within the substance of the disc, whereas astrocytic hamarto-
had originated in the temporal lobe and spread to the chiasm. mas overlie the disc (Fig. 8.21).
In a second patient who presented with a bitemporal field The appearance of an astrocytic hamaratoma is also simi-
defect, the tumor appeared to have originated within the lar to that of an endophytic or regressing retinoblastoma;
chiasm. The third patient had a ganglioglioma that originated however, astrocytic hamartomas do not exhibit the same
within the chiasm and extended to both optic tracts. The rapid growth characteristics as a retinoblastoma. They also
patient was almost completely blind, having only a small tend to be more yellow and glistening than retinoblastomas
left homonymous island of vision remaining. All of these (426). The visual function in an eye with an astrocytic ha-
patients had optic atrophy. martoma of the optic disc is usually normal. Some eyes,
The microscopic appearance of the ganglion cell tumor however, develop a serous detachment of the retina or vitre-
varies according to the extent to which neuronal and glial ous hemorrhage, resulting in variable loss of vision (427).
elements participate in the neoplastic process (416). The Spontaneous regression of such lesions may occur (428).
pure ganglioneuroma is moderately cellular tumor in which Astrocytic hamartomas are composed almost entirely of
the cells are clearly neuronal in origin but are often abnormal acellular laminated calcific concretions. In many specimens,
in appearance. In pure ganglioneuromas, the glial element these concretions are interspersed among areas composed of
consists of a scanty stroma of spindle cells; but in gangliogli- large glial cells (429). Most astrocytic hamartomas occur in
omas there is clear evidence of neoplastic astrocytic prolifer- patients with tuberous sclerosis or NF-1 (430). In about 30%
ation. Gangliogliomas thus contain glial cells that show his- of cases, however, the patient has no evidence of any of the
tologic differentiation that parallels that of neurons. The phacomatoses or of any other systemic disorder.
degree of differentiation may be so great that such tumors Both capillary and cavernous hemangiomas can occur
may initially be thought to represent pleomorphic fibrillary within the substance of the optic disc (371,431–434). In
astrocytomas until careful examination reveals their true addition, cavernous hemangiomas can develop at any loca-
composition. tion in the optic nerve and in the optic chiasm (196,
Most ganglion cell tumors, whether ganglioneuromas or 435–440). Capillary hemangiomas may be endophytic or
gangliogliomas, generally have a good prognosis as they exophytic. The endophytic type appears as a circular, red-
behave biologically as low-grade astrocytomas; however, dish, slightly elevated mass internal to the disc vasculature
the survival rates may be somewhat lower for patients with and is represented histologically by a capillary hemangioma
chiasmatic infiltration (422). In addition, some of these tu- lying immediately beneath the internal limiting membrane
mors do have malignant features. In these tumors, the malig- (Fig. 8.22). These lesions may be a manifestation of von
A B
Figure 8.20. Astrocytic hamartoma of the optic disc. A, Before significant calcification, the lesion appears as a pinkish gray
mass rising above the disc. B, When calcification occurs, small globular clusters can be observed within the mass. Eventually,
the entire mass may become calcified.
A B
Figure 8.21. Difference in ophthalmoscopic appearance of optic disc drusen and astrocytic hamartoma of the optic disc. A,
Optic disc drusen are located within the substance of the disc beneath the vessels. B, Astrocytic hamartomas are located above
the optic disc, thus obscuring the vessels.
Figure 8.22. Endophytic capillary angioma. A–C, The lesion appears as a circular, reddish, slightly elevated mass internal
to the disc vasculature. D, Fluorescein angiography of lesion seen in C shows intense staining and leakage from vessels at
inferior aspect of disc.
Figure 8.23. Exophytic capillary angioma of the optic disc.

This lesion appears as diffuse blurring and elevation of the
disc, often associated with a variable degree of serous detach-
ment of the peripapillary sensory retina and a ring of lipid
deposition. (Courtesy of Dr. Andrew Schachat.)
Hippel-Lindau disease (441), or they may occur as an iso- phy are invaluable in making the correct diagnosis. Capillary
lated phenomenon. The exophytic type of capillary hemangi- angiomas do not occur within the substance of the optic
oma is typically seen as blurring and elevation of the disc nerve or chiasm.
margin, often associated with a variable degree of serous Cavernous hemangiomas consist of large-caliber vascular
detachment of the peripapillary sensory retina and a ring channels. When these lesions occur as isolated masses within
of lipid deposition (442) (Fig. 8.23). This lesion is often the orbit, they are well circumscribed and encapsulated.
misdiagnosed as unilateral papilledema or papillitis, but Within the eye, however, their appearance is that of a cluster
fluorescein angiography clearly demonstrates the vascular of small purple blobs located within and above the substance
anomaly (371,432,442–444), as does ultrasonography. of the optic disc (433,445–449) (Fig. 8.24). The blood flow
These tumors may also occur as part of von Hippel-Lindau within the vessels in cavernous hemangiomas is extremely
disease. Rarely, exophytic capillary angiomas are bilateral. slow, indicating that this lesion is more isolated from the
In such instances, they are often misdiagnosed as papille- general circulation than its capillary counterpart. Cavernous
dema; but again, fluorescein angiography and ultrasonogra- hemangiomas of the optic disc are usually unilateral. They
Figure 8.24. Cavernous angioma of the optic disc. A, Note ‘‘cluster of grapes’’ appearance of lesion. B, Histologic appearance
of a cavernous angioma showing multiple dilated vessels above and adjacent to the disc surface. (From Davies WS, Thumin
M. Cavernous hemangioma of the optic disc and retina. Trans Am Acad Ophthalmol Otolaryngol 1956;60⬊217–218. AFIP
Acc. 219953.)
occur more commonly in females than in males, with an that was found to be a hemangioblastoma. These authors
irregularly autosomal-dominant inheritance pattern. The le- reviewed 11 previously reported cases of optic nerve he-
sion is almost always asymptomatic, with visual acuity being mangioblastoma. Five tumors were located within the orbit
normal and visual fields showing only a variably enlarged and frequently produced proptosis (453,454), while four tu-
blind spot; however, rare cases have been reported in which mors were strictly intracranial, and two involved both the
there has been vitreous hemorrhage (384). Although these intracranial and intraorbital portions of the optic nerve.
lesions have been considered not to grow, Kushner et al. The typical patient presents with progressive visual loss
(384) documented growth of a cavernous hemangioma of and evidence of an optic neuropathy that may be anterior or
the optic disc in two patients followed for 5 to10 years. retrobulbar, depending on the location of the lesion, and
Cavernous hemangiomas, unlike capillary hemangiomas, may be bilateral (452,455,456). The degree of visual loss is
can occur within the optic nerves, optic chiasm, or optic variable, and any type of visual field defect may be present.
tracts (196,439) (Fig. 8.25). Similar lesions can occur in the There is always a relative afferent pupillary defect. The
retrolaminar portion of the optic nerve (437), in the intracan- affected portion of the optic nerve is enlarged and has a
alicular portion of the optic nerve (435), and in the intracra- fusiform appearance mimicking an optic nerve glioma on
nial portion of the optic nerve (438,440). neuroimaging (454,456) (Fig. 8.26). Kerr et al. (452) empha-
In some cases, the lesion itself causes slowly progressive sized that hemangioblastomas of the optic nerve, like their
loss of vision. In most cases, however, visual loss is rapidly counterparts elsewhere in the CNS, usually have a plane of
progressive and occurs because of hemorrhage into the sur- section that permits surgical removal without sacrificing the
rounding tissue (450,451). Regli et al. reviewed 28 cases entire optic nerve.
and pointed out that these lesions typically occur in the third Histologically, optic nerve hemangioblastomas are com-
or fourth decade and have a triad of (a) sudden headache; posed of a highly vascular matrix with intervascular stromal
(b) an acute change in visual acuity; and (c) a significant cells containing abundant, clear, foamy cytoplasm. Ultra-
defect in the visual field. Interestingly, up to one third of structurally, the spaces are lined with endothelium and occa-
the previously reported patients had episodes of transient sional pericytes and lipid-containing stromal cells in the in-
visual loss that had been previously diagnosed as optic neuri- tervascular regions. Only 30% of these lesions are associated
tis. Cavernous hemangiomas are not associated with von with the von Hippel-Lindau disease; however, partial expres-
Hippel-Lindau disease; however, they are often associated sion of genetic disorders is being documented with increas-
with similar lesions of the skin and brain. In contrast to the ing frequency, and many of the other lesions associated with
benign nature of the ocular lesion, associated CNS vascular von Hippel-Lindau disease may not become apparent for a
hamartomas may produce convulsions, intracranial hemor- number of years, especially because the previously docu-
rhage, cranial nerve palsies, and multiple neurologic deficits. mented cases were reported in individuals ranging in age
Not all vascular lesions within the substance of the optic from 15 to 44 years. Furthermore, the investigation of family
nerve are benign. Kerr et al. (452) described the case of a members in some of these cases may have been incomplete,
27-year-old woman with von Hippel-Lindau disease who leading to the erroneous conclusion that the disorder was
experienced progressive visual loss in the right eye. She had not familial.
a small capillary angioma of the right optic disc and a vascu- Melanocytomas are intraocular tumors that typically
lar mass of the intracranial portion of the right optic nerve occur within the substance of the optic disc (457–459). Clin-
ically, these lesions are elevated masses that are gray to dark
black in color and are located eccentrically on the disc (Fig.
8.27). About 90% are two disc diameters or less, and the
majority are less than 2 mm in height (459). Swelling of the
disc occurs in about 25% of cases and is thought to be caused
by a disturbance of axoplasmic flow secondary to chronic
compression. Vascular sheathing may be seen in 30% of
eyes, and subretinal fluid is observed in approximately 10%
of patients. A nevus may be seen adjacent to a melanocytoma
in up to 50% of cases (458). Constriction of the visual field
may also occur in patients with a melanocytoma of the optic
disc (355,460). Osher et al. (461) studied 20 patients with
optic disc melanocytomas; 14 of the patients had visual acu-
ity of 20/20 or better, and all patients had visual acuity of
20/50 or better. Only 5 of the patients studied were aware
of any visual distortion, but 18 of the 20 patients had abnor-
Figure 8.25. Neuroimaging appearance of cavernous angioma of the optic
mal visual fields. Three of these patients had minimal blind
nerve. The patient was a 23-year-old woman with progressive loss of vision spot enlargement; the remaining 15 patients had markedly
in the left eye and evidence of a retrobulbar optic neuropathy. T1-weighted enlarged blind spots, of whom 10 also had relative or abso-
MR image, axial view, after intravenous injection of contrast material shows lute arcuate scotomas. Six of these 10 patients had a relative
hyperintense enhancing lesion within the intracranial portion of the left afferent pupillary defect. However, not all patients with a
optic nerve. melanocytoma have good visual acuity. Some patients de-
B C
Figure 8.26. Neuroimaging appearance of hemangioblastomas of the optic nerve. A, In a 37-year-old man with von Hippel-
Lindau disease. CT scan, axial view, after intravenous injection of iodinated contrast material shows that the right optic nerve
has an enhancing fusiform appearance similar to that of an optic nerve glioma. The diagnosis was established at surgery. B,
In a 40-year-old woman, T1-weighted MR image, axial view, shows enlargement of the intracanalicular portion of the right
optic nerve (arrows). C, In the same patient as B, T1-weighted MR image, coronal view after intravenous injection of paramag-
netic contrast material shows enlarged, enhancing right optic nerve within the optic canal. Note normal sized optic nerve on
left (arrow) (A, From Tanaka E, Kimura C, Inoue H, et al. A case of intraorbital hemangioblastoma of the optic nerve. Folia
Ophthalmol Jpn 1984;35⬊1390–1395. B and C, From Kerr J, Scheithauer BW, Miller GM, et al. Hemangioblastoma of the
optic nerve: Case report. Neurosurgery 1995;36⬊573–579.)
velop an associated central retinal artery occlusion, central Histologically, melanocytomas are composed of two types
retinal vein occlusion (462), and some develop ischemic ne- of cells (468). The predominant cells are plump polyhedral
crosis of the tumor and surrounding neural tissue (463–465). nevus cells containing numerous giant melanosomes. These
The underlying mechanism in both settings is believed to cells show advanced differentiation and appear to be meta-
be compression of large and small vessels of the disc and bolically inactive. The second cell type is a smaller, lightly
spontaneous improvement of vision can occur if infarction pigmented, spindle-shaped cell that is more metabolically
of the melanocytoma allows decompression of the remaining active.
nerve fibers(466). Melanocytomas are benign tumors that do not require
A case of apparent neuroretinitis with recovery of vision therapy. The majority are likely congenital but development
was reported by Garcia-Arumi et al. (467) in a patient with of this lesion has been described in an adult (469). Joffe et
a melanocytoma. The disorders may have been coincidental al. obtained follow-up data of 1 year or more in 27 patients
rather than directly related; however, it is possible that an with optic disc melanocytomas (459). No change in the ap-
infarction of the tumor could have caused leakage into the pearance of the lesion had occurred in 22 of the eyes, but 4
retina, clinically mimicking the ophthalmoscopic appear- lesions showed a slight increase in size over a period varying
ance of neuroretinitis. from 5 to19 years. None of the patients showed any changes
A B
Figure 8.27. A, Melanocytoma of the optic disc. The optic disc is almost completely obscured by an elevated black mass.
The mass is much darker than a malignant melanoma. B, Histologic appearance of an optic disc melanocytoma. Note significant
disc elevation. (From Hogan MJ, Zimmerman LE. Ophthalmic Pathology: An Atlas and Textbook, Ed 2. Philadelphia, WB
Saunders, 1962⬊610.)
suggestive of malignant transformation, although a case of larly when the lesion is not changing in size or shape (473)
melanoma occurring within a melanocytoma has been re- (Fig. 8.28). Ocular coherence tomography may ultimately
ported (470). prove to be a useful tool in the distinct of melanocytoma
The deep black appearance of melanocytomas generally from melanoma (474).
allows them to be differentiated not only from optic disc Green et al. (475) reported the unique case of a 6-year-
swelling, but also from other lesions that infiltrate the optic old girl who developed pain, proptosis, and progressive loss
disc, particularly malignant melanomas. Nevertheless, the of vision in the right eye. The eye was subsequently enucle-
distinction can be difficult in rare cases (471,472), particu- ated, at which time it was noted that the optic nerve was
Figure 8.28. Malignant melanoma of the choroid invading the optic disc. A, The disc tissue is elevated and shows areas of
pigmentation with partial obscuration of vessels and blurring of disc margins. B, Histologic appearance of a juxtapapillary
malignant melanoma invading the optic nerve.
infiltrated by a malignant teratoid medulloepithelioma. curs. This makes the diagnosis relatively straightforward,
The patient subsequently underwent craniotomy and re- whereas most patients with a tumor that spreads contigu-
moval of the entire right optic nerve. ously to the optic nerve are not known to harbor a tumor
when they first experience loss of vision. Nevertheless, any
Secondary Tumors person with known cancer in another part of the body, with
or without other evidence of metastases, who develops an
The most common secondary tumors that infiltrate the
optic neuropathy should be suspected of having cancer as
optic nerve are metastatic and locally invasive carcinomas
the cause until proven otherwise. Similarly, any patient with
and various lymphoreticular malignancies, particularly lym-
a basal skull tumor who develops an optic neuropathy should
phoma and leukemia.
be assumed to have spread of tumor to the optic nerve, unless
Metastatic and Locally Invasive Tumors there has been previous radiation therapy to the region, in
which case the possibility of radiation-induced optic neurop-
The optic nerve may be the site of metastasis from distant athy must also be considered (see Chapter 7).
tumors or of spread of tumor from a contiguous structure. Contiguous spread of primary tumors from the paranasal
Metastases can reach the optic nerve by one of four routes: sinuses, brain, and adjacent intraocular structures to the optic
from the choroid; by vascular dissemination; by invasion nerve occurs much less often than does metastasis to the
from the orbit; and from the CNS (346,476–479). Regardless nerve (491). A unique case of an esthesioneuroblastoma pre-
of the mode of spread, the substance of the nerve is affected senting with unilateral blindness in an 11-year-old girl was
more often than the sheath. In one large series reported by reported by Berman et al. (492). Initially, the child was
Shields et al., metastases to the optic disc occurred in 30 thought to have suffered from a postviral demyelinating le-
(4.5%) of 660 patients with ocular metastases (480). The sion; however, when vision failed to improve, MR imaging
disease occurs more frequently in women. was performed and revealed a lesion in the ethmoid and
Patients with metastases to the optic nerve usually have sphenoid sinuses that pathologically was an esthesioneu-
evidence of an optic neuropathy. The visual loss is usually roblastoma. Adenoid cystic carcinoma of the lacrimal gland
severe, but relatively normal vision may be present in the has been reported to cause a steroid responsive optic neurop-
early stages. Any type of field defect may be present. A athy that simulated an orbital inflammatory syndrome (493).
relative afferent pupillary defect is usually present unless Rarer than cases of metastatic or locally invasive tumors
the patient has bilateral optic nerve metastases or the oppo- of the optic nerve, are cases of ‘‘tumor within a tumor’’ or
site retina or optic nerve has previously been damaged by so-called ‘‘collision tumors.’’ Arnold et al. (494) docu-
some other condition. When the metastasis is located in the mented a case of an adenocarcinoma of the lung metastatic
prelaminar or immediately retrolaminar portion of the optic to an optic nerve meningioma. These authors reviewed the
nerve, the optic disc is usually swollen; a yellow-white mass available literature on this phenomenon and documented 46
can be seen to protrude from the surface of the nerve (Fig. previously reported cases. Renal cell carcinoma seems to be
8.29) and clumps of tumor cells can occasionally be seen in the best recipient or host tumor to ‘‘attract’’ other cancers,
the vitreous overlying the disc (107,478,481,482). A juxta- with lung carcinoma being the most common primary tumor
papillary choroidal component is frequently seen. A central to metastasize to the site.
retinal occlusion occurs in up to 50% of eyes. When the Because of its close anatomic association with the parana-
metastasis is to the posterior aspect of the orbital portion of sal sinuses, the optic nerve is frequently infiltrated or com-
the optic nerve or to the intracanalicular or intracranial por- pressed by cancer that arises in the sinuses or the nasophar-
tions of the nerve, the optic disc initially appears normal. ynx (495). In most cases, the tumor invades the posterior
The most common metastatic tumors to the optic nerve orbit or cavernous sinus, producing a syndrome that is char-
are adenocarcinomas, primarily because these are the most acterized by loss of vision, diplopia, ophthalmoparesis, and
common metastatic tumors to all parts of the body. In trigeminal sensory neuropathy (496). Brain invasion can re-
women, carcinomas of the breast and lung are the most com- sult in the Foster Kennedy syndrome (497). Prasad and Dora-
mon tumors, whereas carcinomas of the lung and bowel are isamy (498) reported five patients with nasopharyngeal can-
most common in men (478,480,483–486). Other tumors that cers that infiltrated the optic nerve. In three of these patients,
can metastasize to the optic nerve include carcinomas of the tumor reached the nerve by extending through the roof
the stomach (487), pancreas, uterus, ovary, prostate, kidney, of the fossa of Rosenmuller. In another patient, the spread
larynx (488), and tonsillar fossa. Shields et al. (480) reported was extracranial via the pterygopalatine fossa and the poste-
that in 6 of 30 (20%) patients the primary tumor was un- rior ethmoid sinus. In the fifth patient, the route of spread
known. Fine needle aspiration can occasionally be used to could not be determined.
establish the diagnosis (480). Skin cancers, malignant mela- Neuroimaging should be performed in all patients sus-
noma, and mediastinal tumors also may metastasize to one pected of having infiltration of the optic nerve by cancer.
or both optic nerves. Isolated metastases to the optic nerve CT scanning typically shows an enhancing nerve that may
of intracranial tumors, such as medulloblastomas, may rarely or may not be enlarged (Fig. 8.30). On MR imaging, either
occur (489,490). a circumscribed area of optic nerve enlargement is identified
Most patients with metastatic tumor to the optic nerve (499) or, more commonly, the nerve is usually diffusely en-
already have a known diagnosis of a primary carcinoma with larged similar to a meningioma (107,108,486) or may show
other evidence of metastases at the time that visual loss oc- varying T1 and T2 values that are presumed to be related
Figure 8.29. Metastatic adenocarcinoma to the optic disc. A, Breast carcinoma in a 47-year-old woman. Entire optic disc is
infiltrated by a large mass of yellow-white tissue. Note loss of normal disc architecture. There were numerous malignant cells
in the vitreous. B, Lung carcinoma in a 56-year-old man. Note white mass protruding from disc surface. C, Breast carcinoma
in a 60-year-old woman. Note the massive infiltration and elevation of disc and surrounding retina. D, Appearance at autopsy
of optic nerve infiltration by adenocarcinoma of the lung.
Figure 8.30. Neuroimaging appearance of infiltration of optic nerve by

metastatic carcinoma. CT scan, axial view, in a 56-year-old woman with
small-cell carcinoma of the lung and progressive loss of vision in the left
eye associated with a massive retinal infiltrate with nasal retinal detachment
reveals that the orbital portion of the left optic nerve is diffusely enlarged.
(From Allaire GS, Corriveau C, Arbour J-D. Metastasis to the optic nerve:
Clinicopathological correlations. Can J Ophthalmol 1995;30⬊306–311.)
to associated hemorrhage or exudates. Tumors with a ten- tration of the retrobulbar optic nerve and optic chiasm occurs
dency to metastasize to bone, such as prostate and carci- in patients with both Hodgkin’s disease and NHL
noma, can present with optic canal involvement and a ret- (517–538). In most of these cases, the infiltration occurs
robulbar optic neuropathy (500). from spread of CNS tumor; however, Park and Goins (539)
Most metastatic optic nerve tumors show at least tempo- reported a patient with Hodgkin’s disease in whom there
rary response to radiation therapy. Some, however, do not was infiltration of the optic nerve, apparently from extension
(499,501). Tumors that spread contiguously to the optic of tumor from the adjacent maxillary and sphenoid sinuses.
nerve from the base of the skull or paranasal sinuses are Patients with systemic lymphoma and orbital mass lesions
typically less radiosensitive than metastatic tumors and also may also develop a compressive optic neuropathy (540).
tend to be less responsive to chemotherapy. A mean survival In many cases of lymphomatous infiltration of the anterior
of 13 months was reported by Shields et al. (480) for their visual sensory pathway, the patient is known to have NHL
30 patients with optic disc metastases. or Hodgkin’s disease at the time visual signs and symptoms
Meningeal tumor cuffing or direct infiltration of the optic develop, and the diagnosis is not in doubt (522). In other
nerve can cause loss of vision in the setting of meningeal cases, however, the visual loss is the presenting sign of the
spread of carcinoma (502–504). This phenomenon is called disease (517,521,529,541) or an isolated manifestation of
carcinomatous meningitis or meningeal carcinomatosis disease recurrence (531).
(the latter being the preferred term because it does not imply The symptoms and signs of patients with lymphomatous
an inflammatory process). The optic neuropathy that occurs infiltration of the anterior visual system depend on the loca-
in the setting of meningeal carcinomatosis is usually associ- tion and extent of the lesion. In some cases, the visual loss
ated with a ‘‘diagnostic quartet’’ that consists of (a) head- is insidious in onset and slowly progressive (534). In other
aches typical of raised intracranial pressure; (b) blindness; cases, the visual loss is acute and mimics optic neuritis or
(c) sluggish or absent pupillary reflexes; and (d) normal- ischemic optic neuropathy (521,531,533). Secondary retinal
appearing optic discs (505). vein and retinal artery occlusions have been described in
The frequency of optic nerve involvement in patients with conjunction with lymphomatous infiltration of the optic
carcinomatosis of the meninges is unclear. Katz et al. (506) nerve (516,538). Successful treatment has been described
reviewed 39 cases from the literature and indicated that vis- with steroids, chemotherapy, and radiation therapy.
ual loss occurred in 30–40% of patients with this disorder. The appearance of optic nerve or chiasm infiltration by
This figure agrees with that of Fischer-Williams et al. (507); lymphoma is nonspecific. The infiltrated structure is en-
however, Little et al. (508) and Olson et al. (509) found larged and reveals increased density on CT scanning; it en-
evidence of involvement of the optic nerves in only about hances after intravenous injection of iodinated contrast mate-
15% of cases of meningeal carcinomatosis in their series. rial. The same structure can be iso-, hyper-, or hypointense
Patients who develop meningeal carcinomatosis with visual on T1-weighted MR images; is hyperintense on T2-weighted
loss may do so after the primary lesion, usually in the lung MR images; and enhances after intravenous injection of
or breast, has already been diagnosed. In other cases, visual paramagnetic contrast material (Fig. 8.31).
loss may occur coincident with other signs of chronic menin- Angioimmunoblastic lymphadenopathy is a proliferative
gitis (510) or as an isolated finding as the first sign of disease disease of the lymphoid system from which a malignant lym-
(511). Although blindness may begin in one eye, both eyes phoma may arise, and for which the etiology is unknown.
are usually affected within a short period of time. In rare Matthews et al. (527) reported the case of a patient with
instances, visual loss remains strictly unilateral (512). A sim- this condition who developed a retrobulbar optic neuropathy
ilar presentation has been described in patients with germi- from infiltration of the nerve by lymphoma cells.
nomas and vision loss resulting from secondary optic nerve Multiple myeloma, lymphomatoid granulomatosis, and
seeding through the CSF (513). Langerhans cell histiocytosis can all produce an optic neu-
Histopathologic examination of cases with meningeal car- ropathy (518,542–546). In some of these cases, the optic
cinomatosis and blindness generally shows marked cuffing neuropathy, which may be of the anterior or retrobulbar vari-
of the subarachnoid space of the optic nerve by sheets of ety, appears to be produced by infiltration of the nerve (547)
malignant cells, with little invasion of the nerves themselves. rather than from compression (548,549). Bourdette and Ro-
Thus, in some cases, there is true infiltration, whereas in senberg (550) reported the case of a patient with polyneurop-
other cases, the lesion is more compressive than infiltrative. athy, organomegaly, endocrinopathy, monoclonal gammop-
athy, and skin changes (POEMS syndrome) who developed
Lymphoreticular Tumors an infiltrative orbitopathy characterized in part by enlarge-
ment of the blind spot in the visual field of the eye on the
CNS involvement in non-Hodgkin’s lymphoma (NHL) affected side. Although it was unclear if the optic nerves
is unusual, but it occurs in about 10% of cases (514). Of were infiltrated or compressed by myeloma cells, the condi-
these, 5% (or a total of 0.5% of patients with NHL) will tion improved after the patient was treated with systemic
have infiltration of the optic nerve at some time during the corticosteroids. Galetta et al. (551) and Anthony (552) re-
course of their disease (515). Isolated optic nerve infiltration ported patients who developed an optic neuropathy in the
can also be the sole manifestation of recurrent non-Hodg- setting of reactive lymphohistiocytosis associated with lym-
kin’s lymphoma (516). Infiltration of the optic nerve in phoma or pseudolymphoma syndrome secondary to the use
Hodgkin’s disease is even less common. Nevertheless, infil- of diphenylhydantoin. Pless et al. (546) reported a patient
globes of 76 patients who died of various neoplastic pro-

cesses of the reticuloendothelial system. The patients ranged
in age from 11 months to 80 years. These authors found
infiltration of the optic disc in five patients with leukemia.
Three of the patients had acute lymphocytic leukemia; one
had acute myelogenous leukemia; and one had monocytic
leukemia. In addition, Allen and Straatsma (553) studied 10
optic nerves in which there was retrolaminar infiltration.
Five of the patients had acute lymphocytic leukemia; two
had monocytic leukemia; one had acute myelogenous leuke-
A mia; one had erythroleukemia; and one had chronic lympho-
cytic leukemia (CLL). Clinically, these patients were said
to have ‘‘blurring of the optic nerve head margins (or) frank
papilledema.’’ However, Allen and Straatsma did not at-
tempt to distinguish between the clinical picture seen in pa-
tients with infiltration of the optic disc and that seen in pa-
tients with retrolaminar infiltration.
Eichholtz (570) reported 11 patients with lymphoprolifer-
ative disorders, primarily leukemia, who developed optic
disc swelling. In 9 eyes of 6 patients, visual acuity was 20/
200 or worse. Visual acuity improved markedly after orbital
B irradiation in four of five patients. Rosenthal et al. (571)
reported five children with leukemia who had infiltration of
the optic nerve (one of whom was the original patient re-
ported by Ellis and Little (572). All of the patients had a
form of acute lymphoblastic leukemia, and in four of the
five patients, optic nerve involvement appeared between 7
and 20 months after their systemic disease had been diag-
nosed. These authors were the first to emphasize the two
distinct clinical patterns of infiltration: (a) infiltration of the
optic disc; and (b) infiltration of the immediate retrolaminar
portion of the proximal optic nerve.
In leukemic infiltration of the optic disc, the features of
the disc are obscured by a whitish fluffy infiltrate that is
often associated with true disc swelling and peripapillary
C hemorrhage (Fig. 8.32). The visual acuity in such patients
is minimally affected, unless the infiltration or associated
Figure 8.31. Neuroimaging appearance of infiltration of the left optic
nerves by a B-cell lymphoma.
edema and hemorrhage extends into the macula. Chalfin et
al. (573) reported an excellent example of this condition.
The patient had acute myelocytic leukemia and experienced
sudden decreased vision in the right eye down to light per-
ception. Ophthalmoscopy revealed a well-circumscribed,
with extranodal Rosai Dorfman disease (sinus histiocytosis white, fairly avascular mass that both infiltrated and ob-
without diffuse lymphadenopathy) who developed a com- scured the optic disc and macula. Postmortem examination
pressive optic neuropathy from an orbital apex lesion associ- revealed that the mass originated from the optic disc and
ated with uveitis and skin nodules. that there was massive infiltration of the disc with leukemic
Leukemia is a well-described cause of infiltrative optic cells with minimal extension of small clusters of cells to the
neuropathy (553–568). In some of the patients, visual acuity laminar and retrolaminar optic nerve and retina. A similar
is lost abruptly, whereas in others, there is a gradual progres- case reported by Ellis and Little (572) noted the presence
sion of visual loss over days, weeks, or months. In still oth- of a clinic picture suggestive of papilledema (high opening
ers, the disc appears swollen, but there is no evidence of pressure and good visual function) in a patient with leukemia
visual dysfunction. Most patients with leukemic infiltration who was subsequently found on postmortem to have leu-
of the optic nerve are known to have leukemia at the time kemic infiltration of the optic nerve extending into the adja-
the visual loss occurs or the patient is found to have asymp- cent retina and overlying vitreous.
tomatic disc swelling; however, in some cases, as occurs in According to Rosenthal et al. (571), infiltration of the
patients with lymphomatous infiltration of the optic nerve proximal optic nerve just posterior to the lamina cribrosa
(see above), the optic neuropathy is the first evidence of the usually produces markedly decreased visual acuity associ-
disease (558,569). Allen and Straatsma (553) studied the ated with true optic disc swelling (Fig. 8.33). Such patients
larged optic nerve that usually enhances after intravenous

injection of contrast material (565). In other patients there
may be a paucity of findings on both ophthalmoscopy and
MR imaging (562,568).
Ridgway et al. (574) examined 657 children with acute
leukemia and found optic nerve infiltration in 29 (4.4%). As
in the patients described by Rosenthal et al. (571), most of
the patients had decreased vision, blurred optic discs and,
rarely, eye pain. All but one of the patients had evidence of
CNS leukemia. Charif Chefchaouni et al. (566) reported on
196 children treated for leukemia and found 12 with ocular,
orbital, or optic nerve involvement. Two of these 12 had
optic nerve infiltrative lesions with the others having either
orbital or anterior segment involvement. Murray et al. (575)
discussed the difficulties involved in identifying the etiology
of elevated, pale, swollen optic discs in patients with leuke-
mia and reported the clinical features in three such patients.
The response of leukemic infiltration of the optic nerve
to radiation therapy is usually rapid and dramatic. In almost
Figure 8.32. Leukemic infiltration of the optic disc mimicking optic disc
all cases, visual function returns to normal or near normal,
swelling in a child with acute lymphocytic leukemia. The child was thought and the disc elevation, if present, resolves (571). Even
to be in remission at the time the abnormality was discovered. The disc is though some patients do not respond to this treatment
whitish gray and markedly elevated with obscuration of vessels. Visual (576,577), radiation therapy is the treatment of choice for
acuity was 20/25. optic nerve infiltration in the setting of acute leukemia
(561,564,578). In addition, Brown et al. (557) successfully
treated a patient with an infiltrative optic neuropathy in the
have a variety of visual field defects, and a relative afferent setting of acute promyelocytic leukemia with transretinoic
pupillary defect is invariably present unless the infiltration acid. This form of acute leukemia results from a chromo-
is bilateral and symmetric. In addition, there are often peri- some translocation that is associated with the retinoic acid
papillary and peripheral retinal hemorrhages (571). Neu- receptor gene (579), and transretinoic acid works by stimu-
roimaging in such cases typically reveals a diffusely en- lating the terminal differentiation of the malignant cells so
that they become normal lymphoid cells.
It must be emphasized that swelling of the optic disc can
occur in patients with acute leukemia when CNS involve-
ment by the disease results in increased intracranial pressure.
Optic disc swelling and neovascularization also occur as a
local phenomenon in the setting of the diffuse retinopathy
of acute leukemia (571,580). Thus, one must consider a num-
ber of pathologic mechanisms in addition to infiltration in
any patient with acute leukemia and apparent optic disc
swelling. Additionally, myeloproliferative disorders associ-
ated with extramedullary hematopoiesis have been reported
to cause both an enhancing lesion of the orbital apex and
canal resulting in an orbital apex syndrome (581) and a com-
pressive optic neuropathy from skull base involvement
(582).
The acute leukemias are responsible for most of the re-
ported cases of infiltrative optic neuropathies caused by lym-
phoreticular disorders; however, patients with chronic forms
of leukemia may also develop optic nerve infiltration. In a
review of autopsy material from the Massachusetts General
Hospital, Cramer et al. (583) found a high percentage of
asymptomatic CNS involvement in patients with CLL. In
addition, they documented 4 cases of infiltrative optic neu-
ropathy among 21 reported cases of CNS CLL. Patients with
Figure 8.33. Optic disc swelling in a child with acute leukemia. The disc optic nerve infiltration in the setting of CLL and other
is swollen and hyperemic. Visual acuity was 20/80, and there was a central chronic leukemias have a more indolent clinical course than
scotoma. The patient was thought to have leukemic infiltration of the proxi- patients with the acute leukemias. Visual loss is less severe,
mal retrobulbar portion of the optic nerve. and retinal changes of the type seen in acute leukemia are
rare. Optic disc swelling, however, is indistinguishable from ropathy with disc pallor, an ischemic optic neuropathy, or
that which occurs in patients with infiltration in the setting anterior or retrobulbar optic neuritis (592). Optic disc pallor
of acute leukemia. is the most common finding. The optic neuritis results from
granulomatous infiltration of the optic disc, anterior orbital,
INFLAMMATORY AND INFECTIOUS INFILTRATIVE posterior orbital, intracanalicular, or intracranial portions of
OPTIC NEUROPATHIES the nerve, or a combination of these. In some cases, more
than one process may be responsible. It is noteworthy that
The intraocular, intraorbital, intracanalicular, and intra- the vast majority of patients do not have associated uveitis
cranial segments of the optic nerve can all be infiltrated by at the time of presentation with optic neuropathy. In Froh-
inflammatory and infectious processes. The most common man et al.’s series (592,595) approximately 70% of patients
inflammatory process that produces an infiltrative optic neu- had elevated angiotensin-converting enzyme (ACE) levels,
ropathy is sarcoidosis. The most common infectious pro- abnormal chest x-rays, and abnormal MR imaging of the
cesses that produce an infiltrative optic neuropathy are syph-
anterior visual pathways. Over 90% had abnormal gallium
ilis, tuberculosis, and opportunistic fungal infections, such as
scans. Pleocytosis or increased spinal fluid protein was noted
cryptococcosis. These conditions are all discussed in greater
in 88% of patients.
detail in other chapters in this text.
Granulomatous infiltration of the optic disc may or may
not be associated with evidence by neuroimaging or ultraso-
Sarcoidosis
nography of diffuse enlargement of the orbital portion of the
Optic nerve dysfunction probably is the most common optic nerve (586,591,596–609). The optic disc in such cases
neuro-ophthalmologic manifestation of sarcoidosis (584– usually is markedly elevated, either diffusely or sectorally
592). The optic nerve may be affected at any time during (Figs. 8.34 and 8.35), and it often has a solid or nodular
the course of the disease and may be the site of its initial appearance that can best be demonstrated using ultrasonog-
presentation in up to 70% of patients (592–594). Women raphy (69,610). There may be dilated vessels resembling
are affected more commonly than men. Sarcoidosis may af- neovascularization on the surface of the disc (601,611–613).
fect the optic nerve in several different ways. It may produce The appearance of optic disc infiltration by sarcoid granu-
papilledema, a compressive anterior or retrobulbar optic neu- lomas may mimic that of papilledema, except that this condi-
Figure 8.34. Sarcoid granulomas infiltrating the optic disc. A, In a 25-

year-old woman with visual acuity of 20/20 OU there is a small elevated
yellow-white mass overlying the nasal portion of the left optic disc. A
small hemorrhage is just nasal to the mass. (From Laties AM, Scheie
HG. Evolution of multiple small tumors in sarcoid granuloma of the optic
disk. Am J Ophthalmol 1972;74⬊60–66.) B, In another patient, the entire
disc is infiltrated by granulomas. Note diffuse symmetric elevation of the
disc substance. C, In a third patient, a multinodular granuloma has infil-
trated the left optic disc. (From Jampol LM, Woodfin W, McLean EB.
Optic nerve sarcoidosis. Arch Ophthalmol 1972;87⬊355–360.)
Figure 8.35. Pathology of granulomatous infiltration

of the left optic disc in sarcoidosis. The eye was enucle-
ated after the patient developed painful glaucoma. A,
Axial section through the left globe shows a mass occu-
pying the optic disc and protruding into the eye. (He-
matoxylin and eosin ⳯2.5.) B, High-power view
shows that the normal architecture of the disc has been
replaced by granulomatous inflammation. (Hematoxy-
lin and eosin ⳯5.) (From Beardsley TL, Brown SVL,
Sydnor CF, et al. Eleven cases of sarcoidosis of the
optic nerve. Am J Ophthalmol 1984;97⬊62–77.)
tion is more often unilateral than bilateral, and it is usually tomas, and menigiomas (618). In other cases, the diagnosis
associated with decreased vision, slit-lamp biomicroscopic is not confirmed until a biopsy of the nerve is performed
and ophthalmoscopic evidence of intraocular inflammation, (591).
neuroimaging evidence of an intracranial process affecting The posterior retrobulbar or intracanalicular portion of the
the base of the skull, or a combination of these. When the optic nerve is occasionally affected by sarcoid (619). In such
process is bilateral, however, the disc swelling may easily cases, the patient develops acute or, more often, progressive
be mistaken for papilledema (614), even though diagnostic loss of vision associated with evidence of an optic neuropa-
studies are nonconfirmatory. James et al. (615), for example, thy. The optic disc in such cases is normal but gradually
described four patients with sarcoidosis who developed becomes pale if no treatment is given. The neuroimaging
‘‘papilledema’’ during the course of their disease. However, appearance is variable. The posterior orbital portion of the
lumbar puncture in three of the four patients revealed normal optic nerve may be enlarged and may enhance after contrast
intracranial pressure, suggesting that the optic disc swelling injection on both CT scanning and MR imaging (Fig. 8.38).
in these cases was caused by inflammation of the intraocular Isolated optic nerve sheath enhancement may also be seen
or anterior orbital portions of the optic nerves and not by on MR imaging (620).
increased intracranial pressure. Peripapillary choroidal gran-
ulomas (without phlebitis or vitritis) (Fig. 8.36) secondary
to sarcoidosis can present with vision loss and visual field
defects and be difficult to distinguish from direct optic nerve
involvement. This can be complicated by peripapillary cho-
roidal neovascularization (616,617).
When the proximal portion of the intraorbital optic nerve
is infiltrated by granulomatous inflammation in patients with
sarcoidosis, the condition typically presents as an acute, sub-
acute, or rarely, chronic optic neuritis. The patient typically
experiences progressive loss of vision, decreased color vi-
sion, and a worsening visual field defect. A relative afferent
pupillary defect is present unless there is also a contralateral
optic neuropathy. The optic disc is swollen. This condition
may be impossible to differentiate clinically from demyelin-
ating optic neuritis and even from certain causes of compres-
sive optic neuropathy, particularly optic nerve sheath menin-
gioma. Even ultrasonography, which reveals enlargement
of the orbital portion of the nerve in almost all cases, and
neuroimaging, which shows enlargement and enhancement
of the orbital portion of the optic nerve (Fig. 8.37) cannot
establish the diagnosis with certainty. In some cases, the Figure 8.36. Fundus photograph of a patient with sarcoidosis who pre-
diagnosis is made by finding clinical, radiographic, or labo- sented with decreased vision and blindspot enlargement. There was no vi-
ratory evidence of sarcoidosis. MRI findings can mimic tritis or phlebitis. Diffuse, nodular, yellow, peripapillary subretinal granu-
those seen in multiple sclerosis, metastatic tumors, astrocy- loma are seen and the optic disc margins are obscured.
Figure 8.37. CT scanning of optic nerve sarcoidosis. A, Bilobed mass

projecting from the medial aspect of the left optic disc in a patient with
sarcoidosis. Note optociliary shunt vessel (arrowhead). B, CT scan, axial
view, after intravenous injection of contrast material shows diffuse thick-
ening and enhancement of the orbital portion of the left optic nerve. C,
CT scan, axial view, after intravenous injection of contrast in another
patient with painless progressive loss of vision in the right eye and biopsy
proven sarcoidosis shows diffuse enlargement and enhancement of the
orbital portion of the right optic nerve. Note the ‘‘kinking’’ of the nerve,
similar to that seen in patients with optic nerve glioma in the setting of
neurofibromatosis type 1. D, CT scan, axial view, after intravenous con-
trast enhancement at a slightly higher plane in the same patient as C shows
intracranial extension of the optic nerve lesion (arrow). E, sarcoidosis at
left orbital apex minimizing an apex meningioma on axial CT scanning.
(A and B, from Lustgarden JS, Mindel JS, Yablonski ME, et al. An unusual
presentation of isolated optic nerve sarcoidosis. J Clin Neuroophthalmol
1983;3:13–18.) (C and D, from Jordan DR, Anderson RL, Nerad JA, et
al. Optic nerve involvement as the initial manifestation of sarcoidosis.
Can J Ophthalmol 1988;23⬊232–237.)
Figure 8.38. MR imaging in patients with sarcoidosis of the optic nerves. A, T1-weighted, fat-suppressed MR image, axial
view, after intravenous injection of paramagnetic contrast material in a 52-year-old woman with progressive loss of vision in
the right eye shows irregular enhancement of the right optic nerve near the apex of the orbit and within the optic canal (open
arrows). The intracranial portions of the optic nerves and the optic chiasm do not enhance and appear normal in size and shape
(solid arrows). B, Enhanced, T1-weighted, fat-suppressed MR image, coronal view, in the same patient shows enlargement
and abnormal enhancement of the orbital portion of the right optic nerve (black arrow). The left optic nerve is normal in size
and does not enhance (large white arrow); however, there is mild enhancement of its leptomeningeal sheath (small white
arrows). A biopsy of the right nerve revealed noncaseating granulomas. C, Enhanced, T1-weighted, fat-suppressed MR image,
coronal view, in another patient with sarcoidosis and progressive bilateral loss of vision with evidence of bilateral optic
neuropathies reveals enlargement and abnormal enhancement of the orbital portions of both optic nerves. The right optic nerve
is slightly larger than the left. Note mild enhancement of the leptomeningeal sheath of the left optic nerve (arrow). D, Enhanced,
T1-weighted, fat-suppressed MR image, axial view, in the same patient shows enlargement and abnormal enhancement of both
optic nerves throughout the orbits, with extension through the optic canal on the right side. (From Engelken JD, Yuh WTC,
Carter KD, et al. Optic nerve sarcoidosis: MR findings. AJNR 1992;13⬊228–230.)
Because of the predilection of neurosarcoidosis to affect have optic nerve meningiomas based on clinical presenta-
the basal meninges, the intracranial portion of one or both tions and imaging studies, but who were ultimately diag-
optic nerves and the optic chiasm may occasionally be af- nosed by pathologic examination as having a perioptic in-
fected by the disease, producing a variety of patterns of vis- flammatory process (two with active inflammation and two
ual loss (621,622). In some patients, loss of vision occurs with only fibrotic changes). These patients had no signs or
as an isolated phenomenon, either simultaneously in both symptoms of a systemic process. They ranged in age from
eyes or in one eye followed within days to weeks by loss 22 to 57 years; 3 were female and 1 was male. Three of
of vision in the other eye (594). In other patients, visual loss these patients had experienced orbital pain. All four had
is associated with evidence of hypothalamic dysfunction, cecocentral scotomas, and one also had significant peripheral
hypothalamic hypopituitarism (particularly gonadotropin constriction. MRI scanning generally showed enhancement
failure), or both (228,622–624). of the optic nerve sheath as opposed to the nerve itself (Fig.
Aszkanazy (625) reported two patients with bitemporal 8.39) (627).
hemianopia. One showed granulomatous infiltration of the Similar cases were reported by other investigators
optic chiasm, the prechiasmal region, and the base of the (49,627–630). Purvin et al. (627) reported 14 patients and
brain at autopsy. The other had a sarcoid granuloma that noted a wide age range and varying levels of visual function.
extended from the chiasm into the 3rd ventricle. Morax (597) Patients responded to steroids, although some had recurrence
described a sarcoid granuloma that infiltrated both optic when steroid doses were reduced. Paracental scotoma and
nerves and the optic chiasm, producing severe bilateral loss arcuate defects were the most common visual field defects.
of vision. This entity also occurs in patients with infections, especially
Tang et al. (623) described four patients with sarcoidosis syphilis which must be excluded (104,631), and has been
who had visual findings similar to those reported by Decker described in a patient who simultaneously had neuroretinitis
et al. (228). All four had profound loss of vision in one (632). The use of enhanced, fat-suppressed MR images has
eye with a temporal field defect in the contralateral eye. significantly increased the ability to visualize inflammatory
Neuroimaging studies showed no abnormalities in one pa- perineuritis (633). This technique is not specific for inflam-
tient (case 1) who was treated with prednisone with recovery matory perineuritis, but in the appropriate clinical setting,
of normal visual function in her previously better eye. In a the finding of an enhancing lesion on T1-weighted, fat-sup-
second patient (case 3), radiographic studies demonstrated pressed images is highly suggestive of this disorder.
enlargement of the right optic canal with enlargement of the
optic chiasm and the intracranial portion of the right optic Infectious Disorders
nerve. The patient eventually underwent a craniotomy, at
which time the right optic nerve and the optic chiasm were According to Paufique and Etienne (634), Cruveilhier de-
indeed found to be enlarged. A biopsy from the region re- scribed the first case of tuberculoma involving the optic
vealed evidence of granulomatous infiltration consistent nerve in 1862. Since this time, approximately 15 cases have
with sarcoidosis. The other two patients (cases 2 and 4) had been reported (635,636). In some cases, the tuberculoma is
evidence of a suprasellar mass by neuroimaging studies that adjacent to the optic nerve and is part of a dense adhesive
was found to be a mass of granulomatous tissue consistent arachnoiditis that may or may not be separable from the
with sarcoidosis by craniotomy in one case and autopsy in surrounding structures (637). In other cases, however, the
the other. inflammatory tissue may actually invade the nerve (635,638)
or be completely contained within the intracranial portion
Perioptic Neuritis of the optic nerve (636).
Dutton and Anderson (626) reported on four patients with It may be inferred from the documented intracranial and
unilateral progressive loss of vision who were thought to intracanalicular optic nerve invasion by tuberculomas and
Figure 8.39. Axial T1-weighted, fat-suppressed, enhanced

MRI scan of optic perineuritis. Optic nerve sheath enhance-
ment (arrows) is seen bilaterally.
sarcoid granulomas that syphilitic gummas may act in a simi- tomographic diagnosis of orbital glioma and meningioma. Ophthalmology 1984;
91:137–155.
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CHAPTER 9
Traumatic Optic Neuropathies
Kenneth D. Steinsapir and Robert A. Goldberg
CLASSIFICATION PATHOGENESIS
EPIDEMIOLOGY Injury Mechanisms
CLINICAL ASSESSMENT PHARMACOLOGY
History Experimental
Examination Clinical Experience
Visual Evoked Potential MANAGEMENT
Visual Field Early Studies
Imaging Megadose Steroids
Differential Diagnosis Surgical Considerations
PATHOLOGY
CLASSIFICATION
Optic nerve injuries are classically divided into direct and Disturbances in retinal circulation can be associated with
indirect injuries. Direct injuries are open injuries where an orbital hemorrhages that compromise the optic nerve. Avul-
external object penetrates the tissues to impact the optic sions of the optic nerve from the globe produce a distinct
nerve. Indirect optic nerve injuries occur when the force of picture with a partial ring of hemorrhage at the optic nerve
collision is imparted into the skull and this energy is ab- head (3) (Fig. 9.2). In contrast, posterior optic nerve injuries
sorbed by the optic nerve. The prognostic value in knowing occur posterior to the site where the central retinal artery
that an injury was direct or indirect is unclear. Historically, enters the optic nerve. The most common site of indirect
direct optic nerve injury is associated with a poor visual optic nerve injury is the bony optic canal, referred to as an
outcome. It may be safe to classify an optic nerve injury as intracanalicular injury (4,5). The intracranial optic nerve is
direct if orbital imaging reveals a bullet at the orbital apex, the next most common site of injury (6). Chiasmal injuries
but this provides no insight into the cellular injury mecha- can be diagnosed on the basis of visual field changes when
nism. The classification does not illuminate whether the this test can be obtained (7). Chiasmal injuries are associated
nerve is severed with no hope of recovery or only mildly with a high incidence of diabetes insipidus, reported to be
injured with significant recovery potential. This becomes 37% in one series (8). Neuroimaging is usually able to sepa-
important as strategies for treating nerve injuries evolve. rate intracanalicular injuries from orbital injuries occurring
Optic nerve injuries are also classified anatomically. Inju- posterior to where the central retinal artery enters the optic
ries that occur anterior to where the central retinal artery nerve. Orbital optic nerve injuries can be associated with
enters the optic nerve produce abnormalities in the retinal intrasheath hemorrhage, which anecdotally have benefited
circulation in association with visual loss (1,2) (Fig. 9.1). from clot drainage (9).
EPIDEMIOLOGY
Traumatic optic neuropathy occurs in association with vehicle and bicycle accidents are the most frequent cause,
high momentum deceleration injuries. Optic nerve injury is accounting for 17–63% of cases, depending on the series.
often associated with midface trauma. Table 9.1 lists the Motorcycle accident victims may be particularly vulnerable
most common causes of traumatic optic neuropathy. Motor to traumatic optic neuropathy. A consecutive series of 101
431
Figure 9.1. Central retinal vein occlusion in a case of anterior (proximal) optic neuropathy. The patient was a 24-year-old
man who was struck in the right eye while playing basketball and who immediately experienced loss of vision in the eye.
Visual acuity was light perception OD and 20/15 OS. A, Ophthalmoscopic appearance of right ocular fundus reveals moderate
swelling of the optic disc. The disc is surrounded by hemorrhage and soft exudates. The retinal veins are dilated and tortuous.
B, Computed tomographic (CT) scan, axial view, shows moderate enlargement of the orbital portion of the right optic nerve.
C, CT scan, coronal view, shows enlargement of right optic nerve compared with left nerve. Note small areas of increased
density, consistent with hemorrhage, with the enlarged nerve. (Courtesy of Dr. Neil R. Miller.)
Figure 9.2. Traumatic avulsion of the optic disc. Note ring

of hemorrhage around the optic disc. The site of avulsion is
clearly visible as a crescentic dark area at the temporal portion
of the disc (arrowhead). (Courtesy of Dr. Neil R. Miller.)
TRAUMATIC OPTIC NEUROPATHIES 433
Table 9.1
Etiology of Traumatic Optic Neuropathy
First Author Cases Motor Vehicle Bicycle Fall Assualt Other
Nau (22) 18 7 (39%) 2 (11%) 5 (28%) 1 (6%) 3 (17%)

Bodin (188) 6 1 (17%) 3 (50%) 2 (33%) – –
Millesi (189) 29 18 (62%) – 6 (21%) 5 (17%) –
Seiff (11) 36 15 (42%) – 13 (36%) 4 (11%) 4 (11%)
Anderson (178) 7 3 (43%) 1 (14%) 2 (12%) – –
Matsuzaki (174) 33 20 (60%) – 7 (21%) 4 (12%) 2 (6%)
Joseph (179) 14 2 (14%) 3 (21%) 4 (29%) 3 (21.4%) 2 (14%)
Spoor (13) 21 9 (43%) – 3 (14%) 4 (19%) 5 (24%)
Kountakis (190) 34 18 (51%) 1 (3%) 9 (26%) 5 (15%) –
Lubben (194) 65 15 (23%) 15 (23%) – 7 (11%) 33 (51%)
Total 263 107 (41%) 23 (9%) 52 (20%) 33 (13%) 51 (19%)
patients with head trauma after a motorcycle accident found matic optic neuropathy has been defined in the past as a
18 cases of traumatic optic neuropathy (18%) (10). Falls are subpopulation of individuals with head trauma (4,24). In a
the next most common cause, producing 14–50% of cases. large study of maxillofacial trauma patients, traumatic optic
Traumatic optic neuropathy has also resulted from frontal neuropathy occurred in 2.5% of patients with midface frac-
impact by falling debris (11,12), assault (11), stab wounds ture (25). The percentage of patients with light perception
(13), gun shot wounds (13,14), skateboarding (11), bottle- and no light perception vision following traumatic optic neu-
cork injuries (15), following seemingly trivial injuries (3,16), ropathy varies from 43% (13,26) to 78% (27) (Table 9.2).
and following endoscopic sinus surgery (17–20). Iatrogenic However, recent studies have higher percentages of patients
optic nerve trauma with visual loss is rare following elective with more subtle forms of traumatic optic neuropathy
LeFort I osteotomy. When it does occur, it may be related to (11,13,26). Patients with mild forms of traumatic optic neu-
uncontrolled and unpredictable pterygomaxillary disjunction ropathy were probably not identified in the older series
with propagation of the fractures into the optic canal (22). Optic nerve injury following orbital hemorrhage defines
Optic nerve injury is usually associated with concomitant an important subset that does not fit well into the classic
multi-system trauma or serious brain injury. Loss of con- delineation of direct and indirect optic nerve injuries (28,29).
sciousness is associated with traumatic optic neuropathy in The mechanism of neuropathy is an orbital compartment
40–72% of cases (11,21–23). The incidence of indirect trau- syndrome resulting in elevated orbital pressure compromis-
Table 9.2
Frequency of Improvement Over Initial Visual Acuity by Series in Chronological Order
Initial Visual Acuity
No Light Perception Light Perception or Better

a
First Author Cases Total Improved Total Improveda Treatment
Hooper (191) 58 14 3 – – –
Hughes (5) 90 51 14 39 NA –
Edmund (192) 22 17 4 5 NA Surgery
Anderson (178) 7 3 1 1 1 Surgery/corticosteroids
Matsuzaki (174) 33 8 0 25 14 Surgery/corticosteroids
Fujitani (175) 113 37 7 76 53 Surgery/corticosteroids
Seiff (11) 36 18 7 18 11 Observation/corticosteroids
Joseph (179) 14 5 3 9 8 Surgery/corticosteroids
Spoor (13) 22 8 5 14 14 Surgery/corticosteroids
Mauriello (57) 23 1 2 11 10 Surgery/corticosteroids
Chou (193) 58 32 13 26 15 Surgery/corticosteroids
Kountakis (190) 34 11 8 23 16 Surgery/corticosteroids
Lubben (194) 65 21 10 25 23 Surgery/corticosteroids
Wang (27) 61 48 13 13 13 Surgery/corticosteroids
Totals 636 274 90 (33%) 285 178 (62%)
Articles listed represent those series where sufficient visual acuity data was published to permit this analysis.
a
Visual improvement was defined as any improvement in visual function according to the authors of each listed article.
ing the circulation to the optic nerve. Orbital hemorrhage is also a recognized cause of potential visual loss (44). Or-
may occur spontaneously following thrombolytic therapy, bital hemorrhage is associated with alloplastic repair of or-
in association with surgery, childbirth, and in the presence bital fractures (45,46). Blood can be dispersed in the orbit,
of sickle cell disease as well as known coagulopathies in the subperiosteal space, and in the optic nerve sheath, or
(30–36). In one report, a subperiosteal orbital hematoma result in a hematic cyst (47,48). Imaging studies can help
with visual compromise occurred due to a subgaleal hemor- localize the hemorrhage (49–51).
rhage in a child following hair pulling (37). The best-studied Orbital emphysema is generally a benign condition. How-
group of patients with orbital hemorrhage are those undergo- ever, air can become trapped in the orbit due to a ball-valve
ing retrobulbar injection of anesthetic for ophthalmic sur- mechanism typically following orbital fracture. Compres-
gery. The prevalence of an orbital hemorrhage following a sive optic neuropathy and visual loss can result (52). Vomit-
retrobulbar block is 0.44–3% (38–41). When orbital hemor- ing and nose blowing in the setting of orbital fracture may
rhage occurs following a retrobulbar block, it is generally be associated with optic nerve compromise when air is
recognized and readily managed with little impact on visual forced into the orbit (53). Optic neuropathy in conjunction
outcome. with simultaneous tension orbital emphysema and pneumo-
Although rare, direct optic nerve injury from a retrobulbar cephalus following blunt trauma has been reported (54). Or-
needle has been reported (42,43). When retrobulbar hemor- bital emphysema with visual loss has also been reported in
rhage occurs in association with trauma, the risk of visual one patient following the use of a high-speed air-cooled drill
loss is much greater. Hemorrhage following blepharoplasty in the dental setting (55).
CLINICAL ASSESSMENT
Traumatic optic neuropathy remains a clinical diagnosis. er’s series, 14 of 21 patients presented with no light percep-
By definition, there must be a history of trauma. Associated tion (56). In the series reported by Edmund, 17 of 22 patients
loss of consciousness is common. A diagnosis of optic nerve presented with no light perception (21). While vision better
trauma should not be made in the presence of normal vision than 20/400 is not inconsistent with traumatic optic neuropa-
and normal pupillary function. Following trauma, respira- thy, it is unusual in older reported cases.
tory and cardiovascular resuscitation are the first priority. As can be seen from Table 9.2, recent reports contain
Every case of optic nerve injury, however mild, represents larger numbers of patients with visual acuity of better than
head trauma. Therefore care of these patients usually occurs 20/200 in the affected eye. In the past, patients with minor
in a team setting involving emergency physicians, trauma decreases in visual function may have gone undetected.
surgeons, head and neck surgeons, neurosurgeons, and Commonly, patients with traumatic optic neuropathy will
ophthalmologists. Under these circumstances, the initial have vision that is 20/400 or less in the affected eye. How-
ophthalmic examination may be limited by other clinical ever, the clinician must maintain a high index of suspicion
considerations. The ophthalmic assessment should be com- to avoid missing more subtle cases of traumatic optic neurop-
pleted at the earliest opportunity. athy. Delayed visual loss is reported to be as high as 10%
in some series (23,57).
HISTORY
Pupillary Reflexes
Clinical evaluation of a patient with visual loss following
trauma should begin with as complete a history as possible. In cases of unilateral traumatic optic neuropathy, the pres-
If the patient is unconscious, the history should be obtained ence of an afferent pupillary deficit is a necessary condition
from significant others when present. Witnesses at the scene, for the diagnosis of traumatic optic neuropathy. Afferent
including responding emergency personnel, may provide an pupillary defects can be quantitated using photographic neu-
understanding of the mechanism of injury. The possibility tral density filters (58). These filters are calibrated in log
of exposure to hazardous materials should be considered. units that measure the reduction in transmitted light. The
An ocular history must be explored to rule out visual loss lenses can be stacked to produce an additive effect in front
prior to the injury. A detailed medical, drug, and drug allergy of the normal eye until the reduction in light reaching the
history is also necessary. Open injury creates a risk for teta- normal eye matches the reduction caused by the relative
nus, and the patient’s tetanus immunization status should be afferent pupillary defect. When the input in both sides is
investigated. equal, the afferent pupillary defect will be neutralized. The
log unit reduction in light reaching the good eye is a measure
EXAMINATION of the afferent pupillary defect. Afferent pupillary deficits
of greater than 2.1 log units are predictive of poor visual
Visual Acuity prognosis (59).
Visual acuity following indirect optic nerve trauma is Biomicroscopy and Fundoscopy
often significantly reduced. Each patient in Hughes’ series
of 56 cases presented with no light perception (5). All 46 A complete and thorough examination of the eye and ocu-
patients described by Turner also presented with no light lar adnexa is essential following trauma. Palpation of the
perception on the side with optic nerve injury (4). In Hoop- orbital rim can identify step-off fractures. Periorbital swell-
ing may mask the presence of proptosis. Resistance to retro- be due to a limited number of still intact axons that are able
pulsion of the globe followed by tonometry can rapidly iden- to conduct.
tify an orbit that is tense from a retro-orbital hemorrhage. Lid
swelling can increase the difficulty of the ocular examination VISUAL FIELD
necessitating an assistant to retract the eyelids. Evidence of Visual fields can be obtained only when sufficient vision
a penetrating ocular injury should be sought. Blunt injury is present following optic nerve trauma. The visual field,
to the iris may result in a hyphema or angle recession. The by virtue of the retinotopic organization of the optic nerve,
force of trauma may dislocate the lens. provides an understanding of the localization of optic nerve
Posteriorly, blood in the vitreous may obscure the fundus. damage. Within the canal, the pial penetrating vessels that
If the patient is neurologically unstable, the treating neuro- provide blood to the optic nerve are subject to shearing
surgeon or trauma surgeon should be consulted prior to dilat- forces at the moment of injury. Since the superior portion
ing the eyes. If a dilated examination is performed, to avoid of the optic nerve is most tightly bound within the canal,
confusion the time of dilation and the type of agents used these pial vessels are thought to be the most susceptible to
must be documented both in the nursing and physician notes, shearing forces. Partial avulsion of the optic nerve at the
and posted prominently at the bedside. Only short-acting globe produces visual field deficits that correspond to the
agents should be used. When intracranial pressure is moni- site of avulsion. However, there is no pathognomonic visual
tored invasively, pupillary response may not be critical. field loss diagnostic of optic nerve trauma. Visual field test-
However, a dilated fundus exam to rule out retinal disinser- ing is useful in documenting the return of visual function
tion and tears may need to be deferred until the patient is following injury (68). As a practical matter, confrontational
neurologically stable. visual fields may be the only type of visual field available
An adequate fundus examination will include assessment at the bedside. Recording the ability to count fingers, detect
of abnormalities of the retinal circulation. Partial and com- hand motion, or light in each quadrant may crudely quanti-
plete avulsion of the optic nerve head produces a ring of tate this. Ambulatory patients should be considered for for-
hemorrhage at the site of injury or the appearance of a deep mal visual field testing.
round pit (3,60). Anterior injuries between the globe and
where the central retinal vessels enter the optic nerve pro- IMAGING
duce disturbances in the retinal circulation including venous The superior imaging afforded by computed tomography
obstruction and traumatic anterior ischemic optic neuropathy and magnetic resonance imaging has made plain films and
(1,61). Hemorrhages in the optic nerve sheath posterior to hypoclinoidal tomograms obsolete. Manfredi and coworkers
the origin of the central retinal vessels may leave the circula- reviewed the medical records of 379 patients with facial
tion of the retina intact, but produce optic nerve head swell- fractures (69). Twenty-one patients lost all vision in one eye
ing (62). Frank papilledema may be seen in the setting of (6%) and 3 of these 21 lost vision in both eyes; 12 of the
raised intracranial pressure despite the presence of traumatic 21 patients with visual loss had CT scans of the head as part
optic neuropathy (63). The presence of choroidal rupture or of the initial assessment and of these 12, visual loss was
commotio retinae may explain visual loss. Clinical judgment attributed to traumatic globe injuries in 7 cases. CT scans
must be exercised to decide if these conditions are consistent in the remaining 5 patients demonstrated a fracture through
with an afferent pupillary defect. The presence of decreased the optic canal. The fracture may injure the optic nerve di-
visual acuity and an afferent pupillary defect in the absence rectly or it may serve as a marker of the severity of force
of intraocular pathology should suggest a posterior orbital, transferred into the optic nerve (Fig. 9.3). Seiff et al. reported
intracanalicular or intracranial optic nerve injury. CT results of nine patients with traumatic optic neuropathy
(70). Six of the nine patients demonstrated fractures of the
VISUAL EVOKED POTENTIAL optic canal. Fractures were present in adjacent structures but
The visual evoked potential (VEP) may be of use in the not extending into the optic canal in two additional patients.
unresponsive patient suspected of having traumatic optic In a follow-up study, canal fractures were found in 16 of 36
neuropathy (22,64,65). This is especially true in possible patients and fractures of the bones adjacent to the optic canal,
bilateral cases where an afferent pupillary deficit may not but not involving the optic canal, in an additional 10 of
be evident. An unresponsive patient with midface fractures 36 patients (11). However, 63% of the patients with canal
and other than normal pupillary responses warrants a VEP fractures presented with no light perception compared with
investigation. Generally, the actual clinical utility of VEP is a 40% incidence of no light perception when there was no
limited logistically. A VEP may not be available at the bed- fracture or the fracture did not extend to the optic canal.
side, when the information is most critical, and moving the CT scanning in the setting of traumatic optic neuropathy
patient to the evoked potential laboratory may not be possi- has demonstrated specific pathology implicated in the com-
ble. In addition, the test requires a highly qualified technician promise of optic nerve function including optic nerve sheath
who may not be available after hours. The VEP is useful hematoma and presumed arachnoid cyst (9,71,72). While CT
only when it is not recordable—in which case the chance scanning is clearly superior to magnetic resonance imaging
of visual recovery is very unlikely (22,66,67). The VEP can (MRI) in delineating fractures of bone, MRI is superior to
frequently be abnormal but recordable in an amaurotic eye CT scanning in its ability to image soft tissue. Often both CT
immediately following optic nerve trauma with subsequent and MRI are required to fully evaluate a particular clinical
extinction (22). It is thought that the false-positive VEP may situation (62,73) (Fig. 9.4). As a note of caution, MRI should
Figure 9.4. Coronal MRI of the brain at the head at the level of the
Figure 9.3. Preoperative axial CT scan of the head at the level of the optic chiasm. Arrow indicates hemorrhage in the optic nerve sheaths. (From
optic canal. Arrow indicates an optic canal fracture in the left lateral sphe- Crowe NW, Nickles TP, Troost T, Elster AD. Intrachiasmal hemorrhage:
noid wall. (Courtesy of Robert A. Goldberg, MD.) A cause of delayed post-traumatic blindness Neurology 1989;39⬊863–865.)
be performed only after a metallic orbital or intraocular for- optic neuropathy can follow trivial head injuries (16,75).
eign body has been ruled out by CT scan or conventional One must also be wary of visual loss that is merely coinci-
x-ray. MR imaging is useful in assessing chiasmal trauma dental to trauma. Monocular visual loss may not be noticed
(74). until the individual has occasion to close the uninvolved eye.
In this setting the patient may attribute the visual loss to a
DIFFERENTIAL DIAGNOSIS recent traumatic event. Deciding if the visual loss is coinci-
dental or caused by recent trauma may be difficult. Any
Causes of visual loss following trauma, other than trau- process that can result in visual loss may be coincidentally
matic optic neuropathy, must be considered. With a thorough associated with a traumatic incident such as decompensation
history and complete ocular examination, the differential di- of a vascular aneurysm, orbital or optic nerve inflammation,
agnosis of visual loss with disturbed pupillary function can anterior ischemic optic neuropathy, or acute sinus disease
be rapidly narrowed. An optic nerve injury can accompany with orbital involvement. A traumatic cavernous sinus fistula
other ocular injuries. If the obvious ocular injuries do not is usually accompanied by numerous orbital findings, per-
account for the loss of vision and altered pupillary function, mitting easy differentiation from traumatic optic neuropathy
traumatic optic neuropathy should be suspected. Traumatic (76).
PATHOLOGY
Pringle conducted 174 autopsies on patients who were left volved in 30 of 37 cases. Significantly, the intracranial optic
unconscious from the time of head injury until death (77). nerve also demonstrated shearing lesions and ischemic ne-
In 16 cases, blood was found in the optic nerve sheath, lead- crosis in 20 of these 37 cases. In Turner’s series, skull frac-
ing him to hypothesize that indirect injury to the optic nerve tures were present in 27 of 46 cases of optic nerve injury.
was caused by hemorrhage compressing the optic nerve. Only four patients demonstrated an abnormality of the optic
These observations are also supported by the work of Hughes canal suggesting, at least on the basis of plain film radio-
who explored six nerves in five patients (5). graphs, the rarity of canal fractures (56). More recently, stud-
Crompton reported the visual lesions from a series of 84 ies utilizing computerized tomography suggest a 50% inci-
autopsies performed soon after closed head trauma (6). Optic dence of sphenoid fractures in cases of traumatic optic
nerve dural sheath hemorrhages were present in 69 of 84 neuropathy (11). However, these studies also demonstrate
cases (83%). Interstitial optic nerve hemorrhages were pres- the important point that traumatic optic neuropathy can occur
ent in 30 of 84 patients (36%). The interstitial hemorrhage in the absence of an optic canal fracture.
was present in the optic canal in 20 of these 30 cases. Shear- Studies using laser interferometry suggest that forces ap-
ing lesions and ischemic necrosis were present in 37 of 84 plied to the frontal bone are transferred and concentrated in
cases (44%) and the intracanalicular optic nerve was in- the area of the optic canal (78) (Figs. 9.5 and 9.6). The entire
Figure 9.5. Photograph of a holographic interferogram with static loading Figure 9.6. Photograph of a holographic interferogram with static loading
over the glabella. Arrow indicates region of maximal deformation. The over the medial brow showing stress lines concentrated in the left orbital
optic foramen (of) and the superior orbital fissure (sof) are also indicated. roof (arrow). The nasofrontal (nf), frontomaxillary (fm), frontozygomatic
(From Gross CE, et al. Evidence of orbital deformation that may contribute (fz), and sphenofrontal sutures are indicated. (From Gross CE, et al. Evi-
to monocular blindness following minor frontal head trauma. J Neurosurg dence of orbital deformation that may contribute to monocular blindness
1981;55⬊963–966.) following minor frontal head trauma. J Neurosurg 1981;55⬊963–966.)
Figure 9.7. Dissection of the intracra-

nial optic nerves and chiasm. Open arrow
indicates the falciform dural fold in close
association to the optic nerve as it enters
the optic canal. The closed arrow indi-
cates where the falciform dural fold has
been reflected exposing the underlying
sphenoid bone. (From Gossman MD,
Roberts DM, Barr CC. Ophthalmic as-
pects of orbital injury. Clin Plast Surg
1992;19⬊71–85.)
force of deceleration can be loaded into the facial bones over ble to ischemic injury (81). At present there is little informa-
milliseconds. Elastic deformation of the sphenoid results in tion on optic nerve swelling within the optic canal (82).
the transfer of force into the intracanalicular optic nerve, However, optic nerve swelling may be less significant than
where it is tightly bound causing contusion necrosis of the thought, and there is evidence that astrocytic swelling in the
nerve by disrupting axons and vasculature (79). The location optic nerve is less significant than in brain injury (83).
of a fracture is determined by the elastic limit of the involved Partial and complete avulsions of the optic nerve from the
bone. Thinner bone is more likely to deform. In contrast, globe result from violent rotations of the globe (3). Trau-
thick bone is inelastic and more likely to fracture (78,80). matic avulsion of the optic nerve can follow self-inflicted
Fractures of the canal occur, but injury of the optic nerve injury, so-called autoenucleation or oedipism (84,85) or
by displaced bone fragments appears to be infrequent (68). from other types of penetrating orbital injury (86). The trans-
The intracranial optic nerve can also be injured against the fer of damaging force to the optic nerve following direct
falciform dural fold which overlies the sphenoid plane or injury does not imply that the nerve has been severed or
where the nerve becomes fixed entering the intracranial precludes visual recovery (14,87). Therefore, a direct optic
opening of the optic foramen (6) (Fig. 9.7). Walsh hypothe- nerve injury may irreversibly injure a portion of the involved
sized that swelling of the optic nerve within the bony canal nerve but leave other areas with the potential for visual re-
may make the intracanalicular portion of the nerve suscepti- covery.
PATHOGENESIS
INJURY MECHANISMS Ischemia is perhaps the most important aspect of second-
ary injury following trauma. Partial ischemia and reperfu-
Optic nerve injury mechanisms are thought of as primary sion of transiently ischemic regions generate oxygen free
and secondary (81). Primary mechanisms result in perma- radicals resulting in reperfusion damage (103,104,122,123).
nent injury to the optic nerve axons at the moment of impact. Until recently there was only indirect evidence for oxygen
Walsh felt that primary injury resulted in mechanical shear- free radical damage such as reduced concentrations of
ing of the optic nerve axon and vasculature. In contrast, ascorbic acid, alpha-tocopherol, and reduced ubiquinones
secondary mechanisms cause damage to the optic nerve sub- following ischemia (105–107). However, PGF2␣ adminis-
sequent to the force of impact. He suggested that these mech- tered via a microdialysis fiber to the rat spinal cord has been
anisms included ongoing vasospasm and swelling of the shown to directly increase extracellular levels of hydroxyl
optic nerve within the confines of the nonexpansile optic radical and malondialdehyde, which are both by-products
canal leading to worsening ischemia and further loss of of lipid peroxidation. Further, methylprednisolone directly
axons that possessed the potential for recovery immediately blocks the release of PGF2␣ following spinal cord injury and
following impact (79). the subsequent rise levels of hydroxyl radical and malondial-
Experimental studies of optic nerve injury and CNS dehyde (108). The cell membranes of axons are composed
trauma support the distinction between primary and second- of high concentrations of polyunsaturated lipids. The release
ary injury mechanisms. These studies have used different of oxygen free radicals that follows trauma or ischemia re-
injury methods depending on the purpose of the study sults in the peroxidation of these lipids damaging the neural
(88–95). Following a severing or severe crush injury of a membrane. This process is thought to play a central role in
mammalian optic nerve, individual axons demonstrate con- cell death following ischemia or traumatic injury (109,110).
siderable variation in their rate of Wallerian degeneration Arachidonic acid released from damaged cells is metabo-
(96). Ultrastructural changes can be seen as early as 4 hours lized to thromboxane, PGE1, PGF2␣, hydroperoxides, and
in some axons with the early formation of ‘‘retraction balls.’’ oxygen free radicals (111–113). Thromboxane induces
However, normal appearing axons can be found out to 21 platelet adhesion and microvascular sludging (114,115). Di-
days. Axonal size does not appear to determine the rate of rect thrombin inhibition has been shown to be neuroprotec-
degeneration (96). Following optic nerve transection, signif- tive following optic nerve injury (116). Treatment with
icant descending degeneration of the retinal ganglion cells cyclooxygenase inhibitors or antioxidants also limits the se-
does not occur until approximately 3 weeks following injury, verity of hypoperfusion that follows brain and spinal cord
with maximal loss by 6 weeks (90). This corresponds to injury (117).
clinical observations (97–99). Several other potential mechanisms exist that can give
There is evidence that the somas of injured and presum- rise to oxygen free radical production following trauma or
ably uninjured adjacent neurons undergo apoptotic degener- ischemia, including the production of xanthine oxidase and
ation. This type of degeneration has been documented fol- the release of elemental iron from hemorrhage (118,119).
lowing ischemic optic neuropathy, experimental glaucoma, The superoxide ion (O2ⳮ) and hydrogen peroxide (H2O2)
and optic nerve injury (100–102). Apoptosis, or so-called are coupled to iron, which serves as a redox metal to produce
programmed cell death, encompasses a variety of secondary the hydroxyl radical (䡠OH) or the feryl ion (FeIII-OH), which
injury mechanisms leading to further axonal death following can the oxidize a large variety of compounds including lipids
the initial injury. It is hoped that apoptotic cell loss can be (120).
interrupted by appropriate treatment which preserves axons Bradykinin and kallidin are agents that are activated fol-
that might otherwise be lost. lowing injury and play an important role in free radical pro-
duction, alterations in intracellular calcium regulation, and strategies (144–146). It has been suggested that the de-
the release of arachidonic acid from neurons (121). The ki- creased blood flow and tissue glial swelling associated with
nins are activated by kallikrein enzymes. At the time of tissue injury and ischemia may serve to limit the influx of calcium
injury the intrinsic coagulation cascade is activated with ex- into the injured region. At the same time the autodestructive
posure of blood to collagen and basement membrane (122). processes that occur in irreparably injured neurons precipi-
Kallikrein, activated by this cascade, coverts high- and low- tate excess calcium ions creating a focal calcium sink. This
molecular-weight kininogens to bradykinin and kallidin, re- last mechanism may be adaptive to limit secondary damage
spectively. The kinins mediate early inflammation resulting to adjacent axons with the potential for recovery (147).
in smooth muscle contraction, venous constriction, dilata- The early events of CNS injury are associated with the
tion of arterioles with resulting edema, and stimulation of release of mediators of inflammation that are chemoattrac-
nociceptive receptors (123–126). Bradykinin binds to cell tive for polymorphic neutrophils and macrophages. In CNS
membrane receptors activating phospholipid metabolism trauma the blood-brain barrier is significantly disrupted per-
(127–129). The effect of these cellular changes results in mitting the passage of these cells. Inflammatory cells have
the release of arachidonic acid from the neuron (130,131). been found to be a prominent feature in an experimental
Once bradykinin has initiated the release of arachidonic acid animal model of optic nerve injury (148). Neutrophils appear
from neurons, the resulting prostaglandins, oxygen contain- to play an important role in the acute inflammatory damage
ing free radicals, and lipid peroxides produce a loss of cere- that follows limb reperfusion injuries (149,150). Inducible
brovascular autoregulation (103,132,133). nitric oxide synthase (iNOS) is not normally present in the
Following brain and spinal cord injury, there is also an normal retina; however, following experimentally induced
indiscriminate release of excitatory amino acids that can retinal ischemia, polymorphonuclear leukocytes containing
open ligand-gated ion channels resulting in the accumulation iNOS can be found in the retinal ganglion cell layer. Treat-
of excessive intracellular calcium (134–136). Intracellular ment with specific inhibitors of iNOS have been shown to
calcium acts as a metabolic toxin leading to cell death. Ex- be neuroprotective against the loss of retinal ganglion cells
cess calcium binds to mitochondrial membranes disrupting that follows retinal ischemia (151). In the first 1–2 days
electron transport and inhibiting ATP production (137–139). after injury, polymorphic neutrophils predominate but are
Elevated levels of intracellular calcium adversely affect en- replaced by macrophages that reach a peak at 5–7 days after
zymes that control glycolysis and activate neutral proteases injury. Macrophages are implicated in delayed tissue damage
and phospholipase (140–142). Activated phospholipase A2 in experimental spinal cord injury models (152). There is
releases arachidonic acid which can be converted to leuko- recent evidence that T-cell-mediated immunity may also
trienes and prostaglandins (143). The reader is referred to serve to limit excitatory amino acid toxicity in CNS injury
several recent reviews that discuss potential neuroprotective (153).
PHARMACOLOGY
EXPERIMENTAL out treatment. Methylprednisolone in this dose range pre-
vents free radical pathology (105). Animals treated with 30
Over the past thirty years, research in acute spinal cord mg/kg doses of methylprednisolone following spinal cord
trauma has demonstrated a pharmacology for very high trauma maintain normal spinal cord blood flow, preventing
doses of corticosteroids that is distinct from the pharmacol- ischemia (159,160).
ogy of steroids in the doses more typically encountered in These studies demonstrate a biphasic dose response to
clinical practice (154,155). In the doses usually encountered methylprednisolone in a range of doses much higher than
in clinical practice, corticosteroids are thought to act by de- usual clinical usage. There appears to be a distinct pharma-
creasing the rate of protein synthesis. Receptor proteins in cology for massive doses of steroids (30 mg/kg). The most
the cytosol mediate this action (156). In lymphocytes, this important of these effects appears to be as an antioxidant
steroid-receptor complex stimulates the synthesis of an in- limiting free radical pathology (159). Very high doses of
hibitory protein (157). In addition, glucocorticoids inhibit steroids may be required because one molecule of antioxi-
the release of arachidonic acid from phospholipids, decreas- dants is used for each free radical produced (105). Limiting
ing the production of prostaglandin endoperoxides and lipid peroxidation that results from free radical formation
thromboxane (158). protects the neural tissue from the secondary effects of
trauma (154). Following injury, the production of prosta-
Following experimental spinal cord injury, the untreated,
glandins PGF2␣ and thromboxane (161) results in worsening
contused segment of spinal cord demonstrates an increase
vasoconstriction, ischemia, disturbances in cellular metabo-
in fluorescent lipid peroxidation products and concentrations lism, and disruptions of neurofilaments (162). Cats with con-
of cyclic GMP, a sensitive indicator of lipid peroxidation tusion injury to the spinal cord treated within the 15–30 mg/
(154). In similarly injured animals treated with 30–60 mg/ kg range demonstrate improved neurophysiologic recovery
kg doses of intravenous methylprednisolone 30 minutes after (162,163).
injury there is a significant decrease in fluorescent lipid per-
oxidation products compared to untreated injured controls. CLINICAL EXPERIENCE
Treatment with 15–30 mg/kg doses of methylprednisolone The application of corticosteroids to the treatment of brain
prevents the increase in cyclic GMP noted after injury with- and spinal cord trauma is based on the demonstrated efficacy
of treating edema associated with brain tumors (164,165). kg/hr. Methylprednisolone was administered with an initial
However, translating the success of treating experimental dose of 30 mg/kg followed by a continuous infusion at 5.4
spinal cord and brain trauma to the clinical setting represents mg/kg/hr. These treatments were provided for 24 hours. Pa-
a decade of frustration. Until the results of the second Na- tients were assessed neurologically by evaluating pinprick,
tional Acute Spinal Cord Injury Study (NASCIS II) in 1990 light touch, and motor function; neurologic scores were as-
(166), the value of methylprednisolone treatment was ques- signed based on these evaluations.
tioned (167). The first National Acute Spinal Cord Injury For the purposes of the study, patients were assessed ini-
Study (NASCIS I) compared the effect of ‘‘high dose’’ tially, at 6 weeks, and at 6 months. This study showed that
methylprednisolone therapy (1 gram bolus followed by 1 treatment with methylprednisolone within 8 hours of injury
gram per day for the next 10 days) to ‘‘standard dose’’ ther- at the therapeutic dose suggested by the animal spinal injury
apy (100 mg initial bolus followed by 100 mg per day for studies resulted in a significant improvement in motor and
the next 10 days) (168). The high dose treatment in this sensory function compared to placebo-treated patients. Pa-
protocol for a 70-kg adult equates to 14 mg/kg of methyl- tients treated with naloxone and patients treated with either
prednisolone in a 24-hour period. This study failed to dem- drug more than 8 hours after injury did not demonstrate
onstrate a beneficial effect of the higher dose of methylpred- an improvement in neurologic scores compared to placebo-
nisolone and lacked a placebo control. treated patients. Post-hoc analysis of the NASCIS II data
The NASCIS II (166) was a multicenter, randomized, dou- suggests that methylprednisolone treatment initiated more
ble blind, placebo-controlled study involving patients with than 8 hours after injury was detrimental (169). In this study,
acute spinal cord injury. Patients enrolled in the study were patients treated with methylprednisolone did have a higher
randomized to one of three treatment arms within 12 hours rate of infection (7.1%) than patients treated with naloxone
of injury. The treatment arms consisted of placebo, nalox- (3.3%) and those receiving placebo (3.6%), but this differ-
one, and methylprednisolone. Naloxone, an opiate receptor ence was not statistically significant. The success of methyl-
partial agonist that has been effective in limiting neurologic prednisolone for the treatment of spinal cord injury encour-
injury in animals, was administered in an initial bolus of 5.4 aged ophthalmologists to empirically adopt this treatment
mg/kg and then at a continuous infusion rate of 4.0 mg/ for optic nerve trauma.
MANAGEMENT
The management of traumatic optic neuropathy should be cal intervention. He also cautioned against operating on un-
guided by the Hippocratic adage to do no harm. Almost all conscious patients. However, in cases of delayed visual loss,
case reports and most case series of traumatic optic neuropa- Walsh suggested that surgical decompression might be more
thy present treated cases. The older series are biased toward promising (79).
cases with severe visual loss. Contemporary studies contain Early papers from Japan reported that traumatic optic neu-
much larger numbers of patients with mild optic nerve inju- ropathy was both more common in Japan and more respon-
ries. Consequently it is very difficult to use the retrospective sive to surgical intervention (172,173). This experience has
data in the literature to characterize the natural history of not been repeated in subsequent series from Japan. Matsu-
traumatic optic neuropathy, making meaningful meta-analy- zaki et al. reported a series of 33 patients with traumatic
sis difficult (170). Without an accurate knowledge of the optic neuropathy (174). Eleven patients received surgical
natural history of this injury, measuring the beneficial effect decompression of the optic canal and 22 were managed med-
of a medical, surgical or combined approach is very difficult. ically. They found optic canal fractures in 51% of patients.
This section will critically review the studies that are in the Patients who presented with no light perception failed to
literature and summarize what is currently known concern- demonstrate visual improvement, irrespective of treatment.
ing the clinical management of traumatic optic neuropathy. Of the 11 cases receiving optic canal decompression, 8 sur-
geries were performed transcranially and in 3 cases the canal
EARLY STUDIES was decompressed transethmoidally. Vision following sur-
Early reports concerning surgical decompression sug- gery improved in 36% of cases. Patients who were managed
gested it to be of little value in treating traumatic optic neu- medically tended to have much better initial visual acuity.
ropathy (56,77,171). In these cases decompression was per- Medical treatment included prednisone 40–100 mg per day
formed transcranially. Hooper (56) operated on five patients for 5–7 days, mannitol for 5 days, and urokinase 12,000
with traumatic optic neuropathy. Two patients recovered vi- units per day when perineural hematoma was suspected. In
sion, but only one patient had optic canal decompression. medically treated patients, 50% of the individuals had im-
Hughes (5) explored 8 cases in his series of 90 patients, proved vision.
with no visual improvement (5). Edmund and Godtfredsen Fujitani and coworkers reported a 16-year series of 110
operated on 6 patients in their series of 22 patients (21). cases of traumatic optic neuropathy (175). In their series, 43
The vision of only one patient improved following surgery, patients were managed medically with corticosteroids and 70
changing from no light perception to light perception. Based eyes underwent transethmoidal optic canal decompression.
on this experience and the available pathologic material, Medical treatment consisted of oral prednisone 60 mg ta-
Walsh felt that visual recovery was unlikely if amaurosis pered over 2 weeks. Patients in the series after 1972 who
occurred at the moment of impact and advised against surgi- failed to respond underwent surgical decompression. The
rate of visual improvement in the medically treated cases with corticosteroids (dexamethasone, 3–5 mg/kg/day). Sur-
was 44.2% (19/43). Nine eyes had an initial visual acuity gery was advocated in cases of delayed visual loss that fail
of no light perception. These eyes failed to improve with to improve with treatment and in cases with initial visual
medical management. Overall, eyes treated within 3 weeks improvement followed by worsening of vision despite treat-
of injury had a 57% rate of improvement. In cases where ment. Three of six patients had return of vision on high dose
treatment was initiated more than 3 weeks following injury, corticosteroids. Four of their patients underwent transeth-
only 15% (2/13) improved. moid-sphenoid optic canal decompression. Postoperatively,
Seventy optic nerves underwent surgical decompression vision returned in only one case. Since this study, subsequent
and canal fractures were found in 25% of cases at the time studies have combined corticosteroid treatment with surgical
of surgery. The overall rate of improvement in these cases intervention, making it difficult to determine the therapeutic
was 47.7% (33/70). Among patients undergoing surgery, 28 value of a particular treatment. Additionally, the percentage
eyes had an initial visual acuity of no light perception. Visual of patients with no light perception vision in these studies
improvement was seen in 7 of 28 cases (25%). Optic canal is smaller that earlier studies (Table 9.2). This most likely
decompression was performed in 38 cases within 3 weeks reflects the greater awareness of the condition and more ag-
with a 45% rate of improvement (17/38). In 32 eyes where gressive recruitment of patients compared to earlier studies.
vision failed to improve with medical management, surgical This difference in recruitment biases these studies to better
decompression was performed after 3 weeks. In these cases outcomes irrespective of treatment when comparison is
16 of 32 eyes (50%) demonstrated improved vision after made to earlier studies.
surgery. In four cases, surgery was not performed until 3 Seiff’s study of high dose corticosteroid treatment of pa-
months after injury. Despite this delay, three cases improved tients with indirect optic nerve trauma was a nonconsecutive
after surgery. The results of these two series are more consis- nonrandomized retrospective series of 36 patients (11). Prior
tent with the Western experience. to 1983 his patients with traumatic optic neuropathy were not
The widespread introduction of orbital imaging and neu- treated with corticosteroids. Therefore his study essentially
roimaging has provided a more accurate method for assess- compares the outcome of patients with traumatic optic neu-
ing the mechanisms of visual loss. This has led to a much ropathy seen prior to 1983 with those seen after 1983. Fifteen
more specific anatomical approach in planning surgical in- patients did not receive corticosteroids. Twenty-one patients
tervention. Imaging can identify pathology that when ad- received dexamethasone (1 mg/kg/day). Therapy was initi-
dressed surgically may result in visual improvement (9). ated within 48 hours. If no improvement was seen within
Computed tomography has also demonstrated impingement 72 hours the corticosteroids were stopped. If improvement
of the optic nerve by bone fragments. Anecdotally, visual occurred, treatment was continued until visual improvement
recovery has followed surgical reduction of such bone frag- leveled off. Steroids were then tapered off over several days.
ments (72). Visual improvement was seen in 13 of 21 treated patients
The management of orbital hemorrhage that creates a (62%) and 5 of 15 untreated patients (33%), but this differ-
compressive orbitopathy is well defined and relatively in- ence was not found to be significant. This study reported
controvertible. The initial diagnosis is clinical. Patients pres- that treated patients recovered more vision and at a faster
ent with a history of trauma. Vision may be extremely poor rate than untreated patients, and that the difference was sig-
due to optic nerve embarrassment or compromise of retinal nificant. However, these conclusions are probably not mean-
perfusion. Proptosis will be present and the intraocular pres- ingful. The two groups differed in initial visual acuity. The
sure may be significantly elevated. Initial treatment is can- untreated group actually had much better overall vision, de-
thotomy and cantholysis to permit expansion of the orbital creasing the opportunity for visual recovery. Four of 15 pa-
contents. If this does not provide sufficient relief, orbital tients in the untreated group had vision that was 20/50 or
decompression may be necessary to provide sufficient space better in the affected eye and 11 of 14 had vision of count
for orbital soft tissue expansion (176,177). These initial ma- fingers or worse; in contrast, all of the affected eyes in the
neuvers should be followed by orbital imaging to rule out treated group had a visual acuity of 20/200 or worse, which
a subperiosteal hemorrhage or other pathology which may suggests that the two groups are probably not comparable.
explain the basis of visual compromise. The role for anterior Additionally, as noted in the discussion of what constitutes
segment paracentesis in the treatment of orbital hemorrhage high dose steroids, 1 mg/kg/day of dexamethasone is un-
is limited. The use of steroids to treat optic nerve compro- likely to provide an antioxidant effect.
mise following orbital hemorrhage is unsettled. Spoor and coworkers presented an uncontrolled, noncon-
secutive, retrospective study of 21 patients (22 eyes) with
MEGADOSE STEROIDS traumatic optic neuropathy studied at two centers (13). Eight
patients at one center received dexamethasone (20 mg every
Anderson et al. introduced the use of high dose corticoste- 6 hours, IV) and 13 patients at the second center received
roids for the treatment of traumatic optic neuropathy based methylprednisolone (30 mg/kg loading followed by 15.0 mg/
on salutary effects of corticosteroids in the treatment of ex- kg every 6 hours, IV). Treatment was initiated at a mean of
perimental CNS injury (178). They proposed a treatment 4.2 days following injury in the methylprednisolone group
protocol formulated on their experiences in treating seven and 17 hours in the dexamethasone group. The authors re-
patients with traumatic optic neuropathy with a combination ported that 7 of 9 eyes in the dexamethasone group and 12
of corticosteroids and surgery. They advised initial treatment of 13 patients in the methylprednisolone group improved.
The study suffers from being uncontrolled and nonconse- chusetts Eye and Ear Infirmary on Extracranial Optic Nerve
cutive. It is not possible to draw conclusions about the effi- Decompression (Extracranial Optic Canal Decompression,
cacy of corticosteroid treatment in the management of trau- November 6–7, 1993, Boston). At this meeting it was clear
matic optic neuropathy based on this study. It is interesting that the Second National Acute Spinal Cord Injury Study
that the methylprednisolone-treated patients appeared to do (NASCIS II) data had a significant impact on how clinicians
as well as dexamethasone-treated patients, despite the fact thought about treating traumatic optic neuropathy. In devel-
that as a group the methylprednisolone patients had treat- oping The International Optic Nerve Trauma Study, it was
ment started 3 days later than the dexamethasone treated felt unethical to have a placebo control and the results of
individuals. the NASCIS II study were used in making this case. The
Joseph and coworkers reported a series of 14 patients with International Optic Nerve Trauma Study was initially con-
traumatic optic neuropathy managed with transethmoidal- ducted as a randomized controlled pilot study to assess re-
sphenoidal optic canal decompression (179). This was also cruitment feasibility. However, recruitment was insufficient
a nonconsecutive retrospective study. The patients in this and the study was converted to a comparative, nonran-
series were treated with dexamethasone both before and after domized interventional study (23). A total of 133 patients
surgery. The interval between injury and surgery varied from met criteria for inclusion and analysis. There were three
one to five days. Patients who were comatose and patients treatment arms: untreated patients, steroid treatment, and
with ‘‘local ocular lesions’’ were excluded from the study. surgery with or without steroids. The authors concluded that
There was no morbidity or mortality associated with the there was no clear benefit for either corticosteroid therapy or
surgeries. Overall, 11 of 14 patients demonstrated visual im- optic canal decompression. The study has some significant
provement, including 3 of 5 patients who had a preoperative limitations, but it represents the largest, most unbiased study
visual acuity of no light perception in the injured eye. De- of traumatic optic neuropathy to date. Further, it will take
spite the lack of nonsurgical control patients, these investiga- considerable effort to mount a better study because traumatic
tors felt strongly that surgical decompression helped their optic neuropathy, while a dramatic and vexing clinical prob-
patients. They proposed that patients with indirect traumatic lem, is relatively rare.
optic neuropathy be immediately treated with both dexa- Critical review of the traumatic optic neuropathy literature
methasone and surgical optic canal decompression if there does not provide statistical evidence to conclude that either
is no contra-indications for surgery and no ocular injuries surgery, corticosteroids, or a combination of corticosteroids
that might preclude visual recovery. They do not recommend is more beneficial than no treatment; yet the International
surgery if more than seven days have past since the injury. Optic Nerve Trauma Study was organized with a strong bias
The retrospective series presented by Mauriello and coau- that these treatments are beneficial. All but 9 out of 133
thors included 23 patients with vision loss after trauma (57). patients enrolled in the International Optic Nerve Trauma
All patients were seen at the same trauma center and treated Study received surgery or corticosteroids within 7 days of
within 48 hours. All patients received an initial loading dose treatment. Despite a strong bias toward treatment, no treat-
of methylprednisolone (1 gram IV) followed by methylpred- ment benefit was found.
nisolone 250 mg IV every 6 hours for 72 hours. Orbital Mounting evidence, including the International Optic
hemorrhages with elevated intraocular pressure were treated Nerve Trauma Study, raises significant questions regarding
with immediate lateral canthotomy. Orbital computed to- the potential benefits of corticosteroids in the treatment of
mography was performed to identify ‘‘surgically treatable traumatic optic neuropathy. First, there are no statistically
pathology.’’ valid studies supporting the use of corticosteroids in the
The authors presumed that optic nerve sheath enlargement treatment of traumatic optic neuropathy. The value of corti-
represented intrasheath hemorrhage. Patients who failed to costeroids in the treatment of CNS injury varies by anatomic
respond to the steroids were considered for optic nerve region and injury circumstance. As noted above, analysis of
sheath decompression if the sheath was distended, or for the NASCIS II data demonstrated that methylprednisolone
transcranial optic canal decompression if ‘‘the optic canal treatment initiated more than 8 hours after spinal cord injury
or optic nerve appeared compressed by bone spicules.’’ Only is detrimental (169). Treatment with glucocorticoids have
2 of 23 had initial vision that was 20/200 or better. Nine of been shown to exacerbate ischemic-induced hippocampal
16 patients who only received steroids improved. The au- excitotoxicity (180,181). Even in the absence of ischemia,
thors note that three of the nine patients who improved in glucocorticoids can induce apoptosis in the hippocampus
this group had immediate canthotomy to treat an orbital hem- (182).
orrhage. Three of the 23 patients additionally had optic nerve Additionally, there are now two lines of experimental evi-
sheath decompression and one improved. Four patients had dence that suggest methylprednisolone is harmful for injured
combined optic nerve sheath decompression and transcranial optic nerves. Steinsapir and coworkers conducted a study
optic canal decompression. Three out of four of these pa- using a moderate crush injury to optic nerves of male rats.
tients had bilateral injuries. Visual improvement could be Thirty minutes after injury, animals received one of five
documented in only two out of seven eyes. Additional small intravenous treatments: saline; or methylprednisolone 30
case series have not greatly contributed to expand our under- mg/kg, 60 mg/kg, 90 mg/kg, or 120 mg/kg. Treatment was
standing of treating traumatic optic neuropathy. Some of repeated at 6-hour intervals for three additional treatments.
these studies are summarized in Table 9.2. Animals were allowed to recover for 6 weeks at which time
In November 1993, a conference was held at the Massa- they were sacrificed and the remaining axons in the injured
nerves were counted. The saline-treated animals retained the percentage of intracanalicular injuries take place at the falci-
greatest number of axons and there appeared to be a dose form dural fold (6). This is a location that will not benefit
dependent decline in residual axons with increasing doses from optic canal decompression. However, it is possible that
of methylprednisolone. Axon counts (means Ⳮ s.e.m.) were subsets of injuries might benefit from surgical intervention.
as follows: For example, reduction of bone fragments impinging on the
optic nerve is a compelling reason for surgical intervention,
Saline ⳱16,670 Ⳳ 8,900 (n ⳱ 5); especially in cases of delayed visual loss, although these
Methylprednisolone 30 mg/kg ⳱ 8,098 Ⳳ 4,741 (n ⳱ 5); may represent untreatable injuries (68). The hypothesis that
Methylprednisolone 60 mg/kg ⳱ 6,925 Ⳳ 6,517 (n ⳱ 4); reducing the canal fracture benefits the injured nerve remains
Methylprednisolone 90 mg/kg ⳱ 2,663 Ⳳ 2,653 (n ⳱ 4); untested. The fracture may just be residual evidence of the
Methylprednisolone 120 mg/kg ⳱ 6,149 Ⳳ 3,487 forces imparted into the nerve at the moment of impact;
(n ⳱ 6). lifting these fragments of bone may not provide any thera-
peutic benefit.
The data revealed that saline-treated animals retained more Case reports and small series demonstrate visual improve-
axons than those administered methylprednisolone (p ⬍ .02) ment following evacuation of intraoptic nerve sheath hema-
(183). In this study, methylprednisolone exacerbated axonal tomas, or subperiosteal hematomas causing optic nerve em-
loss following optic nerve trauma. barrassment (9,188). These examples provide only limited
The second line of evidence comes from work on an ex- experience on which to base recommendations for surgery
perimental model of multiple sclerosis. Diem and coinvesti- for individual patients. Intracanalicular optic nerve injury is
gators looked at the effect of high dose methylprednisolone the most common form of traumatic optic neuropathy. Not
on experimental autoimmune optic neruritis (184). In this surprisingly, decompression of the optic canal is the most
study, methylprednisolone significantly increased apoptotic commonly reported surgical intervention. Theoretically,
retinal ganglion cell loss. As of the writing of this chapter, opening the canal to provide room for the optic nerve to
these results were too new to have been investigated clini- swell into should be beneficial. However, the International
cally. However, such a study will need to be mounted given Optic Nerve Trauma Study failed to demonstrate a beneficial
that methylprednisolone therapy continues to be used to treat effect for surgical decompression. This study had significant
optic neuritis (185–187). limitations and it is possible that the study did not have the
Given the lack of clinical evidence that corticosteroids are power to identify a small beneficial effect for a subsets of
beneficial in the treatment of traumatic optic neuropathy, patients. Consequently, it is difficult to advocate a set of
combined now with two lines of experimental evidence that best practices based on this study. Certainly in the case
methylprednisolone is harmful to the injured optic nerve, of orbital hemorrhage causing optic nerve compromise, there
clinicians should consider abandoning the routine use of is little controversy regarding the need to provide immediate
megadose corticosteroids for the treatment of traumatic optic surgical relief of the compressive orbitopathy.
neuropathy. Our best evidence is inconclusive so there can Lubben and coworkers reported their experience with sur-
be no standard of care regarding a ‘‘best practice.’’ In the gical decompression within hours of trauma (188). As many
setting of severe visual loss, there is often a perceived need of their cases had relatively good visual acuities before sur-
to take heroic actions such as using megadose steroids or gery and their series also included comatose patients, it is
performing optic canal decompression. Informed consent difficult to evaluate the relative success of their approach.
must address the likelihood that megadose steroids may actu- However, it is reasonable to expect that if surgery is to be
ally worsen the visual outcome. Clinicians who feel com- of benefit, then performing it earlier may decrease secondary
pelled to treat traumatic optic neuropathy with megadose axonal loss. An orbitotomy provides the best access for the
steroids because they are beneficial in spinal cord trauma, evacuation of an optic nerve sheath hematoma, reduction of
should keep in mind that methylprednsiolone when adminis- a depressed lateral orbital wall fracture that compromises
tered more than 8 hours after spinal cord injury was harmful the optic nerve, or drainage of a subperiosteal hematoma
to outcome (169). with posterior compression of the optic nerve. Consequently
Further, clinical studies under the auspices of an institu- an accurate anatomical diagnosis must be made to plan ap-
tional review board should strongly shift away from the bias propriate surgical intervention. Walsh’s admonition (81)
that methylprednisolone is beneficial for optic nerve trauma. against operating on the unconscious patient will continue
It can now be argued that it is unethical to enroll patients into to have validity until clear evidence establishes the value of
a megadose corticosteroid for optic nerve trauma treatment surgical intervention. Given the uncertain benefit of these
study without some new experimental evidence showing a procedures, the patient and their significant others need to
benefit in an animal model of optic nerve trauma. This stan- be thoughtfully counseled regarding surgery.
dard was not imposed when organizing the International
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CHAPTER 10
Toxic and Deficiency Optic
Neuropathies
Paul H. Phillips
ETIOLOGIC CRITERIA Other Vitamin Deficiencies

Nutritional Optic Neuropathies Tropical Optic Neuropathy
Toxic Optic Neuropathies SPECIFIC TOXIC OPTIC NEUROPATHIES
CLINICAL CHARACTERISTICS OF NUTRITIONAL AND Methanol
TOXIC OPTIC NEUROPATHIES Ethylene Glycol
DIFFERENTIAL DIAGNOSIS Ethambutol
EVALUATION Halogenated Hydroxyquinolines
SPECIFIC NUTRITIONAL OPTIC NEUROPATHIES Disulfiram
Epidemic Nutritional Optic Neuropathy Sildenafil
Vitamin B12 Deficiency Amiodarone
Tobacco
Physicians have known for centuries that the anterior vis- together. Although evidence for the localization of the pri-
ual pathways are vulnerable to damage from nutritional defi- mary lesions is lacking in many of the so-called toxic and
ciency and chemicals. The resulting disorders share many nutritional ‘‘amblyopias,’’ they are generally assumed to be
signs and symptoms, and several appear to have a multifacto- optic neuropathies and that is the rubric under which they
rial etiology in which both undernutrition and toxicity play are considered here.
a role. In light of these facts, it is reasonable to group them
ETIOLOGIC CRITERIA
Although certain optic neuropathies have an obvious to deplete nutrients. Evidence from epidemics indicates that
toxic or nutritional etiology, the toxic or nutritional basis this requires months (see below). The reports of large num-
of others is merely presumptive, and the attribution may bers of cases of visual loss after economic and political up-
ultimately prove false. It is also likely that a few of the optic heavals suggest the possibility of a nutritional etiology. The
neuropathies now considered idiopathic or ascribed to some patient should show evidence of undernutrition, usually
other etiology, actually result from toxicity or nutritional manifested in such obvious forms as weight loss and wast-
deficiency. The proliferation of drugs and the introduction ing. Victims of nutritional optic neuropathy, however, are
of new chemicals into the workplace and environment guar- not necessarily emaciated. Other signs such as peripheral
antee that additional toxic optic neuropathies will be identi- neuropathy, keratitis, or the cutaneous and mucous mem-
fied. For medical and legal reasons, physicians must be alert
brane stigmata of the avitaminoses are useful, when present.
to the possibility, both in sporadic cases of visual loss and
There is an important exception to the foregoing state-
in epidemics of visual loss, that intoxication or nutritional
deficiency are factors. ments. The optic neuropathy of pernicious anemia or dietary
vitamin B12 deficiency can occur in seemingly healthy indi-
NUTRITIONAL OPTIC NEUROPATHIES viduals without obvious symptoms or signs of nutritional
Proving a nutritional basis for an optic neuropathy is by deficiency (see following).
no means a simple task. The first criterion is that the patient It should go without saying that the symptoms and signs
be nutritionally deficient and has been so sufficiently long should be those typical of nutritional optic neuropathy and
447
that other disorders should be considered and eliminated by substance that has been proved to damage the optic nerve
appropriate investigations. Both in individual cases and in by the same route of exposure. Visual loss may occur from
epidemics, it is especially important to establish if the patient either acute or chronic intoxication depending upon the
has been exposed to substances toxic to the visual pathways. agent, but there should not be a long interval between the
In such cases, intoxication may be the alternative explana- cessation of the exposure and the onset of symptoms. The
tion or be a cofactor. The absence of an optic neuropathy patient must have symptoms and signs that are compatible
in well-nourished individuals in the same environment, and with a toxic optic neuropathy and typical of those in other
recovery of vision in patients with restitution of an improved patients proved to have suffered loss of vision from the same
diet, strongly support, but do not prove, a nutritional basis. agent. Of course, the symptoms cannot have preceded the
Supporting laboratory evidence for the diagnosis of nutri- exposure.
tional optic neuropathy can be obtained in the form of direct The response of patients to rechallenge is helpful in evalu-
or indirect vitamin assays, serum protein concentrations, and ating the validity of presumed intoxications and in helping
antioxidant levels (1,2). to establish the cause of the patient’s optic neuropathy. If
Identifying the specific nutritional deficiency responsible a patient who has recovered vision following cessation of
for an optic neuropathy is very difficult. Undernourished exposure to a drug or chemical loses vision again when reex-
individuals are rarely deficient in only one nutrient; multiple posed, the recurrent loss of vision tends to verify the neu-
deficiencies are the rule. Even if a specific deficiency is rotoxic nature of the agent and the toxic etiology of the
identified in a patient with loss of vision, it does not prove visual loss. Epidemiologic data, especially those showing
that the deficiency caused the visual loss. Nor does recovery correlation of changing disease incidence when and where
when the deficient nutrient is resupplied establish that the specific drugs or chemicals are introduced or withdrawn,
resupplied nutrient affected the cure. With the exception of can also prove quite useful.
vitamin B12 (which only rarely becomes deficient for dietary Confirmatory evidence of exposure from laboratory tests
reasons), no specific nutrient deficiency has been conclu- or from associated nonvisual symptoms is desirable. Non-
sively proved to cause optic neuropathy in humans. At the toxic disorders must be considered in the diagnosis of these
present state of knowledge, one can only speculate about patients and should be ruled out with appropriate investiga-
which specific deficiencies can cause or contribute to nutri- tions.
tional optic neuropathy. Animal models can help to validate the optic nerve tox-
icity of putative intoxicants. Despite such problems as
TOXIC OPTIC NEUROPATHIES species variation in susceptibility and difficulty in measur-
The primary issue in patients suspected of having a toxic ing visual function in animals, some useful models are avail-
optic neuropathy is whether or not they were exposed to a able.
CLINICAL CHARACTERISTICS OF NUTRITIONAL AND TOXIC

OPTIC NEUROPATHIES
Individuals of all ages, races, places, and economic strata Patients with nutritional or toxic optic neuropathies often
are vulnerable to the toxic and nutritional deficiency optic initially notice a blur, fog or cloud at the point of fixation,
neuropathies. Certain groups are at higher risk because they following which the visual acuity progressively declines.
are under treatment with drugs, because of occupational ex- The rate of decline can be quite rapid. Although vision can
posure, or because of habits such as smoking and drinking. decrease to any level, total blindness or vision limited to
Nutritional deficiency optic neuropathy is more likely to light perception is unusual in cases of nutritional optic neu-
occur in the economically disadvantaged and during times ropathy, even if the patient is neglected. With the exception
of war and famine. The value of taking a thorough history, of methanol, which typically produces complete or nearly
including dietary intake, exposure to drugs, use of tobacco, complete blindness, visual loss less than 20/400 is unusual
and social and occupational background is obvious. in the toxic optic neuropathies. Bilaterality is the rule, al-
The symptoms and signs of nutritional and toxic optic though in the early stages, one eye may be affected before
neuropathy are similar and resemble those of most of the the other becomes symptomatic. Profound loss of vision in
other optic neuropathies, primarily those that occur bilater- one eye with completely normal findings in the other eye
ally and simultaneously. No single characteristic or combi- should cast doubt on the diagnosis of a toxic or nutritional
nation of characteristics is pathognomonic. optic neuropathy.
Toxic and nutritional optic neuropathies are not painful. Patients with toxic or nutritional optic neuropathies typi-
Thus, one should inquire carefully about this symptom since cally have central or centrocecal scotomas with sparing of
the presence of pain would suggest some other diagnosis. the peripheral visual field (Fig.10.1). Some perimetrists
Dyschromatopsia is present early and may be the initial claimed that centrocecal scotomas with ‘‘nuclei’’ between
symptom in observant patients. Some patients notice that fixation and the physiologic blind spot were the hallmark
certain colors, such as red, are no longer as bright and vivid of toxic optic neuropathy, especially the variety blamed on
as previously. Others experience a general loss of color per- tobacco (3). There are many who doubt this, and most au-
ception. thorities now recognize that both central and centrocecal
TOXIC AND DEFICIENCY OPTIC NEUROPATHIES 449
Figure 10.1. Visual fields of a patient with a bilateral toxic optic neuropathy caused by chloramphenicol. Note cecocentral
scotomas in the visual fields of the left (A) and right (B) eyes. The peripheral fields were normal.
scotomas may be encountered in either disorder (4–7). Some In the early stages of toxic and nutritional deficiency
patients have a central scotoma in one eye and a centrocecal optic neuropathy, the disc may be normal, slightly hyper-
scotoma in the fellow eye. The anatomic basis of the cen- emic, or swollen (Fig. 10.2). Disc hemorrhages may be
trocecal scotoma has yet to be established (8). Peripheral present in eyes with hyperemic discs, but they are usually
constriction and altitudinal visual field loss are rare. small (9,10). Optic atrophy develops after a variable inter-
Because of the symmetric and bilateral visual impairment val (Fig.10.3).
in toxic and nutritional optic neuropathies, a relative afferent Electrophysiologic examinations of patients with toxic or
pupillary defect is not a common finding in affected patients. nutritional optic neuropathies may reveal changes in the
When the patient is blind or nearly so, as a consequence of electroretinogram (ERG), visual evoked potential (VEP), or
methanol poisoning, the pupillary light response will be ab- both. Ikeda et al. (11) found a reduced amplitude of the VEP
sent or weak and the pupils will be dilated. Otherwise the and of the cone functions in the ERG. There is no tendency
pupils are likely to have relatively normal responses to light for the P100 wave of the VEP to be delayed, however, except
and near stimulation. in pernicious anemia (12,13).
Figure 10.2. Appearance of optic discs in a patient with bilateral toxic optic neuropathy from chloramphenicol. Note that
right (A) and left (B) discs are hyperemic and somewhat swollen nasally. There is already mild pallor of the temporal portions
of both optic discs, associated with early loss of the nerve fiber layer in the papillomacular bundle of both eyes.
Figure 10.3. Appearance of optic discs in a patient with bilateral optic neuropathy in the setting of poor nutrition and alcohol
abuse. Note extent of loss of nerve fiber layer from the papillomacular bundle (arrowheads) and marked temporal disc pallor.
Visual acuity was 20/400 in both eyes, and there were bilateral central scotomas.
DIFFERENTIAL DIAGNOSIS
When an individual complains of bilateral visual loss neuropathies, and optic atrophy is an early finding (22). In
that refraction cannot correct, and has an otherwise normal Leber’s optic neuropathy, the onset of visual loss is not infre-
examination, there are many diagnostic possibilities in addi- quently symmetric or nearly so, and this disorder must there-
tion to the toxic and nutritional optic neuropathies. Certain fore be considered in any patient in whom a toxic or nutri-
maculopathies can present in this guise (14–20). With time, tional optic neuropathy is thought to be present (23–27).
the fundus will show abnormalities, but until then, fluores- Appropriate testing for mitochondrial DNA mutations may
cein angiography or focal electroretinography may be the be required in some cases (see Chapter 11).
only means of establishing the nature of the lesion (20). Full It can be tragic to mistake a compressive or infiltrative
field electroretinography may not reveal the defect. lesion of the optic chiasm for nutritional or toxic optic neu-
One should be alert to the possibility of a conversion dis- ropathy. There are few instances in which one should be
order or malingering in cases of bilateral visual loss. The so confident of the diagnosis of toxic or nutritional optic
absence of optic atrophy is an important clue when the visual neuropathy that neuroimaging is omitted. Centrocecal scoto-
loss is long standing. In the acute phase, the characteristics mas and the bitemporal visual field defects of chiasmal dis-
of the visual field defects may help the clinician recognize
ease resemble each other, and there are many examples of
that the loss of vision is nonorganic. The visual field defects
bilateral central and even centrocecal scotomas from tumors
in the toxic and nutritional optic neuropathies are typically
central or centrocecal. Such defects are exceptional in pa- (28–37).
tients with a conversion reaction or who are malingering If a demyelinating, inflammatory, or infectious optic neu-
(21). In conversion reaction and malingering, the visual ritis begins simultaneously in both eyes, there may be confu-
fields are usually constricted and may show spiraling or have sion with the toxic and nutritional optic neuropathies. The
a tubular configuration. visual field defects are similar, but there is pain in about 90%
Dominantly inherited (Kjer’s) and mitochondria inherited of cases of optic neuritis. In some cases, magnetic resonance
(Leber’s) optic neuropathies can be confused with nutritional (MR) imaging will indicate the nature of the lesion. In others,
optic neuropathy if no other family members are known to however, it may be necessary to examine the cerebrospinal
be affected. The confusion is most likely to occur in patients fluid, perform specific tests for syphilis, sarcoidosis, or sys-
who are first evaluated late in their course. Kjer’s disease temic vasculitis, and perform a complete neurologic exami-
progresses more slowly than the nutritional and toxic optic nation.
EVALUATION
In most cases, analysis of the symptoms and signs ob- unless one is absolutely confident of the diagnosis. MR im-
tained from a detailed history and physical examination will aging before and after intravenous injection of gadolinium-
establish the diagnosis of a toxic or nutritional optic neuropa- diethylenetriamine-pentaacetic acid (gadolinium-DTPA)
thy. As stated above, it is prudent to obtain neuroimaging with special attention to the optic nerves and optic chiasm,
is the optimum investigation in most cases. A vitamin B12 instances. In cases of suspected intoxication, one should at-
level should be determined to identify pernicious anemia, tempt to evaluate or obtain information about other persons
and red blood cell folate levels provide one marker of general who have had similar exposure. The resulting information
nutritional status (1). has potential public health implications and can help to vali-
When a specific intoxicant is suspected, one should try date the toxicity of chemicals not previously recognized as
to identify the toxin or its metabolites in the patient’s tissues dangerous to the human optic nerve.
or fluids. The advice of a toxicologist is invaluable in such
SPECIFIC NUTRITIONAL OPTIC NEUROPATHIES

EPIDEMIC NUTRITIONAL OPTIC NEUROPATHY of the affected persons had evidence of optic neuropathy,
which occurred as a painless rapid loss of vision in both
The most useful observations regarding nutritional optic eyes associated with marked dyschromatopsia, central or
neuropathy have come not from sporadic cases encountered centrocecal scotomas, and normal appearing optic discs. Pa-
in practice, but rather from epidemics during war and famine. tients who did not recover vision (discussed later) developed
Two well-documented epidemics afflicted Allied prisoners temporal pallor of the optic discs, associated with marked
of war of the Japanese during World War II (38–45) and loss of the nerve fiber layer in the papillomacular bundle
Cubans in the early 1990s (46–50). The characteristics of (Fig. 10.4). The majority of cases occurred in people be-
the disorder in those two populations are reasonably consis- tween 25–64 years old, and with a predominance of males
tent and are described as follows (51). being among those with optic nerve disease. The relative
The symptoms developed in an undernourished popula- low incidence of disease in persons outside this age range
tion after four or more months of food deprivation (51). is likely secondary to the extra rations of food provided to
Among prisoners of war, vision loss occurred sooner in those children and older persons (60). Partial and complete recov-
who were undernourished at the time they were first incar- ery occurred following treatment with parenteral and oral
cerated. Only a minority of people at risk developed loss of vitamins (61). In addition, supplementation of the general
vision, and the occurrence of visual loss did not appear to population with B-complex vitamins and vitamin A since
correlate very well with the severity of malnutrition. In some 1993 coincided with a dramatic decrease in new cases of
cases, a superficial keratopathy was a prelude to the visual the condition (49).
loss, but visual loss developed both with and without a pre- Although the loss of vision in the epidemic cases was
ceding keratopathy (51). The visual loss was symmetric and undoubtedly caused by malnutrition, it is impossible to iden-
often appeared suddenly. In up to one-quarter of cases the tify a specific deficient nutrient that caused either of the
visual nadir was reached in one day. Vision plateaued after epidemics (51). Malnourished individuals have multiple de-
one month in the remainder. At the time of visual loss, many ficiencies. Clinical and laboratory data make it unlikely that
victims also had pain or sensory loss in their extremities. nutritional deficiency was the sole factor. Systematic investi-
There was a high incidence of bilateral sensorineural hearing gation of Cuban epidemic optic neuropathy and controls
loss. The fundi were usually normal at first, but a minority showed an increased risk associated with tobacco use and
had peripapillary hemorrhages associated with mild optic cassava consumption and a decreased risk associated with
disc hyperemia and swelling. Optic atrophy was a late devel- high serum levels of antioxidant carotenoids, ingestion of B
opment. The visual field defects were central or centrocecal. vitamins, and ingestion of animal products (49). Physical
Most abnormalities could be reversed with improved nutri- labor also seemed to be a risk factor among the prisoners
tion. of war. In any case, the conclusion that epidemic cases of
Pathologic information on nutritional optic neuropathies nutritional optic neuropathy (and probably sporadic cases as
is scarce. Fisher (52) described the results of postmortem well) are the result of some multifactorial etiology is inescap-
examinations on repatriated Allied prisoners. He found atro- able.
phy of the papillomacular bundle and lesions in the fascicu- The treatment of nutritional optic neuropathy is improved
lus gracilis of the spinal cord. Smiddy and Green (53) re- nutrition and, unless the vision loss is extensive, there is an
viewed the records of civilian patients in whom atrophy in excellent prospect for recovery or at least improvement.
the papillomacular bundle was found at autopsy. They con-
cluded that malnutrition, associated with alcoholism, was VITAMIN B12 DEFICIENCY
common. Although the role of vitamin B12 in the maintenance and
In 1992 and 1993, an epidemic of optic neuropathy and function of the nervous system has yet to be explained, de-
peripheral neuropathy similar to that reported among pris- pletion of the nutrient almost invariably leads to neurologic
oners of war occurred in Cuba (47–49,54–59). The epidemic dysfunction. The body’s nutritional requirements must be
began in the province of Pinar del Rı́o, located at the north- met entirely by food (particularly meat and dairy products).
western tip of Cuba and gradually spread southeastern. More The abundant stores, particularly in the liver, are redistri-
than 50,000 persons were affected with bilateral optic neu- buted so gradually that it takes years for poor intake to cause
ropathy, sensory and dysautonomic peripheral neuropathy, disease. However, a poor diet is rarely the cause of vitamin
sensory myelopathy, spastic paraparesis, or sensorineural B12 deficiency and when it is, it is found only in strict vegans
deafness in various combinations. Slightly more than half (62). Impaired absorption because of diphyllobothriasis (63),
Figure 10.4. Visual fields and appearance of ocular fundi in a patient with Cuban epidemic optic neuropathy. The patient
was a 23-year-old Cuban man who developed progressive loss of vision in both eyes associated with a peripheral neuropathy
in 1993. Examination revealed visual acuity of 20/200 OU. Visual fields performed by kinetic perimetry reveal a cecocentral
scotoma in the field of both the left (A) and right (B) eyes. Photographs of the right (C) and left (D) optic fundi show temporal
pallor of the optic discs associated with marked loss of the retinal nerve fiber layer in the papillomacular bundle.
intestinal disease, or gastrointestinal surgery accounts for and the patient develops spasticity, with hyperactive knee
only a few cases. and ankle jerks and Babinski reflexes. Dementia may also
Pernicious anemia is by far the most common condition develop.
in which vitamin B12 deficiency and its complications are Deficiency of vitamin B12, whether from inadequate diet
encountered. This presumably autoimmune disorder results or interference with absorption, can cause an optic neuropa-
from impaired absorption of the vitamin from the ileum, thy. Lesions in the optic nerves and optic chiasm have been
because the patient lacks the intrinsic factor elaborated by demonstrated in some postmortem examinations of patients
the parietal cells of the gastric mucosa. Pernicious anemia with pernicious anemia (64,65). There are also primate
is most often found in, but is not limited to, middle-aged models of the disease (66–68). Severe optic nerve degenera-
and elderly Caucasians of northern European extraction. The tion is found in experimental vitamin B12 deficiency in mon-
anemia is megaloblastic. It develops slowly and can be se- keys even before there is anemia or a spinal cord lesion (68).
vere. Unless treatment is instituted early, most patients with In light of this finding, it is not surprising that in humans,
pernicious anemia develop neurologic manifestations. The an optic neuropathy may be the first symptom of pernicious
pathologic substrate is a white matter lesion that affects both anemia and may precede the hematologic disturbance. In-
myelin and axons initially in the posterior columns of the deed, abnormal visual evoked responses can be recorded in
upper thoracic and lower cervical portions of the spinal cord patients with pernicious anemia who have no visual symp-
(‘‘subacute combined degeneration’’). The process subse- toms, suggesting that there may also be subclinical damage
quently affects other white matter tracts and other levels of to the visual pathway in this disease (12).
the spinal cord. Paresthesias and weakness in the extremities The optic neuropathy that results from vitamin B12 defi-
are heralding symptoms. With time, vibration sense is lost, ciency resembles the other nutritional optic neuropathies
(69–73). The visual loss is symmetric, painless, and progres- some malnourished patients with optic neuropathy recover
sive. Central and centrocecal scotomas are the rule, and the when treated with folic acid supplements (1,81,82). As dis-
optic disc appears normal in the early stages of the condition. cussed above, however, this does not prove that the folate
Unless optic atrophy becomes well established, one can ex- deficiency caused the loss of vision or that the folic acid
pect recovery of vision with intramuscular injections of hy- supplements affected the recovery.
droxocobalamin. The optic neuropathy of pernicious ane- Despite the lack of definitive evidence, it remains possible
mia, unlike the other deficiency optic neuropathies, does not that there are some patients who develop an optic neuropathy
usually respond to an improved diet. consequent to dietary deficiency of thiamine, folate, and
Since the optic neuropathy of vitamin B12 deficiency is these other vitamins. It thus makes sense to enrich the diet
essentially indistinguishable from many other toxic and nu- of patients with loss of vision and evidence of poor nutrition
tritional deficiency optic neuropathies, can present before with all of the vitamins in which they might be deficient.
there is anemia or myelopathy, and requires parenteral treat-
ment, it is important to obtain a serum vitamin B12 level in TROPICAL OPTIC NEUROPATHY
all cases of unexplained bilateral optic neuropathy.
There are optic neuropathies endemic to tropical regions
OTHER VITAMIN DEFICIENCIES for which a nutritional etiology has been invoked. An early
report by Strachan from Jamaica appeared in 1897 (83). The
The association of visual loss with beriberi, known for clinical features of his patients resemble in some ways those
centuries, focused attention on vitamin B1 deficiency as a of the epidemic cases described above. There was numbness
cause of nutritional optic neuropathy. This vitamin has re- and cramps in the hands and feet. The visual loss was bilat-
ceived more attention in this regard than any other nutrient eral and was sometimes accompanied by hearing loss. How-
and, despite contrary evidence summarized in the following ever, other features were unusual. Muscle wasting often de-
paragraphs, many authorities still consider thiamine (vitamin veloped. The pain was so severe that patients were kept
B1) deficiency an important factor in the causation of nutri- awake. A dermatopathy was a constant finding. In any case,
tional deficiency optic neuropathy (74). Strachan (83) made no claim for a nutritional etiology. When
The role of thiamine deficiency in patients with nutritional the disorder was subsequently reevaluated by others, they
deficiency optic neuropathy is controversial. Some studies concluded that this was not a nutritional disease (84,85).
of thiamine deprivation in rats have shown that an optic Despite that, some authors use ‘‘Strachan’s syndrome’’ to
neuropathy may occur. However, the results of these experi- designate nutritional optic neuropathy. The eponym is inap-
ments are not conclusive, since the animals may have suf- propriate.
fered other deficiencies, and few animals were affected. It should be noted that there is an otherwise unexplained
When chronic thiamine deficiency was produced in human bilateral optic neuropathy, called ‘‘West Indian Amblyopia’’
volunteers, their vision did not suffer (75,76). The prisoner- in black expatriates from the West Indies. Examples of this
of-war studies present strong evidence against a primary role condition have been reported from Great Britain and the
for thiamine deficiency in nutritional optic neuropathy. One United States (86,87). The history is typically that of bilat-
study showed that vision loss developed just as the incidence eral, painless progressive visual decline in a well-nourished
of beriberi was declining. In fact, beriberi was as prevalent adult. The visual field defects tend to be central or centroce-
among prisoners of war with normal vision as it was among cal, but annular scotomas and peripheral constriction have
those who had loss of vision. Finally, among civilians in a been reported. Optic atrophy develops. Deafness is also pres-
Japanese prison camp, nutritional optic neuropathy could not ent in some of the patients. No treatment, including various
be cured with injections of thiamine, and some prisoners vitamin regimens, is effective in reversing either the visual
developed visual loss while being treated with thiamine for or the nonvisual manifestations of the disorder. Although a
beriberi. toxic basis (‘‘bush tea’’) has been postulated, there is no
The disorder consequent to thiamine depletion is Wer- good evidence for either a toxic or nutritional etiology.
nicke’s encephalopathy. There is an excellent primate model A disorder similar to Strachan’s syndrome has been de-
of this disorder, and in this model there are no pathologic scribed in Nigerians (88,89). It differs from the West Indian
changes in the optic nerves (77,78). Indeed, loss of vision is cases (and the epidemic and sporadic nutritional optic neu-
uncommon among patients with Wernicke’s disease (79,80). ropathies) in that the majority of patients have constricted
These observations cast further doubt on a role for thiamine visual fields and that total blindness can occur. Poor diet is
deficiency in human nutritional optic neuropathy. said to be the common denominator in the African cases,
The role of pyridoxine, niacin, folic acid, and riboflavin but investigators have also suggested that exogenous cyanide
deficiencies in causing an optic neuropathy was reviewed in from an excess of cassava in the diet is an etiologic factor.
an earlier edition of this book. As with thiamine, these vita- However, the manner in which cassava is prepared in this
mins are apt to be depleted in patients who are generally population would probably make for minimal exposure to
malnourished, but there is no definitive evidence indicating cyanide (90). The evidence that cyanide plays a role in caus-
that such deficiencies play a primary etiological role in nutri- ing any optic neuropathy is tenuous at best and is discussed
tional optic neuropathy. For example, low folate levels have further in the section on tobacco optic neuropathy. The en-
been documented in the red blood cells and, occasionally, demic tropical neuropathy in Nigeria might result from nutri-
the serum of patients with nutritional optic neuropathy and tional deficiency, but this has not been proved.
SPECIFIC TOXIC OPTIC NEUROPATHIES

No discussion of the toxic optic neuropathies can be con- present at this stage. Coma and death from respiratory failure
sidered complete without reference to the encyclopedic and may follow. Metabolic acidosis is one of the hallmarks of
authoritative text originated by Grant and subsequently methanol intoxication, and it is consequent to the accumula-
coauthored by Schuman (91). The reader who wishes to pur- tion of formate (105). The severity of the acidosis is a rough
sue the subject of the toxic optic neuropathies in greater guide to the severity of the intoxication but the visual com-
detail than is provided in this chapter is well advised to plications are not consequent to the acidosis per se.
consult Grant and Schuman’s ‘‘Toxicology of the Eye.’’ Methanol intoxication can reduce vision to any level, in-
Table 10.1 lists substances that are suggested or presumed cluding total irrevocable blindness. Central and centrocecal
to be toxic to the human optic nerve. It also contains pertinent scotomas predominate in cases of partial visual loss. The
references so that the reader can decide whether the associa- optic disc is often hyperemic, with blurred margins in the
tion of ingestion of, or exposure to a particular substance acute stage, and there may be some edema of the peripapil-
and the subsequent visual loss, is fortuitous or cause and lary retina. The reactions of the pupils to light are reduced
effect. Several of the agents are of academic interest only, in cases of severe, but not complete loss of vision; however,
since they are no longer in use. when the patient is blind, the pupils are dilated and nonreac-
A recurrent dilemma in patients who develop loss of vi- tive to light. Grant and Schuman (91) considered the lack
sion or a clear-cut optic neuropathy is deciding whether the of a pupillary reaction to light as signifying a poor prognosis.
disease or the treatment is responsible for the visual loss. In Patients may regain vision, usually within a week but occa-
some cases, it is impossible to decide. In addition, the sus- sionally later. In some cases, vision fails again weeks after
pected toxin may not be the only agent to which the patient first improving. The optic discs gradually become pale, and
has been exposed, further confounding the issue of causa- there is often cupping of the optic disc that may be indistin-
tion. guishable from that in glaucoma. There may also be thinning
Several toxic-induced optic neuropathies are discussed of retinal arteries.
below in detail. The diagnosis of methanol poisoning can be substantiated
by demonstrating a serum methanol level of greater than 20
METHANOL mg/dL. Other biochemical findings include a large anion
Methanol ingestion is the most widely recognized cause gap, a high serum formate level, and a reduced serum bicar-
of a toxic optic neuropathy, and methanol toxic neuropathy bonate level.
is also the best characterized pathogenetically and clinically. Treatment of methanol poisoning must be instituted
Unlike some of the intoxicants mentioned in this chapter, promptly. In patients seen relatively early, who have in-
which are medications and therefore apt in time to be sup- gested methanol but have not yet developed visual symp-
planted, methanol is likely to remain a permanent threat. toms, there is the potential for preventing loss of vision, and
Hence, it deserves special attention in this chapter. However, even patients who have already lost vision may experience
it must be noted that methanol intoxication is not an ideal some degree of recovery if prompt treatment is instituted
paradigm for the toxic neuropathies. The combination of (106,107). Ethanol should be given, since it interferes with
acute onset, life-threatening systemic symptoms, and severe the metabolism of methanol. The metabolic acidosis re-
irreversible visual loss is atypical. sponds to bicarbonate, and hemodialysis can help eliminate
Cases are encountered in both epidemic and sporadic the toxin.
form. The victim almost always has consumed the poison
accidentally because it was mistaken for, substituted for, ETHYLENE GLYCOL
or added to, ethyl alcohol whose taste and smell it closely Ethylene glycol is the active ingredient in automobile
resembles. Although blindness can result from drinking an antifreeze and may be consumed accidentally or in a suicide
ounce or less of pure methanol, the toxic effect is ameliorated attempt. This poison deserves at least brief mention, since
if it is ingested together with ethyl alcohol. there is evidence that it is toxic to the optic nerve and because
There is a well-studied primate model of methanol intoxi- the metabolic consequences resemble those of methanol poi-
cation (92–94). In this model, there is disc swelling, but the soning with which it could easily be confused (108).
lesion is retrobulbar. The evidence from human postmortem As in methanol intoxication, the victim initially has nau-
examinations also favors a retrobulbar locus (95–97). The sea, vomiting, and abdominal pain. Stupor and coma follow,
early lesion is demyelinating (96); the later lesion is necrotic and there is cardiac failure within a few days. Unlike the
(97). situation in methanol intoxication, however, there is a high
There is extensive literature on the clinical findings in incidence of renal failure. The outcome can be fatal, or re-
methanol intoxication in humans (98–104). Initially, the pa- covery can occur. Patients who survive may have permanent
tient has nausea and vomiting, but these symptoms may seem residual neurologic and ophthalmologic deficits.
so insignificant that the physician falsely concludes that the Despite the metabolic similarities to methanol intoxica-
patient has not been seriously intoxicated. After 18–48 tion, the frequency of visual loss seems to be much lower
hours, however, the patient begins to experience respiratory in patients poisoned by ethylene glycol. Nevertheless, pro-
distress, headache, and visual loss. Abdominal pain, general- found visual loss can occur, with dilated pupils that do not
ized weakness, confusion, and drowsiness are commonly react to light. True papilledema, caused by cerebral edema,
Table 10.1 may occur, or the optic discs can initially appear normal,
Substances Believed or Known to Cause Toxic Optic Neuropathy only to become pale with time. Unlike the situation in metha-
Substance References
nol intoxication, patients with ethylene glycol intoxication
may develop nystagmus and ophthalmoplegia.
Amantadine hydrochloride 223 One clue to the cause of the intoxication is the presence of
Amiodarone 183–207
oxalate crystals in the urine. The accumulation of glycolate
Amoproxan 224,225
Arsenicals 226 causes a metabolic acidosis and a large anion gap. Treatment
Aspidium (male fern) 227,228 is essentially the same as the treatment of methanol intoxica-
Cafergot 229 tion. Bicarbonate is used to combat the acidosis; ethanol is
Carbon disulfide 230–233 administered to retard the metabolism of the ethylene glycol;
Carbon monoxide 234
Carbon tetrachloride 233,235–240
and hemodialysis is employed to promote elimination of the
Catha edulis 241 poison.
Chlorambucil 242
Chloramphenicol 243–249
Chlorodinitrobenzene 250,251 ETHAMBUTOL
Chlorpromazine 252
Chlorpropamide 253–255 Of the drugs in wide use at the time this chapter was
Cisplatin 256–259 compiled, ethambutol is undoubtedly the one most often im-
Clioquinol 152,155,158, plicated in toxic optic neuropathy. The potential for visual
289–293
Clomiphene 260,261
impairment was recognized soon after this antituberculous
Cobalt chloride 262 agent was introduced (109). The original formulation was a
Cyclosporine 263–269 racemic mixture. However, when it was discovered that the
Dapsone 91 D-form was predominantly responsible for the therapeutic
Desferrioxamine (desferoxamine; deferoxamine) 270–272
Dinitrobenzene 250,251
effect and the L-form for the toxicity, the L-form was with-
Dinitrochlorobenzene 250,251 drawn from the market.
Disulfiram 167–171,175, There are good animal models of this disorder. Monkey
273,274 experiments using the racemic mixture showed that etham-
Elcatonin (synthetic analog of calcitonin) 275
Emetine 276
butol intoxication tended to first affect the optic chiasm
Ergot 277 (110,111). Studies in rats using the D-isomer showed that
Ethambutol 109–119,122–151, this was an axonal neuropathy and confirmed the special
278–282 susceptibility of the optic chiasm (112). In rabbits, however,
Ethchlorvynol 283,284
the lesion appeared in the optic nerves (113).
Ethylene glycol 285–287
5-Fluorouracil 288 The biochemical basis of ethambutol toxicity has yet to
Halogenated hydroxyquinolines 152,155,158, be elucidated. Ethambutol’s therapeutic effect is related to
289–293 the metabolism of this drug to an agent that chelates metal-
Hexachlorophene 294,295 containing enzymes essential for bacterial replication. The
Infliximab 296,297
Interferon alpha 298–303
chelation of copper or zinc containing enzymes within
Iodoform 91 human mitochondria has been suggested as a mechanism for
Iodoquinol 152,155,158, the optic neuropathy (114–116). Support for this mechanism
289–293 includes the fact that reduced serum zinc levels are found
Isoniazid 304–313
Lead 314–318
in several toxic optic neuropathies (117) and patients with
Methanol (methyl alcohol) 106,107,319,320 reduced plasma zinc levels maybe at increased risk for eth-
Methyl acetate 321,322 ambutol toxic optic neuropathy (118,119). It is interesting
Methyl bromide 323 in this regard that two other chelators–disulfiram (see later)
Octamoxin 324–329
Organic solvents 330
and DL-penicillamine–have been implicated in toxic optic
Penicillamine 120,331,332 neuropathies (120,121).
Pheniprazine 333–335 Human ethambutol intoxication has been described in nu-
Plasmocid 336,337 merous publications (115,122–134). The occurrence of ocu-
Quinine 338
Sildenafil 176–182
lar toxicity is dose related; loss of vision most likely to occur
Streptomycin 339 in patients receiving 25 mg/kg/day or more. However, vision
Styrene (vinyl benzene) 340 loss has been documented in approximately 1% of patients
Sulfonamides 341,342 receiving the currently recommended therapeutic dose of
Tacrolimus 343
15–25 mg/kg/day (129,135,136). Visual loss rarely occurs
Tamoxifen 344–347
Thallium 315,348–351 before the patient has been receiving the drug for at least 2
Tobacco 352,353 months, with 7 months being the average. There is evidence
Toluene 354–359 that there is greater susceptibility to intoxication and more
Triethyltin 91
severe visual impairment in patients with renal tuberculosis,
Trichloroethylene 360,361
Vincristine 362–366 perhaps because ethambutol depends on the kidneys for ex-
cretion (125,137). Diabetes mellitus, liver damage, poor nu-
trition, as well as tobacco and alcohol use may be additional and visual evoked potentials (133,150,151) to detect the ear-
risk factors for ethambutol optic neuropathy (138–140). liest evidence of a toxic effect on the optic nerves. Regard-
Some authors claim that dyschromatopsia is the earliest less of the screening strategy used, there is a small risk of
symptom of the toxic optic neuropathy produced by etham- permanent visual loss in patients treated with this drug.
butol, with blue-yellow color changes being the most com-
mon (141). In any case, the loss of vision is bilaterally sym- HALOGENATED HYDROXYQUINOLINES
metric and begins insidiously. Reduced visual acuity with a
The halogenated hydroxyquinolines are amebacidal
central scotoma is the rule (134,142,143). However, patients
drugs. One of these (iodochlorhydroxyquin) was promoted
may also present with peripheral visual field constriction
in some parts of the world for preventing or treating travel-
and sparing of the central vision (135) or bitemporal defects
er’s diarrhea and chronic diarrheas. In that setting, it caused
(143,144). An initially normal optic nerve appearance may
a syndrome of optic neuropathy, myelopathy, and peripheral
be followed by the development of optic nerve atrophy.
neuropathy (SMON). This is ironic, since there is no evi-
In some patients, the vision slowly improves over several
dence that the halogenated hydroxyquinolines actually pre-
months if ethambutol therapy is discontinued (129,143).
vent traveler’s diarrhea. The impact on public health was
However, the visual loss that results from ethambutol optic
significant, with over 10,000 cases documented in Japan be-
neuropathy is not necessarily reversible. Kumar et al. (133)
tween 1956 and 1970. SMON virtually disappeared in Japan
described a series of seven consecutive patients with severe
when the use of these drugs was stopped.
visual loss caused by ethambutol toxicity. Only 3 of the 7
Japanese investigators were the first to call attention to
patients (42.2%) achieved a visual recovery of better than
the problem, but the disorder was not limited to geographic
20/200 after an average follow-up of 8.3 Ⳳ 2.1 months after
or ethnic boundaries (152–157). The neurotoxicity of the
stopping the drug. There were no predisposing risk factors
halogenated hydroxyquinolines is dose related (158). Pa-
to contribute toward a poor prognosis. Kumar et al. (133)
tients with gastrointestinal disease, who constitute a high
suggested that in light of their findings, ethambutol should
proportion of those taking these drugs, were especially vul-
not be used in patients with tuberculosis. Other investigators
nerable.
have documented that despite discontinuation of ethambutol
Symptoms can appear as early as five days after beginning
at the onset of visual symptoms, only 40–50% of patients
treatment. Initially, there is abdominal discomfort that is fol-
have improvement of vision and most patients with im-
lowed by paresthesias and dysesthesias in the legs. This may
proved vision still sustain permanent visual deficits (122,
progress to paraparesis or paraplegia. One quarter of the
133,140,143,145).
patients suffer visual impairment in one form or another.
It is important for the clinician to be aware that there are
Dyschromatopsia is an early symptom and occasionally is
reports of patients who develop rapid onset, severe, bilateral,
the only deficit; however, central acuity is usually affected,
permanent visual loss despite treatment with a low therapeu-
and about 5% of these patients become effectively blind.
tic dose of ethambutol (130,133,143,146). In this regard,
Children with acrodermatitis enteropathica, a rare heredi-
Chatterjee et al. (146) described a 26-year-old man who had
tary disease in which there is malabsorption of zinc, appear
‘‘hazy vision’’ 3 days after starting treatment with ethambu-
to have a low threshold for loss of vision from halogenated
tol at a low dose of 15 mg/kg. Despite discontinuation of
hydroxyquinolines (159). Interestingly, they often experi-
the drug 3 days later (6 days after starting treatment), he
ence the visual loss without developing the other neurologic
developed permanent ‘‘total blindness’’ OU.
deficits (160–165).
Beyond stopping the drug, there is no specific therapy for
ethambutol optic neuropathy. Recommendations regard- DISULFIRAM
ing the appropriate screening strategy are controversial
(122,136,139,147). Patients should be instructed to discon- Disulfiram is a drug with a role, albeit a small one, in
tinue ethambutol immediately at the onset of any visual the treatment of chronic alcoholism. Disulfiram interferes
symptoms. Ethambutol is relatively contraindicated in pa- with the metabolism of acetaldehyde, a metabolic product of
tients who are unlikely to notice or describe visual symptoms ethanol. The concurrent ingestion of alcohol and disulfiram
such as adults with communication problems or poor base- causes uncomfortable symptoms, including flushing, nausea,
line vision from unrelated causes and children. Most investi- and vomiting as a result of the accumulation of acetaldehyde.
gators agree that patients should have a baseline (pretreat- Disulfiram can cause an optic neuropathy, and since the
ment) ophthalmologic examination that includes assessment optic neuropathy can occur in patients who have remained
of visual acuity, color vision, and visual fields, and that this abstemious, alcohol toxicity presumably does not play a role
examination should be repeated at the onset of any visual in such cases. The mechanism of this toxicity is unknown,
symptoms. These parameters are often monitored periodi- but disulfiram, like several other optic nerve toxins, is a
cally (every 1–3 months) during the treatment of asymptom- chelating agent (117,166).
atic patients (147). However, there is no consensus regarding The symptoms and signs in patients with toxic optic neu-
the specific visual tests and testing intervals appropriate for ropathy caused by disulfiram are quite typical of those of
monitoring asymptomatic patients during treatment (147). other toxic and nutritional optic neuropathies (167–175).
Some investigators suggest monitoring asymptomatic pa- The visual loss is subacute or chronic, affecting both eyes
tients with more detailed visual testing such as contrast sensi- symmetrically. Pain is not a feature. The visual field defects
tivity (148), Farnsworth-Munsell 100 hue testing (119,149), are central or centrocecal. The optic discs are usually initially
normal in appearance, but they can become pale late in the rone’s therapeutic mechanism of action is related to its abil-
course. Some of the victims also develop a sensorimotor ity to prolong the duration of action potentials and the refrac-
peripheral neuropathy. The prognosis for complete recovery tory period in cardiac-conducting tissues. The most common
is good if the disulfiram therapy is discontinued. ocular side effect is the formation of verticillate, pigmented,
corneal epithelial deposits that eventually occur in most pa-
SILDENAFIL tients (70–100%) treated with the drug. The amount of cor-
Sildenafil citrate (Viagra, Pfizer Pharmaceuticals, New neal epithelial deposits observed in a given patient, as well
York, NY) is a phosphodiesterase type 5 inhibitor that is as the incidence of these deposits in a group of patients, is
prescribed for erectile dysfunction (176). This drug facili- related to the dose of the drug and the duration of treatment.
tates erections by augmenting nitric oxide induced vasodila- With discontinuation of the drug, the deposits resolve over
tion in the corpus cavernosum. Systemic side effects are several months as amiodarone has a long half-life of up to
related to drug induced systemic vasodilation and include 100 days. Other ocular side effects from amiodarone include
headache, flushing, and systemic hypotension. Severe sys- anterior subcapsular lens opacities, multiple chalazia, and
temic hypotension may occur when sildenafil is ingested keratitis sicca. Fortunately, these ocular side effects rarely
with other nitrate medications. The most common ocular cause significant visual impairment and do not constitute a
side effect is a transient alteration of color perception that reason for discontinuing the drug (183).
presumably occurs from sildenafil’s weak inhibitory effect Amiodarone is associated with an optic neuropathy that
on phosphodiesterase type 6, a phototransduction enzyme has many characteristics similar to nonarteritic anterior is-
present in the retinal photoreceptor outer segments (176). chemic optic neuropathy. Gittinger and Asdourian (184) re-
Pomeranz et al. recently described five patients who had ported this association in two patients treated with therapeu-
nonarteritic anterior ischemic optic neuropathy (NAION) tic doses of amiodarone. They described a 45-year-old man
within minutes to hours after ingesting a therapeutic dose who had unilateral, hemorrhagic disc edema noted on a rou-
of sildenafil (177–179). These patients had symptoms and tine examination 8 months after starting treatment with ami-
signs typical of NAION including acute visual loss, altitudi- odarone. He was asymptomatic and had normal visual acu-
nal visual fields deficits, a relative afferent pupillary defect, ity, color vision, and visual fields. His disc edema resolved
and disc edema. Visual deficits did not improve and the 1 month later despite continued treatment with the drug. The
disc edema resolved to disc pallor. Although four of these other patient was a 61-year-old man who complained of hazy
patients did not have vasculopathic risk factors for NAION, vision in his right eye two months after starting treatment
they all had the classic small cupless ‘‘disc at risk’’ associ- with amiodarone. He had a visual acuity of 20/25 OU, a
ated with this entity. Two other patients with sildenafil asso- right relative afferent pupillary defect and hemorrhagic disc
ciated NAION have been described (180,181). edema in the right eye. Several days later, he developed
The association of sildenafil and NAION may be second- hemorrhagic disc edema in the left eye. Three months later,
ary to vascular effects induced by this drug. Nitric oxide he still had bilateral, hemorrhagic disc edema and his dosage
induced vasodilation may precipitate NAION by interfering of amiodarone was reduced. Five months after his visual
with vascular autoregulation at the optic nerve head or by loss, he had a visual acuity of 20/20 OU, an inferior arcuate
inducing systemic hypotension (177). Alternatively, the drug defect in the right visual field, disc edema OD, and resolution
may be directly toxic to the optic nerve as excessive nitric of his disc edema OS.
oxide has been postulated to damage retinal ganglion cell Feiner et al. (185) subsequently described 13 patients who
axons (182). Finally, the association may be coincidental as developed an optic neuropathy during treatment with amio-
patients with vascular disease are at risk for erectile dysfunc- darone. The amiodarone dosage ranged from 200 to 600 mg/
tion and NAION. However, as noted above, most of these day and the time interval between initiation of amiodarone
patients did not have known vasculopathy and the NAION therapy and the manifestation of optic neuropathy ranged
occurred minutes to hours after ingestion of sildenafil. from 1–72 months. Three patients had no visual symptoms
It is important to specifically ask about sildenafil use in and disc edema was noted on a routine examination. The
patients who present with NAION as they often do not vol- remaining 10 patients complained of blurry or decreased
unteer this information. Until this association is better delin- vision and presented with visual acuities ranging from 20/
eated, there is no screening strategy to determine which pa- 20 to 20/400. Nine patients had visual field deficits including
tients are at risk for NAION from sildenafil. However, arcuate scotomas, altitudinal deficits, centrocecal scotomas,
Pomeranz recommends that a history of NAION should enlarged blind spot, and visual field constriction. Among the
probably be a contraindication for sildenafil use (177). 13 patients, 12 had disc edema and 5 had bilateral ocular
Finally, patients contemplating treatment with this drug involvement. Only 3 patients had recovery of vision after
should be informed of the possible side effect of permanent amiodarone was discontinued and 3 patients had a final vi-
visual loss. sual acuity of 20/100 or worse.
Several other investigators have described patients that
AMIODARONE
developed an optic neuropathy while being treated with ami-
Amiodarone is a benzofuran derivative that is primarily odarone (186–197). In 1997, a 50-year-old man who became
used to treat atrial or ventricular tachyarrhythmias that are legally blind from a bilateral optic neuropathy that developed
unresponsive to other antiarrhythmic agents (183). Amioda- 6 weeks after the initiation of amiodarone therapy was
awarded a $20 million judgment in a lawsuit against the darone treatment and repeated this examination every 6
pharmaceutical company that sells this drug (198). months during treatment. Any patient with visual symptoms
The nature of the association of optic neuropathy and ami- during treatment should be promptly evaluated. Amiodarone
odarone treatment is controversial. Many of the patients de- may be a life-saving treatment and the occurrence of an optic
scribed in the above reports developed an optic neuropathy neuropathy is therefore not an absolute contraindication to
that is indistinguishable from nonarteritic anterior ischemic further treatment. However, in patients who have an optic
optic neuropathy. Feiner et al. (185) noted that the 1.79% neuropathy while on amiodarone, discontinuation of amio-
incidence of optic neuropathy among patients treated with darone and treatment with an alternative drug should be con-
amiodarone at the Mayo Clinic was significantly higher than sidered.
the 0.3% incidence of ischemic optic neuropathy in the gen-
eral population 50 years of age or older in Olmsted County, TOBACCO
Minnesota. However, patients treated with amiodarone often
have severe vascular disease and probably have a higher risk Controversy concerning the mechanism, nature, nosol-
of developing anterior ischemic optic neuropathy compared ogy, semiology and existence of a toxic optic neuropathy
with the general population. caused by tobacco has been debated for many years (208).
Macaluso et al. (199) reviewed data from 73 patients who For much of this time, the designation ‘‘tobacco-alcohol am-
developed an optic neuropathy while taking amiodarone. blyopia’’ has obfuscated these issues (209). It is our opinion
They proposed several features that distinguish amiodarone- that although tobacco probably can cause or contribute to a
associated optic neuropathy from typical nonarteritic ante- toxic optic neuropathy, alcohol is not a primary or contribut-
rior ischemic optic neuropathy. Patients with amiodarone- ing factor, and the two do not exert any toxic effect in con-
induced optic neuropathy tend to have insidious bilateral cert. If ever a medical term deserved to be expunged, it is
visual loss and protracted, bilateral simultaneous disc edema ‘‘tobacco-alcohol amblyopia.’’
that resolves several months after the drug is discontinued. In The frequency with which tobacco optic neuropathy is
contrast, patients with typical nonarteritic anterior ischemic encountered varies from time to time and place to place.
optic neuropathy tend to have acute unilateral visual loss This remarkable variability may reflect nothing more than
and disc edema that resolves several weeks after visual loss. the lack of good criteria for proving the diagnosis. In the mid-
Despite these distinctions, there is certainly overlap in the nineteenth century in Scotland, chronic cases were allegedly
clinical spectrum of these two entities and some patients seen every day at one eye infirmary (210). One hundred
reported in the literature as having optic neuropathy from years later, physicians at the Mayo Clinic were not even
amiodarone likely had typical nonarteritic anterior ischemic seeing one case a year (211), and investigators in Australia
optic neuropathy. had also not seen a single case (26). One author essentially
The mechanism of amiodarone-induced optic neuropathy denied the existence of tobacco amblyopia (7). In 1977, most
may be related to the fact that amiodarone binds phospholip- authorities agreed that this was a disease whose incidence
ids within lysosomes and forms a complex that is not degrad- was declining; an apparent paradox, since the consumption
able by phospholipase enzymes (183,200). The amiodarone- of tobacco products actually increased during the same pe-
phospholipid complex accumulates within lysosomes and riod (212,213). A shift away from pipe and cigar smoking
forms cytoplasmic lamellar inclusions. These lamellar inclu- (which carries a higher risk) to cigarette smoking (which
sions have been observed in the cytoplasm of many tissues carries a lower risk) might explain the paradox.
including corneal epithelial, stromal, and endothelial cells; In any case, convincing cases of tobacco amblyopia are
lens epithelium; conjunctival epithelium; extraocular muscle still encountered (214). The field investigation of Cuban pa-
fibers; scleral cells; uvea; blood vessel endothelial cells; reti- tients with epidemic optic neuropathy appears to provide
nal ganglion cells; retinal pigment epithelium; and optic further validation of a role for tobacco in optic nerve disease
nerve axons. Indeed, these inclusions are likely responsible (49).
for the corneal and lens deposits noted above. The mechanism by which tobacco damages the optic
The accumulation of these inclusions in Schwann cells nerves has not been determined. One possibility relates to
has been implicated as a cause of the peripheral neuropathy concurrent malnutrition. The Cuban experience suggests that
that develops in some patients treated with amiodarone tobacco may be a secondary factor in patients predisposed
(201,202). Optic nerve axon inclusions have been observed to an optic neuropathy by malnutrition. Schepens (215) made
by electron microscopy and may be related to the optic nerve a pertinent observation about this relationship. He had rarely
dysfunction and disc edema that occur in association with seen tobacco ‘‘amblyopia’’ in Belgium prior to World War
amiodarone (200). II. However, during the Nazi occupation of Belgium, when
Several investigators have described a pseudotumor there was widespread malnutrition, the incidence of the dis-
cerebri syndrome in patients treated with amiodarone ease increased dramatically.
(203–207). In these patients, amiodarone presumably causes Vitamin B12 deficiency may also play a role in some cases
disc edema by raising intracranial pressure. of tobacco optic neuropathy as reported by Foulds et al.
The available data are insufficient to make firm recom- (216). Impaired vitamin B12 absorption was found in 40%
mendations regarding a screening protocol for patients of their patients, and there was overt pernicious anemia in
treated with amiodarone. Macaluso et al. (199) obtained a 20%. Tobacco itself may actually interfere with the absorp-
baseline examination on all patients prior to starting amio- tion of the vitamin (217). In most cases of tobacco optic
neuropathy, however, there is no defect in vitamin B12 me- 18. Bresnick GH, Smith VC, Pokorney J. Autosomal dominantly inherited macular
dystrophy with preferential short wavelength sensitive cone involvement. Am
tabolism, and blood levels of the vitamin are within normal J Ophthalmol 1989;108:265–276.
limits. 19. Miyake Y, Ichikawa K, Shiose Y, et al. Hereditary macular dystrophy without
visible fundus abnormality. Am J Ophthalmol 1989;108:292–299.
Cyanide is present in tobacco smoke, and this has led to 20. Matthews GP, Sandberg MA, Berson EL. Foveal cone electroretinograms in
a suspicion that tobacco optic neuropathy is a limited form patients with central visual loss of unexplained etiology. Arch Ophthalmol 1992;
of cyanide poisoning (218,219). The rationale for this theory 110:1568–1570.
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CHAPTER 11
Hereditary Optic Neuropathies
Nancy J. Newman
MONOSYMPTOMATIC HEREDITARY OPTIC Opticoacoustic Nerve Atrophy with Dementia

NEUROPATHIES Progressive Optic Atrophy with Juvenile Diabetes Mellitus,
Leber’s Optic Neuropathy Diabetes Insipidus, and Hearing Loss (DIDMOAD/Wolfram’s
Dominant Optic Atrophy Syndrome)
Congenital Recessive Optic Atrophy Progressive Encephalopathy with Edema, Hypsarrhythmia, and
Apparent Sex-Linked Optic Atrophy Optic Atrophy (PEHO Syndrome)
Presumed Autosomal-Recessive Chiasmal Optic Neuropathy Complicated Hereditary Infantile Optic Atrophy (Behr’s
HEREDITARY OPTIC ATROPHY WITH OTHER Syndrome)
NEUROLOGIC OR SYSTEMIC SIGNS OPTIC NEUROPATHY AS A MANIFESTATION OF
Autosomal-Dominant Progressive Optic Atrophy and Deafness HEREDITARY DEGENERATIVE OR DEVELOPMENTAL
Autosomal-Dominant Optic Atrophy, Deafness and DISEASES
Ophthalmoplegia Hereditary Ataxias
Autosomal-Dominant Progressive Optic Atrophy with Hereditary Polyneuropathies
Progressive Hearing Loss and Ataxia (CAPOS Syndrome) Hereditary Spastic Paraplegias
Hereditary Optic Atrophy with Progressive Hearing Loss and Hereditary Muscular Dystrophies
Polyneuropathy Storage Diseases and Cerebral Degenerations of Childhood
Autosomal-Recessive Optic Atrophy with Progressive Hearing Mitochondrial Disorders
Loss, Spastic Quadriplegia, Mental Deterioration, and
Death (Opticocochleodentate Degeneration)
The hereditary optic neuropathies comprise a group of and, in many diseases, progressive. Once optic atrophy is
disorders in which the cause of optic nerve dysfunction ap- observed, substantial nerve injury has already occurred.
pears to be hereditable, based on familial expression or ge- In classifying the hereditary optic neuropathies, it is im-
netic analysis (1,2). Clinical variability, both within and portant to exclude the primary retinal degenerations that may
among families with the same disease, often makes recogni- masquerade as primary optic neuropathies because of the
tion and classification difficult. Traditionally, classification common finding of optic disc pallor. Retinal findings may
has relied on the recognition of similar characteristics and be subtle, especially among the cone dystrophies, where
similar patterns of transmission, but genetic analysis now optic nerve pallor may be an early finding (3–6). Hecken-
permits diagnosis of the hereditary optic neuropathies in the lively et al. (7) reported 20 patients with hereditary, progres-
sive, cone-rod degeneration and temporal optic atrophy, tel-
absence of family history or in the setting of unusual clinical
angiectasia of optic disc vessels, and little or no pigmentary
presentations. As a result, the clinical phenotypes of each
retinal changes. There are several possible explanations for
disease are broader, and it is easier to recognize unusual the presence of optic atrophy in patients with hereditary
cases. cone-rod degenerations. If the pathologic processes have
The inherited optic neuropathies typically present as sym- their primary effect in the bipolar layer of the retina, then
metric, bilateral, central visual loss. In many of these disor- transsynaptic degeneration could occur in both directions.
ders, the papillomacular nerve fiber bundle is affected, with In addition, a disease process affecting the cones could sec-
resultant central or cecocentral scotomas. The exact location ondarily affect the bipolar cells and tertiarily affect the gan-
of initial pathology along the ganglion cell and its axon and glion cells. The possibility of a primary retinal process
the pathophysiologic mechanisms of optic nerve injury re- should be considered in patients with temporal optic atrophy
main unknown. Optic nerve damage is usually permanent even when the retina itself is not obviously abnormal. Retinal
465
arterial attenuation and abnormal electroretinography should defects, making the pattern of familial transmission unavail-
help distinguish these diseases from the primary optic neu- able as an aid in classification.
ropathies. However, optic nerve disease and retinal pathol- In some of the hereditary optic neuropathies, optic nerve
ogy may also coexist. Weleber and Miyake (8) reported two dysfunction is typically the only manifestation of the disease.
families with affected members in two generations who had In others, various neurologic and systemic abnormalities are
optic atrophy, moderate visual loss beginning in the second regularly observed. Additionally, inherited diseases with pri-
or third decades, and negative electroretinograms (ERGs) marily neurologic or systemic manifestations, such as the
(markedly reduced b-wave amplitudes). It was believed that multisystem degenerations, can include optic atrophy. This
the ERG findings alone could not account for the degree chapter continues the fifth edition’s classification of the he-
of central visual loss in this autosomal-dominant disorder. reditary optic neuropathies into three major groups: (a) those
Among the multisystem disorders (see below), primary reti- that occur primarily without associated neurologic or sys-
nal degeneration with secondary optic disc pallor is common temic signs; (b) those that frequently have associated neuro-
and may be difficult to distinguish from primary optic nerve logic or systemic signs; and (c) those in which the optic
neuropathy is secondary in the overall disease process. The
damage. There may be coexistent pathology.
hereditary optic neuropathies reflect a number of different
The customary classification of the inherited optic neurop-
inheritance patterns and can be caused by defects in either
athies is by pattern of transmission. The most common pat- the nuclear or mitochondrial genomes. As more specific ge-
terns of inheritance include autosomal dominant, autosomal netic defects are discovered, our concept of the phenotypes
recessive, and maternal (mitochondrial). The same genetic of these disorders will likely change, as will our classifica-
defect may not be responsible for all pedigrees with optic tion. More accurate definition of the underlying genetic ab-
neuropathy inherited in a similar fashion. Similarly, different normalities will aid in genetic counseling. Furthermore,
genetic defects may cause identical or similar pheno- identification of the gene defect, elucidation of the gene
types—some inherited in the same manner, others not. Alter- product and its normal function, and clarification of the ab-
natively, the same genetic defect may result in different clini- normality caused by the mutation should improve our under-
cal expression, although the pattern of inheritance should be standing of the pathophysiologic mechanisms of optic nerve
consistent. To complicate matters further, single cases are dysfunction and allow for the development of directed thera-
often presumed or proven to be caused by inherited genetic pies.
MONOSYMPTOMATIC HEREDITARY OPTIC NEUROPATHIES

