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Nystagmus in Infancy
and Childhood

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The companion web site for this book

www.oup.com/us/nystagmus
offers video content, clinical tools, and other helpful resources including
– Patient, waveform, and canine videos
– Patient handouts
– Clinical examination forms
– Information on analysis soft ware

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NYSTAGMUS IN
INFANC Y AND
CHILDHOOD
Current Concepts in Mechanisms,
Diagnoses, and Management

Richard W. Hertle

Louis F. Dell’Osso

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1
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It furthers the University’s objective of excellence in research, scholarship,
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Press, at the address above.

Library of Congress Cataloging-in-Publication Data

Hertle, Richard W.
Nystagmus in infancy and childhood: current concepts in mechanisms, diagnoses, and management /
Richard W. Hertle, Louis F. Dell’Osso.
p. ; cm.
Includes bibliographical references.
ISBN 978–0–19–985700–5 (alk. paper)
I. Dell’Osso, Louis F. II. Title.
[DNLM: 1. Nystagmus, Pathologic. 2. Child. 3. Infant. WW 410]
618.92—dc23
2012005642 .

1 3 5 7 9 8 6 4 2
Printed in the United States of America
on acid-free paper

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Th is book is dedicated to my parents, Richard H. Hertle (1934–2008) and Anna Lena Hertle (1934–)
who may seem from the outside as typical fi rst-generation Americans from Brooklyn, New York, but
for my family and me they were far from average. Their values, instilled in me (passion, education,
hard work combined with a dedication to family and friends, and a spiritual soul), have become the
cornerstone of a thoughtful and peaceful way of life.
Richard W. Hertle, MD

The important thing in science is not so much to obtain new facts as to discover new ways of thinking
about them.
—Sir William Lawrence Bragg, 1890–1971

Th is book is dedicated to my grandparents, who had the courage and foresight to emigrate to
America, where they could forge a better life, and to my parents, Frank Dell’Osso (1914–2004) and
Rose Perrone Dell’Osso (1915–2000), also fi rst-generation Italian Americans from Brooklyn, New
York. My genealogical research taught me that we are who they were. It is because of that lineage
that I appreciated the pursuit of knowledge for its own sake, the satisfaction of a job well done (be it
carpentry at home or my research), and the need to fi nd balance while hunting the woods or fields, or
playing on the golf course. They, and my large extended family, provided the confidence needed later
in life to chart my own course and follow it despite the skepticism expressed by either my peers or
other “experts.” Th roughout my adult life I have been fortunate to have the love and support of two
remarkable women. The insightful contributions and guidance in difficult times of Lyn Ferlo and,
for the past 35 years, Charlene Morse were critical to any achievements I may have subsequently
made. Therefore, this book is also dedicated to them.
Louis F. Dell’Osso, PhD

Not a single scientist in the meeting believed a word of what I said. Now, I know I am right.
—Hermann von Helmholtz (1821–1894)

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R.W. Hertle and L.F. Dell’Osso in the latter’s Daroff-Dell’Osso Ocular Motility
Laboratory office.

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foreword
A lot of intensely intelligent and highly dedicated workers have given their lives to this subject of
nystagmus, and very little has come of it.
—Professor Frank A. Elliott , to R. B. Daroff (1965)

M Y I NTER EST in eye movements started correct: in 1965, there was meager information
on the fi rst day of my neurology residency at about nystagmus, which my EMG plan would-
Yale University, in July 1962, when we encoun- n’t have increased. I had been impressed by
tered a patient with a supranuclear ophthal- Goodwin Breinin’s ocular muscle EMG stud-
moplegia. Our attending asked me to read ies on gaze palsies, but except for convergence-
about eye movements and give a report to retraction nystagmus, it has yielded no other
the group. I spent the next 2 months reading useful information.
all that I could fi nd on the subject and essen- Fortunately, in the late 1960s and
tially became the Yale authority on eye move- 1970s, several technologic advances led to
ments while still only a PGY2. I decided to enhanced understanding of eye movements
subspecialize in neuro-ophthalmology, a deci- in general and nystagmus in particular. As
sion strengthened by a 3-month elective with detailed by David Robinson, these included:
J. Lawton Smith at the University of Miami the ability to record from single neurons in
during my PGY3 year. awake animals; the development of tracers
I had an Army commitment after my residency to determine neuronal connections; com-
and planned a neuro-ophthalmology fellowship puters that performed rapid data analysis;
thereafter that involved nystagmus research precise eye-movement recording techniques
using ocular muscle electromyography (EMG). that noninvasively permitted minutes of arc
I discussed these plans with Professor Frank measurements in all planes; and the popular-
Elliott , one of my University of Pennsylvania ization of a systems approach, where models
Medical School Neurology mentors, and his provided the necessary hypotheses to focus
negative response appears above. Elliott was basic and clinical research.

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Such advancements, particularly the last, his interest in understanding this previously
resulted from the entry of biomedical engi- understudied area.
neers into eye-movement research. These Dell’Osso and Hertle described the book’s
included David Robinson and Lou Dell’Osso, organization in their Preface. I can only add that
along with their multiple trainees, whose col- it is authoritative, reader friendly, and, indeed,
laborations with clinicians focused studies that brilliantly constructed. Nystagmus in Infancy
addressed relevant clinical issues. The teams and Childhood will now serve as the defi nitive
included David Robinson with Dave Zee and source for the understanding and treatment of
John Leigh; and Lou Dell’Osso with me, Todd previously ill-understood and untreatable eye-
Troost, John Flynn, and more recently with movement disorders.
the pediatric neuro-ophthalmologist and sur- Robert B. Daroff, MD
geon, Richard Hertle. Dell’Osso’s own con- Professor and Chair Emeritus of
genital nystagmus (now designated “infantile Neurology, Case Western Reserve
nystagmus syndrome”) naturally sparked University School of Medicine

viii • F O R E W O R D

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preface
Never write about nystagmus, it will lead you nowhere.

—Hermann Wilbrand (1851–1953) to Robert Wartenberg (1886–1956) in 1921

THIS BOOK describes, illustrates, and shares Th is text will provide clinicians with algo-
our current understanding, evaluation, and treat- rithms for examination; descriptions of diag-
ments of nystagmus in infancy and childhood. It nostic techniques; and medical, surgical, and
has been over five decades since the pioneering alternative treatments of the visual system in
works Ocular Vertical Deviations and Nystagmus infants and children with nystagmus. Another
by J. Ringland Anderson and Clinical Methods of important goal of this work is to provide scien-
Neuro-Ophthalmologic Examination by Alfred tists with details on methodologies of investiga-
Kestenbaum described what was known about tion, including analysis soft ware, models of the
ocular oscillations and what could be accom- ocular motor system, and current hypotheses on
plished to treat those disorders. Since then the the pathophysiology of ocular motor oscillations.
amount of knowledge regarding the anatomy, Modern media formats are included to visually
physiology, molecular biology, and types of illustrate the varied presentations of these disor-
investigation techniques and treatment options ders with their diagnostic electrophysiology.
for nystagmus have exponentially increased. The roots of this monograph are deep, stem-
We believe this work is timely, aligning it with ming from seeds planted in a lecture, “Nistagmo
advanced concepts of developmental brain- Infantile” presented to Il Gruppo Italiano per
eye diseases and summarizing novel treatment lo Studio del Movimento Oculare, III Incontro
paradigms. By using this medium to consolidate Nazionale, I Corso di Aggiornamento Teorico-
our combined experience, the authors hope to Pratico in Alghero (Sardinia) Italy in 1989.
provide a comprehensive resource for both cli- There, thanks to Dr. Sebastiano Traccis’ invi-
nicians and scientists who care for infants and tation to LFD to speak at this meeting and
children with nystagmus. Dr. Josephine Shallo-Hoff mann’s suggestion

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that a compilation of this information would be sheets, algorithm for computer analysis of
appreciated by clinicians treating these condi- nystagmus waveforms, and so on. Additional
tions, he began to collate ocular motor research resources—including patient, waveform, and
about “congenital nystagmus,” “latent/mani- canine videos—can be found on the companion
fest latent nystagmus,” the nystagmus blockage website for this volume. Please visit www.oup.
syndrome, and “spasmus nutans” with the aim com/us/nystagmus for crucial tools and infor-
of defi ning the critical factors in the differen- mation for clinicians and scientists.
tial diagnosis and treatment of these specific Chapter 1 covers the relevant anatomy
but easily confused types of nystagmus. involved in nystagmus or saccadic intrusions
Clearly, the lure of new research kept this and oscillations. In Chapters 2–4, the results
book on the back burner until the unbounded of ocular motor research into different types of
energy of Rich Hertle was applied to it. In nystagmus of infancy are summarized in a nar-
the more than two decades that have elapsed rative manner, particularly the important ideas
since that first draft, not only has our knowl- and observations that elucidate underlying neu-
edge base expanded tremendously but also the rophysiological mechanisms or have clinical
terminology has changed. In this handbook, relevance. We emphasize the latter since they
we use the more modern CEMAS nomencla- form the foundations for both “clinical pearls”
ture and thereby avoid the misconceptions and the sections on therapeutic options that
and errors inherent in the classical terminol- follow—“science-based,” rather than “evidence-
ogy. Eye-movement data and their analyses based,” medicine. Just as the form and luster of
provide unambiguous, accurate, and repeat- real pearls stem from the grains of sand that are
able waveform criteria and characteristics for their foundation, the diagnostic and therapeutic
infantile nystagmus syndrome, fusion mal- value of these clinical pearls derives from the sci-
development nystagmus syndrome, nystag- entific foundations uncovered in research stud-
mus blockage syndrome, and spasmus nutans ies. Thus, our pearls remain scattered in their
syndrome, allowing definitive diagnoses and research beds, thereby maintaining close prox-
determination of both the type and amount of imity to their scientific grains of sand. Chapter
the most efficacious therapy for each patient. 5 is devoted to the differential diagnoses of both
The resources used in this work include infantile types of nystagmus and saccadic dis-
a summary (review) of much of the current orders. Chapter 6 discusses the afferent-system
knowledge regarding nystagmus in infancy and clinical exam and Chapter 7, nystagmus treat-
childhood, but, in addition, and uniquely, shares ments, including medical, surgical, and others.
the authors’ combined 75 years of experience in Finally, Chapter 8 presents our summary and
studying, diagnosing, and treating thousands of conclusions, including how, through the use of
patients with nystagmus. The book is structured an eye-movement, data-driven function, the
in a logical way to allow a full cover-to-cover eXpanded nystagmus acuity function, we are
read or as a reference resource for those inter- now able to both provide a pre-therapy estima-
ested in a particular topic (e.g., eye-movement tion of the beneficial effects of infantile nystag-
recording techniques, medical treatments, mus syndrome (INS) therapy on an individual
video appearance of periodic alternating nys- patient, as well as directly measuring them post-
tagmus, etc.). Although one may concentrate on therapy. The ability to estimate improvements in
either the research or the clinical sections, the measured peak visual acuity and the breadth of
well-rounded reader would be better served by the high-acuity gaze-angle region for individual
including both; they have been inseparable in INS patients with or without associated sensory
our research approach and neither the “basic” visual deficits has never before been possible and
nor the “clinical” aspects would exist without cannot be accomplished using clinical meas-
the other. We have included appendices that can ures alone. Th is eye-movement-based approach
be used in isolation for special purposes such as allows the physician to make more accurate diag-
clinical examination sheets, patient information noses and to more confidently apply the most

x • PR E FAC E

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suitable therapies to each patient. Hopefully, it learned how ignorant we remain regarding
will also discourage withholding beneficial ther- this group of disorders. It is our hope that it
apies (“Your child has nystagmus and there is will serve as a resource for the next generation
nothing that can be done”) and preclude apply- of clinicians and scientists, thereby encourag-
ing therapies with litt le estimated visual func- ing a newer, deeper, and more profound set of
tion benefits; the net result should be improved discoveries.
visual function and patient satisfaction.
During the 2 years it took to organize, pro- Richard W. Hertle, MD
pose, write, and publish this work we have Louis F. Dell’Osso, PhD

Preface • xi

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acknowledgments
It is better to have nine of your ideas be completely disproved, and the tenth one spark off a revolution, than
to have all ten be correct but unimportant discoveries that satisfy the skeptics.

—Francis Crick (1916–2004)

A LTHOUGH AUTHOR ED by two, this their families who traveled from all parts of the
work could not have been accomplished without world to many places in the United States to visit
continuous support from colleagues and adminis- the author’s professional offices.
trative personnel at multiple medical centers. The following people I could not do, or have
done, without Dongsheng Yang, Robert Daroff,
R. J. Leigh, Larry A. Abel, David Schaffer,
FOR R. W. HERTLE:
Arthur Jampolsky, Marshal M. Parks, Jonathan
The Laboratory of Sensorimotor Research, The Jacobs, Roy W. Beck, Raymond Kraker,
National Eye Institute, National Institutes of Edmond F. Fitzgibbon, Susan B. Mellow, Mitra
Health, Bethesda, MD; The UPMC Eye Center, Maybodi, Robert Williams, David B. Granet,
Pittsburgh, PA; Akron Children’s Hospital Deanna Stevens, William Anninger, Vanessa M.
Medical Center, Akron, OH; Case Western Hill, Joel S. Schuman, Hiroshi Ishikawa, Leah
Reserve University, Cleveland, OH. Granting Reznick, Mingshia Zhu, Albert Maguire, Jean
agencies were as follows: The National Eye Bennett, Kenneth Adams, Matt hew Kaufman,
Institute, National Institutes of Health; The Eric Hald, Tara Cronin, Ellen Mitchell, Jai Jeng,
Veterans Administration Merit Review; and Fight Kristen Carey, Robert Burnstine, Shawn Lyden,
for Sight. Anne Dellinger at Oxford University Stephanie Knox, and Cathy Howe. Lastly, if were
Press was tremendously helpful in advocating not for the love and support of my family, espe-
for, and assisting with, the huge task of publishing cially my wife, Gloriann, and children, Jessika
this work. Most important, this work could never and Jamie, my work on this project would never
have been completed without those patients and had been completed.

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FOR L. F. DELL’OSSO: and many, in my personal life: Robert B. Daroff

(who facilitated my move to the Department of
The Daroff-Dell’Osso Ocular Motility Laboratory Neurology at a critical point early in my career
(formerly The Ocular Motor Neurophysiology and cemented our professional, symbiotic part-
Laboratory), Case Western Reserve University, nership that lasts to this day); Larry Stark (who
and Louis Stokes Cleveland Department of insisted we write a paper based on my thesis and
Veterans Affairs Medical Center, Cleveland, OH visit to his lab); Thorne Shipley, John T. Flynn,
(formerly, University of Miami and Department J. Lawton Smith, and Joel S. Glaser (the Bascom
of Veterans Affairs Medical Center, Miami, Palmer superstars who also were my teachers);
FL). Funding was from the following: The Larry A. Abel (my fi rst and most prominent post-
National Science Foundation (1972); Seeing doc); Jonathan B. Jacobs (grad student, postdoc,
Eye Foundation (1972–73); The National Eye colleague, and Mac guru responsible for all our
Institute, National Institutes of Health (1972; soft ware); Robert M. Steinman; Dieter Schmidt;
1978–79); and The Department of Veterans Sebastiano Traccis; Carl Ellenberger; R. J.
Affairs Merit Review (1973–2011). Th is work Leigh; Han Collewijn; Akio Tabuchi; Barbara
could never have been completed without the Weissman; Josephine Shallo-Hoff mann; Nirav
continuous stream of patients referred over the Sheth; Lea Averbuch-Heller; Bernd Remler;
past 40 years by dozens of physicians (both in Robert Williams; Robert Burnstine; Robert L.
private practice and academia), and the many Tomsak; Jean Bennett; Greg Acland; Alessandro
patients and families who traveled from all parts Serra; and Zhong I. Wang (my fi nal and most
of the world to visit the author’s laboratory for eye- prolific graduate student).
movement recordings, diagnoses, and therapeutic I am especially indebted to Ann Rutledge,
recommendations to their referring physicians. my “secret weapon” who, for the past 16 years,
I am indebted to my many colleagues and insulated me from the ever-increasing adminis-
students for their valuable contributions (both trative intrusions and overzealous committees
indirect, through their research and our long- imposing inane regulations on principal investi-
term collaborations, and direct, during the prep- gators that today stifle innovative research. Such
aration of this book). I have had the privilege intrusions destroy the uninterrupted “think
and pleasure of collaborating with many excel- time” required for a researcher to immerse him-
lent scholars; they are the silent authors, with- self in the work; because of my temperament and
out whose contributions and collaborations this inability to “go along” with irrationality, Ann
monograph would not have been possible. The was the single most important factor allowing
following people played key roles in my research me to maintain the focus I needed.

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contents

1. Relevant Anatomy and Physiology 1 2. Infantile Nystagmus Syndrome 21

1.1 INFRA NUCLEAR OCULAR 2.1 CHARACTERISTICS OF INFANTILE
MOTOR ANATOMY 1 NYSTAGMUS SYNDROME 24
1.1.1 Extraocular Muscles 1 2.1.1 History and Background 24
1.1.2 Extraocular Muscle Pulleys 4 2.1.1.1 Ancient Descriptions and
1.1.3 Orbital Tissues 6 Theories 24
1.1.4 Extraocular Muscle/Orbit Nervous 2.1.1.2 Connection to Fixation
Anatomy 6 Attempt 25
1.2 SUPRA NUCLEAR OCULAR MOTOR 2.1.1.3 Modern Physiological
ANATOMY 8 Investigation 26
1.2.1 Frontal Eye Fields 8 2.1.2 Waveforms, Models, and
1.2.2 Superior Colliculus 9 Mechanisms 26
1.2.3 Brainstem Control of Eye 2.1.2.1 Waveform Types 27
Movements 10 2.1.2.2 Braking and Foveating
1.2.4 Vestibular Nuclei 10 Saccades 35
1.2.5 Cerebellum 11 2.1.2.3 The Foveation Period 35
1.3 AFFERENT SYSTEM 12 2.1.2.4 Foveation Accuracy 35
1.3.1 Retina 12 2.1.2.5 Target Acquisition Time 36
1.3.2 Optic Nerve 13 2.1.2.6 Smooth Pursuit 36
1.3.3 Lateral Geniculate 14 2.1.3 The Static Neutral Zone/Region 39
1.3.4 Geniculostriate 14 2.1.3.1 Latent Component 40
1.3.5 Association Cortex 14 2.1.4 The Dynamic Neutral Zone/Region 40
1.3.6 Ocular Motor Proprioception 14 2.1.4.1 Asymmetric, (a)Periodic
1.4 EFFERENT SYSTEM 15 Alternation 42
1.4.1 Smooth Pursuit System 15 2.1.4.2 Optokinetic, Pursuit, and
1.4.2 Saccadic System 15 Vestibulo-Ocular Responses 44
1.4.3 Vergence System 15 2.1.5 The Null Angle/Zone/Region 46
1.4.4 Vestibulo-Ocular System 16 2.1.6 The Convergence Null 48

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2.1.7 The Saccadic Response 50 2.3.2 Dynamic Deficits 73

2.1.8 Static and Dynamic Head Posturing 51 2.3.2.1 Target Acquisition Time
2.1.9 Foveation and Visual Acuity (High (Stationary Targets) 73
Spatial Frequency Vision) 52 2.3.2.2 Target Acquisition Time
2.1.9.1 The eXpanded Nystagmus Acuity (Moving Targets) 73
Function 53 2.3.3 Clinical 75
2.1.10 Oscillopsia Suppression 54 2.3.3.1 Visual Acuity at Different Gaze
2.1.10.1 Foveation Dynamics 55 Angles 77
2.1.10.2 Temporal Sampling 55 2.4 TREATMENTS OF INFANTILE
2.1.10.3 Efference Copy 56 NYSTAGMUS SYNDROME 77
2.1.11 Afferent Stimulation 56 2.4.1 Goals 77
2.1.11.1 Cutaneous Trigeminal 2.4.2 Nonsurgical 78
Stimulation 57 2.4.2.1 Prisms 78
2.1.11.2 Deep Muscle Stimulation 57 2.4.2.2 Contact Lenses 78
2.1.11.3 Contact Lenses 57 2.4.2.3 Drugs 80
2.1.11.4 Biofeedback 57 2.4.2.4 Gene-Transfer Therapy 80
2.1.12 Canine Nystagmus (Achiasmatic 2.4.2.5 Biofeedback 81
Belgian Sheepdog) 57 2.4.3 Surgical 81
2.1.12.1 Seesaw 58 2.4.3.1 Four-Muscle Resection and
2.1.12.2 Pendular 58 Recession Procedure (Operation 1)
2.1.12.3 Tenotomy and Reattachment (Also Known as Kestenbaum,
Procedure 58 Anderson-Kestenbaum, or
2.1.13 Canine Model of Infantile Nystagmus Anderson Plus Goto) 84
Syndrome with RPE65 Retinal 2.4.3.2 Two-Muscle Recession Procedure
Degeneration (Briard) 60 (Operation 1A) (Also Known as
2.2 ETIOLOGY OF INFANTILE Anderson) 85
NYSTAGMUS SYNDROME 60 2.4.3.3 Bilateral Medial Rectus Recession
2.2.1 Familial (Gene Defect) 61 Procedure (Operation 8) (Also
2.2.2 Developmental Disturbance of Ocular Known as Bimedial Recession) 86
Motor System with Associated Sensory 2.4.3.4 Tenotomy and Reattachment
System Deficit 64 Procedure (Operation 6) 86
2.2.2.1 Albinism 66
2.2.2.2 Achiasma 67
3. Fusion Maldevelopment Nystagmus
2.2.2.3 Infantile Strabismus 67
Syndrome 103
2.2.2.4 Nonvectorial Visual Sensory
Deficits 68 3.1 CHARACTERISTICS OF FUSION
2.2.3 The Direct Cause(s) of Infantile MALDEVELOPMENT NYSTAGMUS
Nystagmus Syndrome with or without SYNDROME 104
Sensory/Genetic Deficits 68 3.1.1 Waveforms, Models, and
2.2.3.1 Loss of Smooth-Pursuit Damping 68 Mechanisms 104
2.2.3.2 Tonic Visual Vestibular 3.1.1.1 Types (Fusion Maldevelopment
Imbalance 70 Nystagmus Plus Nucleus of the
2.3 VISUAL FUNCTION DEFICITS AND Optic Tract) 105
MEASUREMENTS OF INFANTILE 3.1.1.2 The Fixating Eye 105
NYSTAGMUS SYNDROME 70 3.1.1.3 Target Foveation and Dual-Mode
2.3.1 Static Deficits 70 Fast Phases 108
2.3.1.1 The eXpanded Nystagmus Acuity 3.1.1.4 Foveation Accuracy 111
Function and Longest Foveation 3.1.2 Variation with Gaze Angle 112
Domain Measures 70 3.1.3 Head Position 112

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3.1.4 Foveation, eXpanded Nystagmus Acuity 4.2.1.3 Head Nodding 131

Function, and Acuity 114 4.2.2 Treatment of Spasmus Nutans
3.1.5 Efference Copy, Foveation, and Syndrome 132
Oscillopsia Suppression 114
3.2 ETIOLOGY OF FUSION 5. Differential Diagnosis of Nystagmus in
MALDEVELOPMENT NYSTAGMUS Infancy and Childhood 135
SYNDROME 115
3.2.1 Familial (Gene Defect) 115 5.1 NYSTAGMUS WITHOUT
3.2.1.1 Down Syndrome 116 ASSOCIATED NEUROLOGICAL
3.2.2 Optokinetic Asymmetry 116 DISEASE—“BENIGN” 136
3.2.3 Egocentric Direction Confusion 116 5.1.1 Infantile Nystagmus Syndrome 136
3.3 TREATMENTS OF FUSION 5.1.1.1 Association with Strabismus 140
MALDEVELOPMENT NYSTAGMUS 5.1.1.2 Clinical Signs and Symptoms 141
SYNDROME 118 5.1.1.3 Differential Diagnosis 142
3.3.1 Fixation Preference 118 5.1.1.4 Alternate-Cover and Gaze-Angle-
3.3.2 Alexander’s Law 118 Cover Tests 142
3.3.3 Eye-Muscle Surgery 118 5.1.2 Fusion Maldevelopment Nystagmus
Syndrome 145
5.1.2.1 Association with Strabismus 145
5.1.2.2 Clinical Signs and Symptoms 145
4. Other Types of Nystagmus of
5.1.2.3 Differential Diagnosis 146
Infancy 122
5.1.2.4 Alternate-Cover and Gaze-Angle-
4.1 NYSTAGMUS BLOCKAGE Cover Tests 147
SYNDROME 122 5.1.3 Nystagmus Blockage Syndrome 147
4.1.1 Characteristics of Nystagmus Blockage 5.1.3.1 Association with Strabismus 147
Syndrome 123 5.1.3.2 Clinical Signs and Symptoms 147
4.1.1.1 Multiple Types of Nystagmus 123 5.1.3.3 Differential Diagnosis 148
4.1.1.2 Waveforms and Mechanisms 123 5.1.4 Spasmus Nutans Syndrome 148
4.1.1.2.1 Target Foveation 123 5.1.4.1 Association with Strabismus 148
4.1.1.2.2 Foveation Accuracy 123 5.1.4.2 Clinical Signs and Symptoms 148
4.1.1.3 Purposive Esotropia 123 5.1.4.3 Differential Diagnosis 149
4.1.1.4 Head Position 124 5.1.5 Nystagmus and Strabismus 150
4.1.1.5 Blockage Syndrome Types I 5.2 NYSTAGMUS WITH
and II 124 ASSOCIATED NEUROLOGICAL
4.1.1.6 Foveation, eXpanded Nystagmus DISEASE—“SYMPTOMATIC” 150
Acuity Function, and Acuity 126 5.2.1 Vestibular Nystagmus 150
4.1.1.7 Efference Copy, Foveation, and 5.2.1.1 Peripheral Vestibular
Oscillopsia Suppression 127 Imbalance 150
4.1.2 Treatments of Nystagmus Blockage 5.2.1.2 Central Vestibular Imbalance 153
Syndrome 127 5.2.1.3 Central Vestibular Instability
4.1.2.1 Fixation Preference 129 (Periodic Alternating) 155
4.1.2.2 Alexander’s Law 129 5.2.2 Gaze-Holding Deficiency
4.1.2.3 Surgical 129 Nystagmus 156
4.1.2.3.1 Fixating Eye 129 5.2.2.1 Eccentric Gaze, Gaze-Evoked,
4.2 SPASMUS NUTANS SYNDROME 129 Rebound 156
4.2.1 Characteristics of Spasmus Nutans 5.2.2.2 Gaze Instability (“Runaway”) 157
Syndrome 129 5.2.3 “Vision-Loss” Nystagmus 158
4.2.1.1 Waveforms and Mechanisms 130 5.2.3.1 Prechiasmal, Optic Chiasm,
4.2.1.2 Variable Interocular Phase 131 Postchiasmal Vision Loss 158

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5.2.4 Other Pendular Nystagmus Associated 6.1.7 Visual Field Testing 193
with Diseases of Central Myelin 158 6.2 OBJECTIVE TESTING 194
5.2.4.1 Oculopalatal Tremor or 6.2.1 Visual Evoked Potentials 194
“Myoclonus” 159 6.2.2 Electroretinography 197
5.2.4.2 Pendular Vergence Nystagmus 6.2.3 Optical Coherence
Associated with Whipple Tomography 200
Disease 160 6.2.4 Fundus Photography 202
5.2.5 Convergence/Convergence-Evoked
Nystagmus 160
5.2.6 Upbeat Nystagmus 161 7. Treatment 205
5.2.7 Downbeat Nystagmus 161 7.1 MEDICAL 206
5.2.8 Torsional Nystagmus 162 7.1.1 Optical 207
5.2.9 “Seesaw” Nystagmus 162 7.1.1.1 Version Prisms 209
5.2.10 Lid Nystagmus 163 7.1.1.2 Vergence Prisms 209
5.3 SACCADIC INTRUSIONS/ 7.1.1.3 Contact Lenses 210
OSCILLATIONS 164 7.1.1.4 Correction of Ammetropia/
5.3.1 Square-Wave Jerks and Oscillations 165 Anisometropia 212
5.3.2 Square-Wave Pulses 167 7.1.1.5 Intraocular Lenses 213
5.3.3 Staircase Saccadic Intrusions 167 7.1.1.6 Refractive Surgery 213
5.3.4 Macrosaccadic Oscillations 169 7.1.2 Pharmacological 213
5.3.5 Saccadic Pulses (Single and 7.1.3 Botulinum 214
Double) 169 7.2 EYE-MUSCLE SURGERY 215
5.3.6 Convergence Retraction 7.2.1 General Principles 215
“Nystagmus” 171 7.2.2 Classification 218
5.3.7 Dissociated Ocular Oscillations 172 7.2.3 Preoperative Evaluation 228
5.3.8 Dysmetric Saccades 172 7.2.3.1 Visual Acuity 228
5.3.9 Ocular Flutter 172 7.2.3.2 Ocular Motor and Standard Clinical
5.3.10 Flutter Dysmetria 173 Evaluations 228
5.3.11 Opsoclonus 173 7.2.3.3 Strabismus 228
5.3.11.1 Opsoclonus-Myoclonus 173 7.2.3.4 Eye-Movement Recordings 228
5.3.12 Superior Oblique Myokymia 173 7.2.3.5 Head-Posture Measurements (“Null
5.3.13 Ocular Bobbing 174 Zones”) 229
5.3.13.1 Typical 174 7.2.3.6 Laboratory and Special Tests 230
5.3.13.2 Monocular 175 7.2.4 Results 230
5.3.13.3 Atypical 175 7.2.4.1 Visual Acuity 230
5.3.14 Psychogenic (Voluntary) Flutter 175 7.2.4.2 Strabismus 231
7.2.4.3 Eye-Movement Recordings 232
7.2.4.4 Head-Posture Measurements 232
6. Afferent Visual System—Clinical
7.2.5 Complications 232
Examination Procedures 185
7.3 OTHER 234
6.1 SUBJECTIVE TESTING 185 7.3.1 Biofeedback 234
6.1.1 Teller Acuity Card Procedure 185 7.3.2 Acupuncture 234
6.1.2 Visual Acuity Testing (High Spatial 7.3.3 Cutaneous Stimulation 234
Frequency Vision) 187 7.3.4 Gene-Transfer Therapy 234
6.1.3 Stereo Testing 187 7.3.5 Mind-Body Stress Reduction:
6.1.4 Color-Vision Testing 190 Mindfulness Meditation
6.1.5 Contrast-Sensitivity Testing 191 Techniques 235
6.1.6 Gaze- and Time-Dependent Acuity 7.3.6 Occupational and Vision Therapy 236
Testing 192 7.3.7 Educational Assistance 236

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7.4 ASSESSING THERA PEUTIC A.1 RECORDING METHODS 263

OUTCOMES (POST-THERA PY) 237 A.1.1 Contact Electrooculography 263
7.4.1 Direct Outcome Measures (eXpanded A.1.2 Infrared Reflection 264
Nystagmus Acuity Function, Longest A.1.3 Scleral Search Coil 265
Foveation Domain, and Target A.1.4 High-Speed Video
Acquisition Time) 237 Oculography 266
7.4.1.1 Post-Tenotomy and A.2 RESEARCH CRITERIA 268
Reattachment 238 A.3 CLINICAL CRITERIA 268
7.4.1.2 Post-Convergence/Bimedial Rectus A.4 CALIBRATION TECHNIQUES 268
Recession 238 A.4.1 Adults and Children 268
7.4.1.3 Post-Kestenbaum or Anderson A.4.1.1 Infantile Nystagmus 269
Plus Tenotomy and A.4.1.2 Fusion Maldevelopment
Reattachment 238 Nystagmus 269
7.4.1.4 Soft Contact Lenses 239 A.4.2 Infants 269
7.4.1.5 Systemic Acetazolamide and Topical
Brinzolamide 239
7.4.2 Indirect/Clinical Outcome Appendix B. Clinical Examination 271
Measures 239 B.1 GENERA L CLINICAL EXAMINATION
7.4.2.1 Visual Acuity at Different Gaze FORM 272
Angles 240 B.2 STRA BISMUS EXAMINATION
7.5 ESTIMATING THERA PEUTIC FORM 276
OUTCOMES (PRE-THERA PY) 240 B.3 NYSTAGMUS EXAMINATION
7.5.1 Direct Outcome Measures (eXpanded FORM 277
Nystagmus Acuity Function, Longest
B.4 CLINICAL PEARLS 277
Foveation Domain, and Target
B.5 OPHTHALMOLOGICAL MYTHS AND
Acquisition Time) 240
FACTS 279
7.5.1.1 Tenotomy and Reatt achment
(Infantile Nystagmus Syndrome
without Afferent Visual Appendix C. Illustrative Cases and
Deficits) 241 Treatment 280
7.5.1.2 Tenotomy and Reatt achment
(Infantile Nystagmus Syndrome C.1 INFANTILE NYSTAGMUS
with Afferent Visual Deficits) 243 SYNDROME 281
7.5.1.3 Prisms/Bimedial Rectus C.1.1 Gaze-Angle Null Only 281
Recession 243 C.1.1.1 Version Prisms 281
7.5.1.4 Soft Contact Lenses 244 C.1.1.2 Soft Contact Lenses 281
7.5.2 Indirect/Clinical Outcome C.1.1.3 Four-Muscle Resection,
Measures 244 Recession, and Tenotomy and
7.5.2.1 Visual Acuity at Different Gaze Reattachment 281
Angles 244 C.1.1.3.1 Fine Tuning with
Prisms 281
C.1.1.3.2 Soft Contact Lenses 281
8. Summary and Conclusions 253 C.1.2 Convergence Null Only 281
C.1.2.1 Vergence Prisms with Negative
Spheres 282
Epilogue 257 C.1.2.2 Soft Contact Lenses 282
C.1.2.3 Bimedial Recession 282
Appendices 259 C.1.3 Both Gaze-Angle and Convergence
Appendix A. Eye-Movement Recording Nulls 282
Systems and Criteria 259 C.1.3.1 Convergence > Gaze-Angle 282

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C.1.3.1.1 Composite Prisms and Appendix D. Diagnosis and Treatment

Negative Spheres 282 Flowcharts 288
C.1.3.1.2 Base-Out Prisms and Negative
D.1 WAVEFORM-BASED DIAGNOSES 288
Spheres 283
D.2 THERA PEUTICALLY EXPLOITABLE
C.1.3.1.3 Soft Contact Lenses 283
WAVEFORM CHARACTERISTICS 288
C.1.3.1.4 Bimedial Recession 283
C.1.3.2 Gaze-Angle > D.3 CLINICALLY BASED DIAGNOSES
Convergence 283 AND LIMITATIONS 288
C.1.3.2.1 Version Prisms 283 D.4 EXPLOITABLE CLINICAL
C.1.3.2.2 Soft Contact Lenses 283 CHARACTERISTICS 288
C.1.3.2.3 Four-Muscle Resection, D.5 ANALYSIS GRA PHS 293
Recession, and Tenotomy and
Reattachment 283 Appendix E. Online Access Videos 294
C.1.4 No Nulls 283
C.1.4.1 Soft Contact Lenses 283 E.1 “EYEBALLS 3D” EYE-MOTION AND
C.1.4.2 Four-Muscle Tenotomy and WAVEFORM VIDEOS 296
Reattachment 283 MV1 Infantile Nystagmus Syndrome (Pseudo
C.1.4.2.1 Tenotomy and Reatt achment Pendular with Foveating Saccades) 1
with Augmented Tendon Cycle 1/20-Speed Illustrating Foveation
Suture 284 Period 296
C.1.4.2.2 Augmented Tendon Suture MV2 Infantile Nystagmus Syndrome (Jerk
Procedure sans Tenotomy and with Extended Foveation) 4 Cycles 1/
Reattachment 284 3-Speed with Phase Plane 296
C.1.4.3 Faden 284 MV3 Infantile Nystagmus Syndrome (Pseudo
C.2 INFANTILE NYSTAGMUS PLUS Pendular with Foveating Saccades) 3
Cycles 1/2-Speed Illustrating Well-
STRA BISMUS 284
Developed Foveation 296
C.2.1 Gaze-Angle Null Only 284
MV4 Infantile Nystagmus Syndrome
C.2.1.1 Four-Muscle Resection,
(Pseudo Pendular with Foveating
Recession, and Tenotomy and
Saccades) 3 Cycles 1/5-Speed with
Reattachment 284
Phase Plane 297
C.2.2 Vertical and Torsional
MV5 Infantile Nystagmus Syndrome (Pseudo
Nulls 284
Pendular with Foveating Saccades) 1/2-
C.2.3 No Nulls 286
Speed Th ree-Dimensional Motion with
C.2.3.1 Four-Muscle Tenotomy
Subclinical Seesaw Nystagmus 297
and Reattachment and
MV6 Infantile Nystagmus Syndrome 1/5-
Strabismus 286
Speed Subclinical Seesaw Nystagmus
C.3 FUSION MALDEVELOPMENT
Motion Amplified 297
NYSTAGMUS SYNDROME 286 MV7 Infantile Nystagmus Syndrome (Pseudo
C.3.1 Uniocular Fixation 286 Pendular with Foveating Saccades) 1/2-
C.3.2 Alternating Fixation 286 Speed from Ocular Motor System Model
C.3.3 Alexander’s Law Th reshold 286 and Patient 297
C.4 NYSTAGMUS BLOCKAGE MV8 Infantile Nystagmus Syndrome
SYNDROME 287 (Pendular with Foveating Saccades)
C.4.1 Bimedial Recession (Plus Tenotomy and Step Responses Ocular Motor System
Reattachment) 287 Model 297
C.4.2 Recession and Resection Plus Tenotomy MV9 Infantile Nystagmus Syndrome (Pseudo
and Reattachment 287 Pendular with Foveating Saccades) 1/2-
C.4.3 Four-Muscle Tenotomy and Speed Pulse Responses Ocular Motor
Reattachment 287 System Model 297

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MV10 Infantile Nystagmus Syndrome E.1.2 Infantile Nystagmus Syndrome

(Pseudo Pendular with Foveating Latency 299
Saccades) 1/2-Speed Ocular Motor E.1.3 Infantile Nystagmus Syndrome Latency
System Model Ramp and Step-Ramp Poster 299
Responses 297 E.1.4 Infantile Nystagmus Syndrome Model
MV11 Fusion Maldevelopment Nystagmus Poster 300
Syndrome Gaze-Angle Effect Ocular E.2 CANINE VIDEOS (PLUS
Motor System Model 297 OTHERS) 300
MV12 Fusion Maldevelopment Nystagmus CV1 Normal Brittany 300
Syndrome 1/2-Speed Alternate Cover CV2 Achiasmatic Belgian Sheepdog: Pre-
Test Ocular Motor System Model 298 Tenotomy and Reattachment 300
MV13 Fusion Maldevelopment Nystagmus CV3 Achiasmatic Belgian Sheepdog:
Syndrome Adducting Eye Fixation Post-Tenotomy and
Ocular Motor System Model 298 Reattachment 300
MV14 Infantile Nystagmus Syndrome CV4 RPE65-Deficient Canine: Pre-Gene-
Damping with Rapid Therapy Behavior 300
Convergence 298 CV5 RPE65-Deficient Canine: Post-Gene-
MV15 Infantile Nystagmus Syndrome Therapy Behavior 300
1/2-Speed Pre-Tenotomy and CV6 RPE65-Deficient Canine: Pre-Gene-
Reattachment 298 Therapy Eye Movements 301
MV16 Infantile Nystagmus Syndrome CV7 RPE65-Deficient Canine: Post-Gene-
1/2-Speed Post-Tenotomy and Therapy Eye Movements 301
Reattachment 298 CV8 Cat with Infantile Nystagmus 301
MV17 Infantile Nystagmus Syndrome 1/2- CV9 Goat with Seesaw Nystagmus 301
Speed RPE65-Deficient Canine Pre- KeyNote and PowerPoint Files 301
Gene Therapy 298 E.3 PATIENT VIDEOS 301
MV18 Infantile Nystagmus Syndrome 1/2- PV1 Saccadic Initiation Failure 301
Speed RPE65-Deficient Canine Post- PV2 Brainstem Tumor: Tonic Gaze
Gene-Therapy Scan Path 298 Deviation 301
MV19 Infantile Nystagmus Syndrome 1/2- PV3 Acquired Downbeat Nystagmus 301
Speed RPE65-Deficient Canine Post- PV4 Acquired Gaze-Evoked (Gaze-Holding
Gene-Therapy 298 Failure) Nystagmus 301
MV20 Infantile Nystagmus Syndrome 1/2- PV5 Acquired Unidirectional Gaze-Evoked
Speed RPE65-Deficient Canine Post-
(Gaze-Holding Failure) Nystagmus 301
Gene-Therapy Scan Path 298 PV6 Ocular Motor Neuromyotonia of Cranial
MV21 Oscillopsia Simulation 298 Nerve III 301
MV22 Uniocular Acquired Pendular PV7 Ocular Motor Neuromyotonia of Cranial
Nystagmus Pre- and
Nerve VI 302
Post-Therapy 298
PV8 Infant with Opsoclonus (Ocular
MV23 Infantile Nystagmus Syndrome
Flutter—“Saccadomania”) 302
(Alternating Jerk) Ocular Motor
PV9 Acquired Saccadic Oscillations-1 302
System Model 299
PV10 Acquired Saccadic Oscillations-2 302
MV24 Flutter 299
PV11Acquired Saccadic Oscillations-3 302
MV25 Flutter in a Blind Patient 299
PV12 Acquired Nystagmus Plus Saccadic
MV26 Psychogenic Flutter 299
Oscillations 302
MV27 Square-Wave Jerks 299 PV13 Acquired Upbeat Nystagmus with
MV28 Opsoclonus 299 Wiernecke Encephalopathy 302
KeyNote and PowerPoint Files 299 PV14 Acquired Vertical Pendular
E.1.1 Infantile Nystagmus Syndrome Dynamic Nystagmus 303
Visual Acuity 299

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PV15 Fusion Maldevelopment PV40 Albinism, Upgaze Null, and Infantile

Nystagmus-1 303 Nystagmus 306
PV16 Fusion Maldevelopment PV41 Albinism and Infantile Nystagmus 306
Nystagmus-2 303 PV42 “Vertical” Infantile Nystagmus-1 306
PV17 Down Syndrome and Infantile PV43 Retinal Dystrophy and “Vertical”
Nystagmus 303 Infantile Nystagmus-2 307
PV18 Achiasma Plus Seesaw Nystagmus Plus PV44 Spasmus Nutans Nystagmus-1 307
Infantile Nystagmus 303 PV45 Spasmus Nutans Nystagmus-2 307
PV19 Octogenarian with Infantile PV46 Voluntary Ocular Flutter 307
Nystagmus 303 E.4 HISTORICAL 307
PV20 Infantile Nystagmus: Aperiodically E.4.1 Demonstration of Bias and Bias Shift in
Changing Intensity (Not Infantile Nystagmus Waveforms 307
Direction) 303 E.4.2 Demonstration that Cutaneous
PV21 Infantile Nystagmus: Aperiodically Stimulation Damps Infantile
Changing Direction (Not Nystagmus 307
Intensity) 303 E.4.3 First Canine Eye-Movement
PV22 Infantile Nystagmus: Unequal-1 304 Recording 307
PV23 Infantile Nystagmus: Unequal-2 304 E.4.4 First Tenotomy and Reattachment
PV24 Infantile Nystagmus: Unequal-3 304 Surgery for Infantile Nystagmus 308
PV25 Infantile Nystagmus: Jerk with
Extended Foveation 304
PV26 Infantile Plus Nucleus of the Optic Tract Appendix F. Online Access 309
Nystagmus: Dual Jerk 304 F.1 OMLAB REPORTS 309
PV27 Infantile Nystagmus: Pre- and F.1.1 #011105 Recording and Calibrating
Postoperative 304 the Eye Movements of Nystagmus
PV28 Optic Nerve Dysplasia and Infantile Subjects 310
Nystagmus: Multiplanar 304 F.1.2 #111005 Using the eXpanded Nystagmus
PV29 Infantile Nystagmus: Jerk with Acuity Function for Eye-Movement
Extended Foveation 305 Fixation Data Analysis and Display 310
PV30 Infantile Nystagmus: Unequal with a F.1.3 #111905 Nystagmus Therapies: Types,
“Latent Component” 305 Sites, and Measures 310
PV31 Albinism and Infantile F.1.4 #090506 Original Ocular Motor Analysis
Nystagmus 305 of the First Human with Achiasma:
PV32 Optic Nerve Dysplasia and Infantile Documentation of Work Done in
Nystagmus: Multiplanar 305 1994 310
PV33 Albinism, Upgaze Null, and Infantile F.1.5 #123007 The Benefits of Extraocular
Nystagmus: Equal 305 Muscle Surgery in Infantile Nystagmus
PV34 Retinal Dystrophy and Infantile Syndrome 310
Nystagmus: Multiplanar 305 F.1.6 #030509 How Someone “Sees” the World
PV35 Albinism and Infantile Nystagmus: Pre- and How to Clinically Assess Therapeutic
and Postoperative Horizontal Null 305 Improvements in Visual Function 310
PV36 Albinism and Infantile Nystagmus: F.2 PATIENT HANDOUTS 310
Multiplanar 306 F.2.1 Infantile Nystagmus Syndrome
PV37 Infantile Nystagmus: Periodic Information 310
Alternating 306 F.2.2 Infantile Nystagmus Syndrome
PV38 Infantile Nystagmus: Asymmetric Treatments 310
Aperiodic Alternating 306 F.2.3 Tenotomy and Reattachment 310
PV39 Albinism and Infantile Nystagmus: Pre- F.2.4 Infantile Nystagmus Syndrome and
and Postoperative Vertical Null 306 Acuity 310

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F.2.5 INS Miscellaneous 310 F.4 CLINICAL EXAMINATION

F.3 PHYSICIAN/RESEARCH SCIENTIST FORMS 311
WORKSHEETS 310 F.4.1 General Clinical Examination
F.3.1 Recession and Resection Surgical Form 311
Calculation 310 F.4.2 Strabismus Examination Form 311
F.3.2 Estimating Improvement in Peak F.4.3 Nystagmus Examination Form 311
eXpanded Nystagmus Acuity F.5 ANALYSIS SOFTWARE 311
Function 311 F.5.1 OMtools 311
F.3.3 Estimating Improvement in Longest F.5.2 Ocular Motor System Model GUI User
Foveation Domain 311 Guide 311
F.3.4 eXpanded Nystagmus Acuity Function
versus Visual Acuity (Motor and Sensory
Components) 311 Index 313

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1
relevant anatomy and physiology
1.1 INFRA NUCLEAR OCULAR MOTOR 1.2.5 Cerebellum 11
ANATOMY 1 1.3 AFFERENT SYSTEM 12
1.1.1 Extraocular Muscles 1 1.3.1 Retina 12
1.1.2 Extraocular Muscle Pulleys 4 1.3.2 Optic Nerve 13
1.1.3 Orbital Tissues 6 1.3.3 Lateral Geniculate 14
1.1.4 Extraocular Muscle/Orbit Nervous 1.3.4 Geniculostriate 14
Anatomy 6 1.3.5 Association Cortex 14
1.2 SUPRA NUCLEAR OCULAR MOTOR 1.3.6 Ocular Motor Proprioception 14
ANATOMY 8 1.4 EFFERENT SYSTEM 15
1.2.1 Frontal Eye Fields 8 1.4.1 Smooth Pursuit System 15
1.2.2 Superior Colliculus 9 1.4.2 Saccadic System 15
1.2.3 Brainstem Control of Eye 1.4.3 Vergence System 15
Movements 10 1.4.4 Vestibulo-Ocular System 16
1.2.4 Vestibular Nuclei 10

The ocular motor system can make the eyes do anything it wants to.
—Bert L. Zuber (circa 1972)

EY E MOV EM ENTS bring visual stimuli origin are characterized by gaze palsies, tonic
to the fovea and also maintain foveal fi xation gaze deviation, saccadic and smooth pursuit dis-
of stationary and moving targets during head orders, vergence abnormalities, nystagmus, and
movements. These movements are performed saccadic oscillations. Supranuclear disorders
by the ocular motor system that consists of ocu- such as nystagmus in infancy and childhood
lar motor nerves and nuclei in the brainstem result from lesions above the level of the ocular
originating in the cerebral cortex, cerebellum, motor nerve nuclei.
vestibular structures, and the extraocular mus-
cles. Anatomically, the ocular motor system
1.1 INFRANUCLEAR OCULAR
may be divided according to location into infra-
MOTOR ANATOMY
nuclear, nuclear, internuclear, and supranuclear
components. It is important to distinguish
1.1.1 Extraocular Muscles
between supranuclear, internuclear, nuclear,
and infranuclear (orbital, cranial nerves) disor- The insertions of the rectus muscles extend from
ders because the disturbances have highly var- the equator of the eye to the limbus early on
ied causes and present different clinical pictures. in development. By processes of disparate dif-
Eye-movement abnormalities of supranuclear ferentiation between the sclera and the rectus

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tendon, posterior recession of the tendon from fashion (the annulus of Zinn), surrounding the
the limbus, and contemporaneous growth of optic canal and in part the superior orbital fis-
the anterior segment of the eye, these tendons sure. Th rough this oval opening created by the
reach their adult location only between the ages origins of the muscles, the optic nerve, the oph-
of 18 months and 2 years.1,2 The tendons of ori- thalmic artery, and parts of cranial nerves III
gin and insertion of the extraocular muscles and VI enter the muscle cone formed by the
arise from mesenchymal tissue similar to that of body of the rectus muscles. The interlocking of
their respective muscles. These tendon-muscle muscle and tendon fibers at the site of origin
groups have developed from superior and infe- creates an extremely strong anchoring of the
rior mesenchymal complexes. In humans there extraocular muscles. Attachments exist between
are three pairs of extraocular muscles in each the origins of the medial and superior recti and
orbit: a pair of horizontal rectus muscles, a pair the dura of the optic nerve. The medial and lat-
of vertical rectus muscles, and a pair of oblique eral rectus muscles follow the corresponding
muscles. 3 The four rectus muscles are attached walls of the orbit for a good part of their course,
to the sclera anterior to the equator near the and the inferior rectus muscle remains in con-
cornea (see Fig. 1.1). The two oblique muscles tact with the orbital floor for only about half its
approach the globe from in front, at the medial length. The superior rectus muscle is separated
side of the orbit, and continue obliquely and from the roof of the orbit by the levator muscle
laterally to insert on the sclera posterior to the of the upper lid. If the rectus muscles were to
equator on the temporal part of the globe. The continue their course in their original direction,
rectus muscles are almost flat narrow bands that they would not touch the globe; at about 10 mm
attach themselves with broad, thin tendons to posterior to the equator, the muscle paths curve
the globe. There are four of these muscles: the toward the globe rather abruptly and eventually
medial, lateral, superior, and inferior. The ori- insert on the sclera at varying distances from
gins of the rectus muscles, the superior oblique the corneal limbus. The musculoorbital tissue
muscle, and the levator muscle of the upper connections (the muscle pulleys) are responsi-
lid are arranged in an approximately circular ble for their changes in course. The insertions

FIGURE 1.1 Orbital structures controlling eye movements. Parasagitt al section of the orbit showing
bones, extraocular muscles, and cranial nerve III (CN III) of the orbit. CG, ciliary ganglion; ID CN III, infe-
rior division of cranial nerve III; IO, inferior oblique; IR, inferior rectus; LP, levator palpebrae superioris;
LR, cut ends of lateral rectus; MR, medial rectus; ON, optic nerve; SD CN III, superior division of cranial
nerve III; SO, superior oblique; SR, superior rectus.

2 • R E L E VA N T A N A T O M Y A N D P H Y S I O L O G Y

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of the rectus muscles do not lie on a circle that the tendon moves through the trochlea in a slid-
is concentric with it but rather on a spiral (the ing, telescoping fashion with the central fibers
spiral of Tillaux). The insertion of the medial undergoing maximal excursion and the periph-
rectus muscle is closest to the corneal limbus, eral fibers the least excursion. The total travel of
followed by the inferior, lateral, and superior the central fibers appears to be 8 mm in either
rectus insertions, with the superior rectus inser- direction. A bursa-like structure lies between
tion being the most distant. The lines of inser- the trochlear “saddle” and the vascular sheath of
tion are generally not straight; they are curved the superior oblique tendon. At about the distal
and sometimes even wavy. The straightest ones third of the direct portion (10 mm behind the
are the insertions of the medial and lateral rec- trochlea), the muscle becomes tendinous and
tus muscles, but these too are often slightly con- remains tendinous in its entire postt rochlear
vex toward the corneal limbus. The distance of or reflected part. The tendon passes under the
the tendon from the limbus may be influenced superior rectus muscle, fans out, and merges lat-
by age and axial length of the eye. erally with the sclera to the vertical meridian,
From its origin above and medial to the optic forming a concave curved line toward the troch-
foramen, the superior oblique courses anteri- lea. The anterior end of the insertion lies 3.0 to
orly in a line parallel with the upper part of the 4.5 mm behind the lateral end of the insertion of
medial wall of the orbit, reaching the trochlea at the superior rectus muscle and 13.8 mm behind
the angle between the superior and medial wall. the corneal limbus (see Fig. 1.2). The poste-
The trochlea is a tube 4 to 6 mm long formed in rior end of the insertion lies 13.6 mm behind
its medial aspect by bone (the trochlear fossa of the medial end of the insertion of the superior
the frontal bone). The rest of the circumference rectus muscle and 18.8 mm behind the corneal
is composed of connective tissue that may con- limbus. The width of the insertion of the supe-
tain cartilaginous or bony elements. After pass- rior oblique muscle varies greatly (from 7 to 18
ing the trochlea, the superior oblique muscle mm) but is 11 mm on average. The medial end of
turns in laterodorsally, forming an angle of about the insertion lies about 8 mm from the posterior
54° with the pretrochlear or direct portion of the pole of the globe. Near its insertion the poste-
muscle. A fibrillar, vascular sheath surrounds rior border of the muscle is related to the supe-
the intratrochlear superior oblique tendon. Th is rior vortex vein. The length of the direct part of
portion of the tendon consists of discrete fibers the superior oblique muscle is about 40 mm and
with few interfibrillar connections. Each fiber of that of the reflected tendon is about 19.5 mm.

FIGURE 1.2 Insertional anatomy of the extraocular muscles. All numbers are averages in millimeters.

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From a physiologic and kinematic standpoint, rectus muscles are the primary vertical mov-
the trochlea is the origin of the muscle. ers of the eye. The superior rectus acts as the
The inferior oblique muscle is the shortest primary elevator; the inferior rectus acts as
of all the eye muscles, being only 37 mm long. the primary depressor of the eye. This vertical
It arises in the anteroinferior angle of the bony action is greatest with the eye in the abducted
orbit in a shallow depression in the orbital plate of position. The direction of pull of the muscles
the maxilla near the lateral edge of the entrance forms a 23° angle relative to the visual axis in
into the nasolacrimal canal. The origin is read- the primary position, giving rise to secondary
ily located by drawing a perpendicular line from and tertiary functions. The secondary action
the supraorbital notch to the lower orbital mar- of vertical rectus muscles is torsion. The supe-
gin. The muscle continues from its origin back- rior rectus is an incyclotorter, and the inferior
ward, upward, and laterally, passing between the rectus is an excyclotorter. The tertiary action
floor of the orbit and the inferior rectus muscle. of both muscles is adduction. The superior
It inserts by a short tendon (1 to 2 mm) in the and inferior oblique muscles are the primary
posterior and external aspect of the sclera. The muscles of torsion. The superior oblique cre-
width of the insertion varies widely (5 to 14 mm) ates incyclotorsion, and the inferior oblique
and may be around 9 mm on average. The inser- creates excyclotrosion (Table 1.1).
tion forms a curved concave line toward the ori-
gin of the muscle. Its anterior margin is about 10
1.1.2 Extraocular Muscle Pulleys
mm behind the lower edge of the insertion of the
lateral rectus muscle; its posterior end is 1 mm Modern imaging techniques such as computed
below and 1 to 2 mm in front of the macula. Near tomography (CT) scanning and magnetic res-
its insertion, the posterior border of the muscle onance imaging (MRI) have revealed that the
is related to the inferior vortex vein. Unlike the paths of the rectus muscles remain fi xed relative
other extraocular muscles, the inferior oblique to the orbital wall during excursions of the globe
is almost wholly muscular. It forms an angle of and even after large surgical transpositions.4,5
about 51° with the vertical plane of the globe. There is no sideslip of the rectus muscles in rela-
The medial and lateral rectus muscles have tion to the orbital walls when the eye moves from
only horizontal actions. The medial rectus primary into secondary gaze positions. Demer
muscle is the primary adductor of the eye, and coworkers suspected from these fi ndings
and the lateral rectus muscle is the primary that there must be musculo-orbital coupling
abductor of the eye. The superior and inferior through tissue connections that constrain the

Table 1.1 Functions of the Extraocular Muscles

PR I M A RY S E C ON DA R Y TERTI A RY
M USCLE AC T ION AC T ION AC T ION
Medial rectus Adduction ––– –––
Lateral rectus Abduction ––– –––
Superior rectus Elevation Incyclotorsion Adduction
Inferior rectus Depression Excyclotorsion Adduction
Inferior oblique Excyclotorsion Elevation Abduction
Superior oblique Incyclotorsion Depression Abduction
Levator palpebrae Eyelid elevation ––– –––
The superior muscles are incyloductors; the inferior muscles, excycloductors. The vertical muscles are adductors; the oblique muscles,
adductors.

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muscle paths during rotations of the globe.4–10 nonhuman primates, and change their positions
Subsequent studies with high-resolution MRI as a function of gaze direction.4–10 For instance,
confi rmed this notion by demonstrating retro- the pulleys of the horizontal rectus muscle move
equatorial inflections of the rectus muscle paths. posteriorly during muscle contraction. Th is
Gross dissection of orbits and histological and adjustability of pulley positions and the differ-
histochemical studies showed that these inflec- ent insertion sites of the global and orbital lay-
tions are caused by musculo-orbital tissue con- ers of extraocular muscles may play a major but
nections in the form of fibroelastic sleeves that still undefi ned role in ocular kinematics. Several
consist of smooth muscle, collagen, and elastin. lines of evidence, MRI, CT, gross examinations,
During contraction the muscles travel through surgical exposures, and histological studies
these sleeves, which act as pulleys by restraining in humans and monkeys strongly suggest that
the muscle paths. The orbital layer of the rectus the orbital layer of each rectus muscle inserts
muscle inserts directly on the pulley, whereas on its corresponding pulley, rather than on the
the global layer continues anteriorly to insert globe.4–10 These anatomic differences in the two
into the sclera.4–10 As Figure 1.3 shows, these muscle layers suggest differences in their func-
pulleys are located in a coronal plane anterior tions: the orbital layer probably acts against the
to the muscle bellies and about 5 to 6 mm pos- continuous elastic load of the pulley suspension,
terior to the equator. They are compliant rather whereas the global layer acts against the inter-
than rigid, receive rich innervation involving mittent, viscous load of the antagonist extraocu-
numerous neurotransmitters in humans and lar muscle.

Pulley Ring
Pulley
Sling
Orbita al Layer

Orbitaal Layer
l Layer
r
l Laye

Smooth Muscle
b

Glob
Glo

Collagen

Elastin

Trochlea

LPS
SO
SR
LR
Pulley
Pulley Ring
MR
Sling

IO IO
IR
Orbital Layer

FIGURE 1.3 Anatomy of the extraocular muscle “pulley” system around the recti muscles. IR, inferior
oblique; IR, inferior rectus; LG, lacrimal gland; LPS, levator palpebrae superioris; LR, lateral rectus; LR-SR,
lateral rectus-superior rectus; MR, medial rectus; MR-IR, medial rectus-inferior rectus; MR-SR, medial
rectus-superior rectus; SR, superior rectus; SOT, superior oblique tendon.

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1.1.3 Orbital Tissues medial margin of the substantia nigra in a series

of curves and fi nally emerge from the oculo-
The eyeball is suspended within the orbit by a motor sulcus on the medial side of the cerebral
system of fasciae. The bulk of the system is made peduncle. The oculomotor nucleus lies in the
up of Tenon’s capsule, which is a condensation gray substance of the floor of the cerebral aque-
of fibrous tissue that covers the eyeball from the duct subjacent to the superior colliculus and
entrance of the optic nerve to near the corneal extends in front of the aqueduct a short distance
limbus, where it is fi rmly fused with the con- into the floor of the third ventricle. The inferior
junctiva. Except for this area of fusion, the two end is continuous with the trochlear nucleus. It
structures are separated by the subconjunctival is from 6 to 10 mm. The nucleus of the oculo-
space. Tenon’s capsule is also separated from the motor nerve contains several distinct groups of
sclera. Between the two is the episcleral space. cells that differ in size and appearance from each
On its outer aspect the capsule is intimately other and send their axons each to separate mus-
related to the orbital reticular tissue. Its poste- cles. Much uncertainty still exists as to which
rior edge is not clearly delineated; it is thin and group supplies which muscle. There are seven of
more or less continuous with the meshwork of these groups or nuclei on either side of the mid-
the orbital fat. In their extracapsular portions, line and one medial nucleus.13–16
the extrinsic eye muscles are enveloped by the The trochlear nerve (cranial nerve IV) con-
pulley system and muscle sheath.1,11 Th is sheath tains somatic motor fibers only. It supplies the
is a reflection of Tenon’s capsule and runs back- superior oblique muscle of the eye. Its nucleus
ward from the entrance of the muscles into the of origin, trochlear nucleus, is a small, oval mass
subcapsular space for a distance of 10 to 12 mm. situated in the ventral part of the central gray
At the lower aspect of the entrance, Tenon’s cap- matter of the cerebral aqueduct at the level of the
sule is reduplicated. At the upper aspect, it con- upper part of the inferior colliculus. The axons
tinues forward as a single membrane. The muscle from the nucleus pass downward in the tegmen-
sheaths of the four rectus muscles are connected tum toward the pons, but they turn abruptly
by a formation known as the intermuscular dorsalward before reaching it and pass into the
membrane, which closely relates these muscles superior medullary velum, in which they cross
to each other. In addition, there are numerous horizontally to decussate with the nerve of the
extensions from all the sheaths of the extraocu- opposite side; they emerge from the surface of
lar muscles, which form an intricate system of the velum, immediately behind the inferior col-
fibrous attachments interconnecting the mus- liculus. The nuclei of the two sides are separated
cles, attaching them to the orbit, supporting the by the raphé, through which dendrites extend
globe, and contributing to the pulley system.12 from one nucleus to the other.16–19
The trigeminal nerve (cranial nerve V) con-
tains somatic motor and somatic sensory fibers.
1.1.4 Extraocular Muscle/Orbit
The motor fibers arise in the motor nucleus of
Nervous Anatomy
the trigeminal and pass ventrolaterally through
The oculomotor nerve (cranial nerve III) con- the pons to supply the muscles of mastication.
tains somatic motor fibers to the levator palpe- The sensory fibers arise from the unipolar cells of
brae, inferior rectus, medical rectus, superior the semilunar ganglion; the peripheral branches
rectus, inferior oblique, and sympathetic effer- of the T-shaped fibers are distributed to the face
ent fibers (preganglionic fibers) to the ciliary and anterior two-thirds of the head; the central
ganglion. The postganglionic fibers connected fibers pass into the pons with the motor root
with these supply the ciliary muscle and the and bifurcate into ascending and descending
sphincter of the iris. The axons arise from the branches that terminate in the sensory nuclei
nucleus of the oculomotor nerve and pass in of the trigeminal ganglion. The motor nucleus
bundles through the posterior longitudinal bun- of the trigeminal is situated in the upper part of
dle, the tegmentum, the red nucleus, and the the pons beneath the lateral angle of the fourth

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ventricle. It is serially homologous with the above and with the hypoglossal and medial
facial nucleus and the nucleus ambiguus (motor part of the anterior column of the spinal cord
nucleus of the vagus and glossopharyngeal) that below.15,16,27,28 It is situated close to the floor of
belong to the motor nuclei of the lateral somatic the fourth ventricle, just above the level of the
group.19–26 The axons arise from large pigmented striæ medullares. Voluntary impulses from the
multipolar cells. The motor nucleus receives cerebral cortex are conducted by the pyramidal
reflex collaterals and terminals from (1) the ter- tract fibers (corticopontine fibers). The abdu-
minal nucleus of the trigeminal of the same and a cens nucleus probably receives collaterals and
few from the opposite side, via the central sensory terminals from the ventral longitudinal bundle
tract (trigeminothalamic tract); (2) the mesen- (tectospinal fasciculus)—fibers that have their
cephalic root of the trigeminal; (3) the posterior origin in the superior colliculus, the primary
longitudinal bundle; (4) and probably fibers in visual center, and are concerned with visual
the formatio reticularis. It also receives collat- reflexes.15,16,27,28
erals and terminals from the opposite pyram- The sensory innervation of the extraocu-
idal tract (corticopontine fibers) for voluntary lar muscles is a contentious issue. Two distinct
movements.19–26 The terminal sensory nucleus types of sensory receptors have been identified
consists of an enlarged upper end, the main sen- within human extraocular muscles, namely
sory nucleus, and a long more slender descending muscle spindles and palisade endings (myoten-
portion that passes down through the pons and dinous cylinders), but their precise function
medulla to become continuous with the dorsal is not fully understood.19,22,23,25,29–35 The other
part of the posterior column of the gray matter, main sensory receptors found within skele-
especially the substantia gelatinosa of the spinal tal muscle, Golgi tendon organs, have as yet
cord. The main sensory nucleus lies lateral to the not been identified within human extraocular
motor nucleus beneath the superior peduncle. It muscles, although they have been described in
receives the short ascending branches of the sen- monkeys.24,33,34,36–38 Muscle spindles are found
sory root. The cells of the sensory nucleus are of within the proximal and distal regions of human
large and medium size and send their axons into infant and adult extraocular muscles and are
the formatio reticularis, where they form a dis- located at the junction of the orbital and global
tinct bundle, the central path of the trigeminal layers. Although they are found at a density sim-
(trigeminothalamic tract), which passes upward ilar to that of spindles in hand and neck mus-
through the formatio reticularis and tegmentum cles, suggesting a role in fi ne motor control, they
to the ventrolateral part of the thalamus.19–26 also show features that hypothesize an ability to
Most of the fibers cross to the trigeminothalamic generate a proprioceptive signal. Palisade end-
tract of the opposite side. Th is tract lies dorsal ings, a class of muscle receptor found exclusively
to the medial fi llet, approaches close to it in the within extraocular muscles, including those of
tegmentum, and terminates in a distinct part of humans, are located at the distal myotendinous
the thalamus. From the thalamus impulses are junction of the multiply innervated non-twitch
conveyed to the somatic sensory area of the cor- fibers of the global layer.24,33,34,36–38 They may be
tex by axons of cells in the thalamus through the the principal source of proprioceptive feedback
internal capsule and corona radiata. from extraocular muscles. Studies in the mon-
The abducens nerve (cranial nerve VI) con- key suggest that proprioceptive signals ascend
tains somatic motor fibers only that supply the from the extraocular muscles to the central pro-
lateral rectus muscle of the eye.15,16,27,28 The fibers cessing structures via the trigeminal nucleus.
arise from the nucleus of the abducens nerve and The precise pathway in humans has yet to be
pass ventrally through the formatio reticularis established. There is increasing scientific and
of the pons to emerge in the transverse groove clinical evidence that a nonvisual afferent signal,
between the caudal edge of the pons and the most likely to be derived from extraocular mus-
pyramid. The nucleus is serially homologous cle proprioceptors, can under certain conditions
with the nuclei of the trochlear and oculomotor influence visuomotor behavior. It may well be

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that for the majority of individuals with normal is involved in the visual guidance of saccades
visual function and normal oculomotor systems by shaping the visual inputs to the superior
that vision itself, combined with efference copy, colliculus.40 The posterior parietal cortex
is sufficient to determine eye position. In such contains neurons that are modulated by vis-
individuals, extraocular muscle proprioception ual attention, that is, by how behaviorally rel-
may have litt le to contribute to the control of evant are visual stimuli. They respond more
eye movements and the representation of visual effectively when the stimulus is the target for
space. However, under certain circumstances of an eye movement. The frontal eye fields form
reduced or impaired vision or in those with ocu- an executive center that can selectively acti-
lar motility disorders, afferent feedback from vate superior colliculus neurons, playing a
the extraocular muscles might assume greater role in the selection and production of volun-
significance.24,33,34,36–38 tary saccades.40 The frontal eye fields are also
involved in suppressing reflexive saccades and
generating voluntary, nonvisual saccades. The
1.2 SUPRANUCLEAR OCULAR
complementary executive control exerted on
MOTOR ANATOMY
saccade generation by the frontal eye fields and
the superior colliculus is revealed by the effect
1.2.1 Frontal Eye Fields
of selective and combined ablation. 39,41–43
The saccade-related activity of the superior Lesions of the superior colliculus prevent the
colliculus neurons is shaped by inputs from generation short-latency reflexive saccades,
the posterior parietal cortex, the frontal eye whereas the generation of voluntary sacca-
fields, and the substantia nigra pars reticulata des is disrupted by frontal-eye-field lesions.
(see Fig. 1.4). 39 The posterior parietal cortex Although saccades can still be produced after

FIGURE 1.4 Brainstem structures controlling eye movements. Parasagitt al section of the cerebrum and
brainstem showing the areas of the ocular motor nuclei and brainstem structures involved with internuclear
and supranuclear pathways. CN II, second cranial nerve (optic); CN III, third cranial nerve; MLF, medial
longitudinal fasciculus; IC, inferior commissure; SC, superior colliculus.

