Advances in Understanding Mechanisms and Treatment of Infantile Forms of Nystagmus

ADVANCES IN UNDERSTANDING MECHANISMS AND TREATMENT OF INFANTILE FORMS OF NYSTAGMUS Proceedings of a conference held M...

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ADVANCES IN UNDERSTANDING MECHANISMS AND TREATMENT OF INFANTILE FORMS OF NYSTAGMUS

Proceedings of a conference held May 3–4, 2007, under the auspices of Case Western Reserve University, to celebrate the contributions of Louis F. Dell’Osso and the opening of the Daroff-Dell’Osso Ocular Motility Laboratory at Louis Stokes Cleveland Department of Veterans Affairs Medical Center

Advances in Understanding Mechanisms and Treatment of Infantile Forms of Nystagmus

Edited by

R. John Leigh, MD Michael W. Devereaux, MD

1 2008

1 Oxford University Press, Inc., publishes works that further Oxford University’s objective of excellence in research, scholarship, and education. Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With ofﬁces in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam

Copyright © 2008 by R. John Leigh and Michael W. Devereaux Published by Oxford University Press, Inc. 198 Madison Avenue, New York, New York 10016 www.oup.com Oxford is a registered trademark of Oxford University Press All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Oxford University Press. Library of Congress Cataloging-in-Publication Data Advances in understanding mechanisms and treatment of infantile forms of nystagmus / edited by R. John Leigh, Michael Devereaux. p.; cm. Result of a meeting held on May 3-4, 2007 at the Louis Stokes Cleveland Dept. of Veterans Affairs Medical Center. Includes bibliographical references and index. ISBN 978-0-19-534218-5 1. Nystagmus—Congresses. 2. Pediatric ophthalmology—Congresses. 3. Infants—Diseases—Congresses. 4. Vision in infants—Congresses. I. Leigh, R. John. II. Devereaux, Michael. [DNLM: 1. Nystagmus, Congenital—Congresses. 2. Eye Movements—physiology—Congresses. 3. Nystagmus, Congenital—therapy— Congresses. 4. Strabismus—Congresses. WW 410 A244 2008] RE748.A38 2008 618.92’0977—dc22 2007046222

987654321 Printed in the United States of America on acid-free paper

Foreword and Acknowledgments

have been his contributions to developing treatments of infantile forms of nystagmus, especially in suggesting and evaluating new surgical procedures. Beyond his scientiﬁc contributions, Dr. Dell’Osso brings a personal understanding to those individuals who are visually disabled by congenital forms of nystagmus; this empathy is appreciated by the numerous patients that he has evaluated over four decades. This volume is the result of a meeting held May 3– 4, 2007, under the auspices of Case Western Reserve University, to celebrate Dr. Dell’Osso’s contributions and the opening of the Daroff-Dell’Osso Laboratory at the Louis Stokes Cleveland Department of Veterans Affairs Medical Center. The meeting was made possible through generous support from the Mt. Sinai Health Care Foundation and the Garson Fund of Cleveland, Ohio. The goal of the meeting was to apply basic information about eye movements in order to better understand the pathophysiology of infantile forms of nystagmus and develop new therapies. The ﬁrst section of this book, “Basic Concepts of Stable Vision and Gaze,” comprises ﬁve chapters that address psychophysical aspects of vision in normal subjects and individuals with nystagmus and the relative contributions of afference (extraocular proprioception) versus efference (internal copies of the ocular motor commands). The inﬂuence of extraocular proprioception on the control of gaze has been considered minor compared with “efference copy” or “corollary discharge” of the ocular motor commands. However, anatomical studies by Jean Büttner-Ennever and colleagues have identiﬁed a possible mechanism

Since the contributions of Hubel and Wiesel, substantial advances have been made in understanding the developmental biology of the visual system, leading to therapies for amblyopia. However, disorders of eye movements that arise early in life remain a major challenge for ophthalmologists, pediatricians, and neurologists. Recently, basic studies of infantile nystagmus have provided new approaches, including psychophysical techniques, development of animal models, genetic linkage studies, and trials of gene therapy. Over the past 40 years, Louis F. Dell’Osso has made major contributions to our understanding of nystagmus that begins in infancy. Starting with an engineering approach to the control of eye movements, he applied principles of linear control systems to a range of ocular oscillations, including congenital nystagmus (now termed infantile nystagmus syndrome) and latent nystagmus (now termed fusional maldevelopment nystagmus syndrome). Dr. Dell’Osso’s ﬁrst efforts deﬁned these ocular oscillations with reliable measurements and classiﬁed the forms of nystagmus on the basis of their waveforms. He then applied this knowledge to better understand how such nystagmus disturbs a clear view of the world and how reliable measurements of nystagmus can be used to predict each individual’s visual potential. Throughout his career, Dr. Dell’Osso’s engineering background has led to development of mathematical models to account for the underlying pathophysiology of disturbed gaze control. More recently, he has been involved with animal models of infantile nystagmus due to speciﬁc genetic disorders, which hold the promise of human gene therapy. Equally signiﬁcant v

vi FOREWORD AND ACKNOWLEDGMENTS for proprioception located near the insertion of nontwitch extraocular muscles in the eyeball. Recent studies by Michael E. Goldberg et al. have established that extraocular proprioception projects to the frontal eye ﬁelds, where it may inﬂuence the programming and consequences of gaze shifts. In Part 1, Dr. Steinbach, an abiding proponent of extraocular proprioception, reports that in normal subjects the Jendrassik maneuver (voluntary, forceful contraction of arm muscle groups) affects the registered vergence eye position, possibly by changing activity in the non-twitch muscle ﬁbers–proprioceptive loop. Dr. Bedell summarizes a series of studies of the mechanisms for lack of oscillopsia in infantile nystagmus syndrome and provides evidence for reduced perceptual responses when the eyes are in motion. An accessible and useful review of current notions of spatial and temporal visual functions and spatial constancy in infantile nystagmus syndrome and latent nystagmus is provided by Dr. Abadi. Dr. Abel supplements this information by highlighting the effect of psychological factors on infantile nystagmus. Finally, Dr. Proudlock presents evidence that perceptual fading in normal subjects is inﬂuenced by efference commands for eye movements Part 2, “New Models and Techniques for Studying Gaze Stability,” opens with two chapters concerning animal models of disorders causing nystagmus. Developmental models for strabismus and amblyopia in primates also provide an opportunity to study the nystagmus that often coexists with these conditions. Dr. Das reports the effects of experimentally induced strabismus on programming of voluntary saccades, noting that reaction time (latency) depends on whether viewing is monocular or binocular. Cerebellar lesions in adults induce well-deﬁned disturbances of eye movements that resemble human disease syndromes. Dr. Walker extends this work by demonstrating that cerebellar nodulus lesions also impair the linear (translational) vestibulo-ocular reﬂex. The ﬁnal two chapters in this section deal with new technologies. One approach to managing nystagmus has been to attempt to cancel the visual consequences of the ocular oscillations with optical devices. A high-tech version developed by Dr. Stahl incorporates moving prisms that are driven with signals derived from recorded eye movements. Although this device is likely to improve vision in patients with acquired nystagmus, it may not help individuals with infantile nystagmus syndrome. Video displays, including miniaturized portable screens, are now an important part of our lives, especially the lives of our children, who are enchanted by video games. Dr. Tabuchi documents the potential effects of video displays on the response to near viewing by children, of whom 20% show abnormal pupillary responses.

The third section, “New Therapies for Congenital Nystagmus,” applies basic studies to develop a range of new therapies. Dr. Gottlob reports linkage to chromosome Xq26-q27 in patients with idiopathic congenital nystagmus, leading to detection of a novel gene; she also reports that both memantine and gabapentin suppress some forms of infantile nystagmus and support modest improvement of vision. Better identiﬁcation of genotypes of infantile nystagmus may ultimately enhance our ability to treat individual patients. Dr. Dell’Osso summarizes his singular contributions to several approaches to treating infantile forms of nystagmus—the importance of reliable measurements, the use of these measurements to predict potential visual acuity, and evaluation of tenotomy and resuture surgical therapies in clinical trials. Dr. Hertle provides the results of a large study of such surgical treatment of those patients with infantile forms of nystagmus that periodically reverse direction. Dr. Tomsak provides a summary of preliminary studies of tenotomy-and-resuture surgical therapies for acquired pendular and downbeat forms of nystagmus, with promising results in three patients. Finally, Dr. Kaminski and colleagues provide a molecular biological approach to the treatment of a disorder that commonly causes double vision—myasthenia gravis—suggesting that complement inhibitor drugs may usher in a new therapeutic approach. Dr. Dell’Osso’s legacy in training scientists is evident in the ﬁnal section of this volume, “General Aspects of Normal and Abnormal Gaze Control,” which is a compendium of shorter contributions from some of his former students. These chapters deal with a broad range of aspects of normal gaze control, infantile nystagmus, and acquired disorders of eye movements, including new treatment measures. Further information about the conference and some supplementary material are available at the Daroff-Dell’Osso Ocular Motility Laboratory Web site (http://omlab.org). We thank the Mt. Sinai Health Care Foundation and the Garson Fund for providing ﬁnancial support for this conference-symposium. Robert Garson was a longtime member of the Board of Trustees at the Mt. Sinai Medical Center and University Hospitals of Cleveland. The fund was established by his family in his honor, and we thank the Garson family for their generous support. We are grateful to Ann Rutledge, who provided invaluable administrative assistance during the conference and the preparation of this volume. We would also like to take this opportunity to acknowledge support of research at the Daroff-Dell’Osso Laboratory by the U.S. Department of Veterans Affairs, the National Eye Institute, and the Evenor Armington Fund. R. John Leigh, MD Michael W. Devereaux, MD July 2007

Contents

Contributors

7. Effects of Cerebellar Lesions in Monkeys on Gaze Stability 55

ix

Part I Basic Concepts of Stable Vision and Gaze

MARK F. WALKER, JING TIAN, XIAOYAN SHAN, RAFAEL J. TAMARGO, HOWARD YING, AND DAVID S. ZEE

1. Afferent and Efferent Contributions to Knowledge of Eye Position 3

8. Development of Visual Stabilization Devices with Applications for Acquired and Infantile Nystagmus 61

EWA NIECHWIEJ-SZWEDO AND MARTIN J. STEINBACH

JOHN S. STAHL, IGOR S. KOFMAN, AND ZACHARY

2. Perceptual Inﬂuences of the Extraretinal Signals for Normal Eye Movements and Infantile Nystagmus 11

C. THUMSER

9. Pupil Abnormalities of the Near Response in Children with Visual Display Terminal Syndrome 70

HAROLD E. BEDELL, JIANLIANG TONG, SAUMIL S. PATEL, AND JANIS M. WHITE

AKIO TABUCHI, ATSUSHI FUJIWARA, AND

3. Perception with Unstable Fixation

23

MAHMOODI KHADIJA

RICHARD V. ABADI

4. Internal and External Inﬂuences on Foveation and Perception in Infantile Nystagmus Syndrome

Part III New Therapies for Congenital Nystagmus

33

10. Genetics and Pharmacological Treatment of Nystagmus: A Review of the Literature and Recent Findings 79

LARRY A. ABEL AND LINDA MALESIC

5. Perceptual Fading during Voluntary and Involuntary Eye Movements 42

IRENE GOTTLOB

FRANK A. PROUDLOCK, ASTRID Y. JORGENSEN,

11. New Treatments for Infantile and Other Forms of Nystagmus 87

AND IRENE GOTTLOB

LOUIS F. DELL’OSSO

Part II New Models and Techniques for Studying Gaze Stability

12. Clinical and Electrophysiological Effects of Extraocular Muscle Surgery on Fifty-three Patients with Infantile Periodic Alternating Nystagmus 99

6. Alternating Saccades in a Primate Model of Strabismus 47 VALLABH E. DAS

RICHARD W. HERTLE, LEAH REZNICK, DONGSHENG YANG, AND KIMBERLY ZOWORTY

vii

viii CONTENTS

13. Eye Muscle Surgery for Acquired Forms of Nystagmus 112 ROBERT L. TOMSAK, LOUIS F. DELL’OSSO, JONATHAN B. JACOBS, ZHONG I. WANG, AND

21. Posterior Internuclear Ophthalmoplegia of Lutz Revisited: Report of a Case Associated with a Midbrain Lesion 156 BERND F. REMLER AND R. JOHN LEIGH

R. JOHN LEIGH

14. The Complement Hypothesis to Explain Preferential Involvement of Extraocular Muscle in Myasthenia Gravis 117

22. Divergence Insufﬁciency Associated with Hereditary Spinocerebellar Ataxia 162 DAVID G. MORRISON, SEAN P. DONAHUE, AND PATRICK J. M. LAVIN

HENRY J. KAMINSKI, YUEFANG ZHOU, JINDRICH SOLTYS, AND LINDA L. KUSNER

23. Neuromuscular Junction Dysfunction in Miller Fisher Syndrome 167 JANET C. RUCKER

Part IV General Aspects of Normal and Abnormal Gaze Control 15. Studies of the Ability to Hold the Eye in Eccentric Gaze: Measurements in Normal Subjects with the Head Erect 129 JEFFREY T. SOMERS, MILLARD F. RESCHKE, ALAN H.

24. Involuntary Version-Vergence Nystagmus Induced by Ground-Plane Optic Flow: Analysis of Dynamic Characteristics of Nystagmus Quick Phases 170 DONGSHENG YANG, MINGXIA ZHU, AND RICHARD W. HERTLE

FEIVESON, R. JOHN LEIGH, SCOTT J. WOOD, WILLIAM H. PALOSKI AND LUDMILA KORNILOVA

16. Effect of Eye Exercise on Clinical Outcome of Noncompressive Ocular Motor Nerve Palsy 136 ANUCHIT POONYATHALANG, PISIT PREECHAWAT, AND VITOO JANVIMALUANG

25. The Neuro-ophthalmologic Complications of Chiropractic Manipulation 175 MICHAEL W. DEVEREAUX

26. Vergence Hysteresis in Infantile Nystagmus 180 ALESSANDRO SERRA, LOUIS F. DELL’OSSO, AND ZHONG I. WANG

17. Expanding the Original Behavioral Infantile Nystagmus Syndrome Model to Jerk Waveforms and Gaze-angle Variations 139

27. Using Wavelet Analysis to Evaluate Effects of Eye and Head Movements on Ocular Oscillations 184

ZHONG I. WANG, LOUIS F. DELL’OSSO, AND

KE LIAO, SIMON HONG, DAVID S. ZEE, LANCE M.

JONATHAN B. JACOBS

OPTICAN, AND R. JOHN LEIGH

18. Extension of the eXpanded Nystagmus Acuity Function to Vertical and Multiplanar Data 143 JONATHAN B. JACOBS AND LOUIS F. DELL’OSSO

28. Multifocal Electroretinographic Study of Patients with Oculocutaneous Albinism and Infantile Nystagmus Syndrome 189 ELISA BALA, JONATHAN B. JACOBS, AND NEAL S. PEACHEY

19. Inertial and Noninertial Contributions to the Perception of Translation and Path 147 SCOTT H. SEIDMAN

20. The Effect of the Duncker Visual Illusion on Occluded Smooth-arm Tracking 152 ARI Z. ZIVOTOFSKY, ADI BERCOVICH, JASON FRIEDMAN, EVA KELMAN, ELINOR SHINHERTZ, AND TAMAR FLASH

Index

193

Contributors

Louis F. Dell’Osso, PhD Daroff-Dell’Osso Ocular Motility Laboratory Louis Stokes Cleveland Veterans Affairs Medical Center Cleveland, Ohio

Richard V. Abadi, PhD Faculty of Life Sciences University of Manchester Manchester, United Kingdom Larry A. Abel, PhD Department of Optometry and Vision Sciences University of Melbourne Melbourne, Victoria, Australia

Michael W. Devereaux, MD Neurological Institute University Hospitals Case Medical Center Cleveland, Ohio

Elisa Bala, MD Research Service Cleveland Veterans Affairs Medical Center Cleveland, Ohio

Sean P. Donahue, MD, PhD Vanderbilt Eye Institute Vanderbilt University Medical Center/School Nashville, Tennessee

Harold E. Bedell, PhD College of Optometry and Center for Neuro-Engineering and Cognitive Science University of Houston Houston, Texas

Alan H. Feiveson, PhD Neurosciences Laboratories, Johnson Space Center National Aeronautics and Space Administration Houston, Texas Tamar Flash, PhD Department of Computer Science and Applied Mathematics Weizmann Institute of Science Rehovot, Israel

Adi Bercovich Gonda Multidisciplinary Brain Research Center Bar Ilan University Ramat Gan, Israel Vallabh E. Das, PhD Yerkes National Primate Research Center Emory University Atlanta, Georgia

Jason Friedman Department of Computer Science and Applied Mathematics Weizmann Institute of Science Rehovot, Israel ix

x CONTRIBUTORS Atsushi Fujiwara, CO Department of Sensory Science Kawasaki University of Medical Welfare Kurashiki, Okayama, Japan Irene Gottlob, MD Ophthalmology Group University of Leicester Leicester, United Kingdom Richard W. Hertle, MD Division of Ophthalmology Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania

Ludmila Kornilova, MD, PhD Institute of Biomedical Problems Moscow, Russia Linda L. Kusner, PhD Department of Neurology and Psychiatry Saint Louis University St. Louis, Missouri Patrick J. M. Lavin, MD Department of Neurology Vanderbilt University Medical Center Nashville, Tennessee

Simon Hong, PhD Laboratory of Sensorimotor Research National Eye Institute, NIH, DHHS Bethesda, Maryland

R. John Leigh, MD Departments of Neurology, Biomedical Engineering, and Neurosciences Case Medical Center Cleveland, Ohio

Jonathan B. Jacobs, PhD Department of Neurology Case Medical Center Cleveland, Ohio

Ke Liao, MS Department of Biomedical Engineering Case Western Reserve University Cleveland, Ohio

Vitoo Janvimaluang, MD Department of Ophthalmology Ramathibodi Hospital Mahidol University Bangkok, Thailand

Linda Malesic, PhD Department of Clinical Vision Sciences La Trobe University Melbourne, Victoria, Australia

Astrid Y. Jorgensen, BSc University of Leicester Leicester, United Kingdom

David G. Morrison, MD Vanderbilt Eye Institute Vanderbilt University Medical Center/School Nashville, Tennessee

Henry J. Kaminski, MD Department of Neurology and Psychiatry Saint Louis University St. Louis, Missouri

Ewa Niechwiej-Szwedo, BSc, MSc Vision Science Research University of Toronto and Toronto Western Hospital Toronto, Ontario, Canada

Eva Kelman Gonda Multidisciplinary Brain Research Center Bar Ilan University Ramat Gan, Israel

Lance M. Optican, PhD Laboratory of Sensorimotor Research National Eye Institute, NIH, DHHS Bethesda, Maryland

Mahmoodi Khadija, OD Department of Sensory Science Kawasaki University of Medical Welfare Kurashiki, Okayama, Japan

William H. Paloski, PhD Neurosciences Laboratories, Johnson Space Center National Aeronautics and Space Administration Houston, Texas

Igor S. Kofman, BSEE Louis Stokes Cleveland Veterans Affairs Medical Center Cleveland, Ohio

Saumil S. Patel, PhD Departments of Neurobiology and Anatomy University of Texas Medical School Houston, Texas

CONTRIBUTORS xi

Neal S. Peachey, PhD Research Service Cleveland Veterans Affairs Medical Center Cleveland, Ohio

Elinor Shinhertz Gonda Multidisciplinary Brain Research Center Bar Ilan University Ramat Gan, Israel

Anuchit Poonyathalang, MD Department of Ophthalmology Ramathibodi Hospital Mahidol University Bangkok, Thailand

Jindrich Soltys, PhD Department of Neurology and Psychiatry Saint Louis University St. Louis, Missouri

Pisit Preechawat, MD Department of Ophthalmology Ramathibodi Hospital Mahidol University Bangkok, Thailand Frank A. Proudlock, PhD University of Leicester Leicester, United Kingdom Bernd F. Remler, MD Departments of Neurology and Ophthalmology MCW Clinics at Froedtert Milwaukee, Wisconsin Millard F. Reschke, PhD Neurosciences Laboratories, Johnson Space Center National Aeronautics and Space Administration Houston, Texas Leah Reznick, MD Division of Ophthalmology Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania Janet C. Rucker, MD Department of Neurological Sciences Rush University Chicago, Illinois Scott H. Seidman, PhD University of Rochester Medical Center Rochester, New York Alessandro Serra, MD Daroff-Dell’Osso Ocular Motility Laboratory Louis Stokes Cleveland Veterans Affairs Medical Center Cleveland, Ohio Xiaoyan Shan, MD, PhD Department of Neurology Johns Hopkins University School of Medicine Baltimore, Maryland

Jeffrey T. Somers, MS Wyle Laboratories Houston, Texas John S. Stahl, MD, PhD Department of Neurology Case Western Reserve University Cleveland, Ohio Martin J. Steinbach, PhD Vision Science Research Toronto Western Hospital Toronto, Ontario, Canada Akio Tabuchi, MD Department of Sensory Science Kawasaki University of Medical Welfare Kurashiki, Okayama, Japan Rafael J. Tamargo, MD, FACS Departments of Neurosurgery and Otolaryngology—Head and Neck Surgery Johns Hopkins University School of Medicine Baltimore, Maryland Zachary C. Thumser, MBME Louis Stokes Cleveland Veterans Affairs Medical Center Cleveland, Ohio Jing Tian, PhD Department of Neurology Johns Hopkins University School of Medicine Baltimore, Maryland Robert L. Tomsak, MD, PhD Departments of Neurology and Ophthalmology Case Medical Center Cleveland, Ohio Jianliang Tong, PhD College of Optometry University of Houston Houston, Texas

xii CONTRIBUTORS Mark F. Walker, MD Departments of Neurology and Ophthalmology Johns Hopkins University School of Medicine Baltimore, Maryland Zhong I. Wang, MS Department of Biomedical Engineering Case Medical Center Cleveland, Ohio Janis M. White, OD, PhD Veterans Affairs New Jersey Health Care System East Orange, New Jersey Scott J. Wood, PhD Universities Space Research Association Houston Texas Dongsheng Yang, PhD Division of Ophthalmology Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania Howard Ying, MD, PhD Department of Ophthalmology Johns Hopkins University School of Medicine Baltimore, Maryland

David S. Zee, MD Departments of Neurology, Ophthalmology, Otolaryngology–Head and Neck Surgery, and Neuroscience Johns Hopkins University School of Medicine Baltimore, Maryland Yuefang Zhou, PhD Department of Neurology and Psychiatry Saint Louis University St. Louis, Missouri Mingxia Zhu, PhD Laboratory of Visual and Ocular Motor Physiology Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania Ari Z. Zivotofsky, PhD Gonda Multidisciplinary Brain Research Center Bar Ilan University Ramat Gan, Israel Kimberly Zoworty Division of Ophthalmology Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania Advances in Understanding Mechanisms and Treatment of Infantile Forms of Nystagmus

ADVANCES IN UNDERSTANDING MECHANISMS AND TREATMENT OF INFANTILE FORMS OF NYSTAGMUS

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I BASIC CONCEPTS OF STABLE VISION AND GAZE

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1 Afferent and Efferent Contributions to Knowledge of Eye Position EWA NIECHWIEJ-SZWEDO AND MARTIN J. STEINBACH

ABSTRACT

HOW DOES THE BRAIN KNOW WHERE THE EYE IS? OUTFLOW VERSUS INFLOW

To stay informed about the position of the eyes in the orbits, the brain has available two extraretinal signals: a copy of the efferent signal (outﬂow) to the extraocular muscles (EOM) and proprioception (inﬂow) from the EOM. Palisade endings, associated with the multiply innervated ﬁbers of the global layer of EOM, are the putative receptors supplying the inﬂow eye position signal. Büttner-Ennever’s proprioceptive hypothesis for the control of eye movements is based on neuroanatomical tracing studies that identiﬁed a distinct set of non-twitch (NT) motoneurons whose activity does not add to the force used to move the eyes. It has been suggested that NT motoneurons could be involved in modulating the gain of sensory feedback from the eye muscles analogous to the gamma-efferent ﬁbers that control the sensitivity of muscle spindles in skeletal muscles. We tested this in a series of studies where the activity of NT motoneurons was altered using the Jendrassik maneuver (JM). JM facilitates the amplitude of all tendon reﬂexes, most likely due to the general up-regulation of the gamma system. We found that the JM perturbation altered registered vergence eye position when observers localized targets in depth. Surprisingly, the JM did not affect higher-order perceptual judgments (size constancies), nor did it affect the saccadic system. Overall, our studies provide insight into the putative mechanism involved in the control of sensory feedback from the EOM.

The visual direction of an object can only be obtained by taking into account the position of the eyes in the orbit. Thus, knowledge of eye position is essential for accurate visuomotor behavior, such as reaching and grasping. The central nervous system (CNS) can obtain eye position information from two extraretinal sources: efference copy (i.e., a copy of the motor command sent to the eye muscles or outﬂow) and afferent feedback (inﬂow). The debate between outﬂow and inﬂow as the source of the signal is longstanding, going back to Helmholtz and Sherrington.1 There are two major arguments against ocular proprioception. First, unlike skeletal muscles, eye muscles act against a constant load. Consequently, a copy of the motor command should theoretically provide sufﬁcient information about the state of the oculomotor plant. There are some data that suggest that the “constant load” hypothesis may not be true. Steinbach and Lerman showed that the center of mass and the center of rotation of the human eye may not be in the same place.2 This means that the load on the eye muscles will differ as the orientation of the head changes with respect to the gravity vector. Second, an important function of proprioceptors in the skeletal muscles is regulation of muscle length in response to stretch; however, the presence of stretch reﬂexes in extraocular muscles (EOM) is controversial. A classic experiment by Robinson and Keller3 in awake rhesus monkeys found no change in the activity of the 3

4 BASIC CONCEPTS OF STABLE VISION AND GAZE abducens motoneurons in response to muscle stretch. Similar results were also obtained in the oculomotor motor nucleus of cats by Tomlinson and Schwarz.4 In contrast, Dancause and colleagues5 have recently recorded electromyographic activity in the horizontal recti muscles in anesthesized rats and squirrel monkeys in response to passive eye rotation. This is the ﬁrst study to suggest that stretch reﬂexes might be present in the EOM, and more studies are needed to conﬁrm these ﬁndings. Although the presence of monosynaptic stretch reﬂexes in the EOM has been questioned, there is substantial evidence to support the inﬂow theory. First, neural activity in response to passive stretch of the EOM has been recorded in several CNS structures: the cerebellum, superior colliculus, lateral geniculate nucleus, and primary visual cortex (for a review see Donaldson).6 Second, highly trained observers whose eyes were moved passively were able to report the correct direction of their eye movements in 70% of the trials.7 Previous studies have also shown that proprioceptive signals from eye muscles have a signiﬁcant role in programming of eye movements8,9 during egocentric localization tasks10-13 and adaptation of smooth pursuit.14 In addition, registered eye position has been affected in patients whose proprioceptive feedback has been disrupted by surgical treatment15,16 or due to pathology involving the trigeminal nerve.17,18 In summary, proprioceptive signals from the EOM are clearly important for accurate visuomotor behavior. Feedback is an integral part of sensorimotor control of movement. Since the properties of the oculomotor plant can change over time due to growth, aging, or disease, feedback ensures that accuracy is maintained over time. In other words, feedback is necessary to conﬁrm that the motor command that was sent to the muscles to execute a particular movement actually achieved the desired motor output. The “hybrid model” of ocular motor control was ﬁrst proposed by Ludvigh,19 who advocated that for optimal motor performance both the efferent and afferent signals must be used by the CNS. In brief, Ludvigh suggested that parametric control of eye movements is important to maintain accurate visuomotor control.

ANATOMY AND PHYSIOLOGY OF EOM AFFERENCE Although the afferent pathway and the location of the cell body of the EOM proprioceptors have not yet been determined, an elegant study by Wang and colleagues20 has provided evidence that eye position is represented in the somatosensory area 3a. The study involves recordings from neurons in the depth of the central sulcus in behaving rhesus monkeys. The signal

was clearly dependent on the orbital eye position and not gaze-in-space position, and it was not modulated by visual stimuli. In addition, a retrobulbar block of the contralateral eye abolished the eye position signal, which subsequently returned when eye movements returned to normal. Results from the study by Wang et al. also illuminate the reason for apparently conﬂicting reports of the effect of surgical treatment for strabismus. Steinbach and Smith15 reported that patients who had a single surgery on their EOM were able to point accurately to targets as soon as the operated eye was uncovered, which was attributed to the afferent signal that informed the CNS about the change in the eye position. However, Bock and Kommerell21 failed to replicate these ﬁndings. The critical difference between the two studies was the type of anesthetic used: patients tested by Steinbach and Smith were under general anesthesia, whereas Bock and Kommerell used a retrobulbar block (described by Steinbach).22 As shown by Wang and colleagues, retrobulbar block abolishes the proprioceptive signal, which accounts for the discrepancy between the earlier studies. There are two potential receptors in the EOM that could serve a proprioceptive function: muscle spindles and palisade endings. Muscle spindles, which are the primary proprioceptors in the skeletal muscles, are found in the orbital layer of some species, such as humans, sheep, and some primates, but not in other species, such as cats, rats, rabbits, or horses.23 Spindles found in the EOM have been described as “atypical.” For instance, Ruskell24 reported that more than 50% of EOM spindles were indistinguishable from extrafusal ﬁbers, as they were not enclosed in a capsule and did not have a deﬁned equatorial region. He also observed that nuclear bag ﬁbers were virtually absent, a ﬁnding that was subsequently conﬁrmed by others.25,26 It is currently unknown to what extent muscle spindles play a proprioceptive role in the human EOM. Palisade endings (PE), which are associated with the multiply innervated ﬁbers (MIF) of the global layer, are receptors that are unique to the EOM. They are sometimes referred to as innervated myotendinous cylinders and have been found in the EOM of all species tested to date, such as cats, monkeys, sheep, rats, and humans.27-30 Anatomical studies show that the PE are enclosed in a capsule at the distal end of the global MIF. A thinly myelinated axon runs along the muscle ﬁber and then loops back to enter the capsule as it bifurcates into several branches.27,28 Several studies have proposed a sensory function for PE based on structural properties and tracing studies—for example, the presence of a capsule and clear vesicles in the PE, which are also found in other sensory endings such as Golgi tendon organs and muscle spindles.27 Billig and

CONTRIBUTIONS TO KNOWLEDGE OF EYE POSITION

colleagues31 also reported that PE were labeled when anterograde tracers were injected into the Gasser’s (trigeminal) ganglion, which contains only sensory neurons. In contrast, a recent histochemical examination of the musculotendinous junction in the human EOM showed that the myoneuronal region might also contain motor endings. These motor endings were identiﬁed based on staining of the myoneuronal junction with α-bungarotoxin, which labels acetylcholinergic receptors. Upon microscopic examination, the authors also found basal lamina, which is indicative of motor terminals. Based on these results the authors suggested that PE might have a sensory and motor function.32 Additional examination of the musculotendinous junction in the cat and monkey has revealed that the region containing the PE is immunoreactive to histochemical markers for cholinergic nerve ﬁbers and nerve terminals, which have been traditionally associated with motoneurons.33,34

DUAL INNERVATION OF THE EOM: PROPRIOCEPTIVE HYPOTHESIS Although the question of whether PE have a sensory or motor function has not yet been resolved, several authors have proposed that PE, along with the MIF, might have a proprioceptive role in the control of eye movements. Robinson3 was the ﬁrst to use the term inverted muscle spindle to suggest that the non-twitch MIF and the PE might be comparable to the γ-spindle system found in the skeletal muscles.5 This hypothesis has been further extended by Büttner-Ennever and colleagues36,37 based on their neuroanatomical tracing studies, which demonstrated that the singly innervated ﬁber (SIF) and MIF receive innervation from separate groups of ocular motoneurons. The two groups of neurons were identiﬁed when injections of tracer were made at different sites of the EOM. Large motoneurons were labeled when the midregion of the muscle ﬁber close to the endplate was injected (i.e., injection targeting the SIF), whereas smaller motoneurons in a distinct region around the periphery of the large motoneurons were labeled when the distal musculotendinous region of the muscle was injected (i.e., injection that targeted the MIF). These small motoneurons form a cap over the dorsal trochlear nucleus, and they are found in the medial half of the abducens nucleus, bilaterally around the midline of the oculomotor nucleus to the inferior oblique and the superior rectus, and at the dorsal medial border of the oculomotor nucleus to the medial rectus. A subsequent study has shown that the premotor input to the twitch and non-twitch motoneurons also comes from different premotor areas.38 The non-twitch motoneurons receive monosynaptic

5

input from the vestibular areas associated with gazeholding mechanisms, the central mesencephalic reticular formation, and the supraoculomotor area, which are involved in the programming of vergence eye movements and the ocular following response. In contrast, the twitch motoneurons receive input from classical premotor regions, such as the paramedian pontine reticular formation and the magnocellular vestibular nuclei. These results provide some support for Robinson’s claim that the non-twitch motoneurons of the global MIF might be equivalent to the γ motoneurons and control the baseline activity of PE, the putative EOM proprioceptors.

IS THE AFFERENT SIGNAL FROM EOM MODULATED BY GAMMA MOTONEURONS? We have conducted a series of studies to examine the hypothesis that proprioceptive feedback from the EOM might be modulated by γ activity. We used behavioral and psychophysical approaches and a manipulation called the Jendrassik maneuver (JM) to examine the above hypothesis in healthy observers and patients who underwent surgeries for strabismus. The JM refers to a voluntary, forceful contraction of any muscle group, and it has been used extensively to alter the excitability of spinal reﬂexes39-42 and limb position information.43 Brieﬂy, while the JM is performed, the amplitude of all skeletal reﬂexes is facilitated.44 One of the mechanisms proposed to explain the reﬂex reinforcement effect is that the muscle contraction has a general effect that results in up-regulation of the γ motoneuron activity, which increases the baseline activity of muscle spindles and, consequently, results in a larger efferent response when the muscle is stretched. We hypothesized that if the non-twitch motoneurons are analogous to the γ motoneurons the JM should also affect the activity of these neurons and alter the feedback from PE, which would result in misregistration of eye position and localization errors.

Effect of JM on the Vergence System Since the non-twitch motoneurons receive direct premotor input from areas that are known to be involved in the control of vergence eye movements, we ﬁrst examined the hypothesis in two studies in healthy observers while they localized targets in depth.45 In the ﬁrst study, 10 healthy participants were tested on a task that required looking and pointing to targets in three conditions: (1) control (look and point to target); (2) look and point during JM (while performing a muscle contraction with the lower limbs); and (3) look during JM and point after JM (point 2 to 3 seconds

Proportion of “near” responses

6 BASIC CONCEPTS OF STABLE VISION AND GAZE 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 2

JM first condition

Perceived target location

control JM first JM second

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0 Farther

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Standard Comparison target target (JM) (no JM)

JM second condition Standard Comparison target target (JM) (no JM)

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2

Nearer

Location of the comparison target with respect to the standard target (cm)

Figure 1.1 Mean proportion of “near” responses for each comparison target location (at 0, both targets were presented at the same location). In the “JM ﬁrst” condition, participants performed the contraction when the standard target was shown. In the “JM second” condition, the contraction was performed when the comparison target was shown. Bars show ±1 standard errors. JM, Jendrassik maneuver. Source: NiechwiejSzwedo E, Gonzalez E, Bega S, et al. Proprioceptive role for palisade endings in extraocular muscles: evidence from the Jendrassik Maneuver. Vis Res. 2006; 46(14):2268–2279.

after the contraction has been released). In accordance with our hypothesis, results showed that participants systematically overshot the target when pointing in the third condition (p < 0.01), and no signiﬁcant difference was found between the other two conditions. Furthermore, there was no signiﬁcant difference in the vergence angle of the eyes between any of the conditions. Results from this experiment provided preliminary support for the hypothesis that the JM affected registered eye position, but there was a major caveat: since the JM has a general effect on the γ system, the localization errors might have been due to altered feedback from the arm muscles and not the EOM. Our next experiment was designed to address this limitation by using a perceptual localization task that did not require pointing. Participants (n = 21) were tested on a two-alternative forced-choice (2AFC) procedure, which involved looking at a target and, when the target was removed, deciding whether a second target appeared closer or farther away than the ﬁrst one. JM was randomly performed when either the ﬁrst or the second target was presented. The point of subjective equality (PSE) and the y-intercept were both signiﬁcantly different between the conditions (p < 0.0001) (Fig. 1.1). Speciﬁcally, when the afferent feedback was altered

Figure 1.2 Summary and interpretation of results from experiment 2. Participants perceive target location as “farther,” while feedback from the EOM is perturbed by the JM. EOM, extraocular muscles; JM, Jendrassik maneuver. Source: Niechwiej-Szwedo E, Gonzalez E, Bega S, et al. Proprioceptive role for palisade endings in extraocular muscles: evidence from the Jendrassik Maneuver. Vis Res. 2006;46(14):2268–2279. during the presentation of the ﬁrst target, participants perceived the second target as nearer. In contrast, the second target was perceived as farther when the JM was performed during presentation of the second target. In other words, in the case when both targets (standard and comparison) were shown at the same location and the JM was performed when the standard target was presented, participants reported that the comparison target was nearer more frequently. This result suggests that participants perceived the location of the standard target as farther with the JM. In contrast, when the JM was performed while the comparison target was presented, it was reported more frequently as farther, which again suggests that during JM the location of the comparison target was perceived as farther (Fig. 1.2). In summary, results from the second experiment provided strong evidence that eye position is registered as more divergent when feedback from the EOM is perturbed by the JM. The third study was conducted to examine the effect of JM on target localization in patients with strabismus who have had surgeries that most likely compromised the EOM afferent feedback loops. It was hypothesized that patients’ responses would not be affected by the JM perturbation because activity of the PE could not be altered via the γ system. To date we have tested 3 patients, all of whom underwent different surgeries involving resection and/or recession of the EOM for congenital esotropia or fourth nerve palsy. Following the surgery, all patients had binocular vision: two patients had stereoacuity of 40 seconds of arc and the other patient had stereoacuity of 140 seconds of arc as tested by the Titmus test. Patients were tested on a 2AFC task using the methodology used in the second experiment. In accordance with our

CONTRIBUTIONS TO KNOWLEDGE OF EYE POSITION

hypothesis, preliminary data showed that the order of the JM did not signiﬁcantly affect patients’ localization responses. These data provide additional support that the JM alters registered eye position through an EOM proprioceptive feedback loop that has been compromised in patients whose myotendinous region was damaged by the surgery.

Effect of JM on Higher-Order Perceptual Judgments Overall, results from the three studies provided evidence that the JM alters the proprioceptive gain of the vergence system. Thus, we hypothesized that the JM would also affect higher-order perceptual judgments that rely on accurate registration of absolute depth. This was examined in the three experiments. Since the vergence angle of the eyes is an important source of extraretinal information contributing to size constancy, we expected that participants would perceive the size of a constant retinal stimulus as larger when the feedback from the eye muscles was altered via the JM. Participants (n = 20) were seated in the dark and were tested on a 2AFC procedure. The JM was performed while viewing the ﬁrst stimulus (standard square) or the second stimulus (comparison square). In contrast to the hypothesis, data showed no signiﬁcant differences between the two experimental conditions (when the JM was performed and the control condition). In the next two experiments, we examined whether the perceptual phenomenon of depth constancy was affected by the JM perturbation. First, we examined stereoscopic depth constancy. Horizontal disparities must be scaled by viewing distance in order for depth constancy to be preserved, and the vergence angle of the eyes can be used to calibrate horizontal disparities for different viewing distances. If the JM affected the registered eye position as shown in the previous experiments, we hypothesized that for the same disparity the perceived depth would be greater when the JM was performed compared to the condition without the JM. Results from the study (n = 6) showed no signiﬁcant differences between the two conditions. Since the stimulus was presented stereoscopically it is possible that the negative result was partly due to a conﬂict between the ocular motor cues of convergence and accommodation. Therefore, we examined depth constancy using a different paradigm: the Pulfrich illusion. The Pulfrich effect is based on a cortical time delay that is interpreted by the CNS as a disparity. The cortical time delay is induced when a horizontally moving pendulum is seen with one eye viewing it through a neutral density ﬁlter, in which case the pendulum appears to move in an elliptical orbit. Previous work

7

has shown that the perceived depth (i.e., the short axis of the ellipse) is scaled with viewing distance and presumably is dependent on the vergence angle of the eyes.46-48 Therefore, we examined whether the perceived depth during the Pulfrich illusion is also affected by the JM. Participants (n = 5) viewed a moving vertical bar through an apparatus containing a variable ﬁlter, which could be adjusted, over one eye and a constant, nonadjustable ﬁlter over the other eye. The task was to move the variable ﬁlter to match the constant ﬁlter, which would null the illusion. The task was performed with and without the JM. Again, in contrast to the hypothesis, no signiﬁcant effect between the two conditions was found. In summary, the results clearly showed that altering feedback from the EOM via the JM did not affect the perceptual judgments of size or depth.49 The lack of a signiﬁcant effect would not be surprising, given that the JM manipulation affects the registered vergence eye postions, but vergence itself is not a perfect cue to distance. In addition, the relative contribution of EOM afference to registered eye position has been estimated to be approximately 30%,10,11 and it might be even less signiﬁcant for higher order perceptual judgments. In short, the perceptual phenomena of size and depth constancy depend on the perceived distance, which is an internally generated estimate of the viewing distance. In the real world, the neural estimate of viewing distance is based on multiple visual and ocular motor cues. In the present experiments, visual cues were removed, and ocular motor cues provided the only input for distance estimation. Nevertheless, the perturbed vergence signal was not taken into account by the CNS.

Effect of JM on the Saccadic System In the next set of studies, we examined whether the JM affects the saccadic system and localization responses in the median plane.50 Based on the results from our vergence study, we hypothesized that participants would overshoot the target while the JM was performed. Participants (n = 10) were seated in the dark and were tested on a 2AFC procedure. The task was to make a saccadic eye movement to the peripheral target as fast as possible. The JM was performed during the programming and execution of the saccade or during the perceptual judgment task. In the control condition, the JM was not performed. All three conditions were fully randomized. In contrast to the hypothesis, the JM did not affect the localization responses, as shown by the lack of differences between the conditions across examined variables: PSE, slope, and y-intercept values. In addition, the mean amplitude and velocity of saccadic eye

8 BASIC CONCEPTS OF STABLE VISION AND GAZE movements were not signiﬁcantly different between the conditions. Overall, the study showed that the JM perturbation did not affect the saccadic system, which is in contrast to what we had found for the vergence system. The lack of difference can be explained by considering that the input to the non-twitch motoneurons that innervate the MIF comes from areas that are involved with programming of vergence eye movements, the ocular following response, and gaze-holding mechanisms, but which are not associated with the saccadic system.38

SUMMARY Our behavioral studies with binocularly normal observers and people who have undergone strabismus surgery provide preliminary support for the hypothesis that the JM affects the registered eye position, but only for the vergence system, and only when the task requires localization in depth. Higher-order perceptual judgments that require accurate registration of absolute depth are not affected by the perturbation. The fact that the saccadic system was not affected is analogous to the ﬁndings of Guthrie and colleagues,51 who reported that cutting monkeys’ ophthalmic branch of the trigeminal nerve (i.e., deafferentation) altered their vergence responses but had no effect on conjugate eye movements. Our results reinforce the importance of the EOM proprioceptive feedback loop for binocular function. A critical ﬁnding from our studies is the fact that neither vergence nor saccadic eye movements were affected by the JM. Since the non-twitch motoneurons do not add to the force that is used to move the eyes,52 the eye movement data from our study yield further support for our hypothesis that the JM most likely affects the activity of the non-twitch (γ) motoneurons, not the twitch (α) motoneurons. In summary, using a proxy method to alter the activity of the γ system (i.e., the JM manipulation), we have provided behavioral evidence to support Robinson’s original claim that the PE and MIF might be part of an “inverted muscle spindle.”

FUTURE DIRECTIONS FOR RESEARCH Although our research provides novel insights into the mechanism of EOM feedback, it also raises questions. For instance, we have found that the JM affects the vergence system but not the saccadic system, which we believe can be explained by the premotor input to the non-twitch motoneurons. Since the premotor regions identiﬁed by Wasicky and colleagues38 also

include areas involved in gaze-holding mechanisms and ocular following response, the next step will be to examine how these responses are affected by the JM perturbation. An important question that remains is, what is the role of the γ system and proprioception in general in ocular motor control and visuomotor behavior? The unique structure of the EOM and the fact that the cell body and the afferent pathway of the putative proprioceptors—the PE—have not been traced makes it more difﬁcult to study the question. The role of EOM proprioception in the control and execution of different types of eye movements has been reviewed extensively by Donaldson,6 but the possibility that the γ system might modulate the gain of sensory feedback was only brieﬂy mentioned by that researcher. It has been suggested that in the skeletal system, “the fusimotor system allows state dependent parametric adjustment of proprioceptive feedback.”53 The implication of this hypothesis is that the γ loop is important for parametric adjustment of the feedback loops to match the demands of different tasks, and this might also be relevant for the ocular motor system. For example, many studies have shown that the relationship between the eye position and the ﬁring frequency of the ocular motoneurons is highly correlated.54 However, a study by Mays and Porter reported that the relationship between eye position and ﬁring rate is also dependent on the type of eye movement.55 In that study, recordings were made from the abducens nucleus during conjugate adduction and during convergence. Data showed that for a given eye position the ﬁring rate increased during convergence compared to conjugate adduction. Extending these results, Miller and colleagues56 measured the oculorotary forces in the horizontal recti muscles to test whether the force developed in the lateral rectus is in fact higher in the converged state. Paradoxically and in contrast to the hypothesis, they found decreased forces in both the lateral and medial recti muscles during convergence. These results clearly show that the innervation of the EOM is much more complex than previously acknowledged, and it is possible that motor commands to the eye muscles differ during convergence and adduction. In light of our results, it should also be acknowledged that the gain of the proprioceptive system might be set differently for different types of eye movements. In conclusion, after years of neglect, EOM proprioception has recently received its due attention. It is now indisputable that both afferent and efferent signals play a role in ocular motor control and visuomotor behavior and must be taken into account when developing models of ocular motor control. Furthermore, the efferent signals that have to be considered must include the α and γ systems.

CONTRIBUTIONS TO KNOWLEDGE OF EYE POSITION

acknowledgments Funding for the authors’ experiments came from the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, the Krembil Family Foundation, the Sir Jules Thorn Trust, and the Vision Science Research Program of the University of Toronto and the University Health Network. We thank our collaborators and those who have helped with this research in direct and indirect ways: B. Bahl, S. Bega, E. Gonzalez, S. Kraft, L. Lillakas, H. Ono, D. Smith, J. Trotter, R. Steinbach, L. Tarita-Nistor, M. Verrier, and A. Wong.

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43. YaudaT, Izumizaki M, IshiharY, Sekihara C, AtsumiT, Homma I. Effect of quadriceps contraction on upper limb position sense errors in humans. Eur J Appl Physiol. 2006;96(5):511–516. 44. Delwaide PJ, Toulouse P. Facilitation of monosynaptic reﬂexes by voluntary contraction of muscle in remote parts of the body. Mechanisms involved in the Jendrassik Manoeuvre. Brain. 1981;104 (Pt 4):701–709. 45. Niechwiej-Szwedo E, Gonzalez E, Bega S, et al. Proprioceptive role for palisade endings in extraocular muscles: evidence from the Jendrassik Maneuver. Vis Res. 2006;46(14):2268–2279. 46. Lit A, Hyman A. The magnitude of Pulfrich stereophenomenon as a function of distance of observation. Am J Opt Arch Am Acad Opt. 1951;28:564–580. 47. Wallach H, Gillam BC, Cardillo L. Some consequences of stereoscopic depth constancy. Percep Psychophys. 1979;26(3):235. 48. Nakamizo S, Lei C. The Pulfrich effect and depth constancy. Jap Psychol Res. 2000;42(4): 252–256. 49. Niechwiej-Szwedo E, González E, Bahl B, et al. Manipulation of extraocular muscle afference has no effect on higher order perctpual judgments. Vis Res. 2007;47(26):3315–3323. 50. Niechwiej-Szwedo E, González E,Verrier MC, et al. Localization in the frontal plane is not susceptible to manipulation of afferent feedback via the Jendrassik Maneuver. Vision Res. 2008;48(5):724–732. 51. Guthrie BL, Porter JD, Sparks DJ. Role of extraocular muscle proprioception eye movements studied by chronic deafferentation of intra-orbital structures. Soc Neruosci Abst. 1982;8:156. 52. Fuchs AF, Luschei AF. Development of isometric tension in simian extraocular muscle. J Physiol. 1971;219(1):155–166. 53. Prochazka A. Sensorimotor gain control: a basic strategy of motor systems? Prog Neurobiol. 1989; 33(4):281–307. 54. Carpenter RH. Movements of the Eyes. 2nd ed. London: Pion Limited; 1988. 55. Mays LE, Porter JD. Neural control of vergence eye movements: activity of abducens and oculomotor neurons. J Neurophysiol. 1984;52(4):743–761. 56. Miller J M, Bockisch CJ, Pavlovski DS. Missing lateral rectus force and absence of medial rectus co-contraction in ocular convergence. J Neurophysiol. 2002;87(5):2421–2433.

2 Perceptual Inﬂuences of Extraretinal Signals for Normal Eye Movements and Infantile Nystagmus HAROLD E. BEDELL, JIANLIANG TONG, SAUMIL S. PATEL, AND JANIS M. WHITE

ABSTRACT

of the retinal image, which has the potential to degrade a number of visual functions. The beneﬁcial inﬂuence of the low-velocity foveation periods of the IN waveform for visual functions such as visual acuity, contrast sensitivity, and stereopsis has previously been documented.1-8 However, in addition to its inﬂuence on visual function, the retinal image motion produced by IN also has the potential to produce oscillopsia and the perception of motion smear. In normal observers, the introduction of simulated foveation periods into rhythmic motion of the retinal image does little to protect against the perception of either oscillopsia or motion smear.2,9 Our hypothesis is that similar, but not necessarily identical, neural mechanisms facilitate the perception of a stable and relatively clear visual scene during normal eye movements and in IN. The purpose of this chapter is to present arguments and recent evidence that bear upon this hypothesis.

The involuntary eye movements in patients with infantile nystagmus (IN) generate rapid to-and-fro motion of the retinal image, which has the potential to produce oscillopsia and the perception of motion smear. In normal subjects, extraretinal signals can neurally “cancel” the retinal image motion that occurs during eye movements and can reduce the extent of perceived motion smear. Previous studies indicate that extraretinal signals also contribute to perceived stability in subjects with IN. In addition to “canceling” the to-and-fro motion of the retinal image, extraretinal signals also partly compensate for changes in retinal-image orientation that occur during the torsional component of IN. We show that extraretinal signals reduce perceived motion smear in subjects with IN, preferentially for relative target motion in the opposite direction of slow-phase eye movements. A possible mechanism for the reduction of perceived motion smear is a decrease in the duration of the temporal impulse response function during eye movements. Temporal contrast sensitivities measured in normal observers, and subjects with IN are consistent with this possibility. Although extraretinal eye movement signals have similar inﬂuences on perceived stability and clarity in normal observers and subjects with IN, the characteristics of the operative neural mechanisms may not be identical.

PERCEPTUAL STABILITY DURING IN As proposed initially by von Helmholtz10 and elaborated on subsequently by von Holst and Mittelstädt,11 perceptual stability can be maintained during eye movements if the resulting displacement and motion of the retinal image are compared to (and “canceled” by) information about changes in the eye position. During normal eye movements, efference copy information and ocular muscle proprioception are two types of extraretinal signals that inform the brain about changes in eye position.12,13 Several studies

The involuntary eye movements of patients with infantile nystagmus (IN) generate rapid to-and-fro motion 11

12 BASIC CONCEPTS OF STABLE VISION AND GAZE demonstrated that extraretinal signals also accompany the involuntary eye movements of subjects with IN and contribute to the perception of a stable visual world.14-17 For example, we showed that subjects with IN point relatively accurately to visual stimuli that are ﬂashed brieﬂy at various times, and therefore are imaged at different retinal locations, during the IN waveform.16 Because these stimuli were presented in an otherwise dark visual ﬁeld, veridical pointing required accurate information of the eye position at the instant that the ﬂashed stimulus was presented. Subsequently, Abadi et al.17 showed that patients with IN perceive oscillopsia if the magnitude of retinal image motion is either substantially larger or smaller than the amplitude of the nystagmus eye movements. These results also are consistent with the proposition that, as in normal observers, the perception of motion or stability in subjects with IN derives from the comparison of sensory information about the ongoing motion of the retinal image to extraretinal eye position signals. Averbuch-Heller et al.18 reported that, in addition to rhythmic horizontal eye movements, most patients with horizontal IN manifest a torsional component of nystagmus. In 10 of the 13 subjects in this study, clockwise torsion (from the subjects’ point of view) was associated with the rightward horizontal component of IN. More recently, Dell’Osso et al.19 reported that approximately half of their subjects with horizontal IN also had rhythmic torsional and vertical eye movement components, consistent with a small seesaw nystagmus. We recorded horizontal, vertical, and torsional eye movements in a sample of 7 patients with IN using the magnetic search-coil technique as they ﬁxated successively in the straight-ahead direction and at eight additional locations in horizontal, vertical, and oblique gaze. The results demonstrated the existence of a torsional nystagmus component in each subject.20 Across subjects, the mean amplitude of the torsional

component of IN in straight-ahead gaze ranged from 0.3° to 3.7°, which was larger than the amplitude of the vertical eye movements during nystagmus in all 7 subjects (t[6 df] = 7.58; p = 2.7 × 10 −4) (Table 2.1). In all of the subjects, clockwise torsional rotation accompanied rightward fast phases of IN, and counterclockwise torsional rotation accompanied leftward fast phases of IN (Fig. 2.1), consistent with the results reported by Averbuch-Heller et al.18 for the majority of their subjects. In 5 of our 7 subjects, the directions of the torsional and horizontal slow phases of IN also consistently obeyed the same relationship. Based primarily on recordings made in straightahead gaze, Averbuch-Heller et al.18 suggested that the torsional component of their subjects’ IN did not appear to conform to the torsional variations predicted from Listing’s law.10 In 3 of the 7 subjects with IN that we tested, neither the amplitude nor the direction of the torsional component of IN varied systematically with the direction of gaze (evaluated at ±12º from the straight-ahead direction, horizontally and vertically). In the other 4 subjects with IN, the amplitude, but not the direction, of the torsional component of IN varied according to the direction of gaze. In contrast to the subjects with IN, both the amplitude and the direction of the torsional eye movements that accompanied rightward and leftward optokinetic nystagmus (OKN) in normal observers varied with gaze position, as expected from Listing’s law. Figure 2.2 compares the amplitudes of horizontal and torsional eye movements in 3 subjects with IN and during OKN in 1 normal observer for two directions of vertical gaze, that is, 12º up and down from straight ahead at eye level. Straight lines are ﬁt to the data obtained for each subject, separately for the two vertical gaze directions. If the torsional components of IN and OKN vary with the direction of gaze as predicted by Listing’s law, then the slope of the best ﬁtting line is expected to

Table 2.1 Eye Movement Amplitudes in Subjects with IN Observer

Horizontal Amplitude (°)

Vertical Amplitude (°)

Torsional Amplitude (°)

SD of Torsion Eye Position (°)

Orientation Threshold (°)

JH

2.12 ± 0.48

0.11 ± 0.02

2.29 ± 0.33

0.98

0.79 ± 0.05

CFN

2.62 ± 0.61

0.13 ± 0.03

1.14 ± 0.18

0.53

0.58 ± 0.08

FR

5.28 ± 0.52

0.60 ± 0.16

1.59 ± 0.16

0.99

0.61 ± 0.02

MS

5.43 ± 0.65

0.44 ± 0.05

0.62 ± 0.10

0.68

0.70 ± 0.27

AJ

5.45 ± 1.45

0.68 ± 0.36

3.67 ± 1.40

2.00

1.49 ± 0.24

CRN KN

2.29 ± 0.49 1.26 ± 0.17

0.18 ± 0.07 0.16 ± 0.05

0.63 ± 0.25 0.30 ± 0.07

0.87 0.36

0.75 ± 0.25 *

Mean amplitudes (±1 SD) of eye movement in the horizontal, vertical, and torsional meridians during 10-second intervals in subjects with infantile nystagmus (IN), along with the variability (SD) of torsional eye position during IN wave forms and psychophysical orientation thresholds. * Data not obtained for this observer.

PERCEPTUAL INFLUENCES OF EXTRARETINAL SIGNALS

13

Figure 2.1 Horizontal (lower traces) and torsional (upper traces) eye position in degrees as a function of time for the right eye of one subject with IN. The central panel illustrates nystagmus in straight-ahead gaze for subject JH. The other eight panels are for gaze positions on the perimeter of an imaginary 24º square, with ﬁxation directed to a small LED. Upward deﬂections indicate rightward and clockwise eye movements (from the subject’s point of view). The vertical locations of the traces in each panel are arbitrary. Note that both the horizontal and torsional components of JH’s nystagmus reverse direction in right gaze. The intorsional drift that accompanies the reversal of JH’s nystagmus in up-temporal gaze is not a coil-slippage artifact, as video recordings of the eye show similar slow changes in the torsional eye position. IN, infantile nystagmus. change between 12º down and 12º up gaze by approximately +0.21. This value follows from the formula that Helmholtz10 provided to calculate the torsion expected from Listing’s law: Tan(T/2) = Tan(V/2) × Tan(H/2) where T is the angle of torsion and H and V are the horizontal and vertical gaze directions. For small angles, the tangents of the half-angles can be replaced by the half-angles themselves, from which one can deduce that the expected change in slope between down and up gaze in Figure 2.2 does not depend on the location of the primary gaze position. For 3 normal observers, the observed change in slope between down and up gaze during OKN was 0.20 ± 0.003, in excellent agreement with the prediction from Listing’s law. In contrast, the change in slope for the subjects with IN averaged 0.15 ± 0.08, and 4 of the 7 subjects exhibited changes in slope that were less than half of the value predicted from Listing’s law. Even in the 3 subjects with IN whose torsional components changed

in amplitude with vertical gaze direction by amounts that are consistent with Listing’s law, the constant direction of the torsional component of IN for vertical (and horizontal) gaze changes of ±12º suggests substantial deviations of the primary position from the straight-ahead direction. The torsional component of IN is relevant to perceived stability because torsional eye movements alter the orientation on the retina of the images produced by objects in the environment. Psychophysical evidence indicates that extraretinal signals are available to observers with normal eye movement control to compensate partly for the changes in torsional eye position that occur in eccentric positions of gaze.21-23 Less evidence is found for extraretinal compensation when the change in torsional eye position results from natural vestibular stimulation.24,25 We evaluated whether extraretinal signals compensate for the torsional component of IN by assessing orientation-discrimination thresholds for horizontal and vertical lines that were ﬂashed brieﬂy in darkness. Thresholds were obtained for 6 of the 7 subjects with idiopathic IN.

14 BASIC CONCEPTS OF STABLE VISION AND GAZE

Figure 2.2 The horizontal and torsional amplitudes of individual beats of nystagmus are compared for 3 subjects with IN (FR, JH, and AJ) and for 1 normal observer (LL). Nystagmus was induced in the normal observer by large-ﬁeld optokinetic stimulation to the left and right. Dark, upward-pointing triangles represent nystagmus with gaze directed 12º up from straight ahead. Lighter, downward-pointing triangles are for gaze directed 12º down from straight ahead. Positive values on the x and y axes represent slow phases of nystagmus in the rightward and clockwise directions, respectively. Data are shown in both the positive and negative directions for JH and AJ because the slow phase of their nystagmus reversed direction during recording. Straight lines are ﬁt to each subject’s data in up- and down-gaze. If the changes in torsional eye position obey Listing’s law, then the slopes of the ﬁtted lines should increase by approximately +0.21 between down-gaze and up-gaze. The two dashed lines in the lower right-hand panel represent the Listing’s law predictions if primary position is assumed to coincide with straight-ahead gaze. IN, infantile nystagmus.

PERCEPTUAL INFLUENCES OF EXTRARETINAL SIGNALS

In these 6 subjects, the standard deviation (SD) of torsional eye positions during 10 seconds of recording ranged from 0.53º to 2.0º (Table 2.1). The same subjects’ optimal orientation discrimination thresholds, assessed using 5.6° ﬂashed horizontal lines, ranged from 0.58º to 1.5º.20 These results are in contrast to those of normal subjects, whose orientation-discrimination thresholds are uniformly larger than the SDs of torsional eye position during ﬁxation. Because orientation-discrimination thresholds in 3 of the subjects with IN are reliably smaller than the variability of their torsional eye position, we conclude that extraretinal signals compensate partially for the changes in retinal-image orientation that result from the torsional component of IN.

THEORETICAL CONSIDERATIONS CONCERNING EXTRARETINAL EYE MOVEMENT SIGNALS IN IN An important potential limitation on the usefulness of extraretinal eye movement signals for maintaining perceptual stability in normal observers may be their limited temporal ﬁdelity. A number of observations made by normal observers suggest that extraretinal eye movement signals are temporally low-pass ﬁltered when compared to the time course of the eye movements themselves. For example, Purkinje (as cited by Grüsser et al.26) noted a perceptual lag between the time that he initiated a saccade and the time that he perceived an afterimage to move. Grüsser et al. found that when normal observers make back-andforth saccades in the dark, the perceived amplitude of afterimage displacement decreases systematically with the temporal frequency of the eye movements. Because the afterimage is stabilized on the retina, perceived movement must be attributed to a change in the extraretinal eye movement signal. The observers in this study reported little or no perceived displacement of the afterimage when the frequency of back-and-forth saccades reached approximately 1.75 to 2 Hz, which is substantially lower than the median frequency of IN (ca. 3 to 3.5 Hz27,28). A similar result was reported for an electronically stabilized retinal image during smooth pursuit.29 Finally, normal observers report oscillopsia during high-frequency voluntary nystagmus30 as well as during sequences of uninterrupted eye movements at lower rates.31 If extraretinal eye movement signals are temporally low-pass ﬁltered by as much as these studies suggest, then after ﬁltering they should be much too attenuated to “cancel” the motion of the retinal image that occurs in subjects with IN. Further evidence for temporal low-pass ﬁltering of normal extraretinal eye movement signals comes from

15

reports that a target ﬂashed brieﬂy near the time of a saccade is systematically mislocalized. This mislocalization usually starts substantially before the onset of the saccade and continues for at least 100 milliseconds after the saccade is completed.32-34 The time course of these location errors is consistent with an extraretinal signal for saccades that changes much more slowly than the observer’s eye position. Recently, Pola35 presented modeling results to show that the protracted and non-monotonic time course of visual-location errors around the time of a saccade can be accounted for by the combination of an extraretinal eye position signal that faithfully represents the time course of the saccade and a persisting retinal signal from the ﬂash, which he described using a temporal impulse response function (TIRf) with a duration of approximately 200 milliseconds. Although we agree that the retinal signal from a ﬂash should be ﬁltered temporally in accordance with the TIRf, Pola’s suggestion that the extraretinal signal accurately reﬂects the time course of a saccade is not easily reconciled with the observations of stabilized images by normal subjects, which were summarized earlier. A stabilized image that is viewed in darkness should produce a temporally unvarying retinal signal which, according to our understanding of Pola’s model, should undergo perceived displacements that mirror the movements of the eyes. One way for extraretinal eye movement signals to contribute usefully to perceptual stability is for these signals to undergo less low-pass ﬁltering in persons with IN than in normal observers. This suggested difference between the temporal ﬁltering characteristic of the extraretinal signals in IN and normal observers is presumed to be an adaptive consequence of the early abnormal visual experience in IN. The absence of early abnormal experience and the associated adaptive changes would account for why oscillopsia occurs commonly in patients who acquire nystagmus as adults.36,37 However, an obvious question is why the extraretinal signals that accompany normal eye movements should be temporally low-pass ﬁltered in the ﬁrst place. An important beneﬁt of low-pass ﬁltering is that, after ﬁltering, extraretinal and retinal signals should stay in reasonable temporal alignment regardless of modest relative timing differences that existed beforehand. To clarify, assume that extraretinal eye movement signals are generated, on average, at a ﬁxed time with respect to the movement of the eyes. However, the latency of the information from the retina varies with stimulus characteristics, such as luminance and contrast.38-40 Studies of the Pulfrich, Hess, and ﬂash-lag effects concur that a 2-log unit reduction in target luminance produces about a 40-millisecond increase in visual latency.41,42 If both retinal and extraretinal signals had high temporal ﬁdelity, then

16 BASIC CONCEPTS OF STABLE VISION AND GAZE this change in relative latency would be expected to generate substantial variations in perceived location when these signals are compared. Low-pass ﬁltering of one or both signals has the effect of smoothing these perceptual variations over time.35,43 If our suggestion that extraretinal eye movement signals are less low-pass ﬁltered in subjects with IN is correct, then these subjects should be vulnerable to variations in the latency of retinal signals as indicated by sizeable, systematic changes in perceived stability for either high or low luminance stimuli. Tkalcevic and Abel44 found that subjects with IN most often report oscillopsia when a bright ﬁxation stimulus (440 cd/m2) is superimposed on a much dimmer background ﬁeld (ca. 0.1 cd/m2). However, the oscillopsia that these subjects reported was typically relative motion between the bright ﬁxation stimulus and the dimmer background and is likely to reﬂect the Hess effect (an illusory spatial separation between moving targets of different luminance).41 It therefore remains an open question whether the perception of oscillopsia in IN varies systematically with the luminance of the stimulus.

PERCEIVED MOTION SMEAR DURING NORMAL EYE MOVEMENTS AND IN In addition to the potential for producing oscillopsia, the rapid to-and-fro eye movements in subjects with IN would be expected, on the basis of visual persistence, to generate the perception of motion smear. However, the retinal image motion of a physically stationary object during normal observers’ voluntary45-48 and involuntary49,50 eye movements generates a smaller extent of perceived motion smear than if comparable motion of the retinal image occurs when the eyes remain stationary. Because the reduction of perceived motion smear during normal eye movements can occur when no other visual stimuli are present in the ﬁeld, we attribute this reduction to the action of extraretinal signals. Recently, we found that the extent of perceived motion smear is reduced even when a smooth movement of the eye is produced by pressing on the globe, implicating a contribution from signals of eye muscle proprioception. The reduction of perceived motion smear during normal eye movements is asymmetrical, depending on the relative direction of target motion with respect to the moving eye. Speciﬁcally, the extent of perceived smear is reduced for targets that undergo relative motion in the opposite direction of the eye movement.48,50,51 On the other hand, the extent of perceived smear for a target that moves in the same direction as, but faster than, an ongoing eye movement is the

Figure 2.3 The median duration of perceived motion smear produced by a 100-millisecond bright spot is shown during the leftward and rightward slow-phase IN eye movements of subject SS. On each trial, the bright spot moved to the left or right with respect to the moving eye. Error bars are standard errors. IN, infantile nystagmus. same as that produced by a target that moves physically during stable ﬁxation. Our explanation for this asymmetrical reduction of perceived motion smear is as follows. The visual system interprets the presence of “opposite” target motion during an eye movement as consistent in direction with an object that is stationary in the world. Presumably, the visual system prefers that stationary objects do not appear smeared. On the other hand, a target that moves in the “same” direction as an ongoing eye movement can be assumed to be moving physically in the world. The extent and direction of perceived motion smear has been shown to provide useful psychophysical information about the speed and direction of a target’s motion.52-55 For this reason, it is advantageous for the visual system not to reduce perceived smear for targets that are physically in motion. The essentially incessant eye movements that occur in subjects with IN make it difﬁcult to compare perceived motion smear when the eyes are and are not moving. Instead, we asked observers with IN to report the extent of perceived smear for a target that moved at various speeds in the “opposite” or in the “same” direction as the IN slow phase. The target was a small, bright laser spot that was triggered to occur in an otherwise dark ﬁeld, after the end of a foveation period and near the start of an accelerating IN slow phase. The target was ﬂashed for 100 milliseconds, after which the observer adjusted the length of a continuously visible line to match the extent of perceived motion smear. One observer’s nystagmus alternated periodically between jerk left and jerk right and, across trials, the target was presented in the “opposite”

PERCEPTUAL INFLUENCES OF EXTRARETINAL SIGNALS

and ”same” direction as the rightward and leftward IN slow phases. Consistent with the results described for normal observers, the extent of perceived motion smear is reduced asymmetrically in this subject with IN—it is less when relative target motion is to the left during rightward slow phases and when relative target motion is to the right during leftward slow phases (Fig. 2.3). To allow the measurements obtained for different velocities of retinal image motion to be combined and compared, Figure 2.3 expresses the extent of perceived motion smear as duration in milliseconds. The average duration of perceived motion smear for targets that move in the “same” direction as the leftward and rightward IN slow-phase eye movements is approximately 105 milliseconds, indicating no reduction in the extent of perceived smear. However, the average duration of perceived motion smear for targets that move “opposite” the direction of the IN slow phases is less than 35 milliseconds, which is less than the duration of perceived smear reported by normal observers for a 100-millisecond target that moves “opposite” the direction of pursuit.45,47,51 Results for a second observer with IN, whose predominant slow-phase direction is to the right, show a similar reduction of perceived smear for relative target motion to the left. These data are consistent with a previous report that a physically stationary, continuously visible target generates little or no perceived motion smear in subjects with IN,9 and suggest that the extraretinal eye movement signals for IN may be more effective in reducing the extent of perceived motion smear than the extraretinal signals of normal observers. Although not tested, we anticipate that the perception of motion smear is also reduced during the quick phases of IN, as such a reduction was shown to occur during normal saccades.46

A Possible Mechanism for the Reduction of Perceived Motion Smear In normal observers, the duration of visible persistence and, therefore, the perception of motion smear can be accounted for by the relatively sluggish temporal response of the visual system.56 The response of the visual system in time is described by the temporal contrast sensitivity function or, alternatively, by the inverse Fourier transformation of this function, the TIRf. Consequently, the duration of perceived motion smear should be reduced during eye movement if extraretinal signals act to reduce the duration of the TIRf. Indeed, previous physiological57 and psychophysical results58 are consistent with an increase in speed of the TIRf during normal saccades. We measured temporal contrast sensitivity functions for 6 normal observers during ﬁxation at the center of a 10º vertical sine-wave grating (mean luminance

17

= 65 cd/m2; spatial frequency = 1 cpd), which drifted leftward or rightward to produce temporal frequencies between 6 and 30 Hz. For comparison, we measured the temporal contrast sensitivity for the same sine-wave stimulus during horizontal pursuit at 8 deg/s. During pursuit, the physical drift rate of the grating was varied to generate retinal temporal frequencies between 6 and 30 Hz, both in the “opposite” and “same” directions as the observers’ rightward pursuit movement. Each presentation of the grating target occurred within a smoothed temporal contrast window with a duration of approximately 400 milliseconds. Horizontal eye movements were monitored by infrared limbal reﬂection, and trials were accepted in the absence of blinks or saccades and only if the calculated temporal frequency of retinal image motion was within ±15% of the grating’s nominal temporal frequency. In fact, calculated temporal frequencies were highly similar for motion of the grating in the “opposite” and the “same” directions as pursuit, as the average pursuit gains of the 6 observers ranged from 0.96 to 1.03 (overall mean gain = 0.99). To convert the temporal contrast sensitivity data to TIRfs, we assumed that the visual system can be described at threshold by a linear second-order, low-pass temporal ﬁlter (Eq. 2.2): R(t) = (A × W/ Sqrt[1–D2]) × exp(−D × W × t) × sin(W × Sqrt[(1–D2) × t]) In this equation, R is the response of the visual system in time (t) to a brief pulse, A is the response amplitude, W is the temporal frequency of the response in radians/s, and D is the damping ratio (0 ≤ D < 1). Based on this assumption, we iteratively determined the TIRf that, after Fourier analysis, yielded the best ﬁt to the temporal contrast sensitivity data for grating motion to the left and right during ﬁxation, and for grating motion in the “opposite” and “same” direction as rightward pursuit. As shown in Figure 2.4, the average TIRf ﬁt to the contrast sensitivity for motion “opposite” the direction of pursuit has the shortest duration. Consistent with our results for perceived motion smear,48,50 the TIRfs ﬁt to contrast sensitivities for gratings presented during ﬁxation and for gratings that move in the “same” direction during pursuit have similar but longer durations. The duration of the TIRfs can be described in terms of the inverse of their natural temporal frequencies, which range from 10.7 Hz during ﬁxation to 11.6 Hz during “opposite” motion of the grating during pursuit. Statistical analysis indicates that the natural frequency of the TIRf determined for “opposite” grating motion is signiﬁcantly higher (p < 0.05) than in either of the other two conditions. We also compared estimates of normal observers’ TIRfs during ﬁxation to the TIRfs of subjects with IN.

18 BASIC CONCEPTS OF STABLE VISION AND GAZE

Opposite pursuit Same as pursuit Fixation

0.6 0.4 0.2 0

0.2

1 Relative response

Relative response

1 0.8

Avg. normal (N 4) Subject FR (IN) Subject TF (IN)

0.8 0.6 0.4 0.2 0

0.2 0

25

50

75 100 Time (ms)

125

150

Figure 2.4 Temporal impulse response functions (TIRfs) are presented, estimated from the temporal contrast sensitivity data of 6 normal observers during ﬁxation and rightward pursuit. During pursuit, the relative motion of a 1 cpd grating target was either in the “opposite” or the “same” direction as the observer’s eye movement. Sensitivities measured during rightward and leftward motion of the grating during ﬁxation were averaged. The peak response of each calculated TIRf is normalized to a value of 1 on the y-axis. Note that the TIRfs estimated for ﬁxation and for the “same” direction of motion during pursuit are virtually superimposed.

These TIRfs were ﬁt to temporal contrast sensitivity functions for a 16º horizontal 3 cpd square-wave grating, which underwent temporal frequencies of counterphase ﬂicker between 1 and 40 Hz. Because the normal TIRf is known to speed up during normal saccades,58 we included only subjects with IN whose waveforms were predominantly pendular. The TIRf ﬁtted to the contrast-sensitivity data of the 4 normal observers has a natural temporal frequency of 8.7 ± 0.6 (SE) Hz. The lower natural frequency of this function than for the TIRf shown for ﬁxation in Figure 2.4 is expected from the increase in the grating’s spatial frequency.59,60 Compared to the results of the normal observers, the TIRfs for 3 subjects with pendular IN all have considerably shorter durations, with natural frequencies that range from 11.6 to 14.9 Hz (Fig. 2.5).

ISSUES FOR VISUAL PERCEPTION AND FUNCTIONING IN IN In addition to the “cancellation” of retinal image motion by extraretinal eye movement signals, several studies conducted on normal observers indicate that an extended visual frame of reference can mediate perceived stability during changes in eye position.61-64 For example, Murakami64 proposed recently that the visual system “dismisses” the common motion that occurs in the retinal image, which is interpreted to be a

0

25

50

75 100 Time (ms)

125

150

Figure 2.5 Temporal impulse response functions (TIRfs) estimated from temporal contrast sensitivity data are shown for 4 normal observers (averaged) and 2 individual subjects with pendular IN. The normal observers’ contrast sensitivity was measured during ﬁxation. As in Figure 2.4, the peak of each calculated TIRf is normalized to a value of 1. In contrast to the results shown in Figure 2.4, the TIRfs in this ﬁgure are based on contrast sensitivities for a 3 cpd counterphase ﬂickering grating. IN, infantile nystagmus.

consequence of ongoing ﬁxational eye movements. Clearly, this “dismissing” hypothesis cannot completely account for the perception of stability in subjects with IN, as these subjects report motion of the visual scene when the retinal image is stabilized artiﬁcially.14,17 Further, Abadi et al.17 reported that subjects with IN perceive a small target to be stable over a greater range of nystagmus-induced retinal image motion than a considerably larger target. Similarly, Tkalcevic and Abel44 found that the perception of oscillopsia in subjects with IN is unrelated to the size of the visual target. These data contradict the tendency of normal observers to perceive a large visual frame of reference as stable. However, they may be accounted for by the higher temporal frequencies of retinal image motion in subjects with IN, compared to the temporal characteristics of the image motion in most of the studies that examined visual frame-of-reference effects in normal observers.61,62 Possibly, the visual system sets an upper limit on the amplitude of the common retinal image motion that it is willing to “dismiss,” based on its integrated long-term experience. If so, the upper limit for “dismissing” retinal image motion might be higher in persons with IN, whose visual experience during and after development includes substantially greater amounts of retinal image motion than that of normal observers. This hypothesis could account for why motion thresholds are elevated in subjects with IN, even when the nystagmus is temporarily in abeyance,65 in patients with acquired vestibular66,67 or ocular motor68 deﬁcits,

PERCEPTUAL INFLUENCES OF EXTRARETINAL SIGNALS

and in normal observers who are exposed to retinal image motion to simulate the motion present in IN.69 Our data indicate that extraretinal eye movement signals associated with the slow phase of IN reduce the extent of perceived motion smear for the relative motion of a target in the direction opposite to the movement of the eye. In everyday viewing, objects that are stationary in space generate “opposite” motion during eye movements and therefore should be perceived as relatively clear. Our results so far for subjects with IN are qualitatively similar to results found in normal observers for relative target motion in the opposite direction of pursuit, smooth vergence, and the VOR.45,47-51 In normal observers, the extent of perceived motion smear is reduced also for targets that move in the direction opposite to a head movement— for example, during visual suppression of the VOR when the eyes undergo no movement with respect to the head.50,51 Indeed, during the VOR and the visually enhanced VOR, normal observers report a reduced extent of smear for two directions of target motion — the directions opposite the eye and the head movements, respectively.50 In some patients, IN is accompanied by rhythmic head movements, which typically do not reduce the magnitude of the retinal image motion that results from their nystagmus.70-72 The observation that perceived motion smear is reduced during normal head movements raises the possibility that extraretinal signals associated with these head movements in subjects with IN might supplement the effect of extraretinal eye movement signals to further reduce the extent of perceived motion smear. The results we obtained during passive eye rotation indicate that extraretinal signals from eye muscle proprioception are sufﬁcient to reduce the extent of perceived motion smear in normal observers. It remains unclear whether proprioceptive signals are necessary to reduce the perception of motion smear during eye movements, or whether the reduction found during normal eye movements can be mediated by efference-copy signals alone. A contribution of eye muscle proprioception to perceived clarity during eye movements is relevant because of the recent introduction of tenotomy as a surgical treatment to reduce the severity of eye movements in IN.73-75 Tenotomy disrupts the proprioceptive information that comes from extraocular muscles and could conceivably lead to some compromise of perceptual clarity in patients with IN. Finally, an important and as yet unanswered question is what is the contribution of perceived motion smear, and its reduction during eye (and perhaps head) movements, to visual functioning in IN. To address the inﬂuence of perceived motion smear on visual acuity, we compared the acuity of normal subjects in two experimental conditions. In one condition, the motion

19

of the acuity target simulated that during the complete IN waveform. In the second condition, the acuity target was visible only during simulated foveation periods, and was blanked during all other phases of the waveform. Measured visual acuity was uniformly 0.1 to 0.15 logMAR poorer during the completewaveform condition for simulated foveation durations that ranged from 20 to 120 milliseconds.76 These data indicate that the presence of motion smear during simulated IN slow phases impairs visual acuity, despite the availability to the visual system of a stationary retinal image during simulated foveation periods. Nevertheless, it remains unclear whether the retinal image motion during slow phases contributes also to a reduction of visual acuity in subjects with IN. One alternative possibility is that the reduction of perceived motion smear by extraretinal signals for IN might protect against an impairment of acuity. A second possibility is that visual acuity is limited in subjects with IN by a sensory abnormality, such as amblyopia, rather than by the instantaneous parameters of the retinal image motion.5,8,77 These alternatives can be evaluated by comparing the visual acuity of normal observers and subjects with IN under comparable conditions of retinal image stability and motion.

acknowledgments We thank Susana Chung, Thanh Loan Nguyen, Spencer Obie, Mahalakshmi Ramamurthy, Shobana Subramaniam, and Lan-Phuong Vu-Yu for assistance in collecting, analyzing, and interpreting some of the data presented in this chapter. Support for these studies was provided by grants R01-EY05068, P30-EY07551, and T35-EY07088 from the National Eye Institute and by award 003652-0185-2001 from the Texas Advanced Research Program.