LEBER’S OPTIC NEUROPATHY individuals (91,92). Mackey et al. (93–95) extensively re-
In 1871, Leber (9) first described the disease that bears viewed LHON in Australia and concluded that the disease
accounts for about 2% of cases of legal blindness in individu-
his name, although similar cases were reported 50 years ear-
als under age 65 and for about 11% of all patients with
lier (e.g., von Graefe in 1858 [10]). Leber considered this
bilateral optic neuropathy of uncertain etiology in that
entity an inflammatory neuritis, but others supported an
country.
abiotrophic origin (11,12). Numerous pedigrees of Leber’s
Men are affected with visual loss more frequently than
hereditary optic neuropathy (LHON) have since been re-
women. This male predominance ranges from 80–90% in
ported from Europe, North America, South America, Austra-
most pedigrees reported from North America, Europe, and
lia, and Asia (13–31). Since the late 1980s, LHON has re-
Australia (15–18,20,22–26,28,96–100). Earlier reports in-
ceived notoriety as a maternally inherited disease linked to
dicated a male predominance of only 60% in Japan, but
abnormalities in mitochondrial DNA (32–90a). Genetic
subsequent studies with molecular confirmation of LHON
analysis has broadened our view of what constitutes the clini- revealed that more than 90% of Japanese patients were males
cal presentation of LHON. (27). Earlier reports may have inadvertently included pedi-
Clinical Features grees with autosomal-dominant optic atrophy (Kjer’s dis-
ease) as LHON patients. Approximately 20–60% of men at
Clinical descriptions prior to the availability of molecular risk for LHON experience visual loss (15,17,22,23,93,94).
confirmation must be assessed with caution, because quite Among women at risk, the occurrence rate ranges from 4%
possibly the individuals, and even pedigrees, described were to 32% (15,17,22,23,93,94). Affected women are more
not true cases of LHON. When large, typical pedigrees are likely to have affected children, especially daughters, than
used, individuals with atypical features can be assumed to unaffected female carriers (15,101). Mackey reported that
represent unusual but valid cases of LHON. approximately 20% of male and 4% of female carriers in
Despite multiple studies describing hundreds of patients Australia lose vision (93,94). Mackey and Howell (102)
with LHON worldwide, the actual prevalence and incidence noted that there has been a dramatic decline in the risk of
of visual loss from this disorder have been only rarely and visual loss among pedigrees with LHON in Australia and a
geographically selectively investigated. Among individuals definite decrease in penetrance over the past century.
in Northeast England, there was a minimal prevalence of The onset of visual loss typically occurs between the ages
visual loss from LHON of 3.22 per 100,000 individuals and of 15 and 35 years, but otherwise classic LHON has been
a prevalence for harboring a primary LHON-associated mi- reported in many individuals both younger and older
tochondrial DNA (mtDNA) mutation of 11.82 per 100,000 (13–17,19,20,22,24,26–28,97). The range of age at onset is
HEREDITARY OPTIC NEUROPATHIES 467
1–80 years (15,16,20,22,103–107), but inclusion of all these scotomas only to red test objects or as mild depression on
cases as true examples of LHON may not be accurate. central automated perimetry. Field abnormalities mimicking
Among those cases of molecularly confirmed LHON, the the bitemporal configuration of chiasmal defects have also
age range is 2–80 years. This age variability occurs even been reported (122,123). In a few of these cases, the defects
among members of the same pedigree. We have observed a have strictly respected the vertical meridian.
pedigree in which a boy was affected at age 8 years, two Even the earliest descriptions of this disease noted fun-
other boys at age 15, a woman at age 60, and her brother at duscopic abnormalities other than optic atrophy (9,124,125).
age 67. Especially during the acute phase of visual loss, hyperemia
Visual loss typically begins painlessly and centrally in of the optic nerve head, dilation and tortuosity of vessels,
one eye. Some patients complain of a sensation of mist or retinal and disc hemorrhages, macular edema, exudates, reti-
fog obscuring their vision, whereas others note mild central nal striations, and obscuration of the disc margin were recog-
fading of colors. The second eye is usually affected weeks nized in some cases (9,97,113,124–127). Bell (97) con-
to months later. Reports of simultaneous onset are numerous cluded that the appearance of the disc might vary from
(14,15,24,98) and likely reflect both instances of true bilat- completely normal to that ‘‘indicative of an acute inflamma-
eral coincidence and those in which initial visual loss in the tory reaction.’’
first eye went unrecognized. Rarely, loss of vision in the In 1973, Smith et al. (114) reported a triad of signs be-
second eye occurs after a prolonged interval (more than 12 lieved pathognomonic for LHON: circumpapillary telangi-
years) (107–109). Even more infrequently, visual loss re- ectatic microangiopathy, swelling of the nerve fiber layer
mains monocular (20,28,96,110–112). Nikoskelainen et al. around the disc (pseudoedema), and absence of leakage from
(28) reported one patient with unilateral disease for a 16-year the disc or papillary region on fluorescein angiography (dis-
follow-up period and a few patients with entirely subclinical tinguishing the LHON nerve head from truly edematous
disease. In general, however, greater than 97% of patients discs) (Fig. 11.1). Nikoskelainen et al. (28,128,129) ob-
will have second eye involvement within 1 year (24,26). served these funduscopic changes in all of their symptomatic
The onset of visual loss is usually not associated with patients with LHON, in some of their ‘‘presymptomatic’’
other symptoms. Uhthoff’s symptom (a transient worsening cases, and in a significant proportion of asymptomatic mater-
of vision with exercise or warming) may occur in patients nal relatives. However, having abnormalities of the peripapil-
with LHON, as it does in patients with other optic neuropa- lary nerve fiber layer does not necessarily predict visual loss.
thies (24,26,113–115). Other reported symptoms at the time Furthermore, some patients with LHON never exhibit the
of visual loss are usually minor and nonspecific, such as characteristic ophthalmoscopic appearance, even if exam-
headache; eye discomfort; flashes of light, color, or both; ined at the time of acute visual loss (24,26,27,130,131). In
limb paresthesias; and dizziness (14,15,24,26,114,115). one review, 22 of 52 patients did not have any abnormal
The duration of progression of visual loss in each eye also funduscopic findings (24). In another review, 36% of 33
varies and may be difficult to document accurately. Usually patients examined within 3 months of visual loss did not
the course is acute or subacute, with deterioration of visual have retinal microangiopathy (26). The ‘‘classic’’ LHON
function stabilizing after months (14,15,20,24,98,114,115). ophthalmoscopic appearance may be helpful in suggesting
In one study of molecularly confirmed LHON, progression the diagnosis if recognized in patients or their maternal rela-
of visual loss in each eye ranged from ‘‘sudden and com- tives, but its absence, even during the period of acute visual
plete’’ to 2 years, with a mean of 3.7 months (24). Nikoskel- loss, does not exclude the diagnosis of LHON. As the disease
ainen et al. (28) described rare patients with slowly progres- progresses, the telangiectatic vessels disappear and the
sive visual loss, ultimately with a favorable visual outcome. pseudoedema of the disc resolves. Perhaps because of the
Visual acuities at the point of maximum visual loss range initial hyperemia, the optic discs of patients with LHON
from no light perception to 20/20 (14–16,20,24,25,98). Most may not appear pale for some time. This feature, coupled
patients deteriorate to acuities worse than 20/200 (14–16, with the relatively preserved pupillary responses and the lack
20,24–26,28,111,114,115). Color vision is affected se- of pain, has led to the misdiagnosis of nonorganic visual
verely, often early in the course, but rarely before significant loss in some LHON patients (116,123). Eventually, how-
visual loss (20,21,28,115). The Farnsworth-Munsell 100- ever, optic atrophy with nerve fiber layer dropout most pro-
Hue test may be the earliest indicator of optic nerve dysfunc- nounced in the papillomacular bundle supervenes (Fig.
tion, but subtle abnormalities of color vision can be demon- 11.2). Nonglaucomatous cupping of the optic discs
strated in asymptomatic family members (20,21). Pupillary (132–134) or arteriolar attenuation (111) may also be seen
light responses may be relatively preserved when compared in patients with symptomatic LHON. Reports of other ocular
with the responses in patients with optic neuropathies from manifestations, such as a Stargardt’s-like maculopathy or
other causes (28,116–118), although others have not con- retinal ‘‘vasculitis,’’ are extremely rare and may represent
firmed this finding (119,120). Visual field defects are typi- coincidental findings (135,136).
cally central or cecocentral (15,20,24,25,28,98,111,114, In most patients with LHON, visual loss remains profound
115). The scotomas may be relative during the early stages and permanent. However, not uncommonly, recovery of
of visual loss but rapidly become large and absolute, measur- even excellent central vision occurs years after visual de-
ing at least 25–30⬚ in diameter. A breakthrough of the sco- terioration (15,24–26,28,96,98,104,137–146). Spontaneous
toma is not uncommon, and according to Traquair (121), improvement to some degree was reported in 29% of patients
such an expansion usually occurs in the upper nasal field. in one study (138), 45% in another (15), and in a surpris-
Apparently unaffected eyes may show subtle cecocentral ing 11 of 13 patients in one Canadian pedigree (98). The
Figure 11.1. Leber’s optic neuropathy. A and B, Both optic discs in the acute phase of the disorder. Note hyperemic appearance
of discs. Peripapillary telangiectatic vessels are present. C and D, Both optic discs photographed with red-free (540 nm) light.
Note marked hyperemia of the discs with dilatation of small vessels both on the surface of the disc and in the peripapillary
region. E and F, fluorescein angiogram in arteriovenous (E) and late (F) phases shows dilatation of right disc and peripapillary
vessels but no leakage of fluorescein dye.
Figure 11.2. Progression to optic atrophy in a patient with Leber’s optic neuropathy. A and B, Both discs in acute phase of
the disease. Visual acuity is 20/100 in both eyes with large cecocentral scotomas. Telangiectatic vessels are evident adjacent
to the inferior margin of both discs. The right disc is already pale temporally, and there is atrophy of the papillomacular nerve
fiber layer. C and D, Two months after onset of visual loss, visual acuity is 5/200 in the right eye and 8/200 in the left eye.
Both discs show moderate pallor, particularly temporally, with loss of nerve fiber layer that is especially evident in the
papillomacular region. Previously seen telangiectatic vessels are disappearing. E and F, Six months after onset of visual loss,
visual acuity has remained 5/200 in the right eye and 8/200 in the left eye. Both discs are pale, particularly temporally. The
telangiectatic vessels have completely disappeared. One year after these photographs were obtained, the patient noted gradual,
partial return of visual acuity in both eyes to 20/50.
recovery may occur gradually over 6 months to 1 year after rosis may occur in families with LHON (19,26,111,157,161,
initial visual loss or may suddenly occur up to 10 years after 165,191–196). Harding et al. (197) reported molecularly
onset (140). It may take the form of a gradual clearing of confirmed 11778 pedigrees of LHON with individuals, espe-
central vision or be restricted to a few central degrees, result- cially females, exhibiting symptoms and signs of demyelin-
ing in a small island of vision within a large central scotoma. ating disease combined with nonremitting visual loss typical
Visual field testing may be more sensitive to recovery than of LHON. Cerebrospinal fluid and magnetic resonance (MR)
visual acuity testing, and the size of the central scotoma at imaging findings were characteristic of multiple sclerosis.
the nadir may be one of the factors determining the extent Subsequent population surveys have not found the primary
to which visual function improves (145). Recovery is usually mutations associated with LHON to be overrepresented
bilateral but may be unilateral. Patients whose vision im- among multiple sclerosis patients (194,198). However,
proves most substantially appear to have a lower mean age among multiple sclerosis patients selected specifically be-
at the time of initial visual loss (26,28,55,60,140,146). In cause of their prominent early optic neuropathy, the primary
the review by Riordan-Eva et al. (26) of 79 cases from 55 LHON mutations may be found more frequently (194). It is
families, good visual outcome was strongly correlated with possible that this association between LHON and multiple
age at onset, all those with onset before 20 years having a sclerosis is no greater than the prevalence of the two dis-
final visual acuity better than 20/80. Furthermore, the partic- eases. An underlying LHON mutation, however, may
ular mitochondrial DNA mutation also influences prognosis, worsen the prognosis of optic neuritis in patients with multi-
with the 11778 mutation carrying the worst prognosis for ple sclerosis (196,198,199).
vision and the 14484 mutation the best (see below). Recur-
rences of visual failure are rare among patients both with Ancillary Testing
and without visual recovery (110,147–149). Ancillary tests, aside from genetic analysis, are generally
of limited usefulness in the evaluation of LHON. Fluorescein
Associated Findings angiography is helpful in its illustration and confirmation of
In most patients with LHON, visual dysfunction is the LHON funduscopic features and the lack of disc leakage
only significant manifestation of the disease. However, some (114,129). Electrocardiograms (ECGs) may reveal cardiac
pedigrees have members with associated cardiac conduc- conduction abnormalities (114,151,155). Formal color test-
tion abnormalities (125,133,150–155a). Preexcitation syn- ing with the D-15 panel and Farnsworth Munsell 100-Hue
dromes, specifically Wolff-Parkinson-White and Lown- tests may reveal optic nerve dysfunction in LHON before
Ganong-Levine, were found in 14 of 163 individuals (9%) any measurable visual loss has occurred (20,21,115). How-
with LHON mutations among 10 Finnish families (151,153) ever, asymptomatic maternal relatives who demonstrate
and in 5 of 63 LHON patients (8%) among 35 Japanese color defects and who do not go on to visual loss reduce the
pedigrees (154). Prolongation of the corrected QT interval predictive value of these tests. Pattern-reversal visual evoked
was noted in the maternally related members of one molecu- potentials (VEPs) may be absent or show prolonged latencies
larly confirmed LHON pedigree (133). Palpitations, syn- and decreased amplitudes, usually in eyes already afflicted
cope, and sudden death have been reported (9,23,151,152, with diminished acuity (20,21,23,24,200,201).
155,156), as have myocardial hypertrophy (155a) and iso- Brain stem auditory evoked potentials (BAEPs) were non-
lated left ventricular abnormal trabeculation (155). Familial specifically abnormal in 7 of 11 affected LHON patients in
skeletal abnormalities may also occur in pedigrees with one study (202). A brief report from this same group sug-
LHON (156–163). gested that VEPs and BAEPs may be abnormal in asymp-
Minor neurologic abnormalities, such as exaggerated or tomatic maternal relatives of LHON patients compared with
pathologic reflexes, mild cerebellar ataxia, tremor, move- control subjects (201). The standard flash ERG is typically
ment disorders, myoclonus, seizures, muscle wasting, distal normal (14,15,24,142,203), although occasional attenuation
sensory neuropathy, auditory neuropathy, motor neuropathy, of the b-wave may be noted (26). Cerebrospinal fluid analy-
auditory neuropathy, and migraine, have been reported in pa- sis is usually normal except in patients with a multiple scle-
tients with LHON (13,15,19,103,156,161,164–173a). Less rosis-like syndrome (24,26,197). Electroencephalograms are
commonly, pedigrees have been described in which multiple unremarkable (24).
maternal members demonstrate the clinical features of Computed tomography (CT) scanning and MR imaging
LHON in addition to more severe neurologic abnormalities of the brain are typically normal in patients with LHON
(156,157,159,174–190). We have termed these pedigrees (24,204,205). Exceptions include patients with additional
‘‘Leber’s plus.’’ The maternal members of a large Australian symptoms suggestive of multiple sclerosis and pedigrees
family demonstrated varied combinations of optic atrophy, with dystonia and basal gangliar lesions. One boy with
movement disorders, spasticity, psychiatric disturbances, LHON visual loss but no symptoms or signs suggestive of
skeletal abnormalities, and acute infantile encephalopathic demyelinating disease was found to have extensive T2-hy-
episodes (159). A Leber’s-like optic neuropathy has been perintense periventricular white matter changes (163). Two
associated with dystonia and basal gangliar lesions in several LHON patients were reported with distended optic nerve
pedigrees (178–184). Leigh-like encephalopathy, periaque- sheaths on orbital ultrasonography, CT scanning, and MR
ductal syndrome, and other brain stem involvement have imaging (131,206). MR imaging of the optic nerves of symp-
also rarely been reported (187–189). tomatic LHON patients typically reveals normal nerves in
Disease clinically indistinguishable from multiple scle- the acute phase of visual loss, often followed by high T2
signal in the intraorbital portions of the nerves after several tigators showed that every son or daughter of a female carrier
months (26,204,205,207–209). Rarely, gadolinium enhance- inherited the LHON trait.
ment and enlargement of the optic nerves and even chiasm Both the father and the mother contribute to the nuclear
are demonstrated during the acute phase of visual loss portion of the zygote, but the mother’s egg is virtually the
(210–212). Phosphorus-31 MR spectroscopy suggested im- sole provider of the zygote’s cytoplasmic contents. The sper-
paired mitochondrial metabolism within limb muscle and matozoon contributes only about 1% of that total (41,48,
the occipital lobes in several patients with LHON (213) as 226–228). Therefore, to explain maternal inheritance, a cy-
well as in unaffected carriers with the 11778 mutation (214). toplasmic determinant was sought. Initial theories included
Although morphologic abnormalities of mitochondria on the transfer of a slow virus-like agent in the maternal
skeletal muscle biopsy are rare in LHON (103,215,216), pa- ooplasm or transplacentally. Because the intracytoplasmic
tients and carriers may exhibit abnormal lactate production mitochondria are the only source of extranuclear DNA, mito-
with exercise (217). Sadun et al. (218) found an abundance chondrial inheritance was proposed as an explanation (229).
of mitochondria and accumulation of mitochondrial debris For more detailed reviews of mitochondrial genetics
in the extraocular muscles of one 11778 LHON patient, sug- and diseases of mitochondrial DNA, the reader is referred
gesting a compensatory increase in absolute numbers of mi- to several comprehensive publications (33,41,48,,90a,
tochondria. 226–228,230–237). In brief, every cell contains several
hundred intracytoplasmic mitochondria that generate the cel-
Pathology lular energy necessary for normal cellular function and main-
tenance. Those cells in tissues particularly reliant on mito-
In no case do we have optic nerve pathology from the chondrial energy production, such as the central nervous
early stages of the disease; hence, the location and nature system, will contain more mitochondria. Each mitochon-
of the initial injury remain uncertain. Kwittken and Barest drion contains 2–10 double-stranded circles of mtDNA.
(219) found atrophy of retinal ganglion cells and bilateral Each circle of mtDNA contains only 16,500 bases compared
optic atrophy. The optic cup was shallow and filled with with the 3 ⳯ 109 bases contained within the nuclear genome.
glial cells and connective tissue. There was symmetric de- However, given that there are several mtDNAs in each mito-
struction of the myelin sheaths in the papillomacular bun- chondrion and hundreds of mitochondria per cell, the
dles. The lateral geniculate bodies were shriveled, and the mtDNA represents approximately 0.3% of the cell’s total
optic radiations exhibited demyelination, suggesting trans- DNA. Its small size makes the mtDNA more accessible to
synaptic degeneration. study, and the entire gene sequence has been determined.
Other authors have reported similar findings (156,175, Mitochondrial DNA codes for all the transfer RNAs and
218,220–224). Kerrison et al. (225) noted marked atrophy ribosomal RNAs required for intramitochondrial protein
of the nerve fiber and retinal ganglion cell layers and the production, as well as for 13 proteins essential to the oxida-
optic nerves in a postmortem study of an 81-year-old af- tive phosphorylation system. The majority of proteins cru-
fected woman from the large Australian family with ‘‘Le- cial to normal oxidative phosphorylation function are en-
ber’s Plus’’ (159). Electron microscopy demonstrated retinal coded on nuclear genes, manufactured in the cytoplasm, and
ganglion cell inclusions consisting of calcium circumscribed transported into the mitochondria. Hence, ‘‘mitochondrial
by a double membrane, suggesting intramitochondrial calci- disease’’ could result from genetic defects in either the
fication. Histopathologic and morphometric analysis was nuclear or mitochondrial genomes. Over 100 mtDNA
performed on optic nerves from three other LHON patients, point mutations and countless mtDNA rearrangements have
again years remote from the time of acute visual loss been proposed as etiologic factors in human disease
(222,223). Findings consisted of severe generalized deple- (227,232,236). Expression of these diseases reflects complex
tion of optic nerve fibers (95–99% reduction), with sparing genotypic–phenotypic interactions that likely involve nu-
of only peripheral clusters of fibers, primarily those of larger clear modifying or susceptibility factors.
diameter. There was fibrocytic scarring, scattered ‘‘degener- If a new mutation occurs in the mtDNA, there will be a
ation dust,’’ and evidence of minimal inflammation. These period of coexistence of mutant and normal mtDNA within
authors proposed a selective loss of the ganglion cell P-cell the same cell (heteroplasmy) (41,234,238). At each cell divi-
population (222,223). sion, the mitochondrial genotype may drift toward pure nor-
mal or pure mutant or remain mixed (replicative segrega-
Inheritance and Genetics tion). The phenotype of the cell (and the tissue the cells
comprise) depends on the proportional mixture of mtDNA
All pedigrees clinically designated as LHON have a ma- genotypes and the intrinsic energy needs of the cell. The
ternal inheritance pattern (13,15,17,18,22,23). In maternal mutant phenotype may become apparent only when the
inheritance, all offspring of a woman carrying the trait will amount of normal mtDNA can no longer provide sufficient
inherit the trait, but only the females can pass on the trait mitochondrial function for cell and tissue maintenance
to the subsequent generation. Maternal transmission was ele- (threshold effect). Because of the cytoplasmic location of
gantly demonstrated prior to genetic analysis by Nikoskel- mtDNA, mitochondrial diseases secondary to point muta-
ainen et al. (23) in four of their Finnish pedigrees with tions in the mtDNA follow a pattern of maternal inheritance.
LHON. By using the classic funduscopic appearance as a In 1988, Wallace et al. (32) identified the first point muta-
marker of the disease in asymptomatic relatives, those inves- tion in mtDNA to be linked to an inherited disease. In multi-
ple pedigrees with LHON, a single nucleotide substitution The Wallace mutation has been demonstrated in many
(adenine for guanine) was found at position 11778 in the racially divergent pedigrees with LHON, suggesting that the
mtDNA (Fig. 11.3). This region codes for subunit 4 (desig- 11778 mutation has arisen independently on several occa-
nated ND4) of complex I (NADH dehydrogenase) in the sions (24,26–29,31,32,34–37,39,40,42,48,51,52,55,72,101,
respiratory chain. The mutation at position 11778 changes 103,104,143,238,240). The 11778 mutation is not pres-
an amino acid from arginine to histidine, likely a crucial ent in control subjects. Whereas 31–89% of European,
substitution because arginine is found in this position in the North American, and Australian LHON pedigrees harbor the
ND4 protein in other species (evolutionarily conserved). 11778 mutation (26,28,35,38–40,48,50–52,55,93,94,101,
Using polymerase chain reaction techniques, the ‘‘Wallace 143,241–244), greater than 90% of Japanese and Chinese
mutation’’ can be detected in any tissue sample that contains LHON patients are 11778 positive (27,29,31,72,240).
mitochondria, including whole blood, and even in archival Several other mutations have since been proposed as
preparations (239). causal in LHON (Fig. 11.3). The majority are located within
Figure 11.3. Mitochondrial genome showing the point mutations associated with Leber’s hereditary optic neuropathy. The
three primary mutations, accounting from more than 90% of cases, are shown inside the genome (circle), and the other mutations
are shown outside the genome. Mutations noted with a single asterisk may be primary mutations, but they each account for
only one or a few pedigrees worldwide. Mutations noted with two asterisks are primary mutations associated with Leber’s
optic neuropathy and dystonia. (Adapted from Newman NJ. From genotype to phenotype in Leber hereditary optic neuropathy:
still more questions than answers. J Neuro-ophthalmol 2002;22⬊257–261.)
genes that also code for proteins representing complex 1, The pedigrees with LHON ‘‘plus’’ and severe neurologic
but most within subunits other than ND4. Huoponen et al. abnormalities in multiple family members may be geneti-
(45) and Howell et al. (43) identified a point mutation at cally distinct from those families with more typical, isolated
mtDNA position 3460 within the gene coding for subunit 1 Leber’s-type visual loss. A few exceptions are worth noting,
of complex I in nine independent families with LHON. This including spastic dystonia and basal ganglia lesions in at
mutation has since been found in ethnically divergent least two 11778 families and one 3460 family (103,168); a
pedigrees with LHON and accounts for 4–15% of LHON male 11778 patient with diabetes mellitus since age 2, sei-
cases worldwide (28,29,43,47,50,54,63,64,72,93,94,101, zures and visual loss at age 14, and unilateral sensorineural
242–245). Johns et al. (53) discovered another mutation at hearing loss at age 19 (167); one 3460 and one 11778 patient
position 14484 in the gene coding for the sixth subunit of with asymptomatic periventricular brain lesions (163,168);
complex I. The 14484 mutation accounts for 5–15% of a few patients with the primary LHON mutations and brain
LHON pedigrees worldwide (29,31,72,101), although it has stem syndromes (187–189); one branch of a 11484-homo-
a high prevalence (23 of 28 pedigrees) in French Canada plasmic and 11778-heteroplasmic family with fatal infantile
(71). This high percentage of the 14484 mutation among encephalopathy (190); and one remarkable 11778-positive
French Canadian LHON patients is likely due to a founder pedigree with adult-onset multisystem degeneration with
effect, as further mtDNA haplotype analysis has confirmed parkinsonism but no optic neuropathy (186). The maternal
the same maternal lineage (246). members of the Australian pedigree with optic neuropathies,
The 11778, 3460, and 14484 mutations have been desig- movement disorders, spasticity, and acute encephalopathic
nated ‘‘primary’’ mutations for Leber’s disease because they episodes were found to carry the primary 14484 mutation
confer a genetic risk for LHON expression individually, as well as a mutation at mtDNA position 4160 (ND1) (44).
change the coding for evolutionarily conserved amino acids Additionally, one branch of the family contained a second
in essential proteins, are found in multiple, different, ethni- ND1 mutation (position 4136). Family members with both
cally divergent pedigrees, and are absent or rare among con- ND1 mutations failed to exhibit severe neurologic abnormal-
trols (64). Altogether, they probably account for more than ities, leading the authors to speculate that the second muta-
90% of LHON cases worldwide. Several other mtDNA mu- tion acts as an intragenic suppressor mutation that amelio-
tations may be ‘‘primary,’’ but they account individually for rates the expression of the disease.
only a few pedigrees worldwide (see below) (Fig. 11.3). Among the families with optic neuropathy and basal gan-
Other mtDNA point mutations have been associated with
gliar lesions (178–184), additional mtDNA primary muta-
LHON (Fig. 11.3), but their pathogenetic significance re-
tions have been identified at nucleotide positions 14459
mains less clear. They are considered ‘‘secondary’’ muta-
(178,249,250) and 14596 in the ND6 gene and nucleotide
tions because they are found with greater frequency among
position 11696 in the ND4 gene (183). Other pedigrees with
LHON patients than controls, but they may not in and of
LHON and dystonia are as yet genetically unspecified. Of
themselves confer a risk of blindness.
The other proposed mutations occur in other subunits of note, there is great variability among the maternally related
complex I (nucleotide positions 3308, 3394, 3398, 3472, family members harboring the 14459 mutation, with some
3505, 3547, 3635, 3734, 4136, 4171, and 4216 in ND1; 4640, individuals exhibiting optic neuropathy only, others dystonia
4917, and 5244 in ND2; 10237 in ND3; 10663 and 11253 in only, and still others both (250). mtDNA mutations at nu-
ND4; 13513, 13528, 13708, and 13730 in ND5; and 14482, cleotide positions 13513 and 13045 in the ND5 gene usually
14495, 14498, 14510, and 14568 in ND6), in complex III cause findings typical of the mitochondrial encephalopathy
(nucleotide positions 15257 and 15812 in the cytochrome b with lactic acidosis and stroke-like episodes (MELAS) phe-
subunit), in complex IV (nucleotide position 7444 in cyto- notype (73,251,251a). However, in rare patients with this
chrome c oxidase subunit 1 and positions 9438 and 9804 in mutation, LHON-like visual loss can occur in addition to
cytochrome c oxidase subunit 3), in complex V (nucleotide MELAS symptoms.
position 9101 in the ATPase 6 gene), and in the tRNA Screening for LHON in a patient with visual loss from
leucine 1 gene (46–49,53–59,62,64,66,67,69,70,74,76–80, optic neuropathy should begin with the three primary muta-
84–90a,247,248). They vary markedly in their prevalence, tions (248). In those primary mutation-negative patients in
the degree of evolutionary conservation of the encoded whom suspicion remains high, testing for the other mtDNA
amino acids altered, and their frequency among controls. mutations associated with LHON is probably warranted, es-
Many of these mutations occur in combination with each pecially for those mutations deemed likely causal in a few
other and the primary mutations and may simply define the previous pedigrees (Fig. 11.3). Alternatively, since the ma-
mtDNA haplotypic background of the individual. Hence, jority of these other mtDNA mutations reside in genes en-
caution must be used in assuming a primary causal signifi- coding subunits of complex I, complete sequencing of com-
cance for these mutations. Acknowledging this complexity, plex I, perhaps beginning with the so-called ‘‘hot spot’’ ND6
several of these other mtDNA mutations may indeed be gene (80), might also be considered. Finally, sequencing
causal (‘‘primary’’) LHON mutations, specifically those at the entire mitochondrial genome is possible, although labor
nucleotide positions 3635, 4171, 4640, 5244, 7444, 9101, intensive. This should be performed only in those cases of
9804, 10663, 11253, 13528, 13730, 14482, 14495, 14498, high suspicion and should be interpreted only by those
14510, and 14568. However, they in total represent less than versed in the complexities of mitochondrial genetics
10% of all LHON pedigrees worldwide. (70,236,252–254).
Determinants of Expression mined by random genetic drift (265,266). Among individu-

als, the degree of heteroplasmy in blood generally correlates
Genetic analysis allows a broad view of what constitutes with the risk of visual loss. Additionally, mothers with 80%
the clinical profile of LHON (2,56). Most striking is the or less mutant mtDNA in blood are less likely to have clini-
number of patients without a family history of visual loss. cally affected sons than mothers who are homoplasmic mu-
Although there is undoubtedly a referral bias for the unusual tant (265). However, once a person becomes symptomatic,
cases, it is still remarkable that singleton cases constituted there does not appear to be any clinical difference in disease
57% of one series of molecularly confirmed LHON (24). In expression (260). Meiotic segregation can result in major
contrast, Mackey (93) reported only a small proportion of differences in the proportion of mtDNA among siblings, po-
singleton cases in Australia, suggesting ascertainment diffi- tentially predisposing some individuals to visual loss. How-
culties or low penetrance in America. The use of high-resolu- ever, in most large reviews of molecularly confirmed LHON
tion mtDNA haplotypes to aggregate multiple apparently patients, heteroplasmy is documented in the blood of a mi-
unrelated pedigrees affected with LHON into single large nority of affected individuals (24,84,101). Although most of
maternal lineages descending from the same founder the probands themselves were homoplasmic for the muta-
(246,255) may decrease the number of true singleton cases. tion, it is possible that their unaffected relatives were hetero-
Some of these singleton cases are women, some outside the plasmic, helping to explain the pattern of expression.
typical age range for LHON, some without the classic oph- Different proportions of mutant and normal mtDNA may
thalmoscopic appearance (112,123). Clearly, the diagnosis also exist within the various tissues of the same heteroplas-
of LHON should be considered in any case of unexplained mic individual (238). The degree of tissue heteroplasmy
bilateral optic neuropathy, regardless of age of onset, sex, might help to explain the variable phenotypes seen in pa-
family history, or funduscopic appearance. tients whose mitochondrial genotypes measured in blood
Many questions remain unanswered regarding the deter- alone appear similar (41,238,267), since the amount of mu-
minants of phenotypic expression. For instance, does the tant mtDNA in the optic nerves of individuals at risk may
specific mtDNA mutation dictate particular clinical fea- differ. Howell et al. (268) performed postmortem genetic
tures? Although those pedigrees with LHON ‘‘plus’’ demon- analysis on the optic nerve and retina of an affected LHON
strate that certain mtDNA mutations may result in specific patient who was heteroplasmic in blood and found the ocular
disease patterns of Leber’s-like optic neuropathies with other tissues to be essentially homoplasmic. Leukocyte mtDNA
neurologic abnormalities (84), few significant clinical differ- may be a ‘‘lagging indicator’’ of the mutational burden in
ences have been demonstrated to date among LHON patients other, more pathologically affected tissues, with a high pro-
positive for the 11778 mutation, those with other mtDNA portion of mutated mtDNA in blood correlating with a high
mutations, and those as yet genetically unspecified. One proportion of mutated mtDNA in other tissues (269).
major exception is the difference in spontaneous recovery Other genetic factors besides the specific mtDNA muta-
rates among patients with the 11778 mutation and those with tion and the presence and degree of heteroplasmy may play
the 14484 mutation. Among 136 patients with the 11778 a role in expression. Although some investigators have
mutation, only 5 (4%) reported spontaneous recovery (144), claimed that multiple LHON-associated mtDNA mutations
compared with 37–65% of 14484 patients (26,28,55,60, may be necessary for visual loss, this has not been corrobor-
244). Furthermore, the ultimate visual acuities in patients ated in several studies (26,28,244,270). Indeed, case reports
with the 14484 mutation are significantly better than those of unaffected individuals who even harbor two primary mu-
with the 11778 and 3460 mutations (26,244). Although tations (190,271) make this claim improbable. These rare
Johns et al. (54) and Nikoskelainen et al. (28) reported a pedigrees with two primary mutations exhibit no exceptional
better visual prognosis among their 12 and 10 patients, representation of visual loss, including penetrance, the role of
spectively, with the 3460 mutation, other series have shown heteroplasmy, timing, severity, and even eventual recovery.
little difference between the 11778 and 3460 mutations Similarly, although the underlying mtDNA haplotype may
(26,93,94,243,244). Cardiac conduction abnormalities occur influence the presence, penetrance, or expression of an
in 11778 pedigrees (24,133,154,155a), but the 3460 muta- mtDNA point mutation (272–277), this is unlikely to be
tion appears to have the highest association with the preexci- the major factor in phenotypic expression. Nuclear-encoded
tation syndromes in Finland (45,151,153). factors modifying mtDNA expression, mtDNA products, or
Except for rare examples of de novo occurrence of a pri- mitochondrial metabolism may influence phenotypic expres-
mary LHON mutation (256), a mtDNA mutation will be sion of LHON (278–281). The male predominance of visual
present in all maternally related family members of patients loss in LHON may be explained by a modifying factor on
with LHON, even though many will never become symp- the X chromosome (101,282,283). Most studies have not
tomatic. Hence, whereas the presence of a mtDNA mutation confirmed X-linkage in this disease (284–291), but the X-
may be necessary for phenotypic expression, it may not be linked hypothesis may still be viable (84,101). The apolipo-
sufficient. Does heteroplasmy among individuals in a pedi- protein E (APOE) gene is not a visual loss susceptibility
gree play a role in phenotypic expression? Heteroplasmy gene in LHON (292).
for the primary LHON mutations has been demonstrated Tissue energy utilization and reserve in an individual may
in several affected and unaffected individuals (24,39,43,84, also determine the timing and extent of visual loss. Mito-
104,143,238,257–266). Within pedigrees, the proportion of chondrial energy production decreases with age (293), and
mutant mtDNA in subsequent generations is largely deter- the timing of visual loss in patients at risk for LHON may
reflect the threshold at which already reduced mitochondrial phosphorylation, but rather via more indirect mechanisms.
function deteriorates to a critical level. Immunologic factors Complex I is the site of NADH reoxidation, and it may be
have also been proposed, especially to explain the associa- that maintenance of the proper NAD/NADH redox balance
tion of LHON with multiple sclerosis (196,197,284). How- is particularly important for normal maintenance and func-
ever, no association has been demonstrated between LHON tion of the ganglion cells or their axons, especially for axonal
and any HLA-DR genotype, suggesting that the HLA-DR transport (314,327). Transporter defects involving channels
locus is not a major genetic determinant for the development and pumps particularly reliant on mitochondrial ATP pro-
of visual loss (294). duction could have specific tissue effects (252). Others pro-
Environmental factors may also play a role. Both the inter- pose free radical damage as crucial in LHON pathogenesis
nal and external environment of the organism must be con- (315,328–331). Inhibition of the respiratory chain causes
sidered. Systemic illnesses, nutritional deficiencies, trauma, increased generation of free radicals, and the respiratory
medications, or toxins that stress or directly or indirectly chain in turn may be inhibited by oxidative damage. This
inhibit mitochondrial metabolism have been suggested to self-amplifying cycle of oxidative damage and respiratory
initiate or increase phenotypic expression of the disease chain dysfunction could cause direct or indirect damage to
(60,295–304). Widespread nutritional deficiency in Cuba vulnerable tissues such as the ganglion cell or its axon. The
did not appear to increase the expression of LHON in one different mtDNA mutations may cause different amounts of
large 11778-positive pedigree (305). Similarly, although free radical production at the level of complex I, and this
some case and pedigree reports suggest a possible role for increased production of reactive oxygen species may occur
tobacco and excessive alcohol use as precipitants of visual particularly in a neuronal cell environment (294,328,332).
loss (30a,65,148,170,296,298,306,307,307a), other studies, Even less clear are the subsequent mechanisms by which
including one late case-control study of sibships (308), failed respiratory chain dysfunction or free radical production re-
to confirm this. Other agents known to be toxic to the optic sult in irreversible damage to the ganglion cells and their
nerve, such as ethambutol (303,309), or to mitochondrial axons. Mitochondria play a major role in the induction of
function, such as antiretroviral therapy (300–302), may have apoptosis (333). The collapse of the mitochondrial trans-
a heightened toxicity in patients with the LHON mutations membrane potential and opening of the so-called permeabil-
and already compromised mitochondrial function. The evi- ity transition pore leads to the release of proapoptotic pro-
dence linking an abnormality of cyanide metabolism to pa- teins, including cytochrome c, and resultant cell death
tients with LHON and acute visual loss is inconclusive (315,334,335). Many physiologic and pathologic stimuli can
(203,310–313). directly trigger opening of the mitochondrial transition pore.
If the same clinical phenotype of LHON can arise from It is also probable that multiple consequences of mitochon-
different mutations found in different subunits of complex drial dysfunction, including collapse of the transmembrane
I, and possibly even other complexes, most likely the pheno- potential, uncoupling of the respiratory chain, hyperproduc-
type is not the result of a specific enzyme defect. Indeed, tion of superoxide anions, disruption of mitochondrial bio-
theories on the pathogenesis of LHON must reconcile how genesis, outflow of matrix calcium and glutathione, and re-
multiple different mtDNA mutations located in different lease of soluble intermembrane proteins, can indirectly
genes encoding different proteins result in an essentially activate apoptosis or necrosis (334). Alternatively, excito-
identical clinical phenotype that is expressed only in the toxic death can be initiated directly by reduced mitochon-
optic nerve, suddenly and bilaterally (248,252,314,315). drial energy production, which leads to activation of the
Theories on the pathogenesis of LHON usually begin at NMDA-type glutamate receptors (315). Additionally, free
oxidative phosphorylation and the generation of ATP. After radicals are a key component in some excitotoxicity path-
all, the three primary LHON mutations are found in genes ways and may also trigger apoptotic cell death directly.
that code for protein subunits of complex I of the respiratory Various mechanisms have been proposed on how any of
chain. However, even demonstration of a definite deficiency these theorized pathophysiologic processes result in selec-
of complex I activity and/or ATP synthesis as measured by tive damage to the optic nerve, but supportive evidence is
enzyme assay has proved problematic (43,79,103,267,314, scarce. Based on the abnormal appearance of the papillary
316–324), especially with the 11778 mutation, the most and peripapillary vasculature in many LHON patients, a pri-
common and severe mutation in terms of visual prognosis. mary vascular process with subsequent ischemia has been
Yen et al. (325,326) have shown probable compensatory proposed (28). However, these vascular changes are likely
increases in the absolute amount of mtDNA and in the level secondary, especially given the intact vascular endothelium
of complex II activity (a complex encoded entirely by nu- as demonstrated by the lack of fluorescein leakage, and the
clear genes) in patients with the 11778 mutation. However, absence of these fundus findings in many patients. A me-
although the central nervous system is very reliant on mito- chanical mechanism has also been suggested in which the
chondrial ATP, studies of the bioenergetics of vision do not severe angle turn that the optic nerve axons need to make
indicate that ganglion cell function is markedly dependent in the prelaminar area results in a ‘‘chokepoint’’ region
upon mitochondrial energy production (314). Indeed, it is where there is impaired or labile axoplasmic transport (314).
the photoreceptor layer of the retina rather than the retinal Small-caliber, constantly firing P-cells may be particularly
ganglion cell layer that is richest in enzymes for oxidative vulnerable (223). Histochemical studies of the optic nerve
metabolism (314). This has led some to speculate that the in animals have shown a high degree of mitochondrial respi-
pathogenesis in LHON is not via direct effects on oxidative ratory activity within this unmyelinated, prelaminar portion
of the optic nerve, suggesting a particularly high requirement chondria. This protein increased the survival of cybrids har-
for mitochondrial function in this region (336–338). Of great boring the 11778 mutation threefold and restored ATP
interest in this regard is the recent identification of the causa- synthesis to a level indistinguishable from that in cybrids
tive gene in autosomal dominant optic atrophy (see below) containing normal mtDNA. The relative accessibility of the
as a nuclear-encoded protein destined for the mitochondria eye and its ganglion cells may provide the ideal setting in
and important in the formation and maintenance of the mito- which to test this nuclear solution of a mitochondrial prob-
chondrial network (339). Similarly, a recent genetically lem (357).
induced mouse model of complex I deficiency shows the Nonspecific recommendations to avoid agents that might
histopathologic features of optic nerve degeneration and de- stress mitochondrial energy production have no proven ben-
myelination (332,340). The retinal ganglion cell and its axon efit in LHON but are certainly reasonable. We advise our
appear particularly vulnerable to defects in mitochondrial patients at risk for LHON to avoid tobacco use, excessive
function (90a,248). alcohol intake, and environmental toxins. An ECG should be
obtained and any cardiac abnormalities treated accordingly.
Treatment Considering the degree of visual acuity loss, it is remarkable
that van Senus (15) reported that 82% of patients were gain-
In light of the possibility for spontaneous recovery in fully employed despite their visual handicap. Low vision
some patients with Leber’s disease, any anecdotal reports of assessment may be helpful, especially because much of the
treatment efficacy must be considered with caution. At- useful peripheral vision may remain intact. Finally, the im-
tempts to treat or prevent the acute phase of visual loss with portance of genetic counseling in this disease should not be
systemic steroids, hydroxycobalamin (341), or cyanide an- underestimated (358a).
tagonists have in general proved ineffective (111,114,115,
203,313). Reports from Japan advocated craniotomy with DOMINANT OPTIC ATROPHY
lysis of chiasmal arachnoid adhesions in patients with
Autosomal dominant optic atrophy, type Kjer (McKusick
LHON, with 80% of more than 120 patients reporting visual
no. 165500, gene symbol OPA1) (359), is believed to be
improvement (16,342). Although the data are impressive, it
the most common of the hereditary optic neuropathies. The
is difficult to support a surgical therapy logistically removed
estimated disease prevalence is 1⬊50,000, or as high as
from the site of ocular neurovascular changes. Optic nerve
1⬊10,000 in Denmark (360,361).
sheath decompression after progressive visual loss in two
patients resulted in no improvement (131,206). Clinical Features
Some manifestations of other mitochondrial diseases, spe-
cifically the mitochondrial cytopathies, may respond to ther- In addition to the cases described by Kjer (362,363),
apies designed to increase mitochondrial energy production numerous other studies have established the clinical pro-
(235,236,343–354). Most of the agents used are naturally file of patients with dominantly inherited optic atrophy
occurring cofactors involved in mitochondrial metabolism, (361,364–375). It is generally agreed that dominant optic
while others have antioxidant capabilities. Therapies tried atrophy (DOA) is an abiotrophy with usual onset in the first
include coenzyme Q10, idebenone, L-carnitine, succinate, decade of life; however, no congenital case has been docu-
dichloroacetate, vitamin K1, vitamin K3, vitamin C, thia- mented at birth or shortly thereafter. Kjer (362,363) noted
mine, vitamin B2, and vitamin E. Mashima et al. (351) re- that many of his patients were ignorant of the familial nature
ported on 28 LHON patients, 14 of whom were treated with of their disease and, in fact, did not realize that they, them-
idebenone (a quinol that stimulates ATP formation) com- selves, had visual dysfunction. No individual in the series
bined with vitamin B2 and vitamin C. There was no signifi- by Kline and Glaser (367) could identify a precise onset of
cant difference in the number of eyes with visual recovery, reduced acuity. In Hoyt’s series (368), the majority of af-
although the authors claimed that the treatment seemed to fected patients dated the onset of visual symptoms between
speed recovery when it occurred. Topical agents deemed 4 and 6 years of age, although a few severely affected indi-
neuroprotective or antiapoptotic for ganglion cells could be viduals were noted to have a visual disturbance, primarily
administered directly to the eye (355). It remains to be seen because of nystagmus, prior to beginning schooling. Smith
whether any of these agents alone or in combination will (365) reviewed the literature up to 1972 on this subject and
prove consistently useful in the treatment of acute visual collected 554 clear-cut cases, of whom 442 were actually
loss in LHON, in the prevention of second eye involvement, examined. He emphasized that of this large group, only 15
or in the prophylactic therapy of asymptomatic family mem- patients (2.2%) were actually observed to have optic atrophy
bers at risk. before age 10. Similarly, Johnston et al. (366) reported visual
A promising form of gene therapy known as allotypic symptoms before the age of 10 years in only 58% of their
expression may play a future role in the therapy of LHON 47 affected individuals. Three of the patients (12.5%) exam-
and other mitochondrial diseases (356). In this approach, ined by Kline and Glaser (367), seven of Hoyt’s (368) pa-
a nuclear-encoded version of a gene normally encoded by tients (22.6%), and five of the patients reported by Elliott
mtDNA (in this case, the ND4 gene containing nucleotide et al. (370) (25%) were unaware of visual difficulties and
position 11778) is made synthetically, is inserted via an were discovered to have optic atrophy as a direct conse-
adeno-associated viral vector, and codes for a protein ex- quence of examination of other affected family members.
pressed in the cytoplasm that is then imported into the mito- These phenomena attest to the usually imperceptible onset
in childhood, often mild degree of visual dysfunction, ab- fects are best delineated using red test objects, and in patients
sence of night blindness, and absence of acute or subacute with acuities of 20/50 or better, static perimetry is necessary
progression. to identify the defects. The peripheral fields are usually nor-
Kjer (362,373) emphasized that visual acuity was usually mal in these patients; however, using chromatic testing with
reduced to the same mild extent in both eyes. Visual acuity blue and red objects, there appears to be a characteristic
remained between 20/20 and 20/60 throughout life in 40% inversion of the peripheral field, with the field being more
of his cases, with severe visual loss (20/200 to 20/600) occur- contracted to blue isopters than red (390). Smith (365) col-
ring in only 15%. None of the 200 patients examined by lected 22 cases of ‘‘bitemporal hemianopia’’ detected with
Kjer (362) had visual acuity reduced to hand motion or light colored test objects, and Manchester and Calhoun (391) also
perception levels. His findings are in accordance with the reported this phenomenon. In the large study performed by
cases collected by Smith (365), who found that 37% had Votruba et al. (373), 66% of the visual field defects in 50
visual acuity of 20/60 or better, 46% had visual acuity be- affected patients were predominantly in the superotemporal
tween 20/60 and 20/200, and only 17% had visual acuity visual fields. This pattern of visual field involvement has
below 20/200. Other studies support this wide range of visual been demonstrated using a variety of techniques of field
acuities from 20/20 to light perception (367,368,370–374). testing, and fixation has been monitored with scanning laser
In an analysis of 87 affected patients from 21 molecularly ophthalmoscopy (373), suggesting that these superobitem-
confirmed families with DOA (373), the mean visual acuity poral defects are not an artifact of the testing procedures or
was 20/120. In all studies, a few patients have been found of eccentric fixation.
with striking asymmetry between the acuities of the two The optic atrophy in patients with dominantly inherited
eyes, and there is considerable interfamilial and intrafamilial optic neuropathy may be subtle (363), may be temporal only
variation in acuities (373,376,377). (365,382), or may involve the entire optic disc (363,379)
Kjer (362,363) was able to obtain follow-up data in 98 (Fig. 11. 4). Kline and Glaser (367) found the most character-
patients, 75 of whom were observed for at least 5 years. istic change was a translucent pallor with absence of fine
Some progression occurred in about 50% of the patients. In superficial capillaries of the temporal aspect of the disc, with
addition, in Kjer’s (363) series, no patients younger than 15 a triangular excavation of the temporal portion of the disc.
years of age had visual acuity below 20/200, but 10% of In the Votruba et al. analysis (373), wedge-shaped temporal
patients 15 to 44 years of age and 25% of patients 45 years pallor of the disc was documented in 44% of 172 eyes, total
and older had vision below 20/200. In a study of 20 patients atrophy in another 44%, and subtle diffuse pallor in 12%.
with a mean follow-up of 16 years (370), visual acuity re- Other ophthalmoscopic findings reported in these patients
mained stable in both eyes of 13 patients (65%), decreased included peripapillary atrophy, absent foveal reflex, mild
in one eye in 3 patients (15%), and decreased in both eyes macular pigmentary changes, arterial attenuation, and non-
in 4 patients (20%). There was no correlation between the glaucomatous cupping with absence of a healthy neuroreti-
rate of visual loss and initial visual acuity or individual pedi- nal rim and shallow saucerization of the cup (365,367,370,
grees. Votruba et al. (373) documented deterioration of vis- 392,393). Fournier et al. (394) emphasized several clinical
ual acuity with age in one third of their 21 families. These features that help distinguish patients with DOA from those
figures, as well as data from other reports (361,371, with normal tension glaucoma, including early age of onset,
378–380) suggest a mild, slow, insidious progression of vis- preferential loss of central vision, sparing of the peripheral
ual dysfunction in some patients. The observation that some fields, pallor of the remaining neuroretinal rim, and a family
families have a marked decline in visual acuity with age history of unexplained visual loss or optic atrophy. Sandvig
while others do not has important implications for counsel- (395) reported three families with autosomal-dominantly in-
ing (373). Grutzner (381) commented that rapid deterioration herited excavated cupping and slowly progressive glaucoma-
of vision may occur even after years of stable visual function, tous visual field defects but normal intraocular pressures.
and Kjer et al. (361) also documented such rapid deteriora- Visual loss was noted in the third and fourth decades and
tion in a few patients. Spontaneous recovery of vision is not typically progressed to severe dysfunction. These families
a feature of this disorder. with dominant pseudoglaucoma are probably genetically
In the patients studied by Kjer (362,363), there was often distinct from the more common simple form of DOA.
an inability to perceive blue colors. Some studies (367, Electrophysiologic studies have been performed in several
368,382–384) subsequently demonstrated that tritanopia patients with DOA (367,373,377,388). Visual evoked re-
is the characteristic color vision defect in patients with sponses in affected individuals characteristically show di-
DOA (385,386), particularly when patients are tested with minished amplitudes and prolonged latencies, the latter usu-
the Farnsworth-Munsell 100-Hue test (367,368,387,388). ally less profound than in demyelinating disease (373,
However, other studies suggest that a generalized dyschro- 377,388,396). Pattern ERGs show a reduced N95 compo-
matopsia, with both blue-yellow and red-green defects, is nent, in keeping with primary ganglion cell dysfunction
even more common than an isolated tritanopia (370, (373). The extreme clinical variability among subjects with
373,389). This mixed color defect accounted for more than DOA suggests that on occasion combined clinical and func-
80% of the color deficits documented in a large study of 21 tional evaluation, with computerized perimetry, tests of con-
pedigrees (373). trast sensitivity, and electrophysiologic testing, may be nec-
Visual fields in patients with DOA characteristically show essary to diagnose the most subtle cases (377).
central, paracentral, or cecocentral scotomas. Often the de- Although there are dominantly inherited syndromes of
Figure 11.4. Dominant optic atrophy. A and B, Right and left optic discs in a patient with 20/40 visual acuity in both eyes,
a tritanopic color vision defect, and bilateral, small central scotomas. Note minimal temporal pallor. C and D, Right and left
discs of the above patient’s father. Visual acuity is 20/100 in the right eye and 20/80 in the left eye, with severe dyschromatopsia
and bilateral central scotomas. The pallor is extensive and is primarily temporal in a wedge shape.
optic atrophy associated with neurologic dysfunction, most a family with a typical pedigree of autosomal-dominant he-
of the patients with the syndrome of autosomal-dominant reditary optic atrophy. The patient had a long history of
optic atrophy have no additional neurologic deficits. Nystag- bilaterally reduced vision (20/100 in both eyes), bilateral
mus in some patients likely reflects early visual deprivation central scotomas, and temporal pallor of both discs. In both
rather than central neurologic involvement. Kjer (362,363) eyes, there was diffuse atrophy of the retinal ganglion cell
found mental abnormalities in 10% of his cases, but this layer associated with diffuse atrophy and loss of myelin
feature was not confirmed in subsequent studies. A mother within the optic nerves. Johnston et al. (366) suggested, as
and a daughter with bilateral optic atrophy with onset in did Kjer (362,363), that DOA is a primary degeneration of
infancy also had unilateral facial palsy (397). Eight of 31 retinal ganglion cells. Electrophysiologic studies confirm
patients described by Hoyt (368) had neural hearing loss, loss of ganglion cell function predominantly from the central
clustering in three of six families. Only one patient was retina, but not the exclusive result of either parvocellular or
aware of any hearing difficulties. More severe hearing loss magnocellular cell loss (373).
associated with familial optic atrophy may or may not be a One study of a large pedigree of German descent sug-
genetically distinct syndrome (see later). gested linkage of the gene responsible for DOA with the
Kidd blood group antigen, subsequently localized to chro-
Pathology/Pathophysiology mosome 18q12 (374,398). Further study of this family re-
Johnston et al. (366) performed a histologic examination fined the chromosomal locus to a 3-centimorgan region at
of the eyes and optic nerves of a 56-year-old woman from 18q12.2–12.3 (374). This family is clinically similar to the
other pedigrees of DOA, including its intrafamilial variation, pranormal, whereas with the tapetoretinal degenerations, it
although the median visual acuity was somewhat better at is abolished. This form of optic atrophy is stationary and
20/40. unassociated with other symptoms or signs of systemic or
Most of the other pedigrees with DOA, including several neurologic disease. It is, in our experience, rare, and its very
from Denmark, the United Kingdom, Germany, France, existence as a distinct identity has been questioned (418).
Cuba, Japan, and the United States, have genetic homogene-
ity in their linkage to the telomeric portion of the long arm of APPARENT SEX-LINKED OPTIC ATROPHY
chromosome 3 (3q28–29) (339,360,361,399–403). Between In 1975, Went et al. (419) reported a three-generation
30–90% of these families have been found to harbor over family with eight individuals with optic atrophy, all male
60 different missense and nonsense mutations, deletions, and and all related via the maternal lineage. The onset of visual
insertions in a gene within this region that has been desig- loss was in early childhood, never acutely, with very slow
nated the OPA1 gene (339,401–406). Identification of those progression. Visual acuities ranged from 20/50 to 20/1200.
mutations requires sequencing of the OPA1 gene, a process Visual evoked potentials showed prolonged latencies, and
currently available only on a research basis. The product of an ERG of the proband showed no abnormalities (420). One
the OPA1 gene is targeted to the mitochondria and appears of the affected males had neurologic abnormalities, includ-
to exert its function in mitochondrial biogenesis and stabili- ing ataxia, tremor, absent ankle jerks, and mental retardation.
zation of mitochondrial membrane integrity (339,401,402). Subtle neurologic abnormalities were noted in the other
Downregulation of the OPA1 leads to fragmentation of the males with optic atrophy, including absent ankle jerks, plan-
mitochondrial network and dissipation of the mitochondrial tar responses, mild tremor, and gait disturbances (421). One
membrane potential, with cytochrome c release and caspase- branch of the pedigree had Huntington’s disease, presumably
dependent apoptosis (407). These findings demonstrate the coincidentally. This family has subsequently been found to
crucial role of mitochondria in retinal ganglion cell patho- show close linkage to the Xp11.4–11.2 region of the X chro-
physiology (90a,339). Linkage analysis of patients with nor- mosome and not to harbor any of the common primary
mal tension glaucoma has shown an association with poly- mtDNA mutations associated with LHON (420,422). An-
morphisms of the OPA1 gene (408–410). Interestingly, there other family described by Lysen and Oliver (423) demon-
is a mutant strain of mice with dominantly inherited optic strated transmission from an affected grandfather to his
atrophy with variable expressivity (411). The mutation in grandson through an unaffected daughter, thereby strength-
these mice is located on the mouse chromosome 16, which ening the argument for sex-linked transmission. However,
is homologous to the human chromosome 3. There is cur- the documentation of optic atrophy was uncertain, and some
rently no known treatment for DOA. affected individuals apparently had evidence of chorioreti-
nitis.
CONGENITAL RECESSIVE OPTIC ATROPHY
PRESUMED AUTOSOMAL-RECESSIVE CHIASMAL
This form of optic atrophy is present at birth or develops
OPTIC NEUROPATHY
at an early age and is usually discovered before the patient
is 3 or 4 years old. It was described by Waardenburg (412) In 1999, Pomerantz and Lessell (424) described a unique
and others as having an autosomal-recessive transmission family in which all three siblings of one generation had inci-
(413). According to Kjer (392), there is often consanguinity dentally noted bitemporal visual field defects and optic nerve
between parents. The clinical picture is that of visual acuity pallor with retention of excellent visual acuity and no other
so severely affected that the patient may be completely blind neurologic or systemic symptoms or signs. Tests for the pri-
with searching nystagmus. The visual fields, when they can mary mtDNA mutations associated with LHON were nega-
be tested, show variable constriction, and there are often tive. Of note, two maternal uncles had died in their early
paracentral scotomas (414–416). The optic discs are com- teens form a neurologic disease characterized initially by
pletely atrophic and often deeply cupped. stuttering and loss of balance, progressing to bed confine-
Francois (417) remarked on the difficulty in separating ment and aphasia. Examinations of the parents and children
this entity from infantile tapetoretinal degeneration in pa- of the siblings were normal. The authors proposed an autoso-
tients with both disc pallor and vascular narrowing. How- mal-recessively inherited chiasmal optic neuropathy, but a
ever, in primary optic atrophy, the ERG is normal or su- mitochondrial disorder is also possible.
HEREDITARY OPTIC ATROPHY WITH OTHER NEUROLOGIC OR SYSTEMIC SIGNS
AUTOSOMAL-DOMINANT PROGRESSIVE OPTIC hearing loss. The hearing loss in these pedigrees was severe
ATROPHY AND DEAFNESS at birth, with none of the reported patients having developed
speech. Hearing evaluation in several of the affected individ-
In 1974, Konigsmark et al. (425) described six individuals uals revealed that they could hear amplified speech so that
in four generations who had congenital severe deafness and they might have developed adequate speech if they had been
progressive midlife visual failure. Kollarits et al. (426) sub- provided amplification in early childhood and training in
sequently described a second family with the same syn- oral as well as in manual language. Subtle visual dysfunction
drome. In all of the cases, there were no systemic or neuro- was present at an early age, as demonstrated by the 9-year-
logic abnormalities except for congenital sensorineural old son of the proposita in the family examined by Konigs-
mark et al. (425), who had dyschromatopsia by the Farns- legs, with weakness and muscle wasting mainly affecting
worth-Munsell 100-Hue test and bilateral optic pallor, worse the shoulder girdle and hands. The relationship of this syn-
temporally, despite visual acuity of 20/15 and bilaterally full drome to Friedreich’s ataxia was discussed in detail by
fields. Most of the patients had normal acuity until at least Sylvester (435).
24 years of age. Nicolaides et al. (436) described three family members
Since 1979, several pedigrees with presumed autosomal- with a relapsing, early-onset cerebellar ataxia, progressive
dominant optic atrophy and hearing loss have been described optic atrophy, and sensorineural hearing loss, with areflexia
(368,427–434). There is great inter- and intrafamilial vari- but no peripheral neuropathy and pes cavus deformity. The
ability in the age of onset of the visual loss and the severity authors suggested autosomal-dominant or maternal mito-
of the hearing loss. In most cases, visual loss remains better chondrial inheritance and proposed the acronym CAPOS
than 20/200. In one Turkish family, linkage analysis ex- (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and
cluded the two known genes associated with autosomal dom- sensorineural deafness).
inant optic atrophy (see above) (434). It is unclear whether
these pedigrees represent a phenotypic variant of DOA, a HEREDITARY OPTIC ATROPHY WITH
genetically distinct disorder, or a genetically heterogeneous PROGRESSIVE HEARING LOSS AND
group of disorders with a similar phenotype. POLYNEUROPATHY
AUTOSOMAL-DOMINANT OPTIC ATROPHY, Rosenberg and Chutorian (437) reported the occurrence
DEAFNESS AND OPHTHALMOPLEGIA of progressive optic atrophy, sensorineural deafness, and
polyneuropathy in three men belonging to two generations
Treft et al. (434a) described a syndrome affecting 23
of a single family, two brothers and their nephew. The two
members of five generations of a Utah family characterized
brothers were 32 and 29 years-old and the nephew was 3.5
by optic atrophy, deafness, ptosis, ophthalmoplegia, dys-
years-old when examined. All patients had poor hearing
taxia, and myopathy. The visual loss was first noted between
since childhood, with progression to virtually complete deaf-
the ages of 6 and 19 years, with an average age of onset of
ness. In the two older patients, gait disturbance began be-
11 years. Visual loss was occasionally sudden in onset but
tween 5 and 10 years of age, and the child had an awkward
always progressive to the 20/30 to 20/400 range. Electroreti-
gait, absent deep tendon reflexes, and a partial Gowers’ sign.
nograms were abnormal, although retinal pigmentary
One brother had visual acuity of 20/100 bilaterally with full
changes were absent, suggesting the combination of a pri-
visual fields and bilateral optic atrophy, temporal more than
mary retinal degeneration and a primary optic neuropathy.
nasal. The other brother had visual acuity of 20/400 in both
Hearing loss was sensorineural and progressive, with onset
eyes with constricted fields and bilateral optic atrophy. The
in the first or second decades. Ophthalmoplegia, dystaxia,
nephew had a normal ophthalmoscopic examination. All
and myopathy occurred in midlife. One muscle biopsy
three individuals had abnormally slow nerve conduction ve-
showed ragged red fibers. Male-to-male transmission con-
locities. The two brothers had gastrocnemius muscle biop-
firmed autosomal-dominant inheritance. An unrelated fam-
sies showing severe neurogenic atrophy, whereas their
ily from Belgium was reported with a similar phenotype
nephew had a normal muscle biopsy but a sural nerve biopsy
(434b). Both these families have recently been genetically
showing demyelination with axonal preservation. A similar
confirmed to carry the R445H mutation in the OPA1 gene
family was reported by Iwashita et al. (438), consisting of
(434c), previously reported in a single Japanese patient with
a 25-year-old man and his 15-year-old sister. Both patients
optic atrophy (434d) and a single French woman with optic
had bilateral optic atrophy, although the affected man had
atrophy and deafness (434e). Other OPA1 mutations in this
visual acuity of 20/100 in each eye while his sister had visual
region (the GTPase domain) have been associated with mon-
acuity of 20/20. Neurogenic hearing loss was present in both
osymptomatic autosomal-dominant optic atrophy (Kjer’s
individuals; however, unlike the patients described by Ro-
disease) (404,405; see above). These findings underscore
senberg and Chutorian (437), nerve conduction velocities
the importance of mitochondrial dysfunction, whether the
were normal in both patients, as were muscle biopsies. A
result of nuclear or mitochondrial DNA defects, as a final
sural nerve biopsy in the affected male showed mild demye-
common pathway for many forms of syndromic and non-
lination. Subsequently, Hagemoser et al. (439) reported two
syndromic optic atrophy.
families with autosomal-dominant optic atrophy in the first
AUTOSOMAL-DOMINANT PROGRESSIVE OPTIC decade of life, followed by the development of hearing loss
ATROPHY WITH PROGRESSIVE HEARING LOSS and peripheral neuropathy. These authors differentiated
AND ATAXIA (CAPOS SYNDROME) these families from those of Rosenberg and Chiturian (437)
and Iwashita et al. (438) by the severity and early onset of
In this syndrome, described by Sylvester (435) in 1958, the optic atrophy and by the mode of inheritance. Hagemoser
a father and his six children were found to have bilateral et al. (439) suggested that the Rosenberg and Chiturian (437)
optic atrophy and hearing loss, associated with ataxia and pedigree represents an X-linked disorder and the Iwashita
limb weakness. The onset of visual loss in these patients et al. (438) family an autosomal-recessive disorder. These
was between 2.5 and 9 years of age. The hearing loss was disorders can be included in the spectrum of hereditary poly-
only moderate and, like the optic atrophy, was slowly pro- neuropathies that includes Charcot-Marie-Tooth disease
gressive. The ataxia in these patients primarily affected the (440–442; see following).
AUTOSOMAL-RECESSIVE OPTIC ATROPHY WITH usually worse than 20/200, suggesting progression (457,
PROGRESSIVE HEARING LOSS, SPASTIC 468). Visual fields show both generalized constriction and
QUADRIPLEGIA, MENTAL DETERIORATION, AND central scotomas. Optic atrophy is uniformly severe, and
DEATH (OPTICOCOCHLEODENTATE there may be mild to moderate cupping of the disc.
DEGENERATION) The onset of hearing loss and of diabetes insipidus in this
syndrome is equally variable. Both begin in the first or sec-
An autosomal-recessive syndrome characterized by se- ond decade of life and may be severe. Atonia of the efferent
vere optic atrophy with onset of visual loss in infancy, pro-
urinary tract is present in 46–58% of patients and is associ-
gressive hearing loss resulting in severe deafness, and pro-
ated with recurrent urinary tract infections and even fatal
gressive spastic quadriplegia beginning in infancy with
complications (459,466). Other systemic and neurologic ab-
progressive mental deterioration and death in childhood has
normalities include ataxia, axial rigidity, seizures, startle my-
been described by several authors (443–448). The common
oclonus, tremor, gastrointestinal dysmotility, vestibular mal-
denominator in all these patients is a selective, systematized
degeneration of the optic, cochlear, dentate, and medial function, central apnea, neurogenic upper airway collapse,
lemniscal systems. The basal ganglia are unaffected in this ptosis, cataracts, pigmentary retinopathy, iritis, lacrimal hy-
condition. The diagnosis is made clinically because there are posecretion, tonic pupil, ophthalmoplegia, convergence in-
no pathognomonic histochemical, cytochemical, or electron sufficiency, vertical gaze palsy, mental retardation, psychiat-
microscopic characteristics found on brain biopsy (446). ric abnormalities, nystagmus, short stature, primary gonadal
atrophy, other endocrine abnormalities, anosmia, megalo-
OPTICOACOUSTIC NERVE ATROPHY WITH blastic and sideroblastic anemia, abnormal electroretinogr-
DEMENTIA aphy, and elevated cerebrospinal fluid protein levels
(457,466,467,470–472). Psychiatric disorders are also seen
Jensen (449) described a 3-year-old boy and his two ma- at an increased frequency among heterozygous carriers
ternal uncles with a syndrome characterized by severe senso- (473). Pathology and neuroimaging in some patients reveal
rineural hearing loss with onset in infancy, followed by pro- widespread atrophic changes and suggest a diffuse neurode-
gressive optic atrophy in the second or third decades and generative disorder, with particular involvement of the mid-
progressive dementia in adulthood. Subsequent autopsy brain and pons (467,471,474). Median age at death is 30
studies (450,451) revealed generalized degeneration of the years, most commonly due to central respiratory failure with
central nervous system with extensive calcification. Diffuse brain stem atrophy (466,475).
wasting of skeletal muscles was also found. An X-linked Many of the associated abnormalities reported in Wol-
recessive inheritance was proposed, but mitochondrial in- fram’s syndrome are commonly encountered in patients with
heritance may be as likely. presumed mitochondrial diseases, especially patients with
the chronic progressive external ophthalmoplegia syn-
PROGRESSIVE OPTIC ATROPHY WITH JUVENILE dromes (83,230). This has led to speculation that patients
DIABETES MELLITUS, DIABETES INSIPIDUS, AND with Wolfram’s syndrome may have a unifying pathogenesis
HEARING LOSS (DIDMOAD/WOLFRAM’S in underlying mitochondrial dysfunction (167,476–480).
SYNDROME) Abnormalities of mitochondrial function can result from nu-
In 1938, Wolfram (452) described a family in which four clear or mitochondrial DNA defects because both genomes
of eight siblings had diabetes mellitus and bilateral optic code for proteins essential for normal mitochondrial func-
atrophy. Three of the four affected siblings subsequently tion. Barrientos et al. (480) described a girl with diabetes
developed neurosensory hearing loss and two developed mellitus at age 8, optic atrophy by age 11, bladder atony,
neurogenic bladder. DeLawter (453) later reported a patient diabetes insipidus, and ultimately sensorineural hearing loss.
with diabetes mellitus and optic atrophy in whom diabetes The patient was found to have a heteroplasmic mitochondrial
insipidus was subsequently diagnosed. Since these initial DNA deletion, and the identical deletion was noted in lesser
reports, about 300 cases have been recorded, with a preva- proportions in her asymptomatic sister, mother, and father.
lence of 1 in 770,000 in the United Kingdom (454–471). The presence of this deletion in both parents prompted the
The hallmark of all these cases is the association of juvenile authors to propose that a defect in a nuclear gene was acting
diabetes mellitus and progressive visual loss with optic atro- at the mitochondrial level to cause the disease. Most cases
phy, almost always associated with diabetes insipidus, neu- of Wolfram’s have been classified as sporadic or recessively
rosensory hearing loss, or both (hence the acronym DID- inherited, the latter usually concluded from sibling expres-
MOAD for diabetes insipidus, diabetes mellitus, optic sion (which we now know could also occur from maternal
atrophy, and deafness). The progression and development of transmission). Furthermore, some nuclear genetic defects
this syndrome are variable. Symptoms and signs of diabetes can cause rearrangements of mitochondrial DNA, presum-
mellitus usually occur within the first or second decade of ably if the altered gene codes for proteins involved in
life and usually precede the development of optic atrophy. mtDNA regulation. Other investigators have not found
In several cases, however, visual loss with optic atrophy was mtDNA defects or evidence of mitochondrial dysfunction
the first sign of the syndrome. In the early stages, visual among patients with Wolfram’s syndrome (466,467,477,
acuity may be normal despite mild dyschromatopsia and 481). HLA typing reveals an association with the HLA-DR2
optic atrophy. In later stages, visual loss becomes severe, antigen in some patients, suggesting an influence of HLA
on susceptibility to the disease (482,483). Using linkage ated with variable pyramidal tract signs, ataxia, mental retar-
analysis in 11 families, Polymeropoulos et al. (484) proposed dation, urinary incontinence, and pes cavus. The syndrome
localization of the Wolfram’s gene to the short arm of chro- has been reported in both sexes (380,413,500) and is be-
mosome 4. This locus was refined to chromosome 4p16.1 lieved to be autosomal-recessively inherited. Visual loss usu-
and accounts for many but not all DIDMOAD pedigrees ally manifests before age 10 years, is moderate to severe,
(485,486). The gene responsible at this locus has been desig- and is frequently accompanied by nystagmus. In most cases,
nated WFS1, in which multiple point mutations and dele- the abnormalities do not progress after childhood. In one
tions have been identified (486–488). Some of these muta- case of Behr’s syndrome, MR imaging demonstrated diffuse
tions were subsequently found to be a common cause of symmetric white matter abnormalities (501). Horoupian et
inherited isolated low-frequency hearing loss (489). In one al. (502) reported two sisters with Behr’s syndrome, one of
report, the locus on chromosome 4p16 was proposed as a whom came to autopsy. Findings included moderate atrophy
predisposing factor for the formation of multiple mtDNA of the optic nerves and optic tracts with extensive degenera-
deletions (490). DIDMOAD patients were also found to con- tion of the lateral geniculate nuclei and with mild attenuation
centrate on two major mtDNA haplotypes that are also over- of the visual radiations, but with normal striate cortex. Two
represented among LHON patients (273). A phenotypic var- other patients with Behr’s syndrome were also autopsied,
iant of Wolfram’s syndrome with peptic ulcer disease and but in one patient the findings were overshadowed by an
bleeding secondary to a platelet aggregation defect, but with- intracerebral hemorrhage (503) and in the other by necrotiz-
out diabetes insipidus, was noted in four consanguineous ing encephalopathy (504). Monaco et al. (505) reported a
Jordanian families and linked to a second locus (WFS2) on patient with Behr’s syndrome associated with epilepsy, as
chromosome 4q22–24 (470,491). The Wolfram’s phenotype well as slow motor nerve conduction velocities, a low testos-
may be nonspecific and reflect a wide variety of underlying terone level, and an amino acid imbalance in both plasma
genetic defects in either the nuclear or mitochondrial ge- and cerebrospinal fluid.
nomes. When the syndrome is accompanied by anemia, In several Iraqi-Jewish pedigrees of Behr’s syndrome, 3-
treatment with thiamine may ameliorate the anemia and de- methylglutaconic aciduria was identified, leading to map-
crease the insulin requirement (492). ping of the gene (designated OPA3) to chromosome
19q13.2–13.3 (506–512). These patients had infantile optic
PROGRESSIVE ENCEPHALOPATHY WITH EDEMA,
atrophy and an early-onset extrapyramidal movement disor-
HYPSARRHYTHMIA, AND OPTIC ATROPHY
der dominated by chorea. Approximately half of the patients
(PEHO SYNDROME)
developed spastic paraparesis by the second decade. The
Salonen et al. (493) described 14 patients from 11 families majority of affected individuals were female. In propionic
with a progressive encephalopathy with onset in the first 6 acidemia, a rare autosomal recessive disorder, chronic meta-
months of life, followed by severe hypotonia, convulsions bolic decompensation occurs with paroxysmal ketoacidosis,
with hypsarrhythmia, profound mental deterioration, hyper- failure to thrive, and mild developmental delay (512a). As
reflexia, transient or persistent facial and body edema, and a result of improved clinical intervention, survival has
optic atrophy (494). Optic atrophy is usually noted by the lengthened into adolescence. Male gender and age are asso-
first or second year of life, and nystagmus is common. Mi- ciated with bilateral, progressive optic neuropathy (512a).
crocephaly and brain atrophy develop, especially in the cere- Korn-Lubetzki et al. (513) described a consanguineous
bellar and brain stem areas (495–498). A metabolic defect Israeli-Jewish-Iraqi family with four of nine siblings (all
has yet to be determined, although elevations of nitric oxide males) affected within the first decade of life by a syndrome
have been noted (497), and an autosomal-recessive mode of of optic atrophy, dystonia, and striatal atrophy on imaging,
inheritance is likely. This could be considered a form of but with no identified causative metabolic or genetic defects.
Behr’s syndrome, which probably represents a heterogene- Clinical findings in other patients with Behr’s syndrome may
ous group of disorders (see below). be similar to those in cases of hereditary ataxia; in fact,
Francois (514) suggested that Behr’s syndrome may be a
COMPLICATED HEREDITARY INFANTILE OPTIC transitional form between simple heredofamilial optic atro-
ATROPHY (BEHR’S SYNDROME) phy and the hereditary ataxias. Behr’s syndrome is likely
In 1909, Behr (499) described a syndrome of heredofami- heterogeneous, reflecting different etiologic and genetic fac-
lial optic atrophy beginning in early childhood and associ- tors (515).
OPTIC NEUROPATHY AS A MANIFESTATION OF HEREDITARY DEGENERATIVE OR

DEVELOPMENTAL DISEASES
HEREDITARY ATAXIAS X-linked, and maternal (mitochondrial). Advances in bio-
chemical and genetic analysis reveal a wide variability of
The inherited ataxias represent a group of chronic progres- clinical signs and neuropathology, even within families, and
sive neurodegenerative conditions involving the cerebellum the overlap of clinical and pathologic phenotypes in disor-
and its connections (516,517). The most common classifica- ders now known to be caused by different genetic defects
tion of the hereditary ataxias is by pattern of inheritance: makes diagnostic classification by phenotype often inaccu-
autosomal dominant (most common), autosomal recessive, rate (516,518–520). A genomic classification by chromo-
somal location is available for many of these disorders, and evoked responses in 50% of patients, Durr et al. (544) found
the abnormal gene products involved are under investigation. ‘‘reduced’’ visual acuity in 13% of 140 patients, and
Optic atrophy is not uncommon among individuals with the Montermini et al. (545) reported optic atrophy in 21% of
hereditary ataxias (521,522). 109 patients. It is unclear whether the variability in optic
The prototype of all forms of progressive ataxia was first atrophy relates to the duration of the disease or the underly-
described by Friedreich (523) in 1863. The onset of the dis- ing genetic abnormality. Givre et al. (546) reported a 15-
ease is usually between the ages of 8 and 15 years, almost year-old boy with genetically confirmed Friedreich’s ataxia
always before age 25 (524–528). The disorder is marked by with subacute bilateral optic neuropathies followed by par-
degeneration of the large sensory neurons concerned with tial spontaneous recovery, similar to the pattern of visual
position sense and the afferent spinocerebellar tracts, causing involvement seen in some patients with LHON.
a sensory ataxia. Characteristic clinical features include pro- Other autosomal-recessive ataxias less common than
gressive ataxia of gait and clumsiness in walking and using Friedreich’s ataxia include ataxia telangiectasia, ataxia with
the hands, dysarthria, loss of joint position and vibratory vitamin E deficiency, abetalipoproteinemia, Refsum’s dis-
sensation, absent lower extremity tendon reflexes, and exten- ease, spastic ataxia, infantile-onset spinocerebellar ataxia,
sor plantar responses. Common findings include scoliosis, and ataxia with oculomotor apraxia (527). A condition re-
foot deformity, diabetes mellitus, and cardiac involvement. sembling Friedreich’s ataxia associated with decreased vita-
Other manifestations include pes cavus, distal wasting, deaf- min E levels has been localized to chromosome 8 (547) and
ness, nystagmus, eye movement abnormalities consistent also includes some patients with optic atrophy. Vitamin E
with abnormal cerebellar function, and optic atrophy. The supplementation of these patients may be efficacious early
course is relentlessly progressive, with most patients unable in the course of the disease. Early-onset autosomal-recessive
to walk within 15 years of onset, and death from infectious spinocerebellar ataxia with hearing loss and optic atrophy
or cardiac causes usually in the fourth or fifth decades. A shows linkage at 6p21–23 (548), congenital cerebellar ataxia
later-onset, more slowly progressive form has been de- with mental retardation, optic atrophy, and skin abnormali-
scribed (526,529). ties (CAMOS) links at 15q24–26 (549), and pontocerebellar
Friedreich’s ataxia is inherited in an autosomal-recessive hypoplasia with progressive microcephaly (and optic atro-
manner, and the gene defect has been localized to the phy) (CLAM) links to 7q11–21 (549a). In 1993, Arts et al.
proximal long arm of the 9th chromosome (9q13–21) (550) described what they believed to be a unique clinical
(526,530,531). The vast majority of cases are homozygous syndrome in a five-generation Dutch family. Transmission
for an intronic, unstable, GAA trinucleotide expansion (532) of the disease was X-linked recessive. Affected family mem-
in a gene designated FRDA/X25 that codes for a protein bers demonstrated optic atrophy, ataxia, deafness, flaccid
known as frataxin (516,533). Frataxin is a mitochondrial tetraplegia, and areflexia. The course was generally progres-
protein that appears to regulate iron levels in the mitochon- sive to death. No specific biochemical, immunologic, or ge-
dria. Its absence leads to mitochondrial iron overload and netic defects were identified, although pathologic examina-
overproduction of reactive oxygen species and cell death tion showed almost complete absence of myelin in the
(534,534a). Optic atrophy is present in many cases of posterior columns.
Friedreich’s ataxia, although severe visual loss is uncom- The most common of the hereditary ataxias are inherited
mon. Bell and Carmichael (535) found optic disc pallor in in an autosomal-dominant pattern. The majority of these are
15 of 57 cases (26%), whereas Sjögren (536) noted optic now designated by the term spinocerebellar ataxia (SCA),
atrophy in only 12% of his cases. In the Quebec cooperative reflecting their predominant pathology in the spinal cord
study, Andermann et al. (537) found reduced visual acuity and the cerebellar pathways (516,519,520,551–553). A wide
and optic atrophy in 4 of 13 cases (30%), and Geoffroy et range of clinical and pathologic findings can be seen within
al. (538), reviewing previous studies, reported a 50% preva- and among pedigrees. Although originally classified by clin-
lence of optic atrophy. Despite these figures, Heck (539) ical descriptions within specific families (554), they are now
found no evidence of optic atrophy in members of a large defined by the genetic loci and specific mutations in these
family with this disease. Carroll et al. (540) performed clini- families. Indeed, the same phenotype can be caused by a
cal and electrophysiologic examinations on 22 patients with multitude of different gene defects. These diseases are inher-
Friedreich’s ataxia and found that although no patient had ited in an autosomal-dominant fashion, although sporadic
visual acuity below 20/80, the majority of the patients had cases can occur.
either clinical or electrophysiologic evidence of visual sen- As of 2003, there were at least 23 different genetic loci
sory dysfunction. Livingstone et al. (541) examined 21 pa- for SCAs (SCA 1 to SCA 22) (552,553, personal communi-
tients with Friedreich’s ataxia and found that two thirds of cation, George Wilmot, MD, 2003). The combination of
the patients had some degree of visual impairment and ab- SCA1 (chromosome 6p), SCA 2 (chromosome 12q), SCA 3
normal visual evoked responses. These investigators found (chromosome 14q and allelic with Machado-Joseph disease),
no correlation between the presence and severity of visual SCA 6 (chromosome 19p), and SCA 7 (chromosome 3p)
involvement and the age or duration of other neurologic represents approximately 80% of the autosomal dominant
symptoms. Wenzel et al. (542) found pathologic results on ataxias (516). Many of the SCAs are caused by mutations
visual evoked responses in 25 of 45 patients (55%). Among involving the expansion of a CAG trinucleotide repeat in
series of genetically confirmed patients with Friedreich’s the protein coding sequences of specific genes, resulting in
ataxia, Müller-Felber et al. (543) found abnormal visual a series of glutamines. As with other diseases that involve
abnormal repeats, the expanded regions can become larger that SCA. Some spinocerebellar syndromes may result from
with each successive generation, resulting in a younger age mutations in mtDNA (568,569), including the point mutation
of onset in each generation (anticipation). Anticipation is at position 8993 (570) that is also associated with Leigh’s
seen particularly when the disease is inherited from the fa- syndrome (see later). There are currently no specific thera-
ther. peutic options for the spinocerebellar syndromes.
Clinically, the SCAs are characterized by signs and symp- Melberg et al. (571) described an autosomal dominant
toms attributable to cerebellar degeneration and sometimes Swedish pedigree with five patients affected with cerebellar
other neurologic dysfunction secondary to neuronal loss. ataxia and sensorineural deafness, four of whom also had
Loss of vision is usually mild but may be a prominent symp- narcolepsy. Optic atrophy, other neurologic abnormalities,
tom, occurring in association with constricted visual fields and psychiatric symptoms developed with increasing disease
and diffuse optic atrophy (522,554–556). However, it is not duration. Other inconsistent findings were diabetes mellitus
clear in some cases whether the primary process is retinal and hypertrophic cardiomyopathy. A normal-sized SCA 1
with secondary optic atrophy or primary optic nerve. Living- repeat was observed and mitochondrial dysfunction was sug-
stone et al. (541) examined 17 patients with hereditary cere- gested.
bellar or spastic ataxia, both clinically and electrophysiologi- Lundberg et al. (572) described a family with 29 members,
cally. They found visual sensory abnormalities in only three of whom 15 had an autosomal-dominantly inherited syn-
of the patients (17.6%), of whom only one had evidence of drome of optic atrophy, ataxia, pyramidal tract signs, and
optic atrophy. Koeppen et al. (557) similarly found evidence absent Achilles reflex. Optic atrophy was present in seven
of optic atrophy in 3 of 17 cases of adult-onset hereditary of the family members and appeared to have begun during
ataxia. In an autopsy study of one patient with temporal early life. In some instances, atrophy was severe and associ-
pallor of the discs in life, Staal et al. (558) found the eyes ated with nystagmus. Pes cavus was present even more often
to be normal, including the ganglion cells. The retrobulbar than optic atrophy and was severely disabling. In one third
portions of both optic nerves were atrophic and completely of the cases, there was a mild sensory disturbance in the
demyelinated, with severe axonal degeneration, but the pre- lower limbs, with Achilles reflexes being absent in all cases.
chiasmatic parts of the nerves were normal. Triau et al. (559) An autopsy performed in one patient revealed diffuse atro-
described a three-generation family with six members af- phy of both optic nerves, the optic chiasm, the optic tracts,
fected with progressive ataxia and blindness. The proband and the lateral geniculate bodies. The posterior columns of
initially had optic atrophy but subsequently developed gen- the spinal cord were narrow and pale, and the inferior olives
eralized chorioretinal degeneration. Pathologic examination were firm and gray. The cerebellar cortex was mildly atro-
showed demyelination and gliosis of the optic nerves and phic and most Purkinje cells were missing. Extensive demy-
chiasm and gliosis of the retrochiasmal pathways back to elination was present in the anterior visual sensory system
the striate cortex. Hammond and Wilder (560) demonstrated and both inferior olives, whereas the posterior columns were
abnormal VEPs in two patients with adult-onset spinocere- partially demyelinated. This family appears to have a transi-
bellar atrophy and no optic disc pallor. tional syndrome with features of both the predominantly
Detailed analysis of the prevalence of optic atrophy spinal and the predominantly cerebellar hereditary ataxias.
among the different genotypes now associated with the A similar family was described by Young (573).
spinocerebellar syndromes has not been performed. Prior to
genetic analysis, Harding (554) categorized the autosomal- HEREDITARY POLYNEUROPATHIES
dominant cerebellar ataxias (ADCAs) into four types, with
only the first type having individuals with primary optic In 1886, Charcot and Marie (574), as well as Tooth (575),
atrophy (approximately 30% of cases). We now know that collected 39 cases from personal observations and reports
ADCA type I encompasses multiple genetic loci, including in the literature of a heredofamilial disorder characterized
those pedigrees now classified genetically as SCA1, SCA2, by progressive muscular weakness and atrophy that began
SCA3, and probably SCA4 and SCA5. Initial studies suggest during the first two decades of life. Subsequent classifica-
that patients with the SCA2 genotype do not exhibit optic tions of Charcot-Marie-Tooth disease (CMT) have been by
atrophy (561), whereas SCA3 patients may have optic atro- clinical syndrome, histopathology, and pattern of inheritance
phy, especially if their ataxia is severe (562,563). In a study and, later, by genetic defect and affected gene products
of six patients from three families of molecularly confirmed (576–578). This group of hereditary polyneuropathies ac-
SCA 1, Abe et al. (556) found a gradual decrease in visual counts for 90% of all hereditary neuropathies, with the prev-
acuity and color vision, progressive contraction of visual alence in the United States being about 40 per 100,000. Most
fields, severely decreased corneal endothelial density, mild forms of CMT begin between the ages of 2 and 15 years.
attenuation of oscillatory potentials on ERG, and optic atro- The first signs are usually pes cavus, foot deformities, or
phy with large cupping. Similarly, three patients from one scoliosis. There is slowly progressive weakness and wasting,
molecularly confirmed SCA 1 family had optic atrophy first of the feet and legs and then of the hands. Motor symp-
(564). SCA 7 is essentially the only SCA associated with toms predominate over sensory abnormalities. The most
pigmentary retinal degeneration (565–567). common form of CMT is type 1, a demyelinating neuropathy
As of 2003, genetic testing was commercially available with autosomal-dominant inheritance, mapped most com-
for SCA1, 2, 3, 6, 7, 8, 10, 12, and 17 and detatorubropallido- monly to the short arm of chromosome 17 (17p11.2) (type
luysian atrophy (DRPLA) (516). Each test is specific for 1A), although a few pedigrees with this phenotype are linked
to the long arm of chromosome 1 (type 1B) (579–581). CMT system cause the clinical manifestations of sensory and auto-
type 2 is clinically similar, but nerve conductions are of nomic dysfunction. The gene responsible has been identified
normal velocity, suggesting the process is neuronal rather on chromosome 9q31–33 (597). Optic atrophy has been
than demyelinating. Type 2 can be inherited in an autosomal- demonstrated in patients with familial dysautonomia, usually
dominant fashion (linked to the short arm of chromosome after the first decade of life (598–600). Diamond et al. (599)
1) or autosomal-recessively (linked to the long arm of chro- found optic nerve pallor in all of their 12 patients, and 79%
mosome 8). Type 3 is the most severe form. When type 3 of eyes had abnormal VEPs. Older patients had more severe
is inherited in an autosomal-dominant pattern, the linkage deficits than younger patients, suggesting progression. In
is to the same region on chromosome 1 associated with type some cases of familial dysautonomia, optic atrophy may go
1B; when it is autosomal recessive, the linkage is to the same unrecognized because coincident corneal scarring prevents
region on chromosome 17 associated with type 1A. There adequate fundus examination. However, in most cases, early
are also X-linked forms of CMT, both X-linked dominant mortality from the disease probably precludes the later de-
(linked to defects on the long arm) and X-linked recessive velopment of large myelinated fiber deterioration and optic
(linked to regions on either the long arm or the short arm). atrophy (598). Nevertheless, in those who survive beyond
As of 2002, causative mutations for the hereditary peripheral early childhood, optic atrophy is an important sign of central
neuropathies had been identified in 17 different genes (577). nervous system dysfunction in this disorder.
In 1889, Vizioli (582) reported progressive bilateral blind-
ness and optic atrophy in a 59-year-old man and his 26-year- HEREDITARY SPASTIC PARAPLEGIAS
old son, both of whom had evidence of CMT. Since this The hereditary spastic paraplegias (Strumpell-Lorrain dis-
initial report, numerous patients with CMT and optic atrophy ease) are autosomal-dominant disorders characterized by
have been reported (415,583–589). Alajouanine et al. (585) progressive spasticity of the lower limbs and pathologic re-
reported demyelination of the optic nerves in a postmortem flexes with degeneration or demyelination of the corticospi-
study of a 65-year-old CMT patient in whom blindness and nal system and, to a lesser extent, of the posterior cord and
optic atrophy developed 40–50 years after the onset of the spinocerebellar system (601,602). Several loci have been
his disease. Electrophysiologic testing reveals subclinical identified, the most frequent of which is that linked to chro-
optic neuropathy in a high proportion of CMT patients mosome 2p22, followed by that linked to chromosome
(586,590–593). Tackmann and Radu (590) found abnormal- 14q11–21 (601). Optic neuropathy and dyschromatopsia
ities of VEPs in seven eyes of five patients with no clinical with visual acuities ranging from 20/20 to 20/200 have been
signs of optic nerve involvement. Burki (591) described the reported in a few patients with Strumpell-Lorrain disease
ocular findings in nine patients with CMT. Although only (601,602).
three patients complained of visual problems and all nine Dillmann et al. (603) described two siblings with infantile
patients had normal visual acuity in both eyes, combined spastic paraplegia and motor and sensory axonal polyneu-
VEP and contrast sensitivity testing revealed evidence of ropathy who developed progressive visual loss secondary
optic neuropathy in one or both eyes of seven patients. Bird to optic neuropathy in adolescence. The relationship to the
and Griep (592) performed VEPs on 25 patients with CMT hereditary motor and sensory neuropathy types 5 and 6 are
and demonstrated abnormalities in 4 patients (16%), includ- discussed. Miyama et al. (604) described an 8-year-old girl
ing the only patient with clinical optic atrophy. Carroll et with progressive infantile spastic paraplegia and severe de-
al. (586) performed VEPs on 15 visually asymptomatic CMT velopmental delay who developed peripheral neuropathy
patients and found definite abnormalities in 5 and possible and optic atrophy at age 5 years.
abnormalities in another 3. Taking into account both electro-
physiologic and clinical data, 73% of patients showed some HEREDITARY MUSCULAR DYSTROPHIES
afferent visual pathway dysfunction. Similarly, Gadoth et al. Myotonic dystrophy, a relatively common autosomal
(593) reported prolongation of VEPs in 43.7% of 16 patients dominant disorder with a prevalence of 1 in 20,000, is char-
with CMT and clinically normal optic nerves. acterized by progressive myopathy, cataracts, cardiomy-
Pedigrees specifically designated CMT type 6 show a reg- opathy with conduction defects, and diabetes mellitus
ular association of CMT and optic atrophy (588,589,589a). (516,605,606). Other classic findings include frontal bald-
Indeed, optic atrophy and neuropathy have been described ing, bifacial weakness, ptosis, and cognitive and psychiatric
in families that show autosomal-dominant, autosomal-reces- dysfunction. Less common ophthalmologic manifestations
sive, and X-linked recessive inheritance. This type of CMT can include ocular hypotonia, external ophthalmoplegia, pig-
is as yet genetically unspecified and may prove genetically mentary retinopathy, and optic atrophy (607). Most patients
heterogeneous (588,589a). with myotonic dystrophy have an expansion of an unstable
We have already commented on the cases reported by CTG repeat in a protein kinase gene on chromosome
Rosenberg and Chutorian (437) and their similarity to the 19q13.3, although variants of the disease are genetically het-
hereditary ataxias as well as to CMT. Other cases have been erogeneous (516).
reported (594,595) that also appear to link CMT to the hered-
itary ataxias, particularly Friedreich’s ataxia. STORAGE DISEASES AND CEREBRAL
Familial dysautonomia (Riley-Day syndrome) is an auto- DEGENERATIONS OF CHILDHOOD
somal-recessive disease that almost exclusively affects Ash- About 100 inherited metabolic diseases with ocular mani-
kenazi Jews (596). Abnormalities of the peripheral nervous festations have been described (608,609; see Chapter 46).
Among these, the lysosomal storage disorders are mono- and visual loss. Krabbe’s disease is an autosomal recessive
genic inborn errors of metabolism with heterogeneous patho- disease of both central and peripheral myelin, linked to chro-
physiology and clinical manifestations (610–612). They rep- mosome 14, that results from a deficiency of galacto-
resent more than 40 disorders, each of which is caused by cerebrosidase.
the deficiency of a lysosomal enzyme or other protein. The Adrenoleukodystrophy is an X-chromosome-linked reces-
stored material is usually a complex lipid or saccharide, and sive disorder characterized by primary atrophy of the adrenal
the nervous system is commonly affected. The inheritance glands, with or without Addison’s disease and low plasma
pattern in these diseases is almost always recessive, usually cortisol levels, and a severe degeneration of white matter in
autosomal recessive, but occasionally X-linked. the central nervous system with blindness (638). Symptoms
Of the inborn lysosomal disorders with ocular manifesta- of behavioral changes signal the onset of the disease at the
tions, the major diseases that include optic neuropathy are end of the first decade of life, followed by relentlessly pro-
the mucopolysaccharidoses (MPS) and the lipidoses gressive dementia, pyramidal tract dysfunction, and visual
(613–618). Optic atrophy may occur in patients with MPS loss, with optic atrophy and demyelination of the entire vi-
IH (Hurler), MPS IS (Scheie), MPS IHS (Hurler-Scheie), sual pathway. Hence, visual loss may be of both anterior
MPS IIA and IIB (Hunter), MPS IIIA and IIIB (Sanfilippo), and retrochiasmal origin, although there appears to be an
MPS IV (Morquio), and MPS VI (Maroteaux-Lamy). In early predilection for the more posterior cerebral white mat-
many cases, atrophy is caused by hydrocephalus that pre- ter (639,640). Wray et al. (641) reported the visual system
sumably occurs from meningeal mucopolysaccharide depo- findings in a 10-year-old boy with adrenoleukodystrophy
sition, leading to delayed cerebrospinal fluid absorption and vision of light perception bilaterally with pale discs.
(359,615,619–621). Meningeal or scleral mucopolysaccha- These investigators found extensive demyelination through-
ride accumulation may also cause local compression of the out the visual sensory pathways. Within the optic nerve,
optic nerve, resulting in disc swelling, optic atrophy, or both. some cells, thought by Wray et al. (641) to be either oligode-
In other cases, however, optic atrophy occurs in association ndrocytes or macrophages, contained lipid-filled vacuoles,
with the deposition of mucopolysaccharides within glial presumably myelin breakdown products. Similar findings
cells of the optic nerve (622). Among the lipidoses, optic were reported by others (642–644). The basic defect is accu-
atrophy occurs in infantile and juvenile GM1-gangliosidoses mulation of very long chain fatty acids secondary to a defec-
(GM1-1 and GM1-2), the GM2-gangliosidoses (Tay-Sachs tive enzyme within the peroxisomes, subcellular organelles
disease, Sandhoff disease, and late infantile, juvenile, and that contain enzymes necessary for normal cellular function
adult GM2-gangliosidoses), and the infantile form of Nie- (645). The defective gene in adrenoleukodystrophy is lo-
mann-Pick disease. Although reported in the neuronal ceroid cated at the distal end of the long arm of the X chromosome.
lipofuscinoses, optic atrophy is most frequently a secondary Variants of adrenoleukodystrophy include adrenomyeloneu-
feature of the severe retinal degeneration. ropathy, a clinically similar disorder except for later onset
Other storage diseases in which optic atrophy figures and slower progression, and a syndrome similar to adreno-
prominently include the hereditary leukodystrophies, includ- myeloneuropathy seen in 15% of women heterozygous for
ing the infantile and juvenile forms of Krabbe’s disease, the gene. Kaplan et al. (646) studied the visual system in 59
the Austin variant of sulfatidosis (mucosulfatidosis), and the men with adrenomyeloneuropathy with VEPs, MR imaging,
infantile, juvenile, and adult forms of metachromatic leuko- and clinical examination. They found that 63% of patients
dystrophy. had involvement of the visual pathways from the optic
Metachromatic leukodystrophy (MLD) is an autosomal- nerves to the occipital cortex, presumably on the basis of
recessive, degenerative disorder of central and peripheral primary demyelination. Interestingly, only five of the pa-
myelin, secondary to arylsulfatase A deficiency. The genetic tients had visual complaints.
defect is localized to the long arm of chromosome 22. Optic Zellweger syndrome (cerebrohepatorenal syndrome) is
atrophy occurs in up to 50% of cases, especially in the juve- another peroxisomal disorder associated with optic atrophy
nile and adult forms (623–626). Pathology reveals diffuse (643,645,647,648). In this autosomal-recessive disease,
ganglion cell loss with accumulation of cerebroside sulfate there is dysfunction of multiple peroxisomal enzymes, with
in optic nerve glial cells, with storage of metachromatic com- severe manifestations at birth, including floppiness, dysmor-
plex lipids in the retinal ganglion cells and optic nerves but phic facial characteristics, cirrhosis, genital anomalies, skel-
not in the outer retinal layers (623,625,627–629). etal anomalies, pigmentary retinopathy, and optic atrophy.
Pathologic findings similar to those found in MLD are Another leukodystrophy, Pelizaeus-Merzbacher disease,
seen in the optic nerves of patients with Krabbe’s disease is an X-linked recessive syndrome, and perhaps in some
and optic atrophy (630–633). In the storage diseases that are cases autosomal recessive, that is likely genetically heteroge-
associated with optic atrophy, the atrophy appears to result neous (617,649–651). Symptoms are present either at birth
from abnormal myelin metabolism, with secondary accumu- or within the first year of life. They include nystagmus, head
lation of abnormal storage materials within the optic nerve tremor, ataxia, spasticity, graying of the optic discs or optic
(631). Enlarged optic nerves with numerous globoid cells atrophy, and ultimately seizures, microcephaly, athetoid
have been demonstrated on pathology and on neuroimaging movements, and failure to thrive. There is a frequent associa-
(634,635). Krabbe’s disease usually occurs in infancy, al- tion with pes cavus and scoliosis. The course is progressive
though a few cases with juvenile and even adult onset have for several years, followed by slowing and some degree of
been reported (636,637), some presenting with optic atrophy stability. Pathologic examination reveals severe patchy ab-
sence of myelin in the central but not the peripheral nervous with extensive demyelination from intramyelinic vacuola-
system, suggesting that this is a disorder of oligodendrocytes tion and large abnormal mitochondria. Deficiency of aspar-
rather than Schwann cells. The disease has been linked to a toacylase in skin fibroblasts is diagnostic of the disease. The
gene on the long arm of the X chromosome (Xq22) that abnormal gene is localized to the short arm of chromosome
codes for myelin proteolipid protein and proteins involved 17 (675–677).
in oligodendrocyte maturation (651–653). Pallor of the optic Another cause of macrocephaly, Alexander disease, is be-
discs occurs in some patients with Pelizaeus-Merzbacher lieved to be a disorder primarily of the astrocytes, although
disease, although it is usually not severe, and visual acuity marked cerebral demyelination with frontal predominance is
may not be significantly reduced. Rahn et al. (654) reported characteristic of both the infantile and juvenile forms (678).
severe reduction in ganglion cells, thinning of the retinal Despite the severe demyelination, optic atrophy is not char-
nerve fiber layer, and widespread demyelination with loss of acteristic of this disease, the optic radiations are classically
axon cylinders in the optic nerve of a patient with Pelizaeus- spared, and VEPs are usually normal (679). Nevertheless,
Merzbacher disease. patients with an adult-onset form of the disease have been
Infantile neuroaxonal dystrophy (INAD) is an autosomal- reported with optic disc pallor and homonymous hemianopia
recessive, progressive neurologic disease characterized by (680). The majority of childhood cases of Alexander disease
severe, progressive motor disturbance; arrested mental de- harbor mutations in the gene for glial fibrillary acidic protein
velopment; and blindness with optic atrophy, beginning (GFAP) (681).
within the first year of life. Seizures and myoclonus may be Cockayne syndrome is an autosomal-recessive multisys-
severe, and most patients succumb within the first decade tem disease with both developmental anomalies and progres-
of life (655). Histopathologically, patients with this disorder sive degenerative changes (682). It is characterized clinically
have eosinophilic spheroids in the central, peripheral, and by severe dwarfism, failure to thrive, facial dysmorphisms
autonomic nervous systems; cerebellar degeneration; and (including enophthalmos), skin changes, and neurologic de-
degeneration of various neuronal, myelin, and glial elements terioration, with mental retardation and spasticity. Vision is
(656–661). Optic atrophy is described in 40% of cases by usually impaired as a result of corneal opacities, cataracts,
age 3 years (660,661). Similar pathologic findings occur in retinal degeneration, and optic atrophy (683,684). The dis-
Hallervorden-Spatz disease (pantothenate kinase-associated ease is probably genetically heterogeneous and in some cases
neurodegeneration), an autosomal-recessive disorder that is is related to dysfunctional RNA and DNA repair mecha-
of later onset and is more insidiously progressive (662). The
nisms, with mutations in several developmental genes
clinical syndrome is dominated by motor findings, both ex-
(685–688). Cerebro-oculo-facio-skeletal syndrome (COFS)
trapyramidal and pyramidal. Patients with Hallervorden-
is a progressive disorder similar to Cockayne syndrome re-
Spatz disease will also have spheroids, but this pathology
sulting in optic atrophy, brain atrophy, calcification, cata-
preferentially occurs in the basal ganglia (663). The brown
racts, microcornea, joint contractures, and growth retarda-
discoloration of the globus pallidus, caused by iron-contain-
tion (688,689). COFS also results from mutations in several
ing pigment deposition, serves to distinguish this disease.
MR imaging reveals T2 hypointensities in the globus pal- of the same DNA-repair genes mutated in Cockayne syn-
lidus, the so-called eye of the tiger sign (664), and increased drome (688,690).
uptake of the iron isotope 59Fe in the basal ganglia occurs. The Smith-Lemli-Opitz syndrome (691) is an autosomal-
Visual loss, if present, may reflect retinal degeneration or recessive disorder characterized by microcephaly, ambigu-
primary optic atrophy (665–667), and the syndrome may ous male genitalia, anteverted nostrils, broad maxillary
even present initially with isolated optic atrophy (666). The ridges, syndactyly of the second and third toes, failure to
responsible gene has been designated PANK2 on chromo- thrive, and death occurring in early childhood. It is a disorder
some 20 (662), although the syndrome may be genetically of cholesterol biosynthesis caused by multiple different
heterogeneous. mutations in the DHCR7 gene on chromosome 11q13
Menkes syndrome (kinky hair disease) is an X-linked re- (692,693). Ophthalmologic manifestations include bleph-
cessive disorder with maldistribution of body copper (668) aroptosis, strabismus, cataracts, optic atrophy, and optic
and resultant cerebral copper deficiency. This degenerative nerve hypoplasia (694,695). Atchaneeyasakul et al. (695)
disorder of gray matter manifests in the neonatal period with reported the ocular histopathology in a case of the Smith-
progressive psychomotor retardation, spasticity, seizures, Lemli-Opitz syndrome. These investigators found, in addi-
and colorless, friable hair. Retinal abnormalities are not tion to congenital bilateral cataracts, extensive loss of periph-
uncommon (669,670), and optic atrophy can also occur eral retinal axons with bilateral optic atrophy.
(671,672). Allgrove or ‘‘4 A’’ syndrome is a rare autosomal recessive
Canavan’s disease (N-acetylaspartic aciduria) is an auto- condition with alacrima, achalasia, autonomic disturbance,
somal-recessive cerebral degeneration that occurs during the and ACTH insensitivity (696,697). The syndrome usually
first year of life and is characterized by megalencephaly, presents during the first decade of life with dysphagia or
poor head control, severe floppiness, spasticity, lack of psy- severe hypoglycemic or hypotensive attacks, related to adre-
chomotor development, and optic atrophy (617,673). Neu- nal insufficiency. There are often accompanying signs of
roimaging shows increased lucency of the white matter, poor multisystem neurologic disease, including pupil and cranial
demarcation of gray and white matter, and eventually severe nerve abnormalities, frequent optic atrophy, autonomic neu-
brain atrophy (674). Pathology is notable for ‘‘sponginess,’’ ropathy, upper and lower motor neuron signs, ataxia, and
intellectual impairment. The disorder is caused by mutations ously reported by Warburg et al. (713) and termed the
in the AAAS gene on chromosome 12q13 (696,697). ‘‘micro syndrome.’’
Congential disorders of glycosylation (CDG) are autoso- Optic atrophy may also be a manifestation of quantitative
mal-recessive multisystem disorders in which several differ- chromosomal abnormalities. Bitoun et al. (714) described a
ent underlying enzymatic deficiencies have been identified 12-year-old girl with microcephaly, mild mental retardation,
(698). A 17-month-old girl with CDG-x (unknown enzy- facial dysmorphism, and optic atrophy with 20/100 vision.
matic defect) had typical psychomotor retardation and trun- Karyotyping revealed variegated mosaicism indicative of
cal hypotonia, with additional dystonic hand movements and chromosomal instability. Two female siblings of a consan-
optic atrophy with nystagmus and strabismus (698). guineous Iranian family were found to have spastic paraple-
The combination of growth retardation, alopecia, pseudo- gia, optic atrophy with poor vision, microcephaly, and nor-
anodontia, and optic atrophy (GAPO syndrome) is likely mal cognitive development (715). Karyotype analysis
inherited in an autosomal-recessive fashion (699–701). It showed a normal female constitution in one and a male con-
may be the result of either ectodermal dysplasia or accumula- stitution (46,XY) in the other, leading the authors to con-
tion of extracellular connective tissue matrix (702). Despite clude that the syndrome probably represents a new autoso-
the acronym, optic atrophy is not a constant finding in GAPO mal recessive trait of pleiotropic effects, including XY sex
syndrome (701). The oculocerebrocutaneous syndrome reversal.
(Delleman syndrome) is a rare and sporadic disorder charac- Children with cerebral palsy have a higher prevalence of
terized by congenital abnormalities of the eye, skin, and ocular defects than normal children. Black (716) found optic
central nervous system, rarely with optic atrophy (703). atrophy in 10.3% of 117 children with cerebral palsy. The
Heide (704), and later Al Gazali et al. (705), reported etiology for the atrophy in these patients was not explained,
sibships with osteogenesis imperfecta, infantile blindness, nor were the clinical characteristics of the patients elabo-
optic atrophy, retinal abnormalities, severe developmental rated.
delay, growth retardation, paraplegia, abnormal electroen-
cephalograms, and generalized atrophy on brain CT. This MITOCHONDRIAL DISORDERS
syndrome has overlapping features with the osteopo-
rosis–pseudoglioma syndrome. Chitayat et al. (706) reported The prototype for a mitochondrial abnormality resulting
the association of skeletal dysplasia (dysosteosclerosis), in- in optic nerve dysfunction is, of course, LHON, with its
classically isolated optic nerve involvement and its causal
tracerebral calcifications, hearing impairment, mental retar-
relationship to mtDNA point mutations (see above). Addi-
dation, and optic atrophy. The optic atrophy appeared to be
tionally, Kjer’s DOA likely results from perturbations of
primary and not from compression of the optic nerves within
mitochondrial function secondary to abnormalities in a nu-
the optic canals. Ohtagaki et al. (707) described a 15-year-
clear gene whose product is destined for the mitochondria.
old boy with epilepsy, optic atrophy, intracranial calcifica-
Other multisystem hereditary disorders with prominent optic
tions, and metaphyseal dysplasia. nerve involvement, such as Wolfram’s syndrome, may also
Dumic et al. (708) reported two brothers with mental defi- prove to have a final common pathway in mitochondrial
ciency, short stature, microcephaly, alopecia, follicular ich- dysfunction. Indeed, this apparent selective vulnerability of
thyosis, multiple skeletal anomalies, and recurrent respira- the ganglion cell or its axon to both hereditary and acquired
tory infections, one of whom had optic atrophy. Al-Gazali mitochondrial abnormalities suggests a possible common
(709) described an inbred Arab family with two children pathophysiology for these disorders (90a,717). Given this
affected with mental retardation, iris coloboma, optic atro- relative selective involvement of the optic nerve in these
phy, nystagmus, and a distinctive narrow facial appearance, disorders, however, it is somewhat surprising that other mi-
consistent with a previously undescribed autosomal-reces- tochondrial disorders do not regularly manifest optic neurop-
sive syndrome. athies. Other presumed mitochondrial disorders of both nu-
Two male cousins with consanguineous parents were born clear and mitochondrial genomic origins may manifest optic
with short stature, microcephaly, hypertelorism, ptosis, ab- atrophy, but often only as a secondary clinical feature that
sent ear lobes, high-arched palates, abnormal EEG, severe is variably present (82,83,230).
mental retardation, and optic atrophy (710). This may repre- The subacute necrotizing encephalomyelopathy of Leigh
sent an as yet undefined syndrome. Megarbane et al. (711) (718) is a degenerative syndrome that may result from multi-
reported a large inbred Lebanese pedigree with autosomal- ple different biochemical defects that all impair cerebral oxi-
recessive congenital spastic ataxia, microcephaly, optic atro- dative metabolism (232,719–727). The disorder may be in-
phy, short stature, speech defect, abnormal skin vessels, ce- herited in an autosomal-recessive, X-linked, or maternal
rebellar atrophy, and severe mental retardation. None of the pattern, depending on the genetic defect. The onset of symp-
affected children had a metabolic abnormality or evidence toms is typically between the ages of 2 months and 6 years;
of a respiratory chain complex defect. The same group de- symptoms consist of progressive deterioration of brain stem
scribed four children of both sexes from a highly inbred functions, ataxia, seizures, peripheral neuropathy, intellec-
family with hypotonia, spastic diplegia, microcephaly, mi- tual deterioration, impaired hearing, and poor vision. Visual
crophthalmia, congenital cataract, optic atrophy, ptosis, ky- loss may be secondary to optic atrophy or retinal degenera-
phoscoliosis, short stature, severe mental retardation, and tion. In infants, the onset of the syndrome is insidious, with
cerebral malformations (712). A similar pedigree was previ- initial symptoms including failure to thrive, generalized
weakness, and hypotonia. Three patients with a familial, ragged red fibers [MERRF]); at position 3243 (a mutation
adult form of Leigh’s disease reported by Kalimo et al. (728) classically associated with MELAS); at position 14459 (a
presented with bilateral visual loss, dyschromatopsia, central mutation usually associated with LHON or LHON plus dys-
scotomas, and optic atrophy before developing other neuro- tonia); and with mtDNA deletions (typically a cause of
logic symptoms and signs. These patients were initially chronic progressive ophthalmoplegia [CPEO] and pigmen-
thought to represent examples of Leber’s optic neuropathy tary retinopathy).
(729). Other presumed mitochondrial disorders of nuclear and
Typical pathologic alterations in Leigh’s syndrome con- mitochondrial genomic origins may manifest optic atrophy
sist of spongy necrotizing degeneration of the neuropil, cap- as a variable manifestation of their phenotype (82,83,230).
illary and glial proliferation, and loss of myelin with relative Examples include cases of MERRF, MELAS, and chronic
sparing of neurons. The most commonly affected areas are progressive external ophthalmoplegia, both with and without
the tegmentum of the brain stem, the optic nerves, basal the full Kearns-Sayre phenotype (73,251,743–752).
ganglia, substantia nigra, tectum of the midbrain, cerebellar Taylor et al. (753) described a 42-year-old man with pro-
cortex, dentate nucleus, and inferior olives (728,730,731). gressive epilepsy, stroke-like episodes, cognitive decline,
A predisposition for the periaqueductal and periventricular and bilateral optic atrophy, in whom a muscle biopsy re-
regions of the midbrain, pons, and medulla mimics the find- vealed a defect in complex I activity and a novel heteroplas-
ings in Wernicke’s encephalopathy, but Wernicke’s affects mic mtDNA ND3 gene mutation at position 10191. A point
the lower brain stem less frequently, and Leigh’s syndrome mutation in the mtDNA cytochrome b gene at position 14849
tends to spare the hypothalamus and mammillary bodies. was presumed responsible for septo-optic dysplasia (with
MR imaging demonstrates the distinctive pathologic locali- small, pale optic discs), retinitis pigmentosa, exercise intol-
zation, and MR proton spectroscopy may reveal pathologic erance, hypertrophic cardiomyopathy, and rhabdomyolysis
lactate production (732). in one male patient (754). Two brothers experienced pro-
In reviews of the pathologic ocular findings in patients found irreversible visual loss over 2 months, associated with
with Leigh’s syndrome, many of the cases have optic nerves a metabolic disorder characterized by transient episodes of
with extensive atrophy with varying degrees of demyelin- ataxia and paresis with slight elevation of blood and cerebro-
ation (504,733–736). Ultrastructural changes include dis- spinal fluid lactate; a defect in complex I activity was dem-
tended mitochondria in all ocular tissues, particularly in the onstrated (755). Taylor et al. (756) reported two sisters who
retinal pigment epithelium, nonpigmented ciliary epithe- presented with a late-onset neurodegenerative disease char-
lium, and corneal endothelium (735). acterized by optic atrophy, encephalopathy, and ataxia. The
Enzyme defects associated with Leigh’s syndrome in- optic neuropathy was notable for relatively well-preserved
clude abnormalities of cytochrome c oxidase, the pyruvate visual acuity (20/20–20/60), significant peripheral visual
dehydrogenase complex, biotinidase, and the NADH dehy- field constriction, and optic atrophy with cupping. Mito-
drogenase complex (723,727). The syndrome of Leigh is chondrial analysis revealed a partial deficiency of complex
likely a nonspecific phenotypic response to certain abnor- II, a complex entirely encoded by the nuclear genome. The
malities of mitochondrial energy production. Most genetic other, more constant, phenotypic characteristics of all of
defects that result in Leigh’s syndrome probably occur in these mitochondrial disorders distinguish them from dis-
nuclear genes encoding proteins essential to mitochondrial eases such as Leber’s optic neuropathy, in which visual loss
oxidative phosphorylation, especially those genes involved from optic nerve dysfunction is the primary, and most often
in cytochrome c oxidase assembly (727). Approximately one only, manifestation of the disorder.
third of Leigh’s syndrome cases have been associated with
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CHAPTER 12
Topical Diagnosis of Chiasmal and
Retrochiasmal Disorders
Leonard A. Levin
TOPICAL DIAGNOSIS OF OPTIC CHIASMAL LESIONS TOPICAL DIAGNOSIS OF RETROCHIASMAL VISUAL FIELD
Visual Field Defects DEFECTS
Etiologies of the Optic Chiasmal Syndrome Topical Diagnosis of Optic Tract Lesions
Masqueraders of the Optic Chiasmal Syndrome Topical Diagnosis of Lesions of the Lateral Geniculate Body
Pathophysiology of the Optic Chiasmal Syndrome Topical Diagnosis of Lesions of the Optic Radiation
Neuro-Ophthalmologic Symptoms Associated with Optic Lesions of the Occipital Lobe and Visual Cortex
Chiasmal Syndromes Treatment and Rehabilitation for Homonymous Hemianopia
Neuro-Ophthalmologic Signs Associated with Optic Chiasmal
Syndromes
‘‘Chiasmal Syndrome’’ of Cushing
TOPICAL DIAGNOSIS OF OPTIC CHIASMAL LESIONS

The optic chiasm is one of the most important structures in also called heteronymous field defects, a term that distin-
neuro-ophthalmologic diagnosis. The arrangement of visual guishes them from homonymous field defects.
fibers in the chiasm accounts for the characteristic visual Visual field defects caused by lesions of the optic chiasm
field defects caused by such diverse lesions as tumor, inflam- are often classified according to the general site of the dam-
mation, demyelination, ischemia, and infiltration. In addi- age. In many cases this is an oversimplification, since many
tion, damage to neurologic and vascular structures adjacent lesions that arise in the region of the chiasm affect not only
to the chiasm produces typical additional symptoms. Thus, the entire chiasm but the intracranial optic nerves as well.
accurate diagnosis depends on having knowledge of both Nevertheless, it is reasonable to use this approach because
the neuro-ophthalmologic and non–neuro-ophthalmologic it helps determine the precise management of the lesion and
manifestations of chiasmal lesions. Two early papers are of predict the visual outcome following treatment. This chapter
fundamental importance: Adler et al. (1) described early classifies visual field defects produced by lesions that dam-
field changes in chiasmal lesions, and Gartner (2) outlined age the optic chiasm as a result of damage at one of three
ocular pathology in the chiasmal syndrome. A paper of his- locations: (a) the anterior angle of the chiasm, (b) the body
torical interest describes a case of chiasmal compression of the chiasm, or (c) the posterior angle of the chiasm. A
from the 16th century (3). small number of lesions may damage nerve fibers at the
lateral aspects of the chiasm.
VISUAL FIELD DEFECTS Lesions that Damage the Distal Portion of One Optic
Nerve at the Anterior Angle of the Optic Chiasm
Although there are many variations in the visual field de-
fects caused by damage to the optic chiasm, the essential Traquair (4) pointed out that it is at the anterior angle of
feature is some type of bitemporal defect, the hallmark of the optic chiasm that the ‘‘junction’’ scotoma occurs because
damage to fibers that cross within the chiasm. The bitem- of the separation of nasal crossed and temporal uncrossed
poral defects may be superior, inferior, or complete, as well fibers. When a small lesion damages only the crossing fibers
as peripheral, central, or both. Bitemporal field defects are of the ipsilateral eye, the field defect is monocular and tem-
503
poral and has a midline hemianopic character that extends into the affected ipsilateral optic nerve to form the structure
to the periphery of the field. When only the macular crossed called Wilbrand’s knee (6,7) (see Chapters 1 and 4). Horton
fibers from one eye are damaged, the resultant field defect (8) suggested that this eponymous structure is more likely
is still monocular and temporal but is scotomatous and lo- an artifact that develops during atrophy of the ipsilateral
cated in the paracentral region. If there is extensive damage optic nerve. Against this are findings of superior temporal
to the visual fibers in an optic nerve, an extensive field defect visual field defects in patients with acute avulsion injuries
or total blindness develops in the ipsilateral eye. In such of the anterior chiasm (9,10). Whatever the mechanism, the
cases, but also in less severe cases, the crossed ventral fibers importance of identifying the usually asymptomatic field de-
that originate from ganglion cells inferior and nasal to the fect cannot be sufficiently stressed, because it is at this point
fovea of the contralateral eye may also be damaged, produc- that the examiner can make an absolute diagnosis of an ante-
ing a defect in the superior temporal field of the contralateral rior optic chiasmal (distal optic nerve) syndrome, at a stage
eye (Fig. 12.1). at which treatment of the underlying lesion is most likely to
This contralateral field defect, which occurs in an eye result in improvement in visual function.
without other evidence of visual dysfunction, may be over-
looked when kinetic perimetry is performed unless the supe- Lesions that Damage the Body of the Optic Chiasm
rior temporal region of the ‘‘normal’’ eye is carefully tested
by the examiner, but it is almost always detected when auto- Lesions that damage the body of the optic chiasm charac-
mated static perimetry is used (Fig. 12.1). Bird (5) detailed teristically produce a bitemporal defect that may be quad-
the findings in eight patients with the anterior chiasmal syn- rantic or hemianopic and that may be peripheral, central, or
drome. In each case, a central scotoma was present in the a combination of both, with or without so-called splitting of
visual field of the eye on the side of the lesion, and there the macula (Fig. 12.2). In most cases, visual acuity is normal.
was temporal field loss in the contralateral eye. In five cases, In some patients, however, visual acuity is diminished, even
the contralateral field loss was in the superior temporal field though no field defect other than a bitemporal hemianopia
only, and in two of these five cases, the peripheral field was is present (11). When the lesion compresses the chiasm from
normal by kinetic perimetry, with the defect being scotoma- below, such as occurs with a pituitary adenoma, the field
tous and detectable only in the paracentral upper temporal defects follow a stereotyped pattern (12). When the periph-
field with small test objects. In the remaining three patients, eral fibers are principally affected, the field defects usually
the contralateral field loss was in the paracentral temporal begin in the outer upper quadrants of both eyes (Fig. 12.3).
region, without preferential loss above or below the horizon- In the field of the right eye, the defect usually progresses in a
tal meridian. clockwise direction and in the left eye in a counterclockwise
The mechanism by which the fibers from the contralateral direction (13).
eye are damaged was ascribed to their anterior extension The field defects may be unequal in the two eyes: one
Figure 12.1. Syndrome of the distal optic nerve (anterior chiasmal syndrome). The patient was a 24-year-old woman with
decreased vision in the right eye. Visual acuity was 20/25 OD and 20/20 OS. A, There was a small superior temporal defect
in the visual field of the left eye on static perimetry, using a Humphrey 24-2 Threshold Test. This defect was not detected
with kinetic perimetry. B, There was a dense temporal hemianopic defect in the visual field of the symptomatic right eye. The
patient had a pituitary adenoma.
TOPICAL DIAGNOSIS OF CHIASMAL AND RETROCHIASMAL DISORDERS 505
Figure 12.2. Optic chiasmal syndrome. A, Kinetic pe-

rimetry in a patient with a large pituitary adenoma reveals
a complete bitemporal hemianopia. B, Static perimetry,
using a Humphrey 24-2 Threshold Test, in another patient
with a pituitary adenoma, reveals an incomplete bitemporal
hemianopia.
Figure 12.3. Bilateral superior temporal defects in pa-

tients with a pituitary adenoma. A, Kinetic perimetry in
one patient demonstrates defects that are restricted to the
superior temporal quadrants of the visual fields of both
eyes (a bitemporal superior quadrantanopia). B, Static pe-
rimetry, using a Humphrey 24-2 Threshold Test, in another
patient with a pituitary adenoma demonstrates bitemporal
hemianopic defects that are much denser superiorly.
eye may become almost or completely blind, whereas the culum sellae and medial sphenoid ridge meningiomas, cra-
defect in the field of the other eye remains mild. In the charting niopharyngiomas, and aneurysms, can also produce such
of visual field defects resulting from pituitary adenomas and defects. The field defects caused by such lesions are indistin-
other compressive lesions, scotomas in the peripheral parts guishable from those caused by pituitary adenomas.
of the visual fields are usually dense and are not likely to be Various suprasellar and suprachiasmal compressive le-
overlooked, although small relative paracentral scotomas are sions, such as tuberculum sellae meningiomas (15), cranio-
frequently missed when kinetic perimetry alone is per- pharyngiomas (16,17), aneurysms (18–21), and dolichoec-
formed. Automated perimetry can help in detecting some of tatic anterior cerebral arteries, may damage the superior
the earliest signs of chiasmal compression, such as a subtle fibers of the optic chiasm, as may infiltrating lesions, such
depression respecting the vertical meridian, detected by as germinomas (22–24), benign and malignant gliomas (25),
comparing pairs of thresholds across the meridian (14). and cavernous angiomas (26). The defects in the visual fields
Pituitary adenomas are not, of course, the only lesions in such cases are still bitemporal but are located in the infe-
that can produce bitemporal field defects that are denser rior rather than the superior fields of both eyes (Fig. 12.4).
below. Suprasellar but infrachiasmal lesions, such as tuber- In addition, papilledema, which is quite unusual in patients
Figure 12.4. Bilateral inferior temporal field defects in a 32-year-old man with a suprasellar mass. Kinetic perimetry reveals
inferior temporal quadrantic defects in the visual fields of the left (A) and right (B) eyes. The defects are scotomatous. Static
perimetry, using a Humphrey 24-2 Threshold Test, in the same patient confirms the inferior temporal quadrantic nature of the
defects. C, Visual field of left eye. D, Visual field of right eye. The patient underwent a craniotomy and was found to have
a suprasellar suprachiasmatic germinoma.
with suprasellar, infrachiasmal lesions, is somewhat more may produce bitemporal field defects (Fig. 12.5), but such
common in suprachiasmal lesions because such lesions can lesions may also produce other types of field defects, such
extend into and occlude the third ventricle. Infiltrating tu- as arcuate defects and nonspecific reduction in sensitivity,
mors, such as gliomas and germinomas, as well as inflamma- that do not necessarily correlate with the location, size, or
tory and demyelinating lesions that affect the optic chiasm, extent of the lesion.
Figure 12.5. Optic chiasmal syndrome in multiple sclerosis. The patient was a 50-year-old woman with a previous history
of transient lower extremity weakness who developed progressive loss of vision in both eyes. The patient reported that her
vision would worsen considerably whenever she took a steam bath. Visual acuity was counting fingers at 3 feet OD and 20/
100 OS. Color vision was diminished in both eyes, and there was a right relative afferent pupillary defect. A, Kinetic perimetry
at presentation shows a complete temporal hemianopia in the field of vision of the left eye and only a small nasal island in
the field of vision of the right eye. B, Unenhanced T1-weighted coronal magnetic resonace image shows an apparently normal
optic chiasm. C and D, T1-weighted coronal magnetic resonance images after intravenous injection of contrast show enhancement
of the intracranial portions of the optic nerves (C) and the optic chiasm (D). (Figure continues.)
Figure 12.5. Continued. E–G, Kinetic perimetry after

treatment with intravenous corticosteroids shows progres-
sive improvement in visual fields over the subsequent 10
weeks. (Courtesy of Dr. John B. Kerrison.)
Although most compressive and infiltrative or inflamma- compression of the chiasm in such cases not infrequently
tory lesions that damage the body of the chiasm produce results in improvement in the visual field, an outcome that
defects that are incomplete and that usually have a relative might not have been expected from the severity of the visual
component, it is not uncommon for a tumor to produce a field defect, and which can occur within days of surgery
complete bitemporal hemianopia (Fig. 12.6). Successful de- (27).
Figure 12.6. Complete bitemporal hemianopia in a 53-year-old woman from Bermuda who developed severe headache,
nausea, and vomiting. She then noted difficulty reading. A, The visual field of the left eye shows a complete temporal hemianopia.
B, The visual field of the right eye shows a complete temporal hemianopia. Magnetic resonance imaging revealed a large
pituitary adenoma.
Lesions that Damage the Posterior Angle of the Traquair (4) wrote that a lesion that affects the posterior
Optic Chiasm portion of the optic chiasm may be sufficiently focal that it
damages only the crossed nasal fibers from the opposite ret-
Lesions that damage the posterior aspect of the optic chi- ina, producing a monocular temporal field defect, or only
asm produce characteristic defects in the visual fields, typi- the uncrossed temporal fibers from the ipsilateral eye, pro-
cally bitemporal hemianopic scotomas (28) (Fig. 12.7). Such ducing a monocular nasal field defect. In fact, this is uncom-
defects may be mistaken for cecocentral scotomas and attrib- mon, and most organic monocular nasal or temporal hemia-
uted to a toxic, metabolic, or even hereditary process rather nopic field defects are caused by lesions affecting the optic
than to a tumor; however, true bitemporal hemianopic scoto- nerve rather than the optic chiasm.
mas are almost always associated with normal visual acuity Lesions located toward the posterior aspect of the optic
and color perception, whereas cecocentral scotomas are in- chiasm may damage one of the optic tracts, producing a
variably associated with reduced visual acuity and dyschro- homonymous field defect that is combined with whatever
matopsia. field defect has occurred from damage to the optic chiasm.
Figure 12.7. Bitemporal hemianopic scotomas in a patient with a pituitary adenoma. Such field defects result from damage
to macular fibers in the posterior portion of the optic chiasm.
Bitemporal homonymous scotomas are particularly im- poral field defects. The most common causes of an optic
portant in localizing a lesion, or at least the effects of such chiasmal syndrome are pituitary adenomas, suprasellar me-
a lesion, to the posterior aspect of the optic chiasm. Lesions ningiomas, craniopharyngiomas, gliomas, and aneurysms
that produce such defects may be more difficult to treat suc- originating from the internal carotid artery (34–38). Chias-
cessfully and are more likely to cause permanent residual mitis (39), particularly related to multiple sclerosis, sarcoi-
field defects after surgical therapy or radiotherapy.
Lesions that Damage the Lateral Aspects of the

Table 12.1
Optic Chiasm
Unusual Causes of Optic Chiasmal Syndromes
The lateral aspect of the optic chiasm occasionally is dam-
Cause References
aged by various tumors and, according to some authors, by
pressure from the supraclinoid portion of sclerotic internal Aneurysm of basilar artery 21
carotid arteries. When such damage occurs, both the un- Arachnoid cyst 43,44
crossed temporal fibers from the ipsilateral eye and crossed Arteriovenous malformations (AVMs) 45–47
nasal fibers from the contralateral eye are affected, produc- Brucellosis 48
ing a contralateral homonymous hemianopic defect that can- Cavernous angioma 26,47,49–55
not be differentiated from that produced by damage to the Chondroma 56
Choristoma 57
ipsilateral optic tract (29,30). Although a binasal hemianopia
Choroid plexus papilloma 58
may rarely originate from pressure or other influences affect- Cysticercosis 59–62
ing the lateral aspects of the optic nerves, it probably never Demyelinating disease 63–69
originates from damage to the lateral aspects of the optic Dolichoectatic sclerotic intracranial internal 70,71
chiasm. carotid arteries
Ectopic cerebellum 72
Visual Field Defects Caused by Lesions that Damage Ependymoma 73
the Optic Chiasm After Initially Damaging the Optic Ethchlorvynol (Placidyl) abuse 66
Nerve or Optic Tract Fibrous dysplasia 43
Ganglioglioma 74–77
If there is extension of a lesion from the optic nerve or Germinoma 24,78–80
optic tract to the optic chiasm, the blind eye is usually on Glioblastoma multiforme 81
the side of the lesion. For example, if a patient with a blind Granular cell tumor of neurohypophysis 82,83
right eye exhibits a defect in the temporal field of the left Inflammation (presumed) from Epstein-Barr 84
viral infection
eye, the lesion obviously is on the right. Similarly, if there
Ischemia from small vessel occlusive disease 85–87
has been a left homonymous hemianopia from a right optic Langerhans cell histiocytosis 43,88–90
tract lesion and if there is extension of the lesion to affect Lymphoma 91,92
the optic chiasm, blindness (or an extensive field defect) Malignant melanoma 93
develops in the right eye. Conversely, if a lesion of the optic Medulloblastoma 94
chiasm that has produced a bitemporal hemianopia extends Metastatic carcinoma 95–97
to the right optic nerve, it will eventually produce loss of Multiple myeloma 98
vision of the right eye. Similarly, if a chiasmal lesion extends Nasopharyngeal carcinoma 43
into the right optic tract, there is again loss of vision of the Optochiasmatic arachnoiditis 99–101
right eye. In other words, if there is extension from an optic Pachymeningitis associated with rheumatoid arthritis 102
Paraganglioma 103
nerve or optic tract to the optic chiasm, the blind eye is on
Pituitary abscess 104
the side of the lesion, whereas when there is extension of a Plasmacytoma 98
lesion from the optic chiasm to the optic nerve or to the Pneumatocele 105
optic tract, the blind eye is on the side of extension of the Rathke’s cleft cyst 106–111
lesion. In such cases, it may be impossible to determine Sarcoid granuloma 112,113
the nature and extent of the pathologic process from an exami- Sarcoid occurring in a pituitary adenoma 114
nation of visual sensory function, and particularly visual Septum pellucidum cyst 115
fields, alone. Rather, it is the history of visual loss and its pro- Sinus histiocytosis with lymphadenopathy 116
gression that provides an explanation of the visual findings. Sphenoid sinus mucocele 117
Syphilitic gumma 43
Toxoplasmosis 67
ETIOLOGIES OF THE OPTIC CHIASMAL
Tuberculoma 101,118,119
SYNDROME Varicella-zoster virus 120
Damage to the optic chiasm can occur from the direct or Varix 121
indirect effects of a variety of lesions. Bitemporal field de- Vasculitis 67,69
Venous angioma 122,123
fects are usually caused by damage to the optic chiasm from
Vitamin B12 deficiency 69
a cerebral mass lesion (31,32). In Rosen’s (33) series, for Whipple’s disease 124
example, tumors accounted for 80% of the cases of bitem-
dosis (40), or systemic lupus erythematosus (41,42), is not trauma to the optic chiasm (140–148) (Fig. 12.8). This can
uncommon. Other unusual causes of an optic chiasmal syn- occur as a result of indirect injury (149), similar to that seen
drome are listed in Table 12.1. in indirect traumatic optic neuropathy (see Chapter 9), avul-
During pregnancy, preexisting intrasellar and suprasellar sion from globe traction (9,10), direct injury from a foreign
tumors, most commonly pituitary adenomas, may become body (e.g., chopsticks [150]), or sellar fracture (145). The
symptomatic (125,126). In most cases, visual symptoms re- most likely pathologic mechanisms in traumatic optic chias-
gress after delivery or abortion. In addition, the pituitary mal syndrome are contusion necrosis (151) or avulsion (9).
gland itself enlarges during the third trimester of pregnancy The syndrome of traumatic optic neuropathy is discussed in
and may become sufficiently enlarged so that it compresses more detail in Chapter 9.
the chiasm, producing visual manifestations (127). In such Clinical cases are occasionally observed in which bitem-
cases, visual symptoms resolve spontaneously following de- poral field defects occur not from a tumor compressing the
livery. Another cause of an optic chiasmal syndrome that chiasm but from a posterior fossa lesion that has caused
occurs most often during or shortly after pregnancy is increased intracranial pressure and consequent compression
lymphocytic adenohypophysitis, an autoimmune disorder of of the chiasm by an enlarged third ventricle. Most of these
unknown etiology (128–131), which can rarely cause pitui- cases are also associated with papilledema. Wilbrand and
tary apoplexy (132). Saenger (152) first observed a case of cerebellar tumor with
Extension of the subarachnoid space into the sella turcica associated hydrocephalus in which there was primary optic
through a deficient diaphragma sellae results in the empty atrophy and bitemporal hemianopic scotomas. Cushing
sella syndrome (133). A primary empty sella syndrome oc- (153) and Sinclair and Dott (154) subsequently reported sim-
curs spontaneously and may be associated with an arachnoid ilar cases. Wagener and Cusick (155) initially suggested that
cyst. It is rarely associated with significant visual acuity loss dilation of the optic recess in the anterior extremity of the
or visual field defects (134); however, a secondary empty third ventricle may press directly upon the optic chiasm,
sella syndrome follows surgery or radiation therapy in the producing a typical bitemporal defect. Hughes (156) noted
sellar region. Patients in whom this syndrome develops may that if the chiasm is in normal position, situated over the
develop a true chiasmal syndrome, characterized by bitem- diaphragma sellae and projecting backward over the dorsum
poral field loss with and without a reduction in visual acuity sellae, or is postfixed, overlying and behind the dorsum sel-
and an acquired dyschromatopsia (135,136). lae, the third ventricle may tend to enlarge against its poste-
Occasionally the chiasm fails to develop, a syndrome rior aspect and spread over its superior surface. As a result,
called achiasmia or the non-decussating retinal-fugal fiber a bilateral depression of the inferior temporal central field
syndrome (137,138). In this syndrome the nasal retinal fibers occurs. On the other hand, if the chiasm is prefixed, overly-
do not decussate, resulting in routing of the fibers corre- ing the diaphragma sellae or resting in the sulcus chiasmatis,
sponding to the temporal visual field to the ipsilateral visual the ventricle will tend to exert its pressure effects against
cortex (139). However, the visual fields are full (137), pre- the posterior inferior aspect of the chiasm and may even
sumably as a result of cortical reorganization (139). These appear from beneath the chiasm between both optic nerves,
patients may have congenital nystagmus with or without see- pushing the nerves laterally. In such cases, bilateral central
saw nystagmus (138). scotomas, bilateral nasal and arcuate defects, or even bilat-
A complete bitemporal hemianopia can be produced by eral superior hemianopic scotomas could develop.
Figure 12.8. Complete bitemporal hemianopia in a 24-year-old man who was severely injured in a motor vehicle accident.
Neuroimaging revealed no evidence of an intracranial mass lesion. Visual acuity was 20/20 OU. A, The visual field of the left
eye shows a complete temporal hemianopia. B, The visual field of the right eye shows a complete temporal hemianopia except
for about 15⬚ of macular sparing. The field defects did not improve over a 5-year follow-up period.
Optic chiasmal syndromes can be iatrogenic. Most often, common for the pituitary gland to be physiologically convex
this occurs after attempted removal of a lesion compressing (172), it behooves the clinician to search for other causes
or infiltrating the chiasm. Chiasmal damage most often oc- of bitemporal defects when the chiasm is radiographically
curs during surgery to remove a suprasellar meningioma or normal and the visual field defects are atypical.
craniopharyngioma and least often after surgery to remove
a pituitary adenoma or to clip an intracranial aneurysm. A PATHOPHYSIOLOGY OF THE OPTIC CHIASMAL
catheter placed in the lateral ventricle for hydrocephalus can SYNDROME
migrate into the third ventricle and cause a bitemporal field
The mechanism by which the chiasm is compressed from
defect (157,158). A chiasmal syndrome can also occur from
below was studied by Hedges (173), who used normal, adult,
exuberant packing of the sphenoid sinus with fat following
fresh necropsy material. He removed the pituitary gland and
transsphenoidal resection of a pituitary adenoma (159,160).
inserted the balloon tip of a Foley catheter into the sella
In such cases, the fat is forced superiorly and compresses
turcica and then expanded it. As the balloon expanded and
the inferior aspects of the optic nerves and optic chiasm.
the optic chiasm was elevated, the crossing fibers were first
There is often immediate improvement after emergency re-
affected, initially the lower nasal and later the upper nasal.
moval of the fat. Similarly, a pneumatocele can result arising
The uncrossed upper temporal fibers were put ‘‘on stretch,’’
from the adjacent sphenoid sinus after surgery, for example
whereas the lower temporal fibers, subserving the upper
if the patient sneezes (105,161). As mentioned above, the
nasal visual field, were relatively unaffected. Hedges con-
chiasm can prolapse into an empty sella (162), presumably
cluded that the results of this experiment explained the rela-
as a consequence of traction from postoperative scar tissue.
tive sparing of the upper nasal visual field in even advanced
Another cause of iatrogenic chiasm dysfunction is from
optic chiasmal syndromes. However, Harrington (174) disa-
radiation (163–166). This phenomenon appears to be related
greed with this theory and believed that the explanation for
to a high dosage given over a short period of time. Radiation
relative sparing of the superior nasal visual field in patients
necrosis of the optic nerves and chiasm may begin months
with severe damage to the optic chiasm was related in some
to several years after radiation. This syndrome is discussed
way to the blood supply of the chiasm, although he gave no
in the section on radiation optic neuropathy (see Chapter
definitive evidence to support this contention.
7). Finally, use of dopamine agonists for the treatment of
Support for an ischemic mechanism was provided by
prolactin-secreting pituitary adenomas can result in prolapse
Schneider et al. (175), who reported two patients with visual
of the chiasm into the pituitary fossa (167–169). This syn-
acuity and field loss thought to be secondary to infarction
drome is best treated by reducing the dosage of the dopamine
of the chiasmal and prechiasmal regions, associated with a
agonist.
chiasmal glioma in one case and a pituitary adenoma in the
The noted neuro-ophthalmologist Simmons Lessell once
second case. Although many authors support the concept
remarked, ‘‘Someday, someone will report a meatball’’
that ischemia is the primary explanation for the visual acuity
compressing the optic chiasm, a prediction that reflects the
and visual field loss that accompanies mass lesions that com-
enormous variety of lesions that can produce a chiasmal
press the optic nerves and chiasm, the role of axonal trans-
syndrome, including one that could result from eating an
port and its disruption from compression has yet to be exam-
undercooked meatball (59). More important than the specific
ined in detail. Clearly if there is resolution of visual loss
pathology of the lesion is the ability of the examiner to make
after relief of compression (27,176), permanent axonal loss
the correct clinical diagnosis of an optic chiasmal syndrome
cannot have occurred, absent axonal regeneration. Instead,
at the earliest opportunity, so that confirmation by neuroim-
conduction block, demyelination, and loss of axonal trans-
aging can be performed in a timely fashion and effective
port are more probable causes of decreased vision as a result
management initiated before permanent visual loss occurs.
of chiasmal or optic nerve compression. Finally, patients
receiving radiation to the region of the optic chiasm may
MASQUERADERS OF THE OPTIC CHIASMAL develop progressive acuity and field loss caused by radiation
SYNDROME necrosis. The mechanism of radiation chiasmal damage
probably reflects damage to endothelial cells, similar to the
Manchester and Calhoun (170) reported bitemporal visual
situation in radiation optic neuropathy (177).
field defects in five patients with dominant hereditary optic
atrophy. These and similar patients more likely had cecocen- NEURO-OPHTHALMOLOGIC SYMPTOMS
tral scotomas, diagnosed by the crossing of the vertical mid- ASSOCIATED WITH OPTIC CHIASMAL
line and association with more severely reduced visual acuity SYNDROMES
than would be expected from the field defect alone. Simi-
larly, cecocentral scotomas from toxic, metabolic, or other The most common complaints of patients with lesions
hereditary optic neuropathies can be confused with bitem- that damage the optic chiasm are progressive loss of central
poral hemianopias (171). Patients with nasal fundus ectasia acuity and dimming of the visual field, particularly in its
may also have temporal field defects, which can be confused temporal portion. In addition, bitemporal field defects,
with the optic chiasmal syndrome. These pseudotemporal whether complete or scotomatous, may produce two other
field defects can be distinguished by their failure to respect types of visual symptoms (178,179). One type consists of a
the vertical meridian and their diminution when minus re- disturbance of depth perception, and patients with this symp-
fractive lenses are used in the perimeter. Since it is not un- tom complain of difficulties with such tasks as threading
logic linkage between the two remaining hemifields. In such

patients, a preexisting minor phoria becomes a tropia, and
the consequent vertical or horizontal separation or overlap
of the two heteronymous hemifields causes intermittent sen-
sory difficulties (Fig. 12.10). A similar result may be seen
in patients with heteronymous altitudinal field defects (185)
(see Chapter 4).
Patients with lesions that damage the optic chiasm as well
as one or more of the ocular motor nerves in the subarach-
noid space or within the cavernous sinus on one or both
sides may experience diplopia. The diplopia may be painless
or painful depending on whether the trigeminal nerve is also
affected. In some cases, individual oculomotor, trochlear, or
abducens nerve pareses occur in association with a visual
field defect that indicates optic chiasmal dysfunction. In
other cases, multiple unilateral or bilateral ocular motor
nerve pareses occur. Strabismus associated with evidence of
single or multiple ocular motor nerve pareses in a patient
with a bitemporal field defect suggests a process extrinsic
to the chiasm rather than an infiltrative intrinsic lesion, un-
less there has been pituitary apoplexy that caused rapid chi-
asmal expansion.
Occasionally, patients with mass lesions compressing the
chiasm complain of photophobia (186,187). This occurs via
an unknown mechanism, distinct from thalamic dazzle
Figure 12.9. The blind triangular area of the binocular visual field that
occurs just beyond fixation in patients with a complete bitemporal hemia-
nopia. Such patients have intact binocular vision in the triangular area up
to fixation and intact monocular vision temporal and anterior to the triangu-
lar blind region. (Redrawn from Kirkham TH. The ocular symptomatology
of pituitary tumors. Proc R Soc Med 1972;65⬊517–518.)
needles, sewing, and using precision tools. In such patients,

convergence results in crossing of the two blind temporal
hemifields. This produces a completely blind triangular area
of field with its apex at fixation (Fig. 12.9). The image of
an object posterior to fixation falls on blind nasal retinas and
thus disappears. Testing for stereopsis can also be helpful
in the clinical testing of patients with suspected chiasmal
disorders (180).
Patients with bitemporal field defects may also experience
diplopia or difficulty reading caused by a horizontal or verti-
cal deviation of images unassociated with an ocular motor
nerve paresis (179,181–184). Kirkham (179) called this phe-
nomenon the ‘‘hemifield slide phenomenon.’’ Such patients
have difficulty reading because of doubling or loss of printed
letters or words. The problems encountered by these patients Figure 12.10. The hemifield slide phenomenon experienced by patients
result from loss of the normal partial overlap of the temporal with bitemporal hemianopias. Patients with a preexisting exophoria or inter-
mittent exotropia will have overlapping of the intact nasal fields, whereas
field of one eye and the nasal visual field of the contralateral
patients with a preexisting esophoria or intermittent esotropia will have
eye. This overlap normally permits fusion of images and separation of the nasal hemifields, causing a blind area in the center of the
helps to stabilize ocular alignment in patients with vertical field. Patients with preexisting hyperdeviations will complain of vertical
or horizontal phorias. Because their remaining nasal visual separation of images crossing the vertical meridian. (Redrawn from Kirk-
fields represent only the temporal projection from each eye, ham TH. The ocular symptomatology of pituitary tumors. Proc R Soc Med
patients with bitemporal hemianopia do not have a physio- 1972;65⬊517–518.)
(188,189). Patients may also have decreased contrast sensi- in fibers from peripheral and macular retinal ganglion cells
tivity in the temporal hemifield, testing of which may be located nasal to the fovea. Axons from peripheral retinal
used for early detection of chiasmal compression (190). ganglion cells located nasal to both the disc and fovea course
directly to the nasal aspect of the disc. Fibers from retinal
NEURO-OPHTHALMOLOGIC SIGNS ASSOCIATED ganglion cells located between the disc and fovea make up
WITH OPTIC CHIASMAL SYNDROMES a small portion of the superior and inferior arcuate bundles,
along with a larger number of fibers from peripheral tem-
Patients with chiasmal syndromes may or may not have poral retinal ganglion cells. Finally, fibers from nasal macu-
ophthalmoscopically apparent nerve fiber layer or optic atro- lar retinal ganglion cells course directly to the temporal disc.
phy when first examined. However, when atrophy is present Thus, when there is atrophy of nasal fibers, the normal stria-
in patients with bitemporal hemianopia, its pattern is quite tions of the nerve fiber layer are lost both nasal to the disc
specific, appearing as a band across the disc (i.e., ‘‘band and in the papillomacular region. In addition, nerve fiber
atrophy’’). The reason for this is that degeneration occurs bundle slits or defects can be observed in the superior and
Figure 12.11. Optic chiasmal syndrome. A and B, Both right and left optic discs show ‘‘band’’ atrophy with corresponding
loss of nerve fibers from ganglion cells located nasal to the fovea. C, Diagram of nerve fiber loss in patients with temporal
hemianopia. Regions marked A, B, and C denote areas of nerve fiber layer preservation, partial loss, and complete loss,
respectively. D, Transverse section of orbital optic nerve in a patient with a temporal hemianopia shows ‘‘band’’ or ‘‘bowtie’’
pattern of atrophy with relative sparing of the superior and inferior portions of the nerve. (C, From Hoyt WF, Kommerell G.
Der Fundus oculi bei Homonyer Hemianopia. Klin Monatsbl Augenheilkd 1973;162⬊456–464. D, From Unsöld R, Hoyt WF.
Band atrophy of the optic nerve. Arch Ophthalmol 1980;98⬊1637–1638.)
inferior arcuate bundles. The optic disc shows corresponding have no disturbances of ocular alignment or motility. Never-
atrophy at its nasal and temporal regions with relative spar- theless, as mentioned above, when the ocular motor nerves
ing of the superior and inferior portions, where the majority are also damaged in the subarachnoid space or within the
of spared temporal fibers (subserving nasal field) enter (Fig. cavernous sinus, patients will have a strabismus with the
12.11). Thus, the optic atrophy occupies a more or less hori- characteristics of an oculomotor nerve paresis, trochlear
zontal band across the disc, wider nasally than temporally nerve paresis, abducens nerve paresis, or a combination of
(191). these (Fig. 12.12). When the ocular motor nerves are dam-
It is perhaps clinically more useful when atrophy is absent aged within the cavernous sinus, there may also be evidence
in patients with chiasmal (or optic nerve) compression than of a trigeminal sensory (but not motor) neuropathy. In addi-
when it is present. Whereas patients with significant nerve tion, if the oculosympathetic fibers are damaged, frequently
fiber bundle defects and optic atrophy occasionally have im- with concurrent abducens nerve damage, there will be a post-
pressive return of both acuity and field when successful de- ganglionic Horner’s syndrome characterized by ipsilateral
compression is obtained, patients with normal-appearing ptosis and a smaller but normally reactive pupil. When both
fundi frequently have complete return of visual function with the oculomotor nerve and oculosympathetic fibers are af-
successful decompression. It is crucial that decompression fected, the clinical picture will be one of an oculomotor nerve
be carried out as soon as possible in these patients. paresis with a small pupil that will be normally reactive if
Papilledema is frequently associated with suprachiasmal the paresis is pupil-sparing or poorly or nonreactive if the
tumors but rarely with intrasellar tumors. It is more com- oculomotor nerve paresis has damaged pupillomotor fibers.
monly seen as a result of pre- and postchiasmal tumors. Not all patients with optic chiasmal lesions who develop
The loss of retinal ganglion cells associated with damage strabismus do so because of damage to one or more ocular
to their axons from chiasmal compression (192) can be de- motor nerves. In some cases, as noted above, there is decom-
tected electrophysiologically with the pattern electroretino- pensation of a preexisting phoria caused by loss of the nor-
gram (193,194). Because retinal ganglion cell loss is irrever- mal nasotemporal visual field overlap in patients with a com-
sible, the presence of an abnormal-pattern electroretinogram plete or scotomatous bitemporal field defect (hemifield
presages a worse prognosis (194). slide). This results in a manifest comitant strabismus, which
Most patients with lesions that affect the optic chiasm may be vertical or horizontal.
Figure 12.12. Partial oculomotor nerve paresis in a patient with a pituitary adenoma. The patient was referred to the Neuro-
Ophthalmology Unit of the Johns Hopkins Hospital by an internist who thought he had a Horner’s syndrome. Visual acuity
was 20/20 OU. The pupils were isocoric and normally reactive. A, There is a moderate right ptosis. The patient also had mild
limitation of upgaze in the right eye, and he developed a right hypotropia of about 4 prism-diopters on upgaze. A diagnosis
of a partial right oculomotor nerve paresis was made, and magnetic resonance imaging was obtained. B, Noncontrast T1-
weighted coronal magnetic resonance image reveals a sellar mass with suprasellar extension and invasion of both cavernous
sinuses. The lesion was found to be a pituitary adenoma.
betes insipidus and hypothalamic hypopituitarism; prepuber-

tal children may also suffer both growth retardation and de-
layed sexual development; and young children and infants
may have severe failure to thrive.
‘‘CHIASMAL SYNDROME’’ OF CUSHING
In 1930, Cushing described the importance of optic atro-
phy and bitemporal field defects in adults as indicative of
tumor when the sella turcica seemed normal in the plain
lateral skull x-ray (153). This syndrome is most often pro-
duced by suprasellar meningiomas, aneurysms, and cranio-
pharyngiomas. This notable contribution was once of great
value in eliminating, or at least reducing, misdiagnosis of
sinusitis and retrobulbar optic neuritis as common causes
for slowly progressive bilateral loss of vision. Optic atrophy
in such cases may be very slight, or the optic discs may
Figure 12.13. Seesaw nystagmus. As the right eye elevates, it also intorts. remain normal in appearance for months despite pronounced
At the same time, the left eye depresses and extorts. The right eye then
loss of vision and extensive defects in the visual fields. The
depresses and extorts, as the left eye elevates and intorts.
bitemporal field defects in some cases are extremely mild
and detected only by careful kinetic perimetry or automated
static perimetry. Finally, the normalcy of the sella turcica
The unusual phenomenon of seesaw nystagmus may occur may only be relative. Since Cushing (153) described this
in patients with tumors of the diencephalon and chiasmal syndrome, there have been substantial advances in neuroim-
regions (195–198). This condition is characterized by syn- aging. With the almost universal availability of computed
chronous alternating elevation and intorsion of one eye and tomography (CT) scanning and magnetic resonance (MR)
depression and extorsion of the opposite eye (Fig. 12.13). imaging, most patients with progressive visual loss no longer
The cause of seesaw nystagmus is unknown, but it may be undergo plain skull x-rays. Cushing’s syndrome of the chi-
related to damage to structures near the interstitial nucleus asm is thus more important for its historical significance
of Cajal, but not the nucleus itself (199–201). Rarely, seesaw than for its place in current neuro-ophthalmologic diagnosis.
nystagmus occurs in the absence of a brain stem or dience- Nevertheless, there are still some areas in the world in which
phalic lesion (202), for instance in congenital absence of the skull radiographs are used as the sole or initial step in assess-
chiasm (203). ing patients with an optic chiasmal syndrome. In such cases,
Lesions causing a chiasmal syndrome may arise from or the triad that represents Cushing’s syndrome remains a use-
extend to the hypothalamus. Such patients may develop dia- ful clinical entity.
TOPICAL DIAGNOSIS OF RETROCHIASMAL VISUAL FIELD DEFECTS