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the ablation of either the superior colliculus 1.2.2 Superior Colliculus

or the frontal eye fields, a combined ablation
of these two structures results in the com- The superior colliculus provides both the motor
plete abolition of saccadic eye movements. The command to the PPRF’s burst neurons and the
substantia nigra pars reticulata funnels inputs trigger command to the omnipause neurons.44–46
from the frontal cortex and acts as a gate for the It is a laminated structure situated on the roof
voluntary control of saccades, keeping in check of the midbrain (see Fig. 1.5). It sends projec-
the superior colliculus activity. 39,41–43 The neu- tions to both the horizontal (paramedian pon-
ral activity in the substantia nigra maintains tine reticular formation [PPRF]) and vertical
the superior colliculus tonically inhibited to gaze centers (rostral interstitial nucleus of the
prevent unwanted saccades. Prior to a volun- medial longitudinal fasciculus [riMLF]), pro-
tary saccade, this tonic inhibition is reduced viding the motor command to move the eye to
by inputs from the caudate, which is activated an intended new position for the foveation of
by signals form the cortex. Experimental and a visual stimulus.44–46 The superior colliculus
clinical studies specify the role of frontal eye contains a topographic motor map composed
fields in the volitional, inhibitory control of of neurons that discharge a high-frequency
visually triggered saccades. The parietal lobe burst of action potentials immediately prior
instead seems mainly concerned with privi- to saccades that have a specific vector, that is,
leged target selection. A parallel processing of a direction and amplitude, which is independent
saccade-related signals occurs in corticostri- of the initial position of the eyes in the orbit.47
atal circuits. Evidence for peristriate and pari- The integrity of the superior colliculus is crucial
etal cortical areas to encode the information for the production of short-latency reflexive sac-
relevant to smooth pursuit generation is pro- cades, including the “express” saccades whose
vided by animal and clinical studies.40,43 latency approaches the fastest time for visual

FIGURE 1.5 The superior colliculus are a pair of oval masses composed of alternating layers of gray
and white matter. They are centers for ocular movements. Some of the connections to the superior col-
liculus include the retina, visual and nonvisual cerebral cortex, inferior colliculus, paramedian pontine
reticular formation, thalamus, basal ganglia, and spinal cord ventral gray horn. The fibers of the medial
longitudinal fasciculus form a fringe on its ventrolateral side. 1-Superior colliculus, 2-Brachium of supe-
rior colliculus, 3-Medial geniculate nucleus, 4-Brachium of inferior colliculus, 5-Central gray substance,
6-Cerebralaqueduct, 7-Visceral nucleus of oculomotor nerve (Edinger-Westphal nucleus), 8-Nucleus of
oculomotor nerve, 9-Medial lemniscus, 10-Central tegmental tract, 11-Medial longitudinal fasciculus,
12-Red nucleus, 13-Fibers of oculomotor nerve, 14-Substantia nigra, 15-Basis pedunculi.

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signals to reach the oculomotor system and trig- fi ring during saccades in all directions. The pause
ger a saccade.45,46,48,49 Lesions of the superior col- begins before the discharge of burst neurons and
liculus permanently abolish the production of ends before the end of the saccade. 32,49,54 Long-
express saccades. lead burst neurons (LLBNs) and excitatory burst
neurons (EBNs) generate high-frequency bursts
of activity before ipsilateral saccades. The burst
1.2.3 Brainstem Control of Eye
of LLBNs are not as tightly coupled to saccade
Movements
onset as the burst of EBNs.47 EBNs make excit-
The problem of moving the eyes in the orbit atory, monosynaptic connections with neurons
entails two separate issues: controlling the ampli- in the ipsilateral abducens and provide the main
tude of the movement (how far) and controlling source of excitatory drive for the saccade-related
the direction of the movement (which way).19,49,50 pulse of motor neuron activity.47 The amplitude,
The amplitude of a saccade is determined by the duration, and velocity of saccades are coupled
activity in the lower motor neurons within the to the number of spikes generated, burst dura-
three oculomotor nuclei. The direction of a sac- tion, and peak fi ring rate of the burst of activity,
cade is determined by which muscles are acti- respectively.44,45,47,53 The tonic activity of many
vated, as dictated by the activity in the premotor neurons in the nucleus prepositus hypoglossi
neurons within two separate gaze centers in the and the medial vestibular nucleus is proportional
brainstem. The discharge frequency of extraoc- to horizontal eye position, and these cells pro-
ular motor neurons is directly proportional to vide the excitation that is required for the step
the position and velocity of the eye. 51 The sac- of motor neuron activity.44,45,47,53 Activity in the
cade signal of motor neurons has the form of PPRF is specifically related to the control of hori-
a pulse-step. 51 The height of the step determines zontal saccades and the horizontal component of
the amplitude of the saccade, while the height of oblique saccades (see Fig. 1.6). Premotor neurons
the pulse determines the speed of the saccade. in the rostral midbrain produce the vertical pulse
The duration of the pulse determines the dura- and step commands. Neurons in the riMLF gen-
tion of the saccade. The pulse is the phasic signal erate a high-frequency burst before vertical sac-
that commands the eyes to move. The step is the cades and convey this signal monosynaptically to
tonic signal that commands the eyes to hold in the motor neurons (see Fig. 1.7).44,45,47,53 Vertical
an eccentric position. The direction of saccades EBNs that discharge before upward saccades are
is dictated by premotor neurons in two gaze cen- intermingled with those that discharge before
ters in the reticular formation: (1) the PPRF next downward saccades in the riMLF. Neurons in
to the abducens nucleus is the horizontal gaze the interstitial nucleus of Cajal (INC) and the
center; and (2) the rostral iMLF in the midbrain vestibular nucleus discharge tonically at rates
reticular formation near the oculomotor nucleus that are linearly related to vertical eye position,
is the vertical gaze center.45,47,51–53 To produce and provide the excitatory inputs that produce
a rightward saccade, activation of premotor the step change in motor neuron activity.44,45,47,53
neurons in the right PPRF increases the activ- Many saccades have both horizontal and verti-
ity of lower motor neurons in the right abducens cal components. Although the commands for
nucleus, which innervate the lateral rectus mus- the two components are generated in different
cle of the right eye. Activation in the right PPRF regions of the brainstem, pontine OPNs inhibit
also increases the activity of internuclear neurons both horizontal and vertical EBNs and tend to
in the same (right) abducens nucleus, which send synchronize the onsets of the two components.
their axons along the medial longitudinal fas-
ciculus to innervate the lower motor neurons in
1.2.4 Vestibular Nuclei
the left oculomotor nucleus, which in turn inner-
vate the medial rectus muscle of the left eye. 32,49,54 The vestibular neurons are bipolar with their
Omnipause neurons (OPNs) discharge at a rela- cell bodies located in Scarpa’s ganglion in the
tively constant rate during fi xation, but they stop internal auditory meatus. 55–58 The superior and

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Left Right
Lateral Medial
Rectus Rectus

Right
Left Third
Sixth Nerve
Nerve III

VI
P

FIGURE 1.6 Schematic of brainstem pathways coordinating horizontal saccades. The PPRF, after receiv-
ing input from the ipsilateral cortical centers and superior colliculus, stimulates two sets of neurons in the
abducens nucleus: (1) those that send axons to innervate the ipsilateral lateral rectus and (2) those whose
axons join the medial longitudinal fasciculus and subsequently activate the medial rectus subnuclei of the
contralateral third nerve. III, third cranial nerve nuclei; PPRF, paramedian pontine reticular formation;
VI, sixth cranial nerve nuclei.

inferior vestibular nerves join to form a com- with two additional pathways. One pathway
mon bundle that enters the brainstem. These projects directly to the lateral rectus of eye via
fi rst-order neurons do not cross the midline. the abducens nerve. Another nerve tract proj-
These afferent fibers terminate in the vestibu- ects from the abducens nucleus by the abdu-
lar nuclei in the floor of the fourth ventricle. The cens internuclear interneurons or abducens
nuclei are the superior vestibular nucleus, the interneurons to the oculomotor nuclei, which
lateral vestibular nucleus, the medial vestibular contain motorneurons that drive eye muscle
nucleus, and the descending vestibular nucleus. activity, specifically activating the medial rec-
From the vestibular nuclei projections go to the tus muscles of the eye through the oculomotor
cerebellum, extraocular muscle nuclei, antigrav- nerve.46,59,60 Another pathway directly projects
ity muscles, and opposite vestibular nuclei. 55–58 from the vestibular nucleus through the ascend-
The semicircular canals detect head rotation ing tract of Dieters to the ipsilateral medial rec-
and drive the rotational vestibulo-ocular reflex tus motoneurons.46,59,60 In addition, there are
(VOR), whereas the otoliths detect head transla- inhibitory vestibular pathways to the ipsilateral
tion and drive the translational VOR. The main abducens nucleus. However, no direct vestibular
“direct path” neural circuit for the horizontal neuron to medial rectus motoneuron pathway
rotational starts in the vestibular system, where exists. Similar pathways exist for the vertical and
semicircular canals are activated by head rota- torsional components of the VOR.61,62
tion and send their impulses via the vestibular
nerve through Scarpa’s ganglion and end in the
1.2.5 Cerebellum
vestibular nuclei in the brainstem.46,59,60 From
these nuclei, fibers cross to the contralateral The cerebellum plays an important role in eye
cranial nerve VI nucleus. There they synapse movements.63 Together with several brainstem

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Posterior Commissure Posterior Commissure

Aqueduct Aqueduct

riMLF riMLF riMLF riMLF

INC INC INC INC

III III III III

IV IV IV IV
P P P P
P P P P
R R R R
F F F F

FIGURE 1.7 Th is shows schematics of brainstem pathways coordinating downward (5A) and upward
(5B) saccades. In 5A, the PPRF activates neurons in the riMLF that send fibers caudally to synapse upon the
inferior rectus subnucleus of the ipsilateral third nerve and the contralateral superior oblique nucleus. Not
shown in this diagram, fibers from the contralateral PPRF carry corresponding signals simultaneously. In
5B, the PPRF activates neurons in the riMLF that send fibers through the posterior commissure to the supe-
rior rectus subnucleus of the contralateral third nerve and fibers to the inferior oblique subnucleus of the
ipsilateral third nerve. Not shown in this diagram, fibers from the contralateral PPRF carry corresponding
signals simultaneously. III, third cranial nerve nucleus; INC, interstitial nucleus of Cajal; IV, fourth cranial
nerve nucleus; PPRF, paramedian pontine reticular formation; riMLF, rostral interstitial nucleus of the
medial longitudinal fasciculus.

structures, including the nucleus prepositus hence controls the duration (time constant) of
hypoglossi and the medial vestibular nucleus, the VOR.68 The dorsal vermis and underlying
it appears to convert velocity signals to position (posterior) fastigial nuclei participate in the
signals for all conjugate eye movements through control of the size of the saccadic pulse of inner-
mathematical integration. Because of this, all of vation and hence saccadic accuracy.68
the structures involved in this process are often
referred to as the neural integrator.64 Patients
1.3 AFFERENT SYSTEM
with faulty neural integration may show gaze-
evoked nystagmus, impaired smooth pursuit,
1.3.1 Retina
inability to cancel the VOR during fi xation, sac-
cadic dysmetria, defective optokinetic nystag- The retina is organized both vertically (in col-
mus response, and/or rebound nystagmus.65–67 umns) and horizontally (in layers). The princi-
Various types of image-stabilizing reflexes are pal “vertically oriented” elements are receptors
also “cerebellar” functions. Pursuit, VOR can- (rods and cones), the bipolar cells and the gan-
cellation, and holding the eye steady for fi xa- glion cells. The “horizontally oriented” ele-
tion, both immediately after saccades and in ments are the horizontal, interplexiform and the
eccentric positions of gaze, are controlled by the Meuller cells. The human retina is approximately
flocculus (and probably paraflocculus).68 The 0.2 mm thick and has an area of approximately
nodulus (and ventral uvula) modulates “low- 1100 mm 2 . Each retina possesses about 200 mil-
frequency” aspects of vestibular responses and lion neurons. The human retina is “inverted,”

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because the photoreceptor layer is located poste- 1.3.2 Optic Nerve

riorly and furthest from incident light. Rod and
cone photoreceptors are easily distinguished by The optic nerve (cranial nerve II) is considered
their outer segments.69–71 The outer segment con- to be part of the central nervous system as it
tains photopigment in free-floating disks (rods) is derived from an out-pouching of the dien-
or folded layers (cones). Cone outer segments cephalon during embryonic development.71–73
have a continuous outer membrane, whereas rods Consequently, the fibers are covered with mye-
have discs, stacked like coins, in a sleeve.70 The lin produced by oligodendrocytes rather than
rod and cone outer segment membranes are con- the Schwann cells of the peripheral nervous
stantly being replenished. The capture of indi- system. Similarly, the optic nerve is ensheathed
vidual photons by the photopigment molecules in all three meningeal layers (dura, arachnoid,
in the disk membranes is what initiates neural and pia mater). The optic nerve is composed of
signaling. Photoreceptors are actually special- retinal ganglion cell axons and support cells. It
ized hair cells, and the inner and outer segments leaves the orbit via the optic canal, running pos-
are connected by the cilium. The human retina teromedially toward the optic chiasm, where
contains approximately 120 million rod and there is a partial decussation (crossing) of fibers
1 million cone photoreceptors. Cone density from the temporal visual fields of both eyes
is highest at the fovea, where recent estimates (see Fig. 1.8). Its diameter increases from about
place it at approximately 300,000/mm;2 rod den- 1.6 mm within the eye, to 3.5 mm in the orbit,
sity is highest at about 18° eccentric to the fovea to 4.5 mm within the cranial space. The optic
(see Chapter 6 for electrophysiology).70 nerve component lengths are 1 mm in the globe,

FIGURE 1.8 The retina consists of a large number of rod and cone photoreceptors. The photoreceptors
synapse directly onto bipolar ganglion cells, which in turn synapse onto ganglion cells, which will then
transmit signals through the optic nerve. The optic nerves from both eyes meet and cross at the optic chiasm,
where information coming from both eyes is combined and then splits. Information from the right visual
field (now on the left side of the brain) travels in the left optic tract. Information from the left visual field trav-
els in the right optic tract. Each optic tract terminates in the lateral geniculate in the thalamus. The neurons
of the lateral geniculate nucleus then relay the visual image via the optic radiations to the primary visual cor-
tex. The visual cortex region that receives information directly from the lateral geniculate nucleus is called
V1 or primary visual cortex. Visual information then flows through a cortical hierarchy that includes V2,
V3, V4, and V5 medial temporal areas. After V1 is a further level of specialization of processing into two dis-
tinct pathways: the dorsal stream and the ventral stream occur. The dorsal stream, commonly referred to as
the “where” stream, communicates with regions that control eye and hand movements. The ventral stream,
commonly referred as the “what” stream, is involved in the recognition, identification, and categorization of
visual stimuli.

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25 mm in the orbit, 9 mm in the optic canal, and of the magnocellular and parvocellular layers of
16 mm in the cranial space before joining the the lateral geniculate body terminate in separate
optic chiasm. There, partial decussation occurs sublaminae of layer IV of striate cortex; a more
and about 53% of the fibers cross to form the superficial projection of the parvocellular layers
optic tracts. Most of these fibers terminate in the to a narrow strip at the base of layer III (IVA in
lateral geniculate body. Brodmann’s terminology).73,78,81 Fibers carry-
ing information from the contralateral superior
visual field traverse Meyer’s loop to terminate
1.3.3 Lateral Geniculate
in the lingual gyrus below the calcarine fissure
The lateral geniculate nucleus (LGN) serves as a in the occipital lobe, and fibers carrying informa-
relay station in the projection of the visual path- tion from the contralateral inferior visual field
way to the striate cortex.74–77 The microscopic terminate more superiorly.
structure of the LGN is characterized by a series
of alternating gray matter and white matter
1.3.5 Association Cortex
layers.74–77 The LGN consists of six layers, with
each alternating layer receiving inputs from a dif- As visual information passes forward through
ferent eye, three layers for the left eye and three the visual hierarchy, the complexity of the neu-
layers for the right. Layers 1, 4, and 6 correspond ral representations increases. Whereas a pri-
to information from the contralateral (crossed) mary visual cortex (V1) neuron may respond
fibers of the nasal visual field; layers 2, 3, and selectively to a line segment of a particular
5 correspond to information from the ipsilateral orientation in a particular retinotopic loca-
(uncrossed) fibers of the temporal visual field. tion, neurons in the lateral occipital complex
The outer four layers are composed of small respond selectively to a complete object (e.g.,
cells and, correspondingly, receive inputs from a figure drawing), and neurons in visual associ-
the small ganglion cells of the retina referred ation cortex may respond selectively to human
to as the parvocellular (P) ganglion cells; these faces or to a particular object.77,78,81–83 Along
cells dominate the fovea, are color sensitive, with this increasing complexity of neural rep-
and are “fi ne-grained,” meaning their receptive resentation may come a level of specialization
fields are small enough that they can pick up a of processing into two distinct pathways: the
high level of detail. The two most ventral lay- dorsal stream and the ventral stream fi rst pro-
ers are referred to as the magnocellular layers posed by Ungerleider and Mishkin. 84–86 The
and are composed of large cells, which receive dorsal stream, commonly referred to as the
their input from large ganglion cells referred to “where” stream, is involved in spatial attention
as the magnocellular (M) ganglion cells.76,78–80 (covert and overt) and communicates with
These cells receive information from a wide regions that control eye movements and hand
radius of bipolar cells. They are mostly found movements. 84–86 More recently, this area has
in the peripheral retina, are insensitive to color, been called the “how” stream to emphasize its
and are “coarse-grained,” meaning they are rel- role in guiding behaviors to spatial locations.
atively insensitive to detail. Their main asset is The ventral stream, commonly referred as the
that they are sensitive to motion. Therefore, it is “what” stream, is involved in the recognition,
evident that two types of information, motion identification, and categorization of visual
versus color and form, are kept in separate lay- stimuli.78
ers in the LGN.
1.3.6 Ocular Motor Proprioception
1.3.4 Geniculostriate
Nonhuman primates have eye muscle proprio-
From the lateral geniculate body, fibers of the ceptive signals that provide information used in
optic radiation pass to the visual cortex in the normal sensorimotor functions; these include
occipital lobe of the brain.73,78,81 The projections various aspects of perception and of the control

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of eye movement. It is possible that abnormali- 1.4.1 Smooth Pursuit System

ties of the eye muscle proprioceptors and their
signals may play a part in the genesis of some Smooth pursuit permits us to maintain a steady
types of ocular motor disorders. Studies of image of a moving object on our foveas and to
patients with these disorders in the course of thereby track moving targets with clear vision.
their surgical or pharmacological treatment The pathways for smooth pursuit have not been
have yielded much interesting evidence about fully elucidated, but extrastriate cortex trans-
the central actions of the proprioceptive sig- mits information about the motion of both the
nals from the extraocular muscles. It is argued target and the eyes to the dorsolateral pontine
that such understanding of eye-muscle propri- nuclei (DLPN).87 Th is complex signal travels
oception is a necessary part of the understand- from the DLPN to the cerebellum, and from
ing of the physiology and pathophysiology of the cerebellum to the vestibular nuclei before
eye-movement control. The eye would seem to reaching its fi nal destination—the ocular motor
provide a unique system in which to study the nerve nuclei III, IV, and VI. Unilateral lesions
way in which information derived within the along the pathway result in an ipsilateral deficit
brain about motor actions interacts with signals of smooth pursuit.88
flowing in from peripheral receptors. 23 Muscle
spindles are found within the proximal and dis- 1.4.2 Saccadic System
tal regions of human infant and adult extraocu-
lar muscles and are located at the junction of Several forms of saccades, the fastest eye move-
the orbital and global layers.19,34,35 Palisade ments, can be observed: voluntary saccades to
endings, a class of muscle receptor found exclu- objects of interest, reflex saccades to unexpected
sively within extraocular muscles, including new stimuli, spontaneous saccades that occur in
those of humans, are located at the distal myo- normal inactive subjects, and saccades that form
tendinous junction of the multiply innervated the quick phases of vestibular and optokinetic
non-twitch fibers of the global layer.19,34,35 They nystagmus.47 Pathways descending from areas
may be the principal source of proprioceptive of cerebral cortex that govern saccades appear
feedback from extraocular muscles. Studies in to decussate at the junction of the midbrain and
the monkey suggest that proprioceptive sig- pons.47 The superior colliculus acts as an impor-
nals ascend from the extraocular muscles to tant relay for some of these projections. In the
the central processing structures via the tri- brainstem, the riMLF and the PPRF provide the
geminal nucleus.19,34,35 Based mainly on animal saccadic velocity commands to cranial nerves
studies, Butt ner-Ennever et al. have suggested III, IV, and VI.47 Vertical and torsional compo-
that each layer of the extraocular muscles has nents of saccades are generated in the riMLF,
its own type of sensory receptor to generate which is located at the mesencephalic-dienceph-
afferent signals, with the orbital layer utilizing alic junction, horizontal components are gener-
muscle spindles and the global layer relying on ated in the PPRF, which is found just ventral and
palisade endings.19 These investigators also sug- lateral to the MLF in the pons. If an abnormal-
gest that sensory signals from palisade endings ity of saccadic eye movements is suspected, the
form part of a proprioceptive feedback network quick phases of vestibular and optokinetic nys-
that modulates the non-twitch motor neurons tagmus can be easily evaluated in infants and
that innervate the slow non-twitch extraocular young children.89
muscle fibers.
1.4.3 Vergence System
1.4 EFFERENT SYSTEM
Vergences are eye movements that turn the eyes
The functional classes of eye movements are in opposite directions (convergence, divergence,
listed in Table 1.2 with their functions, stimuli, and cyclovergence) so that images of objects
clinical tests, and latencies/speed. will fall on corresponding retinal points. Th ree

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Table 1.2 Functional Classes of Human Eye Movements

EYE C L I N IC A L L A T E N C Y/
M OV E M E N T F U N C T IO N STI M U LUS TEST SPE ED
Vestibular Maintains steady Head rotation, Fixate on object 15 msec
fi xation during body, and head while moving head Up to 800°/sec
head rotation motion
Saccades Rapid refi xation Eccentric retinal Voluntary 200 msec
to eccentric image movements, 250–800°/sec
stimuli fast phases of OKN
Vergence Dysconjugate Binasal or Fusional 160 msec
slow movements bitemporal amplitudes, 30–150°/sec
to maintain disparity, retinal near point
binocular vision blur, motion convergence
Optokinetic Steadies images Head rotation, Optokinetic drum, 60 msec
of the world on body and world motion Supplements VOR
the retina during movement during low-
sustained head frequency
rotation movements
Pursuit Conjugate Retinal slip Horizontal and 125 msec
continuous (motion) vertical moving 0–30°/sec
target tracking target
OKN, optokinetic nystagmus;VOR, vestibulo-ocular reflex.

major stimuli are known to elicit vergences: The fast vergence system is best elicited by
(1) retinal disparity that leads to fusional ver- stimuli with large retinal disparity errors and/
gences, (2) retinal blur that evokes accommo- or velocities larger than 4°/sec.93,94 The slow ver-
dative vergences, and (3) motion induces both gence system is elicited by small disparity errors
disparity and accommodative vergence. The full and/or disparity velocities of less than 3°/sec.
neuroanatomic substrate for vergence eye move- Tectal and pretectal midbrain areas contribute
ments remains unknown.19,49,90,91 Neurons in the to the near triad, which is simultaneous conver-
medial superior temporal visual area (MST), gence, accommodation of the lens, and miosis,
the supplementary eye field (SEF), the frontal occurring during shifts in fi xation between dis-
eye field (FEF), and the cerebellar vermis are tance and near.93,94
active during vergence eye movements. 39,49
MST and the caudal FEF neurons are likely
1.4.4 Vestibulo-Ocular System
to be involved in the initiation of vergence eye
movements.46,49,91,92 Conjugate and vergence sig- The vestibular apparatus drives reflex eye
nals are generated independently and are com- movements, which allow us to keep images of
bined at the extraocular motoneurons. Both the world steady on the retinas as we move our
convergence and divergence cells are found heads during various activities. The eyes move
intermixed in the mesencephalic reticular for- in the opposite direction to the movement of
mation outside the oculomotor nucleus, most the head so that they remain in a steady posi-
within 1–2 mm of the nucleus.46,49,91,92 The ver- tion in space. The semicircular canals are the
gence system has both a fast and a slow subsys- end organs that provide the innervation to the
tem. Each subsystem has a different property. vestibular nuclei, which in turn drive cranial

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nerves III, IV, and VI to compensate for rota- muscle in monkeys and humans. Invest
tions of the head.95 In contrast, the otoliths Ophthalmol Vis Sci 1997;38(9):1774–1785.
respond to linear accelerations of the head and 10. Porter JD, Poukens V, Baker RS, Demer JL.
Structure-function correlations in the human
to gravity when the head is tilted. The principal
medial rectus extraocular muscle pulleys.
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activity-dependent regulation of type II 89. Gaymard B, Pierrot-Deseilligny C. Neurology

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2
infantile nystagmus syndrome
2.1 CHARACTERISTICS OF INFANTILE 2.1.11.2 Deep Muscle Stimulation 57
NYSTAGMUS SYNDROME 24 2.1.11.3 Contact Lenses 57
2.1.1 History and Background 24 2.1.11.4 Biofeedback 57
2.1.1.1 Ancient Descriptions and 2.1.12 Canine Nystagmus
Theories 24 (Achiasmatic Belgian Sheepdog) 57
2.1.1.2 Connection to Fixation 2.1.12.1 Seesaw 58
Attempt 25 2.1.12.2 Pendular 58
2.1.1.3 Modern Physiological 2.1.12.3 Tenotomy and Reattachment
Investigation 26 Procedure 58
2.1.2 Waveforms, Models, and Mechanisms 26 2.1.13 Canine Model of Infantile Nystagmus
2.1.2.1 Waveform Types 27 Syndrome with RPE65 Retinal
2.1.2.2 Braking and Foveating Saccades 35 Degeneration (Briard) 60
2.1.2.3 The Foveation Period 35 2.2 ETIOLOGY OF INFANTILE
2.1.2.4 Foveation Accuracy 35 NYSTAGMUS SYNDROME 60
2.1.2.5 Target Acquisition Time 36 2.2.1 Familial (Gene Defect) 61
2.1.2.6 Smooth Pursuit 36 2.2.2 Developmental Disturbance of the
2.1.3 The Static Neutral Zone/Region 39 Ocular Motor System with Associated
2.1.3.1 Latent Component 40 Sensory System Deficit 64
2.1.4 The Dynamic Neutral Zone/Region 40 2.2.2.1 Albinism 66
2.1.4.1 Asymmetric, (a)Periodic 2.2.2.2 Achiasma 67
Alternation 42 2.2.2.3 Infantile Strabismus 67
2.1.4.2 Optokinetic, Pursuit, and 2.2.2.4 Nonvectorial Visual Sensory
Vestibulo-Ocular Responses 44 Deficits 68
2.1.5 The Null Angle/Zone/Region 46 2.2.3 The Direct Cause(s) of Infantile
2.1.6 The Convergence Null 48 Nystagmus Syndrome with or without
2.1.7 The Saccadic Response 50 Sensory/Genetic Deficits 68
2.1.8 Static and Dynamic Head Posturing 51 2.2.3.1 Loss of Smooth-Pursuit
2.1.9 Foveation and Visual Acuity Damping 68
(High Spatial Frequency Vision) 52 2.2.3.2 Tonic Visual Vestibular
2.1.9.1 The eXpanded Nystagmus Acuity Imbalance 70
Function 53 2.3 VISUAL FUNCTION DEFICITS AND
2.1.10 Oscillopsia Suppression 54 MEASUREMENTS OF INFANTILE
2.1.10.1 Foveation Dynamics 55 NYSTAGMUS SYNDROME 70
2.1.10.2 Temporal Sampling 55 2.3.1 Static Deficits 70
2.1.10.3 Efference Copy 56 2.3.1.1 The eXpanded Nystagmus Acuity
2.1.11 Afferent Stimulation 56 Function and Longest Foveation
2.1.11.1 Cutaneous Trigeminal Domain Measures 70
Stimulation 57 2.3.2 Dynamic Deficits 73

• 21

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2.3.2.1 Target Acquisition Time 2.4.2.5 Biofeedback 81

(Stationary Targets) 73 2.4.3 Surgical 81
2.3.2.2 Target Acquisition Time (Moving 2.4.3.1 Four-Muscle Resection and
Targets) 73 Recession Procedure (Operation 1)
2.3.3 Clinical 75 (Also Known as Kestenbaum,
2.3.3.1 Visual Acuity at Different Gaze Anderson-Kestenbaum, or Anderson
Angles 77 Plus Goto) 84
2.4 TREATMENTS OF INFANTILE 2.4.3.2 Two-Muscle Recession Procedure
NYSTAGMUS SYNDROME 77 (Operation 1A) (Also Known as
2.4.1 Goals 77 Anderson) 85
2.4.2 Nonsurgical 78 2.4.3.3 Bilateral Medial Rectus Recession
2.4.2.1 Prisms 78 Procedure (Operation 8) (Also Known
2.4.2.2 Contact Lenses 78 as Bimedial Recession) 86
2.4.2.3 Drugs 80 2.4.3.4 Tenotomy and Reattachment
2.4.2.4 Gene-Transfer Therapy 80 Procedure (Operation 6) 86

There are two unsolved questions in the neuronal physiology of nystagmus in the brainstem:
(1) The mechanism of the quick and slow phase; (2) The coordination of vestibular and optokinetic
nystagmus.
—R. Jung, discussing “Vestibular Connections in the Brainstem,” B. E. Gernandt, in
The Oculomotor System, M. B. Bender, editor, Harper & Row, New York, 1964, p. 236

TH ER E A R E several types of benign nys- type of nystagmus when required (e.g., pen-
tagmus usually seen in infancy. The most dular, pursuit-system nystagmus) while still
common are those in the infantile nystagmus allowing for the inclusion of several types found
syndrome (INS; formerly known as “congen- in each syndrome by simply appending the
ital” nystagmus [CN]). Others are the nystag- word “nystagmus” to the syndrome (e.g., INS
mus of the fusion maldevelopment nystagmus nystagmus). Similarly, the shorthand “IN” is
syndrome (FMNS, formerly known as latent/ a general description encompassing all of the
manifest latent nystagmus [LMLN]) and the specific types of nystagmus possible in the INS;
pendular nystagmus of the spasmus nutans syn- the same applies to “FMN.”
drome (SNS). We use the nomenclature recom- INS contains the most common types of
mended by the Classification of Eye Movement benign nystagmus of infancy. Its constellation
Abnormalities and Strabismus (CEMAS) of waveforms and clinical signs allow positive
Working Group1 that eliminates the confus- identification using eye-movement recordings,
ing and misleading terminology of the classi- but similarities in both areas to other types of
cal names found in the literature. The CEMAS nystagmus of infancy can result in misdiagnosis
terminology, now more than a decade old, dif- if the patient workup is limited to clinical signs
ferentiates between a syndrome that includes alone. The past half-century has brought about
nystagmus (often several, different types) and remarkable advances in our understanding of
a specific type of nystagmus. For example, the the ocular motor system (OMS), both normal
nystagmus recorded in a patient with INS may and abnormal. That can be directly traced to
be any combination of two or three mechanis- two things: (1) the development of accurate eye-
tically different types of nystagmus resulting in movement measurement systems and (2) the
16 specific waveforms. Using this terminology application of the engineering approach to study
facilitates more accurate descriptions of each neurological control. Engineering is a discipline

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whose objective is to take what is either known is our destiny. Top-down modeling allows us to
or observed and use it to solve problems; the comprehend complex behavior. We do not wish
objective in science, on the other hand, is to to make virtual models of humans, to replace or
understand the basic origins of nature.2 Pioneers remodel reality.
in the study or normal ocular motility were One key fi nding from the earliest INS model
Larry Stark (who fi rst applied control systems was that the OMS could not be adequately mod-
to model the normal pupillary response), his eled as a simple retinal error-driven control
student, Laurence Young, and David Robinson system because, if that were the case, any oscilla-
(both of whom applied control systems to model tion would produce the perception of oscillopsia
the normal OMS). Each of these researchers was (world movement). 3,4 INS patients do not nor-
either an engineer or had engineering training. mally experience oscillopsia; therefore, to make
Because of Dell’Osso’s interest in INS, he was an OMS model that accurately responded to the
the fi rst to use his engineering training and apply above visual target inputs, it was necessary to use
control systems to model an abnormal OMS (i.e., feedback of the outgoing motor signal (efference
one containing an internal oscillation simulat- copy) to eliminate the effects of the unwanted
ing INS). The resulting behavioral model, and retinal motion on the perceived target signal.
those that followed, demonstrated how, despite Thus, the OMS responds to a “reconstructed
an internal oscillation, the OMS of INS patients perception” of target position and velocity, not
was capable of accurately responding to pulse, directly to retinal error position and velocity.
pulse-step, step, ramp, and step-ramp target An OMS model based on efference copy has no
inputs. 3,4 Each of these bioengineering pioneers oscillopsia (i.e., there exist internal signals that
used the top-down approach to modeling, con- accurately reflect target position and velocity
centrating on the functions necessary in each without the confounding oscillatory motion of
system rather than the details of the neurophysi- the retina). Such models can also simulate the
ology at each level or the anatomical sites of each responses to nonvisual target inputs such as
group of neurons. Many of their students subse- pursuit of the perceived absent hub of a “wheel”
quently also applied the engineering approach that consists of only its circular outline moving
to lower level portions of each functional block across the visual field; retinal error models can-
in the OMS (i.e., the bottom-up approach). not, since there is no “error” signal.
However, the goal of bottom-up modeling is as Th is chapter summarizes the results of rel-
unachievable as it is misdirected. Duplication of evant INS research conducted over the past 45
an actual brain (~100 billion [1011] neurons with years that forms the foundation for the diagnos-
100 trillion [1014] synapses) or even the billions tic criteria and therapies presented in Chapters
of neurons and trillions of synapses comprising 5 and 7, respectively. Sharply focused research
the OMS requires a complexity and magnitude studies posing mechanism-based questions of
of computer functions and interconnections individual (or a small subset of) INS patients
that is unrealizable now, or for the foreseea- form the foundation for our present under-
ble future. Even if that were not so, bottom-up standing of the mechanisms of INS, its accurate
(so-called neuromimetic—the action of a drug diagnosis, characteristics, etiology, objective
that mimics the response of an effector organ to measurements, and effective treatments; the
nerve impulses) modeling of neurophysiological order of the topics in this chapter was chosen
control perpetuates the fundamental mistake to reflect this. Such “basic” clinical research is
that classical behaviorism made, of commenc- different from the evidence-based, statistical
ing from the simple and moving upward. studies traditionally employed during interven-
Paraphrasing the opinions of Thorne Shipley tional drug-related trials; the latter are neces-
(1927–2009), 5 nature has already solved for us sary but not science6 —the systematic study of
the problem of going from the small and creat- the structure and behavior of the physical and
ing the complexities of human neurophysiology. natural world through observation and experi-
Our task in modeling is to go the other way; it ment. By their nature, clinical trials usually do

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not address the types of questions necessary to Zivatofsky uncovered what may be the earliest
advance both our understanding of underlying description of nystagmus dating as far back as
mechanisms of diseases but do have their place 1,500 years ago.14 It was in a Talmudic account
in determining effectiveness and the application of albinism, photophobia, and nystagmus in
of specific therapies to ameliorate their dysfunc- a population living along the River Tigris. In
tion. In addition, because the nature of our INS the more recent past, the distinguished neuro-
research combines both basic and clinical sci- ophthalmologist Wilbrand once advised “never
ence, those restrictive adjectives were neither write on nystagmus, it will lead you nowhere.”15
used nor considered in the organization of this Kestenbaum (a very astute observer) contrib-
chapter. A complete review of the literature on uted much to the understanding of nystagmus
infantile nystagmus is not our purpose; that, in general and INS in particular.16 Kestenbaum’s
along with other types of nystagmus and sac- book is a “must read” for all serious INS inves-
cadic intrusions and oscillations can be found tigators, fi rst, to familiarize themselves with
elsewhere.7–12 Finally, the results of this research what was observed and postulated before the
have provided us with the answers to Jung’s modern era and second, to prevent “reinventing
questions (see epigraph). the wheel.” It contains a wealth of information
with key insights continually emerging with
each reading. Slightly later, Anderson, Bender,
2.1 CHARACTERISTICS OF
Jung and Kornhuber, and Cogan also made
INFANTILE NYSTAGMUS
significant contributions despite the absence
SYNDROME
of modern, accurate eye-movement recording
systems.17–20
2.1.1 History and Background
The nystagmus comprised in the INS is usu-
Early research in INS was accomplished using ally present at birth or noted in early infancy
electro-oculography (EOG) and allowed vis- during the various sensitive periods defi ning the
ualization of some of the waveforms exhibited development of visual fi xation,21 and it persists
by patients with INS. Because of alternating- throughout life. The syndrome consists of one
current coupling, exact eye position was not or more types of nystagmus with characteris-
retrievable from these records and the bandwidth tic waveforms, head turns, tilts, or oscillations.
was too low to reproduce the higher frequency Rarely, the nystagmus becomes manifest later in
components of INS waveforms. Therefore, these life, 22 so the term “congenital” cannot be taken
data provided litt le insight into the mechanism(s) literally but rather as a congenital “predisposi-
causing the oscillations or of how visual acuity tion” for this nystagmus. Unfortunately, it was
could be at or near normal levels in some INS one of Cogan’s papers23 that led to overly sim-
subjects. Reliance on clinical observation alone plistic, erroneous, and stubbornly persistent
gave rise to a number of ophthalmological myths misinterpretations of the origins and character-
about INS, its characteristics, and the effects of istics of INS that were unintended, and later dis-
therapies that would not be disproven until the avowed, by Cogan.24 It was theorized that there
advent of more modern eye-movement data and were two types of INS (then called “congenital
data-analysis techniques. nystagmus” or “CN”); they were called “senso-
ry-defect” and “motor-defect” (also known as
“idiopathic”) CN, respectively. The fi rst, “sen-
2.1.1.1 A N CI E N T D E S C R I P T I O NS A N D
sory nystagmus,” was putatively caused by an
T H EO R I E S
afferent defect in the visual system and was
The word nystagmus is derived from the Greek applied to INS patients who exhibited an asso-
νυσταγμός (meaning “drowsiness”), which is ciated sensory visual disorder. It was originally
derived from νυστάζειν (“to nod in one’s sleep”). proposed that, in sensory nystagmus, the poor
The earliest description of head nodding with visual acuity interrupts sensory afferent input
nystagmus was by Hadden in 1890,13 although to the ocular motor control system, which

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causes fi xation to become unstable and leads to predict the presence or absence of an underlying
a pendular oscillation of the eyes. The second, sensory visual deficit. The neurophysiological
“motor nystagmus,” implied that the oscilla- mechanism by which abnormal sensory visual
tion is driven by a primary abnormality within input from both eyes precipitates or “unhinges”
the ocular motor circuitry and was applied to INS is unknown, although it is our hypothesis
INS patients in whom the sensory visual system that the ocular motor subsystems require cal-
appears intact both clinically and electrophysi- ibration and, in most individuals, poor visual
ologically. Motor nystagmus was att ributed to input interferes with that calibration; in others,
signal errors intrinsic to the ocular motor con- even excellent visual input is insufficient to aid
trol centers, leading to a jerk nystagmus with in that calibration. Th is confusion of genetic
relatively good visual acuity. However, the myth association with true causality was unfortunate
that the presence or absence of a primary sen- and resulted in further muddying of the waters
sory deficit can be predicted on the basis of the when attempts were made to relate etiology to
clinical appearance (i.e., pendular versus jerk assumed waveform (see Section 2.1.2.1).
nystagmus) has long been dispelled.24 In fact, It is obvious that an afferent defect and the
eye-movement recordings demonstrated that presumed failure to develop fi xation reflexes
the specific types of nystagmus found in the INS cannot possibly explain a motor oscillation
had the same waveforms and underlying mecha- that is present at birth, as it is in some INS
nisms, regardless of the coincidental/facilitating patients. The reasoning behind the assertions
existence of any sensory deficits in both child- that nonvectorial defects such as achromatop-
ren and adults.25–27 INS is the direct result of an sia, aniridia, blurring due to cataracts, ocular
ocular motor control instability that may develop albinism, and so on should invariably result in
with or without an accompanying sensory deficit the highly vectorial horizontal INS is obscure at
(see Section 2.2.3). Thus, where INS and a sen- best; no specific mechanisms have ever been pro-
sory deficit coexist, the latter is a subordinate posed to explain exactly how nonvectorial sen-
factor in the development of the nystagmus, sory deficits could cause a vectorial oscillation
perhaps interfering with the normal calibration (e.g., horizontal INS). Since many patients with
of one or more of the ocular motor subsystems, INS have either minimal or no sensory defects,
thereby precipitating instability. Eye-movement it follows that such defects are not necessary con-
recordings of infants when they are attending ditions for INS. Also, since many patients who
to a visual task confi rm that the development of have the aforementioned sensory defects do not
foveation periods in INS waveforms begins early have INS, these defects are not sufficient condi-
in infancy as acuity and fi xation develop. tions for INS. Since they are neither necessary
The presumption that a sensory defect could nor sufficient, they cannot be considered causal.
cause INS was made because of the association Further discussion of the genesis and mecha-
between INS and one or more afferent defects nisms of INS appears in Section 2.1.2.
that were present in many, but not all, patients.
Pendular and jerk waveforms often coexist
2.1.1. 2 CO N N EC T I O N T O F I X AT I O N
in the same individual with INS, so that wave-
AT T E M P T
form analysis alone cannot be used to predict
the presence or absence of afferent visual path- The effects of fi xation, eyelid position, or ambi-
way dysfunction.25,26 In the case of INS, all ent light on IN have long been areas of confusion.
of the known waveforms have been recorded Different investigators arrived at contradictory
in patients with and without sensory visual conclusions concerning both or that IN might
deficits.28,29 INS has also been recorded in persist in darkness but not behind closed lids. 30
patients with visual acuities ranging from 20/20 However, when the experiments were repeated
to no light perception. Thus, infantile nystagmus while controlling for the subject’s visual and ocu-
does not “result” from poor acuity. Similarly, the lar motor intentions, it was found that the attempt
age of onset for the nystagmus cannot be used to to fi xate or direct the eyes in a given direction

Nystagmus in Infancy and Childhood • 25

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was the determining factor in the genesis of IN.31 recording systems and the control-systems
Th is is independent of lid position or ambient approach. Eye-movement data were analyzed
illumination and provides an explanation for the with the intent of determining the underlying
observation that IN could sometimes cease com- control-system mechanisms and producing a
pletely when a subject is not attending to visual or model of the OMS capable of simulating both
ocular motor tasks (i.e., while “daydreaming”). It normal and abnormal responses to controlled
is also consistent with the common observation visual target inputs. 3
that any increased arousal or stress (anxiety, fear,
anger, etc.) usually exacerbates IN.
2.1.2 Waveforms, Models, and
Although visual problems themselves are
Mechanisms
not causal, they may represent simple genetic
association and contribute to the intensity of Quantitative ocular motor data have identi-
the nystagmus. Most waveforms of INS nys- fied three underlying mechanistic slow-eye-
tagmus represent a high-gain instability in a movement defects that produce nystagmus:
slow-eye-movement subsystem, 32 but “fi xation high gain instability, visual-vestibular tone
attempt” (the effort to see) is the main driving imbalance, and integrator leak.
force. The initial observation that increased fi x- In some persons, because of abnormally high
ation attempt exacerbated IN was made while gain in a slow-eye-movement subsystem, a run-
patients attempted to read visual acuity charts; away (increasing velocity) movement or a pen-
it did not separate the increasing visual demand dular oscillation is evoked. The term “high gain”
with each smaller line from the stress associated can also imply excessive delay for the gain pre-
with reading it accurately. Poor vision could sent (i.e., the control loop may have a normal
increase fi xation effort and the accompanying gain but an increased delay). Control theory sug-
stress increase the intensity of the nystagmus. 31 gests how particular changes in gain can result in
Moreover, a subclinical motor instability may either a pendular or a jerk nystagmus. Pendular
become manifest by this exaggerated visual nystagmus can be “congenital” (see Section 2.2)
effort. The observation that IN sometimes per- or acquired, whereas horizontal jerk nystagmus
sists with eyes open in darkness (when the sub- with slow phases of increasing velocity usu-
ject will probably attempt to “see”) and damps ally is associated with “congenital” nystagmus;
behind closed lids (when the subject will, unless however, the latter may result from an Arnold-
instructed to the contrary, reduce any attempt to Chiari malformation. 36 Vertical nystagmus with
“see”) is compatible with its genesis. 33 Because an exponential slow phase of increasing veloc-
the defi ning criterion is fi xation attempt, not ret- ity may be secondary to acquired cerebellar
inal illumination or lid position, reports of the disease. 37
absence of nystagmus with lid closure or dark- Tonic imbalance of the visual-vestibular sub-
ness without a description of the instructions system (i.e., the combined optokinetic and ves-
to the subject, provide litt le useful information. tibular subsystems) results from the imposition
Abel et al. demonstrated that although fi xation of asymmetric input on an inherently normal
attempt was responsible for the genesis of IN, horizontal gaze generator. If one vestibular appa-
stress was the key factor affecting the resulting ratus (labyrinths, nerve, and brainstem nuclei)
intensity of IN. 34,35 Because the driving force in functions abnormally, if both sides are asymmet-
IN is fi xation attempt or effort, with or without rically defective, or if there is a central imbalance
actual fi xation, IN is not a “fi xation” nystagmus. of the optokinetic subsystem, such an asymmet-
ric input results. The nystagmus produced has
a linear (straight line) slow phase, reflecting a
2.1.1.3 M O D E R N P H Y S I O L O G I C A L
persistent tone to drive the eyes toward the side
I N V E S T I G AT I O N
of the relatively damaged vestibular apparatus.
The modern era of INS research began in the The slow-phase amplitude is reduced by fi xation
1960s with the advent of accurate eye-movement and enhanced by darkness, Frenzel (high-plus)

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lenses, or closing the eyes. Fixation inhibition may obviate unnecessary neurodiagnostic pro-
may be related to an opposing smooth-pursuit cedures; its characteristics are listed in Table
force and requires the integrity of the cerebellar 2.1. INS is almost always binocular and rarely
flocculus. shows more than minor amplitude dissociation
“Leaky integrator” nystagmus occurs only in between the two eyes. Clinically, the nystag-
an eccentric gaze position; thus, it is gaze-evoked mus usually appears uniplanar. Like vestibular
(also called “gaze-paretic”) nystagmus. The eyes end-organ nystagmus, horizontal nystagmus
are unable to maintain the eccentric position remains horizontal when the eyes are deviated
and drift back to the primary position with a vertically and does not convert to vertical nys-
decreasing velocity, reflecting a passive move- tagmus. Unfortunately, clinical observation can
ment resisted by the viscous forces of orbital soft only provide superficial, and often incorrect,
tissues. The defect may reside in the brainstem characteristics of INS waveforms. In “pendu-
“neural integrator” or its connections (such as in lar” nystagmus, the eyes appear to oscillate with
the cerebellum), which mediate eye deviation. “equal speed” in either direction and in “jerk”
One can classify nystagmus based on nystagmus, movement in one direction appears
whether it is “gaze evoked” or “gaze modu- faster than in the other; unfortunately, some
lated”; the former category requires that there jerk nystagmus waveforms appear clinically to
be no primary-position nystagmus. INS, FMNS have equal speed in both directions, resulting in
(see Chapter 3), physiologic types (vestibular), misdiagnoses.
and symptomatic types (vestibular) fall in the Even with oculographic recordings, the
gaze-modulated category. Some physiologic direction of the fast phase may be misinter-
types (end point) and symptomatic types (gaze preted unless velocity tracings are obtained. 33
paretic) are gaze evoked. Although these con- In the absence of oculography, clinicians should
cepts of a control mechanism represent useful describe the nystagmus carefully at differ-
approaches toward a more meaningful classifi- ent gaze angles, during convergence, and over
cation of nystagmus, they are far from inclusive. time. The inability to accurately differentiate
pendular from jerk INS waveforms using clini-
cal observation alone was further evidence that
2.1. 2.1 WAV E F O R M T Y P E S
one could not equate “pendular” waveforms
The recognition of INS is of extreme impor- with the so-called sensory CN and jerk wave-
tance, particularly in the adult patient, and it forms with the so-called motor CN. Monocular

Table 2.1 Characteristics of Infantile Nystagmus

Binocular with similar amplitude in both eyes
Usually horizontal and torsional (vertical rare)
Pendular or increasing velocity slow phases
Distinctive waveforms with foveation periods and braking saccades
Asymmetric aperiodic alternation possible (Baclofen ineffective)
Provoked or increased by fi xation attempt
Abolished in sleep or inattention to visual tasks
Gaze modulated, not gaze evoked
Diminished (damped) by gaze-angle or convergence nulls
Superimposition of latent component possible
“Inversion” of the optokinetic reflex (actually, null-shift-induced reversal of the infantile nystagmus)
Associated head oscillation (not compensatory) or turn
No oscillopsia except under rare conditions

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visual deprivation induced, in some monkeys, a there are sufficient differences to further subdi-
diagonal nystagmus whose horizontal compo- vide the latter into unidirectional and bidirec-
nent initially looked like FMN slow phases (see tional jerk waveforms. The latter almost always
Chapter 3) and then developed to resemble IN have the clinical appearance of pendular IN and
slow phases. The deprivation took place from led to the clinical misimpression that pendular
birth to 25 days and was followed by monocular waveforms were more prevalent than they actu-
deprivation of the other eye. 38 In monkeys, the ally are.25 In a study of 224 patients with INS
role of the NOT in FMNS has been more clearly Abadi et al. found conjugate, uniplanar hori-
defi ned. 39,40 zontal oscillations were present in 174 (77.7%)
True pendular nystagmus is sinusoidal, and while 32 (14.3%) had a torsional component.29,43
true jerk nystagmus begins with a slow phase The most common oscillation in their group was
away from the object of regard, followed by a fast, a horizontal jerk with extended foveation (n =
corrective (saccadic) phase toward the target. 49; 27%).
Despite the slow-phase genesis of all types of Eye-movement recordings of INS occasion-
nystagmus, the direction of the fast component ally show a pure pendular waveform (sinusoi-
is used, by convention, to defi ne the nystagmus dal) or a sawtoothed waveform (equiamplitude
direction. Although nystagmus can be described linear slow phase with foveating saccade) typi-
when the globes are inspected under slit-lamp cally seen in vestibular nystagmus. These pure
magnification, or when the fundus is viewed, forms are neither frequent nor pathognomonic
due to the complexity of INS waveforms and the for INS. More often, INS manifests distinctive
probability of combinations of different types waveforms that are not present in acquired nys-
of nystagmus, only ocular motility recordings tagmus. Complex INS waveforms are an expres-
can guarantee accurate and repeatable diagno- sion of the attempts by the ocular motor control
sis and assess complex waveform characteristics. system to achieve and increase foveation time,
It should be noted that nystagmus amplitude imposed on inherently unstable slow control. The
and intensity are purely cosmetic measures and INS waveforms shown in Figures 2.1–2.3 (other
do not accurately represent the potential visual than pure pendular or jerk) have never been
acuity of INS waveforms. To do so, a foveation recorded in acquired horizontal nystagmus.25,29
function, such as the eXpanded nystagmus acu- The target position is indicated by a dashed line;
ity function (NAFX) is required since wavelet target position is problematic for pure and asym-
analysis is too insensitive and failed to identify metric pendular waveforms.
the important foveation periods in INS wave- Our research and OMS modeling demon-
forms.41 One should note the positions of gaze strated that most of the INS pendular and jerk
in which the nystagmus occurs and whether waveforms were manifestations of a single
the intensity changes with gaze direction. Jerk sinusoidal (pendular) velocity oscillation in
nystagmus usually increases in amplitude upon the damping-control feedback loop of normally
gaze in the direction of the fast component, underdamped, smooth pursuit.4,44–52 Based on
a characteristic referred to as Alexander’s law42 these recent demonstrations that most INS
(see Sections 2.2.3.1 and 2.2.3.2). waveforms are derived from the same pendular
Accurate methods of ocular motility record- velocity oscillations of an undamped smooth
ing allowed identification of the various INS pursuit system and the documentation of a
waveforms; this resulted in the ability to defi ni- “dual-pendular” INS waveform, the original
tively diagnose INS and differentiate it from morphologically based classification can now
other types of nystagmus, both benign and be related to presumed ocular motor etiology
symptomatic. A total of 12 waveforms were iden- (Figs. 2.1–2.3). Th is regrouping required dif-
tified, not simply pendular or jerk, as had been ferentiating linear slow phases from the more
claimed based on clinical observations alone.25 common accelerating slow phases of jerk nys-
Although INS waveforms could be classified tagmus, based on presumed mechanisms (visu-
into the general categories of pendular or jerk, al-vestibular and pursuit-system, respectively).

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FIGURE 2.1 Illustrations of pendular and unidirectional jerk infantile nystagmus syndrome
(pursuit-system nystagmus [PSN]) waveforms. Note the accelerating slow phases. Target (foveation) posi-
tion shown by dashed lines. In all figures, by convention, eye motion to the right, up, and clockwise is up, and
to the left , down, and counterclockwise is down; all directions are from the patient’s point of view. When not
labeled, data are from the foveating eye. AP, asymmetric pendular; J, jerk; J EF, jerk with extended foveation;
L, left; P, pendular; PC, pseudocycloid; PFS, pendular with foveating saccades; PJ, pseudojerk; PP, pseu-
dopendular; PPFS, pseudopendular with foveating saccades; R, right.

FIGURE 2.2 Illustrations of jerk infantile nystagmus syndrome (visual vestibular system nystagmus
[VVSN]) waveforms. Note the linear slow phases. Target (foveation) position shown by dashed lines. BDJ,
bidirectional jerk; J, jerk; L, left; R, right; T, triangular.

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FIGURE 2.3 Illustrations of dual-jerk and dual-pendular INS + NOT waveforms. The DPFS, DJR A , and
DJR EF are pursuit-system nystagmus (PSN) and the DJR L is visual vestibular system nystagmus (VVSN).
DJR A , dual-jerk right with accelerating slow phases; DJR EF, dual-jerk right with extended foveation; DJR L ,
dual-jerk right with linear slow phases; DPFS, dual pendular with foveating saccades; INS, infantile nystag-
mus syndrome; NOT, nucleus of the optic tract.

The presence of dynamic overshoots in the fast name). The dual-pendular nystagmus (DPFS)
phases (saccades) of INS waveforms (and in was identified from the fi rst recording of a high-
normal saccades) is both idiosyncratic and var- frequency, pendular NOT nystagmus super-
iable; for simplicity, we have not included them imposed on a low-frequency, pendular with
in Figures 2.1–2.3. Because dynamic overshoots foveating saccades IN; it is shown in Figure 2.4
are not an abnormality per se, their presence (see also Fig. 2.7 bottom right). Twelve of these
does not represent a “different” waveform. waveforms are pathognomonic of INS; P, AP,
The nine waveforms shown in Figure 2.1 J L , and DJ L are not.
are due to pursuit-system instability and are, For pendular waveforms, the target is fove-
therefore, “pursuit-system nystagmus” (PSN- ated at the peaks that are more flattened, indi-
Pendular and Pseudo Pendular and PSN- cating extended foveation. The demonstration
UNIDIRECTIONAL). The three in Fig. 2.2 of extended foveation in an adult with lifelong
are due to visual vestibular imbalance and are nystagmus secondary to a congenital brain-
“visual vestibular system nystagmus” (VVSN). stem hamartoma and in an adult given gabap-
In addition, the four “dual” waveforms (PSN entin for treatment of nystagmus secondary to
+ NOT [DPFS, DJR A , and DJR EF]; and VVSN an arteriovenous malformation53 supports the
+NOT [DRJ L]) shown in Fig. 2.3 are due to hypothesis that extended foveation periods in
the low-amplitude, high-frequency pendular INS waveforms represent the action of a normal
“nucleus of the optic tract” (NOT) nystagmus fi xation system on the underlying INS oscilla-
added to one of the pendular and three of the tion. The pure pendular (P) and jerk (J) wave-
jerk INS waveforms shown in Figures 2.1 and forms in Figures 2.1 and 2.2 are not conducive
2.2 (although other combinations may occur, to good acuity because of the extremely short
they have not yet been recorded). The term foveation times. Although these are common
“dual” in the names refers to either (1) the acquired waveforms, when affl icted with INS,
two independent mechanisms (NOT insta- the developing nervous system “modifies” pen-
bility plus either PS oscillation or VVS imbal- dular and jerk waveforms; therefore, foveation
ance) responsible for the resulting nystagmus time (and thus acuity) is increased. Figure 2.5
or (2) the superimposition of two waveforms demonstrates how these resultant waveforms
(high-frequency, low-amplitude pendular plus serve to increase the time of foveal imaging. In
the INS waveform identified in the particular the pendular nystagmus with foveating saccades

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FIGURE 2.4 Illustration of the dual pendular with (left ward) foveating saccades (DPfs) INS + NOT
waveform. It consists of an ~5°, 3.5 Hz pendular NOT nystagmus superimposed on an ~15°, 2 Hz pendular
with foveating saccades INS waveform. DPfs, dual pendular with foveating saccades; H, horizontal; INS,
infantile nystagmus syndrome; LE, left eye; NOT, nucleus of the optic tract.

waveform (PFS—left ward foveating saccades Both adults and infants show dramatic
shown), there is usually a substantial period of changes in waveform when going from fi xation
time after the foveating saccades when the target to a state of low arousal. 29 In Figure 2.6, the
is imaged on the fovea and the eye is motionless INS waveforms of several subjects are shown.
(after instants 0 and 3 on the time axis). In jerk- During fi xation the waveforms were jerk or
right nystagmus with extended foveation (JR EF), dual jerk with amplitudes up to 8° peak to peak
the position from times 0 to 1 or after 3 are when and frequencies of 2–4 Hz, whereas during the
foveation takes place, and in the bidirectional low state of arousal the waveform became pen-
jerk-left (BDJL) waveform, the position from dular, the amplitudes rose to 15° to 60°, and
instants 4 to 5 is conducive to good acuity. the frequency dropped to about 1 Hz. IN may

FIGURE 2.5 Illustrations of three infantile nystagmus syndrome waveforms with their respective eyeball
rotations showing the periods of extended foveation following each waveform’s foveating saccade. In the
pendular with foveating saccades (PFS) and jerk right with foveating saccades (JR EF) waveforms, the fove-
ation periods after foveating saccades “2–3” and in the bidirectional jerk-left (BDJL) waveform, after foveat-
ing saccade “3–4.”

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FIGURE 2.6 Illustrations of infantile nystagmus syndrome waveform changes of three patients during
periods of inattention (pursuit-system nystagmus) waveforms. Target (foveation) position shown by dashed
lines (left top and bottom) or solid line (right). DJ, dual jerk; J, jerk; Jef, jerk with extended foveation; L, left;
P, pendular; R, right.

also be present during various stages of sleep. eye always accomplishes that fi xation; in fact,
Th is dramatic slowing and/or damping of IN eye-movement data show that it often does not.
with inattention results in intervals of data Analysis of the nonfi xating eye cannot be used
that must be eliminated from analysis when to predict visual function.
attempting to assess the potential visual acu- It should be emphasized that the superim-
ity of the patient’s INS waveform during visual posed pendular component of dual-jerk or dual-
attention to a nonstressful target (e.g., a laser pendular INS waveforms is not synonymous
spot or LED). Th at, and the possibility of alter- with the pendular INS waveforms. The latter
nation of the fi xating eye during an interval of are of lower frequency and higher amplitude
attempted fi xation on a target, precludes accu- than this superimposed pendular component
rate, automatic analysis of long intervals of eye- of dual waveforms, suggesting different mecha-
movement data if that analysis is to correlate nisms and sites of origin. Another distinction is
to visual function. We typically analyze only that pendular INS waveforms may be improved
2–5 seconds of data from the fi xating eye (eas- by braking and foveating saccades. In fact, Tusa
ily determined from monocularly calibrated et al. demonstrated in monkeys that this low-
eye-movement data) at each fi xation point and amplitude, high-frequency pendular nystagmus
do so several times to ensure accuracy. One was due to an abnormality in the circuitry of the
cannot presume the “dominant” or “favored” NOT. 38 Th is NOT nystagmus may appear super-

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imposed on either INS or FMNS (see Chapter 3) making accurate diagnosis of the nystagmus
waveforms and, when INS is damped (e.g., due critical before attempting to determine the best
to convergence, gaze angle, or time variation), therapy or assess its effects on the INS waveform
the NOT nystagmus may persist or be damped (see Chapter 7).
to a lesser degree (Fig. 2.7). The data in the top Figure 2.8 shows outputs from our behav-
panel are from identical twins who both showed ioral OMS model during fi xation at 0°. As shown
INS damping with convergence but litt le damp- in the top left and right panels, these model out-
ing of the NOT component. The bottom panel puts accurately simulate patient eye-movement
is from a patient with only a uniocular NOT recordings of different waveforms. The bottom
component that also damped minimally com- panel demonstrates the accuracy of foveation
pared to the INS component. The bottom data periods in PPFS and J EF waveforms as well as
show both DJ and DP waveforms at near, the lat- the transitions from PPFS to either JR EF or JL EF,
ter, due to inattention. These observations sup- including centripetally accelerating slow phases,
port several conclusions. First, the mechanisms as gaze is directed to the right or left of the neu-
for NOT and pendular INS waveforms differ. tral zone, respectively. Bias shifts that alter the
Second, neuroanatomical sites may also differ. foveation periods from one side of a pendular
Finally, based on Figure 2.7, the responses of nystagmus to the other (common in INS) are
NOT and INS waveforms to therapy can differ, simulated during fi xation on the target 5° to the

FIGURE 2.7 Illustrations of the effects of convergence on both the infantile nystagmus syndrome (INS)
(1.5 Hz) and nucleus of the optic tract (NOT) (5 Hz) components of dual-jerk and pendular waveforms in
identical twins (top) and a patient with a uniocular NOT (8 Hz) component (bottom). Both twins show
greater INS-component damping than NOT-component damping. The uniocular NOT component in the
bottom tracings also was damped less than the INS component. The dual pendular waveforms (INS, 0.5 Hz)
at near occurred when the patient was inattentive (bottom right tracings). Note the square-wave jerk during
the far to near transition. Large spikes in the data are due to blinks. LE, left eye; RE, right eye.

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FIGURE 2.8 Behavioral ocular motor system model simulations of foveation accuracies and waveform
transformations at different gaze angles. In top left panel, accurate foveation at 0° with pseudopendular with
foveating saccades (PPFS), jerk-right nystagmus with extended foveation (JR EF [upper trace]), and jerk-left
nystagmus with extended foveation (JL EF [lower trace]) are shown (the latter two shifted for clarity). In the
top right panel, right pseudocycloid (RPC [upper trace]) and left pseudopsycloid (LPC [lower trace]) are
also shown with RPC shifted. In the bottom panel, both waveform transitions from PPfs to JRef and JLef
and amplitude increases are shown as gaze is directed away from the neutral zone. Note the bias shift at 5°.
Foveal extent (±0.5°) is indicated by dash-dot lines.

right; this is one of the many emergent proper- low-bandwidth, bitemporal EOG. By subtract-
ties of the model. ing the power spectrum of a pure sawtooth
In an attempt to determine whether the pen- waveform from the dual-jerk waveform, the
dular part of dual-jerk waveforms was truly authors were able to emphasize the pendular
sinusoidal, Reccia et al. used spectral analysis. 54 component. Their statistical analysis concluded
Unfortunately, the data were obtained using that a sinusoidal fit would better approximate

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the data than an exponential fit; the latter was there for some time before the oscillation
suggested by Optican and Zee in their attempt causes them to accelerate away from the
to model one of the waveforms of INS.10,55 intended position. 31 These “foveation periods”
Sensitive techniques for recording torsional are repeatable and could last several hundred
eye movements documented small but signifi- milliseconds. Th is demonstration by retinal
cant torsional components in the nystagmus of cinematography and accurate eye-movement
subjects previously thought to have purely hori- recordings was counter to the prevailing clin-
zontal INS. 56 Because the prominent horizontal ical description that INS caused the eyes to
movement masks the usually smaller torsional oscillate about the intended line of regard.
component, the latter appears to be a common Th at putative description failed to account for
characteristic of “horizontal” INS. In most the high acuity possible in INS, whereas the
patients, rightward movements were accompa- discovery of the foveation periods does. They
nied by clockwise torsion and left ward move- provide the needed time for foveal imaging of
ments by counterclockwise torsion. 57 We also a target while retinal slip velocity is low enough
documented a subclinical seesaw nystagmus in not to degrade vision appreciably. The identifi-
INS (see Fig. 2.15 in Section 2.1.10). 58 cation of foveation periods in INS waveforms
was the pivotal discovery responsible for the
development of eye-movement data analy-
2.1. 2.2 B R A K I N G A N D F OV E AT I N G
sis methods coupling the quality of foveation
S A CC A D E S
periods to the best potential visual acuity of
One important feature of INS waveforms is the any INS waveform (see Section 2.1.9).
presence of “braking saccades” that act to stop
runaway slow phases. Braking saccades serve to
2.1. 2. 4 F OV E AT I O N ACCU R A C Y
brake, or even stop, IN slow phases. Their identi-
fication in a study of INS waveforms uncovered Although eye-movement recordings suggested
a stimulus for saccades that was unknown prior that each foveation period brought the eyes to
to that point. 59 That is, saccades could serve the same position vis-à-vis the target, it was not
solely to stop runaway eye movements rather until scleral search coils were introduced that
than their normal function to reposition the a method sensitive and stable enough to study
eyes. In INS waveforms, braking saccades could the accuracy of foveation periods during fi xa-
perform both functions simultaneously; they tion, smooth pursuit, or VOR was available. 62–64
are then called “foveating saccades.” Subsequent The knowledge gained from those seminal
studies demonstrated that braking saccades studies allowed intelligent use of infrared
were triggered by eye velocity approximately 40 measurement systems, which were replaced,
msec prior to their execution and did effectively decades later, by high-speed digital video
brake the slow phases of IN.60 They are triggered systems. If foveation periods could not place
by extraretinal eye-velocity information and the image in the foveal area on a beat-to-beat
when the superimposed slow-phase velocities basis, acuity would suffer and the added prob-
are taken into account, braking saccades have lem of oscillopsia could result. The absence of
the same velocity-amplitude characteristics as oscillopsia in most INS subjects (under nor-
normal saccades and are generated by the same mal viewing conditions) was initially taken
mechanism; the latter was demonstrated using as strong evidence that the foveation periods,
an OMS model.61 by allowing consistent target foveation at least
once during each beat of IN, also suppressed
oscillopsia (see Section 2.1.10).
2.1. 2.3 T H E F OV E AT I O N P E R I O D
Increased foveation time is the most effective
More important than the various waveforms determinant of increased acuity. 31,65–67 The com-
was the demonstration that during each IN bination of foveation time along with foveation-
cycle the eyes begin on target and remain position and foveation-velocity accuracies are

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the three key elements determining foveation 2.1. 2.5 TA R G E T ACQ U IS I T I O N T I M E

quality and, therefore, potential visual acuity.
Extended target acquisition time (i.e., the length
Clearly, they should be measured and serve as
of time required to acquire and accurately fi x-
primary therapeutic outcome measures; ideally
ate each new target in the field of view) is one of
a function like the NAFX, containing all three,
the limitations to overall visual function expe-
should serve that purpose (see Sections 2.1.9.1
rienced by those with INS—they are “slow to
and 2.3.1.1). In most INS subjects, the best
see.” Yet this is not routinely measured either in
waveform (i.e., most foveation time per cycle)
the clinic or the laboratory. In normals, it is very
is in the null region associated with a particular
fast, being limited only by saccadic latency and
gaze or convergence angle. When it is not, the
intersaccadic reaction time; each is on the order
gaze or convergence angle that yields the best
of 200 msec. However, despite having approxi-
waveform is used, even if not the waveform
mately the same saccadic limitations in latency
with the least amplitude. Because decreased
and intersaccadic reaction time, persons with
amplitude is the major determining factor in
INS may take 1–2 seconds to accomplish the
cosmetic improvement, a young patient’s par-
same task. 69 That does not include the extra
ents appreciate it. Despite a damping of the nys-
time and stress involved if one has only a nar-
tagmus, an individual with INS may not show
row range of gaze angles where one’s acuity is
an increase in peak acuity with convergence if
highest (the so-called null region discussed in
the resulting waveform still has litt le foveation
Section 2.1.5). Thus, in a common, real-world
time per cycle (i.e., low NAFX), or if acuity is
situation of entering a crowded room and fi nd-
primarily limited by a visual deficit (i.e., the
ing and identifying those persons you know,
waveform at distance already had well-devel-
what is a simple, easily and quickly done task
oped foveation and a high NAFX). However,
becomes a longer and more stressful one. Target
even in such cases, broadening of the range of
acquisition time is an important visual function
gaze angles where the patient’s acuity is highest
measure that should be included in therapeutic
will still improve visual function sufficiently to
outcome measures.
justify therapy. The fi xation system of someone
with INS is able to repeatedly foveate a target
within minutes of arc, almost as accurately as
2.1. 2.6 S M O OT H P U R S U I T
a normal person.62,65,68 That fi rst use of “phase-
plane” analysis in INS allowed defi nition of a Understanding the smooth pursuit system is
“foveation window” (±0.5° by ±4.0°/second) essential to the understanding of the mecha-
for the study of fi xation, smooth pursuit, and nisms underlying INS. Evidence from the fi rst
the vestibulo-ocular reflex (VOR). 62–64 These study of INS by Dell’Osso implicated smooth
studies demonstrated the extremely accurate pursuit in the generation of INS. 3 Subsequent
fi xation, pursuit, and VOR possible in individu- external feedback experiments on a subject
als with INS. In Figure 2.9, the tight overlap of with INS produced exacerbated IN rather than
foveation periods within the foveation window the saccadic oscillations seen in normals. 32 Th at
in the phase plane demonstrates how accurate is, the normally underdamped smooth pur-
the cycle-to-cycle target foveation in INS can suit system became undamped in INS and its
be despite the variation during the rest of the oscillations grew larger with externally altered
waveform. The foveation window defi nes the feedback of eye motion. Although the exact
time when the eye is within ±0.5° of the tar- anatomical location of the source of the insta-
get and moving with less than ±4°/sec. Thus, bility present in INS nystagmus is unknown,
despite an ocular oscillation whose amplitude is we hypothesized that the various pendular
well outside the foveal extent and whose veloc- waveforms (and some jerk waveforms) are due
ity exceeds ±30°/sec, the OMS can foveate the to a gain/delay problem in an internal (brain-
target with extreme accuracy and allow normal stem) feedback loop in the pursuit subsystem
visual acuity. (i.e., not the actual smooth-pursuit gain, which

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FIGURE 2.9 Th ree cycles of infantile nystagmus syndrome data showing the foveation accuracy of a
pseudopendular with foveating saccades (PPFS) waveform. Eye position and velocity (left panel) and phase
plane (right panel) data contain foveation periods within the ±0.5° foveal and ±4°/sec retinal slip boundar-
ies (dash-dot lines) for good vision. These boundaries determine the foveation window (dashed lines) in the
phase plane.

is normal). 32 Later studies of smooth pursuit the “internal monitor” (i.e., the “brains” of the
demonstrated that despite the superimposed model) to determine ocular motor responses.
INS oscillations, the smooth pursuit system Simulations from this model are used to illus-
performed its task of tracking moving targets trate INS characteristics.
normally. 63,70,71 Thus, the pendular (and most Additionally, this behavioral OMS model
jerk) nystagmus waveforms of INS identi- demonstrated how the same pendular oscil-
fied as “pursuit-system” nystagmus (PSN) in lation in the smooth pursuit’s damping con-
Figures 2.2–2.4 are actually a velocity oscil- trol could produce both the pendular and jerk
lation, modified by the saccadic system’s waveforms of INS. 50,51 The body of this research
attempts to foveate the target and the fi xation provided strong support for the hypothesis that
subsystem’s attempt to extend foveation (pos- the direct cause of INS is an uncalibrated (and,
ition alterations). Th is hypothesis is embod- therefore, undamped) smooth pursuit system.
ied in a physiologically realistic, behavioral See Section 2.1.4.2 for a discussion of smooth-
OMS model.4,44,45,47 Version 1.5 of this model pursuit responses in INS. Recent studies in
is shown in Figure 2.10. Th is model contains juvenile macaques support our hypothesis that
each of the ocular motor subsystems neces- the pendular oscillations that are the basis for
sary for simulation of fi xed-head responses to most INS waveforms are due to oscillation in
common target inputs. Provision has also been the smooth-pursuit damping circuitry.72
made in the model for adding both vestibulo- The much greater frequency of horizontal-
ocular and optokinetic subsystems. The model torsional nystagmus, compared with vertical
is based on reconstructed target position and or diagonal nystagmus, probably reflects inher-
velocity signals to drive the responses and pro- ent differences in the stability of the respective
vide oscillopsia-free perceived target signals. pursuit subsystems (i.e., the horizontal is more
Also, the neural integrator function is split unstable than the vertical). Although there is
into two portions, each responsive to different no torsional smooth pursuit system per se, the
types of signals, in accordance with current torsional component of the nystagmus reflects
neurophysiological data. All sensory input and instability in torsional control. 56 Another fac-
efference-copy motor signals are utilized by tor in support of the hypothesis of PSN is that

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02_Hertle_Ch02.indd 38
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FIGURE 2.10 Block diagram of version 1.5 of a behavioral ocular motor system (OMS) model capable of simulating normal and abnormal (various types of nystag-
mus and saccadic intrusions and oscillations) responses to various target inputs. In addition to the saccadic, smooth pursuit, and fi xation subsystems are two types of
neural integrator networks, provision for efference copy of motor commands, an internal monitor to reconstruct needed target position and velocity signals that are
free of oscillopsia, and the ocular motor plant.