References 1. Dickinson CM, Abadi RV. The inﬂuence of nystagmoid oscillation on contrast sensitivity in normal observers. Vision Res. 1985;25:1089–1096. 2. Currie DC, Bedell HE, Song S. Visual acuity for optotypes with image motions simulating congenital nystagmus. Clin Vision Sci.1993;8:73–84. 3. Sheth NV, Dell’Osso LF, Leigh RJ, Van Doren CL, Peckham HP. The effects of afferent stimulation on congenital nystagmus foveation periods. Vision Res. 1995;35:2371–2382. 4. Chung STL, Bedell HE. Velocity criteria for “foveation periods” determined from image motions simulating congenital nystagmus. Optom Vision Sci. 1996;73:92–103. 5. Bedell HE, Ukwade MT. Sensory deﬁcits in idiopathic congenital nystagmus. In: Lakshminarayanan V, ed.

20 BASIC CONCEPTS OF STABLE VISION AND GAZE

6.

7.

8.

9.

10. 11.

12.

13.

14.

15.

16.

17.

18.

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53. Burr DC, Ross J. Direct evidence that “speedlines” inﬂuence motion mechanisms. J Neurosci. 2002; 22:8661–8664. 54. Tong J, Aydin M, Bedell HE. Direction-of-motion discrimination is facilitated by visible motion smear. Percept Psychophys. 2007;69:48–55. 55. Edwards M, Crane MF. Motion streaks improve motion detection. Vision Res. 2007;47:828–833. 56. Ganz L. Temporal factors in vision. In: Carterette EC, Friedman MP, eds. Seeing. New York: Academic Press; 1975. 57. Reppas JB, Usrey WM, Reid RC. Saccadic eye movements modulate visual responses in the lateral geniculate nucleus. Neuron. 2002;35:961–974. 58. Burr DC, Morrone MC. Temporal impulse response functions for luminance and colour during saccades. Vision Res. 1996;36:2069–2078. 59. Watson AB, Nachmias J. Patterns of temporal interaction in the detection of gratings. Vision Res. 1977;17:893–902. 60. Georgeson MA. Temporal properties of spatial contrast vision. Vision Res. 1987;27:765–780. 61. Matin L, Picoult E, Stevens JK, Edwards MW Jr, Young D, MacArthur R. Oculoparalytic illusion: visual-ﬁeld dependent spatial mislocalizations by humans partially paralyzed with curare. Science. 1982;216:198–201. 62. Bridgeman B, Graziano JA. Effect of context and efference copy on visual straight ahead. Vision Res. 1989;29:1729–1736. 63. Deubel H, Bridgeman B, Schneider WX. Immediate post-saccadic information mediates space constancy. Vision Res. 1998;38:3147–3159. 64. Murakami I. Fixational eye movements and motion perception. Prog Brain Res. 2006;154: 193–209. 65. Shallo-Hoffmann JA, Bronstein AM, Acheson J, Morland AB, Gresty MA. Vertical and horizontal motion perception in congenital nystagmus. Neuroophthalmology. 1998;19:171–183. 66. Grunbauer WM, Dieterich M, Brandt T. Bilateral vestibular failure impairs visual motion perception even with the head still. Neuroreport. 1998;9:1807–1810. 67. Shallo-Hoffmann J, Bronstein AM. Motion detection in patients with absent vestibular function. Vision Res. 2003;43:1589–1594. 68. Acheson JF, Cassidy L, Grunfeld EA, ShalloHoffmann JA, Bronstein AM. Elevated visual motion detection thresholds in adults with acquired ophthalmoplegia. Br J Ophthalmol. 2001;85:1447–1449. 69. Bedell HE. Perception of a clear and stable visual world with congenital nystagmus. Optom Vision Sci. 2000;77:573–581.

22 BASIC CONCEPTS OF STABLE VISION AND GAZE 70. Gresty M, Halmagyi GM, Leech J. The relationship between head and eye movement in congenital nystagmus with head shaking: objective recordings of a single case. Brit J Ophthalmol. 1978;62:533–535. 71. Carl JR, Optican LM, Chu FC, Zee DS. Head shaking and vestibulo-ocular reﬂex in congenital nystagmus. Invest Ophthalmol Visual Sci. 1985;26:1043–1050. 72. Gottlob I, Wizov SS, Reinecke RD. Head and eye movements in children with low vision. Graefe’s Arch Clin Exp Ophthalmol. 1992;234:369–377. 73. Hertle RW, Dell’Osso LF, FitzGibbon EJ, Thompson D, Yang D, Mellow SD. Horizontal rectus tenotomy in patients with congenital nystagmus: results in 10 adults. Ophthalmology. 2003;110:2097–2105.

74. Hertle RW, Dell’Osso LF, FitzGibbon EJ, Yang D, Mellow SD. Horizontal rectus muscle tenotomy in children with infantile nystagmus syndrome: a pilot study. J AAPOS. 2004;8:539–548. 75. Wang Z, Dell’Osso LF, Jacobs JB, Burnstine RA, Tomsak RL. Effects of tenotomy on patients with infantile nystagmus syndrome: foveation improvement over a broadened visual ﬁeld. J AAPOS. 2006;10:552–560. 76. Bedell HE, Chung STL, LaFrance MW. The inﬂuence of motion smear on visual acuity in simulated congenital nystagmus. Invest Ophthalmol Visual Sci. 1997;38(suppl):S651. 77. Hanson KS, Bedell HE, White JM, Ukwade MT. Distance and near visual acuity in infantile nystagmus. Optom Vision Sci. 2006;83:823–829.

3 Perception with Unstable Fixation RICHARD V. ABADI

constancy, form deprivation, and emmetropization are addressed.

ABSTRACT Fixation behavior has an enormous inﬂuence on perception. Too little image motion and the scene fades; too much, and blurring and oscillopsia are experienced. To keep within an optimal operating range, a number of feedback control systems counter drifts and suppress unwanted saccades. Vision, which is driven by both bottom-up and topdown processing, is an important component. Thus physiological microsaccades and saccadic intrusions are modulated by exogenous and endogenous attention, while early onset afferent defects often lead to strabismus and nystagmus. The visual consequences of such ﬁxation failures depend on the onset time of the visual loss, the nature of any attendant afferent defect, and the retinal-image dynamics. This chapter describes psychophysical studies that examine the spatial (contrast sensitivity, visual acuity, vernier acuity, and stereopsis) and temporal (absolute and relative detection and discrimination motion thresholds) visual performance of individuals with idiopathic and nonidiopathic congenital nystagmus. Experiments that investigate the strongly visually driven behavior of manifest latent nystagmus and issues relating to spatial

Visual perception is strongly dependent on the optical quality of the retinal image and its subsequent neuronal processing, and is also intimately linked to ﬁxation control. Ideally, focused images should rest on the fovea and be held relatively steady. Thus retinal-image quality is dependent on both position and velocity. The purpose of this chapter is to describe and explore the bonds that link perception and oculomotor control. Poor retinal-image quality can modify the efﬁciency of gaze-holding, while unstable ﬁxation can degrade visual performance. These symbiotic relationships are all the more critical when failure occurs early in life. This chapter examines the link between involuntary physiological ﬁxation movements and perception, the effects of early ﬁxation failure (infantile nystagmus [IN]) on visual performance, and the effects of early visual loss on the development of normal ﬁxation behavior. Measures of sensory performance in congenital nystagmus (CN) and manifest latent nystagmus (MLN)* include visual and vernier acuity, spatial and temporal thresholds, and spatial constancy. Fixation stability, described in terms of ocular and retinal-image dynamics, is linked with other issues,

* The National Eye Institute’s Classiﬁcation of Eye Movement Abnormalities and Strabismus (CEMAS)1 recently attempted to integrate previous vision and eye movement studies to create a standardized description and disease name for a host of nystagmus and ocular motor oscillations. Thus, congenital nystagmus has now been relabeled infantile nystagmus syndrome (INS) and latent/manifest latent nystagmus is now fusion maldevelopment nystagmus syndrome (FMNS). In the interest of continuity, this text will refer to FMNS by its original subgroups, latent nystagmus (LN) and manifest latent nystagmus (MLN), as deﬁning an oscillation as fusion maldevelopment with less than a 100% prevalence of associated strabismus could be confusing.

23

24 BASIC CONCEPTS OF STABLE VISION AND GAZE including emmetropization, form deprivation, and ocular alignment.

NORMAL FIXATION AND VISION Normal Physiological Fixation Behavior If retinal-image slip velocities exceed 4 deg/s, blurring and the illusionary movement of the visual world (oscillopsia) can occur.2,3 The amount of retinal-image motion that can be tolerated before vision deteriorates depends on what is being viewed and the nature of the task. On the other hand, when retinal-image velocities are dramatically reduced or even stabilized, then fragmentation and the eventual perceptual loss of a scene are experienced due to neural adaptation.4 Clearly, in the interest of achieving high visual acuity (VA), ﬁxation eye movements must be limited to a speciﬁc range by a set of control systems.5 One such system, the ﬁxation system, has three distinct components: (1) the visual system’s ability to detect retinal-image drift and program corrective eye movements, (2) the ability to attend to or “engage” a particular target of interest, and (3) the suppression of unwanted saccades that would otherwise take the eye off target. Whenever there is a change in gaze away from the primary position, the neural integrator is recruited to sustain the desired eye position. Moreover, during locomotion the vestibulo-ocular and optokinetic systems act in unison to reduce retinal-image slip. Thus gaze-holding has both visual (smooth pursuit and optokinetic) and motor (vestibular) inputs that are underpinned by neuronal processes (ﬁxation cells in the superior colliculus, pause cells in the brainstem, and the neural integrators in the brainstem and cerebellum). The desired outcome of steady ﬁxation is also dependent on critical cognitive factors such as attention, alertness, and the saliency of the visual task.6 Under normal circumstances, involuntary ﬁxation eye movements, made up of small disconjugate drifts (1 to 3 minutes of arc) and small multiplanar conjugate microsaccades (5 to 10 minutes of arc, 1 to 2 per second), are ever present.7-10 In addition, a further class of larger-amplitude involuntary physiological eye movements known as saccadic intrusions are also present. Saccadic intrusions consist of conjugate horizontal saccadic eye movements that take the form of an initial fast eye movement away from the desired eye position and are followed, after a variable duration, by a return saccade or drift.5,11-13 Saccadic intrusion amplitude mean and range have been reported to be 0.60˚ ± 0.50˚ and 0.10˚ to 4.10˚ with a saccadic intrusion frequency mean and range of 18.0 ±14.4 per minute and 1.0 to 54.8 per minute, respectively.

A key motor property of both ﬁxation microsaccades and saccadic intrusions is that, like the fast phases of vestibular (optokinetic and IN), they all lie on the main sequence.13 Recent studies indicate that microsaccades and saccadic intrusions are modulated by exogenous and endogenous attention in a similar manner, thereby suggesting that microsaccades and saccadic intrusions lie on a continuum of involuntary ﬁxation instabilities.14-18 Evidence for the effects of attention on saccadic intrusion behavior has been found by varying the “bottom-up” target viewing conditions (target presence, servo control of the target, target background, target size). Saccadic intrusion amplitude has been found to be signiﬁcantly higher when the target is abolished in the dark, and saccadic intrusion frequency is lower during open-loop conditions.16 Saccadic intrusion frequency decreases during the “hold eyes steady” command, and saccadic intrusions are more frequently directed away from exogenous cues during cue-target tasks (i.e., modulating top-down attention).16,17 In contrast to viewing a stationary target in photopic conditions, when subjects sit in darkness and attempt to view the remembered location of a target, the mean velocity of the ﬁxation slow-drifts increases about fourfold. This implies that during active ﬁxation of a stationary target, retinal-image slip is under the control of a feedback system that counters drift and holds gaze steady. This response has been called slowcontrol, or a ﬁeld-holding reﬂex.6 It is pertinent to note that, invariably, reported ranges of ﬁxation stability refer to ﬁxation tasks undertaken in a laboratory using head restraints and bite bars. However, under natural viewing conditions (e.g., standing), when the head is free to move, mean drift velocity can increase by up to a factor of 10.19 In summary, visual inputs have an enormous inﬂuence on physiological ﬁxation behavior. Too little image motion causes the scene to fade, while too great a movement leads to blurring and oscillopsia. Cognitive factors have strong and important inﬂuences on involuntary ﬁxation behavior. Finally, if visual inputs are not appropriate during the early neonatal period, it is highly likely that ﬁxation stability will become compromised.20-24

ABNORMAL FIXATION AND VISION Infantile Nystagmus Unstable ﬁxation in the form of a nystagmus may occur at birth or soon after. The most common type of infantile ﬁxation instability is IN, in which the oscillations are typically involuntary, conjugate, horizontal, and jerky. The oscillations may consist

PRECEPTION WITH UNSTABLE FIXATION 25

entirely of slow phases, as in the case of pendular nystagmus.13,25-29 There are three major manifestations of IN: CN, MLN, and latent nystagmus (LN).13,25-32 The principal differences between these three lie in the form of their slow phases. In CN, the slow phases are typically of an increasing exponential velocity form, whereas in MLN and LN the slow-phase velocity is decreasing or linear.13,25,26,30-35 An additional distinguishing feature relates to the fast phase, which in MLN and LN always beats toward the viewing eye. Many different IN waveform shapes have been described, and their spatial and temporal characteristics have been examined in detail.13,25,26,28,35 Both CN and MLN are associated with a variety of afferent sensory disorders, including albinism, optic nerve hypoplasia, and congenital cataracts. On the other hand, CN and MLN may occur without any detectable ocular or sensory system abnormalities, in which case the nystagmus is designated an idiopathic CN. (The idiopathic category is clearly a clinical convenience rather than an absolute category.) In a recent report, Abadi and Bjerre28 noted that while exclusively conjugate horizontal oscillations were found in 78% of an IN sample (n = 224), 14% (n = 32) also displayed a recordable torsional component to their IN. Neither CN nor MLN waveforms were related to any of the three subject groups (idiopaths, albinos, and ocular anomalies), although MLN was found to occur most frequently in the ocular anomaly group. Visual performance in IN is, for the most part, dependent on three factors: (1) the range of retinalimage slip velocities, (2) foveation, and (3) the state of the eye and visual pathways. Most clinicians are likely to measure the spatial resolution limit (that is, VA) and stereoacuity, and to note the presence of any associated smear or motion of the visual scene. Not surprisingly, the distribution of the retinal-image slip velocities within the slow phase and the duration of the period corresponding to the low-slip velocities are important components in determining visual performance.25,31,36-41

CONGENITAL NYSTAGMUS Waveform and Visual Performance For those individuals with an idiopathic CN, Snellen VA generally ranges between 20/20 and 20/60, and the retinal-image movement is an important cause of the visual degradation.28 Peak slow-phase velocities can reach 180 deg/s, and large portions of the slow phase can exceed velocities greater than 10 deg/s.39 However, periods of low retinal-image velocity (i.e., ≤ 4 deg/s)

can also be present during the slow phase, and if the duration of these low-velocity intervals is long and coincides with the fovea (±0.5°), VA can reach reasonable levels (better than 20/30). This situation is referred to as foveation. Not all subjects with CN foveate, nor should they be assumed to do so. Abadi and Bjerre28 reported that, based on fundus video-oculography, only 41 of their 74 subjects (55%) exhibited foveation. Modiﬁcation of CN waveforms, encountered when subjects make use of their gaze nulls, often improves VA and can minimize oscillopsia.42 However, there appears to be no change in foveation (and thereby VA) with increasing visual task demand,43 although the authors suggest that if the visual task is seen to be personally important, then the additional stress brought on by the motivation to perform well could increase the nystagmus intensity and thereby reduce VA.26,28,44 The length of the foveation period has been shown to be a better predictor of visual performance compared with nystagmus intensity (amplitude × frequency),25,28,45 and VA is also strongly correlated with the duration and beat-to-beat position variability of the foveation periods.46-50 Using a mirror galvanometer arrangement to simulate comparable image motion in normal observers, Currie et al.51 have shown that their control subjects performed better than individuals with IN.

Visual Acuity and Contrast Detection Thresholds Traditional optotype charts (Snellen, LogMAR) measure the ability to recognize high-contrast targets, whereas contrast sensitivity functions describe the threshold detection of sinusoidally modulated gratings. The IN spatial contrast sensitivity function has several distinguishing features compared with the normal function: (a) the low spatial frequency roll-off is either absent or greatly reduced, (b) the peak contrast sensitivities are shifted toward the lower spatial frequencies, and (c) the high spatial frequency cutoff point is signiﬁcantly reduced (Fig. 3.1).38,52,53 That is, the IN contrast sensitivity function has been shifted down and to the left compared with the normal function. This attenuation of the medium-to-high spatial frequency detection threshold does not linearly extrapolate for suprathreshold contrast perception.54 For gratings of the same orientation but different spatial frequency, CN subjects demonstrate suprathreshold contrast matching, which depends on the physical contrast of the gratings rather than the characteristics of the contrast sensitivity function. In this case, the compensation across spatial frequency mechanisms for a threshold difference in sensitivity is as effective as that

26 BASIC CONCEPTS OF STABLE VISION AND GAZE

A 200 100 50 30

B

Contrast sensitivity

100 50 30

10 5 3

1 1

2

3 4 5 Spatial frequency (c/deg)

6

7

Figure 3.1 Contrast sensitivity functions for (A) normal observer and (B) idiopathic congenital nystagmus. (䊉), horizontal gratings; (䊊), vertical gratings.

seen in normal subjects. A lower level of compensation was found for the meridional threshold difference. Line and grating detection thresholds for subjects with CN are higher for targets that are vertically oriented as compared to those that are horizontally oriented.38,40,52-55 This meridional anisotropy is, in part, due to the principal axis of the IN oscillation (i.e., horizontal), together with the associated perceptual smear56,57 and the resultant meridional amblyopia.5355,58 Meridional anisotropy was also found for vernier targets,59 but the variability of the torsional eye position was not considered a factor.60 Albinos often have a VA below 20/60 and lower contrast sensitivity compared with idiopaths, principally because of the presence of foveal hypoplasia.61 Interestingly, even though albinos have poor foveal differentiation, many show foveation.62 VA and contrast sensitivity levels for the ocular-anomaly group are greatly dependent on the underlying pathological state of the eye and the duration of the form deprivation.28

Figure 3.2 The ranges for which spatial constancy was maintained for absolute and relative target motion. The targets for absolute motion were either a small local target or a large global target. The relative motion condition used a local target superimposed on a large stationary background. Feedback gain is deﬁned as target velocity/eye velocity. A 0.0 gain indicates a case in which the observer’s eye movements are decoupled from the target motion. Feedback gains greater than or less than 0.0 decrease or increase the retinal slip motion respectively. The eye position feedback modulated local and global targets separately (absolute motion) or the local target against the stationary background (relative motion). Error bars ± SD.

Pattern contrast threshold measurements of LN and MLN subjects during monocular, binocular, and dichoptic viewing have provided information about binocular summation and suppression.63 Contour interaction or “crowding” is the term given to the adverse effect that the presence of surrounding contours have on the resolution of an acuity target. The magnitude and extent of contour interaction on letter acuity in idiopathic CN is greater than that found in normals,64,65 although this was not the case for the albino group.64 These results suggest that single-letter acuity tests may overestimate VA when compared to a traditional Snellen or a LogMAR chart. Hyperacuity tasks include vernier and stereo detection thresholds. Both are elevated in idiopathic CN and are related to the duration of the foveation periods.59,66 The presence of the afferent defects in the albino and ocular-anomaly groups will clearly affect ocular alignment and increase the likelihood of a strabismus, thereby leading to reduced stereoacuity.28 Patients with MLN have a strong likelihood of exhibiting a strabismus and no detectable TNO stereoacuity.28,34,59,66

PRECEPTION WITH UNSTABLE FIXATION 27

Motion Perception and CN A number of studies have indicated that motion perception thresholds are raised in CN. These include absolute and relative motion,67 displacement thresholds,68 velocity estimation,69 motion discrimination,70,71 and the motion aftereffect.71 A reduced-motion sensitivity in CN does not account for spatial constancy, since the peak slow-phase velocity and the mean slow-phase velocity are both found to be greater than the absolute and relative motion threshold.67

Spatial Constancy and CN Patients with CN rarely experience movement in their visual environment. That is, they are not usually aware of any oscillopsia and report a state of perceptual stability or spatial constancy. Nonetheless, there are occasions when perceptual stability can break down, and these events can provide clues about the underlying mechanisms responsible for spatial constancy. CN observers may experience oscillopsia when a single target is viewed against a background that has no visible structure, such as when viewing a small light in an otherwise dark room. Oscillopsia has also been reported when the CN intensity increases signiﬁcantly beyond its steady-state level, such as when the subject is tired or under stress or experiencing a periodic alternating nystagmus. Patients with eccentric null zones occasionally report oscillopsia when they need to adopt or change their compensatory head posture. Additionally, oscillopsia may be induced in the laboratory when the retinal image is stabilized. This can be achieved either by using an afterimage or by optical stabilization. A number of different mechanisms have been proposed to account for spatial constancy in CN. These include (a) reduced sensitivity to retinal-image motion, (b) adaptation to retinal-image motion, (c) information sampled only when the eyes are moving relatively slowly during foveation periods, and (d) the use of extraretinal information to cancel the effects of the eye movements. Such extraretinal signals include efference copy (outﬂow), in which a copy of the CN oscillation command signal cancels the effect of subsequent retinal-image motion and proprioception. The proposal that extraretinal cancellation (efference copy) is the primary mechanism responsible for spatial constancy has strong support from many sources.57,67,72-75 Using an electro-optical arrangement, Abadi et al.67 were able to vary the retinal-image slip feedback and thereby delineate the spatial constancy ranges for absolute and relative target motion (Fig. 3.2).

MANIFEST LATENT NYSTAGMUS MLN may be divided into four distinct categories,34 which are distinguished by the ﬁxation characteristics seen during binocular and monocular viewing. Type 1 MLN represents the absolute case in which the eyes are stable during binocular viewing but oscillate in a manner consistent with MLN when either eye is covered. In the past, this MLN type was referred to as LN. In type 2 MLN, horizontal conjugate saccadic intrusions are seen during binocular viewing, whereas type 3 MLN exhibits a torsional nystagmus. As in type 1 MLN, subjects with type 2 and type 3 MLN always display conjugate horizontal jerk MLN oscillations during monocular viewing. Patients with type 4 MLN exhibit decelerating or linear slow-phase jerk MLN waveforms during both binocular and monocular viewing. All four types of MLN are visually driven by and greatly dependent on the patient’s state of attention.31,34 Extensions of the slow phase have been reported after prolonged monocular occlusion and during periods of low attention. In addition, the removal or reduction of visual feedback tends to delay the fast phase and reduce mean slow-phase velocity, thereby reducing the number of fast phases.34,76,77 In 1999, a unique case was reported in which an adult patient with a horizontal left-beating MLN converted to a right-beating CN on covering the patient’s only seeing (left) eye.76 Removal of the visual feedback in the left eye (i.e., darkness or stabilizing the retinal image) resulted in the oscillation changing from an MLN to CN. The MLN slow phase also changed to a grossly extended slow phase during periods of visual disengagement. The vast majority of individuals with MLN have squints.28,30-34 Since MLN occurs frequently in individuals who have early-onset bilateral or unilateral vision loss, it has been proposed that a disturbance in egocentric localization may be partly responsible for these oscillations.63 Further evidence for this proposal is found in studies on infantile cataracts, where the presence of an MLN appeared to be linked to the emergence of a squint.20-22,24,28 MLN offers a unique opportunity to investigate oculomotor behavior at the same time as perceptual behavior, since the direction of the fast phase of the jerk nystagmus indicates the viewing eye. Recently, Abadi and Theodorou simultaneously recorded eye movements of patients with MLN as they viewed rival stimuli.78 A method of constant stimuli was used to determine the manner in which the pattern alternations were inﬂuenced by attentional modulations for a number of cuing paradigms. The subjective percept correlated with the direction of the

28 BASIC CONCEPTS OF STABLE VISION AND GAZE fast phase, and the rate of alternation was found to be less frequent compared with the normal controls. Cue position, type, and duration correlated with the MLN beat direction.

EARLY VISUAL LOSS AND FIXATION STABILITY

number of albinos has been carried out by measuring contrast-detection thresholds when a small, discrete light source was directed at the inferior iris.89 These measurements have led to the prescription of speciﬁc pigmented contact lenses to reduce the intraocular light scatter and thereby improve contrast sensitivity.

Albinism

Infantile Cataracts

Albinism represents a heterogeneous group of inherited disorders of pigmentation and is characterized by a cluster of ocular features including IN, foveal hypoplasia, and strabismus.61,79 The presence of IN and the lack of a normally differentiated fovea are primarily responsible for the commonly found low VA.28,39,47,61,79-84 The range and type of waveforms seen in albinos do not differ signiﬁcantly from those in nonalbinos with IN, but albinos do exhibit a greater prevalence of periodic alternating nystagmus (i.e., a dynamic null)28,85 and an exceptionally high incidence of squint.28,47,61,82-84 VA is generally much worse as compared with the idiopaths.28 On occasion, individuals can exhibit the phenotype of albinism without a detectable nystagmus.79,83,84,86,87 Recently, Timms et al.86 reported that a non-nystagmus albino group exhibited frequent macrosaccadic intrusions (amplitude range 0.25° to 4.25°), about twice the mean amplitude found in a random normal population.12 The size of the intrusions found in the albino group was highly correlated with the velocities of steady drifts during ﬁxation, but not with VA. As albinos do not have a differentiated fovea, Abadi and Pascal88 investigated incremental light detection thresholds across the central visual ﬁeld to determine whether albinos had a modiﬁed retinal sensitivity proﬁle. Using a Goldman perimeter and the simultaneous recording of the eye movements in order to trigger target presentation during the foveation interval, they found a great deal of foveal heterogeneity. They also found that, on occasion, the sensitivity proﬁles reached near-normal levels. This ﬁnding further supported a previous study that used fundus videoing to show that albinos can regularly image the target of interest at the retinal location judged to be consistent with the normal anatomical position of the fovea.62 One clinical manifestation of the lack of ocular pigment is the existence of iris trans-illumination, and many albinos experience discomfort and disability even under exposure to quite modest light. This is particularly the case for types 1 and 2 oculocutaneous albinos (OCA); type 1 OCA designates tyrosinase-negative OCA, and type 2 tyrosinase-positive OCA. Quantiﬁcation of the intraocular scatter in a

The magnitude and severity of infantile cataracts varies enormously.90 Recently, Abadi et al.24 examined how the severity and duration of this early-onset form of deprivation affected eye alignment and ocular stability. Thirty-three patients (ranging in age from 1 week to 12.8 years) were examined before and after surgery, over periods of up to 61 months. Of the 23 patients with severe opacities, 9 underwent surgery within eight weeks of birth, and 10 had surgery after eight weeks. Of the 9 patients who underwent early surgery (≤8 weeks postnatally), 2 displayed a preoperative nystagmus. However, 8 of the 9 (89%) exhibited a nystagmus between 10 and 39 months postoperatively. In the late surgery group (≥8 weeks postnatally), 8 of the 13 (62%) exhibited a nystagmus. The most commonly found nystagmus by far was an MLN, making up a combined total for the early and late surgery groups of 75% of all recorded nystagmus types.

Emmetropization A notable feature of the refractive state of individuals with IN is that they have a higher incidence of large refractive errors and, in particular, a greater-than-normal incidence of high-spectacle astigmatism.91,92 The astigmatism is corneal in origin (anterior) and predominantly “with the rule.” The distributions of refractive errors for the idiopath and albino groups exhibit no signiﬁcant kurtosis, unlike those in the normal adolescent and adult population, and suggest that the presence of the nystagmus may interfere with normal refractive development.92 Such a failure to regulate refractive development (i.e., emmetropize) is not an unusual occurrence in systems that have experienced early form deprivation.93,94

CONCLUSION Normal ﬁxation control has a deﬁned operating range beyond which spatial and temporal vision are affected. Sensitivity losses in idiopathic CN are minimized when long foveation periods, with little variability, coincide with a functional fovea. VA is further undermined by the afferent sensory defects found in albinism and in

PRECEPTION WITH UNSTABLE FIXATION 29

individuals who experience early form deprivation. To date, the vast majority of psychophysical studies have been carried out on adults, since the participants are required to cooperate and understand the instructions. The potential VA of an infant is notoriously difﬁcult to predict, due in part to the likely modiﬁcations of the waveform26,95,96 and/or the affect of any attendant afferent defect. Moreover, difﬁculties often remain in correlating preferential looking, single and line optotype, and visually evoked potential procedures.97 Recently, studies have been carried out that establish useful objective VA predictors,48,50,98 which, together with electro-diagnostic techniques, may assist the scientist, clinician, and patient.

acknowledgment Over the years I have had the very good fortune to work closely with many colleagues, and I would like to thank Anne Bjerre, David Broomhead, Richard Clement, Christine Dickinson, Jo Forster, Emma Gowen, Gemma Hocking, Ellen Lee, Chris Lloyd, Mark Lomas, Mark Muldoon, Eric Papas, Eve Pascal, Columba Scallan, Nana Theodorou, Jon Whittle, Ralph Worfolk, and, of course, all of our subjects, who have contributed so much time, fun, and enthusiasm to our pursuit of knowledge.

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41. Dell’Osso LF, Van der Steen J, Steinman RM, Collewijn H. Foveation dynamics in congenital nystagmus. I: Fixation. Doc Ophthalmol. 1992;79:1–23. 42. Abadi RV, Whittle JP. The nature of head postures in congenital nystagmus. Arch Ophthalmol. 1991;109:216–220. 43. Tkalcevic LA, Abel LA. The effects of increased visual tasks demand on foveation in congenital nystagmus. Vision Res. 2005;45:1139–1146. 44. Dell’Osso LF. Congenital nystagmus: basic aspects. In: Lennerstrand G, Zee DS, Keller EL, eds. Functional Basis of Ocular Motility Disorders. Oxford: Pergamon Press; 1982:129–138. 45. Chung ST, Bedell HE. Velocity criteria for “foveation periods” determined from image motions simulating congenital nystagmus. Optom Vis Sci. 1996;73:92–103. 46. Bedell HE, White JM, Abplanalp PL. Variability of foveations in congenital nystagmus. Clin Vision Sci. 1989;4:247–252. 47. Abadi RV, Pascal E. Visual resolution limits in albinism. Vision Res. 1991;31:1445–1447. 48. Cesarelli M, Bifulco P, Loffredo L, Bracale M. Relationship between visual acuity and eye position variability during foveations in congenital nystagmus. Doc Ophthalmol. 2000; 101:59–72. 49. Bifulco P, Cesarelli M, Loffredo L, Sansone M, Bracale M. Eye movement baseline oscillation and variability of eye position during foveation in congenital nystagmus. Doc Ophthalmol. 2003; 107:131–136. 50. Dell’Osso LF, Jacobs JB. An expanded nystagmus acuity function: intra- and intersubject prediction of best-corrected visual acuity. Doc Ophthalmol. 2002;104:249–276. 51. Currie DC, Bedell HE, Song S. Visual acuity for optotypes with image motions simulating congenital nystagmus. Clin Vis Sci. 1993;8:73–84. 52. Abadi RV, Sandikçioglu M. Visual resolution in congenital pendular nystagmus. Am J Optom and Physiol Optics. 1975;52:573–581. 53. Bedell HE. Visual and perceptual consequences of congenital nystagmus. Semin Ophthalmol. 2006; 21:91–95. 54. Dickinson CM, Abadi RV. Suprathreshold contrast perception in congenital nystagmus. Clin Vision Sci. 1992;7:31–37. 55. Abadi RV. The effect of early anomalous visual inputs on orientation selectivity. Perception. 1974;3:141–150. 56. Bedell HE, Bollenbacher MA. Perception of smear in normal observers and in persons with congenital nystagmus. Invest Ophthalmol Vis Sci. 1996;37:188–195.

PRECEPTION WITH UNSTABLE FIXATION 31

57. Bedell HE. Perception of a clear and stable visual world with congenital nystagmus. Optom Vis Sci. 2000;77:573–581. 58. Abadi RV, King-Smith PE. Congenital nystagmus modiﬁes orientation detection. Vision Res. 1979;19:1409–1411. 59. Bedell HE, Ukwade MT. Sensory deﬁcits in idiopathic congenital nystagmus. In: Lakshminarayanan V, ed. Basic and Clinical Applications of Vision Science. Dordrecht, the Netherlands: Kluver Academic; 1999:251–255. 60. Ukwade MT, Bedell HE, White JM. Orientation discrimination and variability of torsional eye position in congenital nystagmus. Vision Res. 2002;42:2395–2407. 61. Abadi RV, Pascal E. The recognition and management of albinism. Ophthalmic Physiol Opt. 1989;9:3–15. 62. Abadi RV, Pascal E, Whittle J, Worfolk R. Retinal ﬁxation in human albinos. Optom Vis Sci. 1989;66:276–280. 63. Abadi RV. Pattern contrast thresholds in latent nystagmus. Acta Ophthal (Kbh). 1980;58:210–220. 64. Pascal E, Abadi RV. Contour interaction in the presence of congenital nystagmus. Vision Res. 1995;35:1785–1789. 65. Chung STL, Bedell HE. Effect of retinal image motion on visual acuity and contour interaction in congenital nystagmus. Vision Res. 1995;35: 3071–3082. 66. Ukwade MT, Bedell HE. Stereothresholds in persons with congenital nystagmus and in normal observers during comparable retinal image motion. Vision Res. 1999;39:2963–2973. 67. Abadi RV, Whittle JP, Worfolk R. Oscillopsia and tolerance to retinal image motion in congenital nystagmus. Invest Ophthalmol Vis Sci. 1999;40:339–345. 68. Bedell HE. Sensitivity to oscillatory target motion in congenital nystagmus. Invest Ophthalmol Vis Sci. 1992;33:1811–1821. 69. Kommerell G, Horn R, Bach M. Motion perception in congenital nystagmus. In: Keller EL, Zee DS, eds. Adaptive Processes in Visual and Oculomotor Systems. Oxford: Pergamon Press; 1986:485–491. 70. Dieterich M, Brandt T. Impaired motion perception in congenital nystagmus and acquired ocular motor palsy. Clin Vision Sci. 1987;1:337–345. 71. Shallo-Hoffman J, Bronstein AM, Acheson J, Morland AB, Gresty MA. Vertical and horizontal motion perception in congenital nystagmus. Neuroophthalmology. 1988;19:171–183. 72. Leigh RJ, Rushton DN, Hertle RW, Yaniglos SS, Thurston SE. Oscillopsia, retinal image stabilisation and congenital nystagmus. Invest Ophthalmol Vis Sci. 1988;29:279–282.

73. Dell’Osso LF, Leigh RJ. Foveation period stability and oscillopsia suppression in congenital nystagmus: an hypothesis. Neuroophthalmology. 1992;12:169–183. 74. Goldstein HP, Gottlob MG. Visual re-mapping in infantile nystagmus. Vision Res. 1992;32: 1115–1124. 75. Bedell HE, Currie DC. Extra retinal signals for congenital nystagmus. Invest Ophthalmol Vis Sci. 1993;34:2325–2332. 76. Abadi RV, Scallan C. Manifest latent and congenital nystagmus waveforms in the same subject: a need to reconsider the underlying mechanisms of nystagmus. Neuroophthalmology. 1999;21: 211–221. 77. Gradstein L, Goldstein HP, Wizov SS, Reinecke RD. Extended slow phase in latent/manifest latent nystagmus. Invest Ophthalmol Vis Sci. 2004;45:1139–1148. 78. Abadi RV, Clement R, Theodorou T, Scallan C. Manifest latent nystagmus: a case of sensori-motor switching. Prog Brain Res. 2008;171:497–502. 79. Van Dorp DB. Shades of grey in human albinism. Amersfoort, the Netherlands: Ophthalmic Publishing Centre; 1985. 80. Wilson HR, Mets MB, Nagy SE, Kressel AB. Albino spatial vision as an instance of arrested visual development. Vision Res. 1988;28:979–990. 81. Abadi RV, Dickinson CM, Pascal E, Papas E. Retinal image quality in albinos. A review. Ophthalmic Paediatr Genet. 1990;11:171–176. 82. Abadi RV, Dickinson CM, Pascal E, Whittle J, Worfolk R. Sensory and motor aspects of congenital nystagmus. In: Schmidt R, Zambarbieri D, eds. Oculomotor Control and Cognitive Processes. Amsterdam, the Netherlands: Elsevier; 1991:249–262. 83. Collewijn H, Apkarian P, Spekreyse H. The oculomotor behavior of human albinos. Brain. 1985;108:1–28. 84. Lee KA, King RA, Summers CG. Stereopsis in patients with albinism, clinical correlates. J AAPOS. 2001;5:9–104. 85. Abadi RV, Pascal E. Periodic alternating nystagmus in humans with albinism. Invest Ophthal Vis Sci. 1994;35:4080–4086. 86. Timms C, Thompson D, Russell-Eggit I, Clement R. Saccadic instabilities in albinism without nystagmus. Exp Brain Res. 2006;175:45–49. 87. Gradstein L, FitzGibbon EJ, Tsilou ET, Rubin BI, Huizing M, Gahl WA. Eye movement abnormalities in Hermansky-Pudlak Syndrome. J AAPOS. 2005;9:369–378. 88. Abadi RV, Pascal E. Incremental light thresholds across the central visual ﬁeld of human albinos. Invest Ophthal Vis Sci. 1993;34:1683–1690.

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4 Internal and External Inﬂuences on Foveation and Perception in Infantile Nystagmus Syndrome LARRY A. ABEL AND LINDA MALESIC

ABSTRACT

Its consequences for vision depend ﬁrst on whether there are concurrent sensory abnormalities present, such as albinism, congenital cataract, or aniridia, as there are in the majority of cases.2-4 A defective sensory pathway will impose a limitation upon visual acuity above and beyond any that arises from the oscillation of the eyes. However, the nystagmus itself also affects visual perception, and its effects vary. The factors that inﬂuence this variability—both internal to the individual with nystagmus and external, or found in the surrounding visual environment—are the focus of this chapter. The variability of these factors distinguishes INS from other forms of visual impairment, which are either stable (e.g., amblyopia post-childhood) or deteriorate inexorably over a period of time (e.g., retinitis pigmentosa). Absence of oscillopsia is a commonly noted diagnostic criterion for INS. However, it is not always absent.4-6 Such exceptions to the rule can tell us something interesting about the phenomenon; it is signiﬁcant that the breakdown in perceptual stability is sometimes a function of the visual environment and sometimes a function of the nystagmus waveform. The other benign form of nystagmus with onset in infancy is manifest latent nystagmus, which has recently been relabeled fusion maldevelopment nystagmus syndrome (FMNS), to acknowledge that a lack of sensory fusion is essential for the development of this condition.1 In many ways this form of nystagmus is simpler than INS—there is little variability of waveform and a more predictable variation with gaze angle.7-10 The two forms may also coexist in the same patient.9,11 Perception in this form of nystagmus can be affected by changes in ocular alignment or degree of binocular input.

Infantile nystagmus syndrome (INS) is a disorder that is inﬂuenced by a range of both internal and external factors, more so than many other disturbances of vision. Manipulation of stimulus characteristics such as contrast have been shown to provoke oscillopsia—a perception of environmental motion often said to be absent in INS. Rapidly ﬂickering stimuli can also lead to multiply perceived images. Some internal factors, such as variability with gaze position, have been well documented. Others, such as exacerbation with visual effort, are widely described but have rarely been formally studied. In one study that did examine this, the expected relationship was not found, but subjects’ comments suggested that an absence of motivation may have been contributory. Although case reports have shown that stress or anxiety can exacerbate INS and provoke oscillopsia, systematic studies have been lacking. Similarly, changes in visual function or ocular alignment in adulthood may decrease foveation and elicit oscillopsia in nystagmus patients who were previously free of this symptom. Future models of INS should incorporate modulatory inputs from the limbic system that represent motivational or stress-related inﬂuences, as well as limits on the functioning of the mechanisms that compensate for retinal-image motion and thus suppress oscillopsia. Infantile nystagmus syndrome (INS)1 is a relatively common ocular motor disorder that presents early in life. 33

34 BASIC CONCEPTS OF STABLE VISION AND GAZE The inﬂuences upon perception and upon the nystagmus itself are important for several reasons. From the perspective of the individual with nystagmus, a vision impairment that varies with circumstance may not be understood by teachers or employers. Frustration may ensue when print of a particular size can be seen clearly when idly viewing a sign but blurs into illegibility when applying for a driver’s license. From the perspective of the researcher, it is important that putative mechanisms for these inﬂuences be incorporated into any comprehensive model of INS. In particular, changes with arousal level or emotional state suggest inputs from areas of the brain that are not usually incorporated into ocular motor models. Variability arising from changes in the internal state may present problems in a clinical assessment or therapeutic evaluation. In some instances, the dividing line between actual treatment and placebo effect may be blurred.5 There is ongoing debate with regard to the aspects and time span of assessment and the degree to which internal inﬂuences should be taken into account.12-16 Also, if changes in a patient’s clinical status occur—for example, in ocular alignment or visual function17—the mechanisms that maintain perceptual stability in the face of the ocular oscillations may not be able to compensate and therefore may impact the stability of the subject. This chapter examines the inﬂuences—both external and internal—upon perception.

EXTERNAL FACTORS INFLUENCING INS AND FMNS Contrast At ﬁrst, it would seem unlikely that varying brightness or contrast of the visual environment should affect whether it is perceived as stable. Regardless of its characteristics, the image moves uniformly across the retina. However, anecdotal reports that objects seen at night or in poor lighting appeared to move prompted us to examine this pheno menon.6 Perhaps because it is so often asserted that individuals with INS do not experience oscillopsia, this was the ﬁrst time that the phenomenon was examined using normal viewing conditions (i.e., without stabilizing all or part of the retinal image).18,19 A bright, central-ﬁxation light-emitting diode (LED) presented in an otherwise dark room was viewed against a series of backgrounds that varied in brightness, contrast, and size. We anticipated that some subjects would experience oscillopsia, and they did. However, in most instances the oscillopsia was spatially inhomogeneous (i.e., only part of the visual stimulus was seen to move). As seen in Figure 4.1, this was most often the case when the LED was seen against a dim background. The background was more frequently

seen as moving when it was dim; the “LED only moving” percept was also most common with the dimmest background. Because most reports of occasional oscillopsia in the literature4,5,17,20 involve exacerbations of the patient’s customary level of nystagmus, we examined whether perception of oscillopsia was associated with poorer foveation; it was not. Although some individual reports of oscillopsia described mouse pointers shimmering against a static screen, the mechanisms underlying the inhomogeneous perception of a uniformly moving stimulus are not immediately apparent. To identify them conclusively we would have to know what mechanisms are used in the suppression of oscillopsia. Although a range of explanations have been offered,18,19,21-29 the most widely supported is that an efference copy signal is subtracted from the cortical representation of the moving visual image, thus stabilizing it perceptually.19,29 It seems implausible that this efference copy signal would be subtracted inhomogeneously from the retinal slip signal, so some other explanation would seem to be necessary. If dim regions generated a weaker retinal slip signal by virtue of their lower luminance, then uniform subtraction of the compensatory efference copy signal would yield a similarly varied difference signal. Another possibility is that neural conduction velocities from retina to cortex vary with the brightness of the stimulus.30 In this case, subtracting the efferent motion signal could not be uniformly compensatory. This explanation seems the most parsimonious. It is still unknown why sometimes the ﬁxation light and sometimes the background appears stable. A light moving against a static background would be most consistent with daily experience. Encountering the opposite situation would be unlikely in normal life. The results are confounded, however, by the fact that that the bright ﬁxation light was also the focus of the subjects’ attention in the preceding experiments. It is unknown how a bright but extrafoveal stimulus would be perceived. It may be that once attention (and ﬁxation) is withdrawn from the bright light, it is seen to behave in the same fashion as its dimmer surroundings.

Flicker Modern display technologies have made ﬂickering stimuli a part of daily life in industrial societies. LEDbased displays, such as clock radios, car taillights, or commercial signage, generally ﬂicker at a rate of several hundred to several thousand Hz to avoid overheating. This is usually so far above the ﬂicker-fusion frequency that we are unaware of it. However, if such displays are viewed in otherwise dark surroundings and a saccade is made across them, a string of lights is seen during the saccade. This arises from the different

INFLUENCES ON FOVEATION AND PERCEPTION

35

Figure 4.1 Instances of perceived oscillopsia under different viewing conditions, where (top) the ﬁxation light was seen as moving against a static background, (center) the light appeared static but the background seemed to move, and (bottom) both moved.

36 BASIC CONCEPTS OF STABLE VISION AND GAZE retinal loci upon which each ﬂash falls,31 and it occurs because saccadic suppression is not absolute. Thus, the sequence of retinal images of the ﬂashing light is seen distributed across space. In normal individuals, this may be nothing more than a curiosity. However, individuals with INS (unless they have a purely pendular waveform) or FMNS are making saccades—fast phases or braking saccades—at a rate of several per second. They are therefore far more likely to see rapidly ﬂickering displays multiply across their visual ﬁeld. This phenomenon was noted in response to our oscillopsia questionnaire6 and is commented upon in nystagmus online discussion boards in regard to car taillights, displays on clock radios, and scrolling text displays. Control subjects making saccades to and from the LED saw a string of lights or a stationary light, depending on whether it ﬂickered or not. When individuals with INS and FMNS were presented with either static or ﬂickering LEDs, those with nystagmus saw the ﬂickering light as either moving or multiple images more often than they did the stationary light. It was not possible in our experiment to relate perceptions to the nystagmus waveforms present at that time. We would anticipate that large, fast phases would be more often associated with multiple images than would small, braking saccades. In the meantime, as LEDs are used in increasingly wide applications because of their longevity, low energy consumption, and ﬂexibility of placement, individuals with nystagmus will be confronted with this problem. A similar perceptual problem has arisen with the use of digital light-processor video projectors, in which an array of digital micromirrors produces a grayscale image by varying the percentage of time during which the mirrors direct light toward the lens. Color is added by placing a rapidly spinning color wheel in the light path, presenting sequences of individual primary colors so rapidly that they are seen as integrated, unless the viewer makes a saccade across the screen. Some individuals may see rainbow fringes around objects in the projected image, for the same reasons as ﬂickering LEDs are seen across the retina. It has recently been reported that this is a particular problem for individuals with INS.32 As the preceding section illustrates, advances in technology may create unanticipated problems for speciﬁc populations, making previously straightforward tasks quite difﬁcult. Even something as simple as reading the destination sign on a streetcar may suddenly become a problem when a printed cloth roll is replaced with a scrolling LED display. More generally, we have found that speciﬁc features of the visual environment, such as high contrast between a small light and a dim background or rapid ﬂicker, can disturb the visual perception of individuals with infantile forms of nystagmus and disrupt a normally accurate internal

representation of their surroundings. These disruptions occur without any corresponding change in the nature of their nystagmus. As we shall see, perception may also be affected when the nystagmus waveform itself changes due to external or internal inﬂuences.

INTERNAL INFLUENCES ON INS AND FMNS So far we have examined how particular aspects of the visual environment can affect the way individuals with infantile forms of nystagmus perceive their environment. Changes in the environment do not alter the waveforms of the nystagmus as the individual’s perceptions change. We will now look at how internal factors inﬂuence the oscillation itself and, in many cases, perception. In one sense, the importance of internal factors to INS seems to be widely known—many descriptions of the condition discuss how stress, fatigue, illness, or, most commonly, the “effort to see” lead to an exacerbation of the condition. Certainly individuals with INS often describe instances where something of interest becomes difﬁcult to see. What is remarkable, however, is that until recently there was almost no published research that attempted to manipulate any of these internal variables in order to observe the effects on an individual’s nystagmus waveforms or visual perception.

Visual Effort Although an increase in visual effort is almost always given as one of the key features of INS, until recently the only demonstration of this in print was one ﬁgure in a study by Abadi et al.33 One of the most basic ways to eliminate “effort to see” would be to turn out all the lights. But this tactic fails to consider the human ability to attempt to see an imaginary object, as in the instance of monocular individuals’ nystagmus spontaneously reversing in darkness, but with direction reversible by act of will.34,35 Sometimes total darkness is not necessary for voluntary effort to change a nystagmus waveform. Figure 4.2 illustrates the nystagmus of a young woman with a microophthalmic right eye, resulting in a coarse left-beating manifest latent nystagmus, which was present as long as she was actively trying to see. When simply passively ﬁxating in dim light, however, her nystagmus underwent a transition through a dual-jerk waveform to an asymmetrical pendular INS waveform. When she resumed active viewing, there was a brief delay before the jerk waveform returned, during which she was aware of better vision. The subject was thus left in the unfortunate position of having a visually preferable waveform only when she was not trying to actively use vision.

INFLUENCES ON FOVEATION AND PERCEPTION

37

pos 0 deg

L 10 deg R

100 deg/s 1s

0 deg/s vel

Figure 4.2 Transition seen as patient ceased to actively read (at the beginning of the ﬁgure) and then passively ﬁxated on a light in a dimly lit room (at right). Note the transition from MLN to dual-jerk nystagmus and ﬁnally to asymmetric pendular CN. CN, congenital nystagmus; MLN, manifest latent nystagmus. The patient described here, as well as one described by Shawkat et al.,35 showed both INS and FMNS waveforms. The switching between them in darkness emphasizes once again the linkage that must exist at some level between these two ocular motor instabilities, even though they remain separate entities. In the patient described here, visual effort itself was the trigger that caused the switch between the two. This effect, however, is not usually ascribed to visual effort. Generally, a vicious cycle is described in which the effort to see something at the limit of resolution causes an exacerbation of nystagmus, which makes the object of regard harder to see, thus provoking more effort, and so on. Somewhat surprisingly, although this concept agrees with anecdotal descriptions of how INS affected the vision of individuals with the condition, experimental examination of this phenomenon was lacking. We therefore undertook what we expected to be a straightforward demonstration of how this occurred. Landolt C’s of varying sizes and orientations were presented to 14 INS patients, who had to identify their orientations in a four-alternative forced-choice paradigm.36 We analyzed their nystagmus waveforms for the duration of foveation periods and expected to ﬁnd that, while their nystagmus remained stable during viewing of easy-to-read optotypes, it would deteriorate rapidly when the targets became harder to resolve. What we found, however, was completely unexpected (Fig. 4.3). Based on the numerous comments regarding the exacerbation of nystagmus with visual effort, we expected to see a well-deﬁned relationship between Landolt C size and foveation duration, with the effort needed to see the smaller optotypes leading to a clear decline in foveation. Instead, there appeared to be no systematic relationship between the ease with which a target could be identiﬁed and the nystagmus waveform, even though the subjects were encouraged to try and

see letter sizes that were at the very limit of their previously measured visual acuity. In trying to explain why anecdote and experiment were so different, we examined the subjects’ comments about their participation in the research study. One observation made repeatedly was that they did not really care how they did in the laboratory, as there was no particular motivation to perform well. In contrast, when trying to pass a driver’s license vision test or get through school examinations, visual performance was of considerable personal importance and, under these conditions, they found their nystagmus, and consequently their vision, worsening. Given that motivation has been shown to modulate neural activity in a number of areas in the basal ganglia and cerebral cortex,37-40

Figure 4.3 Percentage of time spent foveating versus optotype size for idiopathic congenital nystagmus patients. Note the unexpected absence of a relationship between the variables. Source: Tkalcevic L, Abel LA. The effects of increased visual task demand on foveation in congenital nystagmus. Vision Res. 2005;45:1139–1146.

38 BASIC CONCEPTS OF STABLE VISION AND GAZE plausible substrates exist whereby this internal state could inﬂuence ocular motor behavior. What is needed is to evaluate patients’ nystagmus during tasks that provide some sort of motivation to maximize visual performance, possibly by using some sort of reward/ penalty manipulation.41,42

Stress Along with visual effort, stress is often mentioned as an exacerbating factor in INS, but formal studies have been lacking. One possible example of the inﬂuence of stress or anxiety on a patient’s nystagmus waveform, and thereby perception, was the case of a young woman with known INS who developed oscillopsia in her early teenage years.5 Eye movement recordings revealed typical CN waveforms, and discussion with the patient revealed considerable concern about the impact that her eye movements had on her appearance. Reassurance about the inconspicuous nature of her nystagmus was accompanied by a reduction in its clinical appearance. Analysis of her eye movement recordings showed an increase in foveation duration, which was associated with the disappearance of oscillopsia. Even when her nystagmus was at its worst, it never departed from typical waveforms, which in most patients do not lead to oscillopsia. Hence we argued that, for some individuals, compensatory mechanisms to suppress oscillopsia operate over ﬁxed limits. If these limits are exceeded, oscillopsia results. Although we inferred that stress was causing this patient’s nystagmus exacerbation and consequent oscillopsia, we did not monitor any of the accepted physiological indicators used to indicate the experience of stress, such as blood pressure, heart rate, or galvanic skin response.43 To properly examine the inﬂuence of stress on nystagmus, the employment of these measures and the recording of eye movement during tasks involving variable degrees of stress is essential. Such measures have been widely used and can provide a useful correlate of any changes in the nystagmus waveform. Under stressful conditions, we would not generally expect INS patients to develop oscillopsia, but we might expect a deterioration in foveation and a concomitant reduction in visual acuity.16,44-48 In daily life, separating the effects of stress from those of motivation could be difﬁcult, as the act of trying to achieve a highly desired goal (e.g., getting a driver’s license) could be a potent stressor.

Attention Although attention in various forms is a ubiquitous topic of study by psychologists, cognitive scientists, and physiologists, its formal conceptualization is often

credited to William James,49 who said, “Every one knows what attention is. It is the taking possession by the mind, in clear and vivid form, of one out of what seem several simultaneously possible objects or trains of thought …. It implies withdrawal from some things in order to deal effectively with others, and is a condition which has a real opposite in the confused, dazed, scatterbrained state which in French is called distraction, and Zerstreutheit in German.” Many studies focus on the differences between “bottom-up” attention, elicited by some novel stimulus in the external environment, and “top-down” attention, directed toward some object by a conscious act of will, and on how these may be affected by age or disease.50-55 Less often quoted but germane to a discussion of nystagmus is the following statement by James: We all know this latter state, even in its extreme degree. Most people probably fall several times a day into a ﬁt of something like this: The eyes are ﬁxed on vacancy, the sounds of the world melt into confused unity, the attention is dispersed so that the whole body is felt, as it were, at once, and the foreground of consciousness is ﬁlled, if by anything, by a sort of solemn sense of surrender to the empty passing of time. In the dim background of our mind we know meanwhile what we ought to be doing: getting up, dressing ourselves, answering the person who has spoken to us, trying to make the next step in our reasoning. When considering modulating inﬂuences on nystagmus, it becomes apparent that top-down, volitionally directed attention cannot entirely be separated from visual effort. The act of scrutinizing a target requires it to be the object of attention. However, in assessing nystagmus, simple point targets such as LEDs or spots on a computer monitor are generally used. Sustaining attention on these targets for long periods of time is problematic, since they are of no inherent interest. When attention is disengaged from these targets, either by explicitly engaging subjects in a nonvisual task56 or when focus is lost in the way described previously by James, FMNS slow phases have been shown to continue for longer-than-usual periods of time, interrupted less frequently by corrective fast phases. These socalled extended slow phases may also be seen in INS when attention to the ﬁxation target lapses (Fig. 4.4). This phenomenon, in which nystagmus spontaneously changes as engagement with the ﬁxation target is lost, is a particular problem when assessing congenital forms of periodic alternating nystagmus. Shallo-Hoffmann et al.57 attempted to control for this by having patients listen to stories during the recording session. While this was an improvement over simply assuming that an LED in a dark room would maintain its interest

INFLUENCES ON FOVEATION AND PERCEPTION

Figure 4.4 Examples of extended slow phases from approximately 204 to 207 seconds into recording; the slow phases were presumably caused by loss of attention.

for, say, 10 minutes, it is also possible that stories chosen for their neutral tone could also come to be ignored; anyone who has nodded off in a lecture can conﬁrm that the simple presence of auditory and visual stimuli is insufﬁcient to ensure sustained attention. Most studies that have quantitatively examined INS and FMNS have used simple targets, to avoid variations in visual engagement, and selected relatively brief segments of data generated during a period in which it was inferred that subjects were actively ﬁxating. Recently, however, several studies have appeared that dispensed with this approach and instead applied wavelet13 and nonlinear dynamic12 analysis techniques to entire recording sessions of several minutes’ duration. They argued that selection of brief portions of data in order to assess a new therapy16 could not be justiﬁed. This point was strongly argued by authors from the two sets of studies.14,15 It seems clear, however, that analyzing a long recording that included lapses of attention and reductions in arousal would yield results that were not representative of nystagmus behavior during times of active visual processing or even sustained arousal.

Changes in Visual Status The frequency with which changes in nystagmus patients’ clinical condition lead to exacerbations of their nystagmus or even a loss of perceptual stability is not known. At its simplest, the increase in nystagmus intensity that is seen when one eye of someone with FMNS is occluded could be considered an example of this. The change from a manifest latent to a latent nystagmus under these circumstances can even lead to

39

oscillopsia when the better-seeing eye of a child with this condition and amblyopia is patched.58 Interestingly, under these circumstances, adaptation eventually occurs, with a concomitant disappearance of oscillopsia. More recently, Hertle et al.17 found that a change in strabismus angle or loss of visual function in patients with INS could lead to an exacerbation of nystagmus and onset of oscillopsia in adult patients. Quantitative analysis of their nystagmus waveforms showed relatively low periods of foveation. When treatment addressed the problems and their exacerbations, foveation improved and oscillopsia was reduced or eliminated. Like the patient for whom anxiety over her nystagmus led to lower foveation and onset of oscillopsia,5 it appears that both the FMNS and INS patients have oscillopsia-suppression mechanisms that are limited in the range of retinal slip over which they can successfully operate. Why this is only true for a subset of such patients remains an unresolved question.

SUMMARY Although much has been learned, particularly over the last few decades, about the behavior and visual consequences of infantile forms of nystagmus, and though comprehensive models of its origin have begun to appear,59 our understanding remains incomplete. The phenomena reviewed in this chapter indicate that although the mechanisms that give rise to the oscillations themselves may be centred in the brainstem, they are under the inﬂuence of other regions of the central nervous system, apparently including cortical and subcortical regions that underlie such higher cognitive functions as top-down allocation of attention and limbic system processes such as the stress response. Perception in some—but not all—patients with these conditions is susceptible to destabilization when their ocular oscillations worsen under the inﬂuence of the processes discussed here. Perception may also become unstable when nystagmus remains unchanged but speciﬁc changes take place in visual stimuli. These exogenous and endogenous causes of oscillopsia also remain to be adequately modeled. It is hoped that experimental examination of these inﬂuences will contribute to both the comprehensive modeling of nystagmus mechanisms and the evaluation and treatment of patients with this disorder.

References 1. National Eye Institute. The Classiﬁcation of Eye Movement Abnormalities and Strabismus (CEMAS): Report of an NEI Sponsored Workshop, 2001. National Eye Institute Web site. http://catalog

40 BASIC CONCEPTS OF STABLE VISION AND GAZE

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nei.nih.gov/productcart/pc/viewPrd.asp?idcatego ry=0&idproduct=52. Accessed January 21, 2008. Weiss AH, Biersdorf WR. Visual sensory disorders in congenital nystagmus. Ophthalmol. 1989; 96:517–523. Flanders M, Young D. Atypical sensory nystagmus and its surgical management. Can J Ophthalmol. 1983;18:349–351. Abadi RV, Bjerre A. Motor and sensory characteristics of infantile nystagmus. Brit J Ophthalmol. 2002;86:1152–1160. Abel LA, Williams IM, Levi L. Intermittent oscillopsia in a case of congenital nystagmus: Dependence upon waveform. Invest Ophthalmol Vis Sci. 1991;32:3104–3108. Tkalcevic L, Abel LA. Effects of stimulus size and luminance on oscillopsia in congenital nystagmus. Vis Res. 2003;43:2697–2705. Dell’Osso LF. Congenital, latent and manifest latent nystagmus—similarities, differences and relation to strabismus. Jap J Ophthalmol. 1985;29: 351–368. Kommerell G, Mehdorn E. Is an optokinetic defect the cause of congenital and latent nystagmus? In: Lennerstrand G, Zee DS, Keller EL, eds. Functional Basis of Ocular Motility Disorders. Oxford: Pergamon Press; 1982:159–167. Dell’Osso LF, Schmidt D, Daroff RB. Latent, manifest latent and congenital nystagmus. Arch Ophthalmol. 1979;97:1877–1885. Abadi RV, Scallan C. Waveform characteristics of manifest latent nystagmus. Invest Ophthalmol Vis Sci. 2000;41:3805–3817. Abadi RV, Scallan C. Manifest latent and congenital nystagmus waveforms in the same subject. Neuroophthalmology. 1999;21:211–221. Miura K, Hertle RW, FitzGibbon EJ, Optican LM. Effects of tenotomy surgery on congenital nystagmus waveforms in adult patients. Part II. Dynamical systems analysis. Vision Res. 2003;43(22):2357– 2362. Miura K, Hertle RW, FitzGibbon EJ, Optican LM. Effects of tenotomy surgery on congenital nystagmus waveforms in adult patients. Part I. Wavelet spectral analysis. Vision Res. 2003;43(22): 2345–2356. Dell’Osso LF. Tenotomy and congenital nystagmus: a failure to answer the wrong question (letter). Vision Res. 2004;44:3091–3094. Optican LM, Miura K, FitzGibbon EJ. Tenotomy and congenital nystagmus: a null result is not a failure, for “It is not the answer that enlightens, but the question” (letter). Vision Res. 2004;44: 3095–3098.

16. Hertle RW, Dell’Osso LF, FitzGibbon EJ, Thompson D, Yang D, Mellow SD. Horizontal rectus tenotomy in patients with congenital nystagmus: results in 10 adults. Ophthalmol. 2003;110:2097–2105. 17. Hertle RW, FitzGibbon EJ, Avallone JM, Cheeseman E, Tsilou EK. Onset of oscillopsia after visual maturation in patients with congenital nystagmus. Ophthalmol. 2001;108:2301–2308. 18. Leigh RJ, Dell’Osso LF, Yaniglos SS, Thurston SE. Oscillopsia, retinal image stabilization and congenital nystagmus. Invest Ophthalmol Vis Sci. 1988;29:279–282. 19. Abadi RV, Whittle JP, Worfolk R. Oscillopsia and tolerance to retinal image movement in congenital nystagmus. Invest Ophthalmol Vis Sci. 1999;40:339–345. 20. Abadi RV, Dickinson CM. Waveform characteristics in congenital nystagmus. Doc Ophthalmol. 1986;64:153–167. 21. Gottlob I, Goldstein HP, Fendick MG. Visual remapping in patients with infantile nystagmus. Invest Ophthalmol Vis Sci. 1990;31(suppl):602. 22. Bedell HE. Thresholds for unreferenced oscillatory target motion in nystagmus. Invest Ophthalmol Vis Sci. 1989;30(suppl):50. 23. Jin YH, Goldstein HP, Reinecke RD. Absence of visual sampling in infantile nystagmus. Invest Ophthalmol Vis Sci. 1989;30(suppl):50. 24. Waugh SJ, Bedell HE. Sensitivity to temporal luminance modulation in congenital nystagmus. Invest Ophthalmol Vis Sci. 1992;33:2316–2324. 25. Dell’Osso LF, Leigh RJ. Foveation period stability and oscillopsia suppression in congenital nystagmus. Neuroophthalmology. 1992;12:169–183. 26. Dell’Osso LF, Leigh RJ. Ocular motor stability of foveation periods: required conditions for suppression of oscillopsia. Neuroophthalmology. 1992;12:303–326. 27. Dell’Osso LF, Averbuch-Heller L, Leigh RJ. Oscillopsia suppression and foveation-period variation in congenital, latent and acquired nystagmus. Neuroophthalmology. 1997;18:163–183. 28. Shallo-Hoffmann JA, Bronstein AM, Acheson J, Morland AB, Gresty MA. Vertical and horizontal motion perception in congenital nystagmus. Neuroophthalmology. 1998;19:171–184. 29. Goldstein HP, Gottlob I, Fendick MG. Visual remapping in infantile nystagmus. Vision Res. 1992;32:1115–1124. 30. Allik J, Kreegipuu K. Multiple visual latency. Psychol Sci. 1998;9:135–138. 31. Watanabe J, Noritake A, Maeda T, Tachi S, Nishida S. Perisaccadic perception of continuous ﬂickers. Vision Res. 2005;45:413–430.

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32. Ogata M, Ukai K, Kawai T. Visual fatigue in congenital nystagmus caused by viewing images of color sequential projectors. J Disp. Tech. 2005;1:314–320. 33. Abadi RV, Dickinson CM, Pascal E, Whittle J, Worfolk R. Sensory and motor aspects of congenital nystagmus. In: Schmid R, Zambarbieri D, eds. Oculomotor Control and Cognitive Processes. Amsterdam, the Netherlands: Elsevier; 1991: 249–262. 34. Dell’Osso LF, Abel LA, Daroff RB. Latent/manifest latent nystagmus reversal using an ocular prosthesis: Implications for vision and ocular dominance. Invest Ophthalmol Vis Sci. 1987;28:1873–1876. 35. Shawkat FS, Harris C, Taylor DSI. Spontaneous reversal of nystagmus in the dark. Brit J Ophthalmol. 2001;85:428–431. 36. Tkalcevic L, Abel LA. The effects of increased visual task demand on foveation in congenital nystagmus. Vision Res. 2005;45:1139–1146. 37. Cardinal RN, Parkinson JA, Hall J, Everitt BJ. Emotion and motivation: The role of the amygdala, ventral striatum and prefrontal cortex. Neurosci Behav Rev. 2002;26:321–352. 38. Paus T. Primate anterior cingulate cortex: Where motor control, drive and cognition interface. Nature Rev Neurosci. 2001;2:417–424. 39. Lauwereyns J, Takikawa Y, Kawagoe R, et al. Feature-based anticipation of cues that predict reward in monkey caudate nucleus. Neuron. 2002;33:463–473. 40. Kawagoe R, Takikawa Y, Hikosaka O. Rewardpredicting activity of dopamine and caudate neurons—a possible mechanism of motivational control of saccadic eye movement. J Neurophysiol. 2003;91:1013–1024. 41. Schultz W, Tremblay W, Hollerman JR. Reward processing in primate orbitofrontal cortex and basal ganglia. Cereb Cortex. 2000;10:272–283. 42. Tomporowski PD, Tinsley VF. Effects of memory demand and motivation on sustained attention in young and older adults. Am J Psychol. 1996;109:187–204. 43. Richter M, Gendolla GHE. Incentive effects on cardiovascular reactivity in active coping with unclear task difﬁculty. Int J Psychophysiol. 2006;61:216–225. 44. Dell’Osso LF, Daroff RB. Congenital nystagmus waveforms and foveation strategy. Doc Ophthalmol. 1975;39:155–182. 45. Abadi RV, Worfolk R. Retinal slip velocities in congenital nystagmus. Vision Res. 1989;29:195–205.

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46. Zubcov AA, Stark N, Weber A, Wizov SS, Reinecke RD. Improvement of visual acuity after surgery for nystagmus. Ophthalmol. 1993;100:1488–1497. 47. Dell’Osso LF, Jacobs JB. An expanded nystagmus acuity function: intra- and intersubject prediction of best-corrected visual acuity. Doc Ophthalmol. 2002;104:249–276. 48. Chung ST, Bedell HE. Velocity criteria for “foveation periods” determined from image motions simulating congenital nystagmus. Optom Vis Sci. 1996;73:92–103. 49. James W. The Principles of Psychology. New York: Holt, 1890. 50. Posner MI. Orienting of attention. Q J Exp Psychol. 1980;32:3–25. 51. Danckert J, Maruff P, Crowe S, Currie J. Inhibitory processes in covert orienting in patients with Alzheimer’s disease. Neuropsychology. 1998;12: 225–241. 52. Nieuwenhuis S, Ridderinkhof KR, de Jong R, Kok A, van der Molen MW. Inhibitory inefﬁciency and failures of intention activation: age-related decline in the control of saccadic eye movements. Psychol Aging. 2000;15:635–647. 53. Sweeney JA, Rosano C, Berman RA, Luna B. Inhibitory control of attention declines more than working memory during normal aging. Neurobiol Aging. 2001;22:39–47. 54. Ball KK, Beard BL, Roekner DL, Milller RL, Griggs DS. Age and visual search: expanding the useful ﬁeld of view. J Opt Soc Am A. 1988;5:2210–2219. 55. Simons DJ, Chabris CF. Gorillas in our midst: sustained inattentional blindness for dynamic events. Perception. 1999;28:1059–1074. 56. Gradstein L, Goldstein HP, Wizov SS, Reinecke RD. Extended slow phase in latent/manifest latent nystagmus. Invest Ophthalmol Vis Sci. 2004;45: 1139–1148. 57. Shallo-Hoffmann JA, Faldon M, Tusa RJ. The incidence and waveform characteristics of periodic alternating nystagmus in congenital nystagmus. Invest Ophthalmol Vis Sci. 1999;40: 2546–2553. 58. Simonsz HJ. The effect of prolonged monocular occlusion on latent nystagmus in the treatment of amblyopia. Doc Ophthalmol. 1989;72: 375–384. 59. Jacobs JB, Dell’Osso LF. Congenital nystagmus: Hypotheses for its genesis and complex waveforms within a behavioral ocular motor system model. J Vis. 2004;4:604–625.

5 Perceptual Fading during Voluntary and Involuntary Eye Movements FRANK A. PROUDLOCK, ASTRID Y. JORGENSEN, AND IRENE GOTTLOB

simply related to retinal velocity of the target but also to efferent information. Interestingly, patients with involuntary eye movements could also ﬁll in targets, although responses were more variable than in healthy volunteers.

ABSTRACT Perceptual fading (PF) is a phenomenon in which a target in the visual ﬁeld fades from view after a certain fading time (FT). PF is reset by microsaccadic eye movements; however, PF has not been investigated during nonﬁxation eye movements. We compared PF during voluntary eye movements in healthy volunteers and in patients with involuntary eye oscillations caused by nystagmus. Twelve healthy volunteers performed a PF task consisting of following an oscillating ﬁxation cross moving with either a sine wave (pursuit task) or a square wave (saccadic task) proﬁle while viewing a static peripheral spot of low contrast (1.5x threshold). This was compared to FT during a static ﬁxation cross with peripheral spot moving and also when both were moving. FT was also compared in 4 volunteers with nystagmus. During pursuit, FT was signiﬁcantly longer for the static cross + moving target condition compared to the moving cross + static target (p = 0.04) and moving cross + moving target (p = 0.001). In contrast, during the saccadic trial, FT was similar for static cross + moving target and moving cross + static target tasks, but both were lower than the moving cross + moving target task. FT was more strongly correlated to retinal speed of the PF target during square wave than during sine wave tasks. FT was correlated to foveation in the four subjects with nystagmus. We describe the PF during voluntary eye movements when stimuli are applied at low contrast. Fading time was not

Interest in the role of involuntary ﬁxational eye movements for counteracting neural adaptation has recently been revived in studies by Martinez-Conde et al.1,2 They found an association between probability, rate, and magnitude of microsaccades made during ﬁxation and perceptual fading (PF) and reappearing of a target in the peripheral vision. Although the simplest forms of PF could be explained by neural adaptation in the retina, several lines of evidence suggest that PF is an active cortical process in which the perceptual image is represented at a neural level. For example, several animal studies have shown responses in visual cortical neurons during PF of an artiﬁcial scotoma3 and perceptual completion across the blind spot.4,5 Also, PF appears to occur separately for visual features such as texture and color, and visual information is never completely suppressed, even after an image has faded completely from consciousness.6 The microsaccades, drift, and tremor that occur during ﬁxation eye movements are involuntary and unconscious, yet little is known about the inﬂuence of voluntary eye movements, such as smooth pursuit and saccades, on PF. Voluntary eye movements inﬂuence visual perception in a number of ways. During smooth pursuit, pursuit suppression occurs to reduce the optokinesis that should result from global motion that 42

PERCEPTUAL FADING DURING EYE MOVEMENTS

occurs on the retina when tracking a target.7 With the often large and rapid changes in retinal image that occur during saccadic eye movements, saccadic suppression reduces the effects of motion.8 Also, efference copy is used to generate a stable world view from rapidly changing images that fall on the retina.9 To investigate these effects, we have compared PF during voluntary saccadic eye movements and smooth pursuit to tasks that generate similar target motion on the retina when the eyes are ﬁxating. As soon as an image of a target in the peripheral ﬁeld begins to move on the retina it becomes more salient, as neural adaptation is opposed. Since PF is related to the salience of visual stimuli,10 we have applied visual targets at low contrast levels, using a method to measure the contrast increment detection threshold. We have also investigated PF in patients with large involuntary eye movements caused by congenital idiopathic nystagmus. Since the intensity of nystagmus varies at different eccentricities of gaze, we have been able to compare the FT when patients are ﬁxating different eccentricities with velocity of eye movements.

METHODS

43

ﬁve times). For each trial, the intensity of the nystagmus (amplitude × frequency) and the expanded nystagmus acuity function were calculated.11

RESULTS Figure 5.1 shows a representative example of FTs recorded in a healthy volunteer. Analysis of median FTs of all healthy volunteers during the sine wave movements (Fig. 5.1A) showed that FT was signiﬁcantly longer for +st •sin than for +sin •st (p = 0.048) or +sin •sin (p = 0.006). In comparison, during the square wave movements (Fig. 5.1B), FTs were longest for the +sq •sq trial (p = 0.02 for +sq •st versus +sq •sq). An analysis of the velocity of the target on the retina during each task found little difference between the image movement during the three sine tasks (p = 0.92), whereas image movement was greatest during the +sq •sq for the square wave trials (p < 0.0001). FT was more strongly correlated to retinal speed of the PF target during square wave (r = 0.10, p = 0.39) than sine wave tasks (r = 0.32, p = 0.007). Volunteers with nystagmus could also successfully ﬁll in peripheral targets. However, the correlation between fading time and foveation (r = 0.32, p = 0.17)

Twelve healthy volunteers and 4 patients with nystagmus participated in the study. A staircase method was used to measure the contrast detection threshold for each individual. Each of the 12 healthy volunteers performed seven PF trials (shown in Table 5.1), which were pseudo-randomly applied to nasal or upper visual ﬁeld (1.5x threshold, 20° eccentricity, six repeats). An infrared video pupil tracker (250 Hz) was used to record horizontal and vertical gaze position at the same time. For testing FT of the 4 nystagmus patients, the ﬁxation cross appeared in one of ﬁve positions (−20°, −10°, 0, 10°, and 20°), and the PF target was always placed 20° above the ﬁxation cross (repeated

Table 5.1 Combinations of Movements Applied to the Fixation Cross and PF Spot Code

Fixation Target

PF Target

+st •st

static

static

+sin •st +st •sin

sinusoidal static

static sinusiodal

+sin •sin +sq •st +st •sq +sq •sq

sinusoidal square wave static square wave

sinusoidal static square wave square wave

PF, perceptual fading.

Figure 5.1 Fading times recorded for a healthy volunteer when targets were located along the horizontal (H) or vertical (V) meridian. Movement of the perceptual fading target or ﬁxation cross are shown along the x-axis.

44 BASIC CONCEPTS OF STABLE VISION AND GAZE was stronger than for fading time and velocity (r = 0.68, p = 0.0009).

DISCUSSION We describe PF during voluntary smooth pursuit and saccadic tasks in healthy volunteers, as well as during the involuntary eye movements made by patients with nystagmus, but only when stimuli are of sufﬁciently low salience. In healthy volunteers, fading time is not simply related to retinal velocity of the target but also appears to be inﬂuenced by efferent output. For example, FT during pursuit took less time than when targets moved with equivalent motion during ﬁxation. Correlation between FT and velocity of the eyes was also poor during pursuit tasks. Patients with involuntary eye movements could also ﬁll in targets, although their responses were more variable than those of healthy volunteers. The responses were more strongly correlated to foveation than to velocity, possibly because of reduced visibility of targets during faster eye movements. The inﬂuence of the efferent signal in PF implies a role in post-retinal processing of afferent information in the perceived salience to the stimuli.

References 1. Martinez-Conde S, Macknik SL, Troncoso XG, Dyar TA. Microsaccades counteract visual fading during ﬁxation. Neuron. 2006;49:297–305. 2. Martinez-Conde S, Macknik SL, Hubel DH. The role of ﬁxational eye movements in visual perception. Nat Rev Neurosci. 2004;5:229–240.

3. De Weerd P, Gattass R, Desimone R, Ungerleider LG. Responses of cells in monkey visual cortex during perceptual ﬁlling-in of an artiﬁcial scotoma. Nature. 1995;377:731–734. 4. Matsumoto M, Komatsu H. Neural responses in the macaque v1 to bar stimuli with various lengths presented on the blind spot. J Neurophysiol. 2005;93:2374–2387. 5. Komatsu H, Kinoshita M, Murakami I. Neural responses in the primary visual cortex of the monkey during perceptual ﬁlling-in at the blind spot. Neurosci Res. 2002;44:231–236. 6. Ramachandran VS, Gregory RL. Perceptual ﬁlling in of artiﬁcially induced scotomas in human vision. Nature. 1991;350:699–702. 7. Lindner A, Ilg UJ. Suppression of optokinesis during smooth pursuit eye movements revisited: the role of extra-retinal information. Vision Res. 2006;46:761–767. 8. Lee PH, Sooksawate T, Yanagawa Y, Isa K, Isa T, Hall WC. Identity of a pathway for saccadic suppression. Proc Natl Acad Sci USA. 2007;104:6824– 6827. 9. Burr D, Morrone MC. Eye movements: building a stable world from glance to glance. Curr Biol. 2005;15:839–840. 10. Sturzel F, Spillmann L. Texture fading correlates with stimulus salience. Vision Res. 2001;41:2969– 2977. 11. Dell‘Osso LF, Jacobs JB. An expanded nystagmus acuity function: intra- and intersubject prediction of best-corrected visual acuity. Doc Ophthalmol. 2002;104(3):249–276.