With few exceptions, unilateral lesions of the visual sen- pias caused by brain tumors (206–208). When the cerebral
sory pathway posterior to the optic chiasm—affecting the tumor is removed or the visual system is decompressed, im-
optic tract, lateral geniculate body, optic radiation, or striate provement first occurs in the central region and continues
cortex—produce homonymous visual field defects without toward the periphery. Bender and Kanzer (205) also ob-
loss of visual acuity. When such defects are complete, they served that defects for colored objects invariably appeared
do not, in themselves, permit localization. In such instances, before disturbances for either form or for black-and-white
the clinician must rely on other symptoms and signs of neu- objects. This observation may constitute another valid reason
rologic disease or on neuroimaging to define both the area for including colored stimuli or objects in examination of
of damage and the etiology of the lesion (204). Nevertheless, visual fields. This should be done not only when testing for
some general comments about retrochiasmal field defects evidence of optic nerve disease but also when testing for
are worth noting before launching into a comprehensive dis- chiasmal and retrochiasmal lesions, particularly when no de-
cussion of the clinical syndromes associated with specific fect has been found using standard kinetic perimetry with
regions of the retrochiasmal visual sensory system. either white light or white test objects. Static perimetry
Homonymous defects in the visual fields characteristi- seems to be as sensitive as manual testing using colored
cally develop slowly if they are caused by intracranial tumors objects (especially red) for detecting subtle visual field de-
and rapidly when they originate from vascular processes fects (see Chapter 2).
such as hemorrhage or infarction. This applies wherever the The onset of homonymous hemianopias arising as the re-
lesion may be situated. sult of vascular lesions is sudden. Such defects include com-
In the instance of homonymous hemianopia arising from plete homonymous quadrantanopias and hemianopias, in-
cerebral tumor, a paper by Bender and Kanzer (205) is valu- complete homonymous quadrantanopias and hemianopias
able. They noted progression of the field defects from the with varying degrees of congruity, and homonymous para-
periphery of the field to its center in homonymous hemiano- central scotomas. When and if improvement occurs, the cen-
tral field resolves first, and such improvement may be fol- with the greatest number in the sixth decade. The visual field
lowed by gradual enlargement of the peripheral fields if they defects were not necessarily isolated, and the location and
have been affected. properties of the underlying lesions were confirmed by sur-
Younge (209) described midline tilting between seeing gery or CT scanning in about half the cases. Fifty-one per-
and nonseeing areas in the perimetric evaluation of homony- cent of patients had occipital lobe pathology, 29% had le-
mous hemianopic field defects. A deviation from the abso- sions of the optic radiation, and 21% had lesions in the region
lute vertical meridian is often found when careful perimetry of the optic tract and lateral geniculate. Vascular causes,
is performed in such patients. Stone et al. (210,211) and including infarction, hemorrhage, and arteriovenous malfor-
others (212–214) found that in nonhuman primates, a certain mations, were responsible for 71% of cases and mass lesions,
percentage of retinal ganglion cells nasal to the vertical mid- including tumors and abscesses, for another 19%. Other
line bisecting the fovea have axons that do not cross at the etiologies included trauma, inflammation, degeneration, and
optic chiasm, and a certain percentage of ganglion cells tem- presumed demyelinating disease. Molia et al. (219) reported
poral to the same vertical midline have axons that do cross the development of homonymous hemianopic field defects
in the chiasm. It is not surprising, then, that there is some in two children with intracranial shunts. In both cases the
variation from a perfectly vertical separation of seeing and field defect was caused by displacement of the shunt cath-
nonseeing field. Such a variation is rarely more than a few eter.
degrees (see below). Given the preceding, it should be self-evident that neu-
In 1962 Smith reported on the causes of homonymous roimaging (preferably MR imaging) should be the first diag-
hemianopia in 100 patients (215). Forty-three patients had nostic procedure used to determine the location and etiology
proven etiologies, with the location of the lesion being in of a homonymous hemianopia, following a complete history
the occipital lobe in 12 patients, parietal lobe in 17 patients, and examination.
and temporal lobe in 14 patients. Fifty-seven patients had Special consideration is given here to a syndrome origi-
lesions in which the location was assumed on the basis of nally emphasized by Hoyt et al. (220) and later by Bajandas
clinical evidence alone. Of these patients, 27 had lesions et al. (221): homonymous hemioptic (hemianopic) hypopla-
presumed to be in the occipital lobe, 16 had lesions presumed sia. In this disorder, patients with cerebral hemiatrophy, pre-
to be in the parietal lobe, and 10 had lesions presumed to sumably from fetal vascular insufficiency or trauma, suffer
be in the temporal lobe. In addition, three patients had lesions from mental retardation, a seizure disorder, congenital hemi-
presumed to be in the optic tract, and one patient had a plegia, and an ipsilateral complete homonymous hemia-
presumed lateral geniculate lesion. Thus, almost 40% of pa- nopia. Such patients have classic hemianopic ophthalmo-
tients with homonymous hemianopias had proven or pre- scopic findings in the ocular fundi, with the eye ipsilateral
sumed occipital lobe lesions, whereas 33% had parietal lobe to the hemispheric defect showing a slightly small optic disc
lesions and only 24% had temporal lobe lesions. Optic tract with mild temporal pallor and impressive loss of the nerve
and lateral geniculate lesions were rare. Smith found only a fibers subserving ganglion cells temporal to the fovea. The
42% incidence of vascular etiology in his series, compared superior and inferior arcuate bundles in such eyes are thus
with a 38% incidence of intracranial tumor. poorly visible. In the eye contralateral to the hemispheric
Trobe et al. (216) reviewed 104 cases of isolated homony- defect, the optic disc is often small and oval, with a horizon-
mous hemianopia and found, as might be expected, that the tal band of atrophy and loss of nerve fibers from ganglion
vast majority (86%) were caused by vascular disease in the cells nasal to the fovea, as occurs in patients with bitemporal
territory of the posterior cerebral artery. Another three pa- hemianopia from lesions of the optic chiasm. Whether the
tients were believed to have suffered infarctions in the terri- ophthalmoscopic and histologic changes observed in these
tory of the middle cerebral artery, bringing the total percent- patients occur from retrograde degeneration after embryonic
age of isolated homonymous hemianopias thought to be damage to the optic tract or from transsynaptic degeneration
caused by infarction to 89%. These findings are similar to after damage to the optic radiation or striate cortex is un-
those of Shubova (217), although only 21 of the 104 cases known; indeed, either mechanism may be responsible in in-
reported by Trobe et al. (216) had etiologies proven angio- dividual cases (222). It would appear that in humans, clini-
graphically or histologically, and the study was performed cally apparent transsynaptic damage to the visual system
before the availability of modern neuroimaging. The 12 occurs almost exclusively with prenatal or perinatal brain
cases not caused by vascular lesions included occipital por- damage, including brain injury with porencephaly, cerebral
encephaly, neoplasm, multiple sclerosis, and abscess. Inter- ischemia, congenital ganglioglioma, and vascular malforma-
estingly, two thirds of the patients were between the ages tions associated with Sturge-Weber syndrome (222–226).
of 50 and 70 years, and all five patients with isolated homon- Other congenital lesions, such as arteriovenous malforma-
ymous hemianopias under age 30 had nonvascular causes for tions of the retrogeniculate visual pathways, may indirectly
their field defects. Older patients with isolated homonymous damage the optic tract or lateral geniculate body either prena-
hemianopia apparently have an exceedingly high probability tally or postnatally from the progressive effects of abnormal
of vascular lesions, whereas younger patients may have deep venous drainage (222). Patients with such lesions have
either congenital or acquired nonvascular etiologies. retrograde optic nerve degeneration, and they will show
In 1986, Fujino et al. (218) retrospectively reviewed the homonymous hemioptic hypoplasia if the insult occurs early
location and causes of homonymous hemianopia in 140 pa- enough in development.
tients. Patients were between the ages of 9 and 86 years, Another interesting phenomenon that occurs in some pa-
tients with congenital homonymous hemianopia is the devel- temporal field loss). Bell and Thompson (232) believed that
opment of exotropia and anomalous retinal correspondence the most likely etiology for this finding is that the temporal
(227–229). It is thought that in these patients the exotropia is field is 60–70% larger than the nasal field, thus creating a
a compensatory mechanism, allowing for anomalous retinal disparity with respect to light input from the two eyes to
correspondence and, consequently, ‘‘panoramic’’ viewing. the mesencephalic pupillary center. However, more recent
This ‘‘panoramic’’ vision facilitates horizontal enlargement evidence suggests that the relative afferent pupillary defect
of the visual field, with a shift of the hemianopic border associated with an optic tract lesion is due to crossing of
toward the side of the defect. Whether the phenomenon is some fibers from the temporal retina destined for the pretec-
truly compensatory or merely the coincidental occurrence of tal nuclei, and subserving the pupillary light reflex (233).
two common congenital abnormalities of the visual system O’Connor et al. (234) produced a relative afferent pupil-
remains unclear. However, surgical correction of the exotro- lary defect in two monkeys by experimental lesioning of
pia may run the risk of not only intractable paradoxical diplo- the contralateral optic tract under direct visualization. Their
pia, but also possible horizontal constriction of the visual results corroborated the clinical evidence of a relative affer-
field (229). ent pupillary defect in patients with lesions of the contralat-
eral optic tract producing complete homonymous hemia-
TOPICAL DIAGNOSIS OF OPTIC TRACT LESIONS nopia without evidence of optic neuropathy. A relative
afferent pupillary defect was also present at some stage in
Although lesions of the optic tracts are infrequently recog- 8 of 10 patients with optic tract syndromes reported by New-
nized, they are of great importance because they represent man and Miller (235).
the first region beyond the optic chiasm where lesions pro- Unilateral optic tract lesions, like other unilateral retrochi-
duce a homonymous field defect (Fig. 12.14). Common asmal lesions, do not cause loss of visual acuity. Such visual
causes are tumor, vascular processes, demyelinating disease, loss occurs from the effects of the lesion on one or both
and trauma (Figs. 12.15 and 12.16). In his series of 100 optic nerves. It is for this reason that when reduced visual
consecutive homonymous hemianopias, Smith (215) found acuity is present in a patient with a lesion in the region of the
only 3 that he attributed to a lesion of the optic tract. His optic tract, it (and the associated relative afferent pupillary
criteria were extreme incongruity, a negative optokinetic re- defect) is more often on the side of the lesion, as a result of
sponse, a Behr’s pupil (inequality of the pupils with the accompanying optic nerve disease. On the other hand, in
larger pupil on the side of the hemianopia), and evidence of patients with pure optic tract lesions that do not damage
neurologic disease in neighboring structures. Fujino et al. either optic nerve or parts of the optic chiasm, a complete
(178) reported 16 patients with lesions referable to the optic or nearly complete homonymous hemianopia is always asso-
tract among their 140 patients with homonymous hemia- ciated with an obvious relative afferent pupillary defect on
nopia. The causes were vascular in five, tumor in four, and the side opposite the lesion. Such patients have normal visual
miscellaneous in seven. Savino et al. (230) examined 21 acuity and color vision, and they have no sensation of re-
patients who were thought to have lesions of the optic tract. duced light brightness in the eye with the afferent pupillary
The etiologies were primarily tumors, although one patient defect.
had demyelinating disease and two patients had suffered Another pupillary phenomenon that is sometimes associ-
trauma. ated with lesions of the optic tract is pupillary hemiakinesia
Patients with optic tract lesions often have specific find- (hemianopic pupillary reaction or Wernicke’s pupil). Be-
ings that permit the recognition of the location of the lesion cause the pupillary afferents are present in this section of
on clinical grounds. In 1967, Burde (231) theorized that all the visual system, when light is projected onto the ‘‘blind’’
patients with a complete homonymous hemianopia caused retinal elements (subserving the nasal visual field in the ipsi-
by an isolated optic tract lesion should have a relative affer- lateral eye and the temporal visual field in the contralateral
ent defect in the eye with the temporal field loss (contralat- eye), either no pupillary reaction occurs, or the reaction is
eral to the side of the lesion). He made this assumption based markedly reduced. However, when light is projected onto
on three phenomena: (a) the nasal visual field is considerably the intact retinal elements (subserving the temporal visual
smaller than the temporal field; (b) the pupillomotor fibers field in the ipsilateral eye and the nasal visual field in the
within the visual sensory pathway hemidecussate in the optic contralateral eye), a normal pupillary reaction is observed.
chiasm along with or as part of the visual axons; and (c) the Savino et al. (230) found this abnormality in only one of their
pupillomotor fibers are present within the optic tract for most patients and concluded that it is not helpful in diagnosing this
of its extent. Bell and Thompson (232) subsequently con- syndrome; however, most of the patients in this study had
firmed Burde’s (231) theory when they examined four pa- lesions that extended to one or both optic nerves.
tients with optic tract lesions. Each patient had normal visual Patients with a complete or nearly complete homonymous
acuity in both eyes, a complete homonymous hemianopia, hemianopia from an optic tract lesion eventually develop a
and ‘‘band’’ atrophy in the eye on the side of the hemianopia characteristic pattern of optic atrophy (230,235). There is a
(contralateral to the lesion). Color vision as tested with the wedge or ‘‘band’’ of horizontal pallor of the optic disc in
Hardy-Rand-Rittler pseudoisochromatic plates was normal, the eye contralateral to the lesion (i.e., the eye with temporal
and a Pulfrich test gave normal responses in all patients. field loss). This pattern of optic nerve atrophy is associated
However, all patients had an overt relative afferent pupillary with atrophy of retinal nerve fibers originating from retinal
defect in the eye on the side of the hemianopia (with the ganglion cells nasal to the fovea and is identical with that
Figure 12.14. A 65-year-old man developed headache, sleepiness, personality changes, memory difficulties, right hemiparesis,
and difficulty seeing to the right. A, Visual fields revealed an incongruent right homonymous hemianopia. Computed tomography
scans before (B) and after (C) the administration of intravenous contrast revealed an enhancing lesion with surrounding edema
in the region of the left optic tract, diagnosed ultimately as lymphoma.
Figure 12.15. A 40-year-old man noted a ‘‘black spot’’ in front of both eyes that gradually worsened over 2 weeks. A, Visual
acuities were normal, but there was a trace right relative afferent pupillary defect, and visual fields showed a highly incongruous
right homonymous defect. B and C, Magnetic resonance imaging (B, T2-weighted; C, FLAIR) revealed multiple white matter
lesions consistent with demyelinating disease, including a large plaque in the left optic tract (arrows).
Figure 12.16. A 35-year-old man had head trauma in a motor vehicle accident and complained of blurriness in the right eye.
A, Examination was notable for 20/20 vision in both eyes, a right relative afferent pupillary defect, pallor of the optic discs,
and an incongruous right homonymous hemianopia. B and C, Magnetic resonance imaging revealed a subtle lesion in the left
optic tract (arrows), presumably posttraumatic.
seen in both eyes of patients with bitemporal field loss from that represent the majority of fibers subserving the nasal
chiasmal syndromes (see above). At the same time, there is visual field and originating from retinal ganglion cells tem-
generalized pallor of the optic disc in the eye on the side of poral to the fovea (Fig. 12.17).
the lesion, and this is associated with severe loss of nerve Not all patients with optic tract lesions have complete
fiber layer details in the superior and inferior arcuate regions homonymous hemianopias. Many have incomplete hemia-
Figure 12.17. Hemianopic optic atrophy in a patient with a left homonymous hemianopia from a right optic tract lesion. A,
The right optic disc has a somewhat diffuse temporal atrophy from loss of nerve fibers from ganglion cells temporal to the
fovea. B, The left optic disc shows band atrophy from loss of nerve fibers from ganglion cells nasal to the fovea. C and D,
Red-free (540 nm) photographs showing atrophy of right and left optic discs. Note band pattern of atrophy of the left disc. E,
Inferior temporal peripapillary retina of right eye showing relative absence of visible arcuate bundle. F, Inferior temporal
peripapillary retina of left eye showing relative preservation of arcuate bundle.
nopias or quadrantanopias, which as a rule are quite incon- TOPICAL DIAGNOSIS OF LESIONS OF THE
gruous and may even be scotomatous (Fig. 12.18). Indeed, LATERAL GENICULATE BODY
the optic tract is one of only two locations in the postchias-
mal pathway in which homonymous scotomas can occur; Lesions affecting the lateral geniculate body (LGB; also
the occipital lobe is the other. lateral geniculate nucleus [LGN]) are less commonly diag-
Patients with optic tract lesions may have clinical manifes- nosed than those of the optic tract. At the beginning of the
tations in addition to homonymous visual field defects. Le- 20th century, it was accepted that incongruity of homony-
sions that damage the optic tract may also damage adjacent mous field defects is most pronounced with lesions near
neural structures, producing a variety of neurologic deficits the junction of the optic chiasm and tract and diminishes
(Fig. 12.19). Bender and Bodis-Wollner (236) examined 12 progressively with more posterior lesions (237). This diag-
patients with optic tract lesions. Seven of the patients had nostic perimetric axiom was attributed to a gradual align-
disorders of mentation, and several had hypothalamic symp- ment in the optic tract of the crossed and uncrossed visual
toms and signs. Eleven of the 21 patients studied by Savino axons from corresponding retinal areas. However, this the-
et al. (230) had neurologic manifestations in addition to a ory was challenged by several clinicoanatomic case studies
homonymous visual field defect, as did 5 of the 10 patients (238–240) and two clinical reports (241,242) suggesting that
evaluated by Newman and Miller (235). lesions of the lateral geniculate body produce significantly
In summary, a diagnosis of optic tract syndrome can be incongruous homonymous field defects. Gunderson and
made in the setting of a highly incongruous homonymous Hoyt (243) subsequently reported quantitative perimetric
hemianopia, with or without associated bilateral nerve fiber studies in two patients with lesions of the lateral geniculate
layer or optic atrophy, particularly when there is a relative body. One patient had a progressive hemianopia that began
afferent pupillary defect on the side opposite the lesion, de- as an incongruous, relative wedge-shaped homonymous de-
spite normal visual acuity and color vision. In other words, fect and ultimately resulted in a complete homonymous hemi-
a relative afferent pupillary defect in the eye on the side of a anopia with splitting of the macula. At autopsy, the patient
complete homonymous hemianopia in a patient with normal had a diffuse pilocytic astrocytoma in the right temporal
visual acuity and color vision in both eyes indicates a lesion lobe, thalamus, and brain stem that completely replaced the
of the optic tract (232,235). Unilateral lesions of the optic right LGB. The second patient had a small arteriovenous
tract (or lateral geniculate body) that are associated with malformation localized to the LGB. Hoyt (244) later de-
diminished visual acuity almost certainly produce the dimin- scribed these two patients and two others in a more extensive
ished acuity through damage to one or both optic nerves or discussion of perimetric findings in patients with lesions of
the optic chiasm (11). the LGB. The most striking perimetric feature in these pa-
Figure 12.18. A 48-year-old woman with a history of migraines with left-sided visual aura had a typical aura without headache
and without resolution of her visual symptoms. On examination, she had normal visual acuity, a left relative afferent pupillary
defect, mild optic disc pallor in both eyes, and an incongruent left homonymous hemianopia. Magnetic resonance imaging
revealed infarction in the region of the posterior right optic tract and lateral geniculate.
Figure 12.19. A 7-year-old girl presented with precocious puberty

and was found to have a suprasellar mass with hydrocephalus. A, Coro-
nal T1-weighted magnetic resonance image without gadolinium. B,
Axial T1-weighted magnetic resonance image without gadolinium. C,
Axial T1-weighted magnetic resonance image with gadolinium. (Figure
continues.)
Figure 12.19. Continued. D, Examination revealed incongruous right inferior homonymous hemianopic defects consistent
with damage to the left optic tract. Biopsy showed findings diagnostic of craniopharyngioma.
tients was the extensive incongruity of their visual field de- of the LGB. It resulted in complete loss of the superior ho-
fects (Fig. 12.20). monymous field, with minimal damage to the medial aspect,
It was mentioned in Chapter 1 that the dorsal region of causing an incongruous loss of the inferior homonymous
the LGB subserves macular function, that the lateral aspect field. Case 4 had an incongruous, inferior homonymous
of the LGB subserves the superior visual field, and that the hemianopia thought by Hoyt to indicate extensive damage
medial aspect subserves the inferior field. Case 1 of Hoyt to the medial aspect of the LGB. In addition, Hoyt empha-
(244) initially had incongruous, homonymous, wedge- sized the importance of hemianopic optic atrophy as an indi-
shaped paracentral scotomas thought to be from damage to cation of irreversible damage to retrochiasmal visual fibers
the dorsal crest of the LGB. Case 2 had an incongruous proximal to the visual radiations.
homonymous hemianopia, worse superiorly, which Hoyt Frisén et al. (245,246) identified two specific patterns of
thought was caused by extensive damage to the lateral aspect relatively congruous homonymous field defects with sector
Figure 12.20. Incomplete, extremely incongruous, homonymous hemianopia in a patient with a lesion of the left lateral
geniculate body. (Redrawn from Gunderson CH, Hoyt WF. Geniculate hemianopia: Incongruous homonymous field defects
in two patients with partial lesions of the lateral geniculate nucleus. J Neurol Neurosurg Psychiatr 1971;34:1–6.)
optic atrophy, which they attributed to focal disease of the most likely that the lesion was an infarct in the territory of
LGB caused by infarction in the territory of two specific the right lateral choroidal artery, probably caused by shear-
arteries. Frisén et al. (245) described two patients with sector ing forces from the trauma.
optic atrophy and homonymous, horizontal sectoranopia. Rarely, bilateral damage to the LGBs causes complete
One patient had a small arteriovenous malformation in the blindness (239,252). Most cases have resulted from vascular
region of the LGB, whereas the second had a presumed in- disease: syphilitic arteritis in the case reported by Mackenzie
farction of the LGB. These authors believed that this specific et al. (239) and coagulative ischemic necrosis, possibly asso-
pattern of field loss is indicative of ischemia or other damage ciated with methanol ingestion, in the case reported by Mer-
in the territory of the lateral choroidal artery that supplies a ren (252). Donahue et al. (253) described a 37-year-old
portion of the LGB. They emphasized that the concept of woman with central pontine myelinolysis and relatively con-
an incongruous hemianopia as a hallmark of LGB damage gruous visual field defects in both halves of the visual field
is not necessarily correct. In addition, they argued, although in an hourglass pattern (Fig. 12.22). The visual field defects
the intricate retinotopic organization of the LGB may result resembled those described by Frisén (246) in patients with
in the production of relative defects, incongruous defects, anterior choroidal artery infarction, but there was no evi-
and even (theoretically) monocular defects, vascular lesions dence to suggest infarction in this case, leading the authors to
are more likely to respect specific anatomic boundaries postulate a preferential cellular susceptibility to myelinolysis
within the LGB and thus produce homonymous sector de- among those cells supplied by this artery. Greenfield et al.
fects that are, in fact, quite congruous, with abruptly sloping (254) reported a 28-year-old woman who developed left
borders (Fig. 12.21A and B). homonymous wedge-shaped defects consistent with a lesion
In a second paper, Frisén (246) identified a syndrome of the dorsal aspect of the right LGB and an incongruous
characterized by loss of upper and lower homonymous sec- right homonymous hemianopia after an episode of gastroen-
tors in the visual field that followed ligation of the distal teritis. MR imaging revealed lesions of both LGBs and the
portion of the anterior choroidal artery in a patient with a left optic tract.
meningioma of the velum interpositum (Fig. 12.21C and D). The specificity of homonymous sectoranopic visual field
In this patient, a CT scan showed a low-density region in defects for lesions of the LGB is challenged by neuroimaging
the region of the LGB, thought to be compatible with an studies that reveal retrogeniculate lesions in some cases
infarction. Frisén thus postulated that this ‘‘quadruple sec- (255–259). Carter et al. (255), for example, reported three
toranopia’’ syndrome was caused by ischemia or other dam- patients with homonymous horizontal sectoranopias consis-
age to the portion of the LGB supplied by the anterior choroi- tent with the field defects caused by LGB lesions. CT scan-
dal artery. Helgason et al. (247) reported a case similar to ning, however, revealed lesions of the optic radiation in all
that of Frisén (246) and agreed that the field defects were three cases: a presumed low-grade astrocytoma of the poste-
caused by damage to the portion of the LGB supplied by rior temporal lobe in one patient, a large parietotemporal
the distal anterior choroidal artery. Both papers also empha- hemorrhage from an arteriovenous malformation in the sec-
sized the importance of focal nerve fiber layer atrophy with ond patient, and a posttraumatic hematoma in the temporal
corresponding sector optic atrophy in establishing the diag- lobe in the third patient. Grossman et al. (258) reported simi-
nosis of a lesion of the LGB. lar visual field defects in a patient with an infarction in the
It seems clear that although incongruous homonymous occipital lobe.
field defects may arise from lesions in both the optic tract and Although three of the patients that Hoyt (244) described
LGB, lesions of the LGB may also produce fairly congruous had no associated neurologic signs in addition to their visual
defects (248,249). Indeed, Shacklett et al. (250) reported field defects, patients with lesions of the LGB may also have
two patients with lesions of the LGB, both of whom had neurologic symptoms and signs consistent with damage to
homonymous horizontal sectoranopias. One patient with a the ipsilateral thalamus, the pyramidal tract, or both (247).
small arteriovenous malformation had an exquisitely con- As evidence of damage to the thalamus, there may be gross
gruous field defect. The other patient, who had a low-grade impairment of sensation on the side of the body opposite to
astrocytoma, had an incongruous field defect. The authors the lesion, or there may be a complaint of pain of central
postulated that the arteriovenous malformation in the LGB origin that is referred to the opposite side of the body. Dam-
of their first patient produced the highly congruous visual age to the pyramidal tract causes weakness of the side of
field defect by causing an infarction in the region of the the body contralateral to the lesion.
LGB normally supplied by the lateral choroidal artery. The Because the pupillomotor fibers leave the optic tract to
incongruous defect in the second patient was thought to be ascend in the superior brachium, the pupillary reactions in
caused by infiltration of the portion of the LGB supplied by patients with LGB lesions are normal unless the lesion also
the lateral choroidal artery. damages the optic tract or the brachium of the superior colli-
Although vascular lesions of the LGB tend to produce culus. As in lesions of the optic radiation, there is neither a
congruous homonymous field defects rather than incon- contralateral relative afferent pupillary defect nor a hemia-
gruous ones, not all homonymous field defects caused by nopic pupillary phenomenon. On the other hand, the visual
such lesions are congruous. Borruat and Maeder (251) de- axons from retinal ganglion cells first synapse in the LGB.
scribed a patient with an incongruous left homonymous sec- Thus, sectoral or hemianopic atrophy of the retinal nerve
toranopia following head trauma. MR imaging revealed a fiber layer and optic disc occurs in patients with lesions
hypointense lesion in the right LGB. The authors thought it of the LGB. Such defects, when associated with acquired
Figure 12.21. Visual field defects in patients with lesions

of the lateral geniculate body (LGB). Homonymous horizontal
sectoranopia from damage to the LGB in the territory of the
lateral choroidal artery in a patient with a small arteriovenous
malformation (A) and in a patient with presumed thrombosis
of the lateral choroidal artery (B). Note the relative congruity
of the field defect in both cases. Quadruple sectoranopia from
damage to the LGB in the territory of the distal anterior choroi-
dal artery in a patient with occlusion of the distal anterior
choroidal artery (C) and in a patient with occlusion of the distal
choroidal artery (D). (A and B, From Frisén L, Holmegaard
L, Rosencrantz M. Sectorial optic atrophy and homonymous,
horizontal sectoranopia: A lateral choroidal artery syndrome?
J Neurol Neurosurg Psychiatr 1978;41⬊374–380. C, From Fri-
sén L. Quadruple sectoranopia and sectorial optic atrophy:
A syndrome of the distal anterior choroidal artery. J Neurol
Neurosurg Psychiatry 1979;42⬊590–594. D, From Helgason
C, Caplan LR, Goodwin J, et al. Anterior choroidal artery-
territory infarction. Report of cases and review. Arch Neurol
1986;43⬊681–686.)
Figure 12.22. A 37-year-old woman suffered central pontine myelinolysis and complained of bilateral visual loss. Visual
acuity was 20/25 OD and 20/30 OS, and automated static perimetry demonstrated fairly congruous defects having an hourglass
configuration, with near-total depression superior and inferior to fixation. The visual field defects were similar to those reported
after anterior choroidal artery infarction, prompting the authors to propose that the cells supplied by the anterior choroidal
artery in the lateral geniculate might be particularly susceptible to metabolic insult, such as rapid changes in serum sodium
level. (From Donahue SP, Kardon RH, Thompson HS. Hourglass-shaped visual fields as a sign of bilateral lateral geniculate
myelinolysis. Am J Ophthalmol 1995;119⬊378–380.)
Figure 12.23. Specimen showing the corona radiata, internal capsule, and their relationship to the optic tract. The internal
capsule and corona radiata have been exposed by removal of the corpus callosum, caudate nucleus, and diencephalon. The
fibers of the basis pedunculi pass adjacent to the optic tract. CR, corona radiata; IC, internal capsule; BP, basis pedunculi; OT,
optic tract. (From Ghuhbegovic N, Williams TH. The Human Brain. A Photographic Guide. Hagerstown, MD, Harper & Row,
1980.)
homonymous field defects, whether congruous or incon-

gruous, must be taken as evidence of optic tract or lateral
geniculate damage in all cases.
TOPICAL DIAGNOSIS OF LESIONS OF THE OPTIC

RADIATION
Lesions of the Internal Capsule
Efferent projection fibers from and afferent projection fi-
bers to the cerebral cortex traverse the subcortical white mat-
ter, where they form a radiating mass of fibers, the corona
radiata, which converges toward the brain stem (Fig. 12.23).
In the rostral brain stem, the fibers form a broad but compact
fiber band, the internal capsule, that is bordered medially
by the thalamus and caudate nucleus and laterally by the
lenticular nucleus (260). The afferent fibers make up the
thalamocortical radiation in the internal capsule. The efferent
fiber bundles include (a) the corticospinal and corticobulbar
tracts; (b) the frontopontine tract from the prefrontal and
precentral regions of the cerebral cortex; (c) the temporopa-
rietopontine tract from the temporal and parietal lobes; and
(d) the optic radiation, which begins in the lateral geniculate
body and occupies only a small region of the capsule, since
it does not proceed to the brain stem. The internal capsule
is thus composed of all fibers, afferent and efferent, that go
to, or come from, the cerebral cortex.
Because of the curvature of fibers in the internal capsule, Figure 12.24. Horizontal section through the cerebral hemispheres at the
this structure has a broad, V-shaped appearance pointed me- level of the thalamus, showing the relationship of the portions of the internal
dially when viewed in axial sections (Fig. 12.24). The ante- capsule to the surrounding structures. A, anterior limb of the internal cap-
rior limb partially separates two structures of the basal gan- sule; G, genu of the internal capsule; P, posterior limb of the internal cap-
glia, the head of the caudate nucleus and the lenticular sule; H, head of the caudate nucleus; Pu, putamen; T, thalamic nuclei. (From
nucleus (Figs. 12.24 and 12.25). The apex of the V, or genu, Ghuhbegovic N, Williams TH. The Human Brain. A Photographic Guide.
Hagerstown, MD, Harper & Row, 1980.)
separates the head of the caudate nucleus and the thalamus.
The posterior limb separates the thalamus and the lenticular
nucleus (Fig. 12.24). The most posterior component of the
internal capsule is the optic radiation. Interruption of the Ocular findings in lesions of the internal capsule may be
optic radiation is characterized by a contralateral homony- summarized as follows: (a) transient deviation of the eyes
mous hemianopic visual field defect. to the side of the lesion in many instances; (b) weakness of
The internal capsule receives the bulk of its blood supply the frontalis and orbicularis oculi on the hemiplegic side in
from the lenticulostriate and lenticulo-optic branches of the a minority of cases; (c) homonymous hemianopia in cases
middle cerebral artery. In addition, the anterior limb of the in which there is extensive damage to the posterior portion
capsule is supplied by a branch of the anterior cerebral artery of the capsule.
(Heubner’s artery) (247). The homonymous hemianopia that is associated with le-
A variety of clinical syndromes arise from lesions of the sions of the internal capsule is often complete, but there is
internal capsule. Obstruction of Heubner’s artery causes pa- usually some degree of clearing with time. Only rarely does
ralysis of the face, tongue, and arm on the opposite side of complete resolution or no resolution of the hemianopia
the body; if the lesion is on the left, there is also motor occur.
dysphasia. The paralysis of the face spares the frontalis and
Lesions of the Temporal Lobe
orbicularis oculi in many instances, but occasionally during
early stages there is transient lowering of the eyebrow and Unlike lesions of the internal capsule, which are fre-
inability to completely close the eyelids. The sparing is re- quently vascular, temporal lobe lesions are often neoplastic
lated to the bilateral cortical innervation of these muscles. or infectious (i.e., abscess), and it is not until the occipital
The muscles of deglutition and mastication and the larynx cortex is reached that vascular lesions again predominate.
are similarly innervated. The disposition of the visual fibers in the temporal lobe is
If a lesion is extensive and affects the posterior limb of the controversial. One has only to compare the report by Fal-
capsule, there is a complete hemiplegia and hemianesthesia coner and Wilson (261), whose 50 temporal lobectomy pa-
contralateral to the lesion. If there is damage to the posterior tients all had completely congruous hemianopic defects, den-
portion of the capsule, there is contralateral hemianesthesia ser above, with that of Van Buren and Baldwin (262), who
and an homonymous hemianopia. found significant incongruity in their 41 temporal lobectomy
Figure 12.25. Coronal section through the

cerebral hemispheres showing the relationship
of the optic chiasm, third ventricle and internal
capsule. OC, optic chiasm; III, 3rd ventricle;
IC, internal capsule. (From Ghuhbegovic N,
Williams TH. The Human Brain. A Photo-
graphic Guide. Hagerstown, MD, Harper &
Row, 1980.)
patients with hemianopic defects, to realize that the issue is abnormalities in almost all patients after temporal lobe resec-
far from settled. Nevertheless, a few general comments can tion (268). Attempts to prevent visual field defects from
be made regarding the nature of homonymous defects seen temporal lobe epilepsy surgery by doing amygdalohippo-
with lesions of the temporal lobe. campectomy have not been successful (269).
If the temporal lobe is damaged or sectioned far enough The issue of how much temporal lobe can be removed
posteriorly, the patient will have a homonymous visual field or damaged without producing a homonymous visual field
defect. In virtually all cases, the homonymous defect is in- defect is complicated by several factors. First, most studies
complete and either is confined to the superior quadrants or used kinetic rather than static perimetry. It is possible that
is denser above, reflecting the anatomy of Meyer’s loop, some of the patients who had no evidence of a field defect
which courses anteriorly in the temporal lobe around the by kinetic perimetry would have shown a defect if they had
temporal horn of the lateral ventricle and consists entirely been tested with static perimetry, as in the study by Krolak-
of axons subserving the superior visual fields of the two eyes Salmon et al. (267). Second, when temporal lobectomy is
(see Chapter 1). In many cases the homonymous defect is performed for mass lesions, the lesion itself may influence
enough to interfere with everyday activities, particularly the anatomy of the visual fibers within the temporal lobe.
driving (263,264). On the other hand, the anterior temporal Even in studies that limit patient inclusion to epilepsy pa-
lobe may be damaged without producing any visual field tients with mesial temporal sclerosis, thereby excluding pa-
defect. The amount of temporal lobe that may be removed tients with a major structural distortion of the optic radiation,
without a resulting field defect is controversial. Penfield the extent of resection often varies. The approach will de-
(265) reported 51 patients who underwent temporal lobec- pend on the results of electroencephalography, MR imaging,
tomy for temporal lobe epilepsy and wrote, ‘‘When the line electrocorticography, and functional cortical mapping and
of removal is less than 6 cm posterior to the tip, it is apt to the particular vascular anatomy of the patient’s temporal
result in no postoperative visual field defect.’’ Marino and lobe (270). In addition, there may be considerable individual
Rasmussen (266) found that 17 of 50 patients who underwent variability in the spatial distribution of optic radiation fibers
temporal lobectomies had no detectable field defect, even within the temporal lobe (270–272). Finally, infarction in
though some of these patients had resections between 3.0 the distribution of the anterior choroidal artery from surgical
and 8.5 cm as measured both along the base of the middle manipulation and resultant vasospasm may complicate tem-
fossa and along the sylvian fissure. On the other hand, Fal- poral lobectomy in some cases (247,273), causing more ex-
coner and Wilson (261) found visual field defects when the tensive visual field defects from damage to the optic tract
line of removal was as little as 4.5 cm posterior to the tip or the LGB.
of the temporal lobe. Removal of as little as 2 cm of anterior Several patients in the series reported by Marino and Ras-
temporal lobe can result in a visual field defect detected by mussen (266) had defects following excisions 3.0–4.0 cm
automated perimetry (267), and automated perimetry detects posterior to the temporal tip. However, it would appear that
up to 4.0 cm of anterior temporal lobe can be removed in fect in the visual field of the eye on the side of the lesion,
most patients without interrupting the visual fibers enough whereas 10 patients exhibited the greater defect in the visual
to produce a visual field defect. Once the temporal lobe is field of the eye contralateral to the lesion. Other investigators
sectioned 4 cm or more posterior to its tip, most patients performed studies indicating that the gross dimensions of a
will develop a homonymous field defect. Bjork and Kugel- temporal lobe resection generally correlate poorly with the
berg (274) examined 26 patients who underwent temporal presence, extent, and congruity of the resultant visual field
lobectomy for temporal lobe epilepsy unassociated with defects (270,271,275,276). For example, although Jensen
tumor. All patients had sections made 4.0–6.5 cm from the and Seedorff (275) found a higher frequency of extensive
temporal tip, and all patients had homonymous superior visual field defects after right-sided resections, Tecoma et
quadrantic defects, although none of the patients was aware al. (270) found no such effect of the side of the operation.
of the defect until the examination. Other investigators also Jensen and Seedorff (275) and Babb et al. (271) found a
report homonymous visual field defects after temporal lo- high degree of incongruity in the visual field defects among
bectomies made 4–8 cm from the temporal tip in 74% (51/ their patients and confirmed the finding of Marino and Ras-
69) (275), 59% (13/22) (271), 69% (27/39) (276), and 52% mussen (266) and others of a consistently greater defect in
(17/33) (270) of patients. the field of the eye on the side of the lobectomy; however,
According to Van Buren and Baldwin (262), other charac- Tecoma et al. (270) reported more uniform visual fields with
teristics of these field defects are (a) they do not affect visual no consistent laterality, a finding that reflects the experience
acuity; (b) they do not alter the size of the blind spot; (c) of many clinicians. These authors hypothesized that this
they have sloping inferior margins; (d) they may cross the variability in the congruity of the visual field defects after
horizontal midline; (e) they may be either congruous or in- temporal lobectomy may reflect the individual reorganiza-
congruous but when incongruous, the larger defect is often tion within fiber bundles. The reorganization occurs in the
in the visual field of the eye on the side of the lesion (Fig. optic radiation as the precise retinotopic organization of the
12.26). In addition, the peripheral field, including the mon- LGB with its six monocular layers in vertical register be-
ocular crescent, is never spared in these field defects. Al- comes binocular at the visual cortex.
though Falconer and Wilson (261) concluded that excisions Although there seems to be no correlation between the
of varying magnitude between 4.5 and 8.0 cm produce hom- amount of posterior section in temporal lobectomy and the
onymous defects, usually of the superior field, these investi- severity of the visual field defect when sectioning is per-
gators found that most of the defects were congruous and formed between 4 and 8 cm posterior to the temporal tip,
that there was no significant difference in the severity of the most authors agree that sections beyond 8 cm tend to produce
field defects that were produced when lesions were made a complete homonymous hemianopia (261,262). Even this
between 4.5 and 6.0 cm from the tip and those that were issue is controversial, however. In the study performed by
produced after lesions made 6.0–8.0 cm from the tip. Marino Marino and Rasmussen (266), four patients with excisions
and Rasmussen (266) noted incongruity in 79% of their pa- of 7.5–8.0 cm as measured along the base of the middle
tients with homonymous field defects after temporal lobec- fossa had no visual field defects, and none of the 11 patients
tomy. Sixteen of these 26 patients exhibited the greater de- with such excisions had a complete homonymous hemia-
Figure 12.26. Homonymous quadrantanopia in a patient with a glioblastoma of the left temporal lobe. The defects are primarily
superior and moderately incongruous. The greater defect is on the side opposite the lesion.
nopia. A rule of thumb (for which there are always excep- either temporal lobe. Severe disturbances of language can
tions) is that most patients in whom a temporal lobectomy result from lesions in the dominant, usually left, temporal
is performed that extends at least 4 cm posterior to the tem- lobe. Disturbances of memory are common.
poral tip will have some degree of homonymous field defect Tumors of the temporal lobe frequently cause seizures.
denser superiorly than inferiorly, and patients in whom a Seizures of the temporal lobe often manifest as transient
lobectomy extends posteriorly beyond 8 cm should be ex- changes in emotions, mood, and behavior that are associated
pected to have a postoperative homonymous field defect that with motor automatisms: so-called complex partial seizures
is complete or nearly so. or psychomotor epilepsy. If the lesion is situated anteriorly
Penfield et al. (277) described splitting of the macula as and affects the uncinate gyrus, either directly or through
the result of excision of the posterior portion of the temporal pressure, so-called uncinate fits occur. These are character-
lobe; however, most series report a tendency for macular ized by an aura of unusual taste or smell, followed by abnor-
sparing in patients with partial or complete quadrantic de- mal motor activity of the mouth and lips, during which the
fects. Marino and Rasmussen (266) found macular splitting patient is not in contact with his or her surroundings. There
primarily in patients whose field defects extended into the may be auditory or formed visual hallucinations.
lower quadrants. When the field defect was confined to the
superior quadrants, the macular field in these quadrants Lesions of the Parietal Lobe
tended to be spared.
The visual field defects associated with temporal lobe le- Lesions in the parietal lobe may produce ocular symptoms
sions are summarized as follows: of diagnostic value. Homonymous hemianopia affecting pri-
marily the lower fields is caused by damage to the optic
1. A homonymous wedge-shaped defect in the upper visual radiation in the superior parietal lobe (Fig. 12.29). Such de-
fields, often called a ‘‘pie-in-the-sky’’ defect to empha- fects are usually more congruous than those produced by
size its superior location and wedge shape, almost always lesions of the temporal lobe (Fig. 12.30). Because the entire
indicates damage to the optic radiation in the temporal optic radiation passes through the parietal lobe, large lesions
lobe (Fig. 12.26). may produce complete homonymous hemianopia with mac-
2. A superior homonymous quadrantic defect suggests dam- ular splitting. Unawareness of the field defects characterizes
age to the inferior fibers of the optic tract, the optic radia- many parietal lobe lesions in both the dominant and nondom-
tion in the temporal lobe, or the inferior occipital cortex inant hemispheres (282,283), although this phenomenon is
(Fig. 12.27). When the defect is congruous, an occipital not limited to such lesions. Traquair (284) stated that before
lobe location is most likely, but the lesion may still be the appearance of other symptoms, there may be a distur-
in the temporal lobe. When the defect is incongruous, the bance of fixation reflexes sufficient to interfere with reading
lesion is either in the optic tract or the temporal lobe, but ability. This disturbance is sometimes manifest during visual
not in the occipital lobe. field testing, during which the examiner notes that despite
his or her best efforts, the patient cannot maintain central
Horton and Hoyt (278) suggested that lesions of the occip- fixation. This often causes frustration on the part of the pa-
ital cortex, especially if they affect areas V2 and V3 of ex- tient and exasperation on the part of the examiner or techni-
trastriate cortex, are more likely to produce a sharply defined cian performing the field testing.
horizontal border to the quadrantanopia than are lesions of The anatomy of the optic radiation has been most exten-
the optic radiation, which often produce incongruous defects sively studied in the cat (285). Investigators noted a continu-
with sloping borders. However, exquisite respect of the hori- ous sheet of fibers with no separation of fibers into those
zontal meridian can certainly occur with lesions in the optic ultimately projecting to the superior and inferior visual corti-
radiation, including the temporal lobe (Fig. 12.28). Many ces. Horton and Hoyt (278) argued that this lack of anatomic
but not all field defects associated with temporal lobe lesions separation makes it unlikely that a lesion of the optic radia-
are incongruous. The incongruity, when present, is not as tion could cause a visual field defect that strictly respects
severe as that seen with optic tract and some lateral genicu- the horizontal meridian. Indeed, most field defects in patients
late lesions, and the more extensive defect is usually but not with lesions of the optic radiation in the parietal lobe have
always in the eye on the side of the lesion (Fig. 12.26). sloping borders that do not precisely respect the horizontal
Nonvisual manifestations of lesions of the temporal lobe (262). Exceptions occur, however, especially when the caus-
are described in detail in Chapter 28. Briefly, if there is a ative lesion is in the posterior optic radiation where the fasci-
mass lesion of the temporal lobe, headache is common. Bi- cles approach the calcarine cortex (Fig. 12.31). Borruat et
lateral lesions of the transverse gyri of Heschl can cause al. (286) reported the case of a 45-year-old woman with
cortical deafness, usually associated with aphasia, and uni- probable multiple sclerosis and a congruous inferior homon-
lateral lesions may cause a disturbance of hearing and sound ymous quadrantanopia bordering the horizontal meridian
discrimination contralateral to the lesion (279,280). If the secondary to a small white matter lesion in the contralateral
lesion is in the dominant temporal lobe, the patient may have trigone area (Fig. 12.32).
difficulty memorizing a series of spoken words, whereas if Neuro-ophthalmologic features suggesting a lesion in the
the lesion is in the nondominant temporal lobe, the patient parietal lobe include an incomplete and relatively congruous
may exhibit various forms of auditory agnosia (281). Audi- (or mildly incongruous) homonymous hemianopia that is
tory hallucinations or illusions may occur with lesions of denser below than above, conjugate movements of the eyes
Figure 12.27. A, A 66-year-old woman with open-angle glaucoma

but no visual field deficits was incidentally found to have a left
superior homonymous quadrantanopia. B–D, Magnetic resonance
imaging revealed infarction of the inferior and medial aspects of
the right temporal lobe with extension to the right occipital lobe
(circled areas), consistent with involvement of the inferior optic
radiations.
Figure 12.28. A 29-year-old man presented with 2 months of

headaches with mood swings and mania, and 3 days of intermittent
greenish-blue lines appearing in his superior left visual field. A,
Examination was normal except for papilledema and a left homony-
mous superior quadrantanopia. B–D, T1-weighted magnetic reso-
nance images (B, sagittal precontrast; C, axial postcontrast; D, coro-
nal postcontrast) showed an inhomogenously enhancing cystic mass
in the right temporal lobe. Biopsy was diagnostic of glioblastoma
multiforme.
Figure 12.29. Incomplete mildly incongruous homonymous hemianopia in a patient with a left parietal lobe glioblastoma.
The field defect in both eyes is denser inferiorly. The mild incongruity associated with the inferior nature of the defects is
typical of damage to the optic radiations in the parietal lobe.
Figure 12.30. A 37-year-old woman complained of intermittent headaches associated with

visual hallucinations of ‘‘a swirling black circle in the left eye.’’ A, Examination was normal
except for left homonymous inferior quadrantic visual field defects. B, Computed tomography
scan after the administration of intravenous contrast revealed a large, dural-based homogenously
enhancing right parietal lobe tumor with little mass effect, confirmed at surgery to be a menin-
gioma.
Figure 12.31. A, A 17-year-old man had a complex partial seizure and was found to have a left temporal lobe cystic fibrillary
astrocytoma. The tumor was partially resected and then irradiated. B, Follow-up 6 years later showed a right inferior homonymous
quadrantanopia. (Figure continues.)
to the side opposite the lesion on forced lid closure (Cogan’s disturbances caused by lesions in the parietal lobe include
sign), and an abnormal optokinetic response. The abnormal visual neglect, visual agnosia, and difficulties with word rec-
optokinetic response consists of defective slow and fast ognition (see Chapters 28 and 40 for more detailed discus-
phases when targets are moved toward the side of the lesion, sion). As noted above, patients with parietal lobe lesions and
a maneuver that necessitates pursuit movements to that side homonymous visual field defects are often unaware of their
and saccades to the opposite side (287). The basis for such visual deficits. This phenomenon is more likely to be ob-
a response is discussed in Chapter 17. Other types of visual served when the underlying abnormality is in the nondomi-
Figure 12.31. Continued. C–E, Repeat MR imaging revealed a smaller cystic

lesion in the region of the optic radiations. The lesion does not extend into the
occipital lobe.
nant cerebral hemisphere (usually the right parietal lobe), sense, stereognosis, and visual-spatial coordination (288).
but it can also be observed in patients with dominant parietal Irritative lesions of the postcentral gyrus cause sensory Jack-
lobe lesions. In other patients, the primary visual pathways sonian seizures that begin contralateral to the lesion at the
may be unaffected or minimally affected, but the patient part of the body corresponding to the excitation focus. Tin-
neglects the contralateral visual field (see Chapter 13). gling or numbness spreads to adjacent parts of the body
Parietal lobe lesions cause other symptoms and signs. The according to the order of their representation in the cortex
parietal lobe is the principal sensory area of the cerebral (Jacksonian march). Lesions in the dominant parietal lobe
cortex, and the postcentral gyrus is particularly important. can cause aphasia (usually fluent), apraxia, agnosia, acalcu-
The patient may complain of numbness, but more commonly lia, and agraphia. A lesion in the dominant parietal lobe
there are more complex problems of sensory integration, as affecting the angular gyrus may produce Gerstmann’s syn-
demonstrated on tests of tactile discrimination, position drome (finger agnosia, right–left disorientation, agraphia,
Figure 12.32. A 45-year-old woman with

probable demyelinating disease presented
with blurring of the left lower visual field.
A, Automated static threshold perimetry
showed a dense left inferior congruous
quadrantanopia bordering the horizontal
meridian (top) that improved over time
(middle) to only a residual small left infe-
rior relative scotomatous defect (right). B
and C, Proton-density-weighted magnetic
resonance images (B, axial; C, coronal)
demonstrated multiple periventricular
white matter lesions, including a lesion at
the right trigone (arrow). Diagrams demon-
strate the relationship of this lesion (in
black) to the optic radiations (OR; dashed
lines or stippled area). T, trigone; LGN,
lateral geniculate nucleus. (From Borruat
FX, Zurakowski RM, Schatz NJ, et al. Con-
gruous quadrantanopia and optic radiation
lesion. Neurology 1993;43⬊1430–1432.)
and acalculia) in association with a right homonymous hemi- circumscribed lesions in the occipital lobe, Horton and Hoyt
anopia (289,290). Lesions in the nondominant parietal lobe (298) estimated that the central 10⬚ of the visual field are
may cause impaired constructional ability, dyscalculia, and, represented by at least 50–60% of the posterior striate cortex
most commonly, inattention or neglect (291,292). Indeed, and that the central 30⬚ is represented by about 80% of the
left spatial neglect after right hemisphere lesions may accen- cortex (Figs. 12.34 and 12.35). These findings were corro-
tuate the left hemianopia, hemianesthesia, and hemiplegia borated by McFadzean et al. (299). Instead of using lesions
and contribute to poor recovery (293). for mapping, it is possible to use functional MR imaging to
detect those areas of the cortex activated by visual stimuli,
LESIONS OF THE OCCIPITAL LOBE AND and thus to produce a retinotopic map noninvasively (301).
VISUAL CORTEX Wong and Sharpe used functional MR imaging to map the
In many cases the most posterior visual radiation and vis- retinal representation on the occipital lobe and found that
ual cortex are affected together. Most lesions in the occipital the central 15% of vision occupied only 37% of the cortex
lobe are vascular or traumatic in origin, with tumor, abscess, (302). Probably the most accurate method for determining
demyelination, and toxic disorders of white matter occurring cortical magnification (i.e., the degree by which areas of
less frequently. Cole, a neurologist, has written a first-person central retina are processed by magnified areas of visual
account of his experience as a patient with an occipital cortex) is the use of angioscotoma mapping (303,304).
stroke, which includes some of the symptomatology de- Adams and Horton (305) used this mapping technique in
scribed below (294). squirrel monkeys and found that the central 16⬚ of visual
Because of the close anatomic relationship of fibers from field is represented by approximately 70% of cortex. Similar
corresponding portions of the two retinas, lesions of the oc- cortical magnification of the central visual field is seen in
cipital lobe cause defects that are not only overwhelmingly the extrastriate areas V2 and V3 (306). The detailed anatomy
homonymous but also increasingly congruous the more pos- of the visual cortex is discussed in Chapter 1.
teriorly situated the lesion (295–299). Automated static pe- Lesions located more anteriorly may produce primarily
rimetry may inaccurately portray homonymous visual fields central field defects that break out into the periphery (Fig.
as incongruous, compared to Goldmann or tangent screen 12.36). Impressive congruity is a feature of such field defects
perimetry (300). (257,307,308). The phenomenon of sparing of the macula
is often seen in such cases (see below).
Unilateral Lesions of the Posterior Occipital Lobe An unusual visual field defect is homonymous hemi-
Defects seen with these lesions are exclusively homony- anopia associated with sparing of the horizontal or vertical
mous. With lesions of the tip of the occipital lobe (occipital meridian. This results from sparing from injury of the corre-
pole), the field defects are always central homonymous sco- sponding cortical representation of the meridian, with the
tomas that are exquisitely congruous (257,296,298,299) vertical meridian represented at the lips of the calcarine fis-
(Fig. 12.33). After a detailed examination of three patients sure and the horizontal meridian represented at the base of
with homonymous visual field defects produced by well- the fissure (309,310).
Figure 12.33. Exquisitely congruous homonymous hemianopic scotomas in a patient with an infarct of the inferior lip of the
left calcarine cortex. Note the few degrees of macular sparing.
Figure 12.34. A 30-year-old woman reported several episodes of flashing colored lights in her right upper quadrant of vision.
A, Merged 30-2 and 60-2 full-threshold visual field tests using a Humphrey Field Analyzer. A homonymous, congruous scotoma
was present in the right upper quadrant. In the inset, the visual fields are mapped at the tangent screen. The scotoma extended
from 6⬚ to 18⬚. B, Parasagittal magnetic resonance image of the left occipital lobe. The lesion (cross-hatched area on the right)
is within the visual cortex (stippled area on the right). The calcarine sulcus (solid arrow) and the parieto-occipital sulcus (open
arrow) are marked by dots. On biopsy, the lesion was a presumed tuberculoma. (From Horton JC, Hoyt WF. The representation
of the visual field in human striate cortex. Arch Ophthalmol 1991;109⬊816–824.)
Both Allen and Carman (311) and Barkan and Boyle (312) paired throughout the postchiasmal portion of the visual sen-
reported a syndrome in which an otherwise healthy patient sory pathway. Damage to these unpaired peripheral fibers
develops the sudden onset of an isolated homonymous para- produces a monocular defect in the extreme temporal visual
central scotoma associated with normal visual acuity and field. This field defect is crescentic and its widest extent is
no ophthalmoscopic abnormalities. Clinically, such a lesion in the horizontal meridian, where it extends from 60⬚ out to
must occur as the result of a vascular event in the posterior approximately 90⬚. Because of its peculiar shape, a defect
occipital cortex; however, in both cases, the homonymous in this region has been termed a temporal crescent or half-
scotomas were incongruous. The explanation for this appar- moon syndrome (Figs. 12.35C, 12.37, and 12.38). Brouwer
ent clinical–anatomic discrepancy is unclear. and Zeeman (313) demonstrated that after destruction of the
peripheral nasal retina there was degeneration of a bundle
Unilateral Lesions of the Anterior Occipital Lobe of fibers localized in the median portion of the optic nerve,
Because the temporal field in each eye is larger than the which continued into the optic chiasm to the median portion
nasal field, the fibers subserving that portion of the periph- of the optic tract and spread ventrally into the lateral genicu-
eral temporal field that has no nasal correlate must be un- late body. Wilbrand (6) confirmed that this bundle contained
Figure 12.35. Humphrey visual fields (30-2 program) (A) in a 40-year-old man who suffered a right occipital infarction (B)
involving the superior bank of the calcarine cortex (arrowhead). The infarction spared the posterior striate cortex as well as
the anterior striate cortex at the junction of the parieto-occipital and calcarine fissures (arrow). C, The visual fields showed
sparing of central fixation within 6⬚ as well as sparing of the left monocular temporal crescent. (From McFadzean R, Brosnahan
D, Hadley D, et al. Representation of the visual field in the occipital striate cortex. Br J Ophthalmol 1994;78⬊185–190.)
only crossed fibers. In 1929, Förster (quoted by Walsh [314]) it or eliminate it entirely. Spence and Fulton (318) extirpated
produced the sensation of light in the extreme temporal pe- the entire left occipital lobe in a chimpanzee and later re-
riphery of one eye by electrically stimulating the most ante- sected part of the right occipital lobe. They subsequently
rior portion of the striate cortex. Polyak (315) confirmed observed that the animal had vision only in the temporal
these findings and postulated that the most anterior portion periphery of the left eye. Postmortem examination of the
of the striate cortex harbored the projected monocular tem- brain disclosed that only the anterior portion of the right
poral crescent of the contralateral eye. Ask-Upmark (316) striate cortex was intact, confirming the conclusions reached
and Kronfeld (317) performed further studies in patients in by Polyak (315), Ask-Upmark (316), and Kronfeld (317).
whom the temporal crescent was selectively spared or dam- According to Bender and Strauss (208), the unpaired nasal
aged. They agreed that lesions of the posterior striate cortex fibers corresponding to the extreme temporal peripheral vis-
tended to spare the temporal crescent, whereas lesions of the ual field come together in the most anterior portion of the
anterior striate cortex could selectively produce a defect in striate cortex, with the fibers for the inferior portion of the
Figure 12.36. Inferior homonymous hemianopic scotomas that break out to the periphery in a patient with an infarct of the
left superior occipital cortex.
Figure 12.37. Visual field defects in a 22-year-old woman who suffered bilateral occipital lobe infarctions. There is a complete
left homonymous hemianopia and an incomplete right inferior homonymous quadrantanopia. The temporal crescent is absent
from the right visual field.
Figure 12.38. Visual field defects in a 56-year-old woman with a right occipital lobe infarction. There is a left homonymous
hemianopia with sparing of the inferior portion of the left temporal crescent.
crescent terminating above the calcarine fissure and the fi- the nasal retinal periphery should be carefully examined oph-
bers for the superior portion of the crescent terminating thalmoscopically in such cases. Second, because these de-
below the fissure. fects begin approximately 60⬚ from fixation, central field
Bender and Strauss (208) found that in 100 patients with testing (i.e., that performed using a tangent screen or most
verified cerebral tumor affecting the posterior optic radia- automated static perimetry programs) gives normal results
tion, there was a unilateral temporal crescentic defect in the and will not detect such defects (321,322) (Fig. 12.39).
visual field of 10 patients. The recognition of such a defect
has value in the early diagnosis of a lesion of the posterior Bilateral Effects of Unilateral Occipital Lobe Lesions
optic radiation or anterior visual cortex. Theoretically, a le-
sion anywhere in the postchiasmal visual pathway, from the Although patients with unilateral lesions of the occipital
optic tract to the occipital lobe (and particularly the dorsal lobe typically have visual deficits totally restricted to the
LGB), could produce a monocular field defect in the tem- contralateral field, area V1 and adjacent extrastriate areas
poral periphery (244); however, in practice, only lesions in often function or fail in concert. Pathologic lesions of the
the posterior optic radiation or anterior visual cortex produce occipital lobe thus may disrupt not only area V1 but also
such selective damage. adjacent underlying white matter and extrastriate cortex.
Both upper and lower temporal crescents may be scotoma- Such damage may alter interhemispheric connections along
tous in the field of one eye, or only the upper or lower their presplenial course and even disturb visual cortical–sub-
temporal crescent may be affected. Frequently, such a field cortical connections. Nonetheless, there is excellent evi-
defect is followed later by the development of an homony- dence that there are regions of cortex ipsilateral to the field
mous hemianopia (316). Bender and Strauss (208) fairly defect that process visual information (323,324). Rarely, cor-
often found an unpaired crescentic relative scotoma medial tical plasticity in the setting of congenital cerebral lesions
to the peripheral absolute scotoma, indicating to them that can lead to developmental reorganization of the visual pro-
the optic radiation has a lamellar arrangement. cessing areas so that the visual field is represented ipsi-
Just as the temporal crescent may be affected by lesions laterally (325). There is also indirect evidence for reorgani-
destroying the most anterior occipital lobe, it may likewise zation of projections to extrastriate visual processing areas
be spared when the remainder of the temporal visual field is after injury to V1 (326).
affected in an homonymous hemianopia (284,314,319,320) For example, in a study by Bender and Teuber (327,328),
(Figs. 12.35 and 12.38). Such sparing seems to occur exclu- dark adaptation was delayed in the apparently normal field.
sively in patients with occipital lobe lesions that spare the Rizzo and Robin (329) studied the vision of 12 patients with
anterior aspect of the visual cortex (208). unilateral lesions of the visual cortex. All patients had hom-
Two important facts should be kept in mind when consid- onymous defects in the contralateral visual fields, as ex-
ering the temporal crescent syndrome. First, monocular pe- pected, and all had visual acuity of 20/30 or better in both
ripheral temporal visual field defects are probably caused eyes. The first experiment performed by Rizzo and Robin
most often by retinal lesions, not by intracranial ones. Thus, (329) tested the subjects’ ability to respond to transient sig-
Figure 12.39. Migrainous loss of the temporal crescent. A, A 31-year-old woman with a history of migraine without aura
had the sudden onset of a bright light in the temporal field of vision of the right eye, followed by loss of vision in this same
region, and subsequent headache. The field deficit persisted for a few days and then resolved. B, Visual fields performed 5
days later were full in both eyes. Magnetic resonance imaging performed at the time of the initial deficit was completely
normal.
nals presented at unpredictable temporal intervals and spatial Subsequent experiments by Battelli et al. (329a) showed
locations among many spatially random and identical dis- ipsilateral effects of right parietal lobe lesions on motion
tracter elements. The results showed that compared with con- detection and suggested that some of these effects could be
trols, the lesion group had a significantly reduced sensitivity mediated by specific alterations in attention circuits. Al-
to signal and increased response times in both hemifields. though these disturbances are subtle compared with the hom-
In a second experiment, Rizzo and Robin (329) tested the onymous visual field defects that occur in patients with uni-
useful field of view in two of the patients under conditions lateral occipital lobe lesions, they may be responsible for
of differing attention demand. Both patients showed bilateral various unexplained complaints of reduced performance in
constriction, consistent with the results of the first experi- tasks with high visual information-processing demands such
ment. Rizzo and Robin suggested that one possible explana- as reading and driving.
tion for the bilateral effects of unilateral occipital lobe le-
sions is damage to interhemispheric connections along their Macular Sparing
presplenial course, affecting the synthesis of visual informa-
tion from both hemifields. The disturbances are task-depen- When a portion of the central field of each eye in homony-
dent and seem to result from a global reduction in visual mous hemianopia is preserved as a result of deviation of the
attention capacity. vertical meridian between the functioning and nonfunction-
ing halves of the visual fields, there is said to be ‘‘sparing ing is controversial. Some authors consider it an artifact of
of the macula’’ or ‘‘macular sparing.’’ In a majority of such testing. Others believe it is a real phenomenon related to the
cases, visual acuity is normal, with the zone of preserved representation of a small portion of each macula in each
visual field ranging from 1⬚ or 2⬚ in width to almost 10⬚ occipital lobe. Finally, some authors believe that macular
(Fig. 12.40). Another type of field in which there is sparing sparing results from incomplete damage of the visual path-
is the ‘‘overshot’’ field (284). In such a visual field, the ways or occipital lobe. This section addresses each of these
sparing is not central alone but extends along the entire verti- theories in turn.
cal meridian. A complete discussion of this phenomenon What has been represented as wide sparing may often be
appears in the paper by Safran et al. (330). shown in reality to be much narrower when ocular fixation
Deviation of the vertical meridian accounting for macular is carefully controlled. Hence, imprecisely charted fields
sparing is a much-debated phenomenon. Although it is usu- tend to show a wider sparing than actually exists. In many
ally seen in patients with retrogeniculate (usually occipital) cases of homonymous hemianopia with sparing, it is possible
lesions, the absence of sparing does not imply that the lesion to prove a shift in fixation by charting the blind spot in the
is pregeniculate or noncortical. The etiology of macular spar- single field in which it can be performed. Another method
Figure 12.40. A 28-year-old woman suffered a persis-

tent visual field defect after an unusually severe migraine
attack. A, Full-threshold 60⬚ visual fields using a Hum-
phrey Field Analyzer show the central 15⬚ of the left hemi-
field is intact. In the inset, the visual fields mapped at the
tangent screen show that the field defect bisects the blind
spot representation of the left eye. B, T1-weighted parasag-
ittal magnetic resonance image through the right occipital
lobe shows an arteriovenous malformation involving the
anterior portion of the right calcarine cortex. The posterior
margin of the lesion is situated 31 mm from the occipital
tip, marking the approximate location of the representation
of the left eye’s blind spot. The calcarine (curved arrow)
and parieto-occipital (straight arrow) sulci are indicated.
(From Horton JC, Hoyt WF. The representation of the
visual field in human striate cortex. Arch Ophthalmol
1991;109⬊816–824.)
is performing a tangent screen examination using three or macular splitting. As the hemorrhage resolved, the patient
more identical stimuli slowly brought horizontally from the developed macular sparing, initially of 5⬚ and then of 10⬚.
defective hemifield toward the vertical meridian. One stimu- From a study of reported cases of occipital lobectomy and
lus moves toward fixation, as the others simultaneously five cases studied personally, Dubois-Poulsen et al. (336)
move inward to points 10–15⬚ above and below fixation. also supported the concept of macular representation in both
With genuine macular sparing, the central stimulus is per- occipital lobes as an explanation for macular sparing. These
ceived before those above and below it. If there is defective researchers endorsed a theory that had first been proposed
fixation and shifting of the entire hemifield, however, all by Morax (337), who suggested that in the foveal region of
targets are simultaneously perceived. the retina there is a small vertical band of ganglion cells,
It is impossible to obtain absolutely stable fixation, and some of which have crossed and others uncrossed fibers.
physiologic movements of the fixing eye so slight that they Gramberg-Danielsen (338) supported this thesis in a thor-
cannot be detected by ordinary means probably account for ough review of the problem of macular sparing. He empha-
1–2⬚ of deviation of the vertical meridian about the central sized the inexact nature of the vertical border between the
area. Verhoeff (331) emphasized the importance of the optic two hemifields and called attention to a functional vertical
fixation reflexes in cases of macular sparing. He suggested overlap of the two sides of the visual field in the form of a
that loss of integration between the seeing field and the blind narrow band that is widest near the fovea. At the retinal
field in the conscious visual cortical area in use might result level, ganglion cells and their dendritic processes overlap
in eccentric fixation. As a result of fixation slippage, the and intertwine without any morphologic suggestion of the
original macular field would be split but would appear to functional vertical separation of the two halves of the retina,
be spared during field testing. Sugishita et al. (332) used corresponding to the temporal and nasal halves of the visual
fundus perimetry combined with fundus image analysis in field. Halstead et al. (339) carefully studied the visual fields
two subjects with left occipital lesions and ‘‘macular spar- of two patients who underwent complete occipital lobectomy
ing.’’ Two of the four eyes tested showed eccentric fixation, and found ‘‘splitting’’ in one case and ‘‘sparing’’ in the
and miniature eye movements to the blind hemifield were other. From a study of occipital lobectomy cases, Huber
observed in 4–10% of the trials. Using microperimetry and (340) (who subsequently declared macular sparing to be an
a scanning laser ophthalmoscope, Bischoff et al. (333) also artifact [333,341]) also confirmed the phenomenon of macu-
demonstrated rapid fixation shifts in their patients with lar sparing, favoring the theory of bilateral foveal representa-
‘‘macular sparing’’ of 1–5⬚. These authors concluded that tion probably explained at the level of the retina.
this typical macular sparing may be a functional adaptation Cowey (342) found occasional anomalous receptive fields
of the ocular motor system to enhance the central visual field for cells in the squirrel monkey’s cortical fovea. All of his
toward the blind hemifield. animals had previously had an occipital lobectomy. Record-
In 1928 Lenz (334) proposed that a small fiber tract sub- ing from a microelectrode in a single cortical unit in the
serving the macular region branched from the optic tract foveal area of the monkey’ intact occipital lobe, he was able
through the corpus callosum to the opposite visual cortex, to evoke responses from the parafoveal area of the ‘‘blind’’
providing representation of the macula in both occipital visual field. He recognized the similarity of his experimental
lobes. The presence of bilateral representation of the macula finding to the clinical observation of macular sparing follow-
was further suggested by Penfield et al. (277), who studied ing occipital lobectomy in man.
five patients after radical extirpation of the occipital lobe. It is clear from histochemical studies that, to some extent,
In two instances, the posterior portion of the lobe was ex- a small portion of each macula probably has representation
cised. In both, there was complete homonymous hemianopia in each occipital lobe. As noted in Chapter 1, there is a small
with splitting of the macula. In two other cases, a large por- area of nasotemporal overlap on either side of the vertical
tion of the lobe was removed, and it was thought that the meridian in which some axons from ganglion cells temporal
entire calcarine cortex was included. Nevertheless, follow- to the fovea cross within the chiasm, whereas some axons
ing surgery, the patient had an homonymous hemianopia from ganglion cells nasal to the fovea remain uncrossed
with macular sparing and retention of normal visual acuity. (210,211,213,214,343). In the monkey, the nasotemporal
The fifth and most interesting case studied by Penfield et overlap is smallest (about 1⬚ of visual angle) near the fovea
al. (277) was one in which there was complete destruction and increases at least twofold in more peripheral retina
of the calcarine cortex of one side. This pathologic process (213,214). Scanning laser ophthalmoscopy has demon-
resulted in homonymous hemianopia with sparing. When strated this zone of nasotemporal overlap in humans that
the diseased occipital lobe was extirpated, the line of resec- extends into the blind hemifield, with a slightly concave
tion was so far forward that it was adjacent to the splenium shape (344).
of the corpus callosum. Subsequent to the resection there Despite the presence of a nasotemporal overlap that exists
were further field changes in that the vertical meridian failed in nonhuman primates and presumably in humans as well,
to deviate about the point of fixation. Thus, ‘‘sparing of the the mere presence of an overlap does not necessarily have
macula’’ was converted into ‘‘splitting of the macula.’’ Ohki major visual consequences. Sugishita et al. (332) concluded
et al. (335) described a case that was the reverse of Penfield’s that dual macular representation, if it exists in humans, must
fifth case. The patient was a 62-year-old man who experi- be less than 0.4⬚ wide, and Brysbaert (345) also questioned
enced a left parieto-occipital hemorrhage. When first exam- the clinical significance of bilateral macular representation.
ined, the patient had a right homonymous hemianopia with Of more importance, however, is that a ganglion cell located
on one side of the fovea does not necessarily receive input tion of some functioning posterior occipital cortex. In other
from a photoreceptor located on the same side. The much cases, macular sparing may reflect fixation artifact or bilat-
larger width of the cone pedicle compared with the foveal eral representation. Together, the consequences of these the-
cone soma creates a packing problem that is only partly ories can explain the great variability in macular sparing
resolved by lateral displacement of cone pedicles and via seen in retrochiasmal disease.
the nerve fiber layer of Henle. This lateral shift could theo-
retically connect photoreceptors on one side of the vertical Bilateral Occipital Lobe Lesions
meridian to seemingly distant ganglion cells on the opposite
side (266). Such an anatomic relationship would have no Bilateral lesions of the occipital lobes may occur simul-
visual consequences, because it is the position of the photo- taneously or consecutively. Because such lesions are neuro-
receptor and not the ganglion cell body that determines the logically asymptomatic except with respect to the visual sys-
location of visual input to the brain. The anatomic inexact- tem, patients with unilateral lesions that have caused a
ness of the vertical demarcation can be observed clinically homonymous field defect may not be aware of the defect
by visual field testing (289). until their attention is called to it (e.g., during a routine ocular
Nonetheless, the most likely cause of true macular sparing examination or after a motor vehicle accident) or until they
in clinical practice is incomplete damage to the visual path- experience a similar event on the opposite side.
ways, particularly the occipital lobe. Wilbrand (347) sug- Förster first described a patient with a well-documented,
gested that macular sparing was the result of residual intact partial, bilateral homonymous hemianopia in 1890 (348).
areas of the visual pathways. McAuley and Russell (308) The patient initially sustained a right homonymous hemia-
noted an association between macular sparing and retained nopia followed by a left homonymous hemianopia with spar-
portions of the most posterior portion of the occipital cortex ing of central vision. Numerous case reports subsequently
(Fig. 12.41). These observations are supported by the work documented this condition and its many causes (349–358).
of Horton and Hoyt (298), who demonstrated the extremely Bilateral homonymous hemianopia may appear simul-
high cortical magnification of the macular representation taneously. In a majority of these cases, there is initially com-
(Fig. 12.40). The unique dual blood supply of the occipital plete visual loss; however, this total blindness is usually
cortex from the posterior cerebral and middle cerebral arter- transient, lasting from minutes to days (359,360). Nepple et
ies (see Chapters 1 and 39) provides a mechanism for this al. (356) reviewed the findings in 15 patients with bilateral
partial damage. In patients with homonymous hemianopia homonymous hemianopia. All patients had similarly shaped
and substantial macular sparing, not only is the location of visual field defects on corresponding sides of the vertical
the lesion almost always the occipital lobe, but also the patho- midline for each eye, symmetric (and usually normal) visual
genesis is likely posterior cerebral artery infarction. In these acuity, normal pupils and fundi, and normal ocular motility
cases, the most common cause for macular sparing is reten- unless there was a coexisting brain stem lesion. The majority
Figure 12.41. A 52-year-old man with coronary artery disease and thrombocytopenia purpura noticed trouble seeing to the
left side with his left eye. A, Examination was normal except for visual fields, which showed an incongruous left homonymous
quadrantic defect, denser in the left eye. (Figure continues.)
Figure 12.41. Continued. B and C, Magnetic resonance images (B, T2-weighted; C, T1-weighted after gadolinium) showed
a curvilinear enhancing lesion in the medial, anterior, right occipital lobe consistent with infarction (arrows).
of patients had bilateral posterior cerebral artery insuffi- tumors reviewed by Schaublin (361), there were no patients
ciency caused by arteriosclerosis (40%), uncal herniation with bilateral homonymous hemianopias.
from subdural hematoma (20%), or migraine (13%). Most Bilateral homonymous hemianopia may also occur from
of these patients had a history suggestive of simultaneous consecutive events, invariably vascular (Fig. 12.42). This is
bilateral occurrence. Brain tumor did not occur in this series; a much more common phenomenon than is bilateral simul-
conversely, in 849 patients with visual field defects and brain taneous homonymous hemianopia. In such cases, the patient
Figure 12.42. A, Bilateral homonymous hemianopic defects secondary to bilateral posterior cerebral artery infarction. Note
the dense right homonymous hemianopia combined with a left inferior homonymous quadrantanopia with sparing of the left
temporal crescent. (Figure continues.)
Figure 12.42. Continued. B–D, T2-weighted magnetic resonance

images demonstrated bilateral posterior cerebral artery infarctions,
worse on the left than the right, and extending less inferiorly and less
anteriorly on the right.
experiences an acute homonymous hemianopia with reten- hemianopia from infarction of both occipital lobes is most
tion of normal vision with or without sparing of the macula. frequently observed in elderly atherosclerotic individuals
At a later time, varying from weeks to years, the patient and may be associated with hypertensive crisis. In some
develops a sudden homonymous hemianopia on the opposite instances, there are premonitory visual disturbances such as
side, again with or without macular sparing. After this sec- flashing lights or visual hallucinations. Because the vascular
ond event, the patient is either blind or retains only a small supply to association areas of the visual cortex may be inter-
central field around the point of fixation, similar to that seen rupted, there may also be visual agnosia and other distur-
in simultaneous cases. bances of higher cortical function.
The syndrome of bilateral nonsimultaneous homonymous Bilateral vascular lesions of the occipital lobes produce
bilateral homonymous lesions that are characteristic and sion returned, the patient noted that although he could see
vary only in their extent. They may be complete or scotoma- clearly in the exact center of his field, the paracentral area
tous, and they may or may not be accompanied by macular was blurred. Visual field testing demonstrated bilateral, con-
sparing. Bender and Furlow (362,363), for instance, de- gruous, homonymous scotomas with macular sparing (Fig.
scribed ‘‘central scotomas’’ produced by bilateral lesions 12.43C and D).
of the occipital lobes. Such defects are, in reality, bilateral Bilateral occipital lobe disease, whether from infarction,
homonymous scotomas that may be detected by careful field tumor, or trauma, may result in various degrees of bilateral
testing along the vertical midline (364) (Fig. 12.43A and B). homonymous hemianopia (Fig. 12.44). There may be com-
Occasionally, such scotomas have enough central sparing to plete (cortical or cerebral) blindness. The hemianopia may
produce ‘‘ring’’ scotomas. One such patient had complete be complete on one side and incomplete (and congruous) on
blindness transiently following a tractor accident. When vi- the other, or there may be a hemianopia on one side and a
Figure 12.43. A and B, Bilateral homonymous hemianopic scotomas in a patient with bilateral nonsimultaneous occipital
lobe strokes. C and D, Note vertical step that differentiates these defects from a true central scotoma with macular sparing in
a patient who suffered trauma to the occipital region. The tractor on which he was riding overturned, pinning him underneath
for several minutes. Initially, he was completely blind, but vision returned within several minutes. He subsequently realized
that he had a ‘‘ring’’ of blurred vision around fixation. Note that the homonymous scotomas respect the vertical midline.
Figure 12.44. A 40-year-old man suffered occipital head

trauma with a depressed skull fracture and visual com-
plaints. Visual acuity was 20/20 in both eyes. A, Visual
fields revealed exquisitely congruous bilateral homony-
mous scotomas, larger on the left than the right. A com-
puted tomography scan (B) revealed a right occipital pole
lesion, but magnetic resonance images (C and D) con-
firmed bilateral occipital pole involvement.
Figure 12.45. After strenuous exercise, a 33-year-old man suffered intermittent confusion, gait disturbances, and right facial
weakness, followed by permanent left hemiparesis and difficulties with vision. A, Visual fields revealed a right homonymous
hemianopia with macular sparing and a left superior homonymous quadrantanopia. B, Magnetic resonance imaging revealed
the corresponding infarctions in the occipital lobes bilaterally. Note the involvement of the inferior occipital lobe on the right
and the entire calcarine cortex on the left, with sparing of the most posterior pole. The patient also had cerebellar and brain
stem infarctions, all secondary to artery-to-artery emboli from a vertebral artery dissection.
quadrantanopia on the other (307,365) (Figs. 12.42 and cipital lobe above the calcarine fissure on one side and the
12.45). In some instances, there may be a bilateral homony- inferior occipital lobe below the fissure on the other side.
mous hemianopia with bilateral macular sparing of a differ- Such defects are sometimes called checkerboard fields and
ent degree on each side. The remaining visual field thus are infrequent (Fig. 12.47). Felix (366) described a case and
appears to be severely constricted, and such patients may be reviewed the literature up to 1926, which included only two
thought to have bilateral optic nerve or retinal disease or other cases. In the case reported by Felix and in one other
may even be thought to have nonorganic visual field loss. As case, this field defect followed a simultaneous bilateral hom-
with bilateral homonymous hemianopic scotomas, however, onymous hemianopia, although a case described by Groe-
careful testing along the vertical midline will establish the nouw (quoted by Felix [366]) occurred after two separate
bilateral nature of the field defect and its correct origin (Fig. vascular events occurring 10 months apart.
12.46). Although bilateral altitudinal field defects are usually
Crossed quadrant hemianopia results when patients de- caused by bilateral anterior optic nerve disease (e.g., glau-
velop bilateral quadrantic defects, either simultaneously or coma or nonarteritic anterior ischemic optic neuropathy),
more commonly consecutively, that affect the superior oc- they can also be caused by bilateral occipital lobe disease
Figure 12.46. Bilateral homonymous hemianopias with macular sparing in a patient with severe cerebrovascular occlusive
disease. The patient initially presented with 20/20 vision in both eyes but with ‘‘tubular’’ fields. The macular sparing respects
the vertical midline.
(e.g., from trauma, infarction, hemorrhage, and rarely tu- of the visual cortex or posterior radiations were damaged,
mors). Such lesions were studied extensively by Holmes and however, the patient often survived, and the resultant field
Lister (375) and were subsequently described in more detail defects in such cases were altitudinal, with loss of the entire
by Holmes (367), who observed that bullet wounds interrupt- inferior field of both eyes.
ing both occipital lobes were usually fatal if the lower por- Money and Nelson (1943) described field defects similar
tions were damaged because death occurred from intracra- to those reported by Holmes (367), and Wortham et al. (368)
nial bleeding as a result of laceration of the dural sinuses in reported bilateral inferior hemianopia occurring during
the region of the torcular herophili. When the upper portions or immediately following thoracoplasty. The defect was
Figure 12.47. Crossed quadrant (checkerboard) hemianopia. These field defects occurred suddenly in a 70-year-old woman
with basilar artery disease. Note the quadrantic defects in the right upper field and the left lower field with the narrow congruous
isthmus near fixation. Also note the sparing of the left temporal crescent and the incongruity of the field defects along the
upper vertical meridian and the right horizontal meridian. (Courtesy of University of California Hospital, San Francisco.)
thought to have resulted from anoxia, and slight improve- occurs (378,379). The most common mechanism for the in-
ment occurred over the next several months’ observation. farction is cerebral embolism from either the heart or the
Newman et al. (369) described two cases of bilateral altitudi- more proximal vessels of the vertebrobasilar system
nal hemianopia, one inferior and one superior, secondary to (380,381) (Fig. 12.51). Prolonged hypotension can cause
occipital infarctions that were demonstrated by CT scanning, cortical blindness from bilateral watershed infarctions at the
and a similar case was confirmed both on neuroimaging and parieto-occipital junction. Courville (382), among others,
pathology by Vanroose et al. (370). Other cases secondary recognized that hypoxia causes laminar cortical necrosis and
to occipital infarction or hemorrhage occur, occasionally in that the visual, premotor, and parietal areas are particularly
the setting of cardiac surgery or hypoxia (308,353,368, apt to be damaged by this process. Courville (382) expressed
371–376). the opinion that these areas seemingly had a higher oxygen
Based on the preceding, it can be understood why superior requirement. Lindenberg (383) emphasized that the affected
altitudinal defects from occipital lobe trauma are less com- areas represent the border zones of cerebral circulation.
mon than inferior altitudinal defects. An example of the for- Cortical blindness is observed under many circumstances
mer, occurring in a patient where a bullet passed from right other than infarction, including trauma, neoplasm, malignant
to left through the inferior portions of both occipital lobes hypertension, toxemia of pregnancy, diseases of white mat-
but missing the dural sinuses, is depicted in Figure 12.48. ter (e.g., Schilder’s disease, adrenoleukodystrophy, Peli-
On the other hand, both superior (Fig. 12.49) and inferior zaeus-Merzbacher disease, metachromatic leukodystrophy,
bilateral altitudinal defects can occur with vascular disease progressive multifocal leukoencephalopathy), Creutzfeldt-
affecting the occipital lobes. When the lesion is far posterior, Jakob disease, mitochondrial encephalopathy lactic acidosis
the field defect remains altitudinal but is central and scoto- and stroke-like episodes (MELAS), cerebral angiography,
matous (Fig. 12.50). Spalding (296) confirmed the impres- ventriculography, blood transfusions, uremia, acute intermit-
sive congruity of these small field defects. tent porphyria, syphilis, infectious and neoplastic meningitis,
bacterial endocarditis, subacute sclerosing panencephalitis,
Cortical (Cerebral) Blindness hepatic encephalopathy, sudden elevation or reduction in
intracranial pressure, cardiac arrest, hypoglycemia, correc-
Cortical blindness and cerebral blindness are considered tion of hyponatremia, epilepsy, electroshock, and after expo-
in the same section because in many instances it is impossi- sure to carbon monoxide, nitrous oxide, ethanol, licorice,
ble to differentiate between them on clinical grounds. The methamphetamine, mercury, lead, cis-platinum, cyclosporin
term ‘‘cortical blindness’’ indicates loss of vision in both A, tacrolimus (FK506), methotrexate, vincristine, vindesine,
eyes from damage to the striate cortex. ‘‘Cerebral blind- and interferon (379,384–418). The mechanism of injury un-
ness’’ is a more general term indicating blindness from dam- derlying the cortical blindness caused by these events or
age to any portion of both visual pathways posterior to the substances is not always known, but vascular insufficiency
lateral geniculate bodies. Thus, cortical blindness is a subset plays a role in many of them.
of cerebral blindness. Patients with cerebral blindness may In certain situations, cortical blindness is transient. This
have other neurologic deficits, including hemiplegia, sen- is particularly true in patients who experience transient vas-
sory disorders, aphasia, and disorientation. Because of the cular insufficiency in the vertebrobasilar system, in hyper-
similarity in the visual system symptomatology between tensive syndromes following restoration of normal blood
these two conditions, for the sake of simplicity the term pressure, after removal of many of the toxic agents listed
‘‘cortical blindness’’ will be used in this section. above, and after trauma (417,419–421). Children are more
The essential features of cortical blindness as outlined by likely to experience recovery from cortical blindness than
Marquis (377) are (a) complete loss of all visual sensation, adults, regardless of the underlying cause. Barnet et al. (419)
including all appreciation of light and dark; (b) loss of reflex studied six children who developed transient cortical blind-
lid closure to bright illumination and to threatening gestures; ness after respiratory or cardiac arrest, head trauma, or men-
(c) retention of the reflex constriction of the pupils to illumi- ingitis. In all cases, visual acuity returned to some extent
nation and to convergence movements (the near-response); in 1–10 weeks. Greenblatt (422) emphasized three clinical
(d) integrity of the normal structure of the retinas as verified patterns of transient cortical blindness following head
with the ophthalmoscope; (e) retention of full extraocular trauma:
movements of the eyes, unless there is also damage to ocular
motor structures. Many neuro-ophthalmologists use the term 1. Juvenile (up to age 8 years). These patients experience
‘‘cortical blindness’’ not only where the visual acuity is light blindness of short duration (hours), accompanied by som-
perception or no light perception but also with any level of nolence, irritability, and vomiting, with an excellent prog-
visual acuity, as long as the visual acuity is equal in the two nosis for full recovery.
eyes (assuming the anterior visual pathways are normal). 2. Adolescent (late childhood through teenage years). These
Hypoxia or ischemia of the occipital lobes is the most patients have blindness that does not develop immedi-
common etiologic factor producing cortical blindness. Such ately after the trauma but occurs several minutes later.
damage is necessarily bilateral. Most commonly, an infarc- The blindness lasts minutes to hours, is usually unaccom-
tion in the posterior cerebral artery territory is initially unrec- panied by other neurologic or systemic deficits, and also
ognized, but this previously silent hemianopia contributes tends to resolve completely.
to complete cortical blindness when a contralateral lesion 3. Adult. These patients have immediate blindness, a
Figure 12.48. A 24-year-old man suffered a gunshot wound to the left temporal region with exit of the bullet via the right
occipital pole. Visual acuity was 20/20 in both eyes, but there was cerebral dyschromatopsia and prosopagnosia. A, Visual
fields showed a right superior homonymous quadrantanopia (probably resulting from damage to the left inferior radiations at
the temporal–occipital lobe junction) and a left superior homonymous quadrantic scotoma (probably from damage to the right
inferior occipital pole). B–E, Magnetic resonance images showed the hematoma created by the bullet track.
Figure 12.49. A 71-year-old man had acute onset of complete visual loss, followed by clearing inferiorly. A, Examination
was normal except for visual fields that showed bilateral superior altitudinal visual field defects (bilateral superior homonymous
quadrantanopias). B–F, T2-weighted magnetic resonance images (B–D, axial views; E and F, sagittal views to the right and
left of midline, respectively) demonstrated bilateral posterior cerebral artery infarctions involving primarily the inferior occipital
lobes. (Figure continues.)
Figure 12.49. Continued.
protracted course with other neurologic defects, and a the literature concerning seizure-induced bilateral blindness
variable visual outcome. and divided affected patients into three groups. Fifteen pa-
Postictal cortical blindness is not uncommon (395, tients, all under 12 years of age, had a long succession of
423,424), and ictal cortical blindness as a manifestation of seizures or status epilepticus. They developed blindness that
occipital seizures may occur (409,425–429). Ashby and was permanent or that lasted many months. Ten patients,
Stephenson (430) analyzed 11 cases of blindness after sei- seven of whom were between the ages of 10 and 20 years,
zures and concluded that there is a form of amaurosis that had bilateral occipital seizures with blindness corresponding
occurs in young children and infants that is postictal and is to atypical spike and wave activity. The blindness lasted less
caused by depression of the visual centers. The seizures that than 30 minutes in all cases. Finally, 18 patients had a focal
accompany such blindness are usually violent and may be seizure originating in or adjacent to an occipital lobe, with
associated with aphasia and paresis of hemiplegic distribu- ictal spread to involve both occipital lobes. In these patients,
tion. The hemiplegia may be permanent, although the visual blindness occurred either ictally or postictally. Because focal
loss is generally transient. Joseph and Louis (429) reviewed lesions may be responsible for ictal amaurosis, MR imaging
Figure 12.50. Occipital injury (shell fragment). Bilateral inferior hemianopic quadrantic scotomas, according to Holmes.
(From Traquair HM. An Introduction to Clinical Perimetry, 3rd edition. St Louis, CV Mosby, 1940.)
should be performed in all cases (409). Complete recovery

from ictal or postictal blindness can occur even though the
blindness lasts for several days.
Visual-Evoked Responses in Cortical Blindness

The relationship between cortical blindness and the vis-
ual-evoked response (VER) is unclear. One of the earliest
human studies on this subject was performed by Kooi and
Sharbrough (431). Their patient had suffered head trauma
and was initially blind with no evoked responses to light
stimuli. Subsequently, both visual acuity and VERs under-
went gradual and parallel improvement. This promising cor-
relation was corroborated by other investigators (432–434).
However, Spehlmann et al. (435) reported persistence of the
VER to light in a blind patient who had extensive bilateral
destruction of cortical visual areas and their association
areas. Similarly, Celesia et al. (436) and Hess et al. (437)
demonstrated normal VERs in both complete and incomplete
cortical blindness. Aldrich et al. (379) found abnormal pat-
tern and flash VERs in 15 of 19 patients with cortical blind-
ness, but there was no correlation with the severity of visual
loss or with visual outcome. Indeed, all four patients with
normal VERs during blindness had poor visual outcomes,
and three patients with good outcomes had no initial re-
sponses to pattern-reversal VERs. These investigators found
that electroencephalography was a more helpful diagnostic
indicator: the presence of a posterior dominant alpha rhythm
Figure 12.51. Bilateral simultaneous posterior cerebral artery occlusion
responsive to eye opening appears to be incompatible with
secondary to embolic infarction from a cardiac arrhythmia. The patient was complete or incomplete cortical blindness. Hence, it would
initially cortically blind with no light perception vision. Over the course appear that at least in adults, VERs are not useful in estab-
of a few weeks he had 20/30 vision in each eye because of 5⬚ of macular lishing either the diagnosis or prognosis in patients with cor-
sparing. tical blindness (379,438).
The usefulness of VERs in children with cortical visual examined a patient with total cortical blindness over a 3.5-
dysfunction is controversial. Barnet et al. (419) reported two year period and could never elicit OKN.
children who showed well-formed VERs shortly after the Ter Braak (456) separated OKN into two types: passive
onset of their acute disease, even though they were com- and active. According to this investigator, passive OKN is
pletely blind. Bodis-Wollner et al. (439) described normal produced by the movement of the majority of contrasts in
VERs to both flash and alternating grating patterns in a blind the visual field and may still be present after ablation of the
child in whom CT scanning showed destruction of the cere- visual cortex, whereas active OKN depends on the move-
bral cortex corresponding to areas 18 and 19 bilaterally with ment of specific objects in the visual field and thus requires
preservation of primary visual cortex (area 17). Frank and ‘‘vision’’ for its production. Using these definitions, Ter
Torres (440) recorded VERs to brief light flashes from occip- Braak et al. (457) examined a 71-year-old man with long-
ital regions in a group of 30 cortically blind children aged standing cortical blindness and found passive OKN in one
4 months to 15 years. These investigators compared their direction. Subsequent necropsy revealed almost total de-
results with those obtained from 31 children of similar age struction of both striate cortices and degeneration of both
range who had similar central nervous system diseases but LGBs.
no evidence of blindness. Only one patient with cortical Despite these observations, the presence of OKN in an
blindness showed no response, and the presence of abnormal individual complaining of complete blindness or perception
responses was not incompatible with normal vision. Mellor of light only is almost always evidence of nonorganic visual
and Fielder (441) reported that poor or even absent VERs loss (see also Chapter 21).
in infancy did not always indicate a poor prognosis, and Hoyt
(442) showed a similar lack of correlation. Other authors Cortical Blindness with Denial of Blindness
also noted poor correlation of VERs and visual function in (Anton’s Syndrome)
children with bilateral cerebral abnormalities, especially
those with associated neurologic deficits (443–445), and it Patients with cortical blindness are often unaware of their
is not uncommon to see patients free of clinical neurologic deficit. This denial of blindness, a type of anosognosia, is
or visual deficits who have incidentally discovered abnormal called Anton’s syndrome (458). The syndrome also occurs
VERs. in patients with blindness from causes other than occipital
Nevertheless, some investigators argue that the VER is lobe disease, including cataracts, retinopathies, or optic atro-
indeed helpful in establishing both diagnosis and prognosis phy (459). The explanation for Anton’s syndrome is unclear.
in children with cortical visual dysfunction. In a study of Lessell (459) reviewed the various theories and concluded
six children with cortical blindness after either bacterial that each explains some of the cases. Geschwind (quoted by
meningitis or head trauma, Duchowny et al. (446) found that Lessell [459]) suggested that patients with denial commonly
changes in short-latency VER components correlate with have an alteration in emotional reactivity. Such patients have
visual ability, whereas changes in longer-latency VER com- emotions that are described as coarse and shallow and may
ponents correlate with the level of psychomotor function. predispose them to deny their blindness. Lessell also stated
Kupersmith and Nelson (447) reported that the presence of that ‘‘psychiatric’’ denial may occur as an accentuation of
a VER wave, whether normal or abnormal, indicated the a common response to illness. In patients with Korsakoff’s
future development of vision. Lambert et al. (448) and Ben- syndrome, denial of blindness may represent a memory dis-
civenga et al. (449) also reported some correlation of the order. Such patients cannot remember from minute to minute
VER response to cerebral visual function. McCulloch and that they truly are blind. Finally, it is probable that in many
Taylor (450) argued that flash VERs are an excellent indica- patients with cortical blindness, there are lesions in various
tor of visual recovery for those children who have acute- areas of the brain responsible for recognition and interpreta-
onset cortical blindness and no preexisting neurologic disor- tion of visual images. In such patients, denial of blindness
der. In this subset of patients, many with presumed hypoxia, is caused not by the lesion in the primary visual pathway
those with abnormal VERs had permanent visual impairment but by a lesion in another region of the brain.
or blindness, and all but one patient with absent VERs re-
mained blind (451,452). The variable results from previous Other Visual Features of Occipital Lobe Damage
studies may reflect the many different underlying etiologies
of cortical blindness in children and the many other associ- Bender and Teuber (327) made noteworthy observations
ated neurologic factors that might contribute to poor re- based on their study of 140 individuals who suffered pene-
covery. trating head wounds in World War II. It was their belief that
when macular function is spared, there is either an incom-
Optokinetic Nystagmus in Cortical Blindness plete homonymous hemianopia or development of a pseu-
dofovea. They also noted that when an incomplete homony-
Optokinetic nystagmus (OKN), the slow component of mous field defect is produced by an occipital lobe lesion,
which is generally considered a conscious pursuit move- there are often disturbances in the area of the homonymous
ment, is often used to distinguish patients with true blindness visual fields that seem spared when ‘‘ordinary’’ methods of
from those with nonorganic blindness. Most investigators perimetry are performed. For instance, critical flicker fusion
agree that OKN is absent in patients with total cortical blind- frequency falls in field areas adjacent to the scotoma and to
ness (385,453–455). In fact, Brindley et al. (455) repeatedly a lesser degree in field areas far distant from the scotoma.
Dark adaptation is delayed in the apparently normal field. Lesions of the Striate Cortex Without Defects in the
Luminous objects can be discerned within the scotomatous Visual Field
field when patients are placed in total darkness. Finally,
It is generally assumed that any lesion of the striate cortex
when simple figures are presented to the patient so that part
produces a defect in the field of vision, but there are cases
of the figure is in the area of scotoma and part in the seeing on record that suggest that this assumption may be incorrect.
field, the entire figure is seen (completion phenomenon) Teuber (467) stated that he had records on an extraordinary
(460). There are several different explanations for these ob- case of a 1-year-old child who sustained an accidental gun-
servations. First, the methods of perimetry used in the 1940s shot wound through the right parietal lobe. The bullet re-
were clearly less sensitive than automated static perimetry. mained in the right calcarine area, where it could still be
It thus is likely that many of the patients studied by Bender shown radiologically 30 years later. Teuber et al. could not
and Teuber (327) actually had larger field defects than were demonstrate any evidence of a field defect, even though they
detected by what was then ‘‘routine’’ perimetry. Second, it used refined tests of flicker fusion and light thresholds.
is likely that the observation of luminous objects in blind Weiskrantz (468) stressed that it is conceivable that an injury
areas of the field represented artifacts of testing, since it is of the striate cortex must produce a critical minimum amount
clear that some ‘‘luminous’’ objects have a larger area of of damage before it produces any demonstrable scotoma.
stimulation of the retina than might normally be assumed. Evidence supporting this has been contributed by N. R.
In addition, minor movements of the eyes during testing that Miller, who searched in vain for tiny scotomas produced
might not be detected in total darkness with the equipment by stereotactically implanted depth electrodes (0.5 mm in
available to Bender and Teuber (327) may have moved the diameter) that were inserted directly into and through the
luminous target into the seeing field adjacent to the blind macular area of the occipital pole and the occipital portion
field. of the optic radiations. It is unlikely that standard white-on-
Some patients with homonymous hemianopia, especially white automated perimetry can identify visual field defects
those with a vascular occlusion in the occipital lobe, report associated with these small injuries, although it is possible
phosphenes in the blind visual field, particularly early in the that static color field testing could identify such defects.
course of their disorder (461–464) (see also the section on Similarly, stereotactic pallidotomy, a procedure used to treat
visual hallucinations in Chapter 13). Among 96 patients with patients with Parkinson’s disease, requires precise position-
homonymous hemianopia or quadrantanopia, most of vascu- ing before the electrode is activated. The positioning in-
lar origin, Kolmel (463) noted that 14 had experienced col- cludes placement of the electrode in the ipsilateral optic tract,
ored patterns in their blind hemifield, typically red, green, the cells of which are then identified by recording from the
electrode (468a). The electrode is then pulled back out of
blue, and yellow. Many of the visual field defects in these
the optic tract into the globus pallidus, where a lesion is then
patients resolved substantially, suggesting that the phos-
made. It is difficult to identify visual field defects in the
phenes may be viewed as a prognostically favorable symp-
majority of patients in whom stereotactic pallidotomy is per-
tom. Of 32 patients with ischemic infarction of the retrochi- formed, regardless of whether the testing is performed using
asmal pathways studied prospectively by Vaphiades et al. kinetic or static automated perimetry.
(464), positive spontaneous visual phenomena in the blind Weiskrantz and Cowey (469) contributed neurophysio-
hemifield were present in 13 patients (41%). Classifying logic evidence to support the aforementioned observations
these positive visual phenomena as photopsias, phosphenes, and conclusions. They showed that quantitative lesions in
palinopsia, or visual hallucinations had no value in localizing the macular cortex of the monkey produce a smaller drop
the site of the lesion. However, there was a significant differ- in visual acuity than would be predicted from equivalent
ence in the severity of associated neurologic deficits between lesions of the macula. They suggested that the discrepancy
hemianopic patients with and without these positive visual between retinal and cortical effects is probably best ex-
phenomena; specifically, larger lesions destroying anteriorly plained in terms of lateral interaction of neuronal elements at
located visual association areas precluded the development the retinal level, the geniculate level, or both. An alternative
of these positive phenomena. The authors proposed that vis- explanation is that the visual cortex has a higher relative
ual association areas bordering damaged primary cortex magnification factor for the foveal representation than is ac-
were the source of these visual symptoms when they were counted for by the concentration of retinal ganglion cells in
released from normal inhibitory inputs from primary visual the macula (305).
cortex.
An unusual visual phenomenon associated with unilateral Lesions of the Extrastrate Cortex with Defects in the
or bilateral occipital lesions is cerebral diplopia or polyopia, Visual Field
in which two or more images are perceived monocularly As noted in Chapter 1, the striate cortex (V1, or Brodmann
(465,466). Cerebral polyopia may be due to reorganization area 17) is the primary visual cortex and the principal recipi-
of one or more of the multiple representations of the visual ent of output from the LGB. Surrounding the striate cortex
field in the visual cortex (466). Unlike monocular polyopia within the occipital lobe are two visual association areas,
from irregularities of the ocular refractive media, cerebral Brodmann areas 18 and 19, also called the extrastriate visual
polyopia does not improve with pinhole. This entity is dis- cortex. Studies from primate electrophysiologic and pathway
cussed further in Chapter 13. tracing methods indicate that areas 18 and 19 together repre-
sent at least five distinct cortical areas devoted to visual ‘‘nonvisual’’ lingual and fusiform gyri (373,477). Polyak
processing (278,470–472). These visual areas are designated (478) reported a case in which paracentral quadrantic scoto-
V2, V3, V3a, V4, and V5 in the monkey, and corresponding mas were caused by an infarction primarily located in a re-
regions are present in the human occipital cortex (472). gion corresponding to the ventral portion of areas V2 and
Functional MR imaging has recently been able to demon- V3. Horton and Hoyt (278) reported two patients with hom-
strate multiple visual areas in the human, each with their onymous quadrantic defects caused by tumors, one in the
own retinotopic mapping (473,474). Regions V2 and V3 cuneus of the occipital lobe and the other in the upper peri-
are the major recipient areas for projections from both the striate cortex (Figs. 12.52 and 12.53). These investigators
magnocellular and parvocellular systems in V1, the primary proposed not only that a lesion of V2/V3 may be sufficient
striate cortex. However, V1 also directly projects to areas to create a visual field defect, but also that such lesions are
V4 and V5, bypassing V2 (475). The sizes of V1 and V2 the principal cause of quadrantic defects that strictly respect
are highly correlated, but not V1 and V3 (306). the horizontal meridian. This hypothesis has been supported
Feinsod et al. (476) suggested that a lesion in the extrastri- by functional MR imaging studies demonstrating selective
ate cortex alone might cause defects in the visual field. Oth- loss of activation of extrastriate cortex areas in a patient with
ers reported superior visual field defects from damage to the an upper right homonymous quadrantic defect (479).
Figure 12.52. A 39-year-old woman had experienced multicolored visual hallucinations in her left lower quadrant since
childhood. A, Magnetic resonance imaging revealed a lesion within the cuneus of the right occipital lobe that on en bloc
resection was found to be a grade I astrocytoma. B, Postoperative magnetic resonance image revealed the area of resection.
C, Postoperative visual fields demonstrated a left inferior homonymous quadrantanopia with precise respect of the horizontal
and vertical meridians. The patient could detect gross hand motion within the quadrantic defect. (From Horton JC, Hoyt WF.
Quadrantic visual field defects. A hallmark of lesions in extrastriate [V2/V3] cortex. Brain 1991;114⬊1703–1718.)
Figure 12.53. A 40-year-old man experienced increasing episodes of flashing

lights in the left lower quadrant of vision and was found to have a large tumor
of the right parieto-occipital cortex. A, On magnetic resonance imaging the
calcarine sulcus (between arrows) and the occipital pole are preserved. B, After
resection of the mass, he had a left lower quadrantanopia precisely bordering
the horizontal meridian with sparing of the central 10⬚. (From Horton JC, Hoyt
WF. Quadrantic visual field defects. A hallmark of lesions in extrastriate [V2/
V3] cortex. Brain 1991;114⬊1703–1718.)
Cortical Visual Loss with Normal Neuroimaging tal to the primary visual cortex. Because many of these disor-
ders result from lesions in the extrastriate cortex of the
William F. Hoyt has suggested that the essence of neuro-
occipital lobes, it is worth mentioning a few of the more
ophthalmology is diagnosis in the presence of normal neu-
prominent syndromes in this chapter. As suggested by stud-
roimaging. A not uncommon example occurs when there is
ies in monkeys, the human visual cortex is highly specialized
unilateral or bilateral homonymous hemianopia in the pres-
with respect to specific functions (472). For instance, there
ence of normal MR imaging. Brazis et al. (480) reviewed
are distinct areas of the cortex that subserve color vision.
several causes of this phenomenon, including the Heidenhain These can be identified either by studying patients with
variant of Creutzfeldt-Jakob disease (481,482), variant Alz- known lesions or by functional MR imaging mapping of
heimer dementia (483,484), nonketotic hypoglycemia, and activation of cortex after appropriate stimulation. One area
ischemia without infarction. Many of these disorders can in the lingual and fusiform gyri of the prestriate cortex corre-
be detected with positron emission tomography scanning or sponds to area V4 in the monkey and is responsible for color
functional MR imaging, which is sensitive to the effects of (472,488,489). Other areas adjacent to V3 can be identified
neural activity on blood oxygenation levels (485). Another by functional MR imaging as containing retinotopic maps
etiology for visual loss without abnormalities on conven- for color (473). Lesions in any of these regions may spare
tional MR imaging is occipital lobe seizures, which can dis- the visual field but produce acquired dyschromatopsia in the
rupt visual perception not only during the ictus but also post- contralateral hemifield (477,490,491). The disturbance of
ictally (486) and even permanently (487). color vision in such cases may be permanent, especially if
there are bilateral lesions. Conversely, transient achromatop-
Dissociation of Visual Perception
sia may reflect temporary ischemia in this region, a phenom-
The chapter that follows (Chapter 13) discusses the topo- enon that may occur in migrainous aura (492).
graphic diagnosis of disorders of visual processing more dis- The area of functional specialization for visual motion is
localized to the temporoparieto-occipital junction, a region is one form of a general category of visual phenomena desig-
corresponding to area V5 in the monkey (472,493,494). Le- nated as ‘‘blindsight’’ (468,505–510). In a classic experi-
sions in this region, especially when bilateral, may cause a ment, Mohler and Wurtz (511) removed the occipital lobe
selective deficit in the perception of visual movement within trained monkeys. The monkeys appeared to be blind in
out a visual field defect and without impairment of nonvisual the appropriate hemifield for several weeks but then began
movement perception (i.e., movement perceived by acoustic to make appropriate saccades into the previously blind hemi-
or tactile stimulation) (495,496). A similar loss of motion field. Mohler and Wurtz then extirpated the superior colliculi
detection, but in a single direction at a time, can be repro- in the monkeys, who then became permanently blind in the
duced by electrical stimulation of the posterior temporal lobe hemifield. In another set of monkeys, Mohler and Wurtz
(497). first removed the superior colliculi. The monkeys showed
In some patients, damage to an occipital lobe can cause some mild and transient difficulty with saccadic eye move-
a complete homonymous hemianopia to nonmoving objects, ments but no evidence of visual loss. The monkeys were
with retention of the ability to detect moving objects within then subjected to unilateral occipital lobe excision, following
the blind hemifield: static–kinetic dissociation, also called which they became permanently blind in the contralateral
the Riddoch phenomenon. In 1917 Riddoch (498) noted that hemifield of both eyes. These experiments indicated that
some wounded soldiers with complete homonymous hemia- nonhuman primates have a subcortical vision sensory system
nopia developed or retained the ability to perceive small that likely involves connections between the retina and the
moving objects in the affected hemifield. Riddoch divided superior colliculus in addition to the retinogeniculo-occipital
his cases into three groups: those who perceived motion only pathway for normal visual function. A similar subcortical
on the affected side; those who perceived both moving and pathway may exist in humans. Indeed, some patients with
stationary objects but to a different degree; and those with extensive damage to the occipital lobes appear to retain a
no dissociation between moving and stationary objects. rudimentary form of vision involving the perception of vis-
Static–kinetic dissociation may have prognostic significance ual stimuli other than just moving objects. Most patients are
since it usually means that some degree of recovery can be not consciously aware of this ability to look, point, detect,
expected. Such a phenomenon has been observed not only and discriminate without truly ‘‘seeing.’’ In many cases
after occipital trauma but also after removal of tumor, corti- blindsight is likely a result of islands of preserved area 17,
cal blindness from cardiac arrest, and occipital apoplexy in as demonstrated by positron emission tomography, single
patients with occipital arteriovenous malformations (see also photon-emission computed tomography, and image stabili-
(499)). Preservation of the human correlate of area V5 may zation perimetry (512,513). Celesia et al. (512) argued that
be required for intact visual motion processing, perhaps via the sparing of portions of primary visual cortex, combined
extrageniculostriate pathways (500) (see below). with probable scatter of light into the intact visual field dur-
Static–kinetic dissociation is not a purely pathologic phe- ing testing (514), accounts for blindsight in humans. How-
nomenon, nor is it limited to the striate cortex. In fact, all ever, other investigators contend that blindsight is a genuine
normal individuals perceive moving objects better than static phenomenon that reflects nonstriate visual pathways (see
objects of the same size, shape, and luminance. If objects Cowey and Stoerig [508] for review), which can occur in
are sufficiently small or dull, they will be perceived only the absence of functioning area 17 (515). In humans, exam-
during kinetic perimetry and not during static perimetry. Sa- ples of pathways invoked as an explanation for blindsight are
fran and Glaser (501) demonstrated variable degrees of phys- a retinocollicular projection that reaches extrastriate cortical
iologic dissociation of kinetic and static stimuli in 7 of 15 visual areas via the pulvinar nucleus (516) and a direct
normal subjects. Interestingly, the dissociation occurred for geniculo-extrastriate cortical projection (508). Interestingly,
achromatic target perception but not for chromatic percep- there appears to be an increase in the sensitivity of blindsight
tion of red. Safran and Glaser attributed this physiologic in a given individual over time, suggesting that training of
dissociation to a successive lateral summation of images, as visual function may have rehabilitative implications.
previously noted by Greve (502). Spatial summation is more Another way in which visual perceptions may be disso-
pronounced for rods than for cones, and this may explain ciated is in the syndrome of unilateral inattention or neglect.
the lack of dissociation of static and kinetic targets when hue Patients with this defect may appear to have normal visual
recognition is required. Selective excitation of movement- function if tested in routine fashion, since they can correctly
dependent channels appears to be required for perception perceive objects in each hemifield with either eye. However,
of movement (503). In addition, pathologic static–kinetic when two test objects are presented in the right and left
dissociation occurs in patients with nonoccipital lobe le- hemifields of each eye simultaneously, the patient perceives
sions. Zappia et al. (504) reported two patients, one with a only the test object in the hemifield ipsilateral to the lesion.
lesion in the optic tract and one with a lesion of the optic This phenomenon, called visual extinction, can occur fol-
chiasm. Both patients showed a dissociation between percep- lowing damage to the parietal or occipitoparietal cortex as
tion of static and kinetic objects in their affected hemifields. well as to the frontal lobe and thalamus. It can be demon-
In addition, Safran and Glaser (501) studied 11 patients with strated not only in patients with partial hemianopic defects
compression of the anterior visual pathways and found some on the same side but also in patients with previously re-
degree of static–kinetic dissociation in the defective field of covered hemianopias or no documented visual field defects.
all of them. Unilateral neglect can result from lesions in several different
The Riddoch phenomenon of static–kinetic dissociation regions of the brain. This finding reflects the complex inte-
grated network that exists for the modulation of directed lated to direct downward pressure on the cerebellum by the
attention within extrapersonal space (291). Functional MR tumor.
imaging can demonstrate activation of visual cortex without
activation of more distal cortical processing areas, demon- TREATMENT AND REHABILITATION FOR
strating an anatomic basis for extinction (517). HOMONYMOUS HEMIANOPIA
Nonvisual Symptoms and Signs of Occipital Lobe Spontaneous recovery of homonymous visual field de-
Disease fects occurs in no more than 20% of patients within the first
several months after brain injury (523–525). Thus, despite a
As might be expected, vascular lesions of the occipital certain amount of plasticity even in the adult cerebral cortex
lobe are usually asymptomatic, except with regard to the (526,527), patients with visual field defects have a consis-
visual system. Many patients with occipital infarctions expe- tently poor rehabilitation outcome (528–530). The exact an-
rience acute pain of the head, brow, or eye ipsilateral to the atomic location of the lesion causing the homonymous hemi-
lesion. This presumably reflects the dual trigeminal innerva- anopia does not appear to affect the functional outcome
tion of the posterior dural structures and the periorbital re- (531); however, the greater the number of associated neuro-
gion (518). Patients with homonymous hemianopia may also logic deficits, the more difficult the rehabilitation and the
complain of disturbances of equilibrium, particularly a feel- poorer the functional performance (532). Contributing fur-
ing that their body is swaying toward the side of the hemia- ther to the poor functional improvement is the advanced age
nopia. Rondot et al. (519) called this phenomenon ‘‘visual of most of these patients, a factor associated even in normal
ataxia’’ and proposed that the postural defect reflects unop- individuals with progressive cognitive, sensory, and motor
posed tonic input of vision from the intact hemifield rather deficits (533). Finally, the presence of neglect, especially in
than any true vestibular impairment or neglect. patients with nondominant hemisphere lesions, also inter-
If a homonymous hemianopia is unrecognized by the pa- feres with the rehabilitation process.
tient, the first signs of its presence may be the functional Several techniques may assist in the treatment and rehabil-
consequence of hemifield blindness. Most clinicians have itation of patients with homonymous hemianopia (534). A
never seen the ‘‘door sign’’ (520), in which a patient with mirror attachment can be used to project the mirror image
homonymous hemianopia acquires a linear wound in the of the blind field into the seeing half-field (535). The mirror
forehead ipsilateral to the field defect from inadvertently is attached to the nasal side of the spectacle frame behind
striking the head on a door frame. However, it is not unusual the lens. Burns et al. (536) found that three of six patients
to see patients with homonymous hemianopia that was dis- learned to make some use of the device. For many patients,
covered after a motor vehicle accident in which little or no however, such mirrors do not prove satisfactory because the
injury was sustained to account for the field defect or the patient has to turn the head toward the mirror, because the
infarct in the occipital lobe (subsequently detected by neu- mirror produces a scotoma that blocks a portion of the seeing
roimaging) that clearly predated the accident. field, and because spatial disorientation is common. Images
If the posterior cerebral artery is occluded proximally, seen in the mirror are reversed and projected to the opposite
patients with an infarct in the occipital lobe may also have side of the midline (537), causing confusion. Mirrors on
hemiplegia from damage to the posterior internal capsule prongs fixed to a frame are available, but they are usually
or cerebral peduncle, language dysfunction from damage to discarded by the patient because of the cosmetic appearance
posterior parietal structures, or symptoms reflecting damage of such devices. Mintz (538) devised a small adjustable mir-
to the ipsilateral thalamus (380,521). In addition, because ror that is mounted on a clip placed over the spectacle frames
the condition is ordinarily seen in patients with severe ath- on the nasal side. Waiss and Cohen (539) suggested the use
erosclerosis, there may be other evidence of vertebrobasilar of a temporal mirror coating on the back surface of specta-
insufficiency, including ocular motor abnormalities refer- cles.
able to the rostral brain stem. Patients who develop a bilateral Smith (540) advocated the use of Fresnel press-on prisms
homonymous hemianopia in this setting may be more se- in patients with a homonymous hemianopia. The prism is
verely impaired than patients with blindness from bilateral placed on the outside half of the lens ipsilateral to the hemia-
retinal or optic nerve disease and may be difficult to rehabili- nopia with the base oriented toward that side (i.e., for a
tate (see below). patient with a left homonymous hemianopia, a 30-diopter
Tumors of the occipital lobe may cause nonvisual mani- prism was placed base-out on the left half of the left lens).
festations by virtue of their mass effect. Parkinson and Craig Perlin and Dziadul (537) advocated placing 20 prism-diopter
(522) examined the signs and symptoms of 50 patients with Fresnel prisms in front of both eyes, allowing for a 5⬚ move-
verified tumors limited to the occipital lobe. Headache was ment of the eyes before they encounter the prism edge (see
the most common symptom, occurring in 45 patients (90%). also [541]). Prism power and placement are then modified,
Other symptoms and signs included nausea and vomiting depending on patient adaptation. The goal is to increase the
(46%), ataxia (30%), hallucinations that were usually un- patient’s scanning skills over time. Rossi et al. (542) ran-
formed (24%), seizures (18%), and mental changes (16%). domly assigned 39 patients with stroke and homonymous
Most of the signs and symptoms noted by Parkinson and hemianopia or unilateral visual neglect to treatment with
Craig are nonlocalizing and related to increased intracranial 15 prism-diopter plastic press-on Fresnel prisms or to no
pressure. Ataxia and other cerebellar signs are usually re- treatment. Although the prism-treated group later performed
significantly better than controls on visual perception tests, their physiologic and optical limitations and partly because
there was no difference in activities-of-daily-living function. of other perceptual, sensory, and motor difficulties associ-
Pameijer (543) noted the extent of reading problems in ated with the disease process that damaged the retrochiasmal
patients with hemianopia. Patients with right hemianopias visual system. In many cases the most useful approach for
cannot see which letters or words follow those that they have reading is the use of a ruler placed under each line or having
already deciphered. Patients with left hemianopias may read the patient turn the material 90⬚ and reading vertically in the
without difficulty until they come to the end of the line. In intact hemifield.
attempting to return to the beginning of the next line, they
move into their blind hemifield and lose their place, often
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CHAPTER 13
Central Disorders of Visual Function
Matthew Rizzo and Jason Barton
SEGREGATION OF VISUAL INPUTS ACQUIRED ALEXIA

BLINDSIGHT AND RESIDUAL VISION Pure Alexia (Word Blindness, Alexia Without Agraphia)
Varieties of Blindsight Phenomena Other Disconnection Alexias
Blindsight and Hemidecortication Alexia with Agraphia
Artifact and Blindsight Dyslexia Related to Abnormal Vision, Attention, or Eye
Explanations of Blindsight Movements
CEREBRAL ACHROMATOPSIA Central Dyslexias
Symptoms, Anatomy and Pathology Functional Imaging of Reading
Testing Achromatopsic Patients DISORDERS OF MOTION PERCEPTION (AKINETOPSIA)
Normal Color Perception Symptoms and Signs
Color Constancy and Achromatopsia Motion Perception Deficits with Unilateral Cerebral Lesions
Trichromacy, Color Opponency, and Imagery in Physiology of Motion Perception in Nonhuman Primates
Achromatopsia Functional Imaging and Other Techniques
Parallels with Nonhuman Primates BÁLINT’S SYNDROME AND RELATED VISUOSPATIAL
Functional Imaging DISORDERS
Preserved Color Vision Psychoanatomical Substrates in Bálint’s Syndrome
Color Anomia and Agnosia Perception of Visual Object Structure, Motion, and Depth
PROSOPAGNOSIA AND RELATED DISTURBANCES OF Navigation
OBJECT RECOGNITION DISORDERS OF VISUALLY GUIDED REACHING AND
Clinical Aspects of Prosopagnosia GRASPING
The Specificity of the Prosopagnosic Defect POSITIVE VISUAL PHENOMENA
The Functional Deficit in Prosopagnosia Visual Perseveration
Apperceptive Prosopagnosia Visual Hallucinations
Associative Prosopagnosia Visual Distortions (Dysmetropsia)
People-specific Amnesia VISUAL LOSS IN AGING AND DEMENTIA
Covert Facial Recognition TESTS OF HIGHER VISUAL FUNCTION
Associated Clinical Findings
Anatomy of Face Processing and Prosopagnosia
Other Disorders of Face Perception
This chapter addresses aspects of behavior disorders raising questions about the nature of the visual loss produced
caused by damage to the visual cortex and white matter con- by damage to primary visual cortex.
nections. These conditions are often referred to as ‘‘central Vision was once thought to be primarily a serial (or hier-
disorders of vision,’’ ‘‘cerebral disorders of vision,’’ or archic) process in which visual signals were altered or en-
‘‘higher disorders of vision.’’ The understanding of these hanced at successive way stations from retina to brain until
disorders continues to improve with the development of new an image of the physical world somehow emerged at the
techniques for measuring visual dysfunction, imaging the level of conscious experience. The idea of serial processing
behaving brain, rehabilitating visual dysfunction in patients of visual information was supported in the 1960s by the
with brain damage, and even creating visual sensations in work of Hubel and Weisel (1), who interpreted data from
the blind with prostheses to stimulate visual cortex. Insights experiments using microelectrode recordings in the visual
into how the brain processes visual signals have altered the cortex of cat and monkey in terms of serial connections
classic conceptualization of cerebral visual disorders, even among different functional modules called simple columns,
575
complex columns, and hypercolumns. It subsequently be- visual functions are explained in terms of multiple interac-
came clear that serial processing is only one of several mech- tions among specialized brain regions in the same hemi-
anisms used by the brain to process visual signals. sphere and across the corpus callosum. Felleman and van
The primate visual system also uses parallel processing, Essen (2) catalogued at least 30 functional representations
beginning in the retina. Different types of retinal ganglion of the visual fields in the cortex of the monkey, with over
cells are specialized to transduce different types of physical a hundred interconnections (see Chapter 1). How this model
signals and give rise to different channels (see Chapter 1). corresponds with the human arrangement is unclear, al-
There is cross-talk among these channels at several levels though homologies can be postulated, at least to the level
from the retina to the cortex, and there also are feed-forward of early prestriate cortex. Central disorders of vision thus
and feedback connections between early and late stages of can be interpreted as a consequence of disturbing the pro-
the visual sensory system. Instead of just serial processing, cessing in different sectors or pathways in such a network.
SEGREGATION OF VISUAL INPUTS

For a historical perspective on the understanding of human secondary areas such as V4 and inferior temporal (IT) cortex,
vision, the interested reader is referred to several classic located in the inferior occipital lobe and adjacent temporo-
older references (3–14) and the previous edition of this text. occipital regions (2). These regions, along the ventral or
The functional segregation of visual inputs in the primate temporal cortical pathway (the ‘‘what’’ pathway), are pre-
visual system is now well documented (see Chapter 1). Reti- sumed to play a role in the perception of color, luminance,
nal information is communicated to cortical neurons through stereopsis, and pattern recognition. In contrast, the magno-
a set of pathways that appear specialized to convey a particu- cellular or M-pathway is characterized by large, fast-con-
lar class of visual information. For example, the parvocellu- ducting axons that convey information about more transient
lar or P-pathway, named for its connections to simian striate visual signals. This pathway connects to areas in visual asso-
cortex (area V1) via parvocellular layers 3–6 of the lateral ciation cortex, including the middle temporal (MT) and me-
geniculate nucleus (LGN), is characterized by color oppo- dial superior temporal (MST) areas. These regions, located
nency and slow-conducting axons that convey sustained sig- along the dorsal or parietal cortical pathway (the ‘‘where’’
nals (15,16). This pathway, which corresponds to a psycho- pathway), are thought to analyze the spatial location and
physical sustained channel (17), has stronger projections to movement of objects in the panorama (Fig. 13.1). Recent
Figure 13.1. Parallel pathways for visual function in the cerebral cortex of the nonhuman primate.
Borders between visual areas are indicated by fine dashed lines. The superior temporal sulcus has
been opened to show areas that are normally out of sight. The medial hemisphere is not shown.
The lower panel shows a flow diagram from area V1 (primary visual cortex) to the parietal pathway,
which includes area MT, and the temporal pathway, which includes area V4. The visual information
encoded by neurons varies greatly among these different areas. The human brain is likely to respect
a similar organization. 7a, Brodmann’s area 7a; AIT, anterior inferotemporal area (d, dorsal subdivi-
sion; v, ventral subdivision); CIT, central inferotemporal area (d, dorsal subdivision; v, ventral
subdivision); DP, dorsal parietal area; FST, fundus of the superior temporal area; LIP, lateral
intraparietal area; MST, medial superior temporal area; MT, middle temporal area; PIT, posterior
inferotemporal area (d, dorsal subdivision; v, ventral subdivision); STP, superior temporal polysen-
sory area; V1, visual area 1 (striate cortex); V2, visual area 2; V4, visual area 4; VIP, ventral
intraparietal area; VOT, ventral occipitotemporal area; VP, ventral posterior area. (From Maunsell
JH. The brain’s visual world: Representation of visual targets in cerebral cortex. Science 1995;
270⬊764–768.)
CENTRAL DISORDERS OF VISUAL FUNCTION 577
research has identified a koniocellular or K-channel of reti- posed to grasping of visual objects (32), and for perception
nal information that is distinct from the M- and P-channels; of visual objects versus action upon them (33).
less is known about its central inputs, but it might be impor- Explaining visual phenomena in human subjects on the
tant for color (18,19). basis of a neural substrate requires caution. There is a natural
The notion of two separate visual systems is a useful and tendency to formalize the relationship of perceptual states
fruitful paradigm in the macaque animal model (20), and it to physiologic states (34). Blake (35) emphasized that as we
is also applicable to human vision. Analyses of data from a learn more about the neural organization of the visual sys-
large number of patients with focal lesions of the visual tem, it becomes increasingly tempting to assign particular
cortex and its connections, as defined by computed tomo- visual functions to particular stages. This issue can be ad-
graphic (CT) scanning and magnetic resonance (MR) imag- dressed by using proper tests in a precise manner, such that
ing, support the general concept of separate dorsal and ven- the characteristics of the input stimulus are precisely defined
tral processing pathways as a framework for interpreting (by mathematical techniques and physical measurements)
human clinical disorders (21). For example, damage in the and the perceptual and behavioral outputs are properly
inferior visual cortex, in the occipital lobe and adjoining recorded (36). In this way, we can make inferences on the
temporal regions, impairs pattern recognition and learning, intervening stages of vision in normal healthy observers
producing agnosia for objects and faces (prosopagnosia) or (37), and these strategies can also be applied in patients with
inability to read despite previous literacy (alexia). It can also focal brain lesions to obtain information on the anatomic
reduce color perception in the contralateral field—cerebral constraints for different processing stages (35). Lesions of
achromatopsia (22–24). By contrast, damage in the superior the visual cortex produce relative dissociations of function,
visual cortex, in the occipital lobe and its adjacent parietal such as color versus motion, that reveal the independence
cortex, produces disorders of spatial-temporal analysis (i.e., of certain perceptual properties. Thus, we are able to exam-
inability to judge location, distance, orientation, size, or mo- ine how certain types of information are condensed or dis-
tion of objects), as well as marked disturbances of visually persed, and which stages of visual processing precede others
guided eye and hand control. Bálint’s (25) syndrome is a (35). This can contribute to a flow diagram of perceptual
striking example. processing with potential cross-referencing with human neu-
Although the dorsal visual cortex and the ventral visual
roanatomy at the level of MR imaging analyses. Unique
cortex are associated with different, behaviorally separable
evidence from human lesion studies of vision can also be
functions, there is growing evidence that these two major
complemented by functional imaging (38–44) and by ana-
divisions also have overlapping functions. For example,
tomic studies (45,46).
damage to the dorsal visual pathway is capable of impairing
Behavior studies in patients with brain damage provide
the recognition of shape defined by either motion or static
texture cues (26), even though mechanisms for the process- much of the critical data that underlie our understanding of
ing of shape from static texture cues would be expected to vision. It is therefore important to understand the perspective
depend on ventral pathways. Such findings suggest either a and limitations of these studies, including the nature of the
redundant representation of visual function within the two information they provide and the factors that affect their
major visual pathways or interactions between the two path- interpretation. Some patients with brain lesions can make
ways. sophisticated judgments on a wide variety of psychophysical
The patterns of dissociation of visual function observed procedures and can say what they see, allowing comparisons
with lesions of the dorsal and ventral visual association cor- of their behavior with descriptions of their actual visual ex-
tex further suggest that each of these major divisions has perience, thus motivating further inquiries (47). Other pa-
functional subdivisions. For instance, the dorsolateral visual tients, however, cannot describe their perceptual experience
association cortex may separately process several different because of an acquired damage in language processing areas
types of motion, including first-order, second-order, and at- of the left hemisphere, or because they may not be aware
tention-generated apparent motion (27,28). Similarly, there of their perceptual defect and therefore do not report it, a
may also be separate processing of shape-from-color as op- condition known as anosognosia (48–50). Alternatively, pa-
posed to color sensation in the ventral pathways (29). There tients with cerebral lesions may have evidence of residual
also appears to be significant separation for determining the visual perception, even though they deny the existence of
distance of objects as opposed to their direction with respect such perception (51,52), a phenomenon particularly well il-
to visually guided reaching (30,31), for pointing to as op- lustrated by ‘‘blindsight’’ (53–56).
BLINDSIGHT AND RESIDUAL VISION
Patients with visual loss due to lesions of the striate cortex property of the stimulus: these are said to possess blindsight
or optic radiations may have some remnant visual function (53,60–63). Whether residual vision differs in pathophysiol-
in their ‘‘blind’’ field. Some of these patients, including the ogy from blindsight is unclear. For one, perceptual aware-
often-studied patient G.Y. (Fig. 13.2), retain some awareness ness varies along a spectrum: patients may retain a vague
of visual stimuli and hence have residual vision (57–59), awareness of the presence of a stimulus, particularly of rapid
implying a severe field defect that is relative, not absolute. onset or offset, but not of its particular features, which they
Others deny awareness of stimuli, even though they perform can nonetheless discriminate or act upon (64). Also, stimulus
better than chance when asked to indicate or guess at some parameters can be manipulated so that a patient shows resid-
Figure 13.2. Magnetic resonance imaging of the lesion of patient G.Y., with residual vision. Axial (A) and sagittal (B) images
of the left hemisphere, both T1-weighted, showing destruction of medial occipital cortex and the underlying optic radiation,
from a lesion suffered at age 7 in a car accident. (From Barbur JL, Watson JD, Frackowiak RS, et al. Conscious visual perception
without V1. Brain 1993;116 [Pt 6]:1293–1302.)
ual vision under some conditions and blindsight under others size and target position, mainly for a limited range of para-
(65,66). Similar stimulus manipulations can degrade aware- central locations, as also noted in subsequent reports too
ness and generate blindsight-like performance in normal (60,77,78) (Fig. 13.3). In some cases, localization occurred
subjects (67–69). in regions that later recovered on perimetry (53). Also, sev-
Philosophers have become interested in blindsight as a eral studies have failed to find saccadic localization in the
window into understanding vision and perceptual conscious- absence of awareness (79–81). Targets in blind hemifields
ness (70,71). Blindsight also fuels debates about the ana- also have been localized by hand reaching and pointing. In
tomic substrate of consciousness. In both monkey and some studies manual localization is weak and variable,
human studies, some investigators conclude that conscious sometimes only in patients with residual vision (59,82,83),
visual perception requires striate cortex (72–74), at odds but there are other reports of nearly normal manual localiza-
with claims that hemispherectomized patients can retain tion (64,78).
awareness in the blind hemifield (75). Yet others have con-
cluded that the decreased visual awareness in G.Y. reflects Motion
a defect in attention rather than vision, similar to syndromes
of neglect and simultaneous extinction (64). Many have speculated that target localization is easier
with moving or oscillating rather than stationary targets
VARIETIES OF BLINDSIGHT PHENOMENA (57,76,78,83), a claim supported by some reports (84,85)
but not another (75). This is reminiscent of Riddoch’s phe-
Localization of Targets
nomenon (14), in which movement is appreciated before
Given expectations that the spatial functions of the supe- static targets in recovering hemianopic defects (14). Regard-
rior colliculus would be most likely to persist after cerebral ing perception of motion attributes, patient G.Y. could dis-
lesions, the first demonstration of blindsight asked whether criminate the speed and direction of rapid bright spots
patients could direct saccades to target locations within hem- (57,59,86). With larger stimuli such as optokinetic gratings,
ianopic fields (76). There was a weak correlation of saccadic some patients can discriminate motion direction (87), and a
field (64,94,96). This may be consistent with evidence for

a dissociation between pathways for object recognition and
action (97).
While early studies found no evidence of chromatic per-
ception (59,78), later studies showed detection of colored
targets by 6 of 10 patients (98) and evidence of color-oppo-
nent interactions in the spectral sensitivity curves in three
others (99). Studies of G.Y.’s residual vision showed that
he could discriminate the motion of equiluminant colored
spots (100) and was aware of hue, although these latter re-
sponses seem to represent an average from the entire blind
hemifield (101). G.Y. could match and discriminate the color
and motion of stimuli but could not compare the brightness
of stimuli between his blind and seeing fields (86). The au-
thors suggested that the impairment in perceiving the bright-
ness dimension of color space was the critical factor causing
his degraded awareness in the blind hemifield.
Studies of temporal and spatial contrast sensitivity have
yielded mixed results, even when done on the same patient
G.Y. (102–104). The investigators argued that stimulus pa-
Figure 13.3. Saccadic localization in hemianopia (patient D.B.). Mean
horizontal eye position plotted against target position, for trials with lights
rameters such as size and duration are critical.
(n ⳱ 5 at each point) and control trials with no lights (in which case the Interactions between Blind and Normal Hemifields
meaning of target position is unclear from the study). Bars indicate range
of values for each measure. Much of the correlation appears to rely upon the Traditional blindsight methods are awkward in that they
results for the 5-degree target. Dotted line shows position of ideal saccadic ask a patient to respond to something he or she cannot see.
accuracy. (From Weiskrantz L, Warrington EK, Sanders MD, et al. Visual However, a number of innovative studies have circumvented
capacity in the hemianopic field following a restricted occipital ablation. this by examining how responses to visible stimuli might be
Brain 1974;97⬊709–728.) modified by stimuli in the blind field.
Spatial summation occurs when two simultaneous stimuli
generate faster responses than a single stimulus; temporal
few experience an illusion of self-motion (88). One patient summation is the decrease in reaction time when a stimulus
with bilateral lesions was said to differentiate between ex- is preceded by another that provides a temporal prompt. Evi-
panding and contracting patterns of optic flow, but his an- dence for summation between seeing and blind fields has
swers suggested that scatter into his remaining island of vi- been inconsistent and found in only a minority of subjects
sion could not be excluded (89). Some of the reports of (82,105,106), including G.Y. (107). The opposite, a distrac-
motion detection may actually represent information second- tion effect, in which targets in the blind field slow down
arily derived from spatial position or the detection of flicker response times to stimuli in the seeing field, has been shown
rather than true motion perception. Studies using random for saccades but not manual reaction times (108). This find-
dot stimuli that minimize such positional information and ing could not be replicated in another study of six hemia-
equilibrate flicker found no residual motion perception in nopic patients (109), although it was found in a report on
13 patients, including G.Y. (90,91). hemianopic monkeys (110). ‘‘Inhibition of return’’ is a nor-
Motion information might also guide eye movements. Re- mal phenomenon in which a stimulus delays the detection
covery of optokinetic responses was reported in one patient of a target appearing in the same location a short time later.
with cortical blindness (92) but not in two others (83,93) Taking advantage of the fact that the effect is coded for
nor in three hemianopic patients (87). Pursuit and saccadic position in external space rather than retinal position, one
responses to motion were not found in patients with medial study of a hemianopic patient showed that a light flashed at
occipital lesions sparing the lateral human motion area (80). a spot in the blind field delayed responses to a later target
in the same spatial (not retinotopic) location, after a saccade
Form, Color, and Contrast had placed that location in the seeing field (111). From mon-
key physiology, the authors argued that this was mediated
An early report claimed that patient D.B. could normally by the superior colliculus.
discriminate large X and O stimuli, perhaps through orienta- Evidence for form and letter perception using traditional
tion perception (53,78). However, form discrimination was methods has been mixed. One study of two patients showed
not found in seven other patients (59,77,89) nor orientation that word perception in blindsight could be shown not by
discrimination in two others, including G.Y. (94,95). Thus, traditional methods but by an indirect strategy in which the
these patients cannot use verbal responses to indicate resid- choice of meaning of an ambiguous word (e.g., LIGHT) in
ual form perception. Despite this, G.Y. and two other pa- the seeing field was influenced by a word in the blind field
tients could arrange the orientation, shape, and size of their (e.g., DARK versus HEAVY) (64). Completion effects have
grasp correctly when they reached for objects in their blind been reported for form perception. Three patients could dis-
placed in the blind field in a patient with an occipital lesion,

but not in another with a lesion of the thalamus and optic
radiations (113).
One study examined whether rotating motion in a blind
field could tilt the patient’s sense of the vertical (114). Stimu-
lation of both fields induced more tilt in judgments of the
vertical than stimulating the seeing hemifield alone, and
some tilt was also induced by stimulating the blind hemi-
field. However, inadvertent cues to the true vertical were
Figure 13.4. An experiment of figure completion in blindsight. With cir-
likely present in their half-field stimuli (Fig. 13.5). Another
cular stimuli of radius 10 degrees centered between their seeing and blind study tested whether perception of optic flow in a noise-
hemifields (shaded area), subjects had to draw what they saw in the top filled pattern within the intact hemifield could be enhanced
row, with examples shown in the bottom row. Despite hemianopia, subjects by optic flow in the blind hemifield: this could be shown in
perceived the whole circle as complete and different from the half-circle two patients with very limited damage to striate cortex (106)
but did not tend to complete the half-displaced circle on the right. However, (Fig. 13.6). These subjects could not accurately guess the
all subjects had macular sparing hemianopia and so would have perceived direction of motion when there was no stimulus in the intact
some of the right half of the stimuli, allowing a distinction between circles field.
and half-circles. The placement of the half-displaced circle is such that the
left half-circle is lower than that of the left sides of the other stimuli, afford-
Pupillary Responses
ing another clue. PI, perimetrically intact area; PB, perimetrically blind
area; VM, vertical meridian; FP, fixation point. (From Torjussen T. Visual The pupillary light reflex is preserved in cerebral lesions,
processing in cortically blind hemifields. Neuropsychologia 1978; since the afferent pathway leaves the optic tract to synapse
16⬊15–21.)
in the pretectal nuclei of the midbrain. This light reflex pri-
marily responds to overall luminance. However, responses
to gratings and isoluminant colors also occur. While there is
criminate circles from semicircles when the critical half was evidence that pupillary responses are modulated by cortical
in the hemianopic field, but the macular sparing of their activity, it is unclear whether cortex is critical for responses
hemianopia complicates the interpretation of this result (112) to stimuli lacking a net flux in luminance (115). Neverthe-
(Fig. 13.4). More recently two patients had completion ef- less, pupillary responses to such stimuli in the blind hemi-
fects with awareness for afterimages that were symmetric field have been shown in G.Y., with or without awareness
across the midline or with illusory contours such as the Kani- (116,117). In another study, color stimuli caused afterimages
sza triangle, despite the fact that they had no awareness or that evoked pupillary responses in normal subjects; in the
ability with stimuli restricted to the blind field (64). On a blind hemifield of two patients, including G.Y., there were
related note, the width of G.Y.’s grasp varied with object ‘‘after’’ pupillary responses without any conscious after-
size only when the left-most part of the object fell in his image (115).
seeing hemifield (96). Yet another study used an interference
task with a stimulus flanked by distractors either different Affective (Fear) Responses to Unseen Stimuli
from or identical to the stimulus. Reaction times to seen
letters and colors were prolonged by differing flankers Studies in normal subjects suggest that there may be a
direct pathway between the pulvinar and the amygdala me-
diating emotional reactions to frightening stimuli, even when
those stimuli are not consciously recognized (118). Studies
of G.Y. suggest that he could process fearful and angry faces
in his blind hemifield (119), and this may correlate with
activity in his amygdala (120). Another study of a cortically
blind patient showed that associating a neutral visual stimu-
lus with a painful shock caused the development of startle
reflexes to that stimulus, indicating that the subject could
learn a fear reaction to an object that was not consciously
perceived (121).
Figure 13.5. Display used to examine tilt induced by rotating motion. BLINDSIGHT AND HEMIDECORTICATION
The dotted background rotates either clockwise or counterclockwise (ar-
Patients lacking a cerebral hemisphere are of obvious in-
rows), while the patient rotates the black-and-white disc in the center to
align the line marking the border between black and white with his or her
terest in the debate over the role of extrastriate cortex in
perceived sense of vertical. The half-dotted backgrounds are used to exam- blindsight functions. Visual localization studies in blindsight
ine hemifield responses. Although the curving boundaries exclude local (76) were motivated by the hypothesis that the superior colli-
cues to the true vertical, cues are still available from the overall configura- culus could mediate this function in the absence of striate
tion. (From Pizzamiglio L, Antonucci G, Francia A. Response of the corti- cortex. Indeed, some have found that hemidecorticate infants
cally blind hemifields to a moving visual scene. Cortex 1984;20⬊89–99.) will look toward their blind field when a target is presented
Figure 13.6. Interactions between blind and seeing hemifields in motion perception. Subjects with a discrete occipital lesion
(arrow in D) are shown displays with optic flow patterns: expanding or contracting patterns of moving dots that give the
impression of moving forward or backward in space. In their good hemifield they see a mixture of random noise motion and
signal dots that have this motion. The ratio of this mixture is varied to give a range of performance in accuracy. The subject
must guess whether they are moving forward or backward from these dots. At the same time, in the blind left hemifield, there
is either a strong 100% signal pattern (A) or a meaningless 100% noise pattern. C, Accuracy of responses for different mixtures
of signal and noise in the seeing hemifield. At all levels of signal/noise ratio, accuracy on the task performed with the stimuli
in the good hemifield is enhanced when the blind hemifield contains a strong 100% motion signal.
there (122), and adults with such lesions have some residual The validity of these findings is in question. Several recent
manual localization of blind field targets (75,84), as well as studies have shown that the residual vision in hemi-
a surprising awareness of these targets. Beyond localization, spherectomized patients can be attributed to light scatter
discrimination of motion and speed, but not direction, was (127–130), despite the fact that some of the same authors
reported in three patients, but the results could be explained have argued elsewhere for blindsight retinotectal function
by response bias (75). Some elementary form perception was in hemispherectomized monkeys (131). Another study of
reported in 3 of 10 patients (84,123). A ‘‘spatial summation’’ two patients found that residual vision with preserved aware-
effect, in which normal subjects respond faster to two simul- ness was present in only a thin 3⬚ strip near the vertical
taneous flashes of light than to one, was found in two of meridian, due to scatter or possibly receptive fields overlap-
four patients, even when one of the twin flashes was in the ping from one hemiretina to the other (132): no true
blind hemifield (124). A functional MR imaging (fMRI) blindsight was found.
study of these same patients suggested that blindsight may
not be mediated solely by the superior colliculus, but also ARTIFACT AND BLINDSIGHT
by activity in the ipsilateral V5 area (125). Similar ipsilateral
extrastriate activity was found in a positron emission tomog- The importance of blindsight lies in the potential insights
raphy (PET) study of another patient (126). it provides about the anatomy of vision and conscious experi-
ence. However, such conclusions depend critically on the Many early studies claimed that blindsight performance
exclusion of more trivial explanations of blindsight-like per- required very bright targets on a dark background. This
formance. At least four issues need to be considered in evalu- is precisely the circumstance when light scatter is most
ating any blindsight report: problematic. Indeed, numerous studies have shown
that light scatter can mimic or explain blindsight
1. A stimulus directed at a blind hemifield is actually stimu- (80,127–129,134). Controlling for scatter is difficult and
lating the other (seeing) hemifield because of poor fixa- must take into account two potential sources of scatter,
tion. Inadvertent shifts of fixation can occur, especially that on the screen and that within the eye. Physical mea-
if stimuli are not randomly located and last more than sures of scatter on the screen are inadequate, as the eye
150 ms, providing enough time for a saccade to be made. is more sensitive than electronic equipment (80). As a
Eye position monitors can help but may be falsely reas- physiologic control some have tried to show that similar
suring (Fig. 13.7). Many techniques, such as electro-ocu- blindsight performance could not be obtained with stimuli
lograms or infrared devices, reference eye position to the projected onto the normal blind spot (53). One strategy
head, not to space. Because of this, a combined movement that can potentially control for both screen and intraocular
of the head and eyes can shift gaze into the blind field scatter is to use patients with pregeniculate lesions as
without being detected by the monitor. Thus, these head- controls (76,77,84). Similarly, those who believe that ex-
referenced techniques are inadequate without rigorous trastriate cortex is essential for blindsight also use control
head stabilization (133). A space-referenced system, such patients with thalamic lesions (113) or hemispherecto-
as the magnetic search coil technique, is better. mies (87,129). Flooding of the seeing field with light has
2. A stimulus directed at a blind hemifield is inadvertently also been used to minimize scatter.
stimulating the seeing hemifield because of light scatter. 3. The blind hemifield is not completely blind. Careful per-
Figure 13.7. Problems with eye-head stabilization in perimetry. A, The subject fixates accurately on the fixation spot X,
while a peripheral target (white circle) falls within the boundary of his left scotoma (dashed lines). The eye appears centered
in the perimetric eye position monitor, as shown below. B, The subject fixates off to the left (black circle), rather than at the
fixation spot X, and the target no longer falls within the scotoma. Thus, it is now visible. This off-fixation is detected by the
eye position monitor below. C, If, however, the head is also shifted slightly laterally to the right (straight arrows), the eye
appears to be centered in the monitor, although the patient is fixating off-center. This strategy could be used by patients who
appear to have improving field defects. (From Balliet R, Blood KM, Bach-y-Rita P. Visual field rehabilitation in the cortically
blind? J Neurol Neurosurg Psychiatry 1985;48⬊1113–1124.)
imetry may reveal surviving islands of vision that account subcortical pathway from retina to superior colliculus may
for the residual perception (135–138). The demonstration explain a function like spatial localization (76,132). It is
that patients with optic neuropathy can exhibit blindsight- claimed that better blindsight in the temporal than nasal
like abilities is also consistent with the suggestion that hemifield of patients is a signature of collicular mediation
blindsight is based on residual function in the normal (108,145). Other functions like pattern or motion detection
geniculostriate pathway (139). Some claim to exclude may require extrastriate cortex, through a relay involving the
this hypothesis of surviving striate activation by means superior colliculus and pulvinar. Since the colliculus lacks
of fMRI (140). However, fMRI detects only small per- responses to color opponency, chromatic blindsight (98,
centage changes in MRI signal even with strong stimula- 99,101,113,125,140) may indicate yet another relay, perhaps
tion, and its analysis uses arbitrary statistical thresholds direct projections to extrastriate cortex from surviving lateral
to indicate activation. Its methodology is not designed geniculate neurons (56) (Fig. 13.8).
for or capable of excluding weak residual activation in The monkey evidence most strongly supports the retino-
cortex. tecto-pulvinar relay to extrastriate regions, particularly those
4. Blindsight may simply represent a criterion shift. Sub- involved in motion perception. Lesions of V1 do not abolish
jects may reply more conservatively in detection tasks responses in V5 (146–148) or V3A (149) unless accompa-
than when asked to choose between alternatives (134). nied by lesions of the superior colliculus (146,150). On the
Indeed, normal subjects show criterion shift with very other hand, there is no evidence yet of remnant neuronal
brief stimuli (67,68,134), although this was not replicated responses in regions of the monkey’s ventral stream
recently (69,141). Signal detection analysis has been used (149–151), at odds with the demonstrations of residual color
to answer this criticism by calculating a measure of true and form perception in humans and in some monkeys (152).
sensitivity independent of the response criterion (98, Stabilization of an early direct projection from LGN to V5,
142,143). In G.Y., these have shown that shifts in crite- which normally regresses with development, may occur in
rion may explain some of his test results with motion infant cats with striate lesions (153), but evidence of this
perception but not his blindsight performance with static has not been found in infant monkeys (154).
targets (144). Physiologic techniques in humans have also provided
some support. In normal subjects, evoked potentials (155)
and some transcranial magnetic stimulation studies (156) but
EXPLANATIONS OF BLINDSIGHT
not others (157) suggest that visual motion signals may ar-
Once these objections are met, one can turn to considera- rive in V5 before and independent of V1. PET scans (58),
tion of the anatomic origins of blindsight. The most common magnetoencephalography (158), and evoked responses (159)
explanation invokes alternative visual pathways. A purely have shown residual activation of V5 by rapid but not slow-
Figure 13.8. A geniculo-extrastriate hypothesis for blindsight. A, Neurons in the dorsal lateral geniculate nucleus (dLGN)
normally project point to point to striate cortex, maintaining a strict topography. However, some neurons (black cell bodies)
may project anomalously, either to neighboring striate areas (neuron a) or to extrastriate areas, such as areas V2 and V4 (neuron
b), and either could survive after a restricted striate lesion (shaded area). These hypotheses were tested in a monkey with a
long-standing partial striate lesion. B, After injection of the retrograde marker horseradish peroxidase (HRP) into adjacent
striate cortex, label is present in appropriate parvocellular and magnocellular areas (black dots) adjacent to the region of the
dLGN corresponding to the striate lesion but not in the scattered remnant neurons within the degenerated region (white stars).
C, After injection of HRP into area V4, label is present not only in these remnants but also in scattered neurons throughout
the dLGN, indicating the presence of a direct geniculo-extrastriate pathway. (From Cowey A, Stoerig P. The neurobiology of
blindsight. Trends Neurosci 1991;14⬊140–145.)
moving stimuli in the blind hemifield in G.Y. In one of three

patients with hemispherectomies, fMRI reportedly showed
that moving stimuli activated V5 and V3A but not V1 in
the remaining ipsilateral hemisphere (125). An intriguing
fMRI study of G.Y. that varied stimuli to obtain responses
with and without awareness showed that residual vision was
associated with activation of extrastriate visual areas and
dorsolateral prefrontal cortex, and blindsight was associated
with activation in superior colliculus and medial prefrontal
cortex (65).
One of the most important observations that any theory of
blindsight must explain is its variability. Not all hemianopic
patients have blindsight or residual vision; in fact, recent
large studies, representing 46 patients in total, suggest that
it is rare (90,136,137). One important variable may be how
much the lesion extends beyond striate cortex to the optic
radiations and extrastriate cortex. The pattern of extrastriate Figure 13.9. Learning of blindsight pointing. Median pointer position
damage may also determine the type of blindsight found versus target position in the first trial block (circles) and after 205 trials
(53,160). However, correlations between abilities and lesion (diamonds). The patient had bilateral occipital lesions and bilateral hemia-
anatomy have proven elusive (79,80,90,105,161). A require- nopia, leaving only a small spared hemicentral island of vision from 0 to
ment for very focal striate damage is also difficult to distin- 9 degrees in the right field. The patient locates targets in his right hemifield
guish from a need for partial striate damage (106), leading better with training. The diagonal solid line shows position of perfect accu-
us back to a potential artifactual explanation. racy. (From Bridgeman B, Staggs D. Plasticity in human blindsight. Vision
Res 1982;22⬊1199–1203.)
Another important variable may be the timing of the le-
sion. Blindsight may require neural plasticity. If so, age at
onset, time since lesion, and possibly training may be impor-
tant—of note, G.Y. sustained his lesion at age 8 and has Though some deny that training helps (59,133), others claim
had extensive practice over many years (61). Infants or chil- that practice improves blindsight saccadic or manual locali-
dren may be more likely to develop blindsight or residual zation (85,161,163–165) (Fig. 13.9). There are even claims
vision in both nonhuman primates (162) and man (59, that training may expand visual fields (166,167), a finding
84,153), though not all studies find that age matters (123). in need of verification.
CEREBRAL ACHROMATOPSIA
SYMPTOMS, ANATOMY, AND PATHOLOGY causes achromatopsia frequently extends into either the infe-
rior calcarine cortex or the inferior optic radiation. Similarly,
Deficits in color perception after cerebral lesions have only a few cases without prosopagnosia have been reported
been described for over a hundred years (6,168–172). Ach- (177). Topographagnosia is usually revealed by the patient
romatopsic patients are always symptomatic, complaining becoming lost in familiar surroundings (172,178–180).
that the world appears in shades of gray, like a black-and- Other types of visual object agnosia can also occur
white movie (24,172–174). Some also feel that the world (178,179). Achromatopsic patients with right homonymous
appears less bright (24) or has a ‘‘dirty gray’’ tinge (175). hemianopias may have alexia without agraphia (172,177).
Less frequently, patients note abnormal color to their vision. If the lesions extend into more ventral temporal lobes bilater-
Some find the world tinged with a hue, as if peering through ally, there may also be associated amnesia (172,178). Experi-
a colored filter (171). Others see illusions of the residual mental testing has revealed in some patients a problem with
colors perceived spreading beyond the boundaries of the ob- detecting stimuli with low salience (181), which has also
jects from which they emanate, a type of visual perseveration been described in monkeys with V4 lesions and is thought to
(172). These positive color phenomena may occur tran- indicate inefficient attentional allocation in form processing.
siently as the syndrome evolves after the acute lesion. For Achromatopsia is caused by lesions of the lingual and
achromatopsic patients, daily activities that use color dis- fusiform gyri, in the ventromedial aspect of the occipital
crimination are impaired, such as distinguishing coins, lobe (6,22), as confirmed by modern imaging (24,175,177,
stamps, or traffic lights; a good account of the experience 179,180,182). Lesions of the middle third of the lingual
of an achromatopsic artist exists (176). gyrus or the white matter behind the posterior tip of the
Achromatopsia is seldom an isolated finding. Most com- lateral ventricle are said to be critical (24,183). Bilateral
monly it forms one component of a tetrad that includes supe- lesions are necessary for complete achromatopsia (Fig.
rior quadrantanopia, prosopagnosia, and topographagnosia. 13.10); unilateral right or left occipital lesions may produce
Superior quadrantanopia is almost always present, either bi- a contralateral hemiachromatopsia.
laterally or unilaterally with complete hemianopia in the Since achromatopsia requires bilateral occipital lesions,
other hemifield, as the ventral occipitotemporal lesion that it is most often due to cerebrovascular disease. Bilateral se-
Figure 13.10. Magnetic resonance imaging in a patient with cerebral dyschromatopsia. Nonenhanced sagittal T1-weighted
images show bilateral lesions in the visual cortices. The lesion of the right hemisphere (R) is responsible for the left homonymous
hemianopia. The lesion of the left hemisphere (L) is located below the calcarine fissure in the inferior visual association cortex
in regions thought to process color. (From Rizzo M, Nawrot M, Blake R, et al. A human visual disorder resembling area V4
dysfunction in the monkey. Neurology 1992;42⬊1175–1180.)
quential or simultaneous infarctions in the territories of both Two rare cases with quadrantic field defects for color have
posterior cerebral arteries are not uncommon, given their also been described (191). However, as these quadrantic
shared origin from the basilar artery; multiple infarcts can color defects evolved from more typical quadrantic defects
also occur with coagulopathies (184). With occipital strokes, for white lights, which in turn had evolved from initial hemi-
achromatopsia may be the initial symptom, or an initial corti- anopias, it is not clear if these were true chromatic defects
cal blindness may resolve into achromatopsia. Other bilateral or subtle relative scotomata, particularly as color detection
lesions causing achromatopsia include herpes simplex en- rather than color discrimination was tested. Nevertheless,
cephalitis (179), cerebral metastases (177), repeated focal the quadrantic retinotopic representation of the human V4
seizures (185), focal dementia (186), and even migraine area on functional imaging (192) suggests that a very discrete
aura, causing a transient achromatopsia (187). Subcortical lesion could theoretically create such a defect.
temporo-occipital white matter damage (188) caused a re-
versible dyschromatopsia in one patient with carbon monox- TESTING ACHROMATOPSIC PATIENTS
ide poisoning, a condition that usually causes an appercep-
tive agnosia with relative sparing of color perception (22). Color naming is not an adequate test for cerebral dyschro-
Achromatopsia in the contralateral hemifield alone (hemi- matopsia, since residual color perception may allow an ap-
achromatopsia) can follow unilateral lesions in either the proximate categorization of colors despite inability to make
right or left occipital lobes. In contrast to complete achro- fine judgments about hue and saturation (Fig. 13.11); on the
matopsia, patients are typically asymptomatic until the de- other hand, patients with color anomia may have intact color
fect is demonstrated on a visual examination (189,190), with perception. Achromatopsia may be detected with pseudo-
one exception (175). Likewise, patients with complete ach- isochromatic plates, but some patients can achieve normal
romatopsia after sequential bilateral lesions presumably scores, especially if the plates are shown at a distance suffi-
have hemiachromatopsia after their first lesion but do not cient to obscure the resolution of the individual dots
complain until their second lesion renders them achroma- (172,179,180,193).
topsic in both hemifields (177,182). Hemiachromatopsia is Color sorting or matching tests provide the best evidence
usually associated with a superior quadrantanopia (175, of impaired color perception. Typical sorting tests include
189,190); therefore, the color defect is demonstrable only the Farnsworth-Munsell 100-Hue Test (Fig. 13.12), and the
in the remaining inferior quadrant. The preserved color vi- shorter items of Farnsworth D-15 (Fig. 13.13) and the Lan-
sion in the ipsilateral hemifield allows normal or near-nor- thony New Color Test, which test hue discrimination, and
mal performance on centrally viewed tests of color vision the Sahlgren Saturation Test, which measures saturation dis-
such as pseudo-isochromatic plates and color-sorting tasks. crimination (194). Patients with cerebral achromatopsia are
Rather, the examiner must ask the patient to name or sort impaired on both hue and saturation tests (179,180,195). The
colors presented in the peripheral visual field. The incidence abnormality affects all hue perceptions diffusely, unlike that
of hemiachromatopsia is probably underestimated, given its of congenital color blindness, although the magnitude of
asymptomatic nature and the failure of routine clinical color the defect along red–green and blue–yellow axes may vary
tests to detect its presence. relatively (24). The degree of achromatopsia can vary be-
Figure 13.11. Normalized foci of basic color names in 20 languages. The numbers along the borders of the chart refer to
the Munsell system of color notation. The numbers in the body of the chart refer to the number of languages in the sample
of 20 that encode the corresponding color category. (From Berlin B, Kay P. Basic Color Terms; Their Universality and Evolution.
Berkeley, University of California Press, 1969.)
Figure 13.12. Results of Farnsworth-Munsell 100-Hue Test in the same Figure 13.13. Plot of the Farnsworth D-15 test results in the same patient
subject as in Figure 13.10. The results are abnormal. The error score of with cerebral dyschromatopsia discussed in Figures 13.10 and 13.12. The
492 derived a major component from rack 3, which tests blue–green dis- results are abnormal, showing an axis consistent with a tritan (blue–yellow)
crimination. defect.
tween patients from complete to partial defects. Functional ties in different regions of the light spectrum: this opponent
imaging studies suggest that this may depend on the extent process first occurs in retinal ganglion cells, where one com-
of damage to not just one but a number of color-processing parison is between M-cone and L-cone activity and another
regions in occipitotemporal cortex (196). is between S-cone and combined M- and L-cone activity.
In contrast, perception of brightness, the third (achro- Hence these aspects of retinal physiology account for both
matic) dimension, tends to be normal (24,180,195). Because trichromacy, due to the existence of the three different cones,
of this, care is required with matching tests to ensure that and also for the two axes of wavelength opponency, due to
there are no inadvertent clues from differences in brightness, comparisons occurring at the level of the retinal ganglion
which these patients can perceive. Matching tests that use cells.
reflected colors are particularly vulnerable to this contamina- Wavelength perception is not the same as color percep-
tion. Colors should either vary randomly in brightness or tion, however. Color is a property of the appearance of sur-
have equal brightness (isoluminance), which requires atten- faces and is not inherent in objects (197). Since most objects
tion to the illumination being used. we see are not light sources themselves but are surfaces that
Since most patients view these tests with the fovea, pa- reflect light, the wavelengths that they transmit to our eyes
tients with hemiachromatopsia often score normally (24). are determined by both the reflectant properties of the object
Clinical color-matching tasks can be used in the peripheral and the illuminating light in the scene (198). When the illu-
field but are cumbersome and require monitoring of eye minant changes, so too does the wavelength composition that
movements. reaches our eye from the object. Nevertheless, the perceived
colors of objects are remarkably stable under different light-
NORMAL COLOR PERCEPTION ing conditions, a phenomenon known as ‘‘color constancy.’’
Therefore, wavelength composition alone cannot determine
The perceptions of light by normal human observers can perceived color (199). Rather, it is the relative proportion
be characterized using a three-dimensional ‘‘color space.’’ of received light at each wavelength reflected by the object
The three axes of this space are an achromatic dimension that determines color. To determine proportion one needs to
and two chromatic axes, which can be related to the activity know the spectral composition of the illuminating light
of the three retinal cones. Relative differences in the activity source, but this information is often not directly available.
of the three retinal cones give rise to chromatic differences. To some degree, color constancy may be possible for sim-
Thus, along the deutan chromatic axis, the activity of the ple stimuli by using low-level processes such as chromatic
S-cone (maximally sensitive for Short wavelength light) re- adaptation, local cone ratios (200), and the color opponency
mains constant, but the activity of the M-cone (Medium of retinal ganglion receptive fields. However, for complex
wavelength) changes with respect to that of the L-cone (Long scenes, the nervous system attempts an indirect estimate of
wavelength). Along the tritan axis, the ratio of M-cone to
the illumination. This may involve averaging the spectral
L-cone activity remains constant, but S-cone activity varies
luminance across large regions of the scene, deducing what
relative to the sum of M- and L-cone activity. Variations
kind of lighting is present, and then ‘‘discounting the illumi-
along these two chromatic dimensions cause differences in
nant’’ from the wavelengths reflected by a given object
hue, which is related to the perceived dominant wavelength
(199,201). This generates color as a stable property of ob-
(i.e., red, yellow, blue), and differences in saturation, which
jects, over a fairly wide range of natural illumination.
is related to the purity of the spectral composition, with paler,
less saturated shades representing greater mixture of white
light with the dominant hue (e.g., pink, rose, red). Differ- COLOR CONSTANCY AND ACHROMATOPSIA
ences in brightness (‘‘luminance’’ for light sources, ‘‘reflec-
tance’’ for objects that reflect light) occur when light A defect in color constancy should result in color percepts
changes along the third dimension, the achromatic axis. that vary with changes in illumination. Patients with achro-
Along this axis, the activity of all three cones changes to- matopsia have a more severe deficit in that they lack any
gether, such that the ratio of one cone’s activity relative to color percept at all. Testing such patients for constancy of
another remains constant. Conventional color diagrams such something they do not perceive is paradoxical; however, this
as the CIE (Committee Internationale de l’Eclairage) chart can be done on dyschromatopsic patients, who have some
depict the colors within a plane of the two chromatic dimen- residual hue sensitivity. One such patient was reported to
sions, while omitting brightness. The CIE chart is a roughly have impaired color constancy (202). Three patients, two of
polar diagram with hue represented by the angle of the vector whom had transient symptoms of achromatopsia, and all
from the central point representing white (equal mixture of with subtle color-matching problems at the time of testing,
all hues) and saturation represented by the vector length. had abnormal shifts of color matches when lighting was
No single cone is able to distinguish the wavelength of changed (203). Despite possessing some local color con-
the light it receives. This is because the firing rate of a cone stancy based upon cone contrasts, one patient had impaired
is determined by both the intensity and the spectral composi- constancy for complex scenes, indicating abnormal global
tion of light. Increased firing may indicate either a more constancy mechanisms (200). Another shifted his color nam-
intense light or a change to a wavelength to which the cone ing to black with increasing background luminance (204);
is more sensitive. Wavelength selectivity requires a compari- this indicated that his naming depended heavily on relative
son between the responses of cones with maximal sensitivi- luminance, representing a failure of ‘‘lightness’’ (rather than
hue) constancy. All of these reports included patients with in other regions of macaque extrastriate cortex, including
some dyschromatopsia and bilateral lingual and fusiform V2 (215,216) and inferotemporal cortex (217,218). Never-
gyral lesions, except for one unilateral case (203). However, theless, most attention has been focused on the role of V4
a report of a large series of 27 patients found 5 subjects with in color perception. Several studies suggest that area V4 in
impaired color constancy on matching tasks, all asymptom- monkeys may be the site at which color constancy is gener-
atic, who did not have dyschromatopsia, and who had right ated. Zeki (219) reported that both V1 and V4 contained
or left lateral parietotemporal lesions (205). The authors ar- neurons with wavelength-selective responses, but only V4
gued that this was evidence of a larger network of cortical had cells with responses that did not vary with the illumina-
regions beyond the lingual/fusiform region that participated tion and hence were specific for color rather than wave-
in generating color constancy. length. Schein and Desimone (220) described a possible
mechanism by which the illuminant could be discounted:
TRICHROMACY, COLOR OPPONENCY, AND they found that responses of V4 cells to wavelengths in the
IMAGERY IN ACHROMATOPSIA classical receptive field were suppressed by similar wave-
lengths in a large surrounding region that could even extend
Not all color perception is lost in achromatopsia. Several
into the ipsilateral hemifield. One lesion study has shown
methods have established that some aspects of color process-
that color constancy is impaired by lesions of V4 (221).
ing derived from the function of the cones and retinal gan-
Does achromatopsia result from damage to a human ho-
glion cells of the parvocellular pathway can still be discerned
molog of area V4? This point remains contentious (222).
in achromatopsic patients. Thus, both trichromacy and color
Although defects in color constancy can be demonstrated in
opponency have been shown in photopic spectral sensitivity
at least some achromatopsic patients, these subjects also suf-
curves (179,202,206) and evoked potential or psychophysi-
fer from a more severe defect of hue discrimination (24,195).
cal measures of chromatic contrast sensitivity (206,207).
In monkeys, lesions of V4 impair hue discrimination only
Likewise, performance with anomaloscope testing can re-
mildly, if at all (221,223–227). Lesions of more anterior
semble an anomalous trichromat rather than a monochromat,
areas TE and TEO in inferotemporal cortex do impair hue
despite the personal experience of the world in monochro-
discrimination, but to a less severe degree than in human
matic ‘‘shades of gray’’ (182). On the other hand, some
achromatopsia (228). Rather, severe and permanent deficits
impairment in spectral sensitivity curves occurs in some pa-
in chromatic discrimination with spared achromatic vision
tients, suggesting that there is some extrastriate contribution
appear to require extensive bilateral lesions of inferotemp-
to chromatic contrast (208).
oral cortex (229). Along with the demonstrations on fMRI
There is much evidence that achromatopsics can use
of multiple color-processing regions in human occipitotemp-
color-opponent signals to locate chromatic boundaries, even
oral cortex, this suggests that a severe achromatopsic defect
though they cannot perceive the colors that determine those
may require damage to or disconnection of several compo-
boundaries. In other words, these patients can detect a differ-
nents of a color-processing network rather than just a lesion
ence between colors, although they do not know what the
of the human V4 homolog (192,222,225).
colors are and cannot order them correctly by hue. This may
account for the ability of some patients to read pseudo-iso-
chromatic plates when they are placed far enough away that FUNCTIONAL IMAGING
the individual dots on the plates are not resolvable (29,
A variety of brain-mapping studies support the existence
179,180). Similarly, achromatopsics can detect the move-
of an extrastriate region specialized for color perception.
ment of chromatic stimuli (209,210), even performing at
PET first demonstrated color-selective responses in the lin-
normal levels with suprathreshold chromatic contrast (208).
gual and fusiform gyri (42,230). Selective attention to the
Thus, wavelength variation is still perceived, even if color
color of a stimulus increased blood flow in the lingual and
is not.
fusiform gyri (39). fMRI has shown increased signal with
Also of interest in achromatopsia is the status of color
colored stimuli and also during a color after-effect in the
imagery. This requires careful study, as some stereotyped
posterior fusiform gyri (231). Visual evoked potentials using
color associations can be derived from verbal associations
depth and surface electrodes in epileptic patients have shown
(e.g., yellow banana) without requiring visual imagery.
that stimuli of changing colors were associated with peaks
There is good evidence that at least two patients with com-
at 200 to 300 ms in the lateral lingual gyrus and posterior
plete achromatopsia have normal imagery for colors
fusiform gyrus (232). Also, stimulating at these sites specifi-
(211–213). This contrasts with other patients who can match
cally caused alterations in color perception in some patients
hues correctly but cannot imagine them or associate colors
(232).
correctly with objects (214). This double dissociation may
There is considerable controversy over the homology be-
be explained by a separate ‘‘image buffer’’ that can be dis-
tween monkey V4 and the human color area in the posterior
connected from either perceptual input about color or color
fusiform gyri (192,233). Studies have identified two regions
memories (211).
in the fusiform gyri. One area adjacent to the V3 area may
PARALLELS WITH NONHUMAN PRIMATES contain separate topographic maps for the upper and lower
contralateral quadrants (234). This may be the human homo-
Zeki (170) first described color-selective neurons in area log of V4, which in monkey has both a dorsal and ventral
V4 of monkey. Wavelength selectivity has since been shown component representing the lower and upper fields sepa-
rately. However, adjacent and more anterior to this region tion, and left lingual gyrus that were activated by color
is a second area that contains a nonretinotopic hemifield names (238,246).
representation with even stronger color-specific responses. Color anomia may occur as part of a more general anomia
This has been variably named V8 (235) or V4 alpha (236). in aphasic patients or as an isolated entity. Several types of
Experiments suggest that both V4 and V4 alpha are involved specific color anomia have been described, all occurring
in the ‘‘ratio-taking’’ operations that are important in gener- with left occipital lesions and often an associated right hom-
ating color constancy, without which the stable experience onymous hemianopia, rather than the upper quadrant defects
of color could not occur (236). of achromatopsia. Apart from the disconnection variety,
Thus, these studies suggest that color processing is not color-naming deficits are only rarely reported in the litera-
computed in a single area but in a cortical network. Studies ture; however, it is probable that they are also underdiag-
of more complex tasks besides passive viewing of colors nosed, as well as being unusual, deficits.
have also shown the involvement of additional cortical re- When it accompanies pure alexia and right homonomous
gions. Active color-sorting tasks are associated with signal hemianopia, color anomia may be part of an interhemi-
changes not only in the fusiform gyri but also in more ante- spheric visual-verbal disconnection (214,247–249). Disrup-
rior fusiform areas and the collateral sulci (237). The naming tion of callosal connections in the splenium between the
of colors associated with perceived objects activates the fusi- intact right striate cortex and the left angular gyrus prevents
form gyrus just ventral to the area activated by color percep- accurately perceived colors in the remaining left hemifield
tion (238). Studies of color discrimination have shown activ- from gaining access to language processors. Thus, these sub-
ity in the precuneus, superior parietal parahippocampal, jects cannot read words or name colors that they see accu-
superior and lateral occipital gyri, as well as the lingual gyri rately in the left hemifield. On the other hand, some but not
(239,240). Perception of forms defined by color activates all of these subjects can name visual objects. Preservation
many areas, including the fusiform and lateral occipital gyri of object naming has given rise to hypotheses that, unlike
bilaterally, left precuneus, intraparietal sulcus, and inferior colors, objects can activate not only visual but also somes-
temporal gyrus (240). thetic representations of object shape, and that these more
anterior representations could be transferred to the left hemi-
sphere through more anterior corpus callosum (248). This
PRESERVED COLOR VISION remains to be proven.
Occasionally color discrimination is preserved in patients In color dysphasia, another type of color anomia, patients
cannot name not only visible colors but also the colors of
with other visual perceptual defects, most notably form ag-
familiar objects they see or imagine, tasks that patients with
nosia (241–244). One of these cases provided evidence for
the disconnection anomia can do well (249). This defect is
impaired brightness discrimination with relatively preserved
attributed to loss of an internal lexicon of colors, and indeed
hue discrimination (244): in other words, the converse defect
many have other dysphasic features. Most have left angular
in color space to that of achromatopsic patients. A common gyrus lesions, with associated alexia and agraphia, right
feature of these reports is carbon monoxide poisoning. Zeki hemifield defects, and Gerstmann’s syndrome.
(22) hypothesized that this may reflect a differential toxic A third type of problem with color naming has been con-
or hypoxic vulnerability of the color and form pathways in sidered a short-term color amnesia. This patient could not
cortex, although whether this occurs in striate or prestriate name seen colors but could point accurately to colors named
cortex is unknown. None of these cases provided anatomic by the examiner. Verbal memory for color names was nor-
detail; however, a follow-up report of Adler’s case with CT mal, but visual short-term memory for colors was impaired
and MR imaging many years later showed only occipital (250).
atrophy without a focal lesion (245). Color agnosia is also unusual (251–253). These patients
can sort and match colors, and some can even name colors
COLOR ANOMIA AND AGNOSIA they see. However, they cannot name the colors for either
visually presented or verbally named objects, cannot color
Some patients cannot recognize or name colors even line drawings of objects correctly, and cannot learn paired
though they can perceive them. Thus, while patients with associations between seen objects and seen colors (a vis-
achromatopsia cannot discriminate hue and saturation, ual–visual task). Associated defects include pure alexia, ob-
though some can name some colors, those with color anomia ject anomia, and poor performance on imagery tests for other
and color agnosia can discriminate colors accurately but not object properties, although in at least one case the color
name them. Such patients may not be aware of their deficits. agnosia was a relatively isolated defect (253). Most of these
Relevant to this type of defect, PET studies identified regions subjects had left occipitotemporal lesions, some with a right
in the posterior inferior ventral temporal lobe (just anterior hemianopia, suggesting a left hemispheric dominance for
to that activated by color perception), parieto-occipital junc- semantic color knowledge.
PROSOPAGNOSIA AND RELATED DISTURBANCES OF OBJECT RECOGNITION