9/6/2012 9:48:42 PM
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no oscillopsia is perceived from oscillations in by patients with either the INS or FMNS.78
pursuit velocity, not in normals and not in those Goldstein suggested that INS might be caused
with INS. Thus, no additional “adaptation” by oscillations at two frequencies whose interac-
mechanism need be proposed to account for the tions may approximate some of the known INS
absence of oscillopsia in INS; it is suppressed by waveforms.79 However, such interactions do not
the same efference-copy mechanism by which produce the absolutely motionless (i.e., “flat”)
normals suppress it during pursuit (see Section periods of extended foveation (300–400 msec)
2.1.10). recorded in many patients.
Initially, we proposed that excessive pos-
itive feedback around the common neural Clinical Pearl: Based on the research of
integrator might be responsible for the accel- the past 50 years, the INS in all patients is
erating slow phases of INS nystagmus.73 We directly caused by instability in smooth pur-
subsequently demonstrated that the common suit damping plus a variable amount of tonic
neural integrator is not the site of the INS insta- imbalance in the visual-vestibular system.
bility.74 However, several models have been Thus, INS is a motor oscillation with known
proposed that attempt to explain the genesis of motor causes, making the adjective “motor”
some INS waveforms, based on that disproved (e.g., motor nystagmus or congenital motor
premise. 55,75,76 Although each can generate nystagmus) redundant. Similarly, the terms
limited, specific INS waveforms, such models “sensory” and “idiopathic” are both incorrect
exhibit behaviors inconsistent with data from and misleading. None of these terms should
individuals with INS and, more important, do be used in describing INS.
not simulate the known broad range of human
ocular motor responses (both normal and dur- Therefore, the aforementioned terms are not
ing nystagmus) to common stimuli. Thus, they used herein.
are simply demonstrations of putative computer
mechanisms to generate waveforms rather than
2.1.3 The Static Neutral Zone/Region
physiologically realistic models capable of simu-
lating OMS behavior. The static neutral zone is the range of gaze angles
Because INS appears to be activated and in which a reversal of direction of jerk nystagmus
intensified by fi xation attempt accompanied occurs and in which either no nystagmus, any
by stress, 34 the deficit may also be linked to the of several bidirectional waveforms, or pendular
fi xation subsystem. Stress is the major factor in nystagmus is present. During fi xation of station-
modulating IN. One study found that task-in- ary targets, many individuals with INS also have
duced stress and motivation reduced foveation a permanent null region representing the gaze
periods. 35 However, increased fi xation attempt angle at which the nystagmus is minimal and the
due to increased visual demand in the absence waveform most conducive to highest NAFX and
of stress may increase foveation times,77 sug- acuity. In most cases of IN, the neutral region
gesting that the fi xation system, like the sac- straddles the null and contains either pendular
cadic system, is corrective and part of the OMS’s or bidirectional jerk waveforms. To the left of
attempts to overcome the basic INS oscillation the static neutral zone, the IN is jerk left and to
(i.e., it is not the cause of INS). The coexistence the right, jerk right. The term “static” indicates
of a high-frequency pendular oscillation with a that the region was measured during fi xation
low-frequency INS waveform (resulting in one of stationary targets at different gaze angles. In
of the dual waveforms) in some INS subjects and INS, the static neutral zone may be a function
also in dual-jerk FMN supports the hypothesis of static gaze angle or the fi xating eye (INS with
that the high-frequency pendular oscillation is a latent component, next section). INS patients
due to an instability at a different site and is not often turn their heads to permit straight-ahead
an INS waveform. Available evidence points to viewing with the eyes in the null region. Such
the NOT as the site of this oscillation shared patients benefit from appropriate version prism

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spectacles that alleviate the necessity for the underlying the null shift is thought to stem from
head turn and the resulting increased stressful the Alexander’s law alteration of slow-phase
fi xation attempt. 33,80 However, if the IN damps velocity with gaze angle that is part of the vis-
with convergence, the higher NAFX values will ual vestibular subsystem (see also Chapter 5,
persist over a broader range of gaze angles than Table 5.4). Rarely, a null shift is toward the view-
during fi xation on a far target (see Section 2.1.6). ing eye. 33 There have been, and continue to be,
Th is allows higher acuity over most useful gaze clinical reports of INS patients with “two” nulls.
angles and demonstrates the advantage of either Indeed, one such report contained eye-move-
base-out prisms or the bimedial rectus reces- ment recordings purported to demonstrate
sion procedure over therapies aimed at moving different nulls during near and far fi xation.82
a gaze-angle null to primary position. However, careful review of the eye-movement
data in the aforementioned paper suggests that
the patient had INS plus a latent component (and,
2.1.3.1 L AT E N T CO M P O N E N T
based on the waveforms during near fi xation,
Some INS patients exhibit a “superimposed INS plus FMNS). That combination resulted
latent” component that induces null shifts in the expected shift of the null in the direction
toward an eye that is covered. Figure 2.11 shows opposite to the fi xating eye. At distance, fi xa-
the latent shift for an esotrope (top left panel) tion was with the left eye, resulting in jerk-left
and an exotrope (top right panel) for either the nystagmus with a null to the right and at near,
left or right eye fi xating; both IN magnitude and fi xation with the right eye resulted in jerk-right
NAFX values are shown with their respective nystagmus with a null to the left . Multiple-gaze-
nulls and peaks. For example, in an esotrope fi x- angle monocular calibration records for each
ing with the left eye, the null (or NAFX peak) eye would have made this evident and prevented
shifts into right gaze; the opposite occurs for the misinterpretation. In every case we have
right-eye fi xation. If the null shift is sufficient, a recorded, the appearance of more than one null
direction reversal of jerk IN in primary position in INS resulted from a shift in the fi xating eye in
will be observed each time cover is reversed. The a patient with INS plus a latent component.
right panel shows how an exotrope may exhibit
an opposite shift . The bottom panel demonstrates Clinical Pearl: Patients with INS and two
the latent-component shifts in another way that static (or multiple) head postures should be
helps visualize the INS direction reversal. For examined for a latent component, FMNS or
example, when the right eye is occluded, the APAN.
null shifts right, moving primary position into
the jerk-left INS field and vice versa. Because the
2.1.4 The Dynamic Neutral Zone/
static neutral zone shifts away from the fi xating
Region
eye when the other eye is occluded, the direc-
tion of jerk nystagmus may reverse with alter- If one measures the characteristics of INS wave-
nate cover.81 Th is clinical observation may be forms at various gaze angles while the subject is
mistaken as an indication of FMNS. However, tracking a moving target, the amplitudes will also
without eye-movement recordings to differenti- vary but the neutral zone (and “null” angle) will
ate the two conditions based on the slow phases usually be found to be at an angle displaced from
of the two waveforms, INS with a latent com- the static neutral zone in the direction opposite
ponent may be misdiagnosed as FMNS or vice to the pursuit direction (target motion). Th is
versa. Such misdiagnoses can result in improper neutral zone is referred to as the dynamic neu-
surgeries with problematic results. tral zone and its position is a function of super-
Demonstration of such a shift and mainte- imposed eye velocity, both speed and direction
nance of any of the INS waveforms establishes (due to pursuit, optokinetic, or vestibulo-ocular
the nystagmus as belonging to INS rather eye movements). The importance of recogniz-
than the FMNS (see later). The mechanism ing the existence of dynamic shifts in the static

40 • I N FA N T I L E N Y STAG M US S Y N DROM E

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02_Hertle_Ch02.indd 41
FIGURE 2.11 Illustrations of latent component shifts (eXpanded nystagmus acuity function [NAFX] peak and infantile nystagmus syndrome [INS] null) with alternate occlu-
sion for an esotrope (top left) and an exotrope (top right). The bottom panel illustrates how such shifts affect the movement of primary position with respect to the INS null.
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9/6/2012 9:48:43 PM
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neutral zone became evident when analyzing disease, neurodegenerative conditions such as
the variable and confusing responses meas- Friedreich’s ataxia, or vision loss.
ured during optokinetic, pursuit, and vestibulo- The dynamic neutral zone in INS may also
ocular stimulation. The dynamic neutral zone vary spontaneously with time while fi xating a
shifts occur instantaneously during smooth pur- static target. However, such INS patients exhibit
suit (or optokinetic or vestibulo-ocular eye move- an asymmetric, (a)periodic alternating nystag-
ments) and are evident as waveform changes mus (APAN).29,81 Unlike acquired PAN, APAN
and null shifts during these movements. 32,63,64,70 is usually asymmetric, with unequal time peri-
Based on the instantaneous open-loop responses ods of jerk nystagmus in each direction. APAN
to step-ramp stimuli (i.e., before visual or pro- has all the characteristics of INS except that
prioceptive feedback is possible),83 we hypothe- the null point shifts position in either a regular
size that the dynamic null shift s are initiated by (periodic) or irregular (aperiodic) pattern and
either the reconstructed target velocity, back- is usually also asymmetric (unequal intervals
ground velocity, or head velocity signals or the of jerk nystagmus in each direction).81,85–87 Th is
subsequent motor commands they elicit. results in changes in the intensity and/or direc-
tion of the nystagmus from seconds to minutes.
APAN encompasses all idiosyncratic variations
2.1. 4 .1 A S Y M M E T R I C , ( A ) P E R I O D I C
in intra- and intercycle timing and amplitudes;
A LT E R N AT I O N
more specific nomenclature can be applied when
Most clinicians are familiar with this oscilla- these characteristics are known (see Chapter 5,
tion as acquired periodic alternating nystagmus Table 5.2). In some cases, aperiodic or periodic
(PAN). Acquired PAN has a specific pattern changes in intensity but not direction or direc-
identified by the presence of spontaneous nys- tion but not intensity occur; they represent
tagmus in the primary position, which beats extremes in the broad spectrum of time varia-
horizontally in one direction for 1 or 2 minutes, tion in IN.
followed by a quiet period, and then reappear- Figure 2.12 illustrates how the amplitude
ance of the nystagmus in the opposite direc- and direction of APAN vary with the time
tion for a similar length of time.84 It is usually function describing the null shift . The direc-
seen in association with vestibular cerebellar tion, rate of change, and duration of the null

FIGURE 2.12 Illustration of how a shift ing infantile nystagmus syndrome null angle accounts for the
direction of asymmetric, (a)periodic alternating nystagmus (APAN), the rapidity of its amplitude increases,
decreases, and durations at its maximal values. JL, jerk left; JR, jerk right.

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shift determine the direction of the jerk IN associated with serious central nervous system
(opposite to the null shift), how rapidly the pathology.85,89
jerk IN increases or decreases, and how long it Gradstein et al. diagnosed APAN in 18 (9%)
remains at its maximal value. Also, APAN may of their 200 patients with infantile nystagmus,
exhibit different (aperiodic) or the same (peri- although most had not been diagnosed with
odic) times for each full period of nystagmus APAN before referral, despite changing nys-
reversals; in some cases, the reversals are spo- tagmus reported by referring clinicians. 86 In
radic. Thus, for any give patient, one’s INS neu- those 18 patients they found 5 to have ocular or
tral zone may be a function of gaze angle, eye oculocutaneous albinism and 16 had an alter-
velocity, fi xating eye, or time. The amount that nating anomalous head posture (AHP). The
each of these parameters affects the neutral APAN cycle was of variable duration, often
zone is idiosyncratic. APAN has been att rib- with asymmetric right- and left-beating com-
uted to a time-varying (shift ing) null region. 81 ponents. Although horizontal jerk nystagmus
Albinism has also been linked with APAN. 88 with accelerating slow phase was predominant,
The occurrence of APAN in INS was thought other waveforms were encountered in the active
to be rare, but Shallo-Hoff mann et al. sug- phase of APAN. In the quiet phase (close to
gested otherwise. 89 They also found switching null zone), similar, but less intense, oscillations
between accelerating and linear slow phases than those in the active phase were characteris-
in the two directions and asymmetries, even tic. Half of the patients showed a combination
in those patients whose APAN was essentially jerk and pendular waveforms in both phases. In
periodic. The appearance of both accelerating another report the same authors found ocular
and decelerating slow phases, sometimes seen oscillations consistent with INS evident in 24
during the neutral phase of APAN, has been of 27 patients with oculocutaneous albinism
shown to result from a single mechanism sum- and Hermansky-Pudlak syndrome (HPS) and
mating linear and pendular components.90 The half showed periodic alternating nystagmus.92
recognition of both PAN and APAN is essen- They concluded that most patients with HPS
tial when surgery is being considered for either have INS, and many have periodic alternating
acquired nystagmus or INS.91 Nine to 33% of nystagmus.
patients with INS will have an inherent, rhyth- Shallo-Hoff man et al. studied 18 patients
mic, periodic, or aperiodically changing nys- with INS and found 7 of the 18 patients had
tagmus intensity and/or direction over time. APAN (median cycle: 223 seconds, range 180–
Abadi and Pascal studied 25 subjects with 307 seconds).89 The periodicity of the cycles
oculocutaneous albinism (16 tyrosinase neg- for each adult patient was regular, although
ative and 9 tyrosinase positive) and 7 with the phases within a cycle were often asymmet-
ocular albinism (5 X-linked and 2 autosomal ric. Six of the 7 patients had an AHP, and in
recessive) and found that 12 exhibited APAN.85 5 of 7 with the AHP it was in only one direction
The nystagmus waveforms encountered during (static). Except for one patient, the APAN wave-
the APAN active phases were either jerk-with- forms had an increasing slow-phase velocity in
extended-foveation or pseudocycloid, whereas at least one phase of the cycle; in the other phase
a variety of oscillations (including triangular they were linear. They concluded that the AHP
and bidirectional) were evident during the quiet was dependent on, and could be predicted from,
phases. For most of the 12 subjects, there was the waveforms containing the longest foveation
an asymmetric variation in nystagmus intensity times. Although the waveforms and foveation
during each APAN cycle. Although neuroimag- times may differ among the phases of the APAN
ing is obtained in almost all cases of clinically cycle, the periodicity of the cycle was usually
evident PAN, the defi nitive diagnosis of the regular and therefore predictable.
ocular oscillation is made using eye-movement Hosokawa et al. found periodicity in the time-
recordings. APAN is more common in patients frequency distribution in 3 of 13 patients (23%)
with oculocutaneous albinism and is usually not with INS.93 Eighteen of 91 (19.8%) patients with

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infantile nystagmus who were seen in the Teikyo associated AHP. Some patients exhibit brief peri-
University School of Medicine were diagnosed ods during which their IN stops; they lie at one
with APAN. They found that face turning was end of the APAN spectrum—very aperiodic.
seen between the ages of 3 and 9 years. Visual
acuity no worse than 20/40 with correction was Clinical Pearl: Patients with INS whose
obtained in all their patients and almost all the measured visual acuity changes from one
patients had an asymmetric null cycle mani- office visit to the next may have short periods
fested in an aperiodic alternating head posture. when the nystagmus stops and acuity peaks;
Hertle et al. reported 78 patients with APAN this is an exaggerated form of APAN.
and found that 46% had an associated diagnosis
of oculocutaneous or ocular albinism.87 Most of
2.1. 4 . 2 O P T O K I N E T I C , P U R S U I T, A N D
their patients had strabismus (72%) and an AHP
VEST IBULO - OCUL AR RESPONSES
(87%) with one-third having a visually preferred
eye. The clinical head/face position was evenly Unfortunately, the notions of “inverted pur-
split between those patients with a static head suit movements” and “inverted optokinetic
posture and a dynamic (alternating) posture. responses” have created confusion regarding
Interestingly, those patients with strabismus the roles of both in INS. The smooth pursuit
were more likely to have a static head posture, waveform in the INS does not appear clinically
even with a periodic rhythm detected on eye- normal, and it is widely recognized that patients
movement recordings. Most of their patients with INS often show an apparent reversal of
had best binocular acuity in the 20/50 to 20/100 their optokinetic responses (i.e., during pursuit
range, which probably reflects the large number of left ward optokinetic stimuli, a left-beating
of patients with associated sensory system defi- nystagmus rather than a right-beating nystag-
cits that were referred to their study centers. The mus is seen).94 The absence of any symptoms of
patients were also evenly split between those such grave deficits and the normal abilities of
with a periodic and aperiodic eye-movement individuals with INS in sports should have pre-
rhythm. The periodic rhythm averaged between cluded the notions that either of these important
3 and 4 minutes. ocular motor subsystems was actually reversed.
The occurrence of APAN is not as rare as pre- Also, the perceptions of individuals with INS of
viously suggested and can be missed because of both the direction and magnitude of movements
long or irregular cycles and the patient’s prefer- in the periphery and on the fovea are normal.
ence for only one AHP. The changing null per- When an individual with INS is placed in an
iod is easier to recognize using eye-movement optokinetic drum, where the stripes surround
recordings, but in most clinical environments the subject, the perceived circularvection is
this is not available. The clinician may be able to in the same direction as for a normal (personal
diagnose this disorder if an INS patient is exam- observation by LFD in the laboratory of David
ined in the following way: Cogan, circa 1970). Unfortunately, the clinical
appearance of the nystagmus of a subject with
Clinical Pearl: Occlude the nonpreferred eye INS during optokinetic stimulation is in the
and examine the preferred eye with the head “wrong” direction and led some to conclude that
straight and gaze in primary position over “reversed optokinetic nystagmus (OKN)” was a
at least 5–7 minutes. A regular or irregular clinical indication of INS. True inversion of the
changing oscillation intensity and/or direc- optokinetic reflex would contradict the normal
tion indicates APAN. perceived circularvection experienced by some-
one with INS. Eye-movement recordings cleared
Identification of APAN and possibly its wave- up the mystery when Halmagyi et al. docu-
form characteristics are essential in cases in which mented that, as Dell’Osso et al. demonstrated for
surgical or medical treatment is considered for pursuit, 32,70 the neutral region during OKN also
correction of strabismus, nystagmus, and/or an shifted in the direction opposite to the stimulus

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and resulting slow optokinetic eye movement.95 the jerk-right INS at 0° will increase if pursuing
The resulting nystagmus is either damped or to the right and either decrease or become jerk
opposite in direction from what would be antici- left if pursuing to the left (the latter will depend
pated because the evoked OKN simply sum- on the speed of pursuit). It is common to record
mates with the ongoing nystagmus. “Inversion” a high-amplitude IN waveform during pursuit of
of the optokinetic reflex is present in 67% of INS rapidly moving targets across the whole field of
patients; this clinical observation establishes the gaze, from 20° left to 20° right, despite the fact
nystagmus as IN. Kawai studied the effects of an that the same subject might have a broad null
optokinetic background on INS.96 He concluded region somewhere in this range when looking at
(in agreement with Dell’Osso’s observations stationary targets.
earlier) that the perceived circularvection is in Two interesting cases of INS that became
the proper direction for the background move- manifest only during unidirectional pursuit were
ment and, furthermore, that the OKN dynamics reported.99 In these subjects, no IN was present
were normal in INS subjects. during fi xation of stationary targets at any gaze
There is another problem with the analysis angle. However, when pursuing targets moving
of OKN in INS: whether presenting a slowly in one direction, a nystagmus developed that
moving stimulus to such a person is an adequate had increasing velocity exponential slow phases
OKN stimulus.8 In normals, such a stimulus and was diagnosed as being INS. These patients’
results in slow motion across the retina; that is complaints of oscillopsia only during such pur-
not the case in INS, where the retina is in rapid suit have been with them throughout their life.
motion in both directions. Despite that, the It is interesting that the normal suppression of
subject perceives the correct drift ing gratings oscillopsia seen in INS subjects was not present
and that perception produces a correct OKN in these cases where the nystagmus was only
response superimposed on the INS oscillation; manifest during unidirectional pursuit. Given
that is further evidence that the OMS responds the effects of smooth pursuit on the INS null, the
to perceived target motion, not merely retinal most parsimonious explanation for these obser-
motion. Abadi and Dickenson reached the same vations is that these patients had a very broad
conclusion from their study of OKN and INS.97 null region (see Section 2.1.5) that encompassed
The fundamental error of equating the sum- their whole range of gaze angles when viewing
mation of smooth pursuit movements plus the static targets. When they attempted to pursue in
superimposed INS waveform with the pursuit one direction, that null region was shifted in the
movement alone inevitably leads to the errone- opposite direction, causing a nystagmus in the
ous conclusion that there is an inherent defect in same direction as the pursuit. These would be
the pursuit system, and during pursuit of a visual two extreme examples of the well-known null/
target, the slow phases of IN consist of normal neutral-zone shift seen in most INS subjects.
pursuit movements plus the nystagmus itself but In a study of smooth pursuit, VOR, and OKN
that the eye position consistently matches the in individuals with INS, Kurzan and Bütt ner
target position during foveation periods.63,64,70,98 supported the hypothesis that the measured
It is well documented that the attempts to pur- waveforms are caused by a shift in the static neu-
sue a slowly moving target significantly alter tral zone to a new position (the dynamic neu-
IN (e.g., the static neutral zone is shifted in the tral zone).71 In agreement with Dell’Osso et al.’s
direction opposite to the pursuit). Thus, the observations, they found that even low stimulus
actual IN amplitude at a given gaze angle is dif- velocities caused large shifts in the neutral zone
ferent during pursuit than when viewing a sta- and higher velocities caused an increased shift .
tionary target. It may be greater, less than, or They also confi rmed that this shift has no meas-
even oppositely directed depending on whether urable latency. Th is shift in a subject with INS
the gaze angle is farther from or nearer to the was later quantified.63 Given their verification
dynamic null during pursuit than during steady of the neutral-zone shift, they concluded that
fi xation. For example, if the static null is at –20°, smooth pursuit was normal and that retinal slip

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velocity is adequately utilized for the generation of this nystagmus were presented; this may have
of smooth pursuit eye movements in individuals been a rare form of INS that is related to the two
with INS. unidirectional pursuit cases discussed earlier.99
Dell’Osso et al. studied the foveation periods Th is patient exhibited a jerk-left IN in far left
of an individual with INS during smooth pursuit gaze and when tracking from the right to the
and VOR and demonstrated near unity gains for left . Thus, his neutral zone, which was in left gaze
both over target velocities ranging from a few when fi xating stationary targets, shifted to the
degrees per second to 215°/sec and for rota- right so that the jerk-left IN was superimposed
tions in the normal gaze-angle range.63,64 During on left ward pursuit movements. Th is case is the
the vestibulo-ocular responses, the same type missing link between normal INS (where the
of neutral-zone shift seen during optokinetic nystagmus is present while viewing stationary
and pursuit responses was documented. Also, targets and the neutral zone can easily be seen to
despite the often confusing and misinterpreted shift during pursuit) and those cases previously
combinations of INS waveforms superimposed recorded (where there was no nystagmus during
on VOR eye movements, it was shown that the fi xation of stationary targets and a shift in neu-
VOR was normal in subjects with INS. They also tral zone with pursuit caused the nystagmus to
demonstrated, using phase-plane analysis, that become manifest). The pursuit-induced neutral
both smooth pursuit and VOR were normal dur- zone shift was the explanation offered for the
ing foveation periods. By subtracting the target mechanism involved in producing the IN in the
position and velocity from those of the eye, they two patients previously reported and that expla-
reconstructed the retinal error phase planes dur- nation is also supported by this patient. In a study
ing pursuit and VOR and showed them to virtu- of smooth pursuit in several cases of hereditary
ally duplicate the phase plane of eye movement INS, Takahashi demonstrated smooth pursuit
during fi xation of a stationary target. Thus, by during the foveation periods of his subjects.101
two unrelated methods, these subsystems were The fi nding that there was a distinct difference
proved to be normal in INS, and that hypotheses in the IN of the male subjects from that of the
or models claiming deficits in either of their gains female subjects during pursuit has neither been
or directions as the cause of INS were invalid. reported before nor noted in our data.
Just as the INS waveform is distorted by slow Many attempts to evaluate the VOR in sub-
eye movements (creating periods of extended jects with INS have failed to successfully sepa-
foveation) during fi xation of a stationary tar- rate the slow-phase velocity associated with the
get, the pursuit system generates pursuit move- underlying nystagmus from that due to the VOR
ments with a direction and velocity that match itself. Because of the superimposition of an ever-
those of a moving target during INS foveation present and changing INS waveform on the eye
periods.63,70,71 Th is ensures extended foveation movements resulting from the normal VOR, the
of the moving target and results in accurate measured responses do not resemble normal
smooth pursuit while the target image is on the ones. As previously discussed for smooth pursuit,
fovea. Pursuit during foveation is all that is nec- the calculation of the VOR gain in INS must also
essary for good acuity; the same conditions are be limited to foveation periods.64 At any other
met during smooth pursuit as during fi xation of point in the INS cycle (when there is neither tar-
a stationary target. get foveation nor clear vision due to the obligate
Six patients in whom INS emerged in later retinal slip), the calculation of VOR gain is mean-
life also exhibited the null shift with pursuit and ingless, both in the mathematical sense and as an
OKN that is a characteristic of INS.22 Lueck et indication of the performance of the VOR.
al. studied a patient who presented with episodes
of oscillopsia with smooth pursuit and OKN
2.1.5 The Null Angle/Zone/Region
responses that exhibited nystagmus slow phases
in the direction opposite to the stimulus.100 The field of gaze in which nystagmus intensity is
Several different mechanisms for the etiology minimal is termed the “null zone” and it usually,

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but not always, overlaps with the “neutral zone.” Clinical Pearl: Patients who (taking advan-
A gaze-angle null results in an AHP that allows tage of their null) move their heads word to
use of the null to fi xate targets that are directly word across the line while reading (even those
in front of the patient.102 Nystagmus therapy with high acuity) may have INS with a nar-
aimed at improving visual function is best row range of gaze angles where their acuity
accomplished and more accurately measured is highest.
using the peak and breadth of the NAFX versus
gaze angle curve, not nystagmus amplitude or The null angle is usually at the center of the
intensity, which are not accurate predictors of neutral zone. A defi nition of an INS null is in
visual function. order. For a gaze-angle position of low-ampli-
There are several reasons why an AHP tude nystagmus to be a true null (i.e. in the
should not be used either as a measure of mathematical sense), the nystagmus must be
therapy necessary or as an outcome measure. more intense (amplitude × frequency) at gaze
First, an AHP is under the direct control of angles to either side of it. Those patients who
the patient and is, therefore, unreliable (espe- turn their head in one direction so their eyes are
cially postoperatively in children who know in extreme lateral deviation do not fulfi ll this
the intent of the surgery was to “straighten the defi nition. It is well known that many patients
head”). Second, it is oft en variable, depend- with FMNS put their fi xating eye in extreme
ing on the prevailing conditions, sharpness of adduction and take advantage of Alexander’s law
the NAFX versus gaze angle curve, and need to minimize their nystagmus; this is not a true
to accurately fi xate the target. Th ird, it is more null angle. Similarly, some patients with INS
difficult to measure accurately than eye pos- also adopt an extreme head turn forcing their
ition. Fourth, it is not the primary problem eyes laterally and minimizing their nystagmus;
but rather a patient’s compensatory response this too is not a true null since the eyes cannot be
to the primary problem (i.e., the gaze angle deviated further to test whether the nystagmus
with the best foveation). Finally, an AHP only increases at those gaze angles. INS patients with
translates into the necessary measurement of true nulls have only one such position but those
required gaze-angle shift if the body is per- with APAN may appear to have two. Since the
fectly aligned, straight ahead. Usually both the earliest recordings of INS, “bias reversals” dur-
head and body are turned toward the target so ing steady fi xation were noted.29,31 Some indi-
the required gaze-angle shift is actually the viduals with INS exhibit frequent, sporadic bias
sum of head-on-body rotation and body rota- reversals and the resulting direction reversals of
tion. For these reasons, the discussion of AHP their IN may be considered one end of the spec-
has been placed in this section on null angles trum of APAN, the most aperiodic.
and does not have its own section. An attempt has been made to use electromyo-
By measuring the amplitudes and frequen- graphic (EMG) recordings to examine the possi-
cies of INS waveforms at various gaze angles, bility that there are two types of gaze-angle nulls
it was found that there usually is a small present in INS.103 One type was att ributed to the
range of gaze angles within which one or both active blockage of the nystagmus by an increase
decrease. 31 This damping of IN allows bet- in the discharge of the synergistic extraocular
ter acuity at that gaze angle (the “null” angle) muscles responsible for the gaze angle adopted.
and, in some cases, results in the subject The second type was the classical null position
turning the head opposite to the null angle for which no good explanation has been proven,
to place objects of interest at the null angle. and it is thought to result from an equilibrium
Early attempts at surgical correction in INS position between the forces present in the push-
were directed at the cosmetic improvement pull OMS. According to this paper, the block-
in straightening the head and only second- age type of null occurs at angles greater than
arily (and sometimes not at all) was acuity 10° from primary position and the so-called
improvement considered. Kestenbaum null occurs closer to primary

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position. The key to differentiation, according 2.1.6 The Convergence Null

to these authors, is analysis of time histograms
of the EMG signal since ocular motor activity In some subjects, IN also damps during conver-
reflected in the EOG is the same for both types gence on a near target. Th is convergence null
of nulls. We have measured the IN of patients allows for near acuities that are normal despite
who have true nulls at most gaze angles as well poor distance acuities in these subjects. As
as some whose nulls were so far in lateral gaze Figure 2.13 shows, not only does convergence
that it could not be proven that it was a true null. increase the peak NAFX but it also broadens the
It is too simplistic to pick a number like 10° and range of gaze angles over which the NAFX (and
say that true nulls occur at smaller angles and therefore, acuity) remains high. Such broaden-
that beyond 10° only the so-called blockage null ing greatly improves visual function by allowing
occurs. All nulls will exhibit the change in EMG for rapid and accurate saccadic fi xation of lateral
histograms described earlier since increased targets without the need to align the head for
activity will result in a broader, flatter curve. each refi xation. The variety of clinical conditions
Furthermore, if the mere increase in activity of a under which this occurs suggests that this effect
muscle can be used to block the nystagmus, then is determined by the convergence angle rather
all such patients should be able to do this in both than the state of accommodation. In fact, bin-
directions. Th is is not seen in INS patients with ocular viewing or binocular function is unnec-
good binocular function; it is observed in INS essary to illicit convergence damping in those
patients with strabismus and in FMNS patients. patients with INS in whom it is present.104 Also,
Also, this increase in synergistic activity is not asymmetrical convergence damps IN (this is the
equivalent to the blockage of IN with conver- basis for the use of composite prisms) and, once
gence where the increase in activity is in antag- converged, gaze angle plays no important role
onistic muscles and affects the push-pull system in IN amplitude (if it did, convergence prisms
in a different way. or bimedial recession operations would not be

NAFX, VERGENCE, and GAZE ANGLE

1.000
20/20
0.900
0.800 20/25
0.700
20/30
0.600
FX

Far
NAF

0.500 20/40 Near

Poly. (Far)
0.400 20/50 Poly. (Near)

0.300
20/70
0.200 20/100
0.100 20/200
0.000
-40 -30 -20 -10 0 10 20 30 40
Gaze Angle (º) ]

FIGURE 2.13 Plots of eXpanded nystagmus acuity function (NAFX) versus gaze angle for both far and
near viewing showing increased values at near. Snellen acuities on left correlate with NAFX values and
demonstrate the precipitous decrease in acuity at far compared to the maintained acuity at near as gaze is
directed away from the position with the peak NAFX value.

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of much value since real-life situations require greater damping of INS nystagmus with con-
looking in all fields of gaze). vergence than with gaze angle, in patients who
exhibited both types of null, and this trans-
Clinical Pearl: Patients with INS whose near lated into acuity increases. 62 Comparison of
visual acuity is greater than distant may have the results of the Anderson-Kestenbaum and
INS that damps with convergence. artificial divergence procedures also favored
the latter.111
Although the exact mechanism responsible for In summary, most patients with INS have
this damping in unknown, there was speculation periods where the nystagmus intensity (ampli-
that it might result from co-contraction of antag- tude × frequency) is least. It is usually in these
onist muscles of each eye during convergence. quiet periods (null/neutral times/zones/posi-
However, Miller found no co-contraction.105 We tions) that visual function is the best due to
hypothesized that damping during convergence improved foveation quantity and quality dur-
might result from an effective increase in the stiff- ing each beat of nystagmus. These null times/
ness of the ocular motor plant brought about by zones result from a complex combination of
the increased innervation to the two medial recti individual afferent and efferent patient char-
(i.e., co-contraction of antagonist muscles of the acteristics. However, there are both static and
two eyes, rather than of each eye). The Orbit 1.8 dynamic components, present to some degree
simulation (J. M. Miller, personal communica- in all patients. The static components that either
tion) predicted that the 8 g primary-position ten- produce or modify a null/quiet period include
sion in the medial rectus increased to 13 g at 20° a consistent horizontal/vertical/torsional posi-
adduction (40° of convergence) and to 18 g at 30° tion of gaze (eye in orbit, static gaze angle = Ng)
adduction (60° of convergence), 75% and 125% and convergence at near or distance (vergence
increases, respectively. Because convergence damping, nystagmus blockage, static conver-
results in a change in the muscle pulley system,106,107 gence = Nv).112,113 Most patients’ static null pos-
the latter may play a part in increasing stiffness. ition is in the three-dimensional midline, that
However, when the eyes are converged by equiv- is, straight ahead. However, 10% to greater than
alent amounts, the muscle tension decreases.105 50% of children have their null zone in an eccen-
This decrease may be accomplished by lowered tric position of gaze relative to midline (horizon-
γ-innervation to a proprioceptive feedback loop tally, vertically, torsionally, or a combination of
controlling steady-state muscle tension.108,109 The all three). The null zone/period in patients with
observations of convergence-induced damping INS also has multiple dynamic components.
of other types of nystagmus support this “periph- The dynamic components that either produce
eral” mechanism in preference to one relying on or modify a null/quiet period include the fol-
an inherent property of the nystagmus. Serra et al. lowing: a movement of the null toward a cov-
made the interesting observation that divergence, ered eye (causing a clinical “latent component,”
in addition to convergence, resulted in higher dynamic fi xing eye = Fe), null movement in the
NAFX values (i.e., better foveation quality).110 direction opposite of smooth pursuit, OKN,
They discovered a hysteresis effect of vergence on and VOR stimuli (giving the impression of low-
IN that suggests that during divergence the same gain pursuit [saccadic] and “reversal” of OKN
peripheral mechanism may be operating that induced eye movements, Dynamic SP-VOR-
damps IN during convergence. OKN = E0), and fi nally a change over time in
Waveform, gaze-angle nulls, and conver- both the short term (minutes—periodic/aperi-
gence nulls are affected by heredity. 28 Members odic) and over the long term (years—associated
of the same family show more specific combi- with age) (Dynamic (A)PAN = ∆T). Other well-
nations of waveforms or of either having only a recognized and highly associated developmental
convergence null or no convergence null (i.e., or congenital abnormalities of the visual system
having only a gaze angle null) than do mem- affect the oscillation of infantile nystagmus in
bers of the general INS population. We found general and the null/quiet periods in particular.

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These include high spatial frequency vision velocity storage systems.26,102,113–115 Based on the
(acuity) compromise due to optic nerve and ret- data from this and other reports of patients with
inal disease, heterotopias (and eye dominance), APAN, it is probable that the rhythmic compo-
and amblyopia. nent of APAN and the associated head posturing
Possibly, all of the variables listed earlier (i.e., are heavily influenced by associated heterotopia
the static components, dynamic components, with visual and motor dominance.
and other visual system affecters) combine
in a mathematical way to produce the clinical
2.1.7 The Saccadic Response
null period that is observed and used to guide
much of the medical and surgical treatment of Early studies of INS noted that responses to
INS (Fig. 2.14). The perturbations of the basic changes in target position were often combi-
INS oscillation as a result of gaze, time, binoc- nations of hypometric saccades and the slow
ular/monocular viewing, acuity, heterotopia, phases of the INS waveform. 32 Th is observation
and motion are probably directed by complex led to an early hypothesis that IN was second-
developmental connections between the mul- ary to a primary abnormality in the saccadic
tiple parallel pathways in the afferent visual system; we have long since realized that the sac-
and efferent vestibular, vestibular ocular, and cadic system is normal and the direct cause of

CLINICAL
NULL POSITION
Np

STATIC STATIC DYNAMIC DYNAMIC DYNAMIC

GAZE ANGLE CONVERGENCE FIXING EYE SP-VOR-OKN (A)PAN
Ng Nv Fe E0 ΔT

OPTIC NERVE
AMBLYOPIA HETEROTOPIA
RETINA
a1 a2
a3

Np = f1(Ng) + f2(Nv) + f3(Fe) + f4(E0) + f5(ΔT)

f1 = a1 + a2 + a3; f2 = a1 + a2 + a3; f3 = a1 + a2 + a3

FIGURE 2.14 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 fac-
tors interact in a hierarchical and temporal way to change how any one patient with infantile nystagmus
syndrome may have what appears to be a clinically “changing” null or “multiple” null positions. Np = overall
null position; f 1 (Ng) = static gaze null (horizontal, vertical or torsional) as a function of amblyopia (a1) plus
heterotopia (a 2) plus optic nerve or retinal disease (a 3); f 2 (Nv) = static convergence damping as a function of
amblyopia (a1) plus heterotopia (a 2) plus optic nerve or retinal disease (a 3); f 3 (Fe) = dynamic null influenced
by a fi xing eye (“latent component”) as a function of amblyopia (a1) plus heterotopia (a 2) plus optic nerve or
retinal disease (a 3); f4 (E0) = dynamic null influenced by smooth pursuit, vestibular ocular reflex, or optoki-
netic responses as a function of amblyopia (a1) plus heterotopia (a 2) plus optic nerve or retinal disease (a 3); f5
(ΔT) = dynamic null influenced by an underlying regular or irregular rhythm (periodicity) as a function of
amblyopia (a1) plus heterotopia (a 2) plus optic nerve or retinal disease (a 3).

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INS is in the pursuit system. The responses to INS, one must confi ne the analysis to the fove-
step changes in target position exhibited by INS ation periods. It is during this portion of the INS
subjects contain hypometric saccades or slow- waveform that the oscillation is least, vision is
phase responses that occur most frequently clearest, and some degree of ocular stabiliza-
when the target is displaced in the direction tion is possible. Eye movement recordings and
of the slow phase.116 Since the retinal stimulus phase-plane portraits in INS demonstrate the
produced by step change in a target position is following: the oscillations of INS supersede the
the same stimulus that normals receive from ocular stabilization systems but do not extin-
a step change followed by a ramp motion back guish them; these systems exert their primary
toward the fovea, comparison was made to influence on vision during foveation periods;
responses of normals to the standard Rashbass and defects in ocular stabilization are neither
stimulus. Looked at in that way, the ocular the cause nor the necessary result of INS.62–64
motor responses of INS patients are normal sac-
cadic responses to the sequence of retinal image
2.1.8 Static and Dynamic
motion produced by this stimulus and not con-
Head Posturing
tributions from the pursuit system in response
to position displacements on the retina, as has Many children with INS exhibit spontaneous
been suggested by others. The responses of INS head oscillations; adults, when they are concen-
patients with albinism were less likely to con- trating on a visual task (real or imaginary), may
tain saccades and may be att ributed to their also but they usually learn to keep their heads
impaired sensory functioning. Thus, there is still because it is socially unacceptable to allow
now additional evidence supporting the hypo- the head shaking. These head oscillations use
thesis that both the saccadic and pursuit sys- existing pathways in the neck muscles. EMG in
tems of INS subjects function normally given the neck muscles show that when normals make
the ongoing oscillation; this hypothesis was saccades to the left , the innervation is seen in
contained in the earliest model of the saccadic the left-turning neck muscles and when they
and pursuit systems operating in the presence made them to the right, it is seen in the right-
of an ongoing oscillation. 3 turning neck muscles. Normally, when we look
Although visual feedback provides a means left we are going to turn our head left . The path-
of sampling and assessing the accuracy of fove- ways exist and, if there is an instability causing
ation periods in INS, a number of observations the eyes to oscillate and one records from the
suggest that fast phases are not produced in neck muscles, the same waveform is seen. When
response to a retinal displacement error signal the oscillation grows large enough, the head will
between the fovea and the target image. Worfolk start oscillating. Th is is not something willed
and Abadi have offered the following evidence by the patient to compensate for the IN118; it is
to support this supposition: jerky IN can con- a manifestation of an existing oscillation on
tinue with the eyes closed; IN continues and its existing pathways to the neck. It used to be
parameters remain unchanged as individuals thought that head oscillations were compensa-
track paracentral afterimages; and in pendular tory. The head was supposed to be moved equally
IN with foveating saccades the retinal displace- and oppositely to the IN to stabilize the eye in
ment error signal is opposite in sign to the forth- space. If that were true, the VOR gain would
coming fast phase, allowing insufficient time to have to be zero. Accurate objective observations
program the quick phases using visual informa- of the head movements in patients with INS do
tion.117 Saccades and gaze holding are normal not support that hypothesis.13 In individuals
in INS, and the saccades contained within the with INS, the VOR is normal; it is not affected
nystagmus waveforms are always corrective, by INS.64,71
and not the initiating movement responsible for Therefore, the head oscillations of most
the nystagmus.62 In examining how the ocular with INS are merely an extension of the IN and
stabilization systems function in the sett ing of during the foveation periods, the eyes do not

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move in space and acuity is unaffected by head 2.1.9 Foveation and Visual Acuity
movements.13,119,120 Basically, the head oscilla- (High Spatial Frequency Vision)
tions of an individual with INS and a normal
VOR are equivalent to those of a normal per- Dell’Osso et al. studied the accuracy and cycle-
son moving his or her head and acuity does not to-cycle repeatability of the foveation periods
change.64 For most INS patients (who have good in congenital nystagmus (INS) because vis-
foveation periods), there is no advantage to shak- ual acuity is directly related to these indices. 62
ing the head; if the foveation periods are flat, During a 5-sec interval of fi xation, the SD of
head motion cannot help the patient and head mean horizontal foveal position was ±13 minarc
shaking is, therefore, not an adaptation designed (±5 minarc vertical) and mean foveation time
for increasing acuity.118 A normal VOR is incom- was 59 ms. There were 1-sec intervals of fi xa-
patible with a head movement that compen- tion with SDs of 0 minarc. Position and veloc-
sates for an eye movement. Even with no VOR ity histograms reflected the increase in data
the head would have to move in complex ways about the zero position and velocity points
opposite to the INS waveforms to achieve stabil- caused by the foveation periods of the wave-
ity; that is clearly impossible. The head has too forms. Phase-plane analysis of the INS wave-
much mass to duplicate the waveforms of INS. forms demonstrated beat-to-beat overlap in
The compensatory hypothesis, when you under- the position and velocities during the foveation
stand the VOR, cannot work. Realistic compen- periods (see Fig 2.9). Contrary to the notion
sation could theoretically be accomplished if that INS was due to poor fi xation reflexes, they
one could suppress a normal VOR to near zero concluded that the fi xation reflexes in subjects
and only move the head equally and oppositely with INS were remarkably strong and accurate
to any movements of the eye during the INS despite the large oscillation always present.
foveation periods. Th is would achieve gaze sta- Even in albinos, where the fovea is not normal,
bility during that part of the waveform and is INS foveation periods were found to approxi-
a possible form of compensation useful only if mate those with normal foveae. 68 In a study of
the foveation periods of an individual were not various indices of INS waveforms, the high-
stable with the head still. est correlations were found to be between (1)
The head tremor in INS can be distin- foveation time and the maximum rate of the
guished from that in acquired disease; it is histogram indicating the rate of duration of
easily suppressed voluntarily in the former but the eye in each spatial position, (2) amplitude
not in the latter. and intensity, and (3) mean slow-phase veloc-
ity and intensity.122 Of the three, visual acuity
Clinical Pearl: Point out the head tremor to correlated best with foveation time. The pres-
the patient. If it stops, the nystagmus is that ence of foveation periods in the waveforms of
of INS; if it persists, both are more likely individuals with late-onset INS proves that the
acquired. ability to suppress an acceleration of the eyes
off target is part of our normal ocular motor
For those interested in accurate head posture arsenal and not something developed in early
measurement with minimal artifact, an appa- life by those with INS. 22
ratus was described by Young121 and another, Abadi and Dickenson found both accu-
more recently by Yang et al.115 However, head rate and inaccurate foveation during fi xation.29
posture is neither a repeatable nor an accurate Bedell et al. found similar foveation-period var-
indicator of IN gaze-angle nulls, pre- or post- iations (13–67 minarc horizontally and 8–20
operatively. There is too much variability that minarc vertically).65 They att ributed the vertical
can be introduced by the subject. It is best to fi x variation to crosstalk from the horizontal IN.
the head and record the IN at known, and more Based on their fi nding of a correlation between
accurately measured, gaze angles. the variations in the horizontal and vertical
meridians in both idiopaths and albinos, they

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correctly concluded that INS is a motor and not A paper on the use of telescopic aids for low-
a sensory disorder in both populations. They fur- vision patients (with and without nystagmus)
ther concluded that subjects with nystagmus found that head motion was an important factor
might also exhibit normal ocular motor behavior in preserving the stable retinal images necessary
under certain conditions. for good acuity.124
The accuracy, repeatability, and duration of Hatayama et al. examined several patients with
the foveation periods are the most critical fea- and without base-out prisms.125 Unfortunately,
tures of INS waveforms’ effect on visual acuity. they used bitemporal EOG to record the eye
As a result of his studies of the dynamics of the movements. Four of the five patients showed
foveation periods in INS, Dell’Osso developed a damping of the INS waveform during fi xation
a nystagmus foveation function (NFF) that was in primary position. However, only three of the
the fi rst indicator of the gaze angle of best acu- five showed an increase in acuity and one of the
ity in an individual and a means of correlating three was the patient in whom no damping of
waveform characteristics and acuity between the IN was seen. The use of base-out prisms will
subjects, something that IN intensity cannot usually damp IN and, more important, increase
do.62 Th is function was formed by the quotient foveation time. However, in order to improve
of the product of foveation period per cycle and acuity, –0.50 to –1.00 sphere may need to
IN frequency in the numerator and the product be added to the refraction of patients with ample
of the SDs of the mean foveation-period position accommodation to negate the effect of the con-
and velocity in the denominator. Preliminary vergence-accommodation induced myopia stim-
data demonstrated the direct relation between ulated by the base-out prisms. It was not clear
the value of the NFF and the gaze and conver- whether this spherical correction was added to
gence angles of best acuity. the refraction of these patients. We would antic-
Abadi and Worfolk studied the relationship ipate that, had this been done, the acuity would
between visual acuity and the duration of low have increased in more of the patients.
velocity in IN slow phases.66 They found a sig-
nificant correlation between the duration of
2.1.9.1 T H E E X PA N D E D N Y S TAGM US
slow-phase velocities below 10°/sec and acuity.
ACUIT Y F UNCT ION
Although this was a somewhat cruder meas-
ure of the foveation periods, it does illustrate The NFF led to the development of a more sen-
their importance in acuity. Th is paper contains sitive function, the NAF,126 which, after testing
velocity histograms of various waveforms and and use in a number of INS patients, was altered
their effect on good foveation. Other studies to accommodate the larger foveation windows
also found a correlation between acuity and required by many INS patients.127 The result was
foveation-period duration67 or variability.65 Th is the NAFX, which has undergone over 15 years
latter study did not fi nd a correlation in albinos, of testing, improvements, automation, and use in
whose acuity is limited by afferent defects. One hundreds of patients with uniplanar or biplanar
study of acuity and several waveform variables INS.128 The current version has a GUI and auto-
did not fi nd a correlation across patients.123 Th is matic calculations that makes its use easy and
does not mean that correlations do not exist in rapid (see Appendix F.1.2 for methodological
specific individuals; experience has proven that details). Since, like its predecessors, it contains
damping IN and increasing foveation-period the three waveform factors (foveation time, posi-
duration will improve acuity if it is not severely tion variation, and velocity variation) that defi ne
limited by afferent defects. The reason for the well-developed foveation periods and affect acu-
variability in the results of these studies is prob- ity the most, its value is linearly proportional to
ably due to the correlations of several variables, the best-corrected visual acuity of INS patients
and it is for this reason that the NFF described with no afferent deficits. That is, because the
earlier yielded good results. The NFF con- NAFX is only a function of the INS waveform
tained all the motor variables relevant to acuity. characteristics, it is independent of the state of

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the patient’s visual sensory system. More specif- deficit. That is why IN amplitude, frequency, and
ically, only the foveation characteristics of the their product, intensity, are not good indicators
waveform are used in its calculation; all other, of visual function and should not be used as out-
non-acuity-affecting portions of the waveforms come measures for therapeutic intervention.
are automatically discarded. Clearly, for a given There have been several subsequent attempts
INS waveform, the resulting visual acuity will to duplicate the NAFX, albeit without including
be better when the SD of the foveation-period all of the three acuity-specific, waveform fac-
position is small than when it is large. The same tors of the NAFX. Indeed, during the develop-
applies for the SD of the foveation-period veloc- ment of the NAF, the NAFP, which was limited
ity. Since they may vary independently, both are to position variation, was included.126 Functions
necessary factors in a function that is related to that measure only variations in foveation-period
potential visual acuity. position129 and the others, only velocity130 might
The inclusion of the aforementioned factors provide a measure equivalent to the NAFX for
makes the NAFX a powerful tool in determin- certain specific waveform characteristics (e.g., if
ing, a priori, what improvements in visual func- the SD of velocity was near zero, a function con-
tion may be expected by INS therapies that sidering only position would suffice and if the SD
affect only the nystagmus (e.g., EOM surgery, of position was near zero, a function considering
prisms, soft contact lenses) and do not affect any only velocity would suffice). To do so, such func-
afferent deficit that might or might not also be tions would have to be applied only to the fi xat-
present. Using the NAFX, the physician can, for ing-eye data during periods of attention; claims
the fi rst time, estimate not only improvements to be able to apply them to larger data intervals
in peak visual acuity but also the more impor- with little attention to accurate calibration stretch
tant improvements in the range of gaze angles credibility. As was found from comparisons of the
over which the patient has his or her highest NAFP and NAF (prior to developing the NAFX),
acuity (see Chapter 7, Section 7.5). These esti- given the idiosyncratic nature of INS waveforms
mations can then form data-driven foundations and their intrasubject variation with gaze and
for therapeutic decisions to be made by the phy- convergence angle, such “simpler” methods can-
sician and the patient. Used properly, the NAFX not provide the NAFX’s accuracy over all patients
can more specifically delineate expected visual and waveforms. Attaching the word “acuity” to
function improvements and thereby guide the fundamentally deficient functions is merely an
patient’s expectations. exercise in reification. No such functions have
Part of the NAFX methodology is the graph- been shown to accurately reflect postt herapeu-
ical determination of the position and velocity tic, measured visual acuity changes and there-
boundaries of the foveation window. Although fore cannot be expected to duplicate the NAFX’S
the NAFX was developed to be relatively inde- ability to provide a pretherapeutic estimate of
pendent of those boundaries for a given data therapeutic improvements. Finally, attempts to
interval, using a larger-than-necessary window use more general signal-classifying approaches
(either in position or velocity) raises the possi- (e.g., wavelet analysis) to measure the foveation
bility of including extraneous data that might quality of INS waveforms have been proven to
satisfy the enlarged foveation criteria; that could be too insensitive.41 Negative conclusions regard-
lessen the accuracy of the NAFX’s correlation ing therapeutic efficacy that are based on wavelet
to potential visual acuity and compromise its analysis in INS have no scientific basis and cannot
ability to estimate therapeutic improvements. serve to dispute the demonstrated, NAFX-based
Measures of INS that do not identify and quanti- improvements in foveation quality.
tate well-developed foveation periods are unable
to provide the relationship between measured
2.1.10 Oscillopsia Suppression
acuity and its INS component (“potential” acu-
ity) that is necessary to separate the latter from Most types of nystagmus result in the percep-
the sensory component due to an afferent visual tion of oscillopsia; however, in INS, it is almost

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never constantly present.131,132 In those rare INS that clear and stable images of targets are
patients with intermittent oscillopsia, it tends visible. This was supported by studies that
to occur at gaze angles in which the nystag- induced oscillopsia in a subject with INS and
mus is maximal or after a new sensory system in the study of a subject with INS who experi-
defect develops (e.g., retinal disease).133–135 The enced oscillopsia after loss of consciousness,
absence of oscillopsia is usually not helpful in which suggested that it was these foveation
distinguishing INS from acquired nystagmus in periods that were necessary for the supp
children as it is in adults since, even with nystag- ression of oscillopsia. The mechanism sug-
mus acquired in the fi rst decade of life, children gested incorporated efference copy. Dell’Osso
rarely have a continuation of this complaint. et al. demonstrated that some individuals with
Several mechanisms have been proposed to INS appear to require well-defined, repeatable
account for the stability of the perceived world foveation periods from one cycle to the next
in the face of nearly constant motion across to perceive a nonmoving visual world. 25,28 In
the retinas in individuals with INS.133,134,136,137 two patients with INS plus an acquired nys-
These include the notion of visual information tagmus, their acquired oscillopsia seemed to
sampling only during foveation periods with be related to an inability to maintain repeat-
suppression at other times, use of an extrareti- able periods of good foveation in a particular
nal signal to cancel out the visual effects of eye plane.142,143 However, that inability was an epi-
motion, central elevation of motion detection phenomenon caused by the addition of a tran-
threshold, and postsaccadic backward masking sitory acquired nystagmus to the ever-present
of motion. The thresholds for motion detection INS nystagmus.146
in INS differ from normal and may also have a
role in oscillopsia suppression.138,139 However,
2.1.10. 2 T E M P O R A L S A M P L I N G
such differences are slight compared to the high
velocities of IN slow phases. Based upon these A second hypothesis for oscillopsia suppression
experimental results, an abnormally low sen- in INS was the requirement that waveforms have
sitivity to oscillatory target motion cannot be repeatable, well-developed foveation periods of
invoked to explain the absence of oscillopsia in sufficient time durations simultaneously in both
individuals with INS. Oscillopsia may occur in the horizontal and vertical planes. Furthermore,
some patients with very poor foveation stabil- temporal sampling of these stable foveation peri-
ity140 or may occur in later life secondary to affer- ods may result in normal visual acuities despite
ent deficits.135 Perturbations in the INS cycle INS. These clear and stable “snapshots” allow
related to external or internal factors (e.g., head for high acuity despite being superimposed on
trauma, medications) can result in oscillopsia. the less useful, continuous visual input. A phase-
Finally, certain viewing conditions may cause plane study of a subject with diagonal INS sup-
oscillopsia in some patients with INS.141 ported the aforementioned hypotheses143 as did
The striking difference in oscillopsia between a study of a subject with FMNS who had 20/15
INS and acquired nystagmus led Dell’Osso visual acuity.147 The same foveation-window cri-
et al. to investigate the possible mechanisms teria necessary for good acuity and oscillopsia
that produce oscillopsia by studying subjects suppression in INS were found to be necessary
with INS or FMNS who somehow suppress in FMNS.148
oscillopsia.133,142–145 The suggestion that individuals with INS
periodically sample their visual environment
only during foveation periods with total sup-
2.1.10.1 F OV E AT I O N DY N A M I C S
pression at all other times (i.e. “stroboscopic”
One hypothesis for oscillopsia suppression vision) was a simplistic inference drawn from
in INS was the requirement that waveforms the observation that clear and stable vision was
have repeatable, well-developed foveation possible only during foveation periods, and
periods. It is only during foveation periods it has been dispelled. Temporal modulation

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studies demonstrate that individuals with INS the horizontal-torsional waveforms of INS
process retinal information continuously rather (see Section 2.1.12.1). 58,150 The cortically sta-
than selectively during foveation periods. Bedell ble migraine aura is similar to a retinally
et al. found no evidence of decreased sensitiv- stable afterimage and both produce oscil-
ity to oscillatory target motion in patients with lopsia. The aforementioned studies of oscil-
INS when comparing them to control patients lopsia suppression in INS, and its absence in
viewing a target with sinusoidal or ramp motion FMNS, disproved several possible hypotheti-
to simulate the retinal image motion that cal mechanisms. When taken together, these
occurs with retinal eye movements.123,131,134,137 studies led to the conclusion that efference
Suppression of the perceptions of oscillopsia copy of motor signals was the mechanism by
and motion smear may be mediated by different which oscillopsia is suppressed despite retinal-
but overlapping mechanisms in INS.149 image oscillation in INS and other types of
nystagmus.70,132,133,137,146–148,151,152
As discussed at the beginning of this chap-
2.1.10.3 E F F E R E N C E CO P Y
ter, one of the first conclusions produced by
The third hypothesis for oscillopsia suppression the study of INS was that the normal OMS
in INS was the presence and use of an efference could not be adequately represented by mod-
copy of ocular motor signals to cancel the com- els whose sole inputs in the determination of
ponents of eye movements in retinal motion eye-movement responses was retinal error
signals. Comparison of the foveation dynam- signals. 3 Because subjects with INS exhibited
ics of subjects with INS, FMNS, and both pen- normal responses to various target inputs,
dular and jerk forms of AN argued against the such simplistic models of the normal OMS,
foveation-period hypotheses and concluded which were incapable of reproducing the nor-
that the use of efference copy alone was suffi- mal INS responses, were determined to be a
cient to suppress oscillopsia in all subjects and poor representation of the OMS. Instead of
individually in each plane of eye motion.144 retinal error signals, the OMS responses had
When a person with INS has an afterimage to be driven by perceived target positions and
(e.g., after a bright fl ash bulb), that afterimage velocities. That is, target position and veloc-
oscillates with respect to the rest of the vis- ity signals had to be reconstructed within
ual scene, which is perceived as stable (LFD, the OMS from the retinal error signals and
personal observation, circa 1945). Thus, the efference-copy signals. All of our subsequent
retinally stable afterimage is perceived as oscil- models of INS capable of exhibiting the OMS
lating, whereas the retinally moving images of behavior of INS subjects (as well as that of
the world are perceived as stable. Individuals other ocular motor disorders) were based on
with INS respond normally to all of the com- that first model’s use of efference copy. 4,44–
51,153
mon target inputs (pulse and step changes in These behavioral OMS models had the
position, ramps, and step ramps, etc.) despite added advantage of containing signals devoid
their retinal images, confounded by the INS. 3 of the INS waveforms that could be responsi-
Efference copy was postulated as the means ble for the perceived target position and veloc-
by which that is achieved. Retinal image sta- ity signals of INS subjects (i.e., the absence of
bilization produces oscillopsia in individuals oscillopsia).
with INS, suggesting that an extraretinal sig-
nal (efference copy) may be used by the brain
2.1.11 Afferent Stimulation
to cancel out the INS waveform.133
We also studied oscillopsia of a migraine The response to external trigeminal stimulation,
aura in an individual with INS,145 as well as when present, is robust and stimulus independ-
vertical oscillopsia secondary to a decom- ent; touch, pressure, vibration, and subliminal
pensated phoria; the latter event led to the electrical stimulation have all been found to
discovery of subclinical seesaw nystagmus in damp IN.154

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2.1.11.1 CU TA N EO US T R I G E M I N A L 2.1.11.3 CO N TAC T L E NS E S

S T I M U L AT I O N
Abadi found that contact lenses damped the
Studies of the effects of afferent (cutaneous) nystagmus and improved contrast sensitivity
stimulation of the ophthalmic division of the in a patient with INS158 and others also found
trigeminal nerve on IN were based on observa- increased acuities in seven of eight patients.159
tions of the effects of contact lenses (see Section Although eye-movement data documented that
2.4.2.2). Dell’Osso et al. documented 50% soft contact lenses damped IN, when used with
decreases in IN amplitude with pressure, vibra- an anesthetic (to block afferent input), they did
tion, or electrical stimulation.154 They hypothe- not.160 That latter study, based on an observa-
sized that the afferent stimulation was affecting tion of J. Lawton Smith (personal communica-
the proprioceptive calibration of the extraocular tion to LFD), established for the fi rst time that
muscles since these fibers travel in the trigeminal exteroceptive feedback of the oscillation (via
nerve. These results infer that there is a strong the inner eyelids and the ophthalmic division of
effect on eye movement of changing the propri- the trigeminal nerve) could be used by the brain
oceptive bias to the extraocular muscles despite to damp IN. Slight pressure on the eyelid using
the absence of a classical stretch reflex. Making a cotton swab also damped the INS waveform.
the transition from experimental to therapeu- The contact lenses damped the IN by more than
tically useful methods of external stimulation 50% and increased acuity by 60% (20/40 to
remains. However, these early observations were 20/25).
to be used in developing a new surgical therapy
for INS, the tenotomy and reattachment (T&R)
2.1.11. 4 B I O F E E D B A C K
procedure (see Section 2.4.3.4) and a topical
drug therapy (see Section 2.4.2.3). Auditory biofeedback has been shown to damp
Sheth et al. found afferent stimulation could IN and improve acuity.161–163 Ciufredda also
increase foveation duration and developed an found similar effects of biofeedback on INS.164
“acuity function” (NAFP),126,155 based on a prior Kirschen reported IN damping of 41%–73%.165
function (NFF),62 that was the precursor to the In addition to damping IN, biofeedback has also
NAFX (see Section 2.1.9.1). Their data, derived been reported to increase foveation times by up
from both vibration and electrical stimulation to 180%.166
applied to the forehead, identified foveation
duration as the single most important factor
2.1.12 Canine Nystagmus
determining acuity.
(Achiasmatic Belgian Sheepdog)
After searching in vain for an animal model for
2.1.11. 2 D E E P M US C L E S T I M U L AT I O N
INS that could be used in ocular motor research
Acupuncture involves the insertion of a needle in (Siamese cats notwithstanding) one was fi nally
specific points in the neck muscle and mechani- located in a family of achiasmatic Belgian
cally or electrically stimulating it. Ishikawa et al. sheepdogs.167,168 Eye-movement recordings
found a reduction in the intensity of nystagmus verified the presence of INS waveforms along
in 9 of 16 patients.156 Vibration applied on the with unyoked movements.169 In contradic-
neck was found to be more effective than elec- tion to the then current concepts of vertebrate
trical stimulation in increasing INS foveation physiology,170 these mammals had no crossing
times and changing waveforms.155 Acupuncture optic nerve fibers; essentially they were “anti-
applied to the sternocleidomastoid muscles also chameleons” and almost “anti-albinos.” Th is
produced improved foveation in 4 of 6 patients discovery, and the documentation of seesaw
with two maintaining improvement after nystagmus in the achiasmatic Belgian sheep-
removal of the needles; INS waveforms were dogs, would later give rise to the serendipitous
also modified in this latter study.157

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identification of human achiasma along with coexisted with jerk nystagmus (i.e., dual-jerk
seesaw nystagmus.171 waveforms) in the canines.

2.1.12.1 S E E S AW 2.1.12.3 T E N OT O M Y A N D
R E AT TA C H M E N T P R O C E D U R E
Because of the identification of seesaw nys-
tagmus in two species with either achiasma or In addition to studying INS in a canine model
hemichiasma, its importance as a sign of these and the discoveries associated with achiasma,
structural abnormalities was realized and led to the achiasmatic mutant Belgian sheepdogs
the recommendation that a magnetic resonance presented us with a unique opportunity to
image (MRI) of the optic chiasmal area was test a decades-old hypothesis regarding the
indicated in infants with seesaw nystagmus.172 effects of extraocular muscle surgery on INS.
We documented seesaw nystagmus in all of the Based on observations made during the study
achiasmatic mutant Belgian sheepdogs and com- of the eye-movement improvements in human
pared it to that found in the human achiasmat.173 patients after the Kestenbaum procedure,177 it
We also studied the seesaw nystagmus in canine was hypothesized that the important secondary
hemichiasma and suggested, based on our benefits of broadening the null region and off-
fi ndings, that human hemichiasma might also null damping were due solely to the tenotomy
exist.174 Human hypochiasma was latter found and reatt achment of the muscle tendon, inde-
to exist and also exhibited seesaw nystagmus.175 pendent of its repositioning.178 A new surgical
It would latter be found that “horizontal” INS procedure, the T&R procedure, was hypoth-
could also contain both torsional and subclini- esized to provide these therapeutic benefits to
cal seesaw components. 58 Careful and sensitive INS patients with either no lateral or conver-
recording techniques are necessary to reveal the gence nulls, with a narrow null in primary pos-
subclinical seesaw component to the IN. ition, or with APAN. We performed the T&R
As Figure 2.15 (top panel) shows, the sub- procedure on an achiasmatic mutant Belgian
clinical seesaw nystagmus in INS is phase locked sheepdog in two stages separated by 4 months:
with the horizontal and torsional components, (1) all four horizontal rectus muscles and
allowing foveation periods to occur in all planes (2) all four vertical rectus and four oblique mus-
simultaneously. Torsional motion does not seem cles.179 After each T&R stage, the dog showed
to impair orientation perception thresholds, immediate and persistent visible, behavioral,
perhaps due to extraretinal information.176 We and eye-movement changes. Both the horizon-
hypothesized that subclinical seesaw nystag- tal IN and the seesaw nystagmus were markedly
mus results from slight mismatches between the damped (the latter appeared clinically gone).
forces exerted by the vertical recti and oblique Fixation ability was improved as was the abil-
muscles, and it does not represent a true verti- ity to maintain target centralisation (i.e., within
cal-system instability; this contrasts with clini- the area centralis) (see Section 2.3.1.1 and Figs.
cally visible seesaw nystagmus that accompanies 2.20b and c). Not only was this demonstra-
achiasma (Fig. 2.15, bottom panel). tion therapeutically successful but also it reaf-
fi rmed the importance to ocular motor control
of the proprioceptive feedback loop controlling
2.1.12. 2 P E N D U L A R
extraocular muscle tension. The addition of a
The pendular IN recorded in the two eyes of achi- proprioceptive tension control loop to the ocu-
asmatic Belgian sheepdogs could be independ- lar motor system is illustrated in Figure 2.16.
ent in amplitude and phase.169 Th is reflected the Proprioceptive muscle tension information and
loose yoking of canine eye movements in gen- efference copy of motor signals are fed back
eral. Because of their large temporal monocular to higher centers where target information is
fields, they are able to move their eyes independ- reconstructed, motor calculations and decisions
ently when necessary. Pendular nystagmus also are made, and motor control signals sent to the

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1.4 OU Viewing

REH
1.2
LEH
1

0.8
LET
RET
0.6

0.4

0.2
LEV

REV
-0.2

-0.4

-0.6
4 4.2 4.4 4.6 4.8 5 5.2 5.4 5.6 5.8 6
Time (sec)

30
RE Fixation

20 LEH

10

REH

-10 REV (-15 deg)

-20
See-Saw Nystagmus LEV (-15 deg)
(Pendular)

-30
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Time (sec)

FIGURE 2.15 Horizontal, vertical, and torsional infantile nystagmus syndrome (INS) data demonstrating
the phase relationships between the components in each plane of a patient with a subclinical seesaw vertical
component (top panel). The horizontal and vertical data in the bottom panel are from INS with a clinically
visible vertical component. In both patients, the horizontal INS was conjugate and the vertical, disconjugate;
the torsional component in the top panel was in phase with the horizontal component. The foveation peri-
ods coincided in all planes. H, horizontal; LE, left eye; RE, right eye; T, torsional; V, vertical. In the bottom
panel, the vertical data were shifted by –15° for clarity.