II NEW MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY

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6 Alternating Saccades in a Primate Model of Strabismus VALLABH E. DAS

ABSTRACT

Loss of sensory or motor fusion early in postnatal development leads to binocular misalignment (strabismus).1 Various studies conclude that infantile forms of strabismus occur in as much as 5% of all children.2 For the last few years, our laboratory has pursued studies of eye movements in a primate model for sensory strabismus.3-6 In addition to horizontal misalignment, these strabismic animals also displayed A or V patterns of horizontal deviations and dissociated vertical deviation (DVD), all commonly observed in humans with strabismus.1 Investigation of motoneuron activity in the oculomotor nucleus identiﬁed a neural drive for abnormal eye movements associated with the A/V patterns and DVD. Our strategy thus far has been to utilize concepts, tools, and techniques derived from studies of binocular coordination in normals and apply them to examine binocular mechanisms in the strabismic monkey model. Following along the lines of this general strategy, we examined new eye movement data regarding another strabismus phenomenon—alternating ﬁxation—that we had observed in our animal model and were interested in exploring further. Some humans with strabismus, usually those who do not suffer from signiﬁcant amblyopia, have the ability to ﬁxate a target of interest with either eye and are often capable of spontaneously alternating (or switching) the eye of ﬁxation. A saccadic eye movement in which the eye of ﬁxation is switched is called an alternating saccade. The ability to alternate the eye of ﬁxation depends on visual suppression mechanisms7 In exotropic strabismus, it is usually the temporal retina that is suppressed.8-11 It follows that when the

Alternating ﬁxation is frequently observed in humans with strabismus. We examined this phenomenon in a monkey model for strabismus. An exotropic strabismus was induced in two infant monkeys using an alternate monocular occlusion paradigm for the ﬁrst four months of life. When the animals were about three years old, we measured binocular eye movements, using the scleral search coil technique, as they performed a visually guided saccade task during monocular or binocular viewing. During binocular viewing, monkeys tended to ﬁxate targets in the right hemiﬁeld with their right eye and targets in the left hemiﬁeld with their left eye, consistent with patterns of visual suppression in exotropia. An alternating saccade was executed when the target jumped across the midline. There were no signiﬁcant differences in the amplitude–peak velocity or amplitude– duration main-sequence relationships between alternating and nonalternating saccades (monocular or binocular viewing). Saccade latency tended to be greater during binocular viewing than during monocular viewing. Our study establishes a strabismus monkey model useful for studying neural circuits involved in generating alternating ﬁxation and alternating saccade behavior. Further, alternating saccade behavior may be used as a probe to study mechanisms of visual suppression in strabismus and mechanisms of target selection in normal individuals. 47

48 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY strabismic individual switches the eye of ﬁxation, visual suppression must also be switched from one eye to the other. Steinbach studied this phenomenon and showed that switching of visual suppression coincided with the saccadic eye movement.7 This raises some questions about how an alternating saccade is triggered. In perhaps the only study in the literature that examined characteristics of alternating saccades in humans with exotropia, van Leeuwen et al.12 showed that some metrics of alternating and nonalternating saccades were similar. However, they chose a predictable selfgenerated horizontal saccade task and analyzed only the amplitude–peak velocity relationship in their subjects. Also, the patients in that study had already undergone strabismus correction surgery, which may have altered patterns of saccade alternation. There were two main goals for our study. First, we wanted to establish our animal model as effective in producing alternating ﬁxation and alternating saccade behavior. A second goal was to compare metrics of alternating and nonalternating saccades over a large range of horizontal and vertical amplitudes and orbital positions. A potential advantage of studying alternating behavior in a monkey model is that the animal would not have undergone strabismus surgery. Establishing a monkey model opens the avenue for identiﬁcation of neural substrates involved in generating alternating saccade behavior using conventional neurophysiological methods. Some of these results have appeared before in abstract form.13

METHODS Subjects and Rearing Paradigms Behavioral data were collected from two strabismic (S1 and S2) juvenile rhesus monkeys (Macaca mulatta), each weighing between 8 and 11 kg. Monkeys with strabismus were reared at the Yerkes National Primate Research Center using an alternate monocular occlusion (AMO) paradigm.3,14 In the AMO rearing procedure, soon after birth (within the ﬁrst 24 hours), an occluding patch (either opaque goggles or dark contact lenses) is placed in front of one eye for a period of 24 hours and thereafter switched to the other eye for the next 24 hours. The patch is alternated daily for a period of 4 to 6 months. In this method, binocular vision is severely disrupted during the ﬁrst few months of life, the critical period during which the monkeys would normally develop proper eye alignment, stereovision, and binocular sensitivity in the brain.15-17

Surgical Procedures and Eye Movement Measurements Following special rearing, the animals were allowed to grow normally until they were approximately three

years of age. Sterile surgical procedures carried out under aseptic conditions using isoﬂurane anesthesia (1.25% to 2.5%) were used to stereotaxically implant a head-stabilization post. In the same surgery, a scleral search coil was also implanted in one eye using the technique of Judge et al.18 Later, in a second surgery, a second scleral search coil was implanted in the other eye. All procedures were performed in strict compliance with National Institutes of Health guidelines, and the protocols were reviewed and approved by the Institutional Animal Care and Use Committee at Emory University. Binocular eye position was measured using the magnetic search coil method (Primelec Industries, Regensdorf, Switzerland).19,20 Calibration of the eyecoil signal was achieved by giving the monkey a small amount of juice or some other reward when the animal looked within a small region (±2° window) surrounding a 0.25° target spot that was rear-projected on a tangent screen 60 cm from the animal. All stimuli were under computer control. Calibration of each eye was performed independently during monocular viewing.

Experimental Paradigms and Data Analysis Eye movement data were collected as the strabismic animals performed a visually guided saccade task in which the target appeared at random horizontal or vertical locations within a ±15° grid. Data were collected during both monocular and binocular viewing in separate experimental sessions. Binocular eye-position and target-position feedback signals were digitized at 1 kHz with 16-bit precision (PCI-6025E NI-DAQ board and LabVIEW software; National Instruments, Austin, Texas). The analysis of the saccade data was carried out using custom software built in MATLAB (MathWorks, Natick, MA). Velocity and acceleration signals were generated by digital differentiation of the position signal using a central difference algorithm. Position, velocity, and acceleration signals were ﬁltered using software FIR ﬁlters (80 points; 0 to 80 Hz passband), also designed in MATLAB. Saccade onset was automatically determined by the software as the ﬁrst time point at which eye acceleration was greater than 3 standard deviations from control-eye acceleration (eye acceleration during a period of ﬁxation prior to the saccade), and saccade offset was determined as the last time point at which eye deceleration was less than 3 standard deviations from the same mean eye acceleration. Though detection of saccade onset and offset was automated, the investigator visually examined the velocity and acceleration traces of every saccade and had the option of either accepting or changing the computer selection. Typically, less than 10% of the computer’s marks were changed by the investigator. For the binocular viewing data, the investigator also made the

ALTERNATING SACCADES IN PRIMATE MODEL OF STRABISMUS

49

determination of whether the saccade was of the alternating/nonalternating variety, and this information was recorded along with the saccade parameters. Following data collection and identiﬁcation of saccade onset and offset, the data were parsed into six bins, depending on viewing condition and saccade type: 1. saccades during monocular right-eye ﬁxation (OD); 2. saccades during monocular left-eye ﬁxation (OS); 3. binocular viewing nonalternating saccades with the right eye ﬁxating (OURR); 4. binocular viewing nonalternating saccades with the left eye ﬁxating (OULL); 5. binocular viewing alternating saccades where the eye of ﬁxation was switched from right eye to left eye (OURL); and 6. binocular viewing alternating saccades where the eye of ﬁxation is switched from left eye to right eye (OULR). Saccade metric parameters for each eye were calculated including amplitude, latency, peak velocity, and duration. Amplitude–peak velocity and amplitude–duration main-sequence relationships were plotted, and data were ﬁt according to well-established equations. An exponential curve was ﬁt to the amplitude–peak velocity data, and a linear regression was developed for the amplitude–duration data. Fitting was performed in MATLAB using routines available in the “curveﬁt” toolbox. For saccade latency data, we developed histograms of the inverse of saccade latency and ﬁtted a Gaussian curve to this data. We used the inverse of latency for ﬁtting the Gaussian, because it has been shown that this parameter better represents a Gaussian process than saccade latency directly.21-23 The mean and standard deviation of this Gaussian ﬁt was compared across the six saccade conditions using ANOVA.

RESULTS The two animals included in the study were both exotropic. During right-eye viewing of a straightahead target, S1 showed an exotropia of 10°, and S2 an exotropia of 11°. During left-eye viewing of the same target, S1 showed an exotropia of 15°, and S2 an exotropia of 14°. A-patterns were observed in both animals and were similar to those observed in other animals reared using the AMO paradigm.3 The main focus of the study was alternating ﬁxation behavior. Figure 6.1 shows some raw saccade traces during binocular viewing that illustrate the property of alternating saccades in these animals.

Figure 6.1 Panels (A) and (B) are examples of alternating saccades in exotropic animal S1 during a binocular viewing task. The eye of ﬁxation is switched from the left eye (gray line) to the right eye (black line) as a consequence of the saccade (A). Target position is shown by the black dotted line. The eye of ﬁxation is switched from right eye to left eye (B). (C) and (D) show examples of nonalternating saccades with either the right eye (C) or the left eye (D). OULR, binocular viewing alternating saccades with ﬁxation switch from left to right eye; OURL, binocular viewing alternating saccades with ﬁxation switch from right to left eye; OURR, binocular viewing nonalternating saccades with the right eye ﬁxating; OULL, binocular viewing nonalternating saccades with the left eye ﬁxating.

Spatial Pattern of Saccade Alternation Previous studies have shown that in humans with exotropia, the temporal retina of the nonﬁxating eye is suppressed. We found a corollary in the spatial pattern of alternation behavior within the saccade task that was used. Figure 6.2 plots a spatial view of saccade beginning and ending locations where we observed alternating or nonalternating behavior during the binocular viewing random-saccade task in animal S1. Figures 6.2A and 6.2B show nonalternating saccades with either the right eye or the left eye ﬁxating (OURR and OULL). Figures 6.2C and 6.2D show alternating saccades, where the eye of ﬁxation was switched from right to left (OURL) or from left to right (OULR). In both animals, we observed that targets in the right hemiﬁeld were ﬁxated by the right eye and targets in the left hemiﬁeld were ﬁxated by the left eye. Therefore, target jumps that began and ended either in the right or left hemiﬁeld tended to be nonalternating saccades. When the target jumped across the midline (i.e., from the right to the left as in Figure 6.2C, or from left to right as in Figure 6.2D), an alternating saccade was generated. Approximately 1000

50 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY

Figure 6.2 The spatial pattern of saccade alternation in exotropic animal S1. In each plot, only the position of the ﬁxating eye is shown. Right eye position is shown in black symbols, and left eye in gray. Asterisks (*) show eye position at a single representative time point after the saccade, and dots (·) show eye position at a single representative time point before the saccade. (A) shows that the animal tends to make nonalternating right eye saccades when making saccades that begin and end in the right ﬁeld. Similarly, nonalternating saccadic movements in the left ﬁeld are made with the left eye ﬁxing (B). Alternating saccades were plotted (C) where the animal was ﬁxating with the right eye (black dot) before the saccade and switched to ﬁxating with the left eye (gray asterisk) after the saccade. These saccades occur most often when the animal makes a movement that crosses the vertical meridian from the right to the left. Similarly, in (D), alternating saccades were plotted where the animal was initially ﬁxing with the left eye (gray dot) and after the saccade was ﬁxing with the right eye (black asterisk). These saccades occur most often when the animal makes a movement that crosses the vertical meridian from the left to the right.

binocular viewing saccades (OURR, OULL, OURL, and OULR) and 1000 monocular viewing saccades (OD and OS) were collected in each animal. Of the binocular viewing saccades, 37% in monkey S1 and 25% in monkey S2 were of the alternating variety.

Comparison of Saccade Main-Sequence Relationships The next step was to analyze the metrics of alternating saccades and compare them to nonalternating saccades

and monocular viewing saccades. Figure 6.3 shows the amplitude–peak velocity main sequences from animals S1 and S2 during right-eye viewing for the six different saccade types (also see color insert). The ﬁgure illustrates that there is considerable overlap in the data for the different saccade types. We ﬁt each set of data using an “exponential rise to maximum” curve. Figures 6.3A and 6.3B plot the estimated curves, along with the 95% prediction intervals. There is signiﬁcant overlap in the prediction intervals, which suggests that there was no difference between the saccade types.

ALTERNATING SACCADES IN PRIMATE MODEL OF STRABISMUS

51

Figure 6.3 Main sequence relationships in animals S1 and S2. (A) and (B) show the amplitude-peak velocity relationships for the different saccade types. Also plotted are the exponential curve ﬁts and 95% prediction intervals. There is considerable overlap in the prediction intervals among the different populations of saccades. The amplitude-duration data shown in (C) and (D) along with linear ﬁts and 95% prediction intervals also show considerable overlap among the different saccade types. Histograms (E, F) display inverse of saccade latency along with Gaussian ﬁts. These data show that there is a tendency for monocular viewing saccades to be of slightly shorter latency (right shift in plots) than binocular viewing saccades. OULR, binocular viewing alternating saccades with ﬁxation switch from left to right eye; OURL, binocular viewing alternating saccades with ﬁxation switch from right to left eye; OURR, binocular viewing nonalternating saccades with the right eye ﬁxating; OULL, binocular viewing nonalternating saccades with the left eye ﬁxating; OD, saccades during monocular right-eye ﬁxation; OS, saccades during monocular left-eye ﬁxation. (Also see color insert.)

52 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY We also examined the amplitude–duration relationship in the different types of saccades in two animals. Figures 6.3C and 6.3D show these relationships. A linear ﬁt was applied to the amplitude–duration data, and the regression line, along with 95% prediction intervals, is plotted. Once again there is signiﬁcant overlap in the data and the prediction intervals among the different saccade types, which suggests that the saccade data in the various categories all came from the same population. In summary, we did not observe any consistent differences in the saccade main-sequence relationship that suggested that alternating saccades were different from nonalternating saccades. Similarly, binocular viewing saccades did not show any consistent differences from monocular viewing saccades.

Comparison of Saccade Latency We continued our analysis of saccade metrics by comparing saccade latency across the different saccade types. In normal humans and animals, a histogram of saccade latency follows a skewed distribution, with a rapid rise followed by a long tail-off. Carpenter et al.,23 in their Linear Approach to Threshold with Ergodic Rate (LATER) model for decision making, showed that the reciprocal of the saccade latency is representative of a Gaussian process. Therefore, for each of the saccade types in this study, we developed histograms of the inverse of saccade latency and then ﬁt a Gaussian to the data. Figures 6.3E and 6.3F plot a histogram of the inverse of saccade latency for the different saccade types, along with the Gaussian ﬁts. In animal S2, we found that saccades during binocular viewing were of signiﬁcantly longer latency than saccades during either monocular viewing condition (difference in means, 8 to 15 milliseconds; one-way ANOVA; p > 0.05). In animal S1, we found that saccades during binocular viewing were of signiﬁcantly longer latency than saccades during monocular left-eye viewing (difference in means, 7 to 18 milliseconds; one-way ANOVA; p > 0.05) but not in monocular right-eye viewing. Latency of nonalternating saccades was not consistently different from that of alternating saccades.

Animal Model for Alternating Fixation Behavior We have shown that AMO animals with exotropia demonstrated alternating ﬁxation and alternating saccade behavior similar to that previously reported in humans11,12 and in monkeys with surgical exotropia.24 Thus the AMO strabismus model is appropriate for examining visual and ocular motor mechanisms that drive alternating saccade behavior. Even though we have not directly measured the degree of visual suppression at different parts of retina in the viewing and nonviewing eye, our results appear to suggest that the spatial pattern of saccade alternation is consistent with the pattern of visual suppression that is normally seen in exotropes.8-10 Therefore, alternating ﬁxation and alternating saccade behavior may be used as probes to study visual suppression mechanisms in strabismus24 and how they may relate to developing a command signal for generating a saccade that brings one or the other eye onto the target. Some studies have shown that visual suppression is not complete.1,25 This might lead to a situation where the brain encodes two internal target representations (one for each eye) and must make a choice to generate a saccade that would bring either the previously ﬁxating eye (nonalternating saccade) or the previously nonﬁxating eye (alternating saccade) onto the target. Therefore, studying these issues and understanding brainstem or cortical neural circuitry that might be involved in generating alternating saccades might also provide clues as to how selection between multiple target choices is carried out normally.

Metrics of Alternating Saccades Are Normal It was not surprising that the main-sequence relationships of alternating and nonalternating saccades (monocular or binocular viewing) are similar. Perhaps it was more surprising that a systematic evaluation of the different saccade metrics had not been attempted previously. The basic implication of our result is that alternating and nonalternating saccades are governed by the same brainstem pulse-generation circuit. Any potential differences between alternating and nonalternating saccades must be examined upstream from the brainstem pulse generator.

DISCUSSION

Saccade Latency Differences in Alternating Saccade Behavior

In this study, we sought to analyze alternating saccade behavior from the point of view of (a) establishing the AMO as a suitable animal model to study alternating ﬁxation behavior and (b) comparing metrics of alternating saccade behavior to nonalternating saccades and monocular-viewing saccades.

Our analysis suggested a tendency in monocular viewing saccades (OD and OS) to be of shorter latency than binocular viewing saccades (OURR, OULL, OULR, and OURL). This result may in fact be an indication that visual suppression is not complete. Previous studies that have examined target selection in normal animals

ALTERNATING SACCADES IN PRIMATE MODEL OF STRABISMUS

have consistently shown that saccadic latency is greater when multiple targets are presented to the subject as compared to a single target.26 In our experiments, during binocular viewing, the monkey may be presented with two retinal-error representations (one from each eye, which is equivalent to presenting two targets to a cyclopean eye). Even though the retinal-error representation from the partially suppressed eye is much weaker, the brain must still decide which eye to ﬁxate on the target and must generate an appropriately sized saccade. The superior colliculus is implicated in target selection.27 The superﬁcial layers of the superior colliculus may therefore be an appropriate structure to examine if, in fact, there are representations of visual error corresponding to each eye. There was, however, no clear tendency for latency differences between alternating and nonalternating saccades. In the LATER model for saccade latency developed by Carpenter et al.,23 latency is proportional to the time taken for a decision signal to rise to a threshold value and trigger a saccade. In this model, the linearly increasing decision signal varies from trial to trial in a Gaussian manner. Presumably, in our experiments, the rate of rise of the decision signal is governed by strengths of competing inputs from both eyes. Therefore, distribution of latency may be governed more by the relative probability of generating an alternating or nonalternating saccade at a particular orbital position than whether the saccade itself was of the alternating or nonalternating variety. Therefore, in our exotropic monkeys, binocular viewing saccades that ended either far to the left or far to the right would probably have similar latencies, irrespective of whether they were alternating or nonalternating. However, saccades that ended in the middle of the ocular motor range may have longer latencies, because the probability of generating an alternating or nonalternating saccade is relatively close. A systematic evaluation of saccade latency across the two-dimensional ocular motor range may help to test this hypothesis.

acknowledgments We thank Sunal Patel, Tushar Jha, and Michelle Swann for their help with data collection and analysis. This work was supported by NIH RO-1 EY015312 (VED) and Yerkes Base Grant RR00165.

References 1. von Noorden GK, Campos EC. Binocular Vision and Ocular Motility: Theory and Management of Strabismus. 6th ed. St. Louis, MO: Mosby; 2002.

53

2. Lorenz B. Genetics of isolated and syndromic strabismus: facts and perspectives. Strabismus, 2002;10:147–156. 3. Das VE, Fu LN, Mustari MJ, Tusa RJ. Incomitance in monkeys with strabismus. Strabismus. 2005;13(1):33–41. 4. Das VE, Mustari MJ. Correlation of cross-axis eye movements and motoneuron activity in nonhuman primates with A-pattern strabismus. Invest Ophthalmol Vis Sci. 2007;48(2):665–674. 5. Das VE, Ono S, Tusa RJ, Mustari MJ. Conjugate adaptation of saccadic gain in non-human primates with strabismus. J Neurophysiol. 2004;91(2): 1078–1084. 6. Fu LN, Tusa RJ, Mustari MJ, Das VE. Horizontal saccade disconjugacy in strabismic monkeys. Invest Ophthalmol Vis Sci. 2007;48:3107–3114. 7. Steinbach MJ. Alternating exotropia: temporal course of the switch in suppression. Invest Ophthalmol Vis Sci. 1981;20(1):129–133. 8. Horton JC, Hocking DR, Adams DL. Metabolic mapping of suppression scotomas in striate cortex of macaques with experimental strabismus. J Neurosci. 1999;19(16):7111–7129. 9. Joosse MV, Esme DL, Schimsheimer RJ, Verspeek SA, Vermeulen MH, van Minderhout EM. Visual evoked potentials during suppression in exotropic and esotropic strabismics: strabismic suppression objectiﬁed. Graefes Arch Clin Exp Ophthalmol. 2005;243(2):142–150. 10. Joosse MV, Simonsz HJ, van Minderhout EM, Mulder PG, de Jong PT. Quantitative visual ﬁelds under binocular viewing conditions in primary and consecutive divergent strabismus. Graefes Arch Clin Exp Ophthalmol. 1999;237(7):535–545. 11. Sireteanu R. Binocular vision in strabismic humans with alternating ﬁxation. Vision Res. 1982; 22(8):889–896. 12. van Leeuwen AF, Collewijn H, de Faber JT, van der Steen J. Saccadic binocular coordination in alternating exotropia. Vision Res. 2001;41 (25–26):3425–3435. 13. Patel SS, Jha RT, Swann MH, Das VE. Saccade alternation in non-human primates with strabismus. SFN Abstr. 2006;736.10.. 14. Tusa RJ, Mustari MJ, Das VE, Boothe RG. Animal models for visual deprivation-induced strabismus and nystagmus. Ann N Y Acad Sci. 2002;956: 346–360. 15. Harwerth RS, Smith EL 3rd, Crawford ML, von Noorden GK. Behavioral studies of the sensitive periods of development of visual functions in monkeys. Behav Brain Res, 1990;41(3): 179–198.

54 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY 16. O’Dell C, Boothe RG. The development of stereoacuity in infant rhesus monkeys. Vision Res. 1997;37(19):2675–2684. 17. Boothe RG, Dobson V, Teller DY. Postnatal development of vision in human and nonhuman primates. Annu Rev Neurosci, 1985;8:495–545. 18. Judge SJ, Richmond BJ, Chu FC. Implantation of magnetic search coils for measurement of eye position: an improved method. Vision Res. 1980;20:535–538. 19. Fuchs AF, Robinson DA. A method for measuring horizontal and vertical eye movement chronically in the monkey. J Appl Physiol. 1966;21(3): 1068–1070. 20. Hess BJ, Van Opstal AJ, Straumann D, Hepp K. Calibration of three-dimensional eye position using search coil signals in the rhesus monkey. Vision Res. 1992;32(9):1647–1654. 21. Carpenter RH. Contrast, probability, and saccadic latency: evidence for independence of detection and decision. Curr Biol. 2004;14(17): 1576–1580.

22. Reddi BA, Asrress KN, Carpenter RH. Accuracy, information, and response time in a saccadic decision task. J Neurophysiol. 2003;90(5): 3538–3546. 23. Carpenter RH, Williams ML. Neural computation of log likelihood in control of saccadic eye movements. Nature. 1995;377(6544):59–62. 24. Economides JR, Adams DL, Jocson CM, Horton JC. Ocular motor behavior in macaques with surgical exotropia. J Neurophysiol. 2007;98(6): 3411–3422. 25. Wensveen JM, Harwerth RS, Smith EL 3rd. Clinical suppression in monkeys reared with abnormal binocular visual experience. Vision Res. 2001;41(12):1593–1608. 26. McPeek RM, Keller EL. Short-term priming, concurrent processing, and saccade curvature during a target selection task in the monkey. Vision Res. 2001;41(6):785–800. 27. McPeek RM, Keller EL. Deﬁcits in saccade target selection after inactivation of superior colliculus. Nat Neurosci. 2004;7(7):757–763.

7 Effects of Cerebellar Lesions in Monkeys on Gaze Stability MARK F. WALKER, JING TIAN, XIAOYAN SHAN, RAFAEL J. TAMARGO, HOWARD YING, AND DAVID S. ZEE

ABSTRACT

eye velocity to keep the target’s image on the fovea. Finally, when the head is moving (rotating or translating), the vestibular system calculates head motion and generates an eye movement of the appropriate amplitude and in the opposite direction, in order to stabilize the retinal (foveal) image. Finally, the vergence system maintains alignment of the two eyes. The cerebellum plays a vital function in the control and calibration of all types of eye movements and thus is critical to optimizing gaze. In fact, impaired vision due to abnormal eye movements is a prominent symptom and cause of disability in humans with cerebellar diseases. A number of prior studies in humans and animals have investigated the effects of cerebellar lesions on eye movements and have helped to delineate the speciﬁc roles of particular cerebellar substructures. For example, lesions of the dorsal vermis1 or the associated portions of the fastigial nuclei2 cause inaccurate (dysmetric) saccades because these areas are important for the calibration of saccade amplitude. Lesions of the ﬂocculus and ventral paraﬂocculus, critical for the calibration of the rotational vestibulo-ocular reﬂex (RVOR), impair RVOR plasticity.3-8 Control of pursuit appears to be distributed among several areas of the cerebellum, including the ﬂocculus and paraﬂocculus,9 the vermis10 and fastigial nucleus,11 the uvula,12 and the lateral cerebellar hemispheres.13 The ability to hold the eyes steady at a given position in the orbit is a function of the ﬁxation and gaze-holding systems, which are impaired by lesions of the ﬂocculus and paraﬂocculus, resulting in downbeat and gaze-evoked nystagmus.14

Studies in humans and animals have shown that the cerebellum plays a vital role in calibrating eye movements to maintain gaze stability. In this chapter, we focus on the function of the cerebellar nodulus and uvula in stabilizing the foveal image when the object of regard is moving (smooth pursuit) and during linear motion of the head (the translational vestibulo-ocular reﬂex [TVOR]). Eye movements of two rhesus monkeys were recorded using the magnetic ﬁeld search-coil method, before and after surgical ablation of the nodulus and uvula. Key ﬁndings included the following: (a) there was an asymmetric deﬁcit of vertical smooth pursuit—downward, but not upward, pursuit was impaired; (b) the vertical TVOR was reduced for both upward and downward translation; and (c) the sustained, but not the initial, response to abrupt horizontal translations was impaired. Our results support a critical role for the nodulus and uvula in the control of vertical ocular following reﬂexes, and in the horizontal TVOR, possibly acting as an integrator of head acceleration. The goal of gaze control is to stabilize images on the retina, in particular the fovea, in order to maximize visual acuity. This is accomplished by the eye movement control systems. When the head and the object being viewed are still, the ﬁxation system holds the eyes steady in the orbit. When the object is moving, the pursuit system must determine the speed and direction of target motion and generate the appropriate 55

56 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY In our recent studies, we have focused on the role of the cerebellar nodulus and uvula in pursuit and the translational vestibulo-ocular reﬂex (TVOR). Prior studies have implicated the nodulus and uvula in several other functions. First, they control angular velocity storage, which enhances the response to sustained and low-frequency head rotation or rotational optokinetic stimulation.15 Second, they are responsible for orienting the axis of eye velocity to the gravito-inertial axis.16,17 Third, they control the torsional vestibuloocular reﬂex.18 Some humans and animals with lesions to this part of the cerebellum develop the characteristic eye movement disorder of periodic alternating nystagmus (PAN), which responds well to baclofen.19

METHODS We studied two rhesus monkeys (M1 and M2) before and after surgical aspiration of the cerebellar nodulus and uvula. Before the experiments described here, M1 had had a trochlear nerve section as part of a different study.20 All experimental procedures were approved by the Animal Care and Use Committee of the Johns Hopkins University. Eye movements were recorded using binocular scleral coils.

Pursuit Experiments Animals sat in a primate chair with the head ﬁxed. For pursuit experiments, the target consisted of a small red spot, generated by an LCD projector and backprojected onto a tangent screen that was 66 cm from the animal. There were two pursuit paradigms. For step-ramp pursuit, each trial began with ﬁxation of a stationary center target. At a random time, the target stepped up or down by approximately 4° and then began to move at a constant speed of 20 deg/s in the opposite direction. The target continued to move for approximately 1 second after the eye started to move. Sinusoidal pursuit was elicited by a continuously moving target (0.3 Hz, peak velocity ±37.5 deg/s, amplitude ±20°) in either the vertical or horizontal direction. The animal was rewarded for maintaining ﬁxation of the target. Raw coil signals were converted to rotation vectors and angular velocity vectors, as has been previously described.21 For step-ramp pursuit, we calculated pursuit gain as the ratio of median eye velocity to target velocity during steady-state pursuit (t > 200 milliseconds from the onset of pursuit). For sinusoidal pursuit, the gain was determined by a least-squares linear regression of instantaneous eye velocity to target velocity; this regression was performed separately for each direction of motion.

TVOR Experiments The horizontal TVOR was tested on a belt-driven linear sled. The monkey sat in the primate chair with head ﬁxed. Each trial began with ﬁxation of a laser target back-projected onto a screen that was placed either 70 cm or 27 cm from the monkey in a room that was otherwise dark. The chair moved abruptly along the interaural direction, accelerating at 400 cm/s2 (≈ 0.4 g) to a plateau speed of 40 cm/s. The total amplitude of the translation was 20 cm. Leftward and rightward trials were alternated. For each trial, the target either remained on during the motion or was extinguished when the chair started to move, with chair motion proceeding in complete darkness. The vertical TVOR was studied using a manually driven, spring-assisted chair that was constrained to move vertically along metal support rods. The frequency of chair motion was approximately 1.5 Hz. Chair acceleration was measured by a linear accelerometer and integrated to determine chair velocity.

Lesions Surgical lesions were performed by one of the authors (RT), using general inhalation anesthesia, standard aseptic neurosurgical technique, and postoperative analgesia. A suboccipital craniotomy was performed, the inferior vermis was visualized, and the nodulus and uvula were aspirated. The lesion site was veriﬁed by MRI and postmortem histology. M2 had the most complete lesion, with complete removal of the cortex of the Nod/Uv. In M1, some cortex was preserved, but the underlying white matter was disrupted, suggesting that the remaining cortex was functionally disconnected.

RESULTS Animals tolerated the surgery well. They recovered quickly and had no sustained movement deﬁcits. Neither of the animals had PAN, even in darkness.

Effect of Lesions on Pursuit The main effect of the lesion was to reduce the gain of downward pursuit, elicited by either sinusoidal or stepramp stimuli. In fact, downward pursuit was largely abolished in M2, the animal with the more complete lesion (Fig. 7.1). This was true for both step-ramp and sinusoidal stimuli. Upward pursuit was less affected. Figure 7.2 depicts average pursuit gains, before and after the lesions, for two monkeys. On average, the gain of downward pursuit decreased by 72% for

MONKEY CEREBELLAR LESIONS AND GAZE STABILITY 57

Effect of Lesions on the Interaural TVOR

Figure 7.1 Vertical step-ramp pursuit before (top) and after (bottom) Nod/Uv lesions in M2. Downward pursuit was essentially abolished after the lesion (bottom left); only saccades are seen. Upward pursuit was less affected (bottom right), although the initial acceleration was reduced, resulting in larger catch-up saccades (arrow). Signs reﬂect the right-hand rule (downward is positive).

step-ramp and 59% for sinusoidal pursuit. There was a modest decrease in the gain of upward step-ramp pursuit (21%) and little effect on upward sinusoidal pursuit (4% increase). Horizontal step-ramp pursuit gains decreased by 20% (data not shown).

We studied responses to brief steps of translation. The main effect of the lesions was to reduce the steady-state response to constant-velocity motion; there was little effect on the response during initial chair acceleration. To illustrate this, Figure 7.3 shows the response to interaural translation in M1. Note that the very early response (shaded area) was similar before and after the lesion, but that the eye velocity during the later portion of the response was much lower after the lesion. A similar effect was seen in M2. The Nod/Uv lesions did not eliminate the normal scaling of eye velocity by target distance. When the distance to the ﬁxation target was 27 cm (Fig. 7.3B) rather than 70 cm (Fig. 7.3A), the eye velocity was greater, particularly in the early (acceleration) portion of the response. This was true also for M2.

Effect of Lesions on the Vertical TVOR We also determined the effect of the lesions on the response to sinusoidal vertical translation (bob). For technical reasons, the data for the vertical TVOR are more limited. Most notably, we did not have a displayand-reward setup that would allow for precise control of eye position and vergence angle. Instead, we simply recorded spontaneous responses in the light and in darkness. The most reliable responses were obtained in the light. The viewing distance was the same for recordings before and after the cerebellar lesions (122 cm). As shown in Figures 7.4 and 7.5, after the Nod/Uv lesions the response to vertical translation was reduced.

Figure 7.2 Step-ramp pursuit gains (A). Gains were calculated as the ratio of the median eye velocity during steady-state pursuit (t > ≈200 milliseconds from the onset of the trial) to the target velocity (20 deg/s). Bars show the average of the values for the two animals. Sinusoidal pursuit gains (B): gains were calculated using a leastsquares linear regression of vertical eye velocity to target velocity.

58 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY

Figure 7.3 Horizontal eye velocity in response to steps of interaural translation. The left panel shows the response when the ﬁxation target was at 70 cm, and the right panel when the ﬁxation target was at 27 cm. In all trials, the target was extinguished when the chair started to move, so that actual translation occurred in complete darkness. The dashed line shows chair (head) velocity (cm/s), inverted for easier comparison to eye velocity. In both cases the initial eye acceleration is similar before and after the lesion, but the sustained response is less.

Unlike vertical pursuit, the magnitude of the effect was similar for upward and downward translation. There was no relative sparing of upward slow phases.

DISCUSSION Our study provides important new information regarding the function of the Nod/Uv in the control of eye movements and maintaining gaze stability during selfand object-motion. Speciﬁcally, we have shown that lesions to the Nod/Uv impair downward pursuit, and, to a lesser degree, horizontal pursuit, while largely sparing upward pursuit. We also found a reduced response to vertical translation and an impaired ability to maintain horizontal eye velocity during constantvelocity translation along the interaural axis.

Pursuit In our monkeys, lesions of the Nod/Uv caused a pattern of pursuit deﬁcits that closely resemble common ﬁndings in patients with cerebellar ataxia, in whom downward pursuit is much more profoundly impaired than upward pursuit.22,23 Our ﬁnding supports an important role for the Nod/Uv in this pattern of vertical pursuit. In fact, in one monkey downward pursuit was abolished. However, the degree to which asymmetrical vertical pursuit is speciﬁc to lesions of the Nod/Uv is uncertain. For example, a prior study found that ﬂocculectomy reduced, but did not abolish, vertical eye velocity during smooth tracking.24 Other factors, such as the visual environment, may also be important for vertical pursuit asymmetries. For example, Takeichi et al.25 reported asymmetric vertical pursuit in normal monkeys, but only in young monkeys, and only when

Figure 7.4 Sample eye movement responses to vertical translation (M1) before (left) and after (right) the Nod/ Uv lesion. Note that the chair velocity is greater for the post-lesion data, yet the eye velocity is less. Thus the sensitivity (ratio of eye velocity to head velocity) is reduced by the lesion.

MONKEY CEREBELLAR LESIONS AND GAZE STABILITY 59

Our study is also the ﬁrst to determine the role of the cerebellum in the vertical TVOR. We found that Nod/Uv lesions reduced both upward and downward slow phases during vertical translation in the light. Further study, under more precisely controlled viewing conditions, will be necessary to reﬁne these results. From our data, it is difﬁcult to compare the effects of the lesions on horizontal and vertical translation, as the head-motion stimuli were very different.

CONCLUSION Figure 7.5 Vertical translational vestibulo-ocular reﬂex (TVOR) response sensitivities before and after Nod/Uv lesions. As in Figure 7.2, the symbols show the individual values for each monkey, and the bars show the means. In both animals, the sensitivities for upward and downward translation were reduced after the lesions.

pursuit was performed against a textured background. Under those conditions, upward rather than downward pursuit was impaired. We did not test pursuit against a textured background. Finally, our ﬁndings differ from those of a prior study in which reversible chemical lesions of the cerebellar uvula led to an increase in the open-loop acceleration of horizontal pursuit26; the effect on vertical pursuit was not reported. Here we did not ﬁnd an increased acceleration for either horizontal or vertical pursuit in our monkeys. This difference in our results may relate to the extent of the lesions. In our monkeys, both the nodulus and the uvula were involved.

TVOR No prior studies have investigated the effects of discrete cerebellar lesions on the TVOR. It is known, however, that the cerebellum must play a central role in control of the TVOR, because humans with diffuse cerebellar disease often have dramatically reduced responses to interaural translation.27-29 On the other hand, the speciﬁc functions of individual cerebellar substructures are not known. Our results indicate that the Nod/Uv is most concerned with the maintenance of eye velocity during sustained linear motion; there was little effect of the lesions on initial eye acceleration. This suggests that the Nod/Uv may be part of an integrator of head acceleration signals provided by otolith inputs. Such a function would be analogous to the role of the nodulus in controlling velocity storage for the RVOR.

Our new ﬁndings—that the cerebellar nodulus and uvula have important functions in the generation of pursuit and of the TVOR—further emphasize the central role the cerebellum plays in the control of eye movements of all types. Our results also support several other general principles about the control of eye movements by the cerebellum: (a) reﬂexes subserving the needs of the fovea, such as pursuit and the TVOR, are particularly dependent on an intact cerebellum; (b) the ancient vestibulocerebellum, which includes the nodulus and uvula, has assumed new functions that meet the needs of the more recent ocular motor systems that rely on the fovea and on visual inputs from the cerebral cortex; and (c) there is remarkable overlap of function in the cerebellar cortex, with different areas participating in the control of the same types of eye movements, and single areas participating in the control of multiple eye movement types. This redundancy and compartmentalization of function allows for compensation in the face of lesions in the cerebellum (or the areas that project to speciﬁc parts of it) as well as for interactions between the different eye movement subtypes. acknowledgments This research was supported by National Institutes of Health grant EY001849 (DSZ), the Albert Pennick Fund, and the Arnold-Chiari Foundation. Dr. Walker was a Pollin scholar. Adrian G. Lasker and Dale C. Roberts provided technical assistance. The authors graciously acknowledge the support of Dr. Lloyd Minor, in whose laboratory experiments related to interaural translation were performed.

References 1. Takagi M, Zee DS, Tamargo RJ. Effects of lesions of the oculomotor vermis on eye movements in primate: saccades. J Neurophysiol. 1998;80:1911–1931. 2. Robinson FR, Straube A, Fuchs AF. Role of the caudal fastigial nucleus in saccade generation. II.

60 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY Effects of muscimol inactivation. J Neurophysiol. 1993;70:1741–1758. 3. Robinson DA. Adaptive gain control of vestibuloocular reﬂex by the cerebellum. J Neurophysiol. 1976;39:954–969. 4. Schultheis LW, Robinson DA. Directional plasticity of the vestibuloocular reﬂex in the cat. Ann N Y Acad Sci. 1981;374:504–512. 5. Lisberger SG, Miles FA, Zee DS. Signals used to compute errors in monkey vestibuloocular reﬂex: possible role of ﬂocculus. J Neurophysiol. 1984;52:1140–1153. 6. Rambold H, Churchland A, Selig Y, Jasmin L, Lisberger SG. Partial ablations of the ﬂocculus and ventral paraﬂocculus in monkeys cause linked deﬁcits in smooth pursuit eye movements and adaptive modiﬁcation of the VOR. J Neurophysiol. 2002;87:912–924. 7. Nagao S, Kitazawa H. Effects of reversible shutdown of the monkey ﬂocculus on the retention of adaptation of the horizontal vestibulo-ocular reﬂex. Neuroscience. 2003;118:563–570. 8. Blazquez PM, Hirata Y, Heiney SA, Green AM, Highstein SM. Cerebellar signatures of vestibulo-ocular reﬂex motor learning. J Neurosci. 2003;23:9742–9751. 9. Zee DS, Yamazaki A, Butler PH, Gucer G. Effects of ablation of ﬂocculus and paraﬂocculus of eye movements in primate. J Neurophysiol. 1981;46:878–899. 10. Takagi M, Zee DS, Tamargo RJ. Effects of lesions of the oculomotor cerebellar vermis on eye movements in primate: smooth pursuit. J Neurophysiol. 2000;83:2047–2062. 11. Robinson FR, Straube A, Fuchs AF. Participation of caudal fastigial nucleus in smooth pursuit eye movements. II. Effects of muscimol inactivation. J Neurophysiol. 1997;78:848–859. 12. Heinen SJ, Keller EL. The function of the cerebellar uvula in monkey during optokinetic and pursuit eye movements: single-unit responses and lesion effects. Exp Brain Res. 1996;110:1–14. 13. Straube A, Scheuerer W, Eggert T. Unilateral cerebellar lesions affect initiation of ipsilateral smooth pursuit eye movements in humans. Ann Neurol. 1997;42:891–898. 14. Zee DS, Yamazaki A, Butler PH, Gucer G. Effects of ablation of ﬂocculus and paraﬂocculus of eye movements in primate. J Neurophysiol. 1981;46:878–899. 15. Waespe W, Cohen B, Raphan T. Dynamic modiﬁcation of the vestibulo-ocular reﬂex by the nodulus and uvula. Science. 1985;228:199–202. 16. Angelaki DE, Hess BJ. Lesion of the nodulus and ventral uvula abolish steady-state

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off-vertical axis otolith response. J Neurophysiol. 1995;73:1716–1720. Wearne S, Raphan T, Cohen B. Control of spatial orientation of the angular vestibuloocular reﬂex by the nodulus and uvula. J Neurophysiol. 1998;79:2690–2715. Angelaki DE, Hess BJ. The cerebellar nodulus and ventral uvula control the torsional vestibulo-ocular reﬂex. J Neurophysiol. 1994;72: 1443–1447. Halmagyi GM, Rudge P, Gresty MA, Leigh RJ, Zee DS. Treatment of periodic alternating nystagmus. Ann Neurol. 1980;8:609–611. Shan X, Tian J, Ying H, et al. Acute superior oblique palsy in monkeys: I. Changes in static eye alignment. Invest Ophthalmol Vis Sci. 2007;48: 2602–2611. Tian J, Zee DS, Walker MF. Rotational and translational optokinetic nystagmus have different kinematics. Vision Res. 2007;47:1003–1010. Glasauer S, Hoshi M, Buttner U. Smooth pursuit in patients with downbeat nystagmus. Ann N Y Acad Sci. 2005;1039:532–535. Marti S, Straumann D, Glasauer S. The origin of downbeat nystagmus: an asymmetry in the distribution of on-directions of vertical gazevelocity Purkinje cells. Ann N Y Acad Sci. 2005;1039:548–553. Zee DS, Yamazaki A, Butler PH, Gucer G. Effects of ablation of ﬂocculus and paraﬂocculus of eye movements in primate. J Neurophysiol. 1981;46:878–899. Takeichi N, Fukushima J, Kurkin S, Yamanobe T, Shinmei Y, Fukushima K. Directional asymmetry in smooth ocular tracking in the presence of visual background in young and adult primates. Exp Brain Res. 2003;149:380–390. Heinen SJ, Keller EL. The function of the cerebellar uvula in monkey during optokinetic and pursuit eye movements: single-unit responses and lesion effects. Exp Brain Res. 1996;110:1–14. Baloh RW, Yue Q, Demer JL. The linear vestibuloocular reﬂex in normal subjects and patients with vestibular and cerebellar lesions. J Vestib Res. 1995;5:349–361. Crane BT, Tian JR, Demer JL. Initial vestibuloocular reﬂex during transient angular and linear acceleration in human cerebellar dysfunction. Exp Brain Res. 2000;130:486–496. Zee DS, Walker MF, Ramat S. The cerebellar contribution to eye movements based upon lesions: binocular three-axis control and the translational vestibulo-ocular reﬂex. Ann N Y Acad Sci. 2002;956:178–189.

8 Development of Visual Stabilization Devices with Applications for Acquired and Infantile Nystagmus JOHN S. STAHL, IGOR S. KOFMAN, AND ZACHARY C. THUMSER

ABSTRACT

the treatment of acquired pendular nystagmus, we also describe the application of this instrumentation to a patient with infantile nystagmus, illustrating how a computer-controlled stabilizer can serve as a research tool.

Pathological nystagmus degrades vision because it introduces excessive image motion on the retina. Past studies have demonstrated that vision can be improved using electronic devices that move visual targets in lockstep with the oscillating line of sight. Such optomechanical visual-stabilization devices have multiple applications. They could be used to improve vision in patients whose nystagmus is resistant to other therapies. They could also be used to predict the degree of beneﬁt a patient may expect to receive from a contemplated medical or surgical nystagmus-reducing therapy. A predictive tool is particularly important when the contemplated therapy involves signiﬁcant expenses, risks, or discomforts. Visual stabilization devices can also be applied as research tools to explore the relationships between retinal image velocity, nystagmus waveforms, and oscillopsia. Selective image stabilization systems consist of an eye movement tracking device, a ﬁltering system that extracts the pathological movement from the overall eye movement signal, and an optics or display mechanism (the “stabilizer plant”) that allows the seen world or displayed images to be oscillated synchronously with the extracted nystagmus signals. To date, optomechanical visual stabilization devices have been too complex to use outside the laboratory. In this chapter, we review our progress toward developing a self-contained optomechanical visual stabilization device suitable for use in the clinical setting. Although we focus on

Pathological nystagmus degrades vision by introducing excessive motion of images across the retina. Nystagmus may also cause the unpleasant impression that objects are in motion (oscillopsia), particularly in the acquired forms of the disorder. Optical or optomechanical devices that artiﬁcially stabilize images on the moving retina can ameliorate the deleterious effects of acquired nystagmus on vision.1,2 The perceptual effects of stabilization devices have also been explored in patients with infantile nystagmus (IN).3,4 In most of these studies, the image stabilization was accomplished by projecting visual targets onto a tangent screen via mirror galvanometers and feeding the patients’ eye position signals to the galvanometers. Such arrangements are delicate, and their use is restricted to the experimental laboratory setting. In this chapter we review our efforts to develop an image stabilization system that nulliﬁes the visual effects of nystagmus without interfering with normal eye movements, and that is both self-contained and sufﬁciently robust to be usable in clinical settings. There are several applications for an electromechanical retinal image stabilization device (eRISD). First, the device could potentially be used to treat nystagmus. While many drugs have been reported to be helpful in small series of patients, in practice many patients experience no beneﬁt or incomplete beneﬁt, 61

62 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY or develop intolerable side effects such as sedation or ataxia.5-7 For instance, in a controlled study of the drug gabapentin in acquired pendular nystagmus (APN), 10 out of 15 patients experienced some improvement in acuity or nystagmus velocities, but only 8 of those elected to continue taking the drug.5 Thus one use of a small and user-friendly eRISD would be as a visual aid for patients with intractable nystagmus. Second, an eRISD could be used to assess a patient’s potential to beneﬁt from nystagmus treatment. This application is particularly important in patients whose nystagmus is accompanied by abnormalities of the afferent visual system, as is commonly the case in patients who develop nystagmus due to multiple sclerosis or who have a symptomatic (i.e., nonidiopathic) form of IN. These afferent visual lesions may limit the degree to which vision can be improved by attenuating the nystagmus, and they may create an unfavorable risk-beneﬁt ratio for some nystagmus treatments. Recent reports state that patients with acquired nystagmus can beneﬁt from extraocular muscle surgery.8,9 The existence of an invasive therapy for nystagmus—with the attendant discomforts, costs, and risks—has increased the importance of having a way to predict whether a treatment will produce functionally meaningful beneﬁts. Finally, an eRISD can be used as a tool to study nystagmus, for

instance, to investigate the impact of altering retinal image motion on the nystagmus waveform. Figure 8.1 shows the basic schematic of an eRISD. It consists of some form of noninvasive eye tracker (e.g., one based on electro-oculography, video-oculography, or infrared reﬂectance technologies); a motionprocessing circuit that conditions, scales, or extracts the pathological feature(s) of the eye motion to be nulliﬁed; and image-shifting optics (the “stabilization plant”). An optical stabilization plant might be replaced by a computer screen attached to a computer that has been programmed to oscillate its video display. In this review, as in our work, we concentrate on the motion processor and stabilization plant, since eye trackers are already widely available. It should be recognized, however, that current commercial offerings do not possess the ideal characteristics for this application. For the purposes of use in a clinical eRISD, the ideal eye tracker would possess the following three features: (1) electronics that are entirely contained in a small box (i.e., would not require a personal computer); (2) self-starting and self-adjusting capacity upon activation, and (3) battery-power capability. A sampling rate of 60 Hz would be sufﬁcient to nullify most forms of IN or APN, since the dominant frequencies of these movements are usually well below 10 Hz.10,11 However, the

Image-Shifting Optics “Stabilization Plant”

Visual Target

E

Sensor

Plant Control Signals Mirror Galvanometer Eye Position

Eye Tracker

Motion Processor

Waveform Generator Galvanometer Control Signals

Figure 8.1 Components of an electronic retinal image stabilization device (eRISD). For the purposes of testing the eRISD with normal subjects, nystagmus was simulated by projecting the visual display via mirror galvanometers. A signal from a waveform generator oscillates the mirror galvanometers and is added to the subject’s eye movement signal at the input to the motion processor. The components added to simulate nystagmus are represented by dashed lines.

DEVELOPMENT OF VISUAL STABILIZATION DEVICES

propagation delay of slower oculography systems can be problematic. For instance, one commercially available 60 Hz video-oculography system introduces, on average, 33 milliseconds between the occurrence of an eye movement and the appearance of the signal at the system’s analog output. In a patient with a 4 Hz pendular nystagmus, this 33-millisecond delay would introduce a 48º lag between the eye movement and the corrective motion of the eRISD, substantially reducing the stabilization effect. In the case of a purely pendular nystagmus, a phase-shifting circuit/algorithm can be used to correct the phase relationship,12 but for forms of nystagmus with less predictable waveforms, a tracker with a propagation delay well below 10 milliseconds would be necessary. Since no commercial oculography system possesses all the ideal characteristics enumerated here, there is room for development of the tracker component of the eRISD, as well.

THE STABILIZATION PLANT Table 8.1 summarizes the advantages and disadvantages of a variety of stabilization plants. A computer that is programmed to oscillate its video display is a particularly simple and attractive solution, as it would obviate the need for expensive and delicate optomechanical components. Its disadvantage is that it could only be used to view computer screens. However, for a neurological patient whose activities are constrained by other neurological deﬁcits, the ability to see a computer screen may be enormously important. The signiﬁcance of the limitation has waned in recent years, as the uses of personal computers to enhance daily life have exploded. The concept of the oscillating computer screen could be extended somewhat by placing a miniature computer screen in a head-mounted arrangement along with a forward-directed video camera (a “virtual reality display”). With this arrangement, the patient’s view of the outside world could be

63

stabilized. The latter arrangement shares the advantages of the oscillating computer screen and adds the virtues of portability and the ability to stabilize vision during activities other than computer use. Two disadvantages of this arrangement are the patient’s indirect view of the world through a television camera and the necessity of inconvenient camera adjustments in order to obtain clear images of ﬁnely detailed objects (e.g., a printed page). A beam-steering mirror can be thought of as the next level of complexity. Beam-steering mirrors capable of deﬂecting the image in two dimensions can be purchased as commercial items. They can be constructed to generate large amplitudes of deﬂection, creating the ability to stabilize large-amplitude nystagmus waveforms. The beam-steering mirror would be mounted with a second mirror so as to produce a forward-viewing, periscope-like device. The chief disadvantage of this form of stabilization plant is that a steering device capable of moderate deﬂection amplitudes (≈ ±5°) and shrouded so as to prevent contact with the delicate ﬁrst-surface mirrors would likely be quite bulky. The ﬁnal entry in Table 8.1, “beamsteering lens,” has advantages over mirror arrangements in that it would afford the patient a straight-line (i.e., nonperiscopic) view of the visual world, and the optical housing would likely be more compact. The chief disadvantage of this approach is the greater mechanical complexity of the apparatus. Our own work has concentrated on this type of apparatus.

THE MOTION PROCESSOR The motion processor could be as simple as a circuit that scales the amplitude of the eye movement signal to render it appropriate as a driving signal for the stabilization plant. A major disadvantage of such a “direct drive” approach is that it would nullify normal reﬂexive and voluntary eye movements to the same extent

Table 8.1 Options for Stabilization Plant Mechanism

Advantages

Disadvantages

Oscillating video display

No moving parts to fabricate or maintain

Virtual reality headset

No moving parts, portable, components commercially available Commercial units available, potentially large amplitude range Allows direct viewing of world, potentially compact

Useful only for computer or television viewing World viewed through a video display, image quality may vary World viewed through periscope, bulky

Beam-steering mirror Beam-steering lens

Greatest complexity

64 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY acceleration and disable image stabilization until the saccade had terminated. VOR might be preserved by monitoring head velocity and subtracting it from the eye-velocity signal being fed to the stabilization plant. An alternative to this “rejection ﬁlter” strategy is an “acceptance ﬁlter” motion processor that identiﬁes the nystagmus waveform and passes only that signal to the stabilization plant. Acceptance ﬁlters are a particularly good choice when the nystagmus waveform is highly deterministic (as is the case in APN), as they avoid the difﬁculty inherent in the rejection ﬁlter’s having to recognize each type of desired eye movement. Since our work has focused on developing a visual aid for APN, we have focused on the acceptance ﬁlter strategy.

Horizontal eye position (˚)

14 12 10 8 6 4 2 0 0.0

0.5

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1.5

2.0

Figure 8.2 Fixation instability engendered when a normal subject views through an electronic retinal image stabilization device (eRISD) set to completely nullify eye movements. A voluntary rightward saccade initiates repeated horizontal eye movements.

that it nulliﬁed the nystagmus. For this reason, the passive optical image stabilization device consisting of a negative-power contact lens and a positive-power spectacle (which replicates a direct-drive eRISD) caused oscillopsia in patients during head movements, due to its nullifying effect on the vestibulo-ocular reﬂex (VOR).13 A less familiar consequence of direct drive is that it produces an open-loop condition during smooth pursuit and voluntary saccades. Figure 8.2 illustrates this point, showing the horizontal eye position in a normal subject using an image stabilization device adjusted for a nulliﬁcation gain of 1.0 (device nulliﬁed 100% of any eye movement). At the beginning of the record, the subject attempted a small rightward saccade to ﬁxate a target approximately 1° to the right of the initial ﬁxation point. The device displaced the target further to the right, initiating a staircase of rightward saccades as the subject made a futile attempt to “catch” the target. An attempt to pursue a moving target would have generated an exponentially increasing smooth pursuit velocity, driving the image stabilizer to its deﬂection limit. An important advantage of an eRISD over a passive optical stabilizing device2,13,14 is that the device can be designed to nullify the nystagmus without interfering with normal eye movements. There are two basic strategies by which selective nulliﬁcation can be achieved. In the ﬁrst strategy, the motion processor is designed to recognize normal eye movements and block them from reaching the stabilization plant. For instance, the processor could recognize saccades by their high

FIRST-GENERATION DEVICE Our ﬁrst eRISD was designed as a table-mounted, analog electronic device.12 Horizontal and vertical eye movements were sensed using a battery-powered infrared reﬂectance system. The stabilization plant consisted of a Risley prism driven by a stepper motor. Acceptance ﬁlter motion processing was accomplished using a phase-locked loop (PLL) circuit. The output of the PLL’s voltage-controlled oscillator was a ﬁxed-amplitude sine wave, the phase and frequency of which would match the sinusoidal pendular nystagmus. This output was fed to the Risley prism motor control circuit after passing through additional circuitry that allowed the experimenter to adjust the amplitude of the motion of the stabilization plant, as well as to optimize the phase relationship between the nystagmus and the stabilization plant. The circuit also incorporated aspects of a rejection-type ﬁlter, in that the effects of large saccades on the PLL were ameliorated by a sample-and-hold circuit that, when triggered by a high eye acceleration, maintained the presaccadic velocity signal until the saccade terminated. Although the device was capable of nullifying both vertical and horizontal oscillations simultaneously, in practice we restricted our stabilization to the axis with the larger oscillation amplitude. We tested the effects of this eRISD on monocular acuity in 5 patients with APN due to multiple sclerosis. In each patient we selected one eye and axis of correction (vertical or horizontal), seeking to study the eye in which acuity was least affected by optic nerve damage (due to previous episodes of optic neuritis) and in which the oscillations were most pronounced, most sinusoidal, and closest to pure vertical or horizontal. We assessed acuity using Landolt C optotypes, either presented on cards or displayed as a timed slideshow on a laptop computer. For each optotype size, we scored the number of correct responses, constructed a curve

DEVELOPMENT OF VISUAL STABILIZATION DEVICES

of fraction correct versus optotype size, and ﬁt the curve with a sigmoid. We deﬁned acuity as the optotype size at which the ﬁtted curve fell midway between perfect and chance performance. Four of ﬁve patients experienced an improvement in acuity of at least 0.05 LogMAR. The average increase in LogMAR acuity of the 5 patients was 0.17. This initial work supported the feasibility of an eRISD that could nullify nystagmus selectively and could potentially operate outside the setting of the experimental ocular motor physiology laboratory. The ﬁrst-generation device had a number of important deﬁciencies. Chief among these deﬁciencies was the fact that the PLL ﬁlter was unable to adjust automatically for moment-to-moment ﬂuctuations in nystagmus amplitude. The PLL also required several cycles of nystagmus to achieve lock, reducing the percentage of time that the device was actually improving retinal-image stability. The ﬁdelity of the stabilization plant was also fairly poor (owing in part to mechanical backlash in the prism gearing), resulting in prominent ripples in the retinal-image motion that were appreciated by users as a high-frequency jitter of the optotypes.

SECOND-GENERATION DEVICE Our second eRISD was designed as a head-mounted device with computerized motion processing.15,16 Horizontal and vertical eye movements were sensed using a video-oculography system. The stabilization plant consisted of a three-lens assembly in which the center, biconcave lens was oscillated perpendicularly to the optical axis by electromagnets. This type of image-stabilizing optics is used by Canon Inc. (Tokyo, Japan) for their line of image-stabilizing lenses, and we actually obtained the biconcave lens, lens support, electromagnets, and targets for optical feedback sensors by disassembling one of these commercial lenses. We incorporated these elements, together with our own ﬁxed lenses, optical feedback components, and the ultra-miniature television camera of the videooculography system, into an adjustable head mount. Digital motion-control software was created in RealTime Simulink (MathWorks, Natick, MA) running on a desktop computer. The heart of the motion-processing software was an adaptive interference cancellation ﬁlter.17 This ﬁlter generated sine waves, the amplitude and phase of which matched that of the horizontal and vertical components of the nystagmus waveform. This algorithm is the equivalent of an analog notch ﬁlter, with the center frequency and selectivity determined, respectively, by the frequency of a pair of internal sine wave generators and a constant, µ, which governs the rate at which the ﬁlter adapts. A separate program

65

block, containing a Fourier transform, was used to match the frequency for the internal sine wave generators to that of the nystagmus. Because the ability of an eRISD to improve acuity in patients was already well established, and because our larger goals (which included evaluation of other strategies to improve vision, not discussed here) required multiple lengthy recording sessions, we chose to test this new eRISD using normal subjects in whom the visual effects of nystagmus were simulated by oscillating the visual display. Using normal subjects at this stage also circumvented one of the confounds of working with actual patients with multiple sclerosis: acuity may be signiﬁcantly limited by causes other than nystagmus. In our ﬁrst set of experiments (conducted before the new stabilization plant had been constructed), we also simulated the effects of an image stabilization plant with perfect ﬁdelity, by driving the display oscillation by the difference between the nystagmus waveform (either a recorded patient waveform or the output of a function generator) and the output of the motion processor.15 In a later set of experiments (conducted after the new stabilization plant became available), the display was driven directly by the function generator, and the motion-processing optics were fed the sum of the function generator’s signal and the subject’s own eye movement signals,16 as depicted in Figure 8.1. In this way we were able to test the response of the ﬁlter to a realistic eye movement signal containing both normal eye movements and a pendular component. Acuity was determined in a fashion similar to our tests of the ﬁrst-generation system.12 Eight-position Landolt C optotypes embedded in distraction optotypes were displayed on a computer screen in timed fashion, the percentage of correct responses was recorded, sigmoid curves were ﬁt to the plots of percentage correct versus optotype size, and acuity was deﬁned as the midpoint between perfect and chance performance. In our experiment with the actual (not simulated) stabilization plant,16 acuity was determined with the optotypes and stabilizer stationary (baseline condition), with the optotypes in motion and the device disabled (untreated condition), and with the optotypes in motion and the eRISD operating (treated condition). No subject was able to identify any of the largest optotypes in the untreated condition, while in the treated condition acuity was restored, on average, to approximately one line of the baseline value on a Bailey-Lovie LogMAR acuity chart. The second-generation system represented an important step forward, as it demonstrated the feasibility of a head-mounted stabilization plant and selective nulliﬁcation of the nystagmus using computer-based motion processing. Fidelity, size, and power consumption were tremendously improved over the original

66 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY

B

A

LVDT lens holder

RMS deflection error (˚)

0.5 0.4 0.3 0.2 0.1 0

voice coil

4 6 8 2 Oscillation frequency (Hz)

10

Figure 8.3 Third-generation stabilization plant. (A) Photograph of the portion of the device that moves the biconcave lens. Lens holder (lens removed) is balanced between pairs of commercial voice coils and LVDTtype position sensors. (B) Plot of root mean square (RMS) radial error of the two-dimensional image deﬂection during circular motion. Deﬂection trajectories are shown for 3, 6, and 9 Hz oscillation frequencies. LVDT, linear variable displacement transducers. Risley prism device. The introduction of computerized motion processing, running in Simulink, created the potential to explore more sophisticated tracking algorithms that would have been difﬁcult to implement in analog electronics. Nevertheless, the secondgeneration system had some important shortcomings that would need to be resolved before the system could be useful to patients or clinicians. The control electronics consisted of three desktop computers (one for video oculography and two others to act, respectively, as the host and target for the Simulink-based motion processor) and assorted breadboarded electronics, and experiments usually required the ofﬁces of two engineers. The amplitude range of the stabilization plant was also limited to approximately ±1° of image deﬂection, too small to fully compensate nystagmus in 20% to 50% of APN patients.16 Finally, the ﬁeld of view of the device was quite limited, and it did not permit spectacle-wearing subjects to be tested with their optical correction.

THIRD-GENERATION DEVICE: A WORK IN PROGRESS The main goals for the latest-generation system include developing a stabilization plant capable of nullifying nystagmus up to ±5° amplitude; replacing the desktop computers with dedicated, self-starting microcontrollers integrated in a single, portable package; creating simpliﬁed controls suitable for use by a clinician or

patient; and creating head-mounted optics that can be donned and doffed without the need for repeated optical alignments. Creating a stabilization plant that retained the ﬁdelity of our modiﬁed Canon image-stabilizing device while quintupling its amplitude range has proven to be particularly challenging. A key feature of the Canon design was a pair of “ﬂoating” voice coil electromagnets, each of which could drive the lens in one axis while allowing its actuator to be carried (under the inﬂuence of the second electromagnet) in the orthogonal direction. Since the coils used in our second-generation device were too weak to support a larger lens or lens excursion, and since no ﬂoating voice coils were commercially available, it was necessary to design and fabricate custom units. The oscillation ﬁdelity of the design, however, proved disappointing; owing to the large distances between the centers of the two voice coils and the other bearing points, tiny shifts in the angle of the lens plane caused large excursions of components at the device periphery, causing unpredictable variations in friction and ultimately distorting the lens motion. Additionally, the variations in lens plane caused ﬂuctuations in the optical feedback signals, due to changes in the distance between the optical emitter/sensor mounted on the frame and the optical target mounted on the lens carrier. A major factor in our decision to use ﬂoating voice coils had been their compactness. As it became clear that a device capable of 5° oscillation would be large enough to necessitate some form of auxiliary support (in

DEVELOPMENT OF VISUAL STABILIZATION DEVICES

addition to the patient’s head), the goal of compactness became a lesser concern, behind oscillation amplitude, ﬁdelity, and ﬁeld of view. We designed a radically different device (Fig. 8.3A) that dispensed with the ﬂoating voice coils in favor of commercially available, single-axis voice coils. The fact that each motor would move along a single axis also allowed us to replace the temperamental optical position sensors with precise linear variable displacement transducers (LVDTs). In the new design, the lens is held between the actuators of the voice coils and LVDTs. Each voice coil and its yoked LVDT are staggered to resist torsion motions of the lens. The number of bearing points was minimized, and friction at those points was minimized by using jewels and precision linear bearings. Figure 8.3B shows a plot of root mean square (RMS) error of the image deﬂection versus oscillation frequency for the prototype device during circular oscillation at 75% of full excursion. Distortion was held to below 10% of full deﬂection range for oscillation frequencies up to 10 Hz, comparable to our second-generation device over most of the frequency range.

APPLICATION OF SELECTIVE IMAGE STABILIZATION IN IN In patients with IN, retinal image stabilization produces oscillopsia.3,4 Previous studies were conducted with “direct-drive” type motion processing. The question of how a patient with IN would respond to selective nulliﬁcation of their nystagmus was germane to the theme of this volume. Although the interference cancellation ﬁlter was originally selected to accommodate the sinusoidal waveform of APN, it seemed likely that the ﬁlter could also lock to a quasi-sinusoidal IN waveform. We investigated these questions in a single patient with IN of the pseudo-pendular with foveating saccades (PPfs) waveform. Eye movements were recorded with an EyeLink II (SR Research, Osgoode, Ontario, Canada) videooculography system. Motion processing was accomplished using the interference cancellation ﬁlter running on desktop computers. As our newest stabilization plant had not been completed at the time of these experiments, we accomplished stabilization by oscillating the projected optotype patterns via mirror galvanometers. The overall delay between an actual eye movement and motion of the optotypes on the screen measured 6 milliseconds. We used the same eightposition Landolt C optotype patterns and method of deﬁning acuity described previously.15 At the beginning of the experiment, we adjusted the nulliﬁcation gain by a forced-choice procedure, seeking the highest gain level at which the optotypes were perceived

67

as clear without our engendering oscillopsia. Following the gain determination, we tested acuity with the stabilization on and then off. All procedures were performed with monocular viewing and with the head free. During recording, the subject’s head position was periodically adjusted to maintain a roughly constant average eye-in-head position, sufﬁciently removed from the patient’s “null” position to evoke a clear pendular nystagmus. To determine foveation durations, we ﬁrst removed any gradual variations of average eye position (mostly related to the gradual variations in average head position) by subtracting a polynomial that was ﬁt to the foveation positions of no fewer than 10 cycles of nystagmus. Eye positions were then converted to retinal image position by subtracting the image deﬂection imparted by the mirror galvanometers. (Prior to this subtraction, the galvanometer deﬂection signal was shifted 6 milliseconds in the lagging direction to account for the total system delay.) Finally, foveation times were calculated as the percentage of time that image position was within ±0.5° and velocity was within ±4 deg/s.18 The patient selected a nulliﬁcation gain of 0.3. At this gain, clarity of the optotypes was subjectively improved, and any higher level caused oscillopsia and reduced clarity. He also preferred a relatively high value of the adaptation constant (µ = 0.1, 500 ﬁlter adaptations/s), producing a relatively nonselective gain-versus-frequency function. At a lower value of the adaptation constant (µ = 0.025), nulliﬁcation gain could not be raised above approximately 0.2. The ﬁlter was able to maintain lock to the subject’s nystagmus, as demonstrated in Figure 8.4A. Note how the galvanometer motion was nonsinusoidal, due to the low degree of the ﬁlter’s frequency selectivity. Measured acuity was unchanged by the stabilization, as demonstrated by the essentially identical extinction curves in Figure 8.4B. The lack of any effect on acuity may be explained by a consideration of the effects on foveation duration in plots of eye velocity versus position (not shown). Although image stabilization shrunk the envelope of the “phase plane” trajectories, the time spent in the foveation region was essentially unchanged (1.8% for the original waveform versus 2.6% after subtracting the effect of visual stabilization, as determined from a representative data record spanning several seconds). There are multiple potential explanations for the patient’s failure to tolerate higher nulliﬁcation gains, which might otherwise have resulted in a larger percentage of time in the foveation region. Previous studies demonstrating oscillopsia during image stabilization in IN patients speculated that the usual perception of stability in these patients reﬂects a match between actual image velocity and an internal eye

68 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY

B

A

24 20

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Number correct

Eye

0.5˚

16 12 8

Residual

4 0 0.2 0.5 s

0.4

0.6

0.8 1.0 1.2 Decimal acuity

1.4

Figure 8.4 Response of the adaptive interference cancellation ﬁlter and its effect on acuity in a patient with infantile nystagmus. (A) Horizontal eye position, ﬁlter-driven galvanometer deﬂection, and the difference (residual retinal image motion) plotted versus time. Arrows indicate the beginning of three foveation periods. Image motion at these points is greater during image stabilization than in the original nystagmus waveform. (B) Acuity “extinction” curves with and without image stabilization. Dashed line indicates the criterion level midway between perfect and chance performance. Image stabilization had no effect on measured acuity, despite the patient’s impression that test optotypes were rendered clearer.

movement signal (“efference copy”), and that oscillopsia may emerge when the artiﬁcial reduction of image velocity disrupts the match.3,4 Notably, our patient’s limiting nulliﬁcation gain of 0.3 is essentially identical to the average limit reported in one of these referenced studies3 for their “global motion” condition, the condition most closely approximating the visual characteristics of our oscillating optotype test patterns. Close inspection of the eye position and residual position in Figure 8.4A suggests an additional explanation for visual degradation above a nulliﬁcation gain of 0.3. The residual image motion was actually greater than the original eye motion at the beginning of the foveation periods (arrows), probably because the ﬁlter is destabilized by the foveating saccades. Higher nulliﬁcation would amplify the residual error and actually degrade stability early in the foveation period. Similarly, lower adaptation constants, while rendering the ﬁlter more frequency-selective, would make it less able to follow any departures of the nystagmus from sinusoidal behavior and more disruptive of the foveation period, which may explain why the patient preferred fast adaptation constants. This pilot experiment agrees with a previous report that entirely nonselective electronic visual stabilization fails to improve acuity in patients with IN.4 Our results do not exclude the possibility that other IN patients might behave differently, or that a ﬁltering algorithm that does not destabilize the patient’s own foveation period might be more effective. The experiment does

demonstrate that the adaptive interference cancellation algorithm we used to selectively nullify APN is also able to lock to an IN waveform. Thus, even if it is ineffective for the purposes of improving acuity, the algorithm could ﬁnd uses in the laboratory setting as a method of synchronizing visual stimuli to speciﬁc points in the cycle of a patient’s IN waveform.

acknowledgments This study was supported by a Merit Review award from the Department of Veterans Affairs. We thank Louis F. Dell’Osso and Jonathan B. Jacobs for providing expertise and raw material, without which the IN experiment would not have been possible.

References 1. Leigh RJ, Rushton DN, Thurston SE, Hertle RW, Yaniglos SS. Effects of retinal image stabilization in acquired nystagmus due to neurologic disease. Neurology. 1988;38(1):122–127. 2. Rushton D, Cox N. A new optical treatment for oscillopsia. J Neurol Neurosurg Psychiatry. 1987;50:411–415. 3. Abadi RV, Whittle JP, Worfolk R. Oscillopsia and tolerance to retinal image movement in congenital nystagmus. Invest Ophthalmol Vis Sci. 1999;40:339–345. 4. Leigh RJ, Dell’Osso LF, Yaniglos SS, Thurston SE. Oscillopsia, retinal image stabilization and

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5.

6.

7. 8.

9.

10.

congenital nystagmus. Invest Ophthalmol Vis Sci. 1988;29:279–282. Averbuch-Heller L, Tusa RJ, Fuhry L, et al. A double-blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus. Ann Neurol. 1997;41:818–825. Leigh RJ, Averbuch-Heller L, Tomsak RL, Remler BF, Yaniglos SS, Dell’Osso LF. Treatment of abnormal eye movements that impair vision: strategies based on current concepts of physiology and pharmacology. Ann Neurol. 1994;36:129–141. Stahl J, Averbuch-Heller L, Leigh R. Acquired nystagmus. Arch Ophthalmol. 2000;118:544–549. Wang ZI, Dell’Osso LF, Tomsak RL, Jacobs JB. Combining recessions (nystagmus and strabismus) with tenotomy improved visual function and decreased oscillopsia and diplopia in acquired downbeat nystagmus and in horizontal infantile nystagmus syndrome. J AAPOS. 2007;11: 135–141. Dell’Osso LF, Tomsak RL, Rucker JC, Leigh RJ, Bienfang DC, Jacobs JB. Dual-mode (surgical + drug) treatment of acquired pendular nystagmus and oscillopsia in MS. Invest Ophthalmol Vis Sci. 2005;46:E-abstract 2403. Gresty MA, Ell JJ, Findley LJ. Acquired pendular nystagmus: its characteristics, localising value and pathophysiology. J Neurol Neurosurg Psychiatry. 1982;45:431–439.

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11. Abadi RV, Bjerre A. Motor and sensory characteristics of infantile nystagmus. Br J Ophthalmol. 2002;86:1152–1160. 12. Stahl JS, Lehmkuhle M, Wu K, Burke B, Saghaﬁ D, Pesh-Imam S. Prospects for treating acquired pendular nystagmus with servo-controlled optics. Invest Ophthalmol Vis Sci. 2000;41:1084–1090. 13. Yaniglos SS, Leigh RJ. Reﬁnement of an optical device that stabilizes vision in patients with nystagmus. Optom Vis Sci. 1992;69:447–450. 14. Leigh RJ, Rushton DN, Thurston SE, Hertle RW. Optical treatment of oscillopsia due to acquired nystagmus. Neurology. 1986;36(suppl):252. 15. Smith RM, Oommen BS, Stahl JS. Application of adaptive ﬁlters to visual testing and treatment in acquired pendular nystagmus. J Rehabil Res Dev. 2004;41:313–324. 16. Smith RM, Oommen BS, Stahl JS. Image-shifting optics for a nystagmus treatment device. J Rehabil Res Dev. 2004;41:325–336. 17. Widrow B, Stearns SD. Adaptive Signal Processing. Upper Saddle River, NJ: Prentice-Hall; 1985:474. 18. Dell’Osso LF, Jacobs JB. An expanded nystagmus acuity function: intra- and intersubject prediction of best-corrected visual acuity. Doc Ophthalmol. 2002;104:249–276.

9 Pupil Abnormalities of the Near Response in Children with Visual Display Terminal Syndrome AKIO TABUCHI, ATSUSHI FUJIWARA, AND MAHMOODI KHADIJA

ABSTRACT

experience sustained and prolonged proximity to visual displays with electromagnetic ﬁelds (such as computer screens, televisions, and cellular phone screens). Use of computers in the workplace has increased greatly, and has been accompanied by the development of a number of health concerns. Thus, many individuals who work with VDT, television, television games, personal computers (PCs), mobile video games, and mobile phones have complained of ocular discomfort and eye muscle strain and stress. Several studies reported that the majority of VDT workers experience some eye or visual symptoms,1-3 including eyestrain; headaches; blurred vision; dry, red, or irritated eyes; and double vision. Although there are several reports concerning the effects of prolonged VDT use by adults on eyes and vision, there are few such reports about children. Currently, millions of children use VDT in school4,5 and at home for education and recreation. Thus it might be expected that children would have many of the same symptoms related to VDT use as adults do. However, it seems that most children never make such complaints and, possibly because of their great adaptability, children may ignore problems that would be reported by adults. Children also may have different needs in order to comfortably use a VDT, and we postulate that, with a small amount of effort, it should be possible to reinforce appropriate viewing habits and ensure comfortable and enjoyable VDT use. In healthy eyes, the pupils naturally change size as focus shifts from far to near objects, such as during VDT use. In this study, we investigated the pupil responses during VDT use in children.

The term visual display terminal (VDT) syndrome has been used to describe the complex of eye and vision problems, along with systemic symptoms, reported by individuals with prolonged exposures to electromagnetic displays such as computer monitors, television screens, or even cellular phone graphic displays. Currently, millions of children use VDTs in school and at home for education and recreation. Children may experience many of the same symptoms related to VDT use as adults. In healthy eyes, the pupils naturally change size as focus shifts from far to near objects during VDT use. We measured convergence, accommodation, and pupillary size using a TriIRIS C9000 (Hamamatsu Photonics, Hamamatsu, Japan) in a group of 129 children ranging in age from 12 to 15 years, all of whom used some form of VDT. Pupillary responses were abnormal in 21.7% of subjects. Abnormal pupillary responses associated with prolonged usage of VDTs in children may be due to autonomic disorder induced by sustained near work. Although recent advancements in information technology (IT) have contributed substantially to the quality of leisure time, a range of mental and physical problems have been attributed to sustained use of a range of visual displays, to which the terms IT syndrome1 and visual display terminal (VDT) syndrome2,3 have been applied. This disorder comprises a complex of eye and vision problems and systemic symptoms in individuals who 70

PUPIL ABNORMALITIES OF THE NEAR RESPONSE 71

Figure 9.1 TriIRIS C9000. When the subject looks at the inside target moving from far (50 cm) to near, visual target display 1 shows pupil size and pupil movement, and display 2 shows waveforms of target, vergence, and pupillary change. Target position 3 is indicated by a sideboard ruler.

METHODS This study was carried out on two groups of subjects: normal adults, who served as controls, and children. In the study of children, 378 students at Sho Kurashiki Municipal Junior High School agreed to complete a questionnaire about their use of VDT items in daily life. Eye examinations and near-response tests were performed on 213 students. Testing was conducted by certiﬁed orthoptists and an ophthalmologist. We measured accommodation, convergence, and miosis responses to near stimuli using the TriIRIS C9000 (Hamamatsu Photonics, Japan) (Fig. 9.1). Reliable measurements were dependent on the ability of subjects to concentrate on the visual target. Subjects were required to place their face on chin and forehead rests on the apparatus and were encouraged to look binocularly at three colored targets inside the device at a distance of 50 cm. We adjusted the detection level of the pupil, which was signaled in a white square, and then reset to the center position of display. The tracking function of the white square to the pupil was turned on. Before pushing the start button, we needed to determine the subjective near point, which differs between subjects. Accordingly, we asked the subject to indicate this by pushing a button when the inner accommodative target, which moved progressively closer, ﬁrst became blurred. We selected a speed of 0.3 diopters per second (D/s). As the target moved forward and backward, pupil size and target position were continuously monitored horizontally by a pair of infrared charge-coupled

device (CCD) cameras. The images of the pupils were recorded for about 200 seconds, depending on the subject; the ﬁeld of view was illuminated by a white-lightemitting diode (LED). We asked subjects to hold focus as the target approached; this was done three times. Movements of the center of the pupil of both eyes were measured and converted into vergence eye movement (convergence and divergence), and pupil diameter simultaneously measured at 30 Hz. Stimuli moved 7.5 to 50 cm (corresponding to accommodative stimulation of 13 to 2 D) in children, and 9 to 50 cm (11 to 2 D) in adults. Measurement using TriIRIS C9000 was performed under complete refractive correction. When the display was viewed binocularly, the pupil responses were measured simultaneously in each eye.

Measurements and Data Analysis Normal Adults We studied 36 adults (age 21.6 ± 1.0 years, 8 male), all of whom gave informed consent. All had normal near visual acuity, accommodation, and orthophoria. Although some subjects had a refractive error, none complained of asthenopia. Figure 9.2 shows normal and abnormal waveforms of convergence–divergence and miosis–mydriasis (also see color insert). Three items were analyzed (Fig. 9.3; also see color insert): (1) a pupil-constriction ratio (PCR), expressed as a percentage according to the formula PCR = ([initial pupil size − maximum constricted pupil size] / initial pupil size) × 100; (2) amount of convergence (AOC) in millimeters, AOC = center of the pupil at farthest target − center of the pupil at the nearest target; and (3) a pupil-asthenia ratio (PAR), expressed as a percentage, PAR = ([initial pupil size − ﬁnal pupil size] / initial pupil size) × 100. The dominant eye, decided by a holein-card test, was selected for analysis. In each trial, PCR and PAR were subjected to analysis of variance. In addition, we determined the change in PCR, AOC, and PAR with change of the amount of near accommodative stimulation in 5 normal adults (age 22.2 ± 1.2 years). The far target was positioned at 50 cm (2 D), and the near target was set at four different positions: 14 cm (7 D), 11 cm (9 D), 9 cm (11 D), and 8 cm (12.5 D). We also measured responses during the viewing of near stimuli at 5 D, 7 D, 9 D, and 10.5 D in the same subjects.