Prosopagnosia is the impaired ability to recognize familiar study of prosopagnosia spans only the past 50 years. Early
faces or to learn facial identity (254). While cases were de- reports attributed prosopagnosia to a combination of general-
scribed in the middle of the 19th century (255,256), detailed ized cognitive and visual disturbances (257,258). Indeed,
impaired face recognition is still studied as one facet of more include unfamiliar faces as distractors (282), and the patient
generalized problems of perception, cognition, and memory, should be asked to provide names or biographical data be-
as in macular degeneration (259), Alzheimer’s disease longing to the faces to exclude guessing. Failure should be
(260–262), Huntington’s disease (263), and Parkinson’s dis- contrasted with intact recognition of famous voices. Interpre-
ease (264,265), for example. However, as a diagnostic term, tation of results must take into account the cultural and social
prosopagnosia should be reserved for patients with selective background of the patient to determine which faces should
deficits in face recognition: that is, where the problem recog- be familiar to him or her. If this is a problem, photographs
nizing faces is disproportionately severe compared to other of friends or relatives may be substituted.
visual or cognitive dysfunction. This definition is a relative The Faces subtest of the Warrington Recognition Memory
one, since many patients with prosopagnosia do have some Test (283) is a good test for short-term learning and retention
mild object agnosia, complex visual disturbances, or abnor- of facial identity. This test shows subjects 50 faces and then
mal nonverbal memory. The selectivity of this definition asks them to identify the same faces later, when they are
reflects the modern consensus that prosopagnosia is a spe- presented mixed with 50 other anonymous faces. The advan-
cific functional disorder or family of disorders with specific tage of the Warrington test is that it dispenses with the issue
neuroanatomic bases, as proposed decades ago (254,266). of prior familiarity.
The Benton Face Recognition Test (BFRT) (284) shows
CLINICAL ASPECTS OF PROSOPAGNOSIA subjects an unknown face and asks them to find the matching
face in an array below. This matching test does not tap into
Patients with prosopagnosia cannot recognize most faces the issue of familiarity and hence does not establish a diagno-
as familiar; rather, to identify people they rely mainly on sis of prosopagnosia. However, failure to match faces sug-
voices or nonfacial visual cues, such as gait or mannerisms. gests a degree of impaired face perception. The relevance
On occasion they may use distinct face-related cues such as of difficulties on this test to prosopagnosia is complicated
an unusual pair of glasses, a hairstyle, or a scar, cues that by the fact that some patients are impaired on the BFRT and
bypass the need to recognize the actual face. At other times yet are not prosopagnosic (285).
the context of an encounter can prompt their recognition: There is no known treatment for prosopagnosia. One pa-
they may recognize a physician in the hospital but not on the tient reportedly learned new faces when asked to rate faces
street (267–269). This may have a parallel in the laboratory for a personality trait or remember semantic data about them,
phenomenon of ‘‘provoked overt recognition’’ (270). Here, but not when he focused on visual aspects of faces, but this
when shown faces of people from a related category (e.g., benefit did not translate to recognition of other views of the
sharing the same occupation), some patients with prosopag- same faces (286). Otherwise, patients may benefit socially
nosia can name the faces once they grasp the nature of the from learning to use nonfacial and nonvisual cues more ef-
relationship. Another variation in recognition ability occurs fectively in identifying people.
in patients with the unusual anterograde form of prosopag-
nosia. Patients with this condition cannot learn to recognize THE SPECIFICITY OF THE PROSOPAGNOSIC
new faces after the onset of their lesion, but their recognition DEFECT
of faces encountered before their lesion occurred is intact
(51,271). Can the prosopagnosic defect be truly specific for faces
Most patients with prosopagnosia are aware of their per- only? This point is of great relevance to debates about high-
ceptual problem and its attendant social difficulties, except level visual processing, particularly as to whether its organi-
for some cases with childhood onset (268,272,273). Some zation is highly modular for different stimuli (287,288).
patients find their disability quite distressing and are severely Most patients with prosopagnosia can identify objects at
dysphoric. some basic level or category, unlike patients with severe
Identity is only one type of information present in faces. generalized visual agnosia. However, some cannot identify
Gaze direction, emotional expression, age, and sex can also subtypes (‘‘subordinate categories’’) such as types of cars,
be determined. Some patients with prosopagnosia have a food, or coins, or specific individuals (‘‘exemplars’’) such as
more extensive defect that also impairs these other facial buildings, handwriting, or personal clothing (273,289–291).
functions (268,272,274,275), while others appear to make On the other hand, other patients reportedly can identify
these judgments normally (276–280). Whether these func- personal belongings (292), individual animals (276,293),
tions are ever entirely preserved in prosopagnosia is a matter specific places (276,279), cars (276,294), flowers (279), veg-
of debate, as some argue that these patients may use alterna- etables (294), and different eyeglasses (295). Thus, in some
tive feature cues (such as wrinkles for age) that normal sub- patients the defect appears to be highly specific for faces,
jects do not rely upon (272). However, evidence from func- in support of a modular account. However, a recent review
tional imaging and monkey studies suggests that areas that with detailed measures of reaction time and signal detection
encode facial identity and facial social signals may be sepa- parameters in two patients with prosopagnosia has argued
rate, providing support for hypotheses that these functions that deficits in non-face processing are present even when
are dissociable in brain-damaged patients. accuracy rates suggest otherwise (296).
Objective demonstration of impaired face recognition By the modular account, patients with prosopagnosia vary
usually involves a battery of photographs of public persons, in the specificity of their recognition defect because of the
as in the Famous Faces Test (281). Ideally such a test should variable extent of their lesion: the more other modules are
damaged, the more difficulty with recognizing other object predominate. Nevertheless, one can conceive of prosopag-
classes. However, assessments of specificity must take into nosia as constituting two broad classes, one in which there
account other factors that determine how easily subjects per- is a failure to form a sufficiently accurate facial percept (‘‘ap-
form recognition tasks. First and foremost is premorbid per- perceptive prosopagnosia’’), and one in which there is an
ceptual expertise (297). Some normal subjects can expertly inability to match an accurate percept to facial memories
perceive subtle variations to determine the specific year of (‘‘associative prosopagnosia’’) (299,300). More fine-grain
a single model of car, while others can barely distinguish delineations of disconnections between various elements of
cars from vans. To become expert, subjects must not only the process are also possible (269).
have frequent exposure to objects but also have an interest
in discriminating between them. Thus, while our social inter- APPERCEPTIVE PROSOPAGNOSIA
actions and motivations converge to make us all face experts,
only some of us are car experts, even though we all see cars In apperceptive prosopagnosia, patients cannot form an
daily. Hence it is a challenge to determine what level of accurate picture of the face before them. In the past, this
subordinate categorization to expect for nonfacial objects, diagnosis has usually relied upon indirect deductions from
based on a prosopagnosic patient’s premorbid capability. performance on other visual tests not involving faces
Should one be able to tell the difference between a hawk (299,300). These include overlapping figures, silhouettes,
and an eagle (class: birds of prey), or a buteo and an accipiter Gestalt completion tests (269,279,301), and global texture
(class: hawks)? or moiré patterns (302). However, it is far from proven that
A second potential source of variation in object recogni- the mechanisms probed by such tests are truly related to
tion skills is that the types of perceptual processes needed normal face recognition. Somewhat closer is the use of unfa-
with certain object categories may differ from those needed miliar face-matching tests like the BFRT. Failure to match
with other objects. For example, the rigid linear structures faces seen in different views or lighting may indicate a prob-
of man-made objects like houses and cars differ from the lem in extracting relevant facial structure. Though more logi-
more randomly irregular curved surfaces of natural struc- cally appealing, this argument is problematic because the
tures like faces, vegetables, and animals. Does the ability to BFRT can also be failed by patients without prosopagnosia
distinguish one house from another hinge upon the same (285,303,304). This raises the possibility that performance
perceptual processes as the ability to distinguish between on the BFRT depends upon facial information irrelevant to
faces? This distinction may be reflected in reports of visual
face recognition. (Although it seems counterintuitive that
agnosias where the recognition of man-made objects is dis-
subjects would identify unfamiliar faces using criteria they
sociated from the recognition of natural objects.
do not apply to familiar faces, there is evidence that different
strategies may indeed be used. For example, the internal
THE FUNCTIONAL DEFICIT IN PROSOPAGNOSIA facial features appear to play a greater role in recognizing
In cognitive models, a complex task such as face recogni- familiar faces than in identifying unfamiliar ones (305,306).)
tion is often depicted as a series of stages. The Bruce and Alternatively, prosopagnosia may require additional defects
Young model is typical (298). Visual processing generates besides those that lead to poor BFRT performance.
a face percept. This percept is matched to ‘‘face recognition The specific nature of the processing deficit in appercep-
units,’’ a memory store of previously encountered faces. A tive prosopagnosia remains somewhat elusive. Data from
successful match activates person-identity nodes that contain normal subjects suggest two main hypotheses about the
names and biographical data, nodes that can also be accessed mechanisms of normal face perception. The holistic hypoth-
through other perceptual routes, such as voice or gait anal- esis argues that the elements of a face are integrated and
ysis. processed as a complete whole, not subject to part decompo-
This basic structure can be elaborated. Low-level visual sition (307–309). The configurational hypothesis argues that
processing may generate data for higher-level visual pro- face recognition is a geometric problem in which the precise
cessing in at least two different streams. One analyzes the spatial relations between features encode the unique three-
short- and long-term temporal variations in face structure dimensional structure of a given face (310–312). This con-
that reveal expression and aging; the other ignores these cept derives support from studies showing that IT cells in
temporal variations in favor of the more stable structural monkeys are selective for faces that differ in these internal
characteristics of faces that reveal identity. Top-down infor- spatial relations (313,314).
mation flow is also present in the system. For example, These two different hypotheses are not mutually exclu-
matching of the face percept to face recognition units may sive. There are data that some patients with prosopagnosia
be enhanced by top-down semantic activation from person- are deficient in the perception of whole object structure,
identity nodes, as when the subject knows the name of the seeing only individual elements and relying on a feature-by-
person or his or her contextual category (actor, family, work- feature strategy in face perception (277,301). Recent studies
mate). show that many prosopagnosic patients with occipitotemp-
In such a complex process, defective performance can oral lesions are markedly impaired in perceiving the configu-
theoretically arise at any one of several levels. In patients ration of facial features (315–317) (Fig. 13.14). Further
with extensive natural lesions, damage may not be restricted work is needed to clarify which hypothesis best captures the
to a single level, although a certain type of dysfunction may nature of the prosopagnosic deficit.
Figure 13.14. Stimuli used to test perception of facial configuration. The precise location of features within a face may be
an important aspect of facial geometry that is relevant to identifying faces. Patients with lesions of the fusiform face area are
impaired in perceiving faces that have been altered by moving the eyes closer (left) or the mouth higher (right), compared
with the unaltered base face (center). (From Joubert S, Felician O, Barbeau E, et al. Impaired configurational processing in a
case of progressive prosopagnosia associated with predominant right temporal lobe atrophy. Brain 2003;126⬊2537–2550.)
ASSOCIATIVE PROSOPAGNOSIA is consistent with functional imaging studies showing that

name and face recognition both activate the anterior middle
An associative defect implies failure of perceptual data
temporal gyrus and temporal pole (322,323). A disconnec-
to gain access to memory stores (face-recognition units)
tion between intact face memories and person-identity nodes
(51,299,300). In some cases this may be because of a discon-
was proposed in a patient with an unusual left hemispheric
nection between facial percepts and the face-recognition
lesion who recognized faces as familiar, although he could
units (269). In others the facial memories may be lost. The
provide names or biographical details only to the spoken
diagnosis of associative prosopagnosia has traditionally been
name, not to faces (324).
indirect, based on demonstration of intact face perception,
as from normal performance on the BFRT. However, as has
been pointed out (318), a normal BFRT score does not prove COVERT FACIAL RECOGNITION
normal face perception, as prosopagnosic patients who One of the intriguing observations in prosopagnosic pa-
achieve such scores invariably take a long time to do the tients is that a range of physiologic and behavioral tech-
test, suggesting that they are using abnormal perceptual niques can show that these patients retain some unconscious
strategies. ‘‘covert recognition’’ of these faces (325,326). Investigators
A more direct probe of the status of facial memories is have shown two main effects: covert familiarity, or distin-
imagery (269). Batteries of questions can test whether sub- guishing known from unknown faces, and covert semantic
jects can recall details about the appearance of well-known knowledge, or retained information about name, occupation,
faces, when they are not actually viewing those faces. While and other facts associated with a face.
more posterior occipitotemporal lesions are associated with Covert effects have been shown with physiologic mea-
only mildly impaired face imagery, anterior temporal lesions surements. Electrodermal skin conductance has shown larger
are associated with severe loss, suggesting that facial mem- responses with familiar than unfamiliar faces (51), or when
ory stores are lost in these patients (319). names are paired correctly with faces (327,328). In one pa-
tient visual evoked potentials were used to study the P300
PEOPLE-SPECIFIC AMNESIA
effect, in which the P300 wave is larger when an infrequent
The last element in the cognitive model of face processing event is detected within a set of stimuli (329). Using familiar
is the person-identity node, containing biographic informa- and unfamiliar faces, researchers showed that when familiar
tion about individuals. Because these biographic data can be faces were infrequent they were associated with a large cen-
accessed from several routes, this leads not to prosopagnosia, tral P300 wave, indicating that faces were being categorized
in which patients can still recognize people from other sen- by familiarity.
sory cues, but to a people-specific amnesia, in which no cues Most commonly used are behavioral methods, including
can prompt recollection of other people, while other types both direct and indirect techniques. Direct techniques force
of memories remain intact. This has been described with the subject to engage in a task involving face identity. When
right temporal pole lesions (279,320,321). This localization shown two faces and asked which face belongs to a certain
name, several patients have been able to perform better than bilateral occipitotemporal lesions causing apperceptive de-
chance, even though they were not able to indicate which fects, and those with childhood-onset prosopagnosia. Early-
face was famous when they were not given the name onset prosopagnosia may be particularly problematic for co-
(282,330,331). Numerous studies have shown that prosopag- vert recognition, as it may preclude the formation of facial
nosic patients are quicker to learn to associate a name with memories needed to support it. Indeed, several of the previ-
a famous face when the name is the correct one for that face ous cases without covert recognition had onset in childhood
(276,330–332). When scanning faces, the eye movements (272,273).
of two prosopagnosic patients showed a greater concentra-
tion on internal features when faces were familiar, just as ASSOCIATED CLINICAL FINDINGS
occurs with normal subjects (52).
Prosopagnosia is frequently associated with three other
Indirect techniques ask the subject to perform some task
clinical findings. First is a field defect, commonly a left or
not directly related to facial identity, and observe whether
bilateral upper quadrantanopia but sometimes a left homony-
performance is influenced by the identity of a face shown
mous hemianopia (52,269,342,343). Second is achromatop-
with the task. Normal subjects are quicker at judging whether
sia or hemiachromatopsia, particularly in those with lesions
two facial pictures are from the same person when the face
of the fusiform gyri. Last is topographagnosia, or getting
is familiar, and this difference depends on internal facial
lost in familiar surroundings (344). The latter may be related
features: a similar difference in reaction time and reliance
to a failure to recognize landmarks, as functional imaging
on inner features was shown in one patient (333). Matching
studies suggest that there is a region specialized for building
the old and young faces of individuals across a 30-year gap
recognition adjacent to the fusiform face area (345). These
was easier with famous faces for another patient (278). An-
three findings are not invariably associated, but with proso-
other example is a ‘‘facial interference’’ paradigm, in which
pagnosia they form a loosely associated quartet, likely re-
a subject classifies a famous name by occupation while a
flecting the extent of damage among neighboring structures
face is shown simultaneously (333). If the face belongs to
in the medial occipital lobe.
someone with the alternative occupation, reaction times are
Some patients also have evidence of a mild visual object
normally slowed (the interference), and this was also found
agnosia (272,273), though less severe than their prosopag-
in one prosopagnosic patient (333). A similar phenomenon
nosia. Those with more anterior temporal damage can have
is ‘‘face priming,’’ which measures the effects on name clas-
visual or verbal memory disturbances (328,346). Other occa-
sification of a preceding (not simultaneous) face: here a face
sional deficits include simultanagnosia (276,333), palinop-
related to the name speeds up reaction times, as was found
sia, visual hallucinations, constructional difficulties, and left
in the same prosopagnosic patient (334).
hemineglect (269,346).
Not all prosopagnosic patients have covert recognition
(272,273,277,335). Reasons why some have it and others ANATOMY OF FACE PROCESSING AND
not are unclear. Conjectures upon this point tend to reflect PROSOPAGNOSIA
conflicting views on the origins of covert recognition. One
concept proposes that it is generated by an alternate, ‘‘disso- It is useful to place the anatomic data concerning proso-
ciated’’ route to normal face processing, through dorsal oc- pagnosia in the context of information from nonhuman pri-
cipitoparietal cortex or amygdala (336). Proponents of a dis- mates and normal human functional imaging.
sociated route often posit that to support covert function, In monkeys, face-selective neuronal responses have been
face perception must be intact. Hence, the claim is that covert found in two main regions of cortex (Fig. 13.15). First is
recognition is associated with associative prosopagnosia, in the inferotemporal cortex (IT) (313,347,348). This includes
which accurate facial percepts cannot be matched to facial areas of the lower bank of the superior temporal sulcus
memory stores because of either disconnection or their loss, (STS), such as areas TEa and TEm (349). Second is the
rather than apperceptive prosopagnosia, in which the facial upper bank of the STS (313,350), mainly in a multimodal
percept is degraded (335,337). Another explanation is that area designated the superior temporal polymodal area
covert function reflects residual processing within the sur- (STPa) (351) or area TPO (349). Other areas with face-selec-
viving remnants of the normal face-processing network, a tive responses are located in the basal accessory nucleus of
hypothesis that has been successfully modeled with com- the amygdala (352), the ventral striatum, and the inferior
puter simulations (338–340). In this model, the likelihood prefrontal cortex (353). Face-sensitive neurons are a minor-
and strength of covert recognition would be inversely related ity of cells in all these areas, ranging from 10% to 20%
to the degree of damage across the network (319). (349,354).
Against the claim that covert recognition is absent in ap- The face-selective cells in the STS have been studied the
perceptive prosopagnosia is the demonstration that several most (350,354). They do not respond to simple edges, bars,
patients with impaired configural perception from unilateral or complex nonfacial stimuli. All of the internal facial fea-
right hemisphere lesions had good covert ability (319,341). tures contribute to the face-selective response, and the proper
Evidence for the network hypothesis comes from recent spatial arrangement of these features is crucial. It is debat-
demonstrations that behavioral indices of covert recognition able whether STS cells play a critical role in identifying
are correlated with the degree of residual overt familiarity faces, though. Most STS neurons respond vigorously to all
in prosopagnosia (282). In this series of patients, impaired faces (350). Only about 10% of cells in the fundus have
covert function was found mainly in two groups: those with selective responses to different faces (354), but, on the other
Figure 13.15. Face-processing areas in the

monkey. Bottom left diagram is the lateral
view of the cerebral hemisphere, with the su-
perior temporal sulcus (STS) shaded. Large
diagram is the unfolded STS. Areas TEa and
TEm form part of IT, inferior temporal cor-
tex, and area TPO is part of the dorsal STS.
(From Leonard CM, Rolls ET, Wilson FA,
et al. Neurons in the amygdala of the monkey
with responses selective for faces. Behav
Brain Res 1985;15⬊159–176.)
hand, there are reports claiming that 77% differentiate be- IT profoundly impairs this type of perceptual judgment
tween faces to a degree, with a discriminative ability similar (357). The relevance of this to face recognition comes from
to human observers (355). Perhaps the most important evi- observations that normal humans use internal features more
dence is that bilateral resections of the floor and banks of than external ones to recognize familiar faces (306), and
the STS only mildly affect object and face discrimination prosopagnosic patients can be severely impaired on perceiv-
and do not impair judgments of facial familiarity (356). ing the precise arrangement of internal features (315). IT
Rather, they impair the perception of important facial social neurons are also more sensitive to face orientation (358) than
signals, such as expression and direction of gaze (275). STS cells are (350,354), which is consistent with the fact
IT neurons distinguish between faces that vary in the dis- that face recognition is disproportionately degraded by turn-
tances between internal features (313,314), and cooling of ing faces upside-down (the ‘‘inversion effect’’) (359).
While more data are needed, particularly on the effects

of IT resection on face recognition, these results suggest that
face processing differs in STS and IT (360,361). IT may
play a greater role in facial identification, whereas the chief
function of STS face cells may be the perception of socially
relevant cues, such as gaze direction. In support, STS face
cells also show sensitivity to head orientation and body pos-
ture, other cues to the direction of another animal’s attention
when the eyes are not visible (360).
Functional imaging has expanded our knowledge of the
human anatomy of face processing. Early PET experiments
(362) found that face identification activated the fusiform
gyri and anterior temporal lobes bilaterally and the right
parahippocampal gyrus, whereas object recognition acti-
vated the left occipitotemporal cortex. Another PET experi-
ment confirmed bilateral activation of the fusiform gyri dur-
ing a face-matching task (363,364). Recording from
electrodes implanted in epileptic patients found significant
potentials to faces but not cars, butterflies, or scrambled
faces in the fusiform and inferior temporal gyri bilaterally
(365) (Fig. 13.16). Stimulation of these regions impaired the
naming of familiar faces.
fMRI studies (366) also support localization to the fusi-
form gyri, with a predominance of right-sided activity in Figure 13.17. Activation with fMRI during face perception. Schematic
some studies (367,368), although others found right, left, representation of voxels with increased intensity on MRI during perception
or symmetric activity in individuals, with no overall group of faces, superimposed on a view of the inferior brain surface. Squares
asymmetry (369) (Fig. 13.17). The region on the right has show areas activated within sulci and upon gyral surfaces. For comparison,
been named the fusiform face area (FFA). In addition to this the areas activated in the evoked potential study shown in Figure 13.16 are
superimposed in black. cs, collateral sulcus; fg, fusiform gyrus; itg, inferior
region, face-related activity occurs in the posterior STS and
temporal gyrus; lg, lingual gyrus; ots, occipitotemporal sulcus. (From Puce
in an inferior occipital area (368,370,371). The latter is adja- A, Allison T, Gore JC, et al. Face-sensitive regions in human extrastriate
cent to both the fusiform and posterior STS and may be a cortex studied by functional MRI. J Neurophysiol 1995;74⬊1192–1199.)
perceptual input stage to both regions (366). As predicted
from the monkey data (360), attention to direction of gaze
enhances the activity in the STS locus, whereas attention to

identity enhances activity in the fusiform gyri (371). This has
suggested a processing model with at least three modules: (a)
an early perceptual stage in the inferior occipital area, which
feeds into both (b) a fusiform area (IT homolog) for percep-
tion of identity and (c) an STS region for perception of dy-
namic facial aspects such as expression and gaze. This task
segregation between IT (FFA) and STS (lateral occipito-
temporal cortex) may be more relative than absolute, how-
ever (372).
In addition to localization, fMRI has been used to contrib-
ute to the debate about the face-specificity of the mecha-
nisms involved in face identification (287,288). Faces and
buildings activate separate adjacent structures in the fusi-
form gyrus (373), consistent with high stimulus-specificity
of a face-processing module. The data on animals versus
faces (two natural categories of objects) is mixed, however
(374,375). Also, one study showed that stimuli such as cars
and birds activated the fusiform face area if the subject was
Figure 13.16. Evoked potentials during face perception. Summary of lo-
expert at their recognition (376). According to these authors,
cations from which a surface-negative potential (N200) was recorded (block
dots), and areas where it was not found (dashes), superimposed on a drawing
face recognition may be merely the most dramatic aspect of
of the inferior surface of the brain. cs, collateral sulcus; fg, fusiform gyrus; a type of perception that processes subtle differences in the
itg, inferior temporal gyrus; lg, lingual gyrus; ots, occipitotemporal sulcus. shape of highly similar exemplars that belong to the same
(From Allison T, Ginter H, McCarthy G, et al. Face recognition in human class of object.
extrastriate cortex. J Neurophysiol 1994;71⬊821–825.) In most cases, prosopagnosia is caused by lesions in the
medial occipitotemporal lobes (Figs. 13.18 and 13.19). The

classic lesion is bilateral damage to the lingual and fusiform
gyri of the medial occipitotemporal cortex (291,377) (Figs.
13.20 and 13.21 ). These relatively posterior lesions often
involve the region identified on fMRI as the FFA (315). The
importance of the bilateral nature of the lesions in this group
is underscored by the report of a patient with sequential
lesions, first on the right and then on the left, who became
prosopagnosic only after the second lesion (378).
However, two other important categories of lesions can
be encountered in prosopagnosia. First, there is a significant
body of evidence that in some patients a unilateral right
occipitotemporal lesion is sufficient to cause prosopagnosia
(269,277,332,346,379,380) (Figs. 13.22 and 13.23). Such
lesions may also affect the FFA (315). Second is the associa-
tion of prosopagnosia with more anterior temporal lesions
(279,381) (Fig. 13.24).
Figure 13.19. Pathology of prosopagnosia. Coronal sections through the

brain of the same patient described in Figure 13.18. A, At the level of the
thalamus. B, At the level of the fimbria. C, At the retrosplenial level. D,
2.5 cm caudal to C. As noted in the previous figure, the brain shows destruc-
tion of the occipital pole, pericalcarine tissues, caudal hippocampal gyrus,
and entire fusiform gyrus of the right hemisphere. In the left hemisphere,
Figure 13.18. Pathology of prosopagnosia. The patient was a 59-year- there is some damage to the pericalcarine areas and the most caudal part
old man who 2 years earlier had had sudden onset of cortical blindness of the hippocampal gyrus, with destruction of all the fusiform and most of
that partially resolved, leaving bilaterally constricted visual fields, worse the lingual gyri. (From Cohn R, Neumann MA, Wood DH. Prosopagnosia:
on the left and superiorly. The patient also had prosopagnosia, cerebral a clinicopathological study. Ann Neurol 1977;1:177–182.)
achromatopsia, and memory deficits. Basal view of the brain shows destruc-
tion of the occipital pole, pericalcarine tissues, caudal hippocampal gyrus,
and entire fusiform gyrus of the right hemisphere. In the left hemisphere,
there is some damage to the pericalcarine areas and the most caudal part How these three different patterns of lesions differ in the
of the hippocampal gyrus, with destruction of all the fusiform and most of type of prosopagnosia they cause is not settled. One hypothe-
the lingual gyri. (From Cohn R, Neumann MA, Wood DH. Prosopagnosia: sis is that unilateral right occipitotemporal lesions cause an
a clinicopathological study. Ann Neurol 1977;1:177–182.) apperceptive defect, whereas bilateral, more anterior tem-
Figure 13.20. Prosopagnosia with bilateral occipitotemporal lesions. This 41-year-old man had suffered a subdural hematoma
in a car accident 20 years earlier. He had been cortically blind for a few weeks. He now has right hemianopia, some mild
object agnosia, and partial dyschromatopsia, as well as prosopagnosia.
poral lesions cause an associative one (299). While one study common causes in patients with unilateral lesions (300,
found paradoxically that an apperceptive patient who could 346,383). Progressive forms occur with focal temporal atro-
not match faces had more anterior temporal lesions than one phy (279,317,384). It has been reported as a transient mani-
with intact matching ability (382), the results with a recent festation of migraine (385).
series of prosopagnosic patients are consistent with this hy- There is increasing interest in a developmental form of
pothesis (315,319). Bilateral or unilateral occipitotemporal prosopagnosia also. The acquisition of face recognition de-
lesions that include the right fusiform face area impaired pends on not only prenatal factors but also postnatal develop-
perceptual encoding of facial configuration but only mildly ment in early childhood (268,272,273,386,387). Hence, de-
affected facial imagery, whereas anterior temporal lesions velopmental prosopagnosia covers both.
tended to eliminate facial memories, as accessed by imagery Because acquisition of adult-level face expertise may re-
tests, but had much less effect on perceptual encoding of quire experience in early childhood, defects with onset at or
facial configuration. What remains to be determined is how before this period are considered developmental prosopag-
unilateral occipitotemporal lesions differ from bilateral ones. nosia (268,272,273,316,386,387). This term covers patients
The most common causes of prosopagnosia are posterior with lesions acquired in early childhood and congenital
cerebral artery infarctions, head trauma, and viral encephali- cases, which in turn can be due to either prenatal insults or
tis (269,291,315), partly because of the potential of these an inherited defect, which may be an autosomal-dominant
lesions to cause bilateral damage. Tumors, hematomas, ab- trait. These patients often have associated deficits in judging
scesses, and surgical resections are less frequent, but are social information from faces, and some have social develop-
Figure 13.21. Location of bilateral lesions in three patients with prosopagnosia. Axial template drawings with shaded areas
representing the lesions of three patients with prosopagnosia. Bilateral damage, greater on the left than the right, is present in
all three. (From Damasio AR, Damasio H, Van Hoesen GW. Prosopagnosia: anatomic basis and behavioral mechanisms.
Neurology 1982;32⬊331–341.)
Figure 13.22. Prosopagnosia with unilateral right

occipitotemporal lesion. This 59-year-old man had
had a right posterior cerebral arterial infarct 10
months earlier, involving the approximate level of
the fusiform face area as well as, more posteriorly,
the lateral occipital area, both of which are activated
by faces in fMRI experiments. He has a left hemia-
nopia as well.
Figure 13.23. MRI in a patient who developed prosopagnosia after a right temporo-occipital hematoma that was evacuated
1 year previously. Axial T1-weighted images are shown in the top row and coronal T1-weighted images in the bottom row.
The images all show only a unilateral right temporo-occipital hypointense area with no mass effect. No lesions are seen in the
left hemisphere. (From Michel F, Poncet M, Signoret JL. Les lesions responsables de la prosopagnosie sont-elles toujours
bilaterales? Rev Neurol 1989;145⬊764–770.)
Figure 13.24. Prosopagnosia with bilateral anterior temporal lesions. This

33-year-old woman had a closed head injury and surgical resection of one
temporal lobe 10 years earlier. She has full visual fields and no topographag-
nosia or color deficit. She performs well on tests of face perception but
poorly on tests of face imagery, suggesting she has lost access to facial
memory stores.
mental disorders such as Asperger syndrome (268). In the other problems of identity recognition and face matching, a
congenital cases, neuroimaging tends not to show the corti- selective defect for facial expression alone occurred with
cal lesions seen in adult-onset prosopagnosia, but sometimes left hemispheric lesions (388). Clearly the literature needs
there are more subtle anomalies. a more detailed exploration of relatively selective defects of
dynamic facial interpretation, along with good neuroim-
OTHER DISORDERS OF FACE PERCEPTION aging.
The use of unfamiliar face-matching tests has generated Some patients mistake strangers for people known to them
some interesting data on hemispheric processing of stimuli. (390,391). Some persist in the belief of the mistaken identity,
One of the interesting observations has been that deficits despite evidence to the contrary, and hence have some of
in unfamiliar face matching can occur in subjects without the delusional quality of Capgras syndrome. As with proso-
prosopagnosia (303,304). This too tends to be associated pagnosia, false recognition of unfamiliar faces has been de-
with right hemispheric lesions. Since some prosopagnosic scribed mainly with right-sided lesions. Unlike prosopag-
patients can match unfamiliar faces, though with some effort nosia, the lesions are usually large middle cerebral artery
and increased test time, this raises the possibility of a double strokes, affecting lateral frontal, temporal, and parietal cor-
dissociation. However, a later study of 34 patients found tex (390,391). Nevertheless, some patients appear to have
that most subjects were impaired with both familiar face associated prosopagnosia on testing, although they deny
recognition and unfamiliar face matching (388). Also, in the problems in recognizing people (391). In these cases, the
two patients with preserved accuracy scores on one test but fault may lie with either impaired perceptual input to face-
not the other, the reaction times were prolonged on the test recognition units or poor discriminative function of partial
with the normal accuracy score. The authors concluded that damaged face-recognition units (392).
the processes for familiar and unfamiliar face identity were False recognition without prosopagnosia has also been
not independent. described (390,392). Most have right prefrontal damage,
A less-studied limb of the face-processing model is the which may impair self-monitoring and decision making,
analysis of dynamic facial information, such as gaze, expres- leading to hasty mistaken judgments of facial similarity
sion, and age. Monkey and functional imaging data would based on partial or fragmentary data, and failure to reject
suggest that these are more likely to be associated with dam- incorrect matches (392). These deficits in decision making
age to the lateral occipitotemporal region. There are few data and self-monitoring should be evident in other perceptual
to confirm or refute this at present. An older study did find decisions, but evidence for this has not yet been gathered.
that judgment of facial age could be impaired by right hemi- Frontal lesions may also be responsible for the failure of
spheric lesions, but no detailed neuroanatomic data were some patients with the prosopagnosic variant of false recog-
provided (389). Another study showed that while defects in nition to recognize their impairment and to persist in their
analyzing facial expression were usually associated with mistaken delusions.
ACQUIRED ALEXIA
Acquired alexia is the inability to read in previously liter- of the term ‘‘dyschromatopsia’’ in cases of incomplete color
ate individuals despite adequate visual acuity. The severity vision loss).
of the reading disorder and the pattern of accompanying Dejerine (394) first described a patient with alexia and
neurologic defects vary depending on the location and extent agraphia but no other linguistic or visual defect, caused by
of the underlying brain lesions. Reading is a complex behav- a lesion of the left angular gyrus (Fig. 13.25). In 1892 he
ior involving form perception, spatial attention, ocular fixa- described a case of alexia without agraphia (pure alexia, or
tion, scanning saccadic eye movements, and linguistic pro- word blindness) with incomplete right homonymous hemia-
cessing. Not surprisingly, many types of cerebral or visual nopia, due to a lesion of the left fusiform and lingual gyri
dysfunction can disrupt the reading process; while other clin- (Fig. 13.26). This patient developed agraphia after a second
ical signs may accompany the alexia, impaired reading is infarct of the left angular gyrus, corroborating the findings
sometimes the chief or the only complaint. The severity of of the previous case. Dejerine deduced that the left angular
reading difficulty can range from a mild defect with slow gyrus stored the visual representation of words needed for
reading and occasional errors, which requires comparison reading and writing. Furthermore, disconnecting the visual
with normal controls matched for educational level (393), inputs of both hemispheres from the left angular gyrus could
to a complete inability to read even numbers and letters. disrupt reading but leave writing intact. These early concepts
Analysis of the severity and type of reading errors can help have survived in modern disconnectionist theories of pure
differentiate between the various forms of reading disorders alexia (395), and his localization is consistent with the data
and their causes. Acquired alexia and milder forms of ac- from neuroimaging (396).
quired reading disturbance must be distinguished from ‘‘dys- PURE ALEXIA (WORD BLINDNESS, OR ALEXIA
lexia,’’ a developmental defect that results in much less se- WITHOUT AGRAPHIA)
vere reading difficulties characterized by slow reading, letter
or word reversals, and other inefficiencies. The label ‘‘dys- Signs and Symptoms
lexia’’ has also been applied in acquired reading disturbance The key feature of pure alexia is a dramatic dissociation
where the reading defect is incomplete (analogous to the use between the ability to read and normal writing performance:
road signs, and map symbols (398,399), let alone words. At

the mild end, patients have slow reading with occasional
errors, diagnosable only by comparison with controls of sim-
ilar educational level (393). These patients decipher words
one letter at a time (letter-by-letter reading, or spelling dys-
lexia). The characteristic sign is the word-length effect, in
that the time needed to read a word increases with the num-
ber of letters in the word (400,401).
In Japanese, which has two different writing systems,
kana (phonetically based) and kanji (nonphonetic, ideo-
graphic form), there can be impaired reading of kanji but
not kana (402) or vice versa (403). Dissociations in bilingual
patients can also occur, with the more recently acquired lan-
guage less affected (404), perhaps in keeping with hy-
potheses of right hemisphere involvement in new language
acquisition. In patients with long-standing blindness, alexia
for Braille can be caused by occipital lesions in the absence
of somatosensory deficits (405).
Associated signs with pure alexia are common (396).
There is often a right visual field defect, usually complete
homonymous hemianopia but sometimes only a superior
quadrantanopia, in which case there may also be a right
hemiachromatopsia. Pure alexia cannot be attributed to right
Figure 13.25. Location of the lesion causing alexia with agraphia. Draw- hemianopia, however, as pure alexia can occur without hemi-
ings made by Déjérine of the case he reported in 1891 (see text for details). anopia (406–410), and many patients with right macula-
Top, Lateral surface of the left hemisphere. Bottom, Axial section of the splitting hemianopia do not have pure alexia. While any
same hemisphere. The drawings show a lesion (shaded area) of the left associated dyschromatopsia is restricted to the right hemi-
angular gyrus. (From Black SE, Behrmann M. Localization in alexia. In: field, naming of colors in the left hemifield may be abnormal
Kertesz A, ed. Localization and Neuroimaging in Neuropsychology. San (248,396). Naming problems also extend to other visual ob-
Diego, Academic Press, 1994⬊331–376.) jects and photographs frequently. Anomia is not necessarily
restricted to the visual modality but can include objects per-
ceived by touch, implying some nonvisual language distur-
such patients can write fluently and spontaneously, but hav- bance (411). Verbal memory deficits and visual agnosia can
ing done so cannot read what they have just written. The occur (396,411). Some authors describe a disconnection
severity of this defect can vary. At the severe end, patients optic ataxia in which the dominant right hand has difficulty
with global alexia (397) cannot read numbers, letters, and with purposeful movements to objects in the nondominant
other abstract symbols, such as musical notation for pitch, left visual field (396).
Figure 13.26. Location of the lesion causing alexia without agraphia (pure alexia). Drawing made by Déjérine of the case
he reported in 1892 (see text for details). Drawing of the lateral and medial surface of the left hemisphere. Dark shading shows
the first lesion, affecting the cuneus (C), lingual (TO2), and fusiform (TO1) gyri. (From Black SE, Behrmann M. Localization
in alexia. In: Kertesz A, ed. Localization and Neuroimaging in Neuropsychology. San Diego, Academic Press, 1994⬊331–376.)
Covert Reading (400) but not in another (416). The key distinctions between
those with and without ‘‘covert’’ lexical classification ability
Several studies have shown covert reading ability in pa- remain to be elucidated.
tients with pure alexia. Some patients could indicate whether Covert comprehension of word meaning has been reported
a string of letters formed a word (lexical decision task). This also. Some patients could accurately categorize words se-
ability varied with linguistic features such as the frequency mantically (i.e., indicating which are animals, foods, etc.)
of the word in daily usage, the amount of visual imagery (401), though others could not (416). Words could be
evoked by the word, and the grammatical category of the matched to objects or their pictures by some patients
word, with better performance with nouns (401,412,413). (412,417) but not others (418). Whether these demonstra-
The ability to distinguish words from non-words may use a tions constitute ‘‘unconscious’’ covert ability has been chal-
mechanism separate from the laborious letter-by-letter strat- lenged. One subject could not only make semantic matches
egy used to read words: the time required to make lexical but also was aware of the accuracy of her performance,
decisions in one letter-by-letter reader was much less than showing preserved ‘‘metaknowledge’’ (417). Presence of
the time needed to identify words and did not show the word- metaknowledge may point to partial degradation of informa-
length effect characteristic of the latter (414). Other exam- tion rather than dissociations between conscious and non-
ples of covert determination of lexical status include one conscious processes. Bub and Arguin (414) found that unlike
patient who could indicate which part of a long string of covert lexical decisions, semantic categorizations took
letters formed a word and point to a written word named by longer and also showed the word-length effect, suggesting
the examiner, even though she could not read it aloud (415). that they were accomplished by the same mechanism that
The ability to identify rapidly presented letters was better was used for explicit identification of words. They too con-
when the letters were part of words than if they were parts of cluded that semantic categorization may be due to partially
random letter strings (word superiority effect) in one patient decoded letter information allowing forced-choice responses
Figure 13.27. Pathology of pure alexia. Four axial

sections through the brain of a 68-year-old man with
pure alexia (alexia without agraphia), right homony-
mous hemianopia, color anomia, and optic ataxia. The
infarction involves the left medial temporo-occipital
lobe (arrows 2 and 3) and periventricular white matter
(arrow 1), and also the forceps major (arrow 4). (From
Damasio AR, Damasio H. The anatomic basis of pure
alexia. Neurology 1983;33⬊1573–1583.)
if not verbal report, rather than covert knowledge. However, ital horn of the lateral ventricle (396,424) (Fig. 13.29). Thus,
their findings contrast with the report by Coslett et al. (401) words in the left hemifield also cannot access the left angular
of a patient who could rapidly achieve both lexical decisions gyrus; similarly, other visual information is isolated, causing
and semantic categorizations, suggesting that both types of the associated anomia for colors and objects. Visuolinguistic
covert processing used a ‘‘whole-word’’ identification strat- disconnection may also result from the combined effects
egy rather than the letter-by-letter technique for explicit of bilateral occipital lesions in patients with bilateral field
reading. These authors attributed covert reading ability to defects, without splenial damage (425).
right hemispheric language processing. Cases of pure alexia without hemianopia have been found
with lesions of the white matter underlying the angular
Anatomy, Pathology, and Mechanisms of Pure Alexia gyrus: such ‘‘subangular’’ lesions presumably disconnect
the input from both hemispheres to the angular gyrus very
Lesions causing pure alexia are almost always in the left distally (406–408,410). Some of these reports conclude that
hemisphere, most commonly in the medial and inferior oc- the right hemispheric callosal fibers travel in the white matter
cipitotemporal region (396,397) (Figs. 13.27 and 13.28). ventral to the occipital horn (407,408). Binder and Mohr
Most are due to infarction within the vascular territory of (397) speculated that some callosal fibers travel dorsal to
the left posterior cerebral artery. Other causes include pri- the occipital horn, and that these are preserved in letter-by-
mary and metastatic tumors (406,407,419), arteriovenous letter or spelling alexia, which they consider a partial form,
malformations (414,420), hemorrhage (408), herpes simplex but are destroyed in global alexia, which they consider the
encephalitis (410), multiple sclerosis (421), and posterior complete form.
cortical atrophy (399,422). Other non-disconnectionist interpretations of pure alexia
One popular explanation of pure alexia is a disconnection exist. Some propose that it is a type of simultanagnosia
of visual information from linguistic processing centers (318). However, tests for simultanagnosia in some patients
(395,423). Visual information from the right hemifield is have been negative (418), although the adequacy of these
either absent, in cases with right hemianopia, or interrupted tests has been disputed (318). Others have argued that letter-
in its course through left extrastriate centers to the ‘‘reading by-letter readers cannot access the visual word form, and
center’’ in the left angular gyrus. Callosal pathways trans- that pure alexia may be a specific visual agnosia (418,426).
mitting visual information from visual association cortex of The alexic deficit is magnified with script rather than print
the right hemisphere to homologous regions in the left hemi- and with briefly shown words, maneuvers that stress identifi-
sphere are interrupted by a lesion in the splenium, forceps cation of the word as a whole (418). Their use of a letter-
major, or periventricular white matter surrounding the occip- by-letter strategy in reading and their need for more time
with longer words point to an inability to grasp words as a
whole and may represent residual visual processing in the
right hemisphere (426). Such a visual agnosia may not be
specific for words, but alexia may be its most troublesome
manifestation. Apperceptive defects (302,427), simultanag-
nostic-like defects (418,428–430), and associative defects
(431,432) have been proposed. A patient with pure alexia
had difficulty in perceiving complex textures, a problem
with local pattern analysis that may be relevant to word per-
ception (302). Others have shown that alexia can be associ-
ated with subtle disturbances in visual recognition of nonver-
bal items (427). This agnosia may be restricted to the visual
domain: when tested on imagery of letters and words, a pa-
tient was able to do much better when allowed to trace letters
manually than when he was asked to manipulate visual im-
ages of letters mentally (433).
Some indirect support for the agnosia argument also
comes from pathologic reports inconsistent with disconnec-
tion. One patient had a lesion of the left fusiform and lingual
gyrus but no splenial degeneration, which should have oc-
curred if callosal fibers had been affected (434). Another
without hemianopia had a lesion in the left lateral occipito-
temporal cortex, too ventral to interrupt fibers to the angular
Figure 13.28. Location of lesions causing pure alexia, right homonymous
hemianopia, and color dysnomia. Template drawings of axial computed
gyrus (435). Alexia in the setting of cortical dementia is
tomographic images, combined from five patients, show lesions affecting presumably more likely to be agnosic than disconnective in
the left medial and lateral occipital lobes, medial temporo-occipital lobe nature (430).
and paraventricular white matter, and forceps major, sometimes extending While some cases of pure alexia may be a visual agnosia
into the splenium proper. (From Damasio AR, Damasio H. The anatomic from left extrastriate damage, at least some cases do repre-
basis of pure alexia. Neurology 1983;33⬊1573–1583.) sent a true visual–verbal disconnection. The best evidence
Figure 13.29. The splenium of the corpus

callosum in pure alexia (alexia without
agraphia). Coronal section through the
brain of a 58-year-old man with pure alexia,
a right homonymous hemianopia, color an-
omia, and memory deficits shows infarction
and degeneration of the splenium, with as-
sociated destruction of the left hippocam-
pus. (From Geschwind N, Fusillo M. Color-
naming defects in association with alexia.
Arch Neurol 1966;15⬊137–146.)
Figure 13.30. Neuroimaging in pure alexia (alexia without agraphia) caused

by nonoccipital lesions. Axial magnetic resonance image in a patient with a
right homonymous hemianopia, color anomia, and pure alexia shows an in-
farct of the left posterolateral thalamus affecting the lateral geniculate nucleus
(a) and an infarct of the lateral aspect of the splenium of the corpus callosum
(b). Both infarcts are in the distribution of the left posterior cerebral artery.
An arrow (c) shows the direction of input from the intact right occipital
lobe through the corpus callosum toward the left angular gyrus. cc, corpus
callosum; cal, calcarine cortex. (From Stommel EW, Friedman RJ, Reeves
AG. Alexia without agraphia associated with spleniogeniculate infarction.
Neurology 1991;41⬊587–588.)
for disconnection comes from cases of pure alexia with atyp- and will likely require tailoring to the specific reading defect
ical lesions. Pure alexia can occur with the combination of in a given patient.
a splenial lesion and a left geniculate nuclear lesion causing
right hemianopia (436,437) (Fig. 13.30); there is no damage OTHER DISCONNECTION ALEXIAS
to striate or extrastriate cortex in such patients. These cases
demonstrate that disconnection is sufficient to cause pure The disconnection hypothesis (395,423) involves two
alexia. In that light, any claim that an associated visual agno- deafferentations of the left angular gyrus: the disconnection
sia or simultanagnosia is responsible for pure alexia in a of right hemisphere vision and the disconnection or destruc-
given patient must prove either that no such disconnection tion of left hemisphere vision. Each of these has been de-
exists in that patient or that the case has features distinct scribed in isolation, as hemialexias. In left hemialexia, read-
from the pure alexia caused by verified disconnection above. ing is impaired in the left hemifield only because of isolated
Prognosis and treatment depend on the underlying pathol- damage to the posterior corpus callosum or callosal fibers
ogy as well as the severity of dyslexia. Global alexia can elsewhere (442,443). This disconnection was visualized re-
resolve into a spelling dyslexia (424). Interest in rehabilita- cently in one patient with a combination of fMRI and diffu-
tion of reading in alexic patients is high, with many imagina- sion tensor imaging (443). Right hemialexia has been re-
tive strategies currently evolving. These include altering text ported with a lesion of the left medial and ventral occipital
to highlight the spacing between words or phrases (438,439), lobe that spared other visual functions in the right field (444)
enhancing oral articulation during reading (440), repetitive (Fig. 13.31).
oral reading of text (438), attempts to enhance implicit or Left hemiparalexia is a rare syndrome attributed to
covert processing of whole words (439), and finger tracing splenial damage (445). The reading pattern is similar to that
of letters in patients presumed to have a disconnection syn- in neglect dyslexia, in that substitution and omission errors
drome (439,441). The success of these approaches in im- occur for the first letter of words. However, these patients
proving both speed and accuracy requires further evaluation do not have evidence of hemineglect, and while patients with
Figure 13.31. Neuroimaging in right hemialexia.

Four axial computed tomographic images from a 54-
year-old man with a stroke affecting the left medial
and inferior occipital lobe, sparing striate cortex, and
the forceps major. Although he did not have a homon-
ymous field defect, he could not read letters, words,
digits, or arithmetic symbols in his right homonymous
hemifield. (From Castro-Caldas A, Salgado V. Right
hemifield alexia without hemianopia. Arch Neurol
1984;41⬊84–87.)
Figure 13.32. Neuroimaging in a patient with left hemiparalexia. 1–3, Axial T2-weighted magnetic resonance images at
three successive levels from a 40-year-old woman who underwent embolization of a left medial parieto-occipital arteriovenous
malformation. After the procedure, she had a right homonymous hemianopia, left unilateral tactile dysnomia, and alien hand
syndrome on the left. During reading, she missed the letters on the left side of words, even though she had an intact left
homonymous hemifield and no left hemineglect. The images show changes consistent with infarction in the left ventral-caudal
splenium (arrowhead, level 2) and medial occipital lobe (levels 1 and 2), with sparing of the rostral splenium (arrowhead,
level 3). (From Binder JR, Lazar RM, Tatemichi TK, et al. Left hemiparalexia. Neurology 1992;42⬊562–569.)
neglect dyslexia often have right hemispheric lesions with times termed literal alexia or ‘‘letter blindness.’’ These pa-
left hemianopia, several of the patients reported (445) had tients also have impaired comprehension of syntactic struc-
left occipital lesions with right hemianopia (Fig. 13.32). ture, just as their speech output often demonstrates a greater
There can be other signs of callosal disconnection, such as impairment of syntax, known as agrammatism. The underly-
inability to name objects felt by the nondominant (left) hand, ing mechanism is unknown: gaze paresis and difficulty in
left-hand agraphia, and inability to duplicate the unseen maintaining verbal sequences have been proposed but not
movements of one hand by the other. All the patients re- proven (449). It may be that this frontal alexia is a form of
ported by Binder et al. (445) had undergone surgery for deep dyslexia, a type of central dyslexia (393).
arteriovenous malformations.
DYSLEXIA SECONDARY TO ABNORMAL VISION,
ALEXIA WITH AGRAPHIA ATTENTION, OR EYE MOVEMENTS
A combination of impaired reading and writing with rela- Some patients with visual field defects have reading prob-
tively intact oral and auditory language function constitutes lems despite normal or near-normal visual acuity. Patients
alexia with agraphia. This is associated with lesions of the with complete homonymous hemianopia may complain of
left angular gyrus (394,423,446), although lesions of the ad- reading problems, hence the term hemianopic dyslexia. This
jacent temporoparietal junction have also been implicated mainly occurs when the central 5 degrees are affected (450).
(447). Little is known about this unusual disorder. In keeping Overall reading speed is more prolonged for patients with
with the parietal location, alexia with agraphia may be ac- right hemianopia than for those with left hemianopia
companied by acalculia, right–left disorientation, and finger (450,451). With languages written from left to right, patients
agnosia, the other elements of Gerstmann’s syndrome. with left hemianopia have trouble finding the beginning of
Another form of alexia and agraphia is described as an lines, since the left margin disappears into the field defect
accompaniment of Broca’s aphasia (nonfluent aphasia), as they scan rightwards (452,453) (Fig. 13.33). Marking their
which is due to lesions of the dominant (left) frontal lobe. place with an L-shaped ruler can reduce this frustration.
While the difficulty these patients have with reading aloud Right hemianopia prolongs reading times, with increased
and writing can be attributed to their difficulty with all forms fixations and reduced amplitude of reading saccades to the
of expressive language output, their comprehension of writ- right (451–453) (Fig. 13.33). Smaller type and learning to
ten material is also impaired, in contrast to relatively pre- read obliquely with the page turned nearly 90 degrees may
served comprehension of auditory language (448,449). In help. Reading performance can improve with time as both
contrast with the letter-by-letter reading in pure alexia, these types of patients learn adaptive strategies (450).
patients are better at occasionally grasping a whole word, Complete bitemporal hemianopia from damage to the
while unable to name the letters of the word; thus, it is some- optic chiasm can cause hemifield slide (see Chapter 12).
Figure 13.33. Eye movements during reading in nor-

mal subjects (A and B) and in patients with left homony-
mous and right homonymous hemianopia with either 1-
degree (C and E) or 5-degrees sparing of the macula (D
and F). Horizontal eye positions (on the y axis) are shown
over time (on the x axis) as subjects read lines of a para-
graph (positive visual angle is horizontal eye position to
the right). A and B, Traces from normal subjects. C and
D, Traces from patients with left homonymous hemia-
nopia and either 1 degree (C) or 5 degrees (D) of macular
sparing. Note the interruptions of the return sweeps to
the beginning of the next line in C (curved arrows). E
and F, Traces from patients with right homonymous
hemianopia and either 1 degree (E) or 5 degrees (F) of
macular sparing. Curved arrows in these patients indi-
cate prolonged fixations and regressive leftward move-
ments during line scanning. (From Zihl J. Eye movement
patterns in hemianopic dyslexia. Brain 1995;118[Pt 4]:
891–912.)
With only nasal hemifields, there is no region of the visual the presence of simultanagnosia for other visual items be-
field that has binocular representation, leading to difficulty sides words.
keeping the eyes positionally registered with respect to each Left hemineglect is an attentional deficit that causes neg-
other and a breakdown of binocular alignment (454). The eyes lect dyslexia, manifest by left-sided reading errors (455).
wander slightly, causing episodic horizontal tropias, with This can occur for the whole text, so that the patient misses
transient diplopia or disappearance of objects along the verti- the left side of a line or page. With individual words, the
cal meridian, and episodic vertical tropias, with a vertical step patient may make omissions (FLAME becomes LAME), ad-
in objects crossing the vertical meridian. Thus, when reading, ditions (ACT becomes TACT), or substitutions (TONE be-
letters may disappear or duplicate and lines of words may be comes BONE) at the beginning. These defects are specific
confused as they cross from one hemifield into the other. for left hemispace rather than word beginnings, as such er-
Disturbances of attention can cause a number of ‘‘periph- rors do not occur for vertically printed words (455). Many
eral dyslexias’’ (393). Simultanagnosia, in which perception patients with left hemineglect have left hemianopia as well,
of single items is adequate but perception of several objects and the underlying lesion is often in the right parietal lobe,
simultaneously is impaired, has been implicated in atten- although right frontal and subcortical lesions can also cause
tional dyslexia (428,429). Patients read single words nor- neglect. Recognizing that mistakes are restricted to the left
mally but not several words together; similarly, they identify side of words or text leads to the diagnosis; associated hemi-
single letters but not the letters in a word. Their reading may neglect for nonverbal material is usually present, but neglect
show literal migration errors, in which a letter from one dyslexia dissociated from other manifestations of hemine-
word is substituted at the same place in another (e.g., LONG glect can occur (456).
TURN becomes TONG TURN), and letters of similar ap- Abnormalities of ocular fixation and scanning saccades
pearance are more likely to be confused (e.g., G for C, rather may impair reading. Most cortical lesions are single and
than K for C) (429). Attentional dyslexia has been reported unilateral and tend to cause fairly subtle saccadic abnormali-
with lesions in the left temporo-occipital junction (429) and ties, if any; however, bilateral frontal or parietal lesions can
the left parietal lobe (428). Its diagnosis rests upon the differ- cause an acquired ocular apraxia, in which the ability to
ence between reading of single versus multiple words, and make voluntary saccades to targets is disrupted (11,25,457,
458). As a result, the scanning of a scene is abnormal in hemisphere (466). Surface dyslexia has also been reported
these patients (457,458) and reading is consequently im- in patients with Alzheimer’s disease (467,468).
paired (11,25,459,460). While the saccadic abnormality has The converse of surface dyslexia is phonologic dyslexia
been blamed for the dyslexia by some (459), simultanag- (462–464,469). In the absence of access to grapheme–pho-
nosia may contribute to the saccadic abnormality with bipari- neme correspondence rules for pronunciation, these patients
etal lesions, and the reading disturbance may be attentional can pronounce only words that already have entries in their
dyslexia. More severe and enduring saccadic and fixation internal semantic dictionary. Thus, real words are easily pro-
dysfunction occurs with brain stem pathology. Reading diffi- nounced, whether regular or irregular in spelling, but the
culties from such lesions have not been well studied, but it reading of non- or pseudo-words (e.g., FRINE) is severely
has been reported, for example, that progressive supranu- impaired. Their reliance on whole-word processing rather
clear palsy causes difficulty reading, attributed to the disrup- than component or letter processing is revealed by good per-
tion of fixation by square wave jerks and the disruption of formance in reading handwriting, contrasted with inability
scanning by hypometric and slow saccades (461). to read words printed backwards (462). Friedman (464) ar-
gues that there may be a second form of phonologic dyslexia
CENTRAL DYSLEXIAS in which it is not the direct route but the phonologic lexicon
itself that is impaired, causing impaired repetition of heard
Further types of more subtle acquired dyslexic deficits pseudo-words as well as misreading of written pseudo-
have been described. Many of these occur in association words. The responsible lesion for phonologic dyslexia is not
with other aphasic features and so might be classified as well defined (393). In one patient an associated right inferior
aphasic alexias; however, they occasionally occur as isolated quadrantanopia was present (462), in contrast to the superior
dyslexias also (462). These reading defects are sometimes quadrantanopsias that accompany pure alexia (396).
labeled central dyslexias, as they reflect dysfunction of cen- Deep dyslexia resembles phonologic dyslexia in the ina-
tral reading processes rather than ‘‘peripheral’’ attentional bility to pronounce non-words because of damage to the
or visual processes. Central dyslexias are formulated in phonologic route (470). However, patients with deep dys-
terms of reading models derived from cognitive neuropsy- lexia also make semantic paralexic errors with familiar
chology (393). One of the main concepts involved is that of words, characteristically substituting words with a similar
parallel information processing in reading. The perception meaning for the correct one (e.g., JET for PLANE). Errors
of visual features and the abstraction of letter identity are are more likely with function words (e.g., and, whether) than
followed by at least two distinct modes of processing. One with verbs or nouns, and with abstract than with concrete
route is a ‘‘direct’’ phonologic process, in which the units words. Thus, it is argued that deep dyslexia may represent
of a letter string are converted into units of sound (gra- damage to both the direct and indirect reading routes (464).
pheme–phoneme correspondence), using the generic pro- Extensive damage to the left hemisphere is associated with
nunciation rules of a given language. These components are deep dyslexia, and it has been suggested that deep dyslexia
then assembled into the pronounced whole word, found in represents the remnant reading ability of the right hemi-
an internal dictionary of word sounds (phonologic lexicon) sphere (471).
and linked to information about word meaning in a semantic
lexicon. Another route is an ‘‘indirect’’ lexical one, in which FUNCTIONAL IMAGING OF READING
the whole word is perceived and identified in an internal
dictionary of written words (orthographic lexicon): when the Only a few functional neuroimaging studies of visual lan-
correct word form is activated, a corresponding entry in the guage processing have been published, with conflicting re-
semantic lexicon is also activated, leading in turn to access sults. Interestingly, activation of the left angular gyrus has
to the phonologic lexicon and the pronunciation of the word. not been found, with the possible exception of one study
A possible third ‘‘rule-based’’ phonologic route for pronun- that found spread from the left posterior temporal lobe into
ciation of non-words and unfamiliar words is postulated but the inferior parietal lobe (472). Petersen et al. (473) had
controversial (463,464). The anatomic correlates of these subjects first passively view words, read words aloud, then
different lexical and phonologic reading routes are still un- describe uses for the objects represented by the words, a
certain. task that requires semantic processing. Striate and lateral
Surface dyslexia occurs with disruption of the indirect temporal extrastriate areas were activated by viewing of a
lexical reading process. Word recognition is critical for pro- word, reading aloud recruited motor and articulation areas,
nunciation of words with irregular spelling (e.g., compare and the semantic association task activated a left lateral
LOSE with HOSE). Lacking the ability to access an internal inferofrontal area (474). A later study (475) found activation
semantic dictionary, patients with surface dyslexia are de- of the lateral extrastriate areas not only with words and
pendent on the grapheme-phoneme rules that usually apply pseudo-words but also with complex letter-like forms (false
but that fail with irregularly spelled words. Thus, these pa- fonts), suggesting that this was related to processing of com-
tients are revealed by their correct reading of regular words plex visual features and not specific for words. Words and
and overregularizing mispronunciations of irregular words pseudo-words, but not the letter-like forms, activated a left
(465), just as children might do with unfamiliar words. The medial extrastriate area, which was attributed to activation
best anatomic data on surface dyslexia points to lesions of of visual word forms. Similar preference for alphabetic char-
the posterior superior and middle temporal gyri of the left acters over checkboards has been found in the left medial
occipitotemporal sulcus, a region named the ‘‘visual word found that reading words activated the left posterior middle
form area’’ (426). While Howard et al. (476) confirmed temporal gyrus, which they suggested was the location of
striate and lateral extrastriate activation with false fonts, they the visual lexicon.
DISORDERS OF MOTION PERCEPTION (AKINETOPSIA)

Akinetopsia (cerebral akinetopsia) is the term used to de- tion of differences in temporal frequency or speed of gratings
scribe complete loss of movement perception from an ac- also was impaired (103). The minimum and maximum dis-
quired cerebral lesion. Unlike cerebral achromatopsia, which placements needed by L.M. to distinguish motion direction
was described in the late 1800s (see above), akinetopsia was were abnormal (103). During testing with random-dot kine-
not reported until the 1980s, after the discovery of motion- matograms, small amounts of random motion (noise) or even
selective extrastriate regions in monkeys suggested that stationary dots degraded her performance (26,482). Her use
damage to homologous areas in humans might produce a of motion cues for other tasks was also impaired. In a search
defect in motion perception. Although akinetopsia requires task, she could not restrict her attention to moving targets,
bilateral cerebral lesions, subtler and generally asymptom- although she could focus her attention on objects of certain
atic disturbances of motion perception can occur with unilat- shapes or colors, implying an inability to apply a ‘‘motion
eral cerebral lesions. filter’’ to visual scenes. Her use of motion clues to identify
Motion perception can play many roles in vision (477). both three- and two-dimensional shapes was abnormal, espe-
One is the perception of moving objects in the environment. cially when the image contained background noise (26).
Because objects usually occupy only a small part of the vi- Despite the above deficits, L.M. was able to perform a
sual field, their perception is facilitated by comparing their number of motion tasks well. She could distinguish moving
motion with that of the background. Object motion guides from stationary stimuli (47), although her reaction times
limb-reaching movements and smooth pursuit eye move- were slow (478). Contrast sensitivity testing showed that her
ments, and it influences saccadic accuracy. In addition to detection of moving gratings was only mildly affected (103).
object motion, information about self-motion can be ob- She could discriminate motion direction for small spots
tained from motion perception. As the observer moves or (478) and for random-dot kinematograms that contained
turns the head or eyes, the image of the entire visual environ- very little background noise (26,482).
ment moves in the opposite direction. Thus, motion of large The other patient, A.F., had somewhat similar deficits
portions of the visual field usually implies self-motion rather (483,484). His ability to discriminate differences in speed
than motion of an external object. This large-field motion was severely impaired, and discrimination of direction in
generates optokinetic responses that complement the vestib- random-dot kinematograms with background noise was ab-
ulo-ocular reflex in stabilizing sight during head motion or
normal. His smooth pursuit appeared impaired, although it
self-motion. Information about object identity is also avail-
was not quantified. As with L.M., A.F. could not use relative
able from visual motion. For example, the difference in mo-
speed differences to perceive two-dimensional forms, but in
tion between a figure and its background reveals two-dimen-
contrast to L.M., A.F. could use motion cues to discern three-
sional shape, and the pattern of velocity gradients within a
dimensional forms. He also recognized shapes from biologic
moving object encodes its three-dimensional form.
There are few clinical tests of motion perception. Smooth motion (485).
pursuit and optokinetic nystagmus can be observed and mea- A.F. had a left incomplete homonymous hemianopia with
sured, but only indirect conclusions about the underlying some sparing in the superior quadrant. He was poor at recog-
state of motion perception can be made from these. More nizing objects in noncanonical (unusual) views (486) and in
definitive tests of motion perception, such as animated dis- incomplete outline drawings. Tests of spatial vision, such
plays of moving dots (random-dot kinematogram) or moving as hyperacuity, line orientation, line bisection, and spatial
gratings can be designed to probe discrimination of motion location, gave abnormal results, as did tests of stereopsis.
direction, motion speed, the presence of a motion boundary, L.M.’s perception of form was abnormal, and she had an
and forms defined by motion, but these are still experimental impaired ability to use cues from texture, dynamic stereop-
tools and are not widely used in the clinical setting. sis, or static density to determine form (26).
In L.M., Snellen visual acuity, critical flicker fusion, stere-
SYMPTOMS AND SIGNS opsis using the Titmus test, color discrimination using the
Two cases of cerebral akinetopsia have been well de- Farnsworth-Munsell 100-Hue Test, perimetry using static,
scribed. Patient L.M. was first reported by Zihl et al. in 1983 dynamic, color, form, and flicker targets, object/word recog-
(47) and subsequently was the subject of numerous reports nition, and saccadic accuracy were all normal (47). Further
(26,103,478–481). L.M. had no sensation of motion in depth testing showed normal results on Lanthony gray luminance
or of rapid motion (47). When observing objects that were discrimination, distance perception, subjective vertical/hori-
said to be moving rapidly, she noted that they appeared to zontal, line bisection, line orientation, position matching,
‘‘jump’’ rather than move (478). matching of object or facial parts, and face recognition (478).
On testing, her predictions of target trajectories were im- Similarly, A.F. had normal contrast sensitivity for static and
paired at faster speeds, as was smooth pursuit, although her moving gratings, normal shape discrimination, normal facial
eyes could pursue a moving tactile target (47). Her percep- and object recognition, normal color discrimination (Farns-
Figure 13.34. Conventional coronal magnetic res-

onance images through the occipital lobes in patient
L.M., who developed bilateral temporo-occipital le-
sions from sagittal sinus thrombosis with resultant
cerebral akinetopsia. A, T1-weighted image through
midoccipital region shows hypointense areas, right
greater than left, consistent with infarcts, sur-
rounded by mild hyperintense areas consistent with
edema. B, T2-weighted image at same location,
showing large hyperintense areas with minimal
mass effect on both sides. Note similar areas in cere-
bellum, primarily in right hemisphere and in the
midline. C, T1-weighted image through posterior
occipital lobes shows persistent bilateral hypoin-
tense areas with surrounding minimal hyperinten-
sity. D, T2-weighted image at same location shows
large areas of hyperintensity in both occipital lobes.
(From Zihl J, von Cramon D, Mai N, et al. Distur-
bance of movement vision after bilateral posterior
brain damage. Further evidence and follow-up ob-
servations. Brain 1991;114[Pt 5]:2235–2252.)
worth-Munsell 100-Hue Test), and normal color-naming speed discrimination (487,488) (Fig. 13.35), for detection of
ability. boundaries between regions with different motion (484), and
L.M. had suffered sagittal sinus thrombosis, resulting in for discrimination of direction from backgrounds of motion
bilateral cerebral infarction involving the lateral aspects of noise (489). As in L.M. and A.F., motion detection and con-
Brodmann areas 18, 19, and 39 (lateral occipital, middle trast thresholds for motion direction are normal in patients
temporal, and angular gyri) (42) (Fig. 13.34). Shipp et al. with these deficits (487,488), and lesions are located in lat-
(481) performed PET scanning on the patient, which showed eral temporo-occipital cortex or the inferior parietal lobule,
that visual motion induced activation in the medial cuneus but only on one side of the brain. Hemiakinetopsia may not
bilaterally (probably equivalent to monkey upper V3), the be commonly detected because of masking of the motion-
left fusiform gyrus (possibly the border between lower V3 perception deficits by a homonymous hemianopia caused by
and V4), and the superior temporal lobe (area 7), but not in damage to the optic radiations or striate cortex.
area V5 (42,43). Abnormalities in central motion perception also occur
A.F. had experienced an acute hypertensive hemorrhage with unilateral lesions. Vaina (490) reported that patients
and also had bilateral lesions in the lateral temporo-occipital with right temporo-occipital lesions could not identify two-
regions (483,484). dimensional structures from motion cues, whereas patients
with right parieto-occipital lesions could not discriminate
MOTION PERCEPTION DEFICITS WITH
velocity or detect three-dimensional form-from-motion.
UNILATERAL CEREBRAL LESIONS
Regan et al. (491) reported similar defects in detecting or
Unilateral lesions of extrastriate cortex cause more subtle recognizing two-dimensional form-from-motion in patients
abnormalities of motion perception than cerebral akinetop- with both right- and left-sided lesions in the lateral temporo-
sia. There are reports of contralateral hemifield defects for occipital region (Fig. 13.36). Nawrot et al. (492) found ab-
Figure 13.35. Neuroimaging in a patient with impaired contralateral hemifield motion perception. The patient had undergone
resection of a seizure focus in the left parieto-occipital region. Following surgery, he had a deficit for speed discrimination in
the contralateral (right) homonymous hemifield. T2-weighted axial magnetic resonance images show the extent of the left
parieto-occipital lesion. (From Plant GT, Laxer KD, Barbaro NM, et al. Impaired visual motion perception in the contralateral
hemifield following unilateral posterior cerebral lesions in humans. Brain 1993;116[Pt 6]:1303–1335.)
normal direction discrimination in seven subjects with right temporo-occipital cortex participates in a variety of complex
hemisphere lesions. Five had lesions in the temporoparie- motion tasks, including speed discrimination, motion inte-
tooccipital area, but two patients had lesions in other loca- gration over a display to discern average direction and three-
tions. In one patient, the lesion was in the ventromedial oc- dimensional structure, and separation of regions with differ-
cipital region; the other patient had an insular lesion. ent motion to discern two-dimensional structure. Elementary
Impaired direction discrimination for motion toward the side spatial and temporal aspects of motion perception and sim-
of the lesion was reported by Barton et al. (489) in patients pler tasks such as detection of motion and discrimination of
with lesions of the lateral temporo-occipital area (Fig. direction in the absence of noise are not impaired, however.
13.37). There is also some evidence that lesions of the cere- Hence, motion perception is not completely abolished but
bellum adversely affect the perception of motion (493). is impaired in its more interpretative functions; the more
The patients described above suggest that human lateral elementary motion signals are processed at other cortical
Figure 13.36. Impaired central perception of

motion-defined form. Axial template drawings
from computed tomographic scans showing the
outlines of the lesions of seven patients who
had abnormal speed thresholds for recognizing
letters whose boundaries were defined by dif-
ferences in motion from the background. Ven-
tricles are black, and hatched areas indicate
overlap between three or more patients. Num-
bers indicate Brodmann areas of the right hemi-
sphere. (From Regan D, Giaschi D, Sharpe JA,
et al. Visual processing of motion-defined
form: selective failure in patients with parieto-
temporal lesions. J Neurosci 1992;12⬊2198–
2210.)
Figure 13.37. Abnormal central motion di-

rection discrimination. Axial template draw-
ings from computed tomographic or magnetic
resonance scans, showing lesions (stippled
areas) of six patients with abnormal signal-
to-noise thresholds for the discrimination of
motion direction in foveally presented dis-
plays. In most, the defect affected motion pri-
marily toward the side of the lesion. Numbers
indicate Brodmann areas. Areas of denser stip-
pling indicate greater overlap, with the highest
density at the junction of Brodmann areas 19
and 37. (From Barton JJ, Sharpe JA, Raymond
JE. Retinotopic and directional defects in mo-
tion discrimination in humans with cerebral
lesions. Ann Neurol 1995;37⬊665–675.)
sites, probably at a lower level. The role of lateral temporo- rons are selective for both direction and speed (495–499)
occipital cortex may be to use elementary motion signals to but not for shape or color (497,500,501). MT has two
derive a higher-order representation of motion, much as a major projections: to MST and to the ventral intraparietal
color region may use elementary striate wavelength re- area (VIP) (501–503). The ventral and dorsal regions of
sponses to derive a higher-order perception of color (22). It MST may be functionally distinct. Ventral MST responds
is for this reason that the destruction of lateral temporo- best to the relative motion of small objects, whereas dorsal
occipital cortex does not leave a patient completely motion- MST responds best when visual motion occurs over large
blind. Furthermore, other types of motion perception that do portions of the visual field (307). Dorsal MST neurons
not depend upon derivation of local velocity signals, such as also respond to large complex motion patterns, such as
‘‘attention-based’’ (or long-range) motion perception, may expanding or contracting radial patterns, and rotating or
have a separate neuroanatomic substrate than that involved spiraling motion, which suggests a role in analyzing self-
in akinetopsia. Thus, parietal rather than occipitotemporal motion (504–510). VIP has not been extensively investi-
lesions disrupt attention-based motion perception but do not gated, but it is known to have cells that are sensitive to
affect functioning on the motion tests described above (28). moving stimuli (511).
These deficits in attention-based motion perception correlate The anterior superior temporal polysensory area contains
more with dysfunction in transient attentional processes than form-selective and motion-selective cells (351,512). Some
defects in motion perception (494). of these cells are selective for complex body movements
such as hand actions, gait, and head movement (351,513),
PHYSIOLOGY OF MOTION PERCEPTION IN and these cells may integrate visual input from both cortical
NONHUMAN PRIMATES streams. A potential polysensory function of STP may be to
determine motion relative to the observer by using both vis-
Several areas in the primate brain respond to visual mo- ual motion signals from an object and somatosensory, visual,
tion. The best-known is the middle temporal area. MT neu- or vestibular information about self-motion (514). Regions
in the ventral pathway also have motion responses. Form- Microstimulation in MT affects the direction decisions of
selective neurons in the inferotemporal cortex respond to monkeys viewing a random-dot kinematogram (538–540).
their preferred stimulus regardless of whether the form is Small currents bias the decision in the preferred direction
defined by luminance, texture, or motion information of the stimulated neurons, whereas large currents impair dis-
(515,516). crimination, presumably from motion noise as current
As there are already direction-selective neurons in V1, spreads into adjacent neuronal columns.
several studies have attempted to determine how MT con- Psychophysical and physiologic performance have been
tributes to motion perception. Experiments using transparent assessed simultaneously in monkeys viewing moving dis-
motion (517–519) and moving plaids (520,521) show that plays. ‘‘Neurometric’’ thresholds based on MT and MST
some MT neurons reduce motion noise by averaging motion neuronal firing rates for single neurons are similar to the
vectors over large regions to derive a judgment of common psychophysical performance of the monkey for direction dis-
global motion, and that this averaging function is restricted crimination (537,541,542). Thus, the perceptual perfor-
to the motion in the same depth plane, so that perception of mance in monkeys may be supported by a surprisingly small
moving natural transparent surfaces is not impaired (522). number of MT or MST neurons. In fact, one study found
In contrast, V1 neurons respond whenever a motion stimulus that the perceptual decisions of monkeys could be simulated
in their preferred direction is present, without regard for the by the performance of as few as 100 weakly correlated neu-
presence of other moving stimuli. rons (543).
Motion can also be separated into first- and second-order
types. First-order motion involves displacement of object
FUNCTIONAL IMAGING AND OTHER TECHNIQUES
boundaries that differ in luminance from the background,
whereas second-order motion is movement of objects distin- PET scanning studies during motion perception show acti-
guished by cues other than luminance, such as texture and vation in the lateral occipital gyri, at the junction of Brod-
stereo disparity. Most MT cells respond to both first- and mann’s areas 19 and 37 (39,42,544). This motion-selective
second-order motion, suggesting that MT functions as a gen- area is most consistently related to the conjunction of the
eral motion detector (523,524). anterior limb of the inferior temporal sulcus with the lateral
Another possible role for MT is the analysis of relative occipital sulcus (43). Other areas activated during motion
motion. The direction-selective responses of some MT neu- perception include V1, V2 (43,545,546), and the dorsal cu-
rons are inhibited by motion in a similar direction in the
neus, which may correspond to V3 (43,546) (Fig. 13.38).
surrounding visual field (525–527). This surround inhibition
Viewing of optic flow increases blood flow in the dorsal
may play a role in figure-ground discrimination, perceptual
cuneus, superior parietal lobe, and fusiform gyrus (547).
constancy, and motion cues to depth perception. It may also
More complex biologic motions similar to those that elicit
aid in accurate judgment of object trajectory during eye
responses in monkey area STP were studied by Bonda et al.
movements, by comparing object motion to the movement
of the background across the retina as the eye moves. These (548). Goal-directed hand actions activated left hemispheric
neurons may also play a key role in perception of three- intraparietal sulcus and caudal superior temporal sulcus,
dimensional shape using motion cues (528). which the investigators considered to be related to syn-
Lesion and stimulation studies may elucidate the role of dromes of apraxia with left hemisphere lesions. Expressive
cortical areas in motion perception. MT or MST lesions body movements activated right superior temporal sulcus,
cause pursuit and saccades to targets in the contralateral vis- possibly corresponding to monkey area STP, and the amyg-
ual field to underestimate speed (529–532). Such lesions dala, which is involved in perceiving emotional and social
also cause deficient motion perception in the contralateral signals (271).
hemifield, as determined with the random-dot kinematogram Studies with fMRI show motion-selective responses in the
(533). Schiller (227) also found mild to moderate contralat- lateral temporo-occipital cortex as well as in V2 and the
eral impairments in motion detection, direction discrimina- superior and inferior parietal lobules (549,550). Signal
tion, and speed discrimination in monkeys with MT or MST changes in lateral temporo-occipital cortex also correlate
lesions, although these defects were less severe than those with motion after-effects (551). Both motion perception and
from lesions of the LGN, suggesting that other cortical areas pursuit-related signals are present in lateral temporo-occipi-
contribute to motion processing. Although large bilateral le- tal cortex, suggesting that a possible human homolog of
sions of MT and MST create enduring impairments in a MST is also located here (552).
variety of motion tasks (534,535), some recovery after com- Visual evoked potential dipoles revealed motion re-
plete lesions of MT and MST does occur and presumably sponses in the occipito-temporo-parietal region in a study
is mediated by other cortical areas (536). performed by Probst et al. (553). These results have not been
Lesions of either monkey MT/MST (535) or IT (537) im- corroborated.
pair perception of motion-defined form, implying that both Magnetic stimulation can be used to create temporary dys-
ventral and dorsal streams participate in perceiving form- function within specific cortical areas. Stimulation over lat-
from-motion. Schiller (227) found that lesions of either V4 eral temporo-occipital cortex impairs motion direction dis-
or MT alone produced only mild defects in perceiving form- crimination but not form discrimination in the contralateral
from-motion, but lesions of both together caused a moderate hemifield and, to a lesser degree, in the ipsilateral hemifield
defect. (156,157,554).
Figure 13.38. Positron emission tomographic study of motion perception. Areas with changing regional cerebral blood flow
during motion perception, averaged over all normal subjects. Results are shown in axial section, with numbers indicating
distance from a line joining the anterior and posterior commissures (negative values are inferior). Pixels indicate changes in
blood flow, with black and white pixels indicating areas with highly significant increases in blood flow. Several areas of
activation are seen, including the lateral temporo-occipital cortex. (From Dupont P, Orban GA, De Bruyn B, et al. Many areas
in the human brain respond to visual motion. J Neurophysiol 1994;72⬊1420–1424.)
BÁLINT’S SYNDROME AND RELATED VISUOSPATIAL DISORDERS

In 1909, Bálint (25) described a triad of visual defects in inal case) (Fig. 13.39) (49,558,559), tumor, trauma, prion
a man with bilateral hemispheric lesions. Foremost was an diseases such as Jakob-Creutzfeldt disease, infection by
inability to perceive together at any one time the several human immunodeficiency virus (HIV) type 1 (560), and de-
items of a visual scene, which Bálint interpreted as a ‘‘spatial generative conditions such as Alzheimer’s disease (561,
disorder of attention.’’ Holmes (11) used the term ‘‘visual 562).
disorientation’’ to describe a similar deficit, whereas Wol- Wolpert’s (555) definition of simultanagnosia can be op-
pert (555) coined the term ‘‘simultanagnosia,’’ the ‘‘inability erationalized as an inability to report all the items and rela-
to interpret the totality of a picture scene despite preservation tionships in a complex visual display, despite unrestricted
of ability to apprehend individual portions of the whole.’’ head and eye movements. A suitable screening tool is the
Bálint’s patient was also unable to move the eyes voluntarily Cookie Theft Picture from the Boston Diagnostic Aphasia
to objects of interest despite unrestricted eye rotations. Bálint Examination (563) or any similar picture containing a bal-
(25) called this ‘‘psychic paralysis of gaze,’’ although other ance of information among the four quadrants (Fig. 13.40).
authors subsequently used such terms as ‘‘spasm of fixa- The patient’s report can be correlated with a checklist of the
tion’’ (556) and ‘‘acquired ocular apraxia’’ (557). Finally, items in the picture. Exclusion criteria should include apha-
Bálint’s patient showed ‘‘optic ataxia,’’ a defect of hand sia severe enough to impair the verbal descriptions of a dis-
movements under visual guidance despite normal limb play, so as to avoid confusing a defect of language with one
strength and position sense. Among the many reported of visual perception. It is also crucial to exclude or at least
causes of so-called Bálint’s syndrome are cerebrovascular be aware of defective visual acuity or visual fields. For ex-
disease (especially watershed infarctions, as in Bálint’s orig- ample, objects may seem to vanish into a central scotoma,
Figure 13.39. Drawing of the locations of the major lesions in the case described by Bálint in 1909, as pictured on lateral
views of the hemispheres. The views are idealized and do not convey the full extent of the pathology. The surface of the brain
was actually atrophic. Not seen in this view are several lesions of potential importance to the patient’s behavior presentation.
These included lesions of the posterior white matter in which optic radiations travel on both sides, and of the pulvinar, a critical
structure for visuospatial integration in primates. (From Bálint R. Seelenlahmung des ‘‘Schauens,’’ optische Ataxie, röumliche
Storung der Aufmerksamkeit. Monatschr Psychiatr Neurol 1909;25⬊51–181.)
paracentral scotoma, or hemianopia, causing complaints that ments, as described under the old term ‘‘apperceptive agno-
mimic simultanagnosia. Extensive peripheral scotomata sia’’ (566). This differs from true (associative) agnosia, in
(564) or marked constriction of the visual fields, such as which relatively normal percepts are stripped of their mean-
occurs in patients with retinitis pigmentosa or chronic atro- ings (567; see above).
phic papilledema, may hinder visual search and ‘‘simultane- The terms ‘‘ocular apraxia’’ (from the Greek word mean-
ous perception,’’ despite unrestricted viewing, thus also pro- ing ‘‘not acting’’) and ‘‘optic ataxia’’ (from the Greek word
ducing an incoherent report. ataktos, meaning ‘‘disorderly’’) are also not helpful in con-
Interestingly, the term ‘‘simultanagnosia’’ has little to do veying the underlying mechanisms in cases such as that de-
with the visual disorders now understood by the term ‘‘agno- scribed by Bálint (25), and some original investigators were
sia’’ (565). As noted above, patients with agnosia cannot even confused by the terminology and definitions (457,568).
recognize previously familiar objects or persons (49). Some Also, acquired ocular apraxia must be distinguished from
patients diagnosed with ‘‘Bálint’s syndrome’’ also may not congenital ocular motor apraxia, a childhood disorder in
recognize objects and faces (although Bálint’s patient could). which head thrusts occur with voluntary refixation despite
However, this is caused by their profound perceptual impair- a full range of reflexive saccades (557,569; see Chapter 19).
Figure 13.40. The Cookie Theft Picture from the

Boston Diagnostic Aphasia Examination. This pic-
ture contains a balance of information among the
four quadrants. The patient is asked to describe the
events depicted in the picture.
According to Benton (570), a critical appraisal of a syn- cits of visual short-term memory (working memory) and
drome should include definition, behavior, anatomy, mecha- attention. James (578) defined attention in its modern sense
nism, and theory. Using these guidelines, Bálint’s syndrome as an ability that enhances our performance on behavioral
may not exist as a sufficiently autonomous complex. Af- tasks by focusing the mind on one item and withdrawing
fected patients often have a number of other devastating from other competing items. The report by Bálint (25) pro-
defects in behavior, such as hemineglect (571), and the triad vided preliminary evidence of a neural substrate of attention.
of components in Bálint’s syndrome are not as closely bound The lesions in his patient produced an attentional reduction
as might be expected. Moreover, individual components of in the visual fields manifested by failure to detect objects in
the syndrome appear to represent broad categories compris- the periphery (more so on the left). Indeed, reductions in the
ing other, more specific defects. Furthermore, Bálint’s syn- useful field of vision that are not caused by a visual field
drome does not appear to have the specific neuroanatomic defect of luminance or form are now well described in el-
significance attached to it by Bálint (25) (i.e., bilateral dam- derly or demented patients (579,580; discussion following).
age to the angular gyri), and it is not clear that the compo- This effective field reduction is associated with difficulty
nents of Bálint’s triad have any special status compared with functioning in a complex visual environment, such as en-
other defects associated with lesions in a similar location. countered while driving a motor vehicle (581,582).
Conversely, ‘‘Bálint’s syndrome’’ occurs with bifrontal le- Standard perimetry tasks (such as Goldmann and Hum-
sions (572), and a similar disorder was described by Ogren phrey perimetry) minimize attention demands to gain maxi-
et al. (573) associated with lesions of the pulvinar. Simulta- mal estimates of sensory ability, leading to overestimates of
nagnosia occurs in patients with bilateral lesions of the supe- functional ability in elderly or brain-damaged individuals
rior (dorsal) portions of both occipital lobes in Brodmann’s engaging in real-world tasks that demand peripheral vision
areas 18 and 19 (565,574). Bilateral lesions of Brodmann’s (581,583). Reduction in the useful field of view (UFOV), the
areas 6 and 8 (the frontal eye fields) may cause defective visual area from which information can be acquired without
voluntary saccades, visual search, and scanning, compatible moving the eyes or head, correlates with increased vehicle
with ocular apraxia. Optic ataxia is associated with a wide crash risk (579,582). UFOV task performance depends on
variety of lesions in Brodmann’s areas 5, 7, 19, 39, and 37, speed of processing, divided attention, and selective atten-
and a profound reaching disturbance was even reported with tion. The efficiency with which we can extract information
a relatively mesial right temporo-occipital lesion (575). from a cluttered scene begins to deteriorate by age 20 years
The wide variety of perceptual phenomena reported in (584).
cases such as Bálint’s (including ‘‘vanishing’’ objects, tilted Patients described as having Bálint’s syndrome may have
vision, metamorphopsia, palinopsia, and of the ‘‘positive’’ impaired control over the focus of visual attention. Executive
phenomena described below) are not likely to represent the functions control our allocation of attention between com-
behavioral expression of a single underlying neurophysio- peting sources of information (585,586). Focused attention
logic mechanism. Rather, Bálint’s syndrome may include a helps consolidate information temporarily stored in working
combination of deficits resulting from lesions of the dorso- memory, the process that allows us to store representations
lateral visual association cortices, which include the putative for brief times until they can be attended to. Without focused
human area MT complex and its projections to the parieto- attention, traces of retinal images in working memory fade
occipital cortex. Damage to these areas and to the cortices without being consciously perceived or remembered (inat-
surrounding the angular gyrus and parietal insular cortex can tentional amnesia). We can be unaware of marked changes
disturb multiple aspects of spatial and temporal processing, in an object or a scene (change blindness). The very act of
including the perception of visual motion (47), structure perceiving one item in a rapid series of images briefly inhib-
from motion and dynamic stereopsis, the perception of ego- its ability to perceive another image (the attentional blink).
motion, and coordination of visual (eye-centered) and vestib- Change blindness (CB) is a form of blindness that can
ular (gravity-centered) coordinate systems that orient us in occur despite normal vision and is the inability to detect
the physical world. Bilateral lower quadrantanopias may co- critical changes in a scene due to a brief visual disruption.
occur (11) from damage to the primary visual cortex lining The disruptions can include saccades, flickers, blinks, cam-
the dorsal banks of the calcarine fissure (human area V1), era cuts (587), or gradual image changes (588). CB probably
thus adding to a patient’s overall problem. depends on spatial attention and visual working memory
(589). CB occurs when working memory is occupied by
PSYCHOANATOMICAL SUBSTRATES IN other information, is more likely when working memory
BÁLINT’S SYNDROME capacity or duration is impaired (e.g., due to aging, drugs
or fatigue, or neurologic disease (590,591)), and can help
Twenty-four reports of ‘‘simultanagnosia/Bálint’s syn- explain perceptual problems in patients like Bálint’s.
drome,’’ compiled by the Oxford University Press (576), The attentional blink (AB) is another type of blindness
provide an overview of key theoretical issues, lesion locali- that can occur even in people with normal vision. When we
zation, underlying pathology, and standardized assessment identify a visual object, our ability to perceive a second ob-
techniques employed. A diversity of deficits, lesions, vision ject is impaired for several hundred milliseconds (because
assessment, and opinions is clearly evident in these articles. visual working memory is still occupied by the first object
Rizzo and Vecera (577) reviewed psychoanatomic sub- when the second arrives). This period, known as the AB, is
strates of Bálint’s syndrome and emphasized the role of defi- not due to an eye blink and can be measured in a laboratory
setting using a rapid serial visual presentation (RSVP) of jects. Objects on collision paths with us maintain a fixed
visual targets (often a sequence of letters) on a computer location in the field of view, while ‘‘safe’’ objects will trans-
monitor. The AB can increase pathologically due to reduced late to the left or right side. Time-to-contact (TTC) is esti-
temporal processing speed and working memory in patients mated from the expanding retinal image of the approaching
with a variety of brain lesions (592). object. Older drivers are less accurate than younger drivers
Navigating through the world, which was difficult for Bál- at telling whether an approaching object in the environment
int’s patient, requires ‘‘executive attention’’ to switch the will crash into them (606,607). Performance is worse for
focus of attention between critical tasks such as tracking the longer TTC conditions, possibly due to a greater difficulty
terrain, monitoring the locations of nearby obstacles, finding in detecting the motion of small images in the field of view
landmarks, and perceiving the trajector of self-motion while (608).
walking (593). This involves switching attention between
disparate spatial locations, local and global object details, NAVIGATION
and different visual tasks and is thought to rely on mecha-
nisms in prefrontal areas (594). Navigating a route relies on visual perception, attention,
spatial abilities, and memory. Topographic disorientation
(TD) is a term that has been used to describe patients who
PERCEPTION OF VISUAL OBJECT STRUCTURE,
have navigation problems despite normal or near-normal vis-
MOTION, AND DEPTH
ual sensory abilities (609,610). Patients with TD may have
In addition to the visual attention and working memory lesions in inferotemporal regions, posterior parahippocam-
impairments described above, the lesions in Bálint’s syn- pal regions, and hippocampus, especially in the right hemi-
drome produce various defects in perception of visual object sphere. Causes of TD include stroke, trauma, and neurode-
structure, motion, and depth. Information on object structure generative diseases, including Alzheimer’s disease (611).
and depth is so important for interacting with objects and Associated problems include visual agnosia and other mem-
obstacles that our brains employ multiple cues (595). These ory-related disturbances.
cues include accommodation, convergence, binocular dis- One form of navigation difficulty, ‘‘topographagnosia,’’
parity, motion parallax, texture accretion/deletion, conver- is associated with prosopagnosia and achromatopsia
gence of parallels, position relative to horizon, relative size, (272,273,277,279,327,346,383). In these patients, the prob-
familiar size, texture gradients, edge interpretation, shading lem is an inability to identify familiar landmarks and build-
ings, ‘‘landmark agnosia’’ (612). This form occurs with right
and shadows, and aerial perspective (596). Understanding
ventral temporo-occipital lesions (344,613). The origins of
the relationships among these redundant cues is an active
landmark agnosia are debated. Some propose that it reflects
research topic.
a selective multimodal memory disturbance rather than a
Perception of structure-from-motion (SFM) or kinetic
strictly visual problem (344). However, functional imaging
depth is a real-world use of motion perception that may fail
also suggests that buildings and places activate a specific
in patients with visual cortex lesions due to stroke (597) or region in occipitotemporal cortex, the ‘‘hippocampal place
early Alzheimer’s disease (598). SFM deficits in drivers with area,’’ which is adjacent to the fusiform face area (614).
brain lesions are associated with increased relative risk for Lesions of this region could create an agnosia specific for
safety errors and car crashes in driving simulation scenarios landmarks, and the frequent association with prosopagnosia
(599). Recovery of depth from motion relies on relative may reflect the proximity of face and place processing in
movements of retinal images. For motion parallax, relative cortex.
movement of objects is produced by moving the head along In a second form, the spatial processing needed to de-
the interaural axis. Impairments of motion parallax may be scribe, follow, or memorize routes is disrupted, usually by
a factor in vehicle crashes in drivers with cerebral impair- right parietotemporal lesions (613,615). It has been sug-
ments or drug intoxication, who must make quick judgments gested that the key deficit with such lesions is an ‘‘egocentric
with inaccurate perceptual information regarding the loca- disorientation,’’ in which subjects cannot represent the loca-
tion of surrounding obstacles (600). tion of objects and buildings with respect to themselves
Displacement of images across the retina during self- (609).
motion (ego-motion) produces optic flow patterns that can A third, related form is a ‘‘heading disorientation,’’ in
specify the trajectory of self-motion with high accuracy which there is a failure in representing direction with respect
(601–603). Perception of heading from optical flow patterns to cues in the external environment, rather than in reference
can decline due to aging and drugs such as marijuana (THC) to the subject. This has been associated with posterior cingu-
and Ecstasy (MDMA), presumably due to chronic effects on late lesions (616). This may have also been the case with a
cholinergic receptors (with THC) and serotoninergic/5HT-2 rare patient with a left parahippocampal and retrosplenial
receptors (with MDMA) (604). Processing of visual motion lesion who had defective route-finding associated with
cues also may be impaired in patients taking antidepressants alexia and other severe visual amnestic deficits (617).
such as nefazodone (Serzone) that block serotonin reuptake Parahippocampal lesions have also been implicated in an
(605). ‘‘anterograde topographagnosia,’’ in which new routes can-
Detecting and acting to avoid impending collision events not be learned though old routes are still known (618).
requires information on self-motion and approaching ob- Aspects of complex disorders of visual processing asso-
ciated with navigation impairments can be tested with the plex Figure Test (619,620). Lanca et al. (621) provided test-
Trail Making Test, Benton Visual Retention Test, and Com- ing details in a recent review.
DISORDERS OF VISUALLY GUIDED REACHING AND GRASPING

Reaching and grasping external objects is a fundamental proposed by Soechting and Flanders (626,636,637) takes ori-
activity that demands the coordination of several different gin at the shoulder, is closely related to the representation
nervous system functions (622,623). To accomplish this of object position and motion, and should depend on the
task, the brain transforms a target’s visual coordinates to visual cortex and its connections to other sensory and motor
body-centered space, plans a hand path and trajectory (the maps (638–640).
sequence of hand position and velocity to target), and com- The observations of Bálint (25) on what he called optic
putes multiple joint torques, especially about the shoulder ataxia sparked interest in the neural basis of visually guided
and elbow. It also specifies the necessary limb segment ori- reaching and grasping. In this condition, patients reportedly
entations from among many possibilities, activates appropri- reach as if blind toward targets they nevertheless can see
ate muscle groups, and inhibits others to meet those specifi- and describe (Fig. 13.41). Limb strength and position sense
cations. The sensory feedback, frames of reference, and are normal; however, there is severe visual sensory loss and
neural mechanisms used to solve these complex motor con- poor visuospatial perception, and patients may even appear
trol problems are active research topics (624–628). demented because of their extensive bilateral lesions, as in
Reaching can be separated into two different phases. In the original case reported by Bálint (25) (discussed earlier).
the transport phase of reaching, the hand is moved toward Inability to reach and grasp targets in these cases is often
an object whose position is determined by vision or memory. multifactorial, including V1-type visual field defects, defec-
In the acquisition phase, grasp formation depends on so- tive visual attention, and inability to locate targets with the
matosensory and visual information on the limb and target eyes. Another possibility is abnormal sensorimotor transfor-
(629), familiarity with the target, and, perhaps, predeter- mation, an inability to transform the visual coordinates of
mined motor programs. These two phases mature at different external objects to appropriate limb coordinates for generat-
rates, may be controlled independently before becoming co- ing accurate reaches.
ordinated (630–632), and can be dissociated by focal brain The patient described by Bálint (25) had left hemineglect
lesions (633–635). Posterior parietal damage may affect caused by extensive damage to the right inferior and superior
neurons coding eye position in the head and stimulus loca- parietal lobules. Lesions in these locations are likely to pro-
tion on the retina that, together with neurons in motor and duce visuomotor difficulty in reaches conducted with the
premotor cortex, permit hand movements to visual targets left hand to both visual fields (hand effects) and with both
in a body-centered coordinate system (628). The schema hands to the left visual fields (field effects) (634,641). Thus,
Figure 13.41. The paths of abnormal hand movements under visual guidance in a case of optic ataxia. The patient is viewed
from above as he reaches for highly visible targets located at arm’s length to the left and right of body midline. The recordings
rely on an optoelectronic technique to transduce the position of an infrared light-emitting diode target fastened to the dorsum
of each index fingertip. Multiple reaches are shown with the left hand and right hand. All movements begin from the same
midline position just anterior to the patient. Head movement is unrestricted. The results show that trajectories of the hand
movement are highly variable. The end positions of the movements are quite inaccurate, especially to the left target. The
patient’s hand movements actually improved for reaches to self-bound targets (body parts) and for reaches to remembered
targets in the absence of vision (the latter conditions are not shown here). The patient also had simultanagnosia. (From Rizzo
M. ‘‘Balint’s syndrome’’ and associated visuospatial disorders. Baillieres Clin Neurol 1993;2:415–437.)
although Bálint (25) emphasized that his patient had trouble (e.g., 79,567,575). Patterns of recovery in optic ataxia were
locating visual targets with the right hand, there is reason reported by Goodale et al. (635). Anatomic substrates for
to suspect that left-hand control also was impaired. Observa- visually guided reaching and lesions that affect underlying
tions on the reaching behavior in patients with focal circum- sensorimotor transformations were recently reported by Dar-
scribed lesions of visual cortex can help clarify these issues ling et al. (642,643).
POSITIVE VISUAL PHENOMENA

Most often cerebral lesions affect vision by creating defi- usually fading after a period of several minutes. This type
cits, or ‘‘negative phenomena.’’ On occasion, they may also of palinopsia bears some similarity to the normal phenome-
create ‘‘positive phenomena,’’ when false visual images are non of an afterimage experienced after prolonged viewing
seen by the patient. These false visual images can be classi- of a bright object. Detailed studies of some patients have
fied as visual perseverations, hallucinations, and distortions concluded that the differences between normal afterimages
(dysmetropia). and such palinopsic images are primarily quantitative (651),
although others disagree (645). With the delayed type of
VISUAL PERSEVERATION palinopsia, an image of a previously seen object reappears
after an interval of minutes to hours, sometimes repeatedly
The persistence, recurrence, or duplication of a visual
for days or even weeks (651). Some patients have both im-
image is a rare complaint in patients with cerebral lesions.
mediate and delayed types of palinopsia (651).
Several varieties exist, including palinopsia, polyopia, and
The perseverated image can assume almost any location
illusory visual spread. Palinopsia (or paliopsia) is the persev-
in the visual field. It may persist in the same retinal location
eration of a visual image in time (644). Whereas the content
as the original image, which is usually at the fovea, and thus
of visual hallucinations is often imagery created de novo, or
move as the eyes move, much as a normal afterimage does
sometimes from the distant past (experiential hallucina-
(652). Sometimes the image is translocated into a coexistent
tions), the palinopsic illusion contains elements of a more
visual field defect (644), and indeed this can be a transient
recently viewed scene, or even one that is still being viewed.
feature in the evolution of cerebral homonymous field de-
Nevertheless, the difference is not always distinct, and pa-
fects (645). Sometimes the image is multiplied across other-
tients can have both perseverative and hallucinatory phe-
wise intact visual fields (647) (Fig. 13.42). On rare occa-
nomena concurrently (644,645). Cerebral diplopia or poly-
sions, the location of palinopsic images is contextually
opia is the perseveration of a visual image in space, when
specific, as when patients report that after viewing a face
two or more copies of a seen object are perceived simultane-
on television, everyone else in the room has the same face
ously (646–649).
as the person on television, or that the sign over one shop
Another spatial perseveration is ‘‘illusory visual spread,’’
reappears on the boards over other shops (644,647,653) (Fig.
in which the contents or surface appearance of an object
13.43). While some of these cases may represent a complex
spread beyond the spatial boundaries of the object (644).
form of palinopsic polyopia, others may also be consistent
Thus, wallpaper patterns spread beyond the surface of the
with a constant foveal or perifoveal perseverative image that
wall, and cloth patterns spread from a shirt to the wearer’s
manifests itself repeatedly when the context is appropriate.
face (644). In the experience of some (650), this is invariably
associated with visual field defects, and it is suggested that
the basis of this perseveration is analogous to the ‘‘filling
in’’ process that minimizes the perceptual disruption at the
physiologic blind spot.
Both spatial and temporal perseveration can occur in the
same patient, as in palinopsic polyopia (647,651). Some pa-
tients report that as an object moves they see multiple copies
of the object in its trail: though this may be considered an
example of cerebral polyopia, it is clearly a form of palinop-
sia also. As yet another possible combination, Bender et al.
(645) argued that since palinopsic images were often larger
than the original images in their experience, this represented
an illusory visual spread frequently concomitant with pali-
nopsia; however, Critchley (644) thought that this combina-
tion was the exception rather than the rule.
Palinopsia Figure 13.42. Palinopsia. Illustration of visual images experienced by a

71-year-old woman with complaints of seeing multiple objects. In this case,
It is suggested that there are at least two forms of abnormal she had just peeled a banana and now saw multiple vivid images of the
persistence of a visual image in time, an immediate and a banana projected over the wall. She realized that they were only images
delayed type. With the immediate type of palinopsia, an and were not real. (From Michel EM, Troost BT. Palinopsia: cerebral locali-
image persists after the disappearance of the actual scene, zation with computed tomography. Neurology 1980;30⬊887–889.)
eral patients in early reports had other features that suggested

seizures, such as episodic loss of consciousness, tongue bit-
ing, and confusion (644,645). More recently, epileptiform
abnormalities on EEG and a good response to anticonvul-
sants have been reported in some patients with the immediate
type of palinopsia (267,655,658), and in one patient with a
delayed form (659), although improvement with anticonvul-
sants does not prove ictal origin.
The third hypothesis is that palinopsia may be a nonictal
hallucinatory state. Some patients have both palinopsia and
coexistent nonpalinopsic visual hallucinations. Also, the lo-
cation of perseverative images within visual field defects is
reminiscent of the release hallucinations of the Charles Bon-
Figure 13.43. Palinopsia. The patient experienced the illusory image of net syndrome. Furthermore, drugs that induce hallucinations
hands rubbing across his wife’s face after seeing an actress rubbing her
can cause palinopsic illusions as well (651). Cummings et
own face on television. (From Bender M, Feldman M, Sobin A. Palinopsia.
Brain 1968;91⬊321–338.)
al. (652) suggested that delayed palinopsia with hemianopia
was a release hallucination, whereas immediate palinopsia
was more likely due to a seizure, especially when there was
no accompanying visual field defect. The mechanistic value
A wide range of other symptoms can accompany palinop- of this distinction has not yet been validated.
sia. An associated homonymous visual field defect is vir- Psychogenic palinopsia was considered by Critchley
tually always present, with reports of both upper (651,653) (644), who postulated that palinopsic reports may be a con-
quadrantanopias. There may be other spatial illusions, such fabulatory response to other visual dysfunction. Palinopsia
as metamorphopsia, macropsia, and micropsia (267,644,645, may also occur without visual dysfunction in a psychiatric
651). Less frequently, ‘‘ventral stream’’ deficits have been context, where it may be associated with other perseverative
reported, such as topographagnosia, prosopagnosia, and ach- and misidentification delusions like Capgras syndrome (the
romatopsia (346,645). Cummings et al. (652) reported an belief that familiar people have been replaced by duplicates)
unusual patient with perseveration in both visual and so- (660).
matosensory modalities, and another patient with a left tem- Drug-induced palinopsia must first be considered. Intoxi-
poroparietal tumor had both auditory and visual palinopsia cation with hallucinogens such as mescaline, LSD, and Ec-
(654). stasy (MDMA) can cause palinopsia, sometimes perma-
The prognosis for visual perseveration is not clear. Bender nently (661,662). Isolated reports have asserted that
et al. (645) considered palinopsia to be a rare transient phase palinopsia and other visual illusions may occur with pre-
in either the resolution or progression of a visual field defect, scribed medication, such as clomiphene (663), interleukin-
which usually lasted from days to months. However, other 2 (664), trazodone (665), nefazodone (666), mitrazapine
cases of palinopsia have persisted for months and years (667), or withdrawal from paroxetine (668). Second, it can
(651,652,655,656). Anticonvulsant medication such as car- occur with metabolic states such as nonketotic hyperglyce-
bamazepine may help some patients (655,657) but not others mia (669). Third, palinopsia can occur in psychiatric condi-
(652). tions such as schizophrenia (660,670) and psychotic depres-
The pathophysiologic mechanism of palinopsia is still un- sion (671), but it is always accompanied by other signs of
clear. Four main hypotheses have been advanced (645): a mental illness.
pathologic exaggeration of the normal afterimage, a seizure Once intoxication and metabolic and psychiatric condi-
disorder, hallucinations, and psychogenic origin. tions are excluded, however, visual perseveration suggests
Kinsbourne and Warrington (651) found many features the possibility of a cerebral lesion. As always, a variety of
in two patients that suggested that their (immediate-type) lesions are possible, including brain abscess (672), tubercu-
palinopsia represented an exaggeration of the normal after- loma (673), and hemorrhage (674). However, there are sev-
image. The vividness of the palinopsic image correlated with eral cases of perseverative phenomena with other visual
the intensity and duration of the initial stimulus. When the damage. Palinopsia has been reported in two patients with
palinopsic image was visualized against a light background, optic neuritis, one with Leber’s hereditary optic neuropathy
it appeared as a negative (complementary color) afterimage. and one after photocoagulation for diabetic maculopathy
After monocular viewing of an object, the palinopsic image (675,676). A survey of 50 patients with severe visual loss
appeared binocularly. Lastly, the afterimage moved in the from ocular lesions found that in addition to release halluci-
same direction as active eye movements but in the opposite nations, one or two had palinopsia, polyopia, or illusory vi-
direction when the eyes were moved passively. However, sual spread (650). Also, some patients with palinopsia have
not all cases of immediate palinopsia exhibit these features; apparently normal neurologic and ophthalmologic function
the color of palinopsic images does not depend strongly on and no history of drug use (676).
the colors of the original stimulus, for one (645,656). The localizing value of palinopsia is not clear. Bender et
The hypothesis that palinopsia is a manifestation of epi- al. (645) found a predominance of right parieto-occipital
lepsy is supported mainly by circumstantial evidence. Sev- lesions, although they acknowledged that left hemispheric
lesions may have been underrepresented because of aphasia. nize these experiences as being ‘‘not real.’’ Some propose
Critchley (644) documented right, left, and bilateral lesions. the term ‘‘pseudohallucinations’’ for experiences with pre-
While others have also found parietal pathology (674,677), served insight. However, insight can fluctuate over time in
there are also reports of medial occipital and occipitotem- an individual (sometimes it is gained only after attempted
poral lesions in some cases with CT and autopsy specimens interaction with the phantom) and can vary within a group
(647,653,673,678). In two cases, no lesion was found with with a common pathology. Also there is no proof that insight
neuroimaging (656,679), although in one the patient was has any pathogenetic significance, other than that it may
eventually found to have Creutzfeldt-Jakob disease. correlate with the degree of associated cognitive or psychiat-
ric impairment. Therefore, the term ‘‘hallucinations’’ is
Cerebral Polyopia probably best used for all such experiences, regardless of
insight.
Cerebral polyopia or diplopia is much less frequently de-
Hallucinations are also sometimes divided into simple and
scribed than palinopsia. It occurs with monocular viewing,
complex forms. Simple hallucinations consist of brief flashes
distinguishing it from diplopia due to tropic misalignment
of points of light, colored lines, shapes, or patterns (phos-
of the eyes. As a cause of monocular polyopia, it must be
phenes) (685–687) (Figs. 13.44 and 13.45). Complex hallu-
distinguished from polyopia due to abnormalities of the re-
cinations contain recognizable objects and figures (688),
fractive media, which often have specific treatments
such as scenes of humans and animals moving (689–692),
(680–682). However, unlike refractive polyopia, it does not
with a potential for bizarre, dreamlike imagery of considera-
resolve with viewing through a pinhole, and it is present with
ble detail and clarity, including dragons, angels, and minia-
either eye viewing alone. In some patients cerebral polyopia
ture policemen (693,694). There is considerable debate over
occurs only in certain gaze positions, causing confusion with
the value of the simple/complex dichotomy in terms of its
tropic diplopia until its monocular nature is realized (646).
diagnostic and localizing value.
The number of images seen can range up to over a hundred,
in one unique case of ‘‘entomopia’’ (649). Associated signs In the differential diagnosis of hallucinations, one of the
in Bender’s series included frequent visual field defects, dif- chief considerations is whether there is any associated men-
ficulties with visually guided reaching (optic ataxia), achro- tal or cognitive dysfunction. When this is present, hallucina-
matopsia, object agnosia, fluctuations in the visual image, tions can be associated with other conditions, the three most
and abnormal visual afterimages. However, the diplopia in important being intoxication, psychiatric illness, and cogni-
Meadows’ (648) case was associated only with a small hom-
onymous inferior left scotoma. The patient described by
Lopez et al. (649) had no signs at all, although his symptoms
were very brief, lasting only minutes, and a transient associ-
ated defect may have escaped detection. A recent review
suggests that apart from such highly atypical cases, coexis-
tent hemifield defects are the rule (683).
Among Bender’s (646) wartime cases, cerebral polyopia
often occurred as a transient phase in the recovery from
cortical blindness due to occipital missile wounds. In two
cases recovery followed a progression from cortical blind-
ness to cerebral polyopia, then cerebral diplopia. Other
causes in the older literature include encephalitis, multiple
sclerosis, and tumors (646). A more recent patient had an
infarct in peristriate cortex (683).
The origins of this rare symptom are obscure. It may be
that polyopia is merely a variant of palinopsia, with persever-
ated and real images coexisting in time (683). Bender (646)
suggested an analogy with the monocular diplopia that some-
times develops in strabismic patients who have both a true
and a false macula, along with a disorder of unstable fixation
that would cause the retinal image to shift over these falsely
localizing regions. Gottlieb (684) also noted a correlation of
polyopia with eye movements into the hemianopic field, but
both Meadows (648) and Lopez (649) have contested the Figure 13.44. Appearance of simple hallucinations. Drawing by a patient
necessity of the abnormal fixation or eye movements. with simple hallucinations in the left homonymous hemifield shows a pat-
tern of pyramids adjacent to one another. The sides of each pyramid were
VISUAL HALLUCINATIONS colored red, yellow, green, or blue. The hallucinations gradually subsided,
coincident with the development of a left homonymous hemianopia. Neu-
Hallucinations are perceptions without external stimula- roimaging revealed changes consistent with an infarct in the right occipital
tion of the relevant sensory organ. Individuals vary in the lobe. (From Kölmel HW. Colored patterns in hemianopic fields. Brain 1984;
degree of insight they possess—that is, whether they recog- 107⬊155–167.)
lucinations in other sensory modalities (especially auditory)

and by other signs of mental illness.
Hallucinations with Cognitive Dysfunction

Hallucinations are not rare in patients with dementia (704)
or confusional states secondary to metabolic insults, includ-
ing alcohol withdrawal, where they form the predominant
type of hallucination (705). Among patients with Alzhei-
mer’s disease, hallucinations may be more common in pa-
tients with poor refraction or cataracts (706), and are corre-
lated with atrophy of the occipital lobe (707). Other risk
factors for hallucinations in Alzheimer’s disease include not
only greater cognitive deficits and accelerated rate of decline
but also associated parkinsonism (708).
Of note, hallucinations are one of the defining criteria
for diffuse Lewy body dementia, along with parkinsonism,
dementia, and fluctuating levels of arousal. They occur in
over 90% of patients with this condition, compared to 25%
of patients with Alzheimer’s (709). In diffuse Lewy body
disease their incidence appears to correlate with the density
of Lewy bodies in inferior temporal cortex (710).
Hallucinations also occur in about 25% of patients with
Parkinson’s disease (711). These are almost exclusively vi-
sual and almost always complex (712). While in some cases
these can be caused by medications, it appears increasingly
likely that they are a manifestation of the underlying disease
process (712,713). A number of studies have shown that risk
factors for hallucinations in this disease are longer duration
and greater severity of the disease, depression and sleep dis-
turbances, and some cognitive impairment (712–715). Many
factors may contribute to the pathogenesis of hallucinations
in Parkinson’s disease. REM-sleep anomalies have been de-
scribed, raising analogies with the hallucinatory experience
Figure 13.45. Appearance of both simple and complex hallucinations. in narcolepsy (716,717) and implicating cholinergic and se-
Drawing by a patient with occipital lobe damage showing his most frequent rotonergic pathways in the brain stem (688). Impaired visual
hallucinations. Some are complex (top); others are simple (middle and bot- function may play a role, as some studies have shown that
tom). (From Anderson SW, Rizzo M. Hallucinations following occipital hallucinations are associated with worse visual acuity (713),
lobe damage: the pathological activation of visual representations. J Clin defective visual memory (715), and poor performance on
Exp Neuropsychol 1994;16⬊651–663.) object-recognition tasks (718). Cognitive problems are more
common and may contribute through a general degradation
in information processing or a disruption in the ability of
tive dysfunction associated with neurodegenerative condi- subjects to monitor reality and the origins of internal experi-
tions. ence (715,718).
Treatment of hallucinations in neurodegenerative disor-
Hallucinations with Altered Mental States ders involves consideration first of drugs that might be exac-
erbating the problem. A visual examination should deter-
Drugs and intoxicants are particularly important cause of
mine whether there are any correctible causes of visual
hallucinations. These include bupropion (695), baclofen
decline, such as cataracts or inadequate refraction (719). Bet-
withdrawal (696), dopaminergic agonists (697,698), gan-
ter refraction can improve hallucinations in Alzheimer’s dis-
ciclovir (699), vincristine (700), and serotonin reuptake in-
ease (706). Last, medications could be used. In Parkinson’s
hibitors such as fluoxetine and sertraline (701). With illicit
disease, there has been some success with cholinesterase
drugs, hallucinations can occur for several months after use,
inhibitors, such as rivastigmine (720), and with agents that
sometimes recurring years later in relation to use of alcohol
treat REM-sleep disorders, such as clonazepam (717).
or medication (702). A transcranial magnetic stimulation
study has shown that subjects with hallucinations related to ‘‘Release Hallucinations’’ (Charles Bonnet Syndrome)
Ecstasy (MDMA) use have hyperexcitable occipital cortex,
probably related to alterations in serotonin levels (703). Visual loss of any origin can result in visual hallucinations
Hallucinations also occur in psychiatric disorders, al- (721). These are called ‘‘release hallucinations’’ because it
though visual hallucinations are usually accompanied by hal- is thought that they arise or are ‘‘released’’ in visual cortex
through the absence of incoming sensory impulses. Release 13 patients. On the other hand, Schultz and Melzack (731)
visual hallucinations are associated with central or peripheral found no evidence of cognitive dysfunction or depression
visual field defects, which are usually binocular. Estimates in 14 patients on a psychological test battery, suggesting that
of their prevalence vary, from 15% among patients with cognitive decline is not a necessary factor. Hallucinations in
retinal disease (722) to 57% of patients with a variety of some cases have been potentiated by drugs, such as estrogen
causes of visual loss (692). (732).
The true incidence is underestimated because of the reluc- Hallucinations often begin close to the time of visual loss.
tance of patients to mention hallucinations for fear of being Most often they follow the onset of visual loss by several
labeled ‘‘crazy’’: 73% of patients in one series had never days or weeks, but this delay can be even longer (690,691).
mentioned the hallucinations to a physician (694). In fact, When the disease causing visual loss is ocular and occurs
patients with release hallucinations are mentally lucid; most first in one eye and then in the other, it is often not until
are aware that the visions are not real, and in general they the second eye loses vision that hallucinations develop
are not distressed by them (694). Notable is the absence of (690,726). Among patients undergoing photocoagulation for
other sensory hallucinations, although there are some excep- macular degeneration, hallucinations occur in about 60%,
tions. usually a few days after the procedure (426). Hallucinations
Release hallucinations can be either simple or complex. may also occur simultaneous to the onset of visual loss, so
Simple stimuli can include flashes or highly intense colors, that in some cases it is the complaint of visual hallucinations
termed ‘‘hyperchromatopsia’’ by some (650). Sometimes that leads to the discovery of a visual field defect. Rarely it
the vision is a recognizable image from the patient’s past, has been possible to show that hallucinations actually pre-
such as a deceased relative (689,691,694,723). There are ceded hemianopia by a few days (685). Among four patients
even reports of hallucinations of the self. Lepore (692) esti- with visual loss from giant cell arteritis, hallucinations were
mated that simple hallucinations are at least twice as com- reported to begin 1–10 days before visual loss, and to disap-
mon as complex ones. Even complex hallucinations may pear within a few weeks (733).
not be unusual, though, as several series have suggested an The hallucinations can be brief, with each episode lasting
incidence of 10–30% for complex hallucinations in visual a few seconds or minutes, or they can be virtually continuous
loss (692,693,724,725). Some authors reserve the term (693). Frequency varies from several per day to twice a year
‘‘Charles Bonnet syndrome’’ for the association of visual (694). They tend to occur in the evening and night, under
loss with complex formed hallucinations (693,725). How- poor lighting, and during periods of inactivity or solitude
ever, some patients have simple hallucinations initially that (694). The time during which patients suffer from continu-
evolve into complex ones (689,691,726). A similar progres- ous or recurrent hallucinations may be limited in some cases,
sion in visual hallucinatory content is reported in normal lasting from a few days to a few months, but they often
people subject to sensory deprivation (727). Since the type persist for long periods, sometimes years or decades
of release hallucination also does not correlate with the site (690,691,694). In Kölmel’s series (724), the mean duration
of visual loss (689), the distinction between complex and of complex hallucinations was 11.5 days. Kölmel (685) also
simple release hallucinations lacks diagnostic value. felt that the occurrence of colored patterns in hemianopia
Some of these visual hallucinations have perseverative indicated transient damage to the optic radiations rather than
features. A recent survey coined several terms for these a permanent striate lesion, and that they were a good prog-
(650). Among patients with ocular causes of severe visual nostic sign for the recovery of hemianopia.
loss, 37% had tessellopsia, in which the hallucinations had Release hallucination do not bother many patients, and
a fine repetitive geometric pattern, and 14% had dendropsia, some subjects are reported to even enjoy them (693,694).
in which a repetitive branching motif is seen. Most patients have insight that the hallucinations are not
There must be other contributing factors besides visual real, although this can fluctuate and may be achieved only
loss in the development of release hallucinations, since they after an attempt to interact with the hallucinations (721). For
do not develop in all patients with visual loss: of 505 patients these, treatment of the visual disturbance is not indicated,
with visual loss, only 60 (12%) met one study’s criteria for beyond reassurance concerning the significance of the hallu-
complex release hallucinations (694). Age is one possibility. cinations. However, a few patients may find them annoying,
In the review by Schultz and Melzack (693), 80% of patients although only 6 of 60 patients studied by Teunisse et al.
with hallucinations were over 60 years old, and the mean (694) were sufficiently troubled to consider pharmacother-
age at onset in the study by Teunisse et al. (694) was 72 apy. Unfortunately, there is no agreement on effective treat-
years. This may simply represent the demographics of bilat- ment. Anticonvulsant drugs have improved the hallucina-
eral visual loss, however, and even subjects as young as 6 tions in some cases (691,734,735) but not others (690,691).
years can have release hallucinations (693,728,729). Social Carbamazepine is probably the treatment of choice (736).
isolation is another potential factor, thought to act by ac- Mixed results have occurred with haloperidol (726,730).
centuating the sensory deprivation of visual loss (730). The There are isolated reports of benefit with tiapride (737), neu-
prospective study of Teunisse et al. (725) found a trend to- roleptics such as risperidone (738) and melperone (736), and
ward hallucinatory patients living alone or being widowed. gabapentin (739). Moving socially isolated patients into a
The dictum that release hallucinations occur in patients with more stimulating environment may lessen the hallucinations
normal mental state has been questioned, as Cole (730) (730).
found that cognitive impairment was a feature in 9 of his Any type of binocular visual loss can lead to release hallu-
cinations (690). The most common damage in Lepore’s generated may reflect the underlying anatomy of the
(692) series of 104 patients was cerebral, mostly infarctions. ‘‘stripes’’ in V2 cortex (741).
Cataracts were most frequent among ocular causes of visual A similar explanation has been invoked for the phantom
loss. In another series of 60 patients, macular degeneration limb phenomenon after amputation, and presumably also un-
and diabetic retinopathy were most common (694). Others derlies other release phenomena such as musical hallucina-
have also reported retinal disease (726) and pathology of the tions in cases of deafness (742). Supporting evidence for the
optic nerves and chiasm (689). It is generally agreed that no analogy with sensory deprivation includes the fact that these
other pathology besides the disorder causing visual loss is hallucinations tend to occur when patients are alone or inac-
required for release visual hallucinations; that is, they are tive, in the evening or night, when the lighting is poor (694).
not a direct manifestation of an underlying cerebral lesion, More recently, single photon emission computed tomogra-
but a physiologic reaction to loss of vision. However, if phy (SPECT) and functional imaging have been used to dem-
so it then remains to be determined why all subjects with onstrate that release hallucinations are associated with hy-
binocular visual loss do not have hallucinations. As well as perperfusion and increased metabolism or activity in ex-
the factors mentioned above such as age, social isolation, trastriate visual areas and thalamus (743–746).
and possibly subtle cognitive impairment, there is one report
of increased incidence of posterior periventricular white Visual Seizures
matter lesions on MRI in patients with hallucinations from
ocular disease (740), an interesting finding in need of verifi- Only about 5% of epileptic patients have visual seizures
cation. (747). These occur exclusively in patients with occipital or
In most reported series, there is some degree of bilateral temporal lesions (748). When they do occur, they can be
visual loss in almost all patients (689,690). However, the confused with migraine and release hallucinations. Indeed,
need for binocular pathology has been questioned (692). much of the confusion around the localizing value of the
Also, occasional patients have no or minimal demonstrable visual content of hallucinations stems from failure to distin-
visual loss and yet have similar visual hallucinations guish between release hallucinations and visual seizures.
(690,692,730). ‘‘Release’’ hallucinations can occur in nor- Conclusions that ‘‘the complexity of the hallucinations has
mal subjects in sensory deprivation experiments (727), and it no localizing value’’ originated in a discussion of release
is possible that some subjects with hallucinations but without hallucinations with optic nerve disease (689). Clearly, the
binocular visual loss suffer a similar deprivation in condi- content of release hallucinations is highly variable and inde-
tions of social isolation, especially since their hallucinations pendent of the site of pathology: rather, it is the associated
can resolve with a change in surroundings (730). field defect that has localizing value in this setting. However,
Schultz and Melzack (693) summarized the various theo- the same conclusion may not be valid for visual seizures
ries about visual release hallucinations. When there has been (690). Older human stimulation experiments (749) found
intracranial pathology, hallucinations have sometimes been that simple unformed flashes of light and colors resulted
attributed to visual seizures (691); however, Cogan (690) from electrical activity in striate cortex, whereas stimulation
distinguished release hallucinations from seizures by their of visual association cortex in areas 19 and temporal regions
longer duration and variable, nonstereotyped content, as well resulted in complex formed images. A similar distinction
as association with visual loss rather than secondary motor probably holds for epileptic visual hallucinations, though
or sensory epileptic events (693). By analogy with epilepsy, there are discrepancies in the literature. Patients with occipi-
earlier reports of visual hallucinations with optic nerve pa- tal lesions are more likely to have ‘‘elementary hallucina-
thology hypothesized a seizure-like ‘‘irritation’’ of the optic tions,’’ meaning simple geometric forms like squares, cir-
nerve (689). With visual loss due to media opacities such cles, zigzag lines, or unformed flashes or lights (748,
as cataracts, another hypothesis was that hallucinations were 750,751) (Fig. 13.46), although there are some exceptional
entoptic phenomena, being the subject’s interpretation of the cases with complex hallucinations (751,752) (Figs. 13.47
image of retinal blood vessels, the retinal ganglion network, and 13.48). In such cases, spread of ictal activity into ex-
and other ocular structures cast upon the retina. The entoptic trastriate cortex is likely responsible for the complex charac-
theory is clearly untenable in patients with enucleations and ter of the hallucinations (751,753). Seizures originating in
hallucinations. Most today believe that all release hallucina- occipitotemporal or anterior temporal structures are more
tions have a similar origin, within the brain rather than in likely to be associated with ‘‘complex hallucinations,’’ such
the eye. In the brain, visual experience is represented by as objects, words, or animals (754), but these can also have
patterns of coordinated impulses within the vast neural net- elementary hallucinations (748). Whether the elementary
work within visual cortex. These patterns are generated by characteristics are due to intrinsic visual properties of certain
sensory stimuli and represent the current experience of the regions of the temporal lobe or to spread of ictal activity to
individual; however, it is proposed that the brain has an the occipital lobe is not clear. Overall, a study of 20 patients
inherent capacity to generate these neural patterns sponta- concluded that elementary hallucinations could occur with
neously, and will in fact do so during sensory deprivation either temporal or occipital foci, but that complex hallucina-
from either imposed isolation (727) or pathologic denervations were far more likely to indicate a temporal origin of
tion (693). These spontaneous neural patterns then corre- seizures (748).
spond to hallucinations. For simple stimuli, it has even been The distinction between visual seizures and release hallu-
proposed that the types of geometric patterns spontaneously cinations can be difficult in patients with cerebral lesions.
Figure 13.46. Visual illusions of occipital lobe epi-

lepsy as perceived by four different patients. (From
Panayiotopoulos CP. Elementary visual hallucinations
in migraine and epilepsy. J Neurol Neurosurg Psychia-
try 1994;57⬊1371–1374.)
Cogan (690) believed that release hallucinations were con- ments of occipital seizures (751). Other features that also
tinuous and nonstereotyped in their content, whereas visual strongly support ictal origin are signs of more distant spread
seizures were brief episodes with the same vision in all sei- of seizure activity, such as confusion, dysphasia, tonic-clonic
zures. However, Schultz and Melzack (693) questioned this limb movements, and the automatisms of complex partial
distinction, pointing out that release hallucinations can be seizures. However, homonymous field defects indicate only
episodic rather than continuous, and that their content can the possibility of release hallucinations, since lesions that
also be repetitive. They suggest that the association with cause epilepsy may also cause visual field defects. In some
other ictal phenomena or a visual field defect is more helpful. cases, it has been felt that complex hallucinations in hemia-
Accompanying head or eye deviation (usually but not always nopia might represent a combination of ictal and release
contralateral) and rapid blinking are common accompani- phenomena (724). The diagnostic uncertainty may be re-
solved by seizure monitoring, although the routine scalp
EEG leads often do not localize the occipital focus accurately
(751,753). Suspicion of such a focus usually requires intra-
cranial electrodes for confirmation (751).
Visual seizures are treated with the same anticonvulsants
used for other focal seizures. Carbamazepine appears quite
effective (747).
Although a variety of pathology in visual cortex may be
associated with visual seizures, one syndrome requiring em-
phasis is ‘‘benign childhood epilepsy with occipital spike-
waves’’ (755). This is an idiopathic epilepsy syndrome that
begins between ages 5 and 9 and ceases spontaneously in
the teenage years. Seizures are characterized by blindness
and/or hallucinations of both simple and formed types and
may progress to motor or partial complex seizures. Some
children develop nausea and headache following the visual
seizure, leading to an erroneous diagnosis of migraine. The
diagnosis is established by occipital spike waves occurring
during eye closure on EEG.
Figure 13.47. Appearance of complex visual hallucination caused by a Migrainous Hallucinations
right-sided occipital lobe cavernous hemangioma. (From Lance JW, Smee
RI. Partial seizures with visual disturbance treated by radiotherapy of cav- A variety of visual phenomena can occur in migraine
ernous hemangioma. Ann Neurol 1989;26⬊782–785.) (756). In classic migraine, the visual phenomena precede the
Figure 13.48. Neuroimaging appearance of the lesion causing the hallucination seen in Figure 13.47. A, T2-weighted MR
image, axial view, shows small circumscribed hypointense lesion (arrow) consistent with a cavernous angioma in the right
occipital lobe. B, Adjacent T2-weighted axial MR image shows small vessel adjacent to the region of the lesion (arrow). (From
Lance JW, Smee RI. Partial seizures with visual disturbance treated by radiotherapy of cavernous hemangioma. Ann Neurol
1989;26⬊782–785.)
headache, whereas in migraine equivalent the visual phe-

nomena occur without a subsequent headache. Photopsic im-
ages are most common, described as spots, wavy lines, or
a shimmering like heat waves over a road on a hot day (757).
The ‘‘scintillating scotoma’’ is a blind region surrounded by
a margin of sparkling lights, which often slowly enlarges
over the time of its presence. In some individuals the spar-
kling margin can be discerned as a zigzag pattern of lines
oriented at 60⬚ to each other (758), usually in one hemifield,
and on the leading edge of a C-shaped scotoma (Fig.
13.49). This is the ‘‘fortification spectrum’’ or ‘‘teichopsia’’
(teichos being Greek for town wall), based on the resem-
blance of the zigzag margin to the ground plan of town forti-
fications in Europe (758) (Fig. 13.50). There may be several
sets of zigzag lines in parallel, often shimmering or oscillat-
ing in brightness (759). They may be black and white (750)
or vividly colored (758,759). These zigzag lines begin near
central vision and expand toward the periphery with increas-
ing speed over a period of about 20 minutes, with both the
speed and the size of the lines increasing with retinal eccen-
tricity (Fig. 13.49). The relation of speed and size to eccen-
tricity is predicted by the cortical magnification factor, Figure 13.49. Photographic negative of a migraine phosphene protocol.
which is a measure of the area of visual field represented The scintillating phosphene was progressing through the lower quadrant
in a given amount of striate cortex as a function of retinal and part of the upper quadrant of the left visual hemifield. Thirteen drawings
were made between 2 and 29 minutes after the phosphene first appeared
eccentricity (758,760). This suggests that these migrainous
near the center of the visual field. To evaluate the distance between the
hallucinations are generated by a wave of neuronal excitation phosphene and the center of the visual field, several radii were drawn across
spreading from posterior to anterior striate cortex at a con- the protocol. The angular distance from the fovea center, computed in de-
stant speed, leaving a transient neuronal depression that grees of visual angle, is indicated by circles. Circles and radii were added
causes the temporary scotoma in its wake (759). It is also to the sheet after the observations were made. Observation distance ⳱
hypothesized that the zigzag nature of the lines reflects the 34 cm. (From Grüsser OJ. Migraine phosphenes and the retino-cortical
sensitivity to line orientation of striate cortex and the pattern magnification factor. Vision Res 1995;35⬊1125–1134.)
this (774) and may even interact with the hallucinations

(772). Similar hallucinations have been described for sounds
(773); some patients have multimodality hallucinations, in-
volving vision, touch, sound, and even the sense of body
posture (767,768).
Unlike release hallucinations with visual loss, peduncular
hallucinations are almost invariably associated with inver-
sion of the sleep–wake cycle, with diurnal somnolence and
nocturnal insomnia (764,766,767,770,774). Other associated
signs from damage to adjacent structures in the midbrain
include unilateral or bilateral third nerve palsy (764,
766,770), hemiparkinsonism (769), hemiparesis (766), and
gait ataxia (764,772). Many patients have had pre-existing
visual loss (766,772), prompting some to speculate that this
may be a contributing factor. However, there are other pa-
tients with relatively intact vision also (768,771).
Figure 13.50. Aerial view of Naarden, a city with typical fortifications Since the original pathologic description by van Bogaert
from which the concept of ‘‘fortification scotomas’’ originated. Note the
(765), there have been reports with neuroimaging demon-
jagged appearance of the walls and moats round the city. (From Plant GT.
The fortification spectra of migraine. Br Med J [Clin Res Ed] 1986;
strating unilateral or bilateral infarction of the peduncles
293⬊1613–1617.) with this condition (766,769). A detailed pathologic study
showed bilateral infarction of the substantia nigra pars reti-
culata (768). The correlation of neuronal activity in this
of inhibitory interconnections within and between striate col- structure with REM-sleep stages and its connections to the
umns (759,760). pedunculopontine nucleus suggested an anatomic correlate
Distinguishing migraine from epilepsy is an important to the disturbed sleep–wake cycle thought to underlie both
problem for hallucinations, especially as visual seizures the hallucinations and the associated inversion of the
rarely progress to other clearly ictal symptoms (747). Both sleep–wake pattern in these patients. Others have postulated
migraine and visual seizures can feature abnormal hallucina- damage to the reticular formation and the ascending reticular
tions followed by headache and vomiting (747,761). It has activating system with similar consequences (772). There
been suggested that the two disorders can be distinguished are also a few cases with similar hallucinations from lesions
by their visual content, with black and white zigzag lines in restricted to the paramedian thalamus, which may affect the
migrainous hallucinations and colored circular patterns in thalamic reticular nucleus (772,774,775).
ictal hallucinations (750,762). However, migraine-like hal- The most frequently described etiology is infarction
lucinations have been described with occipital seizures from (766,768,769,772), with peduncular hallucinosis included as
cysticercosis (763). Other important distinguishing features one of the top-of-the-basilar syndromes (776). It has also
are that seizures are briefer, usually lasting a few seconds been described as a vascular complication of angiography
or minutes, spread more rapidly than migrainous hallucina- (771) and transiently after microvascular decompressive sur-
tions, and always occur in the same hemifield (747). Epi- gery for trigeminal neuralgia (767). There are two cases with
sodes are also more frequent for visual seizures than mi- extrinsic midbrain compression by tumors, a craniopharyn-
graine. Accompanying eyelid fluttering or eye deviation gioma (777) and a medulloblastoma (770). In cases with
would also suggest seizure rather than migraine. infarction, the hallucinations can persist indefinitely (768),
though the episodes may become shorter (774) or disappear
Other Hallucinatory States (772). Hallucinations have resolved after relief of extrinsic
Hallucinations with midbrain lesions were first described tumor compression (770,777).
by Lhermitte (764), with coining of the term ‘‘peduncular Miller Fisher has described a number of patients with hal-
hallucinations’’ and its first pathologic verification by van lucinations only with eye closure (778,779). In two cases
Bogaert (765). They are still considered rare. Their nature the visual hallucinations were attributed to drug toxicity, due
has many similarities to complex release hallucinations with to atropine and probably lidocaine given for local anesthesia;
visual loss, as described above. They can be continuous in the other the hallucinations occurred during a respiratory
(766,767) or episodic (768,769), with detailed formed im- infection with high fever. Parallels were drawn with hypna-
agery such as flying birds, dogs, roaring lions (768), crawl- gogic hallucinations, and Fisher hypothesized a disturbance
ing snakes, gangsters with knife wounds (767), and men in sleep–wake cycle mechanisms. While these may be
herding cattle (770), for example. These hallucinations are thought rare, we recently encountered two similar cases of
not stereotyped, varying from one episode to the next. As visual hallucinations with eye closure occurring in the post-
with release hallucinations, in some cases with thalamic operative period after major surgery.
rather than midbrain infarcts the hallucinations are from Local retinal dysfunction can cause hallucinations. These
events in the patient’s past (774). Patients often have insight are being increasingly recognized as a common but transient
that they are not real (766,768,771), but some do not possess side effect of photodynamic therapy for macular degenera-
tion, for example, often developing several days after the it is binocular. Unusual variants include hemimicropsia in
procedure (426). the contralateral hemifield (789,790). One unusual case had
hemimicropsia only for faces (791). Given the small number
VISUAL DISTORTIONS (DYSMETROPSIA) of cases, the localization value of cerebral micropsia is un-
certain. Occipitotemporal lesions have been reported, with
Illusions about the spatial aspect of visual stimuli include
either medial (791,792) or lateral (790) involvement.
three main categories: micropsia, the illusion that objects
A recent survey of over 3,000 adolescent students re-
are smaller than in reality; macropsia, the illusion that ob-
vealed that complaints of episodic micropsia or macropsia
jects are larger than in reality; and metamorphopsia, the illu-
were not rare, occurring in 9% (793). Some occurred in the
sion that objects are distorted. Of these, micropsia is proba-
hypnagogic state or during fever, and there was a correlation
bly the most common and has the largest variety of possible
with a history of migraine. This possible migrainous mi-
etiologies.
cropsia, which we would presume to be a variant of cerebral
Micropsia micropsia, is reminiscent of an earlier description of mi-
cropsia occurring during migraine (794) (Fig. 13.51).
Etiologically, several types of micropsia exist. Conver-
gence-accommodative micropsia is a normal and long-rec- Macropsia
ognized phenomenon in which an object at a set distance
appears smaller when the observer focuses at near rather Macropsia is much less frequently described than mi-
than far, although there has been no change in the retinal cropsia. Retinal macropsia can occur in the late scarring
angle covered by the object and no change in its spatial stage of macular edema. It has been reported as a side effect
relations to the surround. Investigations of this induced mi- of zolpidem use (795). Wilson (794) had a case of cerebral
cropsia at near (or alternatively, macropsia at far) conclude macropsia occurring during seizures. Cerebral hemimacrop-
that vergence rather than accommodation is responsible sia has also been reported with a left occipital tumor (796)
(780–782). Convergence micropsia may play a role in pre- and with a right occipital infarct (797). Both macropsia and
serving size constancy at small distances (781). Its origins micropsia occurred in a large sample of students surveyed
remain unclear, although there are older suggestions that (793).
the size of visual receptive fields is modified by the act of
convergence (783). It is unusual for accommodative mi- Metamorphopsia
cropsia to be a source of complaint. Peripheral causes of metamorphopsia are probably more
Psychogenic micropsia has also been reported among psy- common than cerebral metamorphopsia. Most often this oc-
chiatric patients, where it has been subject to psychoanalytic curs as a result of retinal pathology. Most often this is related
interpretations, with subjects literally trying to ‘‘distance’’ to macular edema, and it may coexist with micropsia as a
themselves from environments fraught with conflict result (788), but disorders that cause traction on the retina
(784–786). may also distort the retinal map, such as an epiretinal mem-
Retinal micropsia occurs in conditions where the distance brane (798). Amemiya et al. (799) suggested a correlation
between photoreceptors is increased. The micropsia usually with the segmental buckling procedure. As with retinal mi-
occurs in foveal vision, secondary to macular edema. There cropsia, the metamorphopsia from ocular disease is monocu-
may be associated metamorphopsia if the edema and recep- lar; if due to binocular disease, it is unlikely that the distor-
tor separation is irregular. Visual acuity is also reduced due
to photoreceptor separation, and it has been found that grat-
ing acuity correlates with psychophysical measures of mi-
cropsia (787). Causes of macular edema and micropsia in-
clude central serous retinopathy, severe papilledema (787),
and retinal detachment (788). A prior history of macular
detachment for at least 10 days was noted in a small sample
by Sjostrand and Anderson (788), with the development of
cystoid macular edema in some patients. In others, the mi-
cropsia was thought to indicate subclinical macular edema.
The condition may resolve or may persist for years. While
it has been suggested that retraction with scarring may cause
micropsia to change into a more permanent macropsia, other
studies show that micropsia from separation of photorecep-
tors can be long-standing (788). Retinal micropsia is often
monocular but can be binocular, depending on the type of
ocular pathology. Matching techniques that demand relative Figure 13.51. Drawing of cerebral micropsia by a child with migraine.
size judgments in relation to the normal eye have been devel- The child stated that during some of her attacks, other children (right)
oped and can serve as a useful monitor of disease progression appeared unusually small to her (left). (From Hachinski VC, Porchawka J,
(787,788). Steele JC. Visual symptoms in the migraine syndrome. Neurology 1973;
Cerebral micropsia is rare. In contrast to retinal micropsia, 23⬊570–579.)
tions will be identical in the two eyes. Psychophysical tests nous malformation, whose metamorphopsia was limited to
of hyperacuity that require the alignment of dots or compari- faces (802). It has also occurred with posterior cerebral in-
son of dot spacing in a dot bisection task have been devel- farction (803), once as a transient stage in the development
oped to quantitate metamorphopsia in these conditions of cortical blindness (804). The lesions with infarcts have
(800). been medial, however, with one lesion said to involve only
Cerebral metamorphopsia has been described with sei- the left cingulate gyrus and retrosplenial area (803). There is
zures (267,801,802). One patient had a right parietal glioma also one report of metamorphopsia due to brain stem lesions
(267), and another was a boy with a right parietal arteriove- (805).
VISUAL LOSS IN AGING AND DEMENTIA

Many adults experience a decline in their ability to func- recover more slowly from the effects of visual stimulation,
tion effectively and independently in later life. Such a de- compatible with an overall slowing in processing time.
cline is multifactorial and includes impairment of vision Aging also impairs inductive reasoning, spatial orienta-
from common eye conditions, such as age-related macular tion, verbal memory, and perceptual speed (818). Such de-
degeneration, glaucoma, and cataract. For instance, cataract cline generally does not occur before age 60 and is not mean-
can cause yellowing of the lens, producing a relative tritano- ingful until age 80. After this, most abilities (except verbal
pia; glaucoma causes visual field defects; and macular de- and fund of knowledge) decline by about one standard devia-
generation impairs central visual acuity and spatial contrast tion, mostly from slower processing speed (818–821). These
sensitivity and may also be associated with visual hallucina- reductions in the function of normally aging brain tissues
tions, as described above. The risk of cerebrovascular dis- add to the complications and symptoms in patients who have
ease increases with age, and ischemia with infarction causes cerebral disturbances of vision from destructive lesions and
the majority of visual impairments described earlier in this also impair the ability of such patients to recover.
chapter. Slowing of neuronal processing speed can hinder function
Another cause of visual dysfunction in aging persons is at each level of information processing in the central nervous
dementia. Alzheimer’s disease is the most common cause system (822) and provides an adequate explanation for the
of dementia in the elderly, and the number of persons with cognitive decline with advancing age (823,824) that causes
this condition is projected to increase sharply by the middle difficulties in a range of tasks from simple memory to com-
of the 21st century. Alzheimer’s disease often impairs recog- plex reasoning and spatial abilities (819,825–828). These
nition and visuospatial processing, and visual dysfunction effects increase with the complexity of the task (824,
can be the dominant early manifestation in a visual variant 829,830). Fortunately, various strategies can be learned to
of the disease known as posterior cortical atrophy (576). In mitigate the effects of slowed processing speed on the day-
these patients, visuospatial dysfunction can be so marked as to-day functioning of elderly adults. For example, older typ-
to suggest Bálint’s syndrome (806). Impairment of motion ists can compensate for reduced speed of processing by plan-
perception (807) and visual recognition (260,562) also oc-
ning and reading further ahead in the text (821,831), and
curs in patients with Alzheimer’s disease. Visual complaints
older chess players with worse recall can plan their moves
may also be the earliest manifestation of Jakob-Creutzfeldt
further ahead (832,833). External memory aids are also use-
disease (808). However, visual abilities also decline as a
function of normal aging of the nervous system in the ab- ful compensatory devices for such patients (834).
sence of any diagnosable eye or brain disease. This important Many of the tests commonly employed to test the vision
factor is often ignored in the interpretation of visual dysfunc- of older subjects do not measure age-related decline. For
tion. example, older adults can experience a reduction in the use-
Aging of the nervous system affects information process- ful field of view (UFOV) because of reduced processing
ing at several levels, from the coding and storage of sensory speed. Standard visual field testing using such instruments
inputs to the retrieval and modification of that stored infor- as the Goldmann perimeter for kinetic perimetry and the
mation (809). There may also be a reduction in the powers Humphrey field analyzer for static perimetry will fail to de-
of attention. Attention is needed to allocate a finite set of tect such deficits because they ignore speed of processing
cognitive resources to a barrage of external and internal stim- and intentionally minimize the role of attention to gain maxi-
uli. Deterioration at one or more of these levels reduces the mum estimates of sensory ability (835). This approach is
speed of processing and overall performance on a wide vari- effective for gauging retina or optic nerve function or for
ety of everyday tasks ranging from walking and dialing a plotting a bitemporal or homonymous visual field defect,
telephone to highly visual tasks such as driving, reading, or but it may overestimate the visual capacity in the elderly or
searching for a familiar face in a crowd. in brain-damaged patients (836). The UFOV, defined as the
Aging can also affect the temporal resolution of the visual visual area within what targets can be perceived without
system (810,811). Older adults require longer delays be- moving the eye in the head, can be markedly impaired in
tween successive stimuli before both are seen as separate such persons under conditions of increased attention load
percepts (812). Related changes also occur in critical flicker (582). Practically speaking, the UFOV can be assessed using
fusion (813,814), visual masking (815,816), and after- a commercially available instrument, the Visual Attention
images (817). In short, the aging nervous system appears to Analyzer Model 3000 (Visual Resources, Inc, Bowling
Green, KY). The results can be interpreted literally as a unacceptable crash risk in older drivers in state crash records
shrinkage of the visual fields, or may reflect a general loss (582) and with a greatly increased relative risk of crashes in
of efficiency throughout the visual fields (584). More severe collision avoidance scenarios tested in high-fidelity driving
levels of UFOV impairment have been correlated with an simulations (599).
TESTS OF HIGHER VISUAL FUNCTION

Chapter 2 contains detailed descriptions of the standard Theft Picture, line bisection task); (f) visuoconstruction
vision tests used by ophthalmologists, neurologists, and (drawing to dictation and copy, writing to dictation copy and
neuro-ophthalmologists to measure patients’ visual abilities spontaneously, 3-D Block Construction Test); and (g) visual
and track deficits (621). However, as indicated above, stan- memory (the Benton Visual Retention Test). Some of these
dard vision and screening tools generally do not provide a tests are described next.
measure of higher-order visual functions, nor are they meant The Rey-Osterreith Complex Figure Test (CFT) requires
to do so. Tranel (837) and Anderson and Rizzo (838) re- subjects to copy a complex geometric figure. An extensive
viewed the assessment of high-order visual functions, in- scoring system is provided. The CFT provides a reliable
cluding the proper selection and interpretation of tests and index of visuoconstructional ability independent of memory
the categories of available tests. Basic categories of higher function (Fig. 13.52).
visual function tests included tests of (a) reading (e.g., the The Benton Visual Retention Test—Revised (BVRT) re-
reading subtest of the Wide Range Achievement Test, the quires a subject to reproduce, by drawing, several line draw-
Chapman-Cook Speed of Reading Test); (b) visual recogni- ings depicting geometric designs (839). Typically, the sub-
tion (the recognition of famous faces, Boston Naming Test, ject is shown each plate for 10 seconds. The plate is then
Visual Naming Test from the Multilingual Aphasia Exami- withdrawn and the subject is asked to reproduce the figure
nation); (c) mental imagery (the Hooper Visual Organization on a piece of white paper (Fig. 13.53). The BVRT is sensitive
Test); (d) visual perception (Facial Recognition Test and to visual memory, perception, and visuoconstructional im-
Judgment of Line Orientation); (e) visual attention (Cookie pairments. It is well standardized and takes only about 10
minutes to administer in most subjects.
The Hooper Visual Organization Test (840) requires the
subject to identify 30 different items (e.g., room, shoe, fish,
scissors) from cut-up, rearranged line drawings of those
items (Fig. 13.54). This test is memory-dependent in that it
depends on the history of exposure to the items represented
in the test.
Figure 13.53. Tests of higher visual function. A, Plate (design 5) from

Figure 13.52. Tests of higher visual function. A, The Rey-Osterreith the Benton Visual Retention Test (BVRT). B, Defective reproduction by
Complex Figure. B, Defective copy of this figure by a 74-year-old woman a patient with Alzheimer’s disease. C, Omission of one of the left figures
with Alzheimer’s disease. in a patient with a right hemisphere lesion causing left hemineglect.
Figure 13.54. Tests of higher visual function. A plate

(number 22/30) from the Hooper Visual Organization
Test (HVOT). The patient is required to identify each
of the 30 items on the plate from their cut-up, rear-
ranged line drawings. This test is memory-dependent
in that it depends on the history of exposure of the
patient to the items on the plate.
Figure 13.55. An item from the Benton Facial Recognition Test. This test measures visuoperceptual capacity. The subject
is asked to choose which three of six face pictures below match the unfamiliar face pictured above. (Courtesy of Arthur Benton.)
Mooney’s Closure Faces Test (841–843) is a ‘‘closure faces from memory but to match similar, although unfamil-
test’’ that provides information similar to that provided by iar, faces. Thus, a patient can have severe prosopagnosia and
the Hoopes Visual Organization Test. The patient is pre- still make the appropriate visual perceptive discriminations
sented with 44 black-and-white, incomplete cartoons of to pass this test (see above).
faces and asked to judge the age and sex of the faces de- In the Judgment of Line Orientation Test, the patient must
picted. Performance on this test is memory-dependent, but select, from an array of 11 line segments radiating from a
recognition of previously familiar faces or famous faces is semicircle, those segments that lie at the same angle as two
not required. target line segments. Performance on this test depends on
The Cookie Theft Picture (563) is a black-and-white line visual perceptual discrimination and visuospatial judgment.
drawing of a complex picture from the Boston Diagnostic The findings from the tests described above can help pro-
Aphasia Examination. It was designed with a balance of vide a signature of the visuoperceptive impairments in a
information among the four quadrants and tells a story. The patient. For example, patients with right hemispheric dys-
subject is asked to view the picture and to report what he function may perform poorly on the Judgment of Line Orien-
or she sees. Scoring is qualitative and depends on the report tation, BVRT, and Block Design tasks. However, a patient’s
of the major items in the display (Fig. 13.40). results cannot be properly interpreted without also having a
The Block Design subtest from the WAIS-R provides a clear idea of basic visual functions (such as spatial acuity
very reliable measure of nonverbal intellectual capacity. It and contrast sensitivity, visual fields, color perception, and
is highly correlated with performance IQ (844). It can be motion perception) and intellectual capacities (such as verbal
administered in a few minutes and is easily scored. In older and performance IQ). More exhaustive reviews of neuro-
populations, normative information is more robust for this psychological tests, including tests of visual cognition, are
subtest than for several other tests from the WAIS-R. available in the large compendia by Spreen and Strauss (846)
The Facial Recognition Test (845) measures visual per- and Lezak (620).
ceptual capacity. The subject is asked to match unfamiliar
faces under different lighting conditions and viewing angles Acknowledgments
or to match a face in one booklet with one of several faces
in another booklet (Fig. 13.55). This is not a face-recognition This work was supported by NIA AG 17177 and NIH PONS 19632 (M.R.),
test per se because the patient is being asked not to recognize and NIMH MH 069898 and the Canada Research Chair program (J.B.).
GLOSSARY OF CEREBRAL VISUAL DEFICITS

Agnosia (also known as associative agnosia): The inability direction, shape from motion, and other ‘‘higher-order’’
to recognize previously familiar objects despite adequate motion processes may be impaired.
perception. Objects are effectively stripped of their mean- Color agnosia: Inability to identify colors despite preserved
ings. ability to discriminate among colors
Alexia without agraphia (also known as pure alexia or ac- Color anomia: Inability to name colors despite adequate
quired dyslexia): The acquired inability to read in previ- color perception and recognition
ously literate subjects. Should not be confused with devel- ‘‘Cortical blindness’’ (cerebral blindness): Inability to see
opmental dyslexia. following bilateral lesions of visual cortex and optic radia-
Anosognosia: Failure to recognize one’s own impairment tions. Affected patients generally have considerable dam-
(see Anton’s syndrome) age that extends well beyond V1.
Anton’s syndrome: The denial of cerebral blindness ‘‘Foveal sparing’’: A homonymous hemianopia in which
Apperceptive agnosia: Failure to identify previously familiar the few degrees of vision near fixation are preserved
objects due to impaired perception ‘‘Foveal splitting’’: A homonymous hemianopia that in-
Bálint’s syndrome. Simultanagnosia, ocular apraxia, and cludes the entire foveal representation on the affected side
optic ataxia Hemianopia (or hemianopsia, or homonymous hemianopia):
Blindsight: Residual vision in the fields of a putative striate A visual field defect that occupies both the upper and
scotoma; later redefined more broadly by Weiskrantz as lower visual portions of the same hemifield of both eyes
Keyhole vision (cerebral tunnel vision): Homonymous hemi-
a ‘‘visual capacity in a field defect in the absence of ac-
anopias may be bilateral (double homonymous hemia-
knowledged awareness’’
nopia), leading to a severe loss of peripheral vision; if
Central (paracentral) scotoma: A visual field defect at (or there is foveal sparing, a tunnel or keyhole of vision
near) the fixation point around fixation remains.
Cerebral achromatopsia (also known as central achromatop- Metamorphopsia: The distortion of visual images due to a
sia): An uncommon defect of color perception caused by carnival mirror-like effect
damage to the visual cortex and connections. The term Monocular temporal crescent: The peripheral-most sector
‘‘achromatopsia’’ implies complete color loss. The term of the visual fields of the eye represented in the depths
‘‘dyschromatopsia’’ should be used when there is some of the contralateral calcarine fissure
sparing of color sensation. Ocular apraxia (also called ‘‘psychic paralysis of gaze’’ and
Cerebral akinetopsia: Defective processing of visual motion ‘‘spasm of fixation’’): Inability to move the eyes to ob-
cues due to cerebral lesions. The ability to perceive motion jects of interest despite unrestricted ocular rotations
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SECTION II:
The Autonomic Nervous System
Neil R. Miller, section editor
The autonomic nervous system provides innervation to nomic nervous system. The second chapter describes the
the pupil, ciliary body, and lacrimal gland, all of which can techniques used to examine pupillary function, accommoda-
be adversely affected by a variety of ocular, orbital, and tion, and lacrimation. The final chapter describes disorders
neurologic disorders. This section contains three chapters. of pupillary function, accommodation, and lacrimation of
The first deals with the anatomy and physiology of the auto- neuro-ophthalmologic importance.
CHAPTER 14
Anatomy and Physiology of the
Autonomic Nervous System
Randy Kardon
GENERAL ORGANIZATION OF THE AUTONOMIC ACCOMMODATION AND THE AUTONOMIC NERVOUS

NERVOUS SYSTEM SYSTEM
Central Levels of Autonomic Regulation Pathways for Accommodation
Peripheral Autonomic Nervous System Characteristics of Accommodation
THE PUPIL LIGHT AND NEAR REFLEXES AND THEIR Methods of Measuring Accommodation
RELATIONSHIP TO THE AUTONOMIC NERVOUS ANATOMY AND PHYSIOLOGY OF NORMAL LACRIMAL
SYSTEM FUNCTION
The Afferent Arc of the Pupil Light Reflex Anatomy of Tear Secretion by the Lacrimal Glands
The Inter-Neuron of the Pupil Light Reflex Parasympathetic Pathway for Lacrimation
Excitatory Influences of Visual Cortex on the Pupil Light and Sympathetic Pathway for Lacrimation
Near Reflexes Supranuclear Pathways Mediating Tear Secretion
Inhibitory Influences on the Pupil Normal Tear Film
The Efferent Arc of the Pupil Light Reflex Types of Tear Secretion
The Iris Muscles Regulation of Tear Secretion
Integrated Activities that Influence Pupil Size and Movement Reflexes Associated with Lacrimation
Normal Pupillary Reflexes
GENERAL ORGANIZATION OF THE AUTONOMIC NERVOUS SYSTEM