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FIGURE 2.16 Block diagram showing how a proprioceptive tension-control feedback loop provides
information from the ocular motor (OM) plant (specifically the extraocular muscles) that, combined with
efference copy of motor signal outputs, aids in the reconstruction of target information from retinal input
signals. The presence or absence of oscillopsia (OSOP) depends on the accuracy of these signals and the
internal calculations that result.

ocular motor plant. The suppression of oscillop- response) leading to either unilateral or bilateral
sia depends on the accuracy of these signals and IN damping were seen in different dogs. Th is
the internal calculations that result. pioneering work led to successful safety and effi-
cacy trials of AAB2-mediated gene transfer in
these canines182 and in humans.183
2.1.13 Canine Model of Infantile
Nystagmus Syndrome with RPE65
Retinal Degeneration (Briard) 2.2 ETIOLOGY OF INFANTILE
NYSTAGMUS SYNDROME
Not only has the ocular motor study of “man’s best
friend” resulted in the discovery of mammalian The term “congenital” is fundamentally inac-
achiasma and a new INS therapy, but dogs have curate since the nystagmus only occasionally
also played a key role in a new genetic treatment appears at birth. When questioned, parents and
for Leber’s congenital amaurosis and the accom- relatives will usually relate an onset of nystag-
panying damping of the associated IN. A colony mus between 8 and 12 weeks of age.184 In hered-
of Briard dogs with RPE65 deficiency was used itary cases, however, INS has been documented
to document the INS changes subsequent to at birth by the obstetrician and the families, who
gene therapy applied subretinally.180 The NAFX are aware of the possibility and carefully observe
values were substantially increased after gene the baby’s eyes. 33,185 Rarely, INS can manifest for
therapy as the IN was clinically undetectable. In the fi rst time in the teens or beyond, and it can
a second study, the time course of improvements cause blurred vision and oscillopsia by disrupt-
was studied.181 INS waveforms were pendular, ing the long-standing sensory and motor adap-
jerk, and dual-jerk in different dogs. It was found tations that the patient has developed to remain
that the INS improvements occurred no sooner asymptomatic.1
than 10 weeks after treatment in all but one case, Although numerous studies have described
which occurred in 4 weeks. Both unilateral treat- INS pathophysiology and its effect on the visual
ment leading to bilateral IN damping and bilat- system, until recently its etiology remained elu-
eral treatment (but unilateral electroretinogram sive. Defects involving the saccadic, optokinetic,

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smooth pursuit, and fi xation systems as well as periodic motion of the eyes away from and back
the neural integrator for conjugate horizontal gaze to an intended gaze angle or target (not across
have been proposed. Many clinical conditions, the target). 31 The pendular waveforms of INS
including genetic predisposition, are associated look sinusoidal, but they are usually distorted
with the INS oscillation. Regardless of these clin- by both flattening and the presence of small
ical associations, nearly all patients with INS have foveating saccades on the peaks corresponding
infantile onset in common; strongly suggesting to where target foveation occurs. The jerk wave-
that this oscillation is most likely to occur in an forms of INS are caused by an instability that
immature ocular motor system.186–189 leads to an acceleration of the eyes away from the
Early theories regarding the cause of INS intended gaze angle or target and requires a sac-
focused on the notion that the oscillation must cade (“braking” saccade) in the opposite direc-
result from an inherent abnormality in one tion to stop that runaway. Th is braking saccade
of the ocular stabilization systems (i.e., the might return the eyes back to the target (“fove-
smooth pursuit system, the optokinetic system, ating” saccade) or begin a slow eye movement
the VOR, or the fi xation system). Patients with back to the target for refoveation. The direction
INS do not have any known “focal lesion,” only of IN is defi ned by the direction of that saccade,
miscalibrated motor control systems. Dell’Osso although it is the slow eye movement that causes
et al. have proposed that INS seems to conform the IN. Th is is consistent with the convention
to an increase in the damped oscillation of the used to defi ne the direction of all types of jerk
normally functioning pursuit system.49,190 Th is nystagmus. IN is usually horizontal but occa-
loosely translates as an error in “calibration” sionally may have vertical components in some
of smooth pursuit that becomes evident dur- patients; torsional components are common and
ing attempted fi xation or other ocular motor there may be a subclinical seesaw component. 58
tasks. A behavioral, biomedical control-system Because INS is a motor instability, its direct
model based on that hypothesis has reproduced cause in all patients with INS is the failure of one
INS waveforms, characteristics, and ocular or more parts of the OMS to develop (calibrate)
motor responses. properly in order to maintain stable eye position.
As has been previously stated, in addition to Many different types of afferent visual deficits may
IN, other types of nystagmus (and saccadic oscil- contribute to, or even facilitate, that failure in ocu-
lations) may also occur at, or shortly after, birth lar motor calibration but none of them are truly
and should not be confused with, or lumped causative. Harris and Berry proposed the INS may
together with, IN. The other types of nystagmus develop as a developmental response to reduced
are different from IN in waveform (mechan- contrast sensitivity to high-spatial frequencies in
ism) and clinical characteristics. Other benign an early critical period.191 In many INS patients,
types of nystagmus appearing in infancy are the there are no afferent visual deficits. Therefore, it
nystagmus of FMN, spasmus nutans, and the is both misleading and incorrect to infer causality
nystagmus blockage syndrome (NBS). The phy- by (1) classifying IN as consisting of “sensory” and
sician need not be concerned with whether the “motor” subtypes; (2) to state that IN is a disor-
nystagmus appeared “at birth” or in the fi rst few der indicative of “a primary disturbance of either
weeks after birth as INS has been documented to the ocular motor or visual sensory systems”; or
appear at any time from birth through infancy; (3) using the term “idiopathic” when no sensory
indeed in rare cases, it may appear later in life. 22 abnormality is found. The primary disturbance
More important is (1) determining whether this responsible for all IN is known and it lies within the
is a benign nystagmus or one that suggests dis- OMS (see Section 2.2.3).
ease and, (2) if benign, determining whether it is
INS, FMNS, spasmus nutans, or the NBS.
2.2.1 Familial (Gene Defect)
The motor eye sign, IN, is defi ned as follows:
either a pendular or jerk nystagmus resulting INS may appear spontaneously or, in some
from a slow eye movement instability producing families INS is hereditary, as can be seen by its

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presence in more than one member. However, and limbs in the early infantile period and later
when information about other members of the paresis. Unfortunately, the method for record-
family is unavailable or if the individual with INS ing the eye movements was poor and it was
is the only known member of the family to have impossible to identify the INS waveforms from
this disorder, one still cannot rule out a hered- the figures provided. If the time constant given
ity component (spontaneous genetic mutation, was correct, the recordings more accurately
capable of familial transmission). reflect eye velocity than position. Given their
Shallo-Hoff mann et al. studied the eye other abnormalities, it is possible that these
movements of family members of subjects with patients had both INS and other neurological
INS.192 In each of five families, abnormalities of disorders as suggested by the authors. Leigh
seemingly nonaffected members were demon- and Khanna raised the possibility that INS
strated; in four, saccadic instabilities were found could result from a congenital channelopathy,
and in the fi ft h, an INS waveform. Increased fre- which causes similar hereditary acquired forms
quencies of square-wave jerks and square-wave of nystagmus such as episodic ataxia type 2. 205
oscillations were seen in family members. Th is An animal model for IN was thought to have
is a curious fi nding since INS is due to a slow- been produced in monkeys by monocularly
eye-movement instability, not saccadic. Neither depriving them of vision at birth, then reversing
the reason why unaffected family members their sutures 25 days later. 38 A variable nystag-
would demonstrate saccadic instabilities nor the mus that could be jerk, pendular, or combina-
relationship of such instabilities to INS is clear. tions of both was observed; the slow phases of
The results of this study suggest that, in isolated the jerk nystagmus were of increasing velocity.
cases of INS, the presence of saccadic instabili- Also, a latent component was noted on cover
ties in family members might be indicative of testing. At the time of that study, there was no
hereditary INS. Hereditary vertical pendular IN known animal model for IN and one would not
was documented in two sisters193 and carriers of be confi rmed until the eye movements of mem-
blue-cone monochromatism may have vertical bers of a family of achiasmatic Belgian sheep-
(upbeat and downbeat) nystagmus and FMNS.194 dogs were recorded.167,173,206
Nystagmus has been reported with many other Hereditary INS may be sex-linked, recessive
hereditary conditions, but these reports usually or dominant; the dominant form has been linked
do not contain accurate eye movement records with chromosome 6p12.207 A genetic study of
and preclude the identification of the nystagmus INS (including APAN) revealed mutations of
as IN.195–201 In one report of three patients with the FRMD7 gene in 10 families; however, not all
congenital absence of conjugate horizontal eye in those families had APAN.208 In recent years,
movements and nystagmus, recordings did show there has been an explosion of genetic studies of
a pendular nystagmus in two of the three.202 INS families.185,209–223 One study found no caus-
An interesting Japanese pedigree of hered- ative mutations and no correlation between nys-
itary INS in fi ve generations was att ributed to tagmus and X-linked ocular albinism.224
X-linked irregular dominant transmission. 203 We know that the FRMD7 mutation, which
Absence of male-to-male transmission and is associated with X-linked INS, is expressed
generation skipping was noted. The INS wave- in the ventricular layer of the forebrain, mid-
forms were predominately pendular and there brain, cerebellar primordium, spinal cord, and
was good central vision and an absence of sen- the developing neural retina.210,225 To date, five
sory defects in this pedigree. These patients nystagmus loci (NYS 1–5) have been described
are further examples that waveform cannot be in the literature associated with INS; they are
used to classify IN as “sensory-defect” nystag- shown in Table 2.2.185,210,225 Within the NYS1
mus. In another paper, fi ve male infants who locus (Xq26.2), the FRMD7 gene was identi-
showed fi ndings of abnormal auditory brain- fied. Subsequently other groups have also con-
stem response and pendular IN were report- fi rmed this.226–228 Th is protein is homologous to
ed. 204 Also exhibited were hypotonia of head another protein that is known to alter the length

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Table 2.2 Genetic Loci of Infantile Nystagmus

LOCUS O M I M NO. GENE I N H E R I TA N C E P U B L IC A T ION

NYS 1 (Xq26.2) 310700 FRMD7 X-linked (Tarpey et al., 2006)
NYS 2 (6p12) 164100 No Autosomal dominant (Kerrison et al., 1996)
NYS 3 (7p11.2) 608345 No Autosomal dominant (Klein et al., 1998)
NYS 4 (13q31–33) 193003 No Autosomal dominant (Ragge et al., 2003)
NYS 5 (Xp11.4-p11.3) 300589 No X-linked (Cabot et al., 1999)

and degree of branching of neurons as they factors to the direct cause of most INS wave-
develop in the midbrain, cerebellum, and retina, forms (i.e., a developmental failure in the deli-
which could provide a motor and combined vis- cate calibration of the smooth pursuit damping
ual and motor underpinning for the occurrence circuitry).48
of INS. The expression of FRMD7 has been Claiming several different “genetic causes”
shown in neuronal tissue in the developing ret- of INS229 mimics the aforementioned logical
ina, midbrain, and hindbrain, although it is not error exactly—many “causes” means a failure to
clear which specific gaze control systems may be identify the direct cause. The continued use of
involved.210,225 The predominant clinical pheno- the term “idiopathic,” restricted to only those
type associated with FRMD7 mutations has also with no clear “sensory” deficit, perpetuates
been characterized and it has been reported that the discredited notion of sensory causality for
unaffected carriers can have a subnormal OKN some cases of INS. Failure to identify a single
gain.185 Recently it was shown in Neuro-2A cells cause for the IN in any of the putative patient
that FRMD7 has a role in neuronal outgrowth subtypes leads to the conclusion that they
and development.225 should all be called “idiopathic.” The driving
Furthermore, detailed discussion of genetics force behind the aforementioned paper appears
is beyond the scope of this chapter. However, to be the medical classification of subtypes of
it should be remembered that even in “heredi- INS patients rather than of IN itself, although
tary” INS, an identified gene variant is not the the distinction went unappreciated.
direct cause of INS and the conclusions reached Clearly, INS patients with various types of
in many genetic studies of INS claiming cau- sensory deficits (including none) differ medi-
sality are both premature and unwarranted. cally and therapeutically, although not so much
There is neither proof of causality nor any spe- as had been thought regarding IN treatment. Just
cific mechanism known by which that particu- as clearly, eye-movement data from thousands of
lar gene variant causes INS. The tendency by INS patients (recorded in several laboratories)
some to consider genes as if they acted alone, demonstrate that their IN, or its direct cause,
is simplistic and inaccurate. Specific genes act does not differ. Despite extensive investigation,
in concert with all other genes, not in a vacuum. only some “subtle” differences in IN frequency
Researchers studying the genetics of INS face (uncorrelated to visual function) were found
the danger of making the same unfounded log- from the sample of patients with albinism in that
ical errors, as did their predecessors who erro- study; all other IN characteristics important
neously att ributed causality to sensory deficits to visual function (e.g., foveation time and the
that were merely associated with INS. Like the NAFX values) were the same. 229 Unfortunately,
plethora of associated sensory deficits, the ever- the IN data were taken only in the ±15° range
increasing gene variants found in families with of gaze angles, thereby limiting amplitude and,
INS should be considered associated, facilitating more important, waveform variations. It is not

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surprising that patients with foveal hypoplasia of all parallel afferent visual system processes.
would be slower to insert braking and foveating As mentioned previously, this new knowledge
(i.e., resett ing) saccades into their “pendular” caused us to abandon the classic “motor” and
waveforms, thereby exhibiting a slightly lower “sensory” classification introduced by Cogan
frequency—that does not equate to either a dif- over 30 years ago. 24
ferent type of nystagmus or a different cause. The block diagram in Figure 2.17 summa-
Although the genetic association listed ear- rizes the concepts regarding the direct cause
lier provides a possible causal relationship, the of INS and those other conditions that may
etiology of the INS oscillation may be multifac- facilitate the development of INS in a par-
torial (genetic, infl ammatory, developmental, ticular subject. The ocular motor oscillation
infectious, etc.) if the fi nal common pathway in INS develops directly from deficits within
is interference with ocular motor calibration the smooth pursuit (most waveforms) and vis-
during a developmental period of “sensitiv- ual vestibular (some waveforms) subsystems.
ity,” at which time an insult results in possibly Many factors determine whether miscalibra-
irreversible changes. Sensitive periods dur- tion of these subsystems develops or to what
ing development of visual functions are well degree that miscalibration develops in each.
recognized, for example, contrast sensitivity, These factors may facilitate miscalibration to
stereopsis, visual acuity, and binocularity. 230,231 various degrees but cannot be considered the
Motor-system calibration is an active process direct cause of INS. As Figure 2.17 indicates,
that may start in utero and continues at least ocular motor research has eliminated many of
through early infancy. Sensory-system devel- the components of the OMS as possible causes
opment is a parallel visual process that has of INS, including fi xation, saccadic, and fi nal
been more thoroughly studied and also contin- common neural integrator.
ues to develop through the fi rst decade of life.
Previous studies have documented connec-
2.2.2 Developmental Disturbance
tions between parallel visual processes (cross-
of the Ocular Motor System with
talk) that modify, instruct, and coordinate
Associated Sensory System Deficit
these systems, resulting in smooth and coordi-
nated function. 232,233 Although INS may result Several papers emphasize the associated sen-
from a primary genetic defect directly affect- sory defects found in individuals with INS.234–236
ing ocular motor calibration, it may also result Some have stressed the high percentage of INS
from abnormal cross-talk from a defective sen- patients with these defects, but this may reflect
sory system to the developing motor system at the authors’ patient population more than the
any time during the motor system’s sensitive INS population in general. Whatever the num-
period. Th is can occur from conception due to bers, two things are clear: (1) physicians do have
a sensory defect (e.g., retinal dystrophy), during to look for any sensory defects that may be pre-
embryogenesis due to a developmental abnor- sent in an individual with INS and treat them;
mality (e.g., optic nerve hypoplasia), or after (2) no matter what the sensory defects are,
birth during infancy (e.g., congenital cataracts). the INS is still a motor instability. The sensory
Th is theory of the genesis of INS incorporates defects discussed next are commonly associated
a pathophysiologic role for the sensory system with INS of all waveforms.
in its genesis and modification. While the set INS is caused by a primary motor defect
of physiologic circumstances may differ, the and there is no preponderance of any specific
fi nal common pathway is abnormal calibration waveform with the presence or absence of an
of the ocular motor system during its sensitive associated sensory defect. One of the initial
period. The primary ocular motor instabil- fi ndings that resulted from accurate eye-move-
ity underlying INS is the same but its clinical ment recordings was that both the etiology and
and oculographic expression are modified by the mechanisms underlying INS waveforms
both initial and fi nal developmental integrity are independent of accompanying sensory

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FIGURE 2.17 Block diagram summarizing the differences between the many possible conditions that may
facilitate the development of infantile nystagmus syndrome (INS) in an individual and the fi nal direct cause
of INS itself. Cong Cat, congenital cataracts; FCP, fi nal common pathway; Fix, fi xation subsystem; IM,
internal monitor; NI, neural integrator; OMS, ocular motor system; Sacc, saccadic subsystem; SP, smooth
pursuit subsystem; VVS, visual vestibular subsystem; X, subsystems whose deficits do not cause INS; + and
±, subsystems whose deficits do cause INS.

defects. 33 Therefore, although there is an asso- than accepting the factual data, some have inverted
ciation between many sensory defects and the (perverted) them by claiming that eye movement
presence of INS,235 the former appear to be sec- data “cannot differentiate” between these two puta-
ondary factors provoking the manifestation tive types of INS.118 That is similar to claiming that
of INS in individuals where there is already fingerprint analysis cannot differentiate between
a primary predisposition for the latter. In many two prints left by the same person. Totally lost in
patients, sensory defects are the precipitating such an argument are the facts that the same sen-
factors of INS. Th is correlation is particularly sory defects (including albinism, which has incor-
high in chiasmal disorders, such as found in albi- rectly been claimed to always be accompanied by
nism or in achiasma (Belgian sheepdogs167,169 or INS) exist in patients without INS, and INS exists
human172,173). In the former there are too many in many individuals who have no sensory defects.
crossing fibers and in the latter, none. Thus, two Simple logic dictates that sensory defects are nei-
opposite deficits induce the same ocular motor ther the necessary nor sufficient conditions for the
instability; this supports the hypothesis that any development of INS.
disruption to the afferent visual system in the One should not, however, ignore the asso-
early stages of development may result in INS. ciation between sensory defects and INS pre-
To put is quite simply, due to the inherent insta- sent in many individuals. Since any of several
bility in normal ocular motor development, INS different sensory abnormalities (each affecting
is a disorder waiting to happen. the primary visual signal in unrelated ways) can
Despite the eye-movement data that prove affect the developing motor system such that it
conclusively that INS is a unitary entity (i.e., a becomes unstable, the following possibilities are
motor sign indicating ocular motor instability) suggested: (1) a small percentage of individuals
the early, erroneous idea that there existed two are born with a motor system that is precariously
types of INS, “sensory” and “motor,” persists.23,235 close to oscillation or (2) nature has evolved the
The term “motor INS” is redundant and “sensory OMS in such a way that the horizontal system
INS” is misleading (meaningless) for the reasons is close to instability in many individuals. The
discussed earlier; neither should be used. Rather reason for the latter hypothesis may lie in our

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need for rapid horizontal eye motion to survive. one, or the other; this has not been worked out
Whatever the underlying reason, the developing and is outside the scope of this chapter. The
motor system seems to require early visual input diagnosis and treatment of the various sensory
to assure its stability and any sensory defect system abnormalities that may accompany
interfering with the acquisition of that early vis- INS also will not be extensively covered in this
ual input might result in the INS instability. In text; rather, we will concentrate on the proper
those individuals actually born with INS, the management of INS and other forms of nystag-
motor system may have developed with such a mus in infancy and childhood.
strong instability (owing to hereditary or spon-
taneous genetic factors) that even the presence
2. 2. 2.1 A L B I N IS M
of adequate visual input after birth (i.e., no sen-
sory defects) is not enough to stabilize it. Th is One specific group of patients who usually
latter group, where the INS is truly “congeni- have INS are those with albinism. Here, as
tal,” can include both those with only INS and with INS, what was once a “clinical” diagno-
those with associated sensory defects, not just sis can now be made defi nitively by a simple
the former. diagnostic test based on the visual evoked
In individuals who have a sensory defect, it, potential (VEP). If performed properly using
instead of the nystagmus, may be the limiting a pattern-onset paradigm, the VEP is highly
factor for acuity and even halting eye motion sensitive and specific. 237,238 Th is paradigm uses
using forceps may not result in an acuity full-field, monocular pattern (checkerboard)
improvement; in other such individuals, acu- onset/off set stimuli instead of pattern rever-
ity can be improved by damping the IN. One sal stimuli; the latter contain motion artifacts
must perform the necessary diagnostic tests and should not be used in individuals with IN
(e.g., the electroretinogram, visual evoked or any other nystagmus. For children below
response, etc.) to correctly assess the func- the age of about 4 years, reliable results are
tional integrity within the visual system and obtained with a luminance fl ash paradigm.
diagnose any sensory abnormalities present Th is paradigm demonstrated the unequivo-
but that diagnosis is not sufficient to describe cal dissociation between the misrouted fi bers
the motor defect causing the nystagmus. The found in albinos and their INS since no indi-
latter requires motility recordings for abso- viduals with hereditary or only INS had mis-
lute diagnosis since those with sensory defects routing. Thus, the hypothesis that misrouting
might have one of the other types of nystag- is the cause of INS is incorrect and lacks phys-
mus and not IN. If a patient with nystagmus iological foundation; misrouting is but one of
has a best-corrected binocular visual acuity several sensory defects that may impede the
worse than 20/40, one should look carefully development of a stable OMS.
for other associated sensory system defects. One area that has received much attention
Sensory defects may be more prominent in and is the result of some confused ideas about
pediatric patient populations than in adult the etiology of INS is in individuals with albi-
populations where there is a higher incidence nism. Most, but not all, albinos also have IN. All
of INS unassociated with visual defects. 235 It albinos exhibit asymmetry in the monocular
is possible that there are two different genes visual evoked potential (VEP). 239 However, not
with variable probabilities of the one facilitat- all albinos demonstrate nystagmus and there-
ing the slow-eye-movement instability, IN and fore the link between aberrant projections and
the other, the afferent defect. The presence of organization of the OMS in nonalbinos with
either of these genes might be related to the INS is in question. They found no crossed pro-
presence of the other by some third proba- jections in a nonalbino with nystagmus. A case
bility. Another possibility is that there is one of albinism with FMNS has also been report-
gene with different probabilities for an affer- ed. 240 Apkarian and Spekreijse also reported
ent defect and INS; a patient may have both, another nonalbino with nystagmus who had

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no crossed fibers. 241 In a test of 14 patients with putative causal mechanism causing INS that is
INS, they found none with optic pathway mis- related to “reversed” signals.
routing (personal communication to LFD).
In a study of 18 albinos, 5 of which had no
2. 2. 2.3 I N FA N T I L E S T R A B IS M US
noticeable nystagmus, all showed global ster-
eopsis. 242 These fi ndings are interesting when Strabismus may or may not accompany INS,
contrasted with the investigations in albino unlike in FMNS, where it is mandatory.
animal models where a paucity of binocularly Strabismus complicates both the differential
driven cortical neurons is found in visual areas diagnosis and treatment of INS. Because those
17, 18, and 19. Other studies have also verified with strabismus can change their fi xating eye,
that albinos demonstrate VEP asymmetries, the analysis of eye-movement data is made
whereas those with only INS do not. 243,244 Thus, difficult, especially when trying to determine
since electrophysiological evidence has proven the foveation qualities of INS waveforms in
that individuals with INS do not have crossed the fi xating eye. Without accurate monocular
fibers, hypotheses and models that rely on calibration, such determinations are highly
crossed fibers and “reversed” pursuit have no problematic and may lead to errors in deter-
basis in fact. 55,63,70,71 mination or prediction of visual acuities cor-
Rosenberg and Jabbari suggested that a hori- related to foveation functions applied to INS
zontal grating stimulus might be used where the waveform data.
conventional check stimulus for VEP produces The problem of strabismus is misalignment
poor results due to horizontal nystagmus. In of the eyes (i.e., a relatively static problem)
a paper on the recognition and management of and the aim of strabismus therapy is correct
albinism, Abadi and Pascal described twin girls alignment of the two eyes (i.e., a static out-
who had similar INS waveforms but whose fast come, easily measured by the position of the
phases were in opposite directions. In this paper eyes). Although restoring binocularity is also
the authors stated that all forms of albinism are a medically desirable outcome, it is not the
characterized by nystagmus; this appears to be standard measure for successful strabismus
in contradiction to the studies mentioned ear- therapy. INS, in contrast, causes an oscillation
lier. As a fi nal note on albinism and ISN, it has of both eyes that degrades foveation of targets
been suggested that although acuity is prima- of interest (i.e., a dynamic problem), and the
rily limited in albinism by retinal factors, reduc- aim of INS therapy is to reduce the oscillation
ing the IN can lead to an improvement.245 The and improve foveation quality (i.e., a dynamic
value of the electroretinogram in the evaluation outcome, easily measured by analysis of eye-
of children with early-onset nystagmus has also movement data). Although improvement of
been examined.246 peak visual acuity is also one of the medically
desirable outcomes, it is not the standard meas-
ure for successful INS therapy. A far more
2. 2. 2. 2 AC H I A S M A
important medical outcome is improvement
After the discovery of achiasma and hemichi- of the range of gaze angles with high acuity; in
asma in canines,167,174 it was confi rmed and stud- some cases, that may be the standard measure.
ied in humans.102,175,247–251 As in albinism, the Other INS problems may include a head pos-
absence or diminished number of crossing optic ture, adopted to exploit the gaze angle with
fibers is strongly associated with INS and addi- maximal acuity. Head posture is not the vari-
tionally, with seesaw nystagmus.173,248,252 Indeed, able to measure to quantify the problem nor is
the latter is a sign that imaging of the chiasm is it the means to determine the therapeutic out-
indicated. The addition of achiasma to the long come of INS therapy. Rather, in all such cases,
list of sensory deficits associated with INS and only measurements made from eye-movement
specifically its opposite effect on crossing fibers data provide direct outcome measures of each
than albinism should fi nally lay to rest any of these INS-induced problems.

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2. 2. 2. 4 N O N V EC T O R I A L V I S U A L originally identified in INS25 are pathognomonic

SENSORY DEFICITS of INS except pure pendular or linear (saw-
tooth) jerk; either of these could be an acquired
Visual sensory deficits that are nonvectorial
nystagmus and the latter, FMNS. However, the
but yet have been claimed to cause horizon-
pendular nystagmus of INS is usually distorted
tal INS include achromatopsia (lack of color
so the patient can foveate, whereas in acquired
vision); aniridia (absence of irides); congenital
nystagmus it is not. In acquired nystagmus, the
stationary night blindness (deficient rod-cell
slow phases can be linear, of increasing veloc-
response); foveal hypoplasia (maldevelopment
ity, of decreasing velocity, or pendular. IN slow
of the fovea); optic nerve aplasia/dysplasia/
phases can be pendular, increasing velocity, or
hypoplasia/atrophy/colobomas; infantile reti-
some may be linear. Within the pendular or jerk
nal dystrophy/degeneration; and infantile visual
major INS waveform categories, three different
deprivation. To date, no mechanistic hypotheses
forms of pendular and eight of jerk (four unidi-
have been presented to support such claims. The
rectional and four bidirectional) were identified.
incidence of congenital achromatopsia in a group
Additionally, dual-jerk is the superimposition of
of otherwise undiagnosed children was 29%,
a high-frequency, low-amplitude pendular nys-
with 40% being erroneously classified as having
tagmus of different origin on a jerk INS wave-
“idiopathic” INS.246 The authors concluded that
form with either increasing velocity or linear
there was a need to use the electroretinogram
slow phases; illustrations and examples are avail-
in children where the diagnosis was uncertain.
able in the literature25,254 and in Figure 2.4. In a
It has been claimed that those with congenital
group of patients with INS, 87% had more than
achromatopsia have a slow buildup of OKN in
one INS waveform; they had various combina-
the temporal-to-nasal direction compared to
tions of the 12 originally described waveforms.
the nasal-to-temporal direction, whereas others
A small percentage of patients (13%) exhibited
with INS do not.253
only one waveform. Distinguishing the sub-
tle characteristics of INS waveforms required
2.2.3 The Direct Cause(s) of Infantile DC-coupled, high-bandwidth recordings of
Nystagmus Syndrome with or without both eyes simultaneously.
Sensory/Genetic Deficits
A significant portion of this chapter contains 2. 2.3.1 L OSS O F S M O OT H - P U R S U I T
information that dispelled long-held myths, DA M P I N G
misinformation, and erroneous conclusions
Most INS waveforms are directly caused by a
regarding the direct cause(s) of INS. The diag-
failure in calibration of an internal feedback
nostic characteristics for each of the benign
loop in the smooth pursuit subsystem; they
types of nystagmus of infancy are unambiguous.
are the pendular and most jerk waveforms and
Each type can be differentiated by simple eye-
are identified in Figure 2.2 as PSN. Our behav-
movement recordings that simultaneously pro-
ioral ocular motor system model demonstrates
vide the data necessary for effective therapeutic
how this simple, albeit evolutionarily probable,
intervention. Regardless of time of onset, the
miscalibration in an otherwise normal ocular
waveforms recorded from individuals with INS
motor system can produce the complex wave-
are overlapping combinations from the same
forms recorded in INS. For all INS waveforms,
group. Not only are the waveforms the same but
the intersection of the Alexander’s law relation-
also the motor mechanism(s) in all instances
ships (see Section 2.2.3.2) in the two directions
are the same; there is only one INS, independ-
results in a null centered in primary position,
ent of time of onset or associated sensory or
and asymmetry of those relationships results
genetic deficits. With the aid of recorded eye
in an eccentric null position. The steeper the
movements, the diagnostic criteria for INS are
slopes of the Alexander’s law relationships, the
defi nitive. Many of the 12 waveforms that were
faster will be the rise in IN amplitude as gaze is

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FIGURE 2.18 Simulation of pseudopendular with foveating saccades (PPfs) waveform variation as a result
of a centered intersection of the Alexander’s law (AL) relationships with moderate slopes. As gaze is directed
away from the null, the infantile nystagmus syndrome amplitude increases slowly. The eXpanded nystagmus
acuity function (NAFX) versus gaze angle curve corresponding to such a variation is also shown with its
moderate sharpness.

directed away from the null position. To illus- and 2.19 show simulations of an individual with
trate the effects of different Alexander’s law INS whose waveforms remain constant with
relationships on INS without the confounding gaze angle rather than the more common simu-
influence of changing waveforms, Figures 2.18 lations shown in Figure 2.8, where neutral-zone

FIGURE 2.19 Simulation of pseudopendular with foveating saccades (PPfs) waveform variation as a result
of a right-gaze intersection of the Alexander’s law (AL) relationships with steep slopes. As gaze is directed
away from the null, the infantile nystagmus syndrome amplitude increases rapidly. The sharp eXpanded nys-
tagmus acuity function (NAFX) versus gaze angle curve corresponding to such a variation is also shown.

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pendular waveforms become jerk waveforms Finally, changes in peak visual acuity is a poor
with lateral gaze. Figure 2.18 shows the gradual direct outcome measure of INS therapy and, in
rise in PPFS waveform amplitudes produced by some cases, may show no improvement despite
relatively moderate slopes intersecting at pri- significant improvements in other factors defi n-
mary position. The corresponding NAFX versus ing overall visual function; that can obscure the
gaze angle curve is shown below the Alexander’s success of INS therapies by incorrectly classify-
law relationship. In Figure 2.19, the steeper ing these patients as “not improved.” INS defi-
slopes and eccentric intersection produce a null cits are an addition to, and complicated by, those
in right gaze and a rapid increase in PPFS ampli- caused by associated visual sensory deficits. It is
tudes with corresponding sharper NAFX curve, important to both understand the differences
as gaze is directed lateral to that null (see also between INS deficits and purely visual deficits,
Chapter 5, Table 5.3). to be able to separate and quantify both types
of deficits, and to be able to measure and pre-
dict the improvements to the former (i.e., INS
2.2.3. 2 T O N I C V I S U A L V E S T I B U L A R
deficits) from INS therapies. Only then can the
IMBAL ANCE
proper treatment be prescribed and its expected
A small number of INS waveforms are directly effects accurately measured.
caused by a tonic imbalance of steady-state neu-
ral signals in the visual vestibular subsystem;
2.3.1.1 T H E E X PA N D E D N Y S TAGM US
they are those with linear slow phases identified
ACUIT Y FUNCT ION AND LONGEST
in Figure 2.3 as VVSN. Our behavioral ocular
F OV E AT I O N D O M A I N M E A S U R E S
motor system model produces linear slow phase
jerk nystagmus when such a tonic imbalance is The nystagmus acuity function (NAF) provides
present. The model contains Alexander’s law an objective determination of potential visual
relationships that increase the tonic imbalance acuity from measurements of the key character-
as gaze is directed laterally. istics of the INS waveform: foveation time and
the standard deviations of foveation position
and velocity means (for NAF) or position mean
2.3 VISUAL FUNCTION DEFICITS
alone (NAFP).155 For those subjects whose
AND MEASUREMENTS OF
foveation ability is not well developed (i.e., the
INFANTILE NYSTAGMUS
target image always falls within the default fove-
SYNDROME
ation window), the window used for its calcula-
tion can be enlarged and the “expanded” NAF
2.3.1 Static Deficits
(NAFX) plotted versus gaze or convergence
Static visual function in INS is diminished in angle. Thus, the NAFX reverts to the original
several ways that are not adequately detected or NAF when the default foveation window is cho-
measured by current clinical examination. The sen. Because of inter- and intrasubject variation
restriction of the patient’s high-acuity range of in INS waveforms, the relative impact of each of
gaze angles by the characteristic worsening of the three foveation characteristics on visual acu-
the INS waveform at gaze angles lateral to the ity varies. Thus, despite claims to the contrary,
“null” is a major impediment to good visual attempts to correlate only one or two of them to
function. Simply assessing the BCVA, either in visual acuity130,255 can only be approximate or
primary position, at the “null” angle, or both limited to specific waveforms and cannot accu-
does not identify the true visual function deficit rately duplicate either the analytic or predictive
in INS. Such restricted measures also fail to dif- abilities of the NAFX in most cases.
ferentiate the amount of visual function loss that The current NAFX soft ware can assess hori-
is directly att ributable to either an associated vis- zontal, vertical, or multiplanar foveation quali-
ual sensory loss or to the INS itself. Th is can only ty.128 The soft ware calculates the NAFX from
be done using analysis of eye-movement data. eye-movement data and provides a quantitative

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method for evaluating different therapies for H. Collewijn in Rotterdam (see Albinism and
their effect on potential visual acuity.127 Plots of Achiasma sections 2.2.2.1 and 2.2.2.2).171 As
the NAF or NAFX versus visual acuity reveal the NAFX clearly shows, conditions for high-
the linear relationship that allows intersubject est visual acuity occurred during near fi xation
prediction of potential visual acuity.190 The where (as the bottom panels show) a smaller
NAFX can also be used to compare potential foveation window could be used to calculate the
acuity across subjects with different types of NAFX. Figure 2.20b shows the NAFX outputs
nystagmus (IN or FMN) or to predict the acuity from an achiasmatic Belgian sheepdog, pre- and
increase possible after therapeutic intervention post-T&R, demonstrating the effectiveness of
in a given subject. The latter is accomplished by the T&R treatment. As the bottom panels show,
plott ing the NAFX versus gaze or convergence the post-T&R nystagmus is subclinical and well
angle. Figure 2.20a shows the NAFX outputs within the boundary of the area centralis; the
during far and near and far fi xation from a sub- nystagmus during the whole interval qualified
ject with achiasma, recorded in Laboratory of as a foveation period. Figure 2.20c shows the

FAR FIXATION NEAR FIXATION

6

5
4

0 2

0
-5

-2
1 2 3 4 5 6 0 0.5 1 1.5 2 2.5
Time (sec) Time (sec)

5 5

0 0

-5 -5
10 Foveation Periods Identified by Algorithm
19 Foveation Periods Identified by Algorithm

1 2 3 4 5 6 0 0.5 1 1.5 2 2.5

Time (sec) Time (sec)

FIGURE 2.20 (A, above) The eXpanded nystagmus acuity function (NAFX) output for a subject with achi-
asma during far and near fi xation, demonstrating improvement at near by the smaller foveation window and
lower variation of foveation position. (B) The NAFX for an achiasmatic Belgian sheepdog demonstrating
dramatic postoperative improvement by the relative sizes of the nystagmus and the ±3° centralis window.
(C) NAFX versus visual acuity for both humans and canines, demonstrating improvement at near fi xation
(humans S1 and S2), at far with base-out prisms (S1), and after tenotomy and reatt achment (canine S3). The
dot-dashed lines indicate the extent of the foveal window (humans) or area centralis (canines). The thick-
ened areas identify foveation (human) or centralisation (canine) periods in NAFX outputs.
(continued)

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PRE-TENOTOMY POST-TENOTOMY
6
4 0.5
2
0
0
-2 -0.5
-4
-6 -1
-8
-1.5
16 17 18 19 20 25 30 35
Time (sec) Time (sec)

6 6
4 4
2 2
0 0
-2 -2
-4 -4
-6 -6 16 Foveation Periods Identified by Algorithm
-8 14 Foveation Periods Identified by Algorithm -8
16 17 18 19 20 25 30 35
Time (sec) Time (sec)

EXPANDED NYSTAGMUS ACUITY FUNCTION

1.4
20/15
S1 S2S3 S3 Human
1.2
Far
Near
1 Prisms 20/20

S1: NAF=NAFX
0.8 S2 Far: NAFX 20/25
S2 Near: NAF
S3 Pre/Post-Tenotomy: NAFX 20/30
Visual Acuity

0.6 ( ) ( )

20/40

0.4 20/50

0.2 Canine 20/100

(Presumed)
20/200

0
0 0.2 0.4 0.6 0.8 1
Nystagmus Acuity Function (NAF/NAFX)

FIGURE 2.20 B. top, C. bottom.

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NAFX versus potential (solid and dashed lines) both new stationary targets and moving targets.
and measured (symbols for the human data) Thus, the usually simple and rapid task of scan-
visual acuity for two humans (S1 and S2) and ning a room full of people to identify familiar
a canine (S3). The NAFX (and potential visual faces becomes both difficult and slow; also, per-
acuity) is higher at near than at far (S1 and S2) formance in sports is diminished. Currently,
or while using base-out prisms at far (S1). For neither these visual function measures nor
the canine, the post-T&R NAFX is higher than their possible improvement after therapy is
preoperatively and the dashed line is inferred assessed clinically. Th at omission, plus the fail-
from veterinary data. ure to use eye-movement data to assess all of
Because of its direct relationship to potential the pre- and postt herapy measures, introduces
visual acuity (specifically, the motor component false-negative fi ndings in clinical trials limited
of visual acuity), the NAFX is the best available to peak visual acuity or other static measures as
outcome measure of therapies designed to affect their outcome measures.115,258
the INS waveform.256 Although amplitude is
related to cosmetic appearance, neither it nor fre-
2.3. 2.1 TA R G E T ACQ U IS I T I O N T I M E
quency is closely correlated with acuity. Bedell
(S TAT I O N A R Y TA R G E T S )
suggested that some INS patients have ambly-
opia that is amenable to treatment with proper Wang et al. found that the acquisition time to
refraction.257 Although that may be true, INS static targets is increased in INS patients; that
itself does not produce amblyopia since improv- is, they are “slow to see.”69 The saccadic latency
ing foveation periods in INS by surgical, optical, (i.e., time from target step to fi rst saccade) is
or other means immediately results in improved not appreciably different from normal in INS.
visual acuity in most INS patients. It appears However, it takes several IN cycles before the
that the existence of foveation periods in the new target is foveated; thus, target acquisition
INS waveforms is sufficient to prevent amblyo- times are longer than simple saccadic laten-
pia in cases where there is no other underlying cies. The amount of time added to acquire new
cause present. targets was related to the interaction between
For multiplanar INS, the foveation periods in target motion and intrinsic saccades in INS
each plane must be phase locked for maximum waveforms. Target steps occurring at or near
acuity. As a practical matter, the horizontal and foveating or braking saccades increases tar-
vertical foveation periods are more important get acquisition times. Our behavioral ocular
since torsion contributes litt le retinal motion at motor system model predicted this when sim-
small distances from the center of the fovea. 56 ulations were run with targets stepping at dif-
Fortunately, from data taken so far, it appears ferent times in the IN cycle. The OMS model
that the foveation periods in all three planes simulations in Figure 2.21 demonstrate that
are phase locked (see Fig. 2.15). The horizontal despite similar saccadic latencies, target acqui-
foveation periods are phase locked to both the sition times for step-change targets are longer
subclinical torsional and seesaw components of for individuals with INS.
the oscillation. The current NAFX soft ware can
be used to measure the potential acuity of mul-
2.3. 2.2 TA R G E T ACQ U IS I T I O N T I M E
tiplanar INS.128
(M OV I N G TA R G E T S )
In addition to longer acquisition times for
2.3.2 Dynamic Deficits stationary targets, the time to acquire a mov-
In addition to the static deficits in visual func- ing target is similarly increased in INS if tar-
tion (lower peak visual acuity and narrow get motion begins near the intrinsic saccades
range of gaze angles with high acuity), there within the INS waveforms. 259 Furthermore, the
are dynamic deficits associated with INS. They timing of these saccades sometimes introduces
include increased times to acquire (i.e., foveate) errors in calculating target position, resulting

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FIGURE 2.21 Step response simulations of the behavioral ocular motor system model for a normal subject
(left panel) and one with a pseudopendular with foveating saccades (PPFS) infantile nystagmus syndrome
waveform. Note that although the saccadic latencies are similar, the target acquisition time is much longer
for the subject with infantile nystagmus syndrome. Shown are target motion (dashed), reconstructed target
motion (dot-dashed), retinal error position (thin trace), and eye (heavy trace).

in steady-state position errors during smooth life and impair his or her abilities in tasks such
pursuit of moving targets. Thus, although the as driving and sports (e.g., lagging a flying clay
eyes move with the correct (i.e., target) veloc- or game bird results in shooting behind it and
ity, they are consistently behind the moving tar- missing the target). The OMS model simula-
get. Our behavioral ocular motor system model tions in Figure 2.22 demonstrate that despite
predicted both the acquisition time increases similar smooth pursuit latencies, target acqui-
and the steady-state position errors during sition times for ramp-change targets are longer
pursuit simulations. These deficits negatively for individuals with INS. In Figure 2.23, the
affect the patient’s professional and personal model simulations show how target timing

FIGURE 2.22 Ramp response simulations of the behavioral ocular motor system model for a normal
subject (left panel) and one with a pseudopendular with foveating saccades (PPFS) infantile nystagmus syn-
drome (INS) waveform. Note that although the saccadic latencies are similar, the target acquisition time
is much longer for the subject with INS. Shown are target motion (dashed), reconstructed target motion
(dot-dashed), retinal error velocity/10 (thin trace), and eye (heavy trace).

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FIGURE 2.23 Ramp response simulations of the behavioral ocular motor system model for a subject with
a pseudopendular with foveating saccades (PPFS) infantile nystagmus syndrome (INS) waveform when the
target velocity onset occurs at different times in the INS cycle. Motion onsets (earliest to latest) are as fol-
lows: during the foveation period, during the slow phase, and during the breaking saccade. The respective
target acquisition times (Lt) are >2 sec, 1.6 sec, and >2 sec, respectively. Also there is a steady-state position
error for the fi rst response.

can introduce steady-state position errors dur- pretherapy values—the therapeutic improve-
ing pursuit. Not only does target motion near ment domain [TID]110) or even clinical measures
intrinsic INS saccades extend target acquisi- of gaze-dependent visual acuity. As a result, such
tion times but it also causes calculation errors studies do not provide useful information about
leading to steady-state eye position errors. either the mechanisms important to the improve-
ments of each procedure or the specific visual
function improvements that resulted, and they are
2.3.3 Clinical
also subject to false-negative outcomes. Second,
Visual acuity is a secondary measure of INS ther- studies that used measures of head posture were
apy; because of its idiosyncratic variation with doubly confounded by lack of accurate measure-
stress and monocular occlusion, it is not a reliable ment and patient control of that outcome measure;
outcome measure, especially if patients have not the shift in NAFX peak is a much more accurate
been screened for the foveation quality of their and repeatable outcome measure. Several reviews
waveforms. Also, because of the latter variation, of the therapies for INS and other forms of nystag-
monocular acuity is not a valid outcome meas- mus incorporate current research findings.261–263
ure. A clinical study of the effects of T&R, or the The block diagram in Figure 2.24 illustrates the
Anderson procedure plus T&R of the remaining anatomical sites and physiological signals that
two extraocular muscles (EOM) (as was suggested determine both the therapeutic options and the
by the positive results of the T&R procedure), sup- best direct outcome measures of each type of ther-
ported our predictions.260 However, this and sim- apy. Despite the central source of the INS, thera-
ilar clinical studies (not cited herein) have had the pies may be aimed at the afferent system (Ta),
expected variable and confounded results. First, centrally (Tc), or, as is most often the case, periph-
they failed to use the direct outcomes of EOM erally (Tp). Direct and indirect effects of each type
surgery (e.g., the peak NAFX and, more impor- of therapy are listed, as are the direct and indirect
tant, the broader ranges of gaze angles where the outcome measures of each. For both central and
NAFX was either within 10% of the peak—the peripheral therapies, the NAFX is the most accu-
longest foveation domain [LFD] or greater than rate direct outcome measure of INS therapy.

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[Measures of therapeutic effectiveness]

Ta = afferent therapy; Tc = central therapy; Tp = peripheral therapy
* or *’ = site of primary effect of therapy; ’ = motor commands
Tp damps the nystagmus (N) which improves potential acuity [NAFX] and may improve measured acuity [VA] or oscillopsia [OSOP]
Tc damps the nystagmus signal (N’) which damps the nystagmus (N), improves potential acuity [NAFX], and may improve measured acuity [VA] or oscillopsia [OSOP]
Ta improves retinal function which improves [ERG, PLR, VEP, and VA] and damps both the nystagmus signal (N’) and the nystagmus (N), improving potential acuity [NAFX]

FIGURE 2.24 Block diagram illustrating afferent (Ta), central (Tc), and peripheral (Tp) intervention points for infantile nystagmus syndrome therapies and exam-
ples of each. Also shown are the outcome measures that are possible at each anatomical site.

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2.3.3.1 V I S U A L ACU I T Y AT D I F F E R E N T as their foundation. INS treatments and their

GA ZE ANGLES application are discussed in detail in Chapter
7, but it is important to note that INS research
A reduction in contrast sensitivity for medium
using eye-movement data analysis has uncov-
to high spatial frequency vision and increased
ered both the inadequacy of using clinical meas-
pattern detection thresholds in INS impairs the
ures alone as outcome measures and the danger
detection of vertically oriented stationary and
of using them as primary outcome measures.
moving grating patterns more so than horizon-
The most common measure, peak visual acuity,
tal ones. The increased contrast sensitivity and
is both indirect and insufficient and peak acuity
pattern detection thresholds are secondary to
may not improve in some successful cases of INS
the oscillation itself and improve when the INS
therapy. The following summarizes the contri-
oscillation is reduced.264,265
butions to INS treatment made by ocular motor
Individuals with INS suffer reduced visual
research.
acuity as they direct their gaze lateral to their
Weiss et al. suggested that improving fove-
null region. That is the major visual function
ation-period quality would not improve acuity
limitation att ributable to INS in most patients,
in INS associated with albinism, and that the
not low peak acuity. As the NAFX versus gaze
acuity of such patients was not related to the
angle curves demonstrate, visual acuity can
INS but rather, to macular hypoplasia. 266 In
drop off sharply as gaze is directed away from its
light of the number of such patients whose visual
peak. Thus, patients cannot simply and rapidly
function improvement following EOM surgery
scan their visual environment by using saccades
has been documented in the literature, both
to acquire lateral targets; if they do so, they may
the assumptions and methods used to arrive
not be able to identify such targets (e.g., people’s
at those contrary conclusions need to be seri-
faces) because their INS waveforms have poor
ously reexamined. First, only in those few cases
foveation quality. That necessitates the time-
where both the pretherapy NAFX and LFD val-
consuming and less accurate strategy of turning
ues are high is the presumption that acuity is
one’s head for each target so that it appears at the
not related to the INS true and, therefore, there
null angle. Th is deficit in visual function is nei-
would be limited expectation of improvements.
ther appreciated by most clinicians nor tested
Second, contrary to the suggestion that those
for, either before or after therapy. Broadening the
with visual sensory deficits that limit their peak
range of gaze angles with high acuity should be
visual acuity would not benefit from INS ther-
the major outcome measure of the effectiveness
apy, five decades of eye-movement-based INS
of any INS therapy. Unlike peak acuity, which
research demonstrates conclusively that not
can be diminished by various sensory deficits as
only will they benefit but also the percentage
well as INS, the breadth of this function is solely
improvement in their outcome measures will
due to the characteristics of the INS and is a
be greater than those INS patients with higher
direct outcome measure. The therapeutic effects
pretherapy acuity. 267
of broadening the range of gaze angles with high
acuity can be appreciated from the figures in the
Clinical Pearl: INS therapy is not contrain-
next section.
dicated in patients with associated visual
sensory deficits; in fact, these patients have
the greatest chances for significant (i.e., life-
2.4 TREATMENTS OF INFANTILE
changing) improvements in their visual
NYSTAGMUS SYNDROME
function.
The past 50 years have produced numerous stud-
ies of the effects of INS treatment, both nonsur-
2.4.1 Goals
gical and surgical. Most important, in terms of
increasing our understanding of INS, have been The goals of INS therapy that emerge from
those studies that utilized eye-movement data our research are to improve the foveation

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characteristics of the waveforms such that convergence nulls, is summarized in Table 2.3.
one or more of the following is achieved: (1) the Note that for patients with both convergence
range of high NAFX values is broadened; (2) the and gaze-angle nulls, exploitation of the former
peak NAFX value is increased; and (3) target (surgically or with vergence prisms) usually
acquisition speed is increased. These therapeu- damps the nystagmus and increases acuity
tic improvements will translate into a broader most; it is necessary to add –1.00 S (OU) to
range of high-acuity gaze angles, higher peak vergence prisms for pre-presbyopic patients
acuity, and reduction of the “slow-to-see” phe- (and to remove it later in life when presbyopia
nomenon. The actual improvements in each of appears). Studies of the broad damping effects
these visual function factors will depend on the of convergence (at all gaze angles) on IN (see
values of pretherapy NAFX and LFD and may Fig. 2.13 and discussion of convergence in
be estimated before therapy (see Chapter 7, Section 2.1.6) suggest that the originally used
Section 7.5). composite prisms (unequal base-out)32 are
not necessary in these cases; vergence prisms
(equal base-out) will achieve the same damp-
2.4.2 Nonsurgical
ing. 268 As indicated in Table 2.3, regardless of
Nonsurgical therapies for INS include the use the presence of nulls, afferent stimulation can
of optical methods (prisms, both version and be used in all patients who exhibit nystagmus
vergence, soft contact lenses), oral and/or topi- damping with active stimulation.
cal medications, and a variety of nontraditional
medical approaches (e.g., biofeedback, acupunc-
2. 4 . 2. 2 CO N TAC T L E N S E S
ture). When indicated, low-vision aids are used
for associated visual system deficits. In many individuals with INS, afferent
stimulation of the ophthalmic division of
the trigeminal nerve or of the neck may
2. 4 . 2.1 P R I S M S
damp the nystagmus and improve the wave-
The various therapies available for INS, form, allowing increased visual acuity.154,155
based on the presence or absence of gaze and Neck or forehead vibration prolonged

Table 2.3 Therapies for Infantile Nystagmus (IN)

If the IN nulls ONLY with lateral gaze:
Resection and recession (four-muscle)
Version prisms (useful only for small angles)
Afferent stimulation (passive or active)
If the IN nulls ONLY with convergence:
Bimedial recession1 (artificial divergence)
7D BO vergence prisms with –1.00 S1 (OU)
Afferent stimulation (passive or active)
If the IN nulls with BOTH lateral gaze and convergence:
Bimedial recession1 possibly combined with resection and recession
7D BO vergence prisms with –1.00 S1 (OU)
Afferent stimulation (passive or active)
If the IN nulls with NEITHER lateral gaze nor convergence or is asymmetric aperiodic alternating IN:
Four-muscle tenotomy and reatt achment
Afferent stimulation (passive or active)
Therapies include surgical, optical, and mechanical; for drug therapies, see text.
1
Damps IN only for nonstrabismic, binocular patients.

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foveation periods, yielding higher values similar to the proprioception mechanism

of the NAF and improved visual acuity in of the T&R and convergence therapies. 270
9 of 13 patients with INS.155 This nonin- Figure 2.25 demonstrates the effects of con-
vasive and benign therapy (active afferent tact lenses and compares them to conver-
stimulation) may prove useful in both INS gence in the same subject. Note from panels
and acquired nystagmus. The use of contact (a)–(c), that the NAFX values of INS wave-
lenses (of any materials) to improve the acu- forms are not determined by amplitudes; (a)
ity of individuals with INS takes advantage and (c) have the same NAFX despite the dif-
of the damping effect on nystagmus of (pas- ference in amplitudes and (b) has the highest
sive) afferent stimulation.158–160,269 Contact NAFX value despite an amplitude between
lenses damp the IN and broaden the LFD those in (a) and (c). In (d), the contact lenses
using an exteroception mechanism that is achieved the same gaze-angle broadening as

FIGURE 2.25 The effects of contact lenses compared to convergence in a subject with infantile nystagmus
syndrome. Fixation data (eye position vs. time) for the subject during far viewing with contact lenses at dif-
ferent gaze positions: −20° (a), 0° (b), and 25° (c). The corresponding eXpanded nystagmus acuity function
(NAFX) values are also shown. The NAFX algorithm automatically thickened foveation periods. The area
between the dash-dotted lines represents the foveation position window used to calculate the NAFX. In
(d), plots of NAFX versus gaze angles for far viewing, far viewing with contact lenses, and while converged
(60 PD). Fitted polynomial curves are shown. NAFX-correlated potential visual acuities are adjusted for the
subject’s age. Conv, convergence. The dot-dashed lines indicate the extent of the foveal window. The thick-
ened areas identify foveation periods in NAFX outputs.

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convergence albeit with a lower peak NAFX by the hypothesized proprioceptive mechanism
value. of the T&R procedure. The effects of four differ-
ent types of therapy on the same INS patient and
Clinical Pearl: Contact lenses are not con- their comparison to the effects of the T&R on
traindicated in INS and can provide better other patients is shown in Figure 2.26. The left
acuity than spectacles in patients whose nys- panel shows that, as expected, the highest per-
tagmus damps with afferent stimulation. cent increase in peak NAFX was during conver-
Plano soft contact lenses can be used if no gence. Both systemic acetazolamide and topical
refractive correction is required. Four advan- brinzolamide achieved results comparable to
tages of contacts in the INS patient are better the T&R procedure, and contact lenses had less
optical quality, improvement in nystagmus of an effect on peak NAFX. In the right panel,
foveation, move with eye to utilize eccentric again convergence had the greatest broadening
gaze null, and ability to decrease light sensi- effect on the LFD with systemic acetazolamide
tivity/interference via tinting or painting. and contact lenses comparable to the T&R pro-
cedure with topical brinzolamide slightly lower.
Our ability to study the effects of these therapies
2. 4 . 2.3 D R U G S
on the same patient provided the data for this
Both memantine and gabapentin may improve unique figure.
INS waveforms and visual acuity.271–274 More
recently, an oral systemic carbonic anhydrase
2. 4 . 2. 4 G E N E-T R A N S F E R T H E R A P Y
inhibitor (CAI) (acetazolamide) was shown to
improve visual function in INS by both increas- We were fortunate to have the opportunity to
ing peak NAFX and LFD values.275 With the use study the eye movements of RPE65-deficient
of a topical CAI (brinzolamide), a whole new canines both pre– and post–gene therapy.180
area of INS-therapy research that may revolu- These canines had the equivalent of human
tionize the treatment of INS has now been dem- congenital stationary night blindness, whereas
onstrated to improve visual function.276 Th is in humans, this retinal function deficiency
potentially far-reaching fi nding was suggested causes Leber congenital amaurosis (LCA), a

FIGURE 2.26 Plots of the percent increase in peak eXpanded nystagmus acuity function (NAFX) (left
panel) and longest foveation domain (LFD) (right panel) after treatments with base-out prisms, contact
lenses, systemic acetazolamide, and topical brinzolamide in the same infantile nystagmus syndrome patient.
Shown for comparison are the respective curves from tenotomy and reatt achment (T&R) data averaged for
other patients.

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previously untreatable, autosomal-recessive mal adverse effect and modest improvement in

retinal dystrophy. Both humans with LCA retinal function.183
and these canines have INS. Thus, the second An important fi nding from our canine stud-
animal model of INS whose eye movements ies is that the ocular motor system appears to be
we were able to study were also canines. Gene capable of recalibration when the visual deficit
therapy applied to the retina virtually abol- that interfered with that calibration is removed.
ished (i.e., not clinically detectable 90% of the That recalibration damps the IN significantly
time) the IN in these canines. Postt reatment and seems to be possible even in later life; that
NAFX values were higher than pretreatment. is, the OMS does not have a sensitive period
Uniocular treatment also was able to damp the beyond which change is precluded.
IN in both eyes. Figure 2.27 shows the differ-
ence in nystagmus of littermates, one untreated
2. 4 . 2.5 B I O F E E D B A C K
and the other treated; the latter being of much
lower amplitude. The IN of the treated dog was Some studies of the effectiveness of auditory
clinically undetectable and comparison of the biofeedback on INS have claimed that the tech-
area centralis indicated on each figure shows niques learned in the laboratory can be main-
that the oscillation never left that high-acuity tained and used later.162,163,277 It is not clear
area in the treated dog, whereas it was mostly however that when needed most, that is, when
outside in the untreated dog. Figure 2.28 (top under stress, such techniques can be applied
panels) shows the large pre- to postt reatment to increase acuity. Unlike other therapies that
increases in the NAFX in two canines. In one, reduce the baseline INS oscillation and improve
the NAFX increases from 0.46 to 0.73 (58.7%), foveation quality so that any deterioration due
with the initial DJ waveform damped to only to stress begins from a much better waveform,
its small pendular component, and in the other, biofeedback requires maintenance of a state of
from 0.0.375 to 0.74 (97.3%). mind to damp the INS waveform; that is the
Translating the latter dog’s improvements to very thing that would be interfered with dur-
a human patient with poor vision due to both a ing stressful conditions. Other investigators
sensory deficit (like LCA) and INS means that did not fi nd that their patients could maintain
this therapy not only would improve acuity improved acuity after training.166,278 Therefore,
by increasing retinal function but also would biofeedback has not proven to be a widely useful
improve the motor portion of peak visual acu- or practical therapeutic approach to improving
ity (i.e., that due to the INS waveform) by nearly INS waveforms and, with them, acuity.
100%. We have no data on how or if the LFDs of
patients will improve after gene therapy but, if
2.4.3 Surgical
they do not, a T&R (or other INS surgery) can
be used to achieve this important visual func- Surgical therapies for INS have two main goals:
tion improvement. (1) mechanical, that is, reposition the eye(s) to
Data taken to assess the time course of the treat associated strabismus, move an eccen-
INS improvements showed improvements in tric INS “null” region to primary position, or
from 4 (1 dog) to 10 weeks.181 Figure 2.28 (bot- exploit the convergence-induced INS damp-
tom panel) shows the postt reatment damping in ing; and (2) neurological, to improve the INS
one dog and the difference between the damp- waveform characteristics. Operations used to
ing in one treated eye and the other eye that did treat nystagmus have been classified based on
not respond to treatment. There were no adverse analysis of hundreds of nystagmus operations
effects in the canines. A study of the safety and into nine types. A clinical algorithm for clini-
efficacy of gene therapy using an optimized cians and details of all those procedures are
adeno-associated virus was successful.182 In a presented in Chapter 7. A detailed analysis of
subsequent study, in patients, there was mini- the more common operations is discussed in
the following sections.

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02_Hertle_Ch02.indd 82
BR58
4

2
BR57 LEH
0
15
10 LEH REH
2

Hor. Eye Pos. ( )

5
0 REH 4
5 1.5 1.6 1.7 1.8 1.9 2 2.1 2.2 2.3 2.4 2.5

Hor. Eye Pos. ( )

10
2
15
7 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8
1
10 LEV
0
REV REV
5
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Vert. Eye Pos. ( )

0 LEV
2

Vert. Eye Pos. ( )

1.5 1.6 1.7 1.8 1.9 2 2.1 2.2 2.3 2.4 2.5
5 Time (sec)
7 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8 2
Time (sec)
10
1
REcw RE
5 0
Area Centralis
0 1 LE
Area Centralis

Vert. Eye Pos. ( )

Vert. Eye Pos. ( )

LEccw
5 2
15 10 5 0 5 10 15 4 3 2 1 0 1 2 3 4
Hor. Eye Pos. ( ) Hor. Eye Pos. ( )

FIGURE 2.27 Horizontal (H) and vertical (V) right (RE) and left (LE) eye-position and scan-path data from an untreated RPE65-deficient canine (BR57) and a littermate
(BR58) treated with gene therapy. The dot-dashed lines indicate the area centralis.

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02_Hertle_Ch02.indd 83
FIGURE 2.28 eXpanded nystagmus acuity function (NAFX) pre- and post-gene-therapy outputs from two RPE65-deficient canines, one with jerk (top left panel)
and one with pendular (top right panel) infantile nystagmus syndrome. Horizontal (H) right (RE) and left (LE) eye-position data from a gene-therapy-treated
RPE65-deficient canine showing the difference between the successfully treated LE and the unsuccessfully treated RE (bottom panel). The dot-dashed lines indicate
the extent of the area centralis. The thickened areas identify centralisation periods in NAFX outputs.
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2. 4 .3.1 F O U R- M US CL E R E S EC T I O N A N D using the patient’s head turn both to estimate

R EC E SS I O N P R O C E D U R E (O P E R AT I O N the surgery necessary and as an outcome meas-
1) ( A L S O K N O W N A S K E S T E N B A U M , ure and the use of fi xed formulae, not tailored
ANDERSON-KESTENBAUM, OR to each patient (see later). The null broadening
A N D E R S O N P L US G OT O) observation was to have a profound effect on our
understanding of the effects of extraocular mus-
In 1979 the fi rst eye-movement study of the
cle surgery and would lead to the hypothesis,
results of the Kestenbaum procedure was
and later demonstration of, the T&R procedure.
published.177,279 It demonstrated that this four-
Accurate eye-movement data also were
muscle recession and resection procedure had
responsible for producing a curve that allowed
several therapeutically beneficial effects beyond
the determination of the total amount of sur-
the shift ing of an eccentric INS null to primary
gery necessary for each desired amount of null
position. Prior to this study with eye-movement
shift. Figure 2.30 shows this curve that provides
data, it was mistakenly believed that the only
the physician with an accurate method of deter-
effect was to shift the null region to primary pos-
mining the surgery necessary and predicting the
ition with no improvements in visual acuity. The
resulting postoperative null shift. For example, a
expected (based on the then current literature)
20° shift would require 10 mm (5 mm recession
and actual effects of this procedure are illus-
and 5 mm resection) of rotational surgery on each
trated in Figure 2.29. In fact, the most impor-
eye. Not only can it be used to determine the nec-
tant effect was the broadening of the null area so
essary surgery but also (as the authors showed),
that it allowed better acuity over a larger range of
in cases where too litt le surgery was performed,
gaze angles than preoperatively. As Figure 2.29
it can be used to determine the amount needed
shows, INS magnitude was also lowered at all
to center the null in primary position. Th is is a
gaze angles, also improving acuity. Subsequent
far better approach than using a fi xed formula for
longitudinal eye-movement studies verified
all patients based on whether their required null
that these therapeutic effects were permanent
shift was large or small. To the extent that the
and dispelled the myth that “the eccentric null
tenotomy (enthesiotomy) and reattachment con-
returned” at a later date.280 We att ribute those
tained within the Kestenbaum procedure caused
erroneous observations to the combination of

FIGURE 2.29 Illustration of the expected and actual results of resection and recession surgery. L, left ; |N|,
nystagmus magnitude; Nf,fi nal null; Ni, initial null; R, right.

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FIGURE 2.30 The relationship to determine the total amount of resection and recession surgery needed
for each eye to achieve the required shift in the eXpanded nystagmus acuity function (NAFX) peak.

null broadening, the errors inherent in such fi xed acuity in primary position that exceeded that at
formulae were ameliorated and good results were the preoperative null should be anticipated.
possible despite the coarse approach. However,
with the use of this more accurate eye-movement
2. 4 .3. 2 T W O - M US C L E R ECE SS I O N
data, the null can be shifted to accurately place it
P R O C E D U R E (O P E R AT I O N 1 A ) ( A L S O
in primary position regardless of its initial eccen-
KNOWN AS ANDERSON)
tricity. To maintain homeostasis as much as pos-
sible, the total amount of surgery dictated by About the same time as Kestenbaum proposed
the curve was split evenly into the recession and the four-muscle recession and resection proce-
resection amounts. Th is approach to nonstrabis- dure, Anderson proposed the two-muscle reces-
mic INS surgery remains as the gold standard. sion procedure that could be used for smaller
Although the cosmetic disfigurement and lateral gaze nulls. 281 Although it is clear that,
possible neck problems of the patient’s com- for moderate angles, the null-shift ing goal may
pensatory AHP were appreciated, they would be accomplished by recessions alone, it has not
disappear once the primary deficit, the eccen- been demonstrated that this two-muscle pro-
tric position of the best INS waveforms, was cedure will result in broadening of the NAFX
broadened and moved to primary position. The peak or, if it does, that the broadening will
authors of that 1979 study neither measured equal that from four-muscle procedures. Until
nor used AHP in their treatment. Although a carefully done study of the NAFX changes
the use of IN intensity was not optimal and the following two-muscle recessions is done and
authors recognized that foveation time (which comparison made to the therapeutic benefits
would later be replaced by the NAFX) would from four-muscle procedures on patients with
be a better indicator of visual acuity, the impor- different initial peak NAFX values, 267 we rec-
tant but litt le appreciated therapeutic effects of ommend that Anderson recessions be aug-
the Kestenbaum procedure were demonstrated. mented by T&R of the other two horizontal
Th is study documented visual acuity improve- rectus muscles. We have documented that,
ments in these patients and dispelled the myth when all four muscles are operated on in this
that they did not occur; the authors stated that way, the same NAFX peak broadening results.

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2. 4 .3.3 B I L AT E R A L M E D I A L R EC T US had no null, a primary-position null, or pos-

R EC E SS I O N P R O C E D U R E (O P E R AT I O N sibly APAN). However, the fi rst study of the
8) ( A L S O K N O W N A S B I M E D I A L Kestenbaum (four-muscle resection and reces-
R EC E SS I O N ) sion) procedure using analysis of eye-movement
data uncovered secondary improvements in the
Cüppers proposed the bimedial recession proce-
INS characteristics that resulted in improve-
dure to treat INS.282 As the research presented
ments in visual function that had gone unrec-
in this chapter demonstrates, the single most
ognized.177 It was found that the null region was
effective INS therapy is the inducement of con-
broadened, its peak reduced in intensity, as well
vergence in those patients who have sufficient
as shifted to primary position. No explanation
fusional vergence and whose IN damps with con-
for these improvements was evident at the time,
vergence. In all such patients we found greater
but they did result in a hypothetical new pro-
damping with convergence than with gaze angle
cedure, the T&R procedure.178 Th is procedure
and in those we studied, therapy that induced
consisted of performing an enthesial tenotomy,
convergence (e.g., near targets or base-out
dissection, and reatt achment at its original
prisms) always produced the greatest improve-
insertion of each of the four horizontal rectus
ments in peak NAFX and LFD. Kaufmann and
muscles. The efficacy of the T&R procedure was
Kolling discussed the advantages of bimedial
fi rst demonstrated on an achiasmatic Belgian
recession in those patients with CN who have
sheepdog with INS and seesaw nystagmus.179 In
good binocular function and a decrement of IN
two procedures (fi rst, T&R of the four horizon-
intensity during near vision.283 They recommend
tal rectus muscles and, after 4 months, T&R of
this operation regardless of whether the patient
the four vertical rectus and four oblique mus-
has an abnormal head position, that is, a lateral
cles), the INS was damped and the seesaw nys-
null angle, and claim that the results are better
tagmus abolished. A proprioception hypothesis
than the Kestenbaum/Anderson operation.
was advanced to explain the improvements in
Although we initially recommended that the
INS waveforms.
two lateral rectus muscles receive a T&R proce-
Results of a masked clinical trial of this
dure in addition to recessing the two medial rec-
surgery were positive in a Phase 1 study of
tus muscles, current research casts doubt that
adults284,285 and Phase 2, in children.286 Since
there is an additional benefit to associated lateral
those initial studies, there have been a number
rectus T&R. The increased damping secondary
of others demonstrating the positive therapeutic
to convergence and its relaxation of steady-state
effects of the T&R procedure in INS and even
muscle tension exceeds that obtained from sur-
acquired pendular nystagmus.258,267,287–290 The
gery on the four extraocular muscles. Thus, the
T&R procedure was to be used for INS patients
bimedial recession procedure is the only two-
with no nulls and added to those other proce-
muscle surgery recommended for INS in those
dures that did not include all four muscles. For
patients for whom it is indicated. The bimedial
example, the Anderson (two-muscle recession)
recession procedure, like the T&R, is indicated
procedure would be augmented by performing
in only a small percentage of INS patients, but
a T&R on the other two horizontal rectus mus-
for them it has no equal.
cles. That was shown to add the therapeutic ben-
efits of a four-muscle T&R to the null shift ing of
the two-muscle recession procedure.288 Although
2. 4 .3. 4 T E N OT O M Y A N D
it was originally thought that a two-muscle T&R
R E AT TA C H M E N T P R O C E D U R E
should also be added to the bimedial recession
(O P E R AT I O N 6)
procedure for INS patients with convergence
Prior to 2000, there were no surgical thera- damping, data from base-out prisms indicated
pies for INS patients that did not have associ- that convergence alone produced these desired
ated strabismus, a static eccentric gaze-angle benefits; thus, no additional T&R was necessary
null position, or convergence null (i.e., they for that procedure.110

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The positive therapeutic effects of the T&R vertical strabismus) or equal horizontal strabis-
procedure specifically, thus all eye muscle surgical mus recessions. 288 The top and second panels
procedures generally, includes higher peak NAFX show the left and right eye data, respectively,
values and broader LFD values. The therapeutic from an exotropic INS patient (lateral rectus
benefits documented for horizontal INS were also recessions plus medial rectus T&R procedures).
found in the vertical plane.291 Visual function defi- The third (left eye in primary position) and fi ft h
cits that were not improved by therapy were both (right eye in primary position) panels show data
the increased target acquisition times and posi- from a patient with acquired downbeat nystag-
tion errors introduced during smooth pursuit that mus and vertical strabismus (unequal supe-
are characteristic of INS.292 Preliminary evidence rior rectus recessions plus inferior rectus T&R
indicates that this is a limitation present in the procedures). The fourth panel shows the data
normal smooth pursuit mechanism.293 Our expe- from an INS patient (T&R procedure). Starting
rience is that for patients in whom convergence at the top with the lowest preoperative values,
damps their IN, the increases in peak NAFX, the NAFX improvements were 0.107 to 0.696
LFD, and TID are greater after induced conver- (550%); 0.279 to 0.609 (118%); 0.391 to 0.733
gence (by prisms or bimedial horizontal rectus (87.5%); 0.565 to 0.748 (32.4%); and 0.652 to
recession surgery) than by any other therapeutic 0.845 (29.6%). NAFX percent improvements
measures (e.g., surgical, contact lenses, or pharma translate directly into visual acuity percent
cological).110,270,275,276 increases. As the figure demonstrates, the T&R
The currently accepted mechanism respon- portion of each procedure damped the IN and
sible for the damping effects of T&R is alter- improved the waveforms. Both the foveation
ation of a proprioceptive tension-control times per cycle and the mean foveation posi-
loop.179,289,294 Th is is supported by the discover- tions improved and the postoperative foveation
ies of the neural substrate for such a loop in both windows were smaller in position, velocity, or
the musculotendon 295–304 and enthesial end of both for all but the 0.652 case, where the mini-
the tendon (where the surgery takes place). 305 mum window was used preoperatively.
Proprioceptive signals representing the eye in In Figure 2.32 the results of T&R in four cases
head are also present in the cortex. 306 In rab- are shown. In the top left panel, a low, sharp
bit, T&R and recession surgeries both cause the NAFX peak was improved to a high, broad peak.
same adaptive changes in EOM, suggesting that In the top right panel, a medium, broad NAFX
it is the former that is responsible. 307 Thus, the peak was improved to a high, broad peak. In the
alteration of a proprioceptive feedback loop con- bottom left panel, a high, sharp NAFX peak was
trolling steady-state muscle tension in a manner improved to a high, broad peak. In each of these
that reduces that tension shares the same mech- cases, visual function is improved, albeit differ-
anism by which convergence can reduce IN (see ently. In the bottom right panel are the results
earlier). That is, lowered γ-innervation reduces from an exotropic patient who, by virtue of alter-
muscle tension, placing it on a lower gain portion nating fi xation, appeared clinically to have two
of the length-tension curve, thereby decreasing “nulls.” As the preoperative data show, there
the IN. Proprioception has become an impor- was a high, sharp peak in left gaze when the left
tant factor in new therapies for INS, 308 as well eye was fi xating and a high, sharp peak in right
as given rise to a hypothetical modification to gaze when the right eye was fi xating; this led to
existing surgeries that needs to be investigated low NAFX values (poor vision) in primary pos-
for efficacy. 309 Before any surgery is contem- ition. After bilateral, lateral rectus recessions
plated, INS should be defi nitively diagnosed and bilateral, medial rectus T&R, the data show
using ocular motility recordings. 310 Figure 2.31 that despite the alternate fi xation, the compos-
shows the improvements in NAFX outputs of ite NAFX peak was high, broad, and centered in
three patients after either a four-muscle T&R 267 primary position. Th is 43% increase in primary
or two-muscle T&R combined with either position NAFX resulted in a 92.3% increase
unequal vertical (i.e., vertical Anderson plus (20/150 to 20/80) in visual acuity.