Children Questionnaire The participants for this study were 378 students (both girls and boys) from three grades in middle school (grade 1, 132; grade 2, 116; grade 3, 130 students) with ages ranging from 12 to 15 years.

72 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY

Figure 9.2 Waveforms in near response by TriIRIS 9000. Target (top) is shown moving from far to near three times. Vergence (center) and pupil (bottom) simultaneously show convergence/divergence and constriction (miosis)/dilation (mydriasis), respectively. The black line shows the right eye, and gray line the left eye. (Also see color insert.)

All students and their parents agreed to ﬁll out a questionnaire that requested age, gender, and ﬁve VDT items (PC, television, television games, mobile games, and phones), which provided indices of the nature and duration of VDT usage. We analyzed answers of all subjects concerning the ﬁve VDT items and divided them into three levels of frequency: low, middle, and

high (Table 9.1). We also measured near visual acuity at 33 cm; performed autorefractometry; examined ductions, versions, and vergence eye movements; had subjects perform the alternate prism cover test, near point of convergence test, and stereo acuity (Titmus stereo) test; and conducted general ocular examinations.

RESULTS Adults

Figure 9.3 Methods of analysis. Pupil constriction ratio (PCR) of the three responses (1) are measured according to the formula PCR = [(Initial pupil size − Maximum constricted pupil size) / Initial pupil size] × 100. Amount of convergence (AOC) of the three responses (2) are measured according to the formula AOC = Center of the pupil at farthest target – Center of the pupil at the nearest target. Pupil asthenia ratio (PAR) (3) is measured according to the formula PAR = [(Initial pupil size − ﬁnal pupil size) / Initial pupil size] × 100 (Also see color insert.)

PCR for the ﬁrst trial was 47.4 ± 10.6%. For the second trial it was 49.0 ± 8.2%, and for the third trial, 51.0 ± 8.1%. There was no signiﬁcant difference between the trials. AOC for the ﬁrst trial was 2.4 ± 0.7 mm; it was 2.4 ± 0.4 mm in the second and 2.4 ± 0.4 mm in the third. There was no signiﬁcant difference between the trials. The ﬁnal pupil size of the third trial was reduced by 9.0 ± 6.4% from the initial pupil size of the ﬁrst trial. The change in each item, with change in the amount of near stimulation, PCR for near stimuli of 5 D, 7 D, 9 D, and 10.5 D, is shown in Figure 9.4. There was a gradually increasing value with increase of near stimulation: 28.2 ± 1.0% at 5 D, 43.2 ± 2.6% at 7 D, 51.5 ± 0.7% at 9 D, and, at the highest near stimulation of 10.5 D, 50.9 ± 1.1%. AOC at near stimulation of 5 D, 7 D, 9 D, and 10.5 D is summarized in Figure 9.5. This shows gradually increasing values with increase of near stimulation: 1.3 ± 0.1 mm at 5 D, 2.0 ± 0.1 mm at 7 D, 2.9 ± 0.2 mm at 9 D, and 2.8 ± 0.2 mm at 10.5 D. PAR at near stimulation of 5 D, 7 D, 9 D, and 10.5 D is summarized in Figure 9.6. At 5 D the pupil size returned

PUPIL ABNORMALITIES OF THE NEAR RESPONSE 73

Table 9.1 Point of Usage of VDT Items Point

PC and TVG (days/wk)

PC and TVG (hr/day)

TV (hr/day)

MG and Phone (days/wk)

MG and phone (hr/day)

0 1 2 3

not used ≤ 3 days ≥ 3 days

not used ≤1h ≥ 1 to 2 h ≥2 h

not used ≤2h ≥ 2 to 4 h ≥4h

not used ≤ 3 days ≥ 3 days

not used ≤ 0.5 h 0.5 to 1 h ≥1h

MG, mobile game; Phone, cellular telephone; PC, personal computer; TVG, terminal velocity game.

almost to the initial size, and PAR was 2.4 ± 6.1%. PAR increased gradually with increasing near stimulation: 7.5% ± 6.8% at 7 D, 10.9% ± 6.2% at 9 D, and 15.7% ± 5.5% at 10.5 D.

Pupil-Asthenia Ratio (PAR)

The total usage of VDT items by students in all three grades is shown in Figure 9.7. Among 378 students, the PC was listed by the highest percentage of students in all three grades. There was no difference between male and female students concerning usage of any particular type of VDT. All students used some type of VDT item, and at least one item each day. Usage of VDT (Fig. 9.8) was categorized into three levels: low (1 to 5 instances), middle (6 to 12), and high (13 to 23). Of the 378 subjects, 100 students (26.5%) were at the low level, 229 (60.5%) at the middle level, and 49 students (13%) at the high level of frequency.

Out of 213 students in whom eye examinations were performed, 84 students (42 with strabismus, 36 with anisocoria, and 6 who could not be recorded) were excluded from the PAR analysis. Based on the remaining group of 129 students, PAR was 12.4% ± 13.2% (mean ± standard deviation). We deﬁned normal pupillary responses when PAR measurements were within the range of 0.8% to 25.6%, and abnormal responses when PAR measurement lay outside that range. Among 129 students, 101 (78.3%) had normal pupillary responses and 28 students (21.7%) had abnormal responses (Fig. 9.9). We attempted to relate pupillary near response and frequency of use of any kind of VDT item in the 129 students studied. The percentage of students with normal and abnormal pupillary near responses was similar for each of the levels of usage. For students with normal pupillary response, there were 78.8% in the lowlevel category of usage, 78.2% at the middle level, and 82.4% at the high level. For students with abnormal

Figure 9.4 Pupil constriction ratio (PCR) of four different near stimulations. PCR is a gradually increasing value with increase of near stimulation: at 5 D, 7 D, 9 D, and the highest near stimulation of 10.5 D.

Figure 9.5 Amount of convergence (AOC) of four different near stimulations. AOC shows gradually increasing values with increase of near stimulation: at 5 D, 7 D, 9 D, and the highest near stimulation of 10.5 D.

Children Usage of VDT Items and Frequency

74 MODELS AND TECHNIQUES FOR STUDYING GAZE STABILITY

Figure 9.6 Pupil asthenia ratio (PAR) of four different near stimulations. PAR increases gradually with increasing near stimulation.

Figure 9.8 Frequency of usage of any kind of visual display terminal (VDT) items. Proportion of low frequency is 26.5%, middle frequency 60.5%, and high frequency 13%. Low level = 1 to 5 points; middle level = 6 to 12 points; high level = 13 to 23 points (see Table 9.1).

pupillary responses: low level, 21.2%; middle level, 21.8%; and high level, 17.6%.

We have demonstrated that children who frequently use VDT items show pupil abnormalities as part of the near response. Prior studies have only reported the VDT syndrome in adults.4,5 In the study presently under discussion, we selected junior high school

students. There were three main ﬁndings: (1) there was no difference in VDT usage between males and females from all three grades represented in the sample; (2) the pupillary component of the near response in 129 students, measured by the TriIRIS C9000 system, was abnormal in 21.7%; and (3) there was no relationship between the frequency of use of VDT items and abnormalities of the pupillary near response. Together, these ﬁndings suggest potentially important effects of VDT devices on near responses in children. The high prevalence (over one in ﬁve)

Figure 9.7 Usage of visual display terminal (VDT) items in total students. There was no difference between males and females in all three grades concerning usage of any particular type of VDT. G1, G2, G3, grade 1, 2, 3 of junior high school students; MG, mobile game; PC, personal computer; phone, cellular telephone; TVG, terminal velocity game.

Figure 9.9 Proportion of pupil asthenia ratio (PAR). Among 129 students, 101 students (78.3%) had normal pupillary responses and 28 students (21.7%) had abnormal responses.

DISCUSSION

PUPIL ABNORMALITIES OF THE NEAR RESPONSE 75

of pupillary responses to near stimuli in junior high school children should be considered seriously, since it could be interpreted as an abnormal behavior of the autonomic nervous system. When a target that is illuminated constantly approaches the eyes, parasympathetic innervation constricts the pupil (miosis). When the target recedes from the eyes, sympathetic innervation dilates the pupil (mydriasis). Continuous use of VDT items could pose excessive demands on components of the near response. In our study, we used the TriIRIS C9000 device, which was convenient for children and allowed simultaneous measurement of the near response components: convergence, divergence, and accommodation. Prior studies have used different instruments. Within a small range of ages, our data appear to be reliable, and we believe that our study is unique and points to the need for further research into the relationship between ocular responses and VDT items.

CONCLUSION Prolonged and sustained use of VDT in children may lead to abnormalities of the pupillary near response. Abnormal pupillary responses to near stimulation may reﬂect changes in the autonomic nervous system and deserve further study.

acknowledgments We gratefully acknowledge our subjects and their great interest in this study, and we wish to thank the junior high school health teacher, Ms. Hayashi, and Hamamatsu Photonics Company for its help with the equipment, and also orthoptists and students of Kawasaki University of Medical Welfare were gratefully appreaciated. This study was supported by Mishima Sai-chi Foundation for the International Research Student of Ophthalmology (Mahmoodi Khadija).

References 1. Hiraoka M. [IT eye strain]. Gannka. 2005:47(1); 63–70. 2. Sheedy JE. Vision problems at video display terminals: a survey of optometrists. Am Optom Assoc. 1992;63(10):687–92. 3. Bergqvist UO, Knave BG. Eye discomfort and work with visual display terminals. Scand J Work Environ Health. 1994;20(1):27–33. 4. Yamamoto M, Nakabashi K. [Inﬂuence of video game in children from view point of visual function]. In: Ishikawa S, ed. [VDT Medicine Manual]. Tokyo: Kanehara; 1989:99–100. 5. Sano H. [Inﬂuence of video games in children from viewpoint of school health care]. In Ishikawa S, ed. [VDT Medicine Manual]. Tokyo: Kanehara; 1989:101–102.

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III NEW THERAPIES FOR CONGENITAL NYSTAGMUS

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10 Genetics and Pharmacological Treatment of Nystagmus: A Review of the Literature and Recent Findings IRENE GOTTLOB

ABSTRACT

found, in a study speciﬁcally directed at people with nystagmus using capture–recapture statistics, that it is more common (approximately 24 per 10,000 population) (The Leicestershire Nystagmus Survey, unpublished data, 2007). Nystagmus has a signiﬁcant impact on vision—visual function questionnaire scores are worse in people with nystagmus than with age-related macular degeneration—and a signiﬁcant impact on social functioning.3 Congenital nystagmus can be idiopathic (ICN) or associated with albinism and retinal diseases, such as congenital stationary night blindness, achromatopsia, or blue cone monochromatism (secondary nystagmus [SN]). There is some evidence that in these diseases nystagmus is not caused by low vision but is intrinsic to the disease. For example, carriers of blue cone monochromatism with normal visual acuity have eye movement abnormalities.4 In albinism, neurodevelopmental abnormalities are indicated by misrouting of the nerve ﬁbers in the optic chiasm, with more ﬁbers crossing than in normal individuals. The congenital form of nystagmus can occur in association with visual deprivation in early infancy, for example, due to congenital cataract or optic nerve hypoplasia. This review will focus on two areas where new knowledge has recently emerged: genetics of idiopathic nystagmus and pharmacological treatment.

New developments in genetics and pharmacological treatment of nystagmus are reviewed in this chapter. While cases of nystagmus are frequently sporadic, kindreds in which nystagmus segregated as an autosomal dominant, autosomal recessive, or X-linked trait have been reported. Of these, X-linked pedigrees are the most frequent. By linkage analysis, the major X-linked locus for nystagmus, NYS1, was localized to chromosome Xq26-q27. Linkage analysis and DNA-sequence analysis performed in 26 families with idiopathic congenital nystagmus (ICN) led to the detection of a novel gene named FERM domain containing 7, FRMD7, at Xq26.2 in which we have identiﬁed 22 different mutations. Mutations in the FRMD7 gene encode a previously unidentiﬁed member of the protein 4.1 superfamily. Several drugs have been used to treat acquired nystagmus; however, pharmacological treatment has so far not been used in congenital nystagmus. A randomized study showed that memantine (up to 40 mg) and gabapentin (up to 2400 mg) can signiﬁcantly improve visual acuity in ICN and reduce nystagmus in ICN and in nystagmus associated to ocular disease. Nystagmus consists of periodic to-and-fro movement of the eyes, which can be pendular or jerk type with a slow and fast component. It can be congenital or acquired due to neurological disease.1 The prevalence was estimated at 1 in 10002; however, we have recently

GENETICS OF IDIOPATHIC NYSTAGMUS ICN is frequently sporadic, but kindreds in which nystagmus segregates as an autosomal dominant, autosomal 79

80 NEW THERAPIES FOR CONGENITAL NYSTAGMUS recessive, or X-linked trait have been reported.5 Of these, X-linked pedigrees are most frequently recognized, although penetrance may reach as high as 50% in obligate female carriers.6 By linkage analysis, gene NYS1 has been localized to chromosome Xq26-q27 in three families, ascertained in the United States.6,7 Recently, in a study of extended kindred from China, data were presented showing overlap with NYS1 and potential reﬁnement of the candidate interval.8 Recently, Guo et al.9 also performed linkage analysis in two Chinese families and found that they matched to the NYS1 locus, but they could not reduce the possible genetic interval. Cabot et al.10 reported a large French family with ICN in which linkage to chromosome Xp11.4p11.3 was demonstrated. However, this region contains several genes implicated in forms of congenital nystagmus associated with retinal diseases. These include congenital stationary night blindness, retinitis pigmentosa, cone dystrophy, and X-linked optic atrophy, thereby raising the possibility that congenital nystagmus in this kindred is allelic with one of these disorders. We recently identiﬁed a novel gene associated with X-linked idiopathic nystagmus.11 We have collected DNA from 26 affected families in which there were multiple affected members, as well as from a cohort of singleton affected subjects (n = 42) with idiopathic congenital nystagmus. Families were of English, Irish, Scottish, German, Italian, Indian, Romanian, Madagascan, and Austrian origin. Only families with no ophthalmic or neurological abnormalities other than nystagmus were included. We performed detailed clinical, electrophysiological studies and eye movement recordings in order to exclude other associated causes of nystagmus, such as retinal diseases or albinism. Electroretinograms and visual evoked potentials (International Society for Clinical Electrophysiology of Vision standards) were obtained from at least one member of each family, and all were normal. All affected subjects had horizontal conjugate nystagmus with predominantly jerk waveforms with increasing slow-phase velocities, typically for idiopathic congenital nystagmus. We found signiﬁcant variation within and between families in nystagmus amplitude and visual acuity. About 50% of female carriers were affected with nystagmus. For two out of 15 gene carriers analyzed with eye movements, subclinical nystagmus was detected only on eye movement recordings. In the 16 largest families, linkage analysis conﬁrmed linkage to Xq26. Microsatellite analysis reduced the linkage interval to 80 genes in Xq26 (Fig. 10.1). Systematic screening of more than 40 genes within this interval revealed mutations in a novel gene named FRMD7 (FERM domain containing 7, known as LOC90167) at Xq26.2. We have identiﬁed 22 mutations in FRMD7 in 26 families with X-linked idiopathic nystagmus, which suggests that mutations in FRMD7 are a common

cause of familial nystagmus. Screening of 42 singletons cases of idiopathic congenital nystagmus (28 males and 14 females) yielded 3 mutations (7%). (see Fig. 10.2)

EXPRESSION OF FRMD7 Studies of the expression of FRMD7 in human tissue using reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the mRNA is present in most tissues at a low level. RT-PCR detected expression in human adult kidney, liver, pancreas, heart, and brain. We have also shown, using in situ hybridization probes from the 3’UTR FRMD7, that it is expressed in early human embryos at ≈ 56 days post-ovulation, where there is expression in the ventricular layer of the forebrain, midbrain, cerebellar primordium, spinal cord, and developing neural retina. Mutations in FRMD7 encode a previously unidentiﬁed member of the protein 4.1 superfamily. The function of the FRMD7 protein is unknown, but blast search analysis revealed that it has close amino acid sequence homology to FARP1 (FERM, RhoGEF, and pleckstrin domain protein 1; chondrocyte-derived ezrin-like protein) and FARP2 proteins.12,13 The homology is concentrated at the N terminus of the protein, where B41 and FERM domains are present. The location relative to these domains is shown in Figure 10.2. The length and the degree of branching in neurons and organization of cytoskeleton of the embryonic rat cortex is modulated by the homologous protein FARP2.12,13 Similarly, it is possible that changes in neurite length and branching caused by mutations in FRMD7 during development, for example, in the midbrain, cerebellum, and retina, lead to nystagmus. Taken together, these data implicate FRMD7 as the major X-linked idiopathic nystagmus locus. Knowledge about the gene function will shed light on the mechanism of nystagmus and possibly other eye movement disorders.

PHARMACOLOGICAL TREATMENT OF NYSTAGMUS Treatment of nystagmus remains largely empirical. One symptomatic approach is to weaken the extraocular muscles by botulinum toxin injections,14-16 but the effect is transient and carries signiﬁcant side effects. Optical methods to stabilize images on the retina17 have not proved practical. Prisms or surgery of extraocular muscles can be used to dampen nystagmus.18-20 Studies using pharmacological inactivation have clariﬁed the neurotransmitters involved in neuronal integration of ocular motion. Microinjection of drugs into the region of the nucleus prepositus hypoglossi– medial vestibular nucleus showed that agents with either

GENETICS AND PHARMACOLOGICAL TREATMENT OF NYSTAGMUS

81

A I II III IV V VI

N1

C

130.1 Mb DXS8072

130.8

B DXS1047 DXS8072 DXS8071 DXS6748 DXS1114 DXS8041 DXS8033 DXS134.1 DXS134.2 DXS134.6 DXS134.9 DXS691 GDB:204469 DXS8094 DXS1041 DXS8050 DXS998

V2 199 222 199 211 114 155 258 243 157 207 216 155 246 235 169 197 114

VI2 199 222 199 211 114 115 258 243 157 207 216 155 235 157 199 114

IV9 203 222 199 211 144 115 258 243 157 207 216 155 246 235 169 197 114

MST

130.9

LOC90167 131

RAP2C 131.1 DXS8071 131.2

MBNL3 131.3

Figure 10.1 (A) Pedigree N1 (critical individuals marked with an arrow) whose haplotype deﬁne the minimum critical linkage interval. (B) Genomic location of LOC90167, FRMD7 on the X chromosome. Source: Tarpey P, Thomas S, Sarvananthan N, et al. Mutation FRMD7, a newly identiﬁed member of the FERM family, causes X-linked idiopathic congenital nystagmus. Nat Genet. 2006;38(11):1242–1244. Reprinted with permission. agonist or antagonist action of GABA, glutamate, and kainate receptors all caused gaze-evoked nystagmus.21-24 Several reports note nystagmus improvements in response to pharmacological substances. For example, GABAb agonist baclofen was reported to abolish periodic alternating nystagmus due to clinical or experimental lesions,25,26 as well as downbeat nystagmus.27 In one patient with multiple sclerosis, smoking cannabis reduced nystagmus.28 Anticholinergic drugs, sodium or potassium channel blockers, alcohol, clonazepam, and other anticonvulsants have been administered for nystagmus.29 Potassium channel blocker 3,4-aminopyridine has been effective in downbeat nystagmus.30 The reports of GABAergic projection into the neural integrator21-24 prompted a double-blind study of two

GABAergic agents, baclofen and gabapentin.31 Gabapentin, but not baclofen, reduced nystagmus substantially in 10 out of 15 patients with pendular acquired nystagmus. In a single-masked study comparing gabapentin to vigabatrin, gabapentin was more effective.32 Since vigabatrin is a pure GABAergic drug but gabapentin is not selectively GABAergic, the authors postulated that the effect of gabapentin is related to non-GABAergic mechanisms of action, such as interference with glutamate transmission. This hypothesis is further supported by a report about memantine, which also has antiglutaminergic action, on acquired pendular nystagmus. Memantine caused complete cessation of nystagmus in 11 out of 11 patients with acquired pendular nystagmus.33

82 NEW THERAPIES FOR CONGENITAL NYSTAGMUS 1 14 dell

G24R/E

IVS25GA

IVS32TG

L142R 160fs

N221D L231V 260

A266P C271Y

FERM_C

A226T

180

IVS71GC Q201X

V84V

B41

IVS41GA

G296fs Y301C

R335X S340L

IVS111GC 421fs

714

Figure 10.2 Schematic diagram of FRMD7 showing the location and mutations identiﬁed to date. Source: Tarpey P, Thomas S, Sarvananthan N, et al. Mutation in FRMD7, a newly identiﬁed member of the FERM family, causes X-linked idiopathic congential nystagmus. Nat Genet. 2006;38(11):1242–1244. Reprinted with permission.

These results make memantine a strong candidate for pharmacological treatment of acquired nystagmus. Memantine preferentially blocks excessive glutaminergic activity, and its actions involve effects on NMDA, AMPA, and dopaminergic pathways.34 Gabapentin likely acts by binding to the α-2 δ subunit of voltagedependent calcium channels.35 The mechanisms by which these drugs suppress nystagmus are currently unclear. The recent discovery of FRMD7, a novel gene mutated in X-linked ICN, may lead to the elucidation of nystagmus mechanisms and the beneﬁcial effects of these drugs.11

Congenital nystagmus is usually not treated pharmacologically. Since there have been no reports of drugs being effective in congenital nystagmus, we ﬁrst investigated the effect of gabapentin in congenital nystagmus in case studies. Gabapentin reduced the nystagmus in a patient with congenital corneal dystrophy, increasing his visual acuity by two lines.36 In a retrospective case series including 16 patients with neurological nystagmus and 7 with congenital nystagmus, we found that all 7 congenital patients improved in visual function and had reduced nystagmus amplitude with gabapentin. 37 These results encouraged us to perform a randomized, placebo-controlled study in congenital nystagmus using gabapentin and memantine.38 We included 48 patients (47 completed the ﬁrst four examinations) with ICN and patients with SN associated to ocular disease, mainly albinism, who were randomized in six groups: (1) ICN receiving up to 40 mg memantine (n = 6); (2) SN receiving up to 40 mg memantine (n = 10); (3) ICN receiving up to 2400 mg gabapentin (n = 8); (4) SN receiving up to 2400 mg gabapentin (n = 8); (5) ICN receiving placebo (n = 6); and (6) SN receiving placebo (n = 9). We found LogMAR visual acuity (VA) improved signiﬁcantly with memantine and gabapentin but not with placebo for the ICN group. Figure 10.3 illustrates that LogMAR VA in ICN improved up to the last visit where drugs were administered and, after drug cessation, had not returned to baseline after 2 weeks. However, at the last examination, 2 months after cessation of drug intake, ICN had returned. Figure 10.4 shows the absolute (A) and relative (C) improvement of VA before and after memantine, gabapentin, and placebo administration. Quantitative analysis of nystagmus showed signiﬁcant improvements in eXpanded Nystagmus Acuity Function (NAFX) (predicted VA estimated from foveation) and nystagmus intensity for both drugs for patients with ICN and SN (Figs. 10.4B,10.4D, 10.4E, 10.4F). Drug tolerability was good. There were no serious adverse events and no major side effects. In the memantine group, 9 out of 16 patients had side effects (6 reduced the dosage). In the gabapentin group, 9 out of 16 patients had side effects (2 reduced the dosage). In the placebo group, 5 out of 15 subjects had side effects (none reduced the number of capsules). Side effects were similar in all groups and included dizziness, tiredness, sleeplessness, light-headedness, nausea, headaches, shakiness, weakness, and drowsiness. On reduced dosage, participants tolerated drugs well. Twenty-six patients opted to continue drug treatment, and a long-term effect for up to 18 months was documented. Several patients were able to start driving on treatment, and 2 patients started to work. Our ﬁndings show for the ﬁrst time that pharmacological agents

GENETICS AND PHARMACOLOGICAL TREATMENT OF NYSTAGMUS

A

CIN

83

B

SN

0.8

medication

0.8

no medication

no medication

0.6 LogMAR VA

0.6 LogMAR VA

medication

0.4

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such as memantine and gabapentin can improve VA, reduce nystagmus intensity, and improve foveation in congenital nystagmus.

CONCLUSIONS Mutations in the newly detected FRMD7 gene are a major cause of X-linked ICN. The ﬁrst insights into the potential function of FRMD7, and thus to the understanding of the mechanisms of nystagmus, are emerging. On the one hand, there is a homology between FRMD7 and FARP2, which modulates the

Figure 10.3 LogMar visual acuity (mean and standard deviation) for participants treated with memantine (A), gabapentin (B), and placebo (C) before drug administration (exam 1); two weeks (exam 2), ﬁve weeks (exam 3), and eight weeks (exam 4) after drug administration; and two weeks (exam 5) and two to three months (exam 6) after the drug was stopped. CIN, congenital idiopathic nystagmus; SN, secondary nystagmus. Source: McLean RJ, Proudlock FA, Thomas S, Degg C, Gottlob I. Congenital nystagmus: randomized, controlled, double-masked trial of memantine/gabapentin. Ann Neurol. 2007;61:130–138. Reprinted with permission.

length and degree of branching of neurites in rat embryonic neurons. On the other hand, expression of FRMD7 has been shown in brain areas likely to be responsible for eye movements and the retina. Our ﬁnding that neurotransmitters can reduce congenital nystagmus supports a new treatment approach. We hope that advances in genetics and pharmacological treatment will lead to better understanding and, ultimately, new possibilities of treatment for nystagmus. acknowledgments The authors wish to acknowledge The Ulverscroft Foundation, Medisearch, and the Nystagmus Network, UK, for supporting this study.

84 NEW THERAPIES FOR CONGENITAL NYSTAGMUS Change in Visual Acuity NAFX (Predicted change in VA using eye movements)

Measured change in VA

A

Gabapentin

Placebo

B

Memantine 0.3

0.2

0.2

Change in VA (LogMAR)

Change in VA (LogMAR)

Memantine 0.3

0.1 0.0

0.1

Gabapentin

Placebo

0.1 0.0

0.1

C

D % change in VA

40 30 20 10 0 10 20 30

% change in VA

40 30 20 10 0 10 20 30 CIN

SN

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CIN

SN

CIN

SN

CIN

SN

CIN

SN

CIN SN

Change in Nystagmus Intensity At null region

E

Gabapentin

Placebo

60

F

Memantine % change in intensity

% change in intensity

Memantine

Across all positions

40 20 0

20

Gabapentin

Placebo

60 40 20 0

20

40

40

CIN

SN

CIN

SN

CIN

SN

CIN

SN

CIN

SN

CIN

SN

Figure 10.4 Absolute change (mean and standard deviations) in (A) measured LogMAR VA, (B) predicted change in LogMAR from eye movement recordings (using NAFX), (C) change in measured LogMAR VA (%), and (D) change in predicted LogMAR VA from eye movement recordings (%). The change measured was before and after 56 days of treatment with memantine or gabapentin for patients with CIN and SN. The lower ﬁgures show mean % change of nystagmus intensity (E) in the null region and (F) across all points measured from −24° to 24° over the same time period. CIN, congenital idiopathic nystagmus; NAFX, eXpanded Nystagmus Acuity Function; SN, secondary nystagmus; VA, visual acuity. Source: McLean RJ, Proudlock FA, Thomas S, Degg C, Gottlob I. Congenital nystagmus: randomized, controlled, double-masked trial of memantine/gabapentin. Ann Neurol. 2007;61:130–138. Reprinted with permission.

GENETICS AND PHARMACOLOGICAL TREATMENT OF NYSTAGMUS

References 1. Gottlob I. Nystagmus. Curr Opin Ophthalmol. 2001;12:378–383. 2. Stayte M, Reeves B, Wortham C. Ocular and vision defects in preschool children. Br J Ophthalmol. 1993;77:228–232. 3. Pilling RF, Thompson JR, Gottlob I. Social and visual function in nystagmus. Br J Ophthalmol. 2005;89:1278–1281. 4. Gottlob I. Eye movement abnormalities in carriers of blue-cone monochromatism. Invest Ophthalmol Vis Sci. 1994;39:3556–3560. 5. McKusik V. Mendelian Inheritance in Man: a Catalog of Human Genes and Genetic Disorders. 11th ed. Baltimore, MD: Johns Hopkins University Press; 1994. 6. Kerrison JB, Vageﬁ MR, Barmada M, Maumenee IH. Congenital motor nystagmus linked to Xq26q27. Am J Hum Genet. 1999;64:600–607. 7. Kerrison JB, Giorda R, Lenart TD, Drack AV, Maumenee IH. Clinical and genetic analysis of a family with X-linked congenital nystagmus (NYS1). Ophthalmic Genet. 2001;22:241–248. 8. Zhang B, Ding M, Liang D, et al. Conﬁrmation and reﬁnement of a genetic locus of congenital motor nystagmus in Xq26.3-q27.1 in a Chinese family. Human Genet. 2005;116:128–131. 9. Guo X, Li S, Jia X, Xiao X, Wang P, Zhang Q. Linkage analysis of two families with X-linked recessive congenital motor nystagmus. J Hum Genet. 2006;51:76–80. 10. Cabot A, Rozet JM, Gerber S, et al. A gene for X-linked idiopathic congenital nystagmus (NYS1) maps to chromosome Xp11.4-p11.3. Am J Hum Genet. 1999;64: 1141–1146. 11. Tarpey P, Thomas S, Sarvananthan N, et al. Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation. Am J Hum Genet. 2004;75(2):318–324. 12. Kubo T, Yamashita T, Yamaguchi A, Sumimoto H, Hosokawa K, Tohyama M. A novel FERM domain including guanine nucleotide exchange factor is involved in Rac signaling and regulates neurite remodeling. J Neurosci. 2002;22:8504–8513. 13. Toyofuku T, Yoshida, Sugimoto T, et al. FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nat Neurosci. 2005;8:1712–1719. 14. Leigh RJ, Tomsak RL, Grant MP, et al. Effectiveness of botulinum toxin administered to abolish acquired nystagmus. Ann Neurol. 1992;32: 633–642. 15. Repka MX. Treatment of acquired nystagmus with botulinum neurotoxin A. Arch Ophthalmol. 1994;112:1320–1324.

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16. Tomsak RL. Unsatisfactory treatment of acquired nystagmus with retrobulbar botulinum toxin. Am J Ophthalmol. 1995;119:489–496. 17. Yaniglos SS, Leigh RJ. Reﬁnement of an optical device that stabilizes vision in patients with nystagmus. Optom Vis Sci. 1992;69:447–450. 18. Von Noorden GK, Sprunger DT. Large rectus muscle recession for the treatment of congenital nystagmus. Arch Ophthalmol. 1991;109: 221–224. 19. Wang Z, Dell’Osso LF, Jacobs JB, Burnstine RA, Tomsak RL. Effects of tenotomy on patients with infantile nystagmus syndrome: foveation improvement over a broadened visual ﬁeld. J AAPOS. 2006;10:552–560. 20. Spielmann A. Nystagmus. Curr Opin Ophthalmol. 1994;5:20–24. 21. Stahl JS, Averbuch-Heller L, Leigh RJ. Acquired nystagmus. Arch Opthalmol. 2000;118:544–549. 22. Straube A. Differential effects of bicuculline and muscimol microinjections into the vestibular nuclei on simian eye movements. Exp Brain Res. 1991;86:347–358. 23. Mettens P. Effect of muscimol microinjections into the prepositus hypoglossi and the medial vestibular nuclei on cat eye movements. J Neurolphysiol. 1994;72:785–802. 24. Arnold DB. Nystagmus induced by pharmacological inactivation of the brainstem ocular motor integrator in monkeys. Vision Res. 1999;39: 4286–4295. 25. Halmagyi GM, Rudge P, Gresty MA, et al. Treatment of periodic alternating nystagmus. Ann Neurol. 1980;8:609–611. 26. Waespe W. Dynamic modiﬁcation of the vestibulo-ocular reﬂex by the nodulus and uvula. Science. 1985;228:199–202. 27. Dieterich M. The effects of baclofen and cholinergic drugs on upbeat and downbeat nystagmus. J Neurol Neurosurg Psychiatry. 1991;54:627–632. 28. Schon F. Suppression of pendular nystagmus by smoking cannabis in a patient with multiple sclerosis. Neurology. 1999;53:2209–2210. 29. Büttner U. Drug therapy of nystagmus and saccadic intrusions. Adv Otorhinolaryngol. 1999; 55:195–227. 30. Strupp M, Schüler O, Krafcyk S, et al. Treatment of downbeat nystagmus with 3,4-diaminopyridine. A placebo controlled study. Neurology. 2003:61:165–170. 31. Averbuch-Heller L, Tusa RJ, Fuhry L, et al. A double-blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus. Ann Neurol. 1997;41:818–825.

86 NEW THERAPIES FOR CONGENITAL NYSTAGMUS 32. Bandini F, Castello E, Mazzella L, et al. Gabapentin but not vigabatrin is effective in the treatment of acquired nystagmus in multiple sclerosis: how valid is the GABAergic hypothesis? J Neurol Neurosurg Psychiatry. 2001;71:107–110. 33. Starck M, Albrecht H, Pöllmann W, et al. Drug therapy for acquired pendular nystagmus in multiple sclerosis. J Neurol. 1997;244:9–16. 34. Lipton SA. The molecular basis of memantine action in Alzheimer’s disease and other neurological disorders: low-afﬁnity, uncompetitive atagonism. Curr Alzheimer Res. 2005;2155–2116. 35. Sills GJ. The mechanism and action of gabapentin and pregabalin. Curr Opin Pharmacol. 2006;6:108–113.

36. Sarvananthan N, Proudlock FA, Choudhuri I, Dua H, Gottlob I. Pharmacologic treatment of congenital nystagmus. Arch Ophthalmol. 2006;124:916–918. 37. Shery T, Proudlock FA, Sarvananthan N, McLean RJ, Gottlob I. The effects of gabapentin and memantine in acquired and congenital nystagmus: a retrospective study. Br J Ophthalmol. 2006;90:839–843. 38. McLean RJ, Proudlock FA, Thomas S, Degg C, Gottlob I. Congenital nystagmus: randomized, controlled, double-masked trial of memantine/ gabapentin. Ann Neurol. 2007;61:130–138.

11 New Treatments for Infantile and Other Forms of Nystagmus LOUIS F. DELL’OSSO

in visual function that is not possible from acuity measurements alone.

ABSTRACT Our objective was to translate the past 40 years of infantile nystagmus syndrome (INS) research (i.e., ocular motor recording and control-systems analysis) into a therapeutic approach. Our eye movement recordings use infrared reﬂection, magnetic search coil, and high-speed digital video systems. Each eye was calibrated during monocular ﬁxation (fellow-eye occluded). We analyzed and displayed all data using software developed and written in our laboratory in the MATLAB (MathWorks, Natick, MA) environment, including the eXpanded Nystagmus Acuity Function (NAFX). Analysis of ≈ 1000 INS subjects over 40 years revealed waveform characteristics that can be exploited therapeutically. Analysis of postoperative INS data suggested that tenotomy and resuture (at the original insertions) of the extraocular muscles in the plane of the IN would improve foveation. The NAFX across normal gaze angles showed both peak-value increases and NAFX-curve broadening. We have concluded that all patients with nystagmus should have eye movement recording and analysis. The resulting accurate diagnosis and documentation of INS characteristics (undetectable by clinical observation) identify the best therapy. NAFX analysis allows estimation of postoperative acuities and determination of the most appropriate therapies. This eye movement–based procedure is the ﬁrst to provide both the physician and patient with a posttherapeutic estimation of speciﬁc improvements

The most common types of benign nystagmus seen in infancy consist of the mixture found in the infantile nystagmus syndrome (INS), also known as congenital nystagmus, followed by the fusion maldevelopment nystagmus syndrome (FMNS), also known as latent/manifest latent nystagmus; additional types include the nystagmus blockage syndrome (NBS) and the spasmus nutans syndrome (SNS).1 FMNS shares some clinical characteristics with INS, but it is always associated with strabismus and has a directional change with ocular cover, beating toward the ﬁxating eye; it is rarely only present with occlusion of one eye. NBS is a special case of INS in which a purposive esotropia either damps the INS or converts it to a low-amplitude FMNS; both of the resulting waveforms allow higher acuity. SNS is a rare, disconjugate pendular nystagmus with head-nodding and tilt.2 Accurate diagnosis of each type is necessary, because each has a different mechanism and relationship to strabismus, and each requires different therapy. This review concentrates on INS and the conclusions and recommendations that have resulted from ocular motility analysis. Commonly held clinical impressions about INS and FMNS have been found to be less than helpful, while others are simply wrong. INS can appear at birth but is usually noted in early infancy (at the time of development of both motor and visual function) and persists throughout life. This is an ocular motor disorder that may (>50%) or may not be associated with afferent visual abnormalities 87

88 NEW THERAPIES FOR CONGENITAL NYSTAGMUS (e.g., albinism, aniridia, retinal dystrophies, optic nerve/foveal hypoplasia, retinal disease, ammetropia, or congenital cataracts). Therefore, all INS patients should have a thorough examination of the eye (including slit-lamp examination for iris transillumination and fundus examination) and afferent visual system. This includes testing monocular and binocular vision, refraction, and ophthalmoscopy. Additional tests may also be indicated, such as color vision and visual ﬁelds, dark adaptation, electroretinography, visual evoked potentials, or orbital and central nervous system imaging such as MRI. A combination of visual and ocular motor system evaluations helps in understanding systemic diagnosis, visual system prognosis, and potential treatment options.

METHODS Recording and calibrating the eye movements of subjects with nystagmus (or with saccadic intrusions or oscillations) is fundamentally equivalent to recording and calibrating normal eye movements. Most of the recording systems that are currently available (infrared reﬂection [IR], magnetic search coil, or high-speed digital video) are adequate to record horizontal eye movements. The latter two are better suited when both horizontal and vertical eye movements are required; electro-oculography is not acceptable. Both IR and digital video are noninvasive and suitable for infants and children; the search coil requires placing a contact lens containing a coil of wire in each eye. Each eye must be calibrated monocularly (i.e., with the other occluded) by using only the foveation periods of the waveforms and simple, non-stress-inducing LED targets, not acuity targets. Further details of recording and calibrating nystagmus may be found elsewhere.3 Analysis of INS recordings is aimed at evaluation of the waveform at different gaze angles and its foveation quality, an objective measurement of which is the eXpanded Nystagmus Acuity Function (NAFX). It uses the time intervals of foveation periods and their position and velocity standard deviations to establish a measure of the “quality” of an INS waveform (i.e., how likely it was to allow good acuity). The details of using the NAFX software may be found elsewhere.4

CLINICAL AND OCULAR MOTOR CHARACTERISTICS The INS consists of one or more types of nystagmus with characteristic waveforms, head turns, tilts, or oscillations; rarely, the nystagmus becomes manifest later in life.5 The term congenital should be thought of as a congenital “predisposition” for this particular type

of ocular motor instability, rather than taken literally. The mistaken presumption that the nystagmus was caused by poor vision and that two different types, “sensory-defect” and “motor-defect,” existed grew from the common association of INS with primary visual defects. The simplistic claim (mistakenly attributed to Dr. David Cogan) that these two putative types of INS could be identiﬁed by their waveforms (i.e., “sensory” = pendular and “motor” = jerk) has no basis in either clinical or eye movement data. In fact, Cogan speciﬁcally warned against such a distinction.6,7 Eye movement recordings subsequently demonstrated that INS had the same waveforms and underlying mechanism, regardless of the coincidental, facilitating existence of a sensory deﬁcit. Thus, the nystagmus is the direct result of an ocular motor control instability that may develop with or without an accompanying sensory deﬁcit. INS may appear spontaneously or be familial. Hereditary INS may be sex-linked, recessive, or dominant; the dominant form has been linked with chromosome 6p12.8 Recent genetic studies have identiﬁed genes and genetic loci associated with INS and retinal developmental defects accompanying some forms of INS.9 Although INS waveforms may appear to be either pendular or jerk, eye movement recordings have revealed that both stem from the same underlying pendular oscillation.10 Because of this, the originating slow phases of jerk waveforms have increasing velocities with the normal saccadic fast phases bringing the eye back to target. Pure pendular and jerk waveforms are not conducive to good acuity because of their extremely short foveation times (i.e., the time intervals when eye position maintains the target image within the foveal area and in which eye velocity is less than 4 deg/s); hence, in INS we seldom see pure pendular or jerk waveforms but rather waveforms with extended foveation. Many of the resulting INS waveforms are pathognomonic and are an expression of the attempts of the saccadic and ﬁxation subsystems to increase foveation time; therefore, they are diagnostic, as they are found in no other type of nystagmus. Individuals in families with INS may display the same subset of the 12 known INS waveforms.11,12 Infants may exhibit mature jerk INS waveforms, or they may change with age. Waveform maturation reﬂects saccadic modiﬁcation of the underlying pendular waveform by the developing visual and motor systems, and also reﬂects the infant’s state of visual attention. Eye movement recordings can accurately diagnose infants based on those waveforms that are pathognomonic for INS, whether or not mature waveforms are present. All INS patients, regardless of the clinical appearance of their nystagmus (pendular or jerk), should have a thorough eye and afferent visual-system examination in conjunction with eye movement recordings.

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The clinical characteristic features of INS summarized in Table 11.1 are not speciﬁc enough to reliably differentiate INS from FMNS; many erroneous clinical interpretations are listed, the most important of which is the mistaken belief that a direction reversal with alternate eye cover is diagnostic of FMNS, which it is not. The nystagmus that is present may be either INS with a latent component or FMNS (see Table 11.1 and subsequent sections). Because only eye movement recordings can accurately diagnose nystagmus and are necessary for the highest standard of care for nystagmus patients, this review will presume eye movement recordings are available for determining diagnosis, treatment, and the direct effects of treatment. Most INS patients have a mainly horizontal nystagmus, albeit many times with a minor torsional component; vertical, oblique, and circular waveforms of INS may also be present (see Table 11.1). Horizontal INS remains horizontal, even in vertical or oblique directions of gaze, and may not change on occlusion of either eye; this is an important diagnostic indicator. Some INS patients may have a latent component that results in a direction reversal with occlusion—the INS waveform reverses direction due to a shift in the “null” position. Although this mimics FMNS clinically, the waveforms can be only be accurately differentiated by eye movement recordings. The presence of a “null” position of gaze, the socalled gaze-angle null, where nystagmus damps is an important diagnostic feature of INS. However, the NAFX “peak,” where the nystagmus waveform is best for acuity, is a more accurate and clinically useful characterization. A preferred head-turn may appear if the NAFX peak is narrow and not straight ahead (i.e., gaze-angle null); even very young children may adopt this to improve their vision. Although primary-position visual acuity and stereo acuity are all that are usually measured clinically, visual function depends on other factors. A more important measure of both visual function and therapeutic improvement may be the degradation of a patient’s acuity with lateral gaze (lateral to their idiosyncratic angle of maximal acuity, formerly known as their “null” angle). Therefore, visual acuities should be measured by the clinician at different gaze angles by ﬁxing the visual stimuli and moving the head to known angles.13 Also needed are head-posture assessment, identiﬁcation of asymmetric (a)periodic alternating nystagmus (APAN), and cycloplegic refraction. APAN often goes undetected,14-16 which results in improper muscle-shifting surgery.17 Any refractive error should be corrected with glasses or contact lenses (the latter being preferred). Figure 11.1 shows how the NAFX peak may shift with changes in the ﬁxating eye in cases of INS (with a latent component) plus strabismus (esotropia, left,

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Table 11.1 Characteristics of Infantile Nystagmus Syndrome Clinical observations Binocular with similar amplitude in both eyes Usually horizontal (vertical, diagonal, or elliptical rare and small components missed) “Pendular” or “jerk” appearance (often misdiagnosed) Apparent jerk direction not always correct (often misdiagnosed) Asymmetric aperiodic alternation possible (baclofen ineffective) Provoked or increased by “ﬁxation attempt” and stress Abolished in sleep or inattention to visual tasks Diminished (damped) by gaze-angle or convergence nulls Reversal with cover (often misdiagnosed as FMNS) Apparent “inversion” of the optokinetic reﬂex (misinterpreted) Apparent “reversal” of smooth pursuit (misinterpreted) Associated head oscillation (misinterpreted as compensatory) Associated head turn and/or tilt No oscillopsia except under rare conditions Patients complain of being “slow to see” Ocular motor ﬁndings Increasing-velocity slow phases (some linear) Distinctive waveforms with foveation periods and braking saccades Many INS waveforms cannot be differentiated, nor can their direction be determined, clinically (misdiagnosed as nystagmus type or jerk direction) “Horizontal” INS actually has a torsional component and subclinical SSN Gaze-modulated, not gaze-evoked, nystagmus Normal smooth pursuit, optokinetic, and vestibulo-ocular systems (each causing a shift in the INS “null”) Reversal of the IN with alternate cover due to INS “null” shift (INS with a latent component misdiagnosed, “FMNS”) Two head postures due to the INS “null” shift in INS with a latent component (misdiagnosed as INS with “two nulls”) Reversal of the IN during optokinetic stimulation (misinterpreted as “inversion” of the optokinetic reﬂex) Reversal of the IN during smooth pursuit (misinterpreted as “reversal” of smooth pursuit) Associated head oscillation not compensatory due to normal vestibuloocular reﬂex Head turns or tilts provide waveforms with the best foveation quality Convergence damping improves foveation over a broader range of gaze angles Tenotomy portion of EOM surgery improves foveation over a broader range of gaze angles Target acquisition time much longer than saccadic reaction time, reducing visual function FMNS, fusion maldevelopment nystagmus syndrome; IN, infantile nystagmus; INS, infantile nystagmus syndrome; SSN, see-saw nystagmus.

90 NEW THERAPIES FOR CONGENITAL NYSTAGMUS

Figure 11.1 Demonstration of the infantile nystagmus syndrome (INS) “null” and eXpanded Nystagmus Acuity Function (NAFX) peak shifts due to a latent component in patients with INS plus esotropia (left) and exotropia (right). Large shifts result in head turns that lead to the clinical misimpression of INS with “two nulls,” when in fact there is one null that shifts with changes in the ﬁxating eye. and exotropia, right). Such cases are often misdiagnosed as INS with “two nulls” when, in fact, there is one null, the position of which is determined by which eye is ﬁxating. These cases, although diagnostic challenges, may be successfully treated by combining the four-muscle tenotomy procedure described below with strabismus recessions.18 Convergence may also damp INS (called a vergence null), allowing near visual acuity to be better than distance acuity; this, too, should be measured by the clinician. Convergence also broadens the NAFX-versus-gaze-angle peak, allowing better acuity over a larger portion of the visual ﬁeld; this is called the “longest foveation domain” (LFD).19,20 Increasing visual attention (“ﬁxation attempt”) may increase the intensity of INS (as well as the head oscillations that often accompany INS), and visual inattention damps it (it is also diminished during sleep).21 Recent evidence isolated the stress often associated with increased ﬁxation attempt as the factor that exacerbates INS rather than the simple act of trying to see higher acuity targets.22 However, ﬁxation attempt is responsible for the genesis of INS, which disappears when the patient is inattentive or sleeping. Individuals with INS usually do not experience an illusory oscillatory movement of their environment (oscillopsia).23,24 The absence of oscillopsia in INS, and also in FMNS, suggests that both oscillations occur within an efference copy feedback loop that serves to nullify the effects of retinal-image oscillation induced by either of these instabilities.25 Any patient with a primary complaint of oscillopsia should be assumed to have an acquired condition until proven otherwise. However, nearly 40% of INS patients may, at least occasionally, experience oscillopsia.26 Most of

these instances are associated with exacerbations of the patient’s nystagmus by fatigue, illness, stress, or looking in a “nonpreferred” gaze direction. Attempting a visually demanding task may cause head nodding in some INS patients. This reﬂects the effects of the nystagmus signal that drives both the eyes and the neck muscles, to which the signal has access via the semilunar ganglion.27 Head nodding is not compensatory, as the patient’s normal VOR cancels the effects of head oscillation during the periods of target foveation normally present in the INS waveform. The head tremor in INS is easily suppressed voluntarily, but this is not the case in acquired disease.

THERAPIES Current therapies for nystagmus may act either centrally or peripherally. Central therapies (neurosurgical or pharmacological) are directed at the central source of the nystagmus with the aim of directly reducing the initiating brainstem nystagmus signal (the motor command). Peripheral therapies (pharmacological, optical, or surgical) are directed at a peripheral mechanism to directly reduce the resulting eye oscillation without affecting the brainstem nystagmus motor command. An additional, new therapy to treat nystagmus is afferent therapy. An example is gene therapy applied to the retina to correct genetic deﬁcits that impair vision directly and may facilitate the development of nystagmus (e.g., RPE65 deﬁciency and INS).28 Figure 11.2 illustrates the anatomical sites of each type of therapy, the neurophysiological signals present, and the measurements of each therapy’s direct and indirect effects.

NEW TREATMENTS FOR INFANTILE AND OTHER NYSTAGMUS

91

EN T 1

Retinal feedback EN Retina

Optic nerve, chiasm, tract

[ERG] Ta*

Target position Ta

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Visual cortex

[PLR]

[VEP] Efference copy

Gene therapies

Tc* Therapy Ta

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Tc Tp

(N’, N) N

Indirect effects (pupillary, visual cortical, VA) (N’, N) VA, OSOP VA, OSOP

Tc*

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Higher cortical centers

[VA] [OSOP]

Neurosurgical & drug therapies

Efferent System E’ N’

EOM

F Fn Tp*

Therapy Ta Tc Tp

Direct measure Indirect measure ERG PLR, VEP, VA NAFX, OSOP NAFX, EMG VA, OSOP NAFX, EMG VA, OSOP

Tp

Tc

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EN

Eye

Tp* 1 [NAFX]

[EMG]

1

Eye Position

[Measures of therapeutic effectiveness]

Figure 11.2 A block diagram of the ocular motor system indicating the types of therapeutic intervention for nystagmus, their anatomic sites, and direct and indirect measurements of their effectiveness. Ta is afferent therapy for deﬁcits in the visual system (shown here, gene therapy for retinal deﬁciencies), Tc is central (neurosurgical or drug) therapy for nystagmus, and Tp is peripheral (surgical, optical, or drug) therapy for nystagmus. Shown in square brackets are the sites of therapeutic tests of visual and ocular motor function. The direct and indirect effects of each type of therapy and the direct and indirect outcome measures for each are listed in the legend boxes. e, retinal error; E, eye position; EMG, electromyogram; ERG, electroretinogram; F, extraocular muscle force; Fn, extraocular muscle nystagmus force; n, nystagmus error; N, nystagmus; NAFX, eXpanded Nystagmus Acuity Function; PLR, pupillary light reﬂex; VEP, visual evoked potential; +, improved, higher or better; −, diminished, lower or less; * or *1, site of primary effect of therapy; ’, motor commands. The most accurate measure of any therapy is a measure of its direct effects, rather than an indirect measure of a neurophysiological function that is dependent on other intervening functions, each subject to idiosyncratic deﬁcits. For visual performance measures, before and after therapy in nystagmus, most clinicians only measure resolution limit; visual acuity is the standard for most visual disorders. However, in nystagmus (especially INS) this is not an accurate or inclusive measure, because the nystagmus may vary with gaze angle and worsen with ﬁxation effort. Also, many patients with INS have one or more afferent visual deﬁcits that limit potential visual acuity, whether or not they were related to the series of events in the motor system that resulted in ocular motor instability. Finally, even for those with no afferent deﬁcits, mental status (stress) often results in a measured visual acuity that is lower than the acuity achieved during normal life when there is no stress. Visual performance in nystagmus is dependent on three factors: retinal image slip velocities, foveation accuracy and variability, and the presence of ocular and visual pathway anomalies. NAFX analysis of the foveation-period quality for the ﬁxating eye in primary position and the gaze-angle

modulation of the NAFX provide direct measures of most therapies and can accurately gauge the improvement of visual function in INS. Therefore, we recommend the use of the NAFX to measure therapeutic effectiveness in nystagmus. When recorded under the same nonstressful conditions used in our lab, the INS waveforms and their measures (e.g., the NAFX) are consistent over time, and any changes post-therapy can be ascribed to the therapy. Eye movement recordings document the characteristic waveforms of the nystagmus that deﬁnitively distinguish INS from FMNS and other, acquired forms of nystagmus. This diagnostic information, along with the patient’s idiosyncratic INS variation with both gaze angle and convergence, form the foundation for effective therapeutic intervention. The NAFX values over different gaze and convergence angles can be used to predict the expected therapeutic improvement in peak visual acuity and the range of gaze angles with high acuity.20 Different therapies have been tried for INS, from prisms to biofeedback, including recently reported improvement with gabapentin in a small number of patients.29 However, the mainstay of therapy is surgery.

92 NEW THERAPIES FOR CONGENITAL NYSTAGMUS

Surgical Surgical treatment has classically been performed for two main reasons: (1) correction of anomalous head posture and (2) improvement of visual performance. Oscillopsia is not a problem in INS and thus not an indication for treatment, unlike in acquired nystagmus. There have been two main types of surgery advocated: (1) Kestenbaum surgery—horizontal rectus-muscle paired recessions and resections to shift the eye position to take advantage of a gaze-angle null, and (2) artiﬁcial divergence surgery—bimedial rectus-muscle recessions to create mild divergence (exophoria) of the eyes and take advantage of a convergence-angle null. We recommend the following combinations of surgery based on preoperative eye movement recordings and analysis. 1. If the NAFX improves with convergence and/or convergence damps nystagmus in nonstrabismic, binocular patients, “artiﬁcial divergence” plus tenotomy surgery is recommended.30 This consists of bimedial horizontal rectus recessions plus bilateral horizontal rectus tenotomies. The recessions create mild divergence (exophoria) of the eyes such that the patient is forced to employ fusional vergence to see, and this convergence damps the nystagmus, possibly due to pulley repositioning. This surgery should only be used if the patient has fusion, and it is usually offered to patients who have responded to a trial with base-out prisms (with -1.0S if pre-presbyopic). 2. If there is a sharp NAFX peak and/or compensatory head posture with a “null” zone, the Kestenbaum surgery is the best approach.31 This is a four-muscle surgery consisting of yoke-paired recessions (Anderson)32 and resections (Goto)33 of the horizontal rectus muscles to shift the eyes opposite to an eccentric NAFX peak (i.e., in the direction of the head turn). The two muscles that move the eyes in the direction opposite to the head turn are recessed, and the two muscles that move the eyes in the direction of the head turn are resected (see Lee34 for a discussion of these surgical techniques). The resulting innervation to primary position places the eyes at the new centered NAFX peak. Although the Kestenbaum surgery was originally used only for large head turns, the discovery of important waveform improvements due to the tenotomies that are an integral part of the procedure now indicate its use for any narrow, eccentric NAFX peak, regardless of the amount of eccentricity or the presence of a head turn. The same therapeutic beneﬁts may be achieved by a combined Anderson-plus-tenotomy procedure, whereby yoke-paired recessions of two

horizontal rectus muscles (to shift the eyes opposite to an eccentric NAFX peak) plus tenotomies and reattachments to their original insertions of the other pair of horizontal rectus muscles (to complete the four-muscle tenotomy damping effect) are performed. Because tenotomy has been identiﬁed as the underlying reason for damping INS, two-muscle procedures like the Anderson or Goto should not be used without combining them with tenotomy of the remaining two muscles in the plane of the nystagmus. 3. If both 1 and 2 apply, bimedial horizontal rectus recessions plus bilateral horizontal rectus tenotomies are recommended; vergence NAFX peaks are higher than version peaks.35 4. If there are neither convergence nor gaze-angle improvements in the INS, the four-muscle tenotomy procedure is recommended.36-39 As indicated above, we use the NAFX values to (a) determine which patients should have surgery and (b) predict the expected improvements in both best acuity and the gaze-angle range of high acuity.20 Tenotomy is thought to affect eye muscle proprioception and reduce the small-signal (slow-phase) gain to improve nystagmus with or without a “null” zone.40 Large recessions of all the horizontal rectus muscles have been recommended by some strabismus surgeons41,42 for similar indications, with the premise that the force exerted by all the muscle is weakened, thereby damping nystagmus. However, this affects the ocular motility and can cause undesirable exotropia. Because tenotomy accomplishes INS damping without altering ocular motor homeostasis (i.e., no muscles are moved), we do not recommend maximal recessions of the four horizontal rectus muscles for INS patients, especially those who have binocularity and are at risk to develop diplopia as a result of weakening the eye muscles. Tenotomy’s efﬁcacy has been demonstrated in an animal study, a masked-data clinical trial, and subsequently in INS patients in whom the “null” broadening effects were demonstrated. It has also been used successfully to damp acquired nystagmus and reduce oscillopsia in acquired pendular nystagmus secondary to MS43 and downbeat nystagmus of unknown etiology.44 INS patients who also have strabismus should have strabismus correction added to either of the nystagmus surgeries described in 2 or 4; convergence-damping surgery of INS is contraindicated by strabismus. However, if an esotropia is present, bimedial horizontal rectus recessions may be added to the nystagmus surgery to correct the strabismus. Tables 11.2 and 11.3 summarize the different conditions that may be present in INS (Table 11.2) and FMNS (Table 11.3) and provide guidelines for the respective types of nystagmus and

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93

Table 11.2 Surgical Treatment Guidelines for Infantile Nystagmus Syndrome* Without strabismus Vergence “null”1 Gaze-angle “null”2 Both types of “nulls”2 No or 0° “null”1

Bimedial rectus recessions (±bilateral rectus tenotomies) Kestenbaum (4-muscle R&R) Anderson (2-muscle recessions) + 2-muscle tenotomies Bimedial rectus recessions (±bilateral rectus tenotomies) Tenotomy (4-muscle)

With strabismus ± Near “null”1 Gaze-angle “null”2

Both types of “nulls”2

No or 0° “null”1

ET: Bimedial rectus recessions (for strabismus) + bilateral rectus tenotomies (for INS) XT: Bilateral rectus recessions (for strabismus) + Bimedial rectus tenotomies (for INS) Kestenbaum (4-muscle, 2 resections and 2 recessions) + Strabismus recession of the deviated eye (ET or XT) Anderson (2-muscle recessions) + 2-muscle tenotomies + Strabismus recession of the deviated eye (ET or XT) Kestenbaum (4-muscle, 2 resections, and 2 recessions) + Strabismus recession of the deviated eye (ET or XT) Anderson (2-muscle recessions) + 2-muscle tenotomies + Strabismus recession of the deviated eye (ET or XT) Tenotomy (4-muscle) + Strabismus recession of the deviated eye (ET or XT)

* Diagnosed by eye-movement recordings, not clinically. 1 With or without asymmetric (a)periodic alternating nystagmus (APAN); 2 No APAN; E/XT, eso-/exotropia; R&R, recession-resection. Tenotomy procedure is detachment and reattachment of the muscle at its original insertion. 4(2)-muscle means the 4 (or 2) muscles—2 (or 1) per eye—in the major plane of the nystagmus. Source: National Eye Institute. The Classiﬁcation of Eye Movement Abnormalities and Strabismus (CEMAS): Report of an NEI Sponsored Workshop, 2001. National Eye Institute Web site. http://catalog.nei.nih.gov/productcart/pc/viewPrd.asp?idcategory=0&idproduct=52. Accessed January 21, 2008; Weissman BM, Dell’Osso LF, Abel LA, Leigh RJ. Spasmus nutans: a quantitative prospective study. Arch Ophthalmol. 1987;105:525–528.

strabismus surgery recommended for each; the patient’s individual afferent and efferent characteristics should determine the speciﬁc surgical approach taken. The addition of tenotomies to strabismus surgeries for FMNS reﬂects our expectation that they will prove to be as beneﬁcial as in INS and acquired nystagmus. These tables are only guidelines for uniplanar nystagmus; more complete details, including multiplanar nystagmus and anomalous head positions, may be found elsewhere.1 With precise eye movement recording, accurate identiﬁcation of NAFX peaks allows surgeons to more accurately plan eye muscle surgery without having to

rely on the measurement of head posture, which is under the patient’s control and is therefore both variable and unreliable. The eye movement analysis of tenotomy has shown that because of the NAFX peak broadening, the various surgical formulas derived for strabismic eye alignment are unnecessary for nystagmus rotations in binocular patients, and the more homeostatic equal resections and resections would be preferred. Postoperative recordings of waveforms have shown the predicted shift in the NAFX peak, broadening of the LFD, and improvement in the NAFX, thereby increasing the visual performance outcome. Multiplanar INS may require two-stage surgeries, ﬁrst

Table 11.3 Surgical Treatment Guidelines for Fusion Maldevelopment Nystagmus Syndrome* ET (Adducting >> Abducting eye ﬁxation) XT (Adducting >> Abducting eye ﬁxation)

Bimedial rectus recessions (for strabismus) (+ > −) Bilateral rectus tenotomies (for FMNS) Bilateral rectus recessions (for strabismus) (+ > −) Bimedial rectus tenotomies (for FMNS)

Uniocular ﬁxation Primary position ET (Adduction >> Abduction) XT (Abduction >> Adduction)

Strabismus recession of the deviated eye (ET or XT) (+ > −) 3-m tenotomies (for FMNS) Bimedial rectus recessions (for strabismus) (+ > −) Bilateral rectus tenotomies (for FMNS) Bilateral rectus recessions (for strabismus) (+ > −) Bimedial rectus tenotomies (for FMNS)

* Diagnosed by eye-movement recordings, not clinically. E/XT, eso-/exotropia; FMNS, fusion maldevelopment nystagmus syndrome. Tenotomy procedure is detachment and reattachment of the muscle at its original insertion. 3-m means the 3 muscles—2, ﬁxating, and 1, deviated eye—in the major plane of the nystagmus.

94 NEW THERAPIES FOR CONGENITAL NYSTAGMUS in the plane of the major component of the INS and then, if necessary, in the secondary plane; in some cases, the improvements from the ﬁrst stage will negate the necessity for the second.

Nonsurgical Base-out (BO) prisms may be used to exploit convergence nulls in binocular INS patients. Usually 7 diopter (D) BO prisms are added to the patient’s refraction with -1.0S added for pre-presbyopic patients (the latter must be removed when presbyopia occurs). Once converged, INS remains damped at most gaze angles (especially those in the central ±20° of gaze)19; therefore, we recommend equal-value, BO prisms rather than composite prisms for those with both eccentric and near NAFX peaks. This minimizes the amount of prism in each eye and reduces chromatic distortion. For those whose INS damps with afferent stimulation of the ophthalmic division of the trigeminal nerve, soft contact lenses will both correct refractive errors and improve the nystagmus waveform.45-47 For other INS patients, contact lenses may also be prescribed for their optical correction and for use in sports. Contact lenses may be prescribed in addition to surgical therapy, providing additional improvement.

NAFX-BASED THERAPY DETERMINATION AND PREDICTED OUTCOMES Using the NAFX to Determine Post-Therapy Efﬁcacy Based on the NAFX data gathered in the study of the effects of tenotomy, two curves were produced: (1) pretenotomy NAFX versus percent of NAFX improvement and (2) pretenotomy LFD versus percent of LFD improvement.20 The highest percentage improvements were found for those patients with the worst pretenotomy values (i.e., corresponding to the worst visual acuities and the narrowest high-acuity range of gaze angles). The least improvements were found for patients whose INS waveforms were conducive to high acuity and/or allowed a broad high-acuity range of gaze angles. Thus any patient with a low NAFX, a low LFD, or both should beneﬁt from tenotomy (or other four-muscle) surgery. Conversely, only those patients whose NAFX and LFD were both high would not beneﬁt from surgical therapy, at least for these two static measures of visual function.

they can be used in conjunction with the measured presurgical peak visual acuity to estimate the expected post-surgical improvement in visual acuity and in the breadth of the high-acuity range of gaze angles. Finally, they can also be used to measure the actual improvements in both measures of visual function. The following example demonstrates how this is done. Our ﬁctional patient is a 9-year-old child with nystagmus whose visual acuity is 20/200 and, for simplicity, who has no strabismus. The patient has one of the many afferent deﬁcits associated with INS (any one will do here). The results of the patient’s ocular motor recordings and analysis yield a diagnosis of INS with a primary position peak NAFX of 0.3 and an LFD of 15°. First, we choose the proper NAFX-versus-acuity line based on the patient’s age (Fig. 11.3, top left, heavy line). Second, we plot the NAFX point on the agematched line. This establishes a potential visual acuity of 20/70. That is, if a patient with an NAFX of 0.3 had only INS, the measured acuity would be 20/70. Because the measured acuity was actually 20/200, we know there is an afferent deﬁcit. To determine its effect on visual acuity, we draw another line with the same slope as the age-matched line through the NAFX = 0.3 point plotted at the measured acuity (Fig. 11.3, top right, dashed line). The intercept of the dashed line at NAFX = 1 (i.e., if there were no INS) shows that the afferent deﬁcit above would have reduced the visual acuity from 20/20 to 20/25, or 25%. To determine whether surgery (in this case, a fourmuscle tenotomy) is indicated, we plot the presurgical NAFX on the NAFX improvement curve (Fig. 11.3, middle left). The expected NAFX improvement is 60% and thus surgery is indicated. To estimate the expected post-tenotomy improvement in NAFX and measured acuity, we plot the calculated post-tenotomy NAFX point (0.3 + 0.3[0.60] = 0.48) on the dashed line (Fig. 11.3, middle right). Thus the post-tenotomy visual acuity should improve to 20/70, or 185.7%. To estimate the expected post-tenotomy improvement in LFD, we plot the pretenotomy LFD point on the LFD improvement curve (Fig. 11.3, bottom). The expected LFD improvement is 120%, yielding an estimated post-tenotomy LFD of 15° + 1.2(15°) = 33°. From the post-tenotomy eye movement data, we can calculate the actual improvements in both the NAFX and LFD and measure the visual acuity. We can then compare our estimates with the actual results.

Using the NAFX to Predict and Determine Post-Therapy Outcomes

DISCUSSION

Once the NAFX and LFD percent-improvement curves are used to determine whether surgery is indicated,

The ideal measure of any nystagmus therapy is one that is both a direct outcome measure of that therapy

NEW TREATMENTS FOR INFANTILE AND OTHER NYSTAGMUS

95

Figure 11.3 Demonstration of the use of the eXpanded Nystagmus Acuity Function (NAFX) and longest foveation domain (LFD) function to estimate post-tenotomy improvements in visual acuity and broadening of high-acuity gaze-angle range, respectively. NAFX vs. visual acuity lines for different patient age ranges (top left). Plots of the patient’s pretenotomy NAFX and measured visual acuity points (top right) when (A) there is no signiﬁcant sensory deﬁcit accompanying the INS or (B) there is a sensory deﬁcit and a dashed line is drawn through it. (A) Determination of estimated NAFX improvement (bottom left). Determination of estimated visual acuity improvement (bottom right). Bottom center: Determination of estimated high-acuity gaze-angle range improvement. INS, infantile nystagmus syndrome.

96 NEW THERAPIES FOR CONGENITAL NYSTAGMUS and, if possible, a predictive measure of the medical goals of improved primary-position acuity and improved visual function. As Figure 11.2 shows, the electroretinogram, pupillary light reﬂex, and visual evoked potential are the most direct measures for afferent therapies. Each is predictive of visual acuity, which is determined slightly upstream, albeit requiring higher cortical function. In animal studies, where visual acuity is not easily measured, the NAFX provides an easily obtainable, in vivo measure of gene therapy’s effectiveness by measuring nystagmus waveform improvements. Although an indirect measure of afferent therapy, the NAFX predicts potential acuity. For central and peripheral therapies, the best and least invasive direct measure is the NAFX; the electromyogram is both invasive and not easily related to visual acuity. Because the NAFX both predicts acuity improvements and measures increases in the range of gaze angles over which those improvements are present, it was chosen as the primary outcome measure of the effectiveness of tenotomy36,37 and in two masked clinical trials of tenotomy for INS in adults38 and children.39 In many patients with INS, increasing the effective high-acuity visual ﬁeld does more to improve visual function than increasing Snellen acuity in one small region of the visual ﬁeld—unfortunately, this is neither appreciated nor measured in the physician’s ofﬁce. It does explain why a given therapy may result in a patient reporting that he can “see better” even when the pre- and post-therapeutic primary-position Snellen acuities are essentially equal. As Figure 11.2 illustrates, peripheral surgical therapy acts at the muscle to damp the resulting nystagmus; it does not change the brainstem nystagmus signal itself. Also, it is equally effective in damping both infantile and acquired nystagmus (the muscle cannot determine the origin of the nystagmus signal). Central pharmacological therapy is administered to damp the brainstem nystagmus signal. Because of their independence, if both central and peripheral therapies are applied together (in either order), the result will be the multiplicative damping from both therapies. This type of “dual-mode” therapy has been shown to maximally damp the nystagmus and maximally improve visual function.43 We have shown, for the ﬁrst time and with the use of eye movement data and the NAFX analyses, that we can accurately determine a priori whether the patient has INS or some other form of nystagmus, whether surgery will improve visual function enough to justify it, what surgery is best for each patient, how much visual acuity will improve, and how much the highacuity range of gaze angles will broaden. None of these diagnostic or therapeutic assessments is possible from only a clinical examination and visual acuity measurement.

Finally, we have recently uncovered a “dynamic” source of visual function deﬁcit in INS that causes patients to complain that they are “slow to see.” They have an elevated target acquisition time (far longer than their slightly elevated saccadic reaction time).44 This raises the question, “Does nystagmus surgery (speciﬁcally, four-muscle tenotomy) also improve visual function by reducing target acquisition time?” Preliminary data suggest that it does. Eye movement recordings and NAFX analysis used in the diagnostic workup and therapeutic decision processes should produce accurate and repeatable diagnoses and reduce repeat (i.e., corrective) nystagmus surgeries. Complex cases combining INS, strabismus, latent components, and even FMNS require eye movement recordings and analyses.

acknowledgments The author acknowledges the following colleagues, whose collaboration during the past 40 years of INS research formed the foundation for this data-based approach to diagnosis, therapy, and evaluation of visual function improvement (listed chronologically): L. Stark, G. Gauthier, R. B. Daroff, J. T. Flynn, L. A. Abel, D. Schmidt, S. Traccis, C. Ellenberger, R. J. Leigh, A. Tabuchi, R. M. Steinman, H. Collewijn, J. Van der Steen, B. M. Weissman, R. W. Hertle, N. V. Sheth, J. Shallo-Hoffmann, R. W. Williams, L. Averbuch-Heller, J. B. Jacobs, B. F. Remler, D. W. Hogan, D. M. Erchul, R. L. Tomsak, G. M. Acland, J. Bennett, R. A. Burnstine, A. Serra, and Z. I. Wang. This work was supported in part by the Ofﬁce of Research and Development, Medical Research Service, U.S. Department of Veterans Affairs.

References 1. National Eye Institute. The Classiﬁcation of Eye Movement Abnormalities and Strabismus (CEMAS): Report of an NEI Sponsored Workshop, 2001. National Eye Institute Web site. http://catalog.nei. nih.gov/productcart/pc/viewPrd.asp?idcategory=0 &idproduct=52. Accessed January 21, 2008. 2. Weissman BM, Dell’Osso LF, Abel LA, Leigh RJ. Spasmus nutans: a quantitative prospective study. Arch Ophthalmol. 1987;105:525–528. 3. Dell’Osso LF. Recording and calibrating the eye movements of nystagmus subjects. OMLAB Report #011105, 2005:1-4. Ocular Motility Laboratory Web site. www.omlab.org/OMLAB_page/Teaching/ teaching.html. Last updated February 7, 2005. Last accessed March 3, 2008. 4. Dell’Osso LF. Using the NAFX for eye-movement ﬁxation data analysis and display. OMLAB

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ophthalmology at the Beginning of the New Millennium. Englewood, NJ: Medimond Medical Publications; 2000:125–129. Wang ZI, Dell’Osso LF, Tomsak RL, Jacobs JB. Combining recessions (nystagmus and strabismus) with tenotomy improved visual function and decreased oscillopsia and diplopia in acquired downbeat nystagmus and in horizontal infantile nystagmus syndrome. J AAPOS. 2007;11:135–141. Serra A, Dell’Osso LF, Jacobs JB, Burnstine RA. Combined gaze-angle and vergence variation in infantile nystagmus: two therapies that improve the high-visual acuity ﬁeld and methods to measure it. Invest Ophthalmol Vis Sci. 2006;47:2451– 2460. Wang Z, Dell’Osso LF, Jacobs JB, Burnstine RA, Tomsak RL. Effects of tenotomy on patients with infantile nystagmus syndrome: foveation improvement over a broadened visual ﬁeld. J AAPOS. 2006;10:552–560. Dell’Osso LF. Fixation characteristics in hereditary congenital nystagmus. Am J Optom Arch Am Acad Optom. 1973;50:85–90. Tkalcevic LA, Abel LA. The effects of increased visual task demand on foveation in congenital nystagmus. Vision Res. 2005;45:1139–1146. Dell’Osso LF, Leigh RJ. Foveation periods and oscillopsia in congenital nystagmus. Invest Ophthalmol Vis Sci. 1990;31:122. Dell’Osso LF, Leigh RJ. Foveation period stability and oscillopsia suppression in congenital nystagmus. An hypothesis. Neuroophthalmology. 1992;12:169–183. Dell’Osso LF, Averbuch-Heller L, Leigh RJ. Oscillopsia suppression and foveation-period variation in congenital, latent, and acquired nystagmus. Neuroophthalmology. 1997;18:163–183. Abadi RV, Bjerre A. Motor and sensory characteristics of infantile nystagmus. Br J Ophthalmol. 2002;86:1152–1160. Sheth NV, Dell’Osso LF, Leigh RJ, Van Doren CL, Peckham HP. The effects of afferent stimulation on congenital nystagmus foveation periods. Vision Res. 1995;35:2371–2382. Jacobs JB, Dell’Osso LF, Hertle RW, Acland GM, Bennett J. Eye movement recordings as an effectiveness indicator of gene therapy in RPE65-deﬁcient canines: implications for the ocular motor system. Invest Ophthalmol Vis Sci. 2006;47:2865–2875. Shery T, Proudlock FA, Sarvananthan N, McLean RJ, Gottlob I. The effects of gabapentin and memantine in acquired and congenital nystagmus: a retrospective study. Br J Ophthalmol. 2006;90(7): 839–843.

98 NEW THERAPIES FOR CONGENITAL NYSTAGMUS 30. Cüppers C. Probleme der operativen Therapie des okulären Nystagmus. Klin Monatsbl Augenheilkd. 1971;159:145–157. 31. Kestenbaum A. Nouvelle operation de nystagmus. Bull Soc Ophthalmol Fr. 1953;6:599–602. 32. Anderson JR. Causes and treatment of congenital eccentric nystagmus. Br J Ophthalmol. 1953;37:267–281. 33. Goto N. A study of optic nystagmus by the electro-oculogram. Acta Soc Ophthalmol Jpn. 1954;58:851–865. 34. Lee J. Surgical management of nystagmus. J Roy Soc Med. 2002;95:238–241. 35. Dell’Osso LF, Van der Steen J, Steinman RM, Collewijn H. Foveation dynamics in congenital nystagmus I: Fixation. Doc Ophthalmol. 1992; 79:1–23. 36. Dell’Osso LF. Extraocular muscle tenotomy, dissection, and suture: a hypothetical therapy for congenital nystagmus. J Pediatr Ophthalmol Strab. 1998;35:232–233. 37. Dell’Osso LF, Hertle RW, Williams RW, Jacobs JB. A new surgery for congenital nystagmus: effects of tenotomy on an achiasmatic canine and the role of extraocular proprioception. J AAPOS. 1999;3:166–182. 38. Hertle RW, Dell’Osso LF, FitzGibbon EJ, Thompson D, Yang D, Mellow SD. Horizontal rectus tenotomy in patients with congenital nystagmus. Results in 10 adults. Ophthalmology. 2003;110:2097–2105. 39. Hertle RW, Dell’Osso LF, FitzGibbon EJ, Yang D, Mellow SD. Horizontal rectus muscle tenotomy

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12 Clinical and Electrophysiological Effects of Extraocular Muscle Surgery on Fifty-three Patients with Infantile Periodic Alternating Nystagmus RICHARD W. HERTLE, LEAH REZNICK, DONGSHENG YANG, AND KIMBERLY ZOWORTY

population had either the periodic or aperiodic form of alternating nystagmus. This report adds to the evidence that surgery on the extraocular muscles in patients with INS has independent neurological and visual results from simply repositioning the head, eye(s), or visual axis.

ABSTRACT This chapter reports the effect of extraocular muscle surgery on the clinical and ocular motility characteristics of infantile periodic and aperiodic alternating nystagmus. Of 1423 recordings performed between the years 1998 and 2006 in 506 patients with infantile nystagmus syndrome (INS), 78 had ocular oscillations consistent with infantile periodic alternating nystagmus. Fifty-three patients had virgin eye muscles operated on for strabismus alone, nystagmus alone, a static head posture alone, or a static head posture plus strabismus. Outcome variables were vision, strabismus, head position, periodic cycle and null period duration, foveation time, and waveforms. Age range was 1 to 67 years; 57% had pure periodic and 43% the aperiodic form of nystagmus, 42% had albinism, 42% had strabismus, 40% had amblyopia, and 32% had other eye disease. Asymmetry was present in 65%, while 35% were symmetric about the null period. Head posture and strabimsus improved in all patients. Average LogMAR acuity increased from 0.55 preoperatively to 0.42 postoperatively (p < 0.01). The average, pure periodic alternating nystagmus (PAN) cycle duration increased from 221 seconds to 266 seconds after surgery (p < 0.01), the average pure PAN null period duration increased from 11.2 to 20.0 seconds after surgery (p < 0.05), and the average best duration foveation increased from 132 to 178 milliseconds after surgery (p < 0.05); post-surgery waveform changes during the null period were those associated with improved visual function. Fifteen percent of our total INS

Distinguishing neurologically serious forms of nystagmus in infancy and childhood are important because of the implications for diagnosis, prognosis, and treatment of the neurological disease or the nystagmus directly. Any pattern of nystagmus with onset in the ﬁrst two months of life could be considered congenital nystagmus. The term congenital nystagmus is only appropriate when the nystagmus is present at birth (and presumably also in utero). This term, however, has become synonymous with the most common form of neonatal nystagmus, which is characterized electrophysiologically by an accelerating slow phase on eye movement recordings and is termed infantile nystagmus syndrome (INS).1 The recently sponsored National Eye Institute Workshop on Classiﬁcation of Eye Movement Abnormalities and Strabismus (CEMAS) has attempted to resolve some of these issues. This report utilizes the CEMAS working group deﬁnition of INS.2 Other clinical characteristics, with variable association, include increased intensity with ﬁxation and decreased intensity with sleep or inattention; variable intensity in different positions of horizontal, vertical, or torsional gaze (about a null position); with monocular cover, a changing direction in different positions of gaze (about a neutral position) and decreased intensity (damping) with convergence or induced esotropia (“blockage”); and anomalous head 99

100 NEW THERAPIES FOR CONGENITAL NYSTAGMUS posturing, strabismus, and the increased incidence of signiﬁcant refractive errors. INS can occur in association with congenital or acquired defects in the visual sensory system (i.e., optic nerve hypoplasia, achromatopsia, foveal hypoplasia, congenital cataracts).3-5 In addition to the above characteristics, 9% to 33% of patients with INS will have an inherent, rhythmic, periodic, or aperiodically changing nystagmus intensity and/or direction over time.6-9 Most clinicians are familiar with this oscillation as acquired periodic alternating nystagmus (PAN). Acquired PAN has a speciﬁc pattern identiﬁed by the presence of spontaneous nystagmus in the primary position, which beats horizontally in one direction for 1 or 2 minutes, followed by a quiet period, and then reappearance of the nystagmus in the opposite direction for a similar length of time. It is usually seen in association with disease affecting the cerebellar nodulus and uvula, such as Friedreich’s ataxia, but also with vision loss.10-13 Infantile periodic alternating nystagmus (IPAN) has all the characteristics of INS, except that the null point shifts position in a regular (periodic) or irregular (aperiodic) pattern. This results in changes in the intensity and/or direction of the nystagmus from seconds to minutes. Although neuroimaging is obtained in almost all cases of clinically evident PAN, the deﬁnitive diagnosis of the ocular oscillation is made using eye movement recordings. IPAN is more common in patients with oculocutaneous albinism and is usually not associated with serious central nervous system pathology.6-8,14 There are clinical and scientiﬁc data that show that if the slow foveation periods occurring during each beat of nystagmus can be lengthened or increased by the patient (adaptation) or by therapeutic interventions (e.g., medicines, surgery, contact lenses, biofeedback), some of a patient’s visual function may be increased.15-17 The purpose of this chapter is to describe the effect of extraocular muscle surgery on the electrophysiological and clinical characteristics of 53 patients with IPAN.

surgery prior to one performed by the author (RWH), (b) follow-up for at least 6 months after surgery, (c) eye movement recordings with waveforms characteristic of INS, and (d) periods of changing oscillation direction and/or intensity. The periodic changing eye intensity and/or direction is independent of a changing eye ﬁxation and is present during continuous, binocular eye movement recordings over a 10- to 15-minute period. All patient data were obtained from a prospectively collected computerized database.