Body functions that are regulated independently of volun- the hypothalamus (2). Thus, coordination and integration of
tary activity using reflex mechanisms involving afferent somatic and autonomic activities from the highest level of
nerve input, efferent nerve output, and central integrating neurologic activity in cortex down to the spinal cord and
nerve pathways are part of the autonomic nervous system peripheral nervous system (PNS) are used to attain funda-
(1). Although the activity of this system is essentially auton- mental adjustments of the organism to its environment.
omous, at higher levels of the central nervous system (CNS) Viewed broadly, the autonomic system ensures self-pres-
voluntary modulation is still possible. As early as 1875, ervation of the organism by making continuous automatic
Hughlings Jackson offered clinical, physiologic, and experi- adjustments so as to maintain homeostasis in the face of
mental evidence to show that the autonomic nervous system, major and minor environmental changes. Sympathetic and
like the somatic nervous system, is integrated at all levels parasympathetic elements in this system act in a balanced
of nervous activity and that autonomic and somatic activities fashion to maintain homeostasis in bodily dynamics such as
are closely correlated. Segmental autonomic reflexes are co- respiration, circulation, body temperature, and heart rate. At
ordinated in the spinal cord, but regulation of functions such one extreme, sympathetic activity mobilizes mechanisms of
as respiration, blood pressure, swallowing, and pupillary the body to meet conditions of stress: the vessels of the
movement requires suprasegmental integration higher in the skin and viscera constrict, and blood is shunted into dilated
brain stem. The autonomic subsystems in the brain stem are, vessels of the skeletal muscles; the heart rate increases; respi-
in turn, influenced by more complicated integrating systems ration deepens; gastrointestinal activity ceases; skin is mois-
in the hypothalamus. Finally, certain cortical areas, particu- tened with perspiration; hairs stiffen; and the pupils dilate. At
larly the frontal cortex, govern many of the activities of the other extreme, parasympathetic activity has an opposite
649
function, that of conservation and restoration of bodily re- collectively known as the limbic system exert some degree
sources: the heart is slowed, intestinal activity is increased, of central control over the autonomic system by modulating
and the pupils constrict (3,4). the more direct influence of the hypothalamus.
In addition to direct neural control of homeostatic func-
tions, an autonomic neuroendocrine system is intimately Cerebellum
linked to the same activities. For example, sympathetic nerve
fibers stimulate the adrenal glands to liberate adrenaline to The cerebellum is involved to some degree in the control
act on sympathetic effector organs in a manner homologous of the autonomic nervous system (22,23). Stimulation of
to their direct stimulation by sympathetic nerves. Similarly, both anterior and posterior lobes produces changes in blood
the posterior lobe of the pituitary gland is stimulated by pressure and heart rate. Pupillary constriction and dilation
parasympathetic pathways from the hypothalamus to pro- also occur when portions of the cerebellum are stimulated,
duce circulating hormones that participate in the homeostatic and accommodation can also be modulated by the cerebel-
control of the organism’s internal environment. lum. Chemical stimulation of the posterior lobe of the cere-
Neuro-ophthalmologic focus on the autonomic nervous bellum by local application of glutamate augments both
system is concerned primarily with the control of the intrin- sympathetic and parasympathetic tonic discharges (9).
sic muscles of the eye (the iris sphincter and dilator muscles Therefore, although the full significance of cerebellar auto-
and ciliary accommodative apparatus), lacrimation, and ce- nomic representation is not yet completely appreciated, it
rebral and orbital blood flow. In this chapter, we describe should be recognized that the cerebellum is capable of modu-
the basic anatomy, physiology, and pharmacology of the lating different aspects of autonomic nervous system func-
system as it pertains to the field of neuro-ophthalmology. tion.
A complete discussion of the autonomic nervous system is
beyond the scope of this work; however, several excellent Hypothalamus
texts and monographs are available to the interested reader Anatomy
(5–13).
In the broadest sense, the autonomic nervous system cov- The hypothalamus is the primary area of the brain con-
ered in this chapter includes cortical and subcortical regions cerned with the integration of autonomic functions. It forms
(including the hypothalamus), parts of the brain stem and the anterior inferior wall of the third ventricle and is located
spinal cord, and the peripheral sympathetic and parasympa- posterior and superior to the optic chiasm, and its superior
thetic nerves and ganglia. border is the hypothalamic sulcus (Fig. 14.2). As noted pre-
viously, autonomic function is influenced from many re-
CENTRAL LEVELS OF AUTONOMIC REGULATION gions of the brain, including parts of the cerebral cortex and
Limbic System thalamus, the hippocampus, the entorhinal area, the basal
ganglia, the reticular formation, and the cerebellum. Gener-
The term ‘‘limbic system’’ was applied by MacLean (14) ally, these influences appear to be mediated through involve-
to several areas within the CNS influencing autonomic func- ment of the hypothalamus, which receives direct or indirect
tion and emotional behavior (15) through direct connections connections from most of these regions. Although the ana-
with the hypothalamus. The limbic cortex consists of an tomic border of the hypothalamus is somewhat ill defined,
arcuate band of cortex that includes the cingulate and para- the hypothalamus contains several cell clusters or nuclei (Fig
hippocampal gyri and the orbitofrontal and pyriform areas 14.3).
(Fig. 14.1). The concept of a greater limbic ‘‘system’’ was The anterior group of nuclei includes the supraoptic and
proposed to unite the limbic cortex and those structures with paraventricular nuclei, which differ in size and structure
primary connections: the olfactory system, the preoptic area, based on whether the brain is from a male or female (24,25).
the septum, the amygdala, the hypothalamus, and adjacent The supraoptic nucleus is believed to have parasympathetic
areas of neocortex (14,16–21). function (26) and is located just superior and lateral to the
From our standpoint, it is sufficient to be aware that stimu- optic chiasm, connecting to the pars intermedia and pars
lation of the limbic cortex produces visceral effects, such as posterior of the hypophysis by the supraopticohypophyseal
vasomotor changes and gastrointestinal activity, as well as tract (Fig. 14.4). The paraventricular nucleus lies immedi-
somatic and autonomic reactions that typify excitement and ately beneath the anterior third ventricle. It undergoes atro-
rage. Removal causes changes in behavior associated with phy after destruction of the nucleus of the vagus nerve or
a loss of emotional expression. Stimulation of the hippocam- removal of the superior cervical ganglion.
pus elicits involuntary movements, rage reactions, sexual The middle group of nuclei includes the tuberal nuclei,
activity, and general hyperexcitability. Stimulation of the situated just posterior to the supraoptic nucleus within and
amygdala produces a mixture of parasympathetic and sym- near the surface of the tuber cinereum, and the ventromedial,
pathetic reactions, including changes in respiration, blood dorsomedial, and lateral hypothalamic nuclei, located above
pressure, and heart rate; pupillary constriction and dilation; the tuberal nuclei. The tuberal nuclei contain small multipo-
and defecation or micturition. Ablation of the amygdala pro- lar cells, whereas the cells of the ventromedial, dorsomedial,
duces placidity. Stimulation in the septal region affects blood and lateral hypothalamic nuclei are somewhat larger.
pressure, whereas injury to the septum reduces susceptibility The posterior group of nuclei includes the nuclei of the
to fear and anxiety. Thus, the regions of the CNS that are mammillary body and the posterior hypothalamic nucleus.
ANATOMY AND PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM 651
Figure 14.1. Components of the limbic system seen from below. The cerebellum, brain stem, thalami, and most of the
basal ganglia have been removed. A, amygdaloid nuclear complex; AC, anterior commissure; D, dentate gyrus; F, fornix; H,
hippocampus; M, mammillary body; PH, parahippocampal gyrus. (From Ghuhbegovic N, Williams TH. The Human Brain: A
Photographic Guide. Hagerstown, MD, Harper & Row, 1980.)
The mammillary bodies are located in the interpeduncular of the thalamus. The posterior hypothalamic nucleus lies
space and are composed of two nuclear masses, the medial above and just rostral to the mammillary bodies. It is com-
and lateral mammillary nuclei. Each mammillary body posed of large cells scattered among numerous smaller cells.
forms the posterior termination of the ipsilateral fornix and The hypothalamus also contains smaller nuclei, including
is also connected directly with the ipsilateral anterior nucleus the suprachiasmatic nucleus, located close to the midline
Figure 14.2. Hypothalamus and related structures. AC, anterior commissure; CC, corpus callosum; F, fornix; H, hypothalamus;
HS, hypothalamic sulcus; I, infundibular recess; M, mammillary body; OC, optic chiasm; O, optic recess; SP, septum pellucidum;
T, thalamus. (From Ghuhbegovic N, Williams TH. The Human Brain: A Photographic Guide. Hagerstown, MD, Harper &
Row, 1980.)
above the optic chiasm, and the arcuate nucleus, a group of Fiber Connections
small cells located in the most ventral part of the third ventri-
cle near the infundibular recess and extending into the medial Knowledge of the hypothalamic connections to the brain
eminence. and spinal cord is derived from comparative studies using
anterograde and retrograde tracers in animals and from the
Neuromediators study of normal and pathologic human material (28). These
Many different neuromediators are produced in various connections include afferent and efferent nerve fiber connec-
sites in the hypothalamic region, including angiotensin II, tions, as well as humoral connections to the hypophysis via
delta sleep-inducing peptide, dynorphin, enkephalin, endor- a venous portal system (Figs. 14.5 and 14.6).
phin, growth hormone release-inhibiting hormone (GHRIH, Afferent nerve pathways to the hypothalamus originate
somatostatin), growth hormone-releasing factor (GHRF, so- from ascending visceral sensory input, somatic sensory sys-
matocrinin), prolactin-releasing factor (PRF), prolactin- tems of the visual and olfactory systems, and numerous tracts
inhibiting factor (PIF), gonadotropin-releasing hormone from the brain stem, limbic structures, and neocortex. The
(GnRH), corticotropin-releasing factor (CRF), thyrotropin- hippocampal formation sends fibers directly to the hypothal-
releasing hormone (TRH), vasopressin (antidiuretic hor- amus, primarily via the fornix to the mammillary bodies
mone [ADH]), oxytocin, neurotensin, cholecystokinin, (Figs. 14.2 and 14.5). Other hypothalamic afferents from
vasoactive intestinal peptide (VIP), substance P, glycine, cortical or subcortical structures include those from the cin-
glutamate, aspartate, gamma-aminobutyric acid (GABA), gulate gyrus, the piriform cortex, and the amygdala (10,12).
histamine, serotonin, adrenalin, noradrenaline, dopamine, Afferent projections to the hypothalamus from the spinal
and acetylcholine (27). cord and brain stem also exist (29–31). Efferent nerve path-
Figure 14.3. Diagram of the ventricular surface of the human hypothalamus, showing the position and extent of the major
hypothalamic nuclei. (From Brodal A. Neurological Anatomy. New York, Oxford University Press, 1981.)
Figure 14.4. Drawing of the hypophysis (pituitary gland)

showing the origin and distribution of the hypothalamo-hypo-
physeal tract. (Redrawn from Crosby EC, Humphrey T, Lauer
EW. Correlative Anatomy of the Nervous System. New York,
Macmillan, 1962.)
Figure 14.5. Diagram of the main afferent and efferent connections of the hypothalamus. The connections of the mammillary
body and the hypothalamohypophyseal projections are not included. AV, anterior ventral thalamic nucleus; BL, basolateral
amygdaloid nucleus; Ce, central amygdaloid nucleus; Co, cortical amygdaloid nucleus; H, hypothalamus; M, mammillary body;
MD, dorsomedial thalamic nucleus; RF, reticular formation; S, septum pellucidum; VM, ventromedial hypothalamic nucleus.
(From Brodal A. Neurological Anatomy. New York, Oxford University Press, 1981.)
Figure 14.6. The blood supply of the pituitary

gland. The major arteries that supply the gland
are the superior, middle, and inferior hypophy-
seal arteries, all of which are branches of the
internal carotid artery. The arteries that supply
the median eminence and the superior portion of
the pituitary stalk terminate in a host of capillary
tufts and loops. In humans, blood is collected
from this capillary plexus into several large
trunks that carry it downward, chiefly on the
anterosuperior surface of the pituitary stalk, to
become continuous with sinusoids in the pars
distalis. These trunks are called the hypophyseal
portal system. (From Crosby EC, Humphrey T,
Lauer WE. Correlative Anatomy of the Nervous
System. New York, Macmillan, 1962.)
ways from the hypothalamus project reciprocally to these decrease. The three blind patients reported no difficulty
same sites, providing feedback control over brain stem, sleeping, and they maintained apparent circadian condition-
spinal cord, and peripheral autonomic nervous function ing to the 24-hour day. Plasma melatonin concentrations did
(32–34). In addition, the hypothalamus influences the not decrease during exposure to bright light in seven of the
body’s endocrine system via important connections with the remaining blind patients; in the eighth, plasma melatonin
anterior and posterior lobes of the pituitary gland. Fibers was undetectable. These eight patients reported a history of
that pass from the supraoptic and paraventricular nuclei of insomnia, and in four of them, the circadian tempera-
the hypothalamus to the hypophysis make up the supraop- ture rhythm was not conditioned to the 24-hour day. On the
ticohypophyseal tract (35–38). Besides abundant nerve con- basis of these findings, Czeisler et al. concluded that the
nections from the hypothalamus to the posterior lobe of the visual subsystem that mediates the light-induced suppres-
hypophysis, there is a vascular link between the hypophyseal sion of melatonin secretion remains functionally intact in
stalk and the anterior lobe—the hypophyseal portal sys- some sightless patients, probably via a retinohypothalamic
tem—that brings the anterior lobe under control of the hypo- pathway.
thalamus (Fig. 14.6). Some hypothalamic neurons sense var- The fascinating story of the retinohypothalamic pathway
ious chemical constituents and the temperature of the blood was unraveled even further with the discovery of melanop-
directly, whereas other neurosecretory neurons produce and sin-containing ganglion cells in the retina that are photosen-
release hormones that act on the anterior pituitary and on sitive, independent of rod and cone input (48–52,52a). These
various organ systems. Thus, neural and endocrine links to ganglion cells mediate the pupillary light reflex to the mid-
and from the hypothalamus combine to exert control over brain and also form projections to the suprachiasmatic nu-
almost all autonomic functions. cleus in the hypothalamus. The discovery of this unique class
From a neuro-ophthalmologic standpoint, the sensory of retinal neuron that is capable of modulating the circadian
input from the visual system to the hypothalamus has clini- cycle may also explain why some patients blind from photo-
cal significance. Autoradiographic studies demonstrate def- receptor disease may still be capable of melatonin modula-
inite retinohypothalamic projections in various mammals tion by light, whereas other patients blind from optic nerve
(39–42), including humans (43). These projections, which disease may lose this function. This topic is covered in
are both crossed and uncrossed from the retina of each eye, greater detail later in this chapter in the section devoted to
were found to terminate in the midline hypothalamic supra- the anatomy of the pupil light reflex pathway.
chiasmatic nucleus, and degenerate following retinal lesions
(40,41). Function
The function of retinohypothalamic afferents is concerned
with photoneuroendocrine reflexes and photoperiodic func- The hypothalamus is the coordinating center for the auto-
tions, termed circadian cycles. The suprachiasmatic nucleus nomic system complex. It mediates a vast number of auto-
is the major center controlling circadian rhythms (44), and nomic mechanisms that adapt the body to its environment
sensory input concerning the daily light cycle is essential and control its reproductive activity, emotional behavior, and
for this function. There is strong evidence supporting a rela- endocrine secretion (53). The complexity of hypothalamic
tionship between exposure to light and gonadal function in function reflects the intricacy of its anatomy. The posterior
certain birds and mammals. Likewise, there are widely part of the hypothalamus seems essential for functions asso-
quoted anecdotes that connect the increase in springtime ciated with increases in sympathetic activity. Stimulation of
light in the Arctic with heightened sexual activity in the the posterior hypothalamus induces vasoconstriction, heat
native Inuit people (ovulation is supposedly infrequent dur- production, increased metabolism, and pupillary dilation.
ing the long winter nights). Zacharias and Wurtman (45) The anterior part of the hypothalamus appears to be devoted
studied normal subjects who had been functionally blind to activity mediated by the parasympathetic system. Brooks
since infancy and found that the onset of puberty was earlier and Koizumi (54) reviewed the role of the hypothalamus in
in both boys and girls. In children who had no perception the control of the endocrine system through the pituitary
of light in either eye, the onset of puberty was even earlier. gland, reproduction, thirst and the control of water balance,
The authors suggested that this neuroendocrinologic phe- control of body weight (hunger and satiation), temperature
nomenon in blind children could be caused by altered retino- regulation, reactions to stress, control of emotional reactions,
hypothalamic stimulation. sleep and arousal, and control of somatic reactions.
The existence of a functional retinohypothalamic pathway Vasopressin and oxytocin, once thought to be produced
in humans also comes from the work of Czeisler et al. (46), and released by the posterior pituitary gland, are now known
who evaluated the input of light to the circadian pacemaker to be formed in the neurosecretory cells of the supraoptic
by testing the ability of bright light to decrease plasma mela- and paraventricular hypothalamic nuclei (38,55,56). They
tonin concentrations in 11 blind patients with no conscious reach the pituitary by axon transport along the fibers of the
perception of light and in six normal subjects. These investi- supraopticohypophyseal tract and then pass through the fe-
gators found that plasma melatonin concentrations decreased nestrated capillaries within the pituitary into the bloodstream
during exposure to bright light in three sightless patients by (57). Neurons in the supraoptic and paraventricular nuclei
about 70% and in all six normal subjects by about 66%. also contain other biologically active substances, including
When two of these blind patients were tested with their eyes metenkephalin, cholecystokinin, glucagon, dynorphin, an-
covered during exposure to light, plasma melatonin did not giotensin, and CRF (58).
The hypothalamic influence on the anterior lobe of the animals indirectly through their action on the hypothalamus.
pituitary gland involves nerve fibers from the tuberal region The tuberal region of the hypothalamus maintains basal lev-
of the pituitary gland and the hypophyseal portal vascular els of the gonadotrophic hormones, but the preoptic area is
system. The nerve fibers can be traced only to the median essential for the cyclic changes that induce ovulation (66,67).
eminence and infundibular stem of the pituitary and are Radioactive-labeled estrogens accumulate in highest con-
known collectively as the tuberohypophyseal or the tuber- centrations in the anterior hypothalamus, but they also accu-
oinfundibular tract (Fig. 14.4) (38,59,60). Although the fi- mulate in the amygdaloid complex.
bers are thin, secretory granules are found in their axons. A number of studies indicate that the supraoptic and para-
Various releasing substances (GHRF, CRF, TRH, GnRH, ventricular nuclei are specifically responsible for the mainte-
PRF) and inhibiting substances (GHRIH, PIF) are manufac- nance of water balance by controlling the rate of vasopressin
tured in regions of the hypothalamus (Fig. 14.7). These sub- secretion. Destruction of these areas results in diabetes insip-
stances are transported by the fibers of the tuberoinfundibu- idus—an excessive loss of water via the kidneys (68). Al-
lar tract to the median eminence and infundibulum, where though the hypothalamus is obviously important in regulat-
they are released into the portal vascular system that provides ing water intake, it is only part of a much more extensive
essentially all of the blood supply to the anterior lobe of the system concerned with consumption of both food and water
pituitary gland (60–64). Thus, the hypothalamus is inti- (69).
mately involved in the synthesis and transmission of factors Certain regions of the hypothalamus appear to control as-
that either stimulate or inhibit the secretion of hormones by pects of food intake. Medially placed hypothalamic lesions
the anterior pituitary (65). may result in hyperphagia and obesity (70–72), indicating
Sexual behavior and reproduction are directed by the hy- a medial satiety center, whereas lateral lesions often produce
pothalamus and hypophysis and are different in males and aphagia and consequent emaciation, indicating a lateral feed-
females. Estrogens and androgens influence the behavior of ing center (72–76). Detailed neural models have been pro-
posed to explain more fully homeostatic feeding behavior
and may be more accurate (77,78).
The hypothalamus plays a major role in the regulation of
body temperature. The anterolateral part of the hypothala-
mus appears to control the mechanism of heat loss, whereas
the posterolateral part contains an area that regulates heat
production. For example, some cells in the hypothalamus
are sensitive to heating or cooling of the blood. These cells,
which are found only in the anterolateral hypothalamus, ap-
pear to act as thermoreceptors, and it is this region of the
hypothalamus that appears to act as the principal ‘‘thermo-
stat’’ of the body, activating the posterior area when in-
creased heat production is required. Catecholamines (adren-
aline, noradrenaline, and dopamine) lower body temperature
when injected into the anterior hypothalamic area, and sero-
tonin increases body temperature. Thus, it is hypothesized
that when a rise in body temperature is required, specific
cells in the anterior hypothalamus release serotonin, which
then triggers the specific pathways that induce heat produc-
tion. When body cooling is needed, another group of cells
in the same region release a catecholamine that activates the
appropriate pathways promoting heat loss (79,80).
The response to stress occurs in two phases, short and
prolonged, and the hypothalamus is involved in both. Ini-
tially, acute stressful stimuli of short duration evoke a strong
sympathoadrenal discharge. Stored catecholamines are re-
leased and produce characteristic cardiovascular and meta-
bolic reactions that may restore, or at least maintain, an ac-
ceptable degree of normality. Severe or prolonged stress is
Figure 14.7. Diagram of sagittal section through the hypothalamus show- counteracted by additional reactions, including the release
ing the areas that have been implicated in the elaboration of some major
of corticosteroids from the adrenal cortex. These severe, per-
releasing and inhibiting factors. AC, anterior commissure; AH, anterior
hypothalamic area; ARC, arcuate nucleus; DM, dorsomedial nucleus; FX,
sistent stress stimuli act on the hypothalamus either directly
fornix; M, mammillary body; MTT, mammillothalamic tract; OC, optic or via afferent neurons to promote secretion of CRF and the
chiasm; PM, premammillary nucleus; PO, preoptic area; PV, paraventricu- subsequent release of ACTH. Lesions of the hypothalamus
lar nucleus; SC, suprachiasmatic nucleus; SEP, septal nuclear complex; interfering with the secretion of CRF result in an impaired
THAL, thalamus; VM, ventromedial nucleus. (From Brodal A. Neurologi- resistance to infection and injury (81).
cal Anatomy. New York, Oxford University Press, 1981.) Von Economo (82) found that lesions to the posterior hy-
pothalamus and rostral mesencephalon were usually asso- of the pons and are connected to the respiratory areas by
ciated with hypersomnia, whereas lesions in the anterior descending fibers (89). Many cardiovascular reflexes depend
hypothalamus often resulted in insomnia. Subsequent inves- upon an intact medulla (90). The clustering of these essential
tigators (83,84) confirmed the important role of the anterior functions in such a small area within the medulla explains
hypothalamus and neighboring regions in the induction of the occasional catastrophic loss of neurologic function from
sleep. Several studies also show that histamine-containing small lesions. The ‘‘centers’’ that control and coordinate
neurons in the posterior hypothalamus, including the tubero- life-dependent functions are actually neural networks that
mammillary nucleus, are involved with the mechanism of are scattered over a region of brain stem and are not strictly
arousal (85–87). These hypothalamic areas clearly play a localized to any single anatomic nuclear group.
role in the modulation of sleep but are highly influenced by
afferents from the forebrain and brain stem and, therefore, do PERIPHERAL AUTONOMIC NERVOUS SYSTEM
not function as the only ‘‘control center’’ for wakefulness.
The hypothalamus functions in modulating cardiovascular The peripheral component of the autonomic nervous sys-
and digestive activities. For example, hypothalamic influ- tem provides innervation to viscera, glands, blood vessels,
ences on the cardiovascular system can be demonstrated by and smooth (nonstriated) muscle, forming the visceral por-
stimulation of the posterior lateral hypothalamus, causing tion of the nervous system. Peripheral autonomic nerves also
an increase in blood pressure and heart rate, whereas stimula- gather impulses from peripheral receptors whose input is
tion of the anterior hypothalamic regions causes vasodilation used to modulate signals in the brain stem and spinal cord
and lowering of blood pressure (88). Hypothalamic influ- prior to the initiation of effector responses. The receptors and
ences on digestion can be demonstrated by stimulation of afferent fibers that transmit impulses to autonomic neurons
the anterior hypothalamus, producing an increase in secre- within the spinal cord and brain stem are elements of the
tion and peristalsis in the stomach and intestines. If the poste- visceral sensory system. The efferent autonomic nerves be-
rior part of the hypothalamus is stimulated, these activities long to the visceral motor system.
are depressed, coinciding with a general increase in sympa-
thetic-induced behavior.
The hypothalamus plays a role not only in the control of Anatomy of the Peripheral Autonomic Nervous System
visceral and endocrine function but also in the regulation of There are two major subdivisions of the efferent auto-
somatic activity. An intact hypothalamus helps to integrate
nomic system, sympathetic and parasympathetic (91). Al-
reflex motor activity. In the absence of the hypothalamus,
though both sympathetic and parasympathetic efferent
walking, running, and righting reflexes are imperfectly dis-
nerves have cell bodies within the neural axis, there is always
played and coordinated (54).
a synapse between the cell of origin and the cell of termina-
Of neuro-ophthalmologic interest is the influence of the
tion, and the ganglia where these synapses occur are always
hypothalamus on the intrinsic muscles of the eye, the posi-
located outside the CNS. Both the sympathetic and parasym-
tion of the lids mediated by sympathetically innervated
smooth muscle, the secretion of tears, the vasomotor system, pathetic efferent systems therefore contain two types of fi-
and intraocular pressure. These are discussed later in this bers: the preganglionic fiber, with its cell of origin in the
chapter. CNS, either in the visceral efferent nuclei of cranial nerves
(i.e., parasympathetic) or in the lateral gray columns of the
spinal cord (i.e., sympathetic), and the postganglionic fiber,
Brain Stem with its cell of origin in one of the ganglia outside of the
Preganglionic autonomic nerves, which originate in the CNS. In general, preganglionic fibers are finely myelinated,
visceral efferent columns of the brain stem, exit along var- whereas postganglionic fibers are unmyelinated.
ious cranial nerves to connect with visceral, glandular, and There are several morphologic and anatomic differences
vascular structures, as well as smooth muscles. The cell bod- between the sympathetic and parasympathetic systems. The
ies of the brain stem preganglionic autonomic nerves form preganglionic efferent neurons of the sympathetic system
subnuclei of the oculomotor (3rd), facial (7th), glossopha- receive input from the hypothalamus and have their cell bod-
ryngeal (9th), vagus (10th), and spinal accessory (11th) ies in the lower cervical, thoracic, and first two lumbar seg-
cranial nerves and are concerned with pupillary, lacrimal, ments of the spinal cord, whereas the preganglionic fibers
salivary, cardiovascular, respiratory, alimentary, and other of the parasympathetic system have cell bodies located in
visceral activities. specific regions of the brain stem and in the second, third,
Apart from the autonomic neurons that make up the vis- and fourth sacral segments of the spinal cord.
ceral efferent nuclei, there is also an autonomic representa- Another morphologic difference between the sympathetic
tion of cell bodies in the gray matter of the reticular forma- and parasympathetic systems involves the location of the
tion of the medulla, which modulate critical respiratory and postganglionic cell bodies. In the sympathetic system, post-
cardiovascular functions. An inspiratory area lies in the ven- ganglionic cell bodies are found in the ganglia of the sympa-
tral part of the medullary reticular formation adjacent to the thetic trunk and, therefore, are almost always adjacent to the
inferior olive, whereas an expiratory area is located dorsal spinal cord. In contrast to the sympathetic system, cell bodies
and slightly cephalic. Pneumotaxic centers are located near of postganglionic parasympathetic neurons are positioned
the midline in the ventral and rostral part of the tegmentum farther from the CNS, either within or on the walls of the
organ they supply or in ganglia close to the structure inner- Of specific interest to neuro-ophthalmologists, the para-
vated. sympathetic preganglionic lacrimal secretomotor efferents
There are three types of sympathetic ganglia, named ac- arise from the superior salivatory nucleus and travel with
cording to their location. The three types are: (a) paraverte- the facial nerve along the nervus intermedius and then via
bral—pairs of ganglia arranged in two chains close to each the greater superficial petrosal nerve through the pterygoid
side of the vertebral column (e.g., superior, middle, and infe- canal to synapse in the pterygopalatine (sphenopalatine) gan-
rior cervical ganglia; 10 or 11 thoracic ganglia; 4 lumbar glion. The postganglionic course is somewhat variable, with
ganglia; and 2 to 6 sacral ganglia); (b) prevertebral—the some evidence suggesting that the postganglionic fibers
celiac, mesenteric, and hypogastric ganglia lying in the ab- travel via the zygomatic nerve to the lacrimal gland (Fig.
dominal cavity; and (c) terminal—several ganglia lying on 14.8) and via ganglionic branches to the nasal and palatal
or near the bladder and rectum. glands. The vagus nerve distributes large numbers of pregan-
The superior cervical ganglion, a structure of major inter- glionic fibers to the lungs, bronchi, heart, stomach, and small
est to neuro-ophthalmologists because of its role in the anat- intestine, and to part of the large intestine. As noted previ-
omy of the oculosympathetic fibers to the pupil and to the ously, its ganglia are located close to, or embedded in, the
upper and lower eyelids, is the largest of the cervical chain. visceral structures innervated, and the postganglionic fibers
It is located adjacent to the second and third cervical verte- are very short.
brae, just behind the internal carotid artery. It gives off lat- Finally, the relationship between the number of pregangli-
eral, medial, and anterior branches and is the origin of the onic to postganglionic autonomic nerve fibers seems to differ
internal carotid nerve. The anterior branches of the superior among the sympathetic and parasympathetic divisions. In
cervical ganglion generate a plexus along the common and the sympathetic division, each sympathetic preganglionic
external carotid arteries. Within the neck, the external carotid neuron synapses with a large number of postganglionic neu-
plexus supplies various exocrine glands of the face and neck, rons, and the postganglionic fibers ramify widely. In one
including the sweat glands of the face; however, sweat study of the human superior cervical ganglion, Ebbesson
glands within a small area of skin just above the brow usually (93) found a pre- to postganglionic fiber ratio of 1 to 196.
are supplied by branches from the internal carotid nerve. In contrast, in the parasympathetic division, each parasym-
Therefore, a specific pattern of sudomotor loss on the face pathetic preganglionic neuron typically synapses with one
may sometimes help to localize a lesion. The internal carotid postganglionic neuron, and the distribution of its terminal
nerve ascends behind the internal carotid artery and enters arbors is much more limited. The anatomic arrangement of
the carotid canal, where it forms a plexus surrounding the these two systems suggests that, physiologically, the sympa-
intracranial portion of the carotid artery, and finally along thetic system is involved predominantly with diffuse reac-
the ophthalmic artery to enter the orbit. tions affecting the entire organism, whereas the parasympa-
In the parasympathetic system, the preganglionic fibers thetic system produces more restricted, localized effects.
originate within the CNS at the level of the midbrain However, the sympathetic system is also capable of produc-
(Edinger-Westphal nucleus), the medulla, and the second, ing localized discrete effects to different organs in response
third, and fourth sacral segments of the spinal cord. In the to specific stimuli. For example, postganglionic sympathetic
midbrain, parasympathetic preganglionic cell bodies give neurons may be activated independently or in concert de-
rise to axons that travel peripherally with axons of the oculo- pending on the stimulus and include the following: vasocon-
motor nerves and pass with the inferior division of the oculo- strictor fibers to blood vessels supplying organs, vasodila-
motor nerve to synapse with the ciliary ganglion. Postgangli- tory fibers to skeletal muscle, secretomotor fibers to sweat
onic parasympathetic fibers exit the ciliary ganglion as short glands, motor fibers to the erector pili muscles of skin, fibers
ciliary nerves to innervate the muscles of the ciliary body to the pulmonary airways causing dilation of the bronchi
and the sphincter pupillae muscle of the iris (27). In the and bronchioles, and fibers producing pupillary dilation.
medulla, myelinated preganglionic fibers travel with the fa- They can also alter glandular secretion and inhibit muscle
cial, glossopharyngeal, vagus, and spinal accessory cranial contraction in the alimentary tract.
nerves to synapse in the parasympathetic ganglia of the head:
the pterygopalatine, submandibular, and otic ganglia. Neu- Physiology of the Peripheral Autonomic
rons and synapses situated in these ganglia are exclusively Nervous System
efferent and parasympathetic, although afferent fibers and
postganglionic sympathetic fibers do pass through the gan- Many organs innervated by the autonomic nervous system
glia without interruption. Postganglionic parasympathetic receive fibers from both the sympathetic and parasympa-
efferents from these ganglia transmit the bulbar outflow to thetic divisions. Among these organs are the pupil, ciliary
the lacrimal glands, salivary glands, and mucous membranes body, heart, bronchi, stomach, intestines, salivary glands,
of the nose, mouth, and pharynx. In the sacrum, the pregan- sex organs, and bladder. Other organs receive innervation
glionic parasympathetic cell bodies lie in the second, third, from only one division of the autonomic system, such as the
and fourth sacral segments of the spinal cord. From this sweat glands, the piloerector muscles in the skin, the smooth
region, the preganglionic fibers exit the spinal cord with the muscles of the eyelid (Müller’s muscle), the spleen, the arte-
sacral nerves and pass to ganglia located in or near the distal rioles, and probably the uterus.
portion of the large intestine, the rectum, the bladder, and When an organ receives both sympathetic and parasympa-
the organs of reproduction (10,12,92). thetic innervation, the effects produced by the two subsys-
Figure 14.8. Diagram showing the postganglionic parasympathetic pathway for lacrimal secretion. The cell bodies of the
postganglionic fibers originate in the sphenopalatine (pterygopalatine) ganglion, where they synapse with axons from the greater
superficial petrosal nerve. The postganglionic fibers then leave the ganglion, join the maxillary nerve, and enter the zygomatic
branch of the nerve. The fibers next enter the lacrimal nerve, a branch of the ophthalmic nerve, via anastomotic channels
between the zygomatic and lacrimal nerves. The fibers ultimately enter the lacrimal gland within the lacrimal nerve. (Redrawn
from Ruskell GL. The distribution of autonomic post-ganglionic nerve fibres to the lacrimal gland in monkeys. J Anat 1971;
109⬊229–242.)
tems are usually antagonistic. Heart rate, for example, is tion called the ‘‘excitatory postsynaptic potential.’’ This po-
accelerated by stimulation of the sympathetic division and tential in turn initiates an action potential in the postgangli-
slowed by stimulation of the parasympathetic division. The onic neuron. Once its action is completed, acetylcholine is
tone of the small intestine increases with parasympathetic promptly hydrolyzed by acetylcholinesterase.
stimulation (along the vagus nerve) and decreases with sym- Acetylcholine is also the transmitter substance released by
pathetic stimulation (4). The iris sphincter muscle contracts, parasympathetic postganglionic fibers at the neuroeffector
causing pupil constriction with parasympathetic stimulation, junction (94), whereas with few exceptions sympathetic
whereas the iris dilator muscle dilates the pupil with sympa- postganglionic neurons typically release the catecholamine
thetic stimulation. Similarly, the ciliary muscle contracts norepinephrine at the neuroeffector junction. Norepineph-
with parasympathetic stimulation, causing active accom- rine, bound loosely to adenosine triphosphate (ATP), is
modation at near, whereas sympathetic stimulation inhib- stored in the cytoplasmic granules of the nerve ending and
its accommodation. On the other hand, actions of the two is released from these concentrated stores when the nerve is
divisions are not always antagonistic; they may actually stimulated. The action of norepinephrine on the effector cell
summate. Salivary glands secrete profusely in response to is quickly terminated by reuptake of all available free norepi-
stimulation of the parasympathetic division, but sympathetic nephrine into the cytoplasm of the presynaptic nerve ending.
stimulation also produces secretion from these glands. Thus, Norepinephrine is also broken down and inactivated by two
both systems participate in the intricate regulation of visceral relatively slow-acting enzymes: catechol-O-methyltransfer-
functions, ensuring a proper balance in the action of various ase (COMT) and monoamine oxidase (MAO). The norepi-
organs. nephrine that is recovered by the nerve ending is retained,
concentrated, and stored in the granules, or it is metabolized
Pharmacology of the Autonomic Nervous System by intraneuronal monoamine oxidases.
The terms ‘‘adrenergic’’ and ‘‘cholinergic’’ were first
Chemical Transmission of Autonomic Impulses
used by Dale (95) to describe substances with sympathomi-
Both sympathetic and parasympathetic preganglionic fi- metic and parasympathomimetic properties, respectively.
bers release acetylcholine (94). For both of these subsystems, For many years, the idea of sympathetic adrenergic and para-
the neural action potential originating in an autonomic neu- sympathetic cholinergic systems, operating antagonistically
ron in the CNS is conducted along a myelinated nerve fiber to control visceral function, has been accepted; however,
to the presynaptic terminal, where it causes the release of there are many exceptions to this general concept. For
acetylcholine from stores within the nerve ending. The ace- example, the postganglionic fibers to the sweat glands are
tylcholine crosses the narrow synaptic gap and combines anatomically part of the sympathetic system, but they are
with receptors located on the cell body of the postsynaptic cholinergic. Also, as noted above, acetylcholine is the neuro-
(postganglionic) neuron, producing a localized depolariza- transmitter for both sympathetic and parasympathetic pre-
ganglionic fibers. In addition, some autonomic nerves are pathetic nerves, supersensitivity can be demonstrated within
nonadrenergic and noncholinergic (NANC nerves). Such a few days and is fully developed within 1–2 weeks. In both
nerves, called ‘‘purinergic’’ by Burnstock (96), use ATP as the parasympathetic and sympathetic systems, the supersen-
their neurotransmitter. Nitric oxide (NO) and related sub- sitivity slowly declines if the efferent axons regenerate.
stances also appear to mediate transmission from some auto-
nomic nerves to smooth muscle (97,98), and many other Regeneration of Autonomic Fibers
substances that modulate neural activity in adjacent cells,
It once was thought that if a nerve was interrupted by
including various peptides, are present in autonomic nerves
injury or disease, no recovery could take place until new
(96).
fibers grew out from the central stump. Murray and Thomp-
Most autonomic nerves release more than one transmitter
son (101) showed, however, that when a nerve fiber is dam-
substance, a phenomenon called cotransmission. The princi-
aged and degenerates, adjacent normal fibers are stimulated
pal cotransmitters in most sympathetic nerves are noradrena-
to give off tiny side branches or sprouts. The stimulus for
line, ATP, and neuropeptide Y (NPY). In parasympathetic
this growth is unknown but may be some humoral agent
nerves, the principal transmitters are acetylcholine and VIP,
released from the degenerating fiber. In any event, the sur-
although a minority of nerves use ATP, NO, or both. Another
face of adjacent normal fibers becomes locally disorganized,
concept is that of neuromodulation, a term that refers to the
and tiny axonal strands develop on their surface and grow
effects that certain locally released agents have on neuro-
toward the degenerating fibers. These strands penetrate the
transmission. These effects are produced either by varying
fiber sheath and grow into the neural tubes of adjacent degen-
the amount of transmitter released from the presynaptic ter-
erated fibers, where they make contact with the adventitial
minal or by acting on the postsynaptic neuron so that its
or Schwann cells that presumably guide them toward the
response to the neurotransmitter is altered. A variety of inter-
effector organ. Normal undamaged fibers thus actively con-
actions between cotransmitters and neuromodulators that in-
tribute to the recovery of function (102).
fluence neurotransmission have been described. In contrast
The process of sprouting is very rapid. The new branches
to striated muscle, not all smooth muscle cells are activated
are visible by light microscopy within 4 or 5 days after the
directly by neurotransmitter released from terminal branches
nerve axons are sectioned (101) and within 24 hours of the
of the autonomic fibers. Instead, entire smooth muscle bun-
injury using electron microscopy (103). The sprouts continue
dles can be stimulated via low-resistance pathways between
to enlarge for at least 1–2 months (101).
the individual smooth muscle cells. The electric coupling
Collateral nerve sprouting is particularly vigorous in the
between adjacent cells takes place at gap junctions that trans-
autonomic nervous system. Fibers from nearby nerves con-
mit and spread nerve impulses within the muscle bundle
taining the same neurotransmitter, but often entirely unre-
(99,100).
lated in function, may send sprouts into the damaged nerve,
Denervation Supersensitivity and the impulses that these new collaterals carry may cause
inappropriate activation of the end organ. Throughout this
Destruction and degeneration of preganglionic or postgan- book, many clinical phenomena are described that are best
glionic autonomic axons is followed by greatly increased explained by just this sort of uncontrolled sprouting of collat-
sensitivity of the deafferented autonomic effectors to their erals among the regenerating fibers. These include the
specific transmitter substances and to pharmaceutical com- pseudo-Argyll Robertson phenomenon with misdirection of
pounds that mimic those transmitters. This supersensitivity regenerating oculomotor fibers, the light-near dissociation
of the denervated effector cell usually appears within 1 or of the tonic pupil, gustatory sweating, crocodile tears, and
2 days after a parasympathetic nerve is sectioned. For sym- postherpetic pain.
THE PUPIL LIGHT AND NEAR REFLEXES AND THEIR RELATIONSHIP TO THE
AUTONOMIC NERVOUS SYSTEM
The major function of the pupil is to aid in optimizing In addition to its role in regulating the amount of light
retinal illumination to maximize visual perception. In dim energy entering the eye, the iris can improve image quality
light, dilation of the pupil provides an immediate means for on the retina by constricting, thus increasing the depth of
maximizing the number of photons reaching the retina, focus of the eye’s optical system (105) and reducing the
which supplements the dark-adaptive mechanisms of retinal- degree of chromatic and spherical aberration (106,107).
gain control. Under bright light, pupil constriction can re- There is a limit to this beneficial effect, however, because
duce retinal illumination by up to 1.5 log units. Although
constriction beyond a certain diameter results in image deg-
this reduction in retinal illumination is only a portion of the
12-log unit range of light sensitivity of the retina (104), it radation secondary to increased diffraction (108). Because
provides an important and immediate contribution to early of the forward convexity of the anterior lens surface, the
light adaptation. Patients with a fixed immobile pupil are pupillary plane of the iris is farther forward in the eye than
usually very symptomatic under conditions of changing illu- the iris root, and the iris plane thus forms the sides of a
mination, emphasizing the important role of the pupil in truncated cone. The magnification produced by the cornea
optimizing visual perception over a wide range of lighting causes the iris to appear one-eighth larger (and the pupil
conditions of the environment. wider) than it actually is. Nevertheless, differences in corneal
refractive power among eyes contribute only a minor degree threshold are compared with pupillary threshold to light
to the difference between actual and apparent pupil size stimuli (112).
(109). Under conditions of dark adaptation, low-intensity light
In this section, the anatomy and physiology of the normal stimuli that are below the level of cone threshold produce
pupil will be presented, including the afferent, efferent, and small-amplitude pupil reactions that are only contributed to
supranuclear pathways involved in the regulation of pupil by rods. The recorded pupillary waveform movements
size. The reader interested in pursuing these subjects in more caused by rod input under stimulus conditions of dark adap-
detail is advised to consult the excellent book by Loewenfeld tation are indistinguishable in shape from those produced by
(109). dim stimuli under conditions of photopic light adaptation,
where cone input is the primary source of signal to the pupil-
THE AFFERENT ARC OF THE PUPIL LIGHT lary motor center. Under dark adaptation, the threshold pu-
REFLEX pillary response also favors a blue wavelength, as would be
expected for a rod-dominated response. In fact, under these
The neuronal integration of the pupillary light reflex be- conditions, there is a worsening of pupil threshold sensitivity
gins in the retina with the photoreceptors that pass informa- at the fovea, causing a scotoma at the center of the visual
tion to the retinal ganglion cells by way of synapses with field where rods are lacking. This is observed when the
bipolar cells (110,111). For many years, it was assumed that threshold for pupil contraction is observed using low-inten-
only the photoreceptors contributed to the pupillary light sity lights below the level of cone threshold. As the intensity
reflex (109). It is now clear that other retinal elements—par- of light stimulus is increased above the cone threshold, pupil
ticularly certain ganglion cells—also play a role. contractions can be recorded at the fovea, as the cone contri-
bution comes into play. Under these stimulus conditions,
Rod and Cone Contribution to the Pupillary both rods and cones contribute to the pupil response, a condi-
Light Reflex tion called ‘‘rod intrusion’’ (109). If a background light is
used to adapt the eye to a photopic, relatively light-adapted
The extent and nature of the contribution of rod and cone state, the rod contribution is suppressed, and cones then pro-
input to the pupillary light reflex was confusing for many vide the primary contribution to the pupillary light reflex.
years, because the responses measured were highly depen- Another important difference between the cone and rod
dent upon the conditions of retinal adaptation, characteristics contribution to the pupillary light reflex relates to the concept
of the light stimulus (e.g., intensity, wavelength, and size), of pupillary threshold sensitivity versus pupillary amplitude
location of the portion of the retina that was stimulated, and of response. As stated above, under conditions of dark adap-
sensitivity of the recording apparatus used to detect threshold tation, the rods are far more sensitive than cones. The amount
pupil movements. Once sensitive infrared recording devices of light it takes to elicit a small, threshold pupillary response
for precise measurement of small pupil movements and care- is over 2 log units less than what it would take to elicit a
fully controlled stimulus conditions were used, it became threshold pupil response from cone activation. Above the
clear that both rods and cones contribute to the pupillary level of threshold, however, the amplitude of pupil contrac-
light reflex. tion has a much greater valence from cone contribution com-
The relative contribution of the rods and cones depends pared with that of the rods. Therefore, although the rods are
on the conditions under which the pupil responses are mea- more sensitive in terms of the amount of light it takes to
sured. The same rods and cones that process light input for elicit a threshold pupil response in the dark-adapted state, the
visual perception modify the pupillary response; there are amount of pupil contraction produced at light levels above
no separate photoreceptors for vision and for the pupil. Thus, threshold for each photoreceptor type is greater for cones.
almost all modifications of stimulus conditions that produce With focal light stimuli given at suprathreshold intensity
a difference in visual perception also produce a comparable levels, the amplitude of the pupillary light reflex has a large
change in pupillary responsiveness. These modifications in- cone contribution for reasons stated above and is greater in
clude changes in retinal adaptation, wavelength of light, amplitude at the center of the visual field and falls off in the
stimulus duration, and stimulus light intensity. In fact, in peripheral field as shown by pupil perimetry. The density
almost every way in which responses are measured, the pu- distribution of rods and cones (and bipolar cells) accounts
pillary responses to light parallel those of visual perception. for only one aspect of the pupillomotor response across the
For example, the wavelength sensitivity profile of pupil visual field.
threshold as the color of light is changed from blue to red
exactly parallels the same wavelength sensitivity of visual Retinal Ganglion Cell Contributions to the Pupillary
perception. The shift in sensitivity is also the same as the Light Reflex
eye is changed from a condition of light adaptation to dark
adaptation (Purkinje shift), providing further evidence that Contributions from Ganglion Cells in General
the same photoreceptors are used for both pupillary re-
sponses and vision. In fact, patients with various abnormali- Rods and cones relay the light signal to the retinal gan-
ties of either rods or cones can be shown to have the same glion cells via synapses with bipolar cells (110,111). The
deficits in color vision or lack of appropriate sensitivity ganglion cell distribution within the retina and receptive field
change during dark adaptation when the results of visual properties thus provide the primary basis for the degree of
pupillary response from light stimuli at different visual field ily to the LGN, but some of their axons have collateral
locations. branches that project to the tectum and pretectum.
The ganglion cells that serve the pupillomotor afferent The major contribution to the pretectal olivary neurons in
input are densest in the central retina. The ganglion cells in the midbrain serving the classic pupillary light reflex path-
the central area also have more of a one-to-one relationship way comes from the ␥ cells, which now appear to have
with photoreceptor and bipolar cells, in contrast to those in been identified as the melanopsin-containing ganglion cells.
the peripheral retina, where many more photoreceptors and These cells may also play a role in other visually evoked
bipolar cells map to one ganglion cell. Therefore, it is the reflexes (such as circadian rhythm), because they also
central density of ganglion cells, their approximate one-to- project to the superior colliculus and to the accessory optic
one mapping with photoreceptors and bipolar cells, and their system. The ␥ cells have small cell bodies and thin, slowly
receptive field properties that account for the greater ampli- conducting axons, with large-sized receptive fields. They
tude of pupillary response to stimuli in the central visual respond primarily to incremental changes in light intensity
field. and are relatively insensitive to movement. These cells
The retinal ganglion cells, the first neurons in the chain project almost exclusively to the midbrain and not to the
to give rise to action potentials (the photoreceptors and bipo- LGN. They are densest in the central retina (posterior pole
lar cells give rise to generator potentials), are made up of of the eye) and are less dense in the periphery. This accounts
different classes of neurons based on morphology, physiol- in large part for the central field weighting of pupillary re-
ogy, and projections. Although it appears that the pupillary sponse.
and visual systems share the same photoreceptor input (and The proportion of ␥ ganglion cells that serves the pupillary
presumably bipolar cell input), the situation is more compli- light reflex is not known; the answer awaits specific labeling
cated for ganglion cell input. It appears that melanopsin- studies in primates. Such studies are technically difficult to
containing ganglion cells primarily serve the classical perform, because the retrograde label must be microinjected
midbrain pupillary light reflex and circadian centers of the into the specific pretectal olivary area where light-respond-
hypothalamus (discussed later). Other ganglion cells, which ing neurons can be identified using electric recordings. Even
primarily serve visual perception via their synapses with the then, the label reaching the retinal ganglion cells is only
lateral geniculate nucleus (LGN) and the visual cortex, may weakly visible, and these neurons, once identified in flat
also modulate the pupil light reflex under certain conditions mount preparations, must be individually injected using a
of light stimulus. Over the years, many anatomic and physio- micropipette containing a more visible dye that fills each
logic studies have been performed in an attempt to classify cell body, dendrites, and axon (P.D.R. Gamlin, personal
retinal ganglion cells based on the size of their cell body, communication). At present, it is not known how many reti-
their dendritic field, their axon diameter, and their firing nal ganglion cells project directly to the pretectal midbrain
properties. This information has been collected in a number neurons serving the pupillary light reflex, but their number
of species, most notably the cat and monkey, and with label- must be relatively small (on the order of 1%) in proportion
ing techniques, the projections of the cell axons to the LGN to the total number of ganglion cells.
and midbrain have been studied. Loewenfeld (109) summa- In summary, it would appear that the ␥ cells are primarily
rized the properties of the major classes of ganglion cells in light-sensitive neurons with melanopsin that are activated
the retina and their projections. Based on these studies, it by either rod or cone input but that also can be activated
appears that in primates there are three main types of gan- directly by light. These cells subserve the midbrain pupillary
glion cells in the retina: ␣, ␤, and ␥ cells. light reflex. The ␣ cells are primarily movement-sensitive
Two classes of ganglion cells—the ␣ and ␤ cells—have and provide afferent information for control of eye move-
properties different from the ␥ cells. The ␣ cells constitute ments and foveation of peripherally moving targets. The ␤
1–2% of the cells in the central retina and 10% in the periph- cells are mainly sensitive to high-contrast detail and proba-
ery. They are densest in the parafoveal region and have the bly provide the visual cortex with spatial frequency and ori-
largest cell body size, which increases further in the periph- entation information used to interpret form. In view of evi-
eral retina. The axons of these cells are thick and have a dence for cortical mediation of the pupillary movement to
corresponding fast conduction speed. Their receptive fields perimetric stimuli and isoluminant complex stimuli (gratings
are large and have a phasic discharge. These cells respond and randomly modulated patterns of varying spatial fre-
to fast-moving stimuli, and they discharge in a transient fash- quency), it is possible that other ganglion cells besides the
ion. The ␣ cell axons project to the LGN, but almost 50% ␥ type play a role in mediating the pupil response to other,
have attenuated branches that also project to the midbrain nontraditional types of stimuli (113–121).
in areas such as the superior colliculus.
The ␤ cells are the most numerous of all the ganglion Contributions from Melanopsin-Containing
cell classes, representing 50–60% of the total ganglion cell Photoreceptive Ganglion Cells
population. Like the ␥ cells, they are densest in the central
retina. They have medium-sized cell bodies and axons, and In addition to the rods and cones, another retinal cell can
they possess small-sized receptive fields. These ganglion modulate pupil size. Genetically altered mice that com-
cells fire tonically and are most responsive to contrast of pletely lack functional rods and cones nevertheless show a
small areas, such as fine-grating stimuli. They discriminate rather robust pupil light reflex (46–52). These mice possess
detail within the central field. The ␤ cells also project primar- a specific ganglion cell that contains melanopsin, a protein
that is itself photosensitive, with a broad spectral peak cen- this neuron to the pupil light reflex that can occur without
tering on about 490 nm. Melanopsin-containing ganglion photoreceptor input can help explain why some patients with
cells project to the suprachiasmatic nucleus in the hypothala- extensive photoreceptor damage may still exhibit an intact
mus and also to the pretectal nucleus (the site of the first pupil light reflex. This could also explain why such patients
midbrain interneuron synapse for the pupil light reflex path- still maintain a circadian cycle. It may also explain other
way). Elegant electrophysiologic recordings coupled with clinical examples that support the concept that separate gan-
the study of response properties of these ganglion cells have glion cells exist for visual perception and the pupillary light
revealed that the cells provide the midbrain pathway for the reflex. These include cases of complete noncerebral monoc-
pupil light reflex and also provide light sensing information ular or binocular blindness in which the pupillary reaction
for the diurnal regulating areas of the hypothalamus that to light persists, cases of recovered optic neuritis in which
modulate the circadian rhythm (46–52,52a). Thus, although visual function has apparently returned to normal but the
as noted above the melanopsin-containing ganglion cells re- pupillary light reflex has not, and instances in which pupillo-
ceive rod and cone input to the pupil light reflex, they also motor activity returns to normal before visual function in
are capable of transduction of light directly, without photore- cases of amaurosis (122). Although the correlation between
ceptor input. This helps explain why some patients blind visual field loss and pupillary reactivity is sufficiently strong
from photoreceptor loss continue to exhibit a circadian to be clinically useful (123), the correlation is not strong
rhythm, whereas others blind from optic nerve lesions (and enough in optic nerve disease (124–126) to allow one to
thus loss of melanopsin-ganglion cell input) lack a circadian feel confident that the same ganglion cells serve both the
rhythm. visual and pupillomotor systems. Our own work comparing
With the discovery of a melanopsin-containing ganglion visual perimetry with pupil perimetry (Fig. 14.9) reveals
cell that is capable of direct activation by light in addition many examples where the two types of perimetry correlate
to photoreceptor input, a number of clinical observations beautifully (e.g., anterior ischemic optic neuropathy) and
may be unraveled in the near future. For example, input of other cases of optic nerve damage where large differences
Figure 14.9. Clinical examples of the correlation between visual light sense perimetry and pupil perimetry in patients with
optic nerve damage from anterior ischemic optic neuropathy (left) and acute optic neuritis (right). In the patient with anterior
ischemic optic neuropathy there is good correlation between the areas of visual field loss (top left) and those with loss of
pupillomotor sensitivity (bottom left). However, in the patient with acute optic neuritis there is much more damage to the
‘‘pupil field’’ (bottom right), showing poor correlation between the visual and pupillary systems.
exist between visual perimetry and pupil perimetry (e.g., optic (mapping to the same homonymous field) in the left optic
neuritis and glaucoma) (127,128). Clinical examples such as tract to distribute to the left pretectal olivary nucleus. In this
this indicate that there may be differences between the gan- way, ganglion cell axons serving homonymous portions of
glion cell integration of the pupillary response to light and the the visual field distribute to the same pretectal nucleus. In
visual perception of light, and that separate ganglion cells and other words, the axons serving right homonymous visual
fibers may exist for each system, with different susceptibili- field space distribute to the left pretectal olivary nucleus,
ties to optic nerve damage. It is also possible that some gan- and the axons serving left homonymous visual field space
glion cells subserve each function independently, whereas distribute to the right pretectal olivary nucleus. At each pre-
others are shared by the visual and pupillary systems. tectal olivary nucleus, a great deal of convergence occurs,
with many ganglion cell axons forming connections with a
THE INTER-NEURON OF THE PUPIL LIGHT relatively small number of dendritic processes of pretectal
REFLEX olivary neurons. Once the pupillary light signal is integrated
The axons of the ganglion cells travel intracranially within at the level of the pretectal olivary nucleus, the signal is
the optic nerve, optic chiasm, and optic tract. Just before distributed in humans approximately equally to the right and
these axons reach the LGN, some of them (or some of their left Edinger-Westphal nuclei, which in turn produce a right
branches) leave the optic tract (primarily the ␥ cell type) to and left pupil contraction of similar amplitude.
reach the pretectal olivary nucleus in the mesencephalon via The hemifield organization of the pupillary light reflex
the brachium of the superior colliculus (129). As mentioned and the resulting degree of decussation in the chiasm and in
above, a small contribution of bifurcating fibers from the ␣ the pretectum is specific to different species. In lower ani-
and ␤ ganglion cell axons also travel within the brachium. mals with little binocularity, such as the rabbit, almost all
As depicted in Figure 14.10, the ganglion cell axons from of the visual and pupillary input decussates in the chiasm
the nasal retina (temporal field) of the right eye cross at from one eye to the opposite side. The pretectal decussation
the chiasm and distribute to the contralateral (left) pretectal back to the opposite side is almost complete, thus producing
(olivary) nucleus. The ganglion cell axons from the temporal a direct pupil response only in the eye being stimulated.
retina (nasal field) of the left eye remain on the same side In the cat, there is some binocularity, and there are more
and join the axons from the nasal retina of the right eye uncrossed fibers in the chiasm and pretectum, producing
Figure 14.10. Diagram of the path of the pupillary light reflex.

an incomplete consensual pupil response. In primates with pupillomotor input (per unit area of retina stimulated) com-
significant binocularity, the uncrossed component of visual pared with the intact nasal field of the eye on the opposite
and pupillary input is even greater in both the chiasm and the side of the tract lesion. In addition, our own studies demon-
pretectum, producing an almost equal direct and consensual strate absence of pupillary responses when hemifield stimuli
pupil contraction when light is shined in only one eye (Fig. are placed in the blind homonymous hemifields in patients
14.11). with optic tract lesions. Thus, both experimental and clinical
Proof of a hemifield organization and hemidecussation of evidence supports the concept that the hemifield organiza-
pupillomotor fibers at the chiasm in humans comes from tion of visual and pupillomotor afferent fibers in humans is
sagittal sectioning of the chiasm, which does not abolish similar.
either the direct or consensual reaction to light of either eye Ganglion cell fibers destined for the pretectal region of
(130). Similarly, in nonhuman primates and in humans, de- the mesencephalon leave the optic tracts before reaching
struction of an optic tract has only a small, subclinical effect the LGN. This anatomic feature is demonstrated by intact
on the symmetry of the direct and consensual reaction of pupillary light responses in experimental animals following
either pupil to light but instead produces a relative afferent extirpation of the LGN. These pupillary fibers enter the mes-
pupillary defect in the eye opposite the side of the lesion encephalon via the brachium of the superior colliculus. Cut-
(131,132). This is because the intact temporal field of the ting the brachium to the superior colliculus on each side
eye on the same side of the tract lesion provides greater abolishes the light reflexes, whereas stimulation of the bra-
Figure 14.11. Chiasmal and pretectal decussations in rabbit, cat, and monkey as determined by light stimulation in the left
eye. The proportion between crossed and uncrossed fibers in the central pretectal decussation of the light reflex arc parallels
that between crossed and uncrossed chiasmal fibers. As a consequence, rabbits, with few uncrossed fibers in either decussation,
have no consensual light reflex (interrupted line); cats, with many more crossed than uncrossed fibers in both decussations,
have imperfect consensual reactions; and primates, with almost symmetric fiber distribution in the central pretectal decussation,
have symmetric direct and consensual reactions. In no species is the consensual response larger than the direct one. (From
Loewenfeld IE. Mechanisms of reflex dilatation of the pupil: historical review and experimental analysis. Surv Ophthalmol
1958;12⬊185–448.)
chium produces pupillary constriction (133). In humans with The pretectal region of the mesencephalon is located at the
unilateral lesions of the brachium of the superior colliculus level of the posterior commissure, just rostral to the superior
or of the pretectal olivary nucleus itself, pupillary responses colliculus. Although this region is quite small, and there are
to corresponding hemifield light stimuli are reduced even considerable anatomic differences among species, various
though visual field responses are normal (134,135). These investigators have proposed separation of the pretectum into
rare lesions are often referred to as having a ‘‘tectal relative several subnuclei. The names given to these subnuclei are
afferent pupil defect’’ with normal visual fields. This is in the nucleus of the optic tract, the sublentiform nucleus, the
contrast to optic tract lesions, in which both visual and pupil- nucleus of the pretectal area, the pretectal olivary nucleus,
lary responses are reduced or absent when light is shined in the posterior nucleus, and the principal pretectal nucleus
the affected hemifield. These clinical cases provide further (138–143) (Fig. 14.12). Several of these subnuclei have been
evidence for segregation of the pupillary and visual systems implicated as the sites of termination of afferent pupillomo-
and also provide additional evidence for a hemifield organi- tor fibers from the retina, including the sublentiform nucleus,
zation of the pupillary light reflex pathway. nucleus of the optic tract, nucleus of the pretectal area, and
It once was assumed that pupillomotor fibers entered the pretectal olivary nucleus (143–147). Of these subnuclei, the
superior colliculus, but this seems improbable because elec- pretectal olivary nucleus is the region that most investigators
tric stimulation of that surface does not produce constriction favor as the primary site for the integration of the pupillary
of the pupil, and its removal does not impair the light reflex light reflex.
(136,137). Furthermore, Ranson and Magoun (138) obtained Kourouyan and Horton (148) injected tritiated proline uni-
pupillary constriction by stimulation in the pretectal region laterally into the vitreous of monkeys and followed the distri-
and showed that bilateral destruction of the pretectal area bution of anterograde transport of the tracer into the mid-
abolished the light reflex under their conditions of light stim- brain. They found label almost exclusively in the pretectal
ulus and observation. It is thus clear that the fibers that sepa- olivary nucleus on both sides of the midline. The tracer was
rate from the optic tract and enter the brachium of the supe- also transported anterograde across the next synapse, label-
rior colliculus synapse in the pretectal region of the ing the lateral visceral cell columns of the Edinger-Westphal
mesencephalon (Fig. 14.10). nucleus, further solidifying the pretectal olivary nucleus as
Figure 14.12. Drawing of the major

pretectal nuclei and their relationship to
the visceral and anterior median oculo-
motor nuclei. (From Carpenter MB, Pier-
son RJ. Pretectal region and the pupil-
lary light reflex: an anatomical analysis
in the monkey. J Comp Neurol 1973;
149⬊271–300.)
the integrating site of the pupillary light reflex. Fibers to the milliseconds. For this long delay in timing to occur, the pre-
visceral cells of the Edinger-Westphal nucleus also were tectal neuron must be capable of summating input over a
traced from the pretectal olivary nuclei by Carpenter and relatively long period of time before having to ‘‘start over.’’
Pierson (141), whereas Benevento et al. (143) and Burde Therefore, the pupillary light reflex may be an indicator of
(149) traced fibers to the visceral nuclei from both ipsilateral damage to the retina or optic nerve by showing both a de-
and contralateral olivary and sublentiform pretectal nuclei. crease in amplitude of pupil contraction and a prolongation
Clarke and Gamlin (150) also labeled the pretectal olivary of the latency time (Fig. 14.13).
nucleus following tracer injections (WGA-HRP) into the ret- Hess (154) thought that almost all pupillary responses to
ina. Furthermore, they recorded from units in the pretectal light were restricted to stimulation of an area of the retina
olivary nucleus that fired in response to retinal light stimuli 3 mm in diameter and centered at the macula. However, it is
(discussed later). In addition, a stimulus current given at
the pretectal recording site produced pupillary constriction.
These results provide overwhelming evidence that the pre-
tectal olivary nucleus is the mesencephalic relay station for
the pupillary light reflex (151).
The pretectal olivary nucleus in primates consists primar-
ily of neuronal cell bodies located in the periphery of the
nucleus in the shell surrounding the central neuropil
(148,150). The integration and convergence of retinal impul-
ses probably occurs in the central neuropil of the nucleus.
The firing properties of the neurons within the pretectal
olivary nucleus and their relationship to stimulus luminance
and pupil response were elucidated for monkeys studied in
the awake state by Gamlin et al. (152). In response to a 5-
second stimulus, these neurons respond with a phasic burst
of action potentials at high frequency, followed by a transient
sustained volley of action potentials at a lower frequency.
Of the 16 separate neurons studied by these investigators,
all had very linear increases in the sustained component of
discharge frequency as the log stimulus intensity was in-
creased linearly, and this corresponded to linear changes in
pupil diameter. However, the slope of the response relation-
ship between firing rate and log luminance was not the same
for every neuron; some had a greater gain (steeper slope of
the line) than others. In fact, in some cases where stimulus
intensity was very low, an individual pretectal neuron could
show an increase in firing frequency without any change in
pupil size, demonstrating that the amount of neuronal in-
crease in firing necessary to produce a measurable change
in pupil diameter may be a summation of input from a num-
ber of pretectal neurons, especially at low-light levels of
stimulation. It is not known whether the gain of individual
pretectal neurons or the summation properties of many neu-
rons firing in unison is regulated by higher supranuclear
inputs. Perhaps the modulation of this firing rate and summa-
tion properties produce hippus, the random fluctuations of
the pupil that are often observed under continual retinal illu-
mination (discussed later). It is also of interest that Reiner et
al. (153) reported specific neuropeptides within the pretectal
nucleus that act as neuromodulators in other areas of the
brain. The role of these neuropeptides in modulation of the
pretectal response and the origin of these peptidergic nerve
endings has not yet been completely elucidated.
Figure 14.13. Example of pupil contraction amplitude as a function of
The pretectal neurons possess temporal summation prop- stimulus luminance (top) and latency time as a function of stimulus lumi-
erties different from neurons involved in visual perception. nance (bottom) in an eye with optic neuropathy and in the normal fellow
The intensity-dependent time delay in the pupillary light re- eye. The response function of pupil contraction in the top graph shows
flex is longer than that which occurs at other synapses. For more effects of damage at the brighter stimulus intensity range, whereas
every log unit reduction in light intensity, the latency of the the latency time is more prolonged in the damaged eye at the dimmer light
pupillary contraction may be prolonged by another 30–45 intensity range.
clear from studies using sensitive pupil-recording techniques tions point toward cortical modulation of pathways for both
and from clinical observations that stimulation of the retinal the pupillary constriction to near and the light reflex.
periphery can also produce constriction of the pupil and that With regard to the possible modulation of the pupil light
lesions of the peripheral retina can produce an afferent pupil- reflex by visual cortex, numerous investigators have demon-
lary defect (125,126) and corresponding decreases in the strated pupillary hemiakinesia or hemihypokinesia in re-
pupil contraction to small focal stimuli (127,128). There ap- sponse to focal light stimuli placed in the blind hemifield in
pear to be two major classes of pretectal neurons, based patients with suprageniculate lesions (i.e, posterior to the
on their firing properties to stimuli presented in different LGN) (115,117,127,128,158–164). Studies using pupil per-
locations within the visual field. One type of pretectal neuron imetry show homonymous pupil field deficits that corre-
responds with greater frequency to stimuli located toward spond to the borders of the visual field defects in patients
the center of the visual field, and it responds with reduced with isolated occipital lesions (Fig. 14.14), anatomically
frequency to stimuli at the periphery of its receptive field. confirmed by magnetic resonance (MR) imaging. Many of
This type of pretectal neuron has a foveal, center-weighted these patients were tested when the lesion was acute (within
receptive field. The second type of pretectal neuron has a 1 week of onset), making transsynaptic degeneration un-
flatter response to stimuli placed in different locations within likely. Thus, there may also be a significant, direct connec-
the visual field. Its discharge frequency does not change tion between the occipital cortex and the pretectal or
substantially regardless of the location of the light stimulus. Edinger-Westphal region of the mesencephalon. That such
Despite these experiments, it still is not clear how the topo- a connection between the occipital cortex and ocular motor
graphic distribution of ganglion cells throughout the retina brain stem centers does in fact exist is also suggested by
is distributed to these populations of pretectal neurons and studies of the role of the superior colliculus in the mediation
how the simultaneous firing of these neurons is integrated of visually guided behavior in the cat (165), monkey (166),
within the Edinger-Westphal nucleus. and human (167).
If the cortical injury occurs early in life, the phenomenon
EXCITATORY INFLUENCES OF VISUAL CORTEX might result from transsynaptic degeneration across the
ON THE PUPIL LIGHT AND NEAR REFLEXES LGN. Although Miller and Newman (168) found no clinical
evidence of transsynaptic degeneration in an 86-year-old
In addition to the classic midbrain afferent pathway to the woman evaluated 57 years after suffering a cerebrovascular
pupillomotor center, a second important excitatory influence accident that resulted in a complete left homonymous hemia-
on the pupillary constrictor neurons in the visceral nuclei of nopia, Beatty et al. (169) used a paraphenylenediamine stain-
the oculomotor complex arrives via centrifugal pathways ing technique to demonstrate such degeneration in a patient
from the occipital cortex. These excitatory pathways almost who died at 86 years of age, 40 years after a craniotomy for
certainly follow the same general route to the midbrain as removal of a right parieto-occipital arteriovenous malforma-
the occipital motor pathways to somatic components of the tion that left him with a complete left homonymous hemia-
oculomotor complex. Some of these centrifugal fibers appear nopia.
to modulate pupil constriction to near stimuli and are distrib-
uted in a more ventrolaterally location in the upper midbrain INHIBITORY INFLUENCES ON THE PUPIL
compared with the light reflex pathways, as evidenced by Role of the Dark Reaction in Causing Pupil Dilation
their relative invulnerability to midline lesions in the region
of the tectum or posterior commissure. Indeed, the supranu- When a light-adapted eye is suddenly exposed to a short
clear pathways for pupillary constriction associated with vol- period of darkness, the pupils dilate after a short latency
untary or involuntary effort to look at a near object are unaf- period of about 300–400 milliseconds. This dilation still
fected by many pretectal lesions that interrupt the pupillary occurs, although it is slightly diminished, after the sympa-
light reflexes, producing a dissociation between the ampli- thetic innervation to the dilator muscle is interrupted. Thus,
tude of the light and near reflexes—light-near pupillary dis- it must be partly caused by inhibitory impulses that affect the
sociation. Edinger-Westphal nucleus. Because darkness is a positive
Physiologic connections have been demonstrated between stimulus for the photopic retina and evokes an ‘‘off-re-
areas in the occipital lobes (areas 18 and 19 of Brodmann) sponse’’ in the electroretinogram, it is reasonable to assume
and pupillary constrictor neurons; Barris (155), working with that this ‘‘off-stimulus’’ produces inhibitory impulses that
cats, found that stimulation of the occipital cortex produced are relayed to the mesencephalon, where they act on neurons
constriction of the pupils as part of a near reaction. When concerned with pupillary constriction (170).
these cortical areas were destroyed, degenerated fibers could
Cortical and Hypothalamic Inhibition of Pupillary
be followed into the superior colliculus and the pretectal
Constriction
region. Jampel (156) confirmed these findings in nonhuman
primates and found that stimulation of additional areas of It is clear that the varying size of the normal pupil under
the cortex resulted in pupillary constriction together with different circumstances is primarily an expression of a vary-
convergence and accommodation. In addition, tracer studies ing tonic influence by the parasympathetic system and that
using tritiated leucine injected into cerebral cortex in pri- the sympathetic system plays a supporting role. It is believed
mates reveal specific connections to various pretectal nuclei, that in the awake subject, impulses travel via corticothalamo-
including the olivary nucleus (157). Such anatomic connec- hypothalamic pathways or corticolimbic pathways to inhibit
Figure 14.14. Example of a corresponding

loss of pupil response in the same area of ho-
monymous visual field loss in a patient with
an acute, isolated occipital infarct. This result
provides strong evidence for a cortical pupil
light reflex pathway. Pupil perimetry was per-
formed with 1.7⬚ light stimuli given as a 6⬚
grid pattern over the 30⬚ visual field (same
locations as in the visual perimetry). Grey
scale of pupil field corresponds to amplitude
of pupil contraction in each area of the visual
field.
the mesencephalic parasympathetic outflow. Electric stimu- and is present even in a decerebrate, sympathectomized
lation of the diencephalon or the cortex of sympathectomized preparation. Inhibition of a pupillary constriction ‘‘center’’
cats and monkeys causes pupillary dilation and abolishes the in the midbrain contributes to this reflex dilation (178,179).
light reflex (170). In addition, cortical stimulation of the Thus, the dilation appears to depend in part on inhibition of
sensorimotor areas of the brain and of the frontal lobes pro- neurons in the Edinger-Westphal nucleus. These pathways
duces dilation of the pupil. We have found that transcranial are located superficially in the anterolateral funiculus along
magnetic stimulation placed over the occipital cortex in hu- with the descending sympathetic pupillodilator pathways
mans does not cause pupil dilation, but it does inhibit the (180). In the cat, the pathways extended from the dorsal root
pupil constriction elicited by a light stimulus given to the entry zone to the insertion of the dentate ligament. In the
retina at the same time. This finding provides additional primate, they are located somewhat more anteriorly. Loewy
evidence for a modulating role of cerebral cortex on the et al. (181) identified two ascending pathways in the brain
pupillary light reflex. Fatigue and drowsiness in humans and stem that produced pupillary dilation when stimulated, even
in animals result in loss of this normal inhibition of the if both sympathetic trunks were sectioned, and Kerr (182)
pupillary light reflex. During sleep, the pupils are small but traced some of these fibers from the spinal cord to the vis-
retain their reaction to light. This miosis is a release phenom-
ceral oculomotor nuclei. Many of these inhibitory fibers are
enon; that is, the central sympathetic inhibitory influences
located in the periaqueductal gray area on their way to the
on the visceral oculomotor nuclei that originate in the cortex,
the hypothalamus, and the reticular activating system are visceral neurons of the Edinger-Westphal nucleus. Thus, it
diminished during sleep. Conversely, stimulation of regions seems reasonably certain that ascending spinoreticular path-
in the hypothalamus may provoke a burst of impulses that ways produce direct inhibition of the motor neurons for pu-
cause mydriasis, often with eyelid elevation and a rise in pillary constriction. Pharmacologic evaluation of inhibition
blood pressure (171–175). of the Edinger-Westphal nucleus using microcannulae indi-
cates that central adrenergic ␣2 receptors play an important
Brain Stem and Spinal Cord Inhibition of Pupillary role (183,184). This work is also important because it pro-
Constriction vides an understanding of how centrally acting drugs that
The mydriasis that occurs with arousal or painful stimuli affect the sympathetic nervous sytem (e.g., antihypertensives
is reduced but not eliminated by sympathectomy (176,177) such as clonidine) can affect pupil size.
THE EFFERENT ARC OF THE PUPIL LIGHT REFLEX pretectal olivary nucleus on each side of the midbrain (the
site of the first synapse) and to the paired lateral visceral
Midbrain Parasympathetic Outflow Pathway cell columns dorsal to the oculomotor nerve complex. These
All neural impulses that reach the sphincter of the pupil experiments provided strong evidence that the lateral vis-
travel via a preganglionic parasympathetic pathway from the ceral cell columns probably are the cells involved in the
rostral midbrain to the ciliary ganglion in the orbit and then pupillary light reflex. To avoid confusion over nomencla-
to the iris sphincter muscle via a postganglionic pathway ture, these authors recommended that only neurons sub-
within the short ciliary nerves (Fig. 14.15). serving pupillary constriction should be called the Edinger-
Westphal nucleus. Jampel and Mindel (192) performed mi-
croelectrode studies in macaque monkeys and found that
Visceral Oculomotor Nuclei cells in the visceral nuclei that were concerned with pupillary
The visceral nuclei of the oculomotor nucleus, the nuclei constriction were located ventrally and somewhat caudally
that are believed to contain cell bodies of preganglionic, to those concerned with ciliary body constriction and accom-
parasympathetic neurons that project to the ciliary ganglion modation. This finding suggested that the anterior median
and synapse with neurons that eventually produce both pu- nuclei are the primary neurons involved in producing accom-
pillary constriction and accommodation, are located in the modation. According to Szentágothai (193), the number of
dorsal midbrain. These consist of the Edinger-Westphal nu- preganglionic fibers from visceral cells of the oculomotor
clei (185,186) (also called the dorsal visceral cell columns), complex is about five times that of the postganglionic fibers
the anterior median nuclei (187,188), and the nucleus of that arise from the ciliary ganglion.
Perlia (187). The Edinger-Westphal nuclei are located dor-
Pupillary Fibers in the Oculomotor Nerve
somedial to the somatic nuclei of the oculomotor nuclear
complex (Fig. 14.16). Akert et al. (189) indicated that the The determination of the position of the pupillomotor fi-
origin of all parasympathetic neurons projecting to the ciliary bers in the oculomotor nerve is based on both anatomic and
ganglion in the monkey is limited to the Edinger-Westphal function studies. Within the brain stem, the pupillomotor
nucleus, but projections also arise from the ipsilateral half of fibers are located in the oculomotor fasciculus rostral to fi-
the anterior median nucleus (145,149,190,191). In addition, bers originating from the other oculomotor subnuclei, con-
Burde and Loewy (191) found that cell bodies in Perlia’s sistent with the rostral location of the Edinger-Westphal nu-
nucleus also send axons that project to (or through) the cili- cleus (194) (Fig. 14.17). Sunderland and Hughes (195) found
ary ganglion in macaque monkeys. that between the brain stem and the middle of the cavernous
Kourouyan and Horton (148) used unilateral injections of sinus in humans, the pupillary fibers were concentrated at
radioactively labeled proline into the vitreous of six monkeys and around the superior surface of the nerve. In the anterior
to identify which neurons in the oculomotor nerve complex cavernous sinus and in the orbit, pupillary fibers were usu-
in the midbrain were involved in the pupil light reflex. After ally distributed among the somatic fibers of the inferior divi-
allowing sufficient time for the label to be transported to the sion of the oculomotor nerve.
midbrain (7–10 days), the authors localized the label to the Kerr and Hollowell (196) studied the location of the pupil-
Figure 14.15. Parasympathetic pathway to the iris and ciliary body. 1, Edinger-Westphal and anterior median nuclei of the
dorsal mesencephalon; 2, oculomotor nerve; 3, branch to the inferior oblique muscle; 4, motor root of the ciliary ganglion;
5, short ciliary nerves; 6, iris sphincter and ciliary muscle. (Chart prepared by Dr. H.S. Thompson and drawn by J. Esperson.)
Figure 14.16. Visceral cells of the oculomotor nucleus, labeled by injection of horseradish peroxidase into the ciliary ganglion.
The sagittal diagram E shows the levels of brain stem cross-sections A to D, where the tracer was found. The sections are
arranged in rostral caudal order. AC, anterior commissure; AM, anteromedian nucleus; CG, central grey; EW, Edinger-Westphal
nucleus; FR, fasciculus retroflexus; ICA, interstitial nucleus of Cajal; IP, interpeduncular nucleus; MB, mammillary body;
MLF, medial longitudinal fasciculus; NP, nucleus of Perlia; PC, posterior commissure; OC, oculomotor nucleus; RN, red
nucleus. (Redrawn from Burde RM, Loewy AD. Central origin of oculomotor parasympathetic neurons in the monkey. Brain
Res 1980;198⬊434–439.)
lomotor fibers in the oculomotor nerve of humans and non- the medial and superior portion of the oculomotor nerve
human primates. Although the results were much clearer in the subarachnoid space. The preganglionic pupillomotor
in the nonhuman primates than in human specimens, these fibers occupy a very superficial location on the oculomotor
investigators confirmed the observations of Sunderland and nerve, with most lying immediately beneath the epineurium.
Hughes (195) (Fig. 14.18). They found that the pupillomotor Indirect evidence that the pupillomotor fibers occupy a su-
fibers are concentrated on the medial superior aspect of the perficial location in the subarachnoid portion of the oculo-
oculomotor nerve as it leaves the brain stem and that they motor nerve also comes from histopathologic observations
gradually move medially and slightly inferiorly as they run in diabetic patients with pupil-sparing oculomotor nerve pal-
forward toward the cavernous sinus. This conveniently ex- sies (197–199). In all cases in which the subarachnoid por-
plains the propensity for pupil involvement by aneurysms tion of the nerve is affected, the lesion is centrally located,
of the posterior communicating artery that often compress sparing peripheral fibers.
Figure 14.17. Schematic drawing of position

of fibers in fascicle of human oculomotor nerve.
Fibers destined for pupillary sphincter (P) occupy
a rostral and medial position in the fascicle. CCN,
central caudal nucleus; CN III, oculomotor nerve;
IO, inferior oblique; IR, inferior rectus; LP, leva-
tor palpebrae superioris; MR, medial rectus;
MRa, medial rectus subnucleus a; MRb, medial
rectus subnucleus b; MRc, medial rectus sub-
nucleus c; SR, superior rectus. (From Ksiazek S,
Slamovits TL, Rosen CE, et al. Fascicular ar-
rangement in oculomotor paresis. Am J Ophthal-
mol 1994;118⬊97–103.)
Figure 14.18. Course of preganglionic autonomic nerve fibers from the

brain stem to the ciliary ganglion. A sagittal reconstruction of the brain stem
with the course of the oculomotor nerve is shown at top. The corresponding
locations of the preganglionic autonomic fibers for pupilloconstriction and
accommodation within the right (R) and left (L) oculomotor nerves are shown
in black in coronal sections through slices at 1 (emergence from the brain
stem), 2 (midpoint in the subarachnoid space), 3 (at the point where the third
nerve enters the dura), and 4 (in the anterior cavernous sinus where the fibers
have entered the anatomic inferior division of the third nerve). The autonomic
fibers are located superiorly as the oculomotor nerve exits the brain stem and
then come to lie more medially as the oculomotor nerve passes toward the
orbit. A, dorsal and B, ventral side of brain stem. P, pons; M, medulla; EW,
Edinger-Westphal nucleus; IIIn, somatic portion of third nerve nucleus; III,
third nerve; ID, inferior division of third nerve; SD, superior division of third
nerve; NCilV, nasociliary branch of fifth nerve; CG, ciliary ganglion; Sym,
sympathetic route; m, medial; l, lateral. (From Kerr FWL, Hollowell OW.
Location of pupillomotor and accommodation fibres in the oculomotor nerve:
experimental observations on paralytic mydriasis. J Neurol Neurosurg Psy-
chiatry 1964;27⬊473.)
Ciliary Ganglion and Short Ciliary Nerves vertical direction. It is located in the loose fatty tissue about
1 cm anterior to the medial end of the superior orbital fissure
The ciliary ganglion contains the postganglionic neurons and the annulus of Zinn, and 1.5–2 cm behind the globe
that innervate the iris sphincter and the ciliary body. It is the (Figs. 14.19 and 14.20). It lies on the temporal side of the
site of the synapse with the preganglionic parasympathetic ophthalmic artery between the optic nerve and the lateral
fibers. The ganglion is a small, irregular structure measuring rectus muscle in close association with the inferior division
2 mm in the horizontal direction and about 1 mm in the of the oculomotor nerve. Although Sinnreich and Nathan
Figure 14.19. Superior view of the orbit. The inferior division of the oculomotor nerve supplies branches to the ciliary
ganglion, which in turn gives off numerous short posterior ciliary nerves. (Redrawn from Wolff E. Anatomy of the Eye and
Orbit. 6th ed. Philadelphia, WB Saunders, 1968.)
Figure 14.20. View of the posterior orbit showing the relationship of the optic nerve to the ocular motor nerves and extraocular
muscles. Note the location of the ciliary ganglion. (Redrawn from Wolff E. Anatomy of the Eye and Orbit. 6th ed. Philadelphia,
WB Saunders, 1971.)
(200) examined 30 orbits and found the location of the gan- plexus in the suprachoroidal space (between the choroid and
glia to be quite constant, other investigators (201,202) have sclera) to innervate the anterior structures of the eye (200).
found that the size, shape, and location of the human ciliary
ganglion are extremely variable. The arterial branches sup- Sympathetic Outflow Pathway
plying blood to the ganglion most frequently originate from The final common path of active dilator impulses extends
the posterior lateral ciliary artery (supplying the anterior half from the hypothalamus to the iris. This path consists of a
of the ganglion) and from the lateral muscular arterial trunk long three-neuron arc: (a) from the hypothalamus through
(entering the ganglion from its lateral side) (202). the brain stem to the lateral cervical cord; (b) back out from
Most investigators agree that a majority, if not all, of the the spinal cord to the cervical sympathetic chain and superior
cell bodies in the ganglion are parasympathetic. Of consider- cervical ganglion in the neck; and (c) along the course of
able significance is the finding by Warwick (190) that only the internal carotid artery through the base of the skull and
a small percentage of these cell bodies give rise to axons into the orbit and iris.
that supply the iris sphincter (3%), whereas a much larger
percentage reaches the ciliary muscle (94%). This finding Hypothalamus
is consistent with the relative muscle mass of the iris sphinc-
ter and the ciliary muscle. Thus, over 90% of the mesence- Karplus and Kreidl (171) and many subsequent investiga-
phalic parasympathetic outflow is concerned with accommo- tors observed that maximum pupillary dilation could be in-
dation and not with pupillary constriction. duced by electric stimulation in the hypothalamus (172,175).
In humans, there are 8–20 short ciliary nerves that leave This reaction can still be produced some weeks after the
the ciliary ganglion in two or three bundles and carry three cortex is ablated. Thus, the efferent pathway destined for
types of fibers: (a) postganglionic, parasympathetic fibers the pupillary dilator either originates in, or has a cell station
to the iris sphincter and ciliary muscle; (b) postganglionic, in, the hypothalamus. Destruction of these hypothalamic
sympathetic vasomotor fibers that originate in the superior centers, which are located mainly in the posterolateral region
cervical ganglion; and (c) afferent, sensory fibers of the tri- of the hypothalamus, results in miosis, ptosis, and reduction
geminal nerve. The short ciliary nerves are very tortuous of pupillary reflex dilation.
and are intertwined with the posterior ciliary arteries. Most
Brain Stem and Spinal Cord Sympathetic Pathways
of these nerves pierce the sclera at the posterior pole of the
globe temporal to the optic nerve. After the nerves enter the As noted above, the descending sympathetic pathways
eye, they run anteriorly, first in the sclera and then in a arise from the posterolateral region of the hypothalamus.
There may be a partial crossing in the decussation of Forel, plexus (Fig. 14.21). The close anatomic relationship between
but the fibers are largely uncrossed below that point. As these the superior cervical ganglion and the lower cranial nerves
fibers run caudally, they come to occupy a lateral position in explains the frequent simultaneous involvement of the cervi-
the brain stem. The pathway probably contains one or more cal sympathetic trunk (producing a Horner syndrome) and
synapses in the pontine and mesencephalic tegmentums, al- the lower cranial nerves in cases of trauma, tumors, and
though some of the fibers descend directly, without synapse, infections at the base of the skull and in the retroparotid
to the ‘‘ciliospinal center of Budge and Waller’’ in the spinal space.
cord (203–205). Within the spinal cord, the fibers are located
superficially in the anterolateral columns (180). Postganglionic Sympathetic Pathway
The fibers descend within the substance of the spinal cord
to the cervicothoracic region, where they pass medially to The postganglionic oculosympathetic fibers leave the su-
synapse with the preganglionic neurons of the peripheral perior cervical ganglion as a fairly thick bundle from its
sympathetic pathway at C8 to T2. Apparently, descending cephalic pole and accompany the internal carotid artery into
vasomotor and pupillomotor fibers are in juxtaposition until the skull. These fibers form a plexus, first on the lateral
they leave the intermediolateral cell column, because stimu- surface of, and then surrounding, the artery. At the time of
lation of the cervical cord in the intermediolateral cell col- a carotid dissection, expansion of the arterial wall stretches
umn causes both pupillary dilation and associated vasopres- this plexus, resulting in facial pain and a Horner syndrome.
sor responses, whereas the pupillomotor fibers can be Almost immediately after joining the internal carotid artery,
stimulated separately as they approach the ventral (motor) most of the sweat fibers (and piloerector fibers) to the face
root. exit from the carotid plexus by following the external carotid
artery to their effector organs in the skin (Fig. 14.21). The
Preganglionic Sympathetic Fibers remainder of the carotid plexus extends upward through the
carotid canal and the foramen lacerum to the region of the
The preganglionic sympathetic fibers pass via the ventral
gasserian ganglion and cavernous sinus.
root to the paravertebral sympathetic chain as the white rami
As the internal carotid plexus enters the skull, it gives off
communicants (206). They then proceed without synapsing
fibers that join the tympanic branch of the glossopharyngeal
through the first thoracic or stellate ganglion close to the
nerve to form the tympanic plexus on the promontory of the
pleura at the apex of the lung. The fibers travel mainly in
middle ear. These fibers are designated collectively as the
the anterior loop of the ansa subclavia (of Vieussens) and
caroticotympanic nerves and are located within the mucous
continue through the inferior and middle cervical ganglia to
membrane as well as in bony grooves of the promontory.
terminate in the superior cervical ganglion.
After passing through the tympanic plexus, the sympathetic
Superior Cervical Ganglion fibers rejoin the internal carotid plexus, at which point the
plexus enters the skull with the internal carotid artery
This is the largest of the sympathetic ganglia and is often through the carotid canal, after which it is in close relation
2–3 cm long. It is located below the base of the skull between to the trigeminal ganglion. Within the carotid canal, some
the internal jugular vein and the internal carotid artery and fibers leave the internal carotid plexus to form the deep pe-
constitutes a fusion of the sympathetic ganglia associated trosal nerve that joins the greater superficial petrosal nerve
with the first three or four cervical segments to which it to form the vidian nerve. This nerve courses through the
sends gray rami. Histologically, the human superior cervical pterygoid or vidian canal and then joins the sphenopalatine
ganglion is composed of three different kinds of neural struc- ganglion. It carries visceral efferent fibers of the facial nerve,
tures. There are cholinergic preganglionic sympathetic nerve some of which supply the lacrimal gland.
terminals, adrenergic postganglionic cell bodies, and cate- The remainder of the sympathetic fibers continue through
cholamine-containing chromaffin cells, all in close proxim- the carotid canal into the cavernous sinus. Within the sinus,
ity (207). In addition, Kondo and Fujiwara (208) described the oculosympathetic fibers, the largest component of the
large, granule-containing cells in the human superior cervi- sympathetic plexus, fuse with the abducens nerve for a short
cal ganglion that they believed to be a special type of post- distance before separating and joining the ophthalmic nerve
ganglionic aminergic neuron. By far the most common type (210,211) (Fig. 14.22). Most, if not all, of the pupillary sym-
of nerve endings present are the cholinergic, preganglionic pathetic fibers join the ophthalmic division of the trigeminal
sympathetic nerve terminals. nerve and enter the orbit with the nasociliary nerve (Figs.
Postganglionic fibers exit from the superior cervical gan- 14.19 and 14.22). The remainder of the sympathetic plexus
glion in great numbers. Wolf (209) found that the ratio be- distributes some of its fibers to the ocular motor nerves
tween preganglionic and postganglionic fibers in the cat var- within the cavernous sinus. It then exits the sinus with the
ied from 1⬊11 to 1⬊17. These postganglionic fibers leave internal carotid artery, at which point some of its branches
the superior cervical ganglion as two main sets of branches: are distributed along the ophthalmic artery and along the
(a) communicating branches composed of gray rami to the anterior cerebral, middle cerebral, and anterior choroidal ar-
first four cervical segments and communicating branches to teries.
the glossopharyngeal, vagus, and hypoglossal nerves; and Postganglionic fibers of the sympathetic pathway include:
(b) branches to the pharynx, the heart, and the sympathetic (a) vasomotor fibers to the orbit; (b) oculosympathetic fibers
effectors in the head via the internal and external carotid to the intrinsic muscles of the eye; (c) fibers to the branched
Figure 14.21. Sympathetic pathways to the face and eye. The solid line indicates the pathway of the pupillary dilator fibers,
while the dashed lines show some of the other sympathetic pathways to the orbit and face. 7, superior cervical ganglion; 8,
internal carotid artery; 9, external carotid artery; 10, sudomotor fibers to face; 11, carotid plexus; 12, caroticotympanic nerve;
13, tympanic plexus; 14, deep petrosal nerve; 15, lesser superficial petrosal nerve; 16, sympathetic contribution to vidian nerve;
17, ophthalmic division of the trigeminal nerve; 18, nasociliary nerve; 19, long ciliary nerve; 20, ciliary muscle and iris dilator
muscle; 21, probable pathway of sympathetic contribution to retractor muscles of the eyelids; 22, vasomotor and some sudomotor
fibers; 23, ophthalmic artery; 24, lacrimal gland; 25, short ciliary nerves; 26, sympathetic contribution to salivary glands; 27,
greater superficial petrosal nerve. (Chart prepared by Dr. H.S. Thompson and drawn by J. Esperson.)
melanocytes of the uveal tract; (d) fibers to the extrinsic Thompson believes that the nerves of the iris maintain a
ocular muscles; (e) fibers to the smooth muscle of Müller; segmental organization, specific with regard to their ultimate
(f) fibers to the lacrimal gland; and (g) possibly fibers to the destinations to muscle bundles. Trauma to the nerves from
pigment layer of the retina (212). heat during retinal or trabecular meshwork laser photocoagu-
Despite the apparent variability of peripheral sympathetic lation treatment or from cryotherapy may damage the short
pathways, it seems certain that the fibers that innervate the ciliary nerves. This may result in a tonic pupil with loss of
pupillary dilator muscle enter the orbit with the nasociliary the light reflex.
nerve, bypass the ciliary ganglion, and reach the eye as the
long ciliary nerves (203,213) (Figs. 14.19 and 14.21). As Peptidergic Innervation to the Iris
noted above, other sympathetic fibers do pass through the
ciliary ganglion but do not synapse there. They apparently In addition to the autonomic nerves supplying the iris,
serve a vasomotor function for the eye (201,214). Thus, sym- sensory innervation is provided by the ophthalmic division
pathetic fibers are present in both the long and short ciliary of the trigeminal nerve (215,216). These sensory nerves may
nerves that enter the eye. The short and long ciliary nerves play an additional role in modulating pupil size. Every ante-
begin to cross each other as they pass forward between cho- rior segment surgeon knows that mechanical and chemical
roid and sclera, and by the time they have reached the iris irritation of the eye can cause a strong miotic response that
root, they have all blended together to form a rich plexus is noncholinergic and fails to reverse with autonomically
from which the iris muscles, ciliary muscle, and vessel walls acting drugs. In rabbits and cats, the response seems to be
are supplied. Despite this appearance, Dr. H. Stanley caused by the release of substance P or closely related pep-
tides from the sensory nerve endings, but in monkeys and

humans, substance P has little or no miotic effect. Almegaãrd
et al. (217) reported that cholecystokinin (in nanomolar
amounts) caused contraction of isolated iris sphincter from
monkeys and humans. Intracameral injections in monkeys
caused miosis that was not prevented by tetrodotoxin or in-
domethacin, indicating that the miosis was not caused by
stimulation of nerve endings or release of prostaglandins, but
by direct action on sphincter receptors. The cholecystokinin
antagonist lorglumide caused competitive inhibition of the
response.
THE IRIS MUSCLES
The iris can be divided into four main parts from anterior
to posterior: (a) the anterior border layer; (b) the stroma
and sphincter muscle; (c) the anterior epithelium and dilator
muscle; and (d) the posterior pigmented epithelium (Fig.
14.23). Light and electron microscopic, histochemical, and
angiographic techniques have been used to elucidate the fea-
tures of these structures (218–220). The color of the iris is
determined by its mesodermal and ectodermal components.
In Caucasians, the stroma is relatively free of pigment at
birth. The stroma absorbs the long wavelengths of light, al-
lowing the shorter (blue) wavelengths to pass through to the
pigmented epithelium where they are reflected back, causing
the iris to appear blue. If the stroma is dense and contains
numerous, heavily pigmented melanosomes, the delicate
lacework of iris vessels is hidden by the pigment, and the
surface of the iris looks brown and velvety.
Iris Sphincter Muscle
The sphincter muscle is a ribbon-like, meridionally ori-
ented band that measures 0.75–0.80 mm in diameter and
0.10–0.17 mm in thickness (Figs. 14.23 and 14.24). The
sphincter muscle cells are spindle-shaped and are oriented
parallel to the pupil margin. At the pupil margin, the muscle
Figure 14.22. Course of the sympathetic, postganglionic fibers from the edge is separated from the pigment epithelium by a narrow
internal carotid plexus. They join briefly with the abducens nerve (VI) band of collagen. Posteriorly, it is bound firmly to a dense
before entering the orbit with the nasociliary nerve, a branch of the ophthal-
layer of connective tissue that continues to the dilator mus-
mic division (V1) of the trigeminal nerve. After reaching the nasociliary
nerve, the sympathetic fibers reach the iris dilator muscle as the long ciliary
cle. This collagen layer contains arterioles, capillaries, and
nerves. ICA, internal carotid artery; ON, optic nerve. (Modified from Solnit- both sensory and motor nerves. The iris sphincter can be
zky O. Horner’s syndrome: its diagnostic significance. Georgetown Univ visualized in different states of contraction using infrared
Med Cent Bull 1961;14⬊204–222.) transillumination, in which case it appears as a darkened
circumferential band adjacent to the pupil. During contrac-
tion, the sphincter becomes denser and thicker (Fig. 14.25).
Figure 14.23. Schematic of the iris structure in sagittal cross-section. (From Loewenfeld IE. The Pupil: Anatomy, Physiology,
and Clinical Applications. Ames, IA, Iowa State University Press, and Detroit, MI, Wayne State University Press, 1993⬊6.)
Figure 14.24. Schematic drawing of the pupillary portion of the iris showing the major layers. a, Anterior border layer; b,
pigment ruff at the pupillary margin; c, sphincter muscle; d, vascular arcades within the anterior border layer and iris stroma;
e, clump cells; f, dilator muscle; g, anterior epithelium anterior to termination of the dilator muscle (arrow); h and i, spur-like
extensions from the dilator muscle that blend anteriorly with the sphincter muscle; j, posterior pigmented iris epithelium. (From
Hogan MJ, Alvarado JA, Weddell JE. Histology of the Human Eye: An Atlas and Textbook. Philadelphia, WB Saunders,
1971.)
tion that projects into the iris stroma and an epithelial apical
portion adjacent to the posterior epithelial layer of the iris
(Figs. 14.23 and 14.24). The muscular portions of the cells
are oriented in a radial direction from the iris root toward
the pupillary border and form three to five layers of dilator
muscle. The myoepithelial processes are spindle-shaped and
contain numerous myofilaments, although myofilaments are
also present in the epithelial portion of the cells. Tight junc-
tions and gap junctions similar to those described in the
sphincter muscle are commonly found between the dilator
muscle fibers. When the dilator contracts, it draws the iris
up into folds and dilates the pupil. Interestingly, it would
appear that during adrenergic mydriasis, the dilator muscle
is the only part of the iris that is not thrown into folds
(221–223) (Fig. 14.26).
Vascular Supply to the Iris Muscles

The iris has a rich supply of radially arranged vessels that
arise from the greater or major arterial circle near the anterior
part of the ciliary body and enter the iris between the ciliary
crypts. They anastomose in an arteriovenous circle, the lesser
or minor arterial circle, near the collarette. The major arterial
circle is discontinuous and derives its blood supply partly
from the nasal and temporal long posterior ciliary arteries
that originate from the ophthalmic artery and the anterior
ciliary arteries (109) (Fig 14.27). The anterior ciliary arteries
are branches of the muscular arteries that also originate from
the ophthalmic artery and reach the globe with the four rectus
muscles and enter it from perforating branches. The relative
contribution of each of the vessels to the iris varies among
individuals, but the temporal iris seems the most susceptible
to ischemia, particularly when multiple muscles are disin-
Figure 14.25. Changes in the iris sphincter during pupil contraction. The serted from the globe during strabismus or retinal reattach-
iris sphincter can be visualized in the human eye using infrared transillumi- ment surgery. The capillaries of the iris are formed by a
nation of the iris. The sphincter muscle has at least 20 segments, each
single layer of unfenestrated endothelium with a rather thick
innervated in series by separate branches of the parasympathetic postgangli-
onic nerve. As the sphincter muscle shortens during contraction (series on
basement membrane. These vessels are relatively imperme-
the left), it transilluminates less, appearing as a denser darker band as the able to small molecules under normal conditions because of
pupil becomes smaller. On the left is the same normal iris viewed with tight junctions between endothelial cells. In inflammatory
frontal illumination. The sphincter can often be distinguished within the conditions causing iritis, the tight junctions become incom-
iris stroma (border outlined by broken circle). (From Kardon RH, Corbett petent, and permeability increases (109). The blood vessels
JJ, Thompson HS. Ophthalmology 1988;105:313–321.) of the iris have a serpentine course that allows them to ac-
commodate to the changes in the length of the iris during
dilation and constriction.
The sphincter muscle bundles are composed of small
groups of five to eight muscle cells. The fibers of these cells Nerve Supply to the Iris Muscles
are closely spaced and are in contact with each other by The iris muscles, like other many other autonomic effector
means of tight junctions and gap junctional complexes be- organs, are reciprocally innervated by both sympathetic and
tween the plasma membranes of adjacent cells. As with other parasympathetic fibers. Immunohistochemistry and electron
smooth muscles, nerves do not enter these tight groups of microscopy of nerve terminals in the iris reveal adrenergic
muscle cells but lie close to their periphery. Because of this terminals innervating the iris sphincter that are thought to
arrangement, it is believed that each muscle group functions arise from branches of adrenergic sympathetic nerves sup-
as a unit. Apparently only one cell is innervated, and the plying the dilator muscle and cholinergic nerves innervating
junctional complexes spread the depolarizing current to the the dilator muscle that are thought to arise from branches
other cells of the group. of the cholinergic parasympathetic nerves supplying the
sphincter (109). It is suspected that the adrenergic terminals
The Dilator Muscle–Anterior Iris Epithelial Layer
innervating the sphincter inhibit that muscle during active
This layer measures about 12.5 microns in thickness and dilation and that cholinergic terminals within the dilator are
contains myoepithelial cells that have a muscular basal por- inhibitory during parasympathetic constriction of the sphinc-
Figure 14.26. Structural changes in miosis and mydriasis in the monkey iris. Left
series of drawings depict cross-sections of monkey iris in miosis (top), in moderate
mydriasis (center), and in extreme mydriasis (bottom). The corresponding light micro-
scopic sections on the right show the changes in the posterior epithelial layers as the
iris dilates. Weigert-Gieson stain, depigmented sections, phase-contrast microscopy.
(Drawings from Loewenfeld IE. The Pupil: Anatomy, Physiology, and Clinical Applica-
tions. Ames, IA, Iowa State University Press, and Detroit, MI, Wayne State University
Press, 1993⬊6. Light micrographs from van Alphen GWHM. The structural changes in
miosis and mydriasis of the monkey eye. Arch Ophthalmol 1963;69⬊802–814.)
ter (225–231) (Table 14.1). In other words, cholinergic exci- a significant decrease in the amplitude of pupil redilation
tatory nerves to the sphincter cause it to contract, but at the after a light stimulus, possibly by producing a ␤-adrenergic
same time, branches to the dilator are inhibitory and cause blockade of the inhibitory fibers to the sphincter, keeping the
it to relax, thus enhancing the miosis. On the other hand, sphincter from relaxing properly and thus slowing dilation.
mydriasis consists of adrenergic excitatory input to the dila- It is likely that with thoughtful selection of receptor-spe-
tor, causing it to contract. At the same time, not only is the cific agonists and antagonists and continuous recording of
central, cholinergic output to the sphincter inhibited, but also the behavior of both pupils to dark and light stimuli, the
inhibitory branches of adrenergic nerves to the sphincter are pharmacology of the human iris can be better understood.
activated, resulting in brisk dilation of the pupil. In the meantime, it should be considered that every time a
One clinical correlate of the adrenergic inhibition of the dilating drop is used, it is probable that one of the iris mus-
sphincter is that a Horner pupil dilates very slowly. In some cles is being stimulated and its antagonist is being inhibited.
cases, interruption of the sympathetic nerves may cause a
deficit not only in dilator activation, but also in sphincter INTEGRATED ACTIVITIES THAT INFLUENCE
inhibition. Also interesting are the effects of topical timolol PUPIL SIZE AND MOVEMENT
(0.5%), as studied in humans with pupillography by Johnson Pupillary reflexes appear in the 5th month of development
et al. (232). These investigators found that this drug causes and are active by the 6th month. In infancy, the pupil is
Figure 14.27. Pattern of blood supply of the iris and of other structures of the anterior ocular segment, as seen from frontal
(A) and sagittal view (B). (A, From Loewenfeld IE. The Pupil: Anatomy, Physiology, and Clinical Applications. Ames, IA,
Iowa State University Press, and Detroit, MI, Wayne State University Press, 1993⬊48. B, Modified after Marsh RJ, Ford SM.
Blood flow in the anterior segment of the eye. Trans Ophthalmol Soc UK 1980;100⬊388–397 and after Hayreh SS, Scott W.
Fluorescein iris angiography. Arch Ophthalmol 1978;96⬊1390–1400.)
small; however, during the first 6 months of life, the pupil amount of central inhibition of the Edinger-Westphal nu-
begins to widen, and in adolescence it attains its widest diam- cleus that contributes to the pupil becoming smaller with
eter. This increase in size may be related to an incompletely age (109). Both in infancy and in old age, pupillary responses
developed iris sympathetic system at birth (233,234) and to light and near stimuli appear to be less active than in
growth of the anterior segment of the eye during these years adolescence and adult life.
(235). From 20 to 60 years of age, the pupil steadily becomes
smaller (236–240) (Fig. 14.28). Korczyn et al. (241) per- Influence of Pupil Size on Pupillary Movements
formed pharmacologic studies that suggested that although That the size of the pupil can influence the dynamics of
the iris dilator muscle does not lose its sensitivity to norepi- pupillary movements was shown by several investigators,
nephrine with age, sympathetic tone decreases with age. although there is some discrepancy among their findings.
These investigators postulated that the decrease in sympa- Loewenfeld and Newsome (242) used infrared pupillo-
thetic tone that occurs in persons over 60 years of age results graphic techniques to demonstrate that the pupil has a linear
from either degeneration or functional inactivity of the post- range of movement within which both contractions to light
ganglionic neurons. In addition to a decrease in peripheral and dilations to darkness move freely. Beyond this range,
sympathetic tone, there is also probably a decrease in the the movements decrease abruptly in both extent and velocity.
This reduction in function occurs at a particular pupil diame-
ter that is specific for an individual eye, regardless of the
Table 14.1
Summary of Peripheral Cholinergic and Adrenergic Receptor Studies
intensity of the stimulus or the pupil size at the beginning
on the Iris Sphincter and Dilator Suggesting Reciprocal Innervation of stimulation. The limits of linearity vary slightly among
normal persons but not between a person’s two eyes. Lo-
Iris Sphincter Muscle Iris Dilator Muscle ewenfeld and Newsome (242) used various pharmacologic
agents to prove that linearities of dilation and constriction
Receptor Action Result Action Result
movements were, to a large extent, dependent on mechanical
Cholinergic Excites Miosis Relaxes Miosis rather than pharmacologic factors.
Adrenergic ␣1 Excites Miosis ? ?
Semmlow et al. (243) also studied variations in pupillary
Adrenergic ␣2 Relaxes Mydriasis Excites Mydriasis
responsiveness with pupil size. These investigators were un-
Adrenergic ␤1 Relaxes Mydriasis Relaxes ?
able to confirm a linear range and a nonlinear range sepa-
Some of these actions may not cause any significant effect on static pupil size but rated by a distinct ‘‘breakpoint,’’ as suggested by Loewen-
may influence the rate of pupil constriction or dilation. feld and Newsome (242). Instead, their data demonstrated
Figure 14.28. Age curve of pupil diameter

among 1,263 normal subjects. Pupil diame-
ters were measured from infrared flash photo-
graphs taken after 3 minutes in darkness. For
each subject the average pupil diameters
(right pupil diameter Ⳮ left pupil diameter/
2) were plotted as ordinate (mm) against age
as the abscissa. The average line through this
scatter plot indicates that the pupil size ini-
tially increases from infancy to early teens,
then gradually declines as a function of age.
(From Loewenfeld IE. Pupillary changes re-
lated to age. In Thompson HS, Daroff R, Fri-
sén L, et al, eds. Topics in Neuro-Ophthal-
mology. Baltimore, Williams & Wilkins,
1979⬊124–150.)
a nonlinear process that was active in both constriction and ditions, and/or lack of objective records of measurement. In
dilation throughout the entire pupillomotor range, although addition, the true size of the pupil may be distorted by the
it became most apparent at the extremes of pupil size. Never- cornea by 9–12%, depending upon pupil size (255). Never-
theless, Semmlow et al. (243) found that for pupil sizes be- theless, Loewenfeld (239) examined 1,780 normal subjects
tween 3.5 and 6.0 mm, an assumption of ‘‘approximate line- using infrared flash photography (256) and found pupillary
arity’’ is justified. According to these investigators, this inequality with normal pupillary reflexes in 850 (48%). She
relationship between pupillary size and response also occurs emphasized that because pupillary inequality of less than 0.3
during the near response and is attributable to length-tension mm was very common and difficult to observe clinically,
characteristics of the iris sphincter muscle. only inequality greater than 0.3 mm should be called ‘‘aniso-
To summarize, structural properties of the iris stroma vary coria.’’ Using this criterion, about 200 subjects (11%) in her
among different persons and can limit pupil excursions in study had clinically observable, benign anisocoria. Spencer
response to light or near. If the degree of pupil constriction and Czarnecki (257) found a similar prevalence of anisocoria
is used as an indicator of light input, the pupil size range (16%) in a study of 100 patients admitted to an intensive
over which such measurements of contraction amplitude are care stroke unit over a 1-year period.
made need to be considered. Obviously, a pupil that starts Loewenfeld (239) believed that asymmetries of supranu-
is 3.5 mm at rest will not contract to the same extent as one clear inhibitory control of the dorsal mesencephalic visceral
that is 5.0 mm, even when the same light stimulus is pre- nuclei are responsible for this type of anisocoria and called it
sented to the retina. simple, central anisocoria, which always decreased in light.
Simple anisocoria has no clinical significance with respect
Pupil Size and Intraocular Pressure to visual function, but it is important that this type of anisoco-
ria be recognized and differentiated from the acquired aniso-
Intraocular pressure exerts an influence on the size of the coria that occurs in the setting of direct ocular trauma or
pupil (244–246). Elevation of the intraocular pressure in damage to either the parasympathetic or sympathetic inner-
humans causes mydriasis, apparently through its effects on vation of the iris, so that such patients are not subjected to
the iris sphincter muscle and not the neuromuscular junction unwarranted diagnostic studies. In such instances, the aniso-
(247). Part, but not all, of this effect is related to iris ischemia coria may be benign, but the evaluation may not! Often, a
(248). Iris dilator function seems to be relatively resistant preexisting anisocoria can be detected in previous photo-
to the effects of increased intraocular pressure. graphs of the individual being examined, particularly if some
type of magnification is used. This subject is discussed in
Benign (Simple, Central, ‘‘Physiologic’’) Anisocoria more detail in Chapter 15.
Most normal persons have equal pupils. Nevertheless, pu-
Anisocoria in Lateral Gaze: Tournay’s Phenomenon
pillary inequality can be present in persons with normal pu-
pillary constriction to light and normal dilation in darkness In 1907, Gianelli noted that when some normal persons
(249–251). This ‘‘benign’’ anisocoria is said to be present look in extreme lateral gaze, the pupil of the abducting eye
in about 20% of normal persons (249–254), but this figure becomes larger than the pupil of the opposite adducting eye,
is open to question, primarily because most studies use inad- which becomes smaller (258) (Fig. 14.29). He hypothesized
equate population samples, uncontrolled experimental con- that this phenomenon resulted from mechanical traction
Figure 14.29. Percent changes in pupillary diameter during lateral gaze (Tournay’s phenomenon). A, Changes in pupil size
of a patient with bilateral Tournay’s phenomenon. The pupil of the abducting eye dilates and the pupil of the adducting eye
constricts. B, Pupil appearance in a patient without Tournay’s phenomenon. The patient demonstrates slight pupillary constriction
in both eyes on gaze to the right and left. Top frame is gaze straight ahead, middle frame is gaze to right, and lower frame is
gaze to left. O.D., right eye; O.S., left eye; down-arrow, pupillary contraction; up-arrow, pupillary dilation. (From Loewenfeld
IE, Friedlander RP, McKinnon PFM. Pupillary inequality associated with lateral gaze [Tournay’s phenomenon]. Am J Ophthal-
mol 1974;78:449–469.)
caused by movement of the globe that stimulated the long Tournay’s phenomenon is relatively uncommon and has lit-
ciliary nerves in abduction and the short ciliary nerves in tle or no clinical significance.
adduction. Although this paper was largely ignored, Tournay
(259) subsequently made similar, independent observations, Hippus: Physiologic Pupillary Unrest
emphasizing the dilation of the pupil ipsilateral to the direc-
tion of gaze. Although Tournay later discovered Gianelli’s When observed in ordinary room illumination, the pupils
manuscript and credited him with the initial observation of of a young, healthy person are in almost constant motion
this phenomenon (260), anisocoria that develops on extreme (265). When the eyes are exposed to long-lasting light stimu-
lateral gaze is called ‘‘Tournay’s phenomenon.’’ Some in- lation, both pupils constrict, then partially redilate, and begin
vestigators (261,262) suggested that this phenomenon occurs to oscillate (111). In dim light, the pupils become large and
in almost all normal persons; however, Sharpe and Glaser the rate of oscillation is slow; however, with increasing light
(263) studied 25 normal subjects and 5 patients with Duane’s intensity, the mean diameter of the pupils becomes smaller
retraction syndrome by direct observation, photography, and and the rate of oscillation increases (maximally about 2 per
infrared electronic pupillography and were unable to demon- second). These movements are synchronous in the two eyes
strate anisocoria in lateral gaze in any of the subjects. Lo- and appear to continue indefinitely. This physiologic pupil-
ewenfeld et al. (264) examined 150 normal subjects using lary unrest, also called hippus, is present in all normal per-
infrared flash photography and concluded that Tournay’s sons and is not triggered by accommodation (266). It is re-
phenomenon occurs in normal subjects, but that its preva- duced or absent when the afferent or efferent path of the
lence is low and its extent small (less than 10% of subjects light reflex is impaired or in the presence of spastic miosis.
showed a change in anisocoria greater than 0.3 mm). Lo- Some investigators believe that physiologic pupillary unrest
ewenfeld (109) suggested that Tournay’s phenomenon may modulates the excitability of cells throughout the visual path-
result from ‘‘straying’’ of impulses that were meant for the way by constantly changing the exposure of the retina to
medial rectus subnucleus to the nearby Edinger-Westphal light (267); however, others emphasize that such a function
nucleus. This would cause slight constriction of the pupil of pupillary instability cannot be of major importance to the
when the eye adducts and relative dilation of the pupil when visual process because patients with fixed pupils have no
the medial rectus subnucleus is inhibited (during abduction). impairment of visual function (268).
Whatever the explanation, it is reasonable to conclude that Physiologic pupillary unrest should not be confused with
two similar but unrelated phenomena: oscillatory pupillary the consensual constriction of the contralateral pupil (Fig.
movements that occur with reduced alertness (269) and 14.30). This light-induced anisocoria was said to be ‘‘alter-
edge-light induced pupillary oscillations. nating’’ because it depended on which eye was stimulated.
That oscillatory movements of the pupil occur with chang- Smith and coworkers (279,280) studied 72 normal subjects
ing states of wakefulness is not surprising. The iris is always using television pupillometry and found that the direct light
under the influence of the labile, dynamic equilibrium of reaction exceeded the consensual reaction in 61 of the sub-
sympathetic and parasympathetic innervation, both of which jects (84.7%). The degree of anisocoria was extremely small,
are active in varying degrees. Specific excitatory and inhibi- with a mean value of 0.075 mm. It occurred in the presence
tory reflexes are superimposed on this constantly wandering and absence of previous dark adaptation and increased pro-
baseline of activity that influences the extent and shape of portionally with reflex amplitude as the intensity of the stim-
the reflex response. The same stimulus may, therefore, elicit ulating light was raised. In addition, this light-induced aniso-
an extensive reflex at one moment and none the next, de- coria showed a high degree of repeatability in 20 subjects
pending on the state of alertness of the individual. Thus, who were tested on two occasions, 1 year apart. Smith et al.
these ‘‘fatigue waves’’ increase when a normal person is (280) found three patterns of ‘‘contraction anisocoria’’ in
drowsy or very sleepy (269) and are suppressed by mental their subjects. In the bilateral form, the amplitude of the
activity (270). direct pupillary response was always greater than that of the
As far as edge-light induced pupillary oscillations are con- consensual reflex, no matter which eye was stimulated. In
cerned, the pupil can be made to oscillate vigorously in a one form of unilateral contraction anisocoria, stimulation
dark room by placing the narrow beam of the slit lamp across of only one side gave a greater direct response, whereas
the pupillary margin of the iris (see Chapter 15). This is stimulation of the other side resulted in equal pupillary re-
clearly the result of the photomotor reflex turning itself off sponses. In the second form of unilateral contraction aniso-
and on. This phenomenon is unrelated to physiologic pupil- coria, the pupillary response of one side always exceeded
lary unrest, because the induced oscillations cease when the that of the other side whether the response was direct or
light is presented in ‘‘Maxwellian view,’’ so that the con- consensual, similar to an efferent pupillary defect. Dr. I.E.
stricting iris does not cut into the beam of light (271). Fur- Loewenfeld was unable to confirm the presence of this sec-
thermore, when the iris of one eye is pharmacologically im- ond form of unilateral contraction anisocoria. She believed
mobilized, stimulation of this eye no longer induces that in normal persons, the consensual light response is al-
pupillary oscillations; however, the normal, physiologic un- ways slightly less than the direct response, even though this
rest continues in the consensually reacting, untreated eye difference usually is not clinically evident.
(111). Studies by several groups using temporal and nasal hemi-
Although the term ‘‘hippus’’ is used to describe physio- field light stimuli indicate that contraction anisocoria may
logic pupillary unrest, it is also used in numerous contradic-
tory ways, including: (a) to describe ‘‘fatigue waves’’ re-
lated to the level of individual alertness (268–270); (b) to
describe pathologic pupillary unrest (272–275); (c) to de-
scribe the pupillary changes that accompany Cheyne-Stokes
respiration (276); and (d) to describe all pupillary unrest,
whether physiologic or pathologic. The term ‘‘hippus’’
should be used synonymously with ‘‘physiologic pupillary
unrest’’ because the phenomenon appears to have no clinical
significance in most patients.
NORMAL PUPILLARY REFLEXES

Reaction to Light
When light is shined in either eye, both pupils constrict.
The constriction in the ipsilateral eye is called the direct
reaction to light and that in the contralateral eye is called
the consensual reaction to light. For practical purposes, with
unilateral light (as well as electric) stimulation, the direct
and consensual reactions are of equal magnitude, provided
that there is no lesion in the parasympathetic or sympathetic
pathways (277,278). Figure 14.30. Consensual deficit (contraction anisocoria) unilateral ver-
sus bilateral. In frame 1, the eyes are in darkness, with equal pupils. In
Alternating Contraction Anisocoria frames 2 and 3, one eye is stimulated by light (as indicated), and in frame
4, both eyes are exposed to light. The patient looks far away, except in
In 1954, Lowenstein described a phenomenon that he frame 5, in which the near vision reaction is shown. RE, right eye; LE, left
called ‘‘alternating contraction anisocoria’’ in which the di- eye. (From Loewenfeld IE. The Pupil. Ames, Iowa State and Wayne State
rect pupillary constriction of the illuminated eye exceeded University Press, 1993.)
be related to the degree of crossed versus uncrossed pupillary age, for a given pupil diameter in darkness, the pupillary
light reflex fibers at both the chiasmal and pretectal decuss- light reactions show slightly less amplitude than those of
ations (109,281–283)—that is, when asymmetries of input younger subjects. In contrast to the findings with long flashes
and output of the light signal exist both at the chiasm and of light, the pupillary reactions to short flashes are relatively
the pretectal olivary nucleus, respectively. At the pretectal insensitive to age-related changes in pupillary size (109).
level in some persons, there may be a greater crossed than The mechanism of these age-related changes is unknown.
uncrossed distribution of the light reflex to the recipient Iris degeneration could be responsible, but there are several
Edinger-Westphal nucleus, resulting in unequal contractions reasons why this does not appear to be the case. First, age-
of the right and left pupil to a light stimulus. This would related iris degeneration seldom begins before the age of 40,
become apparent on full-field stimulation of the eye contra- whereas the decline in pupil size and reactivity is already
lateral to the pretectal nucleus with the greater crossed output apparent at the beginning of the third decade of life and
if there were also greater retinal input to this pretectal nu- continues linearly until it levels off in later decades. Second,
cleus from the eye being stimulated. In other words, if the the light reactions of most normal persons remain brisk well
nasal retina (temporal visual field) provided greater input to into the sixth decade and often beyond. They appear to be
the contralateral pretectal nucleus via its decussation at the limited in amplitude only by a smaller resting pupil size.
chiasm compared with the uncrossed input from the temporal Third, as already mentioned, for a given resting pupillary
retina (nasal field) to the ipsilateral pretectal nucleus, full- diameter in darkness, the pupillary reactions in middle-aged
field stimulation of this eye would then favor more input to persons are even more extensive than those in the young.
the contralateral pretectal nucleus. If distribution of output Finally, pupils of elderly persons usually react extensively
from this nucleus was also unequal, favoring crossed output to both adrenergic and cholinergic pharmacologic agents
to the opposite Edinger-Westphal nucleus, the result would (240,285–287). Thus, in persons over about 60 years of age,
be a pupillary response favoring the pupil of the eye being structural changes in the iris tissues cannot be the primary
stimulated; that is, the direct response would be greater than reason for the age-related decline in pupillary size and func-
the consensual pupil response. tion, although such changes probably contribute to the de-
Contraction anisocoria may have clinical significance creased pupil motility.
only in unilateral cases, where clinical observation of the Decreased sympathetic tone could be responsible for de-
direct pupil response during the swinging flashlight test may creased pupillary size and reactivity with advancing age.
give the erroneous impression of a relative afferent pupillary Korcyzn et al. (241) found that although the mydriasis pro-
defect, when in reality only contraction anisocoria is present. duced by topical hydroxyamphetamine (Paredrine) did not
Based on our studies of pupillographic recordings of both decrease with increasing age, the mydriasis produced by top-
pupils in normal subjects and in patients with organic causes ical cocaine did. Nevertheless, the decrease in size with age
of relative afferent pupillary defects who also happen to have is much greater than can be explained solely on the basis of
unilateral contraction anisocoria, this condition may result sympathetic paresis, there are no other signs of sympathetic
in as much as a 0.3 log unit ‘‘pseudo’’ relative afferent pupil- paresis in otherwise normal persons, and the small pupils of
lary defect. However, in most persons, there is no clinical elderly persons usually dilate well to atropinic agents. Thus,
relevance of this condition, and as far as clinical observation the miosis and decreased reactivity that occur with increas-
is concerned, in normal persons the direct and consensual ing age must occur from cholinergic impulses. Loewenfeld
pupillary light responses are almost always equal. (240) believed that reduced central inhibition is responsible
for the age-related changes in pupillary size and reactivity
Effect of Age on the Pupillary Light reflex that occur in most normal persons. She emphasized that the
pupillary changes that appear with increasing age are similar
Both in infancy and old age, the pupillary light reflex is to those that occur with fatigue, except that they are irrever-
less active than in adolescence and middle age. In addition, sible.
increasing age is associated not only with a decrease in rest-
ing pupillary size (239,240,284) but also with a reduction Role of the Pupillary Light Reflex
in maximum constriction velocity and an increased time to
The pupillary light reflex has several roles. One is to set
both maximum constriction velocity and reflex peak (284).
the pupils at a size that is optimal for visual acuity (288,289).
Loewenfeld (240) evaluated pupillary reactivity to both short
In addition, the reflex appears to reduce light adaptation in
(0.8 sec) and long (3 sec) flashes of light in normal persons
order to prepare the eyes in advance for the return to dim
of all ages and found that for long flashes, the amplitude of
lighting (290,291).
the reaction and the resting pupillary diameter in darkness
are related. This relation is linear in older persons, and there Latent Period of the Pupillary Light Reflex
is little individual scatter; that is, the smaller the pupil, the
smaller the amplitude of the light reaction. With decreasing The latent period of the light reflex is relatively long, as
age, there is increasing scatter, although the basic relation- is to be expected in a reflex with a smooth-muscle effector.
ship remains the same. In addition, for a given pupil size in With a bright light, the latent period is about 0.2 second. As
darkness, the light reactions of persons 40–60 years of age the stimulus is dimmed, the latent period is prolonged until
are more extensive than those of children or young adults it approaches 0.5 second (292–294). Although the increase
with pupils of the same size. In persons over 60 years of in latency is mainly linear, the overall curve of normal pupil-
lary latency with decreasing stimulus intensity is somewhat range of about 3 log units, the pupillary constrictions become
nonlinear in response to brighter light stimuli (Fig. 14.13). more extensive and constant. Throughout this low-intensity
This results in a latency period that is about 30–40 msec range of luminance, the responses are, however, typically
per log unit attenuation of light stimulus when given in the shallow; that is, the constriction is preceded by a long latent
mesopic and low photopic-intensity range. However, over a period, and it is slow, small, and of short duration (Fig.
brighter range of light stimuli, the latency period may only 14.31). When the light intensity is increased, the pupillary
be delayed 10–15 msec per log unit attenuation. reactions begin to increase markedly in amplitude, speed of
movement, and duration of constriction until maximal values
Effect of Stimulus Intensity on the Pupillary are reached at about 7–9 log units above the scotopic visual
Light Reflex threshold. This sudden increase in effectiveness of the light
Within a critical period of 100 msec, the pupillary effec- stimuli occurs because the cone threshold has been exceeded,
tiveness of light intensity and duration are interchangeable. and cones produce much greater pupil contractions (111,
When a dark-adapted eye is exposed to light flashes of short 295,296). Very powerful light flashes fail to add further to
duration, the pupillary threshold is very low. Using appropri- the amplitude and speed, and they do not reduce the latent
ate recording techniques, small but distinct pupillary reac- period of the reactions, but they greatly prolong the constric-
tions usually can be obtained well within the first log unit tion. After such stimuli, the pupils may remain in spastic
of stimulus luminance above a subject’s scotopic visual miosis for several seconds.
threshold. When the intensity of the light is increased over a
Spectral Sensitivity of the Pupillary Light Reflex
The pupillomotor effectiveness of a colored light stimulus
is related to its apparent brightness. For each color, the
threshold for pupillary reactions is almost as low as the corre-
sponding visual threshold. This is true for all areas of the
retina and in the dark-adapted as well as the light-adapted
eye. In other words, the Purkinje shift exists for the pupil
as well as for visual sensation (Fig. 14.32). This phenomenon
provides further evidence that pupillary and visual function
share the same photoreceptors (discussed previously). As
described previously, melanopsin-containing retinal gan-
glion cells are capable of direct photic activation and provide
the afferent input to the midbrain pathway of the pupil light
reflex. These photosensitive neurons have a broad spectral
sensitivity that is centered on approximately 490 nm.
Figure 14.31. Reflexes to short and longer light stimuli at low and high
levels of stimulus intensity. Pupillary diameter is recorded as the ordinate
(mm) against time as the abscissa (0.1-second units). The dashed lines show
the pupillary responses to 0.1-second light flashes (double arrows in a);
the solid lines, those to 1.0-second stimuli (double arrows in b). In A (first
line), dim light was used, about 3 log units above the subject’s scotopic
visual threshold. The reactions to short (a) and long (b) light flashes were
similar. Both showed a long latent period, low peak speed, small extent,
and short duration typical for low-intensity reactions. In B (second line),
the light intensity was increased to about 9 log units above the visual thresh-
old of the subject. The long bright light stimulus (b) caused the pupillary
constriction to continue for a longer time and thus to become more extensive Figure 14.32. Purkinje shift in pupillary spectral sensitivity. The two
than the reflex elicited by the short bright light flash (a), even though latent curves were constructed from photographic records of pupil size obtained
period and peak speed of the two reactions were alike. Compared with the after 15 minutes of adaptation to darkness or light of different wavelengths
low-intensity reflexes of line A, the latent period was shortened and the (equal energy stimuli, with a tungsten light source and Hilger wavelength
constriction speed increased. (From Lowenstein O, Loewenfeld IE. Sco- spectrometer). (From Loewenfeld IE. Recent Developments in Vision Re-
topic and photopic thresholds of the pupillary light reflex in normal man. search. Publ No 1272. Washington, DC, National Academy of Sciences,
Am J Ophthalmol 1959;48⬊87–98.) National Research Council, 1966.)
Pupillomotor Sensitivity of the Retina by bleaching and by real backgrounds (297–305), and this
depression of sensitivity can be quantified by the construc-
The retinal periphery is far less efficient than the fovea tion of the equivalent background of the bleach that is used
in producing extensive pupillary constriction, and if the am- to describe psychophysical results (104,306).
plitude of the light reaction were used as a measure of retinal In view of the many kinds of functional parallelism be-
sensitivity, the pupillomotor sensitivity of the fovea would tween pupillary responses and both objective and subjective
seem to be far greater than that of the periphery. However, visual sensory phenomena, it can safely be assumed that
when light stimuli of low intensity are presented, the periph- they use the same retinal photoreceptors. As noted above,
ery of the retina has a much lower pupillomotor threshold the photosensitive melanopsin-containing retinal ganglion
and is thus much more sensitive than the fovea, although cells, which also can be activated by rod and cone input,
the light reactions produced by stimulating the periphery are appear to subserve the pupil light reflex and input to diurnal
of low amplitude. The pupillary sensitivity of the retina is centers in the hypothalamus. It is also possible that a small
thus remarkably similar to the visual sensitivity (Fig. 14.33). number of ganglion cells serve both functions, with the im-
In fact, visual acuity can be measured using pupil responses pulses reaching their separate destinations by collateral
to checkerboard stimuli with a fair degree of accuracy branching in the final third of the optic tract, and the fibers
(113,117,119). In addition, as is the case with vision, the affecting pupillary function descending into the mesenceph-
threshold for pupillary reaction is elevated in a similar way alon to synapse in the pretectal nuclei.
Figure 14.33. Pupillomotor and visual sensitivity to green light in the fovea and in the retinal periphery for the dark-adapted
eye. Log relative effectiveness of 0.25-second test flashes in a 2⬚ area is represented by the ordinate. A tungsten light with a
rotating shutter and interference filter was used. Retinal positions are indicated on the abscissa. The visual thresholds (solid
line) are parallel, with the pupil about 1.5 log units less sensitive than visual perception. In this experiment, the pupillary
reactions were detected by visual observation with an infrared-sensitive image converter. When the pupillary reactions are
recorded graphically and when larger testing areas are used, the pupillary threshold is closer to the visual threshold. Note the
central depression for green light, shown in the pupillary reactions as well as for the visual threshold, and the lack of sensitivity
at the blind spot. (From Loewenfeld IE. Recent Developments in Vision Research. Publ No 1272. Washington, DC, National
Academy of Sciences, National Research Council, 1966.)
Modification of the Pupillary Light Reflex by Emotion

and Fatigue
Fatigue and emotional excitement are so much a part of
everyday life, and their modifying influence upon pupillary
diameter and reactions is so profound, that their effects must
be understood and constantly kept in mind when considering
the pupillary reaction to light. The light response is depen-
dent on a person’s level of consciousness. When a normal
person is alert, the central synapse of the pupillomotor reflex
arc in the Edinger-Westphal nucleus is subject to central
inhibitory influences. At the same time, hypothalamic dis-
charges are produced by sensory or emotional stimuli pro-
vided by the environment or by spontaneous thoughts or
emotions. These impulses travel via the brain stem, cervical
cord, and peripheral sympathetic chain to the dilator muscle
of the iris. As the subject drifts toward sleep, his or her
cerebral and diencephalic centers cease to function in an
orderly sequence. Central inhibition of the visceral oculomo-
tor nuclei decreases, sympathetic activity is gradually lost,
and the consequent relative preponderance of parasympa- Figure 14.34. Mechanisms affecting pupillary size and reactivity. Para-
thetic outflow results in miosis. At the moment of sponta- sympathetic innervation causes active pupillary constriction (black arrow);
neous or reactive awakening, sympathetic activity returns, its central nervous inhibition causes incomplete, passive dilation of the pupil
and this, combined with supranuclear inhibition of the iris (cross-hatched arrow). Sympathetic excitation dilates the pupil rapidly and
sphincter, results in pupillary dilation. completely (white arrow). Adrenergic substances, entering the blood under
the influence of central nervous mechanisms elicited by strong sensory or
Thus, under the influence of the mechanisms described
emotional stimulation, may reinforce and prolong pupillary dilation (dotted
above, the pupil in healthy, alert persons is relatively large, arrow). Finally, the limits of mechanical capacity of the iris muscles may
with only a slight amount of physiologic pupillary unrest. modify the movements when extremes of mydriasis or miosis are ap-
As the subject becomes tired, the pupils gradually become proached (small black arrows). (From Loewenfeld IE. Recent Develop-
smaller, and oscillatory fatigue waves become apparent. At ments in Vision Research. Publ No 1272. Washington, DC, National Acad-
the moment immediately preceding sleep, the pupils are emy of Sciences, National Research Council, 1966.)
quite small, but a psychosensory stimulus such as a sudden
sound will restore the waking condition and redilate them
(307). Pupillary light reflexes thus are superimposed upon Conditioning of the Pupillary Light Reflex
a constantly shifting equilibrium of autonomic innervation
of the iris that can be modified further by humoral adrenergic Attempts to evoke experimentally the light response by
mechanisms (214) and influenced by the mechanical limita- conditioning the photomotor pupillary system to another
tions of the iris (Fig. 14.34). stimulus have produced conflicting results. In such experi-
ments, there are many possible sources of error, especially
in the absence of continuous recording of the pupillary reac-
Binocular Interactions of the Pupillary Light Reflex tions. Some claims of successful conditioning of pupillary
The extent of binocular interaction that exists in normal responses apparently resulted from confusion with unrecog-
individuals has been the subject of much experimentation nized physiologic pupillary unrest and with the miosis of
and controversy and appears to depend to some extent on fatigue. In our opinion, the most careful investigators have
the phenomena studied and the way the study is conducted. been unable to demonstrate any conditioning of the light
Although most investigations dealing with binocular interac- reflex (311,312).
tion have been concerned with sensory phenomena, some
have dealt with the pupillary reaction to light. Bárány and Pupillary Light Reflex as a Servomechanism
Halldén (308) reported that pupillary responses to light stim- The pupillary light response is mediated by fairly well-
uli tended to be inhibited or abolished during suppression defined neuroanatomic processes and has a stimulus that can
phases of binocular (retinal) rivalry; however, Lowe and be quantitatively controlled in a laboratory environment. In
Ogle (309) were unable to confirm these results. Simons addition, it is possible to obtain continuous recordings of
and Ogle (310) performed carefully controlled experiments pupil movement. Thus, the pupillary response system is par-
using infrared electronic pupillography and showed that the ticularly amenable to mathematically oriented studies (313).
light threshold for pupillary constriction by foveal stimula- Stark and Sherman (314) initially constructed a system based
tion in one eye is essentially independent of the light adapta- on feedback control, and an analysis of the stochastic proper-
tion level of the other eye. This finding suggests that there ties of light-induced pupillary movement led Stanten and
is no interocular influence as far as pupillary thresholds are Stark (315) to develop an overall system model, the compo-
concerned. nents of which are related, at least grossly, to anatomic struc-
ture. Using this model, several investigators (243,316) de- from the Edinger-Westphal nucleus to the iris sphincter via
fined the relationship between motor neuron activity and the ciliary ganglion. They differ mainly in the supranuclear
pupil size, and Terdiman et al. (317) described information pathways that are elicited by light and near that both con-
transfer through the entire system (318). These papers as verge on the Edinger-Westphal nucleus. Langley and Ander-
well as a summary of this work by Stark in Chapter 12 of son (326), after careful exposure of a cat’s orbit, painted the
Loewenfeld’s book (109) are recommended to those inter- ciliary ganglion with nicotine and succeeded in blocking all
ested in this approach to pupillary responses. pupillary response obtained by stimulating the oculomotor
nerve, whereas stimulation of the short ciliary nerves re-
Pupillary Reaction to Darkness mained effective. This experiment provided convincing
physiologic evidence that there is a single final common
The pupillary response to darkness is elicited by a short pathway for pupillary constriction with a synapse at the cili-
interval of darkness after an eye has been adapted to light. ary ganglion.
This dilation is bilateral and follows a latent period that is It should be remembered that the pupillary constriction
somewhat longer (about 300 msec) than that preceding pu- that is part of the near response is subject to the same central
pillary constriction to light. The time course of the pupillary inhibitory and sympathetic antagonistic influences as is pu-
dark response does not change with age (319). This dilation pillary constriction to light. For example, the constriction
may result from more than a simple cessation of the constric- associated with a near vision effort may be blocked by a
tion to light. There may be active inhibition of the visceral simultaneous, psychosensory dilation.
oculomotor nuclei because of an ‘‘off’’ discharge in the ret- Schäfer and Weale (327) studied the influence of age on
ina as described above in the section on retinomesencephalic the pupillary near response. These investigators found that
inhibition associated with the dark reaction (320). A disrup- aging results in a reduction of pupillary diameter as well as
tion of the pupillary reaction to darkness may be responsible a reduction in the amplitude of pupillary constriction during
for the ‘‘paradoxic’’ pupillary response—constriction of the the near response. Studies by these investigators and by Roth
pupils in darkness —that is observed in patients with various (328) also indicate an effect of retinal illumination on pupil-
retinal diseases. lary constriction during the near response. It appears that the
pupillary near response is directly related in magnitude to
Pupillary Reflex to Near and the Near Response the existing level of illuminance and that it functions in ac-
As fixation is shifted from a far to a near object, the eyes cord with other adaptive mechanisms that alter the overall
converge, the lenses accommodate, and both pupils constrict. sensitivity of the eye.
This triad of ocular motor, accommodative, and pupillary There appears to be no interocular modification of the
activity is called the near response. Despite many conten- pupillary response to near. Jagerman (329) found that when
one pupil was dilated (but not cyclopleged) and forced to
tions in the literature claiming that the pupillary constriction
fixate a near target, there was no change in the degree of
that occurs during the near response is exclusively dependent
pupillary constriction that occurred in the opposite (unmedi-
on either convergence or accommodation, clinical and exper-
cated) eye. However, Jagerman (329) measured pupillary
imental data indicate that any of the three functions can be
size using a mirror and a gauge with black semicircles of
selectively abolished or elicited without affecting the others various diameters rather than by infrared pupillography.
(156). For example, convergence or accommodation may be The pupillary near reflex can be evaluated in terms of a
eliminated selectively with prisms or lenses (321–323) and servomechanism, just like the pupillary light reflex (315).
pupillary constriction alone can be blocked by weak, para- Using this method, Semmlow and Stark (330) found that the
sympatholytic substances without noticeable cycloplegia. In dynamics of iris movement in the pupillary near response
addition, isolated pupillary constriction, accommodation of provide a relatively linear input to the iris motor system.
the lens, and contraction of the medial rectus muscle can Responses of the iris to step-like changes in target distance
each be separately produced by electric stimulation of differ- show two major nonlinearities: a range-dependent response
ent parts of the cerebral cortex, oculomotor nucleus, or ocu- gain that decreases as pupil size decreases and a direction
lomotor nerve (156,192,324,325). Finally, clinical cases of dependence in which constriction is faster than dilation.
isolated impairment or loss of pupillary constriction, accom- As a diagnostic tool for the physician, the pupillary near
modation, or convergence are not uncommon. These experi- response is less reliable than the light reflex because of its
mental and clinical observations confirm that the impulses subjective features. When pupillary constriction is poor or
that cause accommodation, convergence, and pupillary con- absent during near viewing, it is difficult to be certain that
striction arise from different cell groups within the oculomo- the patient has made a satisfactory effort to obtain clear near
tor nucleus and travel via separate fibers to their effector vision. For practical purposes, the reaction is important diag-
muscles. Accommodation, convergence, and pupillary con- nostically only when it is more extensive than the constric-
striction are associated movements and are not tied to one tion to light, as occurs in many cases of the dorsal midbrain
another in the manner usually referred to by the term ‘‘re- syndrome or in patients with Argyll Robertson or tonic pu-
flex.’’ They are controlled, synchronized, and associated by pils.
supranuclear connections, but they are not caused by one
another. Reflexes Following Eyelid Closure
The miosis of the near response and the pupillary constric- Pupillary movements that occur after spontaneous blink-
tion to light have a single final common efferent pathway ing or voluntary blinking or as a reaction to corneal stimula-
tion may be collectively called the ‘‘pupillary lid-closure scious animals. In anesthetized animals, the active sympa-
reflexes.’’ Considering the many conditions that produce thetic component of pupillary dilation is abolished, and the
eyelid closure, it is not surprising that the associated pupil- pupils are dilated by inhibition of the sphincter nuclei alone.
lary movements vary. When eyelid closure is spontaneous These inhibitory impulses converge upon the oculomotor
or voluntary, the pupillary reaction consists of a short con- nucleus from cortex, thalamus, and hypothalamus and from
striction followed by redilation. When eyelid closure is elic- connections running in the diffuse reticular formation. The
ited by a corneal or equivalent trigeminal sensory stimulus, resulting pupillary dilation is slower and less extensive than
the pupil dilates, and quite often this immediate reaction is reflex dilation in the conscious animal elicited by direct stim-
followed by secondary blinks that produce pupillary con- ulation of the cervical sympathetic chain.
striction. Confirmation of these mechanisms was provided by the
In any given eyelid-closure reaction, pupillary constric- electrophysiologic work of Bonvallet and Zbrozyna (331).
tion or dilation is dependent on: (a) the intensity of the illu- These investigators stimulated the pontomesencephalic re-
mination present in the environment; (b) the duration of ticular formation of the cat while monitoring the activity of
eyelid closure; and (c) the presence of any associated psy- the short ciliary nerves in the retrobulbar space and in the
chosensory stimulus. When observed in light, for example, sympathetic chain in the neck. They showed inhibition of
long intentional closing of the eyes produces the dilation the parasympathetic outflow occurring simultaneously with
phase of the darkness reflex, whereas short intentional or excitation of the cervical sympathetic chain. They also dem-
reflex blinks dilate the pupils when accompanied by emo- onstrated that anesthesia eliminated the sympathetic outflow.
tional overlay and constrict them in the absence of such Humoral mechanisms can also influence pupillary dila-
psychosensory stimuli. tion. Adrenergic substances reaching the dilator muscle via
The cause of the pupillary movements with eyelid closure the blood cause it to contract, even when the sympathetic
becomes clear when it is observed that spontaneous or volun- pathway and the oculomotor nerve have been cut. Norepi-
tary eyelid closure in darkness fails to produce any pupillary nephrine, presumably released from the heart and great ves-
reaction, and eyelid closure from corneal stimulation causes sels, reaches the eye in 2–5 seconds and dilates the pupil.
the usual pupillary dilation. Thus, the constriction on re- Adrenal catecholamines are released in sufficient quantity
exposure to light results from an increase in retinal sensitiv- to affect the eye only after severe, stressful stimulation. Be-
ity during the brief interval of darkness. cause the adrenaline is released into veins, it does not reach
the eye until 12–15 seconds after the stimulus, and in the
Reflex Dilation supersensitive, sympathectomized animal, the pupil may re-
In darkness, the pupils of normal, alert subjects are usually main dilated for several minutes. In humans, pupillary dila-
large and relatively steady. When the same persons are tired, tion can result from any sensory, psychological, or emotional
relatively slow and irregular waves of pupillary contraction stimulus, and after spontaneous or voluntary motor activity;
and dilation accompany the waves of drowsiness and however, humoral mechanisms rarely produce pupillary
arousal. As noted above, when someone is drifting off to changes except under conditions of catastrophic stress or
sleep, there is miosis. This is the extreme example of the following the development of denervation supersensitivity.
observation that arousal or any increase in alertness produces Psychosensory reflex dilation of the pupil may take many
a reflex pupillary dilation. In waking animals or humans, forms and may be produced in many ways. For the cilio-
any sensory or emotional stimulation causes the pupils to spinal reflex, the neck is pinched; for the cochleopupillary
dilate. The mechanisms of this dilation are somewhat contro- reflex, a tuning fork is placed near the ear; and for the vestib-
versial (109,214), but two neural mechanisms appear to be ulopupillary reflex, one labyrinth is stimulated. In ‘‘Flatau’s
involved, one active and one passive. The active component neck mydriasis,’’ the neck is flexed, whereas ‘‘Redlich’s
results from contraction of the radially arranged fibers of phenomenon’’ is produced by a vigorous and sustained mus-
the dilator muscle via the cervical sympathetic pathway, and cular activity. In ‘‘Meyer’s iliac phenomenon,’’ pressure on
the passive component results from relaxation of the sphinc- McBurney’s point produces pupillary dilation.
ter muscle caused by inhibition of the visceral oculomotor In addition to the reflexes described above, psychosensory
nuclei. These pupillary responses to sensory stimuli are part activity is responsible for the pupillary abnormalities once
of a generalized arousal reaction that affects the entire body. thought to be characteristic of schizophrenic and neurotic
The active sympathetic discharges are the chief cause of patients (332,333) and also explains the ability of some per-
rapid and extensive pupillary reflex dilation seen in con- sons to dilate both pupils voluntarily.
ACCOMMODATION AND THE AUTONOMIC NERVOUS SYSTEM

As noted above, when normal persons shift fixation from peripheral motor effector for this mechanism is the muscle
far objects to near objects, the near response occurs. During of the ciliary body. This smooth muscle is activated primar-
this response, both eyes converge, pupillary constriction oc- ily by the mesencephalic, parasympathetic outflow but is
curs, and a change also occurs in the optical system of the also influenced by cervical sympathetic outflow as well. The
eye. This optical change, termed accommodation, is con- ciliary body containing the ciliary muscle encircles the ante-
trolled by an elaborate sensorimotor mechanism that moni- rior, inner surface of the eye as a girdle (Fig. 14.35). It
tors the clarity of the image focused upon the retina. The conforms externally to the curvature of the overlying sclera
Figure 14.35. The inner surface of the ciliary body and lens. The nasal side of the eye is at N and the temporal is at T. a,
pars plicata; b, pars plana; c, ora serrata; d, dentate processes; e, pars plana bays; f, striae of the dentate processes; g, ciliary
processes; arrows, valleys of the pars plicata. (From Straatsma BR, Foos RY, Spencer LM. The New Orleans Academy of
Ophthalmology: Symposium on Retina and Retinal Surgery. St Louis, CV Mosby, 1969.)
and has a triangular shape in cross-section (Fig. 14.36), with entations (Fig. 14.38). Rohen (334) suggested that the whole
the base of the triangle facing the anterior chamber and the muscle is interconnected, with the muscle bundles forming
apex directed posteriorly toward the retina. Anteriorly, the a three-dimensional reticulum consisting of muscle cells that
ciliary body is continuous with the iris, whereas posteriorly, show considerable interweaving from layer to layer.
it is continuous with the rest of the uveal tract and with the
overlying peripheral retina at the ora serrata. The external PATHWAYS FOR ACCOMMODATION
surface of the ciliary body lies adjacent to the sclera, being Parasympathetic Pathway for Accommodation
separated from it by the suprachoroidal space. The internal
surface faces the vitreous. The ciliary body contains three Bender and Weinstein (335) succeeded in producing cili-
layers: (a) unpigmented ciliary epithelium; (b) pigmented ary muscle contraction without pupillary constriction by
ciliary epithelium; and (c) the ciliary muscle, which controls stimulating the caudal portion of the parasympathetic nu-
accommodation (Figs. 14.36–14.38). The ciliary muscle cleus in the midbrain of the monkey. Jampel and Mindel
consists of meridional, radial, and circular muscle fiber ori- (192) passed an electrode stereotaxically in a rostrocaudal
Figure 14.36. Light micrograph of a meridional

section through a normal, human ciliary body. a,
iris root; b, anterior chamber angle; c, pars plicata;
d, pars plana; e, unpigmented ciliary epithelium; f,
pigmented ciliary epithelium; g, connective tissue
of the ciliary body stroma; h, elastic lamina that is
part of Bruch’s membrane; i, j, and k, longitudinal,
radial, and circular portions of the ciliary muscle
respectively. Single arrows and double arrows
mark the extent of basement membrane-like mate-
rial that forms the innermost boundary of the ciliary
body stroma and separates it from the ciliary epi-
thelium. (From Hogan MJ, Alvarado JA, Weddell
JE. Histology of the Human Eye: An Atlas and
Textbook. Philadelphia, WB Saunders, 1971.)
Figure 14.37. Drawing of the inner aspect of the ciliary body to show the pars plicata (a) and the pars plana (b). c, ora
serrata; d, peripheral retina showing cystoid degeneration; e, oral bays; f, dentate processes; g, striae of the dentate processes;
h, radial furrows of iris; i, circular furrows of iris. Note the origin of the zonular fibers from the pars plana and the insertion
of the fibers onto the lens capsule. (From Hogan MJ, Alvarado JA, Weddell JE. Histology of the Human Eye: An Atlas and
Textbook. Philadelphia, WB Saunders, 1971.)
Figure 14.38. Drawing of the ciliary body showing the ciliary muscle and its components. The cornea and sclera have been
dissected away, but the trabecular meshwork (a), Schlemm’s canal (b), two external collecting veins (c), and the scleral spur
(d) remain. The three components of the ciliary muscle are shown separately, viewed from the outside and sectioned meridionally.
Section 1 shows the longitudinal ciliary muscle; in section 2, the longitudinal muscle has been dissected away to show the
radial ciliary muscle; and in section 3, only the innermost circular ciliary muscle is shown. The longitudinal muscle forms
long V-shaped trellises (e) that terminate in the epichoroidal stars (f). The arms of the V-shaped bundles formed by the radial
muscle meet at wide angles (g) and terminate in the ciliary processes. The V-shaped bundles of the circular muscle originate
at such distant points in the ciliary tendon that their arms meet at a very wide angle (h). The iridic portion of this muscle (i)
is shown joining the circular muscle cells. (From Hogan MJ, Alvarado JA, Weddell JE. Histology of the Human Eye: An Atlas
and Textbook. Philadelphia, WB Saunders, 1971.)
direction through the small-cell component of the primate causes 3% of these cells to become chromatolytic (190).
Edinger-Westphal nucleus and observed first a forward dis- These results highlight the fact that the vast majority of cili-
placement of the iris diaphragm (i.e., accommodation) with- ary ganglion neurons innervate the ciliary body, whereas the
out constriction of the pupil. At a more caudal level, stimula- minority provides innervation to the iris sphincter.
tion produced pupillary constriction without evidence of
accommodation. Effect of the Ciliary Muscle on Accommodation
Studies in alert behaving rhesus monkeys have greatly
clarified the details of the parasympathetic outflow to the The ciliary muscle, through its zonular attachments to the
ciliary muscle. Gamlin et al. (336–338) studied single-cell lens, produces distinct changes in its structure, which brings
activity in the Edinger-Westphal nucleus during various about changes in accommodation. The physical changes of
near-viewing tasks. During normal viewing, accommodation accommodation were described in some detail by Adler
and vergence are so closely matched that it is difficult to (341) and consist of the following:
determine whether cellular activity is related to accommoda-
tion or to vergence. By carefully designing stimuli that cre- 1. The anterior pole of the lens moves forward and the ante-
ated specific vergence and accommodative demands, these rior chamber is narrowed.
investigators were able to differentiate various cell types 2. The anterior surface of the lens becomes more convex.
that responded primarily to accommodation (ⳭA cells), to 3. The posterior surface of the lens becomes more convex,
vergence (ⳭV cells), or to both accommodation and but the posterior pole remains fixed.
vergence (ⳭV Ⳮ A cells). 4. The anteroposterior diameter of the lens is increased.
Nearly all Edinger-Westphal cells that respond to pure 5. The anterior surface of the lens assumes a hyperbolic
accommodative stimuli can be antidromically stimulated curve; that is, the center of the lens surface becomes more
from the ipsilateral oculomotor nerve and thus are consid- convex while the periphery becomes flatter.
ered to be preganglionic neurons innervating the ciliary mus- 6. The diameter of the lens is narrowed.
cle (336,337). These cells have a distinct pattern of activity 7. During maximum accommodation, the lens sinks in the
unlike other cells in the vicinity of the oculomotor nucleus direction of gravity about 0.25–0.3 mm.
that respond to vergence stimuli, accommodative stimuli, or
both. They are characterized by a low spontaneous firing The means by which the ciliary muscle accomplishes its
rate in the dark or at optical infinity (mean 11.5 Hz) and a control of lens curvature has been the subject of lively debate
modest increase that is linearly related to the amplitude of for hundreds of years. There are two major theories: the
the accommodative response. On the other hand, cells in the relaxation theory and the tension theory (342). In 1855,
Edinger-Westphal nucleus that respond to near targets but Helmholtz (343) popularized the theory that the lens pos-
cannot be antidromically stimulated through the oculomotor sesses elasticity, and believed that changes in the shape of
nerve are never purely accommodative (i.e., ⳭA cells); they the lens were brought about by an interplay between zonular
respond to either vergence stimuli (ⳭV cells) or to both tension generated by the ciliary body and lens tension gener-
vergence and accommodative stimuli (ⳭV Ⳮ A cells). Their ated from internal elastic properties. For example, increases
spontaneous firing rates and their overall sensitivity to ac- in zonular tension would pull on the lens, resulting in a
commodative stimuli are much higher than purely accommo- shortening of its anterior-posterior axis with an increase in
dative cells. The two cell types that cannot be antidromically equatorial diameter, thus making its surface flatter and less
stimulated are collectively designated as ‘‘near-response’’ curved. When the pull of the zonules is relaxed, the internal
neurons and are presumed not to innervate the ciliary muscle, elastic properties of the lens would allow the equatorial di-
although a nonsynapsing pathway cannot be ruled out for ameter of the lens to diminish, and the lens would get thicker
the ⳭV Ⳮ A cells. Gamlin et al. (337) suggest that these in the middle, with both anterior and posterior surfaces be-
non-preganglionic neurons project efference copies of near- coming more curved. Henderson (344) accepted the princi-
response activity to the spinal cord, cerebellum, or precere- ples enunciated by Helmholtz (343) but proposed that in-
bellar structures, as has been suggested from other studies stead of the elasticity of the lens being balanced by the
in both cats and primates (339,340). Alternatively, these elasticity of the choroid, as Helmholtz believed, it is bal-
Edinger-Westphal neurons may be premotor in nature and anced by the tone of the ciliary muscle. The relaxation theory
may project either directly or indirectly to preganglionic of accommodation, in which focusing at near results in relax-
Edinger-Westphal neurons or to medial rectus motoneurons. ation of zonular tension and thickening of the lens, is sup-
The predominant view of the innervation of the iris ported by both clinical and experimental studies (345–348)
sphincter muscle and ciliary body is that preganglionic para- as well as mathematical modeling (349).
sympathetic fibers from the mesencephalon synapse in the Tscherning (350) proposed a diametrically opposite the-
ciliary ganglion and that postganglionic fibers innervate the ory to the relaxation hypothesis. He visualized the zonular
iris sphincter muscle and ciliary body. En route to the ciliary fibers becoming taut during accommodation, and he thought
ganglion, these fibers travel superficially as part of the oculo- that this accounted for pressure upon the peripheral portions
motor nerve and occupy a topographic location adjacent to of the lens and for bulging of the central portion anteriorly.
the pupillomotor fibers. Surgical removal of the short ciliary He later modified this view but continued to believe that
nerves in macaque monkeys produces chromatolysis in 97% the zonular fibers did not relax but became tighter during
of the cells in the ciliary ganglion, whereas iridectomy alone accommodation. He accepted the idea that the vitreous press-
ing upon the posterior surface of the lens accounted for ante- mechanisms. He recorded accommodative changes in the
rior bulging of the portion of the lens not covered by iris. primate eye by using a retinoscope during faradic stimulation
The tension theory of accommodation is not supported by in overlapping areas of the preoccipital (peristriate) cortex.
clinical observations as is the relaxation theory but is based Accommodation was usually obtained in both eyes by unilat-
upon conclusions drawn from anatomic studies. eral cortical stimulation. It was always accompanied by con-
Most authors favor the relaxation theory of accommoda- vergence and often by pupillary constriction. Jampel (360)
tion, but some remain unconvinced (351). proposed that all three elements of the near response—ac-
commodation, convergence, and pupillary constriction—are
Sympathetic and Parasympathetic Control of the
synthesized in the cerebral cortex and then are modified at
Ciliary Muscle
a functionally lower level, in the pretectum and tectum of
In 1860, Henke proposed that the circular and longitudinal the midbrain, where they are influenced by less malleable
fibers of the ciliary muscle have opposing actions in accom- systems, including the light reflex, afferent input from the
modation, known as reciprocal innervation. Working with extraocular muscles, and vestibular, postural, and cerebellar
animal eyes, Morat and Doyon (352) postulated that the modulatory impulses (361,362). Ultimately, the impulses are
parasympathetic nervous system was responsible for accom- projected onto the cell bodies of the neurons of the final
modation during the near response, whereas the sympathetic common pathway that are located in the oculomotor nucleus
nervous system was responsible for relaxing accommodation and are transmitted separately to their effector organs.
through inhibition of the ciliary body muscle. Henderson Other studies suggest that cortical control of accommo-
(344) believed that the sympathetic system, at least in the dation originates in the lateral suprasylvian (LS) area
monkey, was excitatory to longitudinal and radial fibers of (363–364). This cortical area surrounds the middle suprasyl-
the ciliary muscle and inhibitory to the circular fibers, and vian area in the cat. Descending projections from accommo-
the parasympathetic system acted in the opposite manner. dation-related neurons in this cortical area terminate mainly
Cogan (353) suggested that the sympathetic system func- in the rostral portion of the superior colliculus (363). The
tions in adapting the eye for relatively distant objects and accommodation-related areas of the superior colliculus also
tends to oppose the parasympathetic system that functions in receive retinal afferents from the macular area and project
adapting the eye for near objects. He observed that following to the pretectum. It is possible that the retino-collicular con-
sympathectomy, there was greater accommodation ampli- nections are part of an open-loop control system that is re-
tude, whereas after sympathetic stimulation, there was responsible for the initial phase of the accommodative re-
duced accommodation in patients in whom one eye had sponse and that the LS-collicular-tectal system is responsible
adrenergic supersensitivity brought about by previous uni- for fine-tuning the accommodative response using cortical
lateral section of the cervical sympathetic trunk. Further evi- control (366).
dence for sympathetic modulation of accommodation was
Other supranuclear mechanisms must influence accom-
demonstrated in enucleated cat eyes, where a change in
modation. Hypothalamic pathways exist to inhibit activity
shape of the ciliary body could be observed after application
in the ciliary neurons of the Edinger-Westphal nucleus in the
of adrenergic drugs (354) or when the long ciliary nerves
same way that such pathways inhibit the pupillary constrictor
were electrically stimulated (355).
Fenton and Hunter (356) reported on the histologic exami- neurons. Central sympathetic activity must also modify the
nation of the eyes of two patients with long-standing com- function of the ciliary body. Although clinical evidence sug-
plete oculomotor palsy. Both eyes showed selective loss of gests that this is the case, systematic experimental investiga-
the circular portion of the ciliary muscle, whereas the longi- tions of these autonomic influences on ciliary activity have
tudinal and radial portions of the muscle remained intact. not been pursued with the vigor that has been applied to the
These findings lent support to the concept of a dual nerve problems of pupillomotor control.
supply to the ciliary muscle, with sympathetic innervation
to the longitudinal and radial portions and parasympathetic CHARACTERISTICS OF ACCOMMODATION
innervation to the circular portion. Thus far, we have discussed the process of accommoda-
Hurwitz et al. (357,358) found that parasympathetic inhi- tion in terms of a motor system acting upon an effector organ,
bition was the most potent mechanism in antagonizing ac- the ciliary muscle. We now consider this motor mechanism
commodation in primates. Stimulation of ␣-adrenergic re- in terms of its integrated role in the process of vision.
ceptors produced no significant antagonistic response, Accommodation is controlled by visual sensory inputs and
whereas stimulation of ␤ receptors depressed accommoda- cerebral inputs that drive and monitor the motor output sys-
tion but did not abolish it. Gimpel et al. (359) measured tem. We will examine the control mechanism of accommo-
the effect of topical 2.5% phenylephrine on amplitude of dation in terms of the performance characteristics of the
accommodation in 160 young adults. Although there was a system.
statistically significant mean reduction of 11.7% after treat-
ment, responses varied widely from a 30% increase to a 60% Stimuli to Accommodate
decrease.
During normal binocular viewing, the adjustment of the
Supranuclear Control of Accommodation accommodative mechanism for different distances is pro-
Jampel (360) contributed valuable experimental confirma- duced by a voluntary convergence mechanism and retinal
tion that the cerebral cortex participates in accommodative blur that evoke binocular fusion reflexes (367–371). In addi-
tion, the normal process of accommodation is greatly facili- Stark and Takahashi (368) suggested that the high-frequency
tated by voluntary efforts initiated by the awareness that the component (HFC) did not have a physiologic role but was
object of regard is nearby (367). a ‘‘consequence of important nonlinear characteristics of the
Small scanning movements of the eye represent another accommodative servomechanism.’’ Other studies show that
major factor in the ability of the eye to respond correctly to the peak activity of the high-frequency component of fluc-
a change in the position of an accommodative target. Normal tuations in accommodation (1.0–2.5 Hz) correlates closely
persons, when made to fix steadily on a target, cannot re- with the arterial pulse and probably reflects intraocular
spond with a correct accommodative adjustment as the target tremor created by intraocular blood flow (396). The HFC is
is moved toward or away from them in monochromatic light. therefore unlikely to reflect a purposeful adaptive response
They can respond correctly to a change in the stimulus dis- of the accommodative system. The low-frequency compo-
tance only when ocular scanning movements are permitted nent (LFC), on the other hand, increases in conditions that
(372). It is believed that this scanning permits detection of decrease depth of focus, including increased pupil size
the direction of the retinal defocus by means of the signal (397,398), decreased target luminance (398,399), increased
afforded by directional sensitivity of the cones (the Stiles- target proximity (398,400), and decreased target contrast
Crawford effect). Chromatic aberration is thought to be an- (337,398,401). The HFC is relatively impervious to changes
other cue for evoking accommodation (373,374), as is the in pupil size or these stimulus characteristics.
amount of ambient light in the environment (375–377). Based on early evidence, Alpern (402) first proposed that
accommodative oscillations play an important role in ‘‘fine-
Time Characteristics of Accommodation tuning’’ the accommodative response. The continuous fluc-
tuations may provide information on image quality via nega-
The reaction time of accommodation to rapid changes in tive feedback. However, although the accommodative sys-
the distance of a fixated object is relatively slow. The change tem operates relatively slowly in relation to other motor
in accommodation begins after a time delay of 0.36 second systems, only the HFC fluctuations are fast enough to pro-
(Ⳳ0.09 second) (379). Once the response starts, it continues vide useful information to the accommodative mechanism
in the proper direction in a more or less smooth manner until within its dynamic velocity range. The precise role of accom-
it levels off at the new accommodative level. This process modative fluctuations is therefore not entirely clear. Whether
can be made less exact and less smooth if the target differs these oscillations are similar in any way to the oscillation
only in focus but not in size. Interestingly, the total reaction of the globe during steady fixation or to the oscillations of
time for far-to-near focus is about 20 msec longer than the the pupil (i.e., hippus) during conditions of steady fixation
reaction time from near to far. and illumination is also unclear. Alternatively, the HFC and
the LFC may not play functional roles in human accommo-
Relation Between Pupil Size and Accommodation dation; rather, the LFC may be a vestigial remnant of more
slowly adaptive systems in nonmammalian vertebrates, and
As the size of the pupil diminishes, the speed and amount the HFC may be simply a consequence of ocular pulsations.
of pupillary constriction to either light or near stimulation
also diminishes (380–383). In addition, as pupil size is re- Feedback Control of Accommodation
duced, the amplitude of accommodation generated at differ- Campbell and Westheimer (395) tested the response of
ent target distances up to a distance of 1 meter is diminished the accommodative control system to momentary optic defo-
(384). Very little accommodation is generated at target dis- cusing. These investigators found that the system continu-
tances of greater than 1 meter, regardless of pupil size ously monitors the state of focus and that accommodative
(385–392). responses may be halted and modified according to changing
stimulus conditions. Troelstra et al. (403) analyzed the initial
Stability of Accommodation directional tracking in three subjects. In this experiment, the
investigators attempted to eliminate all extraneous clues,
When normal individuals fixate on a target that is moving such as apparent vertical and horizontal target movement,
gradually toward or away from them, accommodation does size change, blur asymmetry, and illumination differences,
not change in a gradual, steady manner (393). On the con- as well as the possibility of learning the patterns of stimulus
trary, the accommodative response contains definite irregu- presentation. In one of their subjects, the initial direction of
lar fluctuations. It may not track the target accurately, and change in accommodation was in error about 50% of the
it may even make large errors in the opposite direction. Even time. Two other subjects made correct initial changes of
when a target is stationary, there is instability of accommo- accommodation in 100% of the trials. These two subjects
dation. When an eye fixates steadily upon an object inside apparently used subtle perceptual clues afforded by the im-
optical infinity, the refractive power varies constantly over perfect test situation. Troelstra et al. concluded that the ac-
a small range. Whiteside (394) measured fluctuations as commodative system can operate effectively as an ‘‘even-
large as 0.25 diopters, whereas Campbell and Westheimer error servosystem’’ in which the retinal blur evokes
(395) recorded fluctuations as great as 0.4 diopters and noted movement in the system as a trial-and-error function.
that the fluctuations ceased when homatropine was instilled
in the eye and when the subject fixated at optical infinity. Interocular Effects on Accommodation
The frequency characteristics of the fluctuations appeared Jagerman (404) studied eight normal subjects in whom
to be most evident around 0–0.5 cycle/sec and 2 cycles/sec. he dilated one pupil or cyclopleged one eye and measured
the amount of miosis and accommodation in the unmedi- Changes in Accommodation with Age
cated eye when the medicated eye was forced to fixate an
accommodative target. He found that dilation alone pro- Some components of both static and dynamic accommo-
duced no change in the normal miotic or accommodative dation change with age, whereas others remain constant
responses in the opposite eye, but when an eye under cyclo- throughout life (413,414). Specifically, both the speed and
plegia was forced to fixate a near object, ‘‘excessive’’ miosis the amplitude of accommodation are greatest in the young
and accommodation were noted in the opposite (unmedi- and gradually decrease until about age 60 years, by which
cated) eye. time most normal persons have no ability to perform tonic
accommodation. On the other hand, as normal persons age,
Relation Between Accommodation and Convergence they show an increase in their subjective depth of focus,
During normal binocular viewing, accommodation and possibly from an increased tolerance to defocus related to
convergence operate in unison. The basic stimuli for the the gradual onset of presbyopia. Other components of ac-
binocular adjustment for near vision are: (a) change in the commodation, including objective depth of focus and the
vergence of the light reaching the two foveas and (b) tem- peak velocity/amplitude relationship, remain stable, indicat-
poral disparity of the two images relative to the two foveas. ing absence of age effects on the neurologic control of reflex
The relationship between accommodation and the result- accommodation.
ing vergence eye movement may differ depending on
Accommodation in Infants
whether the fixing or non-fixing eye’s movement is moni-
tored. According to most investigators, accommodative When examined under cycloplegia, infants tend to be hy-
vergence is a monocular phenomenon; that is, if one eye is permetropic. Attempts at dynamic retinoscopy in the new-
covered and the viewing eye changes fixation from a far to born indicate that infants can focus their eyes at only one
a near target along its line of sight, the covered eye rotates particular distance, roughly 19 cm (415). Apparently, the
inward (405–409). Although Kenyon et al. (410) used pre- normal infant cannot adjust the focus of its eyes to changes
cise infrared photoelectric eye movement recordings to show in the distance of the object of regard during the 1st month
the presence of movement in the viewing, as well as the of life. Images of targets nearer or farther away are said
nonviewing, eye during accommodation, the total vergence to be proportionally blurred. During the first few postnatal
amplitude in the viewing eye was only about 12% that mea- months, the range of accommodation increases and is said
sured in the covered eye. According to Kenyon et al. (410), to approximate adult performance by the 4th month. Because
a fixation-holding mechanism exists that produces a general the normal newborn infant is functionally decorticate, it
attenuation of both vergence and some saccadic movements seems reasonable to assume that a lack of inhibition of the
in the viewing eye, enabling retention of the target on the Edinger-Westphal and anterior median nuclei would result
fovea. in parasympathetic overactivity in the eye during the first
Accommodation is induced by convergence as an uncon- weeks of life, which may help to explain why the point of
ditioned reflex. The relationship of accommodation and con- focus is relatively close to the eyes during infancy.
vergence is not absolute or fixed, but under normal condi-
tions a unit change in one is accompanied by a unit change Calculation of Accommodation with Age
in the other. A definite range of accommodation is possible
The amplitude of accommodation diminishes gradually
at each position of convergence. Similarly, convergence can
with age. The amount of accommodation remaining at any
vary slightly relative to a fixed state of accommodation. The
given age may be approximated using the ‘‘Rule of 4’s:’’
change in convergence produced by a change in accommo-
dation is termed ‘‘accommodative convergence,’’ whereas Amount of accommodation ⳱ 42 – age/4
the change in accommodation produced by a change in
Thus, for an 8-year-old, the dioptric power of the eye can
convergence is termed ‘‘convergent accommodation’’
be increased about 14 diopters by the contraction of the cili-
(411,412) (see also Chapter 15).
ary muscle and the consequent changes in the lens. By 20
In subjects up to the age of 24 years, convergence-evoked
years of age, this decreases to 11 diopters. For a 30-year-
accommodation is equal to the convergence, but beyond that
old, it decreases to 9 diopters, and by 50 years of age, it is
age it gradually diminishes. The diminution of convergent
about 3 diopters. A 60-year-old normal person has almost
accommodation with age probably is caused by progressive
no accommodation.
sclerosis of the lens and presbyopia, producing a reduced
response to a given innervation and contraction of the ciliary Presbyopia
muscle rather than a change in the relative innervations of
the two functions (412). Although some investigators ex- When the near point has become so far removed that an
plain the relation between convergence stimulus and accom- individual can no longer read fine print, he or she is said to
modation on the basis of an afferent feedback loop from the be presbyopic. Presbyopia commences normally from about
muscle spindles in the medial rectus to the Edinger-Westphal 35–50 years of age, usually somewhat earlier in women than
nucleus, others consider the association of convergence and in men. The principal symptom of presbyopia is inability to
accommodation to be a function of higher nervous activity, read small print. Initially, patients may complain that they
namely a function of the cerebral cortex (see previous section are aware of a finite time that it takes them to focus on a
on supranuclear innervation of accommodation) (360). near object after viewing at a distance. Often, inability to
read is at first present only after prolonged use of the eyes induced by maximum stimulation of the Edinger-Westphal
or when the illumination is poor. It also may become evident nucleus, with preservation of the circumlenticular space, as
during an unassociated illness or after surgery. Uncorrected would be predicted by the classic theory of age-related loss
presbyopia may be responsible for headaches, nonspecific of lenticular elasticity. However, there was a parallel decline
eye pain, and chronic ocular irritation. Such symptoms occur in the centripetal excursion of the ciliary processes (i.e., a
only after prolonged use of the eyes and are actually rela- reduced response of the configurational response of the cili-
tively rare. ary muscle to maximal stimulation of the Edinger-Westphal
Presbyopia is a physiologic process that many investiga- nucleus).
tors once thought was caused by increasing sclerosis or hard- There are several possible explanations for the age-related
ening of the lens nucleus (416). Clinical experience with loss of ciliary muscle responsiveness that produces presby-
lenses dislocated by trauma or removed during cataract sur- opia. Light and electron microscopic studies demonstrate
gery appeared to confirm this theory because the usual age- only modest morphologic changes and suggest that reduced
related cataract is discus-shaped, its shape being maintained muscle contractility is not at fault (427). There is no age-
by the firm lens substance (417). In addition, some investiga- related decline in ciliary muscle muscarinic receptor concen-
tors found normal or even supernormal ciliary muscle func- tration or affinity, nor is there loss of choline acetyltransfer-
tion in prepresbyopic and presbyopic subjects with dimin- ase or acetylcholinesterase activity (428). As noted above, in
ished or absent accommodation (417–422), and in vitro vitro studies of isolated ciliary muscle from rhesus monkeys
studies of isolated ciliary muscle from rhesus monkeys show show no loss of contractility with age (423). It also seems
no loss of contractility with age (423). unlikely that the aging zonule becomes rigid enough to
Despite the attractiveness of progressive nuclear sclerosis ‘‘splint’’ the ciliary muscle. Thus, the best hypothesis, con-
as the cause of presbyopia, this does not seem to be the case. sistent with all available evidence, is that presbyopia is at-
Numerous investigators have found that with increasing age, tributable primarily to deterioration of the elastic compo-
there is progressive sclerosis of the ciliary muscle (343,345). nents of the ciliary body and choroids (350). Indeed, such
When the sclerotic muscle fails to relax the zonular fibers, deterioration has been demonstrated histologically (429).
presbyopia commences. In direct support of the contention
that sclerosis of the ciliary muscle, rather than sclerosis of the
lens, is responsible for presbyopia, there are many patients in METHODS OF MEASURING ACCOMMODATION
whom presbyopia seems to develop within a few days or
The principal difficulties encountered in the clinical quan-
weeks. It is difficult to explain such sudden onset of presby-
titation of accommodation are the subjective nature of the
opia on the basis of lens changes, but it seems rational that
end points and the number of variables that must be con-
a muscle functions only as long as its contraction produces
trolled if meaningful information is to be obtained.
the result for which it was intended.
The accommodative amplitude of an eye is visually esti-
Weale (425) agreed with the ciliary body theory of presby-
opia but offered an alternative explanation for the progres- mated by bringing fine print toward it and recording the
sive ineffectiveness of the ciliary muscle with age. He sug- distance at which the print blurs. However, when the near
gested that the effectiveness of the muscle is decreased by point of accommodation is measured in this manner, the end
the constant approximation of the lens equator to the ciliary point (blurring of the print) is often indistinct because the
body. The cause of the proximity is, of course, the conse- patient is required to make a judgment of the quality of the
quence of steady growth of both the lens and the ciliary image. Egan (430) suggested the use of a cross cylinder in
body. front of the eye with a series of horizontal and vertical lines
Observations using an animal model of presbyopia in rhe- to replace the fine print. Suddenly seeing the vertical lines
sus monkeys show promise of resolving the controversy sur- blur while the horizontal lines remain sharp should result in
rounding presbyopia. When expressed as a percentage of life an accurate and reproducible near point of accommodation.
span, the rate of decline of accommodation in the rhesus However, fine print may well represent a better accommoda-
monkey closely parallels that in humans (426), supporting tive stimulus than nonspecific lines.
the use of this animal as a model for human presbyopia. As Placing minus lenses in front of the eye is a second method
noted above, Neider et al. (350) performed slit-lamp and of measuring accommodative power. Minus spheres of grad-
gonioscopic videography in iridectomized rhesus monkeys ually increasing power are added to the distance correction
with stimulating electrodes implanted in the Edinger-West- until the patient reports a blurred image of a distant accom-
phal nucleus. These techniques permitted real-time observa- modative target. The amount of minus sphere that can be
tions of movements of the ciliary body, lens, and zonules. overcome by the subject’s active focusing is a measure of
The findings suggest that neither of the two previous theories the accommodative amplitude. If the test is performed at
about presbyopia is correct. During centrally induced accom- near (1⁄3 meter) with fine print, 3 diopters is added to the
modation in nonpresbyopic monkeys, Neider et al. observed result.
that: (a) the lens became axially thicker; (b) the ciliary ring Very accurate determinations of accommodative range
narrowed; and (c) at high levels of accommodation, the zo- and amplitude are possible with special instruments such as
nular fibers slackened and even folded, and the lens moved the high-speed infrared optometer devised by Campbell and
downward. In older presbyopic animals, these investigators Robson (431) and the laser optometer designed by Hennessy
noted an age-related decline in sphericization of the lens and Leibowitz (432).
ANATOMY AND PHYSIOLOGY OF NORMAL LACRIMAL FUNCTION