Nystagmus in Infancy and Childhood • 87

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FIGURE 2.31 Patient data showing the pre- (left panels) and postoperative (right panels) eXpanded nys-
tagmus acuity function (NAFX) outputs for three patients (one shown with either eye fi xating and one, at two
gaze angles) whose preoperative values ranged from 0.107 to 0.652 (see Section 2.4.3.4). The pre- and post-
operative scales are the same for ease of comparison and the dash-dot lines defi ne the position boundaries of
the foveation windows used to calculate the NAFX. The improvements are due to longer foveation periods per
cycle and a smaller foveation window in position, velocity, or both in four of the panels. The dot-dashed lines
indicate the extent of the foveal window. The thickened areas identify foveation periods in NAFX outputs.

88 • I N FA N T I L E N Y STAG M US S Y N DROM E

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02_Hertle_Ch02.indd 89
FIGURE 2.32 Pre- and post-tenotomy and reatt achment (T&R) eXpanded nystagmus acuity function (NAFX) versus gaze angle data for patients with a low, sharp
peak (top left); medium, broad peak (top right); or high, sharp peak (bottom left). Also shown are the data from a patient with alternate fi xation (bottom right). In all
cases, visual function improved. BE, both eyes; LE, left eye; RE, right eye.
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9/6/2012 9:49:31 PM
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A number of research publications into the JTW, eds. Neuro-Ophthalmology-1982 . Vol.

effects of the T&R procedure and eye muscle 2. Amsterdam, The Netherlands: Excerpta
surgery in general on INS further supported the Medica; 1982:148–171.
9. Dell’Osso LF. Nystagmus and other ocular
proprioception hypothesis and demonstrated
motor oscillations and intrusions. In: Lessell
new therapeutic improvements in visual func- S, Van Dalen JTW, eds. Neuro-Ophthalmology-
tion. Foveation was improved over a larger 1984. Vol. 3. Amsterdam, The Netherlands:
range of gaze angles.267 It was shown that sacca- Excerpta Medica; 1984:157–204.
des were not affected but “small signals” were. 294 10. Dell’Osso LF. Nystagmus and other ocular
The “slow-to-see” description of the longer tar- motor oscillations and intrusions. In: Lessell
get acquisition times of INS patients was dem- S, Van Dalen JTW, eds. Current Neuro-
onstrated69 and the T&R procedure was shown Ophthalmology. Vol. 1. Chicago, IL: Year Book
Medical Publishers; 1988:139–172.
to reduce target acquisition times.290 It was also 11. Dell’Osso LF. Nystagmus, saccadic intrusions/
demonstrated that target acquisition times were oscillations and oscillopsia. In: Lessell
longer than normal and depended on target S, Van Dalen JTW, eds. Current Neuro-
timing during smooth pursuit by a subject with Ophthalmology. Vol. 2. Chicago, IL: Year Book
INS.259 A new and interesting approach to INS Medical Publishers; 1990:147–182.
research, the “null-zone fMRI technique,” sug- 12. Dell’Osso LF. Nystagmus, saccadic intrusions/
gests that the declive of the cerebellum is pos- oscillations and oscillopsia. In: Lessell
S, Van Dalen JTW, eds. Current Neuro-
sibly involved in INS. 311 Other reviews of INS
Ophthalmology. Vol. 3. Chicago, IL: Mosby
therapies may be found elsewhere.102,312 Year Book; 1991:153–191.
13. Gresty MA, Halmagyi GM, Leech J. The
relationship between head and eye movement
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Vis Sci 2010;51(11):5646–5656. 956. New York: NYAS; 2002:361–379.

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3
fusion maldevelopment
nystagmus syndrome
3.1 CHARACTERISTICS OF Fusion malde- 3.1.5 Efference Copy, Foveation, and
velopment nystagmus syndrome 104 Oscillopsia Suppression 114
3.1.1 Waveforms, Models, and 3.2 ETIOLOGY OF Fusion maldevelopment
Mechanisms 104 nystagmus syndrome 115
3.1.1.1 Types (Fusion Maldevelopment 3.2.1 Familial (Gene Defect) 115
Nystagmus Syndrome Plus Nucleus of 3.2.1.1 Down Syndrome 116
the Optic Tract) 105 3.2.2 Optokinetic Asymmetry 116
3.1.1.2 The Fixating Eye 105 3.2.3 Egocentric Direction
3.1.1.3 Target Foveation and Dual-Mode Confusion 116
Fast Phases 108 3.3 TREATMENTS OF Fusion
3.1.1.4 Foveation Accuracy 111 maldevelopment nystagmus
3.1.2 Variation with Gaze Angle 112 syndrome 118
3.1.3 Head Position 112 3.3.1 Fixation Preference 118
3.1.4 Foveation, eXpanded Nystagmus 3.3.2 Alexander’s Law 118
Acuity Function, and Acuity 114 3.3.3 Eye-Muscle Surgery 118

Galileo may have been the only man of his day who believed the Earth revolved around the Sun, but he
was right!
—S. F. Singer and D. T. Avery, Unstoppable Global Warming—Every 1500 Years

FUSION MALDEVELOPMENT nystagmus be present when both eyes are closed. Rarely,
syndrome (FMNS, also known as latent/man- the nystagmus is only evoked by the “pure” or
ifest latent nystagmus, LMLN) exhibits the “true” latent condition (LN) and occurs only
following: a jerk nystagmus with either a linear with uniocular viewing (i.e., the other eye
or decreasing-velocity exponential slow phase being occluded). Th at is, there is no nystagmus
identical to that of gaze-paretic nystagmus; when both eyes are viewing, but when one eye
strabismus; alternating hyperphoria/dissoci- is occluded, jerk nystagmus develops in both
ated vertical deviation; and pendular torsional eyes, with the fast phases toward the uncovered
nystagmus in primary position.1 The constantly eye. The term “manifest latent nystagmus” was
present, conjugate, horizontal, jerk nystagmus fi rst defi ned by Kestenbaum as being present
increases in intensity by monocular occlu- with both eyes open but only one being used
sion, blurring, or reducing image brightness. for fi xation. 2,3 Using eye-movement record-
A jerk nystagmus with a linear slow phase may ings, mild FMN with both eyes viewing can

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usually be detected in those patients who may nystagmus) or a prominent decreasing-velocity

appear to have “pure” latent nystagmus clini- exponential (following saccadic pulses) and
cally. True/pure FMN “latent nystagmus vera” the fast phase is always in the direction of the
is uncommon. The intensity of FMN decreases eye that is fi xating, the straight eye. Th at is, the
when visual attention declines and increases slow-phase rotation of the fi xing eye is always
during attempted fi xation.4,5 FMN may clini- in adduction and the fast-phase is in abduc-
cally resemble other types of nystagmus (e.g., tion; fi xation with the right eye generates a
INS with a latent component) and require right-beating nystagmus of both eyes, while
eye-movement recordings to differentiate it. fi xation with the left eye produces a left-beating
Indeed, it can even present as spasmus nutans nystagmus of both eyes. Figure 3.1 illustrates
(see Chapter 4). 6 the waveforms usually seen for binocular and
Patients with FMNS always have strabismus monocular viewing. During binocular viewing,
and, to suppress diplopia, vision from the tropic the slow phases are usually linear followed by
eye is suppressed (“occluded”) in the cortex.7 corrective fast phases but upon occlusion, the
The FMN present with both eyes open, but only nystagmus converts to a saccadic pulse train
one fi xating, is the same nystagmus as the rare where the saccades defoveate the target and the
FMN that only appears with occlusion of one decelerating slow phases return the fi xating eye
eye. Thus, the term FMN refers to this single to the target.
type of nystagmus that is present in most FMNS It has long been known that, just as in nor-
patients with both eyes open while one is fi xat- mal saccades, the fast phases of FMN may
ing but, in some patients, may only be present contain dynamic overshoots 3; the dynamic
when one eye is occluded. overshoots’ characteristics in both FMNS
and INS are normal. 8 Figure 3.2 shows FMN
in two patients, one without dynamic over-
3.1 CHARACTERISTICS OF FUSION
shoots (left panel) and one with dynamic
MALDEVELOPMENT NYSTAGMUS
overshoots (right panel). Dynamic overshoots
SYNDROME
are integral parts of the saccadic fast phases
and not the beginnings of the slow phases.
3.1.1 Waveforms, Models, and
The uncommon occurrence of square-wave
Mechanisms
jerks (SWJ, see Chapter 5, Section 5.3.1)
The slow phase of FMN is either linear or a slight mimics their occurrence in normal observers,
decreasing-velocity exponential (initiating the and their presence during binocular viewing

FIGURE 3.1 Illustrations of fusion maldevelopment nystagmus syndrome during binocular viewing (but
monocular fi xation) and during monocular viewing. Nystagmus with linear slow phases (top) may convert
to defoveating saccadic pulses with decelerating slow phases (bottom). Dashed lines indicate target position.
LE, left eye; RE, right eye.

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FIGURE 3.2 Fixating left eye of a patient with fusion maldevelopment nystagmus syndrome (left panel)
and both eyes of another patient with fusion maldevelopment nystagmus syndrome during right-eye fi xa-
tion. Note the prominent dynamic overshoots in the saccadic pulses of the fi xating right eye and their sharp
attenuation in the deviated left eye. Time markers indicate 1-sec intervals; LE, left eye; RE, right eye.

in FMNS is unpredictable and variable. Thus, 3.1.1.1 T Y P E S ( F US I O N

the presence of either dynamic overshoots or M A L D E V E L O P M E N T N Y S TA G M US
SWJ does not represent a mechanistically dif- S Y N D R O M E P L US N U C L E US O F T H E
ferent “type” of FMN8; it is merely the same OP T IC T R ACT )
FMN, including these common, normal
Just as in INS, FMNS may also coexist with
saccadic dynamics or intrusions. This also
NOT nystagmus. That is, superimposed on the
applies to the occurrence of other types of
jerk FMN (with either linear or decelerating slow
nystagmus in addition to FMN (e.g., an unde-
phases) will be a low-amplitude, high-frequency
fined “torsional” nystagmus or the high-fre-
pendular nystagmus. When the additional pen-
quency pendular nystagmus thought to arise
dular oscillation of NOT nystagmus is present,
from the NOT, resulting in a dual-jerk wave-
the resulting waveform would be the same as
form). In an individual patient, both FMNS
shown in Figure 2.3 for linear INS slow phases
and INS may coexist with another type of nys-
(DJR L) or consist of the pendular oscillation
tagmus or saccadic intrusion/oscillation. The
superimposed on the decelerating slow phases
clearest way to delineate a group of patients
illustrated in Figure 3.1.9 Figure 3.3 shows eye-
with two mechanistically independent eye-
movement data from patients with FMNS +
movement characteristics is to describe the
NOT nystagmus (specifically, dual-jerk FMN)
two conditions (e.g., FMN with dynamic
and demonstrates the independence of the two
overshoots, FMN plus SWJ, or FMN plus
types of nystagmus; either one may be damped
“torsional” nystagmus). Attempts to define
without affecting the other.
FMNS as consisting of multiple “types” based
on the presence or absence of these normal
occurrences is both confusing and not mech-
3.1.1. 2 T H E F I X AT I N G E Y E
anistically justified. For simplicity, the basic
FMNS waveforms shown in Figure 3.1 do not The slow phases of FMN are either linear or
contain either dynamic overshoots in their decelerating, and the fast phases are always in
fast phases or the confounding addition of the direction of the fi xating eye. 3 The nystag-
other types of nystagmus. mus of patients with strabismus, alternating

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FIGURE 3.3 Eye movements (position and velocity) of patients with fusion maldevelopment nystagmus
syndrome (FMNS) plus nucleus of the optic tract (NOT) nystagmus illustrating the independent variations
of either component of the dual-jerk FMN waveforms. Shown are damped FMN but consistent NOT nys-
tagmus (left panel) and time-variable NOT but consistent FMN nystagmus (right panel). Numbered arrows
in right panel indicate the time in seconds from a continuous record. Time markers indicate 1-sec intervals;
LE, left eye; RE, right eye.

fi xation, and FMNS with both eyes open has directions involved, fast phases are sometimes
fast phases that are always in the direction of the also diminished.
fi xating eye. Such patients may be easily misdi- In addition to occlusion, intent or darkness
agnosed as having INS, because the nystagmus also may alter FMN. In Figure 3.5 a patient was
is present with both eyes open. Recordings are able to change his FMN by merely attempting to
required to document the decelerating or linear fi xate with either one or both eyes (left panel),
slow-phase waveforms characteristic of FMNS and another patient’s FMN changed when
from the accelerating slow phases predominant placed in darkness (right panel). In both pan-
in the INS. els, both eyes were open at all times (i.e., mani-
Although “conjugate,” FMN exhibits some fest FMN). When the patient in the left panel
morphological differences between the fi xating switched intent from looking with the left eye
and deviated eye, the latter being less precise (so- to looking with both eyes, the manifest FMN
called rubber-band conjugacy); this is evident in damped considerably and the left eye became
Figure 3.2 (right panel), where the deviated left slightly esotropic while the right eye took up fi x-
eye mimics but does not duplicate the motion of ation with no manifest FMN. In the right panel,
the fi xating right eye. It is also consistent with the patient’s jerk right manifest FMN immedi-
the hypothesis that the two eyes are driven inde- ately switched to jerk left in darkness, suggesting
pendently and not by a single composite signal.10 a predisposition for left-eye fi xation (i.e., left-eye
Figure 3.4 shows the effects on FMN of revers- dominant).
ing the occlusion of one eye in either an esotro- The curious observation of a darkness-in-
pic or exotropic patient. In addition to a reversal duced shift in the “fi xating” eye shown in Figure
of the FMN, a position shift to take up fi xation 3.5 was clarified by our study of a patient with
is accomplished by enhanced fast phases and FMNS who had a prosthesis in his congenitally
diminished slow phases. Depending on the blind right eye.11 Not surprisingly, he exhibited

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FIGURE 3.4 Eye movements (position and velocity) of patients with fusion maldevelopment nystagmus
syndrome and either esotropia (left panel) or exotropia (right panel) upon reversing cover to the fi xating
eye. Both a direction reversal of the fusion maldevelopment nystagmus and a position shift of both eyes take
place to allow fi xation by the previously occluded and deviated eye. Arrowheads indicate reversal of cover
from the right to left eye (left panel) and from the left to right and back to left eye (right panel). Time markers
indicate 1-sec intervals; b, blink; LE, left eye; RE, right eye.

jerk-left FMN during normal fi xation but, was able to willfully choose his “fi xating” eye
immediately after the lights were turned off, his (including the prosthetic eye) in the dark and
“manifest” FMN switched to jerk right while his by doing so, change the direction of his FMN.
only intact left eye became esotropic; jerk-left We concluded that eye dominance was corti-
FMN returned when the lights were turned back cally predetermined and not altered by visual
on (see Fig. 3.6, left panel). As we had observed abnormalities.
with many FMNS patients with sight in both Therefore, just as fi xation attempt is responsible
eyes, Figure 3.6 (right panel) shows that he also for the genesis of IN (presumably by modulating

FIGURE 3.5 Eye movements (position and velocity) of patients with fusion maldevelopment nystagmus
syndrome illustrating the effects of “looking” with one eye (left panel) or of darkness (right panel). Before
the arrowhead in the left panel, the patient was “looking” with the left eye and after it, with both eyes. In the
right panel, the patient was in the light and, at the arrowhead, was placed in the dark. Note the spontaneous
reversal of direction in the manifest fusion maldevelopment nystagmus. Time markers indicate 1-sec inter-
vals; LE, left eye; RE, right eye.

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FIGURE 3.6 Eye movements (position and velocity) of a patient with fusion maldevelopment nystag-
mus syndrome and a right-eye prosthesis showing the effects of darkness (left panel) and willful changes in
“viewing” eye in darkness (right panel). LE, left eye; RE, right eye.

the internal feedback loop that controls the damp- time spent during the high-velocity left ward fast
ing of smooth pursuit), monocular/binocular fi xa- phases or their rightward dynamic overshoots,
tion attempt is able to modulate the tonic imbalance which can be seen just above the slow-phase data
(slow-phase velocity) driving FMN. points that appear as the large black area within
the foveation window. In Figure 3.8, the effects
of placing and removing cover over each eye are
3.1.1.3 TA R G E T F OV E AT I O N A N D D U A L-
shown. Initially, both eyes were on target (within
M O D E FA S T P H A S E S
the foveal radius) and there was minimal FMN.
Because the good acuity of INS patients is related Cover resulted in FMN with both foveating or
to the long, postsaccadic foveation periods of defoveating fast phases and esotropia; cover
many waveforms, it was difficult to explain the removal damped the now manifest FMN.
equally good acuity of FMNS patients, given Defoveating saccades result from generating a
the absence of such periods. However, accu- pulse, but not a step, of innervation to drive the
rate studies of FMN foveation in a patient with fast phases of the FMNS nystagmus. Therefore,
20/15 acuity revealed a dual strategy.12 During the common neural integrator controlling eye
the low-amplitude, linear-slow-phase FMNS position must be kept from integrating these
waveform, the saccadic fast phases foveate the defoveating pulses by an internal signal repre-
target, and the low-velocity slow phases take senting the correct/desired eye position vis-à-vis
the eye away from the target with litt le effect the target. These hypotheses were combined in a
on acuity. During the higher amplitude, decel- physiologically realistic, behavioral OMS model
erating slow-phase FMNS waveform, the sac- (see Chapter 2) capable of simulating responses
cadic fast phases defoveate the target, allowing of an individual with FMNS.13–15 The model
foveation during the low-velocity, tail ends of simulated FMN based on the tonic imbalance
the slow phases (see Fig. 3.7); this ensures the hypothesized to be its cause. In Figure 3.9, OMS
best acuity possible and was the fi rst recorded model simulations of the effects on FMN of both
demonstration of the saccadic system acting alternate fi xation (during binocular viewing) and
deliberately to defoveate the target. As the phase alternate cover are shown. During alternate fi xa-
plane in Figure 3.7 (right panel) shows, most of tion, the foveating fast-phase waveform of FMN
the data (i.e., time) is during the slow phases and is likely to remain, whereas during alternate
within the foveation window. There is very litt le cover, defoveating fast phases are more likely.

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10

REV
6

LE FIXATION
4
Eye Position ( )

LEV
0

2 LEH

4
REH

8
0 5 10 15
Time (sec)

30

LE FIXATION
20

10
LEV

10

20

30

LEH
40

50

60
1.5 1 0.5 0 0.5 1

FIGURE 3.7 Horizontal (H) and vertical (V) eye movements of a patient with manifest fusion maldevel-
opment nystagmus (top panel) and phase plane of the fi xating left eye (bottom panel). The fast phases are
defoveating with dynamic overshoots allowing foveation during the decelerating slow phases. LE, left eye;
RE, right eye; dashed lines, foveal extent (top panel) and the foveation window (bottom panel).

Nystagmus in Infancy and Childhood • 109

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10

OU VIEWING LE FIXATION OU VIEWING

8
LE FIXATION
6 REV

2
Eye Position ( )

2 LEH LEV

4
REH
6

10

12
0 5 10 15
Time (sec)

14

OU VIEWING RE FIXATION OU VIEWING

12 RE FIXATION

10
LEV

8
Eye Position ( )

4 LEH

2
REH

REV

2
0 5 10 15
Time (sec)

FIGURE 3.8 Horizontal (H) and vertical (V) eye movements of a patient with manifest fusion malde-
velopment nystagmus showing the effects of placing and removing cover over the right (top panel) and left
(bottom panel) eyes. LE, left eye; OU, both eyes; RE, right eye; dashed lines, foveal extent.

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FIGURE 3.9 Behavioral ocular motor system model simulations of alternate fi xation and alternate cover
on fusion maldevelopment nystagmus (top panel) and of alternate cover in a fusion maldevelopment nystag-
mus syndrome patient for comparison. LE, left eye; RE, right eye.

3.1.1. 4 F OV E AT I O N A CC U R A C Y
in some patients, thereby preserving their vis-
FMNS can cause the patient to have much ual acuity. Foveation can be just as accurate in
worse monocular than binocular visual acuity. some patients with FMNS as it is in others with
However, as the patient whose data are shown INS. The fi xation subsystem can either prolong
in Figures 3.7 and 3.8 demonstrates, accurate foveation periods just after foveating saccades
foveation is still possible under both conditions in INS or at the ends of decelerating, foveating

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slow phases that follow saccadic pulses in conditions albeit with a more damped FMN for
FMNS. However, it cannot create foveation the manifest case.
periods when there is a non-zero velocity slow Finally, to take full advantage of Alexander’s
phase immediately following a foveating slow law in order to minimize the amplitudes of their
phase; that is, as the dashed waveforms in nystagmus, many patients with FMNS alternate
Figure 3.10 illustrate, there exist no waveforms their fi xing eye such that it is always the adduct-
where extended foveation periods precede ing eye. Thus, they fi xate with the left eye when
either linear or decelerating slow phases. looking right and vice versa. Figure 3.12 shows
OMS model simulations of the effects of this
strategy for different gaze angles in both direc-
3.1.2 Variation with Gaze Angle
tions for small and large Alexander’s law effects.
The intensity of FMNS is maximal in abduction
and minimal in adduction, causing an “adduc-
3.1.3 Head Position
tion” null with the fi xing eye and not a true
“gaze” (eye in orbit) null position (see Chapter Because of the propensity to place the fi xating
5, Table 5.3). In Figure 3.11, OMS model simu- eye in adduction, viewing targets directly in front
lations of the Alexander’s law16 effects of gaze of the patient necessitates rotation of the head in
angle on FMN are shown for both small and the opposite direction (e.g., right eye to the left,
large effects during both monocular occlusion in adduction, with head rotated to the right). In
and binocular viewing. For the same FMN in addition to causing the anomalous head posture,
primary position, the larger amplitude var- this may give the mistaken clinical impression of
iation with gaze angle results in a waveform a nystagmus (usually INS) with two “nulls” if the
transition at a more central gaze angle in both clinician fails to detect the change in the fi xating

FIGURE 3.10 Illustrations of the four major nystagmus waveforms (clockwise from the top left , pendu-
lar, jerk with accelerating slow phases, jerk with linear slow phases, and jerk with decelerating slow phases)
coupled with the addition of extended foveation periods in those waveforms where it is possible for the ocu-
lar motor system to produce them. Dashed waveforms do not exist.

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FIGURE 3.11 Behavioral ocular motor system model simulations of gaze angle on fusion maldevelop-
ment nystagmus syndrome amplitude and waveform transition angle (for both small and large Alexander’s
law effects) during both monocular occlusion (top panels) and binocular viewing (bottom panels). BE, both
eyes; LE, left eye; RE, right eye.

eye or realizes that there is no true null (i.e., the when one eye was occluded, and became damped
nystagmus does not increase as the eye is rotated as a dissociated vertical deviation (DVD) devel-
further in adduction). oped with head tilting.17 The damping occurred
Using scleral search coil eye-movement over 0.3 to 3 seconds and was often only par-
recordings of 10 patients with dissociated verti- tial, identified as a decreasing slope of the nys-
cal deviation and FMNS, Guyton et al. showed tagmus slow phases. Occasionally, if the DVD
that nystagmus (horizontal, vertical, and tor- response diminished, the FMN reappeared.
sional) practically always appeared initially, As was discussed earlier for FMN, the DVD

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Adducting Eye Fixatioin MLN

50
40 BE Viewing BE Viewing
30 RE Fixation RE Fixation
Eye Position (deg)

20
10
0
10 BE Viewing
20
LE Fixation
30
40
50
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

Adducting Eye Fixation MLN

50
40 BE Viewing BE Viewing
30 RE Fixation RE Fixation
Eye Position (deg)

20
10
0
10 BE Viewing
20
LE Fixation
30
40
50
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Time (sec)

FIGURE 3.12 Behavioral ocular motor system model simulations of adducting eye fi xation on fusion
maldevelopment nystagmus syndrome for both small (top panel) and large (bottom panel) Alexander’s law
effects. BE, both eyes; LE, left eye; RE, right eye.

response could be recorded in total darkness in phases may still allow for good visual acuity.
those individuals who could voluntarily imag- As long as sufficient data points fall within the
ine switching “fi xation” (attention) from one eye foveation window of the eXpanded nystagmus
to the other. A head tilt also damped the FMN acuity function (NAFX; centered at the ends of
and appeared to decrease the need for DVD. the fast phases) for each FMN cycle, the NAFX
That evidence supports the view that DVD is value, and visual acuity, will be high. When
an acquired (learned), often anticipatory, cyclo- the FMN waveform consists of saccadic pulses
vergence response, occurring upon taking up whose decelerating slow phases foveate the tar-
unilateral fi xation, serving to improve vision by get, the same applies since the NAFX window is
damping or blocking FMN. now centered on the tail ends of the slow phases.
We have documented visual acuities as high as
20/15 in a patient with both waveforms.12
3.1.4 Foveation, eXpanded
Nystagmus Acuity Function, and
Acuity 3.1.5 Efference Copy, Foveation, and
Oscillopsia Suppression
Despite the lack of extended foveation periods
in FMN with linear or slightly decelerating The discussion in Chapter 2, Section 2.1.10
slow phases, the low amplitudes of these slow regarding the roles of efference copy and

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foveation in the suppression of oscillopsia in or “latent” condition),19 thereby supporting a

INS is equally applicable in FMNS. Patients previous hypothesis.7
with FMNS do not normally experience oscil- In children with FMNS and fusion, the devel-
lopsia because their efference-copy signal of the opment of amblyopia with subsequent dimin-
FMN motor command is used to negate the nys- ishing fusion or the recurrence of a frank tropia,
tagmus portion of the retinal signal, leaving the thus disrupting binocular vision, will make an
target portion uncontaminated and allowing for FMN become either more intense or manifest,
the perception of spatial constancy. Thus, in our thus the potential for creating visual symptoms
OMS model of FMNS, that stable reconstructed due to the nystagmus where none were present
target signal is produced internally by the same before. The magnitude of the resulting mani-
mechanism as in INS and is used to drive the fest FMN is proportional to the degree of the
correct ocular motor responses to target posi- interocular visual disparity. However, success-
tion and velocity—analogous to INS and FMNS ful treatment of amblyopia or strabismus will
patients, the model has no oscillopsia when sim- decrease the intensity, occasionally giving the
ulating either. appearance of complete absence. FMNS has
also been reported in children with unilaterally
reduced vision and esotropia associated with
3.2 ETIOLOGY OF FUSION
congenital disorders such as cataract or optic
MALDEVELOPMENT NYSTAGMUS
nerve hypoplasia. These children will often
SYNDROME
maintain a head turn to position the fi xating eye
FMNS is “congenital” in the same sense as INS in adduction.11,20,21
(i.e., a congenital predisposition). However, sev- Various theories have been advanced to
eral cases have been recorded of the manifest explain FMNS. These include a primitive vestib-
form of FMNS (“MLN” occurring with both ular tone imbalance, poor egocentric localiza-
eyes open), associated with retrolental fibropla- tion, a subcortical optokinetic system anomaly,
sia. 3 Early theories postulated that a unilateral a subcortical maldevelopment of retinal slip
retinal stimulus was the necessary condition control, abnormal cortical motion processing,
for FMNS, but this concept was discounted by a disorder of proprioception, and a phylogenic
observations of FMN in monocular fi xation persistence of the dominance of the nasal half
with a blind eye or with an acoustic stimulus in of the retina. 3,22–31 In Chapter 2 we identified
complete darkness. FMNS occurs in patients the direct cause of most IN waveforms as a fail-
with strabismus who, although viewing with ure of calibration in the damping mechanism
both eyes open, are fi xing monocularly. of smooth pursuit. The direct cause of FMN is
Strabismus is a necessary (but not sufficient) a tonic imbalance that drives the eyes with con-
condition for FMNS.7 That is, all individuals stant velocity (producing linear slow phases).
with FMNS have strabismus, consisting of either The source of the imbalance may be the naso-
a phoria or tropia under cover and a tropia with temporal asymmetry present in normal infants
both eyes open, if nystagmus is present under that disappears as fusion develops or, as we
these respective conditions. Conversely, FMNS hypothesized, egocentric direction confusion
is not significantly associated with early-onset (see Section 3.2.3).
strabismus.18 Rarely, on occlusion of a preferred
eye, during which fi xation with an amblyopic eye
3.2.1 Familial (Gene Defect)
is forced, both eyes drift in the direction of the
covered eye without corrections by fast phases; Just as in INS, there are some families whose
this is called “latent deviation.” Early surgical members have FMNS. That suggests that, in
correction of infantile strabismus may convert those families, there is a genetic component
the nystagmus of FMNS present with both eyes that facilitates (not causes) the development of
open (the manifest condition) to nystagmus pre- FMNS (see discussion of genetics and INS in
sent only upon occlusion of one eye (the “vera” Chapter 2, Section 2.2.1).

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3. 2.1.1 D O W N S Y N D R O M E deprived of binocular input early in life may

result from, rather than cause, their nystag-
FMNS is common in Down syndrome, where
mus. In normal monkeys, each NOT is driven
it may coexist with INS. 32 Of 35 adult patients
binocularly; in these monkeys, they are driven
with Down syndrome, 6 (23%) had FMNS; none
by the contralateral eye. 37 Although the result-
had INS. In addition, one child was studied who
ing imbalance may provide the tonic signal that
had some INS waveforms in addition to FMNS.
produces the FMN slow phases (inactivation of
Th is was far above the reported 15% prevalence
the NOT with muscimol abolishes the nystag-
of FMNS in the general population. Near ster-
mus), the cause of the imbalance appears to lie
eopsis was preserved in two of the adults and
in higher centers. The spontaneous reversal of
some fusion (the Worth four-dot test) in two
FMN in the dark has led to the speculation that
others. Five of the six preferred left-eye fi xation
eye dominance is predetermined.11,38 Shallo-
and three were left handed, a high percentage
Hoff mann et al. identified an alternating vertical
suggesting an unusual pattern of hemispheric
component to FMNS39 and Brodsky linked the
dominance.
genesis of FMNS and dissociated vertical diver-
gence (DVD) to the dorsal light reflex present in
many animals.40 In cases of FMNS plus DVD,
3.2.2 Optokinetic Asymmetry
the nystagmus may have a vertical component.41
FMNS has been associated with nasotempo-
ral asymmetry of the horizontal optokinetic
3.2.3 Egocentric Direction Confusion
response and smooth pursuit during monocular
viewing. Roelofs fi rst observed horizontal opto- Cortical switching that must occur in the calcu-
kinetic asymmetry in patients with FMNS. 33 lation of egocentric direction when going from
Kommerell suggested that FMNS could be binocular to monocular viewing. 3 Under binoc-
regarded as the consequence of horizontal ular conditions, egocentric direction, referenced
optokinetic asymmetry. 23 Hoff man developed to the “cyclopean eye,” is obtained by summing
a model to explain nasotemporal asymmetry the gaze angle of each eye with the other and
based on combined cortical and subcortical dividing by two. However, with monocular
input to the nucleus of the optic tract in the viewing, egocentric direction depends only on
cat. 34 In 1983, Schor proposed that FMNS and the viewing eye, and the cortical operation of
nasotemporal optokinetic asymmetry are medi- summing and dividing by two must be altered
ated by the nucleus of the optic tract. 35 Human to process unchanged information from the
nasotemporal asymmetry has received consider- viewing eye. We hypothesized that the shift in
able attention because it persists throughout life egocentric direction toward the non-viewing
in humans with early-onset infantile strabismus. eye causes the slow drift of the eyes in that direc-
Nasotemporal asymmetry is seen in rabbits, kit- tion. Both eyes are then corrected by a saccade
tens, monkey infants, and human infants within in the direction of the viewing eye, which brings
the fi rst 6 months of life. 35 the eyes to the target (or, in darkness, to the
However, the hypothesis that the FMNS is intended gaze angle). Th is hypothesis was sup-
caused by nasal-temporal asymmetries in the ported by unilateral strabismus surgery causing
optokinetic reflex is not supported by evidence central effects on egocentric localization.42 Thus,
that subjects with FMNS are able to use retinal FMNS nystagmus may be generated by this ina-
slip information to adapt motion-detection sen- bility to properly alter the cortical mathematical
sitivities36 and are able to pursue symmetrically.4 operation normally used to defi ne egocentric
Also, because nasal-temporal asymmetries exist direction (i.e., this deficit in higher centers may
in individuals with strabismus but not FMNS, 36 result in a tonic imbalance in the visual-vestibu-
this cannot be the primary causal factor in the lar subsystem, producing the linear slow phases
genesis of the nystagmus. Asymmetries in the of FMN). Our 1979 hypothesis for the cause of
monocular optokinetic response of monkeys FMNS was also supported by Tychsen et al.,

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who studied FMNS in patients and nonhuman brainstem motor pathways was required in this
primates.43 They related egocentric direction model. The binocular maldevelopment origi-
confusion to unbalanced infantile, monocular nating in area V1 is passed on to downstream
interhemispheric MSTd drive, which they found extrastriate regions of cerebral cortex that drive
was necessary and sufficient for FMNS. The shift conjugate gaze, notably MST. Conjugate gaze is
to monocular egocentric localization can also stable when MST neurons of the right and left
produce this mode whereby the saccadic system cerebral hemispheres have balanced binocu-
generates defoveating saccades that momen- lar activity. Fusion maldevelopment in infancy
tarily carry the fi xating eye past the target in causes unbalanced monocular activity.43,46,47 If
a temporal direction, followed by a decelerating- input from one eye dominates and the other is
velocity nasal drift back toward the target.12 suppressed, MST in one hemisphere becomes
Studies in subhuman primates have shown more active. Acting through downstream pro-
that FMNS arises after incomplete development jections to the ipsilateral nucleus of the optic
of visual input from occipitotemporal cortex to tract, the eyes are driven conjugately to that
subcortical vestibular pathways. In monkeys side. The unbalanced MST drive is evident as
with FMNS, there is a loss of binocularity in the the nasalward gaze-holding bias of latent FMN
NOT, the subcortical structure that feeds into when viewing with either eye.
the vestibular system, with most cells driven In summary, most patients have nystagmus
by the contralateral eye. 35 The areas that nor- from either the INS or the FMNS; some have
mally provide binocular input to the NOT are both; and three unambiguous patient groups
the middle temporal (MT) visual area and the have been identified: INS, FMNS, and INS +
medial superior temporal (MST) visual area FMNS.9,48,49 The three groups exhibit different
in occipitotemporal cortex.44,45 When strabis- clinical signs and relations to strabismus; most
mus was surgically induced in infant monkeys series of INS patients show that many have
during the fi rst 2 weeks of life, these monkeys strabismus, but all FMNS are strabismic. 50–53
also developed FMN and visual area MT/MST Thus, INS and FMNS are specific, easily dif-
loses binocularity. If either eye is covered during ferentiated syndromes and do not, as has been
infancy, visual area MT/MST and NOT develop suggested, 29 represent a unitary disorder with
normal binocularity, but the striate cortex still a broad spectrum of expression. Because no
shows loss of binocularity and these monkeys acquired, time-independent, primary-position
do not develop FMN. Th is fi nding suggests that jerk nystagmus reverses direction with alter-
the initial cause of FMNS is loss of binocular- nate eye cover, a simple reverse-cover test can
ity in visual area MT/MST from the misaligned be a powerful clinical tool.
eyes in early infancy. Neuroanatomical experi-
ments have supported the Schor hypothesis that Clinical Pearl: To distinguish between
the NOT may be the site of FMN generation. benign (non–neurologically threatening),
FMNS occurs in nonhuman primates following infantile, primary-position, jerk nystagmus
artificial induction of esotropia within the fi rst 2 and that which is neurologically threatening,
weeks of life.44,45 Experiments have shown that a first verify that there is no periodic alterna-
loss of binocular connections within striate cor- tion in direction and then perform bilateral,
tex (area V1) in the fi rst months of life may be the sequential, cover-uncover testing. If the cover
necessary and sufficient cause of FMNS.43,46,47 test causes a reversal in the nystagmus direc-
The severity of FMNS increases systemati- tion consistent with FMNS, the nystagmus
cally with longer durations of binocular decor- is benign (FMNS or INS with a latent com-
relation and greater losses of V1 connections. ponent). If not, attempt to rule out INS (by
Decorrelation durations that exceed the equiva- history, clinical signs [see Table 2.1], and
lent of 2–3 months in human development result waveforms).
in an FMNS prevalence of 100% in the nonhu- Clinical Pearl: If the results of an alter-
man primate model.43,46,47 No manipulation of nate-cover test indicate a benign, infantile,

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primary-position, jerk nystagmus (i.e., it asymmetry associated with ametropia, ambly-

causes a reversal in the nystagmus direction opia, or structural disease of the eye and brain.
consistent with FMNS or INS with a latent Many of these patients will prefer the fi xing eye
component), perform the test again but in in adduction, thus adopting a head/face turn
far adduction of the fi xating eye (e.g., far left toward the fi xing eye regardless of the primary
gaze when the left eye is occluded). If the nys- position deviation. When forced to fi xate with
tagmus again reverses (i.e., becomes jerk left the nonpreferred eye, the intensity of the FMNS
in left gaze with left eye occluded), it is INS will increase, visual functions will decrease, and
with a latent component. Repeat the test in a new (opposite) head/face position will be evi-
adduction of the other eye fi xating. If the nys- dent. Some patients spontaneously switch fi xat-
tagmus remains in the direction of the fi xat- ing eyes while looking at a single target.
ing eye, it may be either FMNS or INS with a
large latent component.
3.3.2 Alexander’s Law
Taking advantage of Alexander’s law is also a
3.3 TREATMENTS OF FUSION
consideration when determining treatment
MALDEVELOPMENT NYSTAGMUS
options. It would be disadvantageous to move
SYNDROME
the fi xating eye medially as it would require
When considering therapy for FMNS, it is additional abduction innervation to fi xate tar-
important to understand the different compo- gets in either primary position or further in
nents that contribute to the nystagmus and how abduction. In esotropia, the fi xating eye (or,
(and at what site) each proposed therapy works. both eyes) is moved into abduction so that the
Similar to INS, there are both sensory and adduction innervation required to maintain fi x-
motor components. The absence of fusion is the ation damps the FMN by taking advantage of
sensory component that contributes to the tonic Alexander’s law (motor component of FMN). It
motor imbalance that drives FMN. The effect of is also possible to achieve fusion to damp FMN
gaze angle (Alexander’s law) is the motor com- (sensory-motor component of FMN). However,
ponent modulating the FMN. Finally, the pro- in exotropia, if one moves the fi xating eye medi-
prioceptively controlled small-signal gain of the ally to achieve the straightening effect on the
extraocular muscles (a motor component) also exotropic eye for primary position targets, that
can modulate the FMN. Therefore, different may exacerbate the motor component of FMN
therapies and adaptations by the patient can act unless the patient achieves fusion. In the lat-
in distinct mechanistic ways to damp the FMN ter case, the sensory-motor effect of fusion in
and, in some cases, restore fusion. decreasing the FMN could be greater than the
The primary treatment of FMNS is a combi- abduction innervation in increasing the FMN.
nation of medical, optical, and surgical therapy In those exotropic FMNS patients for whom
to create, restore, or improve binocular function. fusion is impossible, recessions of all four hori-
Since the intensity of the FMN is related to the zontal recti with a large differential (more on the
degree of binocular function, improving fusion lateral than the medial recti) has proven success-
will damp the FMN and improve visual function. ful in treating both the exotropia and the motor
The addition of nystagmus surgery, in the form of component of the nystagmus.
tenotomy and reattachment (T&R) of any hori-
zontal rectus muscles not operated on to realign
3.3.3 Eye-Muscle Surgery
the eyes, should also further damp the FMN.
It is also possible to surgically enhance the acu-
ity of some patients with FMNS at the same
3.3.1 Fixation Preference
time as correcting the strabismus and head pos-
Patients with FMNS may be visually guided ture. These operations are considered broadly as
by one eye; this is due, in large part, to afferent treatment of “strabismus and nystagmus with or

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without an anomalous head posture” (see oper- 8. Abadi RV, Scallan CJ. Waveform
ation algorithm, Chapter 7, Appendix C, and characteristics of manifest latent nystagmus.
Appendix D, Figs. D.2 and D.4). In summary, Investigative Ophthalmology and Visual Science
2000;41:3805–3817.
to address both the FMN, head posture (if not
9. Dell’Osso LF. Congenital, latent and manifest
alternating), and strabismus in the same proce- latent nystagmus—similarities, differences
dure, the two horizontal rectus muscles on the and relation to strabismus. Jpn J Ophthalmol
eye responsible for the head posture are recessed 1985;29:351–368.
and resected to straighten the head while the 10. Dell’Osso LF. Evidence suggesting individual
two horizontal recti on the nonfi xing eye are ocular motor control of each eye (muscle).
recessed and resected to correct the resulting J Vestib Res 1994;4:335–345.
strabismus. The advantage of operating on all 11. Dell’Osso LF, Abel LA, Daroff RB. Latent/
manifest latent nystagmus reversal using an
four horizontal recti is that, in addition to treat- ocular prosthesis. Implications for vision and
ing the strabismus and head posture, there is the ocular dominance. Invest Ophthaomol Vis Sci
potential of fusion and further damping of the 1987;28:1873–1876.
FMN produced by the T&R effect on the pro- 12. Dell’Osso LF, Leigh RJ, Sheth NV, Daroff RB.
prioceptive control of the small-signal gain of Two types of foveation strategy in “latent”
the extraocular muscles. Another advantage of nystagmus. Fixation, visual acuity and stability.
the T&R additions to the strabismus procedure Neuro Ophthalmol 1995;15:167–186.
13. Dell’Osso LF, Jacobs JB. A robust, normal
is that, in addition to damping the FMN, those
ocular motor system model with latent/
muscles receiving a T&R are left intact and may manifest latent nystagmus (LMLN) and
be used for future strabismus adjustments that dual-mode fast phases. In: Sharpe JA, ed.
might become necessary. Neuro-Ophthalmology at the Beginning of the
New Millennium. Englewood, NJ: Medimond
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4
other t ypes of
nystagmus of infancy
4.1 NYSTAGMUS BLOCKAGE 4.1.1.7 Efference Copy, Foveation, and
SYNDROME 122 Oscillopsia Suppression 127
4.1.1 Characteristics of Nystagmus Blockage 4.1.2 Treatments of Nystagmus Blockage
Syndrome 123 Syndrome 127
4.1.1.1 Multiple Types of 4.1.2.1 Fixation Preference 129
Nystagmus 123 4.1.2.2 Alexander’s Law 129
4.1.1.2 Waveforms and 4.1.2.3 Surgical 129
Mechanisms 123 4.1.2.3.1 Fixating Eye 129
4.1.1.2.1 Target Foveation 123 4.2 SPASMUS NUTANS SYNDROME 129
4.1.1.2.2 Foveation Accuracy 123 4.2.1 Characteristics of Spasmus Nutans
4.1.1.3 Purposive Esotropia 123 Syndrome 129
4.1.1.4 Head Position 124 4.2.1.1 Waveforms and Mechanisms 130
4.1.1.5 Blockage Syndrome 4.2.1.2 Variable Interocular Phase 131
Types I and II 124 4.2.1.3 Head Nodding 131
4.1.1.6 Foveation, eXpanded Nystagmus 4.2.2 Treatment of Spasmus Nutans
Acuity Function, and Acuity 126 Syndrome 132

The greatest obstacle to discovery is not ignorance—it is the illusion of knowledge.

—Daniel J. Boorstin

I N A DDIT ION to infantile nystagmus syn- by willfully deviating his fi xating eye inward
drome (INS) and fusion maldevelopment (e.g., “convergence”).2–6 The lack of specificity
nystagmus syndrome (FMNS), there are two regarding the nystagmus types or waveforms
rare syndromes found in infants and children: present both before and after “convergence” led
the nystagmus blockage syndrome (NBS) and to problematic diagnoses and interpretations of
the spasmus nutans syndrome (SNS).1 the clinical symptoms. Because of this, the NBS
remains both a poorly understood and an over-
diagnosed phenomenon related to INS. As the
4.1 NYSTAGMUS BLOCKAGE
name suggests, the nystagmus of these patients
SYNDROME
diminishes or disappears clinically with the act
The NBS was defi ned clinically as one in which a of willed esotropia while fi xating a distant target.
patient with nystagmus (type undefi ned) damps This should not be confused with the damping of IN
or changes that nystagmus (again type undefi ned) during true convergence on a near target.

122 •

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Based on our research, the NBS can now be nystagmus waveform and, thereby, visual acu-
more accurately defi ned as a syndrome in which ity. The NBS has been reported in an exotropic
a patient with INS plus a variable esotropia will- patient17 and also in a congenitally blind patient.18
fully deviates the fi xating eye into adduction
to accomplish either a damping of the IN or a
4 .1.1. 2 W AV E F O R M S A N D M EC H A N I S M S
switch from IN to a low-amplitude FMN.1
The reported incidence of NBS in esotropic During the pre-esotropia phase of the NBS,
patients is quite variable and may reflect a geo- the waveforms of the nystagmus are those of
graphical bias (10.2% in Europe and 4%–5% in INS (see Chapter 2, Section 2.1.2). However,
America) as well as overdiagnosing in conjunc- upon the willful esotropia, they may be either
tion with a lack of quantitative data. Although damped INS waveforms or FMNS waveforms
Metz and Smith do discuss NBS,7 their record- (see Chapter 3, Section 3.1.1). As discussed in
ings clearly show that their patient had FMNS Chapter 3, the underlying mechanism for the
and that the amplitude varied in accordance appearance of FMN is hypothesized to be a tonic
with Alexander’s law.8–13 Hoyt, in a letter con- imbalance related to the failure of fusion devel-
taining no eye-movement recordings, claimed opment. Although it is possible that the pur-
that 8 of 32 patients with congenital esotropia posive esotropia induces an actual switch from
had NBS.14 Without recordings, INS cannot be IN to FMN, it is more probable that both types
differentiated from FMNS, and the diagnosis of of nystagmus coexist and the FMN is revealed
NBS cannot be verified. when the IN becomes sufficiently damped by the
esotropia. The second possibility is supported by
the demonstration that IN and FMN can both
4.1.1 Characteristics of Nystagmus be present in some patients.16
Blockage Syndrome
4.1.1.2.1 Target Foveation. Target foveation
4 .1.1.1 M U LT I P L E T Y P E S O F
depends on which type of waveform (INS or
N Y S TA G M US
FMNS) is present and is described in Chapters
The first characteristic revealed by eye-movement 2 and 3. In some cases, the nystagmus is totally
data was that there were two mechanisms by which blocked by the purposive esotropia and fove-
blockage of the ongoing nystagmus can be accom- ation is essentially the same as in unaffected
plished; that resulted in two different types of individuals.
patients with the NBS.15,16 Patients with both types
had IN when their eyes were aligned. In Type I, the 4.1.1.2.2 Foveation Accuracy. Foveation
IN either damped or stopped entirely upon willful accuracy also depends on which type of wave-
esotropia, in much the same way as with true con- form (INS or FMNS) is present and is described
vergence. In Type II of NBS, the INS waveform in Chapters 2 and 3. In the case of complete nys-
converts to a low-amplitude FMNS waveform with tagmus blockage, the accuracy is essentially the
the onset of the strabismus. Normally, the substitu- same as in unaffected individuals.
tion of the FMNS slow phases for the INS wave-
forms that allow for better foveation would not be
4 .1.1.3 P U R P OS I V E E S OT R O P I A
advantageous. However, in these few patients, the
low FMNS amplitude results in better acuity than It had been suggested that the nystagmus is
the larger INS amplitude. NBS is often misdiag- actively blocked by convergence innervation, the
nosed in FMNS patients with a strong Alexander’s esotropia thus being caused by sustained conver-
law variation of their nystagmus, which causes gence and secondary changes in the medial rectus
them to fi xate with their adducting eye.15Thus, the muscles. The differential diagnosis includes infan-
NBS encompasses two different types of infan- tile esotropia with equal and alternating crossed
tile nystagmus and the ability to willfully change fi xation, bilateral sixth nerve paralysis, and bilat-
the amount of esotropia present to improve the eral Type I Duane syndrome. NBS is characterized

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by a reduction of the nystagmus when esotropia in INS are demonstrated in the following figures.
increases. A useful clinical sign in differentiat- The eye movements of a patient with Type II NBS
ing NBS from other forms of convergence excess are shown in Figures 4.1–4.3. The INS waveforms
esotropia is the absence of pupillary constriction. of this NBS patient during binocular fi xation of
These patients are not using their accommodative a target in primary position are shown in Figure
vergence mechanism to block the nystagmus but, 4.1. The jerk and jerk with extended foveation
instead, are depending upon some other mechan- waveforms are predominantly right beating with
ism to bring about damping of the nystagmus. some cycles that are left beating. Figure 4.2 shows
the waveforms of the same NBS patient binocu-
larly fi xating a target in right gaze. As the right
4 .1.1. 4 H E A D P OS I T I O N
eye becomes esotropic and the left eye remains
Prior to the purposive esotropia (i.e., during the on target, the INS waveform abruptly switches
binocular IN phase), there is not likely to be a to a jerk-left FMN. When the right eye returns to
head turn. However, after esotropia (in both the the target, the nystagmus again becomes IN (dual
NBS Types I and II), the fi xating eye is the pur- jerk right with extended foveation).
posively esotropic eye, necessitating a head turn Individuals with FMNS often fi xate stationary
in the opposite direction. In Type II, because of targets with their adducting eye, as is illustrated
the Alexander’s law variation of FMN, a large in Figure 3.12. This strategy is also used during
head turn is common. smooth pursuit, as is shown in Figure 4.3. Initially,
as the target crosses the midline, the right eye takes
up pursuit to the left, while the left eye remains
4 .1.1.5 B L O C K A G E S Y N D R O M E T Y P E S I
esotropic, albeit moving with the same pursuit
AND II
velocity. As the now rightward moving target again
The characteristics of both the NBS Types I and crosses the midline, the left eye takes up smooth
II and the differences from convergence damping pursuit while the right eye remains esotropic.

FIGURE 4.1 Horizontal eye position and velocity right- and left-eye data from a patient with nystagmus
blockage syndrome showing infantile nystagmus syndrome waveforms when the eyes are aligned and fi xating
on a target in primary position. Time markers indicate 1-sec intervals. b, blink; LE, left eye; RE, right eye.

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FIGURE 4.2 Horizontal eye position and velocity right- and left-eye data from the same patient shown in
Figure 4.1 with nystagmus blockage syndrome showing infantile nystagmus syndrome waveforms when the
eyes are aligned (beginning and ending of the interval shown) and conversion to jerk-left fusion maldevel-
opment nystagmus when the right eye became esotropic. Time markers indicate 1-sec intervals. b, blink; LE,
left eye; RE, right eye.

FIGURE 4.3 Horizontal eye position and velocity right- and left-eye data from the same patient shown
in Figures 4.1 and 4.2 with nystagmus blockage syndrome during smooth pursuit with the adducting eye
(i.e., pursuit by the right eye for target positions in left gaze and the left eye in right gaze). Time markers
indicate 1-sec intervals. b, blink; LE, left eye; RE, right eye.

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Without accurate, monocularly calibrated primary position target and then a target 15°
eye-movement data, the relative positions of to the right (between the two was a period of
each eye, the determination of the fi xating eye, conjugate wandering att ributed to inattention).
and differentiating between INS with a latent Again, only INS waveforms were exhibited; fi rst
component, FMNS, or the NBS would not be was jerk right with extended foveation and then
possible. In Figure 4.4, the eye movements of a jerk left with extended foveation. No nystagmus
patient with INS with a latent component are damping accompanied the variable esotropia. In
shown during convergence on a primary position Figure 4.7, this patient demonstrated classic INS
target moving from far to near and back to far. damping with convergence, despite the esotro-
Th roughout the record, the waveforms are those pia of the left eye. Thus, with eye-movement data
of INS only (initially jerk left with extended fove- one is able to differentiate these clinically simi-
ation, then jerk right with extended foveation); lar types of nystagmus characteristics.
no FMNS were exhibited. The left eye tracked
target motion inward (the right eye was esotro-
4 .1.1.6 F OV E AT I O N , E X PA N D E D
pic); at near, the IN of both eyes was damped.
N Y S TA G M US A C U I T Y F U N C T I O N , A N D
However, the right eye tracked target motion
ACUIT Y
outward (the left eye was esotropic). Note that,
unlike in the NBS, there was no nystagmus In Type I, the extended foveation periods will
damping during the times when either the right increase the eXpanded nystagmus acuity function
or left eye was maximally esotropic. Th is same (NAFX) over that measured during binocular fi x-
lack of esotropia-induced damping is evident in ation. The eye-movement data are indistinguish-
Figure 4.5, where spontaneous reversals of the able from convergence damping in a binocular
fi xating eye occurred during fi xation on a sta- INS patient with the exception that only one eye
tionary, distant, primary position target. is adducted in the NBS. In Type II, the very low
In Figure 4.6 we see the eye movements of amplitude FMN will also yield higher values of
another patient who had INS plus a variable the NAFX. During the purposive esotropia, tar-
strabismus during fi xation fi rst on a distant, get foveation is accurate, the NAFX is high, and

FIGURE 4.4 Horizontal eye position and velocity right- and left-eye data from a patient with infantile nys-
tagmus syndrome (INS) with a latent component and esotropia shown fi xating a distant target with the LE
(RE esotropic) as the target is brought inward and then back to its original distant position. During the dis-
tant fi xation and convergence, the INS waveform was jerk left while the LE adducts onto the near target. At
near, the RE takes on fi xation and the INS waveform reverses to jerk right. As the target moves outward, the
formerly fi xating LE remains adducted and the RE maintains fi xation with a jerk-right INS waveform. Time
markers indicate 1-sec intervals. LE, left eye; RE, right eye.

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FIGURE 4.5 Horizontal eye position and velocity right- and left-eye data from the same patient shown in
Figure 4.4 with infantile nystagmus syndrome with a latent component and esotropia during fi xation on a
distant target. At the fi rst arrow, the LE became esotropic (RE fi xation); at the second arrow the RE became
esotropic (LE fi xation); and at the third arrow, the LE again became esotropic (RE fi xation). Time markers
indicate 1-sec intervals. LE, left eye; RE, right eye.

visual acuity is at its maximum for the NBS patient individual nystagmus type(s) and characteris-
regardless of whether it is Type I or II. tics. The medical and surgical therapies applied
to IN and FMN utilize the respective character-
istics of the nystagmus. In much the same man-
4 .1.1.7 E F F E R E N C E CO P Y, F OV E AT I O N ,
ner, INS patients turn their heads to exploit the
A N D OS C I L L O P S I A S U P P R E SS I O N
gaze-angle null of IN, and FMNS patients do the
As was discussed in Chapters 2 and 3, the built-in same to exploit the Alexander’s law variation of
efference copy of motor commands in the OMS their FMN. Patients with NBS also apply these
prevents the perception of oscillopsia in either same “therapeutic” maneuvers. Head turns, for
IN or FMN. Thus, patients with the NBS do not whichever type of nystagmus they are used, may
normally experience oscillopsia regardless of be cosmetically unatt ractive or even may lead
whether it is Type I or II. to neck problems when severe. However, head
turns are not defects associated with the INS,
FMNS, or NBS, but rather, constitute purposive
4.1.2 Treatments of Nystagmus
and therapeutic patient-administered “therapy.”
Blockage Syndrome
Successful amelioration of a head turn can only
The same mechanistic considerations discussed occur if its advantages, vis-à-vis better visual
in Chapters 2 and 3 for INS and FMNS, respec- function, are otherwise achieved (e.g., surgically
tively, apply in the NBS. One must fi rst deter- moving the IN null to primary position or induc-
mine whether the patient is Type I or II. The ing convergence that both damps and broadens
therapeutic choice will depend on the patient’s the IN null).

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FIGURE 4.6 Horizontal eye position and velocity right- and left-eye data from a patient with infantile nystag-
mus syndrome (INS) and variable strabismus. Initially, the patient was fi xating a primary position target with
a jerk right with extended foveation INS waveform. Then there was a conjugate wandering (presumably due to
inattention) until the instruction to look at a target at 15° (right gaze). After the refi xating saccade, the INS wave-
form was jerk left with extended foveation. Time markers indicate 1-sec intervals. LE, left eye; RE, right eye.

FIGURE 4.7 Horizontal eye position and velocity right- and left-eye data from same patient shown in Figure
4.6 with infantile nystagmus syndrome (INS) and variable strabismus while fi xating a distant target with the
RE (LE esotropic) as the target is brought inward. The jerk right with extended foveation INS waveform at dis-
tance damped completely at near. Time markers indicate 1-sec intervals. LE, left eye; RE, right eye.

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4 .1. 2.1 F I X AT I O N P R E F E R E N C E different from ordinary strabismus; the latter

is not under conscious control. Although it has
If the patient fi xates with the straight eye in Type
been suggested that bimedial recession may help
I NBS, there will be no head turn. If the newly
those with NBS, published studies are lacking.
esotropic eye is used, a head turn will be neces-
Similarly, the Faden operation may benefit those
sary and will depend on the amount of esotropia
with NBS. Simple surgical correction in NBS
employed by the patient.
has not proven successful.19

4 .1. 2. 2 A L E X A N D E R ’ S L AW 4.2 SPASMUS NUTANS

The amount of Alexander’s law variation with SYNDROME
gaze angle is idiosyncratic. Its effects on the The spasmus nutans syndrome (SNS)1 includes
amplitude change in FMN were discussed in ocular oscillations, head nodding, and anom-
Chapter 3, Section 3.1.2 and demonstrated in alous head positions that begin in infancy
Figure 3.11. Therefore, the presence or amount (usually between 4 and 18 months of age)
of head turn will also be idiosyncratic and could and disappear clinically in childhood (usu-
affect the optimal therapy. ally before 3 years or age). The nystagmus is
generally bilateral (but can differ in each eye
and may even be strictly monocular), and it
4 .1. 2.3 S U R G I C A L
oscillates in horizontal, torsional, or vertical
The surgery for NBS is aimed at reducing the directions. The average duration of SNS is 12
head turn required after the patient utilizes to 24 months; rarely, it lasts a number of years.
esotropia to damp (Type I) or damp and change It was fi rst described by Raudnitz in 1897, 20
(Type II) the nystagmus. Because the patients followed by others, including several longi-
are able to fuse and only manifest esotropia tudinal studies. 21–29 The pathogenesis of SNS
when they desire, standard strabismus-surgery remains obscure despite some ocular motor
approaches do not apply. If they have strong studies.16,30–33 SNS has been confused with
fusion reflexes, perhaps a bimedial recession other entities, 34–37 but eye-movement record-
procedure would produce the required damp- ings allow accurate differentiation (e.g., FMN
ing for Type I NBS patients in the same man- or uniocular pendular nystagmus). 38 Prior to
ner as in binocular INS patients. For Type II subsequent ocular motility studies, diagnosis
NBS patients, if the INS damping produced was delayed until the clinical symptoms of nys-
by realigning the eyes is sufficient, perhaps the tagmus and anomalous head posture resolved.
switch to FMN would not occur; if the under-
lying mechanism in Type II is not a switch to
4.2.1 Characteristics of Spasmus
FMN but a manifestation of a low-amplitude
Nutans Syndrome
FMN that coexisted with a more prominent
INS, the FMN would then also appear. SNS appears as a high-frequency, asymmetric,
dysconjugate ocular oscillation. It is usually hor-
4.1.2.3.1 Fixating Eye. As stated earlier, if fi xa- izontal in direction but may also be vertical or
tion remains with the stationary eye as the other is torsional. It is often described as an intermittent
deviated inward (as in Fig. 4.2), no head turn would nystagmus that is asymmetrical in appearance
be necessary and surgery would be problematic. If, and occasionally monocular. A key eye-move-
however, fi xation is taken up by the deviated eye ment recording observation is the variable
(the most common scenario), a head turn results phase difference between the two eyes, which is
and surgery can be tailored to reduce that turn. reflected clinically as an asymmetry in the oscil-
In the NBS, it is possible that the bimedial lations between the two eyes. On lateral gaze, the
recession procedure could be therapeutically dissociation may increase, with nystagmus of the
beneficial because the purposive esotropia is abducting eye predominating.

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Some case series suggest an increased preva- parents living together, and more psychiatric dis-
lence of esotropia in SNS. Gottlob et al. found a orders, including alcohol and drug abuse.
high incidence of esotropia, latent nystagmus, For a century, numerous reports emphasized
dissociated vertical divergence, and amblyopia that SNS was a visually and systemically benign
in children with SNS.29 Conversely, rare patients and self-limited clinical entity. 26,46–52 Since 1967,
with infantile esotropia display horizontal or ver- however, many infants with some of the features
tical head oscillations that resolve following surgi- of spasmus nutans have been found to have con-
cal realignment of the eyes. In contradistinction to genital suprasellar tumors (most commonly
INS, visual acuity is minimally affected in SNS. chiasmal gliomas). Suprasellar tumors can pro-
duce a constellation of neuro-ophthalmologic
signs that are clinically and electrophysiologi-
4 . 2 .1.1 W AV E F O R M S A N D M EC H A N I S M S
cally indistinguishable from SNS. Congenital
The nystagmus waveform in SNS is a dissociated head nodding and nystagmus has been reported
pendular nystagmus, and this dissociation may with cerebrocerebellar degeneration. 53 The clin-
be so great that the nystagmus is uniocular.39,40 ical fi ndings of hydrocephalus, café au lait spots,
Ages of onset of the seven patients studied ranged optic atrophy, or other clinical signs of neurofi-
from birth to 14 months; five had head nodding. bromatosis make it more likely that a child with
The dissociated nystagmus is usually of a higher SNS will have a central nervous system glioma.
frequency than INS nystagmus, and the result A substantial proportion of patients presenting
can be disjugate, conjugate, or uniocular. Early with SNS-like nystagmus have important under-
reports considered SNS to be pathogenetically lying ocular, intracranial, or systemic abnor-
related to diverse causes that included light depri- malities. Neurodegenerative disorders such as
vation, dietary factors, season, rickets, epilepsy, Pelizaeus–Merzbacher disease and Leigh dis-
auto-arousal, and poor socioeconomic condi- ease may produce nystagmus and head nodding
tions.34 Hermann noted a strong predisposition that are indistinguishable from SNS. 52,54–57 These
for the onset of SNS to occur during the winter disorders should be suspected in children with
months, with 70% of cases having their onset clinical signs of ataxia or developmental delay or
during December, January, and February.41–44 In with magnetic resonance evidence of white mat-
1897, Raudnitz published the classical description ter signal abnormalities. Achromatopsia, con-
of SNS in which he collated previously reported genital stationary night blindness, and Bardet
cases with 15 cases of his own. He emphasized Biedl syndrome can also masquerade as SNS.
the fact that virtually all of his patients belonged Genetic factors were suggested by the
to a certain dark quarter of Prague. When this dis- descriptions of SNS in identical twins and
trict was later sanitized, no further cases of SNS the fi nding that it is more common in Black
developed. Raudnitz viewed darkness as the pri- children.29,34,40,58,59 However, SNS occurs in
mary etiologic factor, speculating that the eyes neurologically normal children. Weissman et
of affected children were somehow damaged by al. considered vergence, saccadic, and pursuit
the “irritant effect” of insufficient light during a system abnormalities as possible causes of SNS
critical period of fi xation development. Raudnitz but came to no defi nitive conclusion.40 SNS is a
noted that pups that were reared in total darkness diagnosis that can only be made using a combi-
for several months developed eye nystagmus and nation of clinical characteristics and eye-move-
head nystagmus. ment fi ndings, which exclude other visual or
Lower socioeconomic status may represent a nervous system disease. The pathogenesis and
risk factor for the development of SNS. In a study neuroanatomical substrate of this developmen-
comparing SNS with infantile nystagmus, Wizov tally acquired form of asymmetric, dysconjugate
found African American or Hispanic ethnicity to nystagmus are still unknown.
be significantly more common in SNS.45 Patients We hypothesize that SNS reflects a yoking
with SNS also had lower average gestational ages, abnormality, perhaps due to delayed develop-
lower home luminances at birth, fewer married ment. Recordings show that SNS nystagmus

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may not disappear completely but may recede to examined patients with SNS in whom head nod-
a subclinical level; neither INS nor FMNS dis- ding abolished the nystagmus, and a normal VOR
appears with age. stabilized the eyes during head movements. 32
They demonstrated with eye-movement record-
ings that the head nodding in SNS is an adaptive
4 . 2.1. 2 VA R I A B L E I N T E R O CU L A R P H A S E
behavior that serves to improve visual acuity by
The nystagmus of the SNS tends to be asymmet- suppressing the nystagmus, rather than a sepa-
ric in the two eyes, to vary in different directions rate pathological phenomenon. Eye-movement
of gaze, and to be rapid and of small amplitude. recordings from these patients demonstrated
The pendular oscillation of SNS is characterized that the head nodding in SNS functions to abol-
by a variable phase difference between the oscil- ish the nystagmus through some mechanism
lations of each eye.40 These phase differences independent of the vestibulo-ocular response.
can appear from minute to minute and during Gott lob et al. confi rmed and refi ned these con-
the child’s development. As Figure 4.8 shows, the clusions in a large number of patients with SNS
pendular oscillations of each eye may be phase using eye-movement recordings.29,60 In their
locked, slightly out of phase, or even totally out patients, the head nodding changed the SNS
of phase, and this can vary during the course of waveform from a fi ne, pendular, dissociated
the recording anywhere from pure conjugacy to nystagmus of high frequency to a larger slower
pure disconjugacy (0–180° phase shift).40 The waveform that is symmetrical between the two
phase variation usually varies from minute to eyes. There is now general agreement that head
minute. Distinguishing this variable phase rela- nodding in SNS is compensatory.
tionship between the pendular oscillations of Because the vestibulo-ocular reflex (VOR) of
both eyes requires DC-coupled, high-bandwidth these patients is normal, by willfully shaking of
recordings of both eyes simultaneously. the head, the nystagmus is switched off and the
eyes become stable in space because of a good
VOR. A patient may have convergence nystag-
4 . 2.1.3 H E A D N O D D I N G
mus, one eye going left, the other eye going right
The head nodding in SNS is curious. It is incon- at the same time (180° out of phase), while the
stant and irregular and can be horizontal or ver- head is still. When the patient starts shaking his
tical, or both. The head nodding associated with or her head, the nystagmus stops and, owing to
SNS is a combination of vertical head nodding the normal VOR, the eyes begin moving con-
together with a lateral shaking of the head in an jugately equally and oppositely to the head, so
unpredictable pattern. 57,60–62 The head nodding gaze remains constant.
is of lower frequency than the nystagmus and
becomes prominent when the child attempts to “Cultured” Clinical Pearl: Based on the obser-
inspect something of interest. It disappears dur- vation that head nodding is compensatory in
ing sleep but may persist when the child is lying the SNS, if further research on the eye move-
down. Since some children with INS also have ments of the “SN-like” nystagmus associated
head nodding, this fi nding alone cannot be used with brainstem gliomas demonstrates that no
to confi rm the diagnosis of SNS in the child with head nodding is exhibited by these patients,
nystagmus. Studies of quantitative head- and the presence of deliberate, compensatory head
eye-movement recordings indicate that the head nodding is an indication of SNS and is benign.
movement may, using the normal VOR, actu-
ally serve to abolish the eye movements (see Fig. The head tilt in SNS is a variable fi nding that
4.9). 30 In some patients, it may be only compen- is present in less than half of cases. Although
satory with suppression of the VOR. Compare the reason for the associated head tilt is unclear,
this to INS, where the head oscillation is an Gott lob et al. suggested that it may serve to
extension of the nystagmus and the VOR is nor- directionalize the head nodding to its optimal
mal (see Chapter 2, Section 2.1.8). Gresty et al. trajectory.60 Although early authors stated that

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FIGURE 4.8 First example of the phase variation between the two eyes in spasmus nutans syndrome.
(Left) A uniocular, pendular nystagmus in the LE. (Middle) A binocular, pendular nystagmus with both
eyes in phase. (Right) A binocular, pendular nystagmus with the eyes 180° out of phase. The three intervals
were within seconds of each other. Time markers indicate 1-sec intervals. LE, left eye; POS, eye position;
RE, right eye; VEL, eye velocity.

the head nodding was the fi rst sign of SNS to resolution of the condition, suggesting that the
appear and the last to resolve, it is now generally nystagmus diminishes to a subclinical level but
agreed that the nystagmus is the most constant does not entirely resolve.40
feature of SNS and that it probably precedes the
head nodding, although the head nodding may
4.2.2 Treatment of Spasmus Nutans
be the abnormality that fi rst att racts attention.
Syndrome
Weissman found persistence of the nystagmus
in some of their patients, and Gott lob et al. In patients with “SN-like” nystagmus, accurate
found persistence of nystagmus using eye-move- diagnosis is the most important factor. Therefore,
ment recordings in all patients who had clinical until definitive eye-movement-based criteria are

FIGURE 4.9 First demonstration that the head movements in spasmus nutans syndrome are both willful
and compensatory. Time markers indicate 1-sec intervals (From Gresty et al., 1976.)