Ophthalmologic Examination All patients underwent several routine clinical evaluations. Visual acuity testing was performed with refraction in place both binocularly and monocularly, using behavioral methods in infants and the “early treatment for diabetic retinopathy” chart or the amblyopia treatment study single and surrounded, HOTV optotype protocol in those able to cooperate with subjective testing.18 Binocular function was assessed using the Worth 4-Dot test near and at distance and the Randot preschool stereoacuity test at near. Ocular motor examination also included a determination of heterophoria/tropia at distance (3 to 6 m) and near (33 cm) in all diagnostic positions of gaze using the simultaneous prism cover test and alternate prism cover test. Versions and ductions were examined and color vision was tested in those able to cooperate for subjective testing, using D-15 color plates. The ocular examination also included cycloplegic refraction, tonometry in older children, slit-lamp and ophthalmoscopic examination of the anterior and posterior segments, and fundus photographs if an abnormality was detected during the examination. Clinical evaluation of the ocular motor oscillations included examination and measurement of any anomalous head posture using a previously described technique.19 Changes in the oscillation were examined in primary position, at near, and in all positions of gaze under monocular and binocular conditions.

METHODS All testing was approved by the Institutional Review Boards of the National Eye Institute, National Institutes of Health, Bethesda, Maryland; The Columbus Children’s Hospital, Columbus, Ohio; and The Children’s Hospital of Pittsburgh, in Pennsylvania. All procedures observed the declaration of Helsinki, and informed consent/assent was obtained from all family members.

Inclusion Criteria In order to be eligible for this study, nystagmus patients had to meet the following criteria: (a) no eye muscle

Electroretinography and Visual Evoked Potential Testing Electroretinographic (ERG) and/or visual evoked potential (VEP) testing was performed in patients with suspected retinal and/or optic nerve disease to exclude the possibility of a retinal or optic nerve dystrophy/ degeneration associated with the nystagmus. A commercially available electrodiagnostic testing unit (LKC Technologies, Gaithersburg, MD) was used for both ERG and VEP testing. ERG testing included light- and dark-adapted recordings using a corneal contact lens electrode technique and the International Society of

EFFECTS OF EXTRAOCULAR MUSCLE SURGERY

Clinical Electrophysiology in Vision protocol.20 VEP testing was performed in a darkened room using the commercially available LKC sweep and ﬂash programs in each eye.

Eye Movement Recording All subjects had eye movement recordings. The presentation of stimuli and the acquisition, display, and storage of data were controlled by a series of computers using standard Microsoft and MATLAB software, as well as specially designed software such as Visual and Experimentation and Real-time EXperimentation packages (distributed by the Laboratory of Sensorimotor Research NEI/NIH, Bethesda, MD). The horizontal and vertical eye movement recordings of the subjects were made using an infrared (IR) reﬂection method (IOTA Eye Movement Recording, Applied Science Laboratories, Bedford, MA); the system bandwidth was 0–500 Hz. In older children and adults, signals were calibrated (using the end of the fast phase during the nystagmus cycle) at the beginning of the recording session by having the patient ﬁxate on small target lights located on a screen at a distance of 1 meter. Data were sampled at 500 Hz. These patients were seated with their head stabilized by means of a chin cup and headrest and instructed to look at targets at ±15° or ±20° horizontally and ±10° vertically. After calibration, all recording sessions followed the same protocol. The patient was required to ﬁxate between 0°, ±5°, ±10°, ±15°, and ±20° with the right eye, the left eye, and both eyes. The patient was then asked to make binocular step vergence responses from distance to near. Finally, ﬁxation at 0° with both eyes was accomplished for 10 to 15 minutes. Infants were seated in a comfortable position in a parent or caretaker’s lap. The goggles rested comfortably on the infant’s face in front of the visual axis, and the head was held steady by the examiner. After 7.5 to 10.0 minutes of continuous binocular recordings, the left and then the right eye was occluded with an opaque trial lens placed in a holder attached to the front of the goggles. At all times during recording, attempts were made to pacify the child and obtain his or her attention to the ﬁxation screen at 1 m. When possible, attempts were made to have young children look to the right and left as well as near while recording the oscillation’s response to gaze and vergence changes. This method, in use for more than two decades, produces clear, artifact-free records of INS waveforms in infants and young children. Although the amplitude of the INS in either was not always accurately determined (i.e., all the data are not calibrated), all phase and timing information (e.g., periodicity, foveation time, symmetry, waveforms) could be accurately measured. All eye

101

movement data were analyzed ofﬂine. Mathematical and statistical analysis was done on a computer spreadsheet.

OUTCOME VARIABLES Clinical Data Clinical variables included age in years; follow-up from initial diagnosis in months; other eye diagnoses (determined through clinical and electrophysiological examinations); systemic diagnoses (determined through history); best-corrected binocular acuity using the methods listed; anomalous head position; and presence and type of heterotopia deﬁned as esotropia, exotropia, and hypertropia.

Eye Movement Recording Data The PAN cycle duration was deﬁned, in seconds, as the period of time from the beginning of one lowintensity or quiet period to the beginning of the next low-intensity or quiet period, and was calculated from at least 12 continuous cycles, sometimes over many recording sessions, for each patient (Fig. 12.1). Null period duration was deﬁned, for the purposes of this report, as the time in seconds during the quiet period where continuous, individual nystagmus beats had foveation periods 80% to 100% as long as the patients single best (longest duration) foveation period. (Fig. 12.2). Foveation duration was determined by averaging the foveation time from at least 100 beats of nystagmus during the null period (Fig. 12.3).4,5 Patients were deﬁned as having a periodic (regular) rhythm if there were regular cycles of left- and rightbeating nystagmus separated by an almost quiet phase, or regular periods of high intensity followed by low intensity and again by high intensity without a clear change in direction. Patients were deﬁned as having an aperiodic (irregular) rhythm if there were irregular cycles of left- and right-beating nystagmus separated by an almost quiet phase, or irregular periods of high intensity followed by low intensity and again by high intensity without a clear change in direction. These cyclic changes were present under binocular viewing in the absence of a change in eye ﬁxation, thus eliminating the possibility that the change in nystagmus direction was due to a “latent component” in those patients with strabismus. The types of waveforms present were classiﬁed according to the previously described 13 waveforms associated with horizontal INS.1 Symmetry was deﬁned as similar nystagmus beat-to-beat characteristics

102 NEW THERAPIES FOR CONGENITAL NYSTAGMUS

A

R L

180 seconds OD velocity 50

B

100

150

200

250

300

R L

OD velocity

210 seconds 50

100

150

200

250

300

Figure12.1 Eye movement recording velocity data only from patient 33, performed under binocular conditions and using data from the preferred right eye. This illustrates how the periodic alternating nystagmus (PAN) cycle duration is calculated and changed after surgery; preoperative recording (top) and postoperative recording (bottom). The PAN cycle duration was deﬁned in seconds as that period of time from the beginning of one low-intensity or quiet period to the beginning of the next low-intensity or quiet period and was calculated from at least 12 continuous cycles, sometimes over many recording sessions. L, left/down; OD, right eye; R, right/up.

(waveforms, intensity) in both directions prior to and after the low-intensity or quiet period.

RESULTS Clinical Data Of 1423 eye movement recordings performed from 1998 to 2006 in 506 patients with INS, 78 had IPAN (15.4%). Fifty-three who had previously had eye muscle surgery are the subjects of this report. Ages ranged from 1 to 67 years (average 15.5 years, SD 14.1), and 49 (63%) were male. Follow-up has, to the point of this writing, ranged from 7 to 60 months (average 20.5 months). Twenty-three patients (42%) had strabismus,

21 patients (40%) had unilateral amblyopia, 23 patients (42%) had ocular or oculocutaneous albinism, and 1 patient had a systemic disease diagnosis.21 Eight patients (15%) had surgery for strabismus alone, 19 patients (36%) had surgery for an anomalous posture or tenotomy alone, and 7 patients (13%) had surgery for strabismus and an anomalous head posture (Table 12.1). Best binocular acuity did not change in 14%, and it improved 0.10 LogMAR in 33%, 0.20 LogMAR in 37%, 0.30 LogMAR in 14%, and > 0.32 LogMAR in 2% (Table 12.2, Fig. 12.4). The postoperative primary position deviation was less than 10 prsim diopters in each of the 15 patients with strabismus (Fig. 12.5). In the 19 patients with a static head posture, all but 2 had less than a 5º posture after surgery (Fig. 12.6).

EFFECTS OF EXTRAOCULAR MUSCLE SURGERY

103

A

OS position

Foveation maximum 7.5 seconds

R

3.5 seconds

L OS velocity 280

Direction change

285

290

295

300

305

310

315

B

OS position

Foveation maximum 14 seconds

R L

7.0 seconds

OS velocity 125

130

Direction change 135

140

145

150

155

160

165

Figure 12.2 Eye movement recording data only from patient 19, performed under binocular conditions and using data from the preferred left eye. This illustrates how null period duration is calculated and changed after surgery; preoperative recording (top) and postoperative recording (bottom). This is deﬁned, for the purposes of this report, as the time (in seconds) during the quiet period, where continuous, individual nystagmus beats had foveation periods 80% to 100% as long as the patient’s single best (longest duration) foveation period. Upper trace is position and lower trace is velocity. The position trace is used to calculate the null duration (position trace between top two vertical black lines). L, left/down; OD, right eye; PAN, periodic alternating nystagmus; R, right/up.

Eye Movement Recording Variables A periodic (regular) cycle was present in 30 patients (57%), and an aperiodic (irregular) cycle in 23 (43%). The PAN cycle duration averaged 221 seconds (SD 31 seconds) in the 57% with periodicity, and changed postoperatively to 266 seconds (SD 70) (p < 0.01) (Fig. 12.1). The aperiodic cycle varied from as little as 2 seconds to as long as 300 seconds in the 43% with aperiodicity, and did not change after surgery. The duration of the null period in those patients with periodic

cycles, preoperatively, averaged 11.2 seconds (SD 3.9), and this increased to an average of 20.0 seconds (SD 5.1) (p < 0.001) after surgery (Fig. 12.2). The duration of the null period in those patients with aperiodicity was as short as 2 seconds to as long as 366 seconds. Best foveation duration averaged 132 milliseconds (SD 36.5) preoperatively and increased to 178 milliseconds (SD 40.9) postoperatively in all patients (p < 0.05) (Figs. 12.3 and 12.7). The most common waveforms during the null period were jerk with extended

104 NEW THERAPIES FOR CONGENITAL NYSTAGMUS

A

OS position

J and Jef 3 seconds

R L

3 seconds

OS velocity

Direction change 223

224

225

226

227

228

229

230

231

B OS position

R

Jef

L 7 seconds

7 seconds

OS velocity 166

167

168

169

170

171

172

173

174

Figure 12.3 Eye movement recording data from patient 37, performed under binocular conditions and using data from the preferred left eye during the null or quiet period. This illustrates how foveation duration was calculated. Foveation duration was determined by averaging the foveation time from at least 100 beats of nystagmus during the null period. Upper trace is position and lower trace is velocity; the position trace is used to calculate the null duration. L, left/down; OD, right eye; R, right/up.

Table 12.1 Patients Pursuing Surgical Correction Procedure Number of patients %

Strabismus Alone 8 15

AHP Alone

Strabismus and AHP

Tenotomy Alone

19 36

7 13

19 36

Table showing the proportion of patients undergoing surgery with the intent of improving the strabismus alone, the anomalous head posture alone, the strabismus plus an anomalous head posture, or the nystagmus alone (tenotomy). AHP, anomalous head posture.

EFFECTS OF EXTRAOCULAR MUSCLE SURGERY

105

Table 12.2 Change in Acuity LogMar Visual Acuity LogMAR Change No change 0.02 to 0.10 improved 0.12 to 0.20 improved 0.22 to 0.30 improved ≥0.32 improved Mean (95% CI)

n (%) 7 (14) 17 (33) 19 (37) 7 (14) 1 (2) 0.13 (0.19 to 0.10) 0.20 (0.19 to 0.00) (0.80 to 0.00)

Median (quartiles)

Signiﬁcance

p = 0.001

Table showing improvement in best-corrected LogMAR binocular optotype acuity in the 51 of 53 patients for whom optotype acuity could be obtained. LogMAR, logarithm of the minimal angle of resolution; CI, conﬁdence interval.

foveation in 27 (51%), pure jerk in 17 (32%), and asymmetrical pendular in 5 (10%); other variants of jerk waveforms were seen in 4 patients (7%). After surgery, this hanged to jerk with extended foveation in 45 (85%), pure jerk in 5 (10%), asymmetrical pendular in 1 (2%), and other variants of jerk waveforms in 2 (3%) (Fig. 12.8).21

DISCUSSION

LogMAR

Acquired PAN is associated with disorders involving the cerebellum, especially the nodulus and ventral uvula. These conditions include trauma, Chiari malformations, cerebellar mass lesions (cyst, tumor), ischemia,

hereditary cerebellar degenerations, infections (syphilis, encephalitis), and multiple sclerosis.10,11,22,23 Acquired PAN can also occur as an adverse effect of medication such as lithium and anticonvulsants, or it may result from loss of vision (cataracts), vitreous hemorrhage, or syphilitic optic atrophy. Although the mechanism of PAN is not fully understood, lesions of the uvula and nodulus, as well as structures located in the posterior vermis of the cerebellum, can result in PAN.24-27 The nodulus and uvula are also known to control velocity storage, and removal of these structures causes an increase in the duration of the time constant of velocity storage. At the molecular level, it has been demonstrated that control of the velocity storage by the nodulus and uvula is achieved, at least in part, by inhibitory

1.40 1.30 1.20 1.10 1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00

VA-PRE VA-PO

1

3

5

7

9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53

Patient number

Figure 12.4 Summary of individual change in best-corrected LogMAR binocular optotype acuity in the 51 of 53 patients in whom optotype acuity could be obtained. LogMAR, logarithm of the minimal angle of resolution; PT, patient number; VA-PRE, visual acuity preoperatively; VA-POST, visual acuity postoperatively.

106 NEW THERAPIES FOR CONGENITAL NYSTAGMUS 50 45 40 Prism diopter

35 30

STRAB-PRE STRAB-PO

25 20 15 10 5 0 1

4

7

10

13

16

19

22

25

28

31

34

37

40

43

46

49

52

Patient number

Number of patients

Figure 12.5 Individual change in the strabismus deviation in patients after surgery. PT, patient number; STRABPOST, strabismus deviation postoperatively; STRAB-PRE, strabismus deviation preoperatively. 19

20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

5˚ 10˚

2 0 AHP_PRE

AHP_POST

Surgery status

Ms

Figure 12.6 Change in the 19 patients who had an anomalous head posture after surgery. # of PTS, number of patients; AHP, anomalous head posture; POST, postoperatively; PRE, preoperatively. 300 275 250 225 200 175 150 125 100 75 50 25 0

FOV-PRE FOV-PO

1

3

5

7

9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53

Patient number

Figure 12.7 Individual change in the foveation deviation in patients after surgery. FOV-POST, foveation duration postoperatively; FOV-PRE, foveation duration preoperatively; PT, patient number.

107

EFFECTS OF EXTRAOCULAR MUSCLE SURGERY

A OS position

R J and DJ

L

OS velocity 291

292

293

294

295

296

297

298

299

B OS position

R

Jef and BDJ and DJ

L OS velocity

197

198

199

200

201

202

203

204

205

Figure 12.8 Eye movement recording data of OS from patient 12, performed under binocular conditions using data from the preferred left eye illustrating a postoperative change in waveform from dual jerk to jerk with extended foveation and bidirectional jerk. Upper trace is position and lower trace is velocity. L, left/down; OS, left eye; PAN, periodic alternating nystagmus; post-op, postoperative; pre-op, preoperative; PT, patient; R, right/up. pathways that use gamma-aminobutyric acid.13,24,28,29 The time course of post-rotational VOR and velocity storage are both prolonged in patients with acquired PAN.13,24,28,29 In contrast, it has been reported that patients with INS actually have abnormally short velocity storage time constants (≈ 1 to 2 seconds).30 The shortened time constant, plus the observation that acquired PAN patients do not have aperiodicity, implies a different, and as yet unknown, pathophysiology in IPAN patients. In a study of 224 patients with INS, Abadi et al.3 classiﬁed 139 (62%) as idiopaths, 63 (28%) as albinos, and 22 (10%) as having other ocular anomalies. Conjugate, uniplanar horizontal oscillations were found in 174 (77.7%), while 32 (14.3%) had a torsional component; 182 (81.2%) were classed as “congenital” nystagmus, 32 (14.3%) as manifest latent

nystagmus, and 10 (4.5%) as a hybrids. PAN was found in albinos. Albino subjects did not show statistically signiﬁcantly higher nystagmus intensity when compared with the idiopaths (p > 0.01). Of 143 subjects, 105 (73%) had spatial nulls within ±10º of the primary position, although 98 subjects (69%) employed a compensatory head posture. Subjects with spatial null zones at or beyond ±20º always adopted constant head postures. Head nodding was found in 38 subjects (27% of the sample). Horizontal tropias were very common (133 out of 213; 62.4%).3 Abadi and Pascal6 studied 25 subjects with oculocutaneous albinism (16 tyrosinase negative and 9 tyrosinase positive) and 7 with ocular albinism (5 X-linked and 2 autosomal recessive) and found that 12 exhibited IPAN. The nystagmus waveforms encountered during the PAN active phases were either jerk with extended foveation or pseudocycloid,

108 NEW THERAPIES FOR CONGENITAL NYSTAGMUS whereas a variety of oscillations (including triangular and bidirectional) were evident during the quiet phases. For most of the 12 subjects, there was an asymmetric variation in nystagmus intensity during each PAN cycle. None of the 12 demonstrated a convergence null or an abnormal head posture. The authors concluded that IPAN is a common oscillation among humans with albinism and that changes in gaze position markedly inﬂuenced the periodicity of the ongoing nystagmus.6 Gradstein et al.7 diagnosed IPAN in 18 (9%) of their 200 patients with infantile nystagmus, although most had not been diagnosed with PAN before referral, despite changing nystagmus reported by referring clinicians. In those 18 patients they found that 5 had ocular or oculocutaneous albinism and 16 had an alternating anomalous head posture (AHP). The PAN cycle was of variable duration, often with asymmetrical right- and left-beating components. Although horizontal jerk nystagmus with accelerating slow phase was predominant, other waveforms were encountered in the active phase of PAN. In the quiet phase (close to null zone), similar, but less intense, oscillations to those in the active phase were characteristic. Half of the patients showed a combination of jerk and pendular waveforms in both phases.7 In another report, the same authors found ocular oscillations consistent with INS evident in 24 of 27 patients with oculocutaneous albinism and Hermansky-Pudlak syndrome (HPS), and half showed PAN.14 They concluded that most patients with HPS have INS, and many have PAN.14 Shallo-Hoffman et al.8 studied 18 patients with INS and found that 7 of the 18 patients had PAN (median cycle: 223 seconds; range: 180 to 307 seconds). The periodicity of the cycles for each adult patient was regular, although the phases within a cycle were often asymmetric. Six of the 7 patients had an AHP, and in 5 of 7 with AHP it was in only one direction (static). Except for one patient, the PAN waveforms had an increasing slow-phase velocity in at least one phase of the cycle; in the other phase they were linear. The authors concluded that the AHP was dependent on, and could be predicted from, the waveforms containing the longest foveation times. Although the waveforms and foveation times may differ among the phases of the PAN cycle, the periodicity of the cycle was usually regular and therefore predictable.8 Hosokawa et al.31 found periodicity in the timefrequency distribution in 3 of 13 patients (23%) with INS. One of the 3 patients was diagnosed with pure PAN, and the other 2 patients showed aperiodicity manifested by intensity rather than directional changes. Eighteen of 91 (19.8%) patients with infantile nystagmus who were seen in the Teikyo University School of Medicine were diagnosed with IPAN. The researchers found that face-turning was seen in patients between

the ages of 3 and 9 years. Visual acuity no worse than 20/40 with correction was obtained in all patients, and nearly all had an asymmetric null cycle manifested in an aperiodic alternating head posture.32 The 78 patients with IPAN in our study represent a 15.4% incidence of IPAN in our INS population. The indication for extraocular muscle surgery in 53 patients included strabismus with or without a static AHP or the head posture or nystagmus alone. We performed standard extraocular muscle surgery (recession/resection/myectomy) on patients with strabismus and/or an AHP, while those without such conditions had bilateral horizontal rectus tenotomy with reattachment. The data collected on these patients support the hypothesis that surgical manipulation of the extraocular muscles in patients with oculographically diagnosed INS “improves” the oscillation and visual functions. Interestingly, the nature of the “cycle” is also changed, becoming longer in its duration and null period and showing a predominant change to more favorable waveforms and foveation duration during the null period. Although patients will have absolute improvement in visual acuity, it is in the range of 1 to 3 Snellen lines. Other “measures” of visual function have also been reported to improve after surgery, and probably contribute to visual “well-being.” These include vision in eccentric gaze (gaze-dependent visual acuity), absolute recognition time, and improved binocular ﬁeld (due to a more normal head posture).1,16,35,36 The clinical and electrophysiologic consequences of extraocular muscle surgery in patients with INS may be due to interruption of the afferent proprioceptive loop, producing a damped peripheral ocular motor response to the nystagmus signal.31,32 Every patient with INS has periods where the nystagmus intensity (amplitude × frequency) is least. It is usually in these quiet periods (null times/zones/ positions) that visual function is best, due to improved foveation quantity and quality during each beat of nystagmus.1,16,35,36 These null times/zones result from a complex combination of unknown afferent and efferent patient characteristics. What we do know about the null period(s) in INS is that there are both static and dynamic components, present to some degree in all patients. The static components that either produce or modify a null/quiet period include a consistent horizontal/vertical/torsional position of gaze (eye in orbit, static gaze angle = Ng) and convergence at near or distance (vergence damping, nystagmus blockage, static convergence = Nv). The static null position for most patients is in the three-dimensional midline (i.e., straight ahead). However, 10% to more than 50% of children have their null zone in an eccentric position of gaze relative to midline (horizontally, vertically, torsionally, or a combination of all three).1,3,5,9,37,38

EFFECTS OF EXTRAOCULAR MUSCLE SURGERY

The null zone/period in patients with INS also has multiple dynamic components. The dynamic components that either produce or modify a null/quiet period include a movement of the null toward a covered eye (causing a clinical “latent component,” dynamic ﬁxing eye = Fe), null movement in the direction opposite of smooth pursuit, optokinetic (OKN) and VOR stimuli (giving the impression of low gain pursuit [saccadic] and “reversal” of OKN-induced eye movements [Dynamic SP−VOR−OKN = E0]), and ﬁnally a change over time in both the short term (minutes, periodic/ aperiodic) and over the long term (years, associated with age) [Dynamic (A)PAN = ∆T].1,3,5,9,37,38 Other wellrecognized and highly associated developmental or congenital abnormalities of the visual system affect the oscillation of infantile nystagmus in general and the null/quiet periods in particular. These include highspatial-frequency vision (acuity) compromise due to optic nerve and retinal disease, heterotopia (and eye dominance), and amblyopia. We hypothesize that all of the variables listed above— the static components, the dynamic components, and

109

other visual system factors—combine in a mathematical way to produce the clinical null period we observe and use to guide much of our medical and surgical treatment of this ocular oscillation (Fig. 12.9). It is difﬁcult at this point to describe the details of that mathematical or hierarchical structure, or the neurological mechanisms producing the ﬁnal null periods associated with INS. The perturbations of the basic INS oscillation as a result of gaze, time, binocular/monocular viewing, acuity, heterotopia, and motion are probably directed by complex developmental connections between the multiple parallel pathways in the afferent visual and efferent vestibular, vestibular ocular, and velocity storage systems. Based on the data from this and other reports of patients with IPAN, we also hypothesize that the rhythmic component of IPAN and the associated head posturing are heavily inﬂuenced by associated heterotopia with visual and motor dominance. The occurrence of IPAN is not as rare as previously suggested and can be missed because of long or irregular cycles and the patient’s preference for only one AHP. The changing null period is easier to recognize

Figure 12.9 A hypothetical model showing how the clinical null or quiet period is inﬂuenced, and ultimately determined, by a complex and changing combination of dynamic and static factors. These factors interact in a hierarchical and temporal way to change how any one patient with INS may have what appears to be a clinically “changing” null or “multiple” null positions. f1(Ng) = static gaze null (horizontal, vertical or torsional) as a function of a1 + a2 + a3; f2(Nv) = static convergence damping as a function of a1 + a2 + a3; f3(Fe) = dynamic null inﬂuenced by a ﬁxing eye (“latent component”) as a function of a1 + a2 + a3; f4(E0) = dynamic null inﬂuenced by smooth pursuit, vestibular ocular reﬂex, or optokinetic responses as a function of a1 + a2 + a3; f5(∆T) = dynamic null inﬂuenced by an underlying regular or irregular rhythm (periodicity) as a function of a1 + a2 + a3. a1, amblyopia; a2, heterotopia; a3, optic nerve or retinal disease; Np, overall null position.

110 NEW THERAPIES FOR CONGENITAL NYSTAGMUS using eye movement recordings, but in most clinical environments these are not available. The clinician may be able to diagnose this disorder if an INS patient is examined in the following way: occlude the nonpreferred eye and examine the preferred eye with the head straight and the gaze in primary position over at least 5 to 7 minutes. The examiner looks for a regular or irregular changing oscillation intensity and/or direction. Identiﬁcation of IPAN, and possibly its waveform characteristics, is essential in cases in which surgical or medical treatment is considered for correction of strabismus, nystagmus, and/or an associated AHP. At any moment in time (the fourth dimension) the ocular-motor-system abnormality of INS is clinically and electrophysiologically variably expressed. The variability of the oscillation is due in part to a combination of complex visual-system and developmental–neurological modiﬁers. The eye movement abnormality is not present in isolation; it continuously interacts with other ocular motor, vestibular, afferentvisual system, and cognitive factors on a minute-tominute—as well as a year-to-year—basis.1,3,5,9,36,37 The dynamic nature of this abnormality requires that clinicians and scientists evaluate and study this disease in that fourth dimension of time. This conceptual approach will result in a more profound understanding of the disease and how our therapy changes the visual system of these patients.

References 1. Dell’Osso LF, Daroff RB. Congenital nystagmus waveforms and foveation strategy. Doc Ophthalmol. 1975;39(1):155–182. 2. National Eye Institute. The Classiﬁcation of Eye Movement Abnormalities and Strabismus (CEMAS): Report of an NEI Sponsored Workshop, 2001. National Eye Institute Web site. http://catalog.nei.nih. gov/productcart/pc/viewPrd.asp?id-category= 0&idproduct=52. Accessed January 21, 2008. 3. Abadi RV, Bjerre A. Motor and sensory characteristics of infantile nystagmus. Br J Ophthalmol. 2002;86(10):1152–1160. 4. Hertle RW, Dell’Osso LF. Clinical and ocular motor analysis of congenital nystagmus in infancy. J AAPOS. 1999;3(2):70–79. 5. Hertle RW, Maldanado VK, Maybodi M, Yang D. Clinical and ocular motor analysis of the infantile nystagmus syndrome in the ﬁrst 6 months of life. Br J Ophthalmol. 2002;86(6):670–675. 6. Abadi RV, Pascal E. Periodic alternating nystagmus in humans with albinism. Invest Ophthalmol Vis Sci. 1994;35(12):4080–4086.

7. Gradstein L, Reinecke RD, Wizov SS, Goldstein HP. Congenital periodic alternating nystagmus. Diagnosis and management. Ophthalmol. 1997; 104(6):918–929. 8. Shallo-Hoffmann J, Faldon M, Tusa RJ. The incidence and waveform characteristics of periodic alternating nystagmus in congenital nystagmus. Invest Ophthalmol Vis Sci. 1999;40(11):2546–2553. 9. Hertle RW, Yang D, Kelly K, et al. X-linked infantile periodic alternating nystagmus. Ophthalmic Genet. 2005;26(2):77–84. 10. Averbuch-Heller L. Acquired nystagmus. Curr Treat Options Neurol. 1999;1(1):68–73. 11. DiBartolomeo JR, Yee RD. Periodic alternating nystagmus. Otolaryngol Head Neck Surg. 1988;99(6):552–557. 12. Leigh RJ, Khanna S. What can acquired nystagmus tell us about congenital forms of nystagmus? Semin Ophthalmol. 2006;21(2):83–86. 13. Leigh RJ, Robinson DA, Zee DS. A hypothetical explanation for periodic alternating nystagmus: instability in the optokinetic-vestibular system. Ann NY Acad Sci. 1981;374:619–635. 14. Gradstein L, FitzGibbon EJ, Tsilou ET, et al. Eye movement abnormalities in Hermansky-Pudlak syndrome. J AAPOS. 2005;9(4):369–378. 15. Hertle RW, Dell’Osso LF, FitzGibbon EJ, et al. Horizontal rectus tenotomy in patients with congenital nystagmus: results in 10 adults. Ophthalmol. 2003;110(11):2097–2105. 16. Hertle RW, Yang D. Clinical and electrophysiological effects of extraocular muscle surgery on patients with Infantile Nystagmus Syndrome (INS). Semin Ophthalmol. 2006;21(2):103–110. 17. Wang Z, Dell’Osso LF, Tomsak RL, Jacobs JB. Combining recessions (nystagmus and strabismus) with tenotomy improved visual function and decreased oscillopsia and diplopia in acquired downbeat nystagmus and in horizontal infantile nystagmus syndrome. J AAPOS. 2007;11(2):135–141. 18. Holmes JM, Beck RW, Repka MX, et al. The amblyopia treatment study visual acuity testing protocol. Arch Ophthalmol. 2001;119(9):1345–1353. 19. Yang D, Hertle RW, Hill VM, Stevens DJ. Gaze-dependent and time-restricted visual acuity measures in patients with Infantile Nystagmus Syndrome (INS). Am J Ophthalmol. 2005;139(4):716–718. 20. Brigell M, Bach M, Barber C, et al. Guidelines for calibration of stimulus and recording parameters used in clinical electrophysiology of vision. Calibration Standard Committee of the International Society for Clinical Electrophysiology of Vision (ISCEV). Doc Ophthalmol. 1998;95(1):1–14.

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21. Dell’Osso. OMLAB Web site. http://www.omlab. org. Last updated December 30, 2007. Last accessed March 3, 2008. 22. Davis DG, Smith JL. Periodic alternating nystagmus. A report of eight cases. Am J Ophthalmol. 1971;72(4):757–762. 23. Korres S, Balatsouras DG, Zournas C, et al. Periodic alternating nystagmus associated with ArnoldChiari malformation. J Laryngol Otol. 2001;115(12): 1001–1004. 24. Leigh RJ, Das VE, Seidman SH. A neurobiological approach to acquired nystagmus. Ann N Y Acad Sci. 2002;956:380–390. 25. Lewis JM, Kline LB. Periodic alternating nystagmus associated with periodic alternating skew deviation. J Clin Neuroophthalmol. 1983;3(2):115–117. 26. Matsumoto S, Ohyagi Y, Inoue I, et al. Periodic alternating nystagmus in a patient with MS. Neurology. 2001;56(2):276–267. 27. Oh YM, Choi KD, Oh SY, Kim JS. Periodic alternating nystagmus with circumscribed nodular lesion. Neurology. 2006;67(3):399. 28. Furman JM, Wall C 3rd, Pang DL. Vestibular function in periodic alternating nystagmus. Brain. 1990;113(5):1425–1439. 29. Lee MS, Lessell S. Lithium-induced periodic alternating nystagmus. Neurology. 2003;60(2):344. 30. Demer JL, Zee DS. Vestibulo-ocular and optokinetic deﬁcits in albinos with congenital nystagmus. Invest Ophthalmol Vis Sci. 1984;25(6):739–745. 31. Hosokawa M, Hasebe S, Ohtsuki H, Tsuchida Y. Time-frequency analysis of electronystagmogram

32.

33.

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35.

36.

37. 38.

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signals in patients with congenital nystagmus. Jpn J Ophthalmol. 2004;48(3):262–267. Hayashi T, Hasegawa F, Usui C, Kubota N. Pathophysiology and diagnosis of congenital periodic alternating nystagmus. Nippon Ganka Gakkai Zasshi. 2003;107(5):265–272. Dell’Osso LF. Biologically relevant models of infantile nystagmus syndrome: the requirement for behavioral ocular motor system models. Semin Ophthalmol. 2006;21(2):71–77. Hertle RW, Chan CC, Galita DA, et al. Neuroanatomy of the extraocular muscle tendon enthesis in macaque, normal human, and patients with congenital nystagmus. J AAPOS. 2002;6(5): 319–327. Hertle RW, Anninger W, Yang D, et al. Effects of extraocular muscle surgery on 15 patients with oculo-cutaneous albinism (OCA) and infantile nystagmus syndrome (INS). Am J Ophthalmol. 2004;138(6):978–987. Wang ZI, Dell’Osso LF. Being “slow to see” is a dynamic visual function consequence of infantile nystagmus syndrome: model predictions and patient data identify stimulus timing as its cause. Vision Res. 2007;47(11):1550–1560. Gottlob I. Nystagmus. Curr Opin Ophthalmol. 2000;11(5):330–335. Reinecke RD. Costenbader lecture. Idiopathic infantile nystagmus: diagnosis and treatment. J AAPOS. 1997;1(2):67–82.

13 Eye Muscle Surgery for Acquired Forms of Nystagmus ROBERT L. TOMSAK, LOUIS F. DELL’OSSO, JONATHAN B. JACOBS, ZHONG I. WANG, AND R. JOHN LEIGH

ABSTRACT We report 3 patients with acquired nystagmus who were treated with eye muscle tenotomy and reattachment. The ﬁrst patient had acquired pendular nystagmus (APN) associated with multiple sclerosis (MS) and underwent bilateral medial rectus tenotomies and bilateral lateral rectus recessions to correct exotropia. Eye movements were recorded before surgery, after surgery, and after surgery and treatment with memantine. Following surgery, APN decreased by ≈ 50% and the eXpanded Nystagmus Acuity Function (NAFX) increased by 34%. Measured Snellen acuity increased 100%, from 0.125 OD and OS to 0.25. Saccades were unaffected. After treatment with memantine, APN was damped further by 69%, and NAFX was improved an additional 9%; Snellen acuity increased 60% to 0.4. The second patient had monocular APN associated with MS. The horizontal recti were tenotomized and reattached in only the eye with nystagmus. This resulted in damping of the nystagmus by 66%, and Snellen acuity increased 100% from 0.2 to 0.4. The third patient had downbeat nystagmus of undetermined etiology and preferred a chin-down (up-gaze) head position to diminish symptoms. Asymmetrical superior rectus recessions, to address head position and hypertropia, were combined with tenotomy and reattachment of both inferior recti. Surgery resulted in reduction of vertical nystagmus by 46%, improvement of NAFX values by 17%, and improvement in visual acuity from 20/25

to 20/20. These preliminary results support the view that eye muscle tenotomy may diminish acquired forms of nystagmus and improve vision in selected patients. Although eye muscle surgery is established as a treatment modality for congenital forms of nystagmus, its place in the therapy of acquired forms of nystagmus is debated. Currently, there is a dearth of studies that evaluate the results of such surgery using reliable methods for measuring eye movements. In this chapter, we report our experience in studying the effects of surgery on the eye muscles of 3 patients with acquired forms of nystagmus. We have used a procedure developed for the treatment of congenital forms of nystagmus—eye muscle tenotomy and reattachment (T&R).1 Partial descriptions of theses cases have been previously published.2,3

CASE REPORTS Case 1 The ﬁrst patient had acquired pendular nystagmus (APN) from multiple sclerosis (MS) and underwent bilateral medial rectus T&R and bilateral lateral rectus recessions to correct exotropia (i.e., tenotomy combined with recession). Eye movements were recorded by the scleral search coil technique at three times: before surgery, after surgery, and after surgery and treatment with oral memantine (Figs. 13.1 and 13.2). Following surgery, APN decreased by ≈ 50%, and the eXpanded Nystagmus Acuity Function (NAFX)

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Figure 13.1 Presurgery and post-surgery scanpaths (horizontal vs. vertical) from case 1. The horizontal and vertical components of acquired pendular nystagmus were damped by surgery and exotropia was improved postoperatively. RE, right eye; LE, left eye; BE, both eyes. increased by 34%. Measured Snellen acuity increased 100% from 0.125 OD and OS to 0.25. Saccades were unaffected. After treatment with memantine, APN was damped further by 69% and NAFX was improved an additional 9%; Snellen acuity increased 60% to 0.4.

Comment: Vertical components of APN were reduced as well as horizontal components, even though surgery was only done on the four horizontal recti. Memantine appeared to have an additive effect to T&R, presumably by a different, central mechanism.

Case 2 The second patient (Fig. 13.3) had uniocular APN in association with MS. Pre- and post-tenotomy eye movements were studied using digitized video recordings. The horizontal recti were tenotomized and reattached only in the eye with APN; this resulted in damping of the nystagmus by 66% and an increase in Snellen acuity 100% from 0.2 to 0.4. Comment: The addition of gabapentin did not appear to augment effect of T&R in this patient.

Case 3 Figure 13.2 Eye speeds for the ﬁxating right eye (case 1) measured pre– and post–horizontal rectus muscle surgery and also after addition of memantine.

The third patient (Fig. 13.4) had downbeat nystagmus of undetermined etiology, oscillopsia, and vertical

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114 NEW THERAPIES FOR CONGENITAL NYSTAGMUS 0.03 0.02 0.01 0 0.01 0.02 0.03

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diplopia from skew deviation; he preferred a chindown (up-gaze) head position to diminish symptoms. Pre- and post-tenotomy eye movements were recorded by a high-speed digital video system. Asymmetrical superior rectus recessions were done to address head position and hypertropia and were combined with T&R of both inferior recti. Surgery resulted in movement of the NAFX peak from 10º up to primary position, and NAFX values were improved by 17%. Vertical NAFX values increased across the −10º to ±5º vertical range. Foveation time per cycle increased from 88 to 178 milliseconds (102%). Vertical component nystagmus amplitude was reduced by 46%, and frequency was unchanged at ≈ 3 Hz. Visual acuity was improved from 20/25 to 20/20, and the hypertropia was improved. Comment: The vertical NAFX was increased across the −10º to ±5º range, resulting in improved functional vision.

DISCUSSION To put the present results into context, we provide a brief historical review of the surgical treatment of nystagmus. In 1906, Colburn described attaching the

Figure 13.4 Case 3: Vertical eXpanded Nystagmus Acuity Function (NAFX) values increased across the −10º to ±5º range of vertical gaze postoperatively.

lateral rectus to the periosteum of the orbital wall in an attempt to reduce the amplitude of nystagmus.4 Little else was reported until the early 1950s, when Kestenbaum,5 Anderson,6 Goto,7 and Rama8 described surgical techniques to change gaze angle in order to take advantage of nystagmus null positions, mainly in cases of congenital nystagmus.4 (Infantile nystagmus has now replaced congenital nystagmus as the preferred term and will be used in this chapter except when quoting older literature.) Kestenbaum described a resect– recess operation and, in the second edition of his book, Clinical Methods of Neuro-Ophthalmologic Evaluation,5 made the following comment (italics added): “The genesis of the nystagmus is not relevant for the indication of surgery. The nystagmus may be an asymmetric nystagmus from infancy or an acquired nystagmus in a demyelinizing disease or a ‘manifested latent nystagmus.’ ” Anderson6 described recession of yoke muscles in the direction of the slow-phase drift of nystagmus. He came to this idea after observing a change in subjective and objective characteristics of nystagmus in a patient who underwent strabismus surgery. It had been observed that nystagmus is not infrequently lessened after an operation for strabismus had been performed. One man, aged 22 years, at the time of operation for a left convergent strabismus of at least 60 dioptres, had been worried by the apparent movement of a wall from side to side. It is unusual for patients with congenital nystagmus to be conscious of movement of objects, and this man was conscious only of the movement of walls. Vision was 6/9 in the right eye and 6/12 in the left. Both nystagmus and strabismus had been life-long. The conscious movement vanished after a recession

EYE MUSCLE SURGERY FOR ACQUIRED FORMS OF NYSTAGMUS

of each internal rectus muscle and a resection of each external rectus muscle, even though an angle of anomaly of 20 dioptres persisted. (p. 279) Apparently this was one of the rare patients with infantile nystagmus who had oscillopsia, and the oscillopsia resolved following a bilateral recession–resection (i.e., four-horizontal-muscle) surgery, thus implying an improvement in nystagmus. Rama,8 in 1953, reported a technique similar to Anderson’s procedure. One year later, Goto7 described combining recession with advancement of the antagonist muscle. Over time, surgical procedures to realign the eyes of patients with nystagmus and gaze nulls became known as “Anderson-Kestenbaum procedures.” (We refer to “nystagmus surgery” as any eye muscle surgery done primarily to damp nystagmus, and “strabismus surgery” as any procedure done primarily to correct ocular misalignment. Often, nystagmus surgery and strabismus surgery are combined in the same patient.) In 1979, Dell’Osso and Flynn9 recorded eye movements of 3 patients before and after surgery for congenital nystagmus. In addition to shifting the nystagmus null, they observed broadening of the null region and an overall reduction of nystagmus intensity at all gaze angles. This led them to speculate that the surgery caused “nonlinear changes in ocular motor plant dynamics (i.e., changes in the characteristics of the muscles, tendons, Tenon’s capsule, fatty and scar tissue interactions) as a result of the surgical changing of the points of insertion and methods of attachment of the muscles to the globe.” Bosone et al.10 found similar results. Subsequently, Dell’Osso et al. showed that eye muscle tenotomy and reattachment (T&R) alone had salutary effects on nystagmus amplitude and velocity in dogs with nystagmus11 and in humans with infantile nystagmus.1,12 A hypothesis evolved that T&R damaged proprioceptive structures in eye muscle tendon that affected the nystagmus oscillation.13 More recently, Büttner-Ennever et al.14 identiﬁed two separate sets of ocular motor neurons, one of which participates in proprioceptive feedback that aligns and stabilizes the eyes and has palisade endings located in myotendinous junctions of eye muscles. The cell bodies for these neurons are located around the periphery of the brainstem nuclei. Hertle et al.15 found similar structures more distally at the enthesial (tendino-scleral) regions of eye muscle tendons. All of the forgoing support the hypothesis that T&R of selected eye muscles should have a beneﬁcial effect on acquired nystagmus by the same mechanism as it does on infantile nystagmus: reduction of small-signal gain of the ocular motor plant by interfering with

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proprioceptive tension control.16 Our present results support the view that eye muscle tenotomy may have a role to play in acquired forms of nystagmus of differing etiologies, waveforms, planes of action, and even various neuroanatomic sites of origin. This ability to treat different types of nystagmus supports the hypothesized proprioceptive mechanism of action. Controlled, prospective studies of T&R as treatment of acquired nystagmus are called for so that this therapy can be compared with available pharmacological measures.

References 1. Hertle RW, Dell’Osso LF, FitzGibbon EJ, Thomson D, Yang D, Mellow SD. Horizontal rectus tenotomy in patients with congenital nystagmus. Results in 10 adults. Ophthalmol. 2003;110:2097–2105. 2. Tomsak RL, Dell’Osso LF, Rucker JR, Leigh RJ, Bienfang DC, Jacobs JB. Treatment of acquired pendular nystagmus from multiple sclerosis with eye muscle surgery followed by oral memantine. Digital J Ophthalmol. 2005;11(4):1–11. 3. Tomsak RL, Wang Z, Dell’Osso LF, Jacobs JB. Combined tenotomy ± Anderson procedure for treatment of acquired vertical nystagmus and infantile horizontal nystagmus associated with diplopia and oscillopsia. ARVO Annual Meeting Abstract and Program Planner. Invest Ophthalmol Vis Science. 2006;47. E-Abstract 2512. 4. Colburn JE. Fixation of the external rectus muscle in nystagmus and paralysis. Am J Ophthalmol. 1906;23:85–88. 5. Kestenbaum A. Clinical Methods of Neuroophthalmologic Evaluation, 2nd ed. New York, NY: Grune and Stratton; 1961. 6. Anderson JR. Causes and treatment of congenital eccentric nystagmus. Brit J Ophthalmol. 1953;37:267–281. 7. Goto N. Nystagmus surgery. Act Soc Ophth Jap. 1954;58:176. 8. Rama G. Strabismo e nistagmo. Rass Ital Ottal. 1953;22:245. 9. Dell’Osso LF, Flynn JT. Congenital nystagmus surgery: a quantitative evaluation of the effects. Arch Ophthalmol. 1979;97:462–469. 10. Bosone G, Reccia R, Roberti G, Russo P. On the variations of the time constant of the slow-phase eye movements produced by surgical therapy of congenital nystagmus: a preliminary report. Ophthal Res. 1989;21:345–351. 11. Dell’Osso LF, Hertle RW, Williams RW, Jacobs JB. A new surgery for congenital nystagmus: effects of tenotomy on an achiasmatic canine and

116 NEW THERAPIES FOR CONGENITAL NYSTAGMUS the role of extraocular proprioception. J AAPOS. 1999;3:166–182. 12. Hertle RW, Dell’Osso LF, FitzGibbon EJ, Thompson D, Yang D, Mellow SD. Horizontal rectus muscle tenotomy in patients with infantile nystagmus syndrome: a pilot study. J AAPOS. 2004;8:539–548. 13. Dell’Osso LF. Extrocular muscle tenotomy, dissection and suture: an hypothetical therapy for congenital nystagmus. J Pediat Ophth Strab. 1998;35:232–233. 14. Büttner-Ennever JA, Horn AKE. The neuroanatomical basis of oculomotor disorders: the dual

motor control of extraocular muscles and its possible role in proprioception. Curr Opin Neurol. 2002;15:35–43. 15. Hertle RW, Chan CC, Galita DA, Maybodi M, Crawford MA. Neuroanatomy of the extraocular muscle tendon enthesis in macaque, normal human, and patients with congenital nystagmus. J AAPOS. 2002;6:319–327. 16. Wang Z, Dell’Osso LF, Zhang Z, Leigh RJ, Jacobs JB. Tenotomy does not affect saccadic velocities: support for “small-signal” gain hypothesis. Vision Res. 2006;46:2259–2267.

14 The Complement Hypothesis to Explain Preferential Involvement of Extraocular Muscle in Myasthenia Gravis HENRY J. KAMINSKI, YUEFANG ZHOU, JINDRICH SOLTYS, AND LINDA L. KUSNER

ABSTRACT Extraocular muscle (EOM) is nearly always involved in myasthenia gravis. The reasons are multifaceted, but the authors contend that an intrinsic low level of cell surface complement inhibitors is a key factor. Complement inhibitors have been shown to protect the neuromuscular junction (NMJ) from attack by acetylcholine receptor (AChR) antibodies. The EOMs of rodents have a low level of expression of complement regulator genes, and their NMJs have low protein expression, which would put them at greater risk for the antibodymediated, complement-dependent pathology of myasthenia gravis. Preliminary studies support that EOM suffers greater complement damage in experimentally acquired myasthenia gravis. Among ocular myasthenic patients, the serum concentration of AChR antibody is low or absent, which suggests that EOMs are more susceptible to antibody injury. Taken together, these observations support the complement hypothesis of EOM susceptibility to myasthenia gravis, which states that extraocular muscle susceptibility to myasthenia gravis is caused by a low level of intrinsic complement regulators at their neuromuscular junctions. Myasthenia gravis (MG) is a neuromuscular transmission disorder caused by antibody-mediated complement injury to the neuromuscular junction (NMJ).1-3 The resultant damage to the NMJ leads to loss of acetylcholine receptors (AChR) and simpliﬁcation of the postsynaptic architecture.4 Patients with MG demonstrate a

distinct predilection for involvement of extraocular muscle (EOM). While the authors have, in previous reviews, presented arguments for functional and physiological reasons as to why this might be the case,5,6 in this chapter we present mounting evidence that a low level of complement-inhibitory proteins may be the predominant contributor to the differential involvement of EOM by MG. If correct, this contention has signiﬁcant therapeutic ramiﬁcations. Complement inhibitors are being evaluated in human trials, and their application to MG in general, and its ocular complications in particular, may be of signiﬁcant beneﬁt to patients. This chapter provides a brief review of the pathophysiology of MG, followed by a discussion of possible explanations for the differential involvement of EOM by MG. The authors then present their observations to support the “complement hypothesis” as an explanation for the propensity of EOM manifestations produced by MG.

PATHOPHYSIOLOGY OF MG Since the proposals by Simpson and Nastuck in the 1950s that MG was an autoimmune disorder, MG has become one of the few disorders to fulﬁll strict criteria for an antibody-mediated autoimmune disorder: (a) antibody is identiﬁed at the NMJ, the primary site of pathology; (b) when injected into experimental animals, antibody—essentially exclusively the complement-ﬁxing antibody fraction, from sera of MG patients, or antibody directed against the muscle AChR—causes weakness and fatigue—the hallmarks of human MG—and results in electrophysiological

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118 NEW THERAPIES FOR CONGENITAL NYSTAGMUS evidence of a neuromuscular transmission defect; (c) immunization of animals with puriﬁed AChR leads to autoantibody formation, weakness, and pathological ﬁndings of MG; and (d) plasma exchange, which removes antibody, reduces clinical manifestations of MG.1-3 AChR antibody affects neuromuscular transmission by three mechanisms: (1) a process of antigenic modulation, which leads to the accelerated degradation of AChR; (2) block of AChR function; and (3) activation of complement-mediated disruption of the NMJ. Antigenic modulation refers to the ability of an antibody to cross-link two AChRs, which leads to a signal that accelerates endocytosis and degradation of the surface AChR.7 The ability of certain AChR antibodies to produce antigenic modulation is a function of not only all IgG having two antigen binding sites but also the close proximity of AChR on the postsynaptic muscle surface. Therefore, the epitope location on the AChR offers the possibility for a single AChR antibody to bind to two AChR. AChR antibody of MG patients accelerates the degradation rate of the AChR in vivo and in cultured muscle cells.8 AChR antibody may block the acetylcholine (ACh) binding site, and experimentally acquired MG (EAMG) produced in animals by infusion of such antibodies causes rapidly developing, severe weakness.9 However, in humans, such antibodies do not appear to be clinically important.1-3 The unifying mechanism by which AChR antibody causes neuromuscular transmission failure is the reduction of endplate potential to below the required level for achievement of a propagated action potential. Under normal conditions, the endplate potential is well above this level. The endplate potential is a function of (a) the quantal release of ACh, (b) the conduction properties and density of the postsynaptic AChR, and (c) the acetylcholinesterase (AChE) activity concentrated at the NMJ.4,10 The postsynaptic folds form a high-resistance pathway that focuses endplate current ﬂow on voltage-gated sodium channels, which are concentrated at the bottom of the folds, and MG produces a loss of postsynaptic folds.11,12 Compromise of AChR activation decreases the endplate potential, but the potential may still activate an action potential. However, if release of ACh is reduced by repetitive activity, the endplate potential may fall below the threshold needed to trigger the action potential. This difference between threshold and endplate potential is termed the safety factor. A new autoantigen has been identiﬁed as a cause of a subset of so-called seronegative MG patients, or patients with clinical and electrophysiological evidence of MG but an absence of AChR antibody. The muscle-speciﬁc kinase (MuSK) protein is localized to the NMJ and plays a role in clustering of AChR to the postsynaptic surface. Hoch et al.13 found that about

one-third of patients with seronegative MG have antibodies directed against MuSK, and that these antibodies impair clustering of AChR. Since then, there has been a rapid proliferation of discovery that identiﬁes MuSK antibody patients as having a predominance of weakness involving the bulbar musculature (but rarely isolated ocular myasthenia) and being relatively treatment resistant. Immunization of animals with puriﬁed MuSK has produced disease with a neuromuscular transmission defect.14 Whether or not MuSK-related MG is induced by complement mechanisms has not been established.

EXTRAOCULAR MUSCLE SUSCEPTIBILITY TO MG The functional and physiological reasons for the differential involvement of EOM by MG can be enumerated as follows: (a) even a slight reduction of EOM force generation may misalign the visual axes and produce dramatic symptoms; (b) the NMJ of EOM are stimulated at much higher frequencies than those of other skeletal muscles, which, if they function in a similar manner to the NMJ of other skeletal muscle, would be expected to make them more vulnerable to fatigue; (c) anatomic and physiological properties of EOM ﬁbers and their NMJ suggest susceptibility to neuromuscular transmission block; and (d) the autoimmune pathology may contribute to targeting of EOM by MG.5,6 The most obvious explanation for EOM susceptibility is the requirement for perfect alignment of the visual axes to assure clear vision; if they are not aligned, then the dramatic visual complaints of diplopia, dizziness, visual confusion, or blurring occur.15 Such symptoms will bring patients to medical attention early in the course of disease. In contrast, a small reduction of force by a limb muscle may not be symptomatic. In addition, proprioceptive feedback producing compensatory changes that limit clinical manifestations is likely more prominent in other skeletal muscle compared to the ocular motor system.15 The ocular motor neurons have ﬁring stimulation frequencies. Fast EOM motor units appear to normally function at 100 Hz or above, while nonocular motor neurons function at such levels only brieﬂy.16-18 Based on the discussion of the pathophysiology of MG, one would expect such high stimulation rates to put EOM junctions at risk for neuromuscular transmission fatigue. The normally high frequency of stimulation of EOM may be expected to occur at the price of a low safety factor, and therefore any reduction of endplate potential produced by MG would impair neuromuscular transmission.

EXTRAOCULAR MUSCLE INVOLVEMENT IN MYASTHENIA GRAVIS

The NMJs of EOM have structural features that would be expected to place them at risk for transmission failure. Eighty percent of EOM ﬁbers have a single point of neuronal contact, similar to all other skeletal muscles19,20 These are the so-called singly innervated ﬁbers (SIF). Ultrastructural analysis reveals less prominent synaptic folds.19 From this observation, one would predict fewer AChRs and sodium channels on the postsynaptic membrane. A reduction in AChR, sodium channels, and quantal content would reduce the safety factor for transmission at EOM SIFs, putting them at risk for neuromuscular transmission failure. Khanna et al.21 have gone so far as to hypothesize that differential susceptibility among the EOM junctions could explain the observation of “ultra-fast saccades” of MG patients, despite the simultaneous observation of intrasaccadic fatigue. A single study of miniature endplate potential amplitudes surprisingly showed that EOM and leg-muscle junctions have similar levels, which suggests that AChR density and other membrane properties are similar.22 No measures of safety factor at EOM NMJs have been performed. The observation that nearly all neuromuscular transmission disorders affect the ocular muscle would support the idea that physiological reasons are important in their frequent involvement in MG. However, it is important to appreciate that not all patients with MG, or congenital myasthenia patients, have ocular motility defects. Therefore, physiological reasons are not likely to be the only reason for preferential involvement of EOM by MG. About 20% of EOM ﬁbers are innervated at multiple points, and these are the multiply innervated ﬁbers (MIF).19,20 The NMJ of the MIF are smaller than those of the SIF, and they lack postsynaptic folding. The contractile force of the MIF is directly proportional to the membrane depolarization caused by the endplate potential—they contract in tonic fashion, in contrast to the twitch contraction of the SIF. A safety factor does not exist for the MIF NMJ.23 Any reduction of endplate potential induced by AChR loss will decrease contractile force of the MIF. The molecular organization differs slightly between EOM and other skeletal muscle ﬁbers. Alpha-dystrobrevin and syntrophin beta 1 are members of dystrophin-related protein complex localized to the NMJ; however, they are found extrasynaptically at some EOM ﬁbers.20 The potential difference in the expression pattern may contribute to differences in junctional folds. Altered expression of certain structural proteins of NMJ, speciﬁcally rapsyn upregulation, reduces disease severity of EAMG, probably by an increase in the stability of the AChR at the NMJ.24 Although alterations in rapsyn expression are not known in EOM, the lack of junctional folds is evidence that the NMJ of

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EOM may be less structurally stable due to the underlying molecular organization. Preferential immunologic targeting of EOM synapses has been proposed as an explanation for EOM susceptibility.25,26 Sera of some MG patients binds only the MIF synapses, and use of EOM as a source of AChR for AChR antibody assays leads to higher rates of autoantibody detection, which suggests EOM has unique antigenic targets.27,28 Adult EOM uniquely expresses the fetal AChR at MIF and certain SIF endplates.29-31 Therefore, the fetal AChR would be a target for differential antibody attack of EOM NMJ. However, patients with ocular myasthenia have neither antibodies directed primarily toward fetal AChR nor speciﬁc T-cell responses toward fetal AChR epitopes.32,33 The fetal AChR does not appear to be a speciﬁc target. Up to half of ocular myasthenics have nondetectable antibodies to AChR, while 90% of generalized MG patients are seropositive for AChR antibodies. Perhaps the ocular MG patients have antibodies directed at non-AChR antigen.

OVERVIEW OF THE COMPLEMENT SYSTEM AND MG Complement protects the host against invading pathogens by distinct mechanisms, which include cell lysis of pathogens, opsonization with complement fragments, chemotaxis of inﬂammatory cells, and formation of the membrane attack complex (MAC).34,35 MAC is a multimeric protein complex that produces cell lysis (in the case of MG, localized destruction of the NMJ). In adaptive immune response, complement is the effector system for the primary and secondary antibody responses of B cells. Complement activation is regulated by a series of about 30 plasma and membrane proteins participating in classical, alternative, and lectin pathways. For our discussion, the classical pathway is relevant because of its activation by complement-ﬁxing IgG antibodies that target an antigen, which for MG is primarily the AChR. Extensive data support the theory that the complement cascade is the primary mechanism mediating AChR loss at the NMJ in MG. First, C3 activation fragments and the MAC are detected at the NMJ in patients and EAMG animals.11,36,37 Second, if complement is depleted by cobra venom, then EAMG cannot be induced by either infusion of AChR antibody or immunization of rodents with puriﬁed AChR.38 Third, administration of treatments that inhibit complement activity, such an antibody that binds and inhibits the C6 component or the soluble complement receptor 1, protects rodents from EAMG.39,40 Fourth, in EAMG caused by AChR immunization, mice deﬁcient of C5

120 NEW THERAPIES FOR CONGENITAL NYSTAGMUS

Figure 14.1 Complement inhibitors are localized to the diaphragm NMJ. (A) Neuromuscular junction (NMJ) is marked by ﬂuorescently labeled bungarotoxin, which labels the acetylcholine receptor (AChR). (B) Fluorescently labeled antibody against the complement regulator, CD59. (C) Merged image of (A) and (B) demonstrating co-localization of CD59 and bungarotoxin label. (Also see color insert.) or C4 have less severe disease.41,42 Collectively, these data support the proposition that complement deposition and MAC assembly are critical in destruction of the NMJ that causes the defect of neuromuscular transmission. Host tissues are protected from autologous complement-mediated injury by a system of cell-associated and serum-regulatory proteins.43,44 During spontaneous or antibody-initiated activation of the complement cascade, nascent complement components condense with free hydroxyl and amino groups on biological membranes. Because the reactions occur on host cell surfaces as well as on target surfaces, and because, once bound, these fragments serve as assembly points for subsequent components and are the central ampliﬁcation enzymes of the cascade, their activities on host cells must be strictly controlled. The cell-associated regulators include decay-accelerating factor (DAF, CD55), the membrane cofactor protein (MCP or CD46), and the membrane inhibitor of reactive cell lysis (MIRL, CD59).45 DAF, MCP, complement receptor 1-related gene/protein y (Crry), and complement receptor 1 (CR1) are inhibitors of C3 and C5 convertases. CD59 prevents the binding of C9

to C8 and acts as an inhibitor of membrane attack complex (MAC) formation. Collectively, these proteins accelerate the decay of autologous C3 convertases that inappropriately assemble on self cell surfaces,45 promote the cleavage of uncomplexed autologous cell-bound complement components,46 and inhibit the formation of MAC.47-49 DAF forms complexes out of certain complement components. MCP, anchored to the membrane by a polypeptide domain, functions at the level of C3 convertases. CD59 blocks the uptake of the terminal components of the cascade and the assembly of MAC. CD59, as is DAF, is anchored to the cell surface membrane.48,50,51 In mice, the rodent-speciﬁc membrane regulator Crry has activity similar to human MCP, but also has functions that overlap with that of DAF.52 In a series of experiments, we have investigated the importance of complement regulator proteins in EAMG. Mice that are deﬁcient in DAF develop profound weakness when AChR antibodies are administered, while, in marked contrast, wild-type mice show no obvious signs of weakness.53 We extended this investigation to evaluate the respective roles of each of the regulators in protection of the NMJ. We conﬁrmed

EXTRAOCULAR MUSCLE INVOLVEMENT IN MYASTHENIA GRAVIS BTX

Anti-c9

121

Merged

Rat#1 Dia

Rat#6 Dia

BTX

Anti-c9

Merged

Rat#1 EOM

Rat#6 EOM

Figure 14.2 Complement deposition at the neuromuscular junction (NMJ). Top and bottom panels show images of ﬂuorescent bungarotoxin (BTX) in ﬁrst column, C9 deposits identiﬁed with ﬂuorescent antibody in middle column, and merged image in the last column. Rats 1 and 6 received antibody to the acetylcholine receptors (AChR) to induce experimentally acquired myasthenia gravis (EAMG), but rat 6 was treated to eliminate serum complement activity. C9 deposit was eliminated from diaphragm NMJ (top) but not extraocular muscle NMJ (bottom). (Also see color insert.) the original report and demonstrated that mice having an absence of the CD59 had greater evidence of disease, as determined by complement deposition at the NMJ and degree of destruction of NMJ ultrastructure, than normal mice.54 Mice with a deﬁciency of both DAF and CD59 had such severe weakness that even reduced doses of AChR antibody administration (as compared to the original study) required immediate euthanasia. The protective effect of complement regulatory proteins in EAMG has been conﬁrmed by Morgan et al.55

THE “COMPLEMENT HYPOTHESIS” TO EXPLAIN EXTRAOCULAR MUSCLE SUSCEPTIBILITY TO MG In a fundamental look at the differences between EOM and other skeletal muscle, gene-expression studies have been performed on rats and mice to assess speciﬁc markers that create divergence in tissue type.56-59 Using DNA microarray and serial analysis of gene expression, the results identiﬁed signiﬁcant numbers of differentially expressed genes in EOM, compared to

122 NEW THERAPIES FOR CONGENITAL NYSTAGMUS (Fig. 14.3). The result supports the concept that EOMs are subject to greater complement-mediated injury than the NMJ of other muscle. Among ocular myasthenic patients, the serum concentration of AChR antibody is lower (or absent) than in patients with generalized MG. Although correlation of antibody concentration and severity of weakness is not absolute,61,62 it appears that lower titers of antibody are more capable of inducing injury to EOM than other skeletal muscle NMJ. This would be the case if human EOM expressed the complement regulators at low levels. Figure 14.3 Neuromuscular junction (NMJ) of extraocular muscle from an experimentally acquired myasthenia gravis rat. The NMJ shows a wide synaptic cleft and electron-dense material within the synaptic cleft, indicating severe injury. other muscle ranging in number from approximately 100 to 350 genes. The studies indicate expression differences, compared to other skeletal muscle, of genes involved in intermediary metabolism, excitation– contraction coupling, structural organization, transcriptional regulation, and myogenesis. DAF was discovered to have a signiﬁcantly lower expression level in EOM.57 This observation was the ﬁrst suggestion that EOM may not beneﬁt from DAF’s protection in the antibodymediated, complement-dependent disease MG. Complement regulatory proteins are concentrated at the NMJ of other skeletal muscle (Fig. 14.1) (also see color insert), but appear not to be concentrated to the same degree at EOM NMJ. Further, when EAMG is produced, the complement regulatory genes demonstrate a marked down-regulation in expression, and limited to nonexistent up-regulation of complement regulators is observed at the NMJ of EOM. 60 Therefore, EOM does not appear to beneﬁt from having concentrations of complement regulators at the NMJ. We have indirect evidence from preliminary studies that there is a greater degree of complement deposition at EOM NMJ. We ablated serum-complement activity by use of an antibody directed against the C5 component of complement, and thereby induced EAMG. In the same animals (Fig. 14.2A) one cannot detect complement deposition at the non-EOM NMJ, but complement is found at the EOM NMJ (Fig. 14.2B) (also see color insert). This observation supports that a lack of complement inhibitors at the EOM junctions allow complement deposition, even when systemic complement is inhibited. We investigated complement deposition and NMJ damage in EAMG induced by AChR administration and found greater complement component (C3) deposits at EOM NMJ than diaphragm NMJ, as well as a greater degree of ultrastructural injury

FUTURE DIRECTIONS For a clinician, the visual disability produced by MG remains a challenge to treat because of its unpredictable response to therapy and the poor side-effect proﬁle of corticosteroids, the mainstay of immunosuppressive treatment.6 If the complement hypothesis proves correct, complement-inhibitor treatment may be particularly beneﬁcial for the ocular manifestations of human MG. Such treatments are on the horizon. Antibody against the C5 component of complement (Eculuzimab) has exhibited short-term safety in several human disorders, including acute myocardial infarction,63 coronary artery bypass graft surgery,64 and lung transplantation.65 The drug has demonstrated long-term safety and efﬁcacy in paroxysmal nocturnal hemoglobinuria.66 Treatment trials of complement inhibitors for MG would provide proof of concept for the complement hypothesis of EOM susceptibility.

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124 NEW THERAPIES FOR CONGENITAL NYSTAGMUS 33. Wang Z, Diethelm-Okita B, Okita D, Kaminski H, Howard J, Conti-Fine B. T-cell recognition of muscle acetylcholine receptor in ocular myasthenia gravis. J Neuroimmunol. 2000;108:29–39. 34. Kohl J. Self, non-self, and danger: a complementary view. Adv Exp Med Biol. 2006;586:71–94. 35. Walport MJ. Complement. N Engl J Med. 2001; 344:1058–1066. 36. Sahashi K, Engel AG, Linstrom JM, Lambert EH, Lennon VA. Ultrastructural localization of immune complexes (IgG and C3) at the end-plate in experimental autoimmune myasthenia gravis. J Neuropathol Exp Neurol. 1978;37:212–223. 37. Nakano S, Engel AG. Myasthenia gravis: quantitative immunocytochemical analysis of inﬂammatory cells and detection of complement membrane attack complex at the end-plate in 30 patients. Neurology. 1993;43:1167–1172. 38. Lennon VA, Seybold ME, Lindstrom JM, Cochrane C, Ulevitch R. Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis. J Exp Med. 1978;147:973–983. 39. Biesecker G, Gomez CM. Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with Fab antibody to complement C6. J Immunol. 1989;142:2654–2659. 40. Piddlesden SJ, Jiang S, Levin JL, Vincent A, Morgan BP. Soluble complement receptor 1 (sCR1) protects against experimental autoimmune myasthenia gravis. J Neuroimmunol. 1996;71: 173–177. 41. Christadoss P. C5 gene inﬂuences the development of murine myasthenia gravis. J Immunol. 1988;140:2589–2592. 42. Tuzun E, Scott BG, Goluszko E, Higgs S, Christadoss P. Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis. J Immunol. 2003;171:3847–3854. 43. Janeway C, Travers P, Walport M, Shlomchik M. Innate immunity. In: Janeway C, Travers P, Walport M, Shlomchik M, eds. Immunobiology: The Immune System in Health and Disease. New York, NY: Garland Publishing; 2001:35–91. 44. Miwa T, Song WC. Membrane complement regulatory proteins: insight from animal studies and relevance to human diseases. Int Immunopharmacol. 2001;1:445–459. 45. Medof ME, Kinoshita T, Nussenzweig V. Inhibition of complement activation on the surface of cells after incorporation of decay-accelerating factor (DAF) into their membranes. J Exp Med. 1984;160:1558–1578. 46. Seya T, Turner J, Atkinson J. Puriﬁcation and characterization of a membrane protein (gp45-70)

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58. Fischer MD, Gorospe JR, Felder E, et al. Expression proﬁling reveals metabolic and structural components of extraocular muscles. Physiol Genomics. 2002;9:71–84. 59. Fischer MD, Budak MT, Bakay M, et al. Deﬁnition of the unique human extraocular muscle allotype by expression proﬁling. Physiol Genomics. 2005;22:283–291. 60. Kaminski HJ, Li Z, Richmonds C, Lin F, Medof ME. Complement regulators in extraocular muscle and experimental autoimmune myasthenia gravis. Exp Neurol. 2004;189:333–342. 61. Howard FJ, Lennon V, Finley J, Matsumoto J, Elveback L. Clinical correlations of antibodies that bind, block, or modulate human acetylcholine receptors in myasthenia gravis. Ann N Y Acad Sci. 1987;505:526–538. 62. Limburg PC, The TC, Hummel-Teppel E, Oosterhuis H. Anti-acetylcholine receptor antibodies in myasthenia gravis. I. Relation to clinical

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IV GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL

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15 Studies of the Ability to Hold the Eye in Eccentric Gaze: Measurements in Normal Subjects with the Head Erect JEFFREY T. SOMERS, MILLARD F. RESCHKE, ALAN H. FEIVESON, R. JOHN LEIGH, SCOTT J. WOOD, WILLIAM H. PALOSKI, AND LUDMILA KORNILOVA

ABSTRACT We studied the ability to hold the eyes in eccentric horizontal or vertical gaze angles in 33 normal humans, age range 22 to 37 years (mean 29.3). Subjects attempted to sustain visual ﬁxation of a brieﬂy ﬂashed (750 milliseconds) target located ±30° in the horizontal plane and ±15° in the vertical plane in a dark environment. Conventionally, the ability to hold eccentric gaze is estimated by ﬁtting centripetal eye drifts with exponential curves and calculating the time constant (τc) of these slow phases of “gaze-evoked nystagmus.” Although the distribution of time-constant measurements (τc) in our normal subjects was particularly skewed due to occasional gaze-holding that was almost perfectly stable (large τc values), we found that log10(τc) was approximately normally distributed within classes of target direction. Therefore, statistical estimation and inference on the effect of target direction was performed on values of z ≡ log10τc. Subjects showed considerable variation in their eye-drift performance over repeated trials; nonetheless, statistically signiﬁcant differences emerged: values of τc were signiﬁcantly higher for gaze elicited to targets in the horizontal plane than for the vertical plane (p < 10–5), suggesting eccentric gaze-holding is more stable in the horizontal than in the vertical plane. Furthermore, centrifugal eye drifts were observed in 12.0%, 8.5%, 4.3%, and 65.7% of cases for rightward, leftward, upward, and downward gaze tests, respectively.

Fifth-percentile values of the time constant were estimated to be 10.8 seconds, 13.0 seconds, 3.3 seconds, and 3.7 seconds for rightward, leftward, upward, and downward gaze, respectively. Our statistical method for representing the range of normal eccentric gaze stability can be readily applied in the clinical setting of patients with neurological disease and normal subjects exposed to environments that may affect the properties of their ocular motor integrator. Patients with gaze-evoked nystagmus can be identiﬁed by referring to the above-mentioned normative criteria. During natural activities, human subjects often direct their line of sight at an object of interest located off to one side and maintain the eyes at eccentric positions in the orbits while the object is watched. In order to program such “eccentric gaze-holding,” the brain must take into account the mechanical properties imposed by the orbital tissues. Speciﬁcally, a sustained contraction of the extraocular muscles is necessary to oppose the elastic forces that continually pull the eye back to the central position.1,2 To achieve this sustained muscle contraction, the ocular motoneurons must generate commands with an eye position component. Electrophysiological studies conﬁrm that the ocular motoneurons modulate their discharge rate with eye position (and also with velocity during movements),3 although the demonstration of orbital pulleys has indicated that the mechanism may be complex.4 Premotor neurons that send vestibular,5 saccadic,6 and smoothpursuit signals7 to the ocular motoneurons modulate

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130 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL their discharge with eye velocity, not position. Thus an integration of velocity-coded premotor signals to position-coded motoneuron commands is achieved by the nervous system. Important components for carrying out this integration are (a) for horizontal gaze holding, the nucleus prepositus hypoglossi/medial vestibular nuclei complex (NPH/MVN)8,9; and (b) for vertical gaze holding, the interstitial nucleus of Cajal (INC).10 In addition, the cerebellum, especially the ﬂocculus, makes an important contribution to the integration.2,11,12 Lesions in any of these structures may impair the ability to hold the eyes in eccentric gaze, allowing the eyes to drift back toward the center of the orbits, causing corrective quick phases, known as “gazeevoked nystagmus.” Normal subjects also show some centripetal drifts, indicating that the neural integrator for eye movements is not perfect but rather has a “leak” deﬁned by the time constant of the centripetal drift (τc). Most prior reports of gaze-holding ability in normals have studied only a few subjects and have not measured performance in both the horizontal and vertical planes. Thus the main goal of this study was to establish a normative model of eccentric gaze-holding performance, in both planes, in a healthy subject population free from vestibular or visual defects. Because of the reported variability of gaze-holding ability between different subjects,13-16 we attempted to use a simple methodology that can be easily repeated in both clinical and laboratory settings. Preliminary studies indicated that the distribution of time-constant measurements (τc) in normal subjects is particularly skewed due to cases that approached perfect stability (τc = ∞). As a result, statistical estimation and inference on the effect of target direction was performed on values of z ≡ log10τc, which we found to be well modeled by a normal distribution. Lower percentiles of the estimated normal distributions of z for each target direction can be used as standards of comparison for patients when gaze-holding ability is evaluated.

METHODS Subjects Horizontal and vertical gaze-holding for eccentric targets were examined in 33 normal subjects (31 males, 2 females, ages 22 to 37 years, mean 29.3 years). Testing was performed only after each subject signed a consent form approved by the Johnson Space Center’s Institutional Review Board. All subjects were screened medically prior to testing, and none presented with vestibular or neurological symptoms or were any taking medication with effects on the central nervous system. Subjects were either emmetropes or wore their corrective contact lenses during testing.

Equipment The subjects’ eye movements were recorded using a SensoMotoric Instruments (SMI) three-dimensional binocular infrared video eye tracker (VET) (linear range of ±30° horizontal and ±30° vertical; sampling rate of 60 Hz; system noise assessed at <0.5° root mean square [RMS]). The camera system was integrated with an in-house pupil-tracking algorithm as described elsewhere.17 The sampling rate of 60 Hz was determined to be sufﬁcient for this experimental protocol because it encompassed the bandwidth of slow-phase velocity waveforms. The visual stimuli consisted of an array of ﬁve light-emitting diodes (LEDs), located at center, right and left 30°, and up and down 15°, mounted on a cruciform-shaped target positioned 0.5 m from the subject’s outer canthus and parallel to the coronal plane. The cruciform target was solidly mounted to a restraint chair in which the subject was seated. The restraint chair was lightly padded and included a head and neck restraint that prevented unwanted head movements and assisted the subjects in maintaining straight-ahead head and gaze position.

Procedure All eye movements were obtained in a completely dark environment. Eye movements were calibrated by requiring the subjects to visually acquire a series of LEDs that were displayed in both the horizontal and vertical planes. Following calibration, each trial began with the subject ﬁxating on the center (0°) LED, and then subsequently cued to acquire one of the four eccentric LED targets located at right 30°, left 30°, up 15°, or down 15°. The cue was a 750-millisecond-duration ﬂash of the new target LED. Coincident with the ﬂash of the eccentric target, the center LED was extinguished. After 20 seconds, the subject was cued with an audio tone to return gaze to the remembered position of the center LED. Gaze was maintained on the remembered central LED position for an additional 20 seconds, whereupon the center LED was again illuminated and the subject made any necessary correction in gaze to the central target. The sequence described above was then repeated for a new eccentric target location until all four eccentric targets were displayed.

Data Analysis The gaze-holding protocol was designed to measure the subject’s ability to maintain gaze on a remembered target (ﬁrst 2 seconds of data after acquiring the eccentric target) and to charge the neural integrator for an investigation of rebound nystagmus following a return to center (the remainder of the 20-second period).

GAZE-HOLDING IN NORMAL SUBJECTS 131

Statistical Analysis The objective of the statistical analysis was, for each target direction, to estimate the ﬁfth percentile of the distribution of time constants one would see for random normal individuals taking the test one time as in a clinical setting. However, because the data for this experiment comprised multiple trials in a highly unbalanced design (Table 15.1), merely using the sample ﬁfth percentile as the estimate is inﬂuenced too much by the small set of subjects that had many trials. As an alternative, after removal of outliers (τc < 1.1, one point dropped), we assumed a “normal distribution with random effects” model for log (τc) and used

A 35

29

30

Position (˚)

25 28

20

5

6

7

15 10 5 0

5

0

10

20 30 Time (s)

40

50

Horizontal eye position Vertical eye position Horizontal target position

B 3.37

Drift 1 Drift 2 Drift 3 Drift 4

3.36 Position (ln[˚])

The decision to use only the ﬁrst 2 seconds of data for gaze holding is further justiﬁed by the observation that beyond the ﬁrst 2 to 3 seconds, either gaze had stabilized or gaze-holding could be interrupted by random saccadic eye movements. Using programs written in MATLAB (The MathWorks, Natick, MA), the VET signals were ﬁltered using a median and sliding window ﬁlter to remove digitization noise associated with video-oculography.18 The data were then calibrated using the initial calibration targets contained at the beginning of each ﬁle. To obtain the time constant of centripetal eye drift, each target ﬁle was loaded, and the ﬁrst saccade was identiﬁed interactively. The operator then selected all slow-phase drifts within the ﬁrst 2 seconds after the initial saccade (Fig. 15.1A). We assumed that each drift followed resetting of the neural integrator by the prior quick phase; therefore, the onset time for each drift was set to zero, allowing the ﬁtting algorithm to treat each as the beginning of an exponential curve instead of as a continuation of a previous one. Each drift was then ﬁtted using a natural log transformation, after taking the absolute values. After applying the natural log transformation to each drift, we performed a linear regression and used the resultant slope to calculate the time constant (τc = 1/| slope |), as shown in Figure 15.1B. We excluded individual slow phases with τc < 1.1 seconds, since these were more likely due to saccadic pulse-step mismatch than a near-absence of integrator function. All linear regressions with R2 values below 0.8 were discarded as poor ﬁts. In 20% of drifts, the slow-phase drifts moved away from the central position (centrifugally). In these situations, we assumed the drift was moving toward an asymptote located away from center, and we calculated exponential time constants accordingly. For purposes of assessing gaze-holding ability, we assumed time constants were comparable, regardless of the direction of drift. In other words, a drift in the direction away from center was considered to be as detrimental to clear vision as a similar drift toward center.