ANATOMY OF TEAR SECRETION BY THE cells by their role in tear secretion. The collecting channels
LACRIMAL GLANDS are initially intralobular, but later become extralobular, and
finally empty into fine ducts. These ducts are lined with a
The lacrimal gland is situated in the superior lateral corner
double layer of epithelium. The ultrastructure of the human
of the orbit, immediately behind the orbital rim within the
lacrimal gland has been described by several investigators
lacrimal fossa of the frontal bone (Fig. 14.39). Inferiorly, it
(433–435).
is in contact with the globe. Anteriorly, it is divided into an
upper (orbital) and lower (palpebral) lobe by the lateral horn The fluid produced within the acini of the primary lacri-
of the levator aponeurosis. The upper or superior lobe is mal gland and secreted by the gland contains water, electro-
bean-shaped, with its medial extremity lying on the levator lytes, and protein. The concentrations of these components
and its lateral extremity lying on the lateral rectus muscle. are then modified by cells of the duct system (436). Parasym-
The lower or inferior lobe, about half the size of the superior pathetic and sympathetic nerves innervate the acinar cells,
lobe, is situated underneath the levator aponeurosis and conduct cells, and blood vessels of the gland. The parasympa-
nects to the lateral superior conjunctival fornix by a series thetic nerves contain acetylcholine and VIP. Norepinephrine
of excretory ducts. These ducts, about 12 in number, open is contained in the sympathetic nerves, whereas the sensory
into the conjunctival sac 4–5 mm above the upper border nerves contain substance P and possibly calcitonin gene-
of the tarsus. related peptide (CGRP).
The lacrimal gland is a typical tubuloalveolar exocrine Aqueous tear secretion occurs not only from the primary
gland composed of small lobules made up of many fine tu- lacrimal gland but also from the accessory lacrimal glands
bules. Each tubule is composed of a layer of cylindrical cells of Krause and Wolfring. These small glands are similar in
lining the lumen and a layer of flat basal cells lying on a structure to the main lacrimal gland but are much smaller.
basement membrane. The basal cells are myoepithelial and The glands of Krause are located in the upper fornix; the
contractile. The cylindrical cells contain granular cyto- glands of Wolfring are situated further down on the eyelid,
plasmic inclusions that histochemically differentiate these above the tarsus (Fig. 14.39). It has generally been accepted
Figure 14.39. Partial schematic representa-

tion of secretory tear system. Note locations of
primary and accessory lacrimal glands. (Re-
drawn from Jones LT, Reeh MJ, Wirtschafter
JD. Manual of Ophthalmic Anatomy. Roches-
ter, MN, American Academy of Ophthalmology
and Otolaryngology, 1970.)
that the main lacrimal gland, having an efferent, parasympa- vus intermedius passes through the cistern of the pontine
thetic innervation, functions primarily during reflex tear se- angle and then joins with the rest of the facial nerve, occupy-
cretion, whereas the accessory lacrimal glands provide non- ing an anterior superior position within the combined nerve
reflex, basal tear secretion (437–441) (see also Chapter 15). as it courses laterally (443) (Fig. 14.41). The surgical anat-
Afferent stimuli causing discharge of the brain stem lacri- omy of the nervus intermedius is important because it can
mal secretory neurons arise from peripheral sensory nerve be injured during the resection of vestibular schwannomas
endings, usually from the trigeminal nerve, but occasionally and other procedures in this area. Symptoms of such injuries
from the retina. There are two neural pathways by which include crocodile tears (the gustolacrimal reflex), reduced
impulses from the lacrimal nucleus eventually reach the lac- or absent tear production, and taste abnormalities. These
rimal gland to induce tear secretion. The parasympathetic symptoms reflect the sensory and parasympathetic compo-
pathway is primarily responsible for the gross production of nents of the nervus intermedius (444).
reflex and continuous tears, but the role of the sympathetic After joining the nervus intermedius, the facial nerve en-
system remains controversial. ters the internal auditory meatus within the petrous pyramid
of the temporal bone (445–448). From here, the meatal seg-
PARASYMPATHETIC PATHWAY FOR ments of the facial nerve enter the labyrinthine segment of
LACRIMATION the facial canal, having pierced the meninges. After coursing
The cell bodies of the preganglionic neurons responsible above the vestibule of the inner ear and laterally 2.5–6 mm,
for parasympathetic lacrimal secretion are located in the lac- the facial nerve trunk turns posteriorly at the geniculate gan-
rimal nucleus within the tegmental portion of the pons in a glion (Fig. 14.42). The parasympathetic fibers destined for
small area dorsal to the superior salivary nucleus (442). After the lacrimal gland pass through the ganglion without synaps-
traversing the facial nucleus, the preganglionic axons join ing and then separate anteriorly at the apex of the ganglion
the sensory root of the seventh nerve (the nervus interme- to become the greater superficial petrosal nerve (Figs. 14.42
dius) that emerges from the lateral portion of the pons be- and 14.43). The close relationship of the origin of the greater
tween the facial and auditory nerves (Figs. 14.40). The ner- superficial petrosal nerve to the apex of the geniculate gan-
Figure 14.40. Relationships between nervus intermedius, facial nerve trunk, vestibulocochlear nerve trunk, and the superior
cerebellar and anterior inferior cerebellar arteries. Nervus intermedius (VII N.I.) exits from the brain stem between the facial
nerve trunk (VII) and the cochlear (VIII Co.) and superior vestibular (VIII S.V.) nerve trunks. Note relationships of the rostral
(Ro. Tr.) and caudal (Ca. Tr.) trunks of the anterior inferior cerebellar artery (A.I.C.A) to the facial-vestibulocochlear nerve
complex. V, trigeminal nerve; S.C.A., superior cerebellar artery; R.P.A., recurrent perforating artery; I.A.A., internal auditory
artery; Mea. Seg., meatal segment. (From Martin RG, Grant JL, Peace D, et al. Microsurgical relationships of the anterior
inferior cerebellar artery and the facial-vestibulocochlear nerve complex. Neurosurgery 1980;6:483–507.)
sympathetic fibers for tear secretion, emerges from the tem-

poral bone in the floor of the middle cranial fossa (Fig.
14.43). The nerve then passes beneath the dura of the middle
fossa under the gasserian ganglion in Meckel’s cave. It enters
the vidian canal at the anterior end of the foramen lacerum
(Figs. 14.43 and 14.44), joining the deep petrosal nerve from
the carotid sympathetic plexus to form the vidian nerve (450)
(Fig. 14.44). The vidian nerve passes through the vidian
canal directly to the sphenopalatine ganglion, where pregan-
glionic lacrimal axons synapse with postganglionic secreto-
motor neurons (Figs. 14.8 and 14.44).
The sphenopalatine ganglion is a small structure measur-
Figure 14.41. Location of the nervus intermedius within the facial nerve ing about 3 mm along its longest diameter. It is situated deep
trunk just before it reaches the geniculate ganglion. The nervus intermedius in the upper part of the pterygopalatine fossa, close to the
(INT) occupies an anterior, superior position in the segment and makes up
sphenopalatine foramen and immediately below the maxil-
about 25% of the volume of the nerve at this point. Other branches of the
facial nerve include F, frontal; OC, ocular; OR, oral; and ZY, zygomatic.
lary nerve that has exited via the foramen rotundum (Figs.
(From Podvinec M, Pfaltz CR. Studies on the anatomy of the facial nerve. 14.8 and 14.44). The pterygopalatine fossa is directly poste-
Acta Otolaryngol 1976;81⬊173–177.) rior to the maxillary sinus antrum, from which it can be
entered surgically or invaded by tumor or infection.
Secretory postganglionic neurons leave the sphenopala-
glion can be problematic, as this is the area where most of tine ganglion and immediately enter the adjacent maxillary
the facial sensory ganglion cell bodies are located. Thus, a division of the trigeminal nerve and travel into the inferior
geniculate ganglionectomy performed for facial neuralgia orbital fissure with its zygomatic branch (Figs. 14.8 and
may include a section of the nervus intermedius to achieve 14.44). These nerves run in the lateral wall of the orbit,
a more complete deafferentation. Such a procedure may pro- reaching the lacrimal gland through an anastomosis between
duce a severe decrease in tear secretion (449). the zygomaticotemporal branch of this division and the lacri-
The greater superficial petrosal nerve, containing the para- mal nerve, the latter being a branch of the ophthalmic divi-
Figure 14.42. Drawing showing the rela-

tionship of the nervus intermedius to the fa-
cial-vestibulocochlear nerve complex as it
enters the cerebrospinal fluid-filled internal
acoustic meatus, the location of the genicu-
late ganglion within the labyrinthine segment
of the facial (fallopian) canal, and the location
of the greater superficial petrosal nerve
within its canal as it courses up the petrous
pyramid toward the vidian canal. Inset shows
the anatomic relationship of the nervus in-
termedius (1) and the geniculate ganglion (5)
to the facial nerve (2–4) in more detail. 2,
first part of facial nerve; 3, genu of facial
nerve; 4, second part of facial nerve; 6, lesser
superficial petrosal nerve; 7, greater superfi-
cial petrosal nerve.
Figure 14.43. Emergence of the greater superficial petrosal nerve

from the temporal bone in the floor of the middle fossa, viewed from
above. The greater superficial petrosal nerve joins with sympathetic
fibers (the deep petrosal nerve) to form the vidian nerve. Note ana-
tomic relationships of the inferior orbital fissure, sphenopalatine
ganglion in the pterygopalatine fossa, and the maxillary nerve (V2)
behind the posterior wall of the orbit and maxillary antrum. V3,
mandibular nerve.
sion of the trigeminal nerve. The fibers terminate in the gland meatal segment of the facial nerve. The portion of the facial
between the cells and around the ducts. The autonomic fibers nerve within the cerebellopontine angle cistern and internal
of the lacrimal gland surround the acini but do not penetrate auditory canal is not normally enhanced after intravenous
into the glandular cells (451–453). The terminal axons of injection of gadolinium-DTPA (454); however, the intracan-
most of the autonomic fibers to the lacrimal gland contain alicular portion of the facial nerve and the geniculate gan-
vesicle-filled varicosities that contain a cholinergic sub- glion can be enhanced in pathologic settings because they
stance and are thought to be parasympathetic in nature. have a fairly vascular perineurium. The facial canal can also
These parasympathetic nerves to the lacrimal gland also probe imaged by CT scanning (455), which is particularly help-
duce VIP and induce lacrimation by stimulating a cyclic ful in the evaluation of fractures and other lesions of the
adenosine monophosphate (cAMP)-dependent signal transtympanic and more distal portions of the facial canal (455).
duction pathway. The portions of the parasympathetic pathway for lacrimation
Some portions of the parasympathetic afferent pathway at and distal to the sphenopalatine ganglion may be imaged
to the lacrimal gland can be evaluated by neuroimaging. In with CT scanning as a result of the natural contrast supplied
general, MR imaging is superior to computed tomographic by fat both within the pterygopalatine fossa and in the orbit
(CT) scanning in imaging this pathway; however, CT scan- and is complementary to MR imaging of these regions.
ning is more useful in imaging certain portions of the path-
way. The lacrimal nucleus cannot be selectively imaged with SYMPATHETIC PATHWAY FOR LACRIMATION
any study. The nervus intermedius usually is too thin and
too closely related to the main trunk of the facial nerve and As discussed earlier in this chapter, preganglionic sympa-
the vestibulocochlear nerve complex to be imaged sepa- thetic fibers leave the lateral column of the spinal cord, travel
rately; however, the water-rich sleeve of cerebrospinal fluid along the cervical sympathetic chain, and synapse in the
in the internal auditory canal is easily demonstrated and pro- superior cervical ganglion. The postganglionic fibers join
vides an outline for the nerves it contains, including the the carotid plexus, enter the base of the skull, and pass to
Figure 14.44. Vertical section through the axis of the petrous pyramid of the temporal bone showing the location of the
geniculate ganglion and the course of the greater superficial petrosal nerve from the geniculate ganglion to the sphenopalatine
ganglion. Some sympathetic fibers leave the internal carotid artery at the foramen lacerum to form the deep petrosal nerve.
This nerve joins with the greater superficial petrosal nerve to form the vidian nerve. Also note the connections between the
sphenopalatine ganglion and the maxillary nerve trunk (V2). V1, ophthalmic nerve; V3, mandibular nerve.
the lacrimal gland by multiple routes. One recognized route from the amygdala, a region in the anterior temporal lobe
goes to the vidian nerve via the deep petrosal nerve (Fig. that is involved in emotional regulation. It is noteworthy that
14.44). These fibers pass through the sphenopalatine gan- these projections did not pass through hypothalamic syn-
glion, join the zygomaticotemporal nerve, and then pass into apses, suggesting that lacrimation can be directly affected
the lacrimal gland with the parasympathetic motor fibers. by the cerebral cortex. Takeuchi et al. (464) and Botelho et
Other sympathetic fibers reach the lacrimal gland via the al. (457) stated that psychogenic tears may be decreased or
carotid plexus, the ophthalmic division of the trigeminal increased by lesions of the frontal cortex, basal ganglia, or
nerve, and the lacrimal nerve. Still others may reach the hypothalamus. Mizukawa et al. (465) reported that stimula-
gland via the cavernous sinus neural plexus, the ophthalmic tion of the ventromedial hypothalamic nucleus of the rabbit
artery, and the lacrimal artery. causes lacrimation.
Sympathetic nerves play a role in normal continuous tear
secretion in humans (456) and in many animals (457–459), NORMAL TEAR FILM
but the mechanism by which they do so is unclear (436,460).
In addition, some investigators believe that sympathetic fi- The term ‘‘tears’’ refers to fluid that exists as a precorneal
bers to the lacrimal gland serve more of a vasomotor than film and in the conjunctival sac. The volume of tear fluid
a secretory function, as they are sparse in lacrimal glands is about 5–10 ␮L (466). Tears are produced by the lacrimal
of human (451,453,461,462). gland, the accessory lacrimal glands, and the goblet cells of
the conjunctiva. Normal secretion of tears is about 1–2
SUPRANUCLEAR PATHWAYS MEDIATING TEAR ␮⬎L/min (466,467). Except for those tears that evaporate,
SECRETION the tear fluid drains through the lacrimal puncta and canali-
culi to the lacrimal sac, which then communicates with the
The cerebral structures and pathways supporting emo- nasal cavity.
tional tearing include cortical, limbic, and hypothalamic sys- Tears have a physically and chemically complex structure
tems that discharge through descending hypothalamoteg- that interfaces between the ocular surface and the environ-
mental pathways to the parasympathetic lacrimal nuclei of ment (468). The tear film is about 30–40 ␮m thick and is
the pons. Experimental study of these systems is limited by composed of three layers: (a) a thick inner mucous layer
the fact that psychic tearing is a function unique to humans. containing mucins, electrolytes, water, immunoglobulin (Ig)
Pfuhl (463) suggested that psychic lacrimation results from A, and several enzymes; (b) a thinner aqueous middle layer
stimulation of the frontal cortical fields responsible for eye that contains proteins, including several antibacterial en-
motion (the second frontal convolution). In cats, direct pro- zymes; and (c) a very thin outer lipid layer. A detailed de-
jections were demonstrated to the superior salivatory nucleus scription of the composition of the tear film and the lacrimal
secretory system can be found in the volume edited by Sulli- REGULATION OF TEAR SECRETION
van (469) and in Chapter 15 of this text.
Jones (439) hypothesized that tear secretion could be clini-
TYPES OF TEAR SECRETION cally separated into two types: basal secretion, which origi-
Four different types of lacrimation can be identified in nated from the accessory lacrimal glands and occurred
humans: (a) continuous tearing, produced constantly for pro- independent of stimulation, and reflex secretion, which orig-
tection and maintenance of a healthy corneal epithelium and inated from the main lacrimal gland and occurred only in
a perfectly smooth and transparent corneal refractive sur- response to neural stimulation. He believed that the tears
face; (b) reflex tearing, stimulated by exposure of the free that were produced after administration of topical anesthesia
nerve endings in the eye, nose, and face to light, cold, wind, were caused by basal secretion. Regardless of the clinical
foreign bodies, or irritating gases and liquids; (c) induced advantages of this classification, this study may have led to
tearing, which often develops as an allergically or chemi- the false impression that the role of the nervous system in the
cally mediated response to local irritants or by direct nonsyn- regulation of tear production is limited to parasympathetic
aptic parasympathomimetic action of some drugs on the neural stimulation of the main lacrimal gland. Proof that
cAMP-dependent signal transduction pathways in the secre- even basal tear production is neurologically regulated is that
tory cells of the lacrimal glands (Fig. 14.45); and (d) psy- basal tearing is essentially eliminated in humans by the injec-
chogenic tearing or tears of emotion, which are unique to tion of lidocaine anesthetic into the sphenopalatine ganglion
humans. Young infants cry without shedding tears during (471).
the first days of life, and infants born prematurely may not Indeed, the formation of all three layers of the tear film is
shed tears for weeks. This delayed capacity for psychogenic regulated, and much of this regulation is neurally controlled
weeping suggests that the connections within the CNS that (470a), involving either classic innervation via synaptic con-
indirectly innervate the lacrimal system are not fully devel- nections or atypical, nonsynaptic modulation from the re-
oped in most newborns (470). lease of neurotransmitters into the biosphere of cells, such as
Figure 14.45. Schematic of the cAMP-dependent signal transduction pathway used to stimulate or inhibit main lacrimal gland
electrolyte, water, and protein secretion. (From Dartt DA. Regulation of tear secretion. Adv Exp Med Biol 1994;350⬊1–9.)
the conjunctival goblet cells (436) (Fig. 14.46). For example, secretion of these glands is produced by holocrine secretion,
wounding of the corneal epithelium is followed by increased in which entire cells, including their stored lipids, are re-
mucous secretion from conjunctival goblet cells. Secretion leased. Lipid layer secretion is believed regulated primarily
from goblet cells is also increased following the topical ap- hormonally, with modulatory neural influences possible. Fa-
plication of a number of neurotransmitters, including VIP, cial nerve and orbicularis oculi muscle function may play a
serotonin, epinephrine, dopamine, and phenylephrine. Thus, role in both meibomian gland excretion and the maintenance
parasympathetic, serotoninergic, dopaminergic, and sympa- of the lipid layer of tears by maintaining normal pressure
thetic nerves may all be involved in reflex secretion from on the excretory ducts (473).
conjunctival goblet cells (472). The aqueous layer of the tear film most likely includes
Although sympathetic and parasympathetic nerves are water derived not only from the main and accessory lacrimal
present in the meibomian glands within the upper and lower glands but also from the corneal, and possibly the conjuncti-
eyelids, these nerves probably do not regulate the production val, epithelium. Three classic neurologic pathways that stim-
of the lipid layer of tears (473). This is because the oily ulate secretion from the main lacrimal gland have been iden-
Figure 14.46. Schematic of the orbital glands and ocular

epithelia that secrete the different layers of the tear film.
(From Dartt DA. Physiology of tear production. In: Lemp
MA, Marquardt R, eds. The Dry Eye: A Comprehensive
Guide. Berlin: Springer-Verlag, 1992.)
Figure 14.47. Schematic of 1,4,5 inositol triphosphate/Ca2Ⳮ/diacylglycerol-dependent signal transduction pathway used to
stimulate main lacrimal gland electrolyte, water, and protein secretion. (From Dartt DA. Regulation of tear secretion. Adv Exp
Med Biol 1994;350⬊1–9.)
tified: (a) the muscarinic cholinergic (Fig. 14.47); (b) the that phosphorylates protein kinases. The phosphorylated ki-
␣1-adrenergic; and (c) the peptidergic (Fig. 14.45). nases, in turn, cause electrolyte and water secretion from the
Acetylcholine acts on the main lacrimal gland via a classic cytosol. Lacrimal secretion stimulated in this manner can
synaptic pathway in which it stimulates a muscarinic recep- be inhibited by the proenkephalin family of peptides acting
tor and a G protein, leading to a rise of intracellular calcium through G proteins (Fig. 14.45).
concentration and the activation of Ca2Ⳮ/calmodulin protein Tears do not originate solely from the main lacrimal gland.
kinases that phosphorylate specific proteins to activate ion Structures to support neurally regulated secretion have also
channels in the apical and basilateral membranes. There fol- been identified in the accessory lacrimal glands located
lows electrolyte, water, and protein secretion and, thus, the within the eyelids. Parasympathetic axons with large, dense
production of the primary fluid (Fig 14.47). The pathway core vesicles and sympathetic axons with small, dense core
just described is known as the 1,4,5-inositol triphosphate/ vesicles appear to stimulate the cAMP-dependent signal
Ca2Ⳮ/diacylglycerol-dependent signal transduction pathway transduction pathway for secretion of water and electrolytes
and is unique to the main lacrimal gland. by the accessory lacrimal glands in a manner similar to that
The pathway and the mechanism by which ␣1-adrenergic for the main lacrimal gland (474). These nerves use a number
agonists stimulate lacrimal secretion are unknown. The main of hormones, neuromodulators, and ␤-adrenergic agonists
lacrimal gland has a neurally controlled cAMP-dependent to accomplish this process (Fig. 14.45).
signal transduction pathway that can either stimulate or in- Commonly employed pharmacologic therapies also affect
hibit water, electrolyte, and protein secretion. A number of tear secretion. For example, the diuretic hydrochlorothiazide
neurotransmitters and neuropeptides, including ␤-adrenergic depresses basal tear secretion (475). Even the corneal epithe-
agonists, VIP, dopamine, serotonin, and dibutyryl cAMP, all lium contributes cytosolic water by secretion into the aque-
stimulate this cAMP-dependent signal transduction pathway ous layer of the tear film following stimulation by classic
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CHAPTER 15
Principles and Techniques of
Examination of the Pupils,
Accommodation, and Lacrimation
Kathleen B. Digre
ASSESSMENT OF PUPILLARY SIZE, SHAPE, AND ASSESSMENT OF ACCOMMODATION, CONVERGENCE, AND

FUNCTION THE NEAR RESPONSE
History History
Examination Examination
Pharmacologic Testing ASSESSMENT OF LACRIMATION
History
Examination
ASSESSMENT OF PUPILLARY SIZE, SHAPE, AND FUNCTION

As is the case with any assessment in neuro-ophthalmol- photographs that have been taken over time (sometimes jok-
ogy, assessment of the pupils requires a meticulous history ingly called ‘‘family album tomography’’ or ‘‘FAT scan-
and a rigorous examination. This is followed in some in- ning’’) can be performed with the naked eye or with a magni-
stances by pharmacologic testing of the pupil using a variety fying lens and may save both time and money in attempting
of topical agents. The reader interested in a more extensive to determine the date of onset of a pupillary disturbance.
discussion of this topic should read the excellent book by Symptoms that may be elicited in any patient with distur-
Loewenfeld (1). bances of pupillary size and shape include light sensitivity
or photophobia, difficulty focusing when going from dark
HISTORY to light or light to dark, and blurring of vision. The blurred
Patients with disturbances of pupillary size or shape often vision is typically a nonspecific and poorly defined com-
are unaware that any abnormality is present. More often, plaint. If one pupil is large, the blurring may be present when
their spouse, a friend, or a physician brings the abnormality the patient enters brightly lighted environments, and if one
to their attention. The disturbance may appear suddenly, or pupil is abnormally small, images of objects observed with
it may develop gradually over time. It may be present at all that eye may appear slightly dimmer than those observed
times, or it may be episodic. Some pupillary abnormalities with the opposite eye.
may be present for years and are only detected when some- The past medical history also may be helpful in assessing
one looks at the iris. the significance of a disturbance in pupillary size or shape.
In obtaining a history from a patient with a disturbance A history of previous infections (e.g., herpes zoster), trauma,
in pupillary size or shape, particularly anisocoria, dating the surgery (e.g., in the neck or upper chest; cataract extraction),
onset of the abnormality may be important. The easiest and or chronic illnesses such as diabetes or migraine may suggest
most reliable method is to view a driver’s license, credit the etiology of the pupillary disturbance (2). The patient’s
card, or a similar identification card with the patient’s photo- occupation also may be important. A farmer or gardener
graph on it which the patient is likely to have available at may be exposed to plants or pesticides that can produce
the time of the evaluation. The examination of family album pupillary dilation or constriction by topical contamination.
715
A physician, nurse, or other health professional may work conditions has been shown to be helpful to find other defects
with or have access to topical dilating or constricting sub- (6).
stances that may produce changes in pupillary size by design Pupil measurements can be performed in several ways. A
or chance. Medication history also is important because op- simple handheld pupil gauge can be used to determine pupil
iates cause constricted pupils (3) and anticholinergic medica- size in both light and darkness. Pupil gauges may be circular
tions, including atropinic substances used in inhalants for or linear. They consist of a series of solid or open circles or
asthmatics, may cause pupillary dilation (4). half-circles with diameters that increase by 0.2 mm in steps
(Fig. 15.1). They can be held next to the eye to estimate
EXAMINATION the size of the pupil. Other calipers and scales to measure
pupillary size are also available (7).
Simple inspection of the anterior segment at the slit-lamp An accurate method of measuring pupillary size and com-
biomicroscope is helpful in determining whether or not there paring pupils before and after pharmacologic testing is with
is a pupillary abnormality. For example, examination of the a handheld pupil camera. With this device, the pupils can
cornea may reveal an abrasion or injury that could affect the be photographed in various illuminations, although not in
pupillary size, whereas examination of the anterior chamber darkness (8).
may reveal inflammation that explains a small pupil in the Infrared video pupillometry is perhaps the most accurate
setting of ciliary spasm. It may also be important to perform method of assessing the size of the pupil (9). An infrared
gonioscopy to assess the anterior chamber angle in a patient video pupillometer permits observation of the pupils not only
with a dilated pupil, particularly when there is a history of in lighted conditions but also in total darkness. Furthermore,
pain or redness in the eye (5). Assessment of the iris should the iris sphincter can even be transilluminated to show the
include not only inspection of the integrity of the sphincter denervated and reinnervated portions (10). Some computer
muscle but also transillumination to determine if there is programs associated with these pupillometers allow the ex-
evidence of iris damage from previous ocular trauma. To aminer to measure not only the diameter and area of the pupil
retroilluminate the iris, the slit-lamp beam is directed but also the latency and velocity of the pupillary response to
obliquely through the pupil. A normal iris will not show both light and near stimulation (11).
defects, but an abnormality such as atrophy will show re- During the clinical evaluation of the pupils, it is helpful
flected light back to the observer. In addition, by placing a to determine the answers to several certain questions. For
wide beam at an angle to the iris and turning the light off example, because the diameter of the pupil typically de-
and on, the light reflex can be assessed for segmental defects, creases with age (12) (Fig. 15.2), the examiner should deter-
such as those that occur in eyes with tonic pupils or aberrant mine if the pupillary size is appropriate for the patient’s age.
regeneration of the oculomotor nerve. One can even draw a Other important questions to answer include the following:
diagram showing clock hours of denervation; the diagram
can then be used to follow the patient’s status. Transillumi- Are the pupils equal in size? If not, is the difference greater
nation of the iris and ciliary body under infrared lighting in darkness or in the light?
Figure 15.1. Pupil gauges. The best gauges mea-

sure in 0.1-mm steps.
PRINCIPLES AND TECHNIQUES OF EXAMINATION OF THE PUPILS, ACCOMMODATION, AND LACRIMATION 717
Figure 15.2. Graph showing relationship

of age to pupil size in normal individuals.
Note that, in general, pupillary size de-
creases with age. (From Loewenfeld IE.
Pupillary changes related to age. In:
Thompson HS, ed. Topics in Neuro-oph-
thalmology. Baltimore: Williams & Wil-
kins, 1979:124–150).
Do the pupils constrict to light equally and with the same surement of pupillary diameters in darkness clinically impor-
velocity? tant to reduce the risk of nocturnal halos due to the improper
Do they redilate equally and with the same velocity? calculation of pupillary size in darkness. Numerous pupillo-
Is the pupillary reaction to light stimulation equal to the graphic devices are available commercially to measure pu-
pupillary reaction to near stimulation? pillary sizes in darkness (18).
Is there reflex dilation to psychosensory stimulation?
Is there a relative afferent pupillary defect? Testing the Direct Pupillary Reaction to Light
When testing the reaction of a pupil to light shined in the
Assessing Pupillary Size eye—the direct pupillary light reaction—it is important
to have a dimly lit room that is quiet so as to reduce or
The diameter of both pupils should be estimated or mea- eliminate emotional effects on the pupil (19). Furthermore,
sured in light, using either normal room light or a handheld one must be certain that the patient is fixating on a distance
transilluminator or other light source. The diameter of the target to eliminate any effect of accommodation on pupillary
pupils then should be assessed in darkness, using the dim- size. The examiner must be certain that the patient is not
mest room light in which the examiner can still see the edge attempting to close the eyelids during the test, because this
of the pupil (13). Finally, the pupillary size should be as- produces a variable degree of pupillary constriction.
sessed during near stimulation using an accommodative tar- A relatively bright light source should always be used
get to achieve maximum constriction of the pupils. The mea- to illuminate the pupil and produce pupillary constriction,
surements of the two pupils in light and darkness also should because increased stimulus intensity is associated with an
be compared to determine if there is anisocoria: a difference increased light reflex amplitude and a maximum rate of con-
of at least 0.4 mm between the two pupils. A substantial striction and redilation (20,21). If the light source is too
percentage of the normal population has clinically detectable bright, however, a prolonged contraction lasting several sec-
anisocoria of 0.4 mm or more, with the percentage increasing onds (‘‘spastic miosis’’) will occur and make determination
with increasing age (14). Whereas 20% of the general popu- of the normal light reflex difficult or impossible (22). In
lation aged 17 years and under have so-called physiologic general, a fully charged transilluminator or an indirect oph-
anisocoria, the prevalence rises to 33% in otherwise normal thalmoscope with maximum brightness is the optimum light
persons over 60 years of age (15). In addition, anisocoria source. In addition, it is helpful to use a dim secondary light
may be produced by damage to the iris sphincter or dilator source to provide oblique illumination of the pupil in some
muscles or to their nerve supply. The amount of anisocoria cases, because this technique increases visualization of
may be affected by illumination. For instance, a greater de- darkly pigmented irides (Fig. 15.3).
gree of anisocoria is present in darkness than in light in The light source should be shined straight into the eye for
patients with physiologic anisocoria or Horner syndrome a few seconds and then moved downward away from the
(13,16). Anisocoria also can also be affected by the degree eye to eliminate the stimulation. The pupil response should
of accommodation, by patient fatigue, and by sympathetic be assessed during this maneuver, which should be repeated
drive (e.g., anxiety) (13,16,17). several times. The normal response to a bright light is a
Recent advances in refractive surgery have made mea- contraction called pupillary capture (23) (also called the
response should be approximately equal in both velocity and

extent to the direct response, because the pupillary decussa-
tion in the midbrain is about 50% to each eye. In fact, the
consensual reaction to light in normal humans is slightly less
than the direct reaction, producing about 0.1 mm or less of
what has been called alternating contraction anisocoria
(22,31). Contraction anisocoria is difficult to see without
using pupillography.
Testing the Near Response

The near response, a co-movement of the near triad that
also includes accommodation and convergence (discussed
later), should be tested in a room with light that is adequate
for the patient to fixate an accommodative target. A nonac-
commodative target, such as a pencil, pen, or the patient’s
own thumb may not be a sufficient stimulus to produce a
normal near response, even in a normal person, and these
targets should be avoided (except in a patient who is blind,
in which case one must stimulate the pupillary near response
using proprioception from one of the patient’s own fingers
or thumb). Similarly, the near response should not be in-
duced by having the patient look at a bright light stimulus,
Figure 15.3. Indirect lighting to view pupils in darkness is helpful in
because the light itself may produce pupillary constriction.
viewing dilation. The examiner should attempt to test the pupillary near re-
sponse several times to give the patient practice. One can
document the light and near response with photographs or
pupillometry (Fig. 15.4).
phasic response). An abnormal response is pupillary es- If a patient is unable to cooperate for a near effort, some
cape, in which the pupil initially constricts and then slowly authors advocate using the lid closure reflex, in which the
redilates and returns to its original size. Pupillary escape patient attempts to squeeze the eyes shut while the physician
most often occurs on the side of a diseased optic nerve or tries to open them (22). This maneuver typically causes the
retina, particularly in patients with a central field defect, pupils to constrict.
although it also occurs in patients with lesions of the contra-
lateral optic tract, in patients with lesions of the brachium Assessment of Pupillary Dilation
conjunctivum, and in normal persons tested with a low-in-
tensity light source (24,25) (see also Chapter 16). Dilation of the pupils occurs in a variety of settings. Most
The initial size of the pupil is important in assessing both often, the pupils dilate after they have constricted to light
pupillary capture and pupillary escape; a larger pupil is more or near stimulation. In patients with certain retinal and, less
likely to show pupillary escape, whereas a smaller pupil is often, optic nerve disease, they may actually dilate when
more likely to show pupillary capture (26–28). light is shined in one eye, or the pupils may constrict to
The latency and speed with which a pupil constricts to darkness (paradoxical pupillary responses) (32,33). Reflex
light and redilates after light stimulation can be assessed pupillary dilation can be elicited by sudden noise or by
using pupillography. This technique reveals that normal per- pinching the back of the neck (the ciliospinal reflex).
sons have pupillary wave forms with latency of 0.20–0.28 When assessing pupillary dilation, the examiner should
seconds and duration of contraction of 0.45 seconds (29). look specifically for dilation lag (34). This phenomenon is
There is a modest interindividual difference in latency in present when there is more anisocoria 5 seconds after pupil-
normal subjects (between 8.3–35 milliseconds) (30). The lary constriction to light than there is 15 seconds after pupil-
use of pupillography to record wave forms of pupillary con- lary constriction (35). Dilation lag typically occurs in pa-
striction and dilation is generally limited to pupillary re- tients with a defect in the sympathetic innervation of the
search laboratories. pupil (i.e., a Horner pupil).
Dilation lag usually is easy to detect. One method is sim-
Testing the Consensual Response to Light ply to observe both pupils simultaneously in very dim light
after a bright room light has been turned off. Normal pupils
When light is shined in one eye, the contralateral pupil return to their widest size within 12–15 seconds, with most
should constrict. This is the consensual light response. The of the dilation occurring in the first 5 seconds. Pupils that
consensual response to light is best assessed using a light show dilation lag may take up to 25 seconds to return to
source for illumination of the pupil of one eye and a dimmer maximal size in darkness, with most of the dilation occurring
light source that can be held obliquely to the side of the about 10–12 seconds after the light goes out. A second way
contralateral eye to be observed. The consensual pupillary to determine if dilation lag is present is to take flash photo-
sensitive diagnostic test to detect either unilateral or bilateral

Horner syndrome (37).
Testing for Light-Near Dissociation

Dissociation between the pupillary response to light stim-
ulation and the pupillary response to near stimula-
tion—light-near dissociation—occurs in patients with a
variety of disorders, including blindness (from optic nerve
or retinal damage), neurosyphilis, oculomotor nerve paresis
with aberrant regeneration, tonic pupil (e.g., Adie pupil),
hydrocephalus, pineal region tumors, and intrinsic mesence-
phalic disease (see Chapter 16). In almost all cases, the pu-
pillary reaction to light is impaired, whereas the pupil-
lary response to near is normal or near normal. Thus,
the potential for light-near dissociation should be considered
in any patient with an impaired pupillary light reaction.
Although there are rare intracranial lesions that can pro-
duce a light-near pupillary dissociation in which the reaction
to light is normal and the reaction to near is abnormal, the
vast majority of cases of this type of light-near dissociation
are caused by lack of effort on the part of the patient during
attempted near stimulation.
Testing for a Relative Afferent Pupillary Defect

When a patient has an optic neuropathy in one eye or an
asymmetric bilateral optic neuropathy, covering one eye and
then the other reveals that the pupil of the normal eye con-
stricts when it is uncovered and the abnormal eye is covered,
whereas the pupil of the abnormal eye dilates when it is
uncovered and the pupil of the normal eye is covered. (Fig.
15.5). This is known as the ‘‘Marcus Gunn’’ or ‘‘Gunn’’
phenomenon, and the abnormal pupil is often called a Mar-
cus Gunn pupil. In fact, a better term for this phenomenon
is ‘‘relative afferent pupillary defect,’’ because this term,
usually abbreviated as RAPD, describes the nature of the
pupillary abnormality rather than being an eponym.
The concept of an RAPD is not new. In 1884, Hirschberg
described a young woman with retrobulbar neuritis in whom
he diagnosed an organic visual loss because of reduced pu-
pillary light reactions when the affected eye was stimulated
(38). In addition, he noted that the consensual pupillary reac-
tion in the affected eye was better than the direct reaction.
Figure 15.4. A handheld camera documents size of the pupils in light Gunn stated that he was able to differentiate retrobulbar optic
and darkness in a normal subject. A, In room light without any other stimula- neuritis from non-organic loss of vision by the difference
tion. B, In room light during stimulation with a bright light. C, In room in pupillary reactions to prolonged exposure to light and
light during stimulation with an accommodative target. Note associated recommended comparing the behavior of the two pupils
convergence. when one was stimulated directly or consensually for a con-
tinued period. He emphasized that the pupil on the side of
an eye with optic nerve dysfunction dilated spontaneously
graphs at 5 and 15 seconds after the lights are turned off. If after initial constriction if the pupil continued to be exposed
there is a difference in anisocoria of greater than 0.4 mm to light, whereas the pupil in an eye with non-organic visual
at 5 seconds minus the anisocoria at 15 seconds, a Horner loss tended to remain fairly constricted as long as the light
syndrome is present (35). was on (39,40). Kestenbaum subsequently popularized the
Infrared videography beautifully demonstrates dilation concept of the RAPD and credited Gunn with its discovery
lag because even the most darkly pigmented iris will appear (41). The phenomenon described by Kestenbaum and attrib-
bright with this technique (36). Using infrared videography, uted to Gunn thus became known as ‘‘Gunn’’ pupil. Kesten-
some investigators have found that re-dilation lag is the most baum also modified the test by covering each eye individ-
Figure 15.5. Relative afferent pupillary defect in the left eye demon-
strated by the alternate cover test as described by Kestenbaum. The left
pupil dilates (as does the right) when the left eye is uncovered and the right
eye is covered. (From Thompson HS. Pupillary signs in the ophthalmologic
diagnosis of optic nerve disease. Trans Ophthalmol Soc UK 1976;
96⬊377–381.)
ually and measuring the size of each pupil. Indeed, he was

one of the first investigators to quantify the RAPD (41).
Levatin substituted an alternating flashlight for the alter-
nating cover test (42) (Fig. 15.6). His theory was that the
differences in pupillary response to light would be accentu-
ated if, instead of simply covering one eye and then the other
Figure 15.6. Relative afferent pupillary defect in the left eye demon-
in a lighted room, the patient focused on a distant target in
strated using the swinging flashlight test. The pupils constrict when the
a darkened room, and a pocket flashlight was swung back light is shined directly into the right eye; however, when the flashlight is
and forth multiple times to bring out the best response. Leva- swung back to the left eye, both pupils dilate. (From Thompson HS. Pupil-
tin et al. subsequently reported on the use of this swinging lary signs in the ophthalmologic diagnosis of optic nerve disease. Trans
flashlight test to screen patients with possible optic neuropa- Ophthalmol Soc UK 1976;96⬊377–381.)
thies and emphasized that the sign was not always obvious
(43). In fact, in 1998, Enyedi et al. compared the efficacy
of the swinging flashlight test with that of the Gunn test for the general physician because it can detect dysfunction of
detecting an RAPD and found the former to be more sensi- the prechiasmal (and, in fact, pregeniculate) afferent visual
tive (44). sensory system in the absence of any ophthalmoscopic evi-
Indeed, the swinging flashlight test is probably the most dence of such a dysfunction.
valuable clinical test of optic nerve dysfunction available to Thompson and colleagues (45–47) described the method
for performing the swinging flashlight test and emphasized on the other as this might tend to create an RAPD in the
several important points, a few of which are repeated here: eye with the longer light exposure, because the longer the
light is kept on the eye, the more pupillary dilation occurs as
First, a bright handlight and a darkened room are essential. the eye adapts to the light. In addition, if the retina becomes
The more contrast there is between the light beam and bleached in one eye and not in the other, a small RAPD will
the darkened room, the greater will be the amplitude of be produced. Special care must be taken to keep retina bleach
the pupillary movement, and the easier it will be to see a equal, especially when measuring with neutral density filters
small RAPD. It is possible, however, to use too much greater than 1.2 log units in density (50) (see later).
light. In such cases, a bright afterimage is produced that Finally, the swinging flashlight test can be performed as
may keep the pupils small for several seconds, thus ob- long as there are two pupils, even when one pupil is nonreac-
scuring the pupillary dilation in the abnormal eye (48). tive and dilated or constricted from neurologic disease, iris
Second, the patient must fixate on a distant target during the trauma, or topical drugs. Recall that as the light is shifted
test. This prevents the miosis that occurs during the near from the normal to the abnormal eye, the total pupillomotor
response, making the assessment of pupillary constriction input is reduced. Thus, the efferent stimulus for pupillary
difficulty if not impossible. constriction is reduced in both eyes so that both pupils dilate.
Third, in patients with ocular misalignment (i.e., strabismus In performing the swinging flashlight test, one tends to ob-
or displacement of the globe by an orbital or intracranial serve only the pupil that is being illuminated; however, the
process), care must be taken to shine the light along the opposite pupil is responding in an identical fashion. Thus,
visual axis. Shining the light directly into one eye and if one pupil is mechanically or pharmacologically nonreac-
obliquely into the other may produce an RAPD. tive, the examiner can simply perform a swinging flashlight
Fourth, the light should cross from one eye to the other fairly test observing only the reactive pupil. If the abnormal eye
rapidly but should remain on each eye for 3–5 seconds is the eye with a fixed pupil, then the pupil of the normal
to allow pupillary stabilization. eye will constrict briskly when light is shined directly in it
and will dilate when the light is shined in the opposite eye.
Thus, there really are two parts of the pupillary response If the abnormal eye is the eye with the reactive pupil, the
that must be observed during the swinging flashlight test: pupil will constrict when light is shined in the opposite eye
the initial pupillary constriction response, and the pupillary and dilate when the light is shined directly in it. This is
escape that is observed for 2–5 seconds after the light is extremely helpful in attempting to determine if a patient with
shined into the eye. Most examiners vary the rate at which an oculomotor nerve paresis or traumatic iridoplegia also
they move the light from eye to eye, and there is often an has an optic neuropathy or retinal dysfunction (22).
optimum ‘‘swing rate’’ that brings out an RAPD that varies The swinging flashlight test can be refined further in pa-
among patients. Some authors recommend moving the light tients in whom a unilateral optic neuropathy is suspected
from one pupil to the other before the latter can escape from but who do not seem to have an RAPD when a standard
the consensual response to bring out an RAPD (49); how- swinging flashlight test is performed. In such patients, the
ever, the light should never be left longer on one eye than use of a neutral density filter with a transmission of 0.3
Figure 15.7. The use of neutral density filters to bring out a rela-
tive afferent pupillary defect (RAPD). Above, The patient has de-
creased vision in the left eye, but a swinging flashlight test fails to
demonstrate a convincing RAPD in the left eye. Middle, A 0.3 log
unit neutral density filter is placed over the right eye, and a swinging
flashlight test is performed. No relative afferent pupillary defect is
induced. Bottom, The filter is then place over the left eye, and the
test is repeated. There is now a left relative afferent in the left eye,
when the filter is placed in front of the right eye and the swinging
flashlight test is performed, the reduced brightness in the right eye
will tend to balance the reduced brightness in the left eye (from the
optic neuropathy), and no RAPD will be seen. However, placing
the filter in front of the left eye while performing the swinging
flashlight test further reduces the light input in the left eye and
further increases the difference in light input between the two eyes.
Thus, there is now an obvious RAPD during the test.
logarithmic units often permits the detection of the defect absence of the RAPD within 2–3 swings after the filter is
(51) (Fig. 15.7). The test is performed as follows. The filter placed in front of the normal eye. If more swings are needed,
is first placed over one eye, and the swinging flashlight test he or she must rebleach the retina of the covered eye and
is performed. The filter is then placed over the opposite eye, resume measuring. The neutral density filters should be held
and the swinging flashlight is repeated. If there is truly no near the nose, so that stray light does not affect the measure-
defect in the afferent system in either eye, placing the filter ment. Filters more than 1.2 log units in density are so dark
over either eye will simply induce a slight but symmetric that it is hard to see the pupil through them, even when light
RAPD in the eye covered by the filter from reduction in the is shined on the eye. The examiner thus may need to peek
amount of light entering the system through that eye. On the around the filter to make a judgment. To reach the endpoint
other hand, if one eye already has a mild RAPD, placement of the test, the examiner should overshoot the endpoint; i.e.,
of the filter over that eye will further reduce the amount of produce an RAPD in the normal (covered) eye. The exam-
light entering the system through that eye, thus increasing iner should then rebleach the retina of that eye and perform
the previously inapparent or subtle defect and causing it to the swinging flashlight test with another filter at the next
become obvious, whereas placement of the filter over the lower amount. Several ‘‘rules of thumb’’ in measuring the
opposite (normal) eye will simply balance the RAPD in the RAPD for various conditions are found in Table 15.1.
opposite eye, and there will be no significant asymmetry in Although some authors (53) have used a grading scale for
pupillary responses to light. the RAPD based on the initial pupillary constriction and
One can also quantify the RAPD using graded neutral how quickly the pupil redilates (e.g., Grade I: weak initial
density filters that are calibrated in percent transmittance constriction followed by greater redilation; Grade II: a slight
(52). After determining that an RAPD is present, the exam- ‘‘stall’’ in movement, followed by a definite dilation; Grade
iner balances the defect by adding successive neutral density III: immediate pupillary dilation [i.e., pupillary escape];
filters in 0.3 logarithmic steps over the normal eye while Grade IV: pupillary dilation during prolonged illumination
performing the swinging flashlight test, until the defect dis- of the contralateral eye for 6 seconds, followed by constric-
appears (Fig. 15.8). The most useful neutral density filters tion; Grade V: immediate pupillary dilation and no signs
are those ranging in transmission from 80% (0.1 log unit) of constriction), these systems are subject to inter-observer
to 1% (2.0 log units). Separate filters can be used individ- errors and are affected by pupillary size; e.g., the small pupil
ually or in combination in front of the eye (Fig. 15.9). may not show a detectable initial constriction.
When using neutral density filters to quantify an RAPD, There is some correlation between the severity of an
the examiner should make a decision about the presence of RAPD and the size of a peripheral field defect in the eye
Figure 15.8. Quantification of the relative afferent pupillary de-

fect (RAPD) using neutral density filters and the swinging flashlight
test. Neutral density filters of increasing density are placed in front
of the normal eye in a patient with a contralateral RAPD, and a
swinging flashlight test is performed until the RAPD disappears. In
this case, the RAPD is balanced with a 0.9 log unit filter.
Figure 15.9. The equipment needed to quan-

tify or bring out a relative afferent pupillary de-
fect includes a bright handheld light source, a
pupil gauge, and a set of photographic neutral
density filters in 0.3, 0.6, 0.9, and 1.2 steps.
Table 15.1
Expected Relative Afferent Pupillary Defect in Various Settings
Condition Expected RAPD Comment References
Optic nerve 0.3–3 log units If no RAPD, either no optic neuropathy or 22,143
bilateral disease
Chiasm Only if asymmetric
Optic tract 0.4–0.6 log units in the eye with the temporal visual From asymmetry of the pupillomotor 144–146
field defect (contralateral to the tract lesion) fibers (more crossed fibers than
uncrossed)
Pretectal lesion Contralateral RAPD without associated loss of visual 147
acuity, color vision, or visual field
Visual field defect RAPD correlates with severity of visual field loss 55
Central visual field defects Greater pupillary escape 148
Peripheral visual field defects Greater sustained pupillary response 25
Amblyopia ⬍0.5 log unit If ⬎1.0 log unit, look for other explanation 22,149
Anisocoria 0.1 log unit for every 1 mm difference; ⬍3 mm of Must assess in light 150
anisocoria induces RAPD that may be difficult to
measure
Macular disease If visual acuity ⬎20/200, RAPD of ⱕ0.5 log units Even worst macular disease causes RAPD 22,151
of ⬍1.0 log unit
Central serous choridopathy ⬍0.3 log units 152
Central retinal vein occlusion Ischemic: 0.9–1.2 log units; 153
Nonischemic: ⬍0.6 log units
Retinal hemorrhage Small: none; large: major intraocular can produce Depends on amount of light blocked 154
RAPD of ⱕ1.2 log units
Retinal detachment 1 quadrant: 0.3 log units; 2 quadrants: 0.6 log units; 46,155,156
macula: 0.9 log units. Total: 2 log units
Retinitis pigmentosa ⱕ0.3 log units 157
Cataract ⱕ0.3 in opposite eye but only if cataract very dense From upregulation of photoreceptors in 158,159
eye with cataract
Patching; dark adaptation ⱕ1.5 log units in nonoccluded eye Maximum RAPD in 30 minutes; reverses 160,161
in 10 minutes
Glaucoma Usually none unless unilateral or markedly Corresponds with remaining neuroretinal 162,163
asymmetric rim
Refractive error None 164
Nonorganic visual loss None 22,39
RAPD, relative afferent pupillary defect.

detected by kinetic perimetry (54). There is less convincing Other tests of optic nerve function are reviewed in Chapter
evidence of a correlation between the pupillary response and 4 of this text.
a central field defect in the eye detected by static perimetry
(55). Other Clinical Tests of Pupillary Function
Tests other than the swinging flashlight test can be used
The swinging flashlight test provides only relative infor-
to detect a relative afferent pupillary defect. Kestenbaum
mation regarding the visual sensory system of the two eyes,
proposed a test that is loosely based on the Gunn phenome-
because the pupillary light response of one eye is compared
non, in which the patient fixes in the distance with one eye,
with that of the other eye. In order to assess the pupillary
while the other eye is occluded by the palm of the hand (56).
light reflex of each eye separately, however, one can evaluate
The examiner holds a handlight with fresh batteries 1 inch
the number of pupillary oscillations that occur over a fixed
from the uncovered eye for 5 seconds to allow the pupils to
amount of time or determine the time it takes for a pupil to
stabilize. The size of the uncovered pupil is then measured
oscillate a specific number of times when stimulated by light
with a pupil gauge to the nearest 0.25 mm. The size of the
(64–66). In this test, a thin beam of light (0.5 mm wide) is
opposite pupil is then measured in the same fashion, and the
placed horizontally across the inferior aspect of the pupillary
difference between the two eyes is determined after correct-
margin (Fig. 15.10). The light induces pupillary constriction
ing for any initial anisocoria. This result is called ‘‘Kesten-
that moves the light out of the pupil. The pupil then redilates
baum’s number.’’
until the beam is once again at the edge of the pupillary
Jiang and Thompson measured the RAPD in a group of
margin, whereupon the pupil again constricts, creating a
patients using the swinging flashlight test with neutral den-
cycle. A set number of cycles (usually 10, 20, or 30) are
sity filters (57). They compared the results with the results
then timed by a stopwatch to the nearest 0.1 second, and
of the Kestenbaum test and found a distinct relationship be-
the time of the cycle—the edge-light pupil cycle time—is
tween the severity of the RAPD measured with neutral den-
calculated as msec/cycle. Alternatively, the number of cycles
sity filters and Kestenbaum’s number (r ⳱ 0.86). The major
that occur during a fixed period of time, usually 1 minute,
problem with the Kestenbaum test includes the need for two
are counted. In both cases, the results are compared with
intact iris sphincters and the problem of miosis of the elderly
results from normal control subjects. For instance, normal
and hippus in the young (57).
pupils generally cycle at a rate of 900 msec/cycle.
A highly sensitive way to detect an RAPD is by using
Unfortunately, the edge-light pupil cycle time is not a
pupillography (58,59). Pupillary reactions that occur during
particularly sensitive indicator of optic nerve disease com-
stimulation of an eye with a damaged retina or optic nerve
pared with the swinging flashlight test or visual evoked po-
have a prolonged latent period and a shortened duration and
tentials. In addition, it may be difficult or impossible to in-
diminished amplitude of constriction. These parameters can
duce regular oscillations in some patients and, as with other
be evaluated by pupillography. For example, inflammatory
tests of pupillary constriction, the edge-light pupil cycle time
diseases of the optic nerve and optic atrophy are associated
is affected by the efferent arm of the pupillary light reflex
with significant prolongation of the latent period, ischemic
(e.g., oculomotor nerve function). Nevertheless, it is a poten-
optic neuropathy produces a lesser prolongation, and acute
tially useful initial diagnostic test in one-eyed patients or in
papilledema does not affect latency at all (60). Furthermore,
patients with presumed bilateral symmetric retinal or optic
portable pupillography units can detect and measure large
nerve disease (67,68).
RAPDs quickly, even in a clinical setting (61), and such
devices can be linked to computerized systems to test the Pupil Cycle Induction Test
visual field (62,63).
Tests used to detect an RAPD, particularly the swinging The pupil cycle induction test is a variation of the edge-
flashlight test, are sensitive tests for optic nerve dysfunction; light pupil cycle time (69). It is used to assess the difficulty
however, they represent only one type of test used to deter- in producing regular and sustained light-induced pupillary
mine whether or not a patient has an optic neuropathy and, oscillations. In this test, a beam with a thickness of 0.45 mm
if so, the degree of severity of the optic nerve dysfunction. or less is placed horizontally at the lower edge of the pupil-
Figure 15.10. Testing the edge-light pupil cycle time. The pupil can be induced to cycle at the slit lamp by placing a horizontally
oriented slit beam on the lower pupil margin. The beam is then moved slightly upward, inducing pupillary constriction that
moves the light out of the pupil. The pupil then redilates until the beam is once again at the edge of the pupillary margin,
whereupon the pupil again constricts, creating a cycle.
Table 15.2
Pharmacologic Testing in Diagnosing Common Pupil Conditions
Agent Setting/Purpose Dose Time Lighting Measure End Point Caution
Testing for denervation

supersensitivity
Dilute pilocarpine Dilated, poorly reactive or 0.0625–0.1% 30 min Dim light or Change in pupil ⬎0.5 mm difference Limited usefulness-bilateral Adie
(165–167) nonreactive pupil to (168) darkness diameter between two eyes or the pupil; normals can react variably
distinguish tonic pupil larger abnormal pupil to medication; cannot reliably
from 3rd nerve palsy becomes the smaller pupil distinguish between 3rd nerve
pupil or pharmacologic palsy and tonic pupil (167)
blockade
Testing for Pharmacologic
Blockade
Pilocarpine Dilated, fixed pupil 2% 40 min darkness Change in pupil Pupil that is Other causes of dilated pupil may
to distinguish diameter pharmacologically prevent constriction; e.g.,
pharmacologic blockade blockaded should not traumatic or post-herpetic
from tonic pupil or 3rd constrict at all or should iridoplegia; angle-closure
nerve palsy pupil constrict minimally glaucoma; fixed pupil after
cataract surgery (154)
Testing for Horner
Syndrome
Cocaine (169) Anisocoria with normal 2–10% 40–60 min Light Larger pupil ⬎0.8 mm inequality is If the affected pupil dilates ⬎2 mm
pupillary reactions to dilates; smaller positive; ⬍0.3 negative to cocaine, be wary (170); keep
light to determine if pupil either patient alert because sleep may
sympathetic defect dilates poorly or give a false-negative test; always
present not at all assess test result in dark
Hydroxyamphetamine In proven Horner 5% 50–60 min Light Dilation of Horner ⬎1 mm change in anisocoria Should not be performed on same
(and Tyramine) (171) syndrome to differentiate pupil indicates OR a change of anisocoria day as cocaine test; some authors
between first/second first or second (difference in pre to post- suggest waiting 3 days; not
order and third order order Horner anisocoria) of ⬎0.5 mm always accurate in congenital
Horner syndrome syndrome; suggests post-ganglionic Horner syndrome because of
dilation of (171); increased size of trans-synaptic degeneration (154)
normal pupil smaller pupil over
but not of normal pupil suggests
Horner pupil preganglionic defect (154)
indicates third-
order syndrome
Apraclonidine (172,173) Anisocoria with normally 0.5–1% 60 min Light Dilation of the Dilation of smaller pupil Helpful when cocaine not available,
reactive pupils; to smaller pupil with reversal of anisocoria but does not differentiate pre-
determine if sympathetic (reversal of (normal pupils never and postganglionic Horner
defect present anisocoria) dilate ⬎0.5 mm) syndromes
PRINCIPLES AND TECHNIQUES OF EXAMINATION OF THE PUPILS, ACCOMMODATION, AND LACRIMATION
Phenylephrine 2.5% To confirm a Horner 2.5% 30–60 min Light Pupillary size after The Horner pupil should A normal pupil will also dilate
syndrome and to exclude treatment dilate as well as or more
a small immovable pupil than other pupil
causing a positive test
725
lary margin in much the same way as in testing the edge- phetamine (see Chapter 16), the drug should be placed in
light pupil cycle time. The pupils of almost all eyes with both eyes so that the responses of the two eyes can be com-
normal optic nerves can generally be induced to cycle at pared. When the condition is bilateral, no such comparisons
regular intervals, whereas the pupils of almost all eyes with are possible, but an attempt should be made to make certain
optic nerve disease show altered responses, such as complete that the observed response is indeed caused by the instilled
failure to cycle or prolonged pauses in the cycle. We have drug. In such cases, the drug may be placed in one eye only
found the results of testing edge-light pupil cycle time and so that the responses of the medicated and unmedicated eyes
pupil cycle induction difficult to interpret, not particularly can be compared. Occasionally, in patients with presumed
reproducible, and less sensitive than the results of a simple bilateral pupillary abnormalities, we and others (22) place
swinging flashlight test. We thus use these tests only when drops in both of the patient’s eyes and also in one of our
assessing monocular patients. own, to serve as a type of external control.
Finally, the drug should always be placed in the eye of
PHARMACOLOGIC TESTING concern first and then placed in the contralateral eye so that
if there is no response in the presumably abnormal eye, one
A few cautionary comments should be made regarding cannot blame squeezing or tearing as the cause.
the interpretation of pupillary responses to topically instilled Problems can occur when performing pharmacologic test-
drugs. ing of the pupil using topical drugs. The drug may be out-
First, the test variables must be carefully controlled when- dated and thus more or less potent. The patient may develop
ever possible, both before and after pharmacologic testing. sufficient tearing that the strength of the drug is altered by
This means that the ambient lighting should be optimal for dilution, or it is washed out of the inferior conjunctival sac
the test performed, the patient must fixate in the distance before it can be absorbed. The patient may squeeze the eyes
for at least 1 minute to minimize miosis and relax the pupil, tightly during instillation of the drug, thus preventing a suffi-
and the patient should be alert throughout the test, because cient amount of drug from being placed in the inferior con-
the psychic state of the individual can influence pupillary junctival sac. Penetration of the drug through the cornea may
size (e.g., the pupils tend to be miotic in persons who are be altered, especially if other topical medications have been
tired or listless and mydriatic in patients who are upset or used; e.g., anesthetics for testing of intraocular pressure, or
anxious) (70). if the integrity of the corneal epithelium has been altered by
Second, the pupil sizes must be measured as accurately manipulation of the cornea during tonometry or testing of
as possible. The CU-5 camera manufactured by the Polaroid corneal sensation. One must also consider individual varia-
Company allows the direct measurement of pupillary size; tions in the action of the drug on patients of different ages
however, one can simply paste or tape a ruler on the patient’s or with different colored irides.
brow and then use any camera to obtain photographs from Determining the results of pupillary testing can also be
which accurate measurements can be made. Pupillometers difficult depending on the initial size of the pupil. Differ-
also provide accurate measurements but are not well suited ences in pupillary diameter or area can have profound results
to most clinical practices. on the ultimate outcome in pharmacologic testing (Table
Third, it is ideal, whenever possible, to use the presumably 15.2).
normal pupil as an internal control. For instance, if a judg- Finally, it is important to remember why a particular test
ment is to be made about the dilation or constriction of one is being performed in the first place (Table 15.2). The correct
of the pupils in response to a drop of some topical agent, drug must be used and placed in the eyes in the proper
such as 0.1% pilocarpine, 10% cocaine, or 5% hydroxyam- fashion.
ASSESSMENT OF ACCOMMODATION, CONVERGENCE, AND THE NEAR RESPONSE

Most visual problems associated with accommodation report monocular diplopia; others complain of discomfort
occur because accommodation is too great, too little, or too during attempted reading, a noticeable delay in focusing
slow. Disturbances of the other two components of the near when changing fixation from a distant to a near or a near to
response—convergence and pupillary miosis—also can be a distant object, or a combination of these symptoms. Some
of importance if they are too active or if they have reduced patients report headache, light intolerance, and other asthen-
activity. opic symptoms (71). Frequently, presbyopia and other ac-
commodative insufficient states can be precipitated with
HISTORY medications having anticholinergic effects.
The symptoms of patients with disturbances of accommo- Accommodative excess or spasm is typically associated
dation tend to be nonspecific but some aspects of the history with clear vision at near and poor distance vision. Objects
may be important. Patients with accommodative insuffi- may look larger or smaller (macropsia or micropsia) than
ciency, for instance, usually complain of blurred vision at normal in this setting. In addition, patients with accommoda-
near but not in the distance. Patients with the most common tive excess or spasm often complain of brow ache (72).
problem with accommodation—presbyopia—may report When convergence also is affected, other symptoms may be
that the farther away they hold an object, the better they present. For example, convergence excess often is associated
can see it. Some patients with accommodative insufficiency with diplopia in the distance, blurring of vision, oscillopsia,
and/or pain; whereas convergence insufficiency most often depth of focus, and this increased depth of focus may be
is associated with trouble reading, diplopia at near, blurred mistaken for accommodation. Many traditional tests of ac-
vision that clears when either eye is covered, and pain or commodation thus may overestimate the amount or range
discomfort during near tasks. of accommodation in a patient because the tests cannot dis-
In patients with spasm of the near reflex, symptoms are tinguish true accommodation from combined accommoda-
related to dysfunction of all three components. Such patients tion and depth of focus (79).
have accommodative spasm (up to 8–10 diopters), extreme
miosis, an esotropia in primary position, and apparent but Accommodation
inconsistent bilateral limitation of abduction. These patients
There are actually three aspects of accommodation: the
tend to complain of blurred or dim vision, binocular horizon-
near point of accommodation, the accommodative ampli-
tal diplopia at both distance and near, temple or diffuse head-
tude, and the range of accommodation. The near point of
ache, pain in the eyes, and even trouble walking (73,74).
accommodation (NPA) is the point closest to the eye at
Spasm of the near reflex is discussed in detail in Chapter
which a target is sharply focused on the retina. The accom-
16 of this text.
modative amplitude is the power of the lens that permits
EXAMINATION such clear vision. This power is measured in units called
diopters (D) and is calculated by dividing the NPA in centi-
Accommodation is the ability of the lens to change its meters into 100. The accommodative amplitude is thus sim-
refractive power in order to keep the image of an object ply the reciprocal of the NPA (e.g., a patient with an NPA
clear on the retina. The primary stimulus for accommodation of 25 cm has an accommodative amplitude of 100/25 ⳱ 4
is blurring (75), and most tests of accommodation depend D). The range of accommodation is the distance between
on producing or eliminating blur. There are, however, stim- the furthest point an object of a certain size is in clear sight
uli for accommodation other than blur, including chromatic and the nearest point at which the eye can maintain that clear
aberration and perceived nearness (76), and these can also vision.
be used to test accommodation.
Convergence
General Principles Related to the Components of the
Near Triad Convergence is a vergence adduction movement that in-
creases the visual angle to permit single binocular vision
Accommodation is part of a complex triad that maintains during near viewing. Convergence can be voluntary but need
clear near vision and is called the near response or the near not be; i.e., no stimulus need be present to elicit it. It is also
reflex. Even though the components of the near re- reflexive and a co-movement in the near response. Accom-
sponse—accommodation, convergence, and pupillary mio- modation and convergence are related; a unit change in one
sis—normally work together during near viewing, each normally causes a unit change in the other (80).
component can be tested separately. For example, one can Convergence may be separated into four subtypes: (a)
weaken the stimulus to accommodation with plus lenses or tonic convergence; (b) accommodative convergence; (c) fu-
strengthen the stimulus to accommodation with weak minus sional convergence; and (d) voluntary convergence.
lenses without stimulating convergence or miosis. One can The eyes normally tend to diverge. Keeping the eyes
use weak base-out prisms to stimulate convergence without straight thus requires increased tone in the medial rectus
changing accommodation. Under certain conditions, one can muscles. This tone is tonic convergence (81).
test accommodation without inducing pupillary constriction Accommodative convergence is the amount of conver-
(77). In addition, even in presbyopia in which accommoda- gence elicited for a given amount of accommodation. The
tion fails, convergence and miosis continue. Furthermore, relationship between accommodation and convergence is
if one paralyzes accommodation with drugs, convergence usually expressed as the ratio of accommodative conver-
remains intact. Relative accommodation is the term used gence in prism diopters (PD) to accommodation in diopters:
to describe the amount of accommodation that is unrelated the AC/A ratio. Because accommodation decreases with age,
to convergence; relative convergence describes the amount the AC/A ratio increases with age (72,82). Just as conver-
of convergence unrelated to accommodation (78). gence can be stimulated by accommodation, so accommoda-
Depth of focus is slightly different from accommodation. tion can be stimulated by convergence. The ratio of conver-
It is the distance for any given accommodative state that an gence accommodation in diopters to convergence in PD is
object can be viewed without a change in acuity or genera- called the CA/C ratio.
tion of blur. Depth of focus is more dependent on pupillary Fusional convergence is convergence that is stimulated
size and amount of illumination than is accommodation. For not by changes in accommodation but by disparate retinal
example, accommodation is not significantly affected by mi- images (81). It is thought to be used to ‘‘fine tune’’ normal
osis and bright illumination; however, in patients with small convergence. Pupillary constriction can occur with fusional
pupils and bright illumination, the depth of focus is in- vergence, but the amplitude of this form of convergence is
creased. Thus, a patient over 60 years of age will have very not as great as that of accommodative convergence.
little, if any, accommodation; however, if one compares two Voluntary convergence is measured by determining the
patients, one with large pupils and the other with small pu- near point of convergence (NPC)—the nearest point to
pils, the patient with the smaller pupils will have an increased which the eye can converge. It is closer to the eyes than
the near point of accommodation and, in general, does not posite eye occluded, the patient fixes on small (usually 5
deteriorate with age as does the NPA. The NPC usually is point) type on a card that is attached to the rule and that
10 cm or less. can be slid forward and backward. The size of the type is
important, because the smallest type will evoke the strongest
Miosis accommodative response (93). The zero point of the rule
should be 11–14 mm in front of the cornea. This corresponds
The pupil constricts when changing fixation from distance to the approximate position of the spectacle correction. The
to near. This movement can occur in darkness, is slower card is moved from a distance to the closest point at which
than the light reflex, and is maintained as long as the near the patient can see the print before it starts to blur. This is
reaction is maintained. Miosis improves the range through the NPA and, as noted above, is expressed in centimeters.
which an object is seen clearly without any change in accom- The maneuver is repeated several times until the test gives
modation; i.e., the depth of field (see above). The miotic reproducible results.
response to the near effort is directly dependent on that ef- Once the NPA is determined, the accommodative ampli-
fort. Normal persons usually need a visible target to view tude in diopters, as indicated above, is calculated by dividing
to reach maximal pupillary miosis and accompanying ac- 100 by the NPA in centimeters. Using the push-up method,
commodation. This miotic response also can be inadver- Duane (94) developed age-related normative data for the
tently stimulated by forceful eyelid closure (83). In patients accommodative amplitude that are still in use today (Fig.
with presbyopia, pupil size continues to decrease even when 15.12).
accommodation has reached its maximum. This probably Although the push-up method of determining the NPA
occurs because aging changes limit alterations in the lens and the accommodation amplitude has the disadvantage of
or ciliary muscles, whereas the pupillary sphincter is still overestimating accommodation, it is the most widely used
functional and responsive to stimulation (84). On the other method, the quickest in clinical practice, and the most popu-
hand, artificially induced miosis (e.g., pharmacologic) re- lar. When interpreting the results of testing of accommoda-
duces the amplitude of accommodation (85). tion using the push-up method, the examiner must be sure
In testing accommodation and the near vision response, that the patient fully cooperated with the testing. Neverthe-
the above relationships must be remembered. Furthermore, less, if, on repeated testing, the NPA (and thus the accommo-
one must remember that accommodation is never measured dative amplitude) is consistently out of the range considered
or tested in an absolute sense, but rather in response to how to be normal for age, the results should be considered truly
it changes under certain testing conditions (86). abnormal (94).
Adequate room lighting obviously must be available when
Testing Techniques testing accommodation, and it usually is recommended that
The techniques one uses to determine the range and ampli- the light be directed over the right shoulder when testing the
tude of accommodation, degree of convergence, etc. depend right eye and over the left shoulder when testing the left eye.
in part on the setting and the questions to be answered. Indeed, illumination is a critical factor in performing the
test. By increasing illumination from 1 to 25 foot-candles,
Accommodation the accommodative range can be increased by 28% in non-
presbyopes and by 73% in presbyopes (95).
The principal handicaps in the clinical application of ade- The range of accommodation can be tested in a fashion
quate tests of accommodation are the subjective nature of similar to that used to test the accommodative amplitude.
the end points and the number of variables that must be The patient is instructed to indicate when the object blurs
controlled. The first step in any testing of components of at near (the near point or NPA) and when it blurs in the
accommodation or the near triad, is to perform an adequate distance (the far point). The range of accommodation is then
refraction for both distance and near viewing. For children calculated by determining the far point and near point in
and some adults, a cycloplegic refraction with an agent such diopters (i.e., dividing each of the distances in centimeters
as cyclopentolate (Cyclogyl) is needed to prevent the patient into 100) and by subtracting the far point from the near point.
from accommodating and thus increasing the degree of my- For an emmetrope, the range of accommodation corresponds
opia requiring correction during the refraction (87,88). In- to the accommodative amplitude because the far point is at
deed, this ‘‘pseudomyopia’’ may be the first clue to accom- infinity. For a myope whose near point is 10 cm and whose
modative spasm. Conversely, excellent distant vision and far point is 50 cm in front of the eye, the range of accommo-
poor near vision may indicate accommodative insufficiency dation is 100/10 ⳮ 100/50 ⳱ 10 ⳮ 2 ⳱ 8 D. For a hyperope
or presbyopia. with a near point of 10 cm and a far point of 25 cm behind
The NPA is most easily measured clinically using a scale the eye, the range of accommodation is 100/10 ⳮ (ⳮ100/
device such as the Prince, Krimsky, or Berens rules (89–91). 25) ⳱ 10 ⳮ (ⳮ4) ⳱ 10 Ⳮ 4 ⳱ 14 D. If the patient is too
These instruments are simply rulers with markings in both presbyopic or myopic to do the test, corrective lenses should
centimeters and diopters on which there is a small sliding be used. One must then adjust the results to reflect the correc-
chart containing Snellen letters (Fig. 15.11). The technique tion. If a minus lens has been used, the diopter power of the
of testing accommodation with them is called the ‘‘push-up lens is added to the result; if a plus lens has been used, the
method’’ (92) and is performed as follows. diopter power is subtracted.
Wearing an optimum distance refraction and with the op- The push-up method of measuring the NPA and the ac-
Figure 15.11. Photographs of accommodative

rules. A, The Prince Rule. B, The Krimsky-Prince
Rule. C, The Berens Rule. (A, From Wood CA. The
American Encyclopedia and Dictionary of Ophthal-
mology. Chicago, Cleveland Press, 1919⬊10961. B,
Photo courtesy Paul Montague, CRP.)
Numerical Values of Limits for Each Age

Accommodation
Age
Figure 15.12. The relationship between accommodation and age. Note the relatively linear decrease in accommodation with
age until about age 52, when almost all accommodation has been lost. (Graph data from Duane A. The accommodation and
Donders curve and the need of revising our ideas regarding them. JAMA 1909;52⬊1992–1996.)
commodative amplitude is not the only one that can be used. gence. In general, however, the only measurement of impor-
A second method is the method of the spheres. In this tance is the NPC. This measurement usually is determined
test, the patient fixates on a reading target at 40 cm, and by having the patient fixate on an accommodative target held
accommodation is stimulated by progressively adding minus 33 cm from the eyes. The target then is moved toward the
(i.e., concave) lenses until the print blurs. Accommodation nose, with the patient being instructed to try to keep the
is then relaxed by adding stronger plus (i.e., convex) lenses target in focus. The end-point of the test is when the patient
until the print again blurs. The sum of the lenses is the mea- reports horizontal diplopia. The distance at which this occurs
sure of the accommodative amplitude. For example, if a pa- is then measured with a millimeter ruler placed alongside
tient accepts up to a ⳮ4.0 D sphere before print blurs and the patient’s nose.
then accepts the addition of Ⳮ2.50 D sphere before print The NPC also can be determined by placing a red glass
again blurs, the total accommodative amplitude is 4.0 D Ⳮ over one eye and moving a light forward until the patient
2.5 D ⳱ 6.50 D (72). Like the push-up method for determin- experiences diplopia (99) or, more objectively, by perform-
ing the NPA and the accommodative amplitude, the method ing the above test and noting the distance from the nose at
of the spheres depends on patient cooperation. which one of the inward turning eyes is observed to turn
The most objective method of measuring accommodation suddenly outward. In normal persons, the NPC is usually
is the use of refractometers (96,97). Most of these machines between 5–10 cm (100). An NPC greater than 30 cm indi-
use increasingly minus lenses to stimulate accommodation cates convergence insufficiency.
and measure the accommodative response. Alternatively, Yet another way to determine if convergence is normal
one can stimulate accommodation not with lenses but phar- is to perform a cover-uncover test (see Chapter 18) while
macologically by using a topical agent muscarinic agonist the patient is reading. This is helpful only if the patient has
like pilocarpine and measure the response using a refractom- full versions and no previous strabismus.
eter (98). In addition to determining the NPC, it may be useful to
determine if a patient’s convergence is sufficient for the
Convergence amount of accommodation; i.e., the AC/A ratio. There are
Like accommodation, there is a near point of convergence two different methods for measuring the AC/A ratio.
(NPC), a convergence amplitude, and a range of conver- The gradient method determines the AC/A ratio by the
change in deviation in prism diopters (PD) that occurs when for near viewing as expressed in diopters. Normal persons
a lens of a specific power is placed over both eyes to stimu- should have the same ocular alignment when viewing both
late or relax accommodation (101). An accommodative tar- distant and near objects. If a patient is more exotropic or
get must be used, and the working distance is held constant. less esotropic at near compared with distance, this indicates
Plus or minus lenses are used to vary the accommodative less convergence, or a low AC/A ratio; if the patient is more
requirement, and the difference between the ocular align- esotropic or less exotropic at near compared with distance,
ment with and without the lens, divided by the power of this indicates a high AC/A ratio. For example, if a patient
the lens, is the AC/A ratio. For example, a patient’s ocular has an exophoria of 5 PD at distance and an esophoria of 4
alignment is measured with the patient viewing the accom- PD at 33 cm, the AC/A ratio is 5 ⳮ (ⳮ4)/3 ⳱ 9/3 ⳱ 3.
modative target at a specific distance such as 33 cm, and The normal AC/A ratio is between 3 and 6, regardless of
the patient is found to have an esophoria of 2 PD. A ⳮ1.00 the method of testing that is used (72). It should be noted,
D spherical lens is placed over each eye, and ocular align- however, that the AC/A ratio varies from person to person
ment is again measured with the patient viewing the same and from day to day or hour to hour in a given individual
target at the same distance. The patient is now found to have depending on that person’s level of fatigue or alertness. In
an esophoria of 6 PD. The difference between the ocular addition, the AC/A ratio rises sharply after the age of 40 as
alignment with and without the lens, divided by the power accommodation begins to be lost but convergence remains
of the lens, is the AC/A ratio and is 6 ⳮ 2/1 ⳱ 4/1 ⳱
stable (102). Nevertheless, values above 6 usually indicate
4. This means that when 1 diopter of accommodation was
an excess of convergence per unit of accommodation,
stimulated in this patient by placing a ⳮ1.00 D spherical
lens in front of the eyes, the patient’s convergence, measured whereas values below 3 suggest convergence insufficiency.
at the same distance from the eyes, increased from 2 to 6 An elevated AC/A ratio in a cooperative child is a risk factor
PD. In another patient, a Ⳮ3.00 sphere might be used to for the rapid onset of myopia (103).
reduce accommodation, and a change in deviation from an Testing convergence accommodation; i.e., the CA/A ratio,
exotropia of 4 PD to an exotropia of 10 PD might be noted. requires that the patient experience no blur during the test.
The AC/A ratio then would be 10 ⳮ 4/3 ⳱ 6/3 ⳱ 2. This can be accomplished by the use of a pin hole device
The second method for determining the AC/A ratio is the (104), performing the test in dim illumination (105), or using
heterophoria method. This method uses the distance-near a Gaussian target (106). In this test, accommodation is mea-
relationship to determine the AC/A ratio. Instead of measur- sured as convergence is produced using progressively
ing ocular alignment at near with and without a specific stronger base-out prisms. Unlike accommodation, conver-
power lens, ocular alignment is measured at distance and gence does not decline significantly with age (102). Thus,
near, and the difference in alignment in PD between distance just as the AC/A ratio increases with age, the CA/C ratio
and near viewing is divided by the fixation distance used decreases with age (102,105).
ASSESSMENT OF LACRIMATION
The most anterior optical surface of the eye, the tear film, of Wolfring are situated further down on the eyelid, above
is also one of the greatest optical powers of the eye, and a the tarsus. The relative importance of the main and accessory
deficient tear film thus is one of the most common causes of lacrimal glands in the maintenance of normal tear secretion
fluctuating blurred vision in clinical practice. In fact, optical is somewhat controversial. It generally is accepted that the
aberrations caused by an early break-up of the tear film have main lacrimal gland, having an efferent parasympathetic in-
been shown objectively to diminish image quality (107). nervation, functions primarily during reflex tear secretion,
The tear film is a trilaminar structure consisting of a super- whereas the accessory lacrimal glands provide basal tear
ficial lipid layer, an aqueous middle component that ac- secretion (110,110a).
counts for over 90% of the film, and a mucin component in The mucin layer is a biphasic layer that allows the aqueous
the innermost layer. In order to discern a problem of the tear component to adhere to the hydrophobic cornea epithelium.
secretion, one must attempt to determine if only one layer This layer thus helps to maintain the integrity of the aqueous
is affected or all the layers are affected. component of tears and the quality of the tear film. Abnor-
malities in this layer (and also in the oil layer) can create
The main function of the lipid layer is to retard evapora-
tear film disturbances despite good aqueous tear production.
tion of the tear film. Removal of this layer causes a 19-fold
The mucin layer is produced by goblet cells located in the
increase in evaporation (108,109). conjunctiva.
The aqueous layer, being the thickest component of the The normal basal tear volume is 5–9 ␮L, and the normal
tear film, contributes the most to its volume, and most of flow rate averages 0.5 to 2.2 ␮L/min (111). In general, nei-
the tests that measure the quantity of the tear film test this ther basal tear volume nor flow changes with increasing age,
layer. The aqueous layer of the tear film is produced by both but reflex tearing decreases with age (112).
the primary lacrimal gland located in the lacrimal fossa in The main disturbances of lacrimation relate to excess or
the superior lateral orbit and the accessory lacrimal glands insufficient tear production and to obstruction of the normal
of Krause and Wolfring that are similar in structure to the passage of tears through the lacrimal drainage apparatus.
main lacrimal gland but are much smaller in size. The glands Thus, the assessment of patients with difficulties should be
of Krause are located in the upper fornix, whereas the glands oriented to an evaluation of tear production and drainage.
HISTORY Tests of the tear film may be separated into those that test
a particular part of the tear film or a particular function of
Excessive drying of the eyes occurs in several settings,
the tears, those that measure the amount of tear secretion,
including reduced production, increased evaporation, and
and those that detect obstruction of tear drainage (115a).
excessive drainage of tears. Epiphora—excessive tear-
The lipid layer can be studied using optical interference
ing—also occurs under several different circumstances, in-
patterns, matching the color interference with known color
cluding increased production of tears, an obstructed lacrimal
controls. This method is used mainly for research purposes;
drainage system, or excessive dryness of the eyes caused by
however, lipid layer thickness measurements were strongly
a deficiency of normal basal tearing from hypofunction of
correlated with an assessment of fluorescein break-up time
the glands of Krause and Wolfring. In this last setting, the
and the Schirmer 1 test in a series of patients evaluated by
excess tearing is reflexive in nature and results from stimula-
Isreb and colleagues (116) (see later). Thus, it would appear
tion of the primary lacrimal gland in response to dryness
that a deficiency of the lipid layer of the tear film can be
and irritation of the cornea. Indeed, epiphora and irritation
associated with clinical tests of tear film production and
from dry eyes is one of the most common ocular problems
function.
in the United States (113) and the world (114).
An examination of the aqueous layer should begin with
The causes of dry eyes initially may be suspected from
an assessment of the tear meniscus, which should be ob-
the results of a validated short questionnaire developed by
served for evidence of protein precipitates and debris. A
Schein et al. (115) (Table 15.3). This questionnaire consists
normal tear meniscus is about 1 mm; less than 0.3 mm is
of six major questions. Even though these questions do not
abnormal (117). At the same time, the relation of the tear
significantly correlate with tests of reduced tear function
meniscus to the lower eyelid can be assessed. The eyelids
(e.g., lower Schirmer scores or abnormalities on Rose Ben-
and lashes should be observed for evidence of entropion,
gal testing; see below), the questions nevertheless seem to
ectropion, and stray lashes, and for the position and integrity
be able to identify patients likely to have dry eyes.
of the lower lacrimal punctum, because such abnormalities
Like dryness of the eyes, epiphora may cause blurred vi-
may cause disturbances that simulate those caused by abnor-
sion that is present during both distance and near viewing.
mal tear production.
Patients with epiphora should be asked about recent trauma
Specific tests of the mucin layer of the tears include a
to the eyelids or nose and about previous surgery in this
conjunctival biopsy to determine if goblet cells are present
area. They also should be queried about any symptoms or
and, if so, in what number. A qualitative test for mucin also
signs of recent infections or inflammations.
can be performed. In this test, a cotton strip (3 mm ⳯ 10
EXAMINATION mm) is placed in the inferior cul de sac of an unanesthetized
eye for 5 minutes. The strip is then placed on a glass slide
The examination of a patient with a disturbance of lacri- and stained with the periodic acid-Schiff (PAS) stain. If the
mation is directed toward three main abnormalities: de- stain is positive, mucin is present (112).
creased tear production, increased tear production, and par- Impression cytology also can be used to determine if gob-
tial or complete obstruction of the lacrimal drainage let cells are present and in what numbers. In this simple
apparatus. technique, cellulose acetate filter strips are placed on the
Lid function is critical to spreading the tear film and conjunctival epithelium and then transferred to a glass slide
should be assessed in any patient suspected of having an where they are stained with hematoxylin and PAS. This pro-
abnormality of tear function. Disturbances of eyelid structure cedure can be used to diagnose not only dry-eye conditions
and function can be detected both by simple external exami- but also vitamin A deficiencies (118).
nation and by slit-lamp biomicroscopy. Slit-lamp examina- Other qualities of the tear film can be tested individually.
tion can also detect punctate staining of the inferior cornea For example, the tear film contains various proteins includ-
related to dry eyes, exposure (lagophthalmos), or a lid abnor- ing albumin, immunoglobulins, and lysozyme (119). Lyso-
mality (112). zyme, an enzyme that lyses bacterial walls and is reduced
in dry-eye syndromes, can be detected using the lysozyme
lysis test. This test is said to be more reliable and sensitive
Table 15.3 than the Schirmer test (discussed later); however, the lyso-
Questions to Ask to Diagnose Dry Eyes zyme lysis test requires gels, broth cultures, and measure-
ments after incubating tear-soaked filter papers in the gel
1. Do your eyes ever feel dry? for 24 hours, whereas the Schirmer test requires only a strip
2. Do you ever have a gritty or sandy sensation in your eyes?
of filter paper and a topical anesthetic. Other assays, such
3. Do your eyes ever have a burning sensation?
4. Are your eyes ever red?
as an assay for tear lactoferrin (120), also may be useful
5. Do you notice much crusting on your lashes? in diagnosing such conditions as keratoconjunctivitis sicca
6. Do your eyes ever get stuck shut in the morning? (121). The osmolarity of the tear film can be measured. An
increasing osmolarity may be diagnostic of keratoconjuncti-
(From Schein OD, Hochberg MC, Munoz B, et al. Dry eye and dry vitis sicca (122).
mouth in the elderly: A population-based assessment. Arch Intern
Med 1999;159 :1359–1363; and Brewitt H, Sistani F. Dry eye dis-
In patients with symptoms suggesting insufficient tear
ease: The scale of the problem. Surv Ophthalmol 2001;45[Suppl production, the most common tests performed are nonspe-
2]:S199-S202.) cific tests of tear secretion. The sensitivity and specificity
Table 15.4
Sensitivity and Specificity of Tests for Tear Production
Test Name Basis of Test Reference Values Sensitivity Specificity
NIBUT Noninvasive test of tear stability ⬍10 seconds suggests unstable tear film 82% 86%
Rose Bengal Assess ocular surface damage ⬍3 sec, ⬍1 sec 95%, 92% 96%, 86%
Schirmer 1 Assess reflex tear flow ⱕ5.5 mm, ⱕ3 mm, ⱕ5 mm, ⱕ10 mm 85%, 10%, 25%, 79% 83%, 100%, 90%, 97%
Schirmer 2 Assess reflex tear flow
Phenol red thread Assess tear volume ⬍6–10 mm Unknown Unknown
NIBUT, noninvasive tear breakup timen.

(Adapted from Mainstone JC, Bruce AS, Golding TR. Tear meniscus measurement in the diagnosis of dry eye. Curr Eye Res 1996;15:653–661; and from Versura P, Cellini M,
Torreggiani V, et al. Dryness symptoms, diagnostic protocol and therapeutic management: a report on 1200 patients. Ophthalmic Res 2001;33:221–227.)
of these tests vary greatly (Table 15.4), depending on the (125). Total tear secretion usually is tested first, because no
specific test used and the reference criteria for normal values. anesthetic drop is applied to the eye in this test, often called
Judging the height of the tear meniscus may predict the the Schirmer 1 test. In this test, the patient sits in a dimly
amount of tear production and secretion as may assessment lit, quiet room. After drying the inferior conjunctival fornices
of radius of curvature, height, width, and cross-sectional on both sides with a cotton-tipped applicator or the edge of
area; however, there is little correlation between the results a tissue, the examiner places a strip of special absorbent
of this technique and the results of more objective tests of filter paper in the lower conjunctival sac on both sides, with
tear production (e.g., the Schirmer test) unless quantitative care being taken to keep the strip from touching the cornea
measurements of the meniscus are made (123). by placing it either medially or laterally (Fig. 15.13). The
The noninvasive tear film break-up time test is perhaps strips are stabilized by folding the indented end over the lid
the simplest test used to determine the adequacy of the tear margin. The patient is then advised to look straight ahead
film (124). In this test, the examiner touches the conjunctiva or slightly upward for 5 minutes, during which time he or
of an unanesthetized eye with a fluorescein strip or places she can blink normally. After 5 minutes, the strip is removed,
a small drop of fluorescein on the cornea of the eye. The and the amount of wetting is measured from the folded end.
fluorescein stains the mucin layer of the tear film and spreads Because the eyes have not been anesthetized, the irritation
across the cornea, which is then assessed using the cobalt from the filter paper produces wetting of the filter paper
blue filter of the slit lamp. The patient is asked to blink once, from both basal tear secretion and reflex secretion.
then look straight ahead without blinking. A normal test is A variant of the Schirmer 1 test can be performed by
characterized by the persistence of the fluorescein over the anesthetizing the eyes with a topical drug such as propara-
cornea for 10 seconds or longer. A break up and disappear- caine 0.5%. Topical cocaine should not be used as an anes-
ance of the fluorescein in less than 10 seconds is abnormal thetic, because it irritates the cornea and inflames the eye.
and indicates an abnormality in one of the layers of the tear Once the eye has been anesthetized, the paper strips are
film (125). This simple test has relatively good sensitivity placed as indicated above, and the nasal mucosa is stimulated
(82%) and specificity (86%) for adequacy of the tear film
using a cotton-tipped applicator or a tissue or piece of cotton
(126).
that has been soaked with benzene or a similar trigeminal
Another test of tear function is the Rose Bengal test. In
stimulant (129). This test provides a more consistent means
this test, the eye is first anesthetized with a 5% solution of
of stimulating reflex tear secretion (in addition to the basal
proparacaine, and a small drop of a 1% solution of Rose
Bengal is placed either directly on the cornea or just superior secretion that occurs). Regardless of the technique used, nor-
to it. This solution stains dead and degenerating cells. Nor- mal persons have a total tear secretion (e.g., wetting of the
mal patients should have little if any staining of the conjunc- filter paper) of 10–30 mm in 5 minutes (112).
tiva and cornea, whereas patients with a dry eye or a poor Basal tear secretion is determined using the Schirmer 2
mucin layer will have mild to severe staining of both (112). test. In this test, a topical anesthetic is placed in the inferior
Some authors have found that Rose Bengal staining in non- conjunctival sac of both eyes. After a minute or so, the exam-
exposure zones of the bulbar conjunctiva characterize tear iner uses a small piece of cotton or filter paper to dry the
deficiencies caused by an abnormality of the lipid layer and inferior fornices as in the Schirmer 1 test and its variant
help to differentiate it from dry-eye syndromes caused by a described above. The paper strips are then placed in the
deficiency of the aqueous component of the tear film (127). manner of the Schirmer 1 test, and the patient is given in-
As noted above, tear secretion may be classified as basal, structions identical with those given for the Schirmer 1 test.
reflex, or total. Tests of tear secretion can be separated into After 5 minutes, the strips are removed, and the amount of
those that test basal tear production (i.e., from the glands of wetting is measured. The wetting in this test should represent
Krause and Wolfring) and those that test reflex tear produc- only the basal tear secretion, because the topical anesthetic
tion (i.e., from the primary lacrimal gland). should prevent stimulation of the main lacrimal gland. In
The Schirmer test was first described in 1903 (128) and addition, by subtracting the amount of basal tear secretion
remains a simple and practical clinical test of tear secretion obtained from the Schirmer 2 test from the total secretion
Figure 15.13. A, Schirmer filter

strips and measuring scale on packet
of strips. B, Patient with Schirmer
strips properly placed laterally in infe-
B rior fornix of both eyes.
measured in the Schirmer 1 test or its variant, one should cein tear film break-up time or Rose Bengal test as their first
obtain the amount of reflex tearing (see later, however). test. In fact, a study that compared the Schirmer 1 and 2
The phenol red thread test also assesses tear volume and tests, the Rose Bengal test, the tear film break-up time test,
deficient aqueous. It uses a cotton thread that has been and the assay for lactoferrin level in patients with Sjögren
soaked with phenol red. This substance is actually yellow syndrome reported that the best balance between sensitivity
but is sensitive to the pH of tears and will change from and specificity was achieved by performing both a Rose
yellow to red when soaked with tears. One end of the thread Bengal test and a Schirmer 1 test (131).
is placed in the inferior conjunctival sac with the other end Fluorophotometric methods can be used to measure both
hanging over the edge of the lid, and the length of thread that tear volume and flow. These techniques are not clinically
has changed color is measured after 15 seconds. A change of applicable, however, and are best used as research tools
color from yellow to red of less than 6 mm is diagnostic of (132). Corneal sensitivity testing does not correlate with dry
dry eyes (125). eyes (133).
All of the tests of tear secretion described above have Patients who have epiphora, particularly those in whom
their proponents and detractors. Korb surveyed practitioners the epiphora is unilateral, should be evaluated not only for
as to their preferred diagnostic method for the determination excess or reduced tear production but also for possible block-
of dry-eye syndrome (130). Besides a complete history and age of the tear drainage system. The punctae should be exam-
use of the dry-eye questionnaire developed by Schein et al. ined to see if they are patent, and the examiner should gently
described above (115), most practitioners used the fluores- press on the lacrimal sac to see if there is regurgitation of
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120. McCollum CJ, Foulks GN, Bodner B, et al. Rapid assay of lactoferrin in kerato- degeneration. Am J Ophthalmol 1981;92:396–402.
conjunctivitis sicca. Cornea 1994;13:505–508. 152. Han DP, Thompson HS, Folk JC. Differentiation between recently resolved optic
121. Da Dalt S, Moncada A, Priori R, et al. The lactoferrin tear test in the diagnosis neuritis and central serous retinopathy. Arch Ophthalmol 1985;103:394–396.
of Sjögren’s syndrome. Eur J Ophthalmol 1996;6:284–286. 153. Servais GE, Thompson HS, Hayreh SS. Relative afferent pupillary defect in
122. Lemp MA. Recent developments in dry eye management. Ophthalmology 1987; central retinal vein occlusion. Ophthalmology 1986;93:301–303.
94:1299–1304.
154. Kardon R. The pupil. In Kaufman P, Alm A, eds. Adler’s Physiology of the
123. Mainstone JC, Bruce AS, Golding TR. Tear meniscus measurement in the diag-
Eye. Ed 10. St Louis, CV Mosby, 2003:713–743.
nosis of dry eye. Curr Eye Res 1996;15:653–661.
155. Folk JC, Thompson HS, Farmer SG, et al. Relative afferent pupillary defects
124. Norn MS. Desiccation of the precorneal tear film. I. Corneal wetting time. Acta
in eyes with retinal detachment. Ophthalmic Surg 1987;18:757–759.
Ophthalmol 1969;47:856–880.
125. Bron AJ. Diagnosis of dry eye. Surv Ophthalmol 2001;45(Suppl 2):S221–S226. 156. Bovino JA, Burton TC. Measurement of the relative afferent pupillary defect
126. Mengher LS, Pandher KS, Bron AJ. Non-invasive tear film break-up time: Sensi- in retinal detachment. Am J Ophthalmol 1980;90:19–21.
tivity and specificity. Acta Ophthalmol 1986;64:441–444. 157. Jiang MQ, Thompson HS. Pupillary defects in retinitis pigmentosa. Am J Oph-
127. Lee SH, Tseng SCG. Rose Bengal staining and cytologic characteristics associ- thalmol 1985;99:607–608.
ated with lipid tear deficiency. Am J Ophthalmol 1997;124:736–750. 158. Sadun AA, Bassi CJ, Lessell S. Why cataracts do not produce afferent pupillary
128. Schirmer O. Studien zur physiologie und pathologie der tränenabsonderung und defects. Am J Ophthalmol 1990;110:712–714.
tränenabfuhr. Albrecht von Graefes Arch Ophthalmol 1903;56:197–291. 159. Lam BL, Thompson HS. A unilateral cataract produces a relative afferent pupil-
129. Jones LT. Anatomy of the tear system. Int Opthalmol Clin 1973;13:3–22. lary defect in the contralateral eye. Ophthalmology 1990;97:334–338.
130. Korb DR. Survey of preferred tests for diagnosis of the tear film and dry eye. 160. Lam BL, Thompson HS. Relative afferent pupillary defect induced by patching.
Cornea 2000;19:483–486. Am J Ophthalmol 1989;107:305–306.
131. Vitali C, Moutsopoulos HM, Bombardieri S. The European Community Study 161. DuBois LG, Sadun AA. Occlusion-induced contralateral afferent pupillary de-
Group on diagnostic criteria for Sjogren’s syndrome: Sensitivity and specificity fect. Am J Ophthalmol 1989;107:306–307.
for ocular and oral involvement in Sjogren’s syndrome. Ann Rheum Dis 1994; 162. Kohn AN, Moss AP, Podos SM. Relative afferent pupillary defects in glaucoma
53:637–647. without characteristic field loss. Arch Ophthalmol 1979;77:294–296.
132. Afonso AA, Monroy D, Stern ME, et al. Correlation of tear fluorescein clearance 163. Jonas JB, Zach FM, Naumann GO. Quantitative pupillometry of relative afferent
and Schirmer test scores with ocular irritation symptoms. Ophthalmology 1999; defects in glaucoma. Arch Ophthalmol 1990;108:479–480.
106:803–810. 164. Quigley HA, Addicks EM, Green WR. Optic nerve damage in human glaucoma.
133. Bjerrum KB. Test and symptoms in keratoconjunctivitis sicca and their correla- Arch Ophthalmol 1982;100:135–146.
tion. Acta Ophthalmol Scand 1996;74:436–441. 165. Thompson HS. Adie’s syndrome: some new observations. Trans Am Ophthalmol
134. Zappia RJ, Milder B. Lacrimal drainage function. 2. The fluorescein dye disap- Soc 1977;75:587–626.
pearance test. Am J Ophthalmol 1972;74:160–162. 166. Drummond PD. The effect of light intensity and dose of dilute pilocarpine eye
135. Zappia RJ, Milder B. Lacrimal drainage function. 1. The Jones fluorescein test. drops on pupillary constriction in healthy subjects. Am J Ophthalmol 1991;112:
Am J Ophthalmol 1972;74:154–159. 195–199.
136. Toprak AB, Erkin EF, Kayikcioglu O, et al. Fluorescein dye disappearance 167. Jacobson DM, Olson KA. Influence of pupil size, anisocoria, and ambient light
test in patients with different degrees of epiphora. Eur J Ophthalmol 2002;12: on pilocarpine miosis. Ophthalmology 1993;100:275–280.
359–365. 168. Leavitt JA, Wayman LL, Hodge DO, et al. Pupillary response to four concentra-
137. Hurwitz JJ, Victor WH. The role of sophisticated radiological testing in the tions of pilocarpine in normal subjects: Application to testing for Adie tonic
assessment and management of epiphora. Ophthalmology 1985;92:407–413. pupil. Am J Ophthalmol 2002;133:333–336.
138. Rubin PA, Bilyk JR, Shore JW, et al. Magnetic resonance imaging of the lacrimal 169. Kardon RH, Denison CE, Brown CK, et al. Critical evaluation of the cocaine test
drainage system. Ophthalmology 1994;101:235–243. in the diagnosis of Horner’s syndrome. Arch Ophthalmol 1990;108:384–387.
139. Guzek JP, Ching AS, Hoang TA, et al. Clinical and radiologic lacrimal testing 170. Wilhelm H. Neuro-ophthalmology of papillary function: Practical guidelines. J
in patients with epiphora. Ophthalmology 1997;104:1875–1881. Neurol 1998;245:573–583.
140. Loewenfeld IE. Pupillary changes related to age. In Thompson HS, ed. Topics
171. Cremer SA, Thompson HS, Digre KB, et al. Hydroxyamphetamine mydriasis
in Neuro-Ophthalmology. Baltimore: Williams & Wilkins, 1979:124–150.
in Horner’s syndrome. Am J Ophthalmol 1990;110:71–76.
141. Bitsios P, Prettyman R, Szabadi E. Changes in autonomic function with age: A
study of pupillary kinetics in healthy young and old people. Age and Aging 172. Morales J, Brown SM, Abdul-Rahim AS, et al. Ocular effects of apraclonidine
1996;25:432–438. in Horner syndrome. Arch Ophthalmol 2000;118:951–954.
142. Thompson HS. Pupillary signs in the ophthalmologic diagnosis of optic nerve 173. Brown SM, Aouchiche R, Freedman KA. The utility of 0.5% apraclonidine in
disease. Trans Ophthalmol Soc UK 1976;96:377–381. the diagnosis of Horner syndrome. Arch Ophthalmol 2003;121:1201–1203.
143. Cox TA, Thompson HS, Corbett JJ. Relative afferent pupillary defects in optic 174. Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Surv Ophthalmol
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144. Bell RA, Thompson HS. Optic tract lesions and relative afferent pupillary defect. 175. Versura P, Cellini M, Torreggiani V, et al. Dryness symptoms, diagnostic proto-
In Thompson HS, ed. Topics in Neuro-Ophthalmology. Baltimore, Williams & col and therapeutic management: Report on 1,200 patients. Ophthalmic Res
Wilkins, 1979:164–168. 2001;33:221–227.
CHAPTER 16
Disorders of Pupillary Function,
Accommodation, and Lacrimation
Aki Kawasaki
DISORDERS OF THE PUPIL DISORDERS OF LACRIMATION

Structural Defects of the Iris Hypolacrimation
Afferent Abnormalities Hyperlacrimation
Efferent Abnormalities: Anisocoria Inappropriate Lacrimation
Disturbances in Disorders of the Neuromuscular Junction Drug Effects on Lacrimation
Drug Effects GENERALIZED DISTURBANCES OF AUTONOMIC FUNCTION
Light–Near Dissociation Ross Syndrome
Disturbances During Seizures Familial Dysautonomia
Disturbances During Coma Shy-Drager Syndrome
DISORDERS OF ACCOMMODATION Autoimmune Autonomic Neuropathy
Accommodation Insufficiency and Paralysis Miller Fisher Syndrome
Accommodation Spasm and Spasm of the Near Reflex
Drug Effects on Accommodation
In this chapter I describe various disorders that produce mation. Although many of these disorders are isolated
dysfunction of the autonomic nervous system as it pertains phenomena that affect only a single structure, others are
to the eye and orbit, including congenital and acquired systemic disorders that involve various other organs in the
disorders of pupillary function, accommodation, and lacri- body.
DISORDERS OF THE PUPIL

The value of observation of pupillary size and motility in and reactivity because these structural defects may be the
the evaluation of patients with neurologic disease cannot cause of ‘‘abnormal pupils’’ and often are easy to diagnose
be overemphasized. In many patients with visual loss, an at the slit lamp. Furthermore, if a preexisting structural iris
abnormal pupillary response is the only objective sign of defect is present, it may confound interpretation of the neuro-
organic visual dysfunction. In patients with diplopia, an im- logic evaluation of pupillary function; at the very least, it
paired pupil can signal the presence of an acute or enlarging should be kept in consideration during such evaluation.
intracranial mass. An adequate clinical examination of the
pupils requires little time and can be meaningful when ap- STRUCTURAL DEFECTS OF THE IRIS
proached with a sound understanding of the principles of
pupillary innervation and function. In most cases, one needs Congenital Defects
only a hand light with a bright, even beam, a device for Aniridia
measuring pupillary size (preferably in half-millimeter
steps), a few pharmacologic agents, and an examination Aniridia is a rare congenital abnormality in which the
room that permits easy control of the background illumina- iris is partially hypoplastic or completely absent (1,2) (Fig.
tion. 16.1A). Patients with aniridia initially may be thought to
This section commences with an overview of congenital have fixed, dilated pupils until a more careful examination
and acquired diseases of the iris that affect pupil size, shape, is performed. In almost all cases, histologic or gonioscopic
739
Figure 16.1. Iris anomalies that may simulate neurologic pupillary abnormalities. A, Aniridia. Note associated upward lens
dislocation. B, Typical iris coloboma. C, Acquired corectopia in iridocorneal–endothelial adhesion syndrome. D, Persistent
pupillary membrane. E, Pseudopolycoria from iridocorneal–endothelial adhesion syndrome. F, Heterochromia iridis in a patient
with congenital Horner syndrome. The lighter iris is in the eye with Horner syndrome. (A and B, Courtesy of Dr. Irene H.
Maumenee. C, Courtesy of Dr. Harry A. Quigley. D, From Gutman ED, Goldberg MF. Persistent pupillary membrane and
other ocular abnormalities. Arch Ophthalmol 1976;94⬊156–157. E, Courtesy of Dr. Harry A. Quigley.)
DISORDERS OF PUPILLARY FUNCTION, ACCOMMODATION, AND LACRIMATION 741
examination reveals small remnants of iris tissue. The iris A ‘‘complete’’ iris coloboma extends the full thickness
is only minimally developed, and the iris musculature usu- of the iris and typically produces an oval-shaped or keyhole-
ally is hypoplastic. Patients with aniridia often have photo- shaped pupil, whereas an ‘‘incomplete’’ iris coloboma is a
phobia, poor visual acuity, and other ocular defects, includ- partial-thickness defect best seen as a wedge-shaped transil-
ing glaucoma, cataracts, ectopia lentis, corneal opacification, lumination defect of the iris (7). An isolated coloboma in a
ciliary body hypoplasia, optic nerve hypoplasia, foveal hy- microphthalmic eye has an established autosomal-dominant
poplasia, strabismus, and nystagmus (3). The condition usu- inheritance pattern, but penetrance is incomplete. A few ped-
ally is bilateral, and two thirds of cases are inherited in auto- igrees supporting an autosomal-recessive or X-linked–reces-
somal-dominant fashion (4). sive inheritance pattern have been reported. Nevertheless,
The gene defect resulting in aniridia is a nonsense or regardless of the type, location, and completeness of a colo-
frameshift mutation in the large PAX6 gene on chromosome bomatous defect, patients with a coloboma should undergo
11p13 (3). The PAX6 gene is a master regulator gene, critical an evaluation to determine whether it truly is an isolated
in the development of the eye and central nervous tissues. finding or part of a multisystem disorder.
Mutations of this gene are associated with other ocular ab- One well-known congenital multisystem syndrome with
normalities, such as anterior segment defects and foveal hy- heterogeneous etiologies is the CHARGE association (colo-
poplasia, in addition to aniridia. Mutations can be sporadic boma, heart defects, atresia of the choanae, retardation of
or inherited; in most cases, loss of one allele (heterozygous growth and development, genital hypoplasia, and ear anoma-
PAX6 mutation) is sufficient to result in ocular structural lies or hearing loss) (6). Patients with the phenotypic
defects. Detection of a PAX6 mutation necessitates genetic CHARGE association can be given a more specific diagnosis
counseling. if an etiologic basis is found, such as a teratogenic agent
Systemic abnormalities found in patients with aniridia are (retinoic acid) or a gene defect (partial tetrasomy of chromo-
many and varied. They include polydactyly, oligophrenia, some 22, the cat-eye syndrome) (8).
cranial dysostosis, malformations of the extremities and ex- Cat-eye syndrome is one clinical phenotype resulting from
ternal ears, hydrocephalus, and mental retardation (2). The a genomic disorder of 22q11. Specifically, there is a partial
most important association, however, is with the childhood tetrasomy (four copies) of this region of chromosome 22.
cancer, Wilms’ tumor. Aniridia occurs in 1 in 73 patients Patients commonly have ocular colobomata, anal atresia, and
with Wilms’ tumor, compared with a frequency of 1 in preauricular skin tags. Other anomalies include heart defects
50,000–100,000 in the general population (1). The reason (particularly total anomalous pulmonary venous return),
for this high association is the close proximity of the aniridia renal malformations, craniofacial anomalies, genital anoma-
gene to the gene for Wilms’ tumor (WT1) (5). The associa- lies, and mental retardation (9).
tion of Wilms’ tumor, aniridia, genitourinary anomalies, and
mental retardation is known as WAGR syndrome and is due
to a contiguous defect on chromosome 11p13 that encom- Square Pupils
passes both the PAX6 and the WT1 genes. Although sponta- Square pupils are thought to represent incomplete aniridia.
neous deletions can occur simultaneously in both genes, the White and Fulton observed, in homozygous twins whose
detection of an intragenic PAX6 mutation in a patient with mother showed the same defect, large, irregular, roughly
sporadic aniridia can eliminate the need for routine kidney
quadrilateral pupils that responded to constricting stimuli
ultrasounds (3).
only in certain quadrants (10). Similar pupils were observed
in a mother and daughter with incomplete aniridia and cata-
Coloboma of the Iris racts (11).
A coloboma is a notch, hole, or fissure in any of the ocular
structures (cornea, iris, ciliary body, zonules, choroids, ret- Elliptic Pupils
ina, and optic disc) due to defective embryogenesis. Affected
eyes are frequently microphthalmic. The term ‘‘typical’’ col- Elliptic pupils occasionally occur. In strong illumination,
oboma specifically refers to one caused by defective closure such pupils take on the form of elliptical slits (12,13).
of the fetal fissure. Typical colobomata occur in the inferona-
sal quadrant and are the most common type (Fig. 16.1B). Scalloped Pupils
According to Pagon, only iris colobomata that are ‘‘typical’’
are associated with chorioretinal or optic disc colobomas Irregular, cup-shaped indentations in the pupillary mar-
(6). ‘‘Atypical’’ colobomata may result from (a) interference gins have been described as a congenital anomaly in large
with embryonic growth of the neuroepithelial layers; (b) me- pupils that otherwise react normally to light and near stimuli
chanical blockage of the advancing neuroectoderm by meso- (14). Scalloped pupils probably are more commonly an ac-
dermal elements present at the edge of the optic cup; and quired disorder, particularly in familial amyloidosis (15,16).
(c) occlusion of vessels within the embryonic iris tissue, The pupil also may develop a scalloped appearance after
with subsequent iris atrophy. When an atypical iris coloboma trauma to the sphincter muscle, causing multiple tears, seg-
does not extend to the pupillary margin, it produces pseudo- mental sphincter atrophy, or both. A scalloped pupil can
polycoria, a defect in the iris that has the clinical appearance occur after uveitis that is complicated by the development
of an accessory pupil. of posterior synechiae (adhesions between the iris and lens).
Peninsula Pupils membrane, or it may be part of one of several syndromes

characterized by mesodermal dysgenesis (30). A distinctive
Bosanquet and Johnson reported 40 patients from New- feature of pseudopolycoria is passive constriction, distortion,
foundland and Labrador with an unusual form of partial iris or even occlusion of the accessory pupil when the true pupil
sphincter atrophy that resulted in an oval pupil (17). The is dilated (31). More commonly, pseudopolycoria occurs as
condition, called peninsula pupils, was bilateral in most an acquired disorder from direct iris trauma including sur-
cases. The anomaly was confined to the iris, and there were gery, photocoagulation, ischemia, or glaucoma or as part
no associated systemic disorders. Most of the affected indi- of a degenerative process such as the ICE syndrome (Fig.
viduals were male, and all had blue irides. Three of the pa- 16.1E).
tients believed that their pupils had been large and oval since
birth. This pupillary anomaly may be an inherited trait pecul- Congenital Miosis
iar to the Newfoundland-Labrador region.
Congenital miosis usually is bilateral and characterized
Ectopic (Misplaced) Pupils by extremely small pupils that react slightly to light stimuli
and dilate poorly after instillation of sympathomimetic
Misplaced or ectopic pupils (corectopia, ectopia pupillae)
agents (32,33). The anomaly appears to result from congeni-
are observed frequently. Isolated ectopic pupils may be in-
tal absence of the iris dilator muscle. Additionally, the iris
herited as either a dominant or a recessive trait. The condi-
sphincter muscle may be contracted excessively because of
tion usually is usually bilateral and symmetric (18). Al-
the lack of counterpull normally supplied by the dilator mus-
though the pupils may be displaced in any direction, they
cle. Congenital miosis may occur sporadically or may be
often are up and out from the center of the cornea. Such
inherited. Most of the inherited cases are transmitted as an
displacement of the pupils is frequently associated with ec-
autosomal-dominant trait, although pedigrees with autoso-
topia lentis, congenital glaucoma, microcornea, ocular colo-
mal-recessive inheritance have been reported (34,35).
boma, and high myopia (19). Ectopic pupils also occur in
Congenital miosis may be an isolated phenomenon, or it
some patients with albinism and some patients with Axen-
may be associated with other ocular abnormalities, including
feld-Rieger anomaly. In addition, three families were re-
microcornea, iris atrophy, myopia, and anterior chamber
ported in which affected members had ectopic pupils, ptosis,
angle deformities (32). In addition, congenital miosis can
and ophthalmoplegia (20–22).
occur in patients with systemic disorders. Patients with con-
Although acquired corectopia may occur in patients with
genital miosis also may have albinism, the congenital rubella
severe midbrain damage, the clinical setting and the variabil-
syndrome, the oculocerebrorenal syndrome of Lowe, Marfan
ity of the acquired defect usually allow the physician to dis-
syndrome, or multiple skeletal anomalies (33,36–39). Con-
tinguish easily between the congenital and acquired forms
genital miosis was noted in four members of a family with
(23–25). Similarly, the corectopia that occurs during the
hereditary spastic ataxia, and it is one of the main features
course of purely ocular disorders such as the iridocor-
in Stormorken syndrome, a dominantly inherited metabolic
neal–endothelial (ICE) adhesion syndromes and posterior
disorder also characterized by bleeding tendency, thrombo-
polymorphous corneal dystrophy should be differentiated
cytopathia, muscular weakness, postexertional muscle
easily from congenital and neurologic corectopia by the clin-
spasms, ichthyosis, asplenia, dyslexia, and headache (40).
ical setting and the associated ocular signs (Fig. 16.1C).
Congenital Mydriasis
Persistent Pupillary Membrane Remnants
Congenital mydriasis may be similar to or identical with
Persistent pupillary membrane remnants are vestiges of
the condition described above as square pupils. This condi-
the embryonic pupillary membrane that can appear as thread-
tion may be difficult to distinguish from aniridia unless a
like bands running across the pupillary space and attaching
careful ocular examination is performed. Caccamise and
to the lesser circle of the iris (26,27) (Fig. 16.1D). Occasion-
Townes described a 73-year-old woman with bilaterally
ally, such remnants are attached to the lens and may be
large, round pupils that were present from birth (41). The
associated with an anterior capsular cataract. Persistence of
condition appeared to have been inherited as an autosomal-
the entire membrane can block visual input, but most cases
dominant trait, although all other affected family members
are visually insignificant. Excision of the membrane has
were female. Both pupils constricted to topical 4% pilocar-
been performed in young patients who are at risk for ambly-
pine solution, suggesting an intact iris sphincter muscle, and
opia and in others with visual impairment during pupillary
both pupils dilated rapidly to topical 10% phenylephrine so-
constriction (e.g., in bright sunlight) (28).
lution, indicating an intact iris dilator muscle. However, nei-
Polycoria and Pseudopolycoria ther pupil reacted to a potent topical cholinesterase inhibitor,
suggesting an abnormality of acetylcholine production at the
In true polycoria, the extra pupil or pupils are equipped parasympathetic neuromuscular junction.
with a sphincter muscle that contracts on exposure to light Magnetic resonance (MR) imaging has shown an enlarged
(29). This is an extremely rare condition. Most additional fourth ventricle and atrophy of the cerebellar vermis in one
pupils are actually just holes in the iris without a separate case report of congential mydriasis (42). In another patient
sphincter muscle. This pseudopolycoria may be a congenital with bilateral congenital mydriasis and absent accommoda-
disorder, such as an iris coloboma or persistent pupillary tion, the pupils did not react to light, lid closure, or adminis-
tration of topical 1% pilocarpine solution; however, both dilation of the pupil may occur during an episode of monocu-
pupils dilated further after topical administration of 2.5% lar amaurosis associated with carotid occlusive disease, mi-
phenylephrine (43). A patient with the Waardenburg syn- graine, or Raynaud disease. This unilateral pupillary change
drome who had a unilateral, congenitally fixed, dilated pupil is not caused by the blindness but by the hypoxic process
has been reported (44). Pharmacologic studies in this patient that affects the entire eye, including the iris sphincter. Em-
suggested the possibility of congenital agenesis of the iris boli that enter the central retinal artery frequently involve
sphincter muscle. other branches of the ophthalmic artery, particularly the pos-
terior ciliary arteries. If venous outflow from the globe is
Congenital Abnormalities of Iris Color briefly impaired, the retina may shut down temporarily with-
out producing an ipsilateral mydriasis. If the whole globe is
The color of the iris depends on the pigment in the iris
ischemic (as in angle-closure glaucoma), iris ischemia will
stroma. In albinism, there is failure of mesodermal and ecto-
relax the iris sphincter and dilate the pupil (47).
dermal pigmentation. Consequently, the iris has a transpar-
Chronic ischemia of the anterior segment of the globe
ent, grayish-red color and transilluminates readily.
results in neovascularization of the chamber angle and the
In a number of congenital and acquired conditions, the
surface of the iris (rubeosis iridis), producing iris atrophy,
iris of one eye differs in color from the iris of the other eye.
ectropion of the pigment layer at the pupillary margin (ec-
In other instances, one iris is entirely normal, and a part of
tropion uveae), glaucoma, and immobility of the iris. This
the iris in the opposite eye has a different color than the rest
type of chronic ischemia of the anterior segment may result
of the iris surrounding it (iris bicolor). These abnormalities,
from severe occlusive disease in the carotid system or the
collectively called heterochromia iridis, may occur (a) as an
aortic arch. It also may be produced by microvascular dis-
isolated congenital anomaly; (b) in association with other
ease or drug toxicity (e.g., quinine).
ocular abnormalities, such as iris or optic disc coloboma;
Severe, generalized atherosclerosis may result in vascular
(c) in association with systemic congenital abnormalities,
insufficiency of both irides, producing oval pupils from bi-
as in patients with the Waardenburg syndrome, congenital
temporal palsy of the pupillary sphincters (48). Such patients
Horner syndrome, or incontinentia pigmenti; or (d) from
have no evidence of iris atrophy or synechiae. Conversely,
an acquired ocular condition (45) (Fig. 16.1F). When iris
local iris ischemia was postulated to cause focal temporal
heterochromia is part of a pathologic condition, it is neces-
atrophy of the iris and a nonreactive pupil in a patient with
sary to determine which iris is abnormal. For example, the
advanced keratoconus (49).
darker iris is abnormal in patients with a diffuse iris and
ciliary body melanoma and in siderosis from an intraocular
Tumor
foreign body or vitreous hemorrhage. The lighter iris is
pathologic in congenital Horner syndrome, in Fuchs heter- Very few tumors affect the iris, but those that do can cause
ochromic iridocyclitis, and after iris atrophy following a uni- irregularity of the iris border, anisocoria, and an abnormally
lateral iritis or acute glaucoma. reactive pupil. Leiomyoma, malignant melanoma, and lym-
phoma can all present in this fashion.
Acquired Defects
Trauma
Inflammation
Spastic miosis is a constant and immediate result of
Iritis or iridocyclitis in its acute stages produces swelling
trauma to the globe and occurs immediately after blunt
of the iris, miosis, and slight reddening of the circumcorneal
trauma to the cornea. A similar spastic miosis follows perfo-
tissues. The miosis of iritis results from the release of a
rating injury to the eye. The constriction of the pupil is pro-
neurohumor, substance P, that produces miosis through in-
found but usually transient and often followed by iri-
teraction with a specific receptor in the iris sphincter muscle
doplegia. Transient spasm of accommodation often occurs
(46).
in this setting and lasts 1–2 hours.
In patients with intraocular inflammation, dilation of the
Dilation of the pupil frequently occurs after concussion
pupil with mydriatics may be difficult because of adhesions
of the globe and often is followed by paralysis of accommo-
between the iris and the lens (posterior synechiae). These
dation after the initial intense miosis has resolved. Because
adhesions in chronic iritis may distort the shape of the pupil.
both the iris sphincter and dilator muscles are involved, the
They also may fix the pupil in a dilated position. Occasion-
term ‘‘traumatic mydriasis’’ is misleading, as it suggests
ally, the adhesions are not evident until the pupil is further
injury to the sphincter alone. The functions of the iris and
dilated by a mydriatic. Such adhesions and black pigment
ciliary muscle usually are affected together, but occasionally
on the lens suggest iritis, active or inactive. True neurogenic,
one is impaired without the other. The clinical picture is
paralytic mydriasis may occur as part of certain inflamma-
that of a moderately dilated pupil with both the direct and
tory disorders that affect the eye and orbit, such as herpes
consensual reactions to light and near stimuli being dimin-
zoster.
ished or absent. The deformity may resolve in a few weeks,
Ischemia but it usually is permanent. This abnormality may have sev-
eral causes. The frequent absence of detectable pathologic
Ischemia of the anterior segment of the globe may be acute change suggests that the effect may occur from injury of the
or chronic. Both types can produce iridoplegia. Transient fine nerves of the ciliary plexus. These may be damaged or
A B
Figure 16.2. Pupillary changes after direct iris trauma. A, Tears in the iris sphincter causing pupillary dilation. B, Iris dialysis
producing pseudopolycoria. (Courtesy of Dr. Walter J. Stark.)
torn by the tissue distortion caused by a pressure wave initi- Atrophy

ated by the impact. In other cases, contusion necrosis directly
Iris atrophy may be caused by inflammation, ischemia, or
produces a lesion in the iris and ciliary body. Finally, as
trauma (Fig. 16.4). It may be circumscribed or diffuse and
noted above, tears in the iris or rupture of the iris sphincter
may involve the anterior border layer, the stroma and sphinc-
may be identified using slit-lamp biomicroscopy with trans-
ter muscle, the anterior epithelium and dilator muscle, the
illumination (Fig. 16.2A), and a traumatic, peripheral iridodi-
posterior pigmented epithelium, or a combination of these
alysis may be present, with resultant distortion of the nor-
structures. Patients with unilateral iris atrophy that involves
mally round pupil (Fig. 16.2B).
the dilator muscle often develop anisocoria, with the smaller
Traumatic iridoplegia in the unconscious patient with
pupil on the side of the atrophy. Patients in whom iris atro-
multiple head injuries may pose a difficult diagnostic prob-
phy involves the sphincter muscle develop anisocoria with
lem. If it cannot be established beyond question that the
the larger pupil on the side of the atrophy.
iridoplegia is the result of direct ocular or orbital damage,
Feibel and Perlmutter reported that patients with the pig-
it must be assumed that the patient has a tentorial herniation
from subdural or epidural hematoma.
Acute Angle-Closure Glaucoma

An acute attack of angle-closure glaucoma usually pre-
sents no problem in diagnosis, but occasionally the pain is
minimal or nonexistent. Redness of the eye is common. The
pupil is usually mid-dilated and fixed (Fig. 16.3), but it may
be oval. If the acute rise in intraocular pressure abates in an
hour or two, the patient may never complain about the pain
but instead may seek medical attention for iridoplegia. If the
physician fails to notice the shallow anterior chamber or
measure the intraocular pressure, he or she may be unable
to explain the iridoplegia or may mistakenly attribute it to
an oculomotor nerve lesion (11).
The dilated pupil that is associated with acute glaucoma
initially occurs because there is maximum contact between
the iris and the lens when the pupil is in a mid-dilated posi-
tion. Thus, most angle-closure attacks occur when the pupil
is mid-dilated (e.g., in darkness), and tonic pupil has been
reported as a possible risk for angle closure (50). The iris
becomes trapped in this position as intraocular pressure rises.
Eventually, the increased pressure results in iris ischemia so Figure 16.3. Appearance of the eye during an attack of acute angle-
that even when the pressure is reduced, the iris no longer closure glaucoma. The pupil is fixed and asymmetrically dilated. Note the
functions properly and remains in the mid-dilated position. opaque, thickened cornea and dilation of the conjunctival vessels.
causing an acute rise of intraocular pressure and secondary

iris ischemia.
Postoperative mydriasis occasionally occurs after an
otherwise uneventful cataract extraction with placement of
an intraocular lens (58,59). It sometimes is called an ‘‘atonic
pupil.’’ This condition presumably occurs from direct dam-
age to the iris sphincter muscle during surgery.
Surgical or laser-induced damage to the short ciliary
nerves or ciliary ganglion can produce a postoperative tonic
pupil. Affected patients show a mild mydriasis with anisoco-
ria that is less than 1.0 mm. The most common setting is after
excimer laser photorefractive keratectomy. The mechanism
may be a medication effect of topical steroids on a suscepti-
ble cornea. The mydriasis seems to improve with time in
these cases (60).
Figure 16.4. Iris atrophy following several attacks of herpes zoster oph- AFFERENT ABNORMALITIES
thalmicus. (Courtesy of Dr. David L. Knox.)
Relative Afferent Pupillary Defect
The relative afferent pupillary defect (RAPD) is one of the
ment dispersion syndrome and anisocoria had greater transil- most important objective signs of dysfunction in the afferent
lumination defects of the iris on the side of the larger pupil visual pathway. The methods of RAPD detection and quanti-
(51). Histologic studies of affected irides in patients with fication were reviewed in Chapter 15. In this section, we
this syndrome show both atrophic and hypertrophic focal discuss the various conditions that should be considered
changes in the dilator muscle. The etiology of the anisocoria when one finds an RAPD.
in these patients remains unclear; in some cases, it stems
from an unrelated, coexisting condition such as a tonic pupil, Optic Nerve Disorders
Horner syndrome, or physiologic anisocoria. In others, the
anisocoria may be a result of structural change or irritative Most patients with a unilateral or asymmetric bilateral
stimulation of the iris due to pigment dispersion (51–53). optic neuropathy, regardless of the cause, have an RAPD
With age, the iris may become gray and of a more uniform (61). In general, the magnitude of an RAPD correlates with
color. Its stroma becomes thin, and the sphincter appears as the extent of central visual field loss (62–64). The correla-
a gray-brown ring. Stromal fibers may be partly torn and tion is higher with compressive and ischemic optic neuropa-
may float in the anterior chamber (iridoschisis). Typical of thies than with demyelinating optic neuritis (62,65). Patients
the aged iris are changes on the edge of the pupil, which with acute optic neuritis have a substantial RAPD (1.0–3.0
becomes thin and loses its pigment so that it resembles a log units) (66). After recovery, even when there are no re-
fine lacework. Another characteristic finding easily seen by maining visual complaints, there often is a small RAPD
slit-lamp biomicroscopy in elderly persons is the deposition (0.3–0.6 log units) still present in the affected eye. In optic
of hyaline about the pupillary margin (54). Histologic exami- nerve compression, the RAPD can be used as an additional
nation of excised iris tissue in such cases shows deposition test to monitor progression or recovery of optic nerve dam-
of hyaline in the iris stroma and in the muscles of the iris age. Patients with glaucoma have an RAPD when the cup-
that also are atrophic. ping and field loss is unilateral or asymmetric (67,68). Like-
wise, patients with optic disc drusen have an RAPD when
Postoperative Mydriasis there is functional asymmetry of vision between the two
eyes (68).
In 1963, Urrets-Zavalia described several patients who Initial studies of patients with visual loss from Leber he-
suffered an irreversible mydriasis and pupillary immobility reditary optic neuropathy (LHON) found that their pupil re-
after an otherwise uncomplicated keratoplasty for keratoco- sponses were not significantly different from those of normal
nus (55). In the typical case, a patient with keratoconus and persons and suggested that this visual–pupil dissociation
a normally reacting pupil undergoes an uncomplicated pene- was a characteristic finding of this optic neuropathy (69).
trating keratoplasty, following which the pupil dilates and Subsequent studies of patients with LHON, including those
will not react to miotics of any type or strength. The cause with clinical or electrophysiologic evidence of uniocular in-
of this dilation is unknown, but certain patients may be pre- volvement, have demonstrated a pupil response deficit con-
disposed to develop this disorder because of preexisting hy- sistent with the visual deficit (70,71). Bremner et al. quanti-
poplasia of the iris stroma (56). In patients who develop fied the focal pupil and visual sensitivity at various points
microperforations in Descemet’s membrane during deep la- within the visual scotoma of patients with LHON (72). A
mellar keratoplasty, a fixed and dilated pupil can occur after pupil deficit was detected at all test locations, but it was
the air/gas injection into the anterior chamber (57). The smaller than the corresponding visual deficit (about 7.5 dB
mechanism here is speculated to be induced pupil block difference; i.e., a relative pupil sparing). The authors hypoth-
esized that there may be a lower susceptibility of pupil fibers in the amount of light entering the retina. A general rule put
to damage in LHON. forth is 0.1 log unit RAPD on the side of the smaller pupil
The RAPD appears to have some prognostic value in trau- for every 1 mm of anisocoria (83).
matic optic neuropathy. In 19 patients with indirect traumatic
optic neuropathy treated acutely with similar megadoses of Amblyopia
methylprednisolone, patients who had an initial RAPD less
A small RAPD, generally less than 0.5 log units, often
than 2.1 log units improved to visual acuity of 20/30 or
can be seen in an amblyopic eye. The magnitude of the
better. Patients with an initial RAPD larger than 2.1 log units
RAPD does not correlate well with the visual acuity (84,85),
showed little improvement of vision (73).
nor does it predict the effect of occlusion therapy (86). That
Retinal Disease such pupillomotor asymmetry is not always observed sug-
gests that it may be seen only in patients who do not take
Diseases of the retina are uncommon causes of an RAPD. up fixation in the amblyopic eye, even though a bright light
Most of the pupillomotor input derives from the central ret- is effectively blocking the good eye.
ina, so in a suspected retinopathy, the presence of a RAPD
usually indicates macular involvement (see Table 15.1). In Local Anesthesia and RAPD
macular visual loss with visual acuity of 20/200 or better,
A transient RAPD typically is seen following local anes-
the RAPD usually is 0.5 log units or less. A RAPD greater
thesia in the orbit. In one study, the method of anesthetic
than 1.0 log units with a lesion confined to the macula is
delivery (peribulbar versus retrobulbar versus sub-Tenon)
unusual (74,75). Kerrison et al. demonstrated that in mon-
did not affect the degree of induced RAPD or its recovery
keys with controlled laser destruction of the macula, approxi-
time (87).
mately 25–50% loss of ganglion cells was needed to produce
a 0.6 log-unit RAPD (76). Central serous maculopathy pro- Media Opacities
duces very little RAPD, usually 0.3 log units or less. When
the subretinal fluid disappears, so does the RAPD (77). An Dense intraocular hemorrhage that mechanically blocks
RAPD can occur in a patient with a retinal detachment (78). light from reaching the retina can produce an RAPD that
In this setting, each quadrant of a fresh, bullous detachment resolves as the hemorrhage clears (88). In contrast, a dense
produces about 0.3 log of RAPD, and when the macula de- unilateral cataract does not produce an RAPD in the affected
taches, the RAPD increases by about another 0.7 log units eye. Instead, a very small RAPD occasionally is found in
(79). the opposite eye. This may be partly because of the dark-
An RAPD can be used to help separate nonischemic from adapted retina behind the cataract and partly because the
ischemic central retinal vein occlusion (CRVO). Servais et incoming light is scattered by the opaque lens, allowing more
al. studied 120 patients with a unilateral CRVO and found light to hit the macular area directly (89–92). DuBois and
that 90% of nonischemic CRVOs had an RAPD of 0.3 log Sadun also suggested that retinal sensitivity may be upregu-
units or less, and none had an RAPD larger than 0.9 log lated slowly behind a cataract by a neurogenic mechanism
units (80). In contrast, in 33 patients with ischemic CRVO, that is unrelated to routine receptor photochemistry (81).
91% had an RAPD of 1.2 log units or more, and none had
an RAPD smaller than 0.6 log units. In eyes that initially Optic Tract Disorders
were nonischemic, a significant increase in the RAPD was
A complete or nearly complete lesion of the optic tract
an early indicator of ischemic conversion, even when the
produces a contralateral homonymous hemianopia and a
fundus appeared relatively unchanged.
small to moderate RAPD (0.3–1.6 log units) in the contralat-
Induced RAPD from Asymmetric Retinal Adaptation eral eye (i.e., the eye with the temporal field loss) (93–95).
Assuming an asymmetric distribution of crossed and un-
An eye that is occluded by a ptotic lid or eye patch be- crossed pupillomotor fibers in each optic tract similar to that
comes increasingly dark-adapted during the first 30 minutes of visual fibers, the contralateral side of the RAPD found
of occlusion. This can produce up to 1.5 log units of a false in optic tract (and midbrain tectal) lesions can be understood.
RAPD in the unpatched eye (81,82). Therefore, assessment However, the large range and magnitude of tract RAPDs is
of an RAPD in a patient wearing an eye patch should not not explained by the percentage of decussating pupillomotor
be performed immediately after patch removal because of input and may be related instead to individual differences
underlying asymmetry of retinal light sensitivity between in the pupillomotor sensitivity of the temporal and nasal
the two eyes. This is particularly important to remember in retina. Additionally, an asymmetric distribution of efferent
patients with traumatic optic neuropathy (a real RAPD in impulses from each pretectal nucleus to the Edinger-West-
the patched eye may be overlooked) and in patients with phal nuclei would produce an efferent deficit in the eye con-
nonorganic visual loss (an RAPD may mistakenly be attrib- tralateral to the lesion (i.e., the eye with the afferent deficit).
uted to the opposite eye). After 10–15 minutes in room light This relative efferent deficit, which is most evident when
with both eyes open, retinal sensitivity equalizes, and any comparing only the direct pupil response between the two
RAPD detected should be considered valid. eyes in a patient with an optic tract (or tectal) lesion, can
An anisocoria of 2 mm or more, especially if one pupil lead to overestimation of the RAPD. Cox and Drewes sug-
is very small, can produce a clinically significant difference gested that this efferent part of the asymmetry can be avoided
by watching one eye only and comparing its direct and con- (11). Whether further investigation is warranted for such
sensual responses (96). This makes the examination more patients should be individualized based on the clinical set-
difficult, but it is necessary in some clinical settings. ting.
Pretectal Nucleus Wernicke Pupil

A unilateral lesion in the pretectal nucleus or in the bra- When the optic chiasm is bisected sagittally, the nasal
chium of the superior colliculus from an arteriovenous mal- halves of each retina become insensitive to light so that there
formation, infarct, tumor, or other lesion will damage the is not only a bitemporal hemianopia but also a bitemporal
afferent pupillomotor fibers that derive from the ipsilateral pupillary hemiakinesia; that is, light falling on the nasal ret-
optic tract. This can produce a contralateral RAPD without ina of either eye will fail to produce a pupillary constriction.
any visual field defect (97,98). The tectal RAPD occasion- Clinical demonstration of this sign with a flashlight is diffi-
ally is associated with an ipsilateral or contralateral trochlear cult because of intraocular scatter: when light strikes the
nerve paresis if the lesion affects the ipsilateral trochlear retina in one quadrant, it tends to be spread evenly, and the
nerve nucleus, the predecussation portion of the ipsilateral beam from a flashlight directed upon the blind hemiretina
trochlear nerve fascicle, or the postdecussation portion of thus spills onto the seeing half, causing pupillary constric-
the contralateral trochlear nerve fascicle (99,100). tion. Thus, if a very bright but small beam of light such
as that produced by a slit lamp is shined on the nonseeing
Geniculate and Retrogeniculate Lesions hemiretina of a patient with damage to the optic chiasm or
optic tract and then is shined on the seeing hemiretina, it is
Lesions that involve the lateral geniculate nucleus or the
possible to see that the pupil reacts better when the light
proximal portion of the retrogeniculate pathway may be as-
shines on the seeing hemiretina than when it shines on the
sociated with a contralateral RAPD if there is also involve-
nonseeing retina. However, for practical purposes, the results
ment of the adjacent intercalated (pretectal) neurons in the
of this test when performed at the bedside are often inconclu-
dorsal midbrain that serve as the link between the afferent
sive and unreliable, and this has disappointed several genera-
visual pathway (optic tract) and the efferent pupillomotor
tions of ophthalmologists and neurologists since Wernicke
centers (Edinger-Westphal nuclei). These are, then, essen-
popularized the test in 1883.
tially the same as tectal RAPDs (101). Congenital postgenic-
ulate lesions causing homonymous hemianopia also have a Poorly Reacting Pupils from Midbrain Disease
contralateral RAPD, presumably from transsynaptic degen-
eration of the optic tract ipsilateral to the lesion (102). Fixed dilated pupils and pupils that react poorly to both
light and near stimuli may be produced by damage to the
Nonorganic Visual Loss visceral oculomotor nuclei and their efferent fiber tracts. The
precise location of such lesions is almost impossible to deter-
Neither nonorganic loss of visual acuity nor nonorganic
mine unless there is associated evidence of ocular motor
constriction of the visual field in one eye ever produces an
nerve dysfunction. Other midbrain lesions damage the affer-
RAPD (103). This obviously is of great clinical importance.
ent input to the Edinger-Westphal nuclei or cause combined
Although Kosmorsky et al. (104) reported five patients with
afferent and efferent damage. Seybold et al. described a vari-
neurogenic monocular temporal visual field defects who did
ety of pupillary abnormalities in patients with tumors in the
not have an RAPD, the vast majority of patients with mono-
pineal region (107). With a bright light stimulus, four pa-
cular neurogenic loss of the visual field do have one in the
tients had impairment of both light and near reactions, two
eye with visual loss. We have no explanation for the findings
patients had markedly impaired light reactions and relatively
of Kosmorsky et al.
intact responses to near stimuli (classic light–near dissocia-
RAPD in Normal Eyes tion), and two patients had relatively intact light reactions but
impaired responses to near stimuli (inverse Argyll Robertson
Some normal subjects show a small RAPD, clinically and pupils). With a dim light stimulus, five patients had impair-
pupillographically, in the absence of any detectable patho- ment of reactions to both light and near stimuli and three
logic disease (105,106). The RAPD in such cases usually is patients had impaired light reactions but relatively intact re-
0.3 log units or less and variable in degree. It also may actions to near stimuli. In addition, four of the patients had an
vary from side to side. The RAPD in normal subjects was asymmetric sympathetic reflex dilation. It seems that various
hypothesized as representing, in part, a real but ‘‘normal’’ combinations of defects involving the pupil light reflex, the
degree of asymmetry in interocular retinal sensitivity as well pupil near response, and accommodation can occur with le-
as the degree of uncertainty inherent in quantifying a fluc- sions of the rostral midbrain.
tuating, biologic process (i.e., the pupil light reflex). Thus, Bilateral complete internal ophthalmoplegia, when caused
the presence of a very small RAPD in a healthy subject with by damage to the rostral oculomotor nuclear complex, rarely
no visual or neurologic complaints or deficits probably is of occurs in isolation. Lesions that produce these changes must
no significance. It also is possible that some normal patients, be located in the periaqueductal gray matter near the rostral
especially those with a small but persistent RAPD on the end of the aqueduct. Vascular, inflammatory, neoplastic, and
same side, harbor underlying pathology (i.e., an early com- demyelinating diseases that affect this area almost always
pressive lesion of the optic nerve, subclinical optic neuritis) produce associated signs, including nuclear ophthalmople-
gia, paralysis of vertical gaze, loss of convergence, exotro- EFFERENT ABNORMALITIES: ANISOCORIA
pia, ptosis, and other defects of ocular movement.
The presence of anisocoria usually indicates a structural
defect of one or both irides or a neural defect of the efferent
Paradoxical Reaction of the Pupils to Light and pupillomotor pathways innervating the iris muscles in one
Darkness or both eyes. A careful slit-lamp examination to assess the
health and integrity of the iris stroma and muscles is an
Barricks et al. described three unrelated boys, 2, 6, and important step in the evaluation of anisocoria. If the irides
10 years of age, with congenital stationary night blindness, are intact, then an innervation problem is suspected. As most
myopia, and abnormal electroretinograms, who showed a efferent disturbances causing anisocoria are unilateral, two
‘‘paradoxical’’ pupillary constriction in darkness (108). In simple maneuvers are helpful in determining whether it is
a lighted room, all three patients had moderately dilated pu- the sympathetic or parasympathetic innervation to the eye
pils; however, when the room lights were extinguished, the that is dysfunctional: (1) checking the pupillary light reflex
patients’ pupils briskly constricted and then slowly redilated. and (2) measuring the anisocoria in darkness and in bright
Subsequent investigators confirmed this observation and re- light.
ported similar paradoxical pupillary responses in children When the larger pupil has an obviously impaired reaction
and adults with congenital achromatopsia, blue-cone mono- to light stimulation, it is likely the cause of the anisocoria.
chromatism, and Leber congenital amaurosis (109,110). In One can presume the problem lies somewhere along the
addition, such responses occasionally occur in patients with parasympathetic pathway to the sphincter muscle. Common
optic disc hypoplasia, dominant optic atrophy, and bilateral etiologies include an acute tonic pupil, oculomotor nerve
optic neuritis. Flynn et al. suggested that the pupillary re- palsy, or pharmacologic blockade. If both pupils have a good
sponses seen in these patients occur not from abnormalities light reflex and the degree of anisocoria decreases in bright
in the central nervous system (CNS) but from selective de- light (i.e., anisocoria is greater in darkness), then there is
lays in afferent signals from the retinal photoreceptors to the either a deficit of sympathetic innervation to the dilator mus-
pupillomotor center (111). cle in the eye with the smaller pupil (as in Horner syndrome)
Figure 16.5. Steps that assist the evaluation

of anisocoria.
or a physiologic anisocoria. The evaluation of anisocoria is album, can be a valuable diagnostic tool (Fig. 16.7). In the
described in the following sections and outlined in Figure latter case, the anisocoria usually can be traced back to in-
16.5 fancy or early childhood.
Anisocoria Greater in Darkness Horner Syndrome

Physiologic (Benign) Anisocoria When the sympathetic innervation to the eye is inter-
rupted, the retractor muscles in the eyelids are weakened,
Inequality of pupil size becomes clinically observable allowing the upper lid to droop and the lower lid to rise.
when the difference between pupils is about 3 mm. In dim The dilator muscle of the iris also is weakened, allowing
light or darkness, almost 20% of the normal population has the pupil to become smaller, and vasomotor and sudomotor
an anisocoria of 0.4 mm or more at the moment of examina- control of parts of the face may be lost. This combination
tion. In room light, this number drops to about 10% of ptosis, miosis, and anhidrosis is called Horner syndrome
(112–114). This form of anisocoria is known by several (Fig 16.8)
names, including physiologic anisocoria, simple central ani-
socoria, essential anisocoria, and benign anisocoria. It is HISTORICAL BACKGROUND
typically 0.6 mm or less; a difference in size of 1.0 or more
is rare (114–116) (Fig. 16.6). The degree of pupillary ine- In 1869, Johann Friedrich Horner, a Swiss ophthalmolo-
quality in physiologic anisocoria may change from day to gist, published a short case report in which he emphasized
day or even from hour to hour, however. The anisocoria that eyelid ptosis could be caused by a lesion as far away
usually diminishes slightly in bright light, perhaps because from the eye as the neck by denervating the sympathetically
the smaller pupil reaches the zone of mechanical resistance innervated muscle in the upper lid that had recently been
first, giving the larger pupil a chance to make up the size described by H. Müller. Although he was not the first to
difference (117). report the clinical condition, his meticulous and scientifically
Physiologic anisocoria is not caused by damage to the substantiated account of the clinical effects of cervical sym-
peripheral nerves that innervate the sphincter and dilator pathetic paralysis has firmly attached his name to this syn-
muscles of the iris. The pupillary reactions to light and dark- drome (118). In the French literature, this condition is called
ness are normal. Instead, it is presumed to occur because the Claude Bernard-Horner syndrome to honor the work of
the supranuclear inhibition of the parasympathetic pupillo- Claude Bernard in 1852 on the physiology of the sympa-
constrictor nuclei in the midbrain is not balanced with any thetic nerves.
more precision than is necessary for clear, binocular vision. Although Horner and Bernard generally are credited with
It is unrelated to refractive error. Occasionally, a reversal of identifying the clinical signs of oculosympathetic paresis,
physiologic anisocoria is seen, a phenomenon termed ‘‘see- these signs were first produced experimentally in the dog
saw anisocoria’’ (112,116). by François Pourfour du Petit in 1727. Pourfour du Petit was
When physiologic anisocoria is suspected, reviewing old never recognized for these contributions; however, Pourfour
photographs, such as a driver’s license or especially a family du Petit syndrome is the term used for the combination of
Figure 16.6. Physiologic (benign) anisocoria. The patient was a 5-year-old boy whose parents noted that the right pupil was
larger than the other. The anisocoria was more obvious in dark than in light, and both pupils reacted normally to light stimulation.
A, Appearance of the patient. Note anisocoria with right pupil larger than left. B, 45 minutes after instillation of a 10% solution
of cocaine into both inferior conjunctival sacs, both pupils are dilated, indicating that anisocoria is not caused by sympathetic
denervation.
Figure 16.7. Value of old photographs in the assessment of anisocoria. A, This 3-year-old boy was noted by his parents to
have intermittent anisocoria, with the right pupil larger than the left. The anisocoria was greater in darkness than in light, and
both pupils reacted normally to light stimulation. B, Photograph of patient at age 7 months shows obvious anisocoria.
signs caused by sympathetic stimulation (i.e., lid retraction, usually is slightly elevated, producing an ‘‘upside-down pto-
mydriasis, and conjunctival blanching). This eponym is resis,’’ further narrowing of the palpebral fissure, and an ap-
markable because Pourfour du Petit never actually stimu- parent enophthalmos. That the enophthalmos is apparent
lated the sympathetic nerve in his experimental animals rather than real has been confirmed by several studies
(119). (119,121,122).
Pupillary Signs. Miosis. The palsy of the iris dilator
CLINICAL CHARACTERISTICS muscle in Horner syndrome allows unantagonized action of
the iris sphincter, producing a smaller pupil. However, in
Ptosis. The affected eye often looks small or sunken in some patients in the setting of intense emotional excitement,
patients with Horner syndrome. The upper eyelid is slightly the pupil on the side of the sympathetic lesion becomes
drooped because of paralysis of the sympathetically inner- larger than the normal pupil. Likewise, if the dilator muscle
vated smooth muscle (Müller muscle) that contributes to the is stimulated directly (e.g., after an adrenergic eye drop is
position of the opened upper eyelid. This ptosis sometimes used), the pupil will dilate widely. This ‘‘paradoxical pupil-
is so slight and variable that it escapes attention. In one lary dilation’’ is caused by denervation supersensitivity of
study, ptosis was frankly absent in 12% of patients (120). the dilator muscle to circulating and topical adrenergic sub-
Similar smooth muscle fibers in the lower eyelid also lose stances.
their nerve supply in Horner syndrome; thus, the lower lid Topical apraclonidine is an alpha-adrenergic receptor ago-
Figure 16.8. Horner syndrome in two patients. A, Congenital right Horner syndrome. Note associated heterochromia iridis
and minimal ptosis. B, Left Horner syndrome after neck trauma.
nist that has little or no effect on a normal pupil but can eyes tangentially from below with a hand-held flashlight,
dilate a Horner pupil due to denervation supersensitivity of and then abruptly turning the room lights out. The normal
the alpha-1 receptors on the iris dilator muscle. Thus, rever- pupil will immediately dilate, but several seconds will elapse
sal of anisocoria following topical instillation of apracloni- before the Horner pupil begins to dilate. The dilation dynam-
dine has been seen in patients with unilateral Horner syn- ics of a normal pupil compared with a Horner pupil have
drome (123,124). been well documented using continuous recording pupillog-
Anisocoria. Any anisocoria, when caused by weakness raphy (119). Immediately following a bright light flash, both
of a single iris muscle, increases in the direction of action pupils are strongly constricted. In the first second of dark-
of that muscle. With a unilateral oculosympathetic defect, ness, both pupils synchronously enlarge a small degree, pre-
the weakness of the dilator muscle in the affected eye (and sumably from acute inhibition of parasympathetic impulses.
resultant anisocoria) is most apparent in darkness. Con- In the next few seconds, the normal pupil, stimulated by
versely, the anisocoria almost disappears in light because an active burst of sympathetic discharges, rapidly dilates,
the normal action of both sphincters (oculoparasympathetic whereas the Horner pupil, denervated of sympathetic im-
activity) constricts the pupils to almost equal sizes. In regular pulses, hardly moves. This results in an increasing anisocoria
room light, the degree of anisocoria in Horner syndrome is during in the first 5 seconds or so of darkness. Thereafter,
rather small, on the order of 1.0 mm or less, and can be the Horner pupil slowly dilates from decreasing parasympa-
overlooked or mistakenly attributed to simple anisocoria thetic tone and catches up in size to the normal pupil. Thus,
(125). Furthermore, when a patient is fatigued or drowsy, if both pupils are observed simultaneously for 15–20 sec-
the size of the pupils and the degree of anisocoria diminish onds after turning off the room light, one sees an initial
as the hypothalamic sympathetic outflow to both eyes sub- increase in the degree of anisocoria, followed by decreasing
sides and uninhibited parasympathetic outflow augments. anisocoria (Fig. 16.9).
Some patients with Horner syndrome have anisocoria mea- A psychosensory stimulus such as a sudden noise will
suring up to 2.5 mm; such a large anisocoria is not seen cause a normal pupil to dilate. When looking for dilation
with benign anisocoria. The actual amount of anisocoria in lag in darkness, interjection of a sudden loud noise just as
Horner syndrome thus varies with (a) the resting size of the the lights go out tends to augment the initial increase in
pupils; (b) the completeness of the injury; (c) the alertness anisocoria when a unilateral oculosympathetic defect is pres-
of the patient; (d) the extent of reinnervation of the dilator ent. One can also pinch the patient’s neck (the ciliospinal
muscle; (e) the brightness of the examiner’s light or the am- reflex), press over McBurney’s point (Meyer’s iliac sign),
bient light in the room; (f) the degree of denervation super- or flex the patient’s neck (Flatau’s neck mydriasis) to bring
sensitivity; (g) the fixation of the patient at distance or near; this out (126).
and (h) the concentration of circulating adrenergic sub- There remains controversy about which aspect of pupil-
stances in the blood. lary reflex dilation in darkness best identifies the impaired
Dilation Lag. Paresis of the iris dilator muscle results dilation dynamics of a Horner syndrome. Several methods of
in a smaller resting pupil size (miosis) and also in impaired detecting dilation lag have been proposed. Taking Polaroid
pupillary movement during dilation, called dilation lag. Dila- photographs 5 seconds after the lights go out and again after
tion lag can be seen clinically by illuminating the patient’s 15 seconds of darkness is a simple and readily available
Figure 16.9. Pupillogram of a patient with a left Horner syndrome (solid line is a normal pupil; broken line is a Horner
pupil). Point a is the resting size of both pupils (and anisocoria) in darkness. Following a 1-second pulse of light, the pupils
are maximally constricted at b. As the pupils redilate in the darkness, increasing anisocoria seen in c is due to the relative
inactivity of the Horner pupil. Addition of a sensory stimulus after the pulse of light further enhances the asymmetric dilation
dynamics (d) between the normal pupil and the Horner pupil. In e, the dilation of both pupils is observed over a longer period
of time. After the initial increase in anisocoria, there is a gradual decreasing of the anisocoria as the slowly dilating Horner
pupil eventually recovers its baseline size in darkness.
Figure 16.10. Dilation lag in a patient with

a left Horner syndrome, observed using reg-
ular flash color photos. Top, Photo taken 5
seconds after the room lights were turned
off. Bottom, Photo taken after 15 seconds of
darkness. The right pupil is already maxi-
mally dilated within 5 seconds of turning the
room lights off, but the left pupil still has
not dilated maximally after 15 seconds of
darkness.
means to assess for dilation lag. Patients with Horner syn- and neck may have a lower temperature and may be paler
drome show more anisocoria in the 5-second photograph than that of the normal side. This occurs from supersensitiv-
than in the 15-second photograph, emphasizing that the ab- ity of the denervated blood vessels to circulating adrenergic
sence of continued dilation after 5 seconds in darkness (i.e., substances, with resultant vasoconstriction.
demonstration of decreasing anisocoria in the later phase of The distribution of the loss of sweating (anhidrosis) and
dilation) is a defining characteristic of an oculosympathetic flushing depends on the location of sympathetic lesion. For
defect (127,128) (Fig. 16.10). Videography with infrared il- example, in lesions of the preganglionic neuron, the entire
lumination is one of the best ways to show this phenomenon side of the head, the face, and the neck down to the clavicle
(129). Others have reported that a single measurement of usually are involved, whereas in postganglionic lesions, an-
anisocoria taken within the first 5 seconds of darkness (i.e., hidrosis is limited to a patch on the forehead and the medial
assessment of the increase in anisocoria in the early phase side of the nose. In a warm environment, the skin on the
of dilation) is adequate for identifying dilation lag. One study affected side will feel dry, whereas the skin on the nor-
reported that 0.6 mm or more at 4 seconds was 82% sensitive mal side will be so damp that a smooth object, such as a
for diagnosing a unilateral Horner syndrome (130) Using a plastic bar, will not slide easily on the skin but will stick.
binocular infrared video pupillometer with continuous re- Because most persons live and work in temperature-
cording of pupil diameters, Smith and Smith found that after controlled spaces, patients with Horner syndrome rarely
a light flash, a delay in the time needed to recover three complain of disturbances of sweating or asymmetric facial
quarters of the baseline pupil size had a 70% sensitivity flushing.
and 95% specificity of detecting unilateral Horner syndrome Paradoxic unilateral sweating with flushing of the face,
(131). This definition of dilation lag based on a measure of neck, and sometimes the shoulder and arm can be a late
time, instead of the degree of anisocoria, is particularly use- development in patients with a surgically induced Horner
ful for detecting bilateral Horner syndrome. syndrome following cervical sympathectomy (133) or a cer-
Hypochromia Iridis. Depigmentation of the ipsilateral vical injury. Apparently, some axons in the vagus nerve nor-
iris is a typical feature of congenital Horner syndrome and mally pass into the superior cervical ganglion. These para-
occasionally is seen in patients with a long-standing, ac- sympathetic axons can establish, by collateral sprouting,
quired Horner syndrome (132). It is never seen in patients anomalous vagal connections with postganglionic sympa-
with an acute or recently acquired Horner syndrome. thetic neurons to the head and neck. Affected patients may
Anhidrosis. Characteristic vasomotor and sudomotor experience bizarre sudomotor and pilomotor (gooseflesh) ac-
changes of the facial skin can occur on the affected side in tivity and vasomotor flushing geared reflexively to certain
some patients with Horner syndrome. Immediately follow- functions of the vagus nerve. The patterns of anomalous
ing sympathetic denervation, the temperature of the skin sweating vary but often involve the central portions of the
rises on the side of the lesion because of loss of vasomotor face and forehead (119).
control and consequent dilation of blood vessels. Addition- Accommodation. Most reports describe an increase in
ally, there may be facial flushing, conjunctival hyperemia, accommodative amplitude on the side of a Horner syndrome
epiphora, and nasal stuffiness in the acute stage. (119). It would appear that an intact sympathetic innervation
Some time after the injury, the skin of the ipsilateral face of the ciliary muscle helps that muscle loosen and tighten the
zonules with alacrity. This is a minor effect and is clinically nerves of a few lethargic individuals do not release enough
insignificant. norepinephrine for 2% cocaine to have an effect, or because
some heavily pigmented irides bind the drug so that it does
DIAGNOSIS not reach the dilator muscle (11). Whatever the reason, a
10% solution most often is used to test for a Horner pupil
Not all patients with unilateral ptosis and ipsilateral miosis (Fig. 16.11). The first drop stings briefly, then the anesthetic
have Horner syndrome (134). The prevalence of simple ani- effect takes effect and a second drop can be placed about 1
socoria in the normal population is about 20%. A ptosis from minute later. Peak effect is attained in 40–60 minutes. There
any cause, such as dehiscence of the levator insertion, eyelid are no apparent psychoactive effects from a 10% solution
inflammation, or myasthenia gravis, may occur coinciden- of cocaine, but metabolites of the drug can be found in the
tally on the side of the smaller pupil in a patient who also urine in 100% of patients after 24 hours, in 50% at 36 hours,
happens to have simple anisocoria, resulting in a ‘‘pseudo- and in 2% after 48 hours (136,137). The odds of an anisoco-
Horner syndrome.’’ ria being caused by an oculosympathetic palsy increase with
The most widely used confirmatory test for the diagnosis the amount of post-cocaine anisocoria, regardless of the
of Horner syndrome is the cocaine eyedrop test (135). In amount of baseline anisocoria. For clinical purposes, a post-
1884, Koller first described using a 2% cocaine solution as cocaine anisocoria of 0.8 mm measured in standard room
a topical ocular anesthetic, at which time it was noted that light is sufficient to diagnose a Horner syndrome (138).
this substance also dilated the pupil. It was subsequently However, if the smaller (suspected Horner) pupil dilates
noted that cocaine also widened the palpebral fissure and more than 2 mm, even if the post-cocaine anisocoria is
blanched the conjunctiva of a normal eye—the same combi- greater than 0.8 mm, a Horner syndrome is unlikely (125).
nation of signs that was known to occur when the cervical Some patients with very dark irides simply do not dilate
sympathetic nerve was stimulated. Shortly thereafter, Uh- well to cocaine. If the normal pupil has not dilated by 2
thoff suggested that cocaine be used as a clinical test of the mm or more at 40–60 minutes after cocaine instillation, the
sympathetic integrity to the eye (119). differential effect of cocaine on a sympathetically dener-
Cocaine blocks the reuptake of the norepinephrine that is vated iris may not be evident. Apparent inaction of cocaine
released continuously from sympathetic nerve endings at the also can result from an overly bright room and patient drow-
neuromuscular synapse, allowing norepinephrine to accu- siness, both of which promote pupillary constriction.
mulate at the receptors of the effector cells. In a normal eye,
a 2–10% solution of cocaine causes dilation of the pupil. LOCALIZATION
One study noted a mean pupil dilation of 2.14 mm (range,
0.6–4.0 mm) in normal eyes in response to a 5% cocaine Localization of the site of injury of a Horner syndrome
solution (125). A lesion anywhere along the three-neuron often can be determined from associated signs and symptoms
sympathetic pathway that impairs neural impulses will inter- and can be helpful in the appropriate evaluation of these
rupt the normal spontaneous release of norepinephrine from patients.
presynaptic nerve endings. Thus, cocaine has no significant Central Horner Syndrome. The central sympathetic
mydriatic effect on a sympathetically denervated iris. pathway has components in the brain, brain stem, and spinal
Rarely, a normal pupil will fail to dilate after topical appli- cord. Experimental data suggest that this central sympathetic
cation of 2% cocaine, perhaps because the oculosympathetic pathway has cerebral cortical representation and is polysyn-
Figure 16.11. Response of normal pupil and a Horner pupil to cocaine. A, A 55-year-old man with left Horner syndrome
associated with Raeder paratrigeminal neuralgia. B, 45 minutes after conjunctival instillation of two drops of a 10% cocaine
solution in each eye, the right pupil is dilated, whereas the left pupil remains unchanged (small).
aptic (139). A patient with Horner syndrome after a transient drome have other neurologic deficits, occasional patients
ischemic episode showed only a lesion in the ipsilateral insu- with cervical spondylosis present only with a Horner syn-
lar cortex (140). From the posterolateral hypothalamus, sym- drome and perhaps some neck pain. An isolated central Hor-
pathetic fibers pass through the lateral brain stem and extend ner syndrome also can occur from a brain stem syrinx (155).
to the ciliospinal center of Budge in the intermediolateral Lesions of the spinal cord (lower cervical or upper tho-
gray column of the spinal cord at C8–T1. A central Horner racic area) can cause a central Horner syndrome. In most
syndrome caused by damage to any of these structures is cases there are other neurologic deficits, although in some
ipsilateral to the lesion and almost always unilateral. A lesion patients the Horner syndrome is the only neurologic abnor-
in this neuron often produces a hemihypohidrosis of the en- mality. Spinal cord lesions that may cause a central Horner
tire body. Lesions of the hypothalamus such as tumor or syndrome include trauma (most common), inflammatory or
hemorrhage can cause an ipsilateral Horner syndrome infectious myelitis, vascular malformation, demyelination,
(141,142) with contralateral hemiparesis, contralateral hyp- syrinx, syringomyelia, neoplasms, and infarction. What ap-
esthesia, or both. Patients with a central Horner syndrome pears to be an alternating Horner syndrome (i.e., alternating
caused by a lesion of the thalamus also show a contralateral oculosympathetic deficit) can be seen in patients with cervi-
hemiparesis that often is ataxic (143). Contralateral hypes- cal cord lesions and in some patients with systemic dysauto-
thesia, vertical gaze paresis, and dysphasia are other associ- nomias (156–159). Other patients have attacks of autonomic
ated findings. hyperreflexia that excite the ciliospinal center of Budge on
The occurrence of a unilateral Horner syndrome and a the affected side (the C8–T1 intermediolateral gray column
contralateral trochlear nerve paresis indicates a lesion of the may, in fact, be supersensitive as a result of its disconnec-
dorsal mesencephalon. The lesion injures either the trochlear tion). This excess firing of sympathetic impulses (oculosym-
nucleus on the side of the Horner syndrome or the ipsilateral pathetic spasm) dilates the pupils, lifts the eyelid, blanches
fascicle (140,144–146). the conjunctiva, and increases sweating of the face (160).
Although a Horner syndrome associated with an ipsi- When the oculosympathetic spasm occurs unilaterally and
lateral abducens nerve paresis is most often caused by a intermittently on the side of an underlying Horner syndrome,
lesion in the cavernous sinus (see below), this combination the anisocoria appears to reverse; this mechanism may ac-
of signs also may occur in patients with pontine lesions count for some cases of alternating Horner syndrome (161).
(147). In such cases, the Horner syndrome is central rather Preganglionic (Second-Order Neuron) Horner Syn-
than postganglionic. drome. The preganglionic (second-order) neuron exits
The classical brain stem syndrome characterized in part from the ciliospinal center of Budge and passes across the
by a central Horner syndrome is Wallenberg syndrome, also pulmonary apex. It then turns upward, passes through the
called the lateral medullary syndrome. The typical findings stellate ganglion, and goes up the carotid sheath to the supe-
of Wallenberg syndrome are ipsilateral impairment of pain rior cervical ganglion, near the bifurcation of the common
and temperature sensation over the face, Horner syndrome, carotid artery.
limb ataxia, and a bulbar disturbance causing dysarthria and In one large series, malignancy was the cause of about
dysphagia. Contralaterally, pain and temperature sensation 25% of cases of preganglionic Horner syndrome (162). The
is impaired over the trunk and limbs. The symptoms of Wal- most common tumors, not surprisingly, were lung and breast
lenberg syndrome include vertigo and a variety of unusual cancer, but Horner syndrome was not an early sign of either
sensations of body and environmental tilt, often so bizarre of these tumors. Indeed, by the time the Horner syndrome
as to suggest a psychogenic origin (148,149). Patients may had appeared, the tumor already was known to be present.
report the whole room tilted on its side or even upside down; Apical lung lesions that spread locally at the superior tho-
with their eyes closed, they may feel themselves to be tilted. racic outlet cause symptoms of ipsilateral shoulder pain (the
Lateropulsion, a compelling sensation of being pulled to- most common initial symptom) and pain and paresthesia
ward the side of the lesion, is often a prominent complaint along the medial arm, forearm, and fourth and fifth digits
and also is evident in the ocular motor findings (150,151). (the distribution of the C8 and T1 nerve roots) as well as a
If the patient is asked to fixate straight ahead and then gently preganglionic Horner syndrome and weakness/atrophy of
close the lids, the eyes deviate conjugately toward the side the hand muscles. This combination of signs is called the
of the lesion. This is reflected by the corrective saccades Pancoast syndrome. The majority of lesions causing Pan-
that the patient must make on eye opening to reacquire the coast syndrome are carcinomas of the lung (163). Other tu-
target. Lateropulsion may even appear with a blink. Wal- mors and infectious processes, including tuberculosis, bacte-
lenberg syndrome is most commonly caused by thrombotic rial pneumonias, and fungal infection, have been reported. A
occlusion of the ipsilateral vertebral artery, although isolated patient with a preganglionic Horner syndrome and ipsilateral
posterior inferior cerebellar artery disease is occasionally shoulder pain should be investigated thoroughly for neoplas-
seen (152). In a series of 130 patients with lateral medullary tic involvement of the pulmonary apex, the pleural lining,
infarction, the pathogenesis was large vessel infarction in and the brachial plexus.
50%, arterial dissection in 15%, small vessel infarction in Tumors that spread behind the carotid sheath at the C6
13%, and cardiac embolism in 5% (153). Demyelinating dis- level may produce a preganglionic Horner syndrome associ-
ease of the medulla has also been reported in a case of Wal- ated with paralysis of the phrenic, vagus, and recurrent laryn-
lenberg syndrome (154). geal nerves: the Rowland Payne syndrome (164). Just 3
Although most patients with a central neuron Horner syn- inches lower, at the thoracic outlet, these nerves are more
widely separated and less likely to be involved together. ischemic event occurred within a mean of 7 days of the
Thus, if a patient is newly hoarse and has a preganglionic Horner syndrome, emphasizing the need for early recogni-
Horner syndrome, a chest radiograph may be warranted to tion and diagnosis of this cause of Horner syndrome. Carotid
see whether the hemidiaphragm ipsilateral to the Horner syn- dissections are discussed in Chapter 40.
drome is elevated. Pathologic conditions of the internal carotid artery other
Nonpulmonary tumors that produce a preganglionic Hor- than dissection that are associated with a Horner syndrome
ner syndrome include sympathetic chain or intercostal nerve include aneurysms, severe atherosclerosis, acute thrombosis,
schwannoma, paravertebral primitive neuroectodermal tu- fibromuscular dysplasia, and arteritis (174). Mass lesions in
mor, vagal paraganglioma, mediastinal tumors or cysts, and the neck that can compress the carotid sympathetic neuron
thyroid carcinoma. Injury to the brachial plexus or spinal include tumors, inflammatory masses, enlarged lymph
roots, pneumothorax, fracture of the first rib, or neck hema- nodes, and even an ectatic jugular vein (175,176).
toma should be considered in patients whose preganglionic In the deep retroparotid space and around the jugular fora-
Horner syndrome follows neck or shoulder trauma. men, oculosympathetic fibers are in close proximity with
The preganglionic neuron is the most common site of in- several lower cranial nerves. Lesions in this area of the neck,
jury for an iatrogenic Horner syndrome. The varied anes- usually trauma, tumors, and masses, can result in a Horner
thetic, radiologic, and surgical procedures that can produce syndrome associated with ipsilateral paralysis of the tongue,
the condition include coronary artery bypass surgery, lung soft palate, pharynx, and larynx. Such lesions may cause
or mediastinal surgery, carotid endarterectomy, insertion of dysphagia, dysphonia, and hoarseness. The ipsilateral poste-
a pacemaker, epidural anesthesia, interpleural placement of rior pharynx may be hypesthetic. This combination of paral-
chest tubes, internal jugular catheterization, and stenting ysis of the cervical sympathetics and the last four cranial
of the internal carotid artery (165–170). nerves (the glossopharyngeal, vagus, accessory, and hypo-
Despite advances in neuroimaging and other diagnostic glossal nerves) is called Villaret syndrome (177).
tests, many cases of preganglionic Horner syndrome have The superior cervical ganglion lies about 1.5 cm behind
no explanation. In one series, about 28% of cases of pregan- the palatine tonsil and thus can be damaged by iatrogenic
glionic Horner syndrome were of unknown etiology (125). or traumatic penetrating intraoral injury. Tonsillectomy, in-
Postganglionic (Third-Order Neuron) Horner Syn- traoral surgery, peritonsillar injections, and accidental punc-
drome. The postganglionic (third-order) sympathetic neu- tures through the soft palate are some of the etiologies that
ron to the iris dilator muscle begins in the superior cervical have been reported to cause a postganglionic Horner syn-
ganglion and travels in the wall of the internal carotid artery, drome from damage to the superior cervical ganglion
where it is called the carotid sympathetic plexus or some- (178,179).
times the carotid sympathetic nerve. The latter may be a Lesions at the skull base can cause a postganglionic Hor-
more appropriate term, as the majority of sympathetic fibers ner syndrome. A middle fossa mass encroaching on Meck-
ascend as a single bundle. Within the cavernous sinus, the el’s cave and on the internal carotid artery at the foramen
sympathetic fibers leave the internal carotid artery, join lacerum can produce a postganglionic Horner syndrome as-
briefly with the abducens nerve, and then leave it to join the sociated with trigeminal pain or sensory loss. A basal skull
ophthalmic division of the trigeminal nerve, entering the fracture involving the petrous bone can damage the postgan-
orbit with its nasociliary branch (171,172). The sympathetic glionic sympathetic fibers within the carotid canal, produc-
fibers in the nasociliary nerve divide into the two long ciliary ing a postganglionic Horner syndrome associated with an
nerves that travel with the lateral and medial suprachoroidal ipsilateral abduction deficit, facial palsy, and/or sensorineu-
vascular bundles to reach the anterior segment of the eye ral hearing loss (abducens, facial, and vestibulocochlear cra-
and innervate the iris dilator muscle. nial nerves) (180).
Most lesions that damage the postganglionic sympathetic Any lesion in the cavernous sinus may produce a postgan-
neuron are vascular lesions that produce headache or ipsi- glionic Horner syndrome. In many cases, there is associated
lateral facial pain as well and often are lumped under the ipsilateral ophthalmoparesis caused by involvement of one
clinical description of a ‘‘painful postganglionic Horner syn- or more ocular motor nerves as well as pain or dysesthesia
drome.’’ Responsible lesions may be extracranial, affecting of the ipsilateral face caused by trigeminal nerve dysfunc-
postganglionic sympathetics in the neck, or intracranial, af- tion. The occurrence of an abducens palsy and a postgangli-
fecting the sympathetics at the base of the skull, in the carotid onic Horner syndrome (Parkinson sign) without other neuro-
canal and middle ear, or in the region of the cavernous sinus. logic signs should raise suspicion of a cavernous sinus lesion
It is unusual for an orbital lesion to produce an isolated (181–183). When a Horner syndrome and oculomotor nerve
Horner syndrome. palsy occur together, there is combined sympathetic and
Lesions of or along the internal carotid artery are a com- parasympathetic dysfunction of the iris muscles. In such
mon cause of a painful postganglionic Horner syndrome, the cases, the anisocoria is minimal or absent despite the im-
most common being a traumatic or spontaneous dissection paired light reaction of the affected pupil, and pharmacologic
of the cervical internal carotid artery. In 146 such patients, testing may be the only means to detect an underlying sym-
a Horner syndrome was the most common ocular finding pathetic paresis (184).
(44%) (173). In half of these cases, the Horner syndrome Cluster headaches are severe lancinating unilateral head-
was the initial and sole manifestation of the carotid artery aches that usually occur in middle-aged men. The headaches
dissection. In the other half, an associated ocular or cerebral often are nocturnal, last 30–120 minutes, and are accompa-
nied by ipsilateral tearing, nasal stuffiness, conjunctival in- and their stores of norepinephrine; thus, hydroxyamphet-
jection, and ptosis (signs of acute oculosympathetic palsy). amine has no mydriatic effect. With lesions of the pregangli-
A postganglionic Horner syndrome occurs in 5–22% of pa- onic or central neuron, the postganglionic nerve endings,
tients with cluster headache (185,186). Otherwise, no other though nonfunctioning, remain structurally intact. Thus, the
neurologic deficits are present. Cluster headache is thought pupil dilates fully and may even become larger than the
to be a vasospastic process affecting the carotid arterial sys- opposite pupil from upregulation of the postsynaptic recep-
tem. Raeder paratrigeminal neuralgia is an eponym used for tors on the dilator muscle. A postganglionic Horner pupil
a painful postganglionic Horner syndrome characterized by occasionally dilates in response to topical hydroxyamphet-
a persistent ipsilateral trigeminal neuralgia and/or trigeminal amine (false-negative result) when patients are tested within
nerve dysfunction. It is the trigeminal nerve involvement the first week of sympathetic injury before the stores of nor-
(pain or sensory change) that is distinctive and warrants in- epinephrine at the presynaptic nerve endings have been de-
vestigation for a lesion in the middle cranial fossa medial pleted (192). Hydroxyamphetamine hydrobromide 1%
to the trigeminal ganglion (185–187). (Paredrine) is commonly used in the United States but is
The hydroxyamphetamine test can be used to assist the dif- difficult to obtain or unavailable in other countries. Both
ferentiation between a postganglionic and a preganglionic or tyramine hydrochloride 5% and hydroxymethylamphet-
central Horner syndrome (188–190) (Fig. 16.12). Hydroxy- amine (Pholedrine) have a mode of action similar to that of
amphetamine releases stored norepinephrine from the post- hydroxyamphetamine and serve equally well as agents for
ganglionic adrenergic nerve endings, producing variable a localizing pharmacologic test (193,194).
mydriasis in normal subjects (191). A lesion of the post- A smaller pupil that fails to dilate to both cocaine and
ganglionic neuron results in loss of terminal nerve endings hydroxyamphetamine most likely has a lesion of the post-
Figure 16.12. Response of Horner pupils to hydroxyamphetamine. A, Right Horner syndrome in a 45-year-old man with an
apical lung tumor. B, 45 minutes after conjunctival instillation of 2 drops of 1% hydroxyamphetamine solution (Paredrine) in
each eye, both pupils are dilated, indicating an intact postganglionic neuron (i.e., a preganglionic Horner syndrome). C, Left
Horner syndrome associated with cluster headaches in a 55-year-old man. D, 45 minutes after conjunctival instillation of two
drops of 1% hydroxyamphetamine solution in each eye, only the right (normal) pupil is dilated. The left pupil is unchanged,
indicating damage to the postganglionic neuron (i.e., a postganglionic Horner syndrome).
ganglionic sympathetic neuron. Such a pupil should dilate

to a weak, direct-acting topical adrenergic drug, such as a
1% solution of phenylephrine hydrochloride or a 2% solution
of epinephrine due to adrenergic denervation supersensitiv-
ity of the iris dilator muscle. Indeed, such a pupil not only
will dilate but also will become larger than the opposite
normal pupil. Denervation supersensitivity of the iris to ad-
renergic drugs apparently does not occur immediately after
damage to the postganglionic sympathetic nerve but may
take as long as 17 days to develop (195). Occasionally, this
test is used to differentiate a mechanically restricted pupil
(e.g., iris damage) from a postganglionic Horner pupil be-
cause the restricted pupil fails to dilate to direct-acting adren-
ergic agents.
ACQUIRED HORNER SYNDROME IN CHILDREN
Horner syndrome in childhood (under age 18 years) may

be congenital (42%), postoperative (42%), or truly acquired
(15%) (196). It is this last group that often results from an
underlying neoplasm or serious neurologic disease. For ex-
ample, neuroblastoma is responsible for up to 20% of such
cases (197). Other reported etiologies include spinal cord
tumors, brachial plexus trauma, intrathoracic aneurysm, em-
bryonal cell carcinoma, rhabdomyosarcoma, thrombosis of
the internal carotid artery, and brain stem vascular malforma-
tions (196,198). Thus, an acquired Horner syndrome in a
child with no prior surgical history, even if the finding is
isolated, warrants immediate further investigation. This is
particularly important for neuroblastoma because younger
age (less than 1 year) is strongly correlated with better out-
come. Figure 16.13. Lack of atropinic flushing in a child with a congenital left
Horner syndrome. The atropinic flush is present only on the side of the
face opposite the Horner syndrome.
CONGENITAL HORNER SYNDROME
Patients with a congenital Horner syndrome have ptosis, flush. This reaction occurs only when there is an intact sym-
miosis, facial anhidrosis, and hypochromia of the affected pathetic innervation to the skin (Fig. 16.13).
iris (119,199). Even a child with very blue eyes usually has Some patients with congenital Horner syndrome have
a paler iris on the affected side from impaired development clinical evidence that indicates a preganglionic lesion (e.g.,
of iris melanophores, causing hypochromia of the iris facial anhydrosis, evidence of a brachial plexus injury, his-
stroma. This occurs whether the lesion is preganglionic or tory of thoracic surgery), but pharmacologic localization
postganglionic because of anterograde transsynaptic dys- with hydroxyamphetamine indicates a postganglionic lesion.
genesis (200). Children with naturally curly hair and a Possible explanations include an embryopathy directly in-
congenital Horner syndrome have straight hair on the volving the superior cervical ganglion, damage to the vascu-
side of the Horner syndrome (201). The reason for this lar supply of the superior cervical ganglion, and transsynap-
abnormality is unclear, but it probably relates to lack of tic dysgenesis of the superior cervical ganglion following a
sympathetic innervation to the hair shafts on the affected defect located more proximally in the sympathetic pathway
side of the head. (200,204).
Parents of an infant with congenital Horner syndrome Birth trauma probably is the most common etiology of
sometimes report that the baby develops a hemifacial flush congenital Horner syndrome (196). Use of forceps, history
when nursing or crying. The flushed side probably is the of shoulder dystocia, and fetal rotation can lead to injury of
normally innervated side that appears dramatically reddish the sympathetic plexus along its course in the neck or near
when seen against the opposite side with pallor from im- the thoracic outlet. Associated upper extremity weakness is
paired facial vasodilation and perhaps overactive vasocon- indicative of concomitant damage to the ipsilateral brachial
striction as well. In other words, hemifacial flushing in in- plexus (200) (Fig. 16.14). Neuroblastoma was found in one
fants is likely to be opposite the side of a congenital Horner of 31 congenital cases (‘‘congenital’’ being defined as a
syndrome (202,203). Sometimes, a cycloplegic refraction Horner syndrome detected before 4 weeks of age) (196).
unexpectedly answers the question by producing an atropinic Even if the definition of ‘‘congenital’’ is extended to include
Pharmacologic Stimulation of the Iris Sphincter