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identified to differentiate SNS from other, more 15. Dell’Osso LF, Ellenberger JC, Abel LA,
neurologically problematic conditions, imaging is Flynn JT. The nystagmus blockage syndrome:
a necessity. Because SNS is benign, once it is defin- congenital nystagmus, manifest latent
nystagmus or both? Invest Ophthalmol Vis Sci
itively diagnosed, SNS requires no treatment.
1983;24:1580–1587.
16. Dell’Osso LF. Congenital, latent and manifest
REFERENCES latent nystagmus—similarities, differences
and relation to strabismus. Jpn J Ophthalmol
1. CEMAS Working Group. A Classification of 1985;29:351–368.
Eye Movement Abnormalities and Strabismus 17. Kommerell G, Gusek G, Gilles U.
(CEMAS). Available at: htt p://www.nei.nih. Kongenitaler Nystagmus und intermitt ierende
gov/news/statements/cemas.pdf. Accessed Exotropie. Nystagmushemmung durch
April 14, 2012. fusionale Konvergenz. Klin Mbl Augenheilk
2. Adelstein F, Cüppers C. Zum Problem der 1992;200:210–212.
echten und scheinbaren Abducenslahmung 18. Reinecke RD. Nystagmus blockage syndrome
(das sogenannte “Blockierungs-syndrom”). in the unilaterally blind patient. Doc
In: Hamburger FA, Hollwich F, eds. Ophthalmol 1984;58:125–130.
Augenmuskellähmungen, Büch d Augenarzt, Heft 19. Von Noorden GK, Wong SY. Surgical results in
46. Stuttgart, Germany: F Enke; 1966:271–278. nystagmus blockage syndrome. Ophthalmology
3. Haase W. Zur Diagnose und Therapie 1986;93:1028–1031.
des Nystagmusblockierungs-syndroms 20. Raudnitz R. Zer Lehre vom Spasmus Nutans.
(elektromyographische Untersuchungen). Klin Jahrb Kinderh 1897;45:145.
Monatsbl Augenheilkd 1970;157:500. 21. Holmes SWT. The nystagmus of spasmus
4. Von Noorden GK. The nystagmus nutans in infants. Br Med J 1901;1:1120.
compensation (blockage) syndrome. Am J 22. Herrman C. Head shaking with nystagmus in
Ophthalmol 1976;82:283–290. infants. Am J Dis Child 1918;16:180–194.
5. Von Noorden GK. The nystagmus blockage 23. Moorad PJ. Nystagmus in infants. Arch
syndrome. Aust J Ophthalmol 1979;7:31–37. Ophthalmol 1935;13:238–246.
6. Frank JW. Diagnostic signs in the nystagmus 24. Osterberg G. On spasmus nutans. Acta
compensation syndrome. J Pediatr Ophthalmol Ophthalmol 1937;15:457–467.
Strab 1979;16:317–320. 25. Norton EWD, Cogan DG. Spasmus nutans:
7. Metz HS, Smith G. Abduction nystagmus. J a clinical study of twenty cases followed two
Pediatr Ophthalmol Strab 1979;15:312–317. years or more since onset. Arch Ophthalmol
8. Alexander G. Die Ohrenkrankhieten im 1954;52:442–446.
Kindesalter. In: Pfaundler M, Schlossman A, 26. Hoefnagel D, Biery B. Spasmus nutans. Dev
eds. Handbuch der Kinderheilkunde. Leipzig, Med Child Neurol 1968;10:32–35.
Germany: Vlg FCW Vogel; 1912:84–96. 27. Jayalakshmi P, McNair STF, Tucker SH,
9. Kestenbaum A. Mechanismus des Nystagmus. Schaffer DB. Infantile nystagmus: a prospective
Arch f Ophthalmol (Graefe) 1921;105:799. study of spasmus nutans, congenital nystagmus,
10. Doslak MJ, Dell’Osso LF, Daroff RB. A model and unclassified nystagmus of infancy. J Pediatr
of Alexander’s law of vestibular nystagmus. Biol 1970;77:177–187.
Cyber 1979;34:181–186. 28. Farmer J, Hoyt CS. Monocular nystagmus in
11. Doslak MJ, Dell’Osso LF, Daroff RB. infancy and early childhood. Am J Ophthalmol
Alexander’s law: a model and resulting study. 1984;98:504–509.
Ann Otol Rhinol Laryngol 1982;91:316–322. 29. Gott lob I, Wjizov SS, Reinecke RD. Spasmus
12. Robinson DA, Zee DS, Hain TC, Holmes A, nutans. A long-term follow-up. Invest
Rosenberg LF. Alexander’s law: its behavior Ophthalmol Vis Sci 1995;36:2768–2771.
and origin in the human vestibulo-ocular 30. Gresty MA, Leech J, Sanders MD, Eggars H.
reflex. Ann Neurol 1984;16:714–722. A study of head and eye movement in spasmus
13. Takahashi M, Tsujita N, Akiyama I. Vestibulo- nutans. Br J Ophthalmol 1976;160:652–654.
ocular reflex and gaze functions in a patient 31. Gresty MA, Halmagyi GM. Head nodding
with congenital inner ear anomalies. Arch associated with idiopathic childhood
Otorhinolaryngol 1988;245(4):255–258. nystagmus. In: Cohen B, ed. Vestibular and
14. Hoyt CS. Nystagmus compensation Oculomotor Physiology: International Meeting
(blockage) syndrome [letter]. Am J Ophthalmol of the Bárány Society. New York: New York
1977;83(3):432–434. Academy of Sciences; 1981:614–618.

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32. Gresty MA, Ell JJ. Spasmus nutans or 48. Albright AL, Sclabassi RJ, Slamovits TL,
congenital nystagmus? Classification Bergman I. Spasmus nutans associated with optic
according to objective criteria. Br J Ophthalmol gliomas in infants. J Pediatr 1984;105:778–780.
1981;65:510–511. 49. Garty BZ, Weitz R, Mimouni M, Bauman
33. Gresty MA, Page NG, Barratt HJ. The B. Spasmus nutans as a presenting sign
differential diagnosis of congenital nystagmus. of diencephalic syndrome. J Pediatr
J Neurol Neurosurg Psychiat 1984;47:936–942. 1985;107(3):484.
34. Antony JH, Ouvrier RA , Wise G. Spasmus 50. Baram TZ, Tang R. Atypical spasmus nutans
nutans. A mistaken identity. Arch Neurol as an initial sign of thalamic neoplasm. Pediatr
1980;37:373–375. Neurol 1986;2(6):375–376.
35. Sedwick LA, Burde RM, Hodges FJ. Leigh’s 51. Mehdorn E. Spasmus nutans: Leitsymptom
subacute necrotizing encephalomyelopathy bei Hirnerkrankungen im Kleinkindalter.
manifesting as spasmus nutans. Arch [Spasmus nutans: a leading symptom in
Ophthalmol 1984;102:1046–1048. brain diseases in early childhood]. Fortschr
36. Lavery MA, O’Neill JF, Chu FC, Martyn Ophthalmol 1986;83(4):499–502.
LJ. Acquired nystagmus in early childhood: 52. Gott lob I, Zubkov A, Catalano RA , et al.
a presenting sign of intracranial tumor. Signs distinguishing spasmus nutans (with
Ophthalmology 1984;91:425–435. and without central nervous system lesions)
37. Allarakhia IN. Opsoclonus-myoclonus from infantile nystagmus. Ophthalmology
presenting with features of spasmus nutans. 1990;97:1166–1175.
J Child Neurol 1995;10:67–68. 53. Kalyanaraman K, Jagannathan K,
38. Kim JI, Dell’Osso LF, Traboulsi E. Latent/ Ramanujam RA , Ramamurthi B. Congenital
manifest latent and “uniocular” acquired head nodding and nystagmus with
pendular nystagmus: from a diagnostic cerebrocerebellar degeneration. J Pediatr
quagmire to uniocular motor control. 1973;83:1023–1026.
J Neuro-Ophthalmol 2003;22:198–203. 54. Newman SA, Hedges TR, Wall M, Sedwick
39. Weissman BM, Dell’Osso LF, Abel LA, LA. Spasmus nutans—or is it? Surv Ophthalmol
Leigh RJ. Spasmus nutans: a quantitative, 1990;34(6):453–456.
prospective study. In: Keller EL, Zee DS, eds. 55. Good WV, Koch TS, Jan JE. Monocular
Adaptive Processes in Visual and Oculomotor nystagmus caused by unilateral anterior
Systems. Oxford, England: Pergamon Press; visual-pathway disease. Dev Med Child Neurol
1986:479–483. 1993;35(12):1106–1110.
40. Weissman BM, Dell’Osso LF, Abel LA, Leigh 56. Lambert SR, Newman NJ. Retinal disease
RJ. Spasmus nutans: a quantitative prospective masquerading as spasmus nutans. Neurology
study. Arch Ophthalmol 1987;105:525–528. 1993;43:1607–1609.
41. Thomson J. Note on the peculiar nystagmus 57. Gottlob I, Wizov SS, Reinecke RD. Head and eye
of spasmus nutans in infants. Br Med J movements in children with low vision. Graefes
1901;1(2100):763. Arch Clin Exp Ophthalmol 1996;234(6):369–377.
42. Smith EB. Spasmus nutans. Proc R Soc Med 58. Hoyt CS, Aicardi E. Acquired monocular
1911;4(Sect Study Dis Child):75. nystagmus in monozygous twins. J Pediatr
43. A DB. On head nodding (spasmus nutans) in Ophthalmol Strab 1979;16:115–118.
infants. Can Med Assoc J 1931;25(6):716. 59. Katzman B, Lu LW, Tiwari RP. Spasmus
44. Kesson CW. Spasmus nutans. Proc R Soc Med nutans in identical twins. Ann Ophthalmol
1949;42(7):562. 1981;13:1193–1195.
45. Wizov SS, Reinecke RD, Bocarnea M, 60. Gott lob I, Zubcov AA, Wizov SS, Reinecke
Gott lob I. A comparative demographicand RD. Head nodding is compensatory in spasmus
socioeconomic study of spasmus nutans nutans. Ophthalmology 1992;99:1024–1031.
and infantile nystagmus. Am J Ophthalmol 61. Gott lob I, Wizov SS, Reinecke RD.
2002;133(2):256–262. Quantitative eye and head movement
46. Wiedemann HR, Gerken H. Spasmus recordings of retinal disease mimicking
nutans seu rotatorius. Dev Med Child Neurol spasmus nutans. Am J Ophthalmol
1964;6:623–624. 1995;119(3):374–376.
47. Koenig SB, Naidid TP, Zaparackas Z. Optic 62. Gresty MA, Halmagyi GM. Abnormal head
glioma masquarading as spasmus nutans. J movements. J Neurol Neurosurg Psychiatry
Pediatr Ophthalmol Strab 1982;19:20–24. 1979;42(8):705–714.

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5
differential diagnosis of
nystagmus in infancy and
childhood
5.1 NYSTAGMUS WITHOUT 5.2.2 Gaze-Holding Deficiency
ASSOCIATED NEUROLOGICAL Nystagmus 156
DISEASE—“BENIGN” 136 5.2.2.1 Eccentric Gaze, Gaze-Evoked,
5.1.1 Infantile Nystagmus Syndrome 136 Rebound 156
5.1.1.1 Association with Strabismus 140 5.2.2.2 Gaze Instability (“Runaway”) 157
5.1.1.2 Clinical Signs and Symptoms 141 5.2.3 “Vision-Loss” Nystagmus 158
5.1.1.3 Differential Diagnosis 142 5.2.3.1 Prechiasmal, Optic Chiasm, and
5.1.1.4 Alternate-Cover and Gaze-Angle- Postchiasmal Vision Loss 158
Cover Tests 142 5.2.4 Other Pendular Nystagmus Associated
5.1.2 Fusion Maldevelopment Nystagmus with Diseases of Central Myelin 158
Syndrome 145 5.2.4.1 Oculopalatal Tremor or
5.1.2.1 Association with Strabismus 145 “Myoclonus” 159
5.1.2.2 Clinical Signs and Symptoms 145 5.2.4.2 Pendular Vergence Nystagmus
5.1.2.3 Differential Diagnosis 146 Associated with Whipple Disease 160
5.1.2.4 Alternate-Cover and Gaze-Angle- 5.2.5 Convergence/Convergence-Evoked
Cover Tests 147 Nystagmus 160
5.1.3 Nystagmus Blockage Syndrome 147 5.2.6 Upbeat Nystagmus 161
5.1.3.1 Association with Strabismus 147 5.2.7 Downbeat Nystagmus 161
5.1.3.2 Clinical Signs and Symptoms 147 5.2.8 Torsional Nystagmus 162
5.1.3.3 Differential Diagnosis 148 5.2.9 “Seesaw” Nystagmus 162
5.1.4 Spasmus Nutans Syndrome 148 5.2.10 Lid Nystagmus 163
5.1.4.1 Association with Strabismus 148 5.3 SACCADIC INTRUSIONS/
5.1.4.2 Clinical Signs and Symptoms 148 OSCILLATIONS 164
5.1.4.3 Differential Diagnosis 149 5.3.1 Square-Wave Jerks and
5.1.5 Nystagmus and Strabismus 150 Oscillations 165
5.2 NYSTAGMUS WITH 5.3.2 Square-Wave Pulses 167
ASSOCIATED NEUROLOGICAL 5.3.3 Staircase Saccadic Intrusions 167
DISEASE—“SYMPTOMATIC” 150 5.3.4 Macrosaccadic Oscillations 169
5.2.1 Vestibular Nystagmus 150 5.3.5 Saccadic Pulses (Single and
5.2.1.1 Peripheral Vestibular Double) 169
Imbalance 150 5.3.6 Convergence Retraction
5.2.1.2 Central Vestibular Imbalance 153 “Nystagmus” 171
5.2.1.3 Central Vestibular Instability 5.3.7 Dissociated Ocular Oscillations 172
(Periodic Alternating) 155 5.3.8 Dysmetric Saccades 172

• 135

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5.3.9 Ocular Flutter 172 5.3.13 Ocular Bobbing 174

5.3.10 Flutter Dysmetria 173 5.3.13.1 Typical 174
5.3.11 Opsoclonus 173 5.3.13.2 Monocular 175
5.3.11.1 Opsoclonus-Myoclonus 173 5.3.13.3 Atypical 175
5.3.12 Superior Oblique Myokymia 173 5.3.14 Psychogenic (Voluntary) Flutter 175

In the fields of observation, chance favors only the mind that is prepared.
—Louis Pasteur (1854, 1822–1895)

THE DI AGNOSTIC material in this chapter and infantile nystagmus associated with low
results from the past half-century of eye-move- vision (3.4–4.2 per 10,000). Within ethnic
ment-based research (summarized in Chapters groups, nystagmus was significantly more com-
2–4) into the different types of nystagmus found mon in the White European population than in
in infancy; that research forms the foundation the Asian population (Indian, Pakistani, other
for the various “clinical pearls” that have also Asian backgrounds). Other estimations of the
emerged from studying ocular motor data from incidence of INS vary enormously from 1 in 350
patients exhibiting nystagmus. Also, Appendix to 1 in 20,000, although the generally quoted
D contains flowcharts and work sheets useful in estimated incidence to be 1 in 6,550 or .015%.10
differential diagnosis and therapeutic interven- These movements most commonly have a slow
tion. All forms of nystagmus are due to deficits and fast phase, although they may be pendular,
in one or more slow-eye-movement subsystems, with or without braking and foveating saccades.
whereas saccadic intrusions and oscillations They are usually horizontal with a small tor-
are due to deficits in fast-eye-movement sub- sional component and may (rarely) have a ver-
systems.1 There is a large literature on the many tical component. The intensity of INS increases
types of nystagmus listed in Table 5.1 that have on lateral gaze and becomes right beating in
been reviewed elsewhere.2–7 right gaze and left beating in left gaze. The fact
that INS “disobeys” Alexander’s law under bin-
ocular conditions (which states that, in periph-
5.1 NYSTAGMUS WITHOUT eral vestibular nystagmus, the direction of the
ASSOCIATED NEUROLOGICAL nystagmus increases in the direction of the fast
DISEASE—“BENIGN” phase and decreases but never reverses in the
direction of the slow phase) is often useful in
5.1.1 Infantile Nystagmus Syndrome distinguishing it from horizontal peripheral ves-
Familiarity with the clinical features of infan- tibular nystagmus.11–14 Other clinical character-
tile nystagmus syndrome (INS; also known as istics of INS, with variable association, include
congenital nystagmus [CN])8 is essential. INS the following: remains horizontal in upgaze (in
is an ocular motor disorder with the hypoth- contrast to acquired and/or vestibular nystag-
esized etiology of undamped smooth pursuit. mus, which changes direction in vertical gaze);
It presents at birth or early infancy and is clin- increases intensity with fi xation attempt or
ically characterized by involuntary oscillations stress and decreases with sleep or inattention;
of the eyes. The Leicerstershire nystagmus sur- variable intensity in different positions of gaze
vey estimated the prevalence of nystagmus in (usually about a null position); changes direc-
the general population to be 24.0 per 10,000.9 tion in different positions of gaze (about a neu-
The most common forms of nystagmus are neu- tral position); decreased intensity (damping)
rologic nystagmus (6.8 per 10,000 population) with convergence; anomalous head posturing;

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Table 5.1 Forty-Nine Types of Nystagmus

Acquired Gaze-evoked Pursuit-defect1
“Fixation” Deviational Pursuit-system
Anticipatory Gaze-paretic Infantile
Induced “Neurasthenic” Pseudospontaneous
Arthrokinetic “Seducible” Induced
Induced “Sett ing-in” Rebound
Somatosensory Horizontal Reflex
Associated Induced Baer’s
Induced Provoked Seesaw
Stransky’s Infantile Somatosensory
Audiokinetic Congenital Induced
Induced “Fixation” Spontaneous
Bartels’ Hereditary Stepping around
Induced Pursuit-system Apparent/real
Bruns’ Intermittent vertical Induced
Centripetal Jerk Somatosensory
Cervical Lateral medullary Torsional
Neck torsion Lid Rotary
Vertebral-basilar artery insufficiency Miner’s1 Uniocular
Circular/elliptic/oblique Occupational Upbeat
Alternating windmill Muscle-paretic Vertical
Circumduction Myasthenic Vestibular
Diagonal Nucleus of the optic tract A(po)geotropic/geotropic
Elliptic Optokinetic Alternating current
Gyratory Induced Bechterew’s
Oblique “Kinetic” Caloric/caloric-after
Radiary “Optic” Compensatory
Convergence Optomotor Electrical/faradic/
galvanic
Convergence-evoked Panoramic Head shaking
Dissociated “Railway” Induced
Disjunctive Sigma L-
Downbeat “Train” Labyrinthine
Drug-induced Optokinetic after- Perverted
Barbiturate Induced Pneumatic/compression
Bow tie Postoptokinetic Positional/alcohol
Induced Reverse postoptokinetic Positioning
Epileptic Pendular Pseudocaloric
Ictal Talantropia Rotational/perrotary
Fusion maldevelopment Periodic/aperiodic alternating Secondary phase
Latent/manifest latent Alternans
Monocular “fi xation” Physiologic
Unimacular End-point
Flash-induced Fatigue
Flicker-induced Pursuit after-
Induced Induced
Synonyms and other terms are indented under either the preferred (CEMS) or the more inclusive designation; some nystagmus types
may be acquired or congenital; quoted terms are erroneous or nonspecific.
1
May not exist.

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strabismus; and the increased incidence of sig- visual function under these conditions. In most
nificant refractive errors. Th is history is use- individuals with INS, the head position corre-
ful in further distinguishing the nystagmus sponds roughly with the minimal intensity zone
from peripheral vestibular nystagmus, which of the nystagmus. A clinical algorithm to aid in
becomes worse with occlusion and is damped the determination of the etiology of anomalous
by fi xation.11 To confi rm this observation, the head turns in the presence of strabismus and
examiner can observe one optic disc with the nystagmus is shown in Figure 5.1.
direct ophthalmoscope while periodically When the angle of the null zone exceeds 15°,
occluding the other eye. Increased nystagmus however, the angle of the head turn may fall short
intensity with occlusion suggests a peripheral of the null zone. In some children, the anoma-
vestibular nystagmus, whereas no change, a lous head position appears to be dictated by the
direction reversal, or a decrease in nystagmus velocity distribution of the slow phase (i.e., the
intensity suggests INS or fusion maldevelop- percentage of time that the slow phase is less than
ment nystagmus syndrome (FMNS). Anxiety or or equal to 10° per second) and the nystagmus
fatigue will also increase the INS intensity and beat direction (which can be influenced both by
thereby degrade visual acuity. When evaluating the prior position of gaze and by the length of
an infant or child with INS for the fi rst time, time a subject has maintained a fi xed gaze pos-
historical points suggest afferent visual pathway ition). Bagolini et al. suggested that some indi-
dysfunction. If the child’s eyes are light sensi- viduals with INS utilize large head turns to place
tive, this suggests the presence of a congenital their eyes in extreme side gaze and actively block
retinal dystrophy, degeneration, or albinism. If their nystagmus.18 Unlike positioning the eyes in
the child sees better in daytime or at night, this a null zone, in which foveation is optimum, the
suggests congenital stationary night blindness mechanism of such blockage is unknown. Head
or a rod-cone dystrophy.15 oscillations are common in INS, but they are not
The presence or absence of an underlying used as the strategy to improve vision, except in
visual sensory deficit does not affect the time of those rare patients with abnormal gain of their
onset of INS. Often the infant is fi rst evaluated vestibulo-ocular reflex.19
in the fi rst to third months of life when irregu- The INS waveform shown in Figure 5.2 (JR EF)
lar eye movements are noted. When INS fi rst is typical of many with periods of extended fove-
appears, it is often arrhythmic and intermittent, ation. When foveation periods are 100 msec or
consisting of a series of irregular horizontal and greater, normal visual acuity is possible. Some
oblique deviations of the eyes from side to side. studies of INS in infants and children suggest
At this stage, the erratic eye movements may an age-dependent evolution of waveforms dur-
simulate opsoclonus. ing infancy from pendular types to jerk types
INS often occurs in association with congeni- in some patients.20,21 Th is is consistent with the
tal or early onset (fi rst 6 months of life) acquired theory that jerk waveforms reflect modification
defects in the visual sensory system (e.g., sys- of the INS oscillation by growth and develop-
temic and ocular albinism, achromatopsia, ment of the visual sensory system. However,
aniridia, congenital retinal dystrophies and we documented jerk waveforms in other infants
degenerations, visual cortex anomalies, and with and without sensory deficits, suggesting
congenital cataracts, glaucoma and corneal dis- that early development of the ocular motor sys-
eases). Children with this condition frequently tem may be responsible.
present with a head turn, which is used to main- In Figure 5.3, the interactions and effects
tain the eyes in the position of gaze of the null between the developing afferent and efferent
point (point of minimum nystagmus).11,16,17 Th is systems are depicted during several stages from
is particularly prominent when the child is con- conception to infancy. Th is “crosstalk” is essen-
centrating on a distant object, since this form of tial to the normal development of both good
nystagmus tends to worsen with attempted fi x- vision and a stable ocular motor system. Any def-
ation. The head turn is an attempt to improve icits in either during this developmental period

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FIGURE 5.1 A clinical algorithm to aid in diagnosing the etiology of an anomalous head posture in the presence
of strabismus and nystagmus. The first step is to reposition the patient’s head to the neutral position and observe
the consequences on the strabismus or the nystagmus (Step 1) and whether the change improves or worsens the
condition (Step 2). The major clinical differentiation occurs at this step. If the nystagmus is worse, then differenti-
ating between a “gaze” null due to infantile nystagmus syndrome (INS) and an “adduction” null due to fusion mal-
development nystagmus syndrome (FMNS) can be made by looking at the fi xing eye’s (Step 3) and the opposite
nonfi xing eye’s (Step 4) effect on the oscillation in aBDuction and aDDuction.

FIGURE 5.2 Eye-movement recording showing position and velocity of right eye of a patient with INS showing
a typical jerk right with extended foveation (JRef) waveform. These 100-msec periods of high-quality foveation
occur just after the fast phase of the nystagmus; time (in seconds) is shown at the bottom.The numbers outlined in
red show details of foveation encompassed in the black rectangular area. L, left; R, right; RE, right eye.

Nystagmus in Infancy and Childhood • 139

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FIGURE 5.3 A model for development of infantile nystagmus syndrome (INS). Motor-system calibration is an
active process that may start in utero and continue at least through early infancy. Sensory-system development is
a parallel visual process that continues to develop through the first decade of life. Previous studies documented
connections between parallel visual processes (cross-talk) that modify, instruct, and coordinate these systems,
resulting in smooth and coordinated function. INS may result from a primary defect (familial, genetic) of
ocularmotor calibration. INS may also result from abnormal cross-talk from a defective sensory system to the
developing motor system at any time during the motor system’s development. Th is can occur from conception
as a result of a primary defect (retinal dystrophy), during embryogenesis as a result of an intrauterine abnormal-
ity (optic nerve hypoplasia), or after birth during infancy (congenital cataracts). Th is hypothetical genesis of
INS incorporates a pathophysiologic role for the sensory system. Although the physiologic circumstances may
differ, the final common pathway is abnormal calibration of the ocular motor system. The primary ocular motor
instability that underlies INS remains the same, but its clinical and oculographic expression are modified by
both initial and final developmental integrity of all parallel afferent visual system processes. As the bidirectional
arrows suggest, abnormal motor development also affects sensory development.

will negatively affect both the system with the over more than a 45-year span) showed no over-
deficit and the other system. Thus, motor defi- all changes in the important waveform charac-
cits may interfere with visual development and teristics governing visual function.
visual deficits may interfere with motor develop-
ment, as is explained in the figure caption.
5.1.1.1 A SS O C I AT I O N W I T H
Although INS is a lifelong condition, it may
S T R A B I S M US
remain variable over time. Th is includes min-
ute-to-minute variability and long-term changes Estimates of the prevalence of strabismus in INS
associated with age and other ocular and sys- range from 16% to 50%.22–27 Strabismus is essen-
temic conditions. There are no good long-term, tial for FMNS but incidental to INS. Although
multisubject studies (greater than 10 years) that FMNS is intrinsically more likely to be associ-
characterize the aging process and its effects on ated with strabismus than is INS, the greater
INS, but we do know that changes can occur in frequency of INS means that any given patient
the INS oscillation as a result of aging, medica- with strabismus will still be more likely to have
tions, and degenerative and neurological ill- INS (53%) than FMNS (35%).23 The presence
nesses. Th is concept of INS as a dynamic disease and nature of an underlying sensory visual dis-
process may be useful when evaluating and car- order seems to influence the likelihood of asso-
ing for patients with this condition over their ciated strabismus. In a study of 82 children with
lifetime. However, eye-movement data taken INS (diagnosed clinically), Brodsky and Fray
over decades in some subjects with INS (one, found the prevalence of strabismus to be 82%

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in children with optic nerve hypoplasia, 53% a function of the angle of gaze and also a func-
in children with albinism, 36% in children with tion of the velocity of the eyes.29–32 Thus, the null
congenital retinal dystrophies, and 17% in child- angle during fi xation (static null) does not usu-
ren with idiopathic INS.28 ally equal the null angle during pursuit, optoki-
netic nystagmus, or head movement, where the
vestibulo-ocular reflex is stimulated (dynamic
5.1.1. 2 CL I N I C A L S I G N S A N D
null). Usually, the null is shifted in the direction
SYMPTOMS
opposite to the eye movement. During pursuit
Patients with INS typically have several different to the left , the dynamic null moves to the right
waveforms; one study found multiple waveforms of the static null; and during pursuit to the right,
in 87% of patients.23 In addition to the quantifi- the dynamic null moves to the left . In the IN
able and defi nitively diagnostic characteristics population, 48% have both convergence and
of IN available through eye-movement record- gaze angle nulls, 29% only convergence nulls, 9%
ings, there are clinical signs one can observe only gaze angle nulls, and there are 14% with no
in the office. In INS, one should look for a null nulls. Accurate measurement of the null position
angle; an indication of which is the presence of requires a well-calibrated, DC-coupled record-
a head turn. A teenager or an adult may not show ing system. That measurement can then be used
a head turn because of societal pressures. They to prescribe prisms or determine the amount of
have learned to keep their heads straight at the surgery to be performed (see Chapter 7).
expense of vision because it is not “appropriate” In cases with nystagmus plus strabismus,
to walk around with their head turned, but a it is sometimes possible to differentiate INS
child will more likely exhibit a head turn. A pos- from FMNS. For example, if the preferred gaze
itive family history and negative neurological angle places the fi xating eye in abduction, the
examination also suggest INS. One study found nystagmus is most probably IN because, if it
that 48% of patients exhibited both convergence were FMN, the fi xating eye would most prob-
and gaze-angle nulls (28% had only convergence ably be in adduction due to Alexander’s law. If
nulls and 9% only gaze-angle nulls) and 14% had the fi xating eye is in adduction, either IN or
no nulls.23 FMN is possible.
If converging the eyes damps the IN, the
patient will hold reading material close. The Clinical Pearl: When the preferred fi xat-
patient may have a latent component; that can ing eye is kept in abduction, the nystagmus
be checked by the alternate-cover test. If the is most probably IN, not FMN. Caveat:
nystagmus direction reverses with monocular It might still be FMN if the patient has
cover, one still does not know whether it is FMN exotropia or an angle kappa.
or IN with a latent component (they are different
types of nystagmus). They may also have head Children with IN and a static eccentric gaze
nodding that is not compensatory. null position automatically adopt a head turn
Many patients with IN exhibit an eccentric to see better. They do not have to wait to be
null angle of gaze, where the IN magnitude told about the null angle; they know where it is
damps (“null”). A true null position is that pos- because all visual functions improve when they
ition of gaze (eye in orbit) where changing gaze turn their head, placing their eyes at the static
to either side of this minimal nystagmus inten- null angle. One may think of the null as a region
sity position increases the oscillation intensity. of ocular motor equilibrium. The brainstem
That is in contrast to FMN, where monotonic (left and right) generates forces pulling the eyes
variation with gaze angle (Alexander’s law) both ways, and there is a position of equilibrium
causes patients to keep their eyes deviated to of forces, not necessarily in primary position,
one side where the nystagmus is low. FMN does where the nystagmus is minimal. When viewing
not have a true null because there is no increase targets at the null angle, many visual functions
on both sides. In IN, the position of the null is (including acuity) should increase; when there

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is a severe afferent defect, or an INS waveform the timing and amplitudes of the intracycle
with well-developed foveation (i.e., high NAFX) jerk IN, including those that are periodic,
across a large range of gaze angles (high LFD; but all have combinations of IN waveforms,
see Chapter 2, Section 2.3.1.1), acuity may not whereas acquired PAN has a sawtooth jerk
increase measurably. waveform. When the specific intra- and inter-
Sometimes a patient will tilt the head, and cycle characteristics are known, the more
sometimes the patient will turn it (vertically specific nomenclature in Table 5.2 may be
or horizontally) and tilt it. Perhaps the oblique used. Note that the total intercycle periods
muscles are involved; this has not really been (T in Table 5.2) for APAN are usually much
studied well. It represents innervation of mus- longer than for acquired PAN.
cles other than the horizontal muscles that are
somehow helping to reach equilibrium in pre-
5.1.1.3 D I F F E R E N T I A L D I A G N OS IS
dominantly horizontal oscillations; most IN
is primarily horizontal with litt le or no vertical The localizing significance of nystagmus is
components. Again, acuity increases with verti- often a mere indication of dysfunction some-
cal or torsional head positions, especially if there where in the posterior fossa (i.e., vestibular end
are no afferent defects. organ, brain stem, or cerebellum). However,
The mechanism causing an IN reversal when certain nystagmus patterns are quite specific
covering an eye is similar to when the person and permit reasonably accurate neuroanatomic
pursues; the null moves and can cause a direc- diagnosis. When possible, the specific and
tion reversal of the IN if gaze went from one nonspecific forms are separated on the basis
side of the null to the other. 33 Although IN with of clinical appearance and associated signs
a latent component looks clinically like FMN, it and symptoms. Some of the characteristics of
is not (because the waveform remains IN); only IN and their comparison to FMN are listed in
the IN direction changes because the null has Table 5.3. Specifically, the ocular motor sites of
moved with occlusion. the deficits affect both waveforms and the shape
IN with a latent component can behave of the NAFX peak (or “null” depth).
as though there were two null angles since, if Individuals with both INS and FMNS
the fi xating eye changes with gaze angle, the are difficult to diagnose correctly; it is not
induced null shift will appear to be a second usual, but some patients (~5%) have a com-
null. In binocular individuals with IN, there bination of INS and FMNS. 23 One or the
is only one null and in those with strabismus, other might be dominant and result in com-
there is also only one null, although it shift s to plex waveforms and variations of nystagmus
a different gaze angle when fi xation shift s to type with gaze angle. The best approach to
the other eye. A good recording system, prop- diagnosing these patients is to first learn to
erly calibrated for fi xation with each eye, will accurately diagnose the more straightfor-
detect shift s in the fi xating eye (and the tropias ward types. As Table 5.3 indicates, this com-
of the nonfi xating eye) and prevent misread- bination results in many possible waveforms,
ing the records as showing two nulls. Also, IN NAFX peak variations, and also includes IN
and periodic (PAN) or asymmetric, (a)periodic with a “latent component” or the nystagmus
(APAN) alternating nystagmus will mimic two blockage syndrome.
nulls because of the null shift accompanying the
direction reversal. Steady fi xation in primary
5.1.1. 4 A LT E R N AT E- COV E R A N D G A ZE-
position for several minutes will disclose either
A N G L E- COV E R T E S T S
form of alternation.
Table 5.2 summarizes the different types It may be difficult to distinguish FMN from
of APAN seen in INS patients and compares IN when strabismus and a “latent” compo-
them to acquired PAN. The term APAN nent are present (fast phase movement toward
encompasses all idiosyncratic variations in uncovered eye and/or increased intensity of

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Table 5.2 Time-Varying Types of Jerk Nystagmus

I N T R AC YC L E DI R E C T ION
I N T E R C YC L E SPECI F IC T Y PE OR
T Y PE DU R A T ION A M P L I T U DE P E R IOD (T) 1 C H A R AC T E R I S T IC S
APAN = = = IN: PAN
≠ = = Asymmetric duration PAN
= ≠ = Asymmetric intensity PAN
≠ ≠ = Asymmetric duration and
intensity PAN
= = ≠ Symmetric AAN
≠ = ≠ Asymmetric duration AAN
= ≠ ≠ Asymmetric intensity AAN
≠ ≠ ≠ Asymmetric duration and
intensity AAN
Acquired = = = Symmetric duration and
PAN intensity PAN
Saw-tooth waveform
Duration indicates the time period of oscillation in a given direction. Intensity indicates the amplitude × frequency of oscillation in a
given direction.
1
T of APAN is usually >> T of acquired PAN.
T is the sum of left-beating, right-beating, and two neutral interval durations.
AAN, aperiodic alternating nystagmus; APAN, asymmetric (a)periodic alternating nystagmus; IN, infantile nystagmus (with any
combination of IN waveforms); PAN, periodic alternating nystagmus.

Table 5.3 Comparative Characteristics of Infantile and Fusion Maldevelopment

Nystagmus

OCU L A R MOTOR NA F X PE A K OR
S U B S Y S T E M DE F IC I T I N T E N S I T Y “ N U L L”
POSSI BLE
T Y PE PU R SU IT VV WAV E F O R M S G A Z E A NGL E SH A PE
IN Yes No IN: P-SW Idiosyncratic or Broad or none1
none1
No Yes IN: VVSW None1, with low Not applicable
NAFX (<<1)
Yes <<< Pursuit IN: P-SW Idiosyncratic Broad
Yes < Pursuit IN: P-SW Idiosyncratic Variable
Yes = Pursuit IN: P-SW + VVSW Idiosyncratic Sharp or medium
FMN No Yes J L , SPT Far add of FE Linear1
IN + FMN2 Yes Yes All of the above Idiosyncratic Idiosyncratic
FE, fi xating eye; IN, infantile nystagmus; J L , jerk with linear slow phase; NAFX, eXpanded nystagmus acuity function; P-SW,
pursuit-system waveforms (see Chapter 2, Fig. 2.1); SPT, saccadic pulse train; VV, visual vestibular; VVSW, visual vestibular system
waveforms (see Chapter 2, Fig. 2.2).
1
No mathematical peak/null but may vary with gaze angle.
2
Includes IN with a latent component and the nystagmus blockage syndrome.

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nystagmus with monocular cover) since the two alternate cover, it is IN rather than FMN.
patients will appear clinically identical. The only However, if nystagmus direction reverses with
defi nitive way to distinguish between IN with alternate cover (with the direction of the nys-
a “latent component” and FMN is with the use tagmus toward the fi xating eye), then it could
of eye-movement recordings. 34,35 The differ- be either IN with a latent component or FMN.
ences between IN with a “latent component” Reversal of nystagmus direction does not mean
and FMN can be seen in Figure 5.4. FMNS that it is FMN, although this test is oft en mis-
patients have slow phases that are predomi- interpreted that way. One might be tempted
nantly decreasing velocity and linear. Patients to presume that if there is no strabismus and
with frank esotropia may demonstrate FMN. a reversal occurs, then the diagnosis should be
Since these patients usually suppress one eye at INS since FMNS requires strabismus to be pre-
a time, the nystagmus is present even without sent (see Section 5.1.2). However, this is a clin-
covering an eye. The direction of the nystagmus ical test and even an undetectable microtropia
depends on which eye is fi xating. Manifest FMN is sufficient for FMNS.
can clinically appear to be converted to “pure,” The second test, “the gaze-angle-cover” test, is
latent FMN if the strabismus treatment results useful in this latter case where a reversal occurred
in orthophoria. Two tests are useful in attempt- in primary position. While maintaining cover,
ing to differentiate INS from FMNS. move the fi xation target into the adduction field
The fi rst is the “alternate-cover” test, where of the fi xating eye (e.g., move it into the patient’s
each eye is alternately occluded while the left field when the right eye is fi xating). If the
patient is looking straight ahead. If the patient right-beating nystagmus now reverses to a left-
has jerk nystagmus that is stationary with time beating nystagmus in left gaze, the nystagmus is
(i.e., does not change direction while main- IN with a latent component; if not, it still could be
taining fi xation on a primary-position tar- either FMN or IN with a large latent component
get) and the direction does not reverse with (i.e., the neutral-zone shift with occlusion was so

FIGURE 5.4 The differentiation between infantile nystagmus syndrome (INS) with a “latent component”
and fusion maldevelopment nystagmus syndrome (FMNS). Both conditions are clinically identical, that is,
horizontal nystagmus with both eyes open that changes in direction and/or intensity under monocular con-
ditions. The top trace shows jerk-left INS under left-eye monocular fi xation. Th is is different from the bottom
two traces, which show jerk right with linear/decreasing velocity slow phases under right-eye monocular
fi xation and jerk left with linear/decreasing velocity slow phases with left-eye monocular fi xation typical of
FMNS. Deg, degrees; LE, left eye; RE, right eye.

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great as to preclude transversing it in far left gaze individuals with FMNS have strabismus, but not
and obtaining a nystagmus reversal back to left- all with strabismus have FMNS). Summarizing,
beating nystagmus). INS can occur with or without strabismus; all
FMNS patients have strabismus.
5.1.2 Fusion Maldevelopment
Nystagmus Syndrome 5.1. 2.2 CL I N I C A L S I G N S A N D
SYMPTOMS
Fusion maldevelopment nystagmus syn-
drome (FMNS, also known as latent/mani- As stated earlier, the pure, latent form of FMNS
fest latent nystagmus, LMLN)8 is a benign, (pure LN) is extremely rare. That is, when you
binocular horizontal oscillation of infantile record pure FMN, you must fi nd no nystagmus
onset; there is always associated strabismus, with eyes open at all gaze angles. There have
and ocular motor recordings show four types been only a couple of cases proven by recordings
of slow phases with jerk in direction of fi x- to have this pure form. Many patients thought
ing eye.12,35–39 The oscillations appear conju- clinically to have latent FMN really have mani-
gate, horizontal, and uniplanar, and there are fest FMN. When one records them or examines
usually no associated sensory system deficits them with an ophthalmoscope, the FMN is vis-
(e.g., albinism, achromatopsia). Th is form of ible. More common is latent FMN in primary
nystagmus in infancy is generally associated position with manifest FMN in lateral gaze; most
with the best binocular acuity potential of all common is manifest FMN at all gaze angles.
the forms of childhood oscillations. The oscil- The intensity of FMN is greatest with
lations may change with exaggerated conver- gaze toward the direction of the fast phase
gence, resulting in a head posture associated (Alexander’s law). Jerk-right nystagmus is greater
with fi xing eye in adduction. There is no head in right than in left gaze and vice versa. These are
shaking, the eyes may exhibit “reversal” with not true nulls; one cannot show increased nys-
OKN stimulus, and there is no aperiodicity tagmus because the patient is at the end of the
to the oscillation.12,35–39 Constant horizontal excursion of the eye. Instead, this is an example
and dissociated strabismus is often present. of a monotonic relationship of gaze and ampli-
The intensity decreases with increased fusion tude. It would not be uncommon for a person
(binocular function) and movement of the fi x- who fi xates with one eye and has FMNS, to keep
ing eye into adduction (toward the nystagmus that eye in adduction where Alexander’s law will
slow phase) and with increasing age. reduce the nystagmus. In INS there is a null and
increased amplitude (with increasing-velocity
exponentials) as gaze is directed away from the
5.1. 2.1 A SS O CI AT I O N W I T H
null in both directions, whereas in FMNS (right
S T R A B IS M US
eye or left eye fi xating), there is an Alexander’s
FMNS implies strabismus, but the converse law relationship and decreasing-velocity expo-
is not true; strabismus does not imply FMNS nentials. Patients with FMNS usually place their
(50% have no nystagmus at all), but if an indi- fi xating eye in adduction to minimize the nys-
vidual has FMNS, he or she also has strabismus tagmus and thereby maximize acuity. As in INS,
(i.e., strabismus is a necessary, but not sufficient, the head turn minimizes the nystagmus and
condition for FMNS). Even if it is not evident maximizes acuity. A patient might place his or
clinically (it may be a microstrabismus that her eye in other than the minimum position of
can be recorded), it is there. Distinguishing the nystagmus if he or she had an “angle kappa” that
FMNS waveform and the tropia of the nonfi xat- required eccentric fi xation. Better acuity results,
ing eye requires DC-coupled, high-bandwidth although the nystagmus might be a litt le higher
recordings of both eyes simultaneously. In log- where the patient places his or her gaze.
ical terminology, strabismus is a necessary (but We have never recorded the FMNS wave-
not sufficient) condition for FMNS (i.e., all form in patients with orthophoria; they all had

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latent strabismus (when you cover one eye, the pure FMNS waveform (i.e., decreasing-
the other does not remain straight). Similarly, velocity slow phases); therefore, INS is pre-
FMNS has never been recorded in patients with dominant. The other group has mostly FMNS
binocular alignment; all had manifest strabis- (FMNS/INS) and their waveforms are FMNS
mus. Both eyes are open, but one eye must be and dual-jerk FMN. There are some who have
deviated (in or out) to have FMNS. If they can INS and FMNS equally. At various times they
straighten their eyes, the FMN disappears; in exhibit the INS waveform, FMNS waveform,
the blockage syndrome, they have INS when or the dual-jerk waveform. A linear slow phase
their eyes are aligned. is not diagnostic of either INS or FMNS. When
a pendular waveform is superimposed on a jerk
waveform and the slow phase is accelerating, it
5.1. 2.3 D I F F E R E N T I A L D I A G N OS I S
is a dual-jerk IN; if the slow phase is deceler-
Waveform is also the diagnostic criterion for ating, it is a dual-jerk FMN. One has to care-
FMNS (see Chapter 3, Fig. 3.1 and Table 5.3); fully determine what is happening to the axis
recordings show a decreasing-velocity expo- of the pendular slow phase (i.e., whether it is
nential slow phase. All patients (100%) with decelerating or accelerating) to properly cate-
FMNS have strabismus. Included in the defi ni- gorize the nystagmus. Th is small but difficult
tion of strabismus is latent strabismus (i.e., the group of patients must be recorded for accurate
phoria resulting when you cover an eye). Thus, diagnosis. Distinguishing the INS and FMNS
FMNS includes a pure latent form, where the waveforms from the combination waveforms
eyes are straight with no nystagmus when both requires DC-coupled, high-bandwidth record-
eyes are open and when you cover one eye, ings of both eyes simultaneously.
an eso- or exophoria will develop followed by Summarizing, within the different types of
manifest FMN in both eyes. Th is more com- neurologically “benign” infantile nystagmus,
mon, manifest form of FMN is present with there is a large category of pure INS, a signif-
both eyes open and mimics the latent form icant category of pure FMNS, and a small cat-
exactly if it is bidirectional. When it is unidi- egory that is a mixture of the two; there are
rectional and the patient fi xates with one eye, also individuals with the nystagmus block-
there will be no nystagmus and the other eye age syndrome (NBS) or spasmus nutans syn-
will be esotropic, but when the patient fi xates drome (SNS). All are easily diagnosed with
with the other eye and the formerly fi xating eye the aid of ocular motility recordings and just
is esotropic, the patient will have FMN. The as easily misdiagnosed without them. There
latent form of FMN (i.e., no nystagmus with are twelve INS waveforms, two mixed INS
both eyes open) is rare. If you occlude the left waveforms (dual-jerk and dual-pendular IN),
eye and the right eye is fi xating, jerk-right FMN two FMNS waveforms, and one mixed FMNS
with linear or decreasing-velocity slow phases waveform (dual-jerk FMN). If a patient walks
results and vice versa. into your office with wiggling eyes and you
The small group of patients with both INS wish to guess what the patient has before you
and FMNS present a diagnostic dilemma. record him or her, your best guess would be
Some have mostly INS (designated “INS/ INS. A large percentage (80%) will be INS
FMNS”) and their waveforms are any of the and 15% FMNS with only a small percentage
INS waveforms (i.e., pendular or increasing- of mixtures. If you could consider just INS
velocity slow phases) (see Table 5.3) and one patients, 94% will be pure INS and only 6%
other waveform called “dual jerk” or “dual pen- a mixture. If you could restrict the population
dular” (see Chapter 2, Fig. 2.3 and Chapter 3, to FMNS patients, three-fourths of them will
Fig. 3.3). The latter is a waveform where a low- have only FMNS, but many will have mixtures.
amplitude, high-frequency pendular nystag- Thus, more patients with predominantly FMNS
mus is superimposed on a decreasing-velocity will also have some INS than patients with pre-
slow-phase jerk waveform. They do not exhibit dominantly INS having FMNS.

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5.1. 2. 4 A LT E R N AT E- COV E R A N D G A ZE- amplitude of IN, or it may convert the nystag-

A N G L E- COV E R T E S T S mus to a low-amplitude FMN.
The name “nystagmus blockage syndrome”
The same two tests discussed in Section 5.1.1.4
reflects the prevalent assumption that patients
apply here since their purpose is to help differen-
block their nystagmus by adducting one eye. The
tiate INS from FMNS. However, as can be seen
adducted eye may be the fi xing eye (i.e., accom-
from the conclusions that can be drawn from
panied by a head turn) or it may be the nonfi xing
the various observations from the two tests,
eye (i.e., when a patient views an object in pri-
although INS can be identified conclusively in
mary position with his or her head straight). In
some cases, FMNS cannot.
both cases, the nystagmus is reduced when the
esotropia occurs. The diagnosis of NBS is difficult
to make because precise and uniform diagnostic
5.1.3 Nystagmus Blockage Syndrome
criteria are lacking; similar, more common dis-
The nystagmus blockage (blockierungs, com- orders, such as esotropia associated with FMNS,
pensation) syndrome (NBS)8 denotes a par- are mistaken for NBS; and the diagnosis usually
ticular type of nystagmus: onset of esotropia is made by clinical observation rather than by
in early infancy, pseudoabducens paralysis, accurate eye-movement recordings. 36,38,40–42,45–49
head turn toward the side of the fi xating eye, The patients commonly misdiagnosed as having
absence of nystagmus with the fi xating eye in NBS are those with FMNS and esotropia.
adduction, and appearance of a manifest jerky
nystagmus as the fi xating eye moves into pri-
5.1.3.1 A SS O CI AT I O N W I T H
mary position and abduction.40,41 Many reports
S T R A B I S M US
have concluded from eye-movement recording
analysis that patients who habitually hold their Strabismus, albeit a variable strabismus, is a nec-
dominant eye in the position of least nystag- essary but not sufficient condition for the NBS
mus (usually adduction) may develop sup- since a purposive esotropia is required to damp
pression and esotropia in the fellow eye. 38,40–42 the IN and/or transform it into FMN. That is, all
Adelstein and Cuppers analyzed this condi- patients with NBS have strabismus, but clearly
tion further and coined the term “nystagmus all with strabismus do not have NBS.
blockage syndrome” (NBS).43 In the majority
of patients the eyes are in a convergent posi-
5.1.3. 2 CL I N I C A L S I G N S A N D
tion; in others there is alternating fi xation.
SYMPTOMS
Adelstein and Cuppers separated this syn-
drome from bilateral abducens paralysis and Patients with NBS willfully induce esotropia
explained the esotropia on the basis of hyper- while fi xating at distance. Th is is something
tonicity of the medial rectus muscles, resulting that most with INS cannot do unless they have
from the patient’s sustained effort to block the the ability to partially suppress the esotropic
nystagmus by adducting the eye.43 eye. If INS patients with normal binocular-
The diagnosis of nystagmus blockage syn- ity could make one eye esotropic, they would
drome can be made only when the ongoing have oscillating diplopia. When NBS patients
waveform is of INS and the nystagmus mark- turn one eye in and suppress it, their nystagmus
edly diminishes with esotropia.44 Therefore, damps and they may adopt a head turn to place
true NBS is indeed a “blockage” of an ongo- their fi xating eye in adduction. The INS is either
ing nystagmus (i.e., IN) present with both reduced in amplitude or converted to a low-
eyes open, produced by an added or increas- amplitude FMNS by this purposive esotropia;
ing esotropia. The esotropia may reduce the the greater the esotropia, the lower the nystag-
nystagmus by one of two mechanisms: it may mus and, as the fi xating eye moves from adduc-
reduce an ongoing INS much in the same man- tion to abduction, the nystagmus increases and
ner as true binocular convergence reduces the esotropia decreases.

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5.1.3.3 D I F F E R E N T I A L D I A G N OS I S with eye-movement recordings. There is no last-

ing direct effect on vision, although there is high
The NBS is the source of some misunder-
incidence of ametropia and amblyopia in this
standing. Individuals with NBS use a conver-
population of patients.
gence-like movement to damp their INS while
viewing a distant target. Thus, the waveforms in
NBS are those of INS when the patient is look- 5.1. 4 .1 A SS O CI AT I O N W I T H
ing in the distance and the eyes are straight.41 S T R A B I S M US
With the imposition of the purposive esotropia
Gott lob et al. found a high incidence of esotro-
(this is not a strabismus that occurs transiently
pia, latent nystagmus, dissociated vertical diver-
but one that the patient either willfully or
gence, and amblyopia in children with SNS. 55,56
reflexively imposes because he or she has found
Conversely, rare patients with infantile esotropia
that acuity is better under that condition) the
display horizontal or vertical head oscillations
waveform can either become a damped INS
that resolve following surgical realignment of
waveform (Type I NBS) or a small-amplitude
the eyes.
FMNS (Type II NBS). Thus, the NBS implies
ocular motor deficits capable of producing
both IN and FMN waveforms (see Table 5.3). 5.1. 4 . 2 CL I N I C A L S I G N S A N D
Even though the FMNS waveform is usually SYMPTOMS
unsuitable for good acuity (because there are
SNS appears as a high-frequency, asymmetric,
no long, postsaccadic foveation periods), it is of
dysconjugate ocular oscillation. It is usually
low amplitude and acuity increases. Thus, there
horizontal in direction but may also be verti-
are two types of blockage syndrome. NBS is
cal or torsional. 35,50–54 It is often described as an
often misdiagnosed in patients with FMNS and
intermittent nystagmus that is asymmetrical in
alternating fi xation who place their fi xating eye
appearance and occasionally monocular. The
in adduction to reduce their FMNS. Since they
key eye-movement recording observation was
do not have INS, and they do not have NBS.
the variable phase difference between the two
Distinguishing the INS from the FMNS wave-
eyes, which is reflected clinically as an asymme-
forms and the purposive esotropia of one eye
try in the oscillations between the two eyes. On
requires DC-coupled, high-bandwidth record-
lateral gaze, the dissociation may increase, with
ings of both eyes simultaneously.
nystagmus of the abducting eye predominating.
Some case series suggest an increased prevalence
of esotropia in SNS. In contradistinction to INS,
5.1.4 Spasmus Nutans Syndrome
visual acuity is minimally affected in SNS. SNS
The term spasmus nutans (Latin for “nodding is more common in Black children and has been
spasm”) refers to the constellation of nystagmus, reported in several sets of identical twins. 51,53,57
head nodding, and torticollis. Although the term Contrary what was commonly believed, eye-
“acquired nystagmus” has been applied to the movement data showed that the asymmetric
spasmus nutans syndrome (SNS)8 as a differenti- ocular oscillations of SNS did not always dis-
ating feature from INS, it should be remembered appear. 53 There have been patients of 10 or 12
that INS is also “acquired” earlier in infancy. 35,50–54 years of age whose SNS is still clinically evident.
Unlike INS, which usually becomes apparent Many times it disappears to clinical observation
between 8 and 12 weeks of age (although it may (again, like FMNS) but when recorded, a pen-
appear at birth), the age of onset in SNS is gen- dular dissociated nystagmus will be found. As
erally quoted as 6 to 12 months of age, although described in Chapter 4, Section 4.2.1.3, patients
cases with clinically apparent onset ranging from cancel the dysconjugate pendular oscillation
2 weeks to 3 years of age have been documented. of SNS (present with a still head) and substi-
SNS may become clinically “silent” within 1 to 2 tute a conjugate vestibulo-ocular reflex (VOR)
years of onset, but it persists for years if studied when the head is moving; as a result, acuity

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increases. The oscillating diplopia that proba- lait spots, optic atrophy, or other clinical signs
bly results from the out-of-phase oscillations of neurofibromatosis make it more likely that
may be the main reason that head shaking is a child with SNS will have a CNS glioma. A sub-
used to cancel the nystagmus. Thus, unlike the stantial proportion of patients presenting with
low-amplitude, uncontrolled, noncompensatory SNS-like nystagmus have important underlying
head nodding sometimes seen in INS, the larger ocular, intracranial, or systemic abnormalities.
amplitude, purposive head nodding in SNS is Neurodegenerative disorders such as Pelizaeus–
compensatory. 52,58,59 Merzbacher disease and Leigh disease may
produce nystagmus and head nodding that are
indistinguishable from SNS. 54–56,69–73 These
5.1. 4 .3 D I F F E R E N T I A L D I A G N OS IS
disorders should be suspected in children with
SNS may appear at or after birth and usually, clinical signs of ataxia or developmental delay or
but not necessarily, ceases by the age of 3 years. with magnetic resonance evidence of white mat-
The nystagmus is pendular, usually monocular ter signal abnormalities. Achromatopsia, con-
or disconjugate, and is commonly accompa- genital stationary night blindness, and Bardet
nied by a head oscillation. Reports of “spasmus Biedl syndrome can also masquerade as SNS.
nutans” accompanying neurological disease The diagnosis of SNS can only be made using
(e.g., craniopharyngeoma, optic nerve and chi- a combination of clinical characteristics and eye-
asmal glioma, 60–62 or cerebrocerebellar degen- movement fi ndings, which exclude other visual
eration63) have not all included eye-movement or nervous system disease. The pathogenesis and
recordings to prove that the nystagmus was neuroanatomical substrate of this developmen-
the same as that of spasmus nutans. Although tally acquired form of asymmetric, dysconjugate
the nystagmus may clinically resemble that nystagmus are still unknown.
recorded in SNS, until a proper study compar- SNS must fi rst be distinguished from INS
ing the actual waveforms of SNS with those and FMNS. Despite the clinical similarities of
recorded in children with known neurological SNS to INS or FMNS in some patients, eye-
disease, they should not be presumed to be iden- movement data can be used to make the correct
tical. The term “SNS” should be reserved for the diagnosis. The diagnostic criteria for SNS have
specific, benign nystagmus that has been docu- also been defi ned by ocular motility record-
mented (see earlier) and should not also be used ings. 53 Based on that data we can now diagnose
to describe the nystagmus accompanying neu- SNS immediately and distinguish it from INS
rological disease, even if the nystagmus itself and FMNS; it is no longer necessary to wait 3 or
is subsequently found to be identical. Rather, 4 years before making the diagnosis based on its
a descriptive name for the nystagmus should possible clinical disappearance. The diagnostic
be used for the latter. Other signs are needed to key is the variable phase difference between the
distinguish true SNS from similar looking nys- oscillations in both eyes, unlike INS and FMNS,
tagmus associated with central nervous system where the oscillations are always phase-locked,
(CNS) disease. 54 if not totally conjugate.
For a century, numerous reports emphasized At present, however, even positive identifi-
that SNS was a visually and systemically benign cation of SNS or SNS-like waveform is insuf-
and self-limited clinical entity. 54,61,62,64–68 Since ficient to preclude further imaging studies to
1967, however, many infants with some of the rule out neurological disease. However, if it is
features of spasmus nutans have been found to subsequently found that the nystagmus asso-
have congenital suprasellar tumors (most com- ciated with neurological disease differs from
monly chiasmal gliomas). Suprasellar tumors that of SNS, then identification of the latter by
can produce a constellation of neuroophthal- eye-movement data could provide sufficient evi-
mologic signs that are clinically and electro- dence to remove the need for expensive imaging
physiologically indistinguishable from SNS. studies. Similarly, eye-movement identification
The clinical fi ndings of hydrocephalus, café au of a type of nystagmus that is found to be specific

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for neurological disease would require imaging in infancy as well as adulthood. Various types
studies. of acquired nystagmus may be localized, as
Figure 5.5 illustrates. Knowing how each type
of nystagmus varies with gaze angle is impor-
5.1.5 Nystagmus and Strabismus
tant for differential diagnosis. In Figure 5.6,
The prevalence of strabismus in general popu- the waveforms and their variation with gaze
lation has been reported to be between 0.80% angle of INS, FMNS (both linear and decel-
and 6.0%.15,74–77 Chia et al. in a study of 3009 erating slow phases), GEN, and VN are illus-
Singaporean children, aged 6 to 72 months trated. These variations are shown in Figure 5.7
found a prevalence of strabismus of 0.80%.78 as they would appear when recorded. The target
The MEPEDS Study Group found that in position for the FMNS waveforms with decel-
3007 African American children and 3007 erating slow phases has been corrected from
Hispanic children, ages 30 to 72 months, illustrations published prior to the discovery of
incidence of strabismus was similar in both the substitution of saccadic pulse trains for lin-
groups (2.4% for Hispanic children vs. 2.5% ear FMNS when the slow-phase velocities were
for African American children).79,80 Graham too high for good foveation.97
reported that the prevalence of strabismus is
5.66% based on a study done on 4784 child-
5.2.1 Vestibular Nystagmus
ren. 81 Of 1187 children, 4.2% were found to
have strabismus in a study done by Chew et Certain characteristics of vestibular nystag-
al. 82 In a study done in Sweden, the preva- mus can localize the etiology to the peripheral
lence of strabismus was found to be 3.2%. 83 or central neuronal pathways of the vestibular
Compared to the general population, the systems. Central vestibular nystagmus is fre-
prevalence of strabismus in patients with nys- quently uniplanar in contrast to peripheral ves-
tagmus is higher than in the general popula- tibular nystagmus, which is usually torsional or
tion. In a study by Forssman the prevalence multiplanar.98,99 Visual fi xation easily inhibits
of strabismus was reported to be 16%. 84,85 In peripheral vestibular nystagmus, but not central
another study by Brodsky and Fray the prev- vestibular nystagmus. Vertigo and tinnitus are
alence of strabismus was reported to be 17%– common in peripheral vestibular nystagmus and
50%. 28 Self et al. reported that the prevalence uncommon in central vestibular nystagmus.
of strabismus is 44% in INS due to mutations
in FRMD7. 86,87 From a combination of studies
5. 2.1.1 P E R I P H E R A L V E S T I B U L A R
of over 500 infants, children, and adults with
IMBAL ANCE
childhood forms of nystagmus reported by
multiple authors, incidences from 25% to 72% The child with peripheral vestibular nystag-
were reported. 21,25,28,35–37,39,88–96 Thus, those mus has, in many ways, similar etiologies, signs,
eye care professionals who care for patients symptoms, and treatment options as an adult.
with strabismus are as likely, if not more so, The VOR normally generates eye rotations, after
as any in health care to be confronted with a short latency, in the same plane as the head
the disorders of nystagmus and other ocular rotation that elicits them. Disorders of the ves-
oscillations. tibular periphery cause nystagmus in a direction
that is determined by the pattern of involved
labyrinthine-semicircular canals.99–106 The com-
5.2 NYSTAGMUS WITH
plete, unilateral loss of one labyrinth causes
ASSOCIATED NEUROLOGICAL
a mixed horizontal-torsional nystagmus that is
DISEASE—“SYMPTOMATIC”
suppressed by visual fi xation. Another conse-
In addition to the benign types of nystagmus in quence of vestibular disease is a change in the
infancy discussed earlier, there are also symp- size (gain) of the overall dynamic VOR response.
tomatic types of nystagmus that may appear As a result of this change, patients complain

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FIGURE 5.5 Sagitt al section of brainstem, midbrain, cortex, and cerebellum. Anatomical areas responsi-
ble for ocular motor control and nystagmus types localized to brainstem and cerebellar areas are indicated.
CN III, cranial nerve three; MLF, medial longitudinal fasciculus; PAN, periodic alternating nystagmus; PC,
posterior commissure.

of oscillopsia during rapid head movements. quick phases (Alexander’s law). The nystagmus
A VOR gain larger than 1 (eye speed exceeds is suppressed by visual fi xation and increased
head speed) results from a disinhibition of the when fi xation is removed. The horizontal com-
brainstem circuits responsible for the VOR and ponent is diminished when the patient lies with
is caused by vestibulo-cerebellar dysfunction. the intact ear down and is exacerbated with the
Loss of peripheral vestibular function causes affected ear down. The nystagmus is increased
impaired vision and oscillopsia during locomo- or precipitated by changes in head position, vig-
tion, due to the inability to compensate for the orous head shaking, hyperventilation, mastoid
high-frequency head perturbations that occur vibration, or Valsalva maneuver. There is uni-
with body and head movements. Symptoms laterally impaired ability to modulate sponta-
include vertigo, nausea, dizziness, and oscillop- neous nystagmus. A magnetic resonance image
sia, and signs include mixed horizontal-torsional (MRI) or computed tomography (CT) scan of
trajectory of the oscillation (which usually beats the brain may show disease and, importantly,
away from the side of a vestibular lesion), asso- ocular motility recordings show linear (constant
ciated neurologic signs and symptoms, usually velocity) slow phases.99–106 The prognosis of the
acute onset, and unsteady gait. Common asso- oscillation depends on underlying disease. The
ciated fi ndings include relatively preserved sac- characteristics of peripheral vestibular nystag-
cades and smooth pursuit, skew deviation, and mus are listed in Table 5.4; peripheral positional
an increase in the intensity of the oscillation nystagmus, in Table 5.5; and its variation with
when eyes are turned in the direction of the gaze angle is illustrated in Figures 5.6 and 5.7.

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FIGURE 5.6 Waveform variation with gaze angle for different types of nystagmus. Note that the target
positions for FMNS with decelerating slow phases are at the ends of the slow phases; thus, these are defoveat-
ing saccadic pulse trains, not true nystagmus. The basic FMNS waveforms (JR for right-eye fi xation and JL
for left-eye fi xation) have linear slow phases and are shown with VN. FMNS, fusion maldevelopment nystag-
mus syndrome; GEN, gaze-evoked nystagmus; INS, infantile nystagmus syndrome; L, left; |N|, nystagmus
magnitude; R, right; t, time; VN, vestibular nystagmus.

FIGURE 5.7 Waveform variation with gaze angle for different types of nystagmus as would be recorded
by an eye-movement data acquisition system. FMNS, fusion maldevelopment nystagmus syndrome; GEN,
gaze-evoked nystagmus; INS, infantile nystagmus syndrome; JL, jerk left; JR, jerk right; LE, fi xation with
left eye; RE, fi xation with right eye; VN, vestibular nystagmus.

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Table 5.4 Vestibular Nystagmus

S Y M P T O M O R S IG N P E R I P H E R A L (E N D O R G A N) C E N T R A L (N U C L E A R )
Direction of nystagmus Unidirectional, fast phase opposite Bidirectional or
lesion unidirectional
Purely horizontal nystagmus Uncommon Common
without torsional component
Vertical or purely torsional Never present May be present
nystagmus
Visual fi xation Inhibits nystagmus and vertigo No inhibition
Severity of vertigo Marked Mild
Direction of spin Toward fast phase Variable
Direction of past-pointing Toward slow phase Variable
Direction of Romberg fall Toward slow phase Variable
Effect of head turning Changes Romberg fall No effect
Duration of symptoms Finite (minutes, days, weeks) but May be chronic
recurrent
Tinnitus and/or deafness Often present Usually absent
Common causes Infection (labyrinthitis), Meniere Vascular, demyelinating,
disease, neuronitis, vascular, and neoplastic disorders
trauma, toxicity

5.2.1. 2 CE N T R A L V E S T I B U L A R There are almost always associated neuro-

IMBAL ANCE logic signs and symptoms, that is, the acute
onset of vertigo, nausea, dizziness, and oscil-
The child with central vestibular nystagmus
lopsia, associated with other signs of vestibu-
also has, in many ways, similar etiologies,
locerebellar dysfunction. Common associated
signs, symptoms, and treatment options as an
findings may include other ocular oscillations
adult. There is a mixed horizontal-torsional
such as downbeat, upbeat, torsional, horizon-
trajectory to the fast phase with beats away
tal, jerk, and SSN. Slow phases may be linear
from the side of the vestibular lesion.98,103,107,108
or have increasing- or decreasing-velocity

Table 5.5 Positional Nystagmus

FE AT U R ES PER I PH ER A L CENTR A L
Latency 3–40 sec None; nystagmus begins immediately
Fatigability Yes No
Rebound Yes No
Habituation Yes No
Intensity of vertigo Severe Mild
Reproducibility Poor Good
Directionality and waveforms Stereotyped Variable

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FIGURE 5.8 Velocity trace from eye-movement recordings of a patient with infantile nystagmus syn-
drome and periodic alternating nystagmus (PAN) looking in primary position for about 13 minutes showing
classic rhythmic change in intensity and direction of the oscillation. Spontaneous nystagmus in the primary
position, which beats jerk right with increasing then decreasing intensity for 1 to 2 minutes, followed by
a quiet period, and then reappearance of the nystagmus in the opposite direction with similar crescendo-
decrescendo in intensity for a similar length of time. Both eyes had same tracing.

waveforms. The nystagmus is poorly sup- nystagmus and vice versa. The oscillation is
pressed by fixation of a visual target and may commonly associated with impaired smooth
be precipitated, exacerbated, or changed in pursuit, gaze-evoked nystagmus, gait instabil-
direction by altering head position, vigor- ity, and ataxia. An MRI/CT scan of the brain
ous head shaking (horizontal or vertical), or ref lects underlying disease. The prognosis
hyperventilation. Convergence may increase, depends on the underlying disease. The char-
suppress, or convert upbeat to downbeat acteristics of central vestibular nystagmus are

FIGURE 5.9 Eye-movement recording of right eye from a patient with symmetric infantile periodic alter-
nating nystagmus (PAN) performed under binocular conditions over 200 seconds illustrating a typical
periodic, symmetric, jerk right with extended foveation (Jerk Ref) when the infantile nystagmus syndrome
direction was to the right and jerk left with extended foveation (Jerk Lef) when the direction was to the left .
L, left; R, right; OD, right eye; OS, left eye.