3.35

3.34

3.33

0

0.2

0.4

0.6

Time (s)

Figure 15.1 (A) Representative gaze-holding trial. The subject begins by ﬁxating the center LED and then makes a saccade to a left 30° target. The subject maintains the approximate gaze angle for 20 seconds before being cued to return to center by an audio tone. After 20 seconds at center, the center LED is re-illuminated. Insert: During analysis, the drifts from the ﬁrst 2 seconds after the ﬁrst saccade are selected interactively. (B) Natural log transformation and linear regression. Using the same data as in (A), each drift was inverted and reset to a start time of zero. The natural log was applied, and then a linear regression was used to ﬁt the data. The time constants were calculated to be 17.9, 14.6, 19.5, and 29.0 seconds, respectively. Note the variability within one subject’s trial.

132 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL Table 15.1 Test Frequency by Subject and Direction Subject

Right

Left

Up

Down

Total

0017 0622 0846 1328 1717 1818 1868 2598 2607 2999 3065 3809 4204 4447 4467 4481 5000 5212 5799 5906 6101 6774 6781 6888 6930 7049 7173 7885 8335 9027 9134 9529 9994 Total

2 2 4 4 4 18 4 5 3 3 2 0 2 6 3 3 2 3 5 1 2 3 6 3 5 9 2 5 5 2 2 0 21 141

2 4 2 3 2 8 2 2 3 6 5 2 5 5 1 1 0 2 4 3 0 5 13 2 6 15 4 7 4 2 3 0 18 141

2 5 1 3 5 12 1 6 3 1 3 2 3 3 4 1 5 2 4 2 0 3 14 2 2 14 1 6 4 2 0 0 23 139

1 3 10 0 4 6 3 4 4 1 2 2 3 2 3 2 1 2 2 2 1 3 15 1 2 12 3 4 1 1 3 1 4 108

7 14 17 10 15 44 10 17 13 11 12 6 13 16 11 7 8 9 15 8 3 14 48 8 15 50 10 22 14 7 8 1 66 529

estimates of the between- and within-subject variance components to calculate the percentiles of interest. This model, while not perfect (Fig. 15.2), gives a reasonable approximation of the distribution of time constants after removal of outliers (τc < 1.1). The random-effects model is of the form zijk = µk + ai + eijk

(1)

where zijk = log10(τc) for the jth observation on the ith subject for target direction k, µk is the mean value of log10(τc) for target direction k, ai is a between-subject 2 random effect normally distributed as N(0, σ a ), and eijk is a within-subject error term normally distributed as N(0, σ2). All random effects and error terms are assumed statistically independent from one another; however, we considered the possibility that values of

Figure 15.2 Residual plot. Shown is the histogram of the residuals after ﬁtting the mixed model for all target directions (N = 529). Note that the residuals are normally distributed, indicating a reasonable approximation to the distribution of time-constants.

2 the variance parameters σ a and σ2 might depend on the target direction. From Equation 1, it can be seen that the distribution of log10(τc) for a random individual performing the test one time in target direction k would be N(µk, σ a2 +σ2). It follows that the ﬁfth percentile of this marginal distribution of τc is equal to 10 z05 where Z05 = µ − 1.645( σ a2 + σ2)1/2. Statistical estimation and inference on the effect of target direction was performed by restricted maximum-likelihood estimation of the statistical parameters in Equation 1 using Stata Version 9 statistical software (STATA Corporation, College Station, TX) and testing the effect of target direction on the parameters. Because of the monotone log transformation, any signiﬁcant differences (p < 0.05) in the distribution of z correspond directly to signiﬁcant differences in the distribution of τc. Similar statistical inference could be applied to data from clinical studies comparing normal subjects with a group of subjects for whom gazeholding ability is expected to be abnormal. To obtain a measure of uncertainty in estimates of Z05 induced by sampling, we could have used asymptotic standard errors of the model parameter estimates and applied the “delta method.”19 Instead, we chose to estimate Z05 directly, with Bayesian methods using WinBUGS software (Imperial College and Medical Research Council, Cambridge, UK). The posterior distribution of Z05 given the data was then used to construct a “Bayesian credibility interval,” analogous to a conﬁdence interval. The endpoints of this conﬁdence interval were then exponentially transformed to obtain a conﬁdence interval for τ05.

GAZE-HOLDING IN NORMAL SUBJECTS 133

Table 15.2 Parameter Estimates by Target Direction µ

Target Direction Right Left Up Down

1.44 1.52 1.02 1.10

σa

σ

0.13

0.25

0.21 0.22

0.23

RESULTS Distribution of Time Constants Total sample sizes of 141, 141, 139, and 108 (from 33 subjects) were obtained for the rightward, leftward, upward, and downward target conditions, respectively; however, the number of observations per subject varied considerably—from 0 to 21, depending on the target direction (Table 15.1). Because of this imbalance, ﬁtting the multilevel model (Eq. 1) gives a more accurate estimate of population means for each target direction than would simple averaging of the data. For a similar reason, estimates of ﬁfth percentiles obtained from the multilevel model parameters are more accurate than empirical ﬁfth percentiles of the data. After experimentation, we found that the model (Eq. 1) ﬁt best by allowing the mean (µk) of z and the variance component σ a2 to vary with target direction (k). Resulting estimates are shown in Table 15.2. An examination of this table shows signiﬁcant differences in the estimates of the parameter µ between the right and left directions (difference = 0.081, SE = 0.026; p = 0.002). The most salient feature of Table 15.2 is the indication of a substantial decrease in the mean of z (and hence median of τc) for vertical relative to horizontal targets (decrease = 0.412, SE = 0.035; p < 10–5), suggesting eccentric gazeholding is more stable in the horizontal than in the vertical plane. Furthermore, we observed that 66% of drifts elicited to downward targets were away from center (centrifugal), compared to only 4% of drifts associated with upward targets. Therefore, we feel there is, at a minimum, a functional difference between upward and downward vertical gaze, and we suggest using distinct ﬁfth-percentile values for these cases. Table 15.2 also shows the estimates of the median (τ50) and ﬁfth percentile (τ05) of the time-constant distribution, as well as the lower and upper conﬁdence limits for the ﬁfth percentile (τ05).

Applying the Model In a clinical setting, one would simply apply the appropriate ﬁfth percentile from Table 15.2 as a threshold to detect potentially abnormal gaze-holding performance,

τ50 27.6 33.2 10.6 12.4

τ05 10.8 13.0 3.26 3.72

τ05 lower 8.8 10.6 2.42 2.64

τ05 upper 12.6 15.2 4.10 4.79

since these values would lie outside the 95% prediction interval. The probability of being able to detect a particular pathology by this method would depend on how much the time-constant distribution is shifted (presumably downward) for the patient. To illustrate this point, Figure 15.3 indicates how well these thresholds would be able to successfully detect abnormalities (up and down results were averaged for this plot because their difference was relatively small). The ﬁgure depicts the probability that the time-constant distribution of a patient from a degraded population would fall below the ﬁfth-percentile threshold value shown in Table 15.2 as a function of a percent difference between the median time constant for the degraded

Figure 15.3 Detection probability plot. Shown is the probability of a single drift being identiﬁed as abnormal (below the normative ﬁfth percentile) based on the percent difference between the median time constant for the degraded population and the median for a clinically normal population. Note that for a 0% drop in time constant (no change), the probability is 5%, meaning that any particular drift would have a 0.05 probability of 0.05 being identiﬁed as abnormal. If the median time constant for a subject were shifted by 50% from normal, we would expect a single drift to have a probability of 0.33 of being identiﬁed as being abnormal for horizontal targets and of 0.24 for vertical targets.

134 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL population and the median for a clinically normal population. For a zero-percent change in median time constant (no shift in the subject’s distribution relative to the distribution of normal subjects), the probability of a single observed-drift time constant falling below the threshold would be 0.05, as expected. On the other hand, if the patient’s median time constant were 50% lower than that of normal subjects, the probability of a single drift having a time constant falling below the threshold would now be 0.33 for horizontal gaze-holding and 0.24 for vertical gaze-holding.

DISCUSSION We set out to compare the ability to hold steady eccentric gaze in the horizontal versus vertical planes in a large group of healthy human subjects. There are two main ﬁndings of this study. First, using a lognormal distribution to model the time constant of drift is a reasonable approach to dealing with extremely skewed time-constant data. This approach provides a means to summarize the normal range and deﬁne abnormal gaze-holding ability. Second, using this statistical model, we have been able to show that normal subjects show better eccentric gaze-holding ability in the horizontal than the vertical plane.

Development of a New Statistic for Measurement of Gaze-Holding It should be noted that our estimates of the time constant are based on eye drifts when subjects attempted to view a remembered target located at ±30° in the horizontal plane and ±15° in the vertical plane. Although it is convenient to assume a linear model for the ocular motor plant and a neural integrator with a single time constant, in practice this is not observed. Thus it is known that with greater eccentricity, different time constants are observed,20 for which a neural network mechanism has been proposed.21 Application of our statistical results depends on similar target locations being used during testing. How well the lognormal distributions estimated here could ﬁt data generated during attempts to ﬁxate targets at the extremes of gaze requires further study. Nonetheless, the eccentricities that we have chosen challenge gazeholding ability but are within the linear range of most eye movement monitors.

Possible Physiological and Anatomical Basis for Current Findings A number of prior studies have reported that normal subjects show a range of ability (measured by

time constant of centripetal eye drift) to hold steady, horizontal, eccentric gaze in darkness.13,14,16,22 Indeed, some normal subjects show “endpoint nystagmus” when viewing a target.22 In the present study of normal subjects, we show that the range of normal gaze-holding ability in the horizontal plane is less stable than previously reported and, for the ﬁrst time, demonstrate that eccentric vertical gaze-holding is also less stable than horizontal gaze-holding. One possible explanation for the difference in horizontal and vertical gaze-holding relates to the observation that different structures of the brainstem, and perhaps the cerebellum, contribute to horizontal or vertical gaze-holding. For example, in monkeys, chemical lesions of NPH/ MVN in the medulla abolish horizontal gaze-holding ability but leave some gaze-holding ability intact.23 On the other hand, pharmacological inactivation of INC in the midbrain mainly impairs vertical gaze-holding ability.24 Another contributing factor concerns the mechanical properties of the orbital tissues. The discovery of pulleys that guide the extraocular muscles might provide an explanation based on orbital mechanics.4 Thus, each extraocular muscle comprises an outer orbital layer that attaches to a pulley (and moves it) and an inner global layer that passes through the pulley and attaches to the eyeball. For example, Demer4 has suggested that the restricted range of upward gaze movement encountered in normal elderly subjects may be due to changes in the attachment of the orbital layer of the inferior oblique muscle to other connective tissues in the orbit. The subjects that we studied were predominantly young and showed no limitation of upward gaze. Although there was no asymmetry of upward versus downward time constant, we did note a larger percentage of drifts away from center when looking to the downward target. Future studies of older, healthy populations might show signiﬁcant differences. In clinical practice, impaired ability to hold eccentric gaze—manifested as gaze-evoked nystagmus—is a common ﬁnding; frequent causes are drug intoxications (e.g., alcohol) and cerebellar disease.2 In some individuals, there is doubt as to whether gaze-evoked nystagmus is indicative of underlying disease or represents the range of normal behavior (such as physiological “endpoint nystagmus”). In such patients, clinicians traditionally look for other clues of cerebellar disease, but comparison of patients’ values of τc with a large data base, such as is presented here, may aid diagnosis. In preliminary studies we were able to apply part of the data presented in this paper to identify abnormal gazeholding in a group of patients with cerebellar disease.25 However, larger numbers of patients require study to validate these predictions. Finally, rare patients may show an unstable rather than a leaky integrator.12,26 It is therefore of interest that some normals may also show

GAZE-HOLDING IN NORMAL SUBJECTS 135

centrifugal eye drifts but, unlike reported patients with cerebellar disease, only do so while in darkness, when visual ﬁxation is prevented.

acknowledgments This work was supported by the National Space Biomedical Research Institute through the National Aeronautics and Space Administration NCC 9-58 (grant NA00208), National Institute of Health grant EY06717, the Department of Veterans Affairs, and the Evenor Armington Fund.

References 1. Robinson DA. The mechanics of human saccadic eye movement. J Physiol (Lond). 1964;174:245–264. 2. Leigh RJ, Zee DS. The Neurology of Eye Movements. 4th ed. New York, NY: Oxford University Press; 2006. 3. Goldstein HP, Robinson DA. Hysteresis and slow drift in abducens unit activity. J Neurophysiol. 1986;55:1044–1056. 4. Demer JL. Pivotal role of orbital connective tissues in binocular alignment and strabismus: the Friedenwald lecture. Invest Ophthalmol Vis Sci. 2004;45:729–738. 5. Skavenski AA, Robinson DA. Role of abducens neurons in the vestibuloocular reﬂex. J Neurophysiol. 1973;36:724–738. 6. Van Gisbergen JAM, Robinson DA, Gielen S. A quantitative analysis of the generation of saccadic eye movements by burst neurons. J Neurophysiol. 1981;45:417–442. 7. Fukushima K. Roles of the cerebellum in pursuit-vestibular interactions. Cerebellum. 2003; 2:223–232. 8. Arnold DB, Robinson DA. The oculomotor integrator: testing of a neural network model. Exp Brain Res. 1997;113:57–74. 9. Kaneko CRS. Eye movement deﬁcits after ibotenic acid lesions of the nucleus prepositus hypoglossi in monkeys. 1. Saccades and ﬁxation. J Neurophysiol. 1997;78:1753–1768. 10. Helmchen C, Rambold H, Fuhry L, Büttner U. Deﬁcits in vertical and torsional eye movements after uni- and bilateral muscimol inactivation of the interstitial nucleus of Cajal of the alert monkey. Exp Brain Res. 1998;119:436–452. 11. Robinson DA. The effect of cerebellectomy on the cat’s vestibulo-ocular integrator. Brain Res. 1974;71:195–207. 12. Zee DS, Leigh RJ, Mathieu-Millaire F. Cerebellar control of ocular gaze stability. Ann Neurol. 1980; 7:37–40.

13. Becker W, Klein H-M. Accuracy of saccadic eye movements and maintenance of eccentric eye positions in the dark. Vision Res. 1973;13: 1021–1034. 14. Eizenman M, Cheng P, Sharpe JA, Frecker RC. End-point nystagmus and ocular drift: an experimental and theoretical study. Vision Res. 1990;30: 863–877. 15. Hess K, Reisine H, Dürsteler MR. Normal eye drift and saccadic drift correction in darkness. Neuroophthalmology. 1985;5:247–252. 16. Robinson DA, Zee DS, Hain TC, Holmes A, Rosenberg LF. Alexander’s law: its behavior and origin in the human vestibulo-ocular reﬂex. Ann Neurol. 1984;16:714–722. 17. Wood KA, Paloski WH, Reschke MF. Spatial coding of eye movements relative to perceived earth and head orientations during static roll tilt. Exp Brain Res. 1998;121:51–58. 18. Das VE, Thomas CW, Zivotofsky AZ, Leigh RJ. Measuring eye movements during locomotion. Filtering techniques for obtaining velocity signals from a video-based eye monitor. J Vestibular Res. 1996;6:455–461. 19. Greene WH. Econometric Analysis. Upper Saddle River, NJ: Prentice Hall; 2000. 20. Abel LA, Dell’Osso LF, Daroff RB. Analog model for gaze-evoked nystagmus. IEEE Trans Biomed Eng BME. 1978;25:71–75. 21. Cannon SC, Robinson DA. An improved neuralnetwork model for the neural integrator of the oculomotor system: more realistic neuron behavior. Biol Cybern. 1985;53:93–108. 22. Abel LA, Parker L, Daroff RB, Dell’Osso LF. Endpoint nystagmus. Invest Ophthalmol Vis Sci. 1977;17:539–544. 23. Cannon SC, Robinson DA. Loss of the neural integrator of the oculomotor system from brain stem lesions in monkey. J Neurophysiol. 1987;57:1383–1409. 24. Crawford JD, Cadera W, Vilis T. Generation of torsional and vertical eye position signals by the interstitial nucleus of Cajal. Science. 1991;252:1551–1553. 25. Wilson E, Sng K, Somers JT, Reschke MF, Leigh RJ. Studies of eccentric gaze stability: effects of pitch head position on horizontal gaze-holding in patients with cerebellar disease. Ann N Y Acad Sci. 2005;1039:593–596. 26. Barton JJS, Sharpe JA. Oscillopsia and horizontal nystagmus with accelerating slow phases following lumbar puncture in the Arnold-Chiari malformation. Ann Neurol. 1993;33:418–421.

16 Effect of Eye Exercise on Clinical Outcome of Noncompressive Ocular Motor Nerve Palsy ANUCHIT POONYATHALANG, PISIT PREECHAWAT, AND VITOO JANVIMALUANG

ABSTRACT Our objective was to study the effect of eye exercise on noncompressive ocular motor nerve palsies in addition to medical treatment. Traditional treatments to reduce diplopia in ocular motor nerve palsies include occlusion, prisms, and botulinum toxin injection. To reduce recovery time, the use of eye movement exercises has been introduced. Patients with ocular motor nerve palsy were randomly instructed to move their eyes back and forth in the directions of paresis 100 times a day. Time from onset of palsy until return of normal visual fusion was recorded and compared between an exercise and a nonexercise group. Eleven patients had cranial third nerve palsy, 12 had sixth nerve palsy, and 1 had both third and sixth nerve palsy. All patients were treated with oral aspirin or other antiplatelet agent. The eye exercise group included 9 patients, and the non–eye exercise group had 15 patients. The eye exercise group had an average recovery time of 3.8 weeks as compared to the 25.5 weeks for the nonexercise group. Patients who performed eye exercises had shorter recovery times from double vision than patients who were only given medical treatment. However, since our sample size was very small, other factors could be responsible for the results, and further studies are warranted. Patients with extraocular muscle paralysis are often frustrated by double vision and related functional problems. Some patients are also distressed with dizziness

and nausea. Occlusion of one eye, spectacle prisms, and injection of botulinum toxin have been used to reduce diplopia during the recovery period. Usually, occlusion of the paralytic eye is recommended, but without stereopsis patients may encounter difﬁculties in daily activities. Rehabilitation of extraocular muscle palsy has involved exercises that emphasize maximal ocular motor effort1 or invoking the vestibulo-ocular reﬂex.2 However, there is little evidence-based support for such rehabilitation programs. In patients with noncompressive ocular motor nerve palsies, complete recovery of eye movement usually occurs within six months, but in patients with severe nerve injury, recovery is more variable.3 Training using the patient’s ﬁnger provides strong visual and somatosensory feedback, along with the corollary discharge of the motor command (efference copy), thereby providing a strong cue for the patient to make an appropriate eye movement in the correct direction.4 It has been proposed that eye movement exercise can assist not only in promoting movement on the affected side but also in decreasing hyperactivity on the unaffected side that might contribute to a muscular contracture.5 One goal of such eye movement exercises is to reduce recovery time.

PATIENTS AND METHODS Twenty-four patients from our outpatient clinic who had double vision at the onset of their illness were recruited from 127 patients complaining of double vision between January 2003 and July 2004. The inclusion criteria were acute onset of diplopia, paralytic eye

136

137

EFFECT OF EYE EXERCISE ON OCULAR MOTOR NERVE PALSY

movement that eventually subsided, normal imaging studies, and no prior treatment with antiplatelet or anticoagulation. All patients presented for their initial visit within two weeks of onset of symptoms. Patients who failed to recover within one year of the onset of paralysis were excluded from this study. Other exclusion criteria were a history of trauma, orbital accident, tumor, compressive lesion such as aneurysm, autoimmune diseases, chronic disorders such as thyroid-associated ophthalmopathy, myotonic dystrophy, myasthenia gravis, or chronic progressive external ophthalmoplegia. Demographic data such as age; sex; and systemic disorder that may affect the outcome, such as diabetes mellitus, hypertension, or dyslipidemia, were recorded.6 The severity of diplopia was based on the measurement of strabismus in prism diopters. The prism bar was placed in front of the paralytic eye and increased to the point that the subject could see a single target at distance. In individuals who had both horizontal and vertical deviations, we recorded the sum total of both deviations in prism diopters. Patients were randomly assigned to perform exercises or no exercise. Patients assigned to exercises were instructed to move both eyes back and forth, following one of their ﬁngers as it moved slowly in the plane of paresis, 100 times per day every day. As an example, in the case of cranial sixth nerve palsy, patients had to follow ﬁnger motion to extreme left and right, ignoring the limitation of the paretic muscle. At two weeks follow-up, the eye exercise group was rechecked to ensure that the method of exercise was being performed correctly. Patients were reassured about their general prognosis of ischemic ocular motor nerve palsy and the rationale of the exercise. They were encouraged to open both eyes as much as possible while in a safe environment, and to attempt to view binocularly. Ophthalmoplegia was evaluated at study entry, at the end of the two-week session, and every month in both groups. Patients were asked to report when they ﬁrst experienced single vision during binocular straight-ahead viewing of the scene. The time from onset of diplopia to normal fusion in central gaze were recorded in both

the exercise and nonexercise groups. A statistical comparison of the difference between subjects with and subjects without exercise intervention was conducted using an unpaired Student’s t-test. Other parameters thought to have the potential to affect the outcome were similarly analyzed. Differences were considered statistically signiﬁcant at the p < 0.05 level. Patients from both groups were prescribed oral antiplatelet treatment at the ﬁrst visit. If diplopia did not resolve after one year, management was reevaluated. The study was approved by the institutional ethics committee.

RESULTS Twenty-four patients (15 men and 9 women) were studied. The mean age of the individuals was 61.4 years (range: 36 to 80 years). The oculomotor nerve was affected in 11 patients, the abducens nerve was affected in 12 patients, and 1 individual had both oculomotor and abducens nerve palsies. The presumed etiology of the extraocular paralysis in this group of patients was ischemia of the peripheral nerve. The group randomly assigned to eye exercises numbered 9 patients, and the non–eye exercise group numbered 15 patients. All patients in the exercise group followed the instruction on eye movement exercise satisfactorily. The mean deviations in exercise group and non-exercise group were 28.5 and 27.0 diopters, respectively. In all of our patients, diplopia resolved spontaneously; no surgical treatment was required for any patient of either group. Statistical analysis of age, sex, type of cranial nerve involvement (cranial nerve 3 or 6), and size of deviation showed no statistical difference between the exercise and non-exercise groups (p value for age was 0.63, for sex was 1.00, for type of cranial nerve was 0.27, for systemic disorder was 0.83, and for size of deviation was 0.32). The average recovery time of single vision in central gaze signiﬁcantly favored the exercise group over the non-exercise group, with an average recovery time of 3.83 weeks for the exercise group versus 25.47 weeks for the non-exercise group (Student’s t-test; p = 0.0035) (see Table 16.1).

Table 16.1 Numbers and Averages of Variables of Exercise and Non-exercise Groups Assigned Group

Exercise group Non-exercise group

Number of Cases

9 15

DM, diabetes mellitus; HT, hypertension.

Average Age (y)

63.8 61.4

Average Deviation Angle (D)

27 28.54

Number of Cases with Systemic Disorder DM

HT

9 3

3 2

Average Recovery Time of Single Vision in Primary Position Dyslipidemia (wk) 1 1

3.83 25.47

138 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL

DISCUSSION In our study, there were 5 patients in the non-exercise group for which the recovery time was more than six months; all of them occluded their paralytic eye most of the time, either with an eye patch or by squeezing their eyelids shut. Even though these patients eventually regained almost full range of eye movement, they had persistent difﬁculty adjusting to the spatial environment. In the exercise group, 1 patient with case of cranial third nerve palsy initially had difﬁculty conducting the exercises correctly because of ptosis; after reassurance and training, eye movements showed improvement. A few patients reported that their double vision persisted in the paralytic direction, causing difﬁculties especially when driving, even though their eye movement range was near complete. In those patients, we found that the speed of the paralytic muscle was slower than of the conjugate muscle. Since single vision was present in central gaze, we advised using larger head movements, in conjunction with a larger car mirror, to permit driving. The binocular fusion mechanism normally makes it possible to point both eyes at the same visual target.7 Our exercises provide visual, somatosensory, and efference copy signals so that the brain can adapt to the peripheral motor weakness and induce “spread of concomitance.”8 Thus, our eye exercises may have sped up the spread of concomitance, which is part of the natural course of recovery from ocular motor nerve palsy.

CONCLUSIONS This preliminary study demonstrated that patients who performed eye exercises had shorter recovery times from double vision than patients who were only given medical treatment. Patient education and eye movement training should be instituted early to decrease possible stiffness of the unaffected extraocular yoke muscle. It is important for the patient, ophthalmologist, and orthoptist to establish realistic goals within a reasonable time frame. Unfortunately, many patients hope for immediate improvement. Reassurance had to be offered to our patients from time to time. Therapy with prisms or botulinum toxin may require consideration.9,10 Since our sample size was small, other factors could possibly be responsible for our results. The goal of our exercises was to facilitate recovery of voluntary eye movement using attempted conjugate

eye movements along with visual and somatosensory feedback. The purpose of treatment of ocular motor nerve palsy should focus not only on restoring function of the paretic muscle but also on reestablishing the fusional mechanism.

acknowledgment This research was supported by Ramathibodi Foundation.

References 1. Everhard-Halm YS, Koornneef L, Zonneveld FW. Conservative therapy frequently indicated in blow out fractures of the orbit. Ned Tijdschr Geneeskd. 1991; 135(27):1226–1228. 2. Kawahira K, Shimodozono M, Etoh S, Tanaka N. New facilitation exercise using the vestibuloocular reﬂex for ophthalmoplegia: preliminary report. Clin Rehabil. 2005; 19(6):627–634. 3. Golnik KC, Miller NR. Late recovery of function after oculomotor nerve palsy. Am J Ophthalmology. 1991;111:566–570. 4. Leigh RJ, Zee DS. The properties and neural substrate of eye movements. In: Leigh RJ, ed. The Neurology of Eye Movement. New York, NY: Oxford; 2006:3–19. 5. Gonzalez C, Chen HH, Ahmadi MA. Sherrington innervational surgery in the treatment of chronic sixth nerve paresis. Binocul Vis Strabismus Q. 2005;20(3):159–66. 6. Kobashi R, Ohtsuki H, Hasebe S. Clinical studies of ocular motility disturbances. Part 2. Ischemic ocular motor nerve palsy risk factors. Jpn J Ophthalmol. 1997;41:115–119. 7. Leigh RJ, Zee DS. Diagnosis of nystagmus and saccadic intrusion. In: Leigh RJ, ed. The Neurology of Eye Movement. New York, NY: Oxford; 2006: 475–558. 8. Leigh RJ, Zee DS. Diagnosis of peripheral ocular motor palsies and strabismus. In: Leigh RJ, ed. The Neurology of Eye Movement. New York, NY: Oxford; 2006:385–474. 9. Scott AB, Kraft SB. Botulinum toxin injection in the management of lateral rectus palsy. Ophthalmology. 1985; 92:676–683. 10. Kubatko-Zielinska T, Krzystkowz KM, Madroszkiewicz A, et al. Principles and results of treatment in acquired oculomotor paresis. Klin Oczna. 1995;97:147–151.

17 Expanding the Original Behavioral Infantile Nystagmus Syndrome Model to Jerk Waveforms and Gaze-angle Variations ZHONG I. WANG, LOUIS F. DELL’OSSO, AND JONATHAN B. JACOBS

ABSTRACT Our objective was to expand the behavioral ocular motor system (OMS) model for infantile nystagmus syndrome (INS) by (a) incorporating jerk and jerk with extended foveation waveforms using a unifying mechanism for both pendular and jerk waveforms and (b) incorporating idiosyncratic variation of INS amplitude with gaze angles. Ocular motor recordings of humans, using infrared reﬂection, high-speed digital video, and magnetic search coil systems, were used as templates for the computer simulations. All simulations and analyses were performed in MATLAB Simulink environment. Examinations of eye movement data during different states of attention suggested that pendular and jerk INS waveforms came from the same underlying smooth-pursuit-system oscillation. Simulation of unidirectional jerk waveforms required a resettable neural integrator in the pursuit premotor circuitry. Alexander’s law relationships were used to produce desired INS “null” positions and sharpness. At various gaze angles, these Alexander’s law relationships inﬂuenced the INS slowphase amplitudes differently, thus mimicking the same gaze-angle effects observed in INS patients. The simulations of a robust behavioral OMS model demonstrated that both pendular and jerk waveforms can be generated by the same pursuitsystem instability. Alexander’s law output effectively modulates the nystagmus variation at different gaze angles.

The ocular motor system (OMS) model for infantile nystagmus syndrome (INS) simulates the responses of individuals with several pendular waveforms (pendular with foveating saccades [Pfs] and pseudopendular with foveating saccades [PPfs]) based on a loss of damping of the normal pursuit-subsystem instability and its interaction with other OMS components. Accurate model simulations during ﬁxation, saccades to known targets (steps, pulses, and pulse-steps), and smooth pursuit (ramps and step-ramps), as well as many emergent properties and unexpected predictions of the model, duplicate the recorded responses of humans with INS, providing strong support for the hypothetical mechanisms in the model.1,2 There are, however, a number of INS features that were not included in the original OMS model. To expand this behavioral model, we intend to incorporate jerk and jerk with extended foveation waveforms by employing a unifying mechanism for both pendular and jerk waveforms. Alexander’s law variation of slow-phase velocity was included in an interim version of the model; its output will be utilized to simulate slow-phase amplitude changes affecting the eXpanded Nystagmus Acuity Function (NAFX) peak,3 or the INS “null.”

METHODS The ocular motor recordings and observations used for the computer simulation came from approximately 1,000 subjects with INS, who were recorded

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140 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL experimenter), a foveating fast phase was generated and jerk waveforms reoccurred. Examination of these data demonstrated that the underlying pendular oscillation had to be reset when each foveating saccade was made. A resettable neural integrator in the pursuit premotor circuitry (PMC+) was necessary to accomplish the resetting. This neural integrator has the same structure as that found in pulse generators,5-7 and is different from the common neural integrator in the ﬁnal motor pathway. Using the foveating-saccade motor command, the oscillation was reset so that the underlying pendular waveform could be restarted. The time delays in both the feedback and feed-forward loops in PMC+ were also reset (i.e., the stored energy had to be dumped). Figures 17.1C–F show simulations of the model under various visual inputs. Jerk waveforms in both directions consistently arrived at the new target positions; despite slight differences in the sizes of each saccade, foveation always occurred (within ±0.5° of the target). The model also responded correctly to step inputs with different directions, onset times, and durations.

in our laboratory over 37 years. Eye movements were measured using either an infrared reﬂection (Eye-Trac 210, Applied Science Laboratories, Bedford, MA), a magnetic scleral search coil (CNC Engineering, Seattle, WA), or a high-speed digital video (EyeLink II, SR Research Ltd., Mississauga, Ontario, Canada) system. Speciﬁcations of the recording systems can be found elsewhere.4 All simulations were performed in the MATLAB Simulink (MathWorks, Natick, MA) environment.

RESULTS Eye movement data with inattention from INS individuals revealed large pendular oscillations underneath the jerk waveforms (Fig. 17.1A). In Figure 17.1B, the foveating fast phase was delayed, and the accelerating slow phase actually decelerated (with a point of inﬂection) before the fast phase reset the fovea on target. As soon as attention to the target was reestablished (either spontaneously or after verbal prompting by the

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Alexander’s law describes the increase in the amplitude of nystagmus as the eye is moved in the direction of the fast phase in vestibular nystagmus and fusion maldevelopment nystagmus syndrome (FMNS). The Alexander’s law functional block in the internal monitor of the OMS model is based on a tonic imbalance signal modulated by efference copy of the eye position signal. In a previous simulation, gaze-angle effects in FMNS (i.e., foveating and defoveating fast-phase alternation) waveforms were guided by Alexander’s law input.8 For FMNS patients, the two Alexander’s law lines (one for ﬁxation by each eye) operate independently of each other, with only one (depending on the ﬁxating eye) determining the gaze-angle variation. In INS, we hypothesize that both Alexander’s law relationships operate together. This same imbalance, produced by improper calibration of the vestibular system, may also be the underlying reason for INS gaze-angle variation. Figure 17.2A demonstrates the gaze-angle variation model position output, corresponding to the “null” in Figure 17.2B (the NAFX peak in 17.2C) at 10°. Figure 17.2B shows how the two linear functions act simultaneously, with their intersection establishing the “null” position and the slopes of the curves controlling the broadness of the “null.” The modulation was produced by a variable gain in the PMC+ block.

DISCUSSION When the ﬁrst version of the OMS model was completed in 2003,2 it simulated the most complex INS waveforms (Pfs, PP, and PPfs) and the behavioral responses consistent with INS data. It demonstrated that our hypothesis for the generation of P, Pfs, PP, and PPfs could be realized by a functionally normal OMS. We have now demonstrated that, without adding a separate mechanism for jerk waveforms to the prior OMS model, and in agreement with observations and accurate eye movement recordings on inattention and waveform transition, the model can simulate pendular and jerk waveforms and behavioral responses from the same underlying mechanism. This supports the hypothesis that most pendular and jerk INS waveforms are due to a loss of pursuit-system damping. The behavioral output of the OMS model at different gaze angles demonstrated the effectiveness of using Alexander’s law input to simulate the variation of IN waveforms across the whole visual ﬁeld. The Alexander’s law imbalance (possibly asymmetrical) produced by improper calibration of the vestibular system may have caused the INS gaze-angle variation. The Alexander’s law effects on INS amplitude will be used in future versions of the model to control the

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142 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL idiosyncratic transitions between pendular and jerk waveforms. The effects of inattention on INS waveforms will also be incorporated into the model, through the same modulating gain in the PMC+ circuit. These improvements in the OMS model add another step to the implementation of a complete and idiosyncratic OMS model that can simulate normal as well as pathological (e.g., INS) behaviors.

acknowledgments This research was supported by the Department of Veterans Affairs Merit Review.

References 1. Jacobs JB. An Ocular Motor System Model that Simulates Congenital Nystagmus, Including Braking and Foveating Saccades [dissertation]. Cleveland: Case Western Reserve University; 2001. 2. Jacobs JB, Dell’Osso LF. Congenital nystagmus: hypothesis for its genesis and complex waveforms within a behavioral ocular motor system model. JOV. 2004;4(7):604–625.

3. Dell’Osso LF, Jacobs JB. An expanded nystagmus acuity function: intra- and intersubject prediction of best-corrected visual acuity. Doc Ophthalmol. 2002;104:249–276. 4. Wang Z, Dell’Osso LF, Zhang Z, Leigh RJ, Jacobs JB. Tenotomy does not affect saccadic velocities: support for the “small-signal” gain hypothesis. Vision Res. 2006;46:2259–2267. 5. Abel LA, Dell’Osso LF, Daroff RB. Analog model for gaze-evoked nystagmus. IEEE Trans Biomed Engng. 1978;BME(25):71–75. 6. Abel LA, Dell’Osso LF, Schmidt D, Daroff RB. Myasthenia gravis: analogue computer model. Exp Neurol. 1980;68:378–389. 7. Kustov AA, Robinson DL. Modiﬁed saccades evoked by stimulation of the Macaque superior colliculus account for properties of the resettable integrator. J Neurophysiol. 1995;73: 1724–1728. 8. Dell’Osso LF, Jacobs JB. A normal ocular motor system model that simulates the dual-mode fast phases of latent/manifest latent nystagmus. Biological Cybernetics. 2001;85:459–471.

18 Extension of the eXpanded Nystagmus Acuity Function to Vertical and Multiplanar Data JONATHAN B. JACOBS AND LOUIS F. DELL’OSSO

ABSTRACT Our objective was to update and extend the functionality of the eXpanded Nystagmus Acuity Function (NAFX), allowing for its application to biplanar nystagmus and improving its predictive value in clinical evaluations. The original NAFX was based on foveation times taken from a “tau surface,” an array with values calculated for each combination of position and velocity limits of a “foveation window.” For the updated NAFX, we replaced the empirical surface with a mathematically deﬁned surface that matched the original, but without the idiosynchratic irregularities caused by the waveforms of the subjects used for its calculation. For biplanar data, we have investigated combining horizontal and vertical eye movement data into a single radial vector. Age-related relationships were incorporated for more accurate individual visual acuities. Using the same uniplanar patient data, we veriﬁed that the updated NAFX yielded results equivalent to those of the original NAFX for the foveation window limits we tested. For biplanar data, the NAFX values were also comparable to those from uniplanar data of the same magnitude. The new version of the NAFX allows greater accuracy in predicting visual acuity for subjects of all ages, for both uniplanar and, eventually, biplanar nystagmus. This will allow researchers and clinicians to select the best therapies for a wider range of nystagmus patients.

The original eXpanded Nystagmus Acuity Function (NAFX),1 which was based on the Nystagmus Acuity Function (NAF),2 is a mathematically derived relationship that relates visual acuity to the attempts at foveation that occur within nystagmus waveforms, based on the duration and cycle-to-cycle stability of these foveation periods. In the original function, the foveation window was deﬁned as the times at which the target was within ±0.5° of the fovea and not moving faster than ±4.0 deg/s with respect to it. However, there are many patients who could not meet these criteria, so their nystagmus could not be analyzed by the NAF, prompting the development of the NAFX, which allows for larger foveation windows (up to ±6° by ±10 deg/s) by varying τ, the foveation duration constant. The collection of τ for all combinations of position and velocity limits is called the “tau surface,” and is shown in Figure 18.1A. While the shape does, in general, appear to be regular, there are obvious irregularities in the surface, most notably along the lower position values (left side of Fig. 18.1A). This was a consequence of some of the data that were used to generate the original surface: the “pseudopendular with foveating saccades” (PPfs) waveform has two saccades per cycle,3 and as the position limit was increased, the slow phase following the braking saccade was included in the calculation, inadvertently increasing the measured foveation time. As originally developed, the NAFX was applied only to nystagmus that occurred within one plane, as most infantile nystagmus is predominantly horizontal. However, there is no reason why the algorithm cannot be used to evaluate data in the vertical plane as well.

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Figure 18.1 The original tau surface (A) generated from multiple data sets from an individual with infantile nystagmus syndrome and used in the software for the ﬁrst version of the eXpanded Nystagmus Acuity Function (NAFX). Note the unevenness of the surface caused by both ﬁtting the data and the small size of the nystagmus signal from this subject. (B) The revised tau surface. (C) The difference between the revised and original tau surfaces, plotted as a percentage difference. The ﬂat surface is a zero plane, shown for reference. (D) The results of 40 analyses comparing the NAFX using the original tau surface versus the revised tau surface. The 45° line represents perfect equality.

Furthermore, we propose that the NAFX should be suitable for analysis of multiplanar nystagmus waveforms as one operation, by ﬁrst combining the separate horizontal and vertical components into a radial vector. Finally, as the NAFX is intended for use by clinicians as well as researchers, it must have a userfriendly interface while retaining the ability to allow deeper investigation of the data being analyzed.

METHODS Rather than discarding the existing ﬂawed tau surface and calculating a replacement using new data, we elected to reconstruct it by modifying its outlying values. To do this, we took each curve of ﬁxed

velocity at each position limit and performed a double exponential ﬁt (using the MATLAB curve-ﬁtting toolbox [MathWorks, Natick, MA]) of the form a × exp (b × x) + c × exp (d × x) to the non-outlier points, with the resulting curves having r2 values of no less than 0.95. We deﬁned the “velocity= 4 deg/s” border to be a constant, τ = 33.3 milliseconds, the original value from the NAF, and in close agreement with the ﬁt of the tau surface data. We also deﬁned the “position = 6°” line to be linear with the endpoints set by the ﬁt to the endpoint of the “velocity = 10 deg/s” curve and the 33.3 milliseconds from the aforementioned 4 deg/s border and applied small shifts to align the previously ﬁtted curves to this border. Finally, we ﬁt all the original points along the “position = 0.5°” border with a simple polynomial, yielding an r2 value of 0.98 (Fig.18.1B).

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Figure 18.2 (top panel) Combining horizontal (top) and vertical (middle) eye movement data to create a radial nystagmus waveform (bottom). The dashed lines at ±0.5° represent the foveal extent. (bottom panel) The result of 22 biplanar eXpanded Nystagmus Acuity Function (NAFX) analyses compared to analyses of the individual uniplanar components. In most, but not all, cases, the radial NAFX is less than that of both individual components, as expected.

146 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL To convert the independent horizontal and vertical eye movement waveforms to a single radial waveform, we performed a simple vector summation of the form r = √(x2 + y2), while attempting to preserve the sign of the major component wherever possible.

RESULTS The overall differences between the original and revised tau surfaces are generally quite small, averaging 2 milliseconds overall, and no more than 5.1 milliseconds in the worst case. The difference expressed as a percentage between the original and the revised tau surfaces is shown in Figure 18.1C. The mean across all points was 2.17%, with a maximum error reaching 10% at only a few locations. We tested the new surface by reevaluating 40 NAFX calculations that had been performed over a variety of foveation-window position and velocity limits. To compare the results, we plotted NAFXv1 along the x-axis and NFAXv2 along the y-axis, as shown in Figure 18.1D. A ﬁrst-order ﬁt gives a slope of 0.975 (1.0 is ideal) with an r2 value of 0.99, showing that the new function is in close agreement with the original. The average absolute error was 1.2%, with a standard deviation of 1.6%, demonstrating that the NAFX equation is relatively insensitive to the τ parameter. Figure 18.2A shows the creation of a radial waveform from horizontal and vertical components. Here, the horizontal magnitude is approximately ﬁve times that of the vertical, and the resulting combined waveform remains recognizable as PPfs with the same magnitude and foveation characteristics as the horizontal component, as shown by the resulting radial NAFX of 0.46, compared to 0.45 for the horizontal and 0.85 for the vertical. The NAFX analyses of 22 (horizontal, vertical, radial) triplets are plotted in Figure 18.2B. Most of the time, as expected, the radial result was nearly the same as, or just slightly worse than, that of the component with the lower NAFX. However, on several occasions the radial analysis unexpectedly yielded a better result than the poorer component, for reasons that are discussed next.

DISCUSSION The original NAFX has demonstrated its utility as a method to predict best potential visual acuity based solely on waveform and foveation characteristics. Our current work has further reﬁned the technique by (a) removing minor irregularities in the tau surface that is used to calculate the NAFX and (b) extending the algorithm to allow its application to multiplanar nystagmus analysis. The latter part (b) is actually a more difﬁcult problem than it would at ﬁrst appear. We are attempting to map a three-dimensional waveform (h,v versus t) into two dimensions (r versus t) while being mathematically exact, and this is not always possible. There are cases where the mapping will distort the resulting waveform so that, for example, successive foveation periods will appear closer together than they really are, leading to a decreased standard deviation of foveation position, resulting in an artiﬁcially high NAFX. The other challenge is that we would like the resulting waveform to remain recognizable as a nystagmus waveform, so that the investigator can use personal expertise to select appropriate segments of data for analysis and guide (or override) the program’s operations as necessary. Unfortunately, these two directives can sometimes be in conﬂict. acknowledgment This research was supported by the Department of Veterans Affairs Merit Review (to Dr. Dell’Osso).

References 1. Dell’Osso LF, Jacobs JB. An expanded nystagmus acuity function: intra- and intersubject prediction of best-corrected visual acuity. Doc Ophthalmol. 2002;104:249–276. 2. Sheth NV, Dell’Osso LF, Leigh RJ, Van Doren CL, Peckham HP. The effects of afferent stimulation on congenital nystagmus foveation periods. Vision Res. 1995;35:2371–2382. 3. Jacobs JB, Dell’Osso LF, Leigh RJ. Characteristics of braking saccades in congenital nystagmus. Doc Ophthalmol. 2003;107:137–154.

19 Inertial and Noninertial Contributions to the Perception of Translation and Path SCOTT H. SEIDMAN

ABSTRACT The ability to determine the path of travel, or “path integration,” has been reported to be robust in humans, and has been attributed to an accurate double integration of acceleration signals transduced by the otolith organs to yield path information. Vestibulo-ocular responses to translational motion, however, are most robust at high frequencies of motion, and become somewhat feeble at frequencies typically used in the study of path integration; this observation puts the otolith origin of path-integration phenomena in doubt. To determine if path-integration behaviors might be mediated by cues of motion of a noninertial nature, such as vibration and noise that might accompany translational motion, we measured the perception of motion on two different apparatuses: one that minimized noninertial cues of motion and a second that dissociated noninertial cues from actual motion. When noninertial cues are minimized, we observe a variety of high-pass phenomena in the perception of translation, including a decay in magnitude during constant velocity travel and decreasing magnitude accompanied by increasing phase leads as the frequency of sinusoidal translation decreases. When cues are dissociated from motion, the perception of translation is heavily inﬂuenced by the noninertial cues. We conclude that otolith mechanisms are not sufﬁcient to drive path-integration behaviors.

The otolith organs serve as the vestibular system’s detectors of linear accelerations, and are thus ambiguously responsive to accelerations associated with linear translation of the head and to reorientations of the head with respect to gravity (i.e., tilt). The reﬂexive responses that compensate for vestibulo-ocular or postural stimuli, and the perceptions generated by each type of stimulus, must clearly differ, but the mechanism by which the disambiguation of tilt and translational acceleration occurs is a matter of active investigation. Many investigators correctly point out that systems employing otolith inputs to generate orientational and reﬂexive responses rarely have to distinguish tilt from translation in the absence of other information, and thus propose a variety of multisensory approaches to generate appropriate responses.1-5 Information from semicircular canal afferents seems particularly useful for achieving these goals, as tilts are normally accompanied by head rotations that would stimulate the canals. Indeed, there is no a priori reason to believe that sensory and sensorimotor systems do not use all of the information available to generate appropriate responses. However, there is evidence that suggests that the vestibular system makes efforts to distinguish tilt from translation even when there is no stimulusrelated response carried by the semicircular canals. Speciﬁcally, studies of the vestibulo-ocular reﬂex (VOR) response to translation in isolation show translation-compensatory responses (e.g., horizontal eye movement in response to translation along the interaural axis) that become increasingly robust as stimulus frequency increases. Thus, responses to stimuli below

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148 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL approximately 1 Hz show decreasing magnitude and increasing phase lead as stimulus frequency decreases, consistent with a high-pass ﬁltered version of translational acceleration used to generate the eye movement response.6-8 Further, studies of tilt-compensatory VOR responses to acceleration (e.g., torsion during interaural acceleration and vertical eye movements during naso-occipital acceleration) show largest magnitude at low frequency, with decreasing magnitude and increasing phase lag with increased stimulus frequency.9-11 Such ﬁndings build a compelling case that, in the absence of canal signals, high-frequency otolith activity is responded to as if due to translation, and low frequency as if due to tilt. Unfortunately, not all studies support this simplistic approach. Studies of the perception of travel during linear translation show that human subjects accurately perceive their path of travel, even during low-frequency stimuli with large periods of constant-velocity travel.12-15 This path-integration ability is often attributed to mechanisms employing a double-integration of acceleration information transduced by the otolith organs,16-17 and is thus not consistent with the simple frequencyparsing disambiguation scheme suggested above. This response etiology, however, is based on the assumption that only inertial cues are used to generate perception. In addition to otolith-transduced acceleration, there are other noninertial cues of motion present when subjects are translated, such as the vibration and noise associated with the apparatus used to generate motion, and the roles of such cues in the generation of translation perception have not been investigated. In a series of two experiments, we study the relationship between these noninertial cues and the perception of translation. In one experiment, we employ a unique apparatus to dissociate noninertial cues from the actual acceleration proﬁle, and we compare the responses to similar trials in which noninertial cues are highly correlated to actual motion.18 In a second experiment, we employ a large sled on air bearings to minimize noninertial cues of motion.

(IA) axis was generated either using the sled alone (“sled only”) or by a combination of sled motion and counter-rotation of the two rotation axes to describe motion along the chord of a large circle (“R-theta”). During the latter form of motion, sled speed comes to a minimum halfway through the motion proﬁle, and thus the majority of noninertial cues have a “two-humped” appearance. Subjects (n = 12, ages 21 to 31 years) reported continuous perceptions of velocity magnitude and direction during travel in darkness by using a joystick that had a spring-loaded center detent, used to portray zero velocity. Subjects were initially trained to report velocity using the full set of sled-only stimuli in the light. Responses were compared to both actual velocity of travel and sled speed using “mutual information” techniques to assess similarity between responses and stimuli.

Experiment 2 Sinusoidal motion ([0.1 Hz, 0.06g] to [0.25 Hz, 0.17 g]) along the IA axis was generated using a 9 m sled riding on air bearings located at the NASA Vestibular Research Facility (Moffett Field, CA). Bungee cords were used to drive the sled. By virtue of the air bearings and absence of a motor, motion on this sled was very nearly silent and vibration free. Subjects (n = 12, ages 25 to 48 years) reported perceptions of translation

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Figure 19.1 Mean perceptual response of 2 subjects to InterAural translation (25 [cm/s]/s acceleration to 25 cm/s peak velocity) generated by “sled-only” (left, shown for subject A only), and by R-theta stimulus techniques. Dashed lines show translational velocity, and solid lines the response (+/- one standard deviation). During R-theta motion, subjects’ perceptions include a mid-trial diminution following noninertial cues generated by the sled. Subject B shows a marked misperception of the direction of travel for the second half of the trial.

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Figure 19.2 (A) Perceptual responses during target stabilization task at frequencies of (top to bottom) 0.25 Hz, 0.2 Hz, and 0.1 Hz, for one subject. Dashed lines show stimulus, and solid lines show percept. Attention is called to the change in axis scaling for the lower plot. (B) Bode plot of the mean response characteristics across subjects.

150 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL using a target-stabilization task. A small laser target was projected via a mirror galvanometer onto a screen approximately 80 cm in front of the subjects at eye level, in an otherwise dark room. The horizontal position of this target was manipulated by the subject with a joystick (without a spring-loaded detent) so as to maintain its position at a perceived stable point in space. Magnitude and phase of the perceptual response was compared to the motion stimulus using random signal techniques.

RESULTS Experiment 1 Mean responses of 2 subjects to a velocity trapezoid accelerating at 25 (cm/s)/s to a peak velocity of 25 cm/ s are shown in Figure 19.1. For all subjects, velocity percepts were trapezoidal in shape for sled-only stimuli. However, for R-theta stimuli, during which sled speed decreased to a minimum in the middle of the trial, thus producing noninertial cues with a bimodal morphology, percepts often showed a similar bimodal morphology, despite actual motion being quite similar for the two types of trials. This is most clear in subject A. A subset of response morphology, which included 7 of 12 subjects, is apparent in the responses of subject B, for which a directional confusion is apparent during the second half of the R-theta motion proﬁle. Mutual information analysis conﬁrms this qualitative assessment, with a greater similarity found between sled speed and the response than between the velocity of travel and the perceptual response.

Experiment 2 Figure 19.2 shows that responses to sinusoidal stimuli were sinusoidal in nature. Responses were found to be closest to compensatory (i.e., the target maintained closest to stable in space) at the highest frequency of stimulation, with response magnitudes decreasing and phase leads increasing as stimulus frequency declined. Mean magnitude at 0.25 Hz was approximately 0.6, with a phase lead of less than 10°. Magnitude declined to less than 0.1 at 0.1 Hz, with a phase lead of approximately 40°.

DISCUSSION In a sequence of two experiments, we investigated the relationship between noninertial cues and the perception of translation, and the perception of translation in the absence of such cues.

The ﬁrst experiment dissociated noninertial cues from actual translational motion, and results indicate that there is a powerful inﬂuence of such cues on the perception of motion. This should not be surprising to anyone with experience driving an automobile with substantially different noise and vibration characteristics from a car to which one is habituated; such a situation will often result in a misestimation of velocity. Indeed, the safest assumption regarding the incorporation of sensory cues for the achievement of any task would be to assume that any and all cues available will be used. An assertion that sensory information in any way correlated with the goals of a task is unimportant must be substantiated. The second experiment attempts to minimize noninertial cues and demonstrates that in their near absence, perceptual responses to translation are indeed highpass in nature, similar to what is observed in the translational vestibulo-ocular reﬂex. This experiment thus reconciles an important inconsistency in the vestibular literature. Previously, perceptual systems and the VOR response to translation were thought to process otolith information in two very different ways, with the VOR using high-pass otolith information to generate a response and perceptual mechanisms having access to broadband information. We now show that both perceptual and VOR mechanisms use high-pass information to generate translational responses. While we cannot be certain that the otolith information is processed in precisely the same way by both systems, processing is clearly not as dramatically different as previously held. Comparison of ocular motor and perceptual responses to translation remains an active area of investigation.

acknowledgments This work was supported by National Institutes of Health grants DC-04153, DC-01935, DC-005409, EY-01389 (Center for Visual Science), and NASAARC LifeSciDiv (Task 199–97– 62–14).

References 1. Zupan LH, Merfeld DM, Darlot C. Using sensory weighting to model the inﬂuence of canal, otolith and visual cues on spatial orientation and eye movements. Biological Cybernetics. 2002;86:209– 230. 2. Merfeld DM, Zupan LH, Gifford CA. Neural processing of gravito-inertial cues in humans. II. Inﬂuence of the semicircular canals during eccentric rotation. J Neurophysiol. 2001;85:1648–1660. 3. Merfeld DM, Zupan LH. Neural processing of gravitoinertial cues in humans. III. Modeling tilt and translation responses. J Neurophysiol. 2002;87:819–833.

TRANSLATION AND PATH PERCEPTION

4. Merfeld DM, Park S, Gianna-Poulin C, Black FO, Wood S. Vestibular perception and action employ qualitatively different mechanisms. I. Frequency response of VOR and perceptual responses during translation and tilt. J Neurophysiol. 2005;94(1):186–198. 5. Angelaki DE, McHenry MQ, Dickman JD, Newlands SD, Hess BJ. Computation of inertial motion: neural strategies to resolve ambiguous otolith information. J Neurosci. 1999;19:316–327. 6. Telford L, Seidman SH, Paige GD. Linear vestibuloocular reﬂex as a function of frequency and amplitude. Soc Neurosci Abstr. 1994;20:567. 7. Paige GD, Tomko DL. Eye movement responses to linear head motion in the squirrel monkey. I. Basic characteristics. J Neurophysiol. 1991;65: 1170–1182. 8. Paige GD, Telford L, Seidman SH, Barnes GR. Human vestibuloocular reﬂex and its interactions with vision and ﬁxation distance during linear and angular head movement. J Neurophysiol. 1998;80:2391–2404. 9. Zupan LH, Merfeld DM. Human ocular torsion and perceived roll responses to linear acceleration. J Vestib Res. 2005;15:173–183. 10. Seidman SH, Telford L, Paige GD. Roll- and pitch-tilt perception and eye movement during low-frequency linear acceleration. Soc Neurosci Abstr. 1996;22:1094.

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11. Wada Y, Goltz H, Seidman SH, Paige GD. Human vestibulo-ocular reﬂex during low frequency translation. Soc Neurosci Abstr. 1998; 24:416. 12. Berthoz A, Israël I, Vieville T, Zee D. Linear head displacement measured by the otoliths can be reproduced through the saccadic system. Neurosci Lett. 1987;82:285–290. 13. Israël I, Berthoz A. Contribution of the otoliths to the calculation of linear displacement. J Neurophysiol. 1989;62:247–263. 14. Berthoz A, Israël I, Georges-Francois P, Grasso R, Tsuzuku T. Spatial memory of body linear displacement: what is being stored? Science. 1995;269: 95–98. 15. Israël I, Grasso R, Georges-Francois P, Tsuzuku T, Berthoz A. Spatial memory and path integration studied by self-driven passive linear displacement. I. basic properties. J Neurophysiol. 1997;77: 3180–3192. 16. Mittelstaedt H. The role of the otoliths in perception of the vertical and in path integration. Ann N Y Acad Sci. 1999;871:334–344. 17. Mittelstaedt ML, Mittelstaedt H. Idiothetic navigation in humans: estimation of path length. Exp Brain Res. 2001;139:318–332. 18. AuYong N, Paige GD, Seidman SH. Multiple sensory cues underlying the perception of translation and path. J Neurophysiol. 2007;97:1100–1113.

20 The Effect of the Duncker Visual Illusion on Occluded Smooth-arm Tracking ARI Z. ZIVOTOFSKY, ADI BERCOVICH, JASON FRIEDMAN, EVA KELMAN, ELINOR SHINHERTZ, AND TAMAR FLASH

ABSTRACT Motor systems are required to perform coordinate transformations in order to accurately convert the visual information that will be utilized in the execution of a desired task. These transformations can be affected by the presence of a visual illusion. The Duncker illusion, also known as induced motion, is an illusion of motion that occurs in the presence of background movement. Previous studies have shown that certain aspects of the ocular motor system are inﬂuenced by this illusion in the same manner in which the perceptual system is inﬂuenced. The present study examines the effect of the Duncker illusion on hand-tracking movements. Eight subjects were required to track with their hand the trajectory of a smoothly moving target without the beneﬁt of visual feedback. Our results show that in a signiﬁcant number of trials, the hand-tracking trajectory differed signiﬁcantly from the trajectory observed during the control condition. However, this was not due to the inﬂuence of the illusion, because in the overwhelming majority of these trials the hand moved in the direction opposite that of the illusion. This is explainable by positing that ocularfollowing-type eye movements were generated by the ﬂow-ﬁeld movement, which in turn inﬂuenced the arm tracking. This presents another instance of a motor system with a control system that is impervious to inﬂuence by the Duncker visual illusion. The Duncker illusion, also known as induced motion, is the illusory component of motion perceived when the

background against which a target is seen moves.1 For example, if an object moves leftward and its background moves upward, then the object will be perceived to be moving diagonally, downward and to the left. Note that the illusionary component is in the direction opposite to that of the background motion. A common example of the Duncker illusion in the “real world” is when, on a partially cloudy night, the moon appears to slowly move in the direction opposite that of the slowly drifting clouds. The Duncker illusion is easily created in a laboratory setting and neatly dissociates true from perceived motion, thus providing a tool for probing the possible dissociation between perception and motor responses. The visual system is required to provide the information used to generate one’s conscious, internal representation of the external world. In addition, it is tasked with the role of generating the information used to program motor commands. According to a current hypothesis, the primate higher visual system is divided into two subsystems that are distinguishable both anatomically and functionally.2 The “what” stream is responsible for object identiﬁcation and conscious perception. This ventral stream projects from the primary visual cortex (V1) to the inferior temporal lobe. The “how” stream is in charge of visually guided actions. This dorsal stream projects from V1 to the posterior parietal cortex, where it processes the visual information that is aimed at planning and executing action. Dorsal processes are assumed to be fast and not necessarily conscious, and to encode spatial features using egocentric frames of reference. Ventral processes are hypothesized to operate on a slower time scale, to require consciousness, and to use allocentric coding.

152

DUNCKER ILLUSION AND OCCULUDED SMOOTH-ARM TRACKING

It is usually agreed that demonstrating that “action resists visual illusions” supports the “two visual system” theory. According to this theory, the visuomotor mechanism (dorsal) should be able to access accurate spatial information even when that information is not available at levels mediating symbolic decisions (ventral). One way to show the dissociation between perception and motor action is through the study of visual illusions. For instance, in the Müller-Lyer illusion, the same segment appears wider when surrounded by outward-pointing arrows and narrower when surrounded by arrows pointing inward. An action such as picking up a bar should involve egocentric coding of spatial features by the dorsal subsystem, and therefore motor measures of bar length should be unaffected by spatial relations with the nearby elements, even if conscious perception (ventral) is affected. A substantial body of experimental work has attempted to test this prediction, but there remains a great deal of disagreement on the status of the “two visual system” theory. The purpose of the present study was to determine whether there is dissociation between open-loop hand-tracking movements and perception by investigating whether hand tracking is inﬂuenced by the Duncker illusion in the same way that perception is.

METHODS Eight subjects, 4 males and 4 females, participated in the study. Mean age was 33.8 years (SD: 12.8). All were right-handed and used their dominant hand in the experiment. Three-dimensional motion of the ﬁnger was recorded with a Polhemus FASTRAK system. This spatial tracking system (STS) uses an electromagnetic ﬁeld to determine the three-dimensional position (x, y, and z Cartesian coordinates) and orientation (in azimuth, elevation, and roll Euler angles) of a receiver (marker) relative to a stationary system (transmitter). One STS marker was used at a sampling rate of 120 Hz, with a static accuracy of 0.08 cm root mean square (RMS) for the marker position and 0.150 RMS for the marker orientation.3 Stimuli were presented using a projector and a series of mirrors as shown in Figure 20.1. The visual display was projected using a large (100 × 62 cm) overhead mirror that was facing down toward a semitranslucent screen. It was seen by the subject via a second horizontal mirror (40 × 33 cm), at the approximate height of the subject’s neck and facing up toward the screen. The stimulus thus appeared to the subject to be located below the surface of this second mirror. The second mirror was situated in an opaque black frame that prevented visual feedback of the arm movement.

153

The STS transmitter was placed on a stand beneath the lower mirror. The marker was attached to the dorsal surface of the subject’s index ﬁnger by adhesive tape. The wrist was immobilized by means of a splint. The “target” was a large (8°) white dot superimposed against a “background” consisting of 600 white, random dots on an otherwise black background. The room was darkened. All trials started with the subject viewing a static target near either the right or left edge of the screen. After 1.5 seconds, both the background and the target started moving synchronously for 3 seconds at 45 deg/s. The background moved either upward or downward or, in control trials, remained static. The target moved either right or left. Each subject saw all six conditions, and each condition was repeated 10 times, for a total of 60 trials per subject. The order of presentation was randomized. The subjects were instructed to track the target with their right index ﬁnger. The tracking was done beneath the mirror, upon which the visual display was projected. Subjects were also instructed to return their hand to its natural position, near the body, at the end of each trial.

Data Analysis In the coordinate system used, the target moved horizontally parallel to the x-axis, and, based on smoothpursuit eye movement data,4 it was expected that arm movement parallel to the x-axis would accurately track the target. If the illusion affects the tracking, it should result in an unwarranted movement parallel to the y-axis, perpendicular to the subject’s body, which should otherwise show no change during the trial because there was no target movement in that plane. If this y-axis motion were due to the inﬂuence of the illusion, it would be in the direction opposite that of background motion. Arm movement in the y-axis in the other direction would not be explainable as an inﬂuence of the illusion. No motion was expected parallel to the z-axis (i.e., elevation). In order to look for the y-axis motion, the middle 1.675 seconds (i.e., 200 of the middle data points out of 360 samples) of each of the 10 trials for each condition were plotted versus time and then linearized. The angle this line formed with the y-axis was then calculated, and provided a measure of the magnitude of the movement in that direction. Finally, a t-test was used to compare the two illusory conditions (background up and background down) of each target direction (right and left) with its respective controls (background stationary).

RESULTS In the x-axis direction, the subjects all tracked the target accurately both with and without the illusion.

154 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL

B

C

A

D

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Figure 20.1 The experimental setup. Projector (A) projected the visual display to a mirror (B) facing down to a screen (C). A second mirror (D), situated in a black frame (E), was facing up to the screen. The marker (F) was placed on the subject’s index ﬁnger, above the spatial tracking system (STS) transmitter (G).

Five of the subjects never showed a difference between the control and experimental conditions in the x-axis direction, and the other 3 showed a statistically signiﬁcant difference half of the time. Those differences were minute, but they were signiﬁcant due to the extremely small standard deviation in these data, demonstrating how repeatable and accurate the tracking was. In ﬁve out of six cases, the hand velocity was greater in the control condition. In the y-axis direction, there was a statistically signiﬁcant difference in 13 of the 32 comparisons. Of these, 10 were in the direction opposite that predicted by an effect of the illusion (i.e., they were in the direction of the background motion), and three were in the direction predicted by the illusion (i.e., opposite to the background motion) (Table 20.1). Two of these three were observed in the same subject. Because there should have been no movement in the y-axis direction, any difference due to random movements or motor

noise should have yielded between one and two differences when using a 95% conﬁdence level. There seems to be a subject-dependent effect. Three of the subjects showed differences in three of the four comparisons, while the other subjects showed fewer differences, although all of the subjects reported having perceived the illusion. It is known that there is large intersubject variability in the Duncker illusion.5

DISCUSSION Our results indicate that the Duncker illusion does not inﬂuence tracking movements of the hand in the predicted direction in an open-loop condition. This dissociation between what was perceived and what the motor system did lends additional support to the “two visual systems” model. However, our results did show that motion of a large background ﬂow ﬁeld can

DUNCKER ILLUSION AND OCCULUDED SMOOTH-ARM TRACKING

155

Table 20.1 Target Tracking With and Without Illusion Target Right

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0.0296 0.6491 0.2128 0.5026 0.4601 0.9605 0.1884 0.0000

0.0982 0.0002 0.0453 0.0000 0.6536 0.1571 0.9707 0.6924

0.0498 0.0810 0.0012 0.0192 0.1458 0.6043 0.7859 0.6848

0.0285 0.0626 0.0010 0.0077 0.1519 0.5120 0.0203 0.0010

Summary of results for all 8 subjects on all conditions. A t-test was used to compare the two illusory conditions (background up and background down) of each target direction (right and left) with its respective controls (target right and target left with a stationary background). The numbers in the table are the p values for these two-sided t-tests. The values in bold are signiﬁcant values.

inﬂuence arm-tracking movements compared to a control condition when the background is stationary. Previous experiments have shown that the Duncker illusion is a robust illusion perceived to varying degrees by all subjects.5 However, its effect on motor tasks has been shown to vary. Smooth-pursuit eye movements, whether sustained or open loop, track the veridical target and not the illusion. However, in combined eye– head tracking, the head movement is inﬂuenced by the illusory trajectory.4,6 Tasks that use memory have been shown to be particularly sensitive to the inﬂuence of the Duncker illusion. Predictive saccadic tracking of a regular stepping target displays errors. It is as if the remembered location were that of the illusory position, and saccades to remembered targets where there was an illusion during the memory period display errors consistent with correcting for the illusory motion during that period.4,7 How is the lack of inﬂuence of the illusion on the hand-tracking task to be explained? Eye movements were not measured in this experiment, but it is plausible that there was an ocular following-type response in which the eyes are dragged in the direction of the ﬂow ﬁeld (i.e., the direction opposite that of the illusion), similar to what is seen in open-loop smooth pursuit.7 Furthermore, in an experiment where subjects were presented with a moving target that disappeared behind a ﬁeld of moving random dots and were asked to point to where the target would reemerge, pointing errors were inﬂuenced by gaze position, which in turn was inﬂuenced by the illusory trajectory.8 Thus, it is possible that the ocular following-type eye movements postulated to have existed in our experiment in turn inﬂuenced the arm movements, producing the observed results. In summary, our results demonstrate a lack of inﬂuence of the Duncker illusion on arm tracking and present another instance in which it appears that the

motor system is not inﬂuenced by a visual illusion. On the other hand, the arm tracking does appear to be inﬂuenced by the motion of the large background. These results should be treated as preliminary, and further investigation is warranted.

References 1. Duncker K. Uber induzierts Bewegung [Induced motion]. In: Ellis WD, ed. A Source Book on Gestalt Psychology. New York, NY: Humanities Press; 1967. 2. Milner AD, Goodale MA. The Visual Brain in Action. Oxford, UK: Oxford University Press; 1995. 3. Jordan K, Dziedzic K, Jones PW, Ong BN, Dawes PT. The reliability of the three-dimensional FASTRAK measurement system in measuring cervical spine and shoulder range of motion in healthy subjects. Rheumatology. 2000;39:382–388. 4. Zivotofsky AZ, Averbuch-Heller L, Thomas CW, Das VE, Discenna AO, Leigh RJ. Tracking of illusory target motion: differences between gaze and head responses. Vision Res. 1995;35:3029–3035. 5. Zivotofsky AZ. The Duncker Illusion: inter-subject variability, brief exposure, and the role of eye movements in its generation. Invest Ophthalmol Vis Sci. 2004;45:2867–2872. 6. Zivotofsky AZ. A dissociation between perception and action in open-loop smooth-pursuit ocular tracking of the Duncker Illusion. Neurosci Lett. 2005;376:81–86. 7. Zivotofsky AZ, Rottach KG, Averbuch-Heller L, et al. Saccades to remembered targets: the effects of smooth pursuit and illusory stimulus motion. J Neurophysiol. 1996;76:3617–3632. 8. Soechting JF, Engel KC, Flanders M. The Duncker illusion and eye-hand coordination. J Neurophysiol. 2001;85:843–854.

21 Posterior Internuclear Ophthalmoplegia of Lutz Revisited: Report of a Case Associated with a Midbrain Lesion BERND F. REMLER AND R. JOHN LEIGH

ABSTRACT Our objective was to describe a case of pseudoabducens palsy due to a midbrain lesion. The method employed was interpretation of clinical ﬁndings using both old and modern anatomical concepts. A 49-year-old patient presented with insidious onset of double vision on right lateral gaze. His examination demonstrated a minor abduction deﬁcit of the right eye, which remained unchanged over an observation period of 2.5 years. After initially negative neuroimaging, a small lesion appeared at the ipsilateral, posterior mesencephalo-diencephalic junction on follow-up MRIs. An eye movement recording demonstrated ﬁndings indistinguishable from a mild sixth nerve palsy. There was no involvement of vertical gaze or pupillary motility. We found that isolated prenuclear abduction deﬁcits can occur in conjunction with an ipsilateral midbrain lesion. Possible mechanisms of impaired abduction are discussed. In 1923, Anton Lutz (1883–1948) published a detailed review of anatomical structures controlling eye movements in the cerebral hemispheres, the brainstem, and the cerebellum.1 Modern concepts of internuclear connections between the sixth and third nerve nuclei had not yet evolved, and Lutz proposed his own scheme for horizontal gaze control in the brainstem (Fig. 21.1). This consisted of a supranuclear crossed pathway that split into ascending and descending branches at the

level of the mid-pons. Lutz correlated internuclear ophthalmoplegia (INO) with a lesion of the ascending branch and applied the term anterior INO to this condition. In contrast, a lesion of the descending branch at the pontine level would cause a prenuclear palsy of abduction, which Lutz referred to as posterior INO. Lutz’s anatomical conjectures were eventually proved incorrect, but the possibility of prenuclear abduction weakness continues to be discussed in the literature. So far, however, no case of isolated, unilateral abduction weakness with radiological conﬁrmation of a supranuclear lesion site has been identiﬁed. We describe a patient presenting with mild abduction weakness mimicking a peripheral sixth nerve palsy. His ocular motor deﬁcit correlated with a small, upper-brainstem lesion.

CASE REPORT This 49-year-old, otherwise healthy patient presented with a six-month history of mild horizontal image dissociation on rightward gaze of insidious onset. He reported no associated local or generalized symptoms. The ocular history was only signiﬁcant for presbyopia and remote, mild orbital trauma that had resolved without sequelae. Initial neuroimaging and laboratory workup for myasthenia, thyroid disease, and systemic infectious and inﬂammatory disorders was negative. On ﬁrst examination, the patient had a minor abduction deﬁcit to the right (Fig. 21.2; also see color insert ) associated with a 5 prism diopter esophoria in primary gaze that increased to 18 prism diopters on rightward gaze.

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Figure 21.2 Mild limitation of abduction of the right eye on rightward gaze is suggested by the slight temporal scleral showing in the right eye (Also see color insert.)

Figure 21.1 Lutz’s schematic of supranuclear innervation of the contralateral third and sixth nerve nuclei. Note that the pathway splits into an ascending segment to the third nerve nucleus, which controls the opposite medial rectus muscle, and a descending portion to the abducens nucleus. “Posterior INO of Lutz” results from disruption of the descending pathway, while internuclear adduction weakness is caused by lesions involving the ascending portion. This schematic corresponds with Figure 4 in Lutz’s 1923 article. Source: Lutz A. Ueber die Bahnen der Blickwendung und deren Dissoziierung (nebst Mitteilung eines Falles von Ophthalmoplegia internuclearis anterior in Verbindung mit Dissoziierung der Bogengänge) [On ocular motor pathways and dissociated ocular motility disturbances (including a case description of ophthalmoplegia internuclearis anterior occurring in conjunction with dissociated deﬁcits of semicircular canal function)]. Klin Monatsbl Augenheilk. 1923;70:213–235. Reprinted with permission. Abducting saccades were not overtly slowed, and all other eye movements were intact. The abduction defect could not be overcome with the vestibulo-ocular maneuver. Serial MRIs were negative until nearly two years after symptom onset, when a well-demarcated lesion in the region just above and posterior to the right third nerve nucleus (Fig. 21.3) was found. MR spectroscopy was inconclusive but did not support the presence of neoplastic tissue.

A subsequently obtained eye movement recording demonstrated normal vertical gaze range (Fig. 21.4) and saccades. Only minimal asymmetries of horizontal saccadic velocities were noted: abducting saccades of the right eye were slightly slower than the left but largely remained in the normal velocity range (Fig. 21.5). Vestibulo-ocular responses were normal, while esodeviation, limited abduction, and secondary deviation of the left eye were conﬁrmed (Fig. 21.4). Approximately 2.5 years into the course of illness, the patient reported that his visual symptoms were unchanged but that for several months he had noted mild weakness of his left leg and arm after exertion. The only change in his eye movements was a small increase of the esodeviation in primary gaze to 10 prism diopters. However, he also demonstrated subtle weakness of the left arm and leg. The upper- and lower-extremity reﬂexes were brisk bilaterally, and a Babinski sign was present on the left. There were no sensory deﬁcits, cerebellar dysfunction, or facial asymmetries. The jaw jerk was hypoactive. MRIs of the cervical and thoracic spinal cord were normal. A subsequent lumbar puncture yielded no evidence for an inﬂammatory, infectious, or malignant process.

DISCUSSION Lutz’s postulate of a prenuclear abducens palsy was based on incorrect assumptions of the anatomical pathways controlling horizontal gaze in the pons (Fig. 21.1). Thus, “posterior INO of Lutz” does not exist in the originally proposed manner. However, there are reports of midbrain and pontine lesions causing prenuclear abduction deﬁcits.2,3 Thus the question arises: how could prenuclear innervational abnormalities produce an isolated unilateral abduction deﬁcit? Two mechanisms—impaired prenuclear facilitation of abduction and excessive innervation of the antagonistic medial rectus—could lead to this ﬁnding. Each of these mechanisms has two inherent submechanisms: sixth nerve underfunction may be due to (1) increased prenuclear

158 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL

Figure 21.3 MRI ﬁndings. (left) Axial short-tau inversion recovery (STIR) image at the mesencephalodiencephalic junction showing a small lesion in the posterior right tegmentum (arrow). (right) Coronal T2-weighted image demonstrating a well-demarcated lesion (arrow) at the right posterior mesencephalo-diencephalic junction

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inhibitory inﬂuences or (2) impairment of facilitation. Medial rectus overactivity, on the other hand, could reﬂect a loss of inhibitory inﬂuences on its subnucleus in the third nerve nuclear complex, or an increase of direct innervation. Lutz’s1 proposed schematic implied a loss of prenuclear facilitation of the sixth nerve as the mechanism of “posterior INO,” but he did not present a case of his own. Instead, his manuscript referred to 3 patients previously reported by another author4 who had acquired unilateral horizontal gaze palsies. As their gaze palsies improved, adduction weakness resolved, but unilateral abduction deﬁcits remained. Lutz stated that these cases “likely” had posterior INO.1 A contemporary case with such a presentation had a partial lesion of the paramedian pontine reticular formation (PPRF) and its projections to the sixth nerve nucleus.3 This resulted in the claim that “the posterior INO of Lutz is a disconnection of the ﬁbers from the PPRF to the abducens nucleus that causes an abduction abnormality and spares adduction. The posterior INO of Lutz is extremely rare and depends on proof of preserved function of the sixth nerve during pursuit or vestibular eye movements.”5 Loss of prenuclear facilitation of abduction was also experimentally demonstrated by lidocaine-induced dysfunction of interneurons in the oculomotor nucleus projecting to the contralateral sixth nerve nucleus (Fig. 21.6). This inactivation of oculomotor internuclear neurons induced weakness of contralateral abduction6 in experimental animals. However, the ipsilateral location of our patient’s lesion above the level of the third nerve

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Figure 21.4 Gaze plot obtained approximately two years into the course of illness. During viewing of a visual target with the right eye (left eye covered) (A), there is limited abduction of the right eye (gray). Also note the secondary deviation of the left eye (black). During viewing of a visual target with the left eye (right eye covered) (B), there is a right esophoria of about 10º.

POSTERIOR INO OF LUTZ 159 Saccades to Right 600

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Figure 21.5 Saccadic velocity or duration plotted against amplitude, approximately two years after symptom onset. In each panel, dashed lines indicate prediction intervals (PI) for 10 normal subjects of similar age to the patient. There are minor differences in saccadic velocities between the two eyes, with slower velocities on the right; however, most of the patients’ saccades fall within prediction intervals for normal subjects.

nucleus and the absence of other eye movement disturbances preclude these two mechanisms as satisfactory explanations of his isolated, mild abduction deﬁcit. Similarly, the theoretical mechanism of increased prenuclear inhibition of the sixth nerve does not seem to apply to our case. Inhibitory projections from one PPRF to its counterpart have been postulated,7 but such connections are more likely to be concerned with the dynamic control of saccades. Horizontal gaze disturbances, on the other hand, are well documented in midbrain and diencephalic lesions corresponding with the phenomena of convergence excess,2 horizontal gaze paresis,8,9 thalamic esotropia,10 and pseudo–sixth nerve palsies.11,12 This raises the question of whether increased facilitation of the medial rectus or loss of inhibition of this muscle could

produce a picture of mild abducens weakness. In this context, ascending inhibitory projections from the PPRF to contralateral medial rectus motoneurons have been proposed13,14 but are not supported by anatomical studies.15 In prior reports of unilateral abduction weakness in conjunction with midbrain and diencephalic lesions,11,12 all patients had associated vertical gaze disturbances, and some also had convergence-retraction nystagmus. In a detailed study of ocular motor disturbances associated with lesions in the mesencephalo–diencephalic region,12 the laterality of abduction deﬁcits corresponded with the vertical distance from the third nerve nucleus: lesions above the mesencephalo–diencephalic junction resulted in contralateral abduction weakness, while lower lesions produced ipsilateral deﬁcits,

160 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL

LR

MR

CN III Vergence

MIDBRAIN

OIN

CN VI AIN

PONS

Figure 21.6 Schematic summary of important anatomical connections between the oculomotor nucleus (CN III), which contains medial rectus motoneurons supplying the medial rectus (MR) muscle, and the abducens nucleus (CN VI), which contains abducens motoneurons that supply the lateral rectus (LR) muscle. The abducens nucleus also contains abducens internuclear neurons (AIN) that project to contralateral medial rectus motoneurons (synapse not shown). The oculomotor nucleus also contains oculomotor internuclear neurons (OIN) that project to the contralateral abducens nucleus. Experimental inactivation of OIN (arrow) causes contralateral abduction weakness.

suggesting that an inhibitory descending pathway for convergence may decussate in the subthalamic region. A small lesion just above and posterior to the third nerve nucleus has been shown to produce a complete ipsilateral abduction deﬁcit (“pseudoabducens palsy”) in conjunction with vertical gaze limitations and convergence-retraction nystagmus on attempted abduction (Case 5).12 The latter abnormalities were attributed to involvement of structures within the interstitial nucleus of Cajal and the rostral interstitial nucleus of the medial longitudinal fasciculus.12 Our patient’s lesion was located more posteriorly, sparing anatomical structures contributing to vertical gaze. His mild abduction weakness may be explained by only partial disruption of an inhibitory pathway to the medial rectus subnucleus. He manifested no other lesions or disease processes that could explain his esotropia. Thus, he may represent the ﬁrst case of a supranuclear palsy of abduction with a well-deﬁned radiological lesion lacking associated ocular motor deﬁcits. Measurements of the dynamic properties of abnormal eye movements have not been performed in previously reported cases. However, in contrast to persistently diminished peak

saccadic velocities in chronic central sixth nerve palsies,16 our patient’s saccades remained essentially normal. He also showed no overt abnormalities of convergence, suggesting that the presumptive mechanism of loss of inhibitory input to the medial rectus does not produce a picture of convergence excess. Numerous important questions regarding the nature of our patient’s disease process and the involved pathway(s) remain unanswered. The responsible lesion was radiologically silent for an extended period of time, and the patient is manifesting new neurological problems that have no imaging correlate. He may suffer from a demyelinating disorder such as multiple sclerosis, but supportive evidence for this diagnosis is presently lacking. In summary, we present a case of isolated prenuclear abduction weakness associated with a midbrain lesion. It fulﬁlls Lutz’s predictions of the existence of such a syndrome, but not his conjecture of a pontine lesion location. As his anatomical model was incorrect and prenuclear abduction deﬁcits occur with diencephalic, midbrain, and pontine lesions, the syndrome of “posterior INO of Lutz” should be abandoned. Further studies are required to test several possible hypotheses to account for prenuclear abduction deﬁcits.

acknowledgments This research was supported by National Institutes of Health grant EY06717, the Ofﬁce of Research and Development, Medical Research Service, Department of Veterans Affairs, and the Evenor Armington Fund (to Dr. Leigh).