Almost all cases of acute pharmacologically induced ani-
socoria are caused by parasympathetic blockade of the iris
sphincter muscle, resulting in a fixed and dilated pupil. In
such cases, the anisocoria is greater in light than darkness.
However, in rare instances, a pharmacologic agent produces
anisocoria by stimulating the parasympathetic system, thus
producing a fixed miotic pupil in which the anisocoria is
greater in darkness. In such cases, a 1% solution of tropica-
mide typically fails to dilate the pharmacologically con-
stricted pupil. Anisocoria caused by parasympathetic stimu-
lation can occur after handling of a pet’s flea collar (210,211)
that contains an anticholinesterase pesticide or a garden in-
secticide that contains parathion, a synthetic organophos-
phate ester.
Pharmacologic Inhibition of the Iris Dilator

Brimonidine tartrate is an alpha-2-adrenergic agonist that
presumably decreases iris dilator action by its effect at the
presynaptic alpha-2 inhibitory receptors of postganglionic
sympathetic neurons. The resultant pupillary miosis is more
apparent in darkness than in light (212).
Anisocoria Greater in Light

Damage to the Preganglionic Parasympathetic Outflow
to the Iris Sphincter
The efferent pupillomotor pathway for pupillary constric-
tion to light and near stimulation begins in the mesencepha-
lon with the visceral oculomotor (Edinger-Westphal) nuclei
and continues via the oculomotor nerve to the ciliary gan-
glion. The postganglionic impulses are carried through the
short ciliary nerves to reach the iris sphincter (see Chapter
14). Because accommodative impulses begin in the same
Figure 16.14. Horner syndrome (top) associated with injury of the right midbrain nuclei as pupilloconstrictor impulses and follow
brachial plexus at birth. Note the underdeveloped right arm and forearm the same peripheral course to the eye, accommodative paral-
(bottom). ysis frequently accompanies pupillary paralysis in lesions of
the efferent parasympathetic pathway to the iris sphincter.
This combination of iridoplegia and cycloplegia was called
cases of Horner syndrome detected within the first year of internal ophthalmoplegia by Hutchinson to distinguish it
life, the incidence of neuroblastoma is low, less than 10% from the external ophthalmoplegia that occurs when the ex-
traocular muscles are paralyzed in the setting of normal pu-
(200,205). Other etiologies include congenital tumors, post-
pillary responses.
viral complication, iatrogenic Horner syndrome, and abnor-
Lesions anywhere along the two-neuron parasympathetic
malities of the internal carotid artery such as fibromuscular
pathway to the intraocular muscles cause mydriasis at rest
dysplasia and congenital agenesis (206–209).
and impaired reflex constriction that ranges from mildly
Many cases of congenital Horner syndrome are idiopathic,
sluggish light reactions to complete pupillary unreactivity.
even after initial work-up and long-term follow-up. George
Damage to the preganglionic portion of this pathway to the
et al. reported that no etiology was found in 16 of 23 (70%)
iris sphincter is caused by lesions involving the parasympa-
infants who were found to have a Horner syndrome in the
thetic midbrain nuclei and the oculomotor nerve.
first year of life. In young infants with an isolated Horner
syndrome and no history of birth trauma, a congenital basis
The Edinger-Westphal Nuclei
may be suspected. Careful general examination and a urine
test for catecholamines, with regular follow-up thereafter, When there is isolated damage to the Edinger-Westphal
constitutes the minimum evaluation (205). For infants in nuclei, bilateral pupillary abnormalities are the rule. Most
whom the onset of Horner syndrome is firmly established lesions in this region that produce pupillary abnormalities
after the first 4 weeks of life (i.e., an acquired process), also affect other parts of the oculomotor nucleus, causing
immediate and thorough imaging is recommended. ptosis, ophthalmoparesis, or both.
Figure 16.15. Position of the pupillomotor fi-

bers in the fascicle of the human oculomotor
nerve. The fibers destined to innervate the iris
sphincter muscle (P) are located rostral and me-
dial to the fibers that innervate the extraocular
muscles and the levator palpebrae superioris
(LP). IO, inferior oblique; IR, inferior rectus;
MR, medial rectus; SR, superior rectus; MRa,
MRb, and MRc, subnuclei serving medial rectus
function in the oculomotor nuclear complex;
CCN, central caudal nucleus. (From Ksiazek
SM, Slamovits TL, Rosen CE, et al. Fascicular
arrangement in partial oculomotor paresis. Am
J Ophthalmol 1994;118⬊97–103.)
Pupillomotor Fascicle of the Oculomotor Nerve lateral or bilateral poorly reactive pupils with complete or
relative sparing of the extraocular muscles (217,218). In ad-
Because the fibers emerging from the Edinger-Westphal dition, hemosiderin deposits along the superficial surfaces
nucleus are among the most rostral of the oculomotor fasci- of the cranial nerves from recurrent blood in the cerebrospi-
cles in the midbrain tegmentum, it is possible for a lesion nal fluid (CSF) can cause pupillary dysfunction and hearing
to selectively damage the parasympathetic fibers (213) (Fig. loss in patients with superficial siderosis (219).
16.15). Indeed, a unilateral fixed and dilated pupil or bilat- An expanding aneurysm is always a feared potential cause
eral internal ophthalmoplegia may be the sole clinical mani- of a large and poorly reactive pupil. However, aneurysms
festation of a fascicular oculomotor nerve palsy due to a at the junction of the internal carotid artery and the posterior
rostral midbrain lesion (214,215). The fascicular oculomotor communicating artery that compress the oculomotor nerve
nerve can be damaged by a variety of processes, including nearly always produce some extraocular muscle or eyelid
ischemia, hemorrhage, inflammation, and infiltration. Such dysfunction, even if such involvement is subtly or variably
processes often involve other structures in the rostral mesen- present, in addition to the pupil impairment. In the oft-quoted
cephalon, leading to an oculomotor palsy associated with case of Payne and Adamkiewicz, a 35-year-old woman de-
other neurologic signs such as contralateral hemiparesis or veloped an acute unilateral internal ophthalmoplegia as the
tremor. These well-recognized syndromes are considered in ‘‘principal feature’’ of a posterior communicating artery an-
Chapter 20. eurysm (220). It was, however, not the sole manifestation of
her aneurysm: she had noticed slight drooping of her eyelid 6
Pupillomotor Fibers in the Subarachnoid Portion of months previously. At the time her pupil became dilated,
the Oculomotor Nerve a ‘‘slight’’ and inconstant ptosis was noted. A preexisting
strabismus made difficult the possible detection of any subtle
As the separate fascicles of the oculomotor nerve exit the extraocular muscle dysfunction. It appears that a dilated and
mesencephalon, they merge to form one oculomotor nerve poorly reactive pupil in isolation is rarely due to an aneu-
trunk in the interpeduncular fossa. The oculomotor nerve rysm, and in the case where it is, it is more likely due to an
passes between the posterior cerebral and superior cerebellar aneurysm of the tip of the basilar artery than an aneurysm
arteries and courses anteriorly to the cavernous sinus. In this of the internal carotid artery (221,222).
part of the oculomotor nerve pathway, the pupillary fibers Occasionally, intrinsic lesions of the oculomotor nerve in
are superficially located and migrate from a superior medial the subarachnoid space produce only an internal ophthal-
position to the inferior part of the nerve (216). The location moplegia. In two cases of an oculomotor nerve schwannoma
of the pupil fibers makes them particularly susceptible to in the interpeduncular fossa, an isolated dilated pupil and
infectious injury from basal meningitis and direct compres- reduced accommodation were the sole manifestations of the
sion from aneurysms, tumors, and uncal herniation. Basal tumor for 1 year or longer, before ptosis and external oph-
meningitis (bacterial, fungal, tuberculosis) can produce uni- thalmoplegia appeared (223,224).
Cavernous Portion of the Oculomotor Nerve

The pupillomotor fibers are located inferiorly and superfi-
cially in the portion of the oculomotor nerve located within
the cavernous sinus. Any lesion of the cavernous sinus can
potentially compress and damage the oculomotor nerve and
the pupil fibers. When oculosympathetic fibers in the cavern-
ous sinus are damaged as well, the pupil light reflex may
be sluggish, but there may not be an apparent change in the
resting pupil size (i.e., there may be no anisocoria) (184).
Damage to the Ciliary Ganglion and Short Ciliary
Nerves: The Tonic Pupil
Any injury to the ciliary ganglion or the short ciliary
nerves in the retrobulbar space or in the intraocular, supra-
choroidal space will cause internal ophthalmoplegia. Within
a few days, cholinergic supersensitivity may develop. These
findings are due to denervation of the iris sphincter and cili-
ary muscle. In some cases, denervation is the only pathologic
process; when permanent, it results in unilateral paralysis of
accommodation and a dilated pupil that reacts poorly to light
and near stimulation but constricts well to weak topical pilo-
carpine. In others, denervation is followed by subsequent
reinnervation (both appropriate and aberrant) of the iris mus-
cles that results in recovery of accommodation, a pupillary
response to near stimuli that is unusually strong and tonic,
and redilation after constriction to near stimuli that is delayed
and slow. These are the characteristic features of a tonic
pupil (Fig. 16.16). Tonic pupils are generally divided into
three categories: local, neuropathic, and Adie syndrome
(225,226).
LOCAL TONIC PUPILS Figure 16.16. Tonic pupil syndrome. About 4 months earlier, this 38-
This type of tonic pupil, typically unilateral, is due to year-old man noted that his right pupil was larger than his left pupil. A, In
orbital or systemic lesions that affect the ciliary ganglion or the dark looking in the distance, both pupils are dilated and relatively equal
in size. B, In bright light, the right pupil does not constrict, whereas the
short ciliary nerves in isolation. Disorders that have been
left pupil constricts normally, producing a marked anisocoria. C, In room
reported to cause this type of ‘‘local’’ tonic pupil include light looking in the distance, there is a moderate anisocoria. D, During near
herpes zoster, chickenpox, measles, diphtheria, syphilis viewing, however, both pupils constrict. The right pupil constricted much
(both congenital and acquired), Lyme disease, sarcoidosis, more slowly than the left and redilated slowly.
scarlet fever, pertussis, smallpox, influenza, sinusitis, Vogt-
Koyanagi-Harada syndrome, rheumatoid arthritis, polyarte-
ritis nodosa, giant cell arteritis, migraine, lymphomatoid NEUROPATHIC TONIC PUPILS
granulomatosis, viral hepatitis, choroiditis, primary and met-
astatic choroidal and orbital tumors, blunt injury to the globe, This type of tonic pupil, usually with bilateral involve-
intraocular siderosis from foreign body, and penetrating or- ment, represents one manifestation of a widespread, periph-
bital injury (227–237). In some of these cases, the tonic eral, and autonomic neuropathy that also involves the ciliary
pupil may have occurred as happenstance. In others, ancil- ganglion, the short ciliary nerves, or both (248). In some
lary testing such as MR imaging or orbital color Doppler cases, there is evidence of both a sympathetic and a parasym-
imaging have demonstrated clear abnormalities at the ciliary pathetic disturbance. These include syphilis, chronic alco-
ganglion, suggesting local injury related to the primary sys- holism, diabetes mellitus, amyloidosis, systemic lupus ery-
temic disease process (238,239). thematosus, Sjögren syndrome, some of the spinocerebellar
Various ocular or orbital surgical procedures, including degenerations, hereditary motor-sensory neuropathy (Char-
retinal reattachment surgery, inferior oblique muscle sur- cot-Marie-Tooth disease), Landry-Guillain-Barré syndrome,
gery, orbital surgery, optic nerve sheath fenestration, retinal and the Miller Fisher syndrome (249–254). Dysautonomias
photocoagulation, argon laser trabeculoplasty, transconjunc- associated with tonic pupils are subacute autonomic neurop-
tival cryotherapy, transscleral diathermy, retrobulbar injec- athy, Shy-Drager syndrome, and Ross syndrome. Tonic pu-
tions of alcohol, and even inferior dental blocks, can cause pils can occur from the distant effects of cancer, occurring
denervation injury (iridoplegia and cycloplegia) and a either as an isolated phenomenon or as part of a more exten-
‘‘local’’ tonic pupil (240–247). sive paraneoplastic autonomic polyneuropathy (255,256).
They also may develop in patients with trichloroethylene tion of the ciliary body and iris sphincter. The clinical find-
intoxication (257). ings depend in part on the stage of evolution in which the
pupil is examined. Acutely following a denervation injury,
ADIE (HOLMES-ADIE) TONIC PUPIL SYNDROME there is an internal ophthalmoplegia. The pupil is markedly
dilated and appears unresponsive to light or near stimulation.
Adie syndrome is an uncommon, idiopathic condition that At this stage, it often is confused with a pharmacologically
may develop in otherwise healthy persons and in patients induced mydriasis and cycloplegia. However, a careful slit-
with unrelated conditions. It nearly always occurs as a spo- lamp examination using a bright light usually reveals seg-
radic entity, although it has been described in three sisters mental contractions of the iris sphincter (Fig. 16.16). These
and in twins (258,259). Such reports are simply too rare to segmental contractions to bright light represent remaining
suggest any hereditary origin. Adie syndrome is rare before areas of normally innervated iris sphincter. Under the slit
age 15 years (260,261). In a child, secondary causes of a lamp, the iris segments that contract are seen to tighten and
tonic pupil should be ruled out first, and then attention should bunch up like a purse-string bag being closed. Conversely,
be directed to management of the anisometropia to avoid in denervated segments, the iris stroma appears thin and
amblyopia (262). flat. The adjacent pupillary ruff is meager, and the radius of
Most patients with Adie syndrome are 20–50 years of curvature of the pupil margin is flatter. These denervated
age. Although the syndrome occurs in both sexes, there is segments do not contract to a bright light, but the radial
a clear predilection for women (about 70% of cases). Adie markings of the stroma in these denervated segments show
syndrome is unilateral in about 80% of cases. When the a ‘‘streaming’’ movement that is caused by mechanical pull
condition is bilateral, the onset occasionally is simultaneous from normally contracting segments. These findings are
but usually occurs in separate episodes months or even years characteristic of sectoral palsy of the iris sphincter (Fig.
apart (263). 16.17). Sectoral palsy of the iris sphincter is a critical diag-
Historical Background. William Adie’s name most nostic observation, present in about 90% of Adie pupils. In
often is associated with the syndrome of tonic pupil and these cases, the amount of sphincter palsy (estimated in
benign areflexia, but he was not the first to describe the clock-hour segments around the pupil margin) is 70% or
syndrome or its features. The earliest description of a toni- more, so detection requires attentive observation of each
cally reacting pupil was by Piltz, who mentioned the occur- clock-hour segment (269). Sectoral palsy is not seen with
rence of a bilateral, tonic light reflex in patients with general pharmacologic anticholinergic blockade, which paralyzes
paresis (264). Gordon Holmes published a series of 19 cases 100% of the sphincter. About 10% of Adie pupils also have
and reviewed the previous literature on the subject just be- no segmental contraction to bright light (100% sphincter
fore the publications of his student William Adie (265). In palsy), at least not acutely.
the United Kingdom, therefore, this condition is called the The ‘‘vermiform movements’’ of the iris in Adie syn-
Holmes-Adie syndrome. drome probably represent spontaneous pupillary unrest, or
Clinical Characteristics. Symptoms. Around 80% of hippus, in normally innervated segments of the sphincter and
patients with Adie syndrome have visual complaints, usually are essentially the same as segmental contractions of the iris.
related to the iridoplegia. These include photophobia and In a rare patient with Adie tonic pupil in one eye, the ciliary
difficulty with dark adaptation (266). Symptoms related to muscle in the other eye suddenly shows evidence of dysfunc-
ciliary muscle dysfunction are blurred near vision and brow tion, even though the pupillary light and near reactions ap-
ache or headache with near work. Over time, the dilated pear normal (272). This probably is a limited form of Adie
pupil becomes smaller and accommodation improves; how- syndrome.
ever, some patients continue to have difficulty focusing. Accommodative Paresis. In most patients with Adie
Such patients can see clearly at rest for both distance and syndrome, the acute accommodative paresis is moderate to
near; however, they experience visual blur when shifting severe because of ciliary muscle denervation and paralysis.
fixation from near to distance (tonicity of accommodation). Accommodation gradually improves over several months as
This is particularly troublesome if the unaffected eye has injured axons begin to regenerate and reinnervate the ciliary
poor vision from other causes. muscle. Most of the recovery occurs in the first 2 years after
If, some years later, the other eye also develops a tonic the acute injury.
pupil, the condition seems to produce far fewer symptoms Aberrant Reinnervation of the Iris Sphincter. In the
and may even pass unnoticed. This is in part because both acute stage, both the pupil light reflex and pupillary constric-
eyes are now affected and because the patient has become tion to near effort are equally and severely impaired. After
presbyopic in the interim; therefore, less accommodative dif- several weeks or months, the near response of the pupil be-
ference is induced between the two eyes. gins to increase in amplitude while the light response re-
Although patients with Adie syndrome not uncommonly mains severely impaired (light–near dissociation). However,
have abnormal tests of autonomic function, they are rela- the pupil movement now is distinctly different than normal.
tively asymptomatic. Symptoms may include chronic cough, The pupil constriction to a near effort is strong, slow, and
abnormal sweating, or postural dizziness (267,268). sustained (tonic near response). In addition, the redilation
Sectoral Palsy of the Iris Sphincter. As mentioned movement after cessation of near effort is equally slow and
above, the pathophysiology of an Adie pupil is acute dener- sustained, delaying visual refocus by several seconds (tonic-
vation followed by appropriate and inappropriate reinnerva- ity of accommodation). These findings are caused by aber-
A B
Figure 16.17. Segmental palsy of the iris sphincter in Adie tonic pupil syndrome. A, One part of the iris sphincter is denervated
and does not react to light. Another segment (B) of the iris sphincter constricts to light in this irregularly shaped Adie tonic
pupil. B, In another case, the area of iris sphincter between 12 and 4 o’clock demonstrates intact pupillary ruff and puckering
of the iris stroma consistent with active contraction in this segment, but most of the remainder of the iris sphincter is denervated.
The pupillary ruff is mostly absent, the iris stroma is less dense, and the radius of pupil curvature is flatter in this area,
particularly between 5 and 7 o’clock and between 8 and 12 o’clock (sectoral palsy). (Courtesy of Dr. F-X Borruat.)
rant reinnervation of the iris sphincter by regenerating ac- of near reflex fibers, as occurs in some dorsal midbrain le-
commodative fibers. sions.
Warwick and others showed that the pupillomotor fibers Decreased Corneal Sensation. Purcell et al. used the
to the iris sphincter constitute about 3% of the total number Cochet-Bonnet aesthesiometer to demonstrate a regional de-
of postganglionic neurons that leave the ciliary ganglion, crease in corneal sensation in 10 of 11 patients with unilat-
whereas the remaining 97% of neurons innervate the ciliary eral Adie syndrome (acute and chronic), consistent with the
muscle (271). Thus, when the ciliary ganglion is injured, theory that the lesion in Adie syndrome is located in the
there is a numerically greater chance of survival of cells ciliary ganglion or short ciliary nerves (275). Interestingly,
serving accommodation compared with those serving pupil the areas with reduced sensation did not correlate to the
constriction. In 1967, Loewenfeld and Thompson suggested extent or distribution of the iris sphincter denervation.
that the fibers of these surviving cells, originally destined Absent Muscle Stretch Reflexes. Deep-tendon hypor-
for the ciliary muscle, resprouted randomly, with some of eflexia or areflexia can be demonstrated in almost 90% of
the fibers reaching and reinnervating their appropriate target, patients with Adie syndrome. As is the case with the pupil
the ciliary muscle (272). This explained the recovery of ac- light reflex, there can be progressive loss of reflex activity
commodation over time. Other resprouting fibers, however, over time. The reflexes of the upper extremities are abnormal
mistakenly reinnervated the iris sphincter. Thus, pupil con- almost as often as the reflexes of the lower extremities (226).
striction also recovered, but only as a misdirection syn- Electrophysiologic studies suggest that the cause of are-
kinesis. When the patient made a near effort, the accommo- flexia is loss of large-diameter afferent fibers or impairment
dative impulses stimulated both ciliary muscle and iris in their synaptic connections to motor neurons (275–277).
sphincter activity (Fig. 16.18). The long latency and slow, Histopathologic studies in patients with Adie syndrome have
prolonged contraction of the iris sphincter were thought to be demonstrated moderate degeneration of both axons and my-
related to its inappropriate reinnervation and its cholinergic elin sheaths in the fasciculus gracilis and fasciculus cuneatus
supersensitivity (272,273). (278,279). The dorsal and ventral roots appeared normal, as
The light reflex of a tonic pupil remains impaired. Further- did the remaining spinal cord. There appears to be a degener-
more, in about one third of patients, more segments of ation of cell bodies in the dorsal root ganglia similar to that
sphincter become increasingly impaired over time, suggest- which occurs in the ciliary ganglion (280).
ing that the degenerative changes in the ciliary ganglion are Cholinergic Denervation Supersensitivity. In 1940,
progressive. Besides being less numerous in quantity, per- Adler and Scheie reported that the tonic pupil of patients
haps pupillary fibers have an inherently greater susceptibility with Adie syndrome constricted intensely to 2.5% methacho-
to the primary insult that causes these degenerative changes. line chloride (due to cholinergic supersensitivity), whereas
In any event, it is clear that the pupillary light–near dissocia- normal pupils did not (281) (Fig. 16.19). Later studies dem-
tion of a tonic pupil results from impairment of the light onstrated large interindividual variability of pupil responses
reflex with restoration of the near reflex and not from sparing such that it was subsequently dropped as a test for tonic
Figure 16.18. Misregeneration theory as it per-

tains to the findings in the tonic pupil syndrome.
Top, Before injury, most of the fibers in the cili-
ary ganglion are destined for the ciliary muscle
to produce accommodation. Bottom, Following
injury, it is more likely that a regenerating post-
ganglionic fiber will be one for accommodation;
however, many of these fibers send branches or
collaterals to the iris, producing pupillary con-
striction during attempted accommodation-con-
vergence. In this drawing, postganglionic fiber 1,
for accommodation, has not been injured; fibers
2 and 5, also accommodative, have regenerated,
sending sprouts to both the ciliary muscle and
the iris sphincter; fiber 3, for pupillary constric-
tion, has sent a sprout to the ciliary muscle via
the remaining nerve sheath of fiber 4, which has
been damaged; fiber 6, for pupillary constriction,
has been destroyed and has not regenerated.
Thus, accommodation and pupillary constriction
will occur primarily on attempted accommoda-
tion-convergence.
pupils (282). Instead, dilute pilocarpine (0.1% or less) has pilocarpine becomes the smaller pupil after instillation of
become the most popular pharmacologic agent for demon- pilocarpine (286). Cholinergic supersensitivity develops
strating cholinergic denervation supersensitivity of the iris quickly, usually within days after injury. About 80% of tonic
sphincter (283,284). A 0.1% pilocarpine solution can be pre- pupils demonstrate cholinergic supersensitivity; the test re-
pared in a syringe from 1 part commercially available 1% sult is influenced by intersubject variability, differential cor-
pilocarpine and 9 parts normal saline, although bacteriostatic neal penetration, mechanical influence of the iris stroma
water also can be used and may have less constricting effect (how small the pupil is at baseline), and the state of reinner-
on a normal iris sphincter (285). The criterion for diagnosing vation.
cholinergic supersensitivity has been proposed as either (a) As preganglionic injury can also produce end-organ su-
the affected pupil constricts 0.5 mm more than the unaffected persensitivity, oculomotor nerve palsy can also cause a
pupil under dim ambient lighting or (b) the suspected pupil ‘‘positive’’ pilocarpine test. Furthermore, the degree of cho-
that is larger than the normal pupil before instillation of linergic supersensitivity is about the same in patients with
Figure 16.19. A, A right tonic pupil in a 36-year-old woman. B, 45 minutes after conjunctival instillation of two drops of
0.1% pilocarpine solution in each eye, the right pupil is constricted and nonreactive. The left pupil remains unchanged and
normally reactive.
oculomotor nerve palsies and patients with Adie pupils

(287).
Ciliary muscle supersensitivity also can be established by
measuring the near point of accommodation before and after
instillation of dilute pilocarpine, but only if the patient is
under age 45 years and has normal accommodation in the
normal eye.
Long-Term Features and Prognosis. Several features
of Adie syndrome change over time. Accommodation re-
covers significantly over a year or two. The size of the tonic
pupil decreases by 2–3 mm or more over several years (Fig.
16.20). In some patients, it can become the smaller pupil,
even in room light, and bilateral cases of chronic Adie pupils
can be mistaken for Argyll Robertson pupils (288). The ex-
planation for the progressive miosis in Adie syndrome was
proposed by Kardon et al., who used infrared transillumina-
tion to evaluate the distribution of segmental iris sphincter
reactivity under various stimulus conditions (289). In dark-
ness, reinnervated segments of the sphincter appeared
‘‘denser’’ under transillumination compared with normal
pupils and became even denser with near effort (i.e., during
active contraction). This finding suggested that in darkness,
a tonic pupil has a constant volley of low-level impulses
from accommodative neurons that keeps reinnervated seg-
ments of iris sphincter in a greater state of contraction com-
pared with a normally innervated sphincter that receives no
parasympathetic impulses in darkness. In addition, the num-
ber and extent of reinnervated segments appear to increase
with time. Both of these phenomena probably contribute to
Figure 16.21. Six infrared transillumination views of the same iris in a
the decreasing size of a tonic pupil (Fig. 16.21). Addition-
patient with an acute Adie pupil affecting all but one of the segments. The
ally, the active reinnervation process apparently prevents de- middle and lower photographs on the right are from the same eye 6 months
velopment of iris atrophy, a feature not typically found in later. The photographs of the left side show that there is only one small
chronic Adie syndrome. segment (the dense area at the pupil border at the 7 o’clock position) that
Kardon et al. also demonstrated that the degree of cholin- still contracts appropriately to light and near. This example was chosen
because all the rest of the iris sphincter has been denervated so that the
changes in density of the remaining, normally reacting segment can be
discerned in darkness, in light and at near. In the ‘‘acute-dark’’ photograph
(top left), the area of the 7 o’clock position cannot be seen but becomes
dense in response to light stimulation (middle left, ‘‘acute-light’’) and in
response to near stimulation (bottom left, ‘‘acute-near’’). The change in the
sphincter also is shown in response to low-concentration pilocarpine (top
right). All of the denervated segments show an increase in density after
0.1% pilocarpine, except for the one segment that normally is innervated
and, therefore, presumably not supersensitive, which appears translucent
at the 7⬊30 position (top right, ‘‘acute 0.1% pilocarpine’’). This same pa-
tient was examined 6 months later (right side, middle and bottom photo-
graphs), and the results show a light–near dissociation with an increase in
density on near response. The pupil is slightly smaller in light than in the
acute state because of some sustained firing of accommodative fibers that
have started to reinnervate the sphincter areas. (From Kardon RH, Corbett
JJ, Thompson HS. Segmental denervation and reinnervation of the iris
sphincter as shown by infrared videographic transillumination. Ophthalmol-
ogy 1998;105⬊313–321.)
ergic sensitivity decreases as reinnervation increases (289).

Figure 16.20. Changes in size of an Adie tonic pupil over time. Top, Denervated segments that are unreactive to light and near
Appearance of an acute right-sided Adie pupil in a 33-year-old woman. stimulation show an intense increase in density following
Bottom, Appearance of the same patient 10 years later. The right pupil has dilute pilocarpine. However, as these segments are reinner-
become smaller in resting size so that in ambient lighting, there is no appar- vated and become reactive to near effort, they become less
ent anisocoria. (Courtesy of Dr. F-X Borruat.) reactive to the pilocarpine.
The light reaction of the Adie pupil generally does not which are described in the section on drug effects. It suffices
recover. Like the muscle-stretch reflexes, it deteriorates fur- here to emphasize that such agents block the action of acetyl-
ther with passing years in most patients. choline on the iris sphincter and ciliary muscles, that they
Patients with unilateral Adie syndrome tend to develop a produce both mydriasis and cycloplegia, and that the mydria-
tonic pupil in the opposite eye with time. This occurs in sis produced by such drugs is extreme, usually more than 8
about 4% of cases per year (263). Overall, this is a benign mm. It is necessary to differentiate a pupil that is pharmaco-
condition; however, in some patients with shallow anterior logically dilated from one that is neurologically dilated.
chamber angles, an acute tonic pupil can precipitate an attack Thompson et al. suggested using a 0.5–1% solution of pilo-
of angle-closure glaucoma (50,290). carpine for this task (294). A pupil that is dilated from phar-
macologic blockade of the sphincter will be unchanged or
TREATMENT
poorly constricted by a topical solution of pilocarpine strong
Weak solutions of eserine or pilocarpine can be used to enough to constrict the opposite pupil (Fig. 16.22), whereas
constrict a tonic pupil for relief of photophobia and for cos- a tonic pupil that constricts to weak solutions of pilocarpine
metic purposes (reduction of anisocoria, especially in pa- because of denervation supersensitivity should certainly
tients with light-colored irides) (291,292). Most patients do constrict to 0.5–1% pilocarpine. A pupil that is dilated from
not need this treatment for very long because within a year oculomotor nerve dysfunction also will constrict well after
or two, the tonic pupil becomes smaller in size and in dim instillation of pilocarpine.
light, and it soon is the smaller of the two pupils (293). For
symptoms related to abnormal accommodation, a bifocal add Pharmacologic Stimulation of the Iris Dilator
usually suffices, even if it is not yet needed by the unaffected
Topical cocaine placed in the nose for medical or other
eye.
reasons can back up the lacrimal duct into the conjunctival
Damage to the Iris Sphincter sac. Most eye-whitening drops that contain sympathomi-
Tears in the iris sphincter or the iris base may occur from metic components are too weak to dilate the pupil, but if the
blunt trauma to the eye. Such damage may produce a non- cornea is abraded (e.g., by a contact lens) enough of the
reactive or poorly reactive irregularly dilated pupil that may oxymetazoline or the phenylephrine in the solution may get
be mistaken for the dilated pupil of an oculomotor nerve into the aqueous humor to dilate the pupil. In addition, mists
palsy, particularly if the patient is lethargic or comatose from containing adrenergic or anticholinergic drugs for broncho-
the injury. In most cases, careful examination of the dilated dilation may escape around the edge of the facemask and
pupil with a hand light reveals subtle irregularities in its condense in the conjunctival sac, inadvertently causing uni-
normally smooth contour, and the iris tears or dialysis are lateral pupillary dilation.
easily observed using a standard or portable slit lamp (Fig. Anisocoria Due to Sympathetic Hyperactivity
16.2).
Sympathetic hyperactivity occurs in a number of settings,
Pharmacologic Blockade with Parasympatholytic usually as an episodic phenomenon. In several of these set-
Agents tings, the pupils are affected, and in cases of unilateral or
A fixed dilated pupil can be caused by topical administra- asymmetric oculosympathetic hyperactivity, there may be
tion of one of several parasympatholytic agents, many of an anisocoria.
Figure 16.22. Pharmacologically dilated pupil. A, Fixed, dilated right pupil in an 18-year-old woman complaining of headache
and blurred vision. B, 45 minutes after conjunctival instillation of two drops of 1% pilocarpine in each eye, the right pupil is
unchanged, whereas the left pupil is markedly constricted. The patient subsequently admitted having placed topical scopolamine
in the right eye.
The etiology of tadpole pupils is unclear. Presence of an

intact pupil light reflex suggests dilator spasms rather than
sphincter paresis. In a review of 26 cases, Thompson et al.
noted that 11 patients (42%) also had a partial postganglionic
Horner syndrome on the affected side (295). The authors
postulated that repeated bursts of sympathetic impulses
asymmetrically pulled one segment of the iris toward the
limbus and that this repeated irritation eventually could have
caused loss of fibers and the Horner syndrome. Thus, testing
for Horner syndrome is recommended for patients who give
a history of episodic tadpole-shaped pupils (296), even if
there is no anisocoria at the time of the examination.
Another mechanism may be responsible for tadpole pupils
in the setting of a congenital Horner syndrome. Tang re-
ported the case of a young man with a hypoplastic right
internal carotid artery and ipsilateral congenital Horner syn-
drome who experienced exercise-induced pupillary distor-
tion of the right pupil (297). The same segment of the iris
always dilated after strenuous exercise, and it was the same
area that failed to dilate with hydroxyamphetamine. In this
case, the tadpole pupil presumably resulted from local super-
sensitivity of a denervated segment of the iris dilator muscle,
Figure 16.23. Tadpole pupil. Top, Before the episode, the pupils are nor- occurring at moments when the level of circulating cate-
mal in size and shape. Bottom, During the episode, the right pupil develops cholamines was increased.
an eccentric shape, with the 5 o’clock portion of the pupil being displaced
outward. (From Thompson HS, Zackon DH, Czarnecki JSC. Tadpole-
Aberrant regeneration causing segmental spasm of the
shaped pupils caused by segmental spasm of the iris dilator muscle. Am J iris dilator
Ophthalmol 1983;96⬊467–477.) An iris dilator–deglutition synkinesis resulting in episodic
segmental dilator contraction was described in a young boy
with Horner syndrome and paresis of the glossopharyngeal,
Tadpole-Shaped Pupils vagus, and hypoglossal nerves (Villaret-like syndrome) fol-
lowing resection of a neuroblastoma in his right upper neck
An occasional patient reports that the pupil of one eye during infancy (298). Later, he had focal dilator spasms of
becomes distorted for a minute or two. In most cases, the his right pupil that resulted in an elliptical pupil (Fig. 16.24)
eye feels ‘‘funny’’ and the vision in the eye becomes slightly and were associated with swallowing. Presumably, this dila-
blurred. Looking in the mirror reveals that the pupil is pulled tor–deglutition synkinesis was caused by aberrant vagal
in one direction like the tail of a tadpole, hence the term nerve sprouts that made an inappropriate synaptic connec-
‘‘tadpole pupil’’ (Fig. 16.23). Often patients describe the tion at the superior cervical ganglion.
direction of the tadpole tail to be different on different occa-
sions. This phenomenon usually occurs many times a day for Pourfour du Petit Syndrome
several weeks, spontaneously remits, and then recurs several This syndrome is the clinical opposite of Horner syn-
months later. Eventually, the condition abates and does not drome. It represents oculosympathetic overactivity instead
recur (295). of underactivity and usually is caused by lesions along the
Figure 16.24. Iris dilator–deglutition synkinesis causing segmental iris dilator muscle contraction in 10-year-old boy with a
long-standing right Horner syndrome. A, The child has a right Horner syndrome that had been present since removal of a
cervical neuroblastoma when he was 6 days old. At age 2 years, his parents first noted that while he was drinking, his right
pupil would become transiently distorted in shape. B, Appearance of the pupils during the act of swallowing. There is segmental
dilation of the right pupil at the 1 o’clock and 7 o’clock positions, causing a distorted pupil. The dilation occurs only when
the child is swallowing. (From Boehme BI, Graef MH. Acquired segmental iris dilator muscle synkinesis due to deglutition.
Arch Ophthalmol 1998;116:248–249.)
cervical sympathetic chain. The clinical signs are unilateral (306). Gianelli hypothesized that this phenomenon resulted
mydriasis, lid retraction, apparent exophthalmos, and con- from mechanical traction caused by movement of the globe
junctival blanching, all of which may be episodic or constant. that stimulated the long ciliary nerves in abduction and the
The phenomenon is rare and has been described after trauma, short ciliary nerves in adduction. Tournay independently
brachial plexus anesthetic block or other injury, and paroti- made similar observations, emphasizing the dilation of the
dectomy and in patients with tumors of the pleural lining or pupil ipsilateral to the direction of gaze, and later recognized
mediastinum (299,300). The oculosympathetic hyperactivity Gianelli as the first to observe this phenomenon (307,308).
sometimes precedes the development of a Horner syndrome. Nonetheless, an anisocoria that develops on extreme lateral
Presumably, the lesion first irritates the sympathetic fibers gaze is called the Tournay’s phenomenon. Sharpe and Glaser
and later damages them. studied 25 normal subjects and 5 patients with Duane retrac-
tion syndrome by direct observation, photography, and in-
Sympathetic Hyperactivity and Spinal Cord Lesions frared electronic pupillography (309) and could not demon-
strate anisocoria in lateral gaze in any of the subjects (309).
Autonomic hyperreflexia is a phenomenon seen in quadri- Loewenfeld et al. examined 150 normal subjects using in-
plegic patients who have experienced severe spinal cord infrared flash photography and concluded that the Tournay
jury. It usually appears weeks to months after the acute injury phenomenon does exist but that its prevalence is low and its
and results from absent cerebral control of the spinal sympa- extent small (e.g., less than 10% of subjects showed a change
thetic neurons that leads to paroxysms of sympathetic hyperin anisocoria greater than 0.3 mm) (310). Loewenfeld postu-
activity that either occur spontaneously or are triggered by lated that the Tournay phenomenon results from ‘‘straying’’
nonspecific stimuli below the level of cord injury (301). of impulses that were meant for the medial rectus subnucleus
Occasionally, the oculosympathetic pathway is affected uni- to the nearby Edinger-Westphal nucleus (119). This would
laterally or a patient undergoes a local anesthetic procedure cause slight constriction of the pupil when the eye adducts
that blocks sympathetic activity on one side, making evident and relative dilation of the pupil when the medial rectus
the eye findings of autonomic hyperreflexia as episodes of subnucleus is inhibited during abduction. Whatever the ex-
unilateral mydriasis, blurry vision, and lid retraction on the planation, it is reasonable to conclude that the Tournay phe-
unanesthetized side (302,303). In other patients, passive arm nomenon is relatively uncommon and has little or no clinical
or leg stretching or limb movement can induce a transient significance.
asymmetric mydriasis. This may represent a localized form
of autonomic hyperreflexia (oculosympathetic spasm) that Anisocoria During Migraine Headache
occurs in response to proprioceptive impulses that ascend to The best-known association of an anisocoria and vascular
reach the damaged area of the spinal cord (160). headache is the cluster headache syndrome mentioned previ-
Oculosympathetic hyperactivity has been reported after a ously. This section deals with those occasional patients who
relatively minor cord injury. Saito and Nakazawa described report having one dilated pupil or unequal-sized pupils only
a young man who sustained a whiplash injury in a car acci- during a classic or common migraine headache attack. The
dent and shortly thereafter developed episodes of unilateral induced anisocoria generally is rather small but ranges from
mydriasis (304). The episodes lasted several hours to a few 0.3 mm to 2.5 mm (Fig. 16.25) (311–313).
days and occurred once or twice a week. The patient had The mechanism of anisocoria during migraine is not fully
no other neurologic deficits. Radiographic studies revealed established. A study that found diminished velocity and am-
slight narrowing of the disc space at the C5–C6 level. Phar- plitude of the pupil light reflex in 10 migraineurs (312) im-
macologic testing suggested that the mydriasis was caused plicates parasympathetic dysfunction as one possibility. In
by episodic sympathetic irritation. such cases, the abnormal pupil is the larger one, and other
An ‘‘alternating Horner syndrome’’ has been reported in evidence for oculoparasympathetic hypofunction should
patients with lower cervical and upper thoracic cord lesions exist. The series by Woods et al. supports this hypothesis in
and in some patients with primary dysautonomia, such as that it showed reduced light responses in five of seven pa-
the Shy-Drager syndrome (see below). Some authors believe tients examined during their migraine and reduced accom-
that it results from a transient oculosympathetic deficit modation in two others (311). One patient had a history of
that changes sides at intervals of 2 hours or 2 weeks ophthalmoplegic migraines since childhood that evolved
(157,158,305); however, Moniz and Czarnecki studied phar- into an isolated unilateral mydriasis accompanying her mi-
macologically two patients with this phenomenon and con- graine headaches as an adult. Such a limited form of ophthal-
cluded that the clinical findings also could be explained by moplegic migraine must be rare (314,315). Another etiologic
a unilateral lesion that causes alternating oculosympathetic site of oculoparasympathetic dysfunction that has been de-
hypofunction and hyperfunction (161). scribed with migraine is the ciliary ganglion (316,317). Pre-
sumably, migrainous vasospasm can cause local and reversi-
Other Anisocorias ble ischemia of the ciliary ganglion and could also account
Anisocoria in Lateral Gaze: The Tournay Phenomenon for the findings described by Woods et al. (311).
Although parasympathetic hypofunction may be the most
In 1907, Gianelli noted that when some normal persons common cause of unilateral dilation during a migraine at-
look in extreme lateral gaze, the pupil on that side becomes tack, it is not the only possible mechanism. An episodic
larger and the pupil on the opposite side becomes smaller unilateral sympathetic hyperactivity or spasm accompanying
Figure 16.25. Intermittent unilateral pupillary dilation in a young woman during severe migraine headache. A, During the
migraine attack, the left pupil is dilated and poorly reactive. Accommodation is normal, however, suggesting that the dilation
is caused by sympathetic hyperactivity rather than parasympathetic hypoactivity. B, Between attacks, the pupils are isocoric.
the attack might cause a similar process. In such a case, the the same eye. There are no associated neurologic deficits.
patient would experience no loss of accommodation in the The duration of mydriasis averages 12 hours, but the range
affected eye. We have seen such patients and believe that is wide (10 minutes to 7 days). In Jacobson’s series, 11 of
this mechanism is not uncommon. 24 patients were examined during an episode (319). In these
Yet another hypothesis for anisocoria during migraine is patients, the anisocoria ranged from 1 to 3 mm. Associated
sympathetic hypofunction. In some migraineurs, pharmaco- symptoms included blur (62%), orbital pain (21%), and red
logic pupillary testing has suggested that a bilateral postgan- eye (17%). Five patients had a normal pupil light reflex with
glionic oculosympathetic deficit occurs during the headache normal vision, four patients had decreased accommodative
attack, and in those migraineurs who develop a clinically function, and one patient demonstrated cholinergic supersen-
apparent but transient anisocoria, there is asymmetry of their sitivity.
sympathetic dysfunction (313). Because a small but significant percentage of patients with
Finally, it is possible that some cases of anisocoria during benign episodic mydriasis experience simultaneous ipsi-
migraine represent an exaggeration of an underlying benign lateral blurred vision, orbital pain, red eye, or a combination
physiologic anisocoria. At any rate, a transient and isolated of these manifestations, intermittent angle-closure glaucoma
anisocoria that is associated temporally with migraine head- must be eliminated as a possibility in patients in whom such
ache attacks and recurs periodically in stereotypic fashion a diagnosis is considered (47).
in an otherwise healthy person appears to be a fairly benign
syndrome. This clinical picture has not been reported with Differentiation Between Causes of Anisocoria
intracranial aneurysm, midbrain tumor, seizures, or arterial
dissection (316). From a practical standpoint, anisocoria that is more evi-
Sarkies reported that intermittent angle-closure glaucoma dent in darkness than in light indicates that the parasympa-
can produce a clinical picture similar to the episodic mydria- thetic pathway that constricts the pupils and the iris sphincter
sis that occurs in association with a migraine attack (47). muscles are intact (i.e., both eyes have a normal pupil light
Thus, it is important to consider that entity in patients who reflex). The problem thus lies with asymmetric sympathetic
experience intermittent episodes of unilateral mydriasis with activity and dilation in darkness. Most cases represent either
periocular or retrobulbar pain, especially if there is an associ- simple anisocoria or a Horner syndrome. These two entities
ated redness of the eye and blurred vision. are differentiated using 10% cocaine. If the cocaine test indi-
cates that the patient has a Horner syndrome, a hydroxyam-
Benign Episodic Mydriasis phetamine test is performed on another occasion at least 24
hours later to differentiate a central or preganglionic Horner
Benign episodic mydriasis is the term used to describe syndrome from a postganglionic Horner syndrome. Once the
recurrent episodes of unilateral mydriasis that are not associ- Horner syndrome is diagnosed and localized, appropriate
ated with a concurrent headache or migraine (Fig. 16.26). evaluation for the etiology is required (320).
This condition probably is a variant of the transient mydria- Anisocoria that is more evident in light than in darkness
sis that occurs during migraine headaches and that is de- indicates a defect of the parasympathetic system or the iris
scribed above. Indeed, about half the patients with benign sphincter muscle. Thus, the faulty pupil has a poor light
episodic mydriasis have a history of migraines (318,319). reflex. The iris should be examined using a slit-lamp biomi-
Benign episodic mydriasis typically occurs and recurs in croscope to determine whether there is a sphincter tear or
A B
Figure 16.26. Intermittent unilateral pupillary dilation unassociated with migraine. This operating room nurse was noted to
have a dilated left pupil while she was assisting at surgery. She had no headache at the time, nor did she have any visual
symptoms other than a vague sense of blurred vision. A, During the episode, the left pupil is markedly dilated. Visual acuity
at this time was 20/20 OU at both distance and near. The right pupil constricted normally to light stimulation; the left pupil
constricted minimally under the same conditions. B, 2 hours later, the pupils are isocoric. Both pupils now reacted normally
to light stimulation.
other iris damage. If there is no evidence of iris damage, ways of the pupillary light reflex. Bryant concluded that
clinical examination usually bears out a diagnosis of oculo- patients with severe MG tend to show significant interocular
motor nerve palsy or tonic pupil. In uncertain cases, a 0.1% differences in pupil cycle times, with the degree of difference
solution of pilocarpine can be used to test for denervation correlating with the severity of the illness (327).
supersensitivity. If neither pupil constricts, a 1% solution It thus appears that some degree of pupillary dysfunction
of pilocarpine can then be used to distinguish between a can occur from MG but that in the vast majority of patients,
pharmacologically blocked pupil and a neurologically dener- such pupillary dysfunction is not clinically significant and
vated pupil (321) (Fig. 16.5). should not confuse the diagnosis; that is, MG should be
considered in patients with an ocular motility disturbance
DISTURBANCES IN DISORDERS OF THE and clinically normal pupil responses. On the other hand,
NEUROMUSCULAR JUNCTION patients with ocular motility disturbances and abnormally
reactive pupils or anisocoria should first be considered to
Myasthenia Gravis have a neurologic disorder, not myasthenia. MG is described
in detail in Chapter 21.
Myasthenia gravis (MG) is an autoimmune disorder char-
acterized by pathogenic antibodies against acetylcholine re- Botulism
ceptors at motor terminals. Clinically apparent weakness of
the intraocular muscles is rare. Nonetheless, abnormalities Botulinum toxin is produced by one of several strains
of pupillary function and accommodation are occasionally of the organism Clostridium botulinum. The toxin blocks
reported in patients with MG. Two patients with anisocoria cholinergic neurotransmission at the neuromuscular junction
and sluggish pupil light reflexes that resolved following and cholinergic autonomic synapses. Dilated, poorly reac-
treatment with cholinesterase inhibitor have been described tive pupils and paralysis of accommodation are nearly uni-
(322,323). Pupillary fatigue during prolonged light stimula- versally present in patients with clinical botulism (328–331).
tion has also been noted in other patients (323,324). Yama- Interestingly, the accommodation dysfunction often is more
zaki and Ishikawa used an open-loop stimulus and infrared severely affected than the pupillary dysfunction. The reason
video pupillography to record direct pupillary responses to is not clear. There are seven different strains of C. botulinum,
light as well as their velocities and acceleration in seven A–F (including C␣ and C␤), with A, B, and E being of most
patients with MG and in three healthy persons (325). Their clinical importance. In type E botulism, internal ophthal-
results suggest that involvement of the iris sphincter is com- moplegia and ptosis often are the initial neurologic manifes-
mon in patients with MG. Lepore et al. reported abnormali- tations of the disease, whereas in types A and B, systemic
ties of pupil cycle time, but most of these patients were autonomic symptoms tend to occur simultaneously with the
taking anticholinesterase agents, systemic corticosteroids, or onset of ocular symptoms.
both, which may have affected their pupillary movements Common routes of infection are ingestion of contaminated
(326). In addition, it is not clear whether the pupillary abnor- canned goods or meats, wound infection (particularly in her-
malities observed were caused by direct involvement of the oin addicts who use subcutaneous injections known as ‘‘skin
iris musculature, the neuromuscular junction, or central path- popping’’), and gastrointestinal colonization in infants. Bot-
ulism should be considered in any patient with symmetric, Drugs that Dilate the Pupils
descending muscular weakness; blurred near vision; and
Parasympatholytic (Anticholinergic) Drugs (Fig. 16.27)
poorly reactive pupils. The differential diagnosis and details
of this disease are in Chapters 21 and 49. Plants from the family Solanaceae occur naturally and
contain belladonna alkaloids in various proportions. These
plants include deadly nightshade (Atropa belladonna), black
Lambert-Eaton Myasthenic Syndrome
henbane (Hyoscyamus niger), jimson weed (Datura stramo-
Lambert-Eaton syndrome is an immune-mediated disor- nium), ‘‘angel’s trumpet’’ (Datura suaveolens), and morn-
der (primary or paraneoplastic) in which antibodies are di- ing glory. The word belladonna (‘‘beautiful lady’’) was de-
rected against PQ-type voltage-gated calcium channels, rived from the cosmetic use of these substances as mydriatics
resulting in inhibition of neurotransmitter release at choliner- in 16th-century Venice. The mischief caused by the ubiqui-
gic synapses. The pupil dysfunction is one feature of the tous jimson weed is typical of this group of plants. Jimson
cholinergic dysautonomia. One study reported that six of weed has been used as a poison, has been taken as a halluci-
nogen, and has caused accidental illness and death. It also
50 (8%) patients with Lambert-Eaton myasthenic syndrome
can cause a marked accidental mydriasis if it is inadvertently
(LEMS) had sluggish pupil responses to light on clinical
or purposefully applied to the conjunctiva of one or both
examination (332); however, another study using a more
eyes (337).
quantitative technique found abnormal pupil cycle times in Other solanaceous plants like blue nightshade (Solanum
69% of eyes in seven patients with LEMS (333). Tonic pu- dulcamara) and Jerusalem cherry are found in home gar-
pils also have been reported in patients with LEMS. One of dens. They contain solanine, which has effects similar to the
these patients showed some recovery of the light reaction belladonna alkaloids. Inadvertent topical ocular application
following administration of 3,4-diaminopyridine and pyri- with the juice from the plant can produce a dilated nonreac-
dostigmine (334,335). tive pupil that gradually returns to normal in 1–6 days
(338–340).
DRUG EFFECTS Atropine and scopolamine block parasympathetic activity
by competing with acetylcholine at the effector cells of the
The iris is easy to see because it is suspended in a clear iris sphincter and ciliary muscle, thus preventing depolariza-
fluid behind a clear cornea. Thus, the actions of the sphincter tion. Accidental mydriasis and anisocoria can be caused by
and dilator muscles on the size of the pupil can be monitored topical absorption after ocular contact with these drugs in
easily. Parasympathetic and sympathetic neural impulses to their natural form, but the most frequent ways the drug
the iris muscles can be modified by drugs at the synapses reaches the eye is by a finger from a scopolamine patch
and at the effector sites, because it is at these locations that (used for vertigo, seasickness, or postoperative pain) to the
the transmission of the impulses depends on chemical media- conjunctival sac (341), by accidental topical adsorption of
tors. Thus, the pupil can be and frequently is used as an the inhalant used to treat asthma (341a) or by the deliberate
indicator of drug action. instillation of the drug into one or both eyes by a person
A few cautionary words should first be said about the attempting to feign a neurologic disorder. After conjunctival
interpretation of pupillary responses to topically instilled instillation of 1% atropine, mydriasis begins within about
drugs. There are large interindividual differences in the re- 10 minutes and is complete in 35–45 minutes; cycloplegia
sponsiveness of the iris to drugs placed in the conjunctival is complete in about an hour. When concentrations of 2–4%
sac, and this becomes most evident when weak concentra- atropine are used, the pupil may stay dilated for several days,
tions are used. For example, a 0.25% solution of pilocarpine but accommodation usually returns in 48 hours. Scopolam-
will produce a minimal constriction in some patients and a ine (0.2%) causes mydriasis that lasts, in an uninflamed eye,
marked miosis in others. The general status of the patient for 2–5 days. This drug is a less effective cycloplegic than
atropine.
can also influence the size of the pupils (336). If the patient
A dilated, fixed pupil caused by pharmacologic blockade
becomes uncomfortable or anxious while waiting for the
of the iris sphincter by atropine may be difficult to distin-
drug to act, both pupils may dilate. If the patient becomes guish from a denervated iris sphincter. One clinically helpful
drowsy, both pupils will constrict. Thus, if a judgment is to feature is the presence of segmental contractions of the iris
be made about the dilation or constriction of the pupil in sphincter. Atropine weakens the sphincter equally at all seg-
response to a topical drug, one pupil should be used as a ments because convective circulation of the aqueous humor
control whenever possible (119). distributes the drug to all parts of the sphincter (342). Thus,
If only one eye is involved, the drug should be put in both at the slit lamp, if there is still any segment of the sphincter
eyes so that the response of the normal and abnormal eye that constricts to light, the pupil is not pharmacologically
can be compared. When the condition is bilateral, no such dilated, it is denervated. If the sphincter is diffusely para-
comparisons are possible, but an attempt should be made to lyzed (i.e., no segmental contractions seen), then no distinc-
make sure that the observed response is indeed caused by tion between a pharmacologically dilated pupil and a para-
the instilled drug. Thus, if both eyes are involved, the drop sympathetically denervated one can be made. Preganglionic
should be put in one eye only so that the responses of the denervation of the iris sphincter (i.e., oculomotor nerve
medicated and unmedicated eyes can be compared. palsy) may not always be associated with ophthalmoplegia
Figure 16.27. The pharmacology of the parasympathetic innervation of the iris.
or ptosis. A minority (about 10%) of postganglionic iris vated pupil should constrict at least as well as the normal
sphincter denervations (i.e., tonic pupils) involve 100% of pupil and perhaps even more, if denervation supersensitivity
the muscle (255). As noted above, one can use pharmaco- is present.
logic testing to differentiate between a pharmacologically Results of the pilocarpine test may be misleading in cases
dilated pupil and a pupil that is parasympathetically dener- of trauma. A pupil that is dilated because of blunt ocular
vated (one or two drops of a 0.5–1% solution of pilocarpine trauma tends to constrict poorly to pilocarpine, not because
in both conjunctival sacs). This concentration of pilocarpine of pharmacologic manipulation but because the sphincter
will not displace an anticholinergic drug from the receptors muscle itself has been damaged. Other observations suggest-
of the iris sphincter muscle, but it will produce a definite ing related damage to the eye (e.g., tears of the pupillary
constriction of the other normal pupil, and it also will con- margin, Vossius’ ring, lenticular changes, choroidal rupture,
strict a denervated pupil (from oculomotor nerve palsy or scattered pigment on the anterior iris stroma) generally make
tonic pupil) (226). Even a partial response to 0.5–1% pilo- it clear that the globe has been severely injured. Iron mydria-
carpine indicates pharmacologic blockade, because a dener- sis, however, from an unsuspected intraocular iron foreign
body, is mostly caused by toxic damage to the iris nerves hours. Local anesthesia occasionally enters the orbit by other
rather than to the iris muscle, and these pupils constrict vig- means. Unilateral mydriasis following dental surgery has
orously to pilocarpine like a denervated pupil (236,343). been reported after inadvertent injection of lidocaine through
Tropicamide (Mydriacyl) and cyclopentolate (Cyclogyl) the pterygopalatine fossa and inferior orbital fissure into the
are synthetic parasympatholytics with a relatively short dura- orbit (11).
tion of action (344). Tropicamide (1%) is an effective, short- Nebulized treatments for asthma containing anticholiner-
acting mydriatic; its action peaks at 25 minutes and lasts 3–6 gic drugs such as ipratropium bromide sometimes cause a
hours. The 1% drops produce little loss of accommodation, unilateral or bilateral mydriasis when the eye is accidentally
although mild cycloplegia may be detected between the 25th exposed to the aerosol from an incorrectly placed mask
and 35th minutes after instillation. Compared with tropica- (352).
mide, a 1% solution of cyclopentolate is a much more effec-
tive cycloplegic and perhaps a slightly less effective mydri- Sympathomimetic (Adrenergic) Drugs (Fig. 16.28)
atic, especially in dark eyes. Mydriasis and cycloplegia ap-
proach a maximum in about 30 minutes; accommodation Epinephrine (Adrenalin) stimulates the receptor sites of
takes about half a day to return, and the pupil still may the dilator muscle cells directly. When applied to the con-
not be working normally after more than 24 hours. To be junctiva, a 1⬊1,000 solution does not usually penetrate into
completely confident of cycloplegia, second and third drops the normal eye in sufficient quantity to have an obvious
sometimes are used. In a child, especially a small blond mydriatic effect. Indeed, even a solution of 1.25% epineph-
child, enough cyclopentolate may be absorbed through the rine is insufficient to dilate most pupils of normal subjects
nasal mucosa after three drops in each eye to produce mild (353). If, however, the receptors are supersensitive from pre-
transient symptoms of toxicity, such as flushing of the skin vious denervation, or if the corneal epithelium is damaged,
and restlessness (345). allowing more of the drug to get into the eye, these concen-
Because patients with Alzheimer dementia have abnor- trations of epinephrine will dilate the pupil.
malities in the cholinergic pathways of the brain, it has been Phenylephrine (Neo-Synephrine) in a 10% solution has a
hypothesized that the cholinergic pathway to the eye may powerful mydriatic effect. Its action is almost exclusively a
be defective as well. In 1994, Scinto et al. reported that direct ␣-stimulation of the effector cell. The pupil recovers
patients with Alzheimer disease showed greater mydriasis to in 8 hours and shows a ‘‘rebound miosis’’ that lasts several
weak (0.01%) tropicamide (i.e., cholinergic supersensitivity) days. A 2.5% solution most often is used for mydriasis, in
compared with normal controls (346). Some subsequent part because this rarely produces systemic hypertension, as
studies have confirmed these findings, whereas others have does a 10% solution (354). Even weak solutions of phenyl-
refuted them. As the debate continues, recent investigators ephrine may be sufficient to dilate a pupil, but pupils dilated
have suggested that reducing the peak constriction amplitude with this drug should still react to light stimulation. Roberts
is a more sensitive indicator of central cholinergic dysfunc- described a patient thought to be comatose from alcohol
tion compared with tropicamide-induced pupil dilation, and and benzodiazepine (diazepam, lorazepam) overdose who
others have proposed that an even more dilute solution developed a fixed dilated left pupil after nasotracheal intuba-
(0.005%) might lower false-positive rates (347,348). At tion and gastric lavage (355). A diagnosis of possible cere-
present, there are no standardized guidelines for clinical use bral herniation was made, and the patient was treated with
of weak tropicamide eyedrops as a diagnostic or differentiat- intravenous mannitol, furosemide, and hyperventilation. A
ing test of Alzheimer dementia. computed tomographic (CT) scan showed no abnormalities.
Botulinum toxin blocks the release of acetylcholine, and The fixed dilated pupil returned to normal over 3–4 hours,
hemicholinium interferes with the synthesis of acetylcholine and the patient’s condition subsequently improved. It was
both at the preganglionic and at the postganglionic nerve suspected that the fixed dilated pupil was caused by inadvert-
endings, thus interrupting the parasympathetic pathway in ent topical ocular contamination with phenylephrine nose
two places. Topical gentamicin may produce a similar effect spray (0.5%) that had been used in the left nostril in prepara-
(349). The outflow of sympathetic impulses also is inter- tion for the endotracheal intubation; however, we would not
rupted by systemic doses of these drugs, because the chemi- expect a pupil dilated in this manner to be nonreactive to
cal mediator in sympathetic ganglia also is acetylcholine. light stimulation.
Lidocaine and similar anesthetic agents produce a dilated Ephedrine acts chiefly by releasing endogenous norepi-
pupil following intraocular or intraorbital injection (350). In nephrine from the nerve ending. It also has a definite direct
most cases, the anesthetic agent is injected to produce both stimulating effect on iris dilator muscle cells and can produce
anesthesia and akinesia for intraocular or strabismus surgery, significant mydriasis, depending on the concentration used.
and the dilation is expected. In other cases, however, the Tyramine hydrochloride (5%) and hydroxyamphetamine
anesthetic is injected anteriorly but diffuses posteriorly. For hydrobromide (1%) have an indirect adrenergic action on
example, Perlman and Conn described three patients who the pupillary dilator muscle, releasing norepinephrine from
developed transient fixed dilated pupils after undergoing the stores in the postganglionic nerve endings. As far as is
blepharoplasties using a local anesthetic consisting of a 50/ known, this is their only effective mechanism of action.
50 mixture of 2% lidocaine with epinephrine 1⬊200,000 and Cocaine (5–10%) is applied to the conjunctiva as a topical
0.75% bupivacaine with epinephrine 1⬊200,000 (351). In anesthetic, a mydriatic, and a test for Horner syndrome (see
most of these cases, the pupil returns to normal within 24 above). Its mydriatic effect is the result of an accumulation
Figure 16.28. The pharmacology of the sympathetic innervation of the iris.
of norepinephrine at the receptor sites of the dilator cells. The tion of cocaine mydriasis is quite variable. It may last more
transmitter substance builds up at the neuroeffector junction than 24 hours. Pupils that dilate from cocaine do not show
because cocaine prevents the reuptake of the norepinephrine rebound miosis as the effect of the drug dissipates.
back into the cytoplasm of the nerve ending. Cocaine itself Tetrahydrozoline hydrochloride, pheniramine maleate,
has no direct action on the effector cell, nor does it release and chlorpheniramine maleate are sympathomimetic agents
norepinephrine from the nerve ending, and it does not retard often used in topical ocular decongestants. Instillation of eye
the physiologic release of norepinephrine from the stores in drops containing these substances may produce mydriasis,
the nerve ending. Its action is indirect in that it interferes particularly when the drops contain more than one of the
with the mechanism for prompt disposition of the chemical drugs (356).
mediator. In this respect, its action is analogous to that of Ibopamine is an ester of N-methyl-dopamine that is nonse-
the anticholinesterases at the cholinergic junction. The dura- lectively active on DA1 and DA2 dopaminergic receptors
as well as ␤-adrenergic and ␣-adrenergic receptors. Its myd- miosis, but the drug does not penetrate the cornea easily and
riatic action results from ␣-receptor stimulation. Both 1% therefore usually is mixed with a wetting agent (1⬊3,500
and 2% concentrations of ibopamine produce a maximal my- benzalkonium chloride).
driasis to slightly more than 9.0 mm in 50–60 minutes. The Acetylcholine is liberated at the cholinergic nerve endings
mydriatic effect of both agents begins to wear off in less by the neural action potential and is promptly hydrolyzed
than 2 hours, and baseline pupil size is reached by 8 hours. and inactivated by cholinesterase. Cholinesterase, in turn,
The mydriasis can be rapidly reversed with 0.5% dapipra- can be inactivated by any one of many anticholinesterase
zole. Ibopamine has no effect on accommodation; that is, it drugs, which either block the action of cholinesterase or
produces mydriasis without cycloplegia (357). These charac- deplete the stores of the enzyme in the tissue. These drugs
teristics and a good safety profile make ibopamine an alter- do not act on the effector cell directly; they just potentiate
native choice for in-office mydriasis for diagnostic fun- the action of the chemical mediator by preventing its destruc-
duscopy. Unlike other selective dopaminergic drugs that tion by cholinesterase. It follows from their mode of action
reduce intraocular pressure, ibopamine increases aqueous that these drugs lose their cholinergic activity once the inner-
humour production and can increase intraocular pressure in vation is completely destroyed.
patients with outflow impairment. It is being investigated as Physostigmine (eserine) is an anticholinesterase agent that
a ‘‘provocation test’’ for glaucoma. causes marked pupillary constriction (360). Along the Cala-
bar coast of West Africa, the native tribes once conducted
Muscle Relaxants ‘‘trials by ordeal’’ using a poison prepared from the bean
of the plant Physostigma venenosum. The local name for this
Papaverine hydrochloride belongs to the benzylisoquino- big bean was the esere nut. The synthetic organic phosphate
line group of alkaloids. The most characteristic effect of esters (echothiophate [phospholine], isoflurophate [diisopro-
this drug is the relaxation of the tonus of smooth muscle, pyl fluorophosphate, DFP], tetraethyl pyrophosphate, hexa-
especially muscle that is spasmodically contracted. The ac- ethyltetraphosphate, parathion), many of which are in wide-
tion on the smooth musculature of cerebral arteries, espe- spread use as insecticides (see above), cause a much longer-
cially when the vessels are in spasm, provides the basis for lasting miosis than the other anticholinesterases, but even
the clinical use of papaverine in patients with cerebral arte- this potent effect, thought to be caused by interference with
rial vasospasm. The relaxation effect of systemically admin- cholinesterase synthesis, can be reversed by pralidoxime
istered papaverine extends to the bronchial, gastrointestinal, chloride (2-PAM).
biliary, and urinary musculature. Hendrix et al. reported tran-
sient unilateral mydriasis in five patients treated with intra- Sympatholytic (Antiadrenergic) Drugs (Fig. 16.28)
arterial papaverine administered through a catheter posi-
tioned in the ipsilateral internal carotid artery a few millime- Thymoxamine hydrochloride (0.5%) and dapiprazole hy-
ters proximal to the origin of the ophthalmic artery (358). drochloride 0.5% (RevEyes) are ␣-adrenergic blocking
It was postulated that the drug produced relaxation of both agents that can reverse phenylephrine mydriasis by binding
the sphincter and dilator muscles, producing a relative my- the ␣-receptor sites on the iris dilator muscle. Other drugs
driasis, or had a selective effect on the sphincter muscle that block ␣ receptors are less precise in their modes of
alone (359). action and are rarely used in clinical ophthalmology. These
include Dibenzyline (phenoxybenzamine), phentolamine
Drugs that Constrict the Pupils (Regitine), and tolazoline (Priscoline).
Brimonidine tartrate is an ␣2-adrenergic agonist used in
Parasympathomimetic (Cholinergic) Drugs (Fig. 16.27) the treatment of glaucoma. It can produce pupillary miosis
that is observed best in scotopic conditions (362). The pre-
Pilocarpine and methacholine (Mecholyl) are structurally
sumed mechanism of action is increased presynaptic inhibi-
similar to acetylcholine and are capable of depolarizing the
tion of the terminal sympathetic neuron at the neuromuscular
effector cell, thus causing miosis and spasm of accommoda-
junction of the iris dilator.
tion (360). Pilocarpine solutions of 0.5–2% usually are re-
Guanethidine (Ismelin) and reserpine interfere with the
quired to produce miosis of a normal pupil. Methacholine
normal release of norepinephrine from the nerve ending and
can be used in a weak (2.5%) solution to test for cholinergic
deplete the norepinephrine stores. When applied to the eye,
supersensitivity of the sphincter muscle in patients with pre-
they produce a Horner syndrome, complete with ptosis, mio-
sumed tonic pupils, but most physicians prefer to use a weak
sis, and supersensitivity to adrenergic drugs.
solution of pilocarpine (0.1%) (see above).
Arecoline is a naturally occurring substance with an action Other Drugs that Affect the Pupil
similar to that of pilocarpine and methacholine. Its chief
clinical advantage is that it acts quickly (361). A 1% solution Substance P affects the sphincter fibers directly. It will
produces a full miosis in 10–15 minutes (compared with constrict the pupil of a completely atropinized eye. When
20–30 minutes for 1% pilocarpine). given parenterally, the opiate alkaloid morphine interrupts
Carbachol (carbamylcholine, Doryl) acts chiefly at the cortical inhibition of the iris sphincter nucleus in the mid-
postganglionic cholinergic nerve ending to release the stores brain, causing significant miosis. Conversely, topical mor-
of acetylcholine. There also is some direct action of carba- phine, even when given in a strong solution (e.g., 5%), has
chol on the effector cell. A 1.5% solution causes intense only a minimal miotic effect on the pupil.
Nalorphine and levallorphan are antinarcotic drugs. Given trative mesencephalic lesions, and damage to the parasympa-
parenterally, they reverse the miotic action of morphine. Nal- thetic innervation of the iris sphincter.
oxone hydrochloride, a similar drug, dilates the pupils of
opiate addicts but not the pupils of healthy, unmedicated Argyll Robertson Pupils
subjects.
Clinical Characteristics
Intravenous heroin seems to produce miosis in proportion
to its euphoric effect (363). Habituated heroin users require In 1869, Douglas Argyll Robertson published two papers
larger doses than nonhabituated users to produce the same entitled ‘‘On an Interesting Series of Eye Symptoms in a
amount of pupillary constriction. Thus, if one knows the Case of Spinal Disease with Remarks on the Action of Bella-
concentration of heroin in the plasma and the size of the pupil donna on the Iris, etc.’’ and ‘‘Four Cases of Spinal Miosis:
in darkness, it should be possible to determine a measure of With Remarks on the Action of Light on the Pupil.’’ Accord-
the degree of physical dependence in a given individual. ing to his description, the characteristic features of the syn-
During the induction of anesthesia, the patient may be in drome shown by his patients, all of whom had ‘‘spinal dis-
an excited state, and the pupils often are dilated. As the ease’’ (tabes dorsalis), were (a) the retina was sensitive to
anesthesia deepens, supranuclear inhibition of the sphincter light; (b) the pupil did not respond on exposure to light; (c)
nuclei is interrupted, and the pupils become small. If the there was normal pupillary constriction during accommoda-
anesthesia becomes dangerously deep and begins to shut tion and convergence for near objects; (d) the pupils con-
down the midbrain, the pupils become dilated and fail to stricted further with extracts of the Calabar bean (physostig-
react to light. mine), but they dilated poorly with atropine; and (e) the
The concentration of calcium and magnesium ions in the pupils were very small (364,365) (Fig. 16.29). These find-
blood may affect the pupil. Calcium facilitates the release ings are considered in further detail here. The basis for all
of acetylcholine, and when calcium levels are abnormally
low, the amount of acetylcholine liberated by each nerve
impulse drops below the level needed to produce a post-
synaptic potential, thus blocking synaptic transmission.
Magnesium has an opposite effect: a high concentration of
magnesium can block transmission, and this may weaken
the sphincter, resulting in large pupils that react poorly to
light (11).
Iris Pigment and Pupillary Responses to Drugs

In general, the more pigment in the iris, the more slowly
the drug takes effect and the longer its action lingers. This
probably is because the drug is bound to iris melanin and
then slowly released. There are wide individual differences
in pupillary responses to topical drugs. There probably is a
greater range of responses among eyes with blue or light-
green irides than between the average response of eyes with
light-colored irides and the average response of eyes with
irides that are dark brown. Some of these individual differ-
ences are related to corneal penetration of the drug.
LIGHT–NEAR DISSOCIATION
Normal pupils constrict not only from light stimulation
but also during near viewing as part of the near response
of convergence, accommodation, and miosis. Whenever the
pupil light response appears sluggish, inextensive, or weak,
the near response should be checked. Constriction of the
pupils during near viewing that is stronger than the light
response (light–near dissociation) is an important clinical
observation.
Light–near dissociation may be caused by a defect in the
afferent or the efferent system subserving pupillary function.
It is the primary feature of the Argyll Robertson pupils that
occur from efferent dysfunction, mainly in patients with Figure 16.29. Argyll Robertson pupils in a tabetic merchant seaman. Even
neurosyphilis. Light–near dissociation also can be seen in in the semidarkness that preceded the photographer’s flash, the pupils are
patients with pregeniculate blindness, compressive and infil- so small as to be hidden behind the corneal reflection.
the information in this section is the exhaustive review of theory that this reflex is the result of inadvertent conver-
the literature and personal research presented in Irene gence-accommodation impulses.
Loewenfeld’s classic paper on the subject and her superb
textbook (119,366). PUPILS DILATE POORLY TO ATROPINE
RETINA IS SENSITIVE TO LIGHT

In his original papers, Argyll Robertson actually stated
that strong atropine ‘‘induced only a medium dilation.’’
This statement does not mean that patients with visual Over the years, this statement often translated to become
dysfunction do not have Argyll Robertson pupils. The impli- failure to dilate to atropine. This finding is not supported by
cation here is that the degree of retinal or optic nerve disease, careful testing of Argyll Robertson pupils to various mydri-
if present, does not explain the poor light reflex. atic agents. In general, Argyll Robertson pupils dilate well
to atropine, as long as there is no associated iris atrophy.
PUPILS DO NOT RESPOND TO LIGHT Such pupils also constrict well to miotics. Occasional reports
of sensitivity of Argyll Robertson pupils to 2.5% Mecholyl
In the fully developed Argyll Robertson pupil, there is may be explained by the assumption of additional peripheral
complete absence of pupillary constriction to light stimula- damage to the ciliary nerve endings within the eye or iris.
tion. However, pupillographic recordings have shown that
weak, inextensive reactions remain in most Argyll Robertson PUPILS ARE VERY SMALL
pupils. Furthermore, the damaging lesion usually does not
develop acutely; there is usually a period of progression, Whether miosis is an essential part of the syndrome has
sometimes gradually, sometimes asymmetrically, and some- been argued back and forth for many years. The controversy
times at an uneven rate. During this period, the pupillary was settled by qualifying the definition of miosis in this
light reactions progress from sluggish, incomplete constric- syndrome: it is a pupil size that, in darkness, is smaller than
tions to complete loss of the light reflex. those of normal persons in the same age group (Fig. 16.29).
An exceptional patient can have improvement and even Using this definition, the presence of this miosis is consid-
recovery of the light reaction. Lanigan-O’Keeffe described ered an essential feature of the Argyll Robertson syndrome,
a 46-year-old man with neurosyphilis who had anisocoria. as there must be a unique and separate mechanism that keeps
The larger pupil was unreactive to light but reacted to near the pupil so small in the presence of impaired light reflexes.
stimuli (367). The smaller pupil apparently reacted normally Such a mechanism obviously is not present in other
to both light and near stimuli. Two months after a course of light–near dissociation syndromes, such as the dorsal mid-
parenteral penicillin, the patient’s pupils were noted to be brain syndrome, in which the pupils typically are moderate
equal and normally reactive to both light and near stimuli. to large. Because most patients with Argyll Robertson pupils
have normal reflex dilation in darkness and to psychosensory
PUPILS CONSTRICT NORMALLY TO ACCOMODATION- stimulation, the miosis is not related to impaired sympathetic
CONVERGENCE (NEAR RESPONSE) innervation of the iris dilator muscle.
Accommodation is typically normal and the extent of OTHER FEATURES
pupil constriction in response to accommodative (near) ef-
fort often is surprisingly good, particularly when considering One important feature not emphasized by Argyll Robert-
that the baseline size of the pupils is already small. However, son is irregularity of the pupil shape. This finding is quite
the near response is never ‘‘better’’ than normal and never common. Other descriptions for the pupil shape include hori-
tonic in movement. The brisk near constriction and the brisk zontally or vertically directed oval, egg-shaped, teardrop-
redilation after near effort are the distinguishing features shaped, irregularly polygonal, serrated, or eccentric. The ir-
between small, chronic tonic pupils and Argyll Robertson regularity of the shape of Argyll Robertson pupil most likely
pupils. is due to severe syphilitic iritis or uveitis with subsequent
In fact, most Argyll Robertson pupils actually have a structural iris damage. Although frequently observed with
mildly impaired near reaction when objectively tested, but the other aforementioned pupil findings, this feature has a
it is far less impaired than the light reflex. Thus, it is not peripheral etiology (i.e., it is due to a structural abnormality
a normal near response that counts but rather a light–near of the iris, not to its innervation). Thus, it is not considered
dissociation that is essential to the syndrome of an ‘‘Argyll an essential feature of the classic Argyll Robertson syndrome
Robertson pupil.’’ According to Loewenfeld, a significant in which the site of pathology is centrally located (see
number of Argyll Robertson pupils eventually lose the near below). Nevertheless, the presence of iris damage renders
constriction as well and become miotic, immobile pupils. In the pupil rather immobile and may obscure the usual findings
other patients who also develop syphilitic oculomotor nerve of light–near dissociation, dilation in darkness, and respon-
damage, the pupil becomes mydriatic and unreactive to light siveness to pharmacologic agents.
and near stimulation, and accommodation is lost. Argyll Robertson pupils usually are bilateral (80–90%),
Patients with Argyll Robertson pupils have a normal ‘‘or- but there can be asymmetry in both pupillary size and the
bicularis oculi-pupillary reflex.’’ Their pupils constrict nor- degree of light–near dissociation. Rarely, the condition is
mally on forced closure of the eyelids (the Westphal-Piltz strictly unilateral. Most Argyll Robertson pupils remain un-
phenomenon or the Galassi-Gifford reaction), supporting the changed for years, indicating no ongoing lesion activity.
Others become even more miotic and immobile or dilated alcoholism, multiple sclerosis, and age-related dementia,
and nonreactive to both light and near stimulation. were discounted because they predated the development of
serologic tests for syphilis. Only a few years later, however,
Site of Lesion and Mechanism the severe epidemics of lethargic encephalitis struck (espe-
cially the epidemic of 1918–1921), and observations of au-
The rostral midbrain is the probable location for the lesion
thentic cases of Argyll Robertson pupils in these patients
responsible for Argyll Robertson pupils. It is speculated that
began to increase. In addition, the effectiveness of penicillin
a lesion along the dorsal aspect of the Edinger-Westphal
treatment for syphilis has decreased the incidence of tertiary
nucleus damages the pretectal fibers of the pupil light reflex
syphilis, and the percentage of nonsyphilitic patients re-
yet spares the near vision fibers that have a more ventral
ported with Argyll Robertson pupils has grown precipi-
location. This would easily explain the light–near dissocia-
tously. The syndrome is observed in patients with diabetes
tion.
mellitus, chronic alcoholism, encephalitis, multiple scle-
In the rat brain, there is a richly developed group of supra-
rosis, age-related and degenerative diseases of the CNS,
nuclear adrenergic fibers that contact cells of the Edinger-
some rare midbrain tumors, and, rarely, systemic inflamma-
Westphal nuclei but not other cells within the oculomotor
tory diseases, including sarcoidosis and neuroborreliosis
complex (368,369). Damage to this central ‘‘sympathetic’’
(119,366,372–374). Nonetheless, a patient with Argyll Rob-
inhibitory pathway could be responsible for the miosis of
ertson pupils should be assumed to have neurosyphilis until
the Argyll Robertson pupil. Although this pathway has not
proven otherwise. Such a patient should undergo appropriate
been confirmed in humans, the miosis produced by reserpine
testing of both serum and CSF in an attempt to diagnose this
and ␣-methyldopa, drugs that deplete central (as well as
treatable disease.
peripheral) nervous system norepinephrine, suggests that
such an inhibitory supranuclear pathway exists. In addition,
experimental deafferentation of the oculomotor nuclear com- Inverse Argyll Robertson Pupils
plex in a cat demonstrated that the visceral nuclei alone can
This rather awkward term is used to describe pupils that
generate a marked and persistent miosis (370). Lowenstein
react to light but do not constrict during convergence-accom-
suggested that the phenomenon of denervation supersensi-
modation efforts. This diagnosis must be viewed with ex-
tivity known to apply to central nervous structures, as well
treme caution, because it often is impossible to be certain
as to denervated peripheral organs, might further increase
that a patient has made an adequate near-vision effort. In
spontaneous firing of the visceral oculomotor neurons that
unilateral cases, pupillary constriction in the opposite eye
are deprived of their major afferent supply when the light
during efforts to view near objects demonstrates that ‘‘near’’
reflex pathway is interrupted (371). It therefore is reasonable
impulses are being generated. Authentic cases of inverse
to postulate that a lesion in the rostral midbrain could inter-
Argyll Robertson pupils are rare, but they apparently do exist
rupt the descending supranuclear inhibitory fibers to the
and may be caused by neurosyphilis or other diseases that
Edinger-Westphal nucleus. Devoid of its central inhibition,
selectively damage the more ventral portion of the mesence-
this nucleus would continuously release parasympathetic im-
phalic pretectal region (375).
pulses to the iris sphincter, resulting in a tight miosis.
Anatomic evidence also supports the assumption that a
rostral mesencephalic lesion is responsible for Argyll Rob- Mesencephalic Lesions
ertson pupils. Although circumscript focal lesions have not
Damage to the dorsal mesencephalon typically produce
been identified, diffuse damage around the sylvian aqueduct
midposition (3–6 mm) or slightly dilated pupils that fail to
and the posterior portion of the third ventricle is a prominent
constrict to light, or do so very poorly, and yet react well
finding in patients with Argyll Robertson pupils who have
to near stimuli (Fig. 16.30). Dilated pupils from loss of the
died from tabes or general paresis. The ependymitis and
light reaction may be the first sign of a tumor that compresses
subependymal gliosis seen in the area of the light reflex
or infiltrates the dorsal midbrain or a sign of obstructive
pathways are widespread in neurosyphilis. Such damage
hydrocephalus, particularly from aqueductal stenosis or a
may be sufficient to produce Argyll Robertson pupils.
blocked shunt. Freeman et al. reported a 15-year-old girl
Thus, to summarize, the classic Argyll Robertson pupil
with headaches, nausea, and vomiting who was found to
results from neuronal damage in the region around the syl-
have bilaterally dilated pupils with normal ocular motility
vian aqueduct in the rostral midbrain. In this location, the
(376). The right pupil was 7 mm in diameter and had ‘‘slug-
damage interferes with the light reflex fibers and the supra-
gish’’ reactions to light and near stimuli; the left pupil mea-
nuclear inhibitory fibers as they approach the visceral oculo-
sured 10 mm in diameter and showed only ‘‘slight’’ constric-
motor nuclei.
tion to light and near stimuli. Subsequent evaluation revealed
Etiology a large craniopharyngioma that was thought to involve the
dorsal mesencephalon. Following subtotal resection of the
Around 1900, when the syphilitic nature of tabes dorsalis lesion, the pupils reacted normally to near stimuli but re-
and general paresis was firmly established, the Argyll Rob- mained large and poorly reactive to light. In most dorsal
ertson syndrome was considered pathognomonic for syphi- midbrain lesions, the disturbances of pupillary function are
lis. The earlier reports of Argyll Robertson pupils in patients bilateral and accompanied by other deficits such as supranu-
suffering from a variety of other diseases, especially severe clear vertical gaze palsy, eyelid retraction, accommodation
Figure 16.30. Pupillary light–near dissociation in a patient with a germinoma producing a dorsal midbrain syndrome. In a
dimly lighted room, both pupils were large and slightly anisocoric. A, When a bright light is shined in either eye, both pupils
constrict sluggishly and incompletely. B, When the patient is asked to look at an accommodative target, both pupils constrict
briskly and extensively. The patient also had difficulty with upward gaze.
paresis or spasm, and convergence-retraction nystagmus on of the oculomotor nerve constrict briskly to near stimulation
attempted upward gaze. and redilate briskly when near effort ceases.
Lesions of the Afferent Pathway DISTURBANCES DURING SEIZURES

Lesions of the visual sensory pathway from the retina to In 1881, Gowers noted that during the course of a general-
the point at which the pupillomotor fibers exit impair the ized tonic-clonic seizure (grand mal seizure), there was brief
light reaction but spare the near response. If a patient is bilateral pupillary miosis in the tonic phase of the seizure
blind from optic nerve disease, for example, there will be followed by bilateral pupillary dilation in the clonic phase.
no reaction of the pupils to direct light stimulation in the Other authors reported loss of the pupil light reflex as well
blind eye, but the near reaction may be well preserved. during grand mal seizures. These pupil findings also occur
Blindness from retinal, optic nerve, or optic chiasmal disease regularly during generalized seizures without motor activity
is the most common setting in which pupillary light–near (i.e., petit mal or absence seizures). Jammes examined and
dissociation occurs in standard clinical ophthalmologic, neu- photographed the pupillary size and reactivity in six patients
rologic, and neurosurgical practice. during attacks of petit mal seizures (380). He found that
bilateral pupillary dilation with loss of reactivity to light
Aberrant Regeneration After Damage to the
occurred consistently in all six patients during their absence
Innervation of the Iris Sphincter
attacks. Afterwards, when consciousness was regained, there
Light–near dissociation following injury to the short cili- was often mild pupillary miosis and facial flushing. The
ary nerves is due to restoration of the pupillary near response mechanism of the pupillary dilation that occurs during gener-
by aberrant regeneration. When nerve fibers originally des- alized seizure activity appears to be a combination of inter-
tined for the ciliary muscle mistakenly reinnervate the iris ruption of parasympathetic impulses and irritation of the
sphincter muscle instead, then every time a near effort is sympathetic system (119). The postictal miosis probably rep-
made to focus the lens, a strong pupil constriction ensues. resents decreased supranuclear inhibition to the parasympa-
This pathophysiologic process is discussed in the section on thetic midbrain nuclei.
the Adie tonic pupil syndrome (see above). ‘‘Diencephalic seizures’’ is a term coined to describe clin-
A similar phenomenon occurs in the setting of aberrant ical episodes of diffuse sympathetic hyperactivity. Patients
regeneration after structural damage to the preganglionic oc- experience paroxysms of rise in body temperature, blood
ulomotor nerve. Nerve fibers originally headed for extraocu- pressure, heart rate, respiratory rate, and pupil size as well
lar muscles or the ciliary muscle may be diverted into the as hyperhidrosis. An underlying central lesion such as tumor,
iris sphincter, which is such a small muscle that only a few of trauma, subarachnoid hemorrhage, and acute hydrocephalus
these fibers are sufficient to make the iris sphincter contract often is found, but during the acute burst of sympathetic
(377–379). The pupil constricts whenever the patient at- discharges, no corresponding electroencephalographic
tempts an eye movement or near effort. The constriction is changes have ever been recorded. The episodes are unre-
usually segmental, a feature regularly seen with tonic pupils; sponsive to standard antiepileptic medications, although
however, the two cardinal features of a tonic pupil—a slow, clonidine and morphine appear to control symptoms. A
sustained contraction to near effort and a slow redilation newer term proposed for these episodes is ‘‘paroxysmal
after constriction—are absent. In general, pupils that show sympathetic storms’’ as they do not appear to represent a
light–near dissociation in the setting of aberrant regeneration true seizure disorder (381,382).
Rarely, patients experience unilateral pupillary mydriasis dysfunction from a variety of inflammatory, infectious, de-
during seizures, a phenomenon termed ictal mydriasis generative, and metabolic processes. The prevalence of pu-
(383–385). In all these cases, the seizures are focal. In cases pillary abnormalities in comatose patients is high and may,
with a lesion or epileptogenic focus in the frontal lobe or in some instances, help in the initial understanding and local-
amygdala, the mydriasis occurs in the contralateral eye ization of the process. Accordingly, one should carefully
(386–388). If there is contraversive head and conjugate eye examine the pupil size, shape, and reactivity in any patient
deviation during the seizure, the pupillary dilation occurs in who appears to be in a comatose state.
the abducting eye, whereas if the seizures are caused by a
lesion in the temporo-occipital region, the mydriasis occurs Site of Lesion in Coma and Pupil Abnormality
in the adducting eye. Thus, patients who experience contra-
versive conjugate eye deviation from frontal or amygdaloid Cerebral lesions may produce primary abnormalities of
lesions develop mydriasis of the eye on the side opposite the pupil size and reactivity (386,389). Damage to the hypothal-
lesion, whereas patients whose contraversive eye deviation is amus, especially in the posterior and ventrolateral regions,
caused by a temporo-occipital lesion develop mydriasis in may produce an ipsilateral Horner syndrome characterized
the eye on the side of the lesion (385). These clinical exam- by miosis, ptosis, and anhidrosis (142). The anhidrosis af-
ples of ictal mydriasis are consistent with animal studies in fects the ipsilateral half of the body. The recognition of hypo-
which unilateral mydriasis or anisocoria has been induced by thalamic dysfunction in patients with coma may be ex-
electrical stimulation of focal areas of cortex (frontal gyrus, tremely important with respect to ultimate prognosis,
temporal gyrus, occipital lobe) or by chemical lesioning of because downward displacement of the hypothalamus with
areas in the temporal lobe (389,390) unilateral Horner syndrome is often the first clear sign of
Berreen et al. described a 33-year-old woman who devel- incipient transtentorial herniation. Crill reported five cases
oped episodic dilation of her left pupil that lasted about 1 of supratentorial hemorrhage associated with ipsilateral Hor-
minute (391). MR imaging revealed a left frontal lobe mass ner syndrome (396). Of four patients who died and under-
with minimal compression of the frontal horn of the left went autopsy, two had hemorrhages in the thalamus and
lateral ventricle. A left frontal craniotomy was performed, hypothalamus and one had a subdural hematoma with trans-
at which time a low-grade astrocytoma was found and com- tentorial herniation. The fourth patient had hemorrhage into
pletely removed. Postoperatively, the patient had no further a cortical metastatic tumor with no direct hypothalamic de-
episodes of left pupillary dilation. This patient did not struction. That unilateral diencephalic lesions can produce
undergo an electroencephalogram (EEG) to correlate electri- a Horner syndrome is supported by the observation of 15
cal seizure activity with her pupil episodes; however, it is patients in whom stereotactic thalamic surgery produced
possible that these episodes were caused by irritative effects ipsilateral sympathetic defects, including ptosis, miosis, and
of the tumor on sympathetic pathways in the frontal lobe. hemianhidrosis (397).
Ictal miosis appears to be even more rare than ictal mydri- Damage to the diencephalon, particularly during rostral-
asis. Lance and Smee described episodes of left pupillary caudal brain stem deterioration caused by supratentorial le-
constriction, visual hallucinations, and left homonymous sions (see below), produces symmetrically small but briskly
hemianopia in a patient with a cavernous angioma of the reactive pupils. The pupils dilate to psychosensory stimuli.
right occipital lobe (392). Afifi et al. described seizure-in- Lesions of the dorsal tectal or pretectal regions of the
duced unilateral ptosis and miosis in two patients with con- mesencephalon interrupt the pupil light reflex but may spare
tralateral temporal lobe lesions (393). Rosenberg and Jabbari the response to near stimuli (light–near dissociation). The
described a 21-year-old man with postencephalitic complex pupils are either in midposition or slightly dilated and are
partial and tonic-clonic seizures since childhood who began round. They do not react to light, but their size may fluctuate
to complain of episodes of blurred vision (394). During these spontaneously. As with diencephalic pupils, these pupils
episodes, which were usually less than a minute, his pupils may dilate to psychosensory stimuli. Recognition of tectal
constricted to 3 mm and became nonreactive to light stimula- or pretectal effects on the pupil may be important because
tion. Simultaneously, an EEG showed runs of rhythmic 3- to small lesions in this region often affect the periaqueductal
5-Hz sharp and slow activity over the left temporo-occipital gray matter and interrupt consciousness.
region. The internal ophthalmoplegia was the only clinical Mesencephalic lesions in the region of the oculomotor
manifestation of these seizures, which subsequently were nerve nucleus nearly always damage both sympathetic and
controlled with carbamazepine. parasympathetic pathways to the eye. The resulting pupils
usually are slightly irregular and unequal. They are midposi-
DISTURBANCES DURING COMA tion (3–6 mm in diameter) and nonreactive to light stimuli.
Midposition fixed pupils most commonly are caused by mes-
According to Plum and Posner, consciousness is the state encephalic damage from transtentorial herniation, but they
of awareness of the self and environment, whereas coma also occur when neoplasms, hemorrhages, infarcts, or granu-
is a state of unarousable psychological unresponsiveness in lomas damage the midbrain. Lesions that affect the pupillary
which the patient lies with eyes closed (395). Patients in fibers in the fascicle of the oculomotor nerve can produce
coma show no psychologically understandable response to a complete or incomplete oculomotor nerve palsy with a
external stimuli or inner needs. Causes of coma include su- dilated, nonreactive pupil. Such parenchymal lesions fre-
pratentorial lesions, infratentorial lesions, and diffuse brain quently are bilateral. Selhorst et al. described midbrain cor-
ectopia, an upward, inward movement of the pupils in a reaction to light stimulation unless there is concomitant
comatose patient with mesencephalic disease (23). Such pu- compression of one or both oculomotor nerves. Some pa-
pillary abnormalities presumably are caused by incomplete tients show conjugate or slightly divergent roving eye move-
damage to the parasympathetic pupillary fibers in the mesen- ments and have an inconsistent response to oculocephalic
cephalon. Midbrain corectopia is not limited to patients in testing (doll’s head maneuver). More frequently, the eyes
coma, however (24). are conjugate and stable at rest, responding briskly to oculo-
Lesions of the tegmental portion of the pons may interrupt cephalic testing. In such patients, caloric testing using cold
descending sympathetic pathways and produce bilaterally water evokes a full, conjugate, slow tonic movement toward
small pupils. In many cases, especially those with pontine the irrigated side with impairment or absence of the fast
hemorrhage, the pupils are pinpoint, presumably from a component of the response. Early diencephalic dysfunction
combination of sympathetic interruption and parasympa- in such patients is suggested by the development of bilateral
thetic disinhibition. Despite the size of such pupils, a pupil signs of corticospinal or extrapyramidal dysfunction. A few
light reflex usually is present and can be observed with the patients develop diabetes insipidus, reflecting severe down-
aid of magnification within several hours after the onset of ward traction on the pituitary stalk and the median eminence
the primary intracranial event (398). of the hypothalamus.
The pupillary fibers within the peripheral oculomotor The clinical importance of the diencephalic stage of the
nerve are particularly susceptible when uncal herniation central stage of rostral-caudal deterioration caused by a su-
compresses the nerve against the posterior cerebral artery or pratentorial mass lesion is that it warns that a potentially
the edge of the cerebellar tentorium (399). In these instances, reversible lesion is about to become irreversible by progres-
pupil dilation may precede other signs of ocular motor nerve sively encroaching on the brain at or below the level of the
paralysis, and such patients may present with fixed, dilated tentorium. Once signs of mesencephalic dysfunction appear,
or fixed, oval pupils (25,400). however, it becomes increasingly likely that the patient has
The nature of pupillary dysfunction in a comatose patient suffered a brain stem infarction, rather than reversible
often reflects the level and degree of brain stem dysfunction. compression and hypoxia, and the outlook for neurologic
This is particularly true when brain stem dysfunction is pro- recovery is poor.
duced by an expanding supratentorial lesion. Such lesions As mesencephalic and upper pontine damage ensues, ab-
accounted for 20% of patients initially diagnosed as ‘‘coma’’ normally wide fluctuations of body temperature are com-
in the series reported by Plum and Posner (395). Supratentor- mon. Respirations gradually change from the Cheyne-Stokes
ial lesions produce neurologic dysfunction by two mecha- type to a sustained tachypnea. The initially small pupils di-
nisms: primary cerebral damage and secondary brain stem late and become fixed in midposition. It is unclear whether
dysfunction from displacement, tissue compression, swell- this dilation is caused by interruption of the afferent light
ing, and vascular stasis. Of the two processes, secondary reflex pathway, damage to the dorsal visceral nuclei of the
brain stem dysfunction is the more threatening to life. It oculomotor nerve complex, or both. In this stage, the pupils
usually presents as one of two main patterns. Most patients no longer dilate to psychosensory stimuli. Oculocephalic
develop signs of bilateral diencephalic impairment: the testing often fails to elicit appropriate eye movements, and
central syndrome or rostral-caudal deterioration. In this even caloric testing may fail to produce normal tonic move-
syndrome, pupillary, ocular motor, and respiratory signs de- ments toward the irrigated side. Motor dysfunction pro-
velop that indicate that diencephalic, mesencephalic, pon- gresses from decorticate to bilateral extensor rigidity in re-
tine, and, finally, medullary function are being lost in an sponse to noxious stimuli. Of the adult patients examined
orderly rostral to caudal fashion. Other patients develop by Plum and Posner (1980), none with a supratentorial lesion
signs of uncal herniation with oculomotor nerve and lateral recovered full neurologic function once mesencephalic signs
mesencephalic compression (uncal herniation syndrome). were fully developed. The prognosis for recovery is often
The following discussion is obtained from the excellent better in children.
monograph ‘‘The Diagnosis of Stupor and Coma’’ by Plum After the mesencephalic/upper pons stage, ischemia con-
and Posner (395). tinues to progress caudally down the brain stem. Hyperventi-
lation resolves, giving rise to a fairly regular breathing pat-
Central Syndrome of Rostral-Caudal Deterioration tern with a shallow depth and rapid rate (20–40 per minute).
The pupils remain in midposition and do not respond to light
The first evidence that a supratentorial mass is beginning stimulation. Oculocephalic testing elicits no ocular move-
to impair the diencephalon usually is a change in alertness ments, and the extremities become increasingly flaccid.
or behavior. Initially, patients with such lesions find it diffi- The medullary stage is terminal. Respiration slows and
cult to concentrate and tend to lose the orderly details of often becomes irregular in rate and depth; it is interrupted
recent events. Some patients become agitated, whereas oth- by deep sighs or gasps. The pulse is variable, and the blood
ers become increasingly drowsy. Respiration in the early pressure drops. The eyes are immobile and no longer respond
diencephalic stage of the central syndrome is commonly in- to caloric or oculocephalic stimulation. The pupils may di-
terrupted by deep sighs, yawns, and occasional pauses. Many late widely during this stage (terminal mydriasis). In the
patients have periodic breathing of the Cheyne-Stokes type, absence of an intact sympathetic outflow pathway, the my-
particularly as they become increasingly somnolent. The pu- driasis may be caused by hypoxia of the neurons of the
pils are small (1–3 mm) but maintain a small and brisk Edinger-Westphal nucleus that had previously been deaffer-
ented. Alternatively, it may be caused by an agonal release Once the pupil is fully dilated, ophthalmoplegia related
of adrenergic substances into the blood in response to hy- to oculomotor nerve dysfunction soon follows. In this late
poxia, thus causing the pupil to dilate. Both mechanisms third nerve stage, the patient usually becomes deeply stupor-
may occur simultaneously. ous, then comatose. Oculocephalic testing initially shows
The size and reactivity of the pupils should never, by evidence of ocular motor impairment, with eventual disap-
themselves, be used as an indication of irreversible coma pearance of all responses. As the opposite cerebral peduncle
and brain death. In the first place, some comatose patients becomes compressed against the contralateral tentorial edge,
whose mid-dilated pupils are thought to be unreactive to hemiplegia develops ipsilateral to the expanding supratent-
light when examined with a hand-held penlight can be shown orial lesion (409). The signs of mesencephalic damage con-
to react when assessed with infrared pupillometry (401). In tinue to develop. The pupil opposite the one that originally
addition, even widely dilated, fixed pupils can be observed dilated may become fixed and widely dilated or assume a
in comatose patients who eventually recover neurologic midposition (410,411). Eventually, both pupils become di-
function. For example, Cleveland reported the complete neu- lated and nonreactive to light stimulation. Most patients at
rologic recovery of a 14-year-old boy who suffered a cardiac this stage show sustained hyperpnea, impaired or absent ocu-
arrest lasting 3 hours (402). During the entire resuscitation locephalic and caloric responses, and bilateral decerebrate
episode, the patient’s pupils were widely dilated and fixed. rigidity. From this stage, progression of the uncal syndrome
Gauger also emphasized that the observation of widely di- is clinically indistinguishable from that of the central syn-
lated, nonreactive pupils during the period of resuscitation drome.
after a cardiac or respiratory arrest does not, in itself, signify
irreversible brain injury (403). Conversely, some patients Coma from Metabolic Disease
with irreversible coma develop nonreactive small or pinpoint
pupils (404,405). The reason for the small size of the pupils In patients in deep coma, the state of the pupils may be-
in some of these patients is previous use of miotic agents to come the single most important criterion that clinically dis-
treat glaucoma. tinguishes between metabolic and structural disease. Pupil-
lary pathways are relatively resistant to metabolic insults.
Uncal Herniation Syndrome Thus, the presence of preserved pupil light reflexes despite
concomitant respiratory depression, caloric unresponsive-
Patients with the syndrome of uncal herniation have asym- ness, decerebrate rigidity, or motor flaccidity suggests meta-
metric pupillary changes in the early phases of coma. During bolic coma. Conversely, if asphyxia, drug ingestion, or pre-
the early third nerve stage, signs of oculomotor nerve dys- existing pupillary disease can be eliminated as a cause of
function may occur with almost any level of altered con- coma, the absence of pupillary light reflexes in a comatose
sciousness, from slight drowsiness to complete unconscious- patient strongly implicates a structural lesion rather than a
ness. The earliest consistent sign is unilateral dilation of one metabolic process.
pupil that initially is sluggishly reactive to light but soon In a study of 115 patients presenting to the emergency
becomes widely dilated (6–9 mm) and nonreactive to light department with coma (mean Glasgow Coma Scale score
stimulation. This pupillary disturbance may last for several of 4) from a variety of structural and metabolic etiologies
hours before neurologic signs other than an altered state of (cardiopulmonary arrest excluded), both loss of the pupil
consciousness appear (406). light reflex and anisocoria were found to be independent
Traditional teaching held that if a supratentorial mass le- predictors of underlying structural pathology (412). Loss of
sion such as acute hemorrhage causes altered consciousness the light reflex had greater sensitivity (83%) for predicting
and an acutely dilated pupil, the dilated pupil indicates the a structural lesion, whereas the presence of anisocoria was
side of the lesion. The iridoplegia occurs from uncal descent less sensitive (39%) but very specific (96%) for a structural
and compression of the superolateral aspect of the ipsilateral lesion. Structural causes of coma included intracerebral hem-
oculomotor nerve. Occasionally, however, the dilated pupil orrhage, subarachnoid hemorrhage, acute infarction, sub-
is contralateral to the lesion, a finding called a ‘‘false-localiz- dural and epidural hematoma, brain contusion, and tumor.
ing’’ pupil (407,408). This phenomenon occurs from shift In the same series, 16 of 69 patients (23%) with coma of
of the midline away from the lesion, with compression either metabolic origin demonstrated loss of the pupil light reflex;
of the contralateral oculomotor nerve or the contralateral half of these patients were comatose from drug overdose
side of the mesencephalon against the lateral tentorial edge. (412).
The localizing value of this pupil sign is far less important Normal pupil shape, size, and reactivity are highly indica-
in this era of modern neuroimaging, but it remains useful in tive of intact midbrain function. In one series of 162 patients
understanding the sequence of events during uncal hernia- with severe head injury, pupillary dysfunction was the fea-
tion. In any event, during this early phase, respiration may be ture that correlated best with brain stem ischemia from dam-
normal, extraocular movements and oculocephalic responses age to perforating vessels from the basilar artery (413).
may be unimpaired, and motor abnormalities may reflect
only a supratentorial process. Nevertheless, once other signs Cheyne-Stokes Respiration
of herniation or brain stem compression appear, deterioration
may proceed rapidly, with the patient becoming comatose Cheyne-Stokes respiration (CSR) is a pattern of periodic
within a few hours. breathing in which phases of hyperpnea regularly alternate
with apnea. The breathing waxes from breath to breath in a consciousness. During the apneic phase, the patient slips into
smooth crescendo and then, once a peak is reached, wanes a deeper coma; in the hyperpneic phase, the patient may
in an equally smooth decrescendo. CSR implies bilateral become agitated. In humans, the mydriasis of the hyperpneic
dysfunction of neurologic structures usually lying deep in phase is almost, but not entirely, blocked by topical sympa-
the cerebral hemispheres or diencephalon, but rarely as low tholytic drugs (e.g., 5% guanethidine) and does not occur
as the upper pons (414). when there is an associated or unrelated Horner syndrome.
During CSR, the size of the pupils fluctuates. The pupils This suggests that neural activity, mediated by the peripheral
dilate in the hyperpneic phase unless there is a concomitant sympathetic pathway to the eye, plays an important role in
sympathetic nerve paralysis, and they constrict during the the dilation. This suggests, in turn, that the mechanism of
apneic phase unless there is a concomitant oculomotor nerve the mydriasis of the agitated phase of CSR may be similar to
paralysis (415). The cyclic breathing and pupillary move- that of reflex pupillary dilation and related to the intermittent
ment also are associated with cyclic changes in the level of partial arousal of a semicomatose patient.
DISORDERS OF ACCOMMODATION
Abnormalities of accommodation usually are acquired Acquired Accommodation Paresis
and occur most frequently as part of the normal aging pro-
Isolated Accommodation Insufficiency
cess (presbyopia). However, disturbances of accommodation
also may occur in otherwise healthy persons, in persons with Accommodation insufficiency refers to an accommoda-
generalized systemic and neurologic disorders, and in per- tive ability that measures below the minimum for the age
sons with lesions that produce a focal interruption of the of the patient. Most clinicians use the near point of accom-
parasympathetic (and rarely the sympathetic) innervation of modation as their diagnostic criterion for accommodation
the ciliary body. Also, accommodative function can be vol- insufficiency (accommodative amplitude that is 2 diopters
untarily disrupted. or more below the age-appropriate minimum). Isolated ac-
commodation insufficiency occurring in otherwise healthy
eyes can be divided into two groups: (a) static insufficiency
ACCOMMODATION INSUFFICIENCY AND
and (b) dynamic insufficiency (419).
PARALYSIS Static accommodation insufficiency is an inadequate re-
Congenital and Hereditary Accommodation sponse of either the lens or the ciliary muscle, despite normal
Insufficiency and Paralysis ciliary body innervation and neural function. It usually oc-
curs gradually from changes occurring in either the lens or
Congenital defects are a rare cause of isolated accommo- the ciliary body. The most common cause of isolated static
dation insufficiency. The ciliary body is defective in a num- insufficiency is presbyopia. In some patients, however, there
ber of congenital ocular anomalies, but in most cases vision is sudden loss of accommodation that does not recover.
is so defective that an inability to accommodate is never Treatment consists of appropriate spectacle correction.
noted by either the patient or the physician. Aniridia and Dynamic accommodation insufficiency occurs in patients
choroidal coloboma cause obvious defects of the ciliary who have inadequate parasympathetic impulses required to
body. Ciliary aplasia can occur in well-formed eyes in which stimulate the ciliary musculature but have normal pupil size
and reactivity. Such patients usually are asthenopic persons
the iris is intact and reacts normally to light.
who become ill, often hospitalized, with some unrelated con-
Sédan and Roux described three brothers who could see
dition. Dynamic accommodation insufficiency also may
normally for distance without glasses but required Ⳮ4.00
occur in otherwise healthy young individuals, particularly
spherical lenses for reading (416). None of the children had in children with nonspecific viral illnesses (420,421). The
pupillary constriction during near viewing, although their transient loss of accommodation that can occur just before or
other ocular functions were normal. The children’s retino- after childbirth may be another example of this phenomenon
scopic findings were not reported, but neither atropine nor (422). Raskind listed various systemic disorders associated
physostigmine influenced the state of their accommodation. with an acquired accommodation insufficiency (423). In all
Aplasia of the ciliary body was the presumed congenital these cases, it is likely that the accommodation insufficiency
defect. In another family of 10 affected members, an accom- represents a nonspecific manifestation of the systemic dis-
modative defect was present in infancy and thereafter non- order.
progressive by history (417). Pharmacologic assessment The symptoms of dynamic accommodation insufficiency
with various topical agents suggested a difficulty with either are asthenopia, tiring of the eyes sometimes associated with
the ciliary musculature or the lens of the affected eyes. brow ache, irritation and burning of the eyes, blurred vision
Congenital absence of accommodation has been noted in particularly for near work, inability to concentrate, and pho-
combination with congenital mydriasis. In three such cases, tophobia. As a general rule, symptoms resolve and accom-
patent ductus arteriosus was an associated anomaly (43). modation recovers following treatment of the underlying ill-
Defective accommodation was noted in 21 of 78 (27%) dys- ness and restitution of the patient’s former state of health.
lexic children, suggesting an association between the two If accommodation insufficiency remains, the prescription of
disorders (418). convex (plus) lenses is indicated, regardless of the patient’s
age. In patients with an associated convergence insuffi- argon laser trabeculoplasty (244). Transient internal ophthal-
ciency, convergence exercises or base-out prisms added to moplegia also can result from local anesthesia injected into
the near correction may be of benefit. the lids or gums that inadvertently enters into the orbit (see
also the section above on Local Tonic Pupils).
Accommodation Insufficiency Associated with Primary
Ocular Disease Accommodation Insufficiency Associated with
Neuromuscular Disorders
Iridocyclitis may cause profound dysfunction of the cili-
ary body. In the acute stage, there may be ciliary spasm and Some diseases produce myopathic changes in the smooth
loss of accommodation. In the chronic stage, atrophy of the muscle fibers of the ciliary body, but isolated ocular involve-
ciliary body results in accommodation insufficiency. The ment of this type is rare.
more severe the uveitis, the more commonly mydriasis and Myasthenia gravis may cause defective accommodation
cycloplegia (internal ophthalmoplegia) are associated with (428,429). Manson and Stern studied patients with MG and
it. In addition, viruses such as herpes zoster may produce a patients with unexplained accommodation disturbances
uveitis associated with a ciliary ganglionitis, resulting in a (430). All patients were questioned about diplopia, ptosis,
tonic pupil syndrome. and the effects of sustained reading or close work upon their
Glaucoma in children or young adults causes accommoda- vision. Binocular and uniocular accommodation amplitudes
tion insufficiency from secondary atrophy of the ciliary were measured. Of nine patients with MG (six with general-
body. The drugs used in the management of glaucoma affect ized and three with ocular disease), eight had abnormal fa-
the ciliary body as well as the iris. In patients who still tigue of visual accommodation. The accommodation defect
are able to accommodate, miotic drugs frequently produce improved rapidly after an intravenous injection of edropho-
ciliary spasm with symptoms of blurred vision. nium hydrochloride (Tensilon).
Metastases to the suprachoroidal space may produce cy- Botulism nearly always causes an acute accommodation
cloplegia and pupillary dilation from damage to the ciliary paralysis. The toxins produced by C. botulinum interfere
neural plexus. Lymphoma and carcinoma of the breast, lung, with the release of acetylcholine at the neuromuscular junc-
or colon are the most common tumors that produce this con- tion and in the cholinergic autonomic nervous system. Al-
dition. though several different subtypes of toxin exist and routes
Internal ophthalmoplegia associated with contusion of the of human infection can vary (food-borne, wound, gastroin-
globe was discussed in the section above on the pupil. In testinal tract colonization in infants), clinical manifestations
most cases, when accommodation is paralyzed, the pupil is are similar. These include progressive descending skeletal
dilated and fixed. Recovery of accommodation is common, muscle weakness, ocular motor palsies, bulbar paralysis, and
but full recovery of pupillary function is less likely. On rare cardiovascular lability (431). Food-borne botulism produces
occasions, the pupil is spared or recovers fully but the ciliary prominent gastrointestinal symptoms as well.
muscle remains paralyzed. Patients who ‘‘accidentally’’ no- Almost 90% of patients with botulism of any type com-
tice the inability to accommodate in one eye should be ques- plain of blurred vision. Paralysis of accommodation and im-
tioned specifically for previous trauma to that eye (11). pairment of the pupillary light reflex are common and early
Immediately following a concussion injury to the globe, signs of botulism, often appearing suddenly about the 4th
the pupil is small and accommodation is spastic. Subse- or 5th day of the illness. Accommodation is usually more
quently, the pupil dilates and the ciliary muscle becomes severely affected than pupil function, for unclear reasons
paretic. Accommodation usually returns in 1–2 months. The (Fig. 16.31). In some cases, accommodative failure is the
traumatic etiology of the accommodation paresis may be initial and sole sign of nervous system involvement. In a
suspected by slit-lamp biomicroscopic observation of tears series of nine patients with food-borne botulism, all patients
in the iris sphincter, tears at the root of the iris, or recession examined acutely had marked or complete accommodative
of the angle of the anterior chamber with posterior displace- loss but full mydriasis was present in only one patient, and
ment of the ciliary attachment. There also may be associated another patient had sluggish pupillary reactions (328). Rec-
ocular hypotension or glaucoma. Following trauma to the ognition of the clinical syndrome of botulism is critical, as
globe, rupture of zonular fibers with partial subluxation of respiratory failure can result in mortality rates up to 20%
the lens also may produce loss of accommodation. (431).
Iatrogenic trauma to the eye, such as that which occurs Tetanus can produce accommodation paralysis. In most
during retinal reattachment surgery, cryotherapy, or panreti- cases, the accommodation paralysis occurs in the setting of
nal photocoagulation, may injure the ciliary nerves, produc- generalized ophthalmoparesis; however, one patient de-
ing accommodation paresis and mydriasis (424–426). Laser scribed had normal eye movements and normally reactive
applications at or anterior to the equator and long exposure pupils to light stimulation (432).
times are important factors in the development of accommo- Myotonic dystrophy frequently produces degenerative
dation paresis following photocoagulation (427). Optic changes in the lens, the region of the ora serrata, and the
nerve sheath fenestration performed from the lateral ap- anterior chamber angle. It also may be associated with ocular
proach can damage the short ciliary nerves that penetrate the hypotension. It is reasonable to assume that the ciliary mus-
temporal sclera, causing a postoperative tonic pupil (245). cle also is affected, because other smooth muscle dysfunc-
Sector palsy of the iris sphincter has been reported after tion occurs in such patients (433).
light. Histopathologic examination in fatal cases shows dif-

fuse perivenous white-matter lesions throughout the cerebral
hemispheres and brain stem.
An acute focal lesion of the hemispheres may cause acute
bilateral accommodation insufficiency. Specifically, this has
been reported with an acute ischemic stroke in the territory
of the left middle cerebral artery and an acute hematoma
in the left pariteo-occipital region (437,438). The issue is
whether the accommodation insufficiency is related to a di-
rect effect of these lesions on supranuclear pathways for
accommodation or is a nonspecific sequela of a significant
focal cerebral lesion. If the former, it remains to be deter-
mined whether a lesion in either hemisphere can cause ac-
commodation insufficiency or just a lesion in the left hemi-
sphere.
Acute problems with near vision resulting from an abnor-
mality of accommodation can be one of the earliest symp-
toms of pressure on the dorsal mesencephalon such as from
obstructive hydrocephalus or a pineal tumor. These com-
plaints may appear weeks before the pupil light reaction or
ocular motility becomes clinically abnormal. Particularly in
previously healthy children and young adults who suddenly
lose accommodation, a careful evaluation should be under-
taken to exclude lesions in the area of the rostral dorsal
midbrain, including the superior colliculus (439,440). Some
of these patients also demonstrate a sudden increase of my-
opia (pseudomyopia) related to accommodation spasm with
blurring of distant vision.
Figure 16.31. The effect of botulism on the elements of the near reflex. Wilson disease is an hereditary disorder of copper metabo-
The patient was a 33-year-old man with acute food-borne botulism. His lism characterized by progressive degeneration of the CNS
symptoms were 4 days of blurred vision, abdominal pain, nausea, and sweat- associated with hepatic cirrhosis. The neurologic syndrome
ing. Top, The patient’s pupils are large and unreactive to light. Middle, frequently includes rigidity, difficulty speaking and swal-
Simultaneous recordings of pupil size, accommodation, and convergence lowing, and a characteristic tremor of the wrists and shoul-
to near effort confirm complete paralysis of pupil responsiveness and ac- ders. Ocular findings include a peripheral corneal ring of
commodation, whereas convergence is intact. Bottom, Both pupils constrict
copper deposition involving Descemet’s membrane (Kayser-
following instillation of 0.1% pilocarpine. (Courtesy of Dr. Helmut Wil-
helm.)
Fleischer ring), copper pigment under the lens capsule, and
various ocular motor disturbances, including jerky oscilla-
tions of the eyes, involuntary upgaze, paresis of upgaze, and
slowed saccadic movements. Paresis of accommodation is
Accommodation Insufficiency Associated with Focal or
common (441,442), but the location of the lesion responsible
Generalized Neurologic Disease
for the accommodation paresis is controversial. Some inves-
Accommodation paresis may be caused by both focal and tigators favor a supranuclear lesion (441,443), whereas oth-
generalized neurologic disorders that interrupt the innerva- ers postulate a lesion in the region of the oculomotor nucleus
tion of the ciliary body. Supranuclear lesions can influence that serves the near response (442).
the signal inputs to the parasympathetic midbrain nuclei for In contrast to the aforementioned supranuclear lesions that
accommodation, resulting in paresis or even paralysis of ac- result in bilateral paralysis of accommodation with sparing
commodation. Such lesions include damage to the cerebral of the pupil light reflex, lesions of the peripheral oculopara-
cortex, rostral midbrain, superior colliculus, and possibly the sympathetic pathway typically result in unilateral paralysis
cerebellum (434,435). In these cases, convergence insuffi- of accommodation and paralysis of the pupillary light reflex
ciency usually accompanies the accommodation insuffi- in the same eye. This is because the peripheral impulses for
ciency because of cross-coupling between these two sys- pupil constriction and accommodation originate in the same
tems. visceral (Edinger-Westphal) nuclei and follow the same pe-
Acute infectious or epidemic encephalitis as well as post- ripheral pathway to the eye. Thus, the patient with an acute
infectious acute disseminated encephalomyelitis (ADEM) lesion in the peripheral pathway subserving accommodation
such as that which is associated with or follows measles, will more likely seek medical consultation for the associated
chickenpox, or other viral infections can cause accommoda- mydriasis than the blurred near vision. The evaluation of
tive paralysis (436). Typically, patients have loss of the near such an anisocoria was outlined in an earlier section of this
triad (convergence palsy, absence of pupillary near response, chapter. Common types of injury along this oculoparasym-
failure of accommodation) and normal pupil responses to pathetic pathway are infection, ischemia, and compression,
resulting in an oculomotor nerve palsy or a tonic pupil syn- ‘‘central’’ lesion. These findings were reproduced in two
drome. rhesus monkeys experimentally subjected to similar hyper-
Primary and secondary aberrant reinnervation of the ocu- baric conditions.
lomotor nerve also can involve the ciliary muscle. Herzau
and Foerster described three young patients who had in- Accommodation Insufficiency Associated with Trauma
creased myopia during attempted adduction of the affected to the Head and Neck
eye, presumably from aberrant reinnervation (444).
An isolated accommodation paralysis—accommodation Theoretically, any cerebral injury could impair the highly
paralysis without mydriasis—theoretically can be caused by complex neurophysiologic system involved in the coordina-
a lesion of the ciliary ganglion or short ciliary nerves. We are tion of the near response. Similarly, abnormal input from
unaware of any well-documented cases of this phenomenon. the upper posterior cervical roots or contusion to the side of
the cervical cord could disturb transmission in the ascending
Accommodation Insufficiency Associated with spinotegmental and spinomesencephalic pathways that influ-
Systemic Disease ence parasympathetic outflow from the Edinger-Westphal
median nuclei. Symptoms of difficulty with focusing at near
Children and adults may develop transient accommoda- and at far, commonly associated with headache and pains
tion paresis following various systemic illnesses. In such about the eyes, are common complaints in patients who have
cases, the accommodation paresis often appears to occur as suffered cerebral concussion or craniocervical extension in-
an indirect complication of the systemic disorder rather than juries (449). These vague and ill-defined complaints are
from direct damage to the ciliary body or its innervation. most prominent during the first weeks or months after injury.
There are, however, certain systemic diseases that produce The prevalence of accommodation dysfunction in patients
accommodation insufficiency through direct effects on the with head or neck trauma is not exactly defined and may be
ciliary body and lens or on their innervation. influenced in part by the average age of patients studied, as
In patients with diphtheria, accommodative paralysis usu- older patients likely have presbyopia prior to trauma.
ally is bilateral and occurs during or after the 3rd week fol- In a series of 161 patients with head injury (average age
lowing the onset of infection. Recovery is the rule but may 29 years), Kowal found that 16% had poor accommodation,
take several years (445). Because of regular vaccination, the 19% had over-accommodation (pseudomyopia), and 14%
infection from Corynebacteria diphtheriae is now rare in had convergence insufficiency (450). In about half of these
most developed countries. Accommodation paralysis has patients, near vision complaints improved or resolved within
been reported following injection of diphtheria antitoxin. the first year after their injury. Similarly, among 39 patients
The mechanism of diphtheritic accommodation palsy ap- with whiplash or indirect injury to the neck, Burke et al.
pears to be related to toxin-induced segmental demyelination found decreased accommodation and convergence in nine
of peripheral nerves with preservation of axons (446). (23%), six of whom were symptomatic (451). Five of these
Loss of accommodation may occur in patients with diabe- six patients recovered accommodation after 9 months.
tes mellitus from several mechanisms (447). For example, Tests of accommodation depend upon an earnest, voli-
accommodation paresis may develop in young patients with tional effort by a motivated patient. Thus, patients who have
previously uncontrolled diabetes who have just begun treat- cortical deficits, loss of concentration, poor comprehension,
ment. Hyperopia and accommodation weakness develop excessive somnolence, or pain often perform poorly on ac-
concurrently within a few days after the patient’s blood glu- commodative tests. Other patients attempting to gain mate-
cose has been lowered and then gradually return to normal rial or psychological compensation may intentionally per-
over 2–6 weeks. The mechanisms for the refractive and ac- form poorly on these tests (452). The persistence of
commodative changes in diabetes are poorly understood. symptoms for many months or even years is most common
Sorbitol accumulates in the lens during periods of hypergly- in patients who are seeking compensation for their injury
cemia, causing it to swell, and the lens appears responsible through litigation.
for the shifts in refraction because these shifts do not occur
in aphakic or pseudophakic eyes. The same mechanism may Accommodation Insufficiency and Paralysis from
account for accommodation paresis, because lens resiliency Pharmacologic Agents
probably is decreased from the swelling. Persistent loss of
accommodation can occur in patients with both controlled Most topical pharmacologic agents that produce pupillary
and uncontrolled diabetes mellitus from damage to the para- mydriasis also produce cycloplegia, including atropine, sco-
sympathetic innervation to the eye. In this setting, accommo- polamine, homatropine, eucatropine, tropicamide, cyclopen-
dation paresis and mydriasis are due to denervation injury tolate, and oxyphenonium. Various investigators have com-
rather than to effects on the lens. Thus, either metabolic pared the duration and effectiveness of cycloplegia produced
or neurologic mechanisms can be responsible for reduced by these agents when used as ocular solutions (453,454).
accommodation in patients with this disease. None of these agents causes persistent paralysis of accom-
Lieppman described 12 professional divers who had vis- modation after discontinuation, although there may be some
ual complaints after decompression sickness (448). All of confusion when loss of accommodation occurs after treat-
the divers had evidence of severe accommodation and con- ment of a severe viral uveitis (e.g., herpes zoster, varicella)
vergence insufficiency that was thought to be caused by a with a cycloplegic agent. In such cases, the accommodation
paralysis occurs from the effects of the virus on the ciliary eye is patched (monocular ductions testing) or when the ocu-
ganglion and not from the cycloplegic drug. locephalic maneuver is performed. Refraction with and with-
When cycloplegic agents or related substances are incor- out cycloplegia will establish the presence of pseudomyopia
porated in medications that are taken internally or applied as well.
to the skin as ointments or plasters, there may be sufficient
absorption to produce paresis of accommodation. In such Accommodation Spasm Unassociated with
cases, the accommodation deficit is partial and recovery be- Organic Disease
gins shortly after the medication is discontinued.
Most cases of accommodation spasm (usually as part of
spasm of the near reflex) appear to be nonorganic, being
Accommodation Paralysis for Distance: triggered by an underlying emotional disturbance or occur-
Sympathetic Paralysis ring as part of malingering. In such cases, spasm of the near
Lesions of the cervical sympathetic outflow may produce reflex typically occurs as intermittent attacks lasting several
a defect that prevents the patient from accommodating fully minutes (462,463). The degree of accommodation spasm and
from near to far, but most reports describe an increase in convergence spasm in such patients is variable; however,
accommodative amplitude on the side of the Horner syn- miosis is always present and impressive (Fig. 16.32). How-
drome (455). Cogan described an ipsilateral increase in near ever, many young persons, when undergoing a non-
accommodation in five patients with Horner syndrome and cycloplegic refraction, can accept increasing degrees of
noted an apparent paresis of accommodation in one patient overcorrecting concave (minus) lenses. When these same
(456). patients undergo a cycloplegic refraction, they are found to
be emmetropic or at least significantly less myopic than they
ACCOMMODATION SPASM AND SPASM OF THE appeared to be when not cyclopleged. However, unlike pa-
NEAR REFLEX tients with accommodation spasm who prefer the greater
myopic correction, these otherwise healthy young persons
General Considerations prefer their cycloplegic refraction for best-corrected visual
acuity.
Accommodation spasm is due to excessive activity of the
The management of most patients with nonorganic spasm
ciliary muscle that results in an abnormally close point of
of the near reflex begins with simple reassurance that they
focus. Clinically, there is an apparent or increased myopia
have no irreversible visual or neurologic disorder. In other
that disappears following cycloplegia (pseudomyopia). Ac-
instances, referral for psychiatric counseling is appropriate.
commodation spasm typically affects both eyes, but unilat-
Symptomatic relief may be necessary with a cycloplegic
eral cases have been reported (457). It can occur in isolation
agent and bifocal spectacles or reading glasses. Glasses with
as pseudomyopia or in association with convergence spasm
an opaque inner third of the lens to occlude vision when the
and excessive pupillary miosis in varying combinations and
eyes are esotropic have been proposed for the convergence
degrees, all of which probably represent the spectrum of
spasm (464). Nonorganic spasm of the near reflex also is
clinical presentations of spasm of the near reflex (458).
discussed in Chapter 27.
Symptoms of isolated accommodation spasm are blurry
vision, especially at distance, fluctuating vision, asthenopia, Accommodation Spasm Associated with
eyestrain, poor concentration, brow ache, and headaches. Organic Disease
The diagnostic finding is a greater myopia on manifest re-
fraction compared with cycloplegic refraction, the difference Accommodative spasm has been reported, mostly as sin-
ranging from 1 to 10 diopters. Additionally, the patient will gle case occurrences, in association with various organic
not accept the majority of the cycloplegic refraction, prefer- diseases and CNS lesions. These include neurosyphilis, ocu-
ring instead the greater myopic correction for visual im- lar inflammation, Raeder paratrigeminal neuralgia syn-
provement. drome, cyclic oculomotor palsy, congenital ocular motor
In addition to the symptoms of accommodation spasm, apraxia, congenital horizontal gaze palsy, pineal tumor, Chi-
patients with spasm of the near reflex who have convergence ari malformation, pituitary tumor, metabolic encephalopa-
spasm also complain of a horizontal diplopia that often is thy, vestibulopathy, Wernicke-Korsakoff syndrome, epi-
variable in nature. Because of the diplopia and apparent eso- lepsy, cerebellar lesions, and acute stroke (465–471).
tropia, such patients initially may be mistaken as having a Several investigators have reported spasm of the near re-
unilateral or bilateral abducens nerve palsy or ocular myas- flex in patients with MG (472,473). Romano and Stark de-
thenia and undergo extensive neurologic and neuroimaging scribed a 26-year-old man who developed isolated pseu-
investigations (428,459). Spasm of the near reflex should be domyopia as a presenting sign of ocular MG (428). The
suspected in a patient with an apparent unilateral or bilateral pseudomyopia was thought to have occurred from ‘‘substi-
limitation of abduction that is associated with severe bilateral tute convergence’’ that the patient used to compensate for
miosis (459,460). The diagnosis is confirmed by demonstrat- bilateral medial rectus weakness rather than from true ac-
ing that the miosis resolves as soon as either eye is occluded commodation spasm.
with a hand-held occluder or patch (461). Additionally, the Isolated accommodation spasm and spasm of the near re-
apparent abduction weakness present on horizontal gaze test- flex appear to be increasingly recognized as a consequence
ing with both eyes open will disappear when the opposite of head injury (450,474–477). In one series, accommodation
Figure 16.32. Spasm of the near reflex in an otherwise healthy 15-year-

old female. A, In primary position, the eyes are esotropic and the pupils are
constricted. B, On attempted right gaze, the right eye does not abduct and
both pupils become even smaller. C, On attempted left gaze, the left eye does
not abduct and both pupils become smaller. D, With the left eye patched,
the right eye abducts fully on oculocephalic testing and the pupil dilates. E,
With the right eye patched, the left eye abducts fully on oculocephalic testing
and the pupil dilates.
spasm was found in 19% of patients following closed head modation spasm may be a persistent condition, lasting up to
injury (450). Chan and Trobe reported six patients who re- 9 years after head trauma (474,476,478).
covered from severe brain injury (i.e., comatose more than
1 week, increased intracranial pressure, brain stem deficits) DRUG EFFECTS ON ACCOMMODATION
and complained of reduced distance vision (474). Isolated Most of the cholinergic agents mentioned in the earlier
pseudomyopia was found in all six patients, and full manifest section of this chapter concerning pharmacologically in-
correction alleviated the visual blur. Posttraumatic accom- duced miosis also produce an increase in accommodation
and, occasionally, accommodation spasm. Pilocarpine, phy- accommodation, whereas the effect of aceclidine on accom-
sostigmine, and the organophosphate esters produce the most modation is minimal (478).
DISORDERS OF LACRIMATION
Disorders that disrupt the neural control of lacrimation angle or in the petrous bone. The secretomotor fibers for
include cerebral diseases and trigeminal nerve lesions as well lacrimation and salivation exit the brain stem in the nervus
as lesions along the parasympathetic secretomotor pathway intermedius. This nerve is sandwiched between the motor
from pons to lacrimal gland. The disorders of lacrimation trunk of the facial nerve and the vestibulocochlear nerve
produced by these lesions generally can be divided into three as they traverse the cerebellopontine angle and the internal
types: reduced tearing (hypolacrimation), excessive tearing auditory meatus. Lesions in this area, usually tumors, can
(hyperlacrimation), and inappropriate tearing. produce loss of hearing, vestibular dysfunction, facial palsy,
decreased salivation, altered taste sensation, and a dry eye
HYPOLACRIMATION on the affected side.
Pulec and House found that 10 of 15 patients with vestibu-
Lesions of the Trigeminal Nerve
lar schwannomas had demonstrable but asymptomatic defi-
The majority of afferent inputs for reflex lacrimation are ciency of tearing on the side of the lesion (481). Because
carried via the ophthalmic division of the trigeminal nerve. this sign often is present before any overt clinical evidence
Significant hypolacrimation can result from deafferentation of the lesion, such as facial palsy or corneal hypesthesia,
of the tear reflex on one side, such as occurs in severe trigem- careful testing of reflex tearing in such patients may aid in
inal neuropathy. However, lesions that damage the trigemi- initial diagnosis. Dysfunction of the nervus intermedius also
nal nerve at the pontine angle, petrous tip, or Meckel’s cave occurs after surgical resection of vestibular schwannomas.
often simultaneously damage the nearby parasympathetic In a series of 257 patients who had surgical removal of these
lacrimal fibers (either the nervus intermedius or the greater tumors, 72% reported significant ipsilateral dry eye (loss or
superficial petrosal nerve). In these cases, trigeminal nerve- significant reduction of tears) postoperatively compared
related reduction of tears represents combined dysfunction with 4% preoperatively (482). In addition, crocodile tears
in the afferent and efferent limbs of the tear reflex. (see below) and abnormal taste were reported postopera-
tively in 44% and 48% of patients, respectively, compared
Brain Stem Lesions with 2% and 6% preoperatively.
It might be assumed that any lesion of the brain stem that
involves the facial nucleus automatically produces decreased
tearing and loss of taste because of the proximity of the
structures conveying these modalities. In fact, abnormalities
of tear secretion seldom are recognized in patients with le-
sions of the brain stem. Two patients with Moebius syn-
drome had bilateral congenital sensorineural deafness and
facial motor palsy with intact lacrimation and taste sensation,
demonstrating that lesions in this area of the pons can spare
both taste and tearing as these functions are anatomically
separate from the motor function (479).
Crosby and DeJonge called attention to an acquired brain
stem syndrome with unilateral involvement of the superior
salivary nucleus (480). One of the small vessels supplying
the area near the fourth ventricle at the level of the superior
salivary nucleus is prone to develop thrombosis. The vascu-
lar accident that develops when this vessel becomes oc-
cluded is characterized by a peripheral facial motor palsy,
ipsilateral dry eye, and reduced salivary flow from the sub-
Figure 16.33. Relationships between nervus intermedius, facial nerve
maxillary gland. The rostral end of the vestibular nucleus trunk, vestibulocochlear nerve trunk, and the superior cerebellar and ante-
lies in the immediate vicinity, and these patients usually have rior inferior cerebellar arteries. Nervus intermedius (VII N.I.) exits from
vertical or torsional nystagmus. The pathways and neurons the brain stem between the facial nerve trunk (VII) and the cochlear (VIII
concerned with lateral gaze also may be affected, causing Co.) and superior vestibular (VIII S.V.) nerve trunks. Note the relationships
an ipsilateral palsy of horizontal gaze. of the rostral (Ro. Tr.) and caudal (Ca. Tr.) trunks of the anterior inferior
cerebellar artery (A.I.C.A) to the facial-vestibulocochlear nerve complex.
Lesions Affecting the Nervus Intermedius V, trigeminal nerve; S.C.A., superior cerebellar artery; R.P.A., recurrent
perforating artery; I.A.A., internal auditory artery; Mea, Seg., meatal seg-
A peripheral facial palsy associated with ipsilateral loss ment. (From Martin RG, Grant JL, Peace D, et al. Microsurgical relation-
of reflex tearing suggests a more proximal site of damage ships of the anterior inferior cerebellar artery and the facial-vestibulo-
along the facial nerve pathway, either at the cerebellopontine cochlear nerve complex. Neurosurgery 1980;6:483–507.)
At the end of the internal acoustic meatus, the motor trunk herpes zoster, syphilis), and otitis media are common causes
of the facial nerve and the nervus intermedius enter the facial of facial nerve injury at this site.
canal that houses the geniculate ganglion (Fig. 16.33). Pa-
tients with injury to the facial nerve in the facial canal proxi- Lesions Affecting the Greater Superficial Petrosal Nerve
mal to or at the geniculate ganglion do not have hearing
loss; in fact, they may complain of hyperacusis from loss of Any lesion that involves the floor of the middle cranial
the normal damping action of the stapedius muscle. Idio- fossa in the neighborhood of the gasserian ganglion may
pathic and viral inflammation within the facial canal, skull injure the lacrimal fibers in the greater superficial petrosal
base fractures, infection of the geniculate ganglion (e.g., nerve (Figs. 16.34 and 16.35). The resulting deficiency of
Figure 16.34. Secretomotor pathways for lacrimation and salivation: The efferent visceromotor (parasympathetic) outflow.
1, lingual nerve; 2, superior salivatory and lacrimal nucleus; 3, inferior salivatory nucleus; 4, geniculate ganglion of the seventh
nerve; 5, chorda tympani; 6, petrosal ganglion; 7, facial nerve; 8, tympanic nerve; 9, glossopharyngeal nerve; 10, tympanic
plexus; 11, anastomotic branch (cranial nerves 9 to 7); 12, greater superficial petrosal nerve; 13, deep petrosal nerve; 14, lesser
superficial petrosal nerve; 15, otic ganglion; 16, anastomotic branch; 17, auriculotemporal nerve; 18, sphenopalatine ganglion;
19, branches to nasal mucosa and palatine glands; 20, maxillary division of trigeminal nerve; 21, zygomatic nerve; 22, zygomati-
colacrimal anastomosis; 23, lacrimal nerve; 24, submaxillary ganglion; 25, submaxillary gland; 26, sublingual gland; 27, parotid
gland; 28, infraorbital nerve; 29, nervus intermedius.
Figure 16.35. Vertical section through

the axis of the petrous pyramid of the tem-
poral bone showing the location of the
geniculate ganglion and the course of the
greater superficial petrosal nerve from
the geniculate ganglion to the sphenopal-
atine ganglion. Some sympathetic fibers
leave the internal carotid artery at the fo-
ramen lacerum to form the deep petrosal
nerve. This nerve joins with the greater
superficial petrosal nerve to form the vid-
ian nerve. Note the connections between
the sphenopalatine ganglion and the max-
illary nerve trunk (V2). V1, ophthalmic
nerve; V3, mandibular nerve.
Figure 16.36. The greater superficial petrosal nerve. A, Diagram of the proximal facial nerve, including the takeoff of the
greater superficial petrosal nerve (GSPN). B, Axial contrast-enhanced T1-weighted magnetic resonance image with fat suppres-
sion at the level of Meckel’s cave and the temporal bone in a patient with perineural spread of adenoid cystic carcinoma along
the right GSPN. Note tumor in the right cavernous sinus and anterior aspect of Meckel’s cave (black dot). The GSPN courses
directly beneath this area. Note the enhancement of the GSPN (small arrowheads). The geniculate region enhances brightly
and is grossly enlarged (large arrow). The labyrinthine and distal intracanalicular segments of the facial nerve also show
enhancement (small arrows and large arrowhead, respectively); these two segments of the facial nerve normally do not enhance.
On the left side, the geniculate ganglion is of normal size (and enhances normally), and only the proximal GSPN and the
proximal tympanic segment of the facial nerve enhance (brackets). (From Ginsberg LE, De Monte F, Gillenwater AM. Greater
superficial petrosal nerve: Anatomy and MR findings in perineural tumor spread. AJNR Am J Neuroradiol 1996;17⬊389–393.)
tears on the affected side rarely is noted unless the patient

has an associated palsy of the trigeminal or facial nerve and
develops signs of keratitis from drying and exposure of the
cornea. Acquired lesions that may damage the greater super-
ficial petrosal nerve include nasopharyngeal tumors, menin-
geal sarcomas, facial nerve schwannomas, perineural tumor
infiltration, inflammations of the gasserian ganglion (e.g.,
herpes zoster), petrositis, sphenoid sinus disease, aneurysms
of the petrous portion of the internal carotid artery, fractures
through the middle fossa, alcohol injections, and extradural
operations for trigeminal neuralgia (483) (Fig. 16.36).
The finding of impaired tear secretion on the side of an
acquired palsy of the abducens nerve is of great localizing
value because it indicates a lesion (usually extradural) in the
middle cranial fossa. Thus, patients with ‘‘isolated’’ abdu-
cens nerve palsies should undergo careful testing of reflex
tear function in addition to other tests of facial and trigeminal
nerve function. Most patients with a combination of an abdu-
cens nerve palsy and ipsilateral decreased reflex tearing have
nasopharyngeal tumors.
Lesions Affecting the Sphenopalatine Ganglion

Lesions of the sphenopalatine ganglion (also called the
pterygopalatine ganglion) frequently cause pain and hypes-
thesia in the cheek (the area supplied by the maxillary divi-
sion of the trigeminal nerve) in addition to decreased tearing
and dryness of the nasal mucosa on the same side. Thus, the
combination of dry eye and cheek pain or numbness on the
same side should prompt investigation for a lesion, usually
a malignant tumor, in the pterygopalatine fossa (Fig. 16.37).
Similarly, a patient with a known tumor or infection of the Figure 16.37. Anatomic relations of the sphenopalatine ganglion, the vid-
maxillary (or sphenoid) sinus who develops unilateral reduc- ian nerve, and the maxillary nerve behind the posterior wall of the orbit
tion of tear secretion should be suspected to have extension and maxillary antrum, viewed from above.
of the process beyond the confines of the sinus.
Lesions of the Zygomaticotemporal Nerve with serotonin reuptake inhibitors (485). The main character-
istics of pathologic crying are an absence of voluntary con-
Damage to the zygomaticotemporal nerve produces post- trol and a lack of corresponding mood, such as intense sad-
ganglionic denervation of the lacrimal gland. Such damage ness or grief. Pathologic crying and pathologic laughing,
usually occurs from facial trauma involving the posterior often termed emotional incontinence, frequently are associ-
lateral orbital wall. Occasionally, tumors in this area, partic- ated with diverse neurologic and psychiatric findings. Emo-
ularly metastatic carcinoma, will damage these fibers, result- tional incontinence associated with dysphagia and dysarthria
ing in a reduction of reflex tearing. make up the syndrome of pseudobulbar palsy that may be
seen in patients with parkinsonism, various age-related de-
HYPERLACRIMATION mentias, amyotrophic lateral sclerosis, giant-cell arteritis,
Reflex hypersecretion can result from excessive afferent hypothalamic tumors, and encephalitis.
triggers of the tear reflex arc or from overstimulation of the Excessive lacrimation also can be associated with the pho-
efferent parasympathetic fibers. tophobia caused by meningitis or encephalitis. Intermittent
spells of excessive tearing were the first indication of recur-
Supranuclear Lesions rence of a craniopharyngioma in a 14-year-old boy (222).
The lesion was suprasellar in location and compressed hypo-
The tear reflex normally can be elicited by a strong emo- thalamic structures in the floor of the third ventricle.
tion such as sadness. This is called psychogenic tearing or
crying. In cerebral diseases that significantly damage the SUNCT Syndrome
frontal lobes, basal forebrain, thalami, or especially the pos-
terior ventral hypothalamus, unexpected and excessive spells SUNCT syndrome (short-lasting unilateral neuralgiform
of crying (pathologic crying) can occur (484). Pharmaco- headache attacks with conjunctival injection and tearing) is
logic studies suggest dysfunction of the serotoninergic sys- characterized by moderately severe, strictly unilateral at-
tem as the cause of this syndrome, which may be treated tacks of burning or stabbing pain confined to the orbital and
periorbital area associated with excessive lacrimation. The (Fig. 16.38). In the geniculate ganglion, the gustatory fibers
attacks are typically 10–120 seconds in duration, with symp- continue centrally in the nervus intermedius. Upon entering
tomatic periods lasting days to months. Ipsilateral hyperla- the pons, they turn caudally as the tractus solitarius and fi-
crimation and conjunctival injection are considered essential nally synapse in the rostral end of the nucleus solitarius.
to the diagnosis, and rhinorrhea and vasomotor signs such Gustatory afferents from the posterior third of the tongue
as forehead sweating also can occur in patients with this travel via the glossopharyngeal nerve to the brain stem and
condition. Although certain clinical features suggest a simi- also synapse in the nucleus solitarius.
larity to trigeminal neuralgia or cluster headaches, the patho- Anatomy of the Secretomotor (Parasympathetic)
physiology of SUNCT remains unknown. Hyperactivity in Nerves to the Salivary Glands
the thalamus and hypothalamus has been noted using func-
tional MR imaging. Preganglionic salivary neurons arise in two different nu-
clei in the brain stem and follow two separate pathways
to their respective parasympathetic ganglia and end organs.
Sphenopalatine Neuralgia Salivary neurons of the superior salivary nucleus leave the
lower pons with the lacrimal fibers as the nervus interme-
Sphenopalatine neuralgia, also called Sluder neuralgia, is
dius, pass through the geniculate ganglion without synaps-
a syndrome of nasal pain accompanied by ipsilateral hyperla-
ing, proceed down the facial nerve, and leave the facial canal
crimation, rhinorrhea, salivation, photophobia, and hemifa- with the chorda tympani. With this nerve, they join the lin-
cial redness. Anesthesia or ablation of the sphenopalatine gual nerve and pass to the submandibular ganglion and the
ganglion abolishes the symptoms (487). Initially thought to diffuse sublingual ganglia, where they synapse with the post-
be an idiopathic inflammation of the sphenopalatine gan- ganglionic neurons that innervate the submandibular and
glion, this condition more likely is a neurovascular headache sublingual salivary glands.
syndrome (488). Salivary neurons of the inferior salivary nucleus leave the
medulla with the fibers of the glossopharyngeal nerve and
INAPPROPRIATE LACRIMATION pass through the jugular foramen with the vagus and spinal
accessory nerves. These salivary fibers pass through the pe-
Commonly known as crocodile tears (Bogorad syn- trous ganglion of the glossopharyngeal nerve without syn-
drome), the gustolacrimal reflex results from an anomalous apsing, branch off at the base of the skull, and ascend as the
lacrimal gland innervation that causes profuse and inappro- tympanic nerve (of Jacobson) to the tympanic cavity through
priate tearing in response to stimulation of the taste buds. a small canal in the undersurface of the petrous portion of
Most commonly, crocodile tears develop unilaterally in the the temporal bone on the jugular fossa. Within the tympanic
eye on the side of a facial palsy. However, crocodile tears cavity, the tympanic nerve divides into branches that form
should not be confused with the watery eye of an acute facial the tympanic plexus and are contained in grooves on the
palsy that is due to excess pooling and impaired drainage of surface of the promontory. It is in this location that an anasto-
tears from loss of normal orbicularis oculis action (blinking). mosing branch from the tympanic plexus joins the greater
Before discussing the congenital and acquired gustolacrimal superficial petrosal nerve through a foramen in the roof of
reflexes, we will review some of the afferent pathways re- the tympanic cavity. The secretory fibers leave the tympanic
sponsible for transmission of gustatory stimuli and the adja- cavity, course through the anterior surface of the petrous
cent efferent pathways to the salivary glands. bone, enter the middle fossa as the lesser superficial petrosal
nerve, and leave through a foramen in the base of the middle
fossa (or through the foramen ovale) to end in the otic gan-
Anatomy of the Afferent and Efferent Pathways glion, where they synapse with neurons that supply the par-
Involved in the Gustolacrimal Reflex otid gland as the auriculotemporal nerve.
The otic ganglion lies at the base of the skull medial to
Anatomy of the Afferent Gustatory Pathways the mandibular nerve and inferior to the foramen ovale. It
has a sensory root from the fibers of the glossopharyngeal
The taste buds of the tongue are the receptors for gustatory and facial nerves via the lesser superficial petrosal nerve, a
sensation. These afferent impulses are carried by the facial motor root from the nerve to the internal pterygoid muscle,
nerve (mediating taste from the anterior two thirds of the and a sympathetic root from the carotid sympathetic plexus.
tongue) and the glossopharyngeal nerve (mediating taste The otic ganglion gives origin to three communicating
from the posterior third of the tongue). The gustatory afferent nerves: (a) the nerve to the pterygoid canal; (b) a twig to
fibers for the anterior two thirds of the tongue pass centripe- the chorda tympani; and (c) the auriculotemporal nerve. In
tally with the lingual branch of the mandibular nerve, split addition, two motor branches supply the tensor tympani and
off under the base of the skull in the chorda tympani, and the tensor veli palatini.
in this nerve pass through the petrotympanic fissure, the
middle ear, and a special canal in the posterior wall of the General Considerations Concerning the
tympanic cavity to the facial canal, then upward with the Gustolacrimal Reflex
trunk of the facial nerve to the geniculate ganglion, where The syndrome of unilateral lacrimation associated with
the cell bodies of these bipolar sensory neurons are located eating and drinking was described initially by Oppenheim
Figure 16.38. Sensory pathways for lacrimal and salivary reflexes. Afferent components of the trigeminal, facial, and glosso-
pharyngeal nerves (solid lines). The motor outflow to the facial muscles is indicated as a dashed line. 1, motor root of facial
nerve; 2, nervus intermedius; 3, motor nerve to stapedius muscle; 4, sensory fibers from eardrum and external auditory canal;
5, chorda tympani; 6, petrosal ganglion; 7, facial nerve; 8, lingual nerve; 9, glossopharyngeal nerve; 10, greater superficial
petrosal nerve; 11, motor branches to face; 12, sensory fibers from soft palate and tonsillar region; 13, sphenopalatine ganglion;
14, geniculate ganglion; 15, gasserian ganglion; 16, ophthalmic division of the trigeminal nerve; 17, frontal nerve; 18, lacrimal
nerve; 19, nasociliary nerve; 20, sensory root of ciliary ganglion; 21, ciliary ganglion; 22, short ciliary nerves; 23, long ciliary
nerve; 24, infratrochlear nerve; 25, supraorbital nerve; 26, supratrochlear nerve; 27, mandibular nerve.
and later in more detail by Bogorad, who called it the syn- than an inconvenience and medical advice is not sought. In
drome of crocodile tears (489,490). The term appears to have some, however, the tearing is so profuse that they must hold
derived from the notion that the crocodile ‘‘will weep over a handkerchief to their cheek to absorb the flow of tears.
a man’s head after he has devoured the body and then eat up
the head too’’ (491). Bing applied the term ‘‘gustolachrymal Types of Gustolacrimal Reflexes
reflex,’’ a more appropriate designation (492). This reflex It is possible to differentiate at least three separate types
may not be as rare as believed (493). In most patients, the of gustolacrimal reflexes. A congenital variety often is asso-
symptom of tearing during eating or drinking is little more ciated with congenital paralysis of abduction. One acquired
variety has its onset either in the initial stage of a facial Acquired Gustolacrimal Reflex Following Facial Palsy
palsy or without clinical evidence of facial palsy. The second or Sectioning of the Greater Superficial Petrosal Nerve
acquired—and most common—variety develops after a pe-
ripheral facial palsy. The most common type of gustolacrimal reflex develops
weeks or months after a total facial palsy from a lesion in
the proximal portion of the nerve. The syndrome may follow
Congenital Gustolacrimal Reflex skull fracture, herpes zoster oticus, or idiopathic facial palsy
Lutman described three patients with a congenital gusto- (Bell’s palsy) with reduction in reflex tearing and unilateral
lacrimal reflex, two of whom also had congenital paralysis loss of taste in the anterior two thirds of the tongue (503).
of abduction (494). One of these two patients had a unilateral The accepted mechanism in these cases is misdirection of
gustolacrimal reflex and an ipsilateral abduction weakness; secretomotor salivary fibers into the pathway of the secreto-
the other patient had bilateral gustolacrimal reflexes and bi- motor lacrimal fibers at the level of the greater superficial
lateral paralysis of abduction. Other authors have described petrosal nerve.
congenital cases in which mastication (chewing and sucking Initially, it was thought that this condition developed
motions) seemed to provide more powerful stimuli for lacri- when preganglionic salivary fibers in the nervus intermedius
mation than did gustatory stimuli alone (495). It has been mistakenly passed into the greater superficial petrosal nerve
speculated that the etiology of the congenital gustolacrimal with the lacrimal fibers. However, in 1949, Boyer and Gard-
ner reported the syndrome of crocodile tears following surgi-
reflex is related to abnormal differentiation of the lacrimal
cal section of the greater superficial petrosal nerve where it
and the salivary nuclei in the pons associated with a supra-
exits from the petrous bone (504). Their findings indicated
nuclear or nuclear abnormality of the abducens nerve
that salivary fibers could not have established lacrimal inner-
(495,496).
vation via the greater superficial petrosal nerve. On the other
In support of a central developmental origin of the congen-
hand, they found that sectioning of the glossopharyngeal
ital gustolacrimal reflex is the occurrence of the reflex in
nerve relieved crocodile tears in two of their patients, sug-
some patients with the Duane retraction syndrome, a syn-
gesting that this nerve was crucial to the development of the
drome known to result from defective development of the
condition.
abducens nucleus and anomalous reinnervation of the lateral In 1963, Golding-Wood reported additional cases of the
rectus muscle (497–499; also see Chapter 20). An alternative gustolacrimal reflex following proximal sectioning of the
mechanism may be peripheral facial nerve and abducens greater superficial petrosal nerve (505). He proposed that
nerve palsy due to birth trauma with subsequent anomalous collateral axonal sprouting occurs from the glossopharyn-
reinnervation of the former (11). geal preganglionic salivary nerves, where the tympanic
branch joins the greater superficial petrosal nerve (493), and
Acquired Gustolacrimal Reflex with Onset in the that these misdirected salivary branches aberrantly reinner-
Early Stage of Facial Palsy vate the sphenopalatine ganglion and thus stimulate the lacri-
mal gland. These collateral axons are the aberrant sprouts
Kaminsky reported a patient with onset of the gustolacri- of intact salivary fibers that have their normal pathway des-
mal reflex 3 weeks after the appearance of a facial palsy tined to the otic ganglion and the parotid gland. This theory
(500), whereas Christoffel reported another with onset at the would explain how salivary axons could circumvent a proxi-
time the facial palsy began (501). Bauer reported a 15-year- mally sectioned greater superficial petrosal nerve and still
old girl in whom an acquired gustolacrimal reflex was the connect into the pathway of the lacrimal gland.
presenting symptom of an ipsilateral vestibular schwannoma In support of his theory, Golding-Wood demonstrated in
(502). On examination, the patient also had slight facial his patients that electrical stimulation of the glossopharyn-
weakness, moderate corneal hypalgesia, and subtotal hearing geal nerve exposed surgically within the tympanic cavity
loss. Following surgery to remove the tumor, her facial palsy reproduced the patients’ tearing phenomenon (505). Subse-
was complete, but the gustolacrimal symptoms had disap- quent anesthetic block of the glossopharyngeal nerve at the
peared. jugular foramen stopped the reflex lacrimation. In three other
Chorobski argued that crocodile tears occurring simul- patients, surgical section of the glossopharyngeal nerve
taneously with or shortly after the appearance of a facial within the inner ear was performed with immediate and last-
palsy cannot be explained by misdirection of regenerating ing cure of the abnormal lacrimation.
fibers (491). He proposed that such cases are best explained Transtympanic resection of the tympanic branch of the
by compression, demyelination, and cross-stimulation of glossopharyngeal nerve has remained a highly successful
neural impulses between the afferent fibers for taste and surgical treatment of crocodile tears. Other treatment op-
the secretomotor fibers for lacrimation within the nervus tions, including anticholinergic drugs, intraorbital injections
intermedius (i.e., ephaptic transmission between the auto- to destroy the sphenopalatine ganglion, and subtotal resec-
nomic fibers of the proximal seventh cranial nerve). This tion of the lacrimal gland, have had variable success rates.
theory of ephaptic transmission also may be particularly at- Botulinum toxin type A was introduced as an alternative
tractive for patients in whom the gustolacrimal reflex re- treatment for crocodile tears in 1998 (506,507). Due to its
solves either spontaneously or after decompression of the high efficacy in relieving symptoms with minimal complica-
proximal portion of the facial nerve (491). tions, especially when the transconjunctival approach to the
lacrimal gland is used (508), this may be the optimal treat- methacholine and pilocarpine, induce tearing by direct para-
ment. sympathomimetic action on the secretory cells of the lacri-
mal gland (see Chapter 14). Topical drug effects must be
DRUG EFFECTS ON LACRIMATION differentiated from tearing produced through corneal irrita-
Lacrimation may be altered by the effects of topical and tion, local allergic reaction, and so forth. The number of
systemic agents on the main lacrimal gland, its nerve supply, agents that reduce tear secretion is small; they include psy-
or the accessory lacrimal glands. Some drugs, including chotropic drugs and practolol (509,510).
GENERALIZED DISTURBANCES OF AUTONOMIC FUNCTION

‘‘Dysautonomia’’ is a term used to describe any congeni- onic sympathetic denervation of the heart also has been
tal or acquired anomaly in the autonomic nervous system demonstrated in some patients (517). Another study showed
that adversely affects health. This can result in a variety of electrophysiologic evidence of impairment of tactile, tem-
clinical symptoms, ranging from transient episodes of hypo- perature, and pain sensation as well as the histopathologic
tension to tonic pupil syndrome to progressive neurodegen- finding of moderately decreased vasomotor and sensory
erative disease. It is not the intention of this chapter to pro- nerve fibers in the epidermis of three patients with Ross
vide a detailed description on the numerous dysautonomic syndrome, suggesting progressive degeneration in sensory
syndromes; however, a few comments will be made on the myelinated and unmyelinated fiber populations in addition
disorders in which ocular findings are early or prominent to the progressive loss of cholinergic sudomotor fibers (514).
signs. Despite reports of more widespread autonomic and sen-
sory degenerative changes in Ross syndrome, it is the benign
ROSS SYNDROME and slowly progressive course that distinguishes it from
other dysautonomic syndromes (see below).
In 1958, Ross described a 32-year-old man with Adie
syndrome who had become progressively anhidrotic over 12 FAMILIAL DYSAUTONOMIA
years (511). Ross syndrome is the eponym now given to
the triad of tonic pupils, absent muscle-stretch reflexes, and Riley-Day syndrome, also called familial dysautonomia,
progressive segmental impairment of sweating. Some pa- is a rare disorder found almost exclusively in persons of
tients have a compensatory hyperhidrosis in the early stages Ashkenazi Jewish descent. The responsible gene maps to
of the disease. In the late stage, most patients have general- chromosome 9q31–33 and is inherited in autosomal-reces-
ized anhidrosis. sive fashion (521). The diagnosis is suspected from clinical
Histopathologic studies in patients with this condition signs of generalized autonomic instability such as abnormal
demonstrate that severe degeneration and loss of cholinergic sweating, loss of vasomotor control, labile hypertension, epi-
sudomotor neurons and fibers account for the clinical anhi- sodic fever, and attacks of vomiting. Relative pain insensitiv-
drosis (512–514). The tonic pupils observed in the Ross ity and a peripheral sensory neuropathy are other features.
syndrome can be unilateral or bilateral and show the same Two ocular findings are present in all patients: absence or
clinical characteristics as an idiopathic tonic pupil. marked insufficiency of tears and corneal anesthesia. Diag-
The combination of idiopathic tonic pupils and areflexia nosis is based on five clinical signs: (a) lack of flare follow-
without anhidrosis is known as the Adie (or Holmes-Adie) ing intradermal histamine injection; (b) absence of fungi-
syndrome (see above). In fact, many patients with Adie syn- form papillae on the tongue; (c) pupillary miosis to dilute
drome show abnormal sweating patterns when they are for- muscarinic agents such as pilocarpine (cholinergic denerva-
mally tested, thus creating confusion in the clinical distinction supersensitivity); (d) severe hypolacrimation; and (e)
tion between Adie syndrome and Ross syndrome (267, absent muscle-stretch reflexes (522,523).
268,515,516). Furthermore, findings of other autonomic def- Patients with familial dysautonomia produce an insuffi-
icits such as orthostatic hypotension, abnormalities of cardio- cient quantity of tears when crying, an important diagnostic
vascular reflexes, and chronic cough suggest more wide- feature of the disease at all ages other than in infancy (be-
spread autonomic involvement than previously thought in cause the normal infant does not produce tears in any signifi-
both Adie syndrome and Ross syndrome (267,268,516,517). cant quantity before the 6th–8th week after birth). Reflex
Shin et al. speculated that Adie syndrome and Ross syn- lacrimation in response to irritants such as the odor of onions,
drome (as well as another condition called the harlequin scratching of the middle turbinate, or filter paper in the con-
syndrome) may represent a spectrum of clinical manifesta- junctival sac also is deficient (524). Yet these same patients
tions of disorders of neural crest derivatives that include produce a copious flow of tears after a parenteral dose of
the parasympathetic ganglia, sympathetic ganglia, and dorsal methacholine, suggesting parasympathetic denervation su-
root ganglia (518). persensitivity of the lacrimal gland. Histologically, the lacri-
Other studies provide clinical evidence of sympathetic mal glands appear to be normal (525).
nervous system dysfunction in Ross syndrome. An oculo- Topical parasympathomimetic agents administered in low
sympathetic defect (Horner syndrome), usually postgangli- concentration produce miosis in patients with familial dysau-
onic, on the side of the facial anhidrosis occurs in some tonomia. The cholinergic supersensitivity of the pupils most
patients with Ross syndrome (518–520). Mild postgangli- often results from parasympathetic denervation, as occurs in
other tonic pupil syndromes (526,527); however, the authors cantly decreased isotope uptake compared with patients with
of one study proposed increased drug penetration across MSA, consistent with other studies indicating that postgan-
damaged corneal epithelium as another explanation for the glionic sympathetic cardiac denervation occurs in patients
strong miotic effect of dilute pilocarpine in their 10 patients with Parkinson disease and pure autonomic failure but not
with familial dysautonomia who had normal pupil responses in patients with MSA.
to light and near with infrared pupillography (528). Histopathologic findings described in patients with MSA
Ocular findings other than markedly diminished tear se- are inclusion bodies in the oligodendrocytes and neurons
cretion, corneal anesthesia, and pupillary dysfunction in- in the CNS and intact normal postganglionic sympathetic
clude corneal ulceration and/or keratopathy, exodeviation, neurons, further supporting the theory that the degenerative
anisometropia, myopia, optic atrophy, anisocoria, ptosis, and process of MSA is limited to the autonomic neurons in the
tortuosity of retinal vasculature (527,529,530). CNS (538,539).
Consistent histopathologic lesions have not been identi- MR imaging in 29 patients with MSA (subclassified into
fied in familial dysautonomia. Pearson et al. (531,532) de- the syndromes of Shy-Drager, olivopontocerebellar atrophy,
scribed several similar pathologic features in two patients and striatonigral degeneration) included high signal in the
with familial dysautonomia: (a) marked reduction in sympa- basis pontis and middle cerebellar peduncles on T2-weighted
thetic postganglionic neurons and their peripheral axons; (b) images consistent with atrophy, signal abnormalities in the
marked reduction in sensory dorsal root ganglia and small putamen, and cerebral atrophy predominantly involving the
myelinated and nonmyelinated axons in peripheral nerves; frontal and parietal lobes (540). These features were com-
(c) variable reduction in sensory axons and neurons thought monly present in all patients, regardless of their clinical pre-
to be parasympathetic in nature in the submucosa of the sentation.
tongue; and (d) variable reduction of mucosal papillae and Common ocular signs in patients with Shy-Drager syn-
taste buds. These pathologic findings, although not substan- drome include anisocoria, iris atrophy, convergence insuffi-
tiated completely by others, fit well with biochemical find- ciency, and nystagmus. Other patients have evidence of
ings in patients with familial dysautonomia that implicate a significant ocular sympathetic and parasympathetic insuffi-
disturbed catecholamine metabolism (533). On the other ciency, including alternating Horner syndrome, cholinergic
hand, Mittag et al. (534) found evidence of a deficiency or sensitivity, decreased lacrimation, and corneal hypesthesia
absence of choline acetyltransferase enzyme in the choliner- (541,542).
gic nerve terminals of a patient with familial dysautonomia.
Although a cholinergic defect could affect both the sympa- AUTOIMMUNE AUTONOMIC NEUROPATHY
thetic and parasympathetic nervous systems through its ef-
Idiopathic (Primary) Autonomic Neuropathy
fect at the ganglion level, it cannot explain the sensory de-
fects in patients with familial dysautonomia. Two forms of primary or idiopathic autonomic neuropathy
once were classified by the temporal profile of symptomatic
SHY-DRAGER SYNDROME autonomic nervous system dysfunction they produced: (a)
subacute autonomic neuropathy (also called acute pandysau-
Shy-Drager syndrome is a subtype of multiple system at- tonomia), having an acute or subacute onset; and (b) pure
rophy (MSA), one of the three idiopathic neurodegenerative autonomic failure, having a gradual onset and slow progres-
syndromes (onset usually after age 50 years) that primarily sion of symptoms (see the section above on Multiple System
affect the autonomic nervous system. The other two are pure Atrophy). Subsequent studies indicate that these two forms
autonomic failure, in which impairment of the autonomic of idiopathic autonomic neuropathy are, in fact, two pathoge-
nervous system (orthostasis, bladder dysfunction, sexual im- netically different diseases. Idiopathic subacute autonomic
potence) occurs without other neurologic features, and Par- neuropathy is an immune-mediated disorder that often fol-
kinson disease, in which autonomic impairment occurs with lows a viral or systemic illness, progresses over several days
an extrapyramidal movement disorder. In MSA, autonomic to weeks, and then tends to improve spontaneously or after
impairment occurs with an extrapyramidal movement disor- treatment with immunomodulatory drugs, whereas pure au-
der, a cerebellar movement disorder, or both (535). Patients tonomic failure is an idiopathic, progressive, degenerative
with MSA are said to have ‘‘Shy-Drager syndrome’’ when disorder (543).
their symptoms and signs are primarily those related to auto- Idiopathic subacute autonomic neuropathy is character-
nomic failure. ized by findings of autonomic dysfunction, including ortho-
Despite the criteria described above, making the clinical static hypotension with a fixed cardiac rate, decreased saliva-
distinction among MSA, Parkinson disease, and pure auto- tion and lacrimation, impaired pupil reactions, anhidrosis,
nomic failure can be difficult. For example, some patients atony of the bladder, gastroparesis, severe constipation, im-
in the early stages of MSA show only autonomic deficits, potence, and abnormal flushing of the skin (544,545).
and others develop only motor deficits that are strikingly The pupillary disturbances that occur in idiopathic sub-
similar to those that occur in patients with Parkinson disease. acute autonomic neuropathy are seen early in the course of
Certain diagnostic tests may aid in the early differentiation the disease. They include mydriasis, poor or absent constric-
of these disorders, particularly functional tests of myocardial tion to light and near stimuli, and irregularity of the pupillary
sympathetic function, such as myocardial scintigraphy using margin (546,547). Pharmacologic testing of the pupils in
123
I (536,537). Patients with Parkinson disease show signifi- such patients is consistent with both parasympathetic and
sympathetic postganglionic denervation, with denervation (42%) patients in one study (553). Bilateral mydriasis, poor
supersensitivity of both the iris sphincter and iris dilator or no light reaction, anisocoria, and reduced accommodation
muscles (548,549). are typical findings (439,554–556) and indicate primary
Patients with pure autonomic failure generally have less oculoparasympathetic dysfunction. The results from one pa-
prominent pupillary dysfunction, sicca symptoms, and gas- tient whose pupils were studied pharmacologically in the
trointestinal dysmotility compared with patients with subacute and recovery stages of MFS suggested that the pupil-
acute autonomic neuropathy. lary involvement was caused by involvement of both the
sympathetic and parasympathetic nervous systems (557).
Paraneoplastic Autonomic Neuropathy MFS is discussed in more detail in Chapter 61.
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SECTION III:
The Ocular Motor System
Nancy J. Newman
The term “ocular motor system” refers to the entire so- describes the anatomy and physiology of the ocular motor
matic motor system that controls the position and movement system. The second chapter is concerned with the techniques
of the eyes. This system includes the extraocular muscles, used to examine ocular motility and alignment. The remain-
the cranial nerves and nuclei that innervate them, and the ing five chapters are devoted to various neurologic, neuro-
pathways in the cerebral hemispheres, cerebellum, and muscular, and myopathic disorders of neuro-ophthalmologic
brainstem that coordinate and control ocular motility and importance.
alignment. The first of the seven chapters in this section
CHAPTER 17
Anatomy and Physiology of Ocular
Motor Systems
James Sharpe and Agnes M.F. Wong
SIX EYE MOVEMENT SYSTEMS AND THEIR TWO GOALS The Smooth Pursuit System
ANATOMY OF THE EXTRAOCULAR MUSCLES AND Vergence Eye Movement System
OCULAR MOTOR NERVES Fixation System
Extraocular Muscles Vestibulo-Ocular System
Levator Palpebrae Superioris The Optokinetic System
Ocular Motor Nuclei and Nerves SUMMARY OF EYE MOVEMENT CONTROL
THREE DIMENSIONS OF EYE MOTION Saccades
PHASIC VELOCITY AND TONIC POSITION COMMANDS Smooth Pursuit
TO ORBITAL FORCES THAT DETERMINE OCULAR Vergence
MOTILITY Fixation
CENTRAL ORGANIZATION OF THE OCULAR MOTOR Vestibulo-Ocular Reflex
SYSTEMS Optokinetic Movements
Saccadic System
In this chapter we describe physiologic processes and ana- mation obtained from such experimental animals to under-
tomic bases for the control of eye movements. Many con- stand the control of eye movements in humans. Quantitative
cepts in this chapter are based on information from anatomic methods of eye movement recording in normal human sub-
and physiologic experiments on monkeys, and to a lesser jects and patients with brain lesions, together with high-
extent on lower animals. Since the ocular motor behavior of resolution brain imaging, have advanced our knowledge con-
the monkey is similar to that of man, it is valid to use infor- siderably.
SIX EYE MOVEMENT SYSTEMS AND THEIR TWO GOALS

Eye movements are divided into different types called or when the head moves, there must be mechanisms to bring
systems, each of which performs a specific, quantifiable the image of the object on the fovea of each eye and keep
function and has a distinctive anatomic substrate and physio- it there. When an object moves horizontally, vertically, or
logic organization. We can best understand the types of eye obliquely in a frontal plane, both eyes must move simultane-
movements when we consider the major goals of the ocular ously in the same direction. Binocular movements in the
motor systems (1). There are six systems: saccadic, smooth same direction are termed conjugate eye movements or ver-
pursuit, fixation, vergence, vestibulo-ocular, and optoki- sions. When an object moves toward or away from the
netic. All six systems interact during visual tasks. They have viewer in a sagittal plane, the eyes must move in opposite
two goals: attaining fixation with both eyes, and preventing directions. Binocular movements in opposite directions are
slippage of images on the retina. The saccadic system uses termed disjunctive or vergence eye movements; they are
fast eye movements to attain fixation of images that lie off achieved by the vergence system. More than a century ago,
the fovea, whereas the other systems generate slower smooth Hering and Helmholtz debated the neural basis of binocular
eye movements to maintain fixation and prevent image slip coordination (2,3). Helmholtz believed that each eye is con-
on the retina. trolled independently and that binocular coordination is
When an object of interest moves within the environment learned. Hering believed that both eyes are innervated by
809
common command signals that yoke the movements of both the superior orbital fissure within the annulus of Zinn (10).
eyes (Hering’s law of equal innervation). For example, the The trochlear nerve and the frontal and lacrimal branches
right lateral rectus and left medial muscles are yoked ago- of the trigeminal nerve enter the orbit through the superior
nists for rightward version; the left superior oblique and right orbital fissure outside the annulus of Zinn.
inferior rectus muscles are yoked agonists for downward The four rectus muscles pass anteriorly from the orbital
version to the right. Conjugate control remains a subject of apex, parallel to their respective orbital walls. Anterior to
debate (4,5), since anatomic, physiologic, and behavioral the equator, the muscles insert onto the sclera by tendinous
evidence indicates independent supranuclear innervation of expansions. The distance from the corneal limbus to the in-
motoneurons to each eye that are considered to be yoked sertion of each rectus muscle gradually increases around the
(6–9). globe from the medial rectus (5.3 mm) to the inferior rectus
We shall discuss the operations of the six systems and (6.8 mm), lateral rectus (6.9 mm), and superior rectus (7.9
how they generate eye movements to achieve binocular fixa- mm) (11). An imaginary line drawn through these muscle
tion and prevent retinal image slip. First we consider the insertions is called the spiral of Tillaux (Fig. 17.2).
anatomy and functions of the peripheral ocular motor nerves The superior oblique muscle runs forward for a short dis-
and extraocular muscles. tance from its origin at the orbital apex before forming a
long tendon that passes through the trochlea. The trochlea
EXTRAOCULAR MUSCLES is a fibrous cartilaginous structure anchored in the trochlear
Each eyeball is rotated by six extraocular muscles: the fossa of the frontal bone, just inside the superior medial
medial rectus, lateral rectus, superior rectus, inferior rectus, orbital rim (12). After passing through the trochlea, the supe-
superior oblique, and inferior oblique. These muscles, with rior oblique tendon turns obliquely backward and outward
the exception of the inferior oblique, take origin from a fibro- to attach to the upper sclera behind the equator and beneath
tendinous ring at the orbital apex called the annulus of Zinn, the superior rectus (Fig. 17.3).
which surrounds a central opening known as the oculomotor The inferior oblique is the only extraocular muscle that
foramen. The oculomotor foramen encircles the optic fora- does not originate from the annulus of Zinn. It arises from
men and the central part of the superior orbital fissure (Fig. the inferior nasal aspect of the orbit just inside the orbital
17.1). The optic nerve and the ophthalmic artery pass rim and passes obliquely backward and outward to insert on
through the optic foramen, whereas the superior and inferior the lower portion of the globe behind the equator. A more
divisions of the oculomotor nerve, the abducens nerve, and thorough discussion of the gross anatomy of the extraocular
the nasociliary branch of the trigeminal nerve pass through muscles can be found in other sources (10,13,14).
Figure 17.1. View of the posterior orbit showing the origins of the extraocular muscles and their relationships to the optic
and ocular motor nerves. (Redrawn from Warwick R. Eugene Wolff’s Anatomy of the Eye and Orbit. 7th ed. Philadelphia:
WB Saunders, 1976.)
ANATOMY AND PHYSIOLOGY OF OCULAR MOTOR SYSTEMS 811
Figure 17.2. The anatomic relationships of rec-

tus muscle insertions, cornea, and limbus (the spiral
of Tillaux). (Redrawn from Apt L. An anatomical
reevaluation of rectus muscle insertions. Trans Am
Ophthalmol Soc 1980;78⬊365–375.)
The actions that the extraocular muscles exert on the globe mysium; epimysium). This connective tissue contains many
are determined by the axis of rotation of the globe, the bony elastic fibers, as well as blood vessels and nerves.
anatomy of the orbit, and the origin and insertion of the All human extraocular muscle fibers have the light and
muscles. In addition, the orbital layer of each rectus muscle electron microscopic appearance of a typical striated muscle
inserts onto a sleeve and ring of collagen in Tenon’s fascia (20). Likewise, the mechanism of contraction of these fibers
called ‘‘pulleys’’ (Figs. 17.4 and 17.5). The pulleys are is identical to that of voluntary muscles in other parts of the
linked to the orbital wall, adjacent extraocular muscles, and body, with the exception of the multiply innervated fibers
equatorial Tenon’s fascia by sling-like bands that contain (discussed later). The similarities, however, end there, as the
collagen, elastin, and richly innervated smooth muscles muscle fiber types composing the extraocular muscles are
(15,16). Pulleys limit side-slip movement of the muscles very much different from those in any other skeletal muscles
during eye movements and act as the functional origin of (21,22). Each extraocular muscle exhibits two distinct lay-
the rectus muscles (15–18). ers: an outer orbital layer adjacent to the periorbita and or-
bital bone, and an inner global layer adjacent to the eye and
Extraocular Muscle Fiber Types the optic nerve (Figs. 17.6 and 17.7). While the global layer
extends the full muscle length and inserts to the globe via a
Extraocular muscles are composed of a variable number well-defined tendon, the orbital layer ends before the muscle
of fibers. The medial rectus has the largest muscle mass, becomes tendinous and inserts into the pulley of the muscle.
while the inferior oblique has the smallest (19). Although Each layer contains fibers suited for either sustained contrac-
they vary in overall structure such as length, mass, and tention or brief rapid contraction.
don size, certain features are common to all extraocular mus- Six types of fibers have been identified in the extraocular
cles. Each muscle consists of muscle fibers with a diameter muscles (Table 17.1 and Fig. 17.6) (23–26). In the orbital
of 9–30 ␮m, which are smaller than those of muscles in layer, about 80% are singly innervated fibers. These fibers
other parts of the body. Each fiber is surrounded by a sarco- have an extremely high content of mitochondria and oxida-
lemma that covers a granular sarcoplasm in which individual tive enzymes. They have fast-twitch capacity and are the
myofibrils are apparent. Connective tissue surrounds indi- most fatigue-resistant. They are the only fiber type that show
vidual muscle fibers (endomysium), groups of fibers (inter- long-term effects after the injection of botulinum toxin (27).
nal perimysium), and the muscles themselves (external peri- The remaining 20% of orbital fibers are multiply innervated
Figure 17.3. View of the normal orbit from above, showing the relationships of the extraocular muscles, ocular motor nerves,
and vessels. (Redrawn from Warwick R. Eugene Wolff’s Anatomy of the Eye and Orbit. 7th ed. Philadelphia: WB Saunders,
1976.)
fibers. Unlike most mammalian skeletal muscles, the orbital In the global layer, about 33% are red singly innervated
layer multiply innervated fibers exhibit multiple nerve termi- fibers, which are fast-twitch and highly fatigue-resistant. An-
nals distributed along their length. They have twitch capacity other 33% are pale singly innervated fibers with fast-twitch
near the center of the fiber and nontwich activity proximal properties but low fatigue resistance. Intermediate singly in-
and distal to the endplate band (28). nervated fibers constitute about another 23% of fibers. They
Figure 17.4. Structure of the orbital connective tissues, including the rectus muscle pulleys. IO, inferior oblique; IR, inferior
rectus; LPS, levator palpebrae superioris; LR, lateral rectus; MR, medial rectus; SO, superior oblique; SR, superior rectus. The
three coronal views are represented at the levels indicated by arrows in horizontal section. (From Demer JL, Miller JM, Poukens
V. Surgical implications of the rectus extraocular muscle pulleys. J Pediatr Ophthalmol Strabismus 1996;33⬊208–218.)
have fast-twitch properties and an intermediate level of fa- (33–35). Using intraoperative electromyography, Scott and
tigue resistance. The remaining 10% of global layer muscle Collins (33) demonstrated that all muscle fiber types partici-
fibers are multiply innervated fibers, with synaptic endplates pate in all classes of eye movements. In addition, different
along their entire length, as well as at the myotendinous fiber types are recruited at specific eye positions, regardless
junction, where palisade ending proprioceptors are found. of the type of eye movements. Robinson (36) proposed that
The multiply innervated fibers are nontwitch, having tonic the functional arrangement of muscle fiber types is related
properties, with slow, graded, nonpropagated responses to to the threshold at which motor units are recruited. In sac-
neural or pharmacologic activation. The twitch and nontwich cades and quick phases of nystagmus, all motor units are
muscle fibers are innervated by different types of motoneu- recruited and burst synchronously. There is no differential
rons. Large motoneurons within the abducens, trochlear, and in the recruitment order of different muscle fiber or motor
oculomotor nuclei innervate twitch, singly innervated fibers, unit types (36). However, after saccades, or in slow smooth
whereas smaller motoneurons around the periphery of these eye movements, the recruitment of individual motoneurons
nuclei innervate nontwitch, multiply innervated fibers (29). into sustained discharge is dependent on eye position. Motor
It was suggested that different muscle fiber types may units containing orbital singly innervated fibers and global
subserve different types of eye movements; slower or vestib- red singly innervated fibers are recruited first, well in the
ularly induced eye movements were attributed to contraction off-direction of muscle action (36). Those motor units con-
of the slower tonic fibers, while rapid movements were attaining multiply innervated fiber types are recruited next,
tributed to contraction of the faster twitch fibers (30–32). probably near straight ahead position, where their fine incre-
However, more recent studies argue against this concept ments of force would be of value for fixation (36). The in-
Figure 17.5. Photomicrographs of rectus muscle pulley structure. A and B, Light micrographs of dense connective tissue on
the orbital side of a human medial rectus (arrow) pulley. Dense collagen matrix is intermixed with elastin filaments. C and
D, Electron photomicrographs of rectus muscle pulleys. Collagen is arranged in bundles running at right angles to one another
(x-s, bundles cut in cross-section; l-s, bundles cut in longitudinal section). Elastin filaments (e) are scattered individually in
collagen matrix. (From Porter JD, Poukens D, Baker RS, et al. Structure function correlations in the human extraocular muscle
pulleys. Invest Vis Sci 1996;37⬊468–472.)
creasingly faster but fatigable fibers are recruited last, at Another unique feature of the extraocular muscles is their
positions well into the on-direction of muscle action (36). rich nerve supply. Each motoneuron from the ocular motor
Thus, although the global intermediate and global white sin- nerves supplies very few muscle fibers compared with the
gly innervated fiber types are transiently recruited during ratio of motoneurons to muscle fibers in other striated mus-
all on-direction saccades, they are recruited into continuous cles (37–39). Motor unit size is only about one muscle fiber
activity only in intermediate to extreme positions of gaze. per motoneuron in the global layer, and two to five muscle
Figure 17.6. Light photomicrographs of Macaca monkey rectus muscle organization. A, Layered organization of typical
rectus muscle; C-shaped orbital and central, global layers are indicated. B, Fiber types present in orbital muscle layer. Orbital
singly innervated and multiply innervated fibers are present. C, Fiber types present in the global muscle layer. Global red,
global intermediate, and global white singly innervated muscle fiber types and the global multiply innervated fiber type are
indicated. (From Porter JD, Baker RS, Ragusa RJ, et al. Extraocular muscles: basic and clinical aspects of structure and function.
Surv Ophthalmol 1995;39⬊451–484.)
fibers per motoneuron in the orbital layer of human rectus Muscle spindles occur only in the orbital layer of muscles.
muscles (40). The low innervation ratio allows extraocular Golgi tendon organs and palisade endings are found only in
muscles to increase or decrease force in small amounts for nontwich, multiply innervated fibers and only in the global
the precise control of eye position. layer. Palisade endings lie at myotendinous junctions and
have the microscopic features of immature Golgi tendon or-
Extraocular Muscle Proprioception gans (43). The function of muscle spindles and Golgi tendon
organs is not settled. Muscle spindles are positioned to serve
Human extraocular muscles contain neuromuscular spin- as feedback to any adjustment of the pulleys to which the
dles, Golgi tendon organs, and palisade endings (41–43). orbital muscle layers attach. Ocular motoneurons do not par-
Table 17.1
Functional Properties of Extraocular Muscle Fiber Types
Orbital Global
SIF MIF Red SIF Intermediate SIF White SIF MIF
% of layer 80 20 33 23 33 10
Contraction mode Twitch Mixed Twitch Twitch Twitch Nontwitch
Contraction speed Fast Fast/slow Fast Fast Fast Slow
Fatigue resistance High Variable High Intermediate Low High
Recruitment order 1st 3rd 2nd 5th 6th 4th
SIF, singly innervated fiber; MIF, multiply innervated fiber.