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listed in Table 5.4 and central positional nys- childhood. Causes of acquired PAN include
tagmus, in Table 5.5. head trauma, multiple sclerosis, posterior fossa
lesions, vascular insufficiency, spinocerebellar
degenerations, encephalitis, otitis media, syph-
5.2.1.3 CE N T R A L V E S T I B U L A R
ilis, aqueductal stenosis, and Arnold–Chiari
I N S TA B I L I T Y ( P E R I O D I C A LT E R N AT I N G)
malformation.95,110,117 PAN may coexist with
Periodic alternating nystagmus (PAN) is an downbeat nystagmus, which also suggests a
extraordinary ocular motor phenomenon in Chiari malformation. Unlike PAN in the INS,
which a persisting horizontal jerk nystagmus acquired PAN is usually associated with struc-
periodically changes directions; it may be con- tural lesions involving the cerebellum or its
genital or acquired. The congenital variety central connections. Reports of acquired PAN
(i.e., INS nystagmus), which may be associated following visual loss (e.g., vitreous hemorrhage
with albinism,109,110 has slow-phase waveforms or cataract) and its disappearance with restora-
of both linear and increasing velocity, usually tion of vision provide an important clue to the
lacks the well-defi ned stereotyped periodic- underlying pathophysiology.
ity seen in acquired PAN (i.e., it is asymmetric Patients with acquired PAN usually have ver-
(a)periodic alternating nystagmus, APAN), and tigo, nausea, dizziness, and oscillopsia. It can be
can persist for many minutes in either direction associated with other signs of vestibulocerebel-
or spontaneously change direction after a few lar involvement (e.g., Arnold-Chiari, platybasia).
seconds.111,112 The addition of variable pendular The nystagmus is a mixed horizontal-torsional
nystagmus to these APAN jerk waveforms can trajectory showing a peculiar, spontaneous,
produce complex waveforms that may mimic rhythmic, regular, crescendo-decrescendo
those of FMNS nystagmus.113–115 The periodicity intensity and directional change direction of the
of INS APAN is markedly influenced by changes fast phase with the complete cycle lasting about
in gaze position, supporting the hypothesis that 3 minutes. It is usually acute in onset and may
the direction reversals are a result of a temporal be associated with periodic alternating head
shift in the null zone (see Chapter 2, Fig. 2.12). 33 turns—the head turns in the direction of the
INS with APAN may also be hereditary.116 quick phase, and the eyes are moved into a pos-
In contrast, the usual, fi xed sequence in ition in the orbit that is the same as the direc-
acquired PAN consists of about 90 seconds of tion of the slow phase—thereby minimizing the
nystagmus beating in one direction, 10 seconds nystagmus induced by Alexander’s law. The nys-
of a neutral phase in which the eyes stop or beat tagmus cycle is not affected by visual fi xation.
downward irregularly, and 90 seconds of beat- Vestibular stimuli, such as head rotations, can
ing in the opposite direction (see Fig. 5.8 where change or transiently stop nystagmus, downbeat
the velocity trace demonstrated this periodic- nystagmus and square-wave jerks may become
ity). Th is periodicity is continuous during wak- more obvious in the brief null period when the
ing hours and may prevail during sleep. Some horizontal nystagmus wanes and then reverses,
patients demonstrate asymmetries in the timing MRI/CT scan of brain reflects underlying dis-
of the two major phases, but the basic pattern for ease, and ocular motility recordings show linear
each patient is usually invariable; for a contrast (“constant velocity”) slow phases. The prognosis
to APAN, see Table 5.2. In Figure 5.9 the sym- depends on the underlying disease.
metric PAN of a patient with INS is shown. The Campbell described PAN secondary to phen-
JLef waveform is shown gradually diminishing in ytoin intoxication in a patient with alcoholic cer-
amplitude and, after a neutral period, reversing ebellar degeneration.118 The antispasticity drug
to JRef and increasing in amplitude. In acquired baclofen abolishes acquired PAN but does have
PAN the waveform would be a sawtooth jerk some unpredictable effects on the INS varie-
nystagmus. ty.119 The drug abolished experimentally created
Acquired PAN is usually seen in older PAN in the monkey,120 as well as a single case
children or adults but may present in early of aperiodic alternating nystagmus in a patient

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with vertebrobasilar insufficiency.121 Baclofen of the acquired form of PAN with the GABA-
damped the APAN of some patients with INS,122 ergic drug Baclofen.119 The fi nding that acquired
whereas memantine damped acquired PAN in a PAN is abolished by Baclofen, both in humans
case where baclofen was ineffective.123 and in animals following ablation of the nodulus
PAN may be associated with a periodic alter- and uvula, further supports this pathogenetic
nating skew deviation.124 Periodic alternating mechanism in acquired PAN.
gaze deviation (“ping-pong gaze”), regardless of In a clinical and control-system study,129 it
whether associated with alternating nystagmus was proposed that PAN arises from (1) a defect
or alternating head turning, is a rare, related phe- in the brainstem neural networks that generates
nomenon.125 Periodic alternating gaze deviation slow phases of vestibular and optokinetic nys-
is a cyclic disorder of eye (and head) movements tagmus, (2) the action of an adaptive network
characterized by slow, spontaneous, alternating, that normally acts to null prolonged, inappro-
pendular, conjugate, horizontal eye and/or com- priate nystagmus, and (3) an inability to use
pensatory head movements. A complete cycle retinal-error velocity information. They pro-
lasts seconds to minutes and consists of a conju- posed a control system model that denied access
gate horizontal eye movement to one side followed of visual signals to the visual vestibular system.
by a slow conjugate eye movement to the oppo- Th is model is particularly appealing because of
site side. Th is disorder is usually clinically evident the occasional relationship between impaired
as part of a larger cerebral dysfunction such as vision and PAN. Support for their hypothesis of
a cerebrovascular accident, brain tumor, obtunded impairment in the velocity storage element was
states, sleep, anesthesia, and coma. Although the presented by Furman et al.,130 who studied four
exact mechanism is unknown, the midline cere- PAN patients. PAN has occurred after bilateral
bellum, pons, and bilateral cerebral hemisphere vitreous hemorrhages (associated with a mas-
dysfunction have all been postulated. sive subarachnoid hemorrhage) and after cata-
Animal experiments combined with additional racts and disappeared after bilateral vitrectomy
data in humans suggest that acquired PAN proba- and cataract surgery, respectively. Ablation of
bly requires concurrent CNS dysfunction at two the nodulus and ventral uvula of the cerebellum
separate levels.108,126 The nodulus and uvula of the in monkeys produces PAN.120
cerebellum are believed to control postrotational
nystagmus, which is prolonged following abla-
5.2.2 Gaze-Holding Deficiency
tion. PAN can be produced in animals following
Nystagmus
ablation of these structures if visual deprivation is
superimposed. It is believed that normal vestibu- There are several forms of nystagmus that are
lar repair mechanisms act to reverse the direction directly related to problems with gaze holding;
of the nystagmus. Under normal circumstances, they usually manifest at eccentric gaze angles,
the oscillations of PAN would be blocked by vis- although one type may be present in primary
ual fi xation, smooth pursuit, and optokinetic position.
mechanisms. When these visual stabilization sys-
tems do not work (in the setting of visual depri-
5 . 2 . 2 .1 ECC E N T R I C G A Z E , G A Z E-
vation and disease of the cerebellar flocculus),
E VO K E D, R E B O U N D
removal of Purkinje cell inhibition upon the ves-
tibular nuclei allows the central velocity storage Gaze-evoked nystagmus (GEN) is a rhythmic
mechanism to become unstable. oscillation of the eyes while attempting to main-
Pharmacological evidence suggests that the tain an eccentric eye position. It is caused by
nodulus and uvula maintain inhibitory control a deficiency, usually a structural lesion, in the
on the vestibular rotational responses via the neural integrator network.131 Gaze cannot be
inhibitory neurotransmitter gamma-amino- held at an eccentric position, and the eyes drift
butyric- acid (GABA).117,119,127,128 Halmagyi et al. back toward the null point of the integrator,
were the fi rst to report the successful treatment which often is straight-ahead gaze. A corrective

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saccade is attempted to move the gaze back to holding (or attempted holding).134 Included
the eccentric position, and the process repeats. in the causes of GEN are medications and
The variation of GEN with gaze angle is illus- brainstem or cerebellar disorders. Brainstem
trated in Figures 5.6 and 5.7. and cerebellar lesions also cause pathological
Saccadic eye movements are made by a neu- rebound nystagmus. After holding eccentric
ral signal composed of a rapid increase in neu- gaze between 30° and 45° from primary gaze
ral discharge (pulse) and then a rapid decrease for more than 30 seconds, a patient is directed
to a new discharge rate (step). When the pulse to look straight (assume primary gaze). If an
component is not accurate, the eyes will over- or abnormal amount of rebound nystagmus is
undershoot their target and then make a cor- present (more than three beats of nystagmus),
rective second saccade to bring the gaze to the with the jerk directed away from the pro-
intended fi xation. When the step component longed eccentric gaze, it is rebound nystag-
is not maintained, the eyes will drift back to mus. Because the neural integrator is found
primary gaze with a decelerating slow phase, in the brainstem, tumors that favor this area
make a corrective saccade, and repeat to cause should be suspected when GEN is found.
GEN.126 It is the neural integrator that is respon-
sible for mathematically “integrating” the pulse
5. 2. 2. 2 G A Z E I N S TA B I L I T Y
of neural activity into a step discharge. If there
(“ R U N AWAY ” )
is a minimal abnormality in integrator function,
GEN will manifest itself only at extreme angles Th is is usually an acquired oscillation in which
of gaze. However, if there is a major defect in the slow phases are directed centrifugally (away
function, GEN can appear in primary gaze. from) primary position. There are often associ-
It should also be remembered that vertical GEN ated neurologic signs and symptoms. The nystag-
almost always indicates brainstem or cerebel- mus usually has an acute onset and is associated
lar dysfunction. Gaze-evoked nystagmus is the with other signs of vestibulocerebellar involve-
most common form of nystagmus encountered ment. The nystagmus slow phases carry the eyes
in clinical practice. away from a fi xing position and the slow phases
There is an important difference between show an accelerating velocity.135 Th is is different
GEN and physiologic end-point nystagmus from the accelerating slow phases of INS where
(EPN). With EPN, the eyes attempt a saccade they are directed back to the null position (see
out to an extreme gaze position and have an Chapter 2, Section 2.1.2.6, discussion of the neu-
initial difficulty holding this position. After ral integrator). The oscillation may have a vertical
a short amount of jerk nystagmus with fairly or horizontal or horizontal component. An MRI/
linear slow phases, the eyes may be able to CT scan of brain often reflects underlying dis-
maintain the eccentric gaze. EPN is a nor- eases and eye-movement recordings show slow
mal finding and differs from GEN by the phases that are accelerating.126 CNS pathology is
fact that GEN is a constant nystagmus with almost always present.
larger amplitude (defined as 4° or more) and Arnold et al. reported the effects on gaze sta-
is often asymmetric. Physiologic end-point bility of microinjections of eight different drugs
nystagmus is not a type of GEN but a nys- into the NPH-MVN of monkeys.136 Agents with
tagmus that may be inconsistent and that is either agonist or antagonist actions at GABA,
seen in most normal individuals, some when glutamate, and kainate receptors all caused
attempting to fixate an eccentric target of gaze-evoked nystagmus, while agents acting
only 20°132 or even 10°.133 The jerk phase may at the glycine receptor (glycine and strych-
occur for a few beats, and then the integrators nine) had no effect. In contrast, when muscimol
will hold and the nystagmus will disappear. was injected near the center of the MVN, the
Physiologic EPN has been found to occur in eyes sometimes drifted away from the central
up to 60% of individuals and is maximally position with increasing velocity waveforms.
deviated after 30 seconds of eccentric gaze Clinically, patients who show nystagmus with

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increasing velocity waveforms have cerebellar, groups of the paramedian tracts, which lie dif-
not brainstem, lesions. fusely throughout the midline of the brainstem
and receive input from all premotor structures
that project to ocular motor neurons. Lesions at
5.2.3 “Vision-Loss” Nystagmus
any part of this visual motor calibration pathway
Nystagmus may occur in complete blindness and deprive the brain of signals that are essential for
may also accompany incomplete visual impair- fi xation, resulting in drifts of the eyes away from
ment due to lesions anywhere along the visual the target, leading to nystagmus. Th is type of
pathways. Visual loss may facilitate nystagmus nystagmus is similar to that produced by a tonic
in two ways—through loss of visual inputs to imbalance from the visual vestibular system.
the fi xation system that are used to detect and Thus, “vision-loss” nystagmus is not a specific
immediately correct ocular drift and through type of nystagmus but rather nystagmus due
loss of visual signals that are used, over the long to ocular motor system drifts and imbalances
term, to calibrate the ocular motor systems.70,137 that may become manifest when the stabilizing
The first of these components may be regarded effects of vision are absent.
as “visual fi xation,” and it is easily demonstrated
when a normal subject attempts to fi xate on the
5. 2.3.1 P R EC H I A S M A L , O P T I C C H I A S M ,
remembered location of an eccentric target after
A N D P OS T C H I A S M A L V I S I O N L OSS
the room is switched to darkness: the eye drifts
centripetally off target several times faster than These ocular oscillations occur with loss of
when the subject was actually viewing it. The vision after early infancy (~6–9 months) and
visual fi xation mechanism by which smooth eye have associated afferent visual system eye and/
movements correct for drifts of gaze depends on or brain disease. Acquired prechiasmal bilat-
the motion vision system (especially portions of eral visual loss in children causes continuous
the cerebral cortex, such as the middle temporal jerk nystagmus, with horizontal, vertical, and
area or V5). Although such visually mediated eye torsional components, and a drift ing “null” pos-
movements are important for maintaining steady ition. Monocular visual loss causes slow verti-
fi xation, they have one important limitation, cal oscillations and low-amplitude horizontal,
a response time of longer than 70 milliseconds. If mainly pendular, nystagmus predominantly in
this response time is delayed further by disease of the blind eye.20 Lesions at the optic chiasm can
the visual system, then the brain’s attempts at cor- result in SSN with bitemporal visual field loss.
recting eye drifts might actually add to the reti- Postchiasmal vision loss results in low-ampli-
nal error rather than reducing it, leading to ocular tude horizontal nystagmus beating toward the
oscillations. Th is type of nystagmus is similar to side of the lesion.
normal physiological “end-point” nystagmus.
The second component of the visual influ-
5.2.4 Other Pendular Nystagmus
ence on gaze control concerns the need for con-
Associated with Diseases of Central
tinuous calibration and optimizing all types of
Myelin
eye movements.70,137 Th is optimization depends
heavily on visual projections to the cerebellum. Acquired pendular nystagmus usually has hor-
The cerebellum receives visual signals from izontal, vertical, and torsional components
motion vision areas of the cerebral cortex via the with the same frequency, although one com-
pontine nuclei. In addition, visual signals for cal- ponent may predominate.126,137 If the horizon-
ibration probably also pass to the cerebellum via tal and vertical oscillatory components are
the inferior olivary nucleus on climbing fibers. in phase, the trajectory of the nystagmus is
Calibration of the ocular motor system requires diagonal (oblique). If the horizontal and ver-
that visual signals be compared with eye-move- tical oscillatory components are out of phase,
ment commands (efference copy), and the lat- the trajectory is elliptical. A special case is a
ter probably reach the cerebellum from the cell phase difference of 90° and equal amplitude of

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the horizontal and vertical components, when degenerative conditions. The term “myoclo-
the trajectory is circular. When the oscilla- nus” is misleading, since the movements of
tions of each eye are compared, the nystagmus affected muscles are approximately synchro-
may be conjugate, but oft en the trajectories are nized, typically at a rate of about two cycles per
dissimilar, and the size of oscillations is dif- second. The palatal movements may be termed
ferent (sometimes appearing monocular), and “tremor,” rather than myoclonus, and the eye
there may be an asynchrony of timing (phase movements are really a form of pendular nys-
shift). The latter may reach 180°, in which case tagmus. Although the palate is most often
the oscillations are again diagonal. The tem- affected, movements of the eyes, facial muscles,
poral waveform usually approximates a sine pharynx, tongue, larynx, diaphragm, mouth of
wave, but more complex oscillations have been the eustachian tube, neck, trunk, and extremi-
noted. The frequency of oscillations ranges ties may occur. The ocular movements typi-
from 1 to 8 Hz, with a typical value of 3.5 cally consist of oscillations less sinusoidal than
Hz. For any particular patient, the frequency with typical multiple sclerosis, and often with
tends to remain fairly constant; only rarely is a large vertical component, although they may
the frequency of oscillations different in the also have small horizontal or torsional compo-
two eyes. In some patients, the nystagmus nents. The movements may be somewhat dys-
stops momentarily after a saccade. Th is phe- conjugate (both horizontally and vertically),
nomenon is called postsaccadic suppression. with some orbital position dependency. Some
A more common feature is that the oscilla- patients show cyclovergence (torsional ver-
tions are “reset” or phase-shifted by saccades. gence) oscillations.
Acquired pendular nystagmus may be sup- Occasionally, patients develop the eye oscil-
pressed or brought out by eyelid closure or lations without movements of the palate, espe-
evoked by convergence. In some patients with cially following brainstem infarction. Eyelid
this condition, smooth pursuit may be intact. closure may bring out the vertical ocular oscil-
Acquired pendular nystagmus is a common lations. The nystagmus sometimes disappears
feature of acquired and congenital disorders with sleep, but the palatal movements usually
of central myelin, such as multiple sclerosis, persist. The condition is usually intractable,
toluene abuse, Pelizaeus-Merzbacher disease, and spontaneous remission is uncommon. The
and peroxisomal disorders. The observation main pathologic fi nding with palatal myoc-
that acquired pendular nystagmus is “reset” lonus is hypertrophy of the inferior olivary
or phase-shifted after saccades (more so with nucleus, which may be seen during life using
large saccades) suggested that the oscillations MRI.139 There may also be destruction of the
arise in the brainstem-cerebellar gaze-holding contralateral dentate nucleus. Histologically,
network (the neural integrator for eye move- the olivary nucleus has enlarged, vacuolated
ments). Th is form of nystagmus also occurs neurons with enlarged astrocytes. Guillain
with the syndrome of oculopalatal tremor and and Mollaret proposed that disruption of con-
Whipple disease of the CNS. nections between the dentate nucleus and the
contralateral inferior olivary nucleus, which
run via the red nucleus and central tegmental
5. 2. 4 .1 O C U L O PA L ATA L T R E M O R O R
tract, are responsible for the syndrome.141,142
“ M YO C L O N US ”
However, neither the dentate nucleus nor the
Acquired pendular nystagmus may be one com- red nucleus has been shown to have a specific
ponent of the syndrome of oculopalatal (phar- role in ocular motor control. Thus, it has thus
yngo-laryngo-diaphragmatic) myoclonus.138–140 been postulated that the nystagmus results
Th is condition usually develops several months from instability in the projection from the infe-
after brainstem or cerebellar infarction, rior olive to the cerebellar flocculus, a structure
although it may not be recognized until years thought to be important in the adaptive control
later. Oculopalatal myoclonus also occurs with of the VOR. It is also possible that disruption of

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projections from the cell groups of the parame- can be made to oscillate at frequencies up to
dian tracts to the cerebellum leads to the ocu- 2.5 Hz—lower than that reported in patients
lar oscillations. with conditions other than Whipple disease.
To account for these higher frequency oscilla-
tions, it seems necessary to postulate instability
5.2. 4 . 2 P E N D U L A R V E R G E N CE
within the brainstem-cerebellar connections of
N Y S TA G M US A SS O C I AT E D W I T H
the vergence system, for example, between the
WHIPPLE DISE A SE
nucleus reticularis tegmenti pontis and cerebel-
Vergence nystagmus has also been called lar nucleus interpositus, which may help hold
“convergent-divergent” nystagmus, but that vergence angle steady.
redundant term is needlessly convoluted (e.g.,
horizontal is not called “left ward-rightward”
5.2.5 Convergence/Convergence-
nor is vertical called “upward-downward” nys-
Evoked Nystagmus
tagmus). Th is ocular oscillation occurs with
the gastrointestinal disease “Whipple;” thus, The act of convergence usually damps INS (see
patients have associated signs and symptoms Chapter 2, Section 2.1.6). Convergence can also
of gastrointestinal illness with neurological damp146 or evoke147 lid nystagmus and may damp
involvement.143,144 These dysconjugate, ver- or enhance downbeat nystagmus.148 Upbeat nys-
gence, pendular oscillations are often small in tagmus may change to downbeat with conver-
amplitude and thus easily overlooked by clini- gence.149 A slow divergence movement followed
cians. More widespread use of the magnetic by a rapid convergence to the primary position
search coil technique has made it easier to is called “repetitive divergence.” It occurs at
identify the vergence components of this form irregular intervals, distinguishing this from
of nystagmus. Averbuch-Heller et al. reported nystagmus.150 The only reported instance of
three patients with pendular oscillations that this phenomenon was in a patient with hepatic
were about 180° out of phase in the horizontal encephalopathy; an entire cycle lasted from 4 to
and torsional planes but had conjugate verti- 10 seconds, and the interval between cycles was
cal components.145 In one of these patients, the 1 to 15 seconds.
torsional component of the oscillations had the Conjugate nystagmus evoked by conver-
largest amplitude. Thus, the patient actually had gence (convergence-evoked nystagmus) is not
a cyclovergence nystagmus. Vergence, pendular the same as “convergence nystagmus” (a ver-
oscillations also occur in patients with multi- gence nystagmus) and convergence-retraction
ple sclerosis and brainstem stroke. In Whipple “nystagmus” (a saccadic oscillation discussed
disease, the oscillations typically have a fre- in Section 5.3.6). The latter is a manifestation of
quency of about 1.0 Hz and are accompanied the dorsal midbrain syndrome; because the ini-
by concurrent contractions of the masticatory tiating convergence movements are saccadic,151
muscles, a phenomenon called oculomastica- it is not a true nystagmus. Fast divergent
tory myorhythmia. Supranuclear paralysis movements, followed by a slow convergence,
of vertical gaze also occurs in this sett ing and associated with epileptic electroencephalo-
is similar to that encountered in progressive graphic activity, occurred in a neonate with
supranuclear palsy. At least two possible expla- an intraventricular hemorrhage.152 Vergence
nations have been offered to account for the nystagmus must also be distinguished from
vergence nature of these pendular oscillations: psychogenic flutter (the so-called voluntary
a phase shift between the eyes, produced by “nystagmus” discussed in Section 5.3.14),
dysfunction in the normal yoking mechanisms, which is often best induced when the eyes are
or an oscillation affecting the vergence system slightly converged. With the exception of pure
itself. Patients who have been studied show no convergence nystagmus in infants with SNS,
phase shift (i.e., are conjugate) vertically. Under true pendular convergence nystagmus is rare
experimental conditions, the vergence system but does occur most commonly in Whipple

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disease. Th ree patients with convergence nys- to the central position and usually increases on
tagmus with phase shift s of about 180° in both upgaze. Causes of upbeat nystagmus are lesions
the horizontal and torsional planes with conju- in the ascending pathways from the anterior
gate nystagmus in the vertical plane were stud- canals (and/or the otoliths) at the pontomesen-
ied.153 Convergence increased the nystagmus in cephalic or pontomedullary junction, near the
two of the patients. The waveforms were either perihypoglossal nuclei, most often seen after
sinusiodal or complex sums of sinusoids, and medullary lesions. The main causes are multiple
in one patient they were cycloidal. There were sclerosis, tumors of the brainstem, Wernicke’s
no initiating saccades to these cycloidal move- encephalopathy, cerebellar degeneration, and
ments, unlike the pseudocycloid waveform of intoxication (e.g., nicotine).
INS. A visually mediated vergence instability
was hypothesized to induce low-frequency ver-
5.2.7 Downbeat Nystagmus
gence nystagmus, whereas instability of brain-
stem pathways associated with vergence might Downbeat nystagmus occurs in a variety of
have induced high-frequency forms. Backward disorders, but it is most commonly associ-
and forward motion in the ground plane can ated with disease affecting the cerebellum, the
also induce vergence nystagmus in normals.154 craniocervical junction, or the blood vessels in
Nystagmus evoked by convergence is unu- these regions.126,158,159 It may also be a manifes-
sual and may be either conjugate or disjugate, tation of drug intoxication, especially lithium.
congenital or acquired.155 No defi nite clinical Downbeat nystagmus is usually present with
correlation could be made with a specific lesion the eyes in central position, but its amplitude
in the two cases reported. The neuropathologic may be so small that it can only be detected by
examination revealed no morphologic explana- viewing the ocular fundus with an ophthal-
tion for nystagmus in the patient with congeni- moscope. The nystagmus intensity is greatest
tal convergence-evoked nystagmus; the patient in downgaze and down and lateral gaze and
with the acquired form had demyelinating dis- least in upgaze. Usually the waveform is linear.
ease with a spastic paraparesis and no cranial Downbeat nystagmus may also be evoked by
nerve abnormality other than the ocular motor placing the patient in a head-hanging position.
fi ndings. Horizontal pendular nystagmus rarely Some normal subjects may show “chin-beat-
is evoked by accommodative vergence.156 ing” nystagmus when they are placed upside
down in darkness (or wear Frenzel goggles).
Convergence may influence the amplitude and
5.2.6 Upbeat Nystagmus
frequency of the nystagmus or convert it to
Upbeat nystagmus that is present with the eyes upbeat nystagmus. Some patients show com-
close to central position occurs in many clini- bined divergent and downbeat nystagmus. In
cal conditions.157,158 Nystagmus intensity is usu- most patients, removal of fi xation (e.g., with
ally greatest in upgaze, and it usually does not Frenzel goggles) does not substantially influ-
increase on right or left gaze. Removal of vis- ence slow-phase velocity, although the fre-
ual fi xation has litt le influence on slow-phase quency of quick phases may diminish. A variety
velocity. Convergence is variously reported to of ocular motor abnormalities often accompany
enhance, suppress, or convert upbeat nystag- downbeat nystagmus and reflect coincident
mus to downbeat. Placing the patient in a head- cerebellar involvement.160 Vertical smooth pur-
hanging position increases the nystagmus in suit and the vertical VOR are abnormal because
some individuals. As is the case with downbeat of impaired ability to generate smooth down-
nystagmus, patients with upbeat nystagmus ward eye movements. Sometimes, the VOR for
often show asymmetries of vertical vestibular upward eye movements has a gain exceeding
and smooth-pursuit eye movements, as well as 1.0. Impairment of eccentric horizontal gaze
associated cerebellar eye-movement fi ndings. holding, smooth pursuit, and combined eye-
Upbeat nystagmus is present with the eyes close head tracking are coincident fi ndings. Vertical

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diplopia usually reflects associated skew devia- torsional eye movements may be a feature of
tion.161 The visual consequences of downbeat paraneoplastic encephalopathy.164
nystagmus are oscillopsia and postural insta-
bility. Visual fi xation has litt le effect on its
5.2.9 “Seesaw” Nystagmus
slow-phase speed; convergence may suppress
or enhance it in some patients. In general, the In pendular and jerk seesaw nystagmus (SSN),
nystagmus is accompanied by a vestibulocer- one half-cycle consists of elevation and intor-
ebellar ataxia. The pathophysiological mechan- sion of one eye and synchronous depression
ism of downbeat nystagmus appears to be due and extorsion of the other eye; during the next
to a central imbalance of the vertical VOR to half-cycle, the vertical and torsional movements
an abnormality of the vertical-torsional gaze- reverse.165,166 The waveform may be pendular or
holding mechanism (neural integrator). The jerk. In the latter case, the slow phase corresponds
most common cause of downbeat nystagmus is to one half-cycle. A seesaw component is present
cerebellar degeneration (hereditary, sporadic, in many central forms of nystagmus. Seesaw
or paraneoplastic). Other important causes are nystagmus may be congenital or acquired.167–169
Chiari malformation, multiple sclerosis, and Quantitative studies have done much to clarify
a rare congenital form. In practice cerebellar the characteristics and pathogenesis of SSN. It
atrophy, Arnold–Chiari malformation, vari- has been proposed that jerk SSN (hemi-SSN)
ous cerebellar lesions (multiple sclerosis, vas- occurs in patients with lesions in the region of
cular, tumors), and idiopathic causes account the interstitial nucleus of Cajal (INC), although
for approximately one-fourth of the cases each. experimental inactivation of this structure has
Downbeat nystagmus occurs in the channelo- not produced this nystagmus. With a right INC
pathy episodic ataxia type 2.162 lesion, the reaction consists of a left head tilt, a
skew deviation with a right hypertropia, tonic
intorsion of the right eye and extorsion of the
5.2.8 Torsional Nystagmus
left eye, and misperception that earth-vertical
Torsional nystagmus is a less commonly rec- is tilted to the left. Isolated INC lesions may be
ognized form of central vestibular nystagmus characterized by ipsilesional torsional nystag-
than downbeat or upbeat nystagmus.163 To mus and a restricted range of vertical saccades
retain consistency with other forms of nys- that are not slowed. Pendular SSN has most often
tagmus, the clockwise and counterclockwise been reported in patients with large tumors in
torsional directions are based on the patient’s the region of the optic chiasm and diencephalon;
point of view. Thus, clockwise torsional move- thus, these oscillations have been att ributed to
ment describes motion of the top of the eyeball either compression of the diencephalon or to the
toward the patient’s right shoulder. It is often effects of chiasmal visual field defects. Both the
difficult to detect except by eye-movement jerk and pendular variants of SSN probably arise
recordings, careful observation of conjuncti- from imbalance or miscalibration of vestibular
val vessels, or by noting the direction of reti- responses that normally function to optimize
nal movement on either side of the fovea using gaze during head rotations in roll.
an ophthalmoscope or contact lens. Although The frequency is lower in pendular (2–4 Hz)
both peripheral vestibular and INS may have than in jerk SSN.170 The latter has been att ributed
torsional components, purely torsional nystag- to unilateral meso-diencephalic lesions, affect-
mus, like purely vertical nystagmus, indicates ing the interstitial nucleus of Cajal and its ves-
disease affecting central vestibular connec- tibular afferents from the vertical semicircular
tions. Torsional nystagmus shares many of the canals. The term “hemi seesaw” has been used
features of downbeat and upbeat nystagmus, to describe jerk SSN; it is neither accurate (a full
including modulation by head rotations, var- cycle of jerk SSN is the same as for the pendu-
iable slow-phase waveforms, and suppression lar variety) nor descriptive (hemi seesaw motion
by convergence. Nonrhythmic but continuous would stop after one-half cycle). The pendular

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form is associated with lesions affecting the craniofacial or heart. In children this condi-
optic chiasm. Loss of crossed visual input seems tion presents in early infancy or childhood with
to be the crucial element in the pathophysiology decreased visual behavior, nystagmus, and stra-
of pendular SSN. bismus (a fairly common combination of clinical
In the early 1990s a remarkable new visual characteristics). The outstanding clinical sign is
system abnormality (canine “achiasma”) was the presence of SSN in addition to the more typ-
fi rst described by Williams et al. in a group of ical oscillation of INS.169,175 There are fi ndings
Belgian sheepdogs in whom optic nerve fibers of optic pathway (nerve/disc) anomalies (hyp-
fail to cross at the optic chiasm and who mani- oplasia, dysplasia, and coloboma) in all patients
fested SSN. 26,169,171,172 Williams et al. reported seen clearly with three-dimensional volumetric
that the optic nerves, in seven of eight dogs MRI acquisition. Other systemic or CNS signs
studied, did not approach each other to form or symptoms can be present. Due to this we
a chiasm. Achiasma or “nondecussating retinal recommend that these patients be followed for
fugal fiber syndrome” was subsequently recog- signs of central pituitary dysfunction. The pres-
nized in two children who presented with poor ence of the triad of SSN/ISN, strabismus, and
distant vision.173 They had asymmetries in the optic disc anomalies should prompt the clini-
distribution of the monocular, pattern-onset, cian to conduct further electrophysiologic and/
visually evoked potential (VEP) and SSN, sim- or radiographic investigations in search of struc-
ilar to that seen in the achiasmatic dogs; the lat- tural abnormalities of the optic chiasm.
ter was recognized by Dell’Osso in 1993 from
a video of one of these achiasmatic children174
5.2.10 Lid Nystagmus
(see Appendix F, Section F1.4). These fi ndings
suggested a chiasmal anomaly that subsequent Upward movements of the eyelids frequently
MRI scans confi rmed. Hertle et al. reported accompany upward movements of vertical nys-
and reviewed a total of 11 cases and found tagmus. In fact, the absence of lid nystagmus in
that in all a “crossed asymmetry” (right cortex a patient with upbeat nystagmus may suggest
receives the right eye’s visually evoked response disconnection between the premotor signals
and the left cortex receives the left eye’s visu- for the superior rectus and levator palpebrae
ally evoked response) in the monocular VEP superioris, implicating the region between the
occipital distribution existed; this is consistent riMLF and the oculomotor nucleus.176,177 For
with a paucity of fibers crossing at the chiasm.175 the same reasons, lid nystagmus unaccom-
Experimental analysis of the achiasmatic panied by vertical eye nystagmus may reflect
mutant Belgian sheepdogs demonstrated that midbrain lesions. In patients with long-stand-
the entire nasal hemiretina with its misdirected ing compression of the central caudal nucleus,
ipsilateral projection made functional connec- “midbrain ptosis” may occur and this may lead
tions in the thalamus and in the ipsilateral pri- to lid nystagmus. Occasionally, twitches of
mary visual cortex.169,172 A critical fi nding was the eyelid accompany horizontal nystagmus.
that input from nasal and temporal sides of the In other patients, eyelid nystagmus may be
same retina was integrated at the cortical level. induced by convergence. Th is is called Pick’s
Adjacent neurons often responded to visual sign.176 In both cases, lesions are often present
stimuli that were far apart—often on opposite in the medulla, cerebellum, or both structures.
sides of the vertical meridian. Given this radical Eyelid nystagmus has been likened to the
misarrangement of maps of visual space, it is not pathologic form of gaze-evoked nystagmus that
surprising that the ocular motor system of these occurs in patients with cerebellar disease and
achiasmatic dogs did not develop normally. that is often associated with downward drift s of
The syndrome is associated with INS, SSN, the eyelids, followed by corrective rapid upward
and strabismus. Th is condition is a developmen- movements. Eyelid nystagmus can be classified
tal anomaly of the midline CNS that may or may into three types.178 The most common is asso-
not have other systemic fi ndings, for example, ciated with vertical ocular nystagmus with the

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lid movement being synchronous with the eyes, types of ocular motor instabilities that may
but with greater amplitude. The second type is appear in infancy as well as adulthood. They
associated with gaze-evoked horizontal nys- take the form of either saccadic intrusions or
tagmus and may occur in the lateral medullary saccadic oscillations. There is a large literature
syndrome, and the third is Pick’s sign. on the many types of saccadic intrusions and
oscillations listed in Table 5.6 that have been
reviewed elsewhere. 2–7 Several types of inap-
5.3 SACCADIC INTRUSIONS/
propriate saccadic eye movements may intrude
OSCILLATIONS
upon steady fi xation (see Fig. 5.10). Saccadic
In addition to benign and symptomatic types intrusions must be differentiated from nys-
of nystagmus in infancy, there are also other tagmus, in which a drift of the eyes from the

Table 5.6 Saccadic Intrusions and Oscillations

Bobbing/dipping Saccadic lateropulsion
Inverse bobbing Ipsipulsion
Reverse bobbing Contrapulsion
Convergence-retraction “nystagmus” Saccadic pulses/pulse trains
“Nystagmus” retractoris Abduction “nystagmus”
Double saccadic pulses (single/multiple) Ataxic “nystagmus”
Saccadic intrusions/oscillations Saccadic intrusions/oscillations
Dynamic overshoot Stepless saccades
“Quiver” Square-wave jerks/oscillations
Dysmetria Gegenrucke
Flutter Hopping “nystagmus”
Flutter dysmetria “Lightening eye movements”
Macrosaccadic oscillations Myoclonus
Myoclonus Saccadic intrusions/oscillations
Laryngeal “nystagmus” Zickzakbewegungen
“Lightning eye movements” Square-wave pulses (bursts/single)
Pharyngeal “nystagmus” “Macro square-wave jerks”
Opsoclonus Kippdeviationen/ “Kippnystagmus”
“Dancing eyes” “Pendular macro-oscillations”
“Lightning eye movements” Saccadic “nystagmus”
Saccadomania Saccadic oscillations/intrusions
Psychogenic flutter Staircase saccadic intrusions
Hysterical flutter Superior oblique myokymia
Hysterical “nystagmus”
“Ocular fibrillation”
“Ocular shuddering”
Psychological “nystagmus”
Voluntary flutter
Voluntary “nystagmus”
Synonyms and other terms are indented under either the preferred or the more inclusive designation; quoted terms are erroneous or misleading.

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FIGURE 5.10 Diagrammatic representation of ocular motility recordings of major types of saccadic dis-
orders. 0, point of origin of eye; D, dysmetria; DSP, double saccadic pulses; F, flutter; FD, flutter dysmetria;
MSO, macrosaccadic oscillations; SP, saccadic pulses; SPT, saccadic pulse trains; SSI, staircase saccadic
intrusions; SWJ, square-wave jerks; SWO, square-wave oscillations; SWP, square-wave pulses; T, target;
t, time axis.

desired position of gaze is the primary abnor- frontal eye fields, and mesencephalic reticular
mality, and from saccadic dysmetria, in which formation.
the eye over- or undershoots a target, some-
times several times, before achieving stable fi x-
5.3.1 Square-Wave Jerks and
ation. Because all of these movements are often
Oscillations
rapid and brief, it may be necessary to measure
eye and target position, as well as eye velocity, Square-wave jerks (SWJ, also called
in order to identify the saccadic abnormality Gegenrucke) are a common fi nding in healthy
accurately. persons. They have a typical profi le on eye-
The saccadic command is generated by movement records, and it is this profi le from
burst neurons of the brainstem reticular for- which their name is derived.182–184 As illus-
mation that project monosynaptically to ocular trated in Figure 5.10, they are small, conjugate
motoneurons.179–181 The burst neurons for hor- saccadic intrusions, ranging from 0.5 to 5.0° in
izontal saccades are located in the PPRF, and size, that take the eye away from the fi xation
the burst neurons for vertical and torsional sac- position and return it after about 200 milli-
cades are located in the riMLF. Burst neurons seconds. They are often more prominent dur-
discharge only during saccadic eye movements. ing smooth pursuit, are most easily detected
The activity of all saccadic burst neurons is during ophthalmoscopy, and are also present
gated by omnipause neurons, which are crucial in darkness. SWJ with an increased frequency
for suppressing unwanted saccades during fi xa- (up to 2 Hz) occur in certain cerebellar syn-
tion and slow eye movements. The omnipause dromes, in progressive supranuclear palsy, and
neurons are located in the caudal pons within in cerebral hemispheric disease. The character-
the raphe interpositus nucleus (RIP), adjacent istics of SWJ are summarized in Table 5.7.
to the abducens nucleus. Inputs into omni- Although present in many normals, when
pause neurons arise in the superior colliculus, they are prominent during fi xation, they should

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Table 5.7 Characteristics of Saccadic Instabilities

S QUA R E -WAV E S QUA R E -WAV E S QUA R E -WAV E M AC R O S AC C A DIC

JER KS O S C I L L A T ION S P U L S E S * O S C I L L A T ION S
Amplitude 0.5°–5°1 0.5°–5°1 4°–30° 1°–30°
Constant Constant Variable Increasing then
decreasing
Time course Sporadic/bursts Bursts Bursts/sporadic Bursts
Latency 200 msec 200 msec 50–150 msec 200 msec
Foveation Yes Yes Yes No
Presence in Yes Yes Yes No
darkness
*Previously designated macro square-wave jerks.
1
Occasionally up to 10°.

be considered abnormal, although lacking diag- SWJ are also found in 70% of patients with
nostic specificity, much like saccadic pursuit. acute or chronic focal cerebral lesions and are
SWJ are a subtle disturbance that is easily missed the rule in progressive supranuclear palsy and
clinically. However, they are obvious with eye- Parkinson disease. Schizophrenic patients and
movement recordings, which also allow other their parents188 exhibit SWJ, which are also
types of saccadic intrusions to be identified.185 present during smooth pursuit and have been
Because the individual saccades in SWJ are usu- mistaken for a deficit in the pursuit system.
ally small, they may contain dynamic overshoots. The frequency and metrics of SWJ are influ-
Clinically, they are often best identified during enced by the task being performed.189 A post-
slit-lamp biomicroscopy or funduscopy, but they fl ight increase in SWJ in an astronaut may have
may be difficult to distinguish from other intru- been responsible for his increased postfl ight
sions (e.g., square-wave pulses). As was pointed dynamic visual function.190 The mechanism of
out in earlier chapters, SWJ may also appear in SWJ may be linked to attention and its effect on
individuals with nystagmus (benign or symp- the balance between fi xation and saccade gen-
tomatic); they are merely superimposed on the eration191; endogenous rather than exogenous
nystagmus and do not represent a different type attention was the major factor.192 SWJ corre-
of nystagmus. lated with the velocities of steady drift s were
SWJ is significantly more common in the found in albinos without INS, suggesting that
elderly population than in young subjects. Their both might be related to a failure in saccadic
appearance at a rate greater than 9/minute in system development.193
young patients is considered abnormal. SWJ When SWJ form a continuous train, they are
frequency in normals is approximately 7/min called square-wave oscillations (SWO). These
and they were unidirectional in 94% of the continuously occurring SWJ have been recorded
subjects.186 Other types of saccadic intrusions in patients with a variety of neurologic deficits
were also found in this study: saccadic pulses (see Fig. 5.10). The characteristics of SWO are
and double saccadic pulses (see later) were identical to those of SWJ (see Table 5.7). In
found in 22% and 68% of the subjects, respec- a patient with progressive supranuclear palsy,
tively. The effect of age on the prevalence of SWO appeared to be part of a continuum with
SWJ is unclear as that study did not fi nd an age SWJ; at times, single or several SWJ occurred,
factor. However, a subsequent study did fi nd an and at other times there were long runs of SWJ
increase with age.187 that were identified as SWO.194

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During steady fi xation, the threshold for elec- the initial spurious saccade that initially drove
trical stimulation of saccades in either the frontal the eyes off target.196
eye fields or the superior colliculus is elevated,
mediated through the projections of these struc-
5.3.3 Staircase Saccadic Intrusions
tures to the omnipause neurons.195 In the rostral
superior colliculus, a distinct population of “fi xa- We identified a unique type of saccadic intru-
tion neurons” has been identified and in the fron- sion in a patient with cerebellar atrophy,
tal eye fields, neurons active during suppression named “staircase saccadic intrusions” (SSI)
of saccades have been identified. Pharmacologic because of its appearance in eye-movement
inactivation at both sites leads to disruption of recordings.199 Fixation would be interrupted
fi xation by these saccadic intrusions, but not by by a series of saccades in one direction or the
flutter or opsoclonus. Impairment of any projec- other with normal intersaccadic intervals (see
tions to the omnipause neurons can lead to sac- Fig. 5.10). The individual saccades could be
cadic intrusions. of equal amplitude or could vary. Staircase
Mechanistically, SWJ and SWO are hypoth- saccadic intrusions were also present during
esized to occur when there is dysfunction in the smooth pursuit. In normals, such “staircase”
internal reconstruction of target position, as eye movements can be generated by feeding
shown in Figure 5.11. When this hypothesis was back the eye-movement signal and allowing
incorporated into our behavioral ocular motor sys- it to move the target in the same direction.
tem model, SWJ were generated, as demonstrated Th is produces a constant retinal error signal
in Figure 5.12, top left and top right panels. that drives the saccadic system in a staircase
manner with normal intersaccadic intervals,
as shown in the simulation of Figure 5.12,
5.3.2 Square-Wave Pulses
bottom left panel. We modeled SSI using a
Square-wave pulses (SWP), originally given the behavioral OMS model 200 by simultaneously
misleading name “macro square-wave jerks,” interfering with the retinal error signal and
are usually larger in amplitude than SWJ (typi- creating a constant reconstructed error signal
cally greater than 5°), are related to fi xation, and (see Fig. 5.11); the simulation is shown in
have a frequency of about 2 Hz.182,183,196,197 They Figure 5.12, bottom right panel. The individ-
generally occur in bursts but may appear as a ual hypotheses for SWJ/SWO and SSI embod-
single saccadic intrusion. Both eyes suddenly ied in the model were severely tested during
and conjugately move off target with a saccade, simulation of the eye movements of a patient
and after a latent period of only about 80 mil- with Joubert syndrome, shown in Figure 5.13,
liseconds, a non–visually evoked reflex saccade who exhibited SWJ, SWO, and SSI in vari-
brings them back on target (see Fig. 5.10). SWP ous mixtures. 201 By combining our hypothet-
are not merely large SWJ; the characteristics of ical mechanisms for each of the simultaneous
both are summarized in Table 5.7. These sac- dysfunctions, the model accurately simu-
cadic intrusions occur in light or darkness. SWP lated the mixtures recorded from the patient
usually occur in patients with marked extremity (see Fig. 5.14), ruled out the loss of efference
ataxia suggestive of cerebellar outflow disease, copy as a cause, and led us to the specific mech-
especially when the patient has demyelinating anisms for each that are shown in Figure 5.11.
lesions.196 A unique variety of SWP, present with
binocular fi xation at distance but stopping when
5.3.4 Macrosaccadic Oscillations
either eye was closed, prompted the designation
“inverse latent SWP.”198 Macrosaccadic oscillations (MSO) usually con-
The underlying mechanism for SWP was sist of horizontal saccades that occur in bursts,
hypothesized to rely on efference copy of the initially building up and then decreasing in
motor output signal that could program the amplitude, with intersaccadic intervals of about
short-latency return saccade in response to 200 milliseconds. The characteristics of MSO

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FIGURE 5.11 Behavioral ocular motor system (OMS) model with an expanded view (dark lines) of the portion of the relevant functional circuitry within the internal
monitor that is responsible for target reconstruction from retina error and efference copy of eye position, reconstructed sampled target position (i.e., perceived target posi-
tion), reconstruction of retinal position error (sampled), and generation of the saccadic motor command after accounting for internally generated eye movement (e.g., nys-
tagmus). Shown are the mechanistic sites of dysfunction producing square-wave jerks/oscillations (SWJ/SWO), staircase saccadic intrusions (SSI), flutter (FLUT), double
saccadic pulses (DSP), neural integrator leak (NI), or low/no-gain smooth pursuit.

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FIGURE 5.12 Behavioral ocular motor system (OMS) model simulations of the individual components
of the saccadic intrusions and oscillations found in subjects with cerebellar atrophy or Joubert syndrome.
(Top left) Square-wave jerks (SWJ) before and after response to a step change in target position. (Top right)
SWJ before and square-wave oscillations (SWO) after response to a step change in target position. (Bottom
left) Simulation of a rightward, equal-step staircase saccadic intrusions (SSI) due to opening the retinal loop.
(Bottom right) Simulation of a rightward, equal-step SSI during fi xation.

are summarized in Table 5.7. Described origi- by a spurious pulse of innervation, provided by
nally in cerebellar patients, MSO are thought the burst cells without the usual accompanying
to be an extreme form of saccadic dysmetria, in step. The resultant eye movement consists of
which the patient’s saccades are so hypermetric a saccade away from the fi xation position fol-
that they overshoot the target continuously in lowed immediately by a glissadic drift back to
both directions and thus oscillate around the the target (see Fig. 5.10). The glissadic drift in
fi xation point.182,183,197 They are usually induced SP represents failure of the neural integrator to
by a gaze shift, but they may also occur during produce a step of innervation from the burst
attempted fi xation or even in darkness. They producing the SP. Th is difference from SWJ
are often visually disabling and have vertical or suggests dysfunction in the pause cell/burst
torsional components. MSO are occasionally cell circuitry for SP and a more central dys-
encountered in patients with myasthenia gravis function for SWJ. Saccadic pulses may occur
after administration of edrophonium.202 in series or as doublets.164,203 They are encoun-
tered in some normal subjects and in patients
with multiple sclerosis.
5.3.5 Saccadic Pulses (Single and
Saccadic pulse trains (SPT) are contin-
Double)
uous runs of SP and, as Figure 5.10 shows,
Saccadic pulses (SP), originally called “stepless may be easily confused with nystagmus. Even
saccades,” are brief intrusions on fi xation caused on good eye-movement records, SPT cannot

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FIGURE 5.13 Examples of the complex ocular motor disorders occurring during attempted fi xation of a
target in primary position from a subject with Joubert syndrome. (Top left) Left ward, equal-step staircase
saccadic intrusions (SSI) including a left ward square-wave jerks (SWJ) and uniocular neural integrator leak
of the left eye in left gaze (LE, left). (Top right) Rightward, unequal-step SSI with uniocular neural integra-
tor leak of the right eye in right gaze (RE, right) followed by flutter during the refi xation and SWO with neu-
ral integrator leak of both eyes in left gaze (BE, left). (Bottom left) Rightward, unequal-step SSI followed by
divergent flutter during the refi xation. (Bottom right) Divergent-saccade (D-S) followed by D-S nystagmus
with neural integrator leak of both eyes. FLUT, flutter; LEH, left eye horizontal (thin trace); REH, right eye
horizontal (heavy trace), and both eyes were viewing.

be distinguished from jerk nystagmus with fast phase bringing the eye back to the tar-
decreasing-velocity slow phases, unless both get. The so-called abduction “nystagmus” of
eye position and target position are known. internuclear ophthalmoplegia is an SPT. 204
The initiation of an SP is a saccade off tar- Several patients with congenital achromatop-
get, whereas jerk nystagmus is initiated by sia thought to have INS did not contain any
the slow phase off target, with the saccadic of the known INS waveforms but instead had

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FIGURE 5.14 Behavioral ocular motor system (OMS) model simulations of the complex saccadic intru-
sions and oscillations found in a subject with Joubert syndrome by different combinations of their indi-
vidual components. (Top left) Square-wave jerks (SWJ) before and after a rightward, equal-step staircase
saccadic intrusions (SSI) and refi xation during attempted fi xation. (Top right) Square-wave oscillations
(SWO) after a rightward, equal-step SSI and refi xation during attempted fi xation. (Bottom left) Simulation
of a rightward, unequal-step SSI during fi xation, preceded by a SWJ and followed by a SWO. (Bottom right)
Simulation of a rightward, unequal-step SSI during fi xation, followed by a SWO.

oscillations consistent with SPT. Although retractory movements, or both. Affected patients
the waveforms mimicked those of FMNS, usually have impaired or absent upward gaze
there were no effects of monocular fixation. for both pursuit and saccadic eye movements;
however, in some cases upward pursuit appears
normal, whereas upward saccades are obviously
5.3.6 Convergence-Retraction
abnormal. Convergence-retraction “nystag-
“Nystagmus”
mus” is commonly produced by lesions of the
Convergence-retraction “nystagmus” is a misno- mesencephalon that damage the posterior com-
mer since the abnormality is in the vergence and missure, such as pineal tumors. It probable that
fast eye movement systems.153,205 It is character- convergence-retraction nystagmus is, in fact,
ized by quick phases that converge or retract the a vergence and saccadic disorder rather than nys-
eyes on attempts to look up. It is elicited either tagmus because the primary adductive move-
by asking the patient to make an upward sac- ments are asynchronous adducting saccades
cade or by using a handheld optokinetic drum and some studies have indicated that the move-
or tape and moving the stripes or figures down. ments may be vergence in origin. Convergence-
Th is maneuver produces slow, downward, pur- retraction “nystagmus” may also occur with
suit eye movements, but upward quick phases a Chiari malformation or epileptic seizures.206
are replaced by rapid convergent movements, It is usually intermittent, being determined by

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saccadic activity, and it thus can be differenti- 5.3.9 Ocular Flutter

ated from other more continuous forms of dis-
junctive nystagmus, such as pendular vergence The pathogenesis of saccadic oscillations with-
nystagmus and the oculomasticatory myorhyth- out an intersaccadic interval, for example, ocu-
mia characteristic of Whipple disease. A jerk- lar flutter and opsoclonus, seems closely related
waveform divergence nystagmus is rare, but it to the properties of the burst neurons them-
may occur in patients with cerebellar disease, selves.164 Burst neurons have very high discharge
such as the Chiari malformation. In such cases, rates (up to 1000 spikes per second), and they
combined divergent and downbeat nystagmus discharge vigorously even for small saccades.
produces slow phases that are directed upward The anatomical connections between burst neu-
and inward. Other components of this clinical rons in the brainstem and their high discharge
syndrome include light-near dissociation, dorsal rates (“gain”) predisposes to oscillations if the
midbrain lesions, and vertical gaze palsy. omnipause neurons are not actively inhibiting
them and no specific saccadic command has
been issued. Disease affecting omnipause neu-
5.3.7 Dissociated Ocular Oscillations rons, or their afferents, might be expected to
In dissociated nystagmus, there is a signifi- lead to saccadic oscillations such as ocular flutter
cant asymmetry in either amplitude or direc- and opsoclonus. Contrary to this, studies have
tion of the two eyes. The pendular nystagmus shown that chemical lesions of the omnipause
in patients with multiple sclerosis is usually neurons are reported to cause slowing of both
dissociated. There are a variety of nystagmus horizontal and vertical saccades. Attempts to
dissociations with lesions of the posterior fossa demonstrate histopathologic changes in omni-
(e.g., asymmetric vertical nystagmus greater in pause neurons in some patients with paraneo-
one eye on looking up and in the other eye on plastic saccadic oscillations have usually failed
looking down). to show any changes. It has been suggested that,
A common type of dissociation occurs in in paraneoplastic opsoclonus, the tumor and
internuclear ophthalmoplegias, where the most certain CNS structures share an epitope.208 Th is
marked oscillation is in the abducting eye. common epitope elicits an efficient immune
However, this abduction “nystagmus,” some- response against the tumor, thus conferring
times designated by the confusing term “ataxic” a more indolent oncologic course, but it also elic-
nystagmus, is not really a nystagmus. Instead, it its an immune response against normal neural
is a saccadic oscillation secondary to lesions of tissue, causing the neurologic syndrome. There
the medial longitudinal fasciculus and is dis- is some evidence that impaired glycinergic
cussed in Section 5.3.5. transmission may play a role in the pathogenesis
of both ocular flutter and opsoclonus. Poisoning
with a glycinergic antagonist, strychnine, can
5.3.8 Dysmetric Saccades produce both myoclonus and opsoclonus and
Ocular dysmetria is provided by refi xation sac- in hyperekplexia, abnormal receptors to glycine
cades and consists of undershooting (hypome- are found. The concurrent appearance of opso-
tria) or overshooting (hypermetria) followed clonus with myoclonus may suggest a similar
by brief small-amplitude saccadic oscillations mechanism. Glycine is identified as the neuro-
before the eyes come to a new fi xation point, transmitter of the omnipause neurons and their
or conjugate overshooting followed by a single glycinergic dysfunction, presumably caused by
corrective saccade to bring the eye back to the autoantibodies, might be responsible for the
target. There is an intersaccadic latency between opsoclonus-myoclonus syndrome.
the various corrective saccades. One type of Cerebellar dysfunction has traditionally
dysmetria, hypermetria, is illustrated in Figure been blamed for ocular flutter and opsoclonus.
5.10. Dysmetria is a common sign of cerebellar Functional imaging in patients with opsoclonus
system disease.207 has shown activation of deep cerebellar nuclei.

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However, experimental lesions of the cerebellum may also accompany opsoclonus. In about 50% of
do not produce these oscillations, even though cases, the etiology remains obscure. In children,
striking saccadic dysmetria can be produced, about half the cases of opsoclonus are associated
especially when the caudal fastigial nuclei of the with tumors of neural crest origin, such as neu-
cerebellum are inactivated.209,210 roblastoma.203 Low cerebrospinal fluid concen-
trations of 5-hydroxyindolacetic acid (5-HIAA)
and homovanillic acid (HVA) can often be
5.3.10 Flutter Dysmetria
demonstrated in children with the opsoclonus-
Flutter dysmetria (FD) is the occurrence of flut- myoclonus syndrome. However, cerebrospinal
ter immediately after a saccade (Fig. 5.10).211 fluid abnormalities may occur in opsoclonus
It superficially resembles dysmetria, but eye- associated with both tumor and encephalitis;
movement recordings reveal that FD is an oscil- thus, they may not help to distinguish between
lation about the intended fi xation angle and the infectious and paraneoplastic etiologies.
consists of back-to-back saccades with no inter- Various autoantibodies can be detected in sera of
saccadic latencies. Th is contrasts with dysme- some patients with opsoclonus. Of these, anti-Ri
tria in which the saccadic oscillation has normal antibody is the most common.212,213 Anti-Hu
intersaccadic latencies. FD is seen in a sett ing of antibody has been reported with opsoclonus
cerebellar disease. in two children with neuroblastoma and in an
adult with small-cell lung cancer. Th is is an ant
neuronal antibody that binds nuclear RNA and
5.3.11 Opsoclonus
is usually associated with paraneoplastic sen-
There is a continuum between saccadic pulses sory neuronopathy, cerebellar degeneration, and
and saccadic oscillations without an intersacca- limbic encephalitis. The prognosis of idiopathic
dic interval. The latter may occur in one direction, opsoclonus (including patients with manifes-
usually the horizontal plane, in which case they tations of brainstem encephalitis) is generally
are called ocular flutter. If they are multivectorial, good. Some patients with paraneoplastic opso-
they are termed “opsoclonus” or “saccadomania.” clonus myoclonus show spontaneous remissions,
The frequency of oscillations is usually high, typi- irrespective of the underlying tumor. Patients
cally 10–15 Hz, being higher with smaller-sized whose tumor can be identified and treated may
movements. Ocular flutter may be intermittent recover neurologically; those who are not treated
and mainly associated with voluntary saccades have a more severe course.
(flutter dysmetria) or convergence movements.
Occasionally, the amplitude of the oscillations
5.3.12 Superior Oblique Myokymia
is very small (“microflutter”). In such cases, the
movements may be detected only with a slit lamp, Superior oblique myokymia (SOM) was fi rst
an ophthalmoscope, or eye-movement record- described by Duane in 1906, but clinicians
ings. Sustained opsoclonus is a striking finding, became generally aware of the disorder fol-
in which multidirectional conjugate saccades, lowing the description by Hoyt and Keane in
usually of large amplitude, interfere with steady 1970. 214 Typical symptoms include monocu-
fi xation, smooth pursuit, or convergence. These lar blurring of vision, tremulous sensations in
movements may persist during sleep. the eye, brief episodes of vertical or torsional
diplopia, and vertical or torsional oscillopsia. 215
Att acks last less than 10 seconds and may occur
5.3.11.1 O P S O C L O N US - M YO C L O N US
many times per day; they may be elicited on by
Opsoclonus is often accompanied by myoclo- looking downward, by tilting the head toward
nus—brief jerky involuntary limb movements— the side of the affected eye, and by blinking.
hence the term “opsoclonus-myoclonus.” In The majority of patients with SOM have no
children, this syndrome is called “dancing eyes underlying disease, although cases have been
and dancing feet.” Ataxia and encephalopathy reported following trochlear nerve palsy, after

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mild head trauma, in the sett ing of multiple but anticholinergic medicines are ineffective
sclerosis, after brainstem stroke, and in patients in this condition. Other conditions that may
with cerebellar tumor. mimic ocular neuromyotonia include superior
The eye movements of SOM are often difficult oblique myokymia, thyroid eye disease, and
to appreciate on gross examination, although cyclic oculomotor palsy.
they are usually apparent during examination The symptoms of ocular neuromyotonia are
with the ophthalmoscope or slit-lamp biomicro- caused by involuntary, and at times painful, con-
scope. They consist of spasms of cyclotorsional traction of the lateral rectus muscle, the supe-
and vertical movements. Measurement of the rior oblique muscle, or one or more extraocular
movements of SOM using the magnetic search muscles innervated by the oculomotor nerve.
coil technique reveals an initial intorsion and Extraocular muscles innervated by more than
depression of the affected eye, followed by irreg- one ocular motor nerve may occasionally be
ular oscillations of small amplitude and variable affected, and rare patients with bilateral ocular
frequency.216 Some resemble jerk nystagmus, neuromyotonia have been reported. Comparing
with frequencies of 2–6 Hz, but superimposed symptoms with attempts at eccentric gaze hold-
upon these oscillations are low-amplitude, irreg- ing may aid in making the diagnosis, as symp-
ular oscillations with frequencies ranging up toms may be absent in primary position but
to 50 Hz. Electromyographic recordings from evoked by sustained eccentric gaze. The mech-
superior oblique muscles affected by SOM reveal anism responsible for ocular neuromyotonia is
some fibers that discharge either spontaneously unknown, although both ephaptic neural trans-
or following contraction of the muscle. These mission and changes in the pattern of neuronal
muscle potentials are abnormal, with increased transmission following denervation have been
duration (greater than 2 milliseconds) and suggested, since spontaneous activity is seen
amplitude, and they are polyphasic, with a spon- in the ocular electromyogram of some affected
taneous discharge rate of approximately 45 Hz. patients. Axonal hyperexcitability caused by
Spontaneous activity is absent only with large dysfunction of potassium channels has also been
saccades in the “off ” (upward) direction and is implicated in the production of neuromyotonia
less affected by vestibular eye movements. Some by analogy with systemic neuromyotonia.
fi ring units show an irregular discharge follow-
ing muscle contraction before subsiding to a reg-
5.3.13 Ocular Bobbing
ular discharge of 35 Hz. These fi ndings suggest
that the etiology of SOM is neuronal damage Ocular bobbing is a distinctive spontaneous ver-
and subsequent regeneration, leading to desyn- tical eye-movement disturbance, readily distin-
chronized contraction of muscle fibers. Indeed, guished from downbeat nystagmus and ocular
experimental lesions of the trochlear nerve dem- myoclonus. Bobbing refers to fast downward
onstrate regenerative capacities such that the jerks of both eyes followed by a slow drift to
remaining motor neurons increase their num- midposition.218 The downward jerks may be dis-
ber of axons to hold the total constant. Superior jugate in the two eyes, and often the eyes remain
oblique myokymia only rarely is preceded by an deviated for several seconds before returning to
ipsilateral trochlear nerve palsy. midposition. Bobbing can be divided into three
Ocular neuromyotonia is a rare disorder types: typical, monocular, and atypical.219
characterized by episodes of diplopia that are
usually precipitated by holding the eyes in
5.3.13.1 T Y P I C A L
eccentric gaze, often sustained adduction. 217
Most reported patients have undergone radi- Ocular bobbing consists of intermittent, usu-
ation to the parasellar region, but idiopathic ally conjugate, rapid downward movement of
cases have been reported. The episodic nature the eyes, followed by a slower return to primary
of the diplopia associated with ocular neuro- position. Reflex horizontal eye movements are
myotonia often suggests myasthenia gravis, usually absent; that is, it appears in patients with

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paralysis of horizontal conjugate eye movements. occurred in a patient with a pinealoblastoma.

The pathophysiology of all types of ocular bob- A depressed level of consciousness is not a prereq-
bing is uncertain, but putative hypotheses are uisite for its appearance. Some patients in coma
numerous. Bobbing usually occurs in comatose may demonstrate all three types of spontaneous
patients with extensive destruction of the pons, vertical movements: ocular bobbing, ocular dip-
but extrapontine compressions, obstructive ping, and reverse bobbing.232 Ocular dipping
hydrocephalus, metabolic encephalopathy, and may lead to a vertical gaze paresis (e.g. in Jacob-
encephalitis occasionally are causative.220 Creutzfeldt disease)233 or may coexist with ping-
pong gaze (e.g., hypoxic encephalopathy). 234
In addition to these three types of bobbing
5.3.13. 2 M O N O C U L A R
(typical, monocular, and atypical), we described
Monocular bobbing reflects coexisting contra- a phenomenon designated “reverse bobbing,” in
lateral third-nerve paresis.219 In two cases, a pon- which the eyes jerked upward with a fast move-
tine lesion plus an oculomotor lesion resulted in ment and then slowly returned to the horizon-
monocular bobbing221; in some cases, no expla- tal; the patients were deeply comatose as a result
nation could be found.222 of metabolic encephalopathy. Reverse bobbing
may coexist with typical bobbing with lesions
of the dorsal median portion of the pontine
5.3.13.3 AT Y P I C A L
tegmentum.235
The third category, atypical bobbing, includes
downward bobbing with convergence move-
5.3.14 Psychogenic Flutter (Voluntary
ments, asymmetric bobbing without an asso-
“Nystagmus”)
ciated oculomotor palsy, and bobbing with
intact spontaneous or reflex horizontal eye Voluntary (hysterical, psychological) “nystag-
movements; the latter variety suggests diff use mus” is not nystagmus at all but a series of back-
encephalopathy, hydrocephalus, or organophos- to-back saccades, interrupting fi xation, whose
phate poisoning, rather than severe intrinsic timing is such that the waveform traced out
pontine disease.223 Atypical bobbing may be dis- appears to be pendular (i.e., a psychogenic or
conjugate.222 Associated signs and symptoms of voluntary flutter). The most accurate and inclu-
pontine damage, inverse bobbing has an initial sive term for this oscillation (which has also been
downward movement that is slow and the return called “ocular fibrillation” and “ocular flutter”) is
to midposition is rapid; this has also been called “psychogenic flutter,” introduced in 1980.2
ocular dipping.224 Psychogenic flutter consists of bursts of an
Reverse ocular dipping or converse bobbing extremely rapid, conjugate, horizontal oscilla-
has been used to describe a slow upward drift tion that appears pendular but actually consists
of the eyes followed by a rapid return to cen- of back-to-back saccades.236 As shown in Table
tral position; variants of ocular bobbing are less 5.6, voluntary “nystagmus” is actually flutter.211
diagnostically specific. Two reports of comatose It may be used as a party trick or as a conscious
patients who demonstrated a slow downward eye attempt to feign illness. The oscillation is read-
movement, followed, after a variable delay, by ily identified by the extreme rapidity (approxi-
a quick saccade up to midposition. Th is disorder mately 20 Hz, with a range of 8 to 23 Hz) and
was called “inverse bobbing” in one report225 and brevity of each burst (maximum duration usually
“ocular dipping” in the other.226 The latter term less than 30 seconds). Most subjects do not sus-
(dipping) seems to have achieved favor.227–230 The tain the oscillation for more than 10 seconds and
upward jerking of the eyes is occasionally associ- manifest facial distortions with eyelid closure to
ated with contraction of the orbicularis oculi.231 “rest” their eyes in preparation for another out-
The phenomenon is regarded as mechanistically burst. The ability to perform this stunt may be
similar to the sustained downgaze deviation hereditary, and it is present in about 5%–8% of
seen occasionally in comatose patients and has the population but in 79% of their relatives.237,238

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Rarely, psychogenic flutter may be vertical 239 or 9. Sarvananthan N, Surendran M, Roberts

multidirectional, mimicking opsoclonus. 240 In a EO, et al. The prevalence of nystagmus: the
family we recorded in the 1970s, it was exhibited Leicestershire nystagmus survey. Invest
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by a father and two sons, with the father able to
10. Norn MS. Congenital idiopathic nystagmus.
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and converging the eyes; it may also occur with manifest latent, and congenital nystagmus.
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6
afferent visual system—clinical
ex amination procedures
6.1 SUBJECTIVE TESTING 185 6.1.6 Gaze- and Time-Dependent Acuity
6.1.1 Teller Acuity Card Procedure Testing 192
185 6.1.7 Visual Field Testing 193
6.1.2 Visual Acuity Testing (High Spatial 6.2 OBJECTIVE TESTING 194
Frequency Vision) 187 6.2.1 Visual Evoked Potentials 194
6.1.3 Stereo Testing 187 6.2.2 Electroretinography 197
6.1.4 Color-Vision Testing 190 6.2.3 Optical Coherence Tomography 200
6.1.5 Contrast-Sensitivity Testing 191 6.2.4 Fundus Photography 202

One cannot be a good observer unless one is a good theorist.

—Charles Darwin (1809–1882)

THE R ELATIONSHIP between develop- To measure afferent system function separately,

ment of visual function(s) and an ongoing ocular a number of subjective and objective tests can
oscillation in infancy and childhood is complex be used in infants and children with nystagmus.
and dynamic. In addition to an age-dependent There is a voluminous amount of material avail-
suppression of oscillopsia, the oscillation has a able to the reader describing the general history,
direct effect on visual acuity, contrast sensitiv- application, methodology, and results of these
ity, motion detection, visual recognition time, tests. 3–6 It is our purpose here to focus on how
gaze-dependent acuity, size of functional vis- these tests are interpreted, implemented, and/
ual space, possible accommodation, and the or modified for those infants and children with
creation of motion-induced amblyopia.1,2 In nystagmus with emphasis on infantile nystag-
over 50% of infants and children with ocular mus syndrome (INS) and fusion maldevelop-
oscillations, there are, in addition, many possi- ment syndrome (FMNS).
ble types of associated afferent system deficits
(i.e., foveal dysplasia/hypoplasia, photophobia/
6.1 SUBJECTIVE TESTING
light interference, optic nerve dysplasia/hyp-
oplasia, retinal dystrophy/degeneration, ambly-
6.1.1 Teller Acuity Card Procedure
opia, ametropia, cortical-subcortical visual
impairment, and delayed visual maturation). 3 In 1958, Berlyne and Fantz independently
The coexisting presence of nystagmus and an observed what was to be termed preferential
afferent system deficit imposes multifactorial looking (PL) or forced-preferential looking
limitations on all aspects of visual development. (FPL) behavior.7–9 PL behavior is based on the

• 185

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infantile preference to look at a pattern rather side of the card opposite the patch of grat-
than a homogenous background. PL was fi rst ing. Despite these differences, the acuity val-
used in 1962 to test visual acuity by comparing ues obtained with the commercially produced
visual data to mean acuity of specific age groups. cards were similar to acuity values obtained
In the 1970s, Teller introduced the forced- with the prototype cards.
choice preferential looking test, which yielded After the introduction of the commer-
more individualized data.7–9 cially produced TAC, a number of investi-
The acuity card procedure was developed gators published normative monocular and
to allow the rapid measurement of grating vis- binocular grating acuity data for infants and
ual acuity in infants and young children in young children.10–13 The company that pro-
both clinical and laboratory sett ings (Fig. 6.1). duced the TAC (Vistech Consultants, Inc.)
Initially, acuity cards were constructed of gray went out of business, and another company
cardboard, with a grating that varied in spatial (Stereo Optical Co., Inc., Chicago, IL) began
frequency from card to card mounted behind producing a modified version of the cards,
an aperture on one side of the card, and a high the Teller Acuity Cards™ II (TAC II). The
spatial frequency grating, composed of very TAC II differs from the original TAC in two
fi ne black-and-white stripes, mounted behind important ways. First, the face of each of the
an aperture on the other side of the card. Aft er new cards is laminated, producing lower con-
the initial success of the cards in clinical set- trast in the gratings on the new cards. Second,
tings, a commercially produced version of the improved production technology has elimi-
acuity cards became available (Teller Acuity nated the “edge artifact” that appeared as
Cards™ [TAC], Vistech Consultants, Inc., a visible line around the patch of grating on
Dayton, OH). The commercially produced the card in the original TAC that contained
acuity cards differed from the prototype cards the highest spatial frequency grating (38
in three important ways: (1) the patch of grat- cycles/cm). Recently Clifford et al. found that
ing that varied from card to card was square, acuity scores obtained with the original TAC
rather than circular, (2) the grating was printed (Vistech Consultants, Inc.) are approximately
on the card rather than being mounted behind 0.5 octave (one card step) better than acuity
an aperture, and (3) there was no well-defi ned, scores obtained with the newly developed
high spatial frequency “blank” target on the TAC II (Stereo Optical Co., Inc.).14

FIGURE 6.1 Example of Teller acuity card held vertically in front of an infant with nystagmus.