References 1. Lutz A. Ueber die Bahnen der Blickwendung und deren Dissoziierung (nebst Mitteilung eines Falles von Ophthalmoplegia internuclearis anterior in Verbindung mit Dissoziierung der Bogengänge) [On ocular motor pathways and dissociated ocular motility disturbances (including a case description of ophthalmoplegia internuclearis anterior occurring in conjunction with dissociated deﬁcits of semicircular canal function)]. Klin Monatsbl Augenheilk. 1923;70:213–235. 2. Keane JR. The pretectal syndrome. Neurology. 1990;40:684–690. 3. Bogousslavsky J, Regli F, Ostinelli B, Rabinowicz T. Paresis of lateral gaze alternating with so-called posterior internuclear ophthalmoplegia. A partial paramedian pontine reticular formation-abducens nucleus syndrome. J Neurol. 1985;232:38–42. 4. Priestley-Smith. Bilateral deviation of the eyes. Ophthalmology Hospital Reports. 1879;9:22.

POSTERIOR INO OF LUTZ 161

5. Walsh TJ, ed. Neuroophthalmology: Clinical Signs and Symptoms. 3rd ed. Philadelphia, PA: Lea & Febiger; 1992. 6. Clendaniel RA, Mays LE. Characteristics of antidromically identiﬁed oculomotor internuclear neurons during vergence and versional eye movements. J Neurophysiol. 1994;71:1111–1127. 7. Pierrot-Deseiligny C. Circuits oculomoteurs centraux. Rev Neurol. 1985;141:349–370. 8. Zackon DH, Sharpe JA. Midbrain paresis of horizontal gaze. Ann Neurol. 1984;16:495–504. 9. Masdeu JC, Rosenberg M. Midbrain-diencephalic horizontal gaze paresis. J Clin Neuroophthalmol. 1987;7:227–234. 10. Gomez CR, Gomez SM, Selhorst JB. Acute thalamic esotropia. Neurology. 1988;38:1759–1762. 11. Namer IJ, Oeztekin MF, Kansu T, Zileli T. Pseudosixth-nerve palsy with thalamo-mesencephalic junction lesion. Report of two cases. Neuroophthalmology. 1990;10:69–72. 12. Pullicino P, Lincoff N, Truax BT. Abnormal vergence with upper brainstem infarcts.

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Pseudoabducens palsy. Neurology. 2000;55: 352–358. Thömke F, Hopf HC, Krämer G. Internuclear ophthalmoplegia of abduction: clinical and electrophysiological data on the existence of an abduction paresis of prenuclear origin. J Neurol Neurosurg Psych. 1992;55:105–111. Thömke F, Hopf HC. Abduction paresis with rostral pontine and/or mesencephalic lesions: pseudoabducens palsy and its relation to the so-called posterior internuclear ophthalmoplegia of Lutz. BMC Neurology. 2001;1:4. Büttner-Ennever JA: The extraocular motor nuclei: organization and functional neuroanatomy. In Büttner-Ennever JA, ed. Neuroanatomy of the Oculomotor System, Volume 151 (Progress in Brain Research). Amsterdam, the Netherlands: Elsevier; 2006:95–126. Wong AMF, McReelis K, Sharpe JA. Saccade dynamics in peripheral vs central 6th nerve palsies. Neurology. 2006;66:1390–1398.

22 Divergence Insufﬁciency Associated with Hereditary Spinocerebellar Ataxia DAVID G. MORRISON, SEAN P. DONAHUE, AND PATRICK J. M. LAVIN

ABSTRACT Divergence insufﬁciency is characterized by acquired, comitant, uncrossed diplopia at distance, but little or no deviation at near. Ductions are full with no evidence of abducens palsies. Our objective was to describe the association of hereditary spinocerebellar ataxia (SCA) and divergence insufﬁciency using a retrospective case review. We identiﬁed 6 patients with divergence insufﬁciency and spinocerebellar ataxia. All patients had a family history of acquired impaired balance, all patients had gaze-evoked nystagmus, and 4 had evidence of cerebellar atrophy on neuroimaging. Five patients were managed with corrective prisms, while 1 required extraocular muscle surgery. We found that acquired uncrossed horizontal diplopia at distance, but not near, occurs in patients with SCA as a result of divergence insufﬁciency. In most patients, the esodeviations were small and were managed easily with prisms. The clinical ﬁndings implicate predominant midline cerebellar dysfunction in our patients as the likely cause of their divergence insufﬁciency. Divergence insufﬁciency is characterized by ﬁve criteria1: (1) acquired uncrossed horizontal diplopia at distance, but not near; (2) a comitant esotropia at distance; (3) full ductions; (4) normal abducting saccades, with no signs of abducens palsies; and (5) reduced or absent fusional divergence. The diplopia may be intermittent and, like the esotropia, improve on lateral gaze.2

Unfortunately, the terms divergence insufﬁciency (DI) and divergence paralysis (DP) are used interchangeably, despite the fact that the deﬁnition of “paralysis” is “the complete loss of function of one or more muscle groups.” 3 In 1935, Bruce4 distinguished between “divergence insufﬁciency,” in which otherwise healthy patients develop sudden-onset esotropia at distance, and “divergence paralysis,” which is associated with underlying neurological diseases. DI can be distinguished from DP, which occurs as a result of bilateral abducens palsies in patients with severe head injuries, intracranial hypertension from other causes, intracranial hypotension, brainstem tumors, craniocervical junction abnormalities, and Fisher’s syndrome.5 Patients with DP usually have bilateral abduction defects, horizontal diplopia at distance, and quantitatively slowed abducting saccades. Occasionally, DI can be difﬁcult to distinguish from DP, particularly in those patients recovering from DP who go through a phase during which the esotropia becomes comitant with full ductions, mimicking DI; however, abducting saccades are quantitatively slowed.6 Generally, DI occurs in patients who appear to be otherwise neurologically normal; however, occasionally it is reported with Chiari I malformations,7 midline cerebellar degeneration,8 and, rarely, sedation (diazepam). The association of DI and hereditary spinocerebellar degeneration is not well known. The purpose of this study is to report the association of DI with autosomal dominant spinocerebellar ataxia (SCA) in 6 patients and discuss their management.

162

DIVERGENCE INSUFFICIENCY 163

CASE REPORTS Patient 1 A 54-year-old man complained of episodes of intermittent diplopia that had generally occurred in the evenings during the previous year. Gradually the episodes increased in frequency. Also, he complained of progressive difﬁculty with his balance. His mother had impaired balance that began in her 60s, and his 68-year-old brother had a similar balance disorder. Neither he nor his family members had a history of strabismus. With myopic correction his visual acuity was 20/20 in each eye. His eye movements were full, but he had gaze-evoked nystagmus. He was orthophoric at near but had a comitant 4 prism diopter esotropia at distance. The remainder of his eye exam was normal. His neurological exam revealed mild dysarthria and a wide-based gait. MRI of the brain was normal. His diplopia resolved with Fresnel prisms. Over the next ﬁve years, the patient’s ataxia progressed, preventing him from working. His esotropia increased to 20 prism diopters at distance and 12 prism diopters at near. He was able to fuse 20 prism diopters at near through a bifocal, so bimedial rectus recession of 3.5 mm was performed for the distance angle esotropia. Postoperatively, he was orthophoric at near with a 3 prism diopter esophoria at distance, and had no diplopia. However, over the next two years, he regressed to a constant 6 prism diopter esotropia at distance, but remained orthophoric at near. The right medial rectus was re-recessed to 6 mm from the original site of insertion, and orthophoria was again achieved. At his most recent visit he complained of intermittent diplopia alleviated by tilting his head forward; examination revealed a 2 prism diopter esophoria at distance.

Patient 2 A 50-year-old woman had intermittent diplopia for the previous two years. Also, she complained of poor balance and frequent falls. Her father, paternal grandfather, and two paternal uncles had balance disorders; all experienced onset of symptoms in their 40s and had frequent falls. Examination revealed vision correctable to 20/20 in each eye. The patient had full versions but upbeat nystagmus in primary gaze that worsened on up-gaze; also, she had horizontal gaze-evoked nystagmus. She was orthophoric at near but had a 10 prism diopter, comitant esotropia at distance. The remainder of her eye exam was normal. Neurological exam revealed a wide-based gait and inability to perform tandem gait. A brain MRI demonstrated midline cerebellar atrophy

and an incidental frontal venous angioma. Her diplopia resolved with 3 prism diopters of baseout Fresnel prism on each spectacle lens.

Patient 3 An 80-year-old woman with a 10-year history of diplopia complained of difﬁculty with balance and frequent falls. Family history was signiﬁcant for a grandmother with a gait disturbance and balance difﬁculty. Her visual acuity was 20/30 OD and 20/25 OS. She had gazeevoked nystagmus to each side; she had a 2 prism diopter esotropia at distance and a 6 prism diopter exophoria at near. The remainder of the exam was remarkable for bilateral nuclear sclerotic cataracts. Neurological exam demonstrated bilateral ﬁnger-nose ataxia, dysdiadochokinesis, and a wide-based gait. Neuroimaging was not performed. She was given baseout prisms. Over the next eight years, her distance esotropia increased to 6 prism diopters, but her symptoms were relieved with stronger prisms.

Patient 4 A 36-year-old homemaker complained of unsteady gait and visual distortion that she had experienced for the previous ﬁve months. The visual distortion progressed over a few weeks to frank, horizontal diplopia. She said she swayed, as if she were on a boat. Her paternal grandmother had a gait disturbance, beginning at age 40, that caused disability by age 80. Her corrected visual acuity was 20/20 in each eye. She had full versions, but had horizontal gaze-evoked nystagmus with a small, superimposed torsional component. She had a comitant 4 prism diopter esotropia at distance but was orthophoric at near. The remainder of the eye exam was normal. Neurological examination was normal; speciﬁcally, her gait, station, balance, and cerebellar testing were normal. An MRI demonstrated mild midline cerebellar atrophy (Figure 22.1). Her diplopia resolved with a 2 baseout Fresnel prism over each eye. She has remained asymptomatic with the same prisms for the past ﬁve years.

Patient 5 A 64-year-old man complained of intermittent diplopia, present for approximately 20 years. He had difﬁculty with his balance over the same time period. Otherwise, he was healthy and took no medication. His father had impaired balance. His visual acuity was 20/20 with each eye. He had horizontal gaze-evoked nystagmus. His versions were limited symmetrically in all ﬁelds of gaze, but his saccadic

164 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL dysdiadokinesis. An MRI revealed subtle midline cerebellar atrophy. DNA testing for known mutations associated with autosomal dominant SCA was negative. His diplopia resolved with a 2 prism diopter baseout Fresnel prism on each spectacle lens.

DISCUSSION

Figure 22.1 T1 weighted sagittal MRI demonstrating midline cerebellar atrophy.

velocities appeared normal; the restriction was conjugate and minimal. He was orthophoric at near but had a 4 to 6 prism diopter esotropia at distance. The remainder of the eye exam was unremarkable except for red-green color blindness and a small right epiretinal membrane. Neurological examination revealed poor balance and difﬁculty with tandem gait, but no appendicular ataxia. MRI revealed subtle cerebellar atrophy. Fresnel prisms relieved the patient’s diplopia adequately; he was lost to long-term follow-up.

Patient 6 A 64-year-old business analyst complained of an intermittent, horizontal diplopia for two years. Over the same time period, he reported worsening balance. His history was complicated by episodic dysarthria that lasted minutes and was attributed to transient ischemic attacks. He was treated with antiplatelet medication and had been free of the dysarthric episodes for the previous six months. His family history was signiﬁcant for a balance disorder and tremor affecting his mother, maternal grandfather, and a maternal uncle. Examination revealed best-corrected vision of 20/20 in each eye. He had obliquely downward-beating nystagmus on lateral gaze in each direction. He had a small exophoria at near with a variable 6 to 8 prism diopter esotropia at distance. The remainder of his ophthalmic exam was unremarkable. His neurological exam revealed a wide-based gait with difﬁculty performing tandem gait. He had ﬁnger-to-nose ataxia and

All 6 of our patients presented with diplopia at distance only, caused by divergence insufﬁciency; none had hyperopic esotropia, and, surprisingly, none was diagnosed with cerebellar degeneration before presentation. All had symptoms or signs, or both, of predominant midline cerebellar dysfunction; all had strong family histories of gait ataxia or disequilibrium, or both (Table 22.1). In the absence of other causes for cerebellar disease, these ﬁndings strongly suggested they had familial spinocerebellar degeneration (i.e., autosomal dominant cerebellar ataxia [SCA]). All were treated empirically with vitamin E as an antioxidant. Genetic testing was not performed in 5 of our patients, mainly for ﬁnancial reasons: 2 of the 5 patients were offered testing but declined, and 1 had a negative test. Saccadic velocities were measured in 1 patient and were normal. The association of divergence insufﬁciency with cerebellar dysfunction is reported sparsely in the literature. Cunnigham9 and Lepore10 each described patients with divergence insufﬁciency and ataxia; in those with no obvious intracranial pathology, their symptoms were attributed to stroke or microvascular ischemic changes determined by neuroimaging. Jacobsen11 reported divergence insufﬁciency in 2 patients with “cerebellar degenerations” but did not give further details. Versino’s group12 described 6 patients with cerebellar degeneration, gait ataxia, and esophoria but did not report formal ocular motility examinations. The esodeviations in their patients were measured at distance only; also, they did not report family histories. Lastly, Ohyagi’s group2 reported DI in 3 members of a single Japanese family with SCA3. Multiple gene loci are established for a number of SCA subtypes, but many remain to be identiﬁed. Thus, while a positive genetic test is helpful in diagnosis, a negative result does not exclude hereditary disease.13 Radiological evidence of cerebellar atrophy is not always present, particularly early in the course of the disease. Additional study will be necessary to determine whether speciﬁc subtypes of SCA may lead to a greater predisposition to DI. It is unclear whether DI is caused by underaction of divergence or overaction of convergence. The cerebellum has a signiﬁcant role in controlling vergence. The ﬂocculus has neurons that discharge in relation to the

Table 22.1 Treatment and Outcomes of 6 Patients with Divergence Insufﬁciency and Spinocerebellar Ataxia Age Gender

Presentation

1

54

Male

2

50

3

Ocular Deviation (Near)

Ocular Deviation (Distance)

Neurological Exam

Intermittent Orthotropic diplopia for 1 y, generally in the evenings

Comitant 4 PD ET

Horizontal Eye muscle gaze-evoked surgery nystagmus, dysarthria, wide-based gait

Female

Intermittent horizontal diplopia for 2 y

Orthotropic

Comitant Fine upbeat Fresnel prism 3 PD Vision stable for Her father and two pa- Midline cerebellar 10 PD ET nystagmus, worse on BO OU 3 y (happy with ternal uncles had atrophy and a up-gaze; gaze-evoked Fresnel prism) poor balance and frontal venous horizontal nystagmus falls in their 40s angioma

80

Female

Double vision for 10 y

6 PD exophoria

Comitant 2 PD ET

Horizontal Fresnel prisms, then Slight increase of Grandmother had poor Not done gaze-evoked 2 BO OU ground ET to 6 PD at 8 y balance and difﬁculty nystagmus, limb and into spectacles walking gait ataxia

4

36

Female

Visual distortion for Orthotropic 5 mo, becoming frank diplopia after a few weeks

Comitant 4 PD ET

Horizontal gaze-evoked nystagmus with a torsional component

5

64

Male

Intermittent Orthotropic diplopia for 20 y

6

64

Male

Short episodes of Flick horizontal exophoria diplopia at distance for 2 y; occasional blurring at near

Comitant Poor balance, Fresnel prisms 4-6 PD ET unable to perform tandem gait 4 to 6 PD Oblique downbeat Fresnel paste on exotropia nystagmus on lateral prism 2 PD BO gaze; hypometric OU saccades; limb and gait ataxia

BO, baseout; ET, esotropia; OU, oculus uterque (both eyes); PD, prism diopter.

Therapy for Diplopia

Fresnel paste on prism 2 PD BO OU

Progress

Family History

Ataxia and dys- His mother had poor arthria worse, balance in her 60s, disabled by 5 y and a 68-year old brother had poor balance

MRI

Normal

Vision stable for 5 y

Paternal grandmother Mild midline had a gait disorder at cerebellar age 40; she was atrophy disabled by age 80

Lost to follow-up

Father had poor balance

No long-term follow-up

Mother, maternal Mild midline grandfather, and a cerebellar maternal uncle had atrophy impaired balance and tremor

Subtle cerebellar atrophy

DIVERGENCE INSUFFICIENCY 165

Patient

166 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL vergence angle, but it may be more concerned with adjustment of the vestibulo-ocular reﬂex gain as a function of target distance, because monkeys with ﬂoccular lesions are able to adapt. In rabbits, the cerebellar ﬂocculus has a projection to the medial, but not the lateral, rectus muscles, so a lesion of the ﬂocculus could cause a convergence bias12; if this is the case in humans, such a lesion could cause the esotropia of DI. Further, experimental lesions of the ﬂocculus and paraﬂocculus cause downbeat, gaze-evoked, and rebound nystagmus in primates.14 Lesions to the dorsal cerebellar vermis in monkeys cause a small-angle esotropia,15 probably because the dorsal vermis projects to the fastigial ocular motor area. Also, injury to the vermis and ﬂocculonodular lobe causes midline ataxia. All of our patients had gaze-evoked nystagmus, impaired balance, and gait ataxia, and one had downbeat nystagmus; because of these ﬁndings, we believe that their DI was associated with SCA as a result of ﬂocculonodular lobe or midline cerebellar dysfunction. Thus, DI may be an early presenting feature of the midline dysfunction of SCA. Most patients had deviations sufﬁciently small to be managed conservatively with prism therapy. One patient had a larger angle of deviation and responded well to medial rectus recession. In conclusion, horizontal binocular distance diplopia caused by divergence insufﬁciency can be a presenting symptom of autosomal dominant spinocere-bellar ataxia. We strongly urge that patients with uncrossed diplopia greater at distance than at near undergo a detailed neurological history, family history, and examination. Neuroimaging and genetic testing may be helpful in the diagnosis, but normal studies do not exclude SCA.

3.

4. 5.

6.

7.

8.

9. 10.

11.

12.

13.

acknowledgment This research was funded in part by an unrestricted grant from Research to Prevent Blindness.

14.

References

15.

1. Duane A. Paralysis of divergence. Ophthalmology. 1905;2:1–19. 2. Ohyagi Y, Yamada T, Okayama A, et al. Vergence disorders in patients with spinocerebellar atoxia

3/Machado-Joseph disease: a synoptophore study. J Neurol Sci. 2000;173:120–123. Answers Corporation. Wikipedia. Answers.com Web site. http://www.answers.com/library/Wikipedia. Last accessed March 4, 2008. Bruce GM. Ocular divergence: its physiology and pathology. Arch Ophthalmol. 1935;13:639–653. Leigh RJ, Zee DS. The Neurology of Ocular Movements. 4th ed. Oxford, UK: Oxford University Press; 2006. Kirkham TH, Bird AC, Sanders MD. Divergence paralysis with paired intracranial pressure. An electro-oculographic study. Brit J Ophthalmol. 1972;56:776–782. Lewis AR, Kline LB, Sharpe JA. Acquired esotropia due to Arnold-Chiari I malformation. J Neuroophthalmol. 1996;16:49–54. Lavin PJM, Donahue S. Neuro-ophthalmology: the efferent visual system. Gaze mechanisms and disorders. In: Daroff RB, Fenichel GM, Marsden CD, Bradley WG, eds. Neurology in Clinical Practice. 4th ed. Boston, MA: Butterworth-Heinemann; 2004. Cunningham RD. Divergence paralysis. Am J Ophthalmol. 1972;74:630–635. Lepore FE. Divergence paresis: a nonlocalizing cause of diplopia. J Neuro-ophthalmol. 1999;19: 242–245. Jacobsen DM. Divergence insufﬁciency revisited: natural history of idiopathic cases and neurologic associations. Arch Ophthalmol. 2000;118:1237– 1241. Versino M, Hurko O, Zee DS. Disorders of binocular control of eye movements in patients with cerebellar dysfunction. Brain. 1996;119:1933– 1950. Schols L, Bauer P, Schmidt T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004; 3:291–304. Leigh RJ, Zee DS. The Neurology of Ocular Movements. 4th ed. Oxford, UK: Oxford University Press; 2006. Takagi M, Tamargo R, Zee DS. Effects of lesions of the cerebellar oculomotor vermis on eye movements in primate: binocular control. Progr Brain Res. 2003;142:19–33.

23 Neuromuscular Junction Dysfunction in Miller Fisher Syndrome JANET C. RUCKER

ABSTRACT Miller Fisher syndrome (MFS) consists of a triad that includes ophthalmoplegia, ataxia, and areﬂexia with a self-limited monophasic course. Anti-GQ1b antibodies are present in up to 90% of patients. It is considered a variant of GuillainBarré syndrome, with the primary pathology considered to be peripheral nerve demyelination. A 43-year-old man, who was given an acetylcholine receptor antibody–negative diagnosis of myasthenia gravis 15 years ago, presented with binocular diplopia. Electrophysiologic studies prior to neuro-ophthalmologic evaluation revealed a decremental response to repetitive stimulation. Relapse of myasthenia gravis was the working diagnosis. Examination revealed diffuse bilateral ophthalmoplegia, bilateral pupillary light-near dissociation, and areﬂexia. Cerebellar function and cerebrospinal ﬂuid were normal. Anti-GQ1b antibodies were positive, and recurrent MFS was diagnosed. However, decremental response occurred with repetitive stimulation of the left orbicularis oculi and bilateral trapezius muscles. The patient recovered completely in three months. This case study highlights a developing recognition of neuromuscular dysfunction in MFS. Systematic evaluation of neuromuscular junction physiology should be performed in MFS patients to advance understanding of this process.

Miller Fisher syndrome (MFS) is considered a variant of acute inﬂammatory demyelinating polyneuropathy (AIDP), otherwise known as Guillain-Barré syndrome, and classically consists of a triad of bilateral ophthalmoplegia, ataxia, and areﬂexia.1 Anti-GQ1b antibodies are present in up to 90% of patients. The precise location, mechanism, and extent of neurological insult are not completely understood. Peripheral nerve demyelination is regarded as the hallmark of pathological involvement, given the clinical overlap of the syndrome with AIDP and direct pathological evidence,2 but extensive clinical and radiographic evidence of central nervous system involvement exists.3-6 In addition, evidence of direct neuromuscular junction (NMJxn) involvement is mounting in a mouse diaphragm/ phrenic nerve model and in human cases of MFS.7-10 A patient with recurrent MFS and a decremental response to repetitive stimulation on electromyography (EMG) in the absence of electrophysiological evidence of demyelinating peripheral neuropathy is described.

CASE REPORT A 43-year-old Hispanic man presented with a chief complaint of binocular diplopia. Fifteen years prior, he had had an illness that began with vertigo and oscillopsia in right and left gaze and was followed by binocular oblique diplopia, bilateral ptosis, and gait difﬁculty. Records from that time were not available for review. Per patient report, the working diagnosis

167

168 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL

Figure 23.1 Ocular motility at the time of illness onset demonstrating signiﬁcantly impaired bilateral elevation and abduction, moderately impaired bilateral adduction, and nearly normal bilateral depression. One millimeter of ptosis was present on the left. was acetylcholine receptor antibody–negative myasthenia gravis. He was treated with pyridostigmine and had complete resolution of his symptoms over three months. He discontinued pyridostigmine and remained symptom free over the next 14 years. The current illness began with binocular oblique diplopia and bilateral palm paresthesias. Ocular motor examination revealed signiﬁcantly impaired bilateral elevation and abduction (5% to 10% of normal), moderately impaired adduction (60% to 70% of normal), and nearly normal depression (Fig. 23.1). Horizontal and vertical saccades were slow, and motility deﬁcits were not overcome with vestibulo-ocular reﬂexes. There was minimal left ptosis. Orbicularis oculi strength was normal. Pupillary light-near dissociation was present bilaterally. Sensation and motor strength were normal. Reﬂexes were absent. There was no truncal or appendicular ataxia. Gadolinium-enhanced brain MRI was normal. Acetylcholine receptor antibodies and MUSK antibodies were normal. EMG with repetitive stimulation revealed normal nerve conduction studies and needle examination but a pathological decremental response to repetitive stimulation in the left orbicularis oculi and bilateral trapezius muscles. Anti-GQ1b antibodies were elevated. Lumbar puncture was normal (protein 39). All symptoms and clinical ﬁndings resolved spontaneously within three months (Fig. 23.2). Anti-GQ1b antibody titer normalized, but a decremental response to EMG repetitive stimulation remained.

DISCUSSION A decremental response on EMG repetitive stimulation typically represents impaired postsynaptic NMJxn transmission. It may also occur in the setting of severe peripheral neuropathy. However, in this patient, nerve conduction and needle studies were normal, with no evidence of demyelinating polyneuropathy. The NMJxn as an antigenic target and primary site of pathology in MFS is well established in a mouse diaphragm/phrenic nerve model.7,8 Application of serum from anti-GQ1b-positive patients to this model results in immediate, massive acetylcholine release at the NMJxn, followed by complete NMJxn blockade. The predominant effect is presynaptic, but there is some evidence to suggest a component of postsynaptic dysfunction as well.7 In addition to electrophysiological evidence of NMJxn pathology, electron microscopy reveals structural breakdown of the presynaptic NMJxn terminal with loss of synaptic vesicles and fragmentation the NMJxn by Schwann cell processes,11 and immunoﬂuorescence studies reveal direct anti-GQ1b antibody binding to both presynaptic and postsynaptic NMJxn membranes.12 Direct evidence of primary NMJxn dysfunction is suggested in 7 human antiGQ1b-positive patients with MFS and increased jitter on single-ﬁber EMG.9,10 In addition, 3 of these patients exhibited an incremental response to repetitive stimulation.10 The patient in this report provides additional support for the presence of NMJxn pathology in MFS.

MILLER FISHER SYNDROME 169

Figure 23.2 Spontaneous return of normal ocular motility three months after onset of illness.

Systematic evaluation of NMJxn physiology should be performed in MFS patients to advance understanding of the role of NMJxn pathology in the disease process of MFS. Supplementary information (video clips) is available at the Darof–Dell’Osso laboratory Web site (http://www.omlab.org).

References 1. Fisher M. An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia, and areﬂexia). N Engl J Med. 1956;255:57–65. 2. Phillips MS, Stewart S, Anderson JR. Neuropathological ﬁndings in Miller Fisher syndrome. J Neurol Neurosurg Psychiatry. 1984;47:492–495. 3. Ogawara K, Kuwabara S, Yuki N. Fisher syndrome or Bickerstaff brainstem encephalitis? Anti-GQ1b IgG antibody syndrome involving both the peripheral and central nervous systems. Muscle Nerve. 2002;26:845–849. 4. Tezer FI, Gurer G, Karatas H, Nurlu G, Saribas O. Involvement of the central nervous system in Miller Fisher syndrome: a case report. Clin Neurol Neurosurg. 2002;104:377–379. 5. Goldberg-Stern H, Melamed E, Gadoth N. Abnormal evoked potentials in Miller-Fisher syndrome: further evidence of combined peripheral and central demyelination. J Neurol Neurosurg Psychiatry. 1994;57:506.

6. Meienberg O, Ryffel E. Supranuclear eye movement disorders in Fisher’s syndrome of ophthalmplegia, ataxia, and areﬂexia. Report of a case and literature review. Arch Neurol. 1983;40: 402–405. 7. Buchwald B, Buﬂer J, Carpo M, et al. Combined preand postsynaptic action of IgG antibodies in Miller Fisher syndrome. Neurology. 2001;56:67–74. 8. Bullens RW, O’Hanlon GM, Goodyear CS, et al. Anti-GQ1b antibodies and evoked acetylcholine release at mouse motor endplates. Muscle Nerve. 2000;23:1035–1043. 9. Lo YL, Chan LL, Pan A, Ratnagopal P. Acute ophthalmoparesis in the anti-GQ1b antibody syndrome: electrophysiological evidence of neuromuscular transmission defect in the orbicularis oculi. J Neurol Neurosurg Psychiatry. 2004;75:436–440. 10. Lo YL, Leoh TH, Dan YF, et al. Presynaptic neuromuscular transmission defect in the Miller Fisher syndrome. Neurology. 2006;66:148–149. 11. O’Hanlon GM, Plomp JJ, Chakrabarti M, et al. AntiGQ1b ganglioside antibodies mediate complementdependent destruction of the motor nerve terminal. Brain. 2001;124:893–906. 12. Wessig C, Buchwald B, Toyka KV, Martini R. Miller Fisher syndrome: immunoﬂuorescence and immunoelectron microscopic localization of IgG at the mouse neuromuscular junction. Acta Neuropathol (Berl). 2001;101:239–244.

24 Involuntary Version-Vergence Nystagmus Induced by Ground-Plane Optic Flow: Analysis of Dynamic Characteristics of Nystagmus Quick Phases DONGSHENG YANG, MINGXIA ZHU, AND RICHARD W. HERTLE

ABSTRACT We used a new motion stimulus displayed on a computer monitor in the ground plane to induce involuntary version-vergence nystagmus. Eye movements were recorded with a search coil system. The involuntary version-vergence nystagmus had both vertical version and horizontal vergence components. Backward motion induced monophasic divergent quick phases and upward versional quick phases. Forward motion induced biphasic divergence-convergence quick phases and downward versional quick phases. Quick phases of both vergence and version components were analyzed. A time dissociation of about 20 milliseconds between version velocity peak and convergence velocity peak was observed. Dependence of vergence peak velocity on versional saccadic peak velocity was demonstrated. Our data support the hypothesis that the vergence system and the saccadic system can act separately but interact with each other whenever they occur simultaneously. Saccades and vergence eye movements are commonly considered to be two separate subsystems with distinct characteristics in anatomy and neurophysiology. However, combined version-vergence movements are frequently made to shift binocular ﬁxation between objects at different distances and directions under natural viewing conditions. When combined saccadevergence movements occur, vergence movements increase in velocity while versional saccades slow

down (saccade-vergence interactions).1-7 It has been suggested that activity of saccadic burst neurons and vergence neurons might be gated by the same group of neurons—omnipause neurons (OPN). During saccades, inhibition from OPN is lifted not only for saccades but also for vergence. Thus, vergence would be facilitated.3 However, recent evidence does not support this hypothesis. For example, it was found that vergence enhancement increases with saccadic peak velocity in monkeys.8 This cannot be explained with the OPN hypothesis. Another recent ﬁnding beyond the accountability of the OPN hypothesis is time dissociations between saccades and vergence, discovered by Kumar et al.9,10 Most earlier studies on saccade-vergence interaction used small visual targets to induce combined version and vergence eye movements.1-10 In the present study, we used large ﬁeld motion stimuli in the ground plane to induce involuntary version-vergence nystagmus. The version-vergence nystagmus has quick and slow phases for both vertical version and horizontal vergence components. We will summarize dynamic properties of the nystagmus quick phases and analyze relationships between vertical saccadic and horizontal vergence peak velocity, and examine time dissociations between the vertical saccades and horizontal vergence.

METHODS Methodological information is brieﬂy presented in this chapter. Detailed information can be found in our previous paper.11

170

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Subjects Five subjects participated in this study (2 authors and 3 naive volunteers), aged 25 to 44 years, with normal ophthalmic and ocular motor evaluations as well as normal binocular vision. Each had best corrected visual acuity of 20/20 in each eye. All procedures observed the declaration of Helsinki, and informed consent was obtained from all subjects.

Stimuli Motion in the Frontal Plane For the purpose of comparison with experiments in the ground plane, a squarewave-grating pattern displayed on a computer monitor (ViewSonic, Walnut, CA) in the frontal plane was used to induce vertical optokinetic nystagmus (OKN).

Motion in the ground plane The same grating pattern used for the frontal plane experiment was positioned face up and 9 cm below the eye level. The pattern moved forward or backward in the ground plane. Velocities of the motion on the surface were 4, 8, 12, 16, and 20 cm/s (approx. 10, 20, 30, 40, and 50 deg/s to the eyes).

Experimental Paradigms Subjects were seated with their heads stabilized on a chin and forehead rest and performed calibration tasks by ﬁxating on a 0.5° dot displayed at ﬁve different locations, with right eye and left eye viewing separately, before each experiment. After the calibration, the subject was instructed to look at the center of the stationary grating pattern and pressed a button to trigger the motion of the pattern, which lasted for 5 seconds in each trial. During the motion stimulus, subjects were instructed to obtain a clear image of the pattern and not to track any single bar. Ten trials (ﬁve different velocities in two directions) compose one block. Twenty blocks can be obtained in approximately 30 minutes.

Eye Movement Recording and Data Analysis Horizontal and vertical eye movements of both eyes were recorded with an electromagnetic technique (Remmel Labs, Katy, TX) at 1 kHz. The horizontal and vertical eye position data obtained during the calibration procedure were each ﬁtted with a third-order polynomial that was then used to linearize the horizontal and vertical eye position data recorded during the experiment proper. The experimental data were then smoothed with a cubic

spline function with a weight of 107. The vergence position was computed by subtracting the position of the right eye from the position of the left eye. Vergence velocity was obtained by two-point backward differentiation of the vergence-position data. Version position was an average of the right and left eye positions. Estimates of the amplitude of the versional responses were obtained by measuring the change in eye position from maximum point to minimum point using programs written in MATLAB (MathWorks, Natick, MA). A criterion of 3 deg/s was used to decide the beginning and end of version and vergence responses for the purpose of measuring the response duration.

RESULTS Combined version-vergence eye movements showed ocular tracking slow phases and saccadic quick phases in both vertical and horizontal components. Eye movement traces of downward-convergent tracking slow phases and resetting upward-divergent quick phases induced with backward motion (toward subjects) and upward-divergent tracking slow phases and resetting downward-convergent quick phases induced with forward-motion stimuli (away from subjects) are displayed in Figure 24.1. The frontal plane stimuli did not induce any measurable horizontal vergence but did induce regular vertical versional nystagmus. To demonstrate the dynamic properties of the version and vergence components, samples of velocity and position proﬁles for vertical saccades and horizontal vergence saccades are displayed in Figure 24.2. Divergent saccades and upward saccades induced by backward motion stimuli are displayed in Figure 24.2A, and biphasic divergence-convergence and downward saccades induced by forward motion stimuli are displayed in Figure 24.2B. Amplitudes of the vertical versional saccades were about 5° on average but varied at different velocities. The amplitudes of saccadic divergences with backward motion were about 0.5° ± 0.3°. With forward-motion stimuli, amplitudes of divergence were 0.3° ± 0.13°, and amplitudes of convergence were 0.45° ± 0.16°. The average peak velocities of the vertical saccades were about 70 to 110 deg/s, comparable to vertical OKN from frontal plane,12 and the average peak velocities of horizontal vergence quick phases were about 20 to 25 deg/s at various stimulus conditions, which is much higher than the slow-phase velocity of 2 to 4 deg/s.11 Time dissociation (TD) between version velocity peaks and vergence velocity peaks was examined. As shown in Figure 24.2A, the peak of the divergence velocity leads the velocity peak of the upward saccade

172 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL KG

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Figure 24.2 Representative velocity and position proﬁles of vertical version and horizontal vergence. Dashed lines indicate position of traces, and solid lines indicate velocity traces. Negative values on the axes represent downward eye movements and divergence. Positive values represent upward eye movements and convergence. TD1, −3 ms; TD2, −7 ms; TD3, 26 ms. TD, time dissociations..

INVOLUNTARY VERSION-VERGENCE NYSTAGMUS 173

response by a few milliseconds (TD1). In Figure 24.2B, the velocity peak of the divergence component of the biphasic vergence response leads the velocity peak of downward saccades by about 7 milliseconds (TD2). The velocity peak of the convergence followed the velocity peak of downward saccades by about 26 milliseconds (TD3). The mean of TD3 is about 20 milliseconds at varied stimulus velocities. Relationships between peak velocities of horizontal vergence and vertical saccades were analyzed. With backward motion, divergence and upward saccades were induced (Fig. 24.2A). We correlated the peak velocity of divergence with peak velocity of upward saccades. Positive correlations were demonstrated for each of the subjects. The correlation coefﬁcients of regression lines ranged from 0.13 to 0.59 (R2 = 0.13, 0.32, 0.43, 0.58, 0.59 for different subjects and p < 0.0001). With forward motion, biphasic divergence-convergence responses are associated with downward saccades (Fig. 24.2 B). Regression analysis for peak velocities of the divergent components of the biphasic vergence responses and peak velocity of downward saccades showed similar positive, weak correlations. Pooled data from all subjects showed a correlation coefﬁcient of 0.07 (p < 0.0001). Positive correlations were also demonstrated between peak velocities of the convergent components and peak velocities of downward saccades. Pooled data for 5 subjects also showed a dependence of convergent peak velocity on peak velocity of downward saccades (R² = 0.26, p < 0.0001).

DISCUSSION Using large ﬁeld motion in the ground plane, we have induced version-vergence nystagmus. When backward motion stimuli were used, divergent quick phases occurred in association with upward saccades. The quick phases were generated to reset eye positions as required responses to reﬁxate a distant target. When forward motion stimuli were used, we expected to see convergent quick phases and downward saccades. However, a transient divergence occurred prior to a convergence response. Similar transient divergences associated with both horizontal and vertical saccades were observed.3-6,9,13 In a recent study, the divergence occurred in association with upward saccades.9 However, we found that the divergence of the biphasic vergence responses occurred with downward saccades. It is believed that the divergence might be due to a central mechanism,9 although a peripheral mechanism in the ocular motor plant cannot be completely ruled out.14 Since the divergent responses occur independently of

the directions of accompanying saccades (upward, downward, and horizontal), it may be a stereotypical coordinated response with saccades. One of the important observations from this study is the time dissociation between vergence and versional saccades, which has not received enough attention until recently.9-10 It is important to note that the TD3 is longer than that reported by Kumar9 under the “FarUpNearDown” condition, although the vergence (about 0.5°) and version eye movements (about 5°) in the present study were smaller than in the study by Kumar et al.9 We hypothesize that the larger TD3 in this study may be related to the involuntary nature of the nystagmus and less subjective inputs. The vergence and version may act more independently in involuntary version-vergence nystagmus than in voluntary ones. The observation of the time dissociation provides support to the model suggested by Kumar et al.10 The relationships between vergence and vertical saccades, including divergence with upward saccades and biphasic vergence with downward saccades, shows that there is a dependence of vergence peak velocity on vertical version peak velocity. Similar observations were reported by Maxwell et al.,15 Sylvestre et al.,6 and Busettini et al.16 These observations could be explained by the multiplicative model of Busettini et al.,17 but they could not be predicted using Zee’s3 omnipause model. It has been known that saccades enhance other associated eye movements, including disparity and optic ﬂow vergence,17-19 ocular following,20 smooth pursuits,21 accommodation,22 and vestibular ocular responses.23 The nonselective enhancements of saccades on other associated eye movements may play a role in the interaction of saccade and vergence. It has been reported that brief radial optic ﬂow stimuli induced vergence eye movements.17-18 We attribute the version-vergence nystagmus to optic ﬂow inputs, because accommodation and proximal vergence cues may play only a minor role in generating the vergence in a naturalistic world24 and the motion stimuli did not have any horizontal disparity. The demonstration of version-vergence nystagmus responses to groundplane optic ﬂow provides an approach for further study of saccade-vergence interactions. In summary, our ﬁndings support the suggestion that the vergence system and the saccadic system can act separately but interact with each other whenever they occur simultaneously.4, 25

acknowledgment This project was partly supported by a National Eye Institute grant and funding from Research to Prevent Blindness.

174 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL

References 1. Ono H, Nakamizo S, Steinbach MJ. Nonadditivity of vergence and saccadic eye movement. Vision Res. 1978;18:735–739. 2. Enright JT. Changes in vergence mediated by saccades. J Physiol. 1984;350:9–31. 3. Zee DS, FitzGibbon EJ, Optican LM. Saccade– vergence interactions in humans. J Neurophysiol. 1992;68:1624–1641. 4. Collewijn H, Erkelens CJ, Steinman RM. Voluntary binocular gaze-shifts in the plane of regard: dynamics of version and vergence. Vision Res. 1995;35:3335–3358. 5. van Leeuwen AF, Collewijn H, Erkelens CJ. Dynamics of horizontal vergence movements: interaction with horizontal and vertical saccades and relation with monocular preferences. Vision Res. 1998;38:3943–3954. 6. Sylvestre PA, Galiana HL, Cullen KE. Conjugate and vergence oscillations during saccades and gaze shifts: implications for integrated control of binocular movement. J Neurophysiol. 2002;87(1):257–272. 7. Mays LE, Gamlin PDR. A neural mechanism subserving saccade-vergence interactions. In: Findlay JM, Walker R, Kentridge RW, eds. Eye Movement Research: Mechanism, Processes and Applications. Amsterdam, the Netherlands: Elsevier; 1995. 8. Busettini C, Mays LE. Saccade-vergence interactions in macaques. I. Test of the omnipause multiply model. J Neurophysiol. 2005;94:2295–2311. 9. Kumar AN, Han Y, Dell’Osso LF, Durand DM, Leigh RJ. Directional asymmetry during combined saccade-vergence movements. J Neurophysiol. 2005;93(5):2797–2808. 10. Kumar AN, Han YH, Kirsch RF, Dell’Osso LF, King WM, Leigh RJ. Tests of models for saccadevergence interaction using novel stimulus conditions. Biol Cybern. 2006;95(2):143–157. 11. Yang D-S, Zhu M, Kim CH, Hertle RW. Vergence nystagmus induced by motion in the ground plane: normal response characteristics. Vision Res. 2007; 47(9):1145–1152. 12. Garbutt S, Han Y, Kumar AN, Harwood M, Harris CM, Leigh RJ. Vertical optokinetic nystagmus and saccades in normal human subjects. Invest Ophthalmol Vis Sci. 2003;44(9):3833–3841.

13. Collewijn H, Erkelens CJ, Steinman RM. Trajectories of the human binocular ﬁxation point during conjugate and non-conjugate gaze-shifts. Vision Res. 1997;37:1049–1069. 14. Enright JT. Convergence during human vertical saccades: probable causes and perceptual consequence. Br J Physiol. 1989;410:45–65. 15. Maxwell JS, King WM. Dynamics and efﬁcacy of saccade-facilitated vergence eye movements in monkeys. J Neurophysiol. 1992;68(4):1248–1260. 16. Busettini C, Mays LE. Saccade-vergence interactions in macaques. II. Vergence enhancement as the product of a local feedback vergence motor error and a weighted saccadic burst. J Neurophysiol. 2005;94:2312–2330. 17. Busettini C, Masson GS, Miles FA. Radial optic ﬂow induces vergence eye movements with ultrashort latencies. Nature. 1997;390:512–515. 18. Yang DS, Fitzgibbon EJ, Miles FA. Short-latency vergence eye movements induced by radial optic ﬂow in humans: dependence on ambient vergence level. J Neurophysiol. 1999;81:945–949. 19. Yang DS, Fitzgibbon EJ, Miles FA. Short-latency disparity-vergence eye movements in humans: sensitivity to simulated orthogonal tropias. Vision Res. 2003;43(4):431–443. 20. Yang DS, Miles, FA. Short-latency ocular following in humans is dependent on absolute (rather than relative) binocular disparity. Vision Res. 2003;43:1387–1396. 21. Lisberger SG. Postsaccadic enhancement of initiation of smooth pursuit eye movements in monkeys. J Neurophysiol. 1998;79(4):1918–1930. 22. Schor CM, Lott LA, Pope D, Graham AD. Saccades reduce latency and increase velocity of ocular accommodation. Vision Res. 1999;39(22):3769– 3795. 23. Das VE, Dell’Osso LF, Leigh RJ. Enhancement of the vestibulo-ocular reﬂex by prior eye movements. J Neurophysiol. 1999;81(6):2884–2892. 24. Hung GK, Ciuffreda KJ, Rosenﬁeld M. Proximal contribution to a linear static model of accommodation and vergence. Ophthalmic Physiol Opt. 1996;16(1):31–41. 25. Leigh RJ, Zee DS. The Neurology of Eye Movements. 4th ed. New York, NY: Oxford University Press; 2006.

25 The Neuro-ophthalmologic Complications of Chiropractic Manipulation MICHAEL W. DEVEREAUX

ABSTRACT Cervical manipulation, speciﬁcally chiropractic manipulation, is an important cause of vertebral basilar and, rarely, carotid artery distribution strokes. The mechanism of action of vertebral artery distribution strokes is vertebral artery dissection at the level of the atlas as a result of rotation and extension of the head, which can occur in association with chiropractic manipulation. The vertebral arteries are tethered as they pass through the dura. Rotation of the atlas around the axis can lead to stretching of the vertebral artery on the side opposite the direction of head rotation, with a resultant intimal tear, and ultimately occlusion with thrombus formation and embolization. Neuro-ophthalmologic ﬁndings are a common, and at times relatively isolated, feature of strokes secondary to chiropractic manipulation. This is a more frequent occurrence than commonly recognized. A variety of neuro-ophthalmologic disturbances have been recognized, including visual ﬁeld defects due to posterior cerebral artery distribution embolic strokes and oculomotor disturbances due to strokes anywhere in the brain stem, but most commonly in the medulla. Strokes induced by therapeutic manipulation of the neck are not rare. Patients, particularly young patients, with signiﬁcant stroke risk factors presenting with vertebrobasilar strokes should be questioned as to whether they have undergone cervical manipulation. Patients should be routinely instructed to avoid chiropractic neck manipulation.

Neurological complications secondary to neck manipulation, speciﬁcally chiropractic neck manipulation, are known to neurologists but are not well known to the public. The major categories of injury include stroke, myelopathy, and cervical radiculopathy. The frequency, although debated, may be greater even than that stated in the literature.1-16 Neuro-ophthalmologic complications are almost always the result of ischemia/ infarction secondary to injury to one or both vertebral arteries, and far less frequently to a carotid artery.17-18 Most often the neuro-ophthalmologic ﬁndings are a part of a constellation of ﬁndings indicative of a brainstem stroke, usually in the lateral medulla, particularly the lateral medullary tegmentum (Wallenberg’s syndrome).3-16 Occasionally, however, relatively isolated neuro-ophthalmologic symptoms and signs may occur after a chiropractic cervical manipulation, particularly visual ﬁeld disturbances secondary to infarction in the distribution of one or both posterior cerebral arteries. The cause of the stroke may be overlooked unless the patient is carefully questioned. This is particularly true because the stroke may occur several days after the manipulation.16,19,20 The cases of two patients with past chiropractic manipulation strokes are presented below.

CASE REPORTS Patient 1 A 34-year-old, healthy woman with a 2-week history of neck pain had three chiropractic treatments during that 2-week period. On the drive home from the third

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176 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL treatment she noted that she could not see well to the right. She saw her ophthalmologist the next day, and he identiﬁed a right visual ﬁeld disturbance. She was admitted to University Hospitals of Cleveland later the same day. There was no history of visual disturbance, migraine headache, or smoking. She was not taking birth control pills. The only medical problem was asthma. A neurological examination was normal with the exception of a dense right congruous homonymous hemianopsia. Magnetic resonance (MR) brain scan revealed an acute left occipital lobe ischemic infarct. Magnetic resonance angiography (MRA) revealed a right vertebral artery dissection at the C1 (atlas) level and occlusion of the calcarine branch of the left posterior cerebral artery. Intravenous heparin was started, and the patient was discharged on warfarin. A follow-up visit 4.5 months after discharge revealed a persistent right homonymous hemianopsia. An MR brain scan revealed a remote left occipital lobe infarct. An MRA was normal with the exception of slight irregularities of the right vertebral artery lumen. Anticoagulation was stopped and aspirin started. The right homonymous hemianopsia has persisted.

Patient 2 A 26-year-old woman with a 3-week history of nonradiating neck pain following cholecystectomy underwent a series of chiropractic treatments. One week later, over a period of several hours following a manipulation, she had two episodes of vertigo, each lasting between one and two minutes. The next day during a treatment, she developed the following: sudden onset of “dizziness” followed by vertigo, followed by “trouble focusing”/blurring of vision, followed by numbness of all extremities and nausea. She was sent to a hospital emergency room. Past medical history, family history, and social history were unremarkable. She was taking birth control pills. Evaluation in the hospital emergency room revealed generalized numbness and weakness. On day 2 of her hospitalization she underwent a neurological evaluation, which revealed the following symptoms and signs: drowsiness, dysarthria, dysphagia, vertical nystagmus, quadriparesis—left greater than right, slightly hyperactive deep tendon reﬂexes with bilateral Hoffman’s signs, and absent Babinski signs. The sensory examination was normal. MR of the brain revealed evidence of an acute medullary infarct. MRA revealed evidence of an “abnormal” left vertebral artery. It was unclear whether the narrowing was congenital or the result of a dissection. A detailed “stroke in the young” workup failed to uncover any stroke risks.

The patient was evaluated at University Hospitals 2.25 years later. She had persistent mild slurred speech, trouble focusing on objects “when my body is in motion,” intermittent lightheadedness, and persistent mild weakness of the left extremities. A neurological examination revealed upbeat nystagmus, left hemibody dysdiadochokinesis, a broad-based gait, and unsustained left ankle clonus.

DISCUSSION The vertebral arteries pass through the transverse foramina of the ﬁrst six vertebra of the highly mobile cervical spine, which permits approximately 160º of head rotation. Approximately 90º of the rotation is the atlas around the axis. Neck manipulation, particularly a combination of rotation and tilting, can stretch the vertebral artery opposite the direction of rotation, producing a shearing force at the level of the atlantoaxial joint and the potential for dissection with resultant occlusion of the lumen, thrombus formation, and embolization.9,17,21,22 Cadaver studies have demonstrated vertebral artery occlusion with head and neck manipulation.21,23 Repeated neck manipulation also may produce subclinical changes in the vertebral arteries.16,19,20 The accumulation effect then may result in a subsequent stroke at a later date.16,19,20 Far less often, carotid artery dissections may occur with neck manipulation secondary to compression of an internal carotid artery against the upper cervical vertebra.9,17,18 Vertebro-basilar and, less commonly, carotid artery distribution vascular events can be the result of nontherapeutic mechanical injury to the neck (Tables 25.1 and 25.2). Therapeutic neck and back manipulation is an ancient art.24,25 The best-known modern iterations, chiropractic and osteopathy, are both 19th-century American Midwestern inventions.26 Chiropractic manipulation is said to work by reducing subluxations that cause nerve root compression. In 1895, Daniel David Palmer, a dry-goods grocer and later a magnetotherapist, was on a quest to discover a uniﬁed concept to explain human illness. By chance, Palmer manipulated a “vertebra racked from its normal position” on Harvey Lillard, a janitor claiming deafness for 17 years.25 The deafness reportedly resolved. Palmer subsequently theorized that all disease is the result of interference with the body’s “innate intelligence” by misaligned vertebrae.25 He coined the term “chiropractic” from the Greek cheiro (hand) and praktekas (practice). From this humble beginning, chiropractic has grown into a large, commonly utilized alternative health-care delivery system. The chiropractor uses different manipulations and mobilization techniques.

COMPLICATIONS OF CHIROPRACTIC MANIPULATION

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Table 25.1 Vertebrobasilar Stroke: Nontherapeutic Mechanical Causes

Table 25.2 Therapy-Induced Stroke: Potential Sources

Head positioning during medical procedures/treatment

Chiropractic Osteopathy Naturopathy Allopathic (occasional) Physical therapy Kung Fu practitioners Barbers (India) Friend/spouse Self

• • • •

Surgery Cervical traction Emergency resuscitation Perimetry

Exercise • Yoga • Calisthenics (neck exercises) Recreation/sports activities • • • • •

Wrestling Swimming Football Archery Skiing

“Overhead” activities • Work • Stargazing Other • Driving (backing up) • Accidents • Sleeping (unusual position) Source: Sherman D, Hart R, Easton J. Abrupt change in head position and cerebral infarction. Stroke. 1981;12:2–6; Frisoni G, Anzola G. Vertebrobasilar ischemia after neck motion. Stroke. 1991;22: 1452–1460; Caplan L. Posterior Circulation Disease: Clinical Findings, Diagnosis and Management. Boston, MA: Blackwell Science; 1996; Brain D. Some unresolved problems of cervical spondylosis. Br Med J. 1963;1:771–777; deKeyer J, Henrollen L, van Langenhove L. Vertebral artery occlusion complicating perimetry. Am J Ophthalmol. 1991;11:516–517. Adapted with permission from Devereaux MW. The neuro-ophthalmologic complications of cervical manipulation. J Neuroophthalmol. 2000;20:236–239.

Which of the manipulation maneuvers is most likely to cause vertebral artery dissection is uncertain.1,27 Neuro-ophthalmologic symptoms and signs may be the most prominent, and sometimes the primary, manifestation of cerebrovascular insult after chiropractic manipulation (Table 25.3). The most common are visual ﬁeld disturbances secondary to occipital lobe strokes, as in Patient 1.6,8,11,28-31 Does the therapeutic beneﬁt of cervical manipulation justify the complication rate? The ﬁrst problem in answering this question is that the rate of complication is not fully established. The chiropractic literature suggests that stroke risks may be one in 1 million.

Source: Sherman D, Hart R, Easton J. Abrupt change in head position and cerebral infarction. Stroke. 1981;12:2–6; Terrett A. Malpractice Avoidance for Chiropractors: Vertebrobasilar Stroke following Manipulations. West Des Moines, IA: National Chiropractic Mutual Insurance Co.; 1996; Caplan L. Posterior Circulation Disease: Clinical Findings, Diagnosis and Management. Boston, MA: Blackwell Science; 1996; Parkin P, Wallis W, Wilson J. Vertebral artery occlusion following manipulation of the neck. N Z Med J. 1978;88:441–443; Murthy J, Naidu K. Aneurysm of the cervical internal carotid artery following chiropractic manipulation. J Neurol Neurosurg Psychiatry. 1988;51:1237–1238.

Other studies suggest one per 100,000, and one study one per 20,000.32,33 A recent publication indicated that the risk of stroke in patients under 45 years of age is increased ﬁve times following chiropractic manipulation over age-matched controls.33 A survey conducted among California neurologists uncovered 56 strokes.1 I strongly suspect, based on the literature and personal experience, that a large number of cases go unrecognized, and others are recognized but not reported. Regarding beneﬁts from cervical manipulation for neck pain and headache, a meta-analysis by Hurwitz et al.34 concluded that “[c]ervical spine manipulation and mobilization probably provides at least some shortterm beneﬁts for some patients with neck pain and headache,” hardly a ringing endorsement of the practice. Barr,35 commenting on this study in an editorial, stated that there are “no convincing data to support manual therapy.” Table 25.3 Neuro-ophthalmologic Complications of Chiropractic Manipulation Visual ﬁeld loss Horner syndrome Nystagmus Abducens palsy Internuclear ophthalmoplegia Gaze palsy Central retinal artery occlusion Painful ophthalmoplegia Source: Adapted with permission from Devereaux MW. The neuro-ophthalmologic complications of cervical manipulation. J Neuroophthalmol. 2000;20:236–239.

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CONCLUSION Stroke is a well-described consequence of chiropractic manipulation. Neuro-ophthalmologic disorders may be the primary, and occasionally the sole, manifestation of chiropractic-induced cerebrovascular injury. The frequency of chiropractic-induced stroke is uncertain, but it is probably more common than currently appreciated. Patients presenting with stroke, particularly the relatively young without stroke risk factors and with evidence of vertebral artery dissection on neuroimaging procedures, should be questioned about recent chiropractic manipulation. Patients should be made aware of the lack of established beneﬁt of chiropractic cervical manual therapy and the potential risk of neurological injury from manipulation.

References 1. Lee K, Carlini W, McCormick FG, et al. Neurologic complications following chiropractic manipulation: a survey of California neurologists. Neurology. 1995;45:1213–1215. 2. Pratt-Thomas H, Berger K. Injuries after chiropractic manipulation. JAMA. 1947;133:600–603. 3. Mehalic T, Farhat S. Vertebral artery injury from chiropractic manipulation of the neck. Surg Neurol. 1974;2:125–129. 4. Lyness S, Wagman A. Neurological deﬁcit following cervical manipulation. Surg Neurol. 1974;2: 121–124. 5. Davidson K, Weiford E, Dixon G. Traumatic vertebral artery pseudoaneurysm following chiropractic manipulation. Radiology. 1975;115: 651–652. 6. Kreuger B, Okazaki H. Vertebral-basilar distribution infarction following chiropractic manipulation. Mayo Clin Proc. 1980;55:322–332. 7. Schellhas D, Latchaw R, Wendling L, et al. Vertebrobasilar injuries following cervical manipulation. JAMA. 1980;244:1450–1453. 8. Sherman D, Hart R, Easton J. Abrupt change in head position and cerebral infarction. Stroke. 1981;12:2–6. 9. Hart R, Easton J. Dissections of cervical and cerebral arteries. Neurol Clin. 1983;1:155–182. 10. Frumkin L, Baloh R. Wallenberg’s syndrome following neck manipulation. Neurology. 1990; 40:611–615. 11. Frisoni G, Anzola G. Vertebrobasilar ischemia after neck motion. Stroke. 1991;22:1452–1460. 12. Wang J, Lin JJ, Lin JC, et al. Vertebral artery dissection complicated by cervical manipulation: a case report. Chung Hua / Hsueh Tsa Chih. 1995;55(6): 496–500.

13. Sternbach G, Cohen M, Goldschmid D. Vertebral artery injury presenting with signs of middle cerebral artery occlusion: a case report. Angiology. 1995; 46:843–846. 14. Terrett A, Webb M. Vertebrobasilar accidents (VA) following cervical spine adjustment manipulation. J Am Chiropractic Assoc. 1982;12:2407. 15. Terrett A. Malpractice Avoidance for Chiropractors: Vertebrobasilar Stroke following Manipulations. West Des Moines, IA: National Chiropractic Mutual Insurance Co.; 1996. 16. Hufnagel A, Hammers A, Schonle P, et al. Stroke following chiropractic manipulation of the cervical spine. J Neurol. 1999;246:683–688. 17. Stringer W, Kelly D. Traumatic dissection of the extracranial internal carotid artery. Neurosurgery. 1980;6:123–130. 18. Peters M, Bohl J, Thomke F, et al. Dissection of the internal carotid artery after chiropractic manipulation of the neck. Neurology. 1995;45: 2284–2286. 19. Sherman M, Smialek J, Zane W. Pathogenesis of vertebral artery occlusion following cervical spine manipulation. Arch Pathol Lab Med. 1987;111:851–853. 20. Hart R. Vertebral artery dissection [editorial]. Neurology. 1988;38:987–989. 21. Caplan L. Posterior Circulation Disease: Clinical Findings, Diagnosis and Management. Boston, MA: Blackwell Science; 1996. 22. Barton J, Margolis M. Rotational obstruction of the vertebral artery at the atlanto-axial joint. Neurology. 1975;9:117–120. 23. Brown B, Tatlow W. Radiographic studies of the vertebral arteries in cadavers: effects of position and traction on the head. Neuroradiology. 1963;81:80–88. 24. Laban M, Taylor R. Manipulation: an objective analysis of the literature. Orthop Clin. 1992;23: 451–459. 25. Magner G. Chiropractic: The Victims’ Perspective. Amherst, New York: Prometheus Books; 1995. 26. Howell J. The paradox of osteopathy [editorial]. N Engl J Med. 1999;341:1465–1467. 27. Patijn J. Complications of manual medicine: a review of the literature. J Manual Med. 1991;6:89–92. 28. Gittinger J. Occipital infarction following chiropractic cervical manipulation. J Clin Neuroophthalmol. 1986;6:11–13. 29. Donzis P, Factor J. Visual ﬁeld loss resulting from cervical chiropractic manipulation. Am J Ophthalmol. 1997;123:851–852. 30. Jones M, Waggoner R, Hoyt W. Cerebral polyopia with extrastriate quadrantanopia: report of a case with magnetic resonance documentation of

COMPLICATIONS OF CHIROPRACTIC MANIPULATION

31.

32.

33.

34.

35.

V2/V3 cortical infraction. J Neuroophthalmol. 1999;19:1–6. Devereaux MW. The neuro-ophthalmologic complications of cervical manipulation. J Neuroophthalmol. 2000;20:236–239. Vickers A, Zollman C. ABC of complementary medicine. The manipulative therapies: osteopathy and chiropractic. BMJ. 1999;319:1176–1179. Rothwell DM, Bondy SJ, Williams JI. Chiropractic manipulation and stroke: a population based case-control study. Stroke. 2001;32:1054–1060. Hurwitz E, Aker P, Adams AH, et al. Manipulation and mobilization of the cervical spine: a systematic review of the literature. Spine. 1996;21:1746–1760. Barr J. Point of view [editorial]. Spine. 1996;21: 1759–1760.

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36. Brain D. Some unresolved problems of cervical spondylosis. Br Med J. 1963;1:771–777. 37. deKeyer J, Henrollen L, van Langenhove L. Vertebral artery occlusion complicating perimetry. Am J Ophthalmol. 1991;11:516–517. 38. Schneider R, Gosch H, Taren J, et al. Blood vessel trauma following head and neck injuries. Clin Neurosurg. 1972;19:312–354. 39. Parkin P, Wallis W, Wilson J. Vertebral artery occlusion following manipulation of the neck. N Z Med J. 1978;88:441–443. 40. Murthy J, Naidu K. Aneurysm of the cervical internal carotid artery following chiropractic manipulation. J Neurol Neurosurg Psychiatry. 1988; 51:1237–1238.

26 Vergence Hysteresis in Infantile Nystagmus ALESSANDRO SERRA, LOUIS F. DELL’OSSO, AND ZHONG I. WANG

ABSTRACT Our objective was to investigate the previously observed hysteresis effects of multi- and singlestep vergence on visual acuity in a subject with infantile nystagmus syndrome. Eye movements were measured using a high-speed digital video system during ﬁxation of targets at 0º as targets stepped in from far (F) to near (N: 60 D) and back out (5 or 20 s/presentation), as well as during single steps (1 to 5 s/presentation). Higher values of the eXpanded Nystagmus Acuity Function (NAFX) were achieved at far if the previous near target was ﬁxated for 5 seconds. Single steps between near and far (1 and 3 s/presentation) did not improve the following far NAFX. Double-near shifts (F-N-F-N-F) yielded some improvement in far NAFX values in one of two trials with 3-second presentations. Hysteresis was still present for 5-second presentations of multiple-step targets, whereas the NAFX values were high at almost all near targets for 20second presentations; hysteresis was observed only at far. We found that, for better visual acuity at far, a ﬁxation of ≥5 seconds of a near target is required. The time-dependent improvement of visual acuity during convergence or divergence may reﬂect the time required by the pulleys to reduce the plant’s responsiveness, allowing better vision. Subjects with infantile nystagmus syndrome (INS) may exhibit hysteresis during disconjugate vergence

eye movements (i.e., ﬁxation of the same target is associated with a higher eXpanded Nystagmus Acuity Function [NAFX]1 if the subject is diverging rather than converging).2 Hysteresis was found to occur in the central 20º of gaze at all examined vergence angles between far (4.2 diopters [D]) and near (60 D). A peripheral mechanism located either in the muscles or in the pulleys was hypothesized as the cause of hysteresis. It was also suggested that transient ﬁxation of a nearer target, before focusing on the object of interest, might be useful in the daily activities of subjects with INS. To better understand the mechanism of hysteresis associated with INS, its time course, and possible clinical implications, we designed a simple experiment to assess the visual acuity changes of a subject with INS during both multi- and single-step vergence trials.

METHODS Eye movements were measured using a high-speed digital video system (EyeLink II, SR Research, Mississauga, ON, Canada). The NAFX was used to evaluate the IN waveform’s foveation quality at all ﬁxation points. The subject was seated in a chair with a headrest and a chin stabilizer, far enough from an arc where the far LED (4.2 D) was placed to prevent convergence effects (>1.5 m). At this distance, the LED subtended less than 0.1º of visual angle. A stimulus bar containing eight vergence targets was placed along the subject’s line of sight, at eye level, at different increasing vergence angles (LED 1 = 60 D). The room light could be adjusted from dim to blackout to minimize

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VERGENCE HYSTERESIS IN INFANTILE NYSTAGMUS 181

extraneous visual stimuli. The experiment consisted of different multi- and single-step target trials. Multi-step trials included stepping in from far (4.2 D) to near (60 D) and back out to far, allowing 5 or 20 seconds per target interval, to evaluate the time course of hysteresis. Single-step trials, with the target alternating between the far and near positions, were conducted at short intervals (from 1 to 5 seconds per target) and at long intervals (from 10 to 30 seconds per target).

RESULTS In the small, multiple-step target trials, the original hysteresis ﬁrst reported for 5-second intervals was reproduced at all vergence angles (Fig. 26.1A). However, for 20-second intervals, the NAFX values were high during both convergence and divergence at all angles, except for 4.2 D (far) and 7 D, where hysteresis was observed (Fig. 26.1B). Large, single-step trials between near and far (5 seconds per interval) showed a buildup in the NAFX values measured at far. With shorter intervals (1 and 3 seconds per interval), there was no improvement in the following NAFX at far. Double-near shifts (F-N-F-N-F) with 5-second intervals yielded successively higher NAFX values at both near and far (Fig. 26.2A). With 3-second intervals, some improvement in far NAFX values was seen in one of two trials (Fig. 26.2B). When longer intervals were tested (≈ 30 seconds), each initial increase in NAFX was diminished as ﬁxation was maintained at both near and far (Fig. 26.2C). In particular, hysteresis-induced NAFX improvement started to decay after 10 to 20 seconds for the far targets.

Similarly, initial convergence-induced NAFX improvement at near (60 D) began to diminish within 20 seconds.

DISCUSSION The damping of IN with convergence is well known and documented by eye movement data.3,4 This effect in both decreasing the intensity of nystagmus and allowing better waveform foveation quality has been attributed to the reduction of plant’s responsiveness (i.e., gain) during convergence. This might be, in turn, due to the repositioning of the muscle pulleys.2,5 IN damping by means of convergence has been shown to take place over a broad range of gaze angles (±20°), with associated improvement in the high-visual-acuity ﬁeld, based on calculated NAFX values.2 Hysteresis (i.e., system output is dependent on both the current and the previous inputs) was an unexpected ﬁnding in different INS subjects performing vergence tasks. However, neither the time course of hysteresis nor closer simulations of daily-life conditions, where this ﬁnding may be useful, had been investigated before this preliminary study. The multi-step trials showed that hysteresis is present only at far targets (4.2 D and 7 D) if a 20-second target interval is presented, suggesting that, at central near targets (between 10.3 D and 60 D), the NAFX stays high for presentation intervals greater than 5 seconds. Our present study also shows that quickly shifting gaze from a far object of interest to a nearer target, even if done repetitively, might increase the NAFX value for the far target only slightly. The records

Figure 26.1 Plots of eXpanded Nystagmus Acuity Function (NAFX) versus time during small steps of convergence followed by divergence with interstep intervals of 5 (A, left) and 20 (B, right) seconds. Data from convergence are indicated with down triangles and divergence with up triangles.

182 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL

Figure 26.2 Plots of eXpanded Nystagmus Acuity Function (NAFX) versus time during large steps of convergence and divergence between far and near with interstep intervals of 5, 3, and >30 seconds—panels (A, top), (B, center), and (C, bottom), respectively. Data from near are indicated with down triangles and far with up triangles.

VERGENCE HYSTERESIS IN INFANTILE NYSTAGMUS 183

showed that higher values of NAFX were achieved for ﬁxation of the far target only when the previous near target was presented for at least 5 seconds. In order to substantially improve visual performance in ﬁxating a far target, the near target must be presented for at least 5 seconds, preferably shifting ﬁxation between far and near twice before ﬁnally ﬁxating the far target (Fig. 26.2). Therefore, quickly shifting gaze from a road sign to the steering wheel while driving, as previously suggested,2 might not be helpful in increasing visual acuity, unless done twice. Vergence-induced NAFX improvement, with possible associated hysteresis, starts to diminish after approximately 10 to 20 seconds. Therefore, we suggest it is the act of reﬁxation (converging or diverging) that actually provides the initial improvement in visual function in subjects with INS. This also applies under real-life conditions, even in subjects who use baseout prisms to maximize the INS damping associated with convergence. The time-dependent improvement of visual acuity during convergence or divergence may reﬂect the time required by a peripheral mechanism, either at the pulley or the muscle level, to reduce the plant’s responsiveness to nystagmus. The repositioning of the pulleys going from near to far might take place with a higher time-constant proﬁle (slower loss of plant’s stiffness), yielding a transient visual acuity improvement while diverging (hysteresis). In conclusion, our results help clarify the time course of hysteresis in a subject with INS. Further studies are required to explore the possible occurrence and time course of hysteresis in other forms of nystagmus

that damp with convergence, as well as to better characterize hysteresis at different gaze angles.

acknowledgments This research was supported by the Department of Veterans Affairs Merit Review (Dr. Dell’Osso) and the OASI Institute for Research and Care on Mental Retardation and Brain Aging, Troina, Italy (Dr. Serra).

References 1. Dell’Osso LF, Jacobs JB. An expanded nystagmus acuity function: intra- and intersubject prediction of best-corrected visual acuity. Doc Ophthalmol. 2002;104:249–276. 2. Serra A, Dell’Osso LF, Jacobs JB, Burnstine RA. Combined gaze-angle and vergence variation in infantile nystagmus: two therapies that improve the high-visual acuity ﬁeld and methods to measure it. Invest Ophthalmol Vis Sci. 2006;47:2451–2460. 3. Dell’Osso LF. A Dual-Mode Model for the Normal Eye Tracking System and the System with Nystagmus [dissertation]. University of Wyoming: Laramie; 1968. 4. Dell’Osso LF, Gauthier G, Liberman G, Stark L. Eye movement recordings as a diagnostic tool in a case of congenital nystagmus. Am J Optom Arch Am Acad Optom. 1972;49:3–13. 5. Demer JL, Miller JM, Poukens V, Vinters HV, Glasgow BJ. Evidence for ﬁbromuscular pulleys of the recti extraocular muscles. Invest Ophthalmol Vis Sci. 1995;36:1125–1136.

27 Using Wavelet Analysis to Evaluate Effects of Eye and Head Movements on Ocular Oscillations KE LIAO, SIMON HONG, DAVID S. ZEE, LANCE M. OPTICAN, AND R. JOHN LEIGH

ABSTRACT Insights into the pathogenesis of certain ocular oscillations are provided by determining whether eye or head movements can perturb or “reset” the nystagmus, causing a phase shift. When the oscillations are varying slowly, this poses few problems. However, when the oscillations vary rapidly in amplitude, frequency, or phase, it is often difﬁcult to determine whether the perturbation has phaseshifted the nystagmus. The ocular oscillations of oculopalatal tremor (OPT) are a good example of a rapidly varying oscillation. Here, we describe a technique for applying complex wavelet analysis to determine whether OPT ocular oscillations are perturbed by head rotations. By selecting two nystagmus cycles prior to a head rotation and shifting them by twice the period to predict what the nystagmus would have been without the perturbation, we were able to compare this prediction with the two cycles that actually followed the rotation. The phase difference between the cycles before and after head rotation was determined by wavelet coherence analysis. We found that head perturbations caused signiﬁcant (p < 0.05) rates of change of phase shift in both patients that we studied. Thus, this may be a useful technique for testing hypotheses about the pathogenesis of biological oscillations. Oscillations are commonly encountered in biological signals. Studying the properties of oscillations often provides insights about their physiological mechanism, and may also aid understanding of the pathogen-

esis of abnormal oscillations. Important properties of the oscillations include amplitude, phase, and frequency, which are easily visualized with a power spectrum. If the oscillations are pure sinusoidal or combinations of a few sinusoidal waves, these properties are relatively easy to determine by using the traditional Fourier transformation. However, almost all biological signals (for example, from cardiac and skeletal muscle and from brain) have nonperiodic properties, and their frequency components vary with the time, which makes the traditional Fourier analysis impractical for analyzing the waveform’s properties. Short-term Fourier analysis can be used to analyze different frequency components at different times, but it cannot reach high resolution in both frequency and time domains. An alternative approach is wavelet analysis, performed with a wavelet transform (WT). Localized in both time and frequency domains, WT provides detailed information about frequency components at different times, without sacriﬁcing resolution for either frequency or time.1 The WT has good time and poor frequency resolution at high frequencies, and good frequency and poor time resolution at low frequencies, which enables users to separate close frequency components in the low-frequency region and different waveforms on the time axis in the high-frequency region. An example of oscillations with aperiodic properties occurs as a feature of the clinical syndrome of oculopalatal tremor (OPT).2,3 This disorder is characterized by the slow development of oscillations of the eyes (nystagmus), palate, and other branchial muscles, typically at 2 to 4 Hz. OPT develops months after some

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brainstem strokes, in association with hypertrophic degeneration of the inferior olivary nucleus (IO). A recent model has been presented to account for the ocular oscillations of OPT.4 The model has two main features: (1) a pulsatile oscillator at about 2 Hz, created by abnormal electrotonic coupling between cell bodies in the IO; and (2) quasipendular oscillations generated by a learned response from the cerebellum due to the pulsatile IO input. One prediction of this model is that rapid head rotations could “reset” the ocular nystagmus, because the vestibular nuclei project to both IO and vestibulocerebellum. By reset, we mean that the amplitude (energy) of the oscillations will not be changed, but their phase will be changed, by the head movements. Thus, the model predicts that the phase of the waveform will change after the head perturbation, but the energy of the waveform will not.

METHODS We studied 2 patients (aged 46 and 57 years) with OPT syndrome. Each of them wore search coils on the forehead and both eyes while sitting in a 2-meter cube magnetic ﬁeld. We measured gaze angles (eye in space) of each eye using the magnetic search coil technique, as previously described.5 Scleral search coils were precalibrated on a protractor device prior to placement in the subject’s eyes. Zero eye position was determined as each subject viewed a central visual target (laser spot projected onto a tangent screen at a distance of 125 cm) with each eye in turn. Coil signals were lowpass ﬁltered (0 to 150 Hz) prior to digitization at 500 Hz. During each experiment, subjects were asked to ﬁxate the central visual target for 15 to 30 seconds. After that, the investigator manually applied impulsive head rotations to the subjects approximately every 5 seconds for 30 seconds. We analyzed the spectrum information of the signal before and after the head perturbation to evaluate the change in energy. In order to get the characteristic spectrum of the resting nystagmus, we chose the ﬁxation period of each trial and picked out a series of saccade-free eye movements (using a criterion of eye velocity less than 40 deg/s). After resampling these movements, we obtained a total of 100 1-second slices, which allowed us to estimate the spectrum and conﬁdence interval. Since the number of slices was large (100), it was possible to use a normal distribution to obtain the conﬁdence interval. We then calculated the spectrum in a series of 1-second slices after the head was perturbed and compared their spectrum with that of the nystagmus during ﬁxation with the head stationary. The easiest way to measure the phase shift of these ocular oscillations is to compare the waveform with its own shifted version. The OPT oscillations usually

185

cycle around a ﬁxed frequency within a period, so by shifting the OPT waveform on the time axis by a few cycles, we can predict the phase of the waveform if it was not perturbed. (Testing during the ﬁxation period showed the phase changes between original waveform and shifted waveform are relatively small within a unit time period.) Thus we shifted the ocular oscillation by two cycles and compared its phase with that of its unshifted version before and after the head perturbation. We also calculated the rate of change of the phase shift, which is the derivative of the phase difference between the shifted OPT oscillation and its unshifted version during the head perturbation. Since wavelet coherence analysis results in two-dimensional data (time and frequency) and the OPT oscillations lie within a certain range of frequencies, we needed to take a circular mean on the frequency axis to create one-dimensional data before we could perform the derivative operation. As we observed, the OPT oscillations have their major frequency components at 1 to 4 Hz, corresponding to period of 0.25 to 1.0 second. A circular mean is deﬁned as: n

am = atan(X,Y) with X = ∑ cos(ai ) and i =1

n

Y = ∑ sin(ai ) i =1

where am is the circular mean of ai (i = 1 to n). The circular mean is used here to calculate the mean of trigonometric angles.

RESULTS After analyzing the eye movement with the wavelet decomposition and reconstruction package in MATLAB (MathWorks, Natick, MA), we found that the energy of OPT oscillation only resides from level 6 to level 8 of the wavelet decomposition, corresponding to a frequency range of approximately 1 to 4 Hz (Note: there is a simple mapping from wavelet level to frequency range). The energy that resides in levels 9–12 corresponds to the lower frequency components in the waveform, and the residual energy is of high frequency and lower amplitude and can be ignored as noise. Thus our analysis focused on the spectrum of levels 6–8 of the wavelet analysis. A comparison of the energy of resting nystagmus versus that of OPT nystagmus after the head perturbation is shown in Figure 27.1. The solid line and the horizontal bars show the resting nystagmus’s mean, upper, and lower 95% conﬁdence interval. The dashed line is the mean of the OPT oscillations after head perturbations. Within levels 7 and 8, the dashed line is within the conﬁdence interval of the

186 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL 1 0

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resting nystagmus’s spectrum, while at level 6 it is a little higher than the upper bound of the resting nystagmus’s spectrum. Given that level 6 corresponds to about 4 Hz oscillation and that the OPT oscillations are closer to 2 Hz, such a small deviation at level 6 is acceptable, so we conclude that the energy of the

Figure 27.1 Comparison of the energy of oculopalatal tremor (OPT) nystagmus after the head perturbation versus that of resting nystagmus. Solid line is the mean of the spectrum (in log scale) of resting nystagmus at different scales (levels). Horizontal bars are upper and lower 95% conﬁdence interval at each scale. Dashed line is the mean of the spectrum of the OPT nystagmus after the head perturbation. OPT oscillation was not changed by the head perturbation. The original eye movement was shifted by two or more cycles to compare the phase difference between the original and the shifted waveform, as shown in Figure 27.2. (also see color insert) In this case, the

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Figure 27.2 Wavelet coherence analysis. Upper part shows the time course of oculopalatal tremor (OPT) waveform (black), shifted OPT waveform (dark gray), and the head perturbation (lighter gray). Lower part shows the wavelet coherence analysis between OPT waveform and its shifted version during the same time period. The black arrows in the coherence analysis show the phase shift between two waveforms by pointing to different directions. With arrows pointing to the right, the phase shift is 0º, and it is 180º when arrows are pointing to the left. The main area of interest in coherence analysis lies in periods around 0.5 seconds (corresponding to the 2 Hz OPT oscillations) and is divided into four regions on the time axis: (A) far before the head perturbation, (B) just before the head perturbation, (C) at the time of head perturbation, and (D) after head perturbation (Also see color insert).