(Modified from Porter JD, Baker RS, Ragusa RJ, Brueckner JK. Extraocular muscles: basic and clinical aspects of structure and function. Surv Ophthalmol
1995;39:451–484.)
commands (efference copy, or nonretinal feedback, which

we discuss later) provide sufficient information to the brain
for accurate eye movement control, and this information is
modified by visual feedback independently of propriocep-
tion (48). Although visual input and internal (nonretinal)
feedback massively dominate any contribution of propri-
oception to the control of eye motion, extraocular propri-
oception has been implicated in various functions (49). It
may specify visual direction (50–53), modulate visual pro-
cessing (54), contribute to spatial localization (50,55), and
participate in binocular functions (56), particularly during
the critical period of development of the visual sensory sys-
tem (57,58). Proprioception may also participate in the con-
trol of different oculomotor systems (56,59–65). Abnormali-
ties in proprioception might contribute to fixation
instabilities in congenital nystagmus (66) and to strabismus
(56,67). For an in-depth discussion of extraocular muscle
proprioception, see Donaldson’s (49) excellent review.
LEVATOR PALPEBRAE SUPERIORIS

The levator palpebrae superioris arises as a short tendon
that is blended with the underlying origin of the superior
rectus from the undersurface of the lesser wing of the sphe-
noid bone, above and anterior to the optic foramen. The flat
muscle belly passes forward below the orbital roof and just
superior to the superior rectus until it is about 1 cm behind
the orbital septum, where it ends in a membranous expansion
or aponeurosis. The aponeurosis of the levator spreads out in
a fan-shaped manner across the width of the eyelid, inserting
primarily into the tarsal plate that separates the bundles of
the orbicularis oculi muscle in the lower half of the eyelid.
The lateral and medial extensions of the aponeurosis are its
lateral and medial horns. The lateral horn is attached to the
orbital tubercle and to the upper aspect of the lateral canthal
ligament. The medial horn is attached to the medial canthal
ligament (68).
Each levator palpebrae muscle contains the three singly
Figure 17.7. Electron photomicrographs of fiber types present in primate
extraocular muscle. A, Orbital singly innervated. B, Orbital multiply inner-
innervated muscle fiber types found in the global layer of
vated. C, Global red singly innervated. D, Global intermediate singly inner- the extraocular muscles, and a true slow-twitch fiber type.
vated. E, Global white singly innervated. F, Global multiply innervated. The multiply innervated fiber type and the fatigue-resistant
singly innervated type seen in the orbital layer of extraocular
muscles are absent. The levator muscle is also more inter-
ticipate in any stretch reflex. Palisade endings appear to be spersed with fat and less sharply separated from adjacent
the primary proprioceptors (44,45). Extraocular muscle af- connective tissue than are the fibers of the superior rectus.
ferents project from these proprioceptors, via the ophthalmic The nerve supply to the levator muscle is via branches
branch of the trigeminal nerve and the gasserian ganglion, from the superior division of the oculomotor nerve (dis-
to the spinal trigeminal nucleus (46). Proprioceptive inputs cussed later) that reach the muscle either by piercing the
may also project centrally via the ocular motor nerves (47). medial edge of the superior rectus or by winding around its
From the trigeminal nucleus, proprioceptive information is medial border (Fig. 17.1). The vascular supply originates
distributed widely to structures involved in ocular motor from the lateral muscular branch of the ophthalmic artery,
control, including the superior colliculus, vestibular nuclei, the supraorbital artery, the lacrimal artery, and the posterior
nucleus prepositus hypoglossi, cerebellum, and frontal eye ethmoidal artery (69).
fields. Proprioceptive information is also distributed to struc-
tures involved in visual processing, including the lateral ge- OCULAR MOTOR NUCLEI AND NERVES
niculate body, pulvinar, and visual cortex. Oculomotor Nucleus and Nerve
Deafferentation of the eye muscles does not affect ocular
motor control or visually mediated adaptation of eye move- The oculomotor nerve (the third nerve) is the largest and
ments in primates (48). Vision and efferent eye movement most complex of the three ocular motor nerves. It contains
somatic motor fibers that innervate the superior, inferior, and

medial recti, the inferior oblique, and the levator palpebrae
superioris. It also contains visceral (parasympathetic) motor
fibers that innervate the ciliary and the iris sphincter muscles.
In addition to somatic and visceral motor fibers, the oculo-
motor nerve carries fibers from the trigeminal nerve and the
sympathetic plexus. In humans, the oculomotor nerve has
about 15,000 axons (four times the number in the abducens
nerve and seven times the number in the trochlear nerve),
most of which are distributed to about 40,000 muscle fibers.
Oculomotor Nucleus
The oculomotor nucleus consists of an elongated mass of
cells lying ventral to the periaqueductal gray matter of the
mesencephalon. Its rostral extent is the posterior commis-
sure, and its caudal extent is the trochlear nucleus near the
pontomesencephalic junction (Figs. 17.8 and 17.9). Unlike
the trochlear and abducens nuclei, the oculomotor nucleus
has both midline unpaired and lateral paired portions. Con-
temporary neuroanatomic retrograde tracing techniques in
monkeys reveal that the organization of the somatic compo-
nents of the oculomotor nucleus (70–73) is more complex
than that described by Warwick (74) (Fig. 17.10). The supe-
rior rectus is represented on the contralateral side of the
medial portion of the oculomotor nucleus. Fibers from this
subnucleus cross the midline and pass through the superior
rectus subnucleus on the opposite side before turning ven-
trally to enter the fascicle of the oculomotor nerve (75).
The inferior rectus motoneurons lie dorsally, primarily in the Figure 17.8. Sagittal view of a human brain stem showing the location
rostral portion of the ipsilateral nucleus. The medial rectus of saccadic premotor neurons. Shaded areas mark the location of premotor
motoneurons lie in three separate subgroups in the ipsilateral saccadic neurons: excitatory short-lead burst neurons of the horizontal
oculomotor nucleus (70,71) (Fig. 17.11). Inferior oblique (EBNH) system in the nrpc, and of the vertical (EBNV) system in the riMLF;
motoneurons are found ipsilaterally, between the ventral me- inhibitory short-lead burst neurons (IBN) in the pgd and omnipause neurons
dial rectus subgroup and the inferior rectus representation. (OPN) in the rip. The broken lines A to D indicate the planes of the corre-
sponding sections shown in Figure 17.9. III, oculomotor nucleus; IV, troch-
The oculomotor nucleus also contains, in addition to mo-
lear nucleus t; VI, abducens nucleus; XII, hypoglossal nucleus, iC, intersti-
toneurons, many internuclear neurons that project to and tial nucleus of Cajal; io, inferior olive; mb, mammillary body; MLF, medial
from other nuclei concerned with ocular motor function. longitudinal fasciculus; MT, mammillothalamic tract, N III, oculomotor
These internuclear neurons project primarily to the ipsi- nerve; NVI, abducens nerve; lc, locus ceruleus; nrpc, nucleus reticularis
lateral abducens nucleus, with a small population of neurons pontis caudalis; nrpo, nucleus reticular is pontis oralis; nrtp, nucleus reticu-
projecting to the contralateral abducens nucleus (76–79). laris tegmenti pontis; PC, posterior commissure; pgd, nucleus paragiganto-
In addition to motoneurons and internuclear neurons, the cellularis dorsalis; ppH, nucleus prepositus hypoglossi; PX, pyramidal de-
oculomotor nucleus also contains preganglionic, parasympa- cussation; riMLF, rostral interstitial nucleus of the MLF; rip, nucleus raphe
thetic neurons whose axons project to the ciliary ganglion interpositus; rn, red nucleus; sc, superior colliculus; TR, tractus retroflexus.
and ultimately control pupillary constriction and accommo- (From Horn AKE, Büttner-Ennever JA, Büttner U. Saccadic premotor neu-
rons in the brainstem: functional neuroanatomy and clinical implications.
dation. These cell bodies are located in the visceral nuclei
Neuroophthalmology 1996;16⬊229–240.)
of the oculomotor nucleus: the Edinger-Westphal nuclei, the
anterior median nuclei, and, possibly, Perlia’s nucleus (80).
The caudal central nucleus is a single midline structure lo-
cated in the caudal end of the oculomotor nucleus. It supplies caudal ends of the oculomotor nuclear columns explains
both levator palpebrae superioris muscles. their dispersion throughout the ventral mesencephalon. Al-
though this arrangement may seem haphazard, it is clear that
Fascicular Portion of the Oculomotor Nerve the fibers actually are arranged in a divisional pattern within
The fascicular portion of the oculomotor nerve, which lies the brain stem. Indeed, superior and inferior division oculo-
within the substance of the brain stem, arises from the ventral motor nerve pareses frequently occur in patients with intrin-
side of the nucleus. These fibers descend ventrally and sic lesions of the mesencephalon (81–85). As the fibers
spread laterally as they pass through the red nucleus to par- emerge on both sides of the interpeduncular fossa, the fiber
tially penetrate the medial part of the cerebral peduncle (Fig. bundles immediately coalesce to form two large nerve
17.12). The origin of these fibers from the rostral to the trunks.
Figure 17.9. Transverse sections through the human

brain stem at levels indicated in Figure 17.8, showing
the localization of saccadic premotor neuron groups
(shaded areas) from rostral to caudal through the
riMLF (A), the nrpc (B), the rip (C), and the pgd (D).
E–H, Magnification of the areas containing premotor
saccadic neurons in A to D. Immunoreactive human
neurons (only within the relevant areas) are indicated
by dots. E, The riMLF contains vertical short-lead
burst neurons (EBNV) (arrow). The dorsal border of
the riMLF is outlined by the thalamosubthalamic ar-
tery, which serves as a useful landmark. F, The area
containing horizontal excitatory short-lead burst neu-
rons (EBNH) is confined to the medial part of the nrpc
(arrow). G, The saccadic omnipause neurons (OPN)
lie within the rip scattered at the midline (arrow).
H, The horizontal inhibitory short-lead burst neurons
(IBN) lie within the medial part of the pgd. cm, cen-
tromedian nucleus; CTT, central tegmental tract;
dmpn, dorsomedial pontine nuclei; gc, gigantocellular
nucleus; H, field H of Forel; hb, habenular nuclei; LL,
lateral lemniscus; lv, lateral vestibular nucleus; mb,
mammillary body; ML, medial lemniscus; MLF, me-
dial longitudinal fasciculus; mv, medial vestibular nu-
cleus; nd, dorsal thalamic nucleus; nrpc, nucleus retic-
ularis pontis caudalis; nrtp, nucleus reticularis
tegmenti pontis; NV, trigeminal nerve; NVI, abducens
nerve; NVII, facial nerve; ov, nucleus ovalis, pc, par-
vocellular nucleus; pgd, nucleus paragigantocellularis
dorsalis; ppH, nucleus prepositus hypoglossi; riMLF,
rostral interstitial nucleus of the MLF; rip, nucleus
raphe interpositus; rn, red nucleus; sn, substantia
nigra; so, superior olive; sv, superior vestibular nu-
cleus; TR, tractus retroflexus; Vm, motor trigeminal
nucleus; Vs, sensory trigeminal nucleus; VI, abducens
nucleus; VII, facial nucleus. (From Horn AKE, Bütt-
ner-Ennever JA, Büttner U. Saccadic premotor neu-
rons in the brainstem: functional neuroanatomy and
clinical implications. Neuroophthalmology 1996;
16⬊229–240.)
Figure 17.10. Oculomotor nucleus subgroups as determined by contemporary

retrograde tracer techniques in Macaca monkey. (Courtesy of Jean A. Büttner
Ennever.)
Figure 17. 11. Transverse sections of the oculomotor and trochlear nuclei show-
ing multifocal labeling of motoneurons after injection of horseradish peroxidase
into the ipsilateral medial rectus. Top of drawing shows lateral view of nuclei,
with arrows indicating levels at which the transverse sections (below) were taken.
Three separate subgroups (A, B, C) are labeled. Nonlabeled areas include the
motoneurons that innervate the ipsilateral inferior oblique (IO), inferior rectus
(IR), and superior rectus (SR) muscles; LP, motoneuron pool supplying both
levator palpebrae superioris muscles; MLF, medial longitudinal fasciculus; SO,
motoneuron pool supplying the ipsilateral superior oblique muscle. (Redrawn
from Henn V, Büttner Ennever JA, Hepp K. The primate oculomotor system. I.
Motoneurons. Hum Neurobiol 1982;1:77–85.)
Figure 17.12. Section through rostral mesencephalon showing the oculomotor nuclei and the fasciculi of the oculomotor
nerves. 1, superior colliculus; 2, brachium of the inferior colliculus; 3, medial geniculate nucleus; 4, spinal and trigeminal
lemnisci; 5, central gray substance; 6, cerebral aqueduct; 7, visceral (parasympathetic) nuclei of the oculomotor nuclear complex;
8, motor nuclei of the oculomotor nuclear complex; 9, medial lemniscus; 10, central tegmental tract; 11, medial longitudinal
fasciculus; 12, red nucleus; 13, fasciculus of the oculomotor nerve; 14, substantia nigra; 15, cerebral peduncle. (From Gluhbe-
govic N, Williams TH. The Human Brain: A Photographic Guide. Hagerstown, MD: Harper & Row, 1980.)
Oculomotor Nerve enters the cavernous sinus (86). This point is slightly lateral
Most of the axons in the oculomotor nerve are myelinated and anterior to the dorsum sellae and 2–7 mm posterior to
and have diameters that vary from 3 to 18 microns. These the initial segment of the supraclinoid portion of the carotid
fibers may be classified as large (6–18 microns) and small artery.
(3–6 microns). The large-caliber axons originate from moto- Within the cavernous sinus, the oculomotor nerve is lo-
neurons and are destined for the extraocular muscles, cated just above the trochlear nerve, and both, along with
whereas most of the smaller axons transmit parasympathetic the first (and sometimes the second) division of the trigemi-
impulses to the ciliary body and iris. nal nerve, lie within the deep layer of the lateral wall of the
The oculomotor nerve emerges from the interpeduncular sinus (Fig. 17.14). This deep layer is formed by the sheaths
fossa at the ventral surface of the mesencephalon as a num- of these nerves, supplemented by a reticular membrane ex-
ber of horizontally arranged bundles that immediately fuse tending between the sheaths (87) (Fig. 17.15). Anteriorly in
into a single nerve trunk. The nerve, invested by pia, passes the cavernous sinus, the oculomotor nerve apparently re-
obliquely downward, forward, and laterally through the sub- ceives sympathetic fibers from the carotid trunk; however,
arachnoid cistern at the level of the tentorial incisura and the anatomic features of this anastomosis are unclear.
pierces the dura at the top of the clivus just lateral to the The vascular supply of the oculomotor nerve in the sub-
posterior clinoid process. arachnoid space is via vascular twigs from the posterior cere-
Shortly after leaving the mesencephalon, the nerve passes bral artery, the superior cerebellar artery, and the tentorial
between two major branches of the basilar artery, the supe- and dorsal meningeal branches of the meningohypophyseal
rior cerebellar artery and the posterior cerebral artery (Fig. trunk of the internal carotid artery. In the cavernous sinus,
17.13). As it continues distally, the nerve is adjacent to the the tentorial, dorsal meningeal, and inferior hypophyseal
medial inferior surface of the posterior communicating ar- branches of the meningohypophyseal trunk supply the nerve
tery for about 0.5 cm before it penetrates the dura to enter along with branches from the ophthalmic artery (88–91).
the cavernous sinus. As the oculomotor nerve leaves the cavernous sinus
The oculomotor nerve is medial to, and slightly beneath, through the superior orbital fissure to enter the orbit, it is
the ridge of the free edge of the tentorium cerebelli as it crossed superiorly by the trochlear and ophthalmic division
Figure 17.13. The relationship of the oculomotor nerve to the intracranial arteries in the subarachnoid space. A, The oculomotor
nerves (III) are viewed from above. On the left, the posterior communicating artery has been retracted to show the groove that
it may produce through its contact with the oculomotor nerve. RN, red nucleus. B, Lateral view of the left oculomotor nerve
(III) showing its arterial relationships.
Figure 17.14. Transverse section through the optic chiasm, pituitary gland, and cavernous sinuses, showing the location of
the ocular motor nerves. White hollow arrows (right side of photograph) indicate the boundaries of the cavernous sinus. White
solid arrows (left side of photograph) outline boundaries of nerves. 3, oculomotor nerve; 4, trochlear nerve; VI, ophthalmic
division of the trigeminal nerve; VII, mandibular division of the trigeminal nerve; 6, abducens nerve; VN, vidian nerve. (Courtesy
of Dr. William F. Hoyt.)
Figure 17.15. Diagram of the cavernous sinus showing that the lateral wall is
composed of two layers: a superficial layer (sl) and a deep layer (dl). The deep layer
is formed by the sheaths of the oculomotor (III), trochlear (IV), and ophthalmic (V1)
nerves, with a reticular membrane between these sheaths. VI, abducens nerve.
(Redrawn from Umansky F, Nathan H. The lateral wall of the cavernous sinus:
with special reference to the nerves related to it. J Neurosurg 1982;56⬊228–
234.)
of the trigeminal nerves. In this region, the oculomotor nerve pupilloconstrictor fibers appear to be located superficially
divides into two discrete trunks, the superior and inferior in the superior portion of the nerve (94,95). There is strong
divisions. Both divisions pass through the annulus of Zinn clinical evidence to suggest that fibers in this portion of the
adjacent to the abducens nerve (92,93) (Fig. 17.1). The supe- oculomotor nerve are arranged in a ‘‘superior’’ and ‘‘infe-
rior division, the smaller of the two, passes up and over the rior’’ division, but their precise topographic anatomy is not
lateral aspect of the optic nerve, dividing into multiple small known. Within the cavernous sinus and orbit, the pupillary
branches just anterior to the orbital apex. The branches run fibers are located in the inferior division of the nerve, but the
anteriorly for several millimeters before entering the sub- position of the fibers going to specific extraocular muscles is
stance of the superior rectus. The fibers that will supply the unknown except for the major division of the oculomotor
levator palpebrae superioris then coalesce briefly, forming nerve into its superior and inferior divisions.
a few bundles. These bundles pass along the lateral aspect of Morphopathologic and neurogenetic studies reveal that
the superior rectus and reach the undersurface of the levator some developmental ocular motility disorders are a conse-
palpebrae superioris, at which point they penetrate the quence of altered development of oculomotor motoneurons.
muscle. Engle et al. (96) suggested that a syndrome previously
The inferior division divides into multiple branches in thought to be an extraocular muscle disorder, congenital fi-
the posterior orbit. These branches innervate the medial and brosis of the extraocular muscles, may have its origin in
inferior recti and then pass anteriorly beneath the optic nerve oculomotor motoneurons. Individuals with an autosomal-
or through the inferior rectus itself to penetrate the inferior dominant mutation linked to chromosome 12 exhibit con-
oblique. The nerve to the inferior oblique, after running genital, bilateral ptosis, external ophthalmoplegia, and eyes
along the lateral border of the inferior rectus, splays into fixed in down gaze. Morphopathologic analysis revealed ab-
several fascicles that penetrate the posterior lateral border sence of the superior division of the oculomotor nerve, ab-
of the inferior oblique where it is in contact with the lateral sence of the caudal central subnucleus of the oculomotor
border of the inferior rectus (93). The inferior division also nucleus (which innervates the levator palpebrae), apparent
transmits parasympathetic axons to the ciliary ganglion as loss of superior rectus motoneurons, and severe levator pal-
the motor root of the ganglion (Figs. 17.1 and 17.16). pebrae superioris and superior rectus muscle abnormalities
The topographic arrangement of the fibers within the ocu- (97). These data suggest that congenital fibrosis of the extra-
lomotor nerve is unclear. Within the subarachnoid space, ocular muscles results from a developmental abnormality in
Figure 17.16. The human ciliary ganglion and its relationship to the orbital arteries, viewed from the lateral aspect of the
orbit. The lateral rectus has been retracted away from the ganglion and the optic nerve so that the nerves to and from the
ganglion can be identified. (From Elisková M. Blood vessels of the ciliary ganglion in man. Br J Ophthalmol 1973;57⬊766–772.)
the ocular motor lower motor neuron system, much like that curve dorsocaudally, and finally converge to decussate over
proposed for Duane’s retraction syndrome (see Chapter 20). the roof of the aqueduct in the anterior medullary velum
(Fig. 17.18). Each fascicle exits from the dorsal surface of
Trochlear Nucleus and Nerve the brain stem on the opposite side (100). The trochlear nerve
is the only cranial nerve that crosses and exits from the dorsal
The trochlear, or fourth, nerve is the smallest of the ocular side of the brain stem. Thus, the axons from each nucleus
motor nerves, containing only about 2,100 axons and in- innervate the contralateral superior oblique muscle. The de-
nervating only the superior oblique muscle. cussation, however, is incomplete, with about 5% of the
motoneurons passing through the ipsilateral trochlear nerve
Trochlear Nucleus (72). Because of the dorsal location of the trochlear nuclei,
The paired trochlear nuclei are located in the gray matter the fascicles of the trochlear nerves are extremely short and
in the floor of the cerebral aqueduct just caudal to the oculo- are not related to neural structures other than the roof of the
motor nuclear complex (Fig. 17.17). The trochlear nucleus cerebral aqueduct. This explains the virtual impossibility of
lies within the dorsal and medial aspect of the medial longi- differentiating isolated trochlear nerve damage due to intrin-
tudinal fasciculus (MLF) (98). Motoneurons of one trochlear sic brain stem disease from that arising from injury to the
nucleus innervate the superior oblique muscle of the contra- subarachnoid portion of the nerve.
lateral eye, although a few (3%–5%) of them innervate the
ipsilateral superior oblique muscle (72,99). Trochlear Nerve
Fascicular Portion of the Trochlear Nerve The two trochlear nerves emerge on the dorsal surface of
the brain stem just below the inferior colliculi and immedi-
The axons that emerge from the nuclei initially pass lat- ately pass forward around the mesencephalon between the
erally a short distance below the cerebral aqueduct, then posterior cerebral and superior cerebellar arteries. They then
Figure 17.17. Section through the caudal mes-

encephalon at the level of the trochlear nucleus.
1, inferior colliculus; 2, brachium of the inferior
colliculus; 3, cerebral aqueduct; 4, lateral lemnis-
cus; 5, medial longitudinal fasciculus; 6, troch-
lear nucleus; 7, central tegmental tract; 8, spinal
and trigeminal lemnisci; 9, tegmental reticular
formation; 10, decussation of superior cerebellar
peduncles; 11, medial lemniscus; 12, pontine nu-
clei and transverse fibers; 13, corticospinal and
corticonuclear fibers. (From Gluhbegovic N,
Williams TH. The Human Brain: A Photographic
Guide. Hagerstown, MD: Harper & Row, 1980.)
Figure 17.19. Dissection to illustrate the subarachnoid and intracavernous

courses of the ocular motor nerves. Note the long subarachnoid course of
the trochlear nerve as it proceeds around the brain stem compared with the
shorter courses of the oculomotor and abducens nerves. The abducens nerve
penetrates the dura at the base of the skull inferior to the points at which
Figure 17.18. The decussation of the trochlear nerves. In this transverse the oculomotor and trochlear nerves penetrate the dura.
section through the caudal mesencephalon, the trochlear nuclei (IV) can be
seen just dorsal to the medial longitudinal fasciculus (MLF). The fascicles
of the trochlear nerve (F) course dorsally around the cerebral aqueduct (A)
and decussate in the anterior medullary velum (V) before emerging from Abducens Nucleus
the dorsal surface of the brainstem. (From Duke Elder S. System of Ophthal- Each abducens nucleus is located just beneath the floor
mology. Vol 3. London: Henry Kimpton, 1963⬊265.)
of the fourth ventricle and lateral to the midline of the pons
at the junction of the pons and the medulla (Fig. 17.20). A
prominent band of fibers, the genu of the facial nerve, curves
course around the cerebral peduncles and pierce the dura to over its dorsal and lateral surface. Adjacent and medial to
enter the cavernous sinus, where the attached and free bor- each nucleus is the MLF.
ders of the tentorium cross one another (Fig. 17.19). This The abducens nucleus contains two neuron populations,
point is inferior and lateral to the point at which the oculomo- the abducens motoneurons and the abducens internuclear
neurons. The abducens motoneurons innervate the lateral
tor nerve enters the cavernous sinus.
rectus, while the abducens interneurons give rise to axons
Within the cavernous sinus, the trochlear nerve is adjacent
that ascend in the contralateral medial longitudinal fascicu-
and just inferior to the oculomotor nerve, lying in the deep
lus and participate in the internuclear neurons system that
layer of the lateral wall (Figs. 17.14 and 17.15). As the troch- controls horizontal conjugate gaze.
lear nerve leaves the cavernous sinus to pass through the
superior orbital fissure, it crosses over the oculomotor nerve Fascicular Portion of the Abducens Nerve
to lie superior to it. In this region, it receives filaments from
the sympathetic plexus and perhaps from the ophthalmic The fascicular portion of the abducens nerve courses ven-
division of the trigeminal nerve. trally, laterally, and caudally through the pons, passing me-
dial to the superior olivary nucleus to emerge in a groove
The trochlear nerve enters the orbit through the superior
between the pons and medulla. During this passage, the fas-
orbital fissure, outside the annulus of Zinn (Figs. 17.1 and
cicle is adjacent to the motor nucleus of the facial nerve and
17.3). It runs anteriorly and medially beneath the superior
the facial nerve fascicle, the motor nucleus of the trigeminal
periorbita to cross over the superior rectus as a single fascicle nerve, the spinal tract of the trigeminal nerve (and its nu-
until just before it enters the superior oblique at its superior cleus), the superior olivary nucleus, the central tegmental
nasal aspect (93). tract, and the corticospinal tract.
The vascular supply of the abducens nuclei and fascicles
Abducens Nucleus and Nerve is via arteries arising from the basilar artery (101,102). These
arterial branches can be separated into three groups by their
The sixth (abducens) nerve is somewhat larger than the length and the general regions of the brain stem that they
trochlear nerve, but it is only about one-third the size of the serve: (a) the median or paramedian vessels; (b) the short
oculomotor nerve. It innervates the ipsilateral lateral rectus circumferential (or short lateral) branches; and (c) the long
muscle. circumferential (or long lateral) branches.
Figure 17.20. Transverse section through the caudal pons showing the abducens nuclei at the level of the facial genu. 1,
cerebellar vermis; 2, dentate nucleus; 3, fourth ventricle; 4, abducens nucleus; 5, genu of the facial nerve; 6, facial colliculus;
7, lateral vestibular nucleus; 8, spinal nucleus of the trigeminal nerve; 9, spinal tract of the trigeminal nerve; 10, facial nucleus;
11, medial longitudinal fasciculus; 12, reticular formation; 13, fasciculus of facial nerve; 14, central tegmental tract; 15, medial
lemniscus and trapezoid body; 16, spinal and trigeminal nuclei; 17, middle cerebellar peduncle; 18, pontine nuclei and transverse
pontine fibers; 19, pyramidal tract. The arrows show the position of the cerebellar fastigial nuclei. (From Gluhbegovic N,
Williams TH. The Human Brain: A Photographic Guide. Hagerstown, MD: Harper & Row, 1980.)
The median branches emerge from the undersurface of the Abducens Nerve
basilar artery and penetrate the pons and medulla at regular
intervals. Their course is straight or slightly curved. The The abducens nerve emerges from the brain stem between
circumferential branches encircle the brain stem, entering its the pons and the medulla, lateral to the pyramidal promi-
substance laterally and superiorly (102,103). nence. The nerve then turns upward along the base of the
The proximity of the fascicular portion of the abducens pons lateral to the basilar artery (Fig. 17.19). The abducens
nerve to other important neural structures within the brain nerve is usually a single trunk that passes between the pons
stem explains the tendency for lesions that produce abducens and the anterior inferior cerebellar artery; however, it occa-
nerve paresis within the brain stem to cause other neurologic sionally exists as two separate trunks (104–106). In one pat-
signs. tern, the abducens nerve originates as a single trunk but splits
into two branches that enter the cavernous sinus separately; and 17.15). In addition, within the cavernous sinus, the abdu-
in a second pattern, the abducens nerve originates as two cens nerve is fused briefly with a branch of the carotid sym-
separate trunks that also enter the cavernous sinus separately pathetic chain, which then splits off and fuses with the oph-
(107). thalmic division of the trigeminal nerve to enter the orbit
Whether as one trunk or more, the abducens nerve ascends with the nasociliary nerve (108–111). The abducens nerve
through the subarachnoid space along the face of the clivus occasionally divides into up to five rootlets that rejoin later
and perforates the dura of the clivus about 1 cm below the to form a single nerve trunk before entering the orbit (86).
crest of the petrous bone. It bends laterally around or passes The abducens nerve enters the orbit through the superior
orbital fissure within the annulus of Zinn adjacent to the
through the inferior petrosal sinus and under the petroclinoid
lateral rectus (Fig. 17.1). In some individuals, a collagenous
ligament (Grüber’s ligament) to enter the cavernous sinus. septum separates the abducens nerve and the lateral rectus
Within the sinus, the abducens nerve courses anteriorly, from the other nerves at the orbital apex. In others, the nerve
bending laterally around the proximal portion of the cavern- continues for a short distance under the muscle belly before
ous carotid artery and running medially and parallel to the it is separated from the rest of the orbital contents by a sheath
ophthalmic division of the trigeminal nerve (86). The abdu- along the undersurface of the muscle (93). As with the other
cens nerve is not located within the lateral wall of the cavern- ocular motor nerves, the abducens nerve ramifies posteriorly
ous sinus as are the oculomotor and trochlear nerves, but it in the orbit, with the branches gradually entering the lateral
lies within the body of the sinus instead (86,87) (Figs. 17.14 rectus in a diffuse manner.
THREE DIMENSIONS OF EYE MOTION

The eyeball and the head undergo rotation with three de- tions have been heralded as ‘‘laws.’’ Listing’s law specifies
grees of freedom: rotation about the yaw axis is horizontal, the constraint on torsion expressed by Donders’ law. One
about the pitch (interaural) axis is vertical, and about the consequence of Listing’s and Donders’ laws is that motor
roll (naso-occipital) axis is torsional. In theory, the eye could efficiency is optimized. By ensuring that the eye stays near
assume an infinite number of torsional positions for any gaze the center of its torsional range, the laws permit quick re-
direction. However, during fixation, saccades, and smooth sponses to unpredictable targets that may appear from any
pursuit movements, eye rotation has only two degrees of direction.
freedom, with torsion being constrained. In other words, For the vestibulo-ocular and optokinetic reflexes, how-
there is only one fixed torsional eye position for each combi- ever, Listing’s law is violated. This violation is determined
nation of horizontal and vertical eye position. This constraint by the innervation of extraocular muscles in the planes of
on torsion is mediated by neural innervation (112–114), by
the semicircular canals. Head movement about the roll axis
the mechanical properties of the orbital tissue (18,115–120),
or a combination of both. Donders first described this phe- elicits ocular torsion to prevent images from slipping on the
nomenon by observing the rotation of his own eye about the retina (124,125). Similarly, rotation of retinal images around
visual axis using afterimages (121). Listing quantitatively the roll axis elicits torsional optokinetic smooth eye move-
defined the amount of torsion for each gaze direction ments (126). Vestibular and optokinetic movements are dis-
(122,123): any position of the eyeball can be reached from cussed later in the chapter. Here we emphasize that three-
primary position by rotation about an axis that is perpendicu- dimensional control of eye of movements is an important
lar to the line of sight in primary position. The collection of feature of ocular motor systems. For in-depth discussions of
these axes for all rotations that start from primary position three-dimensional eye movements, see Hepp (123) and
constitutes Listing’s plane. Donders’ and Listing’s observa- Wong (127).
PHASIC VELOCITY AND TONIC POSITION COMMANDS TO ORBITAL FORCES THAT

DETERMINE OCULAR MOTILITY
Before discussing the central organization of the different burst that is required to drive the eyes at saccadic speeds is
ocular motor systems, it is useful to review the nature of the called a pulse of innervation (128,130).
mechanical properties of the orbital tissues, since passive Once the eyes have been brought to a new position, they
forces must be overcome to move the eyes and, once the must be held there against orbital elastic forces that tend to
eyes are in position, to hold them in place. The predominant rotate the globe toward the primary position. To prevent
orbital forces are elasticity and viscosity (128,129). The mo- this centripetal drift, a sustained, tonic contraction of the
ment of inertia of the human eye is so small relative to other extraocular muscles must follow the phasic contraction pro-
tissue forces that for practical purposes it can be ignored. duced by the pulse of innervation. This sustained contraction
Viscous forces are the major hindrance to movement of the is called a step of neural activity (Fig. 17.21). For each posi-
globe within the orbit. For fast eye movements, therefore, a tion of the eye there is a specific step discharge rate of ago-
powerful phasic contraction of the extraocular muscles is nist motor units and a reciprocally lower step discharge rate
necessary to overcome viscous drag. This high-frequency for their antagonist motor units. Thus, because of the viscous
phasic discharge provides a ‘‘burst’’ of neural activity that and elastic forces in the orbit, the ocular motor control signal
stimulates muscle contraction. The very-high-frequency for a saccadic eye movement is a pulse and a step of innerva-
Figure 17.21. The pulse and step of force during and after a
saccade. Position (top) and velocity (center) of the right eye during
a rightward saccade and isometric torque developed in the left
eye (bottom) are shown while it is prevented from moving. The
pulse of torque ends with a gradual transition into a slide to the
step of torque required to hold the eyes in about 10⬚ of abduction.
A, saccade onset; B, time of peak velocity; C, time of peak torque;
D, end of saccade. (Adapted from Goldstein H, Reinecke R. Clini-
cal applications of oculomotor plant models. In: AF Fuchs, T
Brandt, U Büttner, D Zee, eds. Contemporary Ocular Motor and
Vestibular Research: A Tribute to David A. Robinson. New York:
Thieme Medical Publishers, 1994⬊10–17.)
tion (128,131). Both the pulse and the step must be of the eye position (tonic) commands. Indeed, ocular motor neu-
correct amplitude and appropriately matched for the eyes to rons discharge in relation to both velocity and position for
be moved rapidly from one position to another and held all types of eye movements. When the discharge occurs for
steady at the end of the movement. The pulse does not actu- low-velocity eye movements (i.e., smooth pursuit, or vestib-
ally have an abrupt offset before the step change in the activ- ular or optokinetic smooth eye movements), the phasic in-
ity of eye muscles. Instead there is a gradual decline (called crease (a velocity command) is usually smaller than that
a slide) in muscle torque after the saccade lands the eye at required for saccades. The tonic firing rate is an eye position
a specified position in the orbit (128,132,133). This slide command. Phasic-tonic (velocity-position) commands are
probably reflects a gradual transition from the high-fre- required for conjugate movements (versions) and vergence
quency discharge of motoneurons during the pulse to a movements (135). Groups of neurons in the brain stem teg-
lower-frequency discharge for the step (134). The innerva- mentum provide the prenuclear velocity and position com-
tion for a saccade then consists of a pulse-slide-step (Fig. mands for the phasic and tonic changes in innervation re-
17.21). quired for eye movements of appropriate speed and
The saccadic pulse and step are eye velocity (phasic) and amplitude.
CENTRAL ORGANIZATION OF THE OCULAR MOTOR SYSTEMS

SACCADIC SYSTEM inetic nystagmus, and the rapid eye movements that occur
during sleep (REM sleep) (136). The involuntary fast eye
Saccades are the rapid eye movements that quickly redi- movements that make up one phase of jerk nystagmus are
rect the eye such that an image of an object is brought to often termed quick phases rather than saccades, but vestibu-
the fovea. Here we use the term ‘‘saccade’’ for all fast eye lar and optokinetic nystagmus quick phases have ampli-
movements, including both voluntary and involuntary tude–velocity relationships like voluntary and visually
changes of fixation, the quick phases of vestibular and optok- evoked saccades (137–141) (Figs. 17.22 and 17.23).
Characteristics of Saccades
The visual stimulus for a saccade is usually an image of
an object of interest seen in the visual periphery. The ocular
motor system responds to the appearance of such a stimulus
with a saccade of the appropriate amplitude after a latency
period of several hundred milliseconds. Saccades can be
identified by their velocities and durations (138,142–148).
Saccadic Speed
Saccades show a relatively invariant relationship between
their peak velocity and their size: the larger the eye move-
ment, the higher its top speed (Fig. 17.22). The values for
most normal subjects fall within a relatively limited range
(137,142,147). This amplitude–peak velocity relationship
has been called the main sequence and can be used to identify
saccades as such (143). In normal individuals, the peak ve-
locity of saccades varies from 30 to 700 deg/sec, and their
duration varies from 30 to 100 msec for movements from
0.5⬚–40⬚ in amplitude (143,149,150). The peak velocity sat-
urates for large-amplitude saccades. This relationship is the
same for vertical and horizontal saccades and changes little
with age (147,148).
Saccadic velocities cannot be voluntarily controlled, but
they are reduced in association with mental fatigue or inat-
tention and are higher when directed to unpredictable visual
Figure 17.22. The relationship of saccadic amplitude to saccadic peak targets than when made to predictable targets or in darkness
velocity and duration in normal individuals. Note the broad range of maxi-
(137,150–152). The saccades of REM sleep are slower
mum and minimum peak velocity. (Redrawn from Zee DS, Robinson DA.
In: Thompson HS, Daroff R, Frisén L, et al, eds. Topics in Neuro-Ophthal-
than saccades made while awake (153). Furthermore, REMs
mology. Baltimore: Williams & Wilkins, 1979⬊266–285.) are not usually conjugate but are disjunctive or even mono-
cular in horizontal or vertical directions. Binocular misalign-
ment and disjunctive (even monocular) REMs during sleep
Figure 17.23. The vestibulo-ocular response to sustained rotation. Horizontal eye position is plotted against time. In the
lower tracing, the arrow represents the beginning of rotation of the patient to the right side in darkness. Note that the nystagmus
dies away after about 30–35 seconds. The nystagmus waveform is enlarged in the upper tracing. The nystagmus can be seen
to consist of slow phases (␤) opposite to the direction of head rotation that hold gaze steady and quick phases (␣) that not
only reset the eyes to prevent them from drifting to the side of the orbit but also move them in the direction of head rotation.
After about 45 seconds of content speed rotation there is reversal of the direction of nystagmus.
provide evidence that separate left eye and right eye path- 10% of the amplitude of the initial saccade (152) but is more
ways generate saccades in each eye and control the position prominent in older individuals (147,148,162) and with fa-
of each eye (6). Although saccadic velocities may be affected tigue or inattention (159).
by the alertness of a subject, they are not reduced by neuro- After a hypometric saccade is made, a corrective saccade
muscular fatigue (154,155). occurs, after a latency of only 100–130 msec, considerably
For a typical saccade, the eye accelerates rapidly, reaching less than the normal saccadic reaction time. Such corrective
its peak velocity between one-third and one-half the way movements can occur even when the target is extinguished
through the movement (Fig. 17.21). The eye then gently before the initial saccade is completed. Therefore, a nonvi-
decelerates but usually stops relatively abruptly (150). Occa- sual or ‘‘extraretinal’’ signal can provide information about
sionally, even in normal individuals, the eye drifts for a few whether the first movement is accurate, so that a corrective
hundred milliseconds after the initial rapid portion of the saccade can be triggered if necessary. This nonvisual infor-
horizontal saccade is finished. Such postsaccadic drift has mation is not proprioceptive (i.e., not using afferent signals
been called a glissade (156,157) and may represent a mis- from the extraocular muscles) but is based upon monitoring
match between the sizes of the phasic (pulse) and tonic (step) of efferent ocular motor commands, called efference copy
innervation that produce saccades. They can be conjugate or corollary discharge (48,169,170). Vision is certainly im-
(version), correcting for undershoot of the target, or disjunc- portant, however, since both the probability and accuracy
tive (vergence), compensating for divergence during the sac- of a corrective saccade increase if visual information about
cade, or purely monocular. Normal human saccades typi- retinal error (the distance of the image of an object from the
cally have no postsaccadic drift in the abducting eye and fovea) is available at the end of the initial saccade (171).
some onward drift in the adducting eye (158). Glissades Undershoots appear to improve the efficiency of the saccadic
occur more frequently in fatigued individuals (157,159). system (172,173).
At the end of a saccade, the eye occasionally makes an Although saccades can be made to imagined target loca-
immediate, oppositely directed, small saccade of about tions in darkness, such saccades are inaccurate. For at-
0.25⬚–0.50⬚ before coming to rest. This small saccade has tempted saccades made in darkness between the remembered
been called a dynamic overshoot (160) The incidence of locations of two targets 5⬚–70⬚ apart, the first attempts de-
dynamic overshoot is idiosyncratic and is thought to be viate by about 5⬚ from the appropriate angle (174). With
caused by a brief reversal of the central saccadic command, successive attempts, there is increasing deviation. In dark-
or by elastic restoring force in the eye muscle (158,161). ness, between saccades to eccentric positions in the orbit,
Dynamic overshoot is most conspicuous after small saccades the eyes drift slowly toward the midposition (175,176).
and often monocular, in the abducting eye. In fact, the mi-
crosaccades (about 0.20⬚) that occur during normal fixation Processing of Visual Information for Saccades
often consist of a pair of to-and-fro saccades of almost equal
size, with the latter saccade being a correction of dynamic During the period between the initial presentation of a
overshoot, so that the eye ends up almost where it started. visual target in the periphery and the subsequent saccade to
that target, if a target suddenly jumps to a new position and
Saccadic Latency (Initiation Time) then rapidly returns to its initial location before a saccade
to the new position, subjects still make a complete saccade
The interval between the appearance of a target of interest
toward the new (transient) target location (177) (Fig. 17.24).
and the onset of a saccade is normally about 150–250 msec.
Then, after a fairly constant interval of about 150–200 msec,
The latency period increases somewhat with ageing
subjects make a corrective saccade back to the original target
(147,162) and varies according to target luminance and pre-
position. The interval between saccades is relatively inde-
dictability (163). The introduction of a brief temporal ‘‘gap’’
pendent of the interval between the changes in target posi-
of several hundred milliseconds between the disappearance
tion. This suggested that (a) the saccadic system reacts to
of an initial fixation point and the presentation of a peripheral
only one stimulus at a time, and (b) there is an obligatory
target leads to a general reduction in saccadic latency to
refractory period following the end of a saccade during
about 100 ms; these short latency saccades are called express
which a second saccade cannot be produced. This is in part
saccades (164–167). Conversely, if the original fixation tar-
the rationale for the characterization of saccades as ‘‘prepro-
get remains on while a saccade is made to a new target, the
grammed’’ (177): once initiated, they cannot be modified
‘‘overlap’’ target condition delays the saccade onset well
and thus run their course unaffected by either visual or non-
over 200–250 msec. These gap and overlap conditions illus-
visual feedback. That behavior led to the ‘‘sampled data’’
trate effects of fixation and attention on the timing of sac-
system hypothesis that visual information is sampled to gen-
cades to new visual targets.
erate saccades (178,179). According to this hypothesis, when
Saccadic Accuracy a decision is made to generate a saccade based on the retinal
error (the distance between the peripheral retinal location of
Small degrees of both conjugate and disconjugate sac- an image and the fovea), the size and direction of the required
cadic dysmetria are normal: slight overshooting (hyperme- saccade are calculated and are irrevocable. A prepro-
tria) tends to occur with small-amplitude saccades and slight grammed saccadic eye movement command is then gener-
undershooting (hypometria) is usual with larger-amplitude ated based upon the visual information that was acquired
saccades (168). The degree of dysmetria is normally about during the initial visual sample. Once the saccade is com-
instant the target was flashed and the retinal error (in this
case, zero). The saccadic system can program movement in
a head coordinate as well as a retinal coordinate scheme
(182,183). Moreover, the amplitude of saccades can be
adapted to increase or decrease by moving a target to a new
position while the saccades are in flight. This adaptation
requires several hundred intrasaccadic movements of a target
A and is a form of motor learning (184,185). Finally, saccade
trajectories of patients with abnormally slow saccades can
be modified when the target position is changed after the
eye has already begun moving (186). Thus, normal saccades
appear to be preprogrammed only because of their high ve-
locities and brief durations. Once a saccade has begun, there
is usually not enough time to process the new visual informa-
tion required to modify the saccade before it has finished.
Vision During Saccades

B Although the visual world is rapidly sweeping across the
retina during a saccade, there is no sense of a blurred image.
Figure 17.24. The apparent ‘‘preprogrammed’’ nature of saccadic eye
movements. A, In response to a double target jump, there is a 150-msec
We do not seem to see during saccadic eye movements.
latency period before the eye moves. The eye then moves to where the However, there are instances where vision is quite clear dur-
target was after its initial movement, stays in this location for a set period ing saccades. For example, when looking at the track from
of time, and then moves back to the new (original) location of the target. a fast-moving train, the sleepers become visible only when
B, Even when the target jumps to a new location and then moves back to we make saccade opposite to the motion of the train, thereby
its original location following the eye movement, the eye remains in its stabilizing their image on the retina. Absence of blurring of
new position for the same amount of time as in A before moving back images during saccades has been called saccadic omission
to the new (original) target position. (Redrawn from Westheimer G. Eye
(187) and is caused by two factors: saccadic suppression,
movement responses to a horizontally moving visual stimulus. Arch Oph-
thalmol 1954;52⬊932–941.)
consisting of elevation of the threshold for detecting light
during a saccade (188,189), and visual masking, a process by
which the presence of a stationary, highly contoured visual
background before or after a saccade eliminates the percep-
pleted, the visual world is again sampled to determine tion of the blurred visual image during the saccade. Visual
whether another saccade is required to bring the image of masking is independent of eye movements, since it also oc-
the object of interest onto the fovea. If a retinal error still curs if a pattern is briefly moved across a stationary retina
exists, the entire process is repeated. at saccadic velocities (190–194).
Although this ‘‘sampled data’’ system hypothesis ac- Visual interactions reduce the response to visual stimula-
counts for some aspects of the saccadic system, it can acquire tion of many neurons in the striate cortex (area V1) and
and use visual information continuously up to about 70 msec the superficial layers of the superior colliculus of monkeys
before a saccade begins (180). This is about the time it takes during saccades (195–197). Reduced sensitivity in the activ-
visual information to traverse the retina and central visual ity in the magnocellular visual pathway is a cellular correlate
pathways and reach brain stem ocular motor structures. In of saccadic omission (198). Many neurons in the middle
addition, under certain conditions, two saccades may occur temporal (MT), middle superior temporal cortical (MST),
back to back with virtually no intersaccadic interval (180). and lateral intraparietal (LIP) (199) areas of monkeys are
Thus, there is no obligatory refractory period between sac- selectively silenced during image motion induced by sac-
cades. Rather, the central nervous system appears to be able cades, but they respond well to identical external image mo-
to process information in parallel and to program more than tion, when no saccades occur. In addition, some neurons in
one saccade at a time (181). Visual information can be ac- areas MT and MST reverse their preferred direction of mo-
quired even during a saccade and influence the time of the tion sensitivity during saccades. Consequently, oppositely
occurrence, size, and direction of subsequent saccades. directed motion signals annul one another, and motion per-
When a target is briefly flashed directly on the fovea during cepts are suppressed (200).
a saccade, a subsequent saccade can be produced that takes Constancy of spatial relations is also maintained during
the eye to the actual location of the target even though no after saccades. Although the visual scene shifts with each
retinal error ever existed (since the target was flashed on the saccade, we maintain our sense of straight ahead and piece
fovea) and the target is no longer visible (182). Thus, the together one view from many ‘‘snapshots’’ taken between
saccadic system can calculate the position of the target rela- saccades. This spatial constancy is probably accomplished
tive to the head using a combination of knowledge of the by extraretinal signals of the eye movement commands (ef-
position of the eye in the orbit during the saccade at the ference copy) to perceptual areas that register retinal input
with motor commands (170,201). Efference copy may re-

duce visual sensitivity, making motion less visible, and ex-
pand receptive fields of neurons to enable a smooth shift of
targets that flash into view at the onset of a saccade
(199,202).
Neurophysiology and Neuroanatomy of Saccadic Eye

Movements
Two classes of cells are essential components of the brain
stem circuits that produce saccades: burst neurons and omni-
pause neurons. Burst neurons are divided into excitatory and
inhibitory types. Excitatory burst neurons in turn are divided
into short-lead burst neurons and long-lead burst neurons
(short-lead burst neurons are sometimes called medium-lead
burst neurons). The immediate premotor command for the
saccadic pulse is generated by excitatory short-lead burst
neurons that lie within the paramedian reticular formation
in the pons (for horizontal saccades) (203) and in the par- Figure 17.25. The relationship among the discharges of excitatory short
amedian mesencephalon (for vertical and torsional saccades) lead burst cells (B), tonic cells (T), and omnipause pause cells (P) in the
(204) (Fig. 17.8). They deliver high-frequency discharges, generation of a saccadic eye movement. Omnipause cells cease discharging
at rates up to 1,000 Hz, to motoneurons 8–15 msec before just before the saccade, allowing the excitatory burst cells to generate a
and during saccades but are silent during fixation and during pulse of innervation with a rapidly increasing firing rate. During this period,
pursuit, vestibular, and optokinetic smooth eye movements. the eye moves to its new position. The tonic firing rate increases during
Long-lead burst neurons discharge irregularly for up to 100 the saccade and at the end of the burst cell activity, tonic firing rate is
msec before a saccade burst, and some are thought to activate appropriate to hold the eye in its new position. The rate remains constant
short-lead burst neurons. Long-lead burst neurons are lo- as long as the eye is held in the new position of gaze. (Redrawn from
Zee DS. In: Lessell S, van Dalen JTW. Neuro-Ophthalmology. Vol. 1.
cated predominantly in the rostral paramedian pontine retic-
Amsterdam: Excerpta Medica, 1980⬊131–145.)
ular formation (PPRF) and the midbrain reticular formation
(205,206); they also show a burst of activity just before and
during the saccade, and they may trigger saccades, encode
their direction or size, or relay saccadic commands from the eral superior colliculus; and ipsilateral projections from
superior colliculus and other areas (207,208). Omnipause brain stem structures, including the nucleus interstitialis of
neurons show a reverse pattern of firing to short-lead burst Cajal, nucleus of Darkschewitsch, and nucleus of the poste-
neurons; they have a high tonic discharge rate (over 100 rior commissure, the mesencephalic reticular formation, the
Hz), which is interrupted 10–12 msec before and during vestibular nuclei, the nucleus prepositus hypoglossi, and the
saccades in any direction (Figs. 17.9 and 17.25). Omnipause cerebellar fastigial nucleus (213–215).
neurons exert a tonic inhibition during fixation and smooth Electric stimulation within the caudal PPRF generates ip-
eye movements on short-lead burst neurons, preventing them siversive saccades (216). Damage that is confined to short-
from firing. During a saccade omnipause neurons are inhib- lead burst neurons in the caudal PPRF causes slow ipsiver-
ited, possibly by long-lead burst neurons in the rostral PPRF sive saccades, having prolonged durations, reduced peak ve-
and superior colliculus. Inhibition of omnipause neurons re-
locities, and normal or near-normal amplitudes (217,218).
leases short-lead burst neurons to activate motoneurons and
Paralysis of all ipsiversive conjugate eye movements was
dispatch a saccade (209) (Fig. 17.25). Inhibitory burst neu-
reported in earlier studies (219,220) and may have reflected
rons are activated by the excitatory short-lead burst neurons
at the same time as the omnipause cells cease firing (210). damage to vestibular nucleus projections carrying eye posi-
Omnipause cells serve as latch to release saccades and stop tion and smooth eye movement signals across the pons to
them. Inhibitory burst neurons inhibit the motoneurons to the abducens nucleus (221). Large, bilateral, pontine lesions
antagonist muscles just before and during the saccade. The that include the midline may also produce a vertical saccadic
discharge rate of motoneurons encodes saccadic velocity, paresis in addition to the horizontal defect (217,220,222).
and the discharge duration encodes saccade duration. Sac- Thus, pontine structures also participate in the generation of
cadic amplitude is consequently a function of both firing vertical saccades.
frequency and duration (211,212). Excitatory short-lead burst neurons in the caudal PPRF
excite the lateral rectus motoneurons and internuclear neu-
Brain Stem Generation of Horizontal Saccades rons that lie within the abducens nucleus (134,209). These
internuclear neurons are surrogate motoneurons for the me-
The PPRF receives bilateral projections from the frontal dial rectus muscle. Their axons cross the midline and ascend
eye field (FEF), in the frontal cortex around the arcuate sul- within the MLF to excite medial rectus motoneurons in the
cus; the intermediate and deep layers of mainly the contralat- contralateral oculomotor nucleus. Interruption of axons of
these abducens nucleus internuclear neurons causes paresis the ipsilateral eye and superior oblique motoneurons inner-
of adduction in the eye on the side of a lesion in the MLF, vate the muscle of the contralateral eye. Thus, these riMLF
the cardinal manifestation of internuclear ophthalmoplegia burst neurons on one side excite downward movements of
(see Chapter 19). About 80% of short-lead burst neurons both eyes and dysconjugate torsion, greater in the contralat-
in the caudal PPRF, which were once thought to encode eral eye, with the upper poles rolling toward the ipsilateral
conjugate velocity commands for saccades, actually encode side. One short-lead burst cell in one riMLF sends axons to
monocular movements of either abduction or adduction (7). motoneurons of yoked pairs of muscles: By this dual projec-
This behavior is contrary to Hering’s law. Moreover, most tion pattern, short-lead burst neurons can each drive vertical
abducens motor neurons, which innervate the lateral rectus motoneuron pools of both eyes during conjugate vertical
muscle, fire with both ipsilateral and contralateral eye move- rapid eye movements (Fig. 17.26); these data support He-
ments (5,7). ring’s law (4,232).
Inhibitory burst neurons for horizontal saccades are lo- The omnipause neurons located in the caudal pons cease
cated just caudal and ventral to the abducens nucleus in the firing to generate vertical and torsional saccades as well as
reticular formation of the rostral medulla (Fig. 17.9) and horizontal saccades (Fig. 17.9). Inhibitory burst neurons for
send their axons across the midline to the motoneurons and vertical and torsional saccades reside within the riMLF
internuclear neurons in the contralateral abducens nucleus (230,231,233,234).
(210,223). Inhibitory burst neurons act to suppress activity Unilateral lesions of the riMLF abolish torsional saccades
of the contralateral (antagonist) abducens nucleus during ip- toward the side of damage and induce torsional nystagmus
siversive saccades. Saccades in one direction are driven by and tonic torsional deviation, with the upper poles of the eyes
yoked agonist muscles in the two eyes. Normal trajectories beating and rotated toward the opposite side, in monkeys
of saccades require reciprocal inhibition of yoked antagonist (235,236) and humans (237,238). Unilateral lesions of the
muscles. Inhibitory burst neurons provide this reciprocal INC cause tonic torsion to the opposite side, like the effect
pulse of inhibition. A pulse-step of excitation in agonist mo- of riMLF lesions. INC lesions also produce torsional nystag-
toneurons is accompanied by a pulse-step of reduced firing mus, but the nystagmus fast phases are directed toward the
rate in antagonist motoneurons. side of the lesion, unlike the effect of riMLF lesions (239).
In humans, excitatory short-lead burst neurons lie in the Unilateral INC lesions also cause the ocular tilt reaction, as
nucleus reticularis pontis caudalis, and inhibitory burst neu- we discuss later in this chapter. While the deficits after a
rons are the medial part of the nucleus paragigantocellularis riMLF lesion result from an imbalance of the saccade gener-
dorsalis (Figs. 17.8 and 17.9) (203). Omnipause neurons re- ator, a vestibular imbalance probably causes the deficits after
side in the nucleus raphe interpositus (rip) in the midline of an INC lesion (239,240).
the caudal pons, between the excitatory burst neurons ros- Effects of discrete lesions on vertical gaze in monkeys
trally and the inhibitory burst neurons caudally, at the level and humans are largely consistent with information that is
of the abducens nuclei (Fig. 17.9) (224,225). emerging from single neuron studies. Lesions in structures
within the mesencephalon, namely the riMLF, the posterior
Brain Stem Generation of Vertical and Torsional commissure, and the INC, create vertical saccadic palsies
Saccades (241–245). The mixture of neurons with up-and-down pre-
saccadic activity in the riMLF and INC indicates that selec-
Vertical saccades are generated by excitatory short-lead tive palsies of upward and downward conjugate eye move-
burst neurons in the rostral interstitial nucleus of the MLF ments are not produced by discrete lesions within these small
(riMLF) (Figs. 17.8 and 17.9). Those for upward and down- nuclei, but rather by lesions that disrupt projections from
ward saccades are intermingled in this nucleus (204, the nuclei to the oculomotor and trochlear nuclei. Such le-
226–228), although in cats upward burst neurons are con- sions are bilateral, or unilateral and so close to the midline
centrated in its caudal part and downward burst neurons are that they involve axons that cross the midline within com-
more rostral (229). In squirrel monkeys, short-lead burst neu- missural fiber tracts. Since excitatory burst neurons with
rons with upward on directions descend directly in the MLF upward on-direction project bilaterally to oculomotor nu-
bilaterally to the superior rectus and inferior oblique sub- cleus neurons, whereas neurons with downward on-direc-
nuclei of the oculomotor nucleus with axon collaterals cross- tions project ipsilaterally to motoneurons of the oculomotor
ing within the oculomotor nucleus. They supply the superior and trochlear nuclei (230,231), isolated lesions of the riMLF
rectus and inferior oblique muscles of both eyes (230,231) are more likely to selectively impair downward saccades
(Fig. 17.26). They also give collateral axons to the interstitial (245). Either unilateral or bilateral pretectal lesion near the
nucleus of Cajal (INC), which integrates the pulse delivered posterior commissure may destroy projections from both
to it from the riMLF into a step and transmits it to motoneu- riMLF and the INC, selectively abolishing upward saccades.
rons (neural integration of the pulse is discussed below). The nucleus of the posterior commissure also contains
riMLF short-lead burst neurons for downward saccades upward short-lead burst neurons that project across the com-
project directly to the inferior rectus subnucleus of the oculo- missure (230). The nucleus of the posterior commissure
motor nucleus and to the trochlear nucleus, on the same side, projects to the contralateral nucleus of the posterior commis-
and send collaterals to the ipsilateral INC (230,231) (Fig. sure, riMLF, and INC and intralaminar nucleus of the thala-
17.26). Inferior rectus motoneurons innervate the muscle of mus. Lesions of the posterior commissure paralyze upward
A B
Figure 17.26. Midbrain pathways for the generation of vertical saccades. Downward acting neurons are shown on the left
side and upward acting neurons on the right side of A and B. A, Projections to superior rectus (SR) and inferior oblique (IO)
motoneurons for upward saccades. B, Projections to inferior rectus (IR) and superior oblique (SO) motoneurons for downward
saccades. Open circles indicate excitatory neurons and filled circles indicate inhibitory neurons. The riMLF provides only
excitatory projections to motoneurons in the oculomotor (III) and trochlear nuclei (IV), and presumably to premotor down-
burst-tonic neurons in the iC, which themselves excite SO motoneurons of the same side. Further, the motoneurons receive
an inhibitory GABA-ergic input from the contralateral iC. These inhibitory neurons could be activated by premotor up-burst
neurons in the riMLF, thereby inhibiting the SO and IR motoneurons during upward saccades. It is not clear whether inhibitory
projection via the posterior commissure (PC) is mediated via collaterals from premotor burst-tonic neurons in the contralateral
interstitial nucleus of Cajal (iC) (question mark) or by separate projections. It is possible that inhibitory neurons in the iC may
include non-premotor saccade-related up- and down-burst neurons in the iC (question mark, left side). Down-burst neurons
project back to the ipsilateral riMLF, and there is some evidence that saccade-related up-burst neurons project to the contralateral
iC (iCc). Aq, aqueduct of Sylvius. (Adapted from Horn AK, Helmchen C, Wahle P. GABA-ergic neurons in the rostral
mesencephalon of the macaque monkey that control vertical eye movements. Ann NY Acad Sci 2003;1004⬊19–28.)
saccades in monkeys and humans (241,243,246) as part of ing signals from the PPRF and descending signals from the
the pretectal syndrome (see Chapter 19); anatomic or electro- superior colliculus (SC) and cerebral hemispheres to the
physiologic evidence that nucleus of the posterior commis- riMLF seems uncertain.
sure fibers transmitting commands for upward saccades tra-
verse this prominent structure is scanty (230,247). Discrete Neural Integration of the Saccadic Pulse
posterior commissure lesions in squirrel monkeys produce
postsaccadic drifts, velocity reduction, and phase advance The pulse-step of innervation that drives ocular motoneu-
of the vestibulo-ocular reflex (VOR). Posterior commissure rons during saccades (Fig. 17.21) is generated by premotor
fibers are necessary for conveying the output of the vertical neurons in the brain stem tegmentum. Short-lead burst neu-
neural integrator to vertical oculomotor neurons (247). rons deliver the pulse, an eye velocity command, to moto-
As noted above, bilateral PPRF lesions that include the neurons. The saccadic step, an eye position command, is
midline may also produce a vertical saccadic paresis in addi- created from the pulse by a neural network that integrates,
tion to a bidirectional horizontal saccadic palsy (217, in the mathematical sense, conjugate eye velocity commands
220,222). The PPRF contains excitatory burst neurons with into the appropriate position-coded information (step) for
on-directions for oblique saccades having either upward or the ocular motoneurons. This neural integrator is reflected in
downward vectors (207,248). Signals from these oblique the activity of neurons located within the INC and vestibular
burst neurons on each side of the PPRF might sum to cancel nucleus for vertical and torsional movements (251–254) and
horizontal vectors in opposite directions, and transmit veloc- in the medial vestibular nucleus (MVN) and adjacent nucleus
ity commands for upward or downward saccades to the prepositus hypoglossi (NPH) for horizontal movement
riMLF neurons on each side. Damage to either the oblique (255–259). Burst-tonic neurons in the MVN and the NPH,
burst neurons in the PPRF or pause neurons in the rip (249) which lies immediately medial to the MVN (Fig. 17.9), carry
might cause paresis of vertical saccades. Direct projections eye position and eye velocity signals during conjugate sac-
from the FEF in the cerebral hemispheres to the riMLF have cades and fixation as well as during disjunctive saccades
been demonstrated (250). The relative importance of ascend- and fixation. Burst-tonic neurons preferentially encode the
position and the velocity of a single eye (9), contrary to ing that certain drugs slow saccades but do not alter their
expectations from Hering’s law. These burst-tonic neurons accuracy (267).
shape the pulse-slide-step saccadic discharges of abducens Saccades are initiated by trigger signals from the cerebral
nucleus neurons to which they project. hemispheres and superior colliculi that inhibit omnipause
The velocity-to-position neural integrator is not perfect. neurons. Inhibition of these omnipause cells releases the dis-
In darkness, after an eccentric saccade, the eyes drift back charge of excitatory burst neurons and the duration of their
toward orbital midposition at a rate that is determined by firing determines the amplitude of saccades. A command
elastic restoring forces in the orbit relative to the opposite signal of desired eye position (e.g., retinal target error),
force generated by the tonic step of muscle discharge (257). which is independent of the trigger signal, determines how
The centripetal drift occurs because the integrator dis- long the burst cells fire (Fig. 17.27). Collaterals of short-
charges. It is said to be ‘‘leaky.’’ Drift rate declines exponen- lead burst neurons excite inhibitory burst neurons, which
tially and can be expressed by a time constant; after one inhibit the omnipause cells and antagonist motoneurons dur-
time constant, the eye velocity declines to 37% of its initial ing the saccade. The burst output provides an eye velocity
value and after three time constants, eye movements have command, which is also integrated to create a new eye posi-
nearly stopped. The time constant of centripetal eye drift in tion command (the step). The pulse is also believed to be
darkness is 20–70 seconds (174,260). The time constant of integrated by another resettable integrator to provide a feed-
orbital restoring forces that return the eye toward midposi- back signal of eye position, which inhibits the excitatory
tion is about 200 msec. Thus, even in darkness, the neural burst neurons (131,208,218,265,268). The eye velocity sig-
integrator greatly prolongs the mechanically determined nal must also be multiplied by an eye position signal before
centripetal drift of the eyes. In the light, visual feedback being transformed by the neural integrator into an eye posi-
prevents the integrator from leaking. This eye position hold- tion command (263). Once the actual eye position matches
ing depends on the integrity of the flocculus, the ventral the desired eye position, the burst cells cease firing, the om-
paraflocculus, or both (261). The activity of the horizontal nipause cells resume their tonic activity, and the saccade
neural integrator is distributed among the NPH, the vestibu- stops.
lar nucleus, and the flocculus. Damage to the NPH and MVN
or flocculus causes gaze-evoked nystagmus with centripetal Cerebral Control of Saccadic Eye Movements
decelerating slow phases (255,259,262). Destruction of the
Two major classes of saccades are generated by the cere-
NPH alone does not eliminate the integrator; rather, the time
bral hemispheres: (a) reflexive visually guided saccades in
constant of centripetal drift decreases to 10% of its normal response to the sudden appearance of targets on the retina
values but remains 10 times longer than that attributable to and (b) volitional saccades that are internally triggered to-
the mechanics of the orbit (257). ward a target. In actual behavior, both modes of saccade
Because the eye moves in three dimensions and the order generation act in concert, as when a person decides to look at
of movements is independent, the integral of angular eye one of several suddenly appearing objects. Visually guided
velocity does not yield angular eye position in three dimen- saccades are often elicited to a newly appearing target while
sions. Therefore, the neural integrator does not process eye a person is looking at a prior target. In the laboratory this
velocity signals alone. Instead, eye position signals must be is tested with a continually appearing target and a sudden
fed back and multiplied by eye velocity signals before they peripheral target that the person is required to refixate; this
are integrated to transform eye velocity into appropriate eye
position commands (263). Velocity-to-position transforma-
tion is used by all eye movement systems, as we discuss
later in this chapter.
Feedback Control of Saccades

Precisely how the central nervous system controls the in-
tensity and duration of the saccadic burst is unknown. Stud-
ies of patients with slow saccades have led to the hypothesis
that saccades may be generated by a mechanism that drives
the eyes to a specific orbital position (186). Through a ‘‘feed- Figure 17.27. Model for generation of saccades. Fixation maintains activ-
back loop’’ that allows continuous comparison of the actual ity of omnipause pause neurons (P) until a trigger signal inhibits them,
(based on monitoring of internal ocular motor com- releasing excitatory short-lead burst neurons (BN). BNs excite inhibitory
mands—efference copy) and the desired (based on visual burst neurons (IBN), which stop pause cell activity and also inhibit motor
information regarding target position) eye position, the burst neurons of antagonist muscles. The burst neurons send a velocity command
(the pulse) to motoneurons (MN) and to the neural integrator (NI), which
neurons could be driven until the eye reaches the target creates a position command (the step) for the eye. Another integrator, reset-
(208,264,265). Further support for this type of mechanism table after each saccade (RI), creates a negative feedback signal of eye
comes from recordings of the activity of burst neurons during position, delivered after a delay (DEL), to BN. When actual eye position
saccades (264), from the behavior of vestibular quick phases equals desired eye position, BNs cease firing, pause cells are disinhibited,
during high-velocity head rotations (266), and from the find- and the saccade stops.
is called the overlap task. The refixation saccade requires tional MRI (fMRI), and cortical stimulation indicate that the
disengagement of attention, shifting of attention from the FEF in humans is located in the posterior part of the middle
fixation target to the new target, and the disengagement of frontal gyrus and the adjacent precentral sulcus and gyrus
fixation. If the original fixation target is extinguished for a (272–277) (Fig. 17.28). The FEF receives projections from
gap of about 200 msec before the new target appears (a several cortical areas, notably the lateral intraparietal area
paradigm named the gap task), fixation is disengaged more (LIP; also called the parietal eye field), supplementary eye
rapidly and many ‘‘express’’ saccades are dispatched at very field in the cingulate gyrus, prefrontal cortex, and superior
short latencies of about 100 msec (165,269). temporal cortex as well as from the pulvinar and intralaminar
Volitional saccades may themselves be of three categor- nuclei of the thalamus. Cerebral metabolism increases in
ies: (a) predictive, when a target is expected at a location the FEF during fixation, self-paced saccades in darkness,
but has not yet appeared or when self-paced saccades are reflexive visually guided saccades, memory-guided saccades
made between preselected targets; (b) memory guided, to- in a delayed task after target disappearance, and antisaccades
ward the remembered positions of targets on the retina (i.e., (270,274,278). Metabolic activity in the human FEF in-
with visual memory) or toward the remembered position of creases progressively from tasks requiring fixation, to para-
gaze direction before the head is rotated (i.e., with vestibular digms that elicit reflexive saccades to visual targets, to para-
input); and (c) saccades directed away from the position of digms for volitional saccades guided by memory or away
a suddenly appearing target; the latter are called antisaccades from targets (274). This is consistent with the observation
since they direct the fovea away from a visual target by Funahashi et al. (279) that FEF lesions in monkeys impair
(182,270,271). Attention and volitional effort are especially memory-guided saccades more than visually guided sac-
demanded when making antisaccades, since reflexive saccades. A population of neurons in the FEF discharge before
cades to the visual target must be suppressed. and specifically in relation to visually guided saccades to
seen or remembered targets (280). Lesions of the FEF pro-
FRONTAL EYE FIELDS
duce deficits in generating saccades to briefly presented
Two structures, the FEF and the SC, appear to be critical targets, in the production of saccades to two or more
for the generation of visually guided and volitional saccadic sequentially presented targets, and in the selection of simul-
eye movements. Positron emission tomography (PET), func- taneously presented targets (281).
Figure 17.28. Probable locations of cortical areas involved in cerebral control of eye movements in humans. MT, middle
temporal visual area; MST, medial superior temporal visual area. (Adapted from Leigh RJ, Zee DS. The Neurology of Eye
Movements. Oxford, UK: Oxford University Press, 1999.)
Stimulation within the FEF produces contralateral sac- burst T neurons, buildup neurons, and fixation neurons. Fix-
cades, usually with a vertical component. The size and direc- ation neurons in the rostral pole of the SC keep the buildup
tion of the saccade are determined by which region is stimu- neurons silent and the eyes still until a new target appears
lated; the organization is in retinal coordinates. Purely and activates the buildup cell population, which discharges
vertical saccades can be produced by simultaneously stimu- as a rostrally spreading wave, or moving hill, to inhibit fixa-
lating corresponding points in the FEF of both hemispheres, tion cells (294,295). Buildup cells (also referred to as prelude
thus nullifying the horizontal components (282). cells) were thought to activate saccades through their trajec-
FEF neurons project caudally in the anterior limb of the tories; however, this spreading wave theory is challenged
internal capsule and reach the premotor structures of the by the finding that buildup activity would arrive at the fixa-
brain stem by four pathways: fibers to the striatum (caudate tion zone much too late to terminate saccades at the appropri-
nucleus and putamen); a dorsal, transthalamic pathway to ate time (296). Instead, buildup neurons may help to trigger
thalamic nuclei; a ventral pedunculo-tegmental pathway; saccades by inhibiting the collicular fixation cells, which
and an intermediate pathway (214,215). Projections are to excite omnipause neurons in the midline of the pons. The
the ipsilateral superior colliculus and to the rip of the caudal colliculus projects to omnipause neurons (297). The rostral
pons, and to the nucleus reticularis tegmenti pontis (NRTP)
SC fixation cells excite them monosynaptically to maintain
and riMLF (Fig. 17.9), and to the caudal PPRF on each side
fixation. Cells in the caudal and rostral SC inhibit the pontine
(213,250,283). Projections to the omnipause neurons in the
omnipause neurons disynaptically (298) (Fig. 17.29). The
nucleus rip probably trigger saccades, whereas projections
inhibitory interneurons may be located close to the omni-
to the NRTP may be important in transmitting saccade direc-
tion and amplitude information to burst neurons in the PPRF pause neurons in the rip, or in the NRTP (298). Short-lead
(214,215,283).
SUPERIOR COLLILCULUS
The paired superior and inferior colliculi appear as four

small swellings or eminences that protrude from the tectum
(i.e., the roof of the mesencephalon; Fig. 17.8). Although
the SC is a brain stem structure, we discuss it here with
cerebral cortical areas because of its close relationship to
cerebral generation of saccades. Each SC has seven alternat-
ing layers of cells and fibers (284) that can be divided into
two functional parts, superficial and deep. The superficial
layers are primarily involved in visual sensory function. The
SC receives visual input both from the retina directly via
the optic tract and indirectly from the visual cortex. The deep
layers of the SC are concerned with ocular motor function.
Cortical afferents to the deep layers include the striate,
prestriate, auditory, and somesthetic cortex, parietal and tem-
poral cortical areas, prefrontal cortex, and FEF.
The SC receives two projections from the FEF: a direct
one (285) and an indirect one via the caudate nucleus and
the pars reticulata of the substantia nigra (SNpr) (286–290).
The parietal eye field (area LIP) also projects to the SC
(291). Intermediate layers of the SC contain saccade-related
burst neurons, called T cells in monkeys because of their
morphology. T cells discharge in relation to contraversive
horizontal and vertical saccades. Saccadic eye movements
of different sizes and directions are represented in an orderly
topographic map across the intermediate and deep layers of Figure 17.29. Frontal eye field projections to brain stem showing hypo-
the SC, where large saccades are encoded caudally and small thetical connections for triggering saccades. Frontal eye field (FEF) neurons
saccades rostrally. T neurons for downward saccades are turn off omnipause neurons (OMP) by exciting inhibitory interneurons.
lateral, neurons for upward saccades are medial, neurons for Signals from FEF or the SC determine saccade amplitude and direction.
large horizontal saccades are caudal, and those for small This spatial command is translated into a temporal code, the duration of
EBN cell discharge. EBN cells are called short-lead burst neurons in the text.
horizontal saccades are rostral in the SC (292,293). Thus, Filled synapses are inhibitory. SCi, intermediate layer of superior colliculus;
the SC contains a retinotopically organized motor map in LLB, long-lead burst neuron; EBN, medium-lead excitatory burst neuron.
which each site is thought to encode a specific saccade (Adapted from Segraves MA. Activity of monkey frontal eye field neurons
vector. projecting to oculomotor regions of the pons. J Neurophysiol 1992;
Three types of SC cells participate in generating saccades: 68⬊1967–1985.)
and long-lead burst neurons in the PPRF receive excitatory lobe will evoke saccades only if either the FEF or SC remains
projections from the SC (205,206,299,300). SC fixation neu- intact. The FEF and SC appear to be parallel gatekeepers of
rons and pontine omnipause neurons are inhibited to dispatch cerebral control of saccadic eye movements.
saccades, and burst T neurons are proposed to activate short- Thus, there are two parallel pathways through which sac-
lead excitatory burst neurons in the PPRF to drive them to cades may be triggered: one through the FEF and the other
their targets (Fig. 17.29). through the SC. Lesions of either pathway alone produce
Damage to either the FEF or the SC alone produces rela- only mild defects, while lesions of both cause profound,
tively subtle ocular motor defects. A unilateral FEF lesion permanent saccadic defects. As noted above, ablation of the
in humans causes increased latency and reduced amplitude SC alone eliminates express saccades, perhaps being acti-
of initial visually triggered random, predictable saccades, vated more directly by visual afferents to the SC (305,310).
and memory-guided saccades contralateral to the lesion or in
both directions (301,302). Patients with large chronic frontal
SUPPLEMENTARY EYE FIELD
lobe lesions on one side involving prefrontal cortex (area
46) show another defect in higher-level control of saccadic The anterior part of the supplementary motor area in the
eye movement. When a visual stimulus is presented in their upper part of the paracentral sulcus of the dorsomedial fron-
contralateral visual field and they are instructed to make tal cortex is also called the supplementary eye field (SEF)
saccades away from it (antisaccades), they cannot suppress (Fig. 17.28) since it contains neurons that discharge before
an unwanted saccades toward that stimulus (303,304). How- volitional and visually guided saccades and stimulation there
ever, according to Rivaud et al. (302), lesions more restricted elicits saccades. The pre-SEF located just anterior to the SEF
to the human FEF do not impair the ability to make antisac- also participates in saccade control (315–317). Unlike the
cades and suppress reflexive saccades. FEF ablation in mon- effect of FEF or SC stimulation, where contralateral sac-
keys does not eliminate express saccades, whereas SC abla- cades of specific amplitude are evoked irrespective of initial
tion does (305). The FEF may participate in the unlocking eye position, stimulation of SEF elicits saccades toward a
of fixation required to dispatch saccades (302,306), but it is specific region of the orbit. In other words, the FEF and the
not critical for this function. SC elicits saccades in retinotopic space, whereas the SEF
Inactivation of the FEF in one hemisphere does not elimi-
elicits saccades in craniotopic space, which is synonymous
nate the generation of contralateral saccades. After intraca-
with eye position in the orbit (317). Neurons in the SEF fire
rotid injection of sodium amobarbital to suspend function
individually in relation to retinal goals (315), but populations
of one cerebral hemisphere, patients can produce both ipsi-
of SEF neurons extract craniotopic information from them
lateral and contralateral saccades similar to those produced
(316). The anterior part of the SEF encodes saccade termina-
before injection (307). In addition, voluntary saccades are
tion zones in the contralateral hemirange of the orbit, and
preserved while visually guided saccades show only pro-
longed latency and mild slowing in both horizontal direc- the posterior SEF encodes saccades that finish straight ahead
tions after chronic hemidecortication (308,309). These find- or in the ipsilateral hemirange. Furthermore, the lateral SEF
ings indicate that other structures, namely the intact cerebral encodes for saccades terminating in the upper orbit, while
hemisphere and the SC, can generate saccades even when the medial SEF encodes saccades ending in the lower orbit.
the FEF and parietal lobe are inactivated, and demonstrate Continuing stimulation of the SEF regions maintains fixation
that the inability to perform contralateral saccades after an in specific fixation regions of the orbit and inhibits visually
acute hemispheric lesion is not caused solely by inactivation evoked saccades.
of the frontal lobe. The SEF has anatomic connections to the parietal eye field
In monkeys, bilateral ablation of the FEF causes a tran- (PEF) in the LIP area, the FEF, and the SC (318). Ablation
sient decrease in frequency and amplitude of saccadic eye of the FEF has a negligible effect on saccades evoked by
movements (305,310,311). Bilateral removal of the SC stimulation of the ipsilateral SEF, and ablation of the SC
causes only a slight increase in saccadic latency and a de- merely increases their latency and reduces their amplitude
crease in saccade amplitude (312,313). Such monkeys also but does not eliminate them (319). The SEF is thought to
show enhanced fixation with decreased distractibility. When mediate saccades to specific orbital positions by projections
viewing a central target, they are less likely to glance at a to the SC and mesencephalic reticular formation and perhaps
distracting stimulus presented in the visual periphery. How- the NRTP (320,321). The SEF’s role in fixation might be
ever, lesions restricted to the rostral pole of the SC impair effected by its excitation of the fixation cells of the rostral
fixation and increase the frequency of express saccades by SC (294,295,314), since ablation of the SC eliminates the
disinhibiting the rest of the intermediate layer (314). inhibition of saccades that occurs during SEF stimulation
In marked contrast to the above findings, sequential bilat- while the eyes are positioned in specific fixation regions
eral ablations or cooling of both SCs as well as both FEFs, (319).
with either structure being removed before the other, pro- Effects of lesions and transcortical magnetic stimulation
duces a marked paralysis of visually guided saccades and study in humans suggest that the SEF participates in learn-
spontaneous saccades in all directions (310,311). The ocular ing, planning, and triggering of memory-guided sequences
motor range for saccades is limited to only 5⬚–10⬚ away of saccades (322,323). PET shows that the SEF and adjacent
from central fixation. Stimulation of the occipital or parietal cingulate gyrus are active during volitional saccades, be they
self-paced, or antisaccades, or memory-guided to previous DORSOLATERAL PREFRONTAL CORTEX

visual targets, but this region is not active during reflexive Neurons in the dorsolateral prefrontal cortex (Fig. 17.28)
saccades to visual targets (272–274,278). It seems that the in Brodmann areas 46 and 9 (Fig. 17.30), located anterior
SEF plays a predominant role in directing voluntary se- to the FEF, are active in visuospatial memory coding and
quences of saccades to positions relative to the head and when making antisaccades and suppressing reflexive sac-
maintaining fixation there. The SEF is more involved in the cades (279). They project to the FEF, SEF, and SC and
learning of new tasks than is the FEF. Also, with continued receive input from the posterior parietal cortex. Lesions to
training on behavioral tasks, the responsivity of the SEF this area impair the ability to make antisaccades and suppress
drops. Accordingly, the SEF is more involved in learning unwanted reflexive saccades to visual targets in humans
operations, whereas the FEF is more specialized for the exe- (304) and impair memory-guided saccade sequences in hu-
cution of saccades (281). The SEF is primarily involved in mans and monkeys (279,322). PET in humans indicates that
the process of planning, decoding, and updating new saccade the dorsolateral prefrontal cortex is not activated during vol-
sequences, whereas the FEF plays a major role in determin- untary self-paced saccades in darkness (325), although it is
ing the direction of forthcoming saccades (324). activated during memory-guided saccades to a single target
Figure 17.30. Cytoarchitectural map of the human cor-

tex showing Brodmann areas. A, Convex surface. B, Me-
dial surface. The cortical areas of greatest importance with
respect to ocular motor activity are areas 6, 8, 19, 37, 39,
40, and 46. (From Strong OS, Elwyn A. Human Neuro-
anatomy. 3rd ed. Baltimore: Williams & Wilkins, 1953.)
(274,278). During antisaccades, the most demanding type ory of a saccade plan, which is probably derived from the
of volitional saccade, the dorsolateral prefrontal cortex, FEF, FEF and dorsolateral prefrontal cortex. The PEF renders the
and SEF are preferentially activated (274). Functional imag- goal of the saccade to a salient location for attentional pro-
ing indicates metabolic activity in a cortical location during cesses and possibly to provide targets for future saccades.
a task relative to fixation, darkness, or another eye movement The PEF contains a salience map that uses the saccade signal
task, whereas the lesion location identified with a behavioral to provide information that updates visual representation to
deficit signifies a critical cerebral area (including subcortical compensate for an eye movement, thus maintaining a spa-
white matter connections), without prompt compensation by tially accurate vector map of the visual world despite a mov-
other cerebral areas that have redundant functions. The dor- ing eye (343).
solateral prefrontal cortex contributes mainly to the ad- The MST and the foveal region of the MT area of monkeys
vanced planning of environmental scanning using memory and its human homolog, area V5, which participate in motion
of target location. perception and smooth pursuit generation (discussed below),
also provide information to generate saccades to moving
PARIETAL CORTEX targets. Lesions to these areas cause retinotopic defects so
that saccades to a target moving in the contralateral visual
Stimulation of the LIP area, in the intraparietal sulcus of field are inaccurate in all directions (344–347). Projections
the inferior parietal lobule of monkeys, elicits saccades, and from striate cortex (area V1) to V5, and from V1 to the lateral
lesions to it delay reflexive saccades to visual targets intraparietal area make up part of the dorsal, magnocellular
(326,327). The LIP area is designated as the PEF (328,329) pathway for processing motion, attention, and visuomotor
(Fig. 17.28). Neurons in this area discharge in relation to interaction (348) that is concerned with generating saccades
visually guided saccades but are independent of visual stimu- to visual targets.
lation since they also discharge during memory-guided and
BASAL GANGLIA
learned saccade tasks (330,331). The PEF receives projec-
tions from the FEF, and PEF neurons project to the FEF and The caudate nucleus receives input from the FEF and
SC (332) While destruction of either the PEF or the FEF projects to the SNpr, which in turn projects to the intermedi-
produces subtle saccadic defects of visually guided saccades ate layer of the SC. Caudate neurons discharge before contra-
in monkeys, combined bilateral ablation of the PEF and abla- lateral memory-guided and visually evoked saccades
tion of one FEF, or bilateral ablation of the FEF and ablation (349–351). Output from the FEF is routed through the cau-
of one PEF, produces paralysis of visually guided saccades date, with the caudonigral circuit disinhibiting the SC. The
for several days, followed by some recovery to profound caudate inhibits the SNpr and the SNpr inhibits the SC, both
delay and hypometria of saccades (333). The recovery may inhibitory synapses being GABA-ergic. SNpr neurons are
be mediated by the SEF, or superior temporal polysensory tonically active during fixation and they pause, disinhibiting
area (334), and their projections to the SC and other brain SC burst neurons that fire before and during saccades to
stem structures. visual and remembered targets (287–290,352,353). Thus,
Area 7a of the monkey posterior parietal cortex in the the FEF has a powerful two-pronged excitatory effect on the
inferior parietal lobule also contain neurons that discharge SC, one direct and the other through the caudate and SNpr.
in relationship to saccades (335–337). These cells, however, The ventral part of the subthalamic nucleus sends excitatory
are more tightly linked to directed visual attention than to signals to the SNpr and might act to suppress unwanted eye
any specific type of motor behavior, since they also dis- movements, and recover fixation after saccades by indirectly
charge with limb movements as well as when the animal is inhibiting burst cells in the SC (354).
simply required to pay attention to—but not saccade to—a Functional imaging indicates that the putamen and globus
peripheral target (338). The superior parietal lobule (Fig. pallidus as well as the thalamus are metabolically activated
17.28) is also concerned with attention shifting as a prelude with voluntary self-paced saccades and memorized se-
to saccades (337,339,340). quences of saccades in darkness, but not with visually guided
Functional imaging has revealed that the human posterior saccades (273,274). Volitional saccades may utilize a basal
parietal cortex is activated during visually guided reflexive ganglia-thalamo-cortical circuit, involving putamen to glo-
saccades, volitional saccades to remembered visual targets, bus pallidus to thalamus to the FEF and SMA. This circuit
and antisaccades (273,278,341). The homolog of the simian is analogous to the striatal, thalamic, and cortical pathways
LIP area is uncertain but possibly includes the angular and described for face, arm, and leg movements, but it is distinct
supramarginal gyri (Brodmann areas 39 and 40) (329) (Figs. from the caudo-nigral collicular circuit responsible for trig-
17.28 and 17.30); lesions of the posterior parietal cortex gering and suppressing both voluntary and visually guided
involving this region delay visually guided saccades in the saccades (349,352,353). Patients with bilateral lesions of the
gap and overlap tasks, but more so in the overlap task putamen and globus pallidus have inaccurate or delayed in-
(304,342). Right-sided lesions impair visually guided sac- ternally triggered voluntary saccades but normal externally
cades more than left-sided lesions, as is the case with other triggered saccades to visual targets (355).
visuospatial functions. Thus, the PEF of the posterior parietal
THALAMUS
cortex participates in visually guided reflexive saccades, and
it might participate in disengaging fixation. The PEF has a The intramedullary nucleus of the thalamus contains long-
signal that describes a saccade target and maintains the mem- lead burst neurons that discharge before mainly contraver-
sive self-initiated and visually triggered saccades in mon- concluded that there is a decussation of an ocular motor
keys. They might provide relevant cortical areas with infor- pathway occurring in the midbrain reticular formation be-
mation on gaze behavior, or to relay command from cortex tween the levels of the oculomotor and trochlear nuclei.
to the deep layers of the SC or other brain stem neurons. Structures above this ocular motor decussation in the mid-
Pause neurons and visual fixation neurons are also found in brain reticular formation govern contraversive gaze, and
this thalamic region (356,357). The central thalamus may structures below it generate ipsiversive gaze. The anatomic
fetch eye movement-related activity of the cortex, signal that and physiologic basis for this decussation remains uncertain,
a target response is imminent, and capture control from other but it may comprise the predorsal bundle from the SC, which
interfering commands (356,357). Lesions of the intramedul- crosses the midline ventral to the oculomotor nucleus in the
lary lamina could contribute to the syndrome of thalamic decussation of Meynert and descends in the contralateral
neglect (356,357). Patterns of saccadic responses in the pre- tegmentum to the PPRF.
geniculate complex of the monkey thalamus suggest its role
as a relay between the parietal cortex and brain stem ocular Cerebellar Regulation of Saccades
motor pathways, such as the SC and pretectal nucleus of the
optic tract (358). Through its connections to the vestibular nuclei and to
the reticular formation by way of the deep cerebellar nuclei,
CENTRAL MIDBRAIN RETICULAR FORMATION the cerebellum participates in three major ocular motor func-
tions: (a) regulation of saccadic amplitude and repair of sac-
An important relay for projections to and from the SC may cadic dysmetria; (b) stabilization of images upon the retina
be the nucleus subcuneiformis, a structure that lies lateral to by regulating smooth pursuit; and (c) regulation of the dura-
the oculomotor nucleus in the central mesencephalic reticu- tion of vestibulo-ocular responses and recalibrating them
lar formation (320,359). Microstimulation in the central when visual or vestibular input is altered. Some details of
mesencephalic reticular formation elicits contralaterally di- cerebellar functions will be discussed in the following sec-
rected saccades; recordings from the nucleus indicate that its tions on the smooth pursuit, vergence, and vestibulo-ocular
neurons discharge in relation to visually guided contralateral systems. Here we describe cerebellar control of saccadic ac-
saccades, and lesions of it impair the generation of contralat- curacy.
eral visually guided saccades but not vestibularly induced Lobules VI and VII of dorsal cerebellar vermis (also called
quick phases. Neurons of the central mesencephalic reticular the ocular motor vermis), the underlying fastigial nuclei,
formation receive collaterals from SC axons in the predorsal and the flocculus are important for saccadic eye movement
bundle descending to the PPRF and receive ascending from control (261,363,364) (Fig. 17.31). Functional imaging re-
the PPRF. They project dorsally to the SC as well as caudally veals increased activity in the human vermis during saccades
to the NRTP and rip. However, inactivation of the central to predictable targets, self-paced and memorized sequences
mesencephalic reticular formation results in hypermetria of of saccades in darkness (273,365). Purkinje cells in lobules
contraversive and upward saccades and reduced latency for VI and VII discharge in relation to saccades, including nys-
initiation of contraversive saccades (360). Fixation is also tagmus quick phases (366–369), and electric stimulation of
destabilized by large square-wave jerks. The hypermetria the dorsal cerebellar vermis in alert monkeys evokes conju-
supports the idea that the central mesencephalic reticular gate saccades with an horizontal ipsiversive component
formation participates in the feedback control of saccade (370). Stimulation of lobule V produces saccades that range
accuracy. Reduction in contraversive saccade latency and from upward to horizontal, while stimulation of lobules VI
development of square-wave jerks after central mesence- and VII produce saccades that range from horizontal to
phalic reticular formation inactivation support its role in sac- downward. Saccadic direction is apparently encoded by ana-
cade triggering (360). The central mesencephalic reticular tomic location in the cerebellum, as it is in the FEF and
formation may also participate in extracting the horizontal SC. Unlike saccades evoked by stimulation of these latter
vector from oblique saccade signals from the SC and relay- structures, however, saccades evoked by cerebellar stimula-
ing feedback of eye displacement from excitatory burst neu- tion are graded in amplitude as a function of stimulus inten-
rons in the PPRF to T burst and buildup cells in the SC sity. The amplitude of the saccade also depends upon the
(361). initial position of the eye in the orbit, and the end of the
Another region of the midbrain reticular formation, just saccade tends to be at the same point in the orbit regardless
lateral to the INC (the peri-INC midbrain reticular forma- of the starting position (370,371). Such saccades are made
tion), contains long-lead burst neurons that play a role in in craniotopic coordinates and are said to be ‘‘goal-directed’’
generating vertical saccades Inactivation of this region pro- since they take the eye to the same orbital position.
duces hypometria and slowing of upward and downward Complete cerebellectomy in monkeys creates persistent
saccades. The vertical saccade hypometria may indicate that saccadic dysmetria without abnormalities in velocity or la-
the peri-INC midbrain reticular formation provides long- tency (372). In this setting, all saccades overshoot, although
lead burst activity to the short-lead burst neurons in the the degree of overshoot is greatest for centripetally directed
riMLF and also activates omnipause neurons (362). movements. The saccadic abnormality in such monkeys con-
On the basis of his pioneering lesion and stimulation stud- sists of both pulse size dysmetria and pulse-step match dys-
ies in the brain stem tegmentum of monkeys, Bender (220) metria. The size of the saccadic pulse is usually too large,
Figure 17.31. The human cerebellum. A, Anterior inferior view shows the cere-
bellar hemispheres (H), vermis (V), flocculus (F), and paraflocculus (PF). White
arrowheads, nodulus; asterisk, fourth ventricle. B, Subdivisions of the human cere-
bellum. The left half of the drawing shows the three main subdivisions: the archi-
cerebellum, the flocculonodular lobe; the paleocerebellum, the anterior vermis, the
pyramis, the uvula, and the paraflocculus; and the neocerebellum. The right half
of the diagram shows the structures of the vestibulocerebellum, the flocculonodular
lobe, and the dorsal and ventral paraflocculi. (A, From Ghuhbegovic N, Williams
TH. The Human Brain: A Photographic Guide. Hagerstown, MD, Harper & Row,
1980. B, After Brodal A. Neurological Anatomy in Relation to Clinical Medicine.
3rd ed. New York: Oxford University Press, 1981.)
creating saccadic overshoot (pulse size dysmetria). At the metria) (363,373), a pattern that is recognized in patients
end of the rapid, pulse portion of the saccade, the eye drifts with cerebellar disease. Acutely, ablation of the ocular motor
on for a few hundred milliseconds toward the final eye posi- vermis increases saccade latency and reduces their speed,
tion, as a glissade (pulse-step match dysmetria). The dysmet- but these deficits recover while hypometria persists (363).
ria is a feature of damage to the ocular motor vermis (363), The cerebellum can adjust saccade amplitude and saccade
and the postsaccadic drift reflects damage to the flocculus dynamics independently. On the other hand, ablation of the
and ventral paraflocculus (261) (Fig. 17.31). In this chapter, cerebellar flocculus creates pulse-step match dysmetria with
both the flocculus and the paraflocculus are often referred postsaccadic drift but no pulse size dysmetria (261,374). The
to as the flocculus. two components of saccadic dysmetria caused by total cere-
In contrast to total cerebellectomy, ablation of only the bellectomy are thus related to ablation of two different re-
dorsal cerebellar vermis and the underlying fastigial nuclei gions of the cerebellum. The dorsal cerebellar vermis and
creates saccadic pulse size dysmetria in monkeys but no underlying fastigial nuclei control of saccadic pulse size,
postsaccadic drift (372). Experimental lesions of the dorsal while the flocculus is responsible for appropriately matching
vermis create a saccadic dysmetria in which centripetal sac- the saccadic pulse and step.
cades overshoot the target (hypermetric dysmetria) while The caudal part of the fastigial nucleus (Figs. 17.20 and
centrifugal saccades undershoot the target (hypometric dys- 17.32) is termed the fastigial ocular motor region (FOR). It
Figure 17.32. Sagittal view of human cerebellum

showing the ocular motor vermis, comprising parts of
the declive, folium, and tuber (large oval), projecting
(large arrow) to the fastigial nucleus (small circle).
The fastigial nucleus projects (small arrow) to the op-
posite side of the brain stem tegmentum. (Adapted
from Leigh RJ, Zee DS. The Neurology of Eye Move-
ments. Oxford: Oxford University Press, 1999.)
receives inhibitory input from Purkinje cells in dorsal vermis Unilateral FOR lesions in patients have bilateral effects,
lobules VI and VII, which receive mossy fiber input from since neurons from the contralateral FOR pass though it.
brain stem nuclei. The FOR also receives projections from Lateropulsion of saccades is a form of dysmetria consist-
the dorsolateral pontine nucleus (DLPN), dorsomedial pon- ing of overshooting of horizontal saccades in one direction,
tine nucleus, NRTP, pontine raphe, paramedian nucleus re- undershooting in the other, and oblique misdirection of verti-
ticularis pontis caudalis, NPH (Fig. 17.8), subnucleus b of cal saccades (Fig. 17.33). Lateropulsion occurs toward the
the medial accessory olivary nucleus, vestibular nucleus side of lateral medullary infarcts, a phenomenon we call
(375,376), and inferior olivary nucleus (377). Neurons in the ipsipulsion to specify the direction of dysmetria relative to
caudal fastigial nucleus project through the opposite fastigial the side of the lesion (383). Ipsipulsion consists of overshoot
nucleus, and then over the contralateral superior cerebellar of ipsiversive saccades, undershoot of contraversive sac-
peduncle in the hook bundle of Russell within the uncinate cades, and ipsiversive deviation of vertical saccades
fasciculus, to the contralateral SC and brain stem tegmen- (383–387). Lateropulsion occurring contralateral to lesions
tum. Their axons terminate in the region of cells in the pons of the superior cerebellar peduncle and uncinate fasciculus
that generate saccades, namely the excitatory and inhibitory is named contrapulsion, which is the combination of over-
burst neurons, and omnipause neurons (376,378). Neurons shoot of contraversive saccades, undershoot of ipsiversive
in the FOR are responsible for accelerating contraver- saccades, and contraversive deviation of vertical saccades
sive saccades and decelerating ipsiversive saccades (364, (388,389) (Fig. 17.33). Ipsipulsion might arise from damage
379,380). Neurons in one FOR fire at the end of ipsiversive to climbing fiber projections from the opposite-side inferior
saccades, but neurons in the opposite FOR fire at their begin- olivary nucleus through the inferior cerebellar peduncle to
ning. Chemical inactivation of the FOR on both sides makes the cortex of the dorsal vermis; climbing fiber damage in-
all saccades hypermetric, indicating that they influence the creases Purkinje cell activity and in turn inhibits the ipsi-
saccade burst generator in the brain stem to make saccades lateral fastigial nucleus (390). If the damage occurs before
more consistent and accurate. Chemical inactivation of the decussation of olivocerebellar projections, contrapulsion re-
FOR neurons on one side makes ipsiversive saccades hyper- sults (389). Contrapulsion of saccades from cerebellar out-
metric and contraversive saccades hypometric (381,382). flow damage can be explained by disruption of the uncinate
Figure 17.33. Unidirectional saccadic dysmetria (contrapulsion of saccades) from an infarct involving the left superior cerebel-
lar peduncle and uncinate fasciculus. A, Rightward saccades are hypermetric and leftward saccades are hypometric. B, Vertical
saccades (lower trace) are accompanied by rightward saccades (middle trace). C, Rightward pulsion of vertical saccades.
Arrows beside misdirected oblique saccades indicate their direction. R, right; L, left; U, up; D, down. (Redrawn from Ranalli
PJ, Sharpe JA. Ann Neurol 1986;20⬊311–316.)
fasciculus, from the contralateral fastigial nucleus, as it guided saccades or memory-guided saccades, with little
passes around the superior cerebellar peduncle (Fig. 17.34) transfer of adaptation among different stimulus conditions
(388,391). (392,397–399).
The ocular motor vermis (lobules VI and VII) and the
Adaptive Control of Saccade Amplitude FOR participate in saccadic adaptation (400–402). Ablation
of lobules VI and VII in monkeys impairs saccadic adapta-
Saccadic adaptation is a process by which errors in the tion (395). Functional imaging in humans shows increased
saccadic amplitude, induced by errors in target position activity in the ocular motor vermis while they learn to change
or weakness of extraocular muscles, can be corrected the amplitude of their saccades (403).
(392,393). It exemplifies motor learning (394). Errors in sac- The mechanism of adaptation could have its origin in a
cadic amplitude can result from brain, peripheral nerve, or signal from a group of saccade-related Purkinje cells in lob-
muscle diseases, and aging. Another function of rapid sac- ules VI and VII that give a precise account of the timing
cadic adaptation is to overcome reduction in saccade ampli- when a saccade ends. The duration of burst responses in
tude caused by fatigue (395). Saccadic dysmetria can be these cells changes with saccadic amplitude (404). Saccadic
simulated by changing the position of a visual target during adaptation could be the consequences of changing time rep-
saccades, forcing the subject to make a corrective saccade resentation in pulse duration of the neural signal in the cere-
after every target jump. After many such trials, subjects un- bellum (405). Studies in rhesus monkeys during saccadic
knowingly adjust the amplitude of their saccades to land adaptation to extraocular muscle weakness (402) or to
closer to the new target position (392,396). Saccadic adapta- changes in target position (406) reported two mechanisms
tion is specific to the direction or amplitude of the target for saccadic adaptation: an earlier burst for ipsiversive sac-
movement so that a change induced in saccade size in one cades in the FOR when saccade size is decreasing, and a
direction and amplitude is not induced for saccades to other change in spike number when saccade size is increasing
directions and amplitudes. Furthermore, saccadic adaptation (402) or decreasing (406).
is specific to the stimulus for saccade, whether visually Adaptation is shown by patients who develop a unilateral
Figure 17.34. Schema of projections from the inferior olivary nu-

clei (IO) through the inferior cerebellar peduncle (ICP) to lobule
VII of cerebellar cortex where Purkinje cells inhibit the fastigial
nucleus (FN). The caudal part of the FN probably excites the contra-
lateral paramedian pontine reticular formation (PPRF) via its projec-
tions in the uncinate fasciculus. A lesion in the left ICP increases
Purkinje cell activity, leading to decreased firing of the ipsilateral
FN and decreased activation of the contralateral (right) PPRF; this
causes ipsipulsion of saccades. A lesion of the left uncinate fascicu-
lus (from the right FN) decreases activity in the ipsilateral (left)
PPRF, causing contrapulsion of saccades. SP, superior cerebellar
peduncle. (From Sharpe JA, Morrow MJ, Newman NJ, et al. Distur-
bances of ocular motility. Continuum 1995;1:41–92.
peripheral ocular motor nerve palsy but for various reasons ary target during locomotion. When one views a target lo-
habitually fixate with their paretic eye (407,408). Such indicated off to one side during locomotion, smooth pursuit
viduals modify their saccadic innervation to compensate for holds its image at the fovea, despite relative motion of the
both the saccadic undershoot and the postsaccadic drift cre- background. The pursuit system ensures optimal visual acu-
ated by the palsy. If the patient is forced (by patching the ity for relative motion of a small visual target by reducing
paretic eye) to use the nonparetic eye for viewing, saccadic the speed of target image movement over the retina; this
innervation will, within a few days, revert to a pattern satis- movement is called retinal slip and it is measured as retinal
fying the visual needs of the nonparetic, viewing eye. velocity error, the difference between target velocity and
After surgically induced ocular muscle weakness, mon- smooth eye movement velocity. Attention and the intent to
keys can adjust the size of the saccadic pulse and suppress pursue are required to sustain smooth tracking with a target
postsaccadic drift (372). Removal of only the dorsal cerebel- image on the central retina. In that sense smooth pursuit is
lar vermis and underlying fastigial nuclei abolishes the abil- voluntary, but in another context it is reflexive since a per-
ity of the monkey to modify the size of the saccadic pulse, cept of retinal image motion is required. Very few individu-
while preserving the ability to suppress postsaccadic drift. als can make conjugate smooth eye movements in darkness
Thus, the dorsal cerebellar vermis and the fastigial nuclei without an externally derived sensory percept of target mo-
(Fig. 17.20) are important for adjustments of the saccadic tion. The speed of retinal images that can be tolerated for
pulse amplitude but not for appropriately matching the size clear vision depends on the spatial frequency of the image.
of the saccadic step to that of the pulse to prevent postsac- Image motion exceeding 5⬚–6⬚ per second reduces visual
cadic drift. This adaptive matching of the saccadic pulse and acuity for the higher spatial frequencies of high-contrast let-
step is controlled by the flocculus (374). Flocculectomized ters (409,410).
monkeys cannot appropriately adjust the saccadic step to
Under normal conditions, retinal slip is detected by the
eliminate postsaccadic drift.
visual system and provides the necessary stimulus for pur-
suit, a velocity error (411,412). Under special circumstances,
SMOOTH PURSUIT SYSTEM however, a stationary target located away from the fovea, a
Characteristics of Smooth Pursuit Eye Movements position error, may also act as a pursuit stimulus (413,414).
Patients with diminished central vision can also generate
Smooth pursuit stabilizes the image of an object on or smooth pursuit movements by using their central scotoma
near the fovea during slow movement of the object or of the as a target, by using peripheral retinal slip as a stimulus, or
body. Smooth pursuit is needed to hold the eye on a station- by using both mechanisms (415).
Image motion on the retina is not the only stimulus capa- steps quickly to one area of retina, then moves at a constant
ble of eliciting smooth pursuit movements. Some subjects velocity, Rashbass (428) showed that this initial pursuit eye
can smoothly track their own outstretched finger when it is movement is in the direction of target velocity, rather than
moving in front of them in darkness. Both knowledge of the target position (Fig. 17.35). Because of processing delays,
motor command to the limb (efference) and its propriocep- the initial 100- to 130-msec interval of pursuit acceleration
tive input (afference) are probably being used to generate is as an open-loop condition, without feedback, while the
these pursuit eye movements (416–418). Certain patients pursuit system is responding only to target motion that took
with acquired blindness can also pursue in this manner (419). place before the eyes started to move.
Very few individuals, however, can generate smooth eye For the first 20–40 msec, pursuit initiation responds only
movements voluntarily, without any external perception of to target direction (412,423,429). After 40 msec, smooth eye
movement (see reference (420) for exception). Conversely, acceleration increases while target stimuli remain off the
the perception of movement itself (for example, induced by fovea (423,430). During the 100- to 130-msec open-loop
pursuing the imaginary center of a rolling wheel when only period, smooth eye acceleration reduces retinal slip, closing
two points on its rim are visible) is an adequate stimulus even the negative visual feedback loop. Smooth eye velocity must
when no actual image motion has occurred in the direction of then be maintained close to target velocity, although retinal
the eye movement (411,421). Therefore, in addition to using slip speeds are a fraction of target speed (410). If pursuit
information from the retina, the brain can generate smooth acted upon retinal slip information alone, smooth eye veloc-
pursuit eye movements by using information about target ity would fall as it approached target velocity, creating insta-
motion from other sensory systems, by monitoring motor bility in the system. This implies that extraretinal signals are
commands, or by higher-level perceptual representations of used to drive pursuit at steady state, called pursuit mainte-
target movement in space (422). nance.
The latency for initiation of smooth pursuit movements Eye motion feedback is a source of extraretinal input. The
is 100 to 130 msec (423,424). When a gap with no target brain adds a signal representing eye velocity to retinal slip
precedes a pursuit target, the shortest latencies are recorded; input to construct a representation of target velocity in space
this phenomenon has been termed express smooth pursuit to drive smooth pursuit (Fig. 17.36). Extraretinal feedback
(425–427). Pursuit initiation consists of smooth eye acceler- of eye velocity, an efference copy (or corollary discharge),
ation. By using step-ramp targets, in which a stimulus spot accounts for sustained smooth pursuit (412,431). Eye veloc-
Figure 17.35. Recordings of pursuit responses to step-ramp stimuli, showing pursuit initiation in a normal subject. A, The
step and ramp are in opposite directions and the eye accelerates toward the ramp after a latency of 110 msec and a saccade
to the step of target position is canceled. The ramp moves toward the fovea at 20⬚/sec. The initial foveal position is at the
primary position (0⬚). D, With the step and ramp again in opposite directions but at a ramp speed of 40⬚/sec, the step elicits
a saccade followed by low-velocity pursuit in the direction of the ramp and a series of catch-up saccades and smooth pursuit
movements to foveate the target. Ramps at 20⬚/sec away from the fovea (B and C) elicit slower pursuit than the 20⬚ ramp
toward the fovea (A). (From Morrow MJ, Sharpe JA. Smooth pursuit initiation in young and elderly subjects. Vision Res 1993;
33⬊203–210.)
Figure 17.36. A model of the smooth pursuit system. A negative feedback loop provides a retinal image slip signal (retinal
velocity error, being target velocity minus eye velocity) to drive smooth pursuit. Maintenance of stable pursuit requires an
internal positive feedback loop that uses a copy of the eye velocity signal. The copy is ‘‘efference copy’’ or ‘‘corollary
discharge.’’ When this eye velocity signal is added to the retinal velocity error, a signal of target velocity in the environment
is reconstructed. When retinal velocity error is reduced to zero by effective smooth pursuit, the positive feedback loop sustains
the smooth eye motion at the speed of the target. (From Lisberger SG, Morris EJ, Tychsen L. Visual motion processing and
sensory-motor integration for smooth pursuit eye movements. Annu Rev Neurosci 1987;10⬊97–129.)
ity feedback becomes available to cortical visual motion pro- less effective as target acceleration exceeds 200⬚/sec2. In-
cessing areas in monkeys 50–100 msec after pursuit is initi- creases in target acceleration best explain decreases in pur-
ated (432). Neural mechanisms that anticipate target suit eye velocity as target frequency rises (429). Initial pur-
trajectory also provide an extraretinal input that enhances suit responses are faster for accelerating targets (430). Inputs
smooth pursuit maintenance (412,429). of retinal image acceleration as well as retinal image velocity
Targets can usually be followed accurately (with eye ve- drive smooth pursuit (412).
locity approximating target velocity) provided that the target Smooth pursuit eye movements follow the trajectory of
velocity is less than about 50⬚ per second and, for periodic predictable targets more faithfully than unpredictable targets
targets such as sine waves, the frequency of oscillation is (429,438). Processing delays of the pursuit system should
less than about 1 Hz. Ongoing smooth pursuit also shows cause phase lag of the eyes behind a target, but smooth pur-
very small oscillations of the smooth eye movements, called suit of predictable targets can often be maintained with no
ringing (431,433). As the retinal image of a stimulus slips phase lag, or even a small phase lead. This phase matching
off the fovea, catch-up saccades are dispatched toward the during pursuit maintenance is probably achieved by an inter-
target to reposition its image near the fovea. Saccadic rather nal positive feedback of the eye velocity command (412)
than smooth pursuit is a sign that the system has reached its (Fig. 17.36). Furthermore, pursuit may continue in the antici-
velocity or acceleration saturation. The efficacy of smooth pated trajectory of a target after the target has been blanked
pursuit is usually measured by its gain, the speed of smooth or stabilized on the fovea or has changed its path (439,440).
eye movement divided by target speed. Ideal gain is 1.0. Subjects can anticipate target motion and initiate predictive
When gain falls much below unity, catch-up saccades are eye acceleration before the target moves, even when target
required to foveate the target, and pursuit is said to be sac- motion is unpredictable (440), but they cannot maintain
cadic rather than smooth. Some human subjects can attain smooth pursuit at the speed of unpredictable target motion.
smooth pursuit eye speeds of up to 150⬚ per second for sinus-
oidal target motion (429) and 100⬚ per second for constant- Neurophysiology of Pursuit Eye Movements
velocity motion (434). However, even the highest pursuit
Cerebral Initiation and Maintenance of Smooth
eye speeds fall well below peak speeds of saccades (137,154)
Pursuit
or the vestibulo-ocular reflex (266). Since it is not due to
ocular motor constraints, smooth pursuit velocity must satu- Visual processing is divided into two parallel but anatomi-
rate because of limits of sensory motion processing, or the cally and functionally interconnected pathways. One, the
conversion of sensory inputs to motor commands. Normal magnocellular (M) pathway, is concerned with motion and
elderly persons have smooth pursuit gains below unity at spatial analysis; the other, the parvocellular (P), is concerned
much lower target velocities and accelerations than younger with form and color perception (441–443). Within the cere-
persons (435–437). bral hemisphere of monkeys, the M pathway is dorsal to the
Smooth pursuit is also limited by eye acceleration. Hu- P pathway, and they are designated as the dorsal and ventral
mans can attain smooth pursuit accelerations of about streams. The dorsal occipito-temporal-parietal stream con-
1,200⬚/sec2, although smooth pursuit becomes considerably veys information about location and motion (the ‘‘where
pathway’’), whereas the more ventral occipito-temporal

stream conveys color, form, and pattern information (the
‘‘what pathway’’). The M visual channel in monkeys
projects to striate cortex (area V1), then to cortical areas V2
and V3, and MT (middle temporal, area V5), then adjacent
area MST (medial superior temporal, area V5a), and then
posterior parietal cortex.
Functional imaging and magnetoencephalography of the
human brain show cortical areas in addition to the ascending
limb of the inferior temporal sulcus (the homolog of MT/
V5) that are activated by moving patterns (444–447). The
ascending limb of the inferior temporal sulcus is considered
to include satellites of MT and has been referred to as hMT/
V5Ⳮ. Other cortical areas that also respond to moving in Figure 17.37. Left cerebral hemisphere of rhesus monkey showing area
preference to stationary patterns are lingual cortex, lateral important in visual motion analysis and smooth ocular pursuit. The lateral
occipital sulcus (area LOS/KO), dorsolateral-posterior- part of the middle temporal (MT) area containing foveal receptive fields
occipitoparietal cortex (hV3A), anterior-dorsal-intraparietal and the lateral part of the medial superior temporal area (MST) participate
sulcus (DIPSA), postcentral sulcus, and a small area in the in generating ipsiversive pursuit by conveying visual signals to the pursuit
precentral cortex, being perhaps the FEF (444,448); these system. VI, striate cortex; V2–V4, prestriate cortical areas; PP, posterior
areas are activated to different amounts in individual sub- parietal cortex; FEF, frontal eye field. Sulci are opened to reveal the arcuate
jects, but not at all in some subjects. Only hMT/V5Ⳮ is sulcus (AS), inferior occipital sulcus (IOS), lunate sulcus (LS), and superior
significantly activated in practically every brain (444). The temporal sulcus (STS). SF, sylvian fissure; CS, central sulcus, IPS, intrapa-
rietal sulcus. (From Tusa RJ, Ungerleider LG. Fiber pathways of cortical
contributions, if any, of the other areas to motion processing,
areas mediating smooth pursuit eye movements in monkeys. Ann Neurol
perception, and behavior are uncertain. Lesion as well as 1988;23⬊174–183.)
fMRI evidence points to the junction of Brodmann areas
19 and 39 as the homolog of simian MT/MST in humans
(344,347,432,449–452).
Humans and monkeys with unilateral striate cortex or Lesions in areas MST and MT cause two types of pursuit
optic radiation lesions cannot pursue a target confined to the defect: retinotopic and directional. Retinotopic pursuit de-
contralateral visual hemifield (453–455). Patients are also fects consist of lower smooth pursuit speed and inaccurate
unable to discriminate motion direction or to perceive mo- saccades in the contralateral area of the visual field sub-
tion in the affected hemifield (456), but there is controversy served by the damaged area; the defects are for pursuit and
about the existence of residual vision after destruction of saccades in all directions. Directional pursuit defects consist
area V1 (457,458) (see also Chapter 13). Monkeys with bilat- of lowered smooth pursuit speed toward the side of the dam-
eral striate ablation eventually recover substantial smooth aged area, in response to a target presented anywhere in
pursuit, implying adaptive use of extrastriate visual motion either hemifield; saccades are not affected (344,345). Both
inputs after cortical blindness (262), but humans with corti- area MT and area MST have retinotopic maps of the contra-
cal blindness cannot pursue visual targets. lateral visual field. Damage to neurons responding to visual
motion in a specific area of visual field causes defective
AREA V5: MIDDLE TEMPORAL AND MEDIAL SUPERIOR smooth pursuit initiation to targets moving in that region
TEMPORAL CORTEX (450). Retinotopic deficits result from damage to any portion
of area MST (345), or to the extrafoveal representation
Neurons in the foveal part of simian area MT (V5) and within area MT (432); receptive fields are larger in MST,
dorsal and lateral area MST discharge during smooth pursuit and retinotopic deficits resulting from MST damage cover
(459,460) (Fig. 17.37). Their receptive fields include the a larger portion of visual field. During smooth pursuit, but
fovea but do not respect the vertical meridian and extend not while the eyes are still, electrical stimulation within
far into the ipsilateral visual field. Every V5 neuron receives either the foveal MT or lateral MST alone causes ipsiversive
input from both eyes (461). Discharge that occurs during smooth eye movements to accelerate (463). Directional pur-
pursuit of a target isolated in darkness can be either a re- suit deficits are caused by lesions in only the foveal region
sponse to the residual retinal slip velocity or an extraretinal of MT or the lateral region of MST (345).
signal of eye velocity. Cells in the foveal region of area MT The ipsiversive smooth pursuit defect is not explained by
respond only to retinal slip, whereas the lateral and dorsal directional motion sensitivity of the MT and MST, because
area MST contain cells that respond even in the absence of all directions of motion are represented in the preferences
retinal image motion, indicating an extraretinal input (432). of their neurons (464,465) and because there is no defect in
The foveal MT and lateral MST provide retinal slip informa- generating ipsiversive saccades to moving targets after MST
tion for pursuit, and the dorsal and lateral MST receive either or foveal MT lesions. Instead, the directional smooth pursuit
a corollary motor discharge or proprioceptive information bias lies in the projection patterns of the population of MST
regarding eye motion (432,462), which is required for pur- neurons to brain stem structures (466,467). Paresis of ipsi-
suit maintenance (412). versive smooth pursuit corresponds to the ipsiversive bias
in the preferred directions of output neurons from MST to the occurrence of latent nystagmus that accompanies strabis-
the brain stem (467). A specific selection of cortical neurons mus (461) (see also Chapter 23).
from areas MT and MST forms the projection to the nucleus Lesions of the posterior limb of the internal capsule also
of the optic tract (NOT) and dorsal terminal nucleus of the lower the speed of ipsiversive smooth pursuit (449,480). Pro-
accessory optic system (AOS), and this subpopulation has jections from V5, at the junction of occipito-temporal cortex,
the same directional bias as their brain stem target neurons are conveyed through the internal sagittal stratum to the in-
(467). Ipsiversive pursuit defects also result from lesions ternal capsule, then to the basis pontis (483). The internal
at subcortical levels of the pursuit pathway, as we discuss sagittal stratum lies medial to the optic radiation. Damage
below. to striate cortex, the optic radiation, or the posterior part
of the internal sagittal stratum does not cause directional
HUMAN HOMOLOGS OF AREA V5
impairment of smooth pursuit but does cause retinotopic loss
of pursuit in the affected hemifield (455,471). Ipsiversive
Patients with lesions at the junction of Brodmann areas smooth pursuit defects from extrastriate cortical lesions are
19, 37, and 39 (Fig. 17.30) and subcortical white matter often associated with optic radiation or V1 damage that
have retinotopic defects of pursuit initiation and directional causes contralateral homonymous hemianopia, but the ipsiv-
defects of pursuit initiation and maintenance (346,347,449, ersive pursuit impairment is independent of the visual field
468). Retinotopic defects are far less commonly detected defect (449,455,471).
than directional defects, unless of course the optic radiation Despite interruption of the optic radiation or area V1, vis-
or striate cortex is damaged. This area (Fig. 17.30) is homol- ual information is delivered from the seeing hemisphere to
ogous to simian MT and MST (Fig. 17.37); a zone within the damaged hemisphere across the splenium of the corpus
this cortical region of humans has the same distinctive my- callosum. Reduced ipsiversive smooth pursuit gain in pa-
elination pattern as simian MT (469). Furthermore, func- tients with normal visual fields results from involvement of
tional imaging in normal human subjects shows increased cortical area V5 or its projections to the basal pontine nuclei,
activity in this region during smooth pursuit (452). Damage or alternatively from damage to subcortical white matter that
in this area, at the lateral junction of the parietal, temporal, disconnects V5 from visual motion information received
and occipital lobes (Fig. 17.28), can account for impairment from areas V1 of both cerebral hemispheres (347,449,480).
of ipsiversive pursuit or optokinetic nystagmus (OKN) slow
ANATOMIC CONNECTIONS OF AREAS MT AND MST
phases after posterior cerebral lobe lesions (470–475,
476,449,477). In addition to direct inputs from areas V1, V2, and V3,
Despite this lateralization of directional pursuit pathways, area MT also has reciprocal direct subcortical connections
each hemisphere contributes to smooth pursuit in both hori- with the pulvinar. Area MT projects to areas MST, ventral
zontal directions. After hemidecortication, monkeys have se- intraparietal area (VIP), floor of the superior temporal sul-
vere impairment of ipsiversive pursuit, but contraversive cus, FEF, ventral bank of the intraparietal sulcus of posterior
pursuit is also impaired for high-speed targets (478). Simi- parietal cortex, and through the forceps major of the corpus
larly, patients with unilateral focal lesions exhibit reduction callosum to the contralateral MT, MST, and V4. Subcortical
of contraversive pursuit velocity, but less reduction than of projections are to the lateral pontine nucleus (LPN) and
ipsiversive pursuit (347,449,477). Contraversive smooth DLPN, striatum, thalamic nuclei (pulvinar, lateral geniculate
pursuit recovers in monkeys 6–8 months after hemispheric nucleus, reticular nucleus), NOT, dorsal terminal nucleus,
damage (478). Humans who have had hemidecortication a and SC (467,483–490).
decade earlier do not have impaired contraversive pursuit Inputs to area MST originate within areas V2, V3a, MT,
(308), but patients with smaller areas of unilateral damage PO, V4, and dorsal prelunate cortex; within V1, only the
that spare V5 may have symmetrically reduced pursuit gain representation of peripheral retina projects to MST. Cortical
in both horizontal directions (347,449,479,480). projections from MST are to the posterior parietal cortex,
In both humans and monkeys, hemidecortication or large inferotemporal cortex, FEF, and contralateral MST (466,
focal hemispheric lesions cause abnormally high contraver- 483,489,491–493). The rich cortical connections of MT and
sive pursuit velocities toward slow targets, with gains above MST engage other cerebral areas in generating pursuit.
unity (308,449,478,481). Ipsiversive pursuit requires catch-
POSTERIOR PARIETAL CORTEX
up saccades and contraversive pursuit requires back-up sac-
cades to foveate a target. The marked asymmetries of hori- Cortical neuronal responses during smooth pursuit were
zontal smooth pursuit, with high contraversive and low ip- first demonstrated in area 7a (or PG) in the inferior parietal
siversive gain, in patients with large cerebral lesions is lobule of the posterior parietal cortex (494,495), although
associated with slow ocular drift away from the damaged some of the visual tracking neurons reported in area 7a
side. Corrective saccades toward the side of damage create (496–498) are actually in the dorsal MST. Among cells in
a low-amplitude nystagmus called pursuit paretic nystagmus area 7a that are active during looking, some discharge only
(308,482). Pursuit paretic nystagmus may be caused by im- when the target is a novel stimulus (494). Area 7a contains
balanced smooth pursuit or optokinetic drive to brain stem (a) visual fixation neurons that discharge during stationary
neurons that generate horizontal smooth eye movements. A fixation or smooth pursuit of an object, (b) visual tracking
cortical bias of smooth pursuit direction might also explain neurons with directionally selective responses during pursuit
but no responses during stationary fixation, and (c) neurons voluntary function. Distracted subjects do not pursue
that discharge during combined eye and hand tracking. smoothly. Areas MT and MST in monkeys project to several
The discharge of fixation neurons and visual tracking neu- cortical areas known to be involved in visual attention, in-
rons in area 7a depends upon the motivational content of cluding area 7a, and the VIP area (486). Functional imaging
the target; unless the target is of interest to the monkey (e.g. shows increased activity in both the parietal (506,507) and
food), pursuit responses cease (495). Saccadic, visual fixa- rostral temporal lobes of humans during smooth pursuit
tion, and visual tracking neurons all respond to visual stimuli (508); these areas correspond to simian posterior parietal
independently of eye motion and lack responses in the ab- cortex and superior temporal polysensory area, a region in
sence of visual stimuli (336). Their sensory responses are the floor and bank of the anterior superior temporal sulcus,
enhanced if the stimulus is the target for a movement, indi- receiving converging input from components of the ventral
cating that activity in area 7a is related to visual attention and dorsal streams of visual processing. Both the inferior
rather than to a command function. A subset of visual track- and superior parietal lobules are probably concerned with
ing cells do retain responses to a target moving in the dark attentive eye movements (339,340,495).
(true pursuit cells) (496). Half of true pursuit cells have di- Some patients with hemineglect due to acute nondominant
rectionally selective visual responses in the direction oppo- parietal lobe lesions are transiently unable to make smooth
site to their preferred pursuit direction, and in all of these pursuit eye movements that cross the orbital midline away
cells the discharge during pursuit with a visible background from the side of damage (473,509). Contralateral pursuit in
is greater than that during pursuit in darkness, suggesting a these patients seems to be impaired in a craniotopic (head-
synergistic convergence of signals from extraretinal pursuit centered) frame of reference. However, inattention to the
activity (efference copy) and background retinal image mo- left visual field after acute right-sided parietal lobe lesions
tion. These ‘‘anti-directional’’ cells are thought to be in- or the frequently associated hemianopia (which causes reti-
volved in perception of relative motion (496). The other true notopic loss of smooth pursuit) might be misinterpreted as
pursuit neurons have similar directional preferences for both a directional palsy of smooth pursuit to the left (510). Law-
pursuit and visual motion. These ‘‘iso-directional’’ cells may den et al. (511) studied the smooth pursuit of a foveal target
represent a converging point for retinal velocity error and against structured backgrounds and in darkness in patients
eye velocity. This could serve to create an efferent motor with unilateral cerebral lesions overlapping in the anterior
signal for pursuit or to signal the trajectory of an object in inferior portion of Brodmann area 40 of the parietal lobe
space, relative to the head rather than the retina. True pursuit and in frontal white matter. The structured background sig-
neurons have ipsidirectional preferences (497,499).
nificantly decreased pursuit gain in patients with either right
Many neurons have no response to vestibular stimulation
or left hemispheric lesions. Some patients had a significant
in the dark but respond similarly during pursuit of a moving
smooth pursuit asymmetry when measured either in darkness
target with the head fixed, and during passive head move-
or with the structured background; however, a few patients
ment with a head-fixed target, so that the vestibulo-ocular
had significant pursuit asymmetry in darkness but not with
reflex is canceled (497); these cells appeared to encode pur-
suit and head motion similar to gaze Purkinje cells of the the background, and others had pursuit asymmetry with the
flocculus. Other neurons increase their firing during head background but not in darkness. Most patients had ipsiver-
motion in the dark to the same side as the preferred direction sive impairment of pursuit, but several patients with pursuit
for pursuit, whereas some neurons have opposite pursuit and asymmetry had a contraversive defect. Those investigators
vestibular responses. Vestibular and smooth pursuit informa- (511) also hypothesized that hemineglect or hemianopia was
tion converges upon these cells, and many receive a smooth responsible for contraversive pursuit defects. Those studies
pursuit signal for head fixed or for combined eye and head did not test eye movements in different orbital positions,
tracking (497). making it difficult to distinguish craniotopic from retinotopic
Evidence for a role of the parietal lobe in generating deficits, since the head-centered and eye-centered frames of
smooth pursuit has been based on clinical observations of reference are the same when the eyes are near the orbital
patients, made before the era of computed tomography (CT) midline (512).
or MRI, of saccadic pursuit toward the side of posterior Morrow (512) has demonstrated craniotopic defects of
cerebral hemispheric lesions (500–502). Modern imaging smooth pursuit speed and saccade amplitude in the hemi-
indicates that unidirectional impairment of smooth pursuit range contralateral to the orbital midline in patients with
and motion perception correlates better with more ventral frontal or parietal lobe lesions. The craniotopic defects did
damage at the temporo-occipital junction (347,449,455,480, not correlate with contralateral neglect and occurred with
503). Nevertheless, Lynch and McLaren (333) found that either right- or left-sided lesions. The patients also had low-
bilateral lesions of the parietal and superior temporal cortex ered ipsiversive pursuit gains. Acutely, hemidecorticate
in monkeys create enduring pursuit deficits, and direction- monkeys also have defects of both pursuit and saccades in
specific pursuit-related responses are found in neurons of the contralateral orbital hemirange, in addition to persisting
areas 7a and LIP (the parietal eye field) (504,505). ipsiversive pursuit defects, but the larger lesions are accom-
panied by neglect of contralateral space (309,478).
VISUAL ATTENTION AND THE PARIETAL LOBES
These varieties of impaired pursuit lead to the classifica-
In addition to visual motion information, the pursuit sys- tion of four categories of defective smooth pursuit caused
tem requires attention on a target of interest. Pursuit is a by cerebral hemispheric damage (513):
Ipsiversive: Pursuit gain is lowered toward the side of le- spond in relation to the initiation of smooth pursuit (524).
sions. Contralateral smooth pursuit velocities may be nor- In humans, lesions involving the SEF and dorsolateral pre-
mal, high, or low (but greater than ipsiversive smooth eye frontal cortex might lower ipsiversive pursuit gain
movement velocities). (477,521), but lesions to the SEF are reported to delay the
Omnidirectional: Gain is reduced for targets in both hemi- reversal of pursuit direction in response to periodic target
fields in all directions, without asymmetry. motion without reduction in smooth pursuit gain (468). Pur-
Retinotopic: Pursuit gain is lowered in all directions in the suit responses are recorded in the VIP (525). In the hierarchy
contralateral visual hemifield. of regions, the VIP is similar to the MST, since it too receives
Craniotopic: Gain is reduced in all directions in the hemi- a heavy projection from the MT. Lesions involving the cor-
range contralateral to the orbital midline, after recent uni- pus striatum are reported to cause errors in the phase between
lateral hemispheric lesions. target and smooth eye motion, attributed to impaired target
prediction (479), but patients with diffuse or focal cortical
lesions do not show phase lag of smooth pursuit behind pre-
FRONTAL EYE FIELDS AND SMOOTH PURSUIT dictably moving targets (449,521,526,527).
Neurons with pursuit responses are also found in the FEF,
Recovery of Smooth Pursuit
in the fundus of the arcuate sulcus of monkeys (514,515).
These cells have excitatory responses to pursuit movements After focal MT and MST lesions, monkeys recover di-
in their preferred direction but minimal activity during sac- rectional and retinotopic pursuit within 1–2 weeks
cades and stationary fixation. Some cells have weaker re- (344,451,528). Complete eradication of areas MT and MST
sponses to visual motion, but since responses begin well together severely prolongs recovery, and it is incomplete
before the onset of pursuit, responses cannot be attributed after 7 months. Area VIP and the FEF may mediate the
to retinal slip of the background, corollary eye movement recovery after MST lesions. Pursuit defects from lesions out-
discharge, or sensitivity to orbital eye position. Directional side the superior temporal sulcus also recover. Partial recov-
tuning is broad, without preponderance of ipsidirectional ery of pursuit defects after bilateral FEF ablations occurs
preferences. The early response of these cells suggests that over 6 weeks and may be mediated by MT and MST or the
they contribute to pursuit initiation. Microstimulation of this SEF (519). Substantial recovery also occurs over weeks to
part of the FEF elicits ipsiversive pursuit when the eyes are months following unilateral FEF ablations in monkeys
still in the dark, during fixation, and during ongoing pursuit (514,517).
(514–516). Patients studied weeks to months after hemispheric dam-
Unilateral lesions of the pursuit region of the monkey age demonstrate that pursuit defects endure beyond the acute
FEF cause ipsiversive or omnidirectional pursuit defects lesion stage (346,347,449,455,503,511,521). Focal lesions
(514,517,518). Bilateral FEF lesions lower pursuit speed in or even total hemidecortication do not eliminate ipsiversive
all directions in monkeys but do not eliminate smooth pursuit pursuit. Persistence of ipsiversive pursuit palsy for some 30
(518,519). However, optokinetic smooth eye movements years after a temporal-parietal cyst (449), and for at least a
evoked by large field stimulation remain normal (520). Spar- decade after hemidecortication (308,478), testifies to limited
ing of large field tracking responses suggests that the FEF adaptation by redundant subcortical pathways in the dam-
pursuit zone has a retinotopic organization, receiving input aged hemisphere or the other, intact, hemispheric cortex.
from neurons in the posterior cortex that detect predomi-
nantly retinal motion close to the fovea, and subserve pursuit. Pursuit Control from Cerebrum to Cerebellum
The ipsiversive bias of the FEF pursuit zone might reflect
Neurons in areas MST and MT and the FEF project to
direction preferences of its neuronal projections to the brain
the DLPN located in the dorsal part of the basal pons
stem, as identified for the output neurons from MST
(483,529–531). DLPN neurons have many properties in
(466,467). The FEF is anatomically positioned to participate
common with MT and MST neurons, and lesions in the
in smooth pursuit; it receives ipsilateral input from MT and
DLPN in monkeys produce ipsidirectional deficits of the
MST (486) and projects to the ipsilateral DLPN and NRTP
initiation and maintenance of pursuit (532). Motor com-
(214,215,318).
mands do not originate in the DLPN, since stimulation there
Functional imaging shows increased activity in the human
produces only smooth eye acceleration when the eyes are
FEF during smooth pursuit (506). Patients with frontal lobe
already engaged in smooth tracking; DLPN neurons carry
lesions that involve the FEF have directional defects of
visual and nonvisual, probably efference copy, signals. The
smooth pursuit toward the side of damage (302,449,521) or
dorsomedial pontine nucleus and the rostral part of the
bidirectional defects (477,521). Step-ramp presentation of
nearby NRTP also participate in smooth pursuit (533). Mi-
targets reveals no retinotopic pursuit defects, but saccades
crostimulation in the rostral part of one NRTP elicits pre-
to contralaterally moving ramps are hypometric (521).
dominantly upward smooth eye movements, perhaps be-
OTHER CEREBRAL REGIONS AND SMOOTH PURSUIT
cause it receives input from both FEFs and their horizontal
components cancel (215,534). Stimulation of FEF or NRTP
Microstimulation of the simian SEF evokes smooth eye evokes smooth eye movements during fixation or in the dark,
motion (522), specifically accelerating the initiation but not unlike the effects of stimulating in DLPN or MT and MST,
the maintenance of pursuit (523). Neurons in the SEF re- which produces pursuit movement only when pursuit is on-
going. Unilateral paramedian chemical lesions in the NRTP Lesions of the vermis at lobules VI and VII of monkeys
severely impair upward pursuit and to a lesser degree hori- cause a small decrease in steady pursuit gain during triangu-
zontal pursuit (535). NRTP is a component of a cortico- lar-wave tracking and a decrease in peak eye acceleration
ponto-cerebellar circuit from the pursuit area of FEF and of initial pursuit. In a pursuit adaptation paradigm, where
projects to the cerebellum. This FEF-NRTP-cerebellum targets change velocity during ongoing pursuit, normal ani-
pathway parallels the MT and MST-DLPN-cerebellum path- mals can adaptively adjust eye their eye acceleration to
way in regulating smooth-pursuit eye movements (535). match the new target velocity. Following lesions in the ocu-
The DLPN and NRTP project mossy fibers through the lomotor vermis, this adaptive capability is impaired (555).
contralateral middle cerebellar peduncle to cortex of the floc- The ocular motor vermis plays a role in smooth pursuit and
culus and vermis lobules VI, VII (the ocular motor vermis), its adaptive control.
and IX (the uvula) and send collaterals to the deep cerebellar Smooth pursuit function is lateralized in the cerebellum.
nuclei (536,537). Their neurons discharge during pursuit, Hemicerebellectomy in monkeys lowers ipsiversive pursuit
and lesions in them impair pursuit (532,533,535,538). Ipsi- velocities more than contraversive velocities (544). Floccu-
versive smooth pursuit deficits occur in patients with unilat- lar Purkinje cells discharge with ipsiversive pursuit more
eral damage in the basis pontis (539–541), possibly by in- than contraversive pursuit (552,553), or more with down-
volving connections of the DLPN or NRTP. The NOT and ward-contraversive pursuit (552). Stimulation of the simian
dorsal terminal nucleus of the AOS receive projection neu- cerebellar cortex produces predominantly ipsiversive
rons from areas MT and MST (467). The NOT is also en- smooth eye movements (370). In humans, unilateral lesions
gaged during pursuit. Electrolytic lesions of NOT in mon- of the cerebellar hemisphere, apparently sparing the vermis
keys reduce ipsiversive pursuit gains to below 0.5, with and fastigial nucleus, have been reported to reduce the gain
partial recovery after about 2 weeks. Vertical pursuit is not of ipsiversive initial pursuit and to mildly reduce the gain
affected by unilateral or bilateral NOT lesions. Rostral le- of maintained pursuit in both horizontal directions (556).
sions of NOT in and around the pretectal olivary nucleus, The fastigial nucleus (Fig. 17.20) receives inhibitory pro-
which interrupt cortical input through the brachium of the jections from the ocular motor vermis (Fig. 17.34), and many
SC, impair smooth pursuit, OKN, and optokinetic after-nys- neurons in the caudal part of the fastigial nucleus discharge
tagmus (OKAN). Cortical pathways through rostral NOT in relation to initial acceleration and maintenance of smooth
play an important role in maintenance of ipsiversive ocular pursuit, especially when it is contraversive and downward
pursuit (542). OKN is discussed later in this chapter. Direc- (557). Chemical inhibition of its caudal part impairs contra-
tionally selective cells in the monkey NOT provide input to versive pursuit acceleration or increases ipsiversive accelera-
the pursuit system through efferent projections: through the tion. However, pursuit maintenance is affected only slightly
NRTP to the cerebellum, as well as to the optokinetic system in all directions. Bilateral inactivation of this FOR leaves
through projections to the inferior olive (543). pursuit acceleration intact and produces moderate decreases
in pursuit speed (558). The role of the FOR may be to add
Cerebellum and Smooth Pursuit a supplementary signal to other pursuit circuits. Nonetheless,
patients with lesions involving the fastigial nuclei on both
The cerebellum is crucial for smooth pursuit. Cerebellec- sides are reported to have saccadic hypermetria but well-
tomy abolishes it and stimulation of cerebellar cortex pro- preserved smooth pursuit (559).
duces smooth eye motion, signifying excitation of pathways
responsible for generating the motor commands for smooth Brain Stem Generation of Smooth Pursuit
pursuit (370,544,545). Flocculectomy in monkeys lowers the
speed of smooth pursuit (261) Unilateral lesions of the ven- Floccular gaze velocity Purkinje cells inhibit floccular tar-
tral paraflocculus alone impair smooth pursuit in all horizon- get neurons (FTNs) in the ipsilateral medial vestibular nu-
tal directions, whereas bilateral lesions of the flocculus alone cleus (560,561). Purkinje cells of the flocculus project cau-
do not impair smooth pursuit in any direction (546). dally and medially between the middle cerebellar peduncle
Neurons in the flocculus and dorsal vermis modulate their and the flocculus, over the caudal surface of the middle cere-
firing during smooth pursuit eye movements (547–552). bellar peduncle, then over the dorsal surface of the cochlear
Purkinje cells in the flocculus and ventral paraflocculus (also nuclei, and then caudally along the lateral surface of the
inclusively referred to as the flocculus in this chapter) encode inferior cerebellar peduncle (the restiform body) to pass over
gaze velocity and acceleration during tracking with the eyes its dorsal surface in the cerebellopontine angle, and they
or with the head and eyes; they do not discharge during terminate exclusively in the ipsilateral vestibular nuclei.
fixation of a stationary target while the head is moved, since Some project medially into the y-group. Others continue
during this activity gaze does not change, even though the rostrally and medially to terminate in the superior vestibular
eyes move in the orbit at the same speed as the opposed nucleus. Many axo

Walsh&Hoyt Clinical Neuro-Ophthalmology

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Walsh and Hoyt’s

Neil R. Miller, MD Nancy J. Newman, MD

Valérie Biousse, MD John B. Kerrison, MD

Copyright 2005 by Lippincott Williams & Wilkins

530 Walnut Street

351 West Camden Street

Printed in the United States of America

Library of Congress Cataloging-in-Publication Data

Walsh and Hoyt’s clinical neuro-ophthalmology.—6th ed. / [editors,

Madhu R. Agarwal, MD Valérie Biousse, MD

Wayne T. Cornblath, MD Robert A. Goldberg, MD, FACS

Robert A. Egan, MD Lynn K. Gordon, MD, PhD

Eric R. Eggenberger, DO Steven R. Hamilton, MD

Steven L. Galetta, MD Chris A. Johnson, PhD

Barrett Katz, MD, MBA Robert L. Lesser, MD

David I. Kaufman, DO Leonard A. Levin, MD, PhD

Nancy J. Newman, MD Matthew Rizzo, MD

Prem S. Subramanian, MD, PhD Joel M. Weinstein, MD

Preface ............................................................................................................................................................................. vii

Section I: The Visual Sensory System

Chapter 3: Congenital Anomalies of the Optic Disc ............................................................................................... 151

Chapter 4: Topical Diagnosis of Acquired Optic Nerve Disorders ....................................................................... 197

Chapter 5: Papilledema ............................................................................................................................................... 237

Chapter 6: Optic Neuritis ........................................................................................................................................... 293

Chapter 7: Ischemic Optic Neuropathy .................................................................................................................... 349

Chapter 8: Compressive and Infiltrative Optic Neuropathies ............................................................................... 385

Chapter 9: Traumatic Optic Neuropathy ................................................................................................................. 431

Chapter 10: Toxic and Deficiency Optic Neuropathies ............................................................................................ 447

Chapter 11: Hereditary Optic Neuropathies .............................................................................................................. 465

Chapter 13: Central Disorders of Visual Function ................................................................................................... 575

Section II: The Autonomic Nervous System

Section III: The Ocular Motor System

Chapter 21: Disorders of Neuromuscular Transmission .......................................................................................... 1041

Chapter 22: Myopathies Affecting the Extraocular Muscles ................................................................................... 1085

Section IV: The Eyelid

Section V: Facial Pain and Headache

Chapter 26: Headache and Facial Pain ...................................................................................................................... 1275

Section VI: Nonorganic Disease

Section VIII: The Phacomatoses

Section IX: Vascular Disease

Section XI: Infectious, Inflammatory, and Demyelinating Diseases

Figure 1.1. The formation of the optic

Figure 1.5. Phototransduction cascade.

Table 1.1 rods are predominately affected in vitamin A deficiency reti-

fellow amacrine cells, forming a lateral pathway within the

Figure 1.11. Müller cell regulation of potassium ions and

Cell Size/Dendritic Concentric Linear/ Sustained/

Beta; P␤; P; Parvo- Medium/narrow and dense X ⫹ Linear Sustained

their development (153), is not one of symmetric opposition.

tials. Nav channels exist in very high density at the axonal

Nerve Fiber Layer

and possibly the presence of xanthophyll within the macula,

Retinal Blood Vessels

Retinal Outflow Site of Termination Function

Parvocellular Layers 3–6 of dLGN Fine spatial detail

Gamma cell Pre-tectal nuclei Pupillomotor function

Figure 1.19. Light photomicrograph showing architectural arrangement of the

Figure 1.23. Cross-section of human optic

of about 35 degrees with the midsagittal plane (Fig. 1.26).

optic chiasm. The length of the intracranial optic nerve varies