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WAVELET ANALYSIS

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Figure 27.3 Phase shift changing rate (PSCR) is the derivative of the phase shift between oculopalatal tremor (OPT) waveform and its shifted version. Dark gray line is the OPT waveform, and lightest gray line is the shifted OPT waveform. Black line is the head perturbation. Medium-gray line is the PSCR divided by a factor of 100 to accommodate display, and the dashed line is the threshold of 2000 deg/s that is used to separate an unusually large PSCR value. Note different scales as indicated in the ﬁgure (Also see color insert.) OPT oscillations are about 2 Hz, so again our interest is at around the period (which can be related to level/ scale) of 0.5 second. We thus divide the interested area into four areas: (A) several seconds before the head perturbation, (B) immediately before the head perturbation, (C) at the time of head perturbation, and (D) after the head perturbation. In the ﬁgures, the small black arrows show the phase difference between two waveforms in each of these areas. With arrows pointing to the left, the phase difference is 0; when arrows are pointing to the right, the phase difference is 180º. In Figure 27.2 we can see the phase difference is generally 0 in area A, meaning the shifted waveform has the same phase as the original waveform. In area B, even though it is before the head perturbation, the phase difference changed to about −20º, mainly due to the aperiodic nature of the waveform. In area C, when the head perturbation took place, the phase difference suddenly changed to −70º to −90º.

During post-perturbation in area D, the phase difference is stabilized to about −90º to −110º. Thus, the phase difference changed dramatically at the moment of the head perturbation. The phase shift changing rate (PSCR) is graphed in Figure 27.3. (also see color insert). We can see that the PSCR is higher than the threshold (2000 deg/s) only during the head perturbation, while before and after the head perturbation the PSCR are all small and well below the threshold.

DISCUSSION We set out to learn whether we could apply complex wavelet analysis to determine if a stimulus (impulse head rotation) induced a shift in the phase (but not the amplitude) of the ocular oscillations of OPT. Since OPT has nonperiodic and nonstationary properties, it was not possible to simply compare the ocular

188 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL oscillations with a reference sine wave, as has been done in prior studies of ocular oscillations that are periodic.5 In these preliminary studies, we were detecting a substantially greater rate of change of phase during the head impulse stimulus compared with changes of phase that occurred during attempted ﬁxation with the head stationary. Thus, this method appeared promising for application in testing a current model for OPT. One possible limitation of this technique is that in some subjects, the level of noise due to other eye movements or blinks will make it difﬁcult to detect an increased rate of change of phase induced by the head rotation. Another possible limitation would occur if OPT itself had a large spontaneous rate of phase change. One possible method to overcome these limitations would be to study component oscillations of eyes (e.g., in the torsional direction) in response to head impulses in the orthogonal direction (e.g., rotation of the head about a vertical axis). Aside from the speciﬁc case of OPT, our results suggest that the approach of using complex wavelet analysis can also be applied to analyzing other biological signals that can be perturbed by external stimuli, even when traditional analysis methods like Fourier analysis have failed. acknowledgments Supported by National Institutes of Health grant EY06717, the Ofﬁce of Research

and Development, Medical Research Service, Department of Veterans Affairs, the Evenor Armington Fund (Dr. Leigh); Intramural Division of the National Eye Institute, NIH, DHHS (Drs. Hong and Optican); and National Institutes of Health grant EY01849 (Dr. Zee).

References 1. Torrence C, Compo GP. A practical guide to wavelet analysis. Bull Am Meteorol Soc. 1998;79: 61–78. 2. Deuschl G, Toro C, Valls-Solo J, Zee DS, Hallett M. Symptomatic and essential palatal tremor. 1. Clinical, physiological and MRI analysis. Brain. 1994;117:775–788. 3. Leigh RJ, Zee DS. The Neurology of Eye Movements. 4th ed. New York, NY: Oxford University Press; 2006. 4. Leigh RJ, Hong S, Zee DS, Optican LM. Oculopalatal tremor: clinical and computational study of a disorder of the inferior olive. Soc Neurosci Abstr. 2005;933.8 5. Das VE, Oruganti P, Kramer PD, Leigh RJ. Experimental tests of a neural-network model for ocular oscillations caused by disease of central myelin. Exp Brain Res. 2000;133:189–197.

28 Multifocal Electroretinographic Study of Patients with Oculocutaneous Albinism and Infantile Nystagmus Syndrome ELISA BALA, JONATHAN B. JACOBS, AND NEAL S. PEACHEY

ABSTRACT Some patients with nystagmus have an outer retinal defect that would be a limiting factor for visual acuity following nystagmus treatment. We evaluated the use of the multifocal electroretinogram (mfERG) as an objective means to evaluate outer retinal function in a series of patients with infantile nystagmus syndrome, with and without oculocutaneous albinism. We recorded mfERGs from 3 patients, 2 of whom were albinos. We used a standard mfERG stimulus consisting of a scaled array with 103 hexagons covering the central 45°. Recordings were made under continuous fundus monitoring, allowing us to re-record segments with insufﬁcient ﬁxation. Ring averaging was used to deﬁne retinal function at six retinal eccentricities. Quantiﬁcation of nystagmus waveforms was made using the eXpanded Nystagmus Acuity Function. Usable data were obtained from each patient tested and from four of six eyes; one eye of each of 2 patients could not be recorded due to large-amplitude nystagmus. Patient data were compared to agematched control data obtained in our lab. In both albino patients, ring average amplitudes were reduced only in central areas, with normal response amplitudes obtained at peripheral loci. The nonalbino patient exhibited a near-normal central amplitude peak. In all cases, implicit times were normal at all locations. Our results indicate that it is feasible to obtain useful mfERG recordings from patients with nystagmus. Neither albino

patient had a normal central response, consistent with anatomical studies indicating that albino retinas do not develop a central area of high cone density, and indicating limited potential for visualacuity improvement after successful nystagmus treatment. Results obtained from the nonalbino patient indicate near-normal central retinal function, and provide support for a greater beneﬁt from therapy to reduce nystagmus. Spatial vision is degraded by nystagmus due to the instability of visual targets on the retina. Strategies to decrease nystagmus could, therefore, improve spatial vision, provided that the individual possesses a normal retinal architecture. This may not be the case, however, in all patients with nystagmus, particularly albinos in whom the fovea is abnormal.1,2 As a result, it would be useful to obtain an objective determination of the retinal architecture prior to initiating any treatment, particularly treatment that involves surgery. There are a number of approaches by which this information could be obtained. Optical coherence tomography (OCT) allows the thickness of the retinal layers to be noninvasively assessed, and has been used to document foveal hypoplasia in albinos.3,4 While the presence of a normal foveal cup would indicate a better chance of improved acuity following treatment to reduce nystagmus, accurate OCT measurements require steady ﬁxation, and signiﬁcant nystagmus may obviate the ability of OCT to collect accurate measurements.5 We have evaluated an alternative approach using the multifocal electroretinogram (mfERG). The mfERG provides a topographical map of retinal function that,

189

190 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL in normal subjects, includes a distinct amplitude peak that corresponds to the fovea.6 While accurate mfERG recordings also require steady ﬁxation on the stimulus array, the recording protocol can be broken up into a series of short, discrete recording epochs that can be separately recorded, evaluated, and repeated as needed. Our mfERG results were obtained from a series of patients with nystagmus. While usable results were not obtained in all eyes, some patients were able to maintain sufﬁcient ﬁxation (either low-enough amplitude or long-enough foveation period) to allow central retinal function to be quantitatively evaluated.

METHODS Patient 1 was a 52-year-old female with oculocutaneous albinism and infantile nystagmus syndrome (INS); visual acuities were 20/60 in both eyes. Patient 2 was a 12-year-old female with oculocutaneous albinism, INS on her right eye, and Duane’s syndrome type 3 on her left eye; visual acuities were 20/200 and 20/80 on her right and left eye, respectively. Patient 3 was a 21year-old nonalbino female with INS; visual acuities were 20/200 on both eyes. The tenets of the declaration of Helsinki were followed, and informed consent was obtained from all subjects. Eye movements were recorded using high-speed video (EyeLink II, SR Research Ltd., Mississauga, Ontario, Canada), with each eye calibrated while the fellow eye was under cover to ensure accuracy. Data were sampled at 500 Hz with 16-bit resolution. The subjects sat in a darkened room with their head stabilized by a chinrest and occiput cushion, and they looked at a laser target projected at a distance of 57 inches. The mfERG recordings were made using the VERIS Science 5.1 system (EDI, Inc., San Mateo, CA). The fundus camera/stimulator/refractor unit was used to monitor ﬁxation, and bipolar Burian-Allen contact lens electrodes were used to perform monocular recording. Pupils were dilated with 1% tropicamide and 2.5% phenylephrine, and the eye not being tested was covered with an eye patch. Recording was done in normal room lighting. The mfERG stimulus given at a frame rate of 60 Hz consisted of 103 black-and-white hexagons that ﬂickered according to a pseudorandom m-sequence. The size of the hexagons was scaled with eccentricity to elicit approximately equal amplitude responses at all locations. Subjects were asked to maintain steady ﬁxation at a red target in the center of the stimulus matrix. Recording segments containing many eye movement artifacts were detected online, discarded, and re-recorded. Analysis of the ﬁrst-order kernels was done using the standard VERIS algorithms after two iterations of

Figure 28.1 Trace array plots of mfERG responses for patient 1 (A), patient 2 (C), patient 3 (E), and corresponding age-matched controls (B, D, F). Grouping of individual traces in six concentric ring averages is shown in gray scale at bottom (Also see color insert.)

artifact removal. No further spatial averaging was used. Patients’ mfERG data were plotted in trace arrays and were analyzed in six concentric ring averages compared with age-matched normals recorded under the same conditions.

RESULTS Patient 1 was able to maintain ﬁxation for limited periods of time, allowing a reliable recording to be obtained from both eyes. Figure 28.1A shows responses plotted in trace arrays for the left eye of patient 1; data obtained from the right eye were comparable. For comparison, Figure 28.1B shows average trace arrays obtained from 9 age-matched control subjects (also see color insert). In comparison to these control data, responses of patient 1 appear diminished centrally but normal peripherally. This impression was conﬁrmed when ring averages were generated for each data set.

ELECTRORETINOGRAMS AND INS 191

responses of patient 2 were somewhat larger than those of control subjects, while the response from the central 2º was reduced (Fig. 28.2B). In patient 3, it was only possible to obtain data from the left eye. Figures 28.1E and F show trace array plots of mfERG responses recorded from the left eye of patient 3 and from 4 age-matched controls, respectively. When ring-averaged (Fig.28. 2C), the peripheral responses of patient 3 were comparable to those of controls, while responses were reduced for stimuli falling in the central 10º. Nevertheless, in patient 3, the normal pattern of response amplitude reduction with increasing eccentricity from the macula was similar to that seen in control subjects (Fig. 28.2C, right). In all 3 patients, implicit times for all response areas fell within the normal limits.

DISCUSSION

Figure 28.2 Ring averages (left) and plots of ringaverage amplitude against ring position (right) for patient 1 (A), patient 2 (B), patient 3 (C), and corresponding age-matched controls. Filled symbols indicate patient data while open symbols indicate data obtained from controls.

Figure 28.2 plots the amplitude of the ﬁrst positive peak of mfERG ring averages (Figure 28.2A, left) obtained from patient 1 and from control subjects (Figure 28.2A, center) against ring position (Figure 28.2A, right). There is very good agreement for peripheral rings, but there is a clear reduction in the two central rings for patient 1. We also recorded mfERGs from both eyes of patient 2. Despite the patient’s effort to maintain ﬁxation, the right-eye data were unreliable due to large-amplitude nystagmus for the majority of the recording segments. Figures 28.1C and D show trace array plots of mfERG responses recorded from the left eye of patient 2 and from 4 age-matched controls, respectively. In this case as well, only the central responses appeared reduced in patient 2. Measurement of response amplitude showed that the peripheral

A key goal of treatment approaches to reducing nystagmus is to improve visual acuity. However, good visual acuity cannot be expected in a retina with a severely hypoplastic fovea. We examined this issue using the mfERG, which provides a functional map of outer retinal function within the central 45º of posterior pole. When expressed in terms of response amplitude per retinal area, the central retina in normal subjects generates a much larger response than do peripheral retinal locations.6 This larger central response reﬂects the higher density of cone photoreceptors in the foveal than in peripheral retina.7 In the present study, we investigated the feasibility of making such recordings in 2 albino subjects and 1 nonalbino subject with INS. While useful data were not obtained in two of six eyes, we obtained a full data set from four eyes. In each case, the central peak was less pronounced than that seen in control subjects. For the albino subjects, patients 1 and 2, this pattern was similar to that published by Kelly and Weiss8 and is consistent with an abnormal development of the foveal architecture in albinos. In comparison, patient 3, who is not albinotic, had a clear central peak, indicative of a near-normal distribution of cone photoreceptors, which was likely underestimated by incomplete suppression of nystagmus. While indicating that albino patients would receive limited beneﬁt from nystagmus treatment compared to nonalbino patients, the current results do indicate the feasibility of obtaining mfERG data from some patients with nystagmus. To obtain the current data set, recording sessions were extended in order to repeat recording epochs in which ﬁxation was not stable. While this places a somewhat greater strain on the patient being examined, and requires greater vigilance

192 GENERAL ASPECTS OF NORMAL AND ABNORMAL GAZE CONTROL on the part of the operator, a positive result identifying a suitable patient for nystagmus treatment is unlikely to be artiﬁcially generated. As a result, we believe that the mfERG should receive further evaluation as an objective tool with which to evaluate patients with nystagmus prior to treatment for their nystagmus.

acknowledgments This work was supported by the Ofﬁce of Research and Development, Medical Research Service, Department of Veterans Affairs, R24 EY15638, and a Research to Prevent Blindness Challenge grant. The material contained in this chapter was presented at the Conference for Advances in Understanding Mechanisms and Treatment of Congenital Forms of Nystagmus, May 3–4, 2007, Cleveland, OH.

References 1. Fulton AB, Albert DM, Craft JL. Human albinism. Light and electron microscopy study. Arch Ophthalmol. 1978;96:305–310.

2. Mietz H, Green WR, Wolff SM, Abundo GP. Foveal hypoplasia in complete oculocutaneous albinism. A histopathologic study. Retina. 1992;2:254–260. 3. Harvey PS, King RA, Summers CG. Spectrum of foveal development in albinism detected with optical coherence tomography. J AAPOS. 2006; 10:237–242. 4. Seo JH, Yu YS, Kim JH, Choung HK, Heo JW, Kim SJ. Correlation of visual acuity with foveal hypoplasia grading by optical coherence tomography in albinism. Ophthalmology. 2007;114(8):1547–1551. 5. Campbell RJ, Coupland SG, Buhrmann RR, Kertes PJ. Effect of eccentric and inconsistent ﬁxation on retinal optical coherence tomography measures. Arch Ophthalmol. 2007;25:624–627. 6. Sutter EE, Tran D. The ﬁeld topography of ERG components in man. I. The photopic luminance response. Vision Res. 1992;32:433–446. 7. Curcio CA, Sloan KR, Kalina RE, Hendrickson AE. Human photoreceptor topography. J Comp Neurol. 1990;292:497–523. 8. Kelly JP, Weiss AH. Topographical retinal function in oculocutaneous albinism. Am J Ophthalmol. 2006;141:156–158.

Author Index

Abadi, RV, 11, 12, 15, 18, 23, 24, 25, 26, 27, 28, 29, 33, 34, 36, 38, 61, 62, 68, 90, 94, 100, 107, 108, 109, 110 Abel, LA, 16, 18, 25, 33, 36, 37, 90, 93, 94, 96, 134, 139, 140 Abplanalp, PL, 25 Abundo, GP, 189 Acheson, J, 18, 27, 34 Acland, GM, 90, 96 Adams, AH, 177 Adams, DL, 47, 52 Adams, RN, 118 Ahmadi, MA, 136 Aigner, M, 4 Aker, P, 177 Albert, DM, 189 Albrecht, H, 81 Allik, J, 34 Alvardo-Mallart, RM, 4 Anderson, JR, 92, 114, 167 Angelaki, DE, 56, 147 Angus, CW, 118 Anniger, W, 108 Anzola, G, 175, 177 Apkarin, P, 28 Appel, S, 119 Arnold, DB, 81, 130 Arnould, VJ, 88 Arstikaitis, MJ, 4 Asress, KN, 49 Assad, JA, 15 Atkinson, J, 120 Atsumi, T, 5

AuYong, N, 148 Avallone, JM, 34 Averbuch-Heller, L, 12, 25, 34, 62, 80, 81, 90, 96, 100, 105, 153, 155 Aydin, M, 16, 19 Bach, M, 27, 100 Bach-y-Rita, P, 3 Bahl, B, 9 Bakay, M, 121 Baker, RS, 4 Balatsouras, DG, 105 Ball, KK, 38 Baloh, RW, 59, 175 Bandini, F, 81 Barber, C, 100 Barmada, M, 80 Barnes, GR, 148 Barr, J, 177 Barton, JJS, 134, 176 Bauer, P, 164 Beard, BL, 38 Beck, RW, 100 Becker, W, 118, 130, 134 Bedell, HE, 11, 12, 15, 16, 17, 19, 25, 26, 27, 28, 34, 38 Beeson, D, 119 Bega, S, 5, 6, 9 Bennett, J, 90, 96 Berger, K, 175 Bergqvist, UO, 70 Berman, RA, 38 Bernshaw, NJ, 120

193

194 AUTHOR INDEX Berthoz, A, 148 Bienfang, DC, 92, 112 Biersdorf, WR, 33 Biesecker, G, 119 Bifulco, P, 25, 29 Billig, I, 4, 5 Bird, AC, 161 Bjerre, A, 15, 25, 26, 33, 62, 90, 100, 107, 109, 110 Black, FO, 147 Blazquez, PM, 55 Block, CH, 119 Blouin, J, 4 Blozani, R, 4 Blumer, R, 4, 5 Bock, O, 4 Bockisch, CJ, 8, 15 Bogousslavsky, J, 158 Bohl, J, 175 Bollenbacher, MA, 11, 26 Bondy, SJ, 177 Boothe, RG, 24, 48 Bosone, G, 115 Boucher, L, 16 Boudreau, CE, 15 Bracale, M, 25, 29 Brandt, T, 15, 18, 27 Bridgeman, B, 4, 7, 11, 15, 18 Brigell, M, 100 Bronstein, AM, 18, 27, 34, 88 Brown, B, 176 Bruce, GM, 162 Büchele, W, 15 Buchwald, B, 167, 168, 169 Budak, MT, 121 Buﬂer, J, 167 Buhrmann, RR, 189 Buijs, AM, 119 Buisseret Delmas, C, 5 Buisseret, P, 5 Bullens, RW, 167 Burke, B, 63, 65 Burnstine, RA, 19, 80, 90, 91, 96, 180, 181 Burr, DC, 16, 17, 18, 43 Busettini, C, 170, 173 Butler, PH, 55 Büttner, U, 58, 81, 130 Büttner-Ennever, JA, 3, 5, 115, 158 Cabot, A, 80 Cadera, W, 134 Campbell, RJ, 189 Campos, EC, 4, 47 Cannon, SC, 134 Caplan, L, 176 Cardillo, L, 7

Cardinal, RN, 37 Carl, JR, 19 Carlini, W, 175 Carpenter, RH, 8, 24, 49, 52, 53 Carpo, M, 167 Cassidy, L, 18 Castello, E, 81 Cesarelli, M, 25, 29 Chabris, CF, 38 Chakrabarti, M, 168 Chamberlain-Banoub, J, 121 Chan, CC, 115 Chan, LL, 167 Cheeseman, E, 34 Chen, HH, 136 Cheng, G, 121, 122 Cheng, P, 130 Chiarandini, DJ, 119 Choi, KD, 105 Choudhuri, I, 82 Choung, HK, 189 Christadoss, P, 120 Christoff, A, 29 Chu, FC, 19, 48 Chung, STL, 11, 15, 16, 17, 19, 25, 26, 38 Churchland, A, 55 Ciuffreda, KJ, 173 Clark, JJ, 24 Clement, R, 24, 28 Clendaniel, RA, 158 Cochrane, C, 119 Cogan, DG, 88 Cohen, B, 56 Cohen, IS, 4 Cohen, M, 175 Colburn, JE, 114 Collewjin, H, 25, 28, 96, 170, 173 Compo, GP, 184 Conti-Fine, BM, 117, 118, 119, 120 Conti-Tronconi, BM, 119 Coupland, SG, 189 Cox, N, 61, 64 Craft, JL, 189 Crane, BT, 59 Crane, MF, 16 Crawford, JD, 134 Crawford, ML, 48, 115 Crowe, S, 38 Cullen, KE, 170, 173 Cunningham, RD, 164 Cüppers, C, 92 Curcio, CA, 191 Currie, DC, 11, 12, 25 Currie, J, 38 Curthoys, IS, 13

AUTHOR INDEX

Dan, YF, 167 Danacause, N, 4, 5 Danckert, J, 38 Darlot, C, 147 Daroff, RB, 24, 25, 33, 36, 38, 88, 96, 99, 101, 108, 109, 110, 134, 139, 140 Das, VE, 24, 42, 47, 48, 49, 105, 107, 130, 153, 155, 173, 185, 188 Davidson, K, 175 Davies, A, 120 Davis, DG, 105 Davis, RD, 122 Davitz, M, 120 Dawes, PT, 153 de Jong, PT, 47 de Jong, R, 38 de Perrot, M, 122 De Weerd, P, 42 Degg, C, 82, 83, 84 Degner, D, 15 Dell’Osso, LF, 11, 12, 19, 24, 25, 27, 33, 34, 36, 37, 38, 39, 43, 61, 62, 67, 68, 80, 87, 88, 90, 91, 92, 93, 94, 96, 99, 100, 101, 102, 105, 108, 109, 110, 112, 115, 134, 139, 140, 141, 143, 170, 173, 180, 181 Delwaide, PJ, 5 Demer, JL, 59, 129, 181 Denk, M, 5 DeSantis, M, 4 Desimone, R, 42 Deubel, H, 18 Deuschl, G, 184 Devereaux, MW, 177 DiBartolomeo, JR, 100, 105 Dickinson, CM, 11, 25, 26, 28, 29, 34, 36 Dickman, JD, 147 Dieterich, M, 18, 27, 81 Diethelm-Okita, B, 119 Ding, M, 80 Discenna, AO, 153, 155 Ditchburn, RW, 24 Dixon, G, 175 Dobson, V, 48 Dominey, PF, 4 Donahue, SP, 162 Donaldson, IM, 4, 8 Donzis, P, 177 Dowman, R, 5 Drachman, D, 118 Drack, AV, 80 Drake, D, 24 Dua, H, 82 Duane, A, 162 Duncker, K, 152 Durand, DM, 170, 173 Dürsteler, MR, 130

195

Dyar, TA, 42 Dziedzic, K, 153 Easton, J, 175, 176, 177 Eberhorn, AC, 4 Eberhorn, N, 4 Economides, JR, 52 Edwards, M, 16 Edwards, MW Jr, 18 Eggert, T, 55 Eizenmn, M, 130 Eldred, E, 4 Ell, JJ, 62 Ellenberger, C, 96 Ellis, FD, 92 Elveback, L, 122 Engbert, R, 24 Engel, AG, 118, 119 Engel, KC, 155 Enright, JT, 15, 170, 173 Erchul, DM, 96 Erkelens, CJ, 170, 173 Erzurum, SI, 94 Esme, DL, 47 Etoh, S, 136 Everhard-Halm, YS, 136 Everitt, BJ, 37 Factor, J, 177 Faldon, M, 38, 89, 100, 108 Farhat, S, 175 Feiveson, AH, 129 Felder, E, 121 Fendick, MG, 12, 34 Findley, LJ, 62 Finley, J, 122 Fischer, MD, 121 Fisher, M, 167 Fitch, JC, 122 FitzGibbon, EJ, 19, 28, 34, 92, 100, 108, 112, 115, 170, 173 Flanders, M, 33, 155 Flynn, JT, 96, 115 Forster, JE, 24, 28 Frecker, RC, 130 Fredrick, LR, 120 Frisoni, G, 175, 177 Frumkin, L, 175 Fu, LN, 47, 49 Fuchs, AF, 8, 48, 55, 118 Fuhry, L, 62, 81, 130 Fujita, T, 120 Fujiwara, A, 70 Fukuoka, Y, 120 Fukushima, J, 58, 129

196 AUTHOR INDEX Fukushima, K, 58 Fulton, AB, 189 Furman, JM, 107 Gadoth, N, 167 Gahl, WA, 28 Galiana, HL, 170, 173 Galita, DA, 115 Gamlin, PDR, 170 Ganz, L, 17 Garbutt, S, 171 Gattass, R, 42 Gauthier, GM, 4, 7, 11, 96, 181 Geisler, WS, 16 Gendolla, GHE, 38 Georges-Francois, P, 148 Georgeson, MA, 18 Gerber, S, 80 Ghose, GM, 15 Gianna-Poulin, C, 147 Gielen, S, 129 Gifford, CA, 147 Gillam, BC, 7 Ginsburg, BL, 24 Giorda, R, 80 Gittinger, J, 177 Glasauer, S, 58 Glasgow, BJ, 181 Goldberg, SJ, 118 Goldberg-Stern, H, 167 Goldschmid, D, 175 Goldstein, HP, 12, 27, 34, 38, 100, 108, 129 Golnik, KC, 136 Goltz, H, 148 Goluszko, E, 119, 120 Gomez, CM, 118, 119 Gomez, CR, 158 Gomez, SM, 158 Gonzalez, C, 136 Gonzalez, E, 5, 6, 7, 9 Goodale, MA, 152 Gorospe, JR, 121 Goto, N, 92, 114, 115 Gottlob, I, 12, 19, 34, 42, 79, 82, 83, 84, 91, 108, 109, 110 Gottlob, MG, 27 Gowen, E, 24 Gradstein, L, 27, 28, 38, 100, 108 Graham, AD, 173 Granger, CB, 122 Grant, MP, 80 Grasso, R, 148 Graziano, JA, 18 Green, AM, 55 Green, WR, 189

Greene, WH, 132 Gregory, E, 5 Gregory, RL, 42 Gresty, MA, 18, 19, 27, 34, 56, 62, 81, 88 Griggs, DS, 38 Groh, JM, 16 Grunbauer, WM, 18 Grunfeld, EA, 18 Grüsser, OJ, 15 Gucer, G, 55, 58 Guo, X, 80 Gurer, G, 167 Guthrie, BL, 8 Haas, R, 120 Haddad, GM, 24 Hafed, ZM, 24 Hain, TC, 130, 134 Hale, G, 120 Hall, J, 37 Hall, WC, 43 Hallett, M, 184 Halmagyi, GM, 19, 56, 81 Hammers, A, 175 Han, YH, 170, 171, 173 Hansen, PC, 24 Hansen, RM, 24 Hanson, KS, 19 Harada, R, 120 Harris, CL, 25, 36, 37, 121 Harris, CM, 171 Hart, R, 175, 176, 177 Harvey, PS, 189 Harwerth, RS, 48, 52 Harwood, M, 171 Hasebe, S, 108, 137 Haustein, W, 13 Hayashi, M, 119 Heinemann, S, 118 Heinen, SJ, 55, 59 Heiney, SA, 55 Helmchen, C, 130 Helms, S, 118 Helveston, EM, 92 Hendrickson, AE, 191 Heo, JW, 189 Hepp, K, 48 Herdman, SJ, 24 Hertle, RW, 14, 15, 19, 25, 27, 29, 34, 39, 61, 68, 88, 89, 90, 92, 96, 99, 100, 101, 108, 109, 110, 112, 115, 170, 171 Hess, BJ, 48, 56, 147 Hess, K, 130 Higgs, S, 119, 120 Highstein, SM, 55

AUTHOR INDEX

Hikosaka, O, 37 Hill, VM, 89, 100 Hillmen, P, 122 Hiraoka, M, 70 Hirata, Y, 55 Hoch, W, 118 Hocking, DR, 47 Hoetzenecker, W, 5 Hogan, DW, 96 Holguin, MH, 120 Hollerman, JR, 38 Holleschall, AM, 29 Holmes, A, 130, 134 Holmes, JM, 100 Homma, I, 5 Honda, H, 15 Hong, S, 185 Hopf, HC, 158 Horn, AK, 4, 5, 115 Horn, R, 27 Horton, JC, 47, 52 Horton, RM, 119 Hoshi, M, 58 Hosokawa, K, 80 Hosokawa, M, 108 Howard, FJ, 122 Howard, FM Jr, 118 Howard, J, 119 Howell, J, 176 Hoyt, W, 177 Hubel, DH, 24, 42 Hufnagel, A, 175 Hughes, BW, 117 Hughes, HC, 16 Huizing, M, 28 Hung, GK, 173 Hung, LF, 28 Hurko, O, 164, 166 Hurwitz, E, 177 Hyman, A, 7 Ilg, UJ, 43 Inoue, I, 105 Isa, K, 43 Isa, T, 43 Ishihar, Y, 5 Israël, I, 148 Izumizaki, M, 5 Jacobs, JB, 11, 12, 19, 25, 38, 39, 43, 62, 67, 80, 90, 91, 92, 96, 100, 112, 115, 139, 140, 141, 143, 180, 181 Jacobsen, DM, 164 Jacoby, J, 119 James, W, 38

197

Janeway, C, 120 Janvimaluang, V, 136 Jasmin, L, 55 Jensen, AA, 29 Jha, RT, 48 Jia, X, 80 Jiang, S, 119 Jin, YH, 34 Jocson, CM, 52 Johnston, WS, 4 Jones, M, 177 Jones, PW, 153 Joosse, MV, 47 Jordan, K, 153 Jorgensen, AY, 42 Joshi, A, 119 Judge, SJ, 48 Kalina, RE, 190 Kaminski, HJ, 117, 118, 119, 120, 121, 122 Kaneko, CRS, 118, 130 Kansu, T, 158 Kao, I, 118 Karatas, H, 167 Kawagoe, R, 37 Kawahira, K, 136 Kawai, T, 36 Keane, JR, 158 Keller, EL, 3, 5, 53, 55, 59 Kelly, D, 175, 176 Kelly, JP, 191 Kelly, K, 100, 108, 109, 110 Kerrison, JB, 80, 88 Kertes, PJ, 189 Keshavjee, S, 122 Kestenbaum, A, 92, 114 Khadija, M, 70 Khanna, S, 100, 119, 121 Kida, K, 119 Kim, CH, 170, 171 Kim, JH, 189 Kim, JS, 105 Kim, SJ, 189 King, RA, 28, 29, 189 King, WM, 170, 173 King-Smith, PE, 26 Kinoshita, M, 42 Kinoshita, T, 120 Kirkham, TH, 162 Kirsch, RF, 170, 173 Kirshner, EL, 4 Kitazawa, H, 55 Klein, H-M, 130, 134 Kline, LB, 105, 162 Knave, BG, 70

198 AUTHOR INDEX Knox, PC, 4 Kobashi, R, 137 Koenekoop, RK, 88 Kofman, IS, 61 Kohl, J, 119 Kok, A, 38 Komatsu, H, 42 Kommerell, G, 4, 27, 33 Konakci, KZ, 5 Koomneef, L, 136 Kornilova, L, 129 Korres, S, 105 Kowler, E, 24 Krafcyk, S, 81 Kraft, SB, 9, 138 Krämer, G, 158 Kramer, PD, 185, 188 Kreegipuu, K, 34 Kressel, AB, 28 Kreuger, B, 175, 177 Krizic, A, 15 Krzystkowz, KM, 138 Kubatko-Zielinsk, T, 138 Kubo, S, 118 Kubo, T, 80 Kumar, AN, 170, 171, 173 Kurkin, S, 58 Kusner, LL, 117, 118, 119, 121 Kustov, AA, 138, 140 Kuwabara, S, 167 Laban, M, 176 LaFrance, MW, 19 Lambert, EH, 118, 119 Langer, T, 118 Lankheet, MJ, 13 Latchaw, R, 175 Lauwereyns, J, 37 Lavin, PJM, 162 Lee, J, 92 Lee, KA, 28, 175, 177 Lee, MS, 107 Lee, PH, 43 Leech, J, 19 Lehmkuhle, S, 15, 63, 65 Leibole, M, 24 Leigh, RJ, 12, 15, 24, 25, 27, 34, 56, 61, 64, 80, 90, 92, 93, 100, 105, 107, 112, 115, 118, 119, 129, 130, 131, 134, 136, 138, 139, 140, 143, 153, 155, 156, 162, 166, 170, 171, 173, 184, 185, 188 Lenart, TD, 80 Lennerstrand, G, 4 Lennie, P, 15 Lennon, VA, 118, 119, 122 Leoh, TH, 167

Lepore, FE, 164 Lerman, J, 3 Lessell, S, 107 Levi, L, 33 Levin, JL, 119 Lewis, AR, 162 Lewis, JM, 105 Li, S, 80 Li, Z, 122 Liang, D, 80 Liao, K, 119 Liberman, G, 181 Lillakas, L, 9 Limburg, PC, 122 Lin, F, 120, 121, 122 Lin, JC, 175 Lincoff, N, 158, 159 Linder, A, 43 Lindstrom, JM, 118, 119 Ling, L, 118 Linstrom, JM, 119 Lipton, SA, 81 Lisberger, SG, 55, 173 Lit, A, 7, 15 Lloyd, IC, 24, 28 Lo, YL, 167 Loffredo, L, 25, 29 Lorenz, B, 47 Losen, M, 119 Loshin, DS, 15, 25, 26 Lott, LA, 16, 17, 19, 173 Louwagie, CR, 29 Low, M, 120 Ludvigh, E, 4 Lukas, JR, 4, 5 Luna, B, 38 Luschei, AF, 8 Lutz, A, 156, 158 Lyness, S, 175 Maas, E, 119 Macknik, SL, 24, 42 MacLennan, C, 119 Maeda, T, 36 Magner, G, 176 Maier, A, 4 Maldanado, VK, 29, 100, 101, 109. 110 Malesic, L, 33 Manfredi, AA, 119 Margolis, M, 176 Marti, S, 58 Martinez-Conde, S, 24, 42 Martinez-Martinez, P, 119 Martini, R, 168, 169 Maruff, P, 38

AUTHOR INDEX

Maruyama, N, 118 Masdeu, JC, 158 Masson, GS, 173 Mathieu-Millaire, F, 130 Matin, L, 15, 18 Matis, L, 122 Matsubayashi, K, 94 Matsuda, H, 119 Matsumoto, J, 122 Matsumoto, M, 42 Matsumoto, S, 105 Maumenee, IH, 80, 88 Maunsell, JHR, 15 Maxwell, JS, 173 Maybodi, M, 29, 100, 101, 109, 110, 115 Mays, LE, 8, 158, 170, 173 Mazzella, L, 81 McAdams, CJ, 15 McArthur, R, 18 McConville, J, 118 McCormick, FG, 175 McHenry, MQ, 147 McKusik, V, 80 McLean, RJ, 82, 83, 84, 91 McPeek, RM, 53 McReelis, K, 159 Medof, ME, 120, 121, 122 Mehalic, T, 175 Mehdorn, E, 33 Meienberg, O, 167 Melamed, E, 167 Mellow, SD, 19, 34, 92, 112, 115 Melms, A, 118 Meredith, MA, 118 Merfeld, DM, 147, 148 Merlie, JP, 118 Mets, MB, 28 Mettens, P, 81 Mietz, H, 189 Milani, M, 117, 118 Miles, FA, 55, 173 Miller, JM, 8, 15, 181 Miller, NR, 136 Miller, RL, 38 Milner, AD, 152 Mittelstädt, H, 11, 13, 148 Mittelstädt, ML, 148 Miura, K, 34 Miwa, T, 120 Mizuno, M, 121 Morgan, BP, 119, 121 Morland, AB, 18, 27, 34 Morrison, DG, 162 Morrone, MC, 17, 18, 43 Mosier, DR, 119

199

Mulder, PG, 47 Muldoon, M, 28 Mülendyck, H, 24 Murakami, I, 18, 42 Murphy, PJ, 4 Murthy, KS, 5 Mustari, MJ, 24, 47, 48, 49 Nachmias, J, 18 Nagao, S, 55 Nagel, M, 15 Nagy, SE, 28 Nakabashi, K, 70, 74 Nakamizo, S, 170 Nakano, S, 119 Nakayama, K, 13 Namer, IJ, 158 Neal, JW, 121 Newlands, SD, 147 Newsom-Davis, J, 118, 119 Nguyen, TL, 19 Niechwiej-Szwedo, E, 3, 5, 6, 7 Nieuwenhuis, S, 38 Nishida, S, 36 Noerager, BD, 15 Nommay, D, 4, 7, 11 Noritake, A, 36 Nurlu, G, 167 Nussenzweig, V, 120 Obie, S, 19 Oda, K, 119 O’Dell, C, 48 Oeztekin, MF, 158 Ogata, M, 36 Ogawara, K, 167 Ögmen, H, 15 Oh, SY, 105 Oh, YM, 105 O’Hanlon, GM, 167, 168 Ohtsuki, H, 108, 137 Ohyagi, Y, 105, 162, 164 Okada, H, 120 Okada, N, 120 Okayama, A, 162, 164 Okazaki, H, 175, 177 Okita, D, 119 Ong, BN, 153 Ono, H, 9, 170 Ono, S, 47 Oommen, BS, 65, 66, 67 Optican, LM, 19, 34, 170, 173, 185 Oruganti, P, 185, 188 Ostinelli, B, 158 Oswald, PJ, 28

200 AUTHOR INDEX Page, NG, 88 Paige, GD, 148 Paloski, WH, 129, 130 Pan, A, 167 Pang, DL, 107 Papas, E, 28 Park, S, 147 Parker, CJ, 120 Parker, L, 134 Parkinson, JA, 37 Pascal, E, 25, 26, 28, 36, 100, 107, 108 Patel, MR, 122 Patel, SS, 11, 15, 16, 17, 19, 48 Patijn, J, 177 Patterson, GA, 122 Paus, T, 37 Pavlovski, DS, 8 Peckham, HP, 90, 143 Pesh-Imam, S, 63, 65 Peters, M, 175 Peterson, J, 24 Phillips, MS, 167 Picoult, E, 18 Piddlesden, SJ, 119 Pierrot-Deseiligny, C, 158 Pilling, RF, 79 Plager, DA, 92 Plomp, JJ, 168 Pola, J, 15, 16 Poliakoff, E, 24 Poljac, E, 13 Pöllmann, W, 81 Poonyathalang, A, 136 Pope, D, 173 Porter, JD, 8, 119, 121, 122 Posner, MI, 38 Poukens, V, 181 Pratt-Thomas, H, 175 Preechawat, P, 136 Prochazka, A, 8 Proske, U, 5 Proudlock, FA, 42, 82, 83, 84, 91 Pullicino, P, 158, 159 Purkinje, JE, 15 Puwanant, A, 117, 118 Rabinowitcz, T, 158 Rama, G, 114, 115 Ramachandran, VS, 42 Ramamurthy, M, 19 Ramat, S, 59 Rambold, H, 55, 130 Raphan, T, 56 Ratcliffe, F, 24 Ratnagopal, P, 167

Reccia, R, 115 Reddi, BA, 49 Reeves, B, 79 Regli, F, 158 Reid, RC, 17 Reinecke, RD, 27, 29, 34, 38, 100, 108, 109 Reisine, H, 130 Remler, BF, 62, 96, 156 Repka, MX, 80, 100 Repko, MX, 24 Reschke, MF, 129, 130, 134 Reznick, L, 99 Richman, DP, 118 Richmond, BJ, 48 Richmond, FJ, 4 Richmonds, C, 119, 120, 121, 122 Richter, M, 38 Ridderinkhof, KR, 38 Riess, O, 164 Riggs, LA, 24 Riordan-Eva, P, 89 Roberti, G, 115 Roberts, WL, 120 Robinson, DA, 3, 5, 48, 55, 100, 107, 129, 130, 134 Robinson, DL, 139, 140 Robinson, FR, 55 Roekner, DL, 38 Roll, JP, 4 Roll, R, 4 Rollins, S, 122 Rosano, C, 38 Rosenberg, LF, 130, 134 Rosenberg, M, 158 Rosenberry, TL, 120 Rosenﬁeld, M, 173 Ross, J, 16 Rothwell, DM, 177 Rottach, KG, 155 Rozet, JM, 80 Rubin, BI, 28 Rucker, JC, 62, 92, 112 Rudge, P, 56, 81, 88 Ruff, RL, 118, 119 Rushton, DN, 15, 27, 61, 64, 68 Ruskell, GL, 4 Russel-Eggit, I, 28 Russo, P, 115 Ryffel, E, 167 Saghaﬁ, D, 63, 65 Sahashi, K, 118, 119 Sampath, V, 28 Sanders, MD, 162 Sandikçioglu, M, 25, 26

AUTHOR INDEX

Sano, H, 70, 74 Sansone, M, 25 Saribas, O, 167 Sarvananthan, N, 80, 81, 82, 91 Scallan, CJ, 25, 26, 27, 33 Schellhas, D, 175 Scherberger, H, 5 Scheuerer, W, 55 Schiavi, C, 4 Schimsheimer, RJ, 47 Schmidt, D, 25, 33, 139, 140 Schmidt, T, 164 Schneider, WX, 18 Schols, L, 164 Schon, F, 81 Schonle, P, 175 Schor, CM, 173 Schubert, J, 122 Schüler, O, 81 Schultheis, LW, 55 Schultz, W, 38 Schwarz, DW, 4 Scott, AB, 138 Scott, BG, 119, 120 Scudder, C, 118 Seidman, SH, 105, 107, 147, 148 Sekihara, C, 5 Selhorst, JB, 158 Selig, Y, 55 Seo, JH, 189 Serra, A, 12, 90, 96, 180, 181 Sestokas, AK, 15 Seya, T, 120 Seybold, ME, 119 Shall, MS, 118 Shallo-Hoffmann, JA, 18, 24, 27, 34, 38, 89, 96, 100, 108 Shan, X, 55, 56 Sharpe, JA, 130, 134, 158, 159, 162 Shawkat, FS, 36, 37 Sheedy, JE, 70 Sherman, D, 175, 177 Sherman, M, 175 Sherrington, C, 3 Shery, T, 82, 91 Sheth, NV, 11, 90, 96, 143 Shibasaki, H, 119 Shigemoto, K, 118 Shimodozono, M, 136 Shinmei, Y, 58 Shlomchik, M, 120 Siklkós, L, 119 Sills, GJ, 82 Simmons, DL, 120 Simons, DJ, 38

201

Simonsz, HJ, 39, 47 Sindou, M, 4 Sireteanu, R, 47 Skavenski, A, 4, 24, 129 Slater, CR, 118 Sloan, KR, 191 Smialek, J, 175 Smith, CB, 24 Smith, DR, 4, 9 Smith, EL, 28, 48, 52 Smith, JL, 105 Smith, P, 158 Smith, RM, 65, 66, 67 Sng, K, 134 Soechting, JF, 155 Soltys, J, 117 Somers, JT, 129, 134 Song, S, 25 Song, WC, 120, 121 Sooksawate, T, 43 Sparks, DJ, 8 Spekreyse, H, 28 Spencer, RF, 119 Spicer, A, 120 Spiegel, P, 119 Spielmann, A, 80 Spillmann, L, 43 Sprunger, DT, 80, 92 Stahl, JS, 12, 61, 62, 63, 65, 66, 67, 80 Starck, M, 81 Stark, L, 4, 7, 11, 15, 96, 180 Stark, N, 38 Stassen, MH, 119 Stayte, M, 79 Stearns, SD, 65 Stefani, E, 119 Steinbach, MJ, 3, 4, 47, 48, 170 Steinbach, R, 9 Steinman, RM, 24, 25, 96, 170, 173 Sternbach, G, 175 Stevens, DJ, 89, 100 Stevens, JK, 18 Stewart, S, 167 Straube, A, 55, 81 Straumann, D, 48, 58 Streicher, J, 5 Stringer, W, 175, 176 Strupp, M, 81 Sturzel, F, 43 Subramaniam, S, 19 Sugimoto, T, 80 Sumimoto, H, 80 Summers, CG, 28, 29, 189 Sutter, EE, 191 Swann, MH, 48

202 AUTHOR INDEX Sweeney, JA, 38 Sylvestre, PA, 170, 173 Tabuchi, A, 70, 96 Tachi, S, 36 Takagi, M, 55, 166 Takeichi, N, 58 Takikawa, Y, 37 Tamargo, RJ, 55, 166 Tamura, O, 119 Tanaka, N, 136 Tarita-Nistor, L, 9 Tarpey, P, 80, 81, 82 Tatlow, W, 176 Taylor, DSI, 36, 37 Taylor, MD, 4 Taylor, R, 176 Telford, L, 148 Teller, DY, 48 Terrett, A, 175 Tezer, FI, 167 Theodorou, M, 27, 29 Thomas, CW, 131, 153, 155 Thomas, S, 80, 81, 82, 83, 84 Thömke, F, 158, 175 Thompson, D, 19, 28, 34, 92, 115 Thompson, JR, 79 Thomson, D, 112 Thumser, ZC, 61 Thurston, SE, 12, 15, 27, 34, 61, 64, 68 Tian, JR, 55, 56, 59 Timms, C, 28 Tinsley, VF, 38 Tkalcevic, LA, 16, 18, 25, 33, 37, 90 Tohyama, M, 80 Tomko, DL, 148 Tomlinson, RD, 4 Tomporowski, PD, 38 Tomsak, RL, 19, 62, 80, 90, 91, 92, 96, 100, 112, 119 Tong, J, 11, 16, 17, 19 Toro, C, 184 Torrence, C, 184 Toulouse, P, 5 Toyka, KV, 168, 169 Toyofuku, T, 80 Traccis, S, 94, 96 Travers, P, 120 Tremblay, W, 38 Troncoso, XG, 42 Trotter, J, 9 Truax, BT, 158, 159 Tsilou, EK, 34, 100 Tsilou, ET, 28, 108 Tsuchida, Y, 108 Tsuneishi, M, 119

Tsuzuku, T, 148 Turner, J, 120 Tusa, RJ, 24, 38, 47, 48, 49, 62, 81, 89, 100, 108 Tuzun, E, 120 Tychsen, L, 24 Ubogu, EE, 117, 118 Ukai, K, 36 Ukwade, MT, 11, 12, 15, 19, 26 Ulevitch, R, 119 Ungerleider, LG, 42 Usrey, WM, 17 Vageﬁ, MR, 80 Valls-Solo, J, 184 van der Berg, AV, 13 van der Molen, MW, 38 Van der Steen, J, 25, 96 van Donkelaar, P, 4 Van Doren, CL, 11, 90, 143 Van Dorp, DB, 28 Van Gisbergen, JAM, 129 van Leeuwen, AF, 48, 170 van Minderhout, EM, 47 Van Opstal, AJ, 48 Velay, JL, 4 Venre-Dominey, J, 4 Vercher, JL, 4, 7, 11 Vermeulen, MH, 47 Verrier, MC, 7, 9 Versino, M, 164, 166 Verspeek, SA, 47 Vickers, A, 177 Vieville, T, 148 Vilis, T, 134 Vincent, A, 117, 118, 119 Vinters, HV, 180 Visco, F Jr, 89 von Helmholtz, H, 3, 11, 13 von Holst, E, 11 von Noorden, GK, 47, 48, 80, 92 Vu-Yu, L, 19 Wada, Y, 148 Wade, SW, 13 Waespe, W, 56, 81 Waggoner, R, 177 Wagman, A, 175 Walker, MF, 55, 56, 59 Wall, C 3rd, 107 Wallach, H, 7 Walport, MJ, 119, 120 Walsh, TJ, 158 Walter, EI, 120 Wang, J, 175

AUTHOR INDEX

Wang, P, 80 Wang, W, 120 Wang, X, 4 Wang, ZI, 19, 62, 80, 90, 91, 92, 96, 108, 110, 112, 115, 119, 139, 140 Wasicky, R, 4, 5, 8 Watanabe, J, 36 Watson, AB, 18 Waugh, SJ, 34 Wearne, S, 56 Webb, M, 175 Weber, A, 38 Weiford, E, 175 Weir, CR, 4 Weiss, AH, 33, 191 Weiss, LR, 15 Weissman, BM, 87, 93, 96 Wendling, L, 175 Wensveen, JM, 52 Wessig, C, 168, 169 White, JM, 11, 12, 15, 19, 25, 26 Whittle, JP, 12, 18, 25, 26, 27, 28, 34, 36, 61, 68 Wilcox, LA, 120 Wildrow, B, 65 Wildsoet, CF, 28 Williams, IM, 33 Williams, JI, 177 Williams, JM, 15 Williams, ML, 49, 52, 53 Williams, RW, 92, 96, 115 Wilson, E, 134 Wilson, HR, 28 Winterson, BJ, 24 Wizov, SS, 19, 27, 38, 100, 108 Wolff, SM, 189 Wong, AMF, 9, 159 Wood, KA, 130 Wood, SA, 5, 147 Wood, SJ, 118, 129 Worfolk, R, 12, 18, 25, 26, 27, 28, 34, 36, 38, 61, 68 Wortham, C, 79 Wu, K, 63, 65 Wyatt, HJ, 15 Wyman, D, 24

203

Xiao, X, 80 Yamada, I, 119 Yamada, T, 162, 164 Yamaguchi, A, 80 Yamamoto, M, 70, 74 Yamanobe, T, 58 Yamashita, T, 80 Yamazaki, A, 55, 58 Yanagawa, Y, 43 Yang, D, 19, 29, 34, 89, 92, 99, 100, 102, 108, 109, 110, 112, 115, 170, 171, 173 Yang, J, 16, 17 Yaniglos, SS, 12, 15, 27, 34, 61, 62, 64, 68, 80 Yauda, T, 5 Yee, RD, 100, 105 Ying, H, 55, 56 Yoshida, J, 80 Young, D, 18, 33 Young, NS, 122 Yu, YS, 189 Yue, Q, 59 Yuki, N, 167 Zackon, DH, 158 Zamora, MR, 122 Zane, W, 175 Zee, DS, 19, 24, 55, 56, 58, 59, 88, 100, 107, 118, 129, 130, 136, 138, 148, 162, 164, 166, 170, 173, 184, 185 Zehr, EP, 5 Zhang, B, 80 Zhang, M, 4 Zhang, Q, 80 Zhang, Z, 92, 115, 139, 140 Zhou, Y, 117 Zhu, M, 170, 171 Zileli, T, 158 Zivotofsky, AZ, 131, 153, 154, 155 Zollman, C, 177 Zoneveld, FW, 136 Zournas, C, 105 Zoworty, K, 99 Zubcov, AA, 38 Zupan, LH, 147, 148

Subject Index

Note: f denotes information in a ﬁgure; t denotes information in a table. Abnormal ﬁxation, vision and, 24–25 Absolute/relative target motion, spatial constancy ranges for, 26f Acetylcholine receptors (AChR), 117, 118, 119 Acetylcholinergic receptors, 5 AChR. See acetylcholine receptors Acquired/infantile nystagmus, visual stabilization devices for, 61–68 abstract, 61–63 ﬁrst-generation device, 64–65 ﬁxation instability in, 64f motion processor, 63–64 second-generation device, 65–66 stabilization plant, 63, 63f third-generation device, 66–67, 66f Acquired pendular nystagmus (APN), 63, 64 eye muscle surgery for, 112–15 abstract, 112 case reports, 112–14 discussion, 114–15 eye speeds, 113f presurgery/post-surgery scanpaths, 113f right eye horizontal nystagmus reconstructed, 114f vertical NAFX, 114, 114f Adaptive interference cancellation ﬁlter, response of, 68f Afferent sensory disorders, 25 Afferent signal modulation, by gamma motoneurons, 5–8 Albinism, 25, 26, 28. See also oculocutaneous albinism Alternate monocular occlusion (AMO) paradigm, 48, 49, 52

Alternating saccades in exotropic animals, 49f, 50f in primate model of strabismus, 47–53 comparison of saccade latency, 52 comparison of saccade main-sequence relationships, 50–52, 51f data analysis, 48–49 discussion, 52–53 experimental paradigms, 48–49 eye movement measurements, 48 goals, 48 methods, 48 results, 49 spatial pattern, 49–50 surgical procedures, 48 AMO paradigm. See alternate monocular occlusion paradigm Amount of convergence (AOC), 71, 73f ANOVA, 49, 52 AOC. See amount of convergence APN. See acquired pendular nystagmus Artiﬁcial scotoma, 42 Attention FMNS and, 38–39 INS and, 38–39 A/V patterns, 47 Baclofen, 56 Bayesian credibility interval, 132 Beam-steering mirror, 63 Behavioral model expansion, for OMS abstract, 139 discussion, 140–41

204

SUBJECT INDEX 205

Behavioral model expansion, for OMS (continued) ﬁxation data, 140f in INS, 139–42 methods, 139–40 model output of PPfs waveform, 141f results, 140–41 Binocular eye position, measurement of, 48 Binocularly normal observers, 8 Blind spot, PF and, 42 Botulinum toxin injections, for ICN, 80 Brain, eye position and, 3–4 α-bungarotoxin, 5 Büttner-Ennever's proprioceptive hypothesis, 3, 5 CEMAS. See Classiﬁcation of Eye Movement Abnormalities and Strabismus Central nervous system (CNS), eye position and, 23 Cerebellar lesions, effects on gaze stability on interaural TVOR, 57 methods, 56 in monkeys, 55–59 pursuit experiments, 56 results, 56–57 step-ramp pursuit gains, 57f surgical lesions, 56 TVOR experiments, 56, 59 vertical step-ramp pursuit, 57f on vertical TVOR, 57–59 Cerebellum, gaze stability and, 55 Chiropractic manipulation, neuro-ophthalmologic complications of, 175–78 abstract, 175 case reports, 175–76 conclusion, 178 discussion, 176–77 therapy-induced stroke, 177t vertebrobasilar stroke, 177t Classiﬁcation of Eye Movement Abnormalities and Strabismus (CEMAS), 23 CN. See congenital nystagmus CNS. See central nervous system Complement deposition, NMJ and, 121f Complement inhibitors, NMJ and, 120f Congenital cataracts, 25 Congenital nystagmus (CN), 23, 25, 26 foveate, 25 motion perception and, 27 spatial constancy and, 27 waveform of, 37f Contrast detection thresholds, 34 VA and, 25–27 Contrast provoked, oscillopsia, 33 Contrast sensitivity functions, 26f Crowding, 26

DAF. See decay-accelerating factor Decay-accelerating factor (DAF), 120, 121 DI. See divergence insufﬁciency Digital light-processor video projectors FMNS and, 36 INS and, 36 Direction of target motion, 16f Dissociated vertical deviation (DVD), 47 Divergence insufﬁciency (DI), associated with hereditary spinocerebellar ataxia, 162–66 abstract, 162 case reports, 163–64 discussion, 164–66 MRI of, 164f outcomes, 165t treatment, 165t Divergence paralysis (DP), 162 Dorsal trochlear nucleus, 5 DP. See divergence paralysis Drift, during ﬁxation eye movements, 42–43 Dual innervation, of EOM, 5 Duncker illusion, occluded smooth-arm tracking and, 152–55 abstract, 152–54 data analysis, 153 experimental setup, 154f methods, 153 results, 153–54 target tracking, 155t DVD. See dissociated vertical deviation EAMG. See experimentally acquired myasthenia gravis Early ﬁxation failure, 23 Early visual loss, ﬁxation stability and, 28 Eccentric gaze-holding, 129–34 abstract, 129–30 basis for ﬁnding, 134 data analysis, 129–30, 130f discussion, 132–33 methods, 130–32 model application, 133, 133f model residuals, 132f new statistic measurement for, 134 parameter estimates, 133t procedure, 130 statistical analysis, 131–32, 132t subjects, 130 test frequency, 132t time constants distribution, 132–33 Efference copy, 43 Efferent signal, 3 Ego-centric localization tasks, 4 Electromechanical retinal image stabilization device (eRISD), 61, 62f, 63, 64, 65

206 SUBJECT INDEX Electroretinography (ERG), 88 for extraocular muscle surgery, for IPAN, 100–101 Emmetropization, 28 EOM. See extraocular muscles ERG. See electroretinography eRISD. See electromechanical retinal image stabilization device Exotropic animals, alternating saccades in, 49f, 50f Exotropic strabismus, 47 eXpanded Nystagmus Acuity Function (NAFX), 88, 112 analysis, 94 -based therapy determination, for INS, 94 post-therapy outcomes, for INS, 94 predicted outcomes, for INS, 94 vertical, APN and, 114, 114f vertical/multiplanar data extension, 143–46 abstract, 143–44 discussion, 146 methods, 144–46 original tau surface, 144f radial nystagmus waveform, 145f results, 146 Experimentally acquired myasthenia gravis (EAMG), 118, 119, 121, 122 Extraocular muscles (EOM), 3 afferent signal anatomy/physiology of, 4–5 gamma motoneurons and, 5–8 dual innervation of, 5 feedback, future research directions in, 8 NMJ of, 122f Extraocular muscle surgery, for IPAN, 99–110 abstract, 99–100 anomalous head posture, 106f change in acuity LogMar, 105t change in best-corrected LogMar, 105f clinical data, 101–102 discussion, 105–10 ERG for, 100–101 eye movement recording data and, 101, 102f, 103f, 104f, 107f eye movement variables and, 103, 105 foveation deviation, 106f hypothetical model of quiet period, 109f inclusion criteria, 100 methods, 100–101 ophthalmologic examination, 100 outcome variables, 101–105 patients pursuing correction, 104t results, 101–105 strabismus deviation, 106f VEP for, 100–101 Extraretinal eye movement signals, 11 in IN, 15–16 low-pass ﬁltering of, 16

Extraretinal signals, 3 Eye/head movements, ocular oscillations and abstract, 184–85 discussion, 188 energy comparison, 186f methods, 185 PSCR, 187, 187f results, 185–87 wavelet analysis for, 184–88 EyeLink II, 67 Eye movement recording data extraocular muscle surgery, for IPAN, 101, 102f, 103f, 104f, 107f ground-plane optic ﬂow, involuntary versionvergence nystagmus induced by, 171 Eye movements. See also speciﬁc eye movements amplitudes, in IN, 12t ﬁxation, 24, 42–43 incessant, 16 involuntary, 11, 42–44 rhythmic horizontal, 12 variables, 103, 105 voluntary, perceptual fading (PF), 42–44 Eye muscle surgery for APN, 112–15 abstract, 112 case reports, 112–14 discussion, 114–15 T&R, 112 Eye position brain and, 3–4 brain signals for, 3–9 CNS and, 23 information sources, 3 Eye speeds, in APN, 113f Fading time (FT), 42, 43 Feedback, sensorimotor movement control and, 4 Field-holding reﬂex, 24 Fixation behavior, 23 perception and, 23 Fixation cross, PF spot and, movement combinations applied to, 43t Fixation eye movements drift during, 42–43 microsaccades during, 42–43 tremor during, 42–43 VA and, 24 Fixation failure, early, 23 Fixation instability, in visual stabilization devices, for acquired/infantile nystagmus, 64f Fixation stability, early visual loss and, 28 Flicker-fusion frequency, 34–36 Floating voice coils, 66

SUBJECT INDEX 207

FMNS. See fusion maldevelopment nystagmus syndrome Foveal heterogeneity, 28 Foveation period, 25 vs. optotype size, 37f FRMD7 gene, 79, 82, 83 expression of, 80 FT. See fading time Fusion maldevelopment nystagmus syndrome (FMNS), 33, 87 attention and, 38–39 digital light-processor video projectors and, 36 external inﬂuences on, 34–36 internal inﬂuences on, 36–39 LEDs and, 34–36 stress and, 38 surgical guidelines for, 93t visual effort and, 36–38 visual status changes, 39 GABAergic agents, for ICN, 81 Gabapentin, 82 Gamma motoneurons, afferent signal modulation by, 5–8 Gamma system, up-regulation of, 3 Gaze control, 55 Gaze-in position, 4 Gaze stability cerebellar role in, 55 effects of cerebellar lesions on interaural TVOR, 57 methods, 56 in monkeys, 55–59 pursuit experiments, 56 results, 56–57 step-ramp pursuit gains, 57f surgical lesions, 56 vertical step-ramp pursuit, 57f on vertical TVOR, 57–58 on TVOR experiments, 56, 59 Goldman perimeter, 28 Ground-plane optic ﬂow, involuntary versionvergence nystagmus induced by, 170–73 abstract, 170 data analysis, 171 discussion, 173 experimental paradigms, 171 eye movement recording, 171 frontal plane motion, 171 ground plane motion, 171 methods, 170–71 results, 171–73 stimuli, 171 subjects, 171 velocity/position proﬁles, 172f

Hereditary spinocerebellar ataxia, DI associated with, 162–66 abstract, 162 case reports, 163–64 discussion, 164–66 MRI of, 164f outcomes, 165t treatment, 165t Higher-order perceptual judgments, JM and, 7 Horizontal eye velocity, to interaural translation steps, 58f Horizontal/torsional amplitude beats, in IN, 14f Horizontal/torsional eye positions, in IN, 13f Hyperacuity tasks, 26 ICN. See idiopathic congenital nystagmus Idiopathic congenital nystagmus (ICN), 25, 28, 79 botulinum toxin injections for, 80 GABAergic agents for, 81 genetics of, 79–80 literature review, 79 non-GABAergic agents for, 81 X-linked, 80, 81f IN. See infantile nystagmus INC. See interstitial nucleus of Cajal Incessant eye movements, 16 Inertial/noninertial contributions, to translation and path perception, 147–50 abstract, 147–48 discussion, 150 methods, 148–50 results, 150 Infantile cataracts, 28 Infantile ﬁxation instability, 24–25 Infantile nystagmus (IN), 11, 23 extraretinal eye movement signals in, 15–16 eye movement amplitudes in, 12t horizontal/torsional amplitude beats in, 14f horizontal/torsional eye positions in, 13f involuntary eye movements of, 11 multifocal electroretinographic study of, 189–92 abstract, 189–90 discussion, 191–92 methods, 190 results, 190–91 ring averages, 191f trace array plots, 190f perceptual stability during, 11–15 slow phase of, 19 stabilization devices for, 61 torsional component of, 11, 12, 13 types of, 25 upper limit amplitude dismissal in, 18 vergence hysteresis in, 180–83 abstract, 180

208 SUBJECT INDEX Infantile nystagmus (IN) (continued) discussion, 181–83 methods, 180–81 plots of NAFX vs. time, 181f, 182f results, 181 visual perception/functioning in, 18–19 visual stabilization devices, selective image stabilization for, 67–68 waveform shapes of, 25 Infantile nystagmus syndrome (INS), 33 attention and, 38–39 central/peripheral therapy for, 90–91 clinical characteristics, 88–90, 89t digital light-processor video projectors and, 36 external inﬂuences on, 34–36 internal inﬂuences on, 36–39 Kestenbaum surgery for, 92 LEDs and, 34–36 NAFX-based therapy for, 94 nonsurgical therapy for, 94 ocular motor characteristics of, 88–90 OMS behavioral model expansion for, 139–42 abstract, 139 discussion, 140–41 methods, 139–40 results, 139–41 stress and, 38 surgery for, 92–93 surgical guidelines for, 93t treatment, 87–96 abstract, 87–88 discussion, 94–96 methods, 88 visual effort and, 36–38 visual status changes, 39 waveforms, 88 Infantile periodic alternating nystagmus (IPAN), extraocular muscle surgery, 99–110 abstract, 98–100 anomalous head posture, 106f change in acuity LogMar, 105t change in best-corrected LogMar, 105f clinical data, 102–5 clinical/electrophysiological effects of, 100–10 discussion, 105–10 ERG for, 100–1 eye movement recording data and, 101, 102f, 103f, 104f, 107f eye movement variables and, 103, 105 foveation deviation, 106f hypothetical model of quiet period, 109f inclusion criteria, 100 methods, 100–101 ophthalmologic examination, 100 outcome variables, 100–102

patients pursuing correction, 104t results, 102–5 strabismus deviation, 104f VEP for, 100–1 Information technology (IT) syndrome, 70 INS. See infantile nystagmus syndrome InterAural translation, mean perceptual response to, in translation and path perception, 148f Interaural translation steps, horizontal eye velocity to, 58f Interstitial nucleus of Cajal (INC), 130 Inverted muscle spindle, 5 Involuntary eye movements of IN, 11 PF during, 42–44 Involuntary ﬁxation eye movements, normal ﬁxation and, 24 Involuntary version-vergence nystagmus, induced by ground-plane optic ﬂow, 170–73 abstract, 170 data analysis, 171 discussion, 173 experimental paradigms, 171 eye movement recording, 171 frontal plane motion, 171 ground plane motion, 171 methods, 170–71 results, 171–73 stimuli, 171 subjects, 171 velocity/position proﬁles, 172f IPAN. See infantile periodic alternating nystagmus IT syndrome. See information technology syndrome Jendrassik maneuver (JM), 3, 5, 6, 7, 8 higher-order perceptual judgments and, 7 saccadic system and, 7–8 on vergence system, 5–7, 6f JM. See Jendrassik maneuver Kestenbaum surgery, for INS, 92 Landolt C optotypes, 37f Latent nystagmus (LN), 25 Leicestershire Nystagmus Survey, 79 LFD. See longest foveation domain Light-emitting diodes (LEDs), INS and, 34–36 Linear variable displacement transducers (LVDTs), 67 Listing’s law, 12, 13 torsion calculation from, 13 LN. See latent nystagmus LogMAR chart, 25, 26 LogMAR visual acuity, 82, 83f, 84f Longest foveation domain (LFD), 90

SUBJECT INDEX 209

Low-pass ﬁltering, of extraretinal eye movement signals, 16 Lutz schematic, of supranuclear innervation, 157f LVDTs. See linear variable displacement transducers MAC. See membrane attack complex Manifest latent nystagmus (MLN), 23, 25, 26, 27–28 categories of, 27 squints and, 27 waveform of, 37f MATLAB, 48, 49, 87, 101, 131, 139, 140, 144, 171, 185 MCP. See membrane cofactor protein Mean drift velocity, 24 Mean perceptual response, to InterAural translation, in translation and path perception, 148f Membrane attack complex (MAC), 119, 120 Membrane cofactor protein (MCP), 120 Membrane inhibitor of reactive cell lysis (MIRL), 120 MFS. See Miller Fisher syndrome MG. See myasthenia gravis Microophthalmic right eye, nystagmus waveform of, 37f Microsaccades, during ﬁxation eye movements, 42–43 Midbrain lesion case study, of posterior internuclear ophthalmoplegia of Lutz revisited, 156–61 abstract, 156 anatomical connections, 161f case report, 156–57 discussion, 157–59 gaze plot, 159f mild right eye abduction limitation, 157f MRI ﬁndings, 158f saccadic velocity/duration plotted, 160f MIF. See multiply innervated ﬁbers Mild right eye abduction limitation, midbrain lesion case study, 157f Miller Fisher syndrome (MFS), NMJ dysfunction in, 167–69 abstract, 167 anti-GQ1b antibodies and, 167, 168 case report, 167–68 discussion, 168–69 ocular motility, 168f spontaneous return of ocular motility, 169f MIRL. See membrane inhibitor of reactive cell lysis MLN. See manifest latent nystagmus Monosynaptic stretch reﬂexes, 4 Motion perception, CN and, 27 Motion processor, for visual stabilization devices, in acquired/infantile nystagmus, 63–64 Müller-Lyer illusion, 153 Multifocal electroretinographic study of IN, 189–92 abstract, 189–90

discussion, 191–92 methods, 190 results, 190–91 ring averages, 191f trace array plots, 190f of oculocutaneous albinism, 189–92 abstract, 189–90 discussion, 191–92 methods, 190 results, 190–91 ring averages, 191f trace array plots, 190f Multiply innervated ﬁbers (MIF), 4, 5, 119 Muscle spindle, inverted, 5 Myasthenia gravis (MG), 117 complement system and, 119–21 EOM involvement in, 117–22 abstract, 117 complement hypothesis for, 121–22 future directions, 122 EOM susceptibility to, 118–19 NMJ injury and, 117 pathophysiology of, 117–18 NAFX. See eXpanded Nystagmus Acuity Function NBS. See nystagmus blockage syndrome Near response, in VDT syndrome, 72f Neuroanatomical tracing studies, 3 Neuromuscular junction (NMJ), 119, 121, 122 complement deposition and, 121f complement inhibitors and, 120f of EOM, 122f injury, MG and, 117 Neuromuscular junction (NMJ) dysfunction, in MFS, 167–69 abstract, 167 anti-GQ1b antibodies and, 167, 168 case report, 167–68 discussion, 168–69 ocular motility, 168f spontaneous return of ocular motility, 169f Neuro-ophthalmologic complications, of chiropractic manipulation, 175–78 abstract, 175 case reports, 175–76 conclusion, 178 discussion, 176–77 therapy-induced stroke, 177t vertebrobasilar stroke, 177t NMJ. See neuromuscular junction Noncompressive ocular motor nerve palsy, eye exercises for, 136–38 abstract, 136 conclusions, 138 discussion, 138

210 SUBJECT INDEX Noncompressive ocular motor nerve palsy, eye exercises for (continued) methods, 136–37 patients, 136–37 results, 137 variables, 137t Non-GABAergic agents, for ICN, 81 Non-twitch (NT) motoneurons, 3 Normal ﬁxation involuntary ﬁxation eye movements and, 24 physiological behavior of, 24 vision and, 24 NPH/MVN. See nucleus prepositus hypoglossi/ medial vestibular nuclei complex NT motoneurons. See non-twitch motoneurons Nucleus prepositus hypoglossi/medial vestibular nuclei complex (NPH/MVN), 130 Nystagmus. See also speciﬁc nystagmus pathological, 61 Nystagmus blockage syndrome (NBS), 87 Nystagmus waveform, of microophthalmic right eye, 37f Ocular control, hybrid model, 4 Ocular motor characteristics, of INS, 88–90 Ocular motor system (OMS) behavioral model expansion for abstract, 139 discussion, 141–42 ﬁxation data, 140f in INS, 139–42 methods, 139–40 model output of PPfs waveform, 141f results, 140–41 block diagram of, 91f Ocular oscillations, eye/head movements and abstract, 184–85 discussion, 188 energy comparison, 186f methods, 185 PSCR, 187, 187f results, 185–87 wavelet analysis for, 184–88 Oculocutaneous albinism. See also albinism multifocal electroretinographic study of, 189–92 abstract, 189–90 discussion, 191–92 methods, 190 results, 190–91 ring averages, 191f trace array plots, 190f Oculopalatal tremor (OPT), 184, 185, 186f OKN. See optokinetic nystagmus OMS. See ocular motor system Opposite target motion, 16

OPT. See oculopalatal tremor Optic nerve hypoplasia, 25 Optokinetic nystagmus (OKN), 12 Optokinetic systems, 24 Optotype charts, 25, 26 Optotype size, vs. foveation period, 37f Original tau surface, vertical/multiplanar data extension, of NAFX, 144f Oscillopsia, 11, 12, 15, 61 contrast provoked, 33 instances of, 35f Palisade endings (PE), 3, 4 PAN. See periodic alternating nystagmus PAR. See pupil-asthenia ratio Pathological nystagmus, 61 PCR. See pupil-constriction ratio PE. See palisade endings Peak slow phase velocity, 25 Perceived distance, 7 Perceived motion smear, 16 contribution of, 19 possible reduction mechanism for, 17–18 Perception ﬁxation behavior and, 23 of motion smear, 11 unstable ﬁxation with, 23–29 Perceptual fading (PF), 42 abstract, 42–43 blind spot and, 42 discussion, 44 during involuntary eye movements, 42–44 methods, 43 pursuit task and, 42 results, 43–44 during voluntary eye movements, 42–44 Perceptual fading spot, ﬁxation cross and, movement combinations applied to, 43t Perceptual responses, during target stabilization task, translation and path perception, 149f Perceptual stability, during IN, 11–15 Periodic alternating nystagmus (PAN), 56, 101 PF. See perceptual fading Phase-locked loop (PLL), 64 Phase shift changing rate (PSCR), 187, 187f PLL. See phase-locked loop Point of usage, of VDT, 73t Polhemus FASTRAK system, 153 Posterior internuclear ophthalmoplegia of Lutz revisited, midbrain lesion case study, 156–61 abstract, 156 anatomical connections, 161f

SUBJECT INDEX 211

Posterior internuclear ophthalmoplegia of Lutz revisited, midbrain lesion case study (continued) case report, 156–57 discussion, 157–59 gaze plot, 159f mild right eye abduction limitation, 157f MRI ﬁndings, 158f saccadic velocity/duration plotted, 160f Primate model of strabismus, alternating saccades in, 47–53 comparison of saccade latency, 52 comparison of saccade main-sequence relationships, 50–52, 51f data analysis, 48–49 discussion, 52–53 experimental paradigms, 48–49 eye movement measurements, 48 goals, 48 methods, 48 results, 49 spatial pattern, 49–50 surgical procedures, 48 Proprioception, 3 Proprioceptive hypothesis, 5 Proprioceptors, function, 3 PSCR. See phase shift changing rate Pulfrich illusion, 7 Pupil abnormalities, with VDT syndrome, 70–75 in adults, 71 analysis methods, 72f in children, 71–72 data analysis, 71–72 measurements, 71–72 methods, 71–72 near stimulation, 74f results, 72–73 Pupil-asthenia ratio (PAR), 71, 73–74, 74f proportion of, 74f Pupil-constriction ratio (PCR), 71, 73f Pursuit task, PF and, 42 Radial nystagmus waveform, vertical/multiplanar data extension, of NAFX, 145f Retinal image slip velocities, 24 visual perception/functioning and, 23 Retinal image cancelling, 11 Reverse transcriptase-polymerase chain reaction (RT-PCR), 80 Rhythmic horizontal eye movements, 12 Right eye horizontal nystagmus reconstructed, for APN, 114f Risley prism, 64, 66

Rotational vestibulo-ocular reﬂex (RVOR), 55 RT-PCR. See reverse transcriptase-polymerase chain reaction RVOR. See rotational vestibulo-ocular reﬂex Saccade latency, 47 Saccadic intrusions, 24 Saccadic system, JM and, 7–8 Saccadic velocity/duration plotted, midbrain lesion case study, 160f Sample eye movement responses, to vertical translation, 58f Secondary nystagmus (SN), 79, 82 Selective image stabilization, visual stabilization devices for, in IN, 67–68 Sensorimotor movement control, feedback and, 4 SIF. See singly innervated ﬁber Simulated foveation periods, 11 Simulink-based motion processor, 66 Singly innervated ﬁber (SIF), 5, 119 Slow-control reﬂex, 24 Slow phase of IN, 19 eye movements, 11 SN. See secondary nystagmus Snellen charts, 25, 26 Snellen visual acuity, 25 SNS. See spasmus nutans syndrome Spasmus nutans syndrome (SNS), 87 Spatial constancy ranges, for absolute/relative target motion, 26f Spatial tracking system (STS), 153 Squints, MLN and, 27 Stabilization devices, for IN, 61 Stabilization plant options for, 63t for visual stabilization devices, in acquired/ infantile nystagmus, 63, 63f Step-ramp pursuit gains, cerebellar lesions, effects on gaze stability, 57f Strabismus, 47 exotropic, 47 Strabismus deviation, IPAN, extraocular muscle surgery, 106f Strabismus surgery, 8 Straight-ahead gaze, recordings of, 12 Stress FMNS and, 38 INS and, 38 STS. See spatial tracking system Supranuclear innervation, Lutz schematic of, 157f Target stabilization task, perceptual responses during, translation and path perception, 149f

212 SUBJECT INDEX Temporal impulse response function (TIRf), 15, 17, 18f Tenotomy, 19, 87, 90, 92, 93t Tenotomy and reattachment (T&R), eye muscle surgery, 112 ThiIRIS C9000, 71f, 74, 75 TIRf. See temporal impulse response function Titmus test, 6 Torsional component, of IN, 11, 12, 13 Torsional nystagmus, 12 T&R. See tenotomy and reattachment Translational vestibulo-ocular reﬂex (TVOR), 55 experiments, on gaze stability, 56, 59 vertical, cerebellar lesions and, 57–58 Translation and path perception inertial/noninertial contributions to, 147–50 abstract, 147–48 discussion, 150 methods, 148–50 results, 150 mean perceptual response, to InterAural translation, 148f perceptual responses, during target stabilization task, 149f Tremor, during ﬁxation eye movements, 42–43 TVOR. See translational vestibulo-ocular reﬂex Unstable ﬁxation, perception with, 23–29 Upper limit amplitude dismissal, in IN, 18 Up-regulation, of gamma system, 3 VA. See visual acuity VDT syndrome. See visual display terminal syndrome VEP. See visual evoked potential Vergence hysteresis, in IN, 180–83 abstract, 180 discussion, 181–83 methods, 180–81 plots of NAFX vs. time, 181f, 182f results, 181 Vergence system, JM and, 5–7 Vertebrobasilar stroke, nontherapeutic mechanical causes, 177t Vertical eXpanded Nystagmus Acuity Function (NAFX), APN and, 114, 114f Vertical/multiplanar data extension, of NAFX, 143–46 abstract, 143–44 discussion, 146 methods, 144–46 original tau surface, 144f radial nystagmus waveform, 145f results, 146

Vertical step-ramp pursuit, cerebellar lesions, effects on gaze stability, 57f Vertical translation, sample eye movement responses to, 58f Vertical translational vestibulo-ocular reﬂex cerebellar lesions, effects on gaze stability on, 57–58 response sensitivities, 59f Vestibulo-ocular reﬂex (VOR), 64 Vestibulo-ocular systems, 24 Vision abnormal ﬁxation and, 24–25 normal ﬁxation and, 24 Visual acuity (VA) contrast detection thresholds and, 25–27 ﬁxation eye movements and, 24 Visual display terminal (VDT) frequency of use, 74f point of usage, 73t student usage, 74f Visual display terminal (VDT) syndrome, 70 near response, 72f PAR, 74f PCR, 71–72 prevalence, 70 pupil abnormalities with, 70–75 in adults, 71 analysis methods, 72f in children, 71–72 data analysis, 71–72 measurements, 71–72 methods, 71–72 near stimulation, 74f results, 72–73 Visual effort FMNS and, 36–38 INS and, 36–38 Visual evoked potential (VEP), for extraocular muscle surgery, for IPAN, 100–101 Visual loss, early, ﬁxation stability and, 28 Visual perception/functioning in IN, 18–19 retinal image and, 23 Visual stabilization devices in IN, selective image stabilization for, 67–68 for acquired/infantile nystagmus, 61–68 abstract, 61–63 ﬁrst-generation device, 64–65 ﬁxation instability in, 64f motion processor, 63–64 second-generation device, 65–66 stabilization plant, 63, 63f third-generation device, 66–67, 66f

SUBJECT INDEX 213

Visual status changes FMNS and, 39 INS and, 39 Visual suppression mechanisms, 47 Voluntary eye movements, PF during, 42–44 VOR. See vestibulo-ocular reﬂex

Waveforms, INS, 88 Wavelet transform (WT), 184 WT. See wavelet transform X-linked, ICN, 80, 81f

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