186 • A FFER ENT V ISUA L S YSTEM—CLI N ICA L E X A M I NATION PROCEDU R ES

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In infants and children with nystagmus it is based on gaze, ocular laterality, mental state,
best to begin the presentation protocol at the and time.
shortest distance with the 0.32 cycles/cm card. We prefer to test visual acuity in the
It is also important to hold the TAC vertically patient’s preferred null zone (INS), deter-
so that the gratings are horizontally oriented. mined by the use of clinical evaluation, head
Binocular acuity is tested fi rst. Patients should posture measuring system, or eye-movement
be tested in their preferred head position. After recordings, or in adduction of the fixating
binocular testing, the right eye is tested fi rst, fol- eye (FMNS). This is accomplished while the
lowed by the left . Although it is generally agreed patient is wearing his or her best optical cor-
that reliable Snellen-equivalent visual acuity rection, first, binocularly, then monocularly,
measurements cannot be obtained until assessed using the PEDIG Study group ATS HOTV©
with a recognition test using linear letters or protocol for subjects ages 3 to < 7 years and
symbols, grating acuity can be used to assess the ATS Electronic Early Treatment Diabetic
a reduction, change, or variation from normal Retinopathy Study (E-ETDRS ©) protocol
visual function in the fi rst 3 years of life.8 for subjects ages ≥7 years (see Table 6.1).16,17
This type of testing has shown validity and
reliability across all age groups. Almost 20%
6.1.2 Visual Acuity Testing (High
of otherwise normal 2-year-olds are able to
Spatial Frequency Vision)
reliably perform matching acuity. Using
Recognition of black letters on a white screen or it allows the clinician to accurately assess
its measure (Snellen, Early Treatment Diabetic the natural progression/regression or the
Retinopathy Study, Cardiff, Landolt-C, Lea impact of interventions on a standard meas-
Symbols, and HOTV acuity) is understanda- ure of high spatial frequency vision in these
bly important to clinicians and their patients. patients (Fig. 6.2).
Unfortunately, high spatial frequency vision
was, is, and continues to be a poor “primary”
6.1.3 Stereo Testing
measure of ocular motor function. For example,
a patient with INS and a latent component has Stereopsis is a neurologically dependent on nor-
multiple optotype measures of acuity depending mal binocular vision. Its presence or absence is
on mental state, attention, and whether fi xation an important indicator of the state of binocular-
is monocular, binocular, at distance or near, or ity in patients with all ocular motility disorders.
at eccentric gaze angles. Another 17% to 33% Several studies using different paradigms such
of patients with INS have a periodically chang- as line stereograms and a preferential looking
ing cycle in which their null zone and best vis- procedure, random dots with a forced-choice
ual function exist not only at a place in space but preferential looking technique, and random
also during a period in time, making measures dots with visually evoked responses have shown
of acuity not only statically but also dynamically stereopsis is absent in almost all infants less
dependent. Vision, used as a measure of visual than 3 months old, after which it rapidly devel-
function in patients with ocular oscillations, ops to normal levels, which are reached by the
must be explicit, because there are at least five sixth month of life. Patients with nystagmus and
psychophysical measures of acuity (i.e., detec- good binocular function will be able to respond
tion, recognition, resolution, hyperacuity, and appropriately when tested for stereopsis.
localization).15 Equipment for testing stereopsis ranges from
In patents with INS, measuring best-cor- simple equipment to complex laboratory appa-
rected binocular vision in and during the null ratus (Fig. 6.3). The two eyes must be dissoci-
zone is a visually unique ocular motor variable ated; that is, each eye must be presented with a
because of the nature of the oscillation. Almost separate field of view, and each of the two fields
all patients with acquired forms of ocular oscil- or targets must contain elements imaged on
lations will have varied measured visual acuity corresponding retinal areas. In the Polaroid

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Table 6.1 Electronic–Early Treatment of Diabetic Retinopathy Study (E-ETDRS)

Vision Testing

E -E T DR S S C R E E N I N G P H A S E
Objective: With single-letter presentations, determine smallest logMAR level at which a letter is
correctly identified
Show one letter per level starting at 20/400 in three-level steps until a letter is missed (20/400,
20/200, 20/100, 20/50, 20/25, 20/12)
• Uses V, R, K, D letters (letter set is limited to intermediate difficulty letters that have
approximately equal difficulty)
• If 20/400 is missed, go to 20/800 and if correct, continue with single letters at 20/640 and
20/500 until one is missed
• If a letter smaller than 20/400 is missed:
1) Go up two levels from the missed level (i.e., one level smaller than last correct level) and
continue with one letter at each level until a letter is missed
• Note: a letter missed the fi rst time will end up being retested unless a larger letter is missed
(this protects against an inadvertent miss well above threshold)
2) If the fi rst letter in this step (step b2) is missed, go back up one level at a time until a letter is
correct (this protects against a lucky guess below threshold)
Scoring: The score in screening phase is the last correct level

E -E D T R S T H R E S HO L D P H A S E
Objective: Based on screening phase score, test five letters at each level until smallest level with 5/5
correct and the smallest level with 0/5 correct are determined.
Start testing letters by intermixing letter sizes of screening phase score and one level smaller.
• Uses same letter sequence for each level as on ETDRS chart
• If a letter is missed at a level, one level larger is added to the testing mix
• If a letter is correct at a level, one level smaller is added to the testing mix
Stop testing a level once five letters at that level have been presented
Continue to add larger levels to the testing mix as long as one letter is missed at a level
Continue to add smaller levels to the mix as long as one letter is correct at a level
Test ends when both the smallest level with 5/5 correct and smallest level with 0/5 correct have been
determined.
Scoring: The letter score is calculated as the number of letters correct on the test plus the number of
letters above the “5 of 5” line through 20/800.

Vectograph® test a gross stereoscopic pattern a lozenge. In this sequence the upper, lower, left,
representing a housefly is provided to orient or right circle is disparately imaged at random
the patient and to establish whether there is with thresholds ranging from 800 to 40 seconds
gross stereopsis (threshold: 3000 seconds of of arc. Both of these tests are used for testing near
arc). The Polaroid test also contains three rows vision. The vectograph test can be supplemented
of animals, one animal in each row imaged dis- with a projected vectograph test at distance fi x-
parately (thresholds: 100, 200, and 400 seconds ation (Polaroid Vectographic Project-O-Chart®,
of arc, respectively). The Titmus® test contains American Optical Reichert) or with the B-VAT®
nine sets of four circles arranged in the form of (Mentor) projection device.

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FIGURE 6.2 Demonstration of amblyopia treatment study single surrounded HOTV vision testing,
which is a computerized visual acuity testing method of single surrounded HOTV optotypes developed by
the Pediatric Eye Disease Investigator Group.

FIGURE 6.3 The standard testing methods for use in measuring stereopsis.

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To avoid monocular visual clues that could accommodation) that may be helpful in pla-
confound the Polaroid tests, random-dot stereo- nning, and/or evaluating the effectiveness of,
grams are much more useful for accurate stereo nystagmus treatments. Of 57 patients with
testing. Reinecke and Simon introduced the infantile nystagmus tested for stereopsis by Liu
random-dot E test, which contains three cards et al., only 8 had normal testing. They found
and Polaroid spectacles. One card is a base-re- damaged stereopsis in most patients with “pen-
lief model of the stereo test figure and is used to dular” and more than half with “jerk” nystag-
show the child what to look for. One of the two mus. They found that the better the acuity, the
other test cards contains the E stereo figure, less the stereopsis was damaged.19
and the other is stereo blank with an identical
random-dot background. The test is perception
6.1.4 Color-Vision Testing
of an image in depth. The TNO® test is graded
to provide retinal disparities ranging from 15 to Proper color discrimination requires the pres-
480 seconds of arc. ence of normal cone function. Color deficiency
Occasionally, young children will refuse is common, with as many as 8% of males and
to wear Polaroid or red-green spectacles, and 0.4% of females having some level of color defi-
observing the position of the eyes while the ciency. Most color vision abnormalities in child-
patient is being tested for stereopsis may be ren are present at birth. Color vision improves
desirable. To overcome these difficulties, Lang greatly over the fi rst 3 postnatal months, and
developed a test based on pantographic presen- it approaches adult values rapidly over the fi rst
tation of a random-dot pattern. Glasses are not 6 months of life.20 The overall insensitivity of
needed to recognize the stereoscopic images of infants to contrast is likely to provide a satis-
a star, a car, and a cat embedded in random dots factory explanation of the poor color vision
on the test card. A separate image is provided to of infants. The critical immaturity primarily
each eye through cylindrical lenses imprinted responsible for the high thresholds and poor
on the surface lamination of the test card. color vision of infants is probably after the site
A revised version of this test (Lang II Test®) with of visual adaptation, although lower level fac-
smaller disparities and a less dense arrangement tors may also play a role. 20 Color-vision deficits
of random dots is available. The advantage of the associated with nystagmus are usually caused
Lang I test is that it can be performed in children by concomitant optic nerve or retinal disease
as young as 6 months of age.18 If the baby stares (e.g., optic nerve hypoplasia, optic nerve atro-
for a few seconds at the card, one can infer the phy, achromatopsia, foveal dysplasia, cone-rod
presence of stereopsis, following the same rea- dystrophy etc.).
soning underlying the preferential looking test- Color-vision testing can be achieved with a
ing technique. Stereo tests that use random dots variety of tests (Fig. 6.4). Pseudo-isochromatic
are an accurate and established method to meas- plates, such as those available with the Ishihara®
ure stereo acuity; however, the results obtained and the Hardy-Rand-Ritt ler® tests, are com-
with different tests will vary widely. Testing monly used color vision tests. More advanced
based on random dots exposes the child to vis- tests, such as the Farnsworth D-15® and
ual demands that are different from and more Farnsworth-Munsell 100 Hue® tests, may be
difficult than those prevailing under more cas- used to better characterize the deficit noted on
ual conditions of seeing. Only when the images screening tests, especially in older children.
from the right and left eye are combined at the Pseudoisochromatic plate tests have lim-
neural level and the object is seen in depth does ited effectiveness for young children. At pre-
recognition take place. sent, there are few tests that are appropriate for
The information obtained by testing for young children that demonstrate good valid-
stereopsis in patients with nystagmus allows ity, are inexpensive, allow rapid assessment,
the clinician to assess other aspects of the vis- and are commercially available. A new pseu-
ual system (binocular function, vergence, do-isochromatic color plate test specifically

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FIGURE 6.4 The matching (drawing) test used in preverbal children to test color vision.

designed for young children, “Color-Vision years of age or older to be easily tested. Verbal
Testing Made Easy” (CVTME), has recently identification, drawing over the figure, or
been introduced. Results of a validation study selecting the matching demonstration replica
indicate that CVTME has a high degree of can all be used as testing methods.
efficacy as a color-vision testing young child-
ren and may be well suited to those with nys-
6.1.5 Contrast-Sensitivity Testing
tagmus. CVTME was 100% compatible with
the Ishihara with the same specificity and The current gold standard in the assessment
sensitivity. There were no false positives. of vision, visual acuity, provides only a limited
The response patterns of normal and color- amount of information, obtained under artificial
deficient children were very clear-cut so that conditions. Contrast-sensitivity testing (CST)
a diagnosis was easy and made with a high measures a range of visual performance under
degree of confidence. The selection of Part II real-life conditions. It measures the least amount
(dog, boat, balloon), together with the dem- of contrast needed to detect a visual stimulus
onstration replicas, allows most children 3 and gives a more complete quantification of

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patients’ visual capabilities. Contrast sensitiv- all, subjects with nystagmus alone are poorer
ity is present in early infancy and improves in than that in normal observers under conditions
visually normal children until about 7 years of of comparable retinal image motion. Dickinson
age.21,22 Several contrast test systems are avail- and Abadi reported that CST did not improve
able (Fig. 6.5). The key differences are whether in many INS subjects when the oscillation was
an optotype or a sine wave grating target is used damped by convergence.23 There is psychophys-
for testing. The Pelli-Robson® chart determines ical evidence that retinal motion may contribute
the contrast required to read large letters of to vision loss via an amblyopic component in
a fi xed size. The Regan® chart, a low-contrast let- patients with INS separate from ametropic and
ter chart having differently sized letters, reduces strabismic components.
the contrast levels of a standard Snellen-type
letter acuity chart, resulting in several charts.
6.1.6 Gaze- and Time-Dependent
The Functional Acuity Contrast Test (FACT ™)
Acuity Testing
and Vector Vision™ both use sine-wave gratings,
which measure specific visual channels. Most Different positions of gaze result in different
of the commercially available CST can be used oscillation intensities in children with many
successfully in older children with nystagmus forms of nystagmus. The null zone is defi ned as
under binocular and monocular conditions. that position of gaze where nystagmus intensity
The absence of stimulation of the size-selec- (amplitude × frequency) is least and is greater
tive detectors processing high spatial frequen- for gaze in either direction lateral to the null.
cies may account for a previously described Children with nystagmus often adopt an anom-
abnormal shape of the CST curve in patients alous head posture (e.g., chin up or down, head
with some forms of nystagmus. A reduction turned or tilted) to improve their vision by
in CST for medium to high spatial frequency maintaining gaze in the direction of an eccen-
vision and increased pattern detection thresh- tric null zone. Both their gaze angle and the
olds in patients with nystagmus impairs the duration of visual stimulus presentation are
detection of vertically oriented stationary and important factors when determining visual
moving grating patterns more so than hori- function in nystagmus patients. We record “bin-
zontal ones. Previous studies have shown that ocular gaze-dependent visual acuity” as meas-
results for contrast sensitivity in some, but not ured using single-surrounded optotypes while

FIGURE 6.5 Example of a contrast sensitivity chart that can be used binocularly and monocularly with
spatial frequency gratings easily tested in patients with nystagmus.

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the heads of subjects are moved between vary- results in compromised visual field function. It
ing angles horizontally and vertically. Optotype is important for the clinician to understand how
recognition has been shown to be dependent on focal or generalized, static or progressive, defects
gaze angle in nystagmus patients versus normal in the visual field of patients with nystagmus add
controls. 24,25 Th is suggests that an INS patient’s to overall visual system dysfunction. The addi-
“real-world” vision, with a panorama of objects tional information regarding the integrity of the
presented for variable periods, may be func- visual field may assist with diagnosis, prognosis,
tionally less than the visual acuity measured in and treatment options of the patient’s nystagmus
a controlled clinical sett ing. in particular, and visual system in general.
If eye-movement recordings are not part of In infants and young children, testing is
the clinical examination, binocular visual acu- accomplished by att racting the child’s atten-
ity measurements should be made at a mini- tion directly forward while introducing a tar-
mum of five gaze angles (e.g., 0°, ±15°, and ±30°). get (small toy) from the periphery. As the child
Although not as accurate or sensitive as a plot perceives the object approaching from the
of the NAFX versus gaze angle (see Chapter 2, periphery, usually a sudden refi xation saccade is
Section 2.1.9.1 and Figs. 2.13, 2.18, 2.19, 2.25, apparent. The examiner also observes the child
and 2.36), plott ing these acuities versus gaze for any changes in attention or behavior. Th is
angle will allow determination of the decre- same technique can be performed monocularly
ment of visual acuity at gaze angles lateral to the in each of the four quadrants if the child will
null angle. A sharp reduction in acuity is indic- tolerate it. A drawback of confrontation visual
ative that therapy would improve overall visual field testing is the subjective interpretation of
function. its results.
The additional variable of time to recog- Simple examination methods such as the
nition of a visual stimulus is another visual arc perimeter can test the visual fields of young
system measure that is anomalous in patients children. 27–31 The arc perimetry test has the child
with nystagmus.24–26 Th is measure manifests in orient to flashing lights on four oblique merid-
real-world situations during body and/or world ians at 20° and 30°. The device has four black
motion. The measure of changes in visual recog- arms at the major oblique meridian (45°, 135°,
nition time may, therefore, be a useful measure 225°, and 315°). At the 36-cm test distance, the
of function in patients with nystagmus and has arms extend to 110°. A 6° white sphere att racted
been shown to improve after intervention(s) for the child’s gaze toward the intersection of the
their oscillation. In one study of patients with arcs. A small white ball travels from the periph-
nystagmus 50% of patients showed two or more ery to the center along an arc perimeter while
lines difference in their visual acuity across the child fi xes on another ball straight ahead.
gaze, while all control subjects showed none.24,25 Once the child perceives the peripheral ball,
During a time-restricted paradigm (TR) acuities a point on the perimeter is measured, indicat-
were significantly decreased in eccentric gaze ing the extent of the visual field in that direc-
positions relative to non-time-restricted (NTR) tion. The arc perimeter has been shown to be of
paradigms in all nystagmus patients whereas the benefit in the measurement of visual field size in
TR and NTR acuities were equal across gaze in healthy infants and infants with visual or neuro-
all control subjects.24,25,27 logic abnormalities.
The hemispheric perimetry test is the next
step up from the arc perimetry (Fig. 6.6). It is
6.1.7 Visual Field Testing
suited for babies who can sit upright. The child
Visual field assessment should be incorporated looks in a dome, which uses smaller static lights
into the initial, comprehensive examination of at the periphery. The results are plotted similarly
the infant and child with nystagmus. Associated to the Goldmann®. It yields more quantitative
disease of the pre- or postchiasmal visual path- data than the arc, though not as detailed as the
way and retina in patients with nystagmus often Goldmann®.27–31

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FIGURE 6.6 Example of a behavioral method of testing visual field in preverbal patients.

Once a developmentally normal child has kinetic (Goldmann®) perimetry. Table 6.2 summa-
reached the age of 7 to 8 years, visual field test- rizes each of the visual field tests.
ing is best performed using Goldmann® or auto-
mated visual field testers. Goldmann® perimetry
6.2 OBJECTIVE TESTING
test is done by having the child look into a globe
with a central target to fi xate upon. The eye that
6.2.1 Visual Evoked Potentials
is not being tested is covered. The globe shows
a light at the periphery that is gradually moved The visual evoked potential (VEP) is an evoked
inward until the child presses a buzzer indicat- electrophysiological potential that can be extracted,
ing that he or she sees the light. Th is is done with using signal averaging, from the electro-encephalo-
many lights from different peripheral points. The graphic activity recorded at the scalp (Fig. 6.7a). The
points the child sees are plotted to make a graph VEP can provide important diagnostic information
of the child’s visual field. The main advantages regarding the functional integrity of the visual sys-
of the Goldmann® test is that it yields the most tem. In patients with nystagmus it is important to
quantitative results. Unfortunately, it requires a go slightly beyond the current international society
lot of cooperation and ability to sit still, so it is for clinical evaluation of vision (ISCEV) criteria.32
difficult to do with very young or very impaired Because chiasmal and retrochiasmal diseases may
children.27–31 be missed using a single channel, three channels
Computerized or automated visual field testing using the midline and two lateral active electrodes
is available by many manufacturers using many are suggested. Pattern reversal is the preferred tech-
protocols. We use a Humphrey® automated testing nique for most clinical purposes but is less reliable
machine and a standard SITA program, which is in patients with unstable fi xation or nystagmus. The
excellent for evaluating visual field defects in child- results of pattern-reversal stimuli are less variable
ren. The shortened test time and decreased variabil- in waveform and timing than the results elicited by
ity described for adults are also present for children. other stimuli. The pattern-onset/offset technique
Using the 24–2 rather than the 30–2 program can can be more useful in patients with nystagmus, and
also reduce variability and test time; it shortens test the flash VEP is particularly useful when optical
time by approximately 30% and improves (lessens) factors or poor cooperation makes the use of pat-
variability. The periphery of the visual field is not tern stimulation unreliable.33,34
tested with either of these programs. Patients with Stimuli for VEP testing are patterns and
degenerative retinopathies should be tested with flashes. Pattern VEP uses black-and-white

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Table 6.2 Visual Field Testing Methods

1. Confrontation Visual Field
a. Easy and rapid to perform
b. Examiner tests the visual field of the patient under sequential monocular testing conditions
using his or her own eye as a control
c. A reasonable screening study but lacks sensitivity, especially for small defects
2. Amsler Grid
a. Excellent tool for assessing the central field subjectively
b. Useful for small central or paracentral defects within a few degrees of fi xation and for assessing
distortion in shape (i.e., metamorphopsia) or size (i.e., micropsia, macropsia)
3. Tangent Screen
a. Useful for rapid testing of the central field
b. Especially helpful for demonstrating a nonorganic tunnel visual field that does not expand at
1-m and 2-m testing distances
4. Goldmann Perimetry
a. Operator dependent tool
b. Qualitative assessment of visual field
c. Kinetic and static testing possible
d. Technician can reassure, reeducate, and retest specific areas of interest in a subject
e. Can test central or peripheral visual field with different size and brightness stimuli
f. Qualitative (subjective) reports of technician can assess patient reliability during testing
5. Automated Computerized Perimetry
a. Provides quantitative (visual threshold) information that is useful for following progression of
disease (e.g., glaucoma or idiopathic intracranial hypertension)
b. Reproducible and reliable technique
c. Formal quantitative assessments of reliability
d. Computerized fi xation and eye-movement monitoring
e. Automated testing and retesting protocols for selected points (false-positive and false-negative
results)

checkerboard stimulation. Flash VEP is a The waveform of the VEP depends upon the
white flash. The VEP is measured and evalu- temporal frequency of the stimulus. At rapid
ated in latency (time from stimulation to peak rates of stimulation, the waveform becomes
response) and amplitude of peak response approximately sinusoidal and is termed steady
(P100). All VEPs in children with or without state (Fig. 6.7b). At low temporal frequencies,
nystagmus should be compared with appropri- the waveform consists of a number of discrete
ate age-related normal values. When recording deflections and is termed a transient VEP. Only
the VEP in infants, the sweep duration should transient VEPs form a part of the ISCEV stand-
be increased due to the increased peak latency ard. VEP peak latency, amplitude, and waveform
in this population. By 6 months of age the peak are age dependent. VEP peak latency refers to
latency of the main positive peak of the pattern the time from stimulus onset to the maximum
reversal VEP for larger checks (>30 sec) is usu- positive or negative deflection or excursion;
ally within 10% of adult values. 33,34 thus, the term “VEP peak latency” corresponds

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(a)

(b)
10 μV
P2
P3

P1
0

N1 N2

–10 N3
0 100 200 300ms

FIGURE 6.7 Child seated with electrodes in place on the scalp in front of LCD screen for flash visual
evoked potential (VEP) testing (a). Normal appearance of positive and negative wave of a normal flash
evoked response (b).

to the term “implicit time” used to describe the N75 peak. The peak latency of P100 shows rel-
time from the stimulus to the maximum deflec- atively litt le variation between subjects, mini-
tion. VEP peak latency may also be referred to as mal within-subject interocular difference, and
“time to peak” or peak time. minimal variation with repeated measurements
The pattern reversal VEP has relatively low over time. P100 peak latency is affected by non-
variability of waveform and peak latency both pathophysiologic parameters such as pattern
within a subject and over the normal popula- size, pattern contrast, pattern mean luminance,
tion. Therefore, it is the preferred procedure in refractive error, poor fi xation, and miosis.
most circumstances. For pattern reversal, the Flash VEPs are much more variable across
VEP consists of N75, P100, and N135 peaks. subjects than pattern responses but show litt le
The nomenclature consists of designating peaks interocular asymmetry (Fig. 6.7b). They may
as negative and positive followed by the typical be useful in patients who are unable or unwill-
mean peak latency. It is recommended to meas- ing to cooperate for pattern VEPs, and when
ure the amplitude of P100 from the preceding optical factors such as media opacities prevent

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the valid use of pattern stimuli. The visual replicate responses from children to assure that
evoked potential to fl ash stimulation consists the response measured is a reliable signal and not
of a series of negative and positive waves. The an artifact.36 As for adults, additional channels
earliest detectable response has a peak latency of recording may be important for diagnosis of
of approximately 30 msec poststimulus, and chiasmal and postchiasmal dysfunction.37 When
components are recordable with peak laten- pattern VEPs cannot be reliably recorded, flash
cies of up to 300 msec. Peaks are designated as testing, which is less dependent upon coopera-
negative and positive in a numerical sequence. tion, can usually be achieved. Pattern-reversal
Th is nomenclature is recommended to auto- VEPs recorded from patients with nystagmus or
matically differentiate the fl ash VEP from the unstable fi xation should be interpreted with cau-
pattern reversal VEP. For the fl ash VEP, the tion. Pattern-onset/offset stimuli can be helpful
most robust components are the N2 and P2 in gaining attention of children and are usually
peaks. Measurements of P2 amplitude should more robust in cases of nystagmus, but the wave-
be made from the positive P2 peak at around form components change with age. We have been
120 msec to the preceding N2 negative peak at able to use the Sweep VEP as a consistent meas-
around 90 msec. ure of visual function, both cross-sectionally
VEPs should be recorded when the infant or and longitudinally in patients with nystagmus.38
child is in an attentive behavioral state.35 Direct The reader is referred to multiple excellent texts
interaction with the child can help maintain regarding the VEP consequences of diseases of
attention and fi xation, and two testers are ben- the postchiasmal, prechiasmal, chiasmal, and ret-
eficial, one to work with the child and the other inal systems in infancy and childhood. Table 6.3
to control data acquisition. The order of stim- summarizes specialized VEP tests.
ulus presentation also should be flexible and
selected to ensure that responses most critical to
6.2.2 Electroretinography
the diagnostic question are obtained within an
individual child’s attention span. Binocular pat- Electroretinography (ERG) evaluation of child-
tern stimulation, which facilitates attention and ren with nystagmus has both diagnostic and
fi xation, may be useful to evaluate overall visual prognostic value. In patients with nystagmus
function (Fig. 6.8). Monocular testing to at least and a normal clinical examination alone, a true
one stimulus is desirable to assess the function diagnosis of infantile nystagmus syndrome
of each eye. It is particularly important to obtain (INS) without associated sensory system deficits

FIGURE 6.8 Normal appearance of positive and negative waves of a normal pattern visual evoked poten-
tial response.

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Table 6.3 Specialized Visual Evoked The global or full-field ERG is a mass electri-
Potential (VEP) Testing cal response of the retina to photic stimulation
and is used worldwide to assess the status of the
Specialized VEP Types (not covered by ISCEV*)
retina in eye diseases in human patients and in
1. Steady-state VEP laboratory animals used as models of retinal dis-
2. Sweep VEP ease (Fig. 6.9). The basic method of recording the
3. Motion VEP electrical response known as the global or full-
4. Chromatic (color) VEP field ERG is by stimulating the eye with a bright
light source such as a flash produced by a strobe
5. Binocular (dichoptic) VEP
lamp. The intense flash of light elicits a bipha-
6. Stereo-elicited VEP sic waveform recordable at the cornea. The two
7. Multichannel VEP components that are most often measured are
8. Hemifield VEP the a- and b-waves. The a-wave is the fi rst large
9. Multifocal VEP negative component, followed by the b-wave,
10. Multifrequency VEP which is corneal positive and usually larger in
amplitude. The amplitude from the baseline
11. LED Goggle VEP
to the negative trough of the a-wave, the ampli-
*ISCEV, international society for clinical evaluatoin of vision tude of the b-wave measured from the trough of
the a-wave to the following peak of the b-wave,
cannot be inferred. In a large study of Ganzfeld the time from flash onset to the trough of the
ERGs recorded from 105 consecutive patients a-wave, and the time from flash onset to the peak
clinically believed to have “idiopathic” INS, ret- of the b-wave are the most common measures.
inal disease associated with INS was diagnosed These times, reflecting peak latency, are referred
in 59 patients (56%). 39 Other visual system to as “implicit times.” The a-wave, sometimes
diseases associated with nystagmus in infancy called the “late receptor potential,” reflects
include Leber’s amaurosis, delayed visual mat- the general physiological health of the photo-
uration, albinism, optic nerve hypoplasia, ach- receptors in the outer retina. In contrast, the
romatopsia, and X-linked congenital stationary b-wave reflects the health of the inner layers of
night blindness. ERGs have been shown to help the retina, including the “on” bipolar cells and
in distinguishing between these conditions. 35 the Muller cells. Two other waveforms that are

FIGURE 6.9 Diagrammatic representation of electroretinographic (ERG) activity in the retina. Color
photography of retinal layer anatomy with labeled areas responsible for ERG waveform components.

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FIGURE 6.10 Photograph of actual setup for intraoperative examination under anesthesia and
electroretinography.

sometimes recorded for clinical purposes are stimulus flash intensity. Either strobe lamp or
the c-wave originating in the pigment epithe- Ganzfeld methods of flash presentation can be
lium and the d-wave indicating activity of the used to record the ERG following a single flash
“off ” bipolar cells. There are also wavelets that or to average responses to several flashes with
occur on the rising phase of the b-wave known the aid of a computer.
as oscillatory potentials, thought to reflect activ- Infants up to about 6 months years of age can
ity in amacrine cells. usually be tested without sedation by the par-
The ERG of a normal full-term infant looks ent holding them bundled in a blanket. Most of
similar to a mature ERG.40 The ERG attains our ERG testing is performed as part of a more
peak amplitude in adolescence and slowly extensive exam under anesthesia (Fig. 6.10).
declines in amplitude throughout life. The ERG Anesthesia affects the ERG varying with type
can be recorded several ways. The pupil is usu- and depth of anesthesia. Some anesthetics can
ally dilated. There are a number of corneal ERG attenuate b-wave amplitude as much as 50%.
electrodes that are in common use. Some are Light levels of anesthesia have litt le effect, and
speculum structures that hold the eye open and most anesthetics do not usually affect a-waves or
have a contact lens with a wire ring that “floats” implicit times.
on the cornea supported by a small spring. Some Most disorders of the retina are detected by
versions use carbon, wire, or gold foil to record an attenuation of amplitude. Implicit times of
electrical activity. There are also cotton wick both a- and b-waves are also affected in some
electrodes. There are yet other simpler ERG conditions (Fig. 6.11). We usually dark-adapt
recording devices using gold Mylar tape that can the patient for a set time of 30 minutes, then
be inserted between the lower lid and sclera/ att ach electrodes using dim red illumination.
cornea. Most electrodes are monopolar, that is, We record the ERG using single, scotopic
they are referred to another electrode site, most white fl ashes. We then turn on moderately high
commonly on the forehead. There are also sev- background illumination for about 10 minutes
eral methods of stimulating the eye. Most labo- and record ERGs using 30 Hertz fl icker and
ratories use a Ganzfeld (globe) with a chin rest bright white fl ashes. The reader is referred to
and fi xation points. The Ganzfeld allows the multiple excellent texts regarding the ERG
best control of background illumination and consequences of diseases of the retina, retinal

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interferometry compares reflected light from

the eye to that reflected from a reference path
of known length. Different internal structures
produce different time delays, and scanning
the incident optical beam can generate cross-
sectional images of the structures. These two-
dimensional scans are then displayed in a color
scale where “warm” colors (red to white) rep-
resent areas of high optical reflectivity, and
“cool” colors (blue to black) represent areas of
FIGURE 6.11 Appearance of positive and nega- low reflectivity (Fig. 6.12). The commercially
tive waves from a normal electroretinogram. available OCT machines were originally devel-
oped by a team of bioengineers and physicians
pigment epithelium, and optic nerve in infancy at the Massachusett s Institute of Technology in
and childhood. Boston, MA. The original machine was brought
to market in 1995 (OCT-1) and revised in 2001
to be more user- and patient-friendly (OCT-2).
6.2.3 Optical Coherence Tomography
The 2002 release of the OCT-3 enabled in vivo
Optical coherence tomography (OCT) is anal- imaging of the posterior segment at resolutions
ogous to ultrasound except that near-infrared of <10 μm. With the advent of spectral domain
light waves instead of acoustic waves are used OCT (SD-OCT, Cirrus OCT; Carl Zeiss
to measure distances of specific structures. Meditec, Dublin, CA), high-resolution three-
OCT depends on optical ranging; in other dimensional macular imaging is possible at
words, shining a beam of light onto the object, greater than 50 times the speed of time domain
then recording the echo time delay of light OCT (TD-OCT), thereby offering new hope
measure distances. Since the velocity of light for imaging. The current technology thus per-
is so high, it is not possible to directly meas- mits excellent resolution and has been used to
ure the echo time delay of reflections; there- help diagnose and guide treatment for macular
fore, a technique known as low-coherence edema, macular and lamellar holes, epiretinal

FIGURE 6.12 Results of ultra high defi nition spectral domain optical coherence tomography (OCT).
showing individual retinal and subretinal anatomy (A–C). Bottom two photos are from a patient with infan-
tile nystagmus syndrome.

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FIGURE 6.13 Example using Optos wide-field fundus camera photography showing a large pigmented
lesion of the peripheral retina.

membranes and pseudoholes, central serous population. In addition to eye motion, compro-
chorioretinopathy, age-related macular degen- mised vision and the shortened attention span of
eration, glaucoma, and optic disc lesions. children often compound the challenge of qual-
Evaluation of the retina in patients with nys- ity TD-OCT macular image acquisition.
tagmus can occasionally be difficult because The new SD-OCT has allowed a more reli-
of the constant motion of the eye. Eye motion able study of patients with nystagmus.41 Its
has impeded the implementation of TD-OCT use for macular imaging has been reported in
for diagnostic purposes in the nystagmus patients with albinism and nystagmus. It has

FIGURE 6.14 A stereo image of the optic nerves in a patient with oculocutaneous albinism and nystagmus
showing optic nerve and peripapillary dysplasia, hypogimentation, and normal vasculature.

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laser ophthalmoscope fundus landmarks, such

as blood vessels, to remove eye motion artifact
caused by microsaccades. Applying this soft ware
to the extreme case of eye motion, nystagmus,
and incorporating it into a technology that is
already available to clinicians would be an excit-
ing and powerful application of the SD-OCT.
Because the nystagmus population can also
fall victim to common ocular diseases, such as
diabetes, glaucoma, and macular degeneration,
the use of SD-OCT, especially with soft ware
that may reduce eye motion and help recover
FIGURE 6.15 A standard 30-degree fundus pho- three-dimensional spatial integrity, would be an
tograph of a patient with oculocutaneous albinism important diagnostic and management tool.
and nystagmus showing optic nerve dysplasia/
hypoplasia, macular/foveal dysplasia, severe hypop-
igmentation, and vascular anomalies. 6.2.4 Fundus Photography
demonstrated several features in this popula- Fundus photography in patients with nystag-
tion, including the persistence of an abnormal, mus can be a very important adjunct in their
reflective nerve fiber layer band; persistence clinical evaluation and follow-up. In those
of multiple inner retinal layers; loss of the patients in whom retinal or optic nerve diseases
normal thickened photoreceptor nerve layer; are suspected, photography may be indispen-
and increased reflectivity of the choroid due sable in assisting with diagnosis and prognosis
to decreased pigmentation.41,42 Chong et al. of associated afferent system diseases.44 There
hypothesized that the most external reti- are multiple methods of obtaining photographs
nal layers, specifically the external limiting (Figs. 6.13, 6.14, and 6.15). The use of stereo
membrane, photoreceptor inner segment photos, narrow-angle, high-magnification, and
layer, and photoreceptor outer segment layer, wide-angle, low-magnification techniques can
appeared normal.42 These foveal morphologic be combined to obtain the best views of the
fi ndings echo the description by Marmor et macula/fovea, optic nerve head, and periph-
al. of an absent foveal pit, or fovea plana, and eral retina. In patients too young to cooperate
agree with histopathological studies and less for photography while awake, there are multi-
detailed TD-OCT reported fi ndings of either ple types of handheld and portable intraocular
absent or rudimentary foveal pits in oculocu- cameras that can be used as part of an exami-
taneous albinism.43 Our observations of the nation under anesthesia. (Some of the more
retinal morphology in the nystagmus popula- popular cameras include TOPCON® Medical
tion reveal that all cases of clinical foveal hyp- systems fundus camera [Paramus, NJ], Optos
oplasia demonstrate a persistence of the outer P200® instrument [Optos Plc, Fife, Scotland],
plexiform layer, inner nuclear layer, inner plex- NIDEK NM- 200D® [Nidek, Gamagori, 30-
iform layer, ganglion cell layer, and nerve fiber degree field], KOWA GENSISI D® [Tokyo,
layer. Our results agree with the description Japan], and RETCAM II® [Clarity Medical
by Chong et al. of the involved retinal layers Systems, Pleasanton, CA]).
responsible for the lack of foveal differentiation
in albinism.41,42
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7
treatment
7.1 MEDICAL 206 7.3.5 Mind-Body Stress Reduction:
7.1.1 Optical 207 Mindfulness Meditation Techniques 235
7.1.1.1 Version Prisms 209 7.3.6 Occupational and Vision Therapy 236
7.1.1.2 Vergence Prisms 209 7.3.7 Educational Assistance 236
7.1.1.3 Contact Lenses 210 7.4 ASSESSING THERA PEUTIC
7.1.1.4 Correction of Ammetropia/ OUTCOMES (POST-THERA PY) 237
Anisometropia 212 7.4.1 Direct Outcome Measures (eXpanded
7.1.1.5 Intraocular Lenses 213 Nystagmus Acuity Function, Longest
7.1.1.6 Refractive Surgery 213 Foveation Domain, and Target
7.1.2 Pharmacological 213 Acquisition Time) 237
7.1.3 Botulinum 214 7.4.1.1 Post-Tenotomy and
7.2 EYE-MUSCLE SURGERY 215 Reattachment 238
7.2.1 General Principles 215 7.4.1.2 Post-Convergence/Bimedial
7.2.2 Classification 218 Rectus Recession 238
7.2.3 Preoperative Evaluation 228 7.4.1.3 Post-Kestenbaum or Anderson Plus
7.2.3.1 Visual Acuity 228 Tenotomy and Reattachment 238
7.2.3.2 Ocular Motor and Standard 7.4.1.4 Soft Contact Lenses 239
Clinical Evaluations 228 7.4.1.5 Systemic Acetazolamide and
7.2.3.3 Strabismus 228 Topical Brinzolamide 239
7.2.3.4 Eye-Movement Recordings 228 7.4.2 Indirect/Clinical Outcome
7.2.3.5 Head-Posture Measurements Measures 239
(“Null Zones”) 229 7.4.2.1 Visual Acuity at Different Gaze
7.2.3.6 Laboratory and Special Tests 230 Angles 240
7.2.4 Results 230 7.5 ESTIMATING THERA PEUTIC
7.2.4.1 Visual Acuity 230 OUTCOMES (PRE-THERA PY) 240
7.2.4.2 Strabismus 231 7.5.1 Direct Outcome Measures (eXpanded
7.2.4.3 Eye-Movement Nystagmus Acuity Function, Longest
Recordings 232 Foveation Domain, and Target
7.2.4.4 Head-Posture Measurements 232 Acquisition Time) 240
7.2.5 Complications 232 7.5.1.1 Tenotomy and Reattachment
7.3 OTHER 234 (Infantile Nystagmus Syndrome with-
7.3.1 Biofeedback 234 out Afferent Visual Deficits) 241
7.3.2 Acupuncture 234 7.5.1.2 Tenotomy and Reattachment
7.3.3 Cutaneous Stimulation 234 (Infantitle Nystagmus Syndrome with
7.3.4 Gene-Transfer Therapy 234 Afferent Visual Deficits) 243

• 205

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7.5.1.3 Prisms/Bimedial Rectus 7.5.2 Indirect/Clinical Outcome Measures 244

Recession 243 7.5.2.1 Visual Acuity at Different Gaze
7.5.1.4 Soft Contact Lenses 244 Angles 244

Every truth passes through three stages before it is recognized. In the first it is ridiculed, in the second it is
opposed, in the third it is regarded as self-evident.
—Arthur Schopenhauer (1788–1868)

TH E NEW treatments discussed in this chap- (“nystagmus blockage”) due to INS, and a
ter result from the past half-century of eye- periodically changing head posture due to
movement-based research (summarized in asymmetric, (a)periodic, alternating nys-
Chapters 2–5) into the different types of nystag- tagmus (APA N). 4 The prevalence of AHP
mus found in infancy; that research forms the in 37 patients with strabismus and nys-
foundation for the various “clinical pearls” that tagmus was INS in 23 (62%); FMNS in 12
have also emerged from studying ocular motor (32%) and incommitant strabismus and SN
data from patients exhibiting nystagmus. were each in 1 patient (3% each). 5 The third
is oscillopsia , which is usually due to either
acquired nystagmus or a change in the sen-
7.1 MEDICAL sory/motor status of the patient with INS
There are a number of signs and symp- (e.g., “decompensated” strabismus, a change
toms due to nystagmus that are amenable in the gaze null angle or decreasing acuity). 6
to treatment. The first and most obvious Other less common associated signs and
is decreased vision (“central visual acuity,” symptoms include hypoaccommodation
“gaze-angle” acuity, near acuity). Correction (can be associated with acquired nystagmus
of significant refractive errors in children and/or INS) and photophobia (INS associ-
with nystagmus is the single most power- ated with the congenital cone dystrophy’s
ful therapeutic intervention for improving and albinism). 2 General treatment medical
vision and visual function in these patients. and surgical indications and guidelines are
Refractive etiologies of decreased “vision” outlined in Tables 7.17–20 and 7.2 (some for
include either one or a combination of con- investigational use only).
ditions, for example, myopia, hyperopia, Nonsurgical treatment of involuntary ocu-
astigmatism, and anisometropia.1–3 These lar oscillations has been part of therapeutic
refractive conditions can contribute signifi- interventions for as long as humans have suf-
cantly to already impaired vision in patients fered from their symptoms. Older treatments
with other “organic” etiologies of decreased include iodide, bromides, atropine, and qui-
vision, for example, amblyopia, optic nerve nine. 21 Knowledge of the pathogenesis of a form
and/or retinal disease, oscillopsia, and the of nystagmus should suggest the treatment. It
oscillation itself. The second is anomalous is essential to carefully evaluate patients before
head posturing (AHP). The etiology of the and during therapy for abnormal eye move-
AHP includes a “gaze-null” due to infan- ments. In the case of new treatments, it is best
tile nystagmus syndrome (INS) or acquired to carry out prospective, controlled, masked
nystagmus (e.g., chin-down in downbeat trials. Careful measurements of binocular and
nystagmus), an “aDDuction null” due to monocular visual acuity using validated, age-
FMNS (FMNS, manifest strabismus with appropriate acuity testing methods and system-
the preferred eye fixing in aDDuction), con- atic eye-movement examination and recordings
vergence damping or purposive esotropia are essential.

206 • TR E ATM ENT

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Table 7.1 Medical Treatment of Nystagmus

N Y S TAG M U S T Y P E T R E ATM EN TS
Infantile nystagmus syndrome Fresnell prisms, orthoptics, gabapentin, baclofen,
biofeedback, acupuncture
Acquired pendular nystagmus Fresnell prisms, orthoptics, gabapentin, baclofen,
clonazepam, cannibis, alcohol, carbamazipine,
5-hydroxytryptophan, scopolamine, memantine, botox,
trihexyphenidyl, cannabis, alcohol as part of the syndrome
of oculopalatal tremor (“myoclonus”): gabapentin,
valproate, trihexyphenidy
Peripheral vestibular Positional exercises, heta-histine, cinnarizine,
acetazolamide, diphenhydramine, promethazine,
prochlorperazine, ondansetron
Downbeat 3,4 Diaminopyridine, clonazepam, gabapentin,
clonazepam, baclofen, trihexyphenidyl. acetazolamide
(associated with episodic ataxia type II),
Upbeat baclofen, clonazepam, gabapentin
Periodic alternating Baclofen, botox
Seesaw Baclofen, clonazepam, alcohol, gabapentin
Saccadic intrusions/oscillations Baclofen, propanolol, clonazepam, methylphenidate
Superior oblique myokymia Carbamazapine, propanolol, timolol (topical)
Opsoclonus Corticosteroids, propanolol, clonazepam, baclofen,
clonazepam, gabapentin, intravenous immunoglobulin,
plasma exchange
Ocular motor neuromyotonia Carbamazpine
Voluntary ocular flutter Prism, orthoptics
Chronic internuclear ophthalmoplegia Prism, orthoptics

7.1.1 Optical spectacle lens worn in combination with a high-

minus contact lens (see Fig. 7.1). The system is
The timely, accurate, and consistent correction designed on the principle that stabilization of
of ametropia in patients with nystagmus is the images on the retina could be achieved if the
single best method of improving vision and power of the spectacle lens focused the primary
visual function. The use of telescopes, magni- image close to the center of rotation of the eye.
fication, and other low-vision aids are valuable However, such images are then defocused, and
refractive adjuncts that can be used situationally a contact lens is required to extend the clear
in nystagmus patients with and without associ- image back onto the retina. Since the contact
ated sensory system deficits. 22 Some US states lens moves with the eye, it does not negate the
allow the use of telescopes to obtain a limited effect of retinal image stabilization produced
driver’s license. by the spectacle lens. With such a system, it is
A different approach to the treatment of possible to achieve up to about 90% stabilization
acquired nystagmus has been the use of an of images upon the retina. However, there are
optical system that stabilizes images on the several limitations to the system. One is that it
retina.23,24 Th is system consists of a high-plus

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Table 7.2 Summary of Nystagmus Intervention

N Y S TAG M U S T R E ATM EN TS R E S U LT S M ECH A NISMS

Infantile Eye-muscle surgery Improvement in Afferent interruption
nystagmus Contact lenses acuity, head turn, Mechanical null-zone
syndrome Prisms contrast sensitivity, repositioning
Memantine gaze-dependent vision, Central nervous system
Gabapentin nystagmus foveation, areas affected by
Biofeedback width of null zone, medications
Acupunture recognition time
Spectacles
Periodic Baclofen Improvement in Central nervous system
alternating Eye-muscle surgery rhythm, foveation, head GABA agonist
nystagmus Gabapentin movements, Null point movement
head posture, acuity Afference interruption
Downbeat 3,4-Diaminopyridine Improved oscillopsia, Restores inhibition of
nystagmus Eye-muscle surgery acuity, head posture upward drift through
(chin-down posture) K+ blockade
Botulinum A injection Muscle paresis
Null-zone shift
Upbeat nystagmus 3,4-Diaminopyridine Improved oscillopsia, Restores inhibition of
Eye-muscle surgery acuity, head posture upward drift through
(chin-up posture) K+ blockade
Botulinum A injection Muscle paresis
Null-zone shift
Acquired pendular Gabapentin Improved acuity, NMDA receptor
nystagmus Memantine nystagmus, oscillopsia inhibition
Eye-muscle surgery Glutamate antagonism
Servomechanical Image stabilization
Fusion Prisms Improved binocular Fusion promotion
maldevelopment Spectacles acuity, head posture, Afference interruption
nystagmus Eye-muscle surgery nystagmus Muscle paresis
syndrome Botulinum A injection

Oculopalatal Vertical rectus Decreased oscillopsia Afference interruption

tremor tenotomy

inhibits eye movements (including the vestibu- INS due to sharp null zones. Some patients with
lo-ocular reflex and vergence) and thus is useful ataxia or tremor (such as those with multiple
only when the patient is stationary and is view- sclerosis) have difficulty inserting the contact
ing monocularly. Another is that with the high- lens. However, initial problems posed by rigid
est power components (contact lens of –58.00 polymethyl methacrylate contact lenses can be
diopters and spectacle lens of +32.00 diopters), overcome by using gas-permeable or even soft
the field of view is limited. The latter degrades contact lenses. Most patients do not need the
visual function and is one of the key problems in highest power components for oscillopsia to be

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(a) of a prototype device may eventually lead to

a spectacle-mounted device that selectively
cancels out the visual effects of pathological
Object Image nystagmus.

(b) 7.1.1.1 V E R S I O N P R IS M S
c
The use of prism treatment is dependent on
whether the AHP is caused by a “gaze null”
associated with INS or acquired nystagmus or
(c)
an “adduction null” associated with FMNS. 25–28
Version prisms move objects in the visual field
to the null position (see Fig. 7.2). Thus, objects
in primary position may be viewed without an
High plus High minus contact AHP. Unfortunately, version prisms are usu-
Lens Lens ally not feasible due to the large gaze angles
needed to minimize the nystagmus which
FIGURE 7.1 Optical method of retinal image
require prohibitive amount of prism correc-
stabilization using a high-power biconvex (+) field
tion in the spectacle plane; that is, a 20° gaze
lens and a high-power concave (–) lens to stabi-
lize a distance image in the center of rotation of null requires ~50 prism diopters spectacles. 26,27
the eye and subsequently move it posteriorly on Thus, only Fresnell type press-on prisms
the retina. (a) Normal inverted projection of an can straighten the head. Since acuity is often
object. (b) The field lens refocuses the inverted decreased with the use of Fresnell and large
image at the center of the globe where it is stable amounts of “ground-in” prism, this method is
despite eye motion. (c) The contact lens refocuses rarely used for treatment. Nonetheless, this
the stable image on the retina. is useful for measuring the AHP in terms of
“prism diopters.” The prism diopter measure-
ment can then be used as a guide for surgical
treatment. It is our experience and that of oth-
abolished or vision to be improved. In selected ers that patients who use a consistent, eccentric
patients the device may prove useful for lim- null zone to improve their vision and visual
ited periods of time, for example, if the patient function benefit from having their nystagmus
wishes to watch a television program. It is not a improved and null zone broadened, deepened,
useful therapy in INS. and moved within 5° of primary position,
A more recent innovation has been to use an regardless of how much of the time they adopt
electronic circuit to distinguish between the a head posture. The use of “time spent postur-
nystagmus oscillations and normal eye move- ing” is not a valid clinical indicator of the need
ments.9 Th is approach is most applicable in for treatment. Many patients do not posture
patients with pendular nystagmus. Eye move- most of the time because they cannot posture
ments are measured using an infrared sensor most of the time, and, if they could, they would.
and, after fi ltering, fed to a phase-locked loop The neck and facial muscles prohibit constant
that generates a signal similar to the nystagmus use of an eccentric head posture. 29 Also, older
but is insensitive to other eye movements, such patients diminish the time they use an AHP
as saccades. Th is electronic signal is then used to because of social pressures.
rotate Risley prisms, through which the patient
views the environment. When the Risley prisms
7.1.1. 2 V E R G E N C E P R IS M S
rotate in synchrony with the patient’s nystag-
mus, they negate the visual effects of the ocular If the patient has congenital nystagmus, fusion,
oscillations. Improvement and miniaturization and “damps” with convergence, the distance

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FIGURE 7.2 Use of bilateral prism with conjugate direction of base and apex to improve a head pos-
ture associated with an eccentric gaze nystagmus “null” position. (A) Right eccentric gaze null position.
(B) Base-out prism over left eye and base-in prism over right eye (i.e., base-right prisms) to move pri-
mary position objects to the preferred null position.

acuity may benefit dramatically from the use edge, and central lens thickness, thereby
of base-out prism spectacles (Fig. 7.3). 26,27,30 minimizing their weight and associated opti-
These “convergence prisms” provide the opti- cal aberrations. The writt en prescription usu-
cal approach for patients with infantile or ally contains the words “small eye size” and
acquired nystagmus whose nystagmus damp- “high index lenses” to assist both the optical
ens when they view a near target. A useful dispenser and the patient. If the patient does
starting point is 7.00-diopter base-out prism respond to the prisms in the office (“fast prism
over each eye with best refraction combined adaptation”), he or she will also respond to a
with –0.50 to –1.00 diopter spheres to com- bimedial rectus recession surgical procedure.
pensate for the vergence-induced accommoda- Th is procedure may be an alternative to prism
tion (although the additional correction may spectacles in patients who have no other signif-
not be needed in presbyopic individuals). Note icant refractive error (see surgical treatments
that although additional vergence will usually in Section 7.2).
further damp and improve INS waveforms, the
total of 14 diopters we use for distance viewing
7.1.1.3 CO N TA C T L E N S E S
allows for the vergence reserve needed for near
viewing. It is fortunate that eyeglass frame From 1973 to 1987, 210 contact lenses were fitted
designs are now smaller. These reduced eye- in 112 patients with nystagmus and a refraction
size spectacles with the combination of new anomaly. In 79%, it was possible to correct myo-
high-index “plastic” lenses decrease weight, pia or a myopic or mixed form of astigmatism.

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they could “see better.” Their contrast sensitivity

(a)
and VFQ-25 scores were improved with contact
lenses compared with spectacles alone. Several
parameters of nystagmus, uncorrelated to acuity
(e.g., frequency, amplitude, and peak slow-phase
velocity) showed no change in two patients,
worsening in one patient and improvement in
one patient. The authors suggested that some
of the clinical improvement may result from
a better optical correction of their refractive error
with contact lenses than with spectacles rather
than due to INS damping as had been previously
demonstrated. 32 However, one patient who used
spectacles plus planar contact lenses also showed
improvement—contradicting their specula-
tion. No eye-movement data were presented to
allow evaluation of the actual nystagmus wave-
form changes nor were the patients prescreened
(b)
to determine which might benefit from the
exteroceptive input produced by the contact
lenses; patients with well-developed foveation
periods (i.e., high eXpanded Nystagmus Acuity
Function [NAFX] values) cannot show much
improvement with any therapy. Also, the only
nystagmus parameter correlated to acuity that
was measured (foveation time) was defi ned by
fi xed position and velocity criteria rather than
the idiosyncratic criteria dictated by the wide
range of INS waveforms in patients; the latter is
used in calculating the NAFX. Finally, the sin-
gle most important factor in improving visual
FIGURE 7.3 Use of base-out prisms to stimulate
convergence and “damp” nystagmus. (a) Prior to function, widening of the gaze-angle range with
placement of base-out prism in front of each eye. high acuity, was not measured. Other studies,
(b) Induced fusional convergence due to base-out using eye-movement data and the NAFX, dem-
prism. onstrated that soft contact lenses improved INS
waveforms over a broad range of gaze angles and
compared favorably with other therapies. 33–35
A special contact lens with a centrally tinted
The visual acuity improved significantly and area (absorption 80%) that is slightly greater
the intensity of the nystagmus was reduced. The in diameter than the pupil under daylight con-
hard lenses were well tolerated in all patients. In ditions can correct ametropia and reduce light
a short report, patients with INS had two evalua- exposure and dazzle in a cosmetically much
tions separated by at least 1 week (one with spec- better way.2 Tinted spectacle or contact lenses
tacles, one with contact lenses), including visual may be useful in relieving photophobia associ-
acuity, contrast sensitivity, oscillopsia scale, ated with a number of cone disorders, including
quality of life questionnaire (NEI VFQ-25), achromatopsia. In addition to decreasing light
and eye-movement recording with an infrared sensitivity, tinted lenses have been reported to
tracking system. 31 All patients subjectively pre- improve visual acuity, decrease the size of cen-
ferred contact lenses to spectacles; some saying tral scotomata, enlarge peripheral visual field,

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and enhance visibility of long wavelength stim- If the patient has INS and is orthophoric, add
uli in bright illumination. 36 7 diopters of base-out prism in front of each eye
with an additional –1.00 sphere (for the coin-
cidental vergence-induced accommodation)
7.1.1. 4 CO R R EC T I O N O F A M E T R O P I A /
to test the effect of “convergence damping” on
ANISOME T ROPIA
acuity at distance. The improvements in acu-
In a report by Egorova, significant ametropia was ity, nystagmus intensity, and AHP obtained
diagnosed in 98.9% of 670 school children with by this maneuver can be quite impressive in
varied ocular pathology. 37 Myopia was detected this subset of INS patients without strabis-
in 48.9%, hyperopia in 50.0%, astigmatism in mus. The second maneuver is to add prisms to
97.8%; in 38.6%, it exceeded 2.0 diopters, which correct the strabismic deviation. If this assists
was mainly encountered at the retinopathy of with sensory fusion or any binocular coopera-
prematurely newborns, albinism, and congenital tion, the patient’s nystagmus is oft en reduced,
myopia. Anisometropia exceeded 2.0 diopters potentially improving acuity and/or other vis-
in 21.8% of cases; with highest anisometropia ual functions. Binocular visual acuity is tested
more frequent in patients with retinopathy of before and aft er these maneuvers, demonstrat-
prematurity, infantile myopia, and aphakia. ing whether they are effective. If they are, they
Nystagmus was present in 46.4% of children. can be incorporated in a treatment approach.
The spectacle vision correction was found to be All nystagmus patients should also be evalu-
effective in improving vision and visual function ated with an objective refraction procedure. In
in 94.8% of patients. children and many adults, a complete cyclople-
In adults and older children, a subjective gic refraction (e.g., 40 minutes after 1% cyclogyl,
refraction is the foundation for any type of 50–60 minutes after 1% atropine) provides addi-
refractive therapy. All “refractionists” develop tional and important data for treatment deci-
their own method in this regard, and each of sions. In many adult patients with nystagmus
their idiosyncrasies assists them with rapid and from childhood, there are uncorrected (and now
accurate subjective refraction. Our method is “latent”) refractive errors. The error is usually
the following. Try to “ignore” the oscillation mixed astigmatism or hyperopia and is not dis-
and start with the distance retinoscopy in a covered with subjective refraction. Start again
phoropter (in those patients without an AHP) with the retinoscopic fi ndings and, if the patient
or trial frame (in those patients who have a sig- is verbal, do binocular refraction for distance, as
nificant AHP). The next step is to do binocular described earlier. In patients whose refraction is
refraction. Th is goes against the classic teaching different under cycloplegia, record both subjec-
for subjective refraction, but it is the most impor- tive and objective refraction for decision making
tant step in evaluating these patients because regarding spectacle prescription. In patients who
many (over 50%) will have significant changes are not verbal, observation of changes in nystag-
in their nystagmus under complete monocular mus, AHP, or strabismus after trying the two
conditions (often decreasing their best possi- prism maneuvers mentioned earlier can assist
ble acuity). The best way to do this is to fog the with deciding their effectiveness. Although
eye that is not being refracted with only enough there are no “universal” rules for amount of cor-
extra plus to decrease the vision in that eye by rection, the following general approaches have
1–3 lines. Many patients with coincidental stra- been successful in our experience with these
bismus (about 50% of the childhood nystagmus patients. The full cycloplegic and anisometropic
population) can fi x well enough with one eye at correction is usually prescribed in children up to
a time, and be subjectively aware of this, so no about 10 years of age. Many adults may not be
fogging is necessary. Now your usual routine for able to tolerate their cycloplegic refraction, and
subjective refraction can be accomplished. they should be given the most they can tolerate
Once subjective refraction is completed, during subjective refraction (see aforementioned
two other optical maneuvers can be performed. technique). In addition, these patients should

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be brought back to the office about 4–6 weeks by oral corticosteroids; in Meniere disease,
later to try to “push” more of the “latent refrac- there is fi rst evidence that high-dose, long-term
tive error” subjectively. Even some adult patients administration of betahistine reduces attack fre-
will respond over time with increased acuity and quency; carbamazepine or oxcarbamazepine is
acceptance of large amounts of hyperopia, astig- the treatment of fi rst choice in vestibular parox-
matism, and anisometropic refractive errors. ysmia, a disorder mainly caused by neurovascu-
lar cross-compression.48
Clonazepam is reported to reduce downbeat
7.1.1.5 I N T R A O C U L A R L E N S E S
nystagmus (DBN) from a variety of causes.49
Implantation of prosthetic iris devices (intraoc- The GABA agonist baclofen is reported to
ular lenses) appears to be useful in the man- reduce DBN and associated oscillopsia. 50 The
agement of patients with nystagmus and iris anticholinergic drug scopolamine reduces DBN
deficiency secondary to albinism or aniridia. 38–42 when given intravenously, but oral anticholin-
Although a long way from being considered ergic agents such as trihexyphenidyl produce
standard of care in patients with nystagmus and only a modest improvement, which is offset by
iris defects, as a whole, this method of treatment substantial side effects. 51 A new approach to
may become acceptable for those who have addi- the treatment of DBN arose out of the seminal
tional ocular morbidity such as severe ametropia observation that nystagmus occurring in epi-
or iris defects. sodic ataxia type 2 responds to acetazolamide;
this disorder is now known to be a calcium
channelopathy.48 Strupp et al. showed that 10
7.1.1.6 R E F R A C T I V E S U R G E R Y
of 17 patients with DBN showed a decrease of
Patients with nystagmus have had successful more than 50% in their nystagmus 30 minutes
refractive surgery to correct their refractive after ingesting 20 mg of 3,4-diaminopyridine
error using a variety of laser systems.43–47 These (DAP). 52 Th is medication was generally well tol-
reports suggest that laser refractive surgery may erated, although it is known to induce seizures
be safely and accurately performed in patients in some subjects. In a study of 10 patients with
with INS. The BSCVA may improve in certain spinocerebellar atrophy, Tsumeniet et al. found
patients postoperatively. By using the Intralase that DAP may be effective on DBN and oscillop-
femtosecond laser and an active tracking sys- sia, although it was not proved to be effective on
tem with or without mechanical fi xation, laser other symptoms of ataxia in these patients. 53
refractive surgery may be safely and accurately Upbeat nystagmus (UBN) is occasionally
performed in selected cases of nystagmus. A suppressed by clonazepam, but it often resolves
large prospective trial aimed at safety and effi- spontaneously over a few months.20 Glauser et al.
cacy needs to be performed to confi rm that the showed that UBN can be reduced DAP causing
device is safe and suitable for patients with INS. relief from distressing oscillopsia, and impaired
upward smooth pursuit. 54 Baclofen also reduces
nystagmus slow-phase velocity and distressing
7.1.2 Pharmacological
oscillopsia in patients with UBN. 55 The response
Nystagmus caused by peripheral vestibular to baclofen appears to be a GABA-B-ergic effect
imbalance usually resolves spontaneously over with augmentation of the physiological inhib-
the course of a few days because of central adap- itory influence of the vestibulo-cerebellum on
tive mechanisms. Drug treatments play only a the vestibular nuclei with subsequent inhibitory
minor role, mainly to control attendant vertigo effect on the velocity storage mechanism.
and nausea. Drugs with antihistamine, anticho- Adaptive mechanisms that attempt to hold
linergic, and phenothiazine properties remain velocity storage in check cause an oscillating
the most popular approach to symptom man- vestibular imbalance, manifest as periodic alter-
agement.18 In vestibular neuritis, recovery of the nating nystagmus (PAN). Baclofen is effective
peripheral vestibular function can be improved treatment in most cases of acquired and some

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cases of infantile PAN.4,56 Individual patients propranolol, verapamil, clonazepam, and gaba-
with seesaw nystagmus (SSN) have been pentin have been reported to suppress them in
reported to benefit from gabapentin, clonaze- individual patients.64
pam, or alcohol. 57 Recovery of opsoclonus associated with
The most effective treatments for acquired brainstem encephalitis may be speeded by
pendular nystagmus (APN) in association intravenous immunoglobulin.10 In opsoclonus
with disorders of central myelin are gabapentin associated with cancer, treatment of the tumor
and memantine.20 Other drugs with presumed itself often does not ameliorate the neurological
GABAergic effects, such as clonazepam and val- syndrome. Carbamazepine may prove effective
proate, also help some patients. Isoniazid has treatment for ocular motor neuromyotonia.65
also been studied as treatment for APN in three Superior oblique myokymia spontaneously
patients with multiple sclerosis, and reduced nys- resolves in some patients and others are not
tagmus and relieved oscillopsia in two. 58 Of 15 sufficiently bothered by their symptoms that
patients with APN studied in a double-blind com- they request treatment. Individual patients
parison with baclofen, visual acuity improved with have responded to carbamazepine, baclofen,
gabapentin, but not with baclofen.11 Memantine b-adrenergic blocking agents, or gabapentin
is a relatively new drug specially developed for given systemically or topically.66,67 Patients who
use in moderate-to-severe dementia. 59 It is an do not respond to drug therapy, who develop
uncompetitive N-methyl-D-aspartate receptor side effects from the drugs, or who do not wish
antagonist and reduces glutamatergic excitotox- to take drugs for their condition may experience
icity. It has recently received approval from the complete relief of symptoms after extraocular
US Food and Drug Administration for treatment muscle surgery.
of Alzheimer disease. Memantine has been in use
in Germany for over 20 years, and it is known to
7.1.3 Botulinum
be a safe and well-tolerated drug. Multiple stud-
ies have confi rmed that APN, especially associ- An approach to treatment of nystagmus that
ated with multiple sclerosis, have shown a good has gained some popularity is injection of botu-
response to oral memantine, with reduced nys- linum toxin into either the extraocular muscles
tagmus and improved vision and decreased visual or the retrobulbar space.68 Using both tech-
symptoms.20 Alcohol has been reported to varia- niques, Ruben et al. reported improvement of
bly suppress many forms of involuntary ocular vision in most of their 12 patients with a variety
oscillations, including APN.60 Smoking canna- of diagnoses. 69 The major side effect was ptosis.
bis has been reported to suppress both APN and However, eye movements were not systemati-
INS but formal evaluations of this potential ther- cally measured and compared before and after
apy are difficult to accomplish.61,62 injection. Repka et al. also described improve-
Although therapy with gabapentin, carba- ment of vision following retrobulbar injection
mazepine, 5-hydroxtryptophan, and scopola- of botulinum toxin in six patients and docu-
mine have been useful in selected patients with mented the effects on eye movements.70 The
ocular palatal myoclonus, most do not respond main reservation expressed by these authors
to drug treatment.20 was the temporary nature of the treatment and
In patients with saccadic oscillations, the necessity for repeated injections. In other
improvement in reading performance may be studies, nystagmus was abolished or reduced
improved if they are suppressed using methy- in the treated eye for about 2–3 months, but no
phenidate.63 Several benzodiazepines (diazepam, patient was pleased with the results because of
clonazepam) and the barbiturate phenobarbital ptosis, diplopia, increase of nystagmus in the
are reportedly effective in abolishing high-am- noninjected eye, or fi lamentary keratitis. The
plitude square-wave jerks and macrosaccadic profound side effect of a poor to absent vestib-
oscillations.64 Symptomatic treatment of the ulo-ocular reflex as a result of the injection con-
saccadic oscillations is unsatisfactory, although tribute a new, and often overwhelming, visual

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symptom to these patients often precluding accurate ocular motor recordings provided the
repeat injections. data necessary for both diagnosis and evaluation
of the efficacy of specific therapies. Evaluation
and comparison of therapies require a quan-
7.2 EYE-MUSCLE SURGERY
titative measure of the change in the specific
There is quantitative data that if the slow fove- waveform characteristic(s); that is the primary
ation periods occurring during each beat of outcome measure.
nystagmus can be lengthened or increased by Although two medical goals of INS ther-
the patient or by therapeutic interventions apy may be reconstructive and visual acuity
(i.e., medicines, surgery, contact lenses, acu- improvements, they are not the primary out-
puncture, biofeedback) some of a patient’s come measures.90 Because measured visual acu-
visual functions may be increased.71,72 In ity is the result of several variables (e.g., stress,
Anderson’s second edition textbook printed afferent deficits, head position, eye position)
in 1959, Ocular Vertical Deviations and the whose relation to the INS (or FMNS) waveform
Treatment of Nystagmus, he states; “It has been is idiosyncratic, it is not always a good measure
found that such operation not only may greatly of real-world visual function.91,92 INS ampli-
lessen torticollis, but may also improve vision tude is the characteristic most directly related
by lessening the nystagmus itself.” 73 The idea to cosmetic appearance; however, amplitude is
that eye-muscle surgery has visual system ben- not a good predictor of acuity or other visual
eficial effects beyond the “mechanical” repo- function. A therapy that reduces amplitude may
sitioning of the muscles or globe is a novel not improve acuity, and one that does improve
concept, initially predicted after post-Kesten- acuity may not reduce amplitude. The waveform
baum eye-movement data analysis,74,75 but only characteristics related to overall visual function
successfully demonstrated after years of care- are foveation time and beat-to-beat foveation
ful analysis of patients, their eye-movement position and velocity variation. The NAFX is
measurements of nystagmus, and hypothesis- a quantitative function that includes all three of
driven animal and human trials.74,76–84 these primary characteristics.93 It predicts best
possible visual acuity.
The indications for eye-muscle surgery in any
7.2.1 General Principles
patient with nystagmus result from a thorough
The fi rst step, before considering therapies, was history, clinical evaluation, and special test-
the establishment of defi nitive, differential diag- ing. Special testing may include neuroimaging,
nostic criteria for INS and other forms of nystag- serological (blood, urine, spinal fluid) testing,
mus.85 Here, accurate ocular motor recordings electrophysiology (eye-movement recordings,
quickly demonstrated that they were both essen- electroretinography, visual evoked responses,
tial and invaluable. The key waveform character- dark adaptation), photography, and angiog-
istics that are pathognomonic for INS became raphy. Once it has been determined that the
easily distinguishable. No longer is “nystagmus” ocular motor abnormality cannot be treated
an acceptable diagnosis. Eye-movement record- or improved as part of coincidental therapy of
ings were to eventually be used to identify many an underlying systemic condition, eye-muscle
different types of nystagmus and saccadic intru- surgery can be considered. There is a two-fold
sions and oscillations (see Chapter 5, Tables 5.1 purpose of eye-muscle surgery in patients with
and 5.6). An integral part of waveform descrip- nystagmus. One is to center the preferred posi-
tions was identification of the portions of each tion of the eye(s) (and, therefore, the head), and
cycle during which the image of the target was on the other is to improve the oscillation’s beat-to-
the fovea (foveation periods) during fi xation71,86 beat characteristics. There is a high association
as well as during smooth pursuit87,88 and vestibu- of strabismus and nystagmus, often allowing the
lo-ocular movements.89 Documentation of these surgeon to treat both at the same time. 5 The two
important characteristics of INS waveforms by conditions often affect each other; improving

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the strabismus may favorably affect the nystag- reattaching each muscle at its original point of
mus and vice versa. The presence of an AHP may insertion. Unfortunately, some took the proce-
be present in both the infantile and acquired dure’s name “tenotomy” literally. Therefore, to
forms of nystagmus and, in both, surgery serves avoid both misunderstanding and problematic
to position gaze (or the eyes) in the straight- surgeries, it is now referred to as the tenotomy
ahead position. and reattachment (T&R) procedure.
It was to take 20 years before access and testing
Clinical Pearl: When performing simultane- of this hypothesis on an animal model of naturally
ous nystagmus and strabismus surgery, the exhibiting the pathognomonic INS waveforms
procedure is determined by a combination of occurred. In 1991, Dell’Osso was contacted by
moving the eccentric null (straightening the Robert W. Williams of the University of Tennessee,
head) using the preferred eye and correcting Memphis who provided videos of the horizontal
the remaining strabismus using the nonpre- nystagmus of several achiasmatic Belgian sheep-
ferred eye. dogs, asking whether they resembled human
INS. LFD was struck by the similarity of the head
The idea that there is “neurological” benefit posturing of the dogs and children with INS and
to surgery on the extraocular muscles has a long arranged to document the waveforms to establish
history.74,78 The postulation and clinical trials of the diagnosis. The videos also revealed an SSN.
a new surgical therapy for INS with far-reach- In 1992, horizontal INS waveforms and vertical-
ing theoretical implications had its roots in two torsional SSN was documented in the dogs.94–96
areas of ocular motor research: documenting the This was the first time nystagmus waveforms (i.e.,
effects of the Anderson-Kestenbaum recession- the horizontal components) were recorded from
resection surgery on humans and studying the an animal that had the characteristics of human
eye movements of achiasmatic Belgian sheep- INS, including foveating and braking saccades. In
dogs with INS and SSN.80 In an early study of subsequent recordings, it was verified that all achi-
INS surgery (circa 1977), a profound change asmatic dogs had both INS and SSN, including a
was noted in the shape of the nystagmus inten- dog with hemichiasma.94–96
sity versus gaze angle function. After Anderson- The animal model for INS that we had been
Kestenbaum surgery, in addition to the expected seeking to test our surgical hypothesis had been
shift of this plot toward primary position, the found. In addition, SSN was identified as a sign of
breadth of the null region increased and the chiasmal abnormalities in canines and humans.
overall nystagmus intensity decreased.74 It was The hypothetical T&R procedure was fi rst per-
reasoned that there were two independent effects formed by Hertle (Dell’Osso assisted) in two
of this surgery due to different mechanisms. The stages: (1) all four horizontal recti were tenoto-
expected null shift toward primary position was mized and immediately reattached at their orig-
mechanical due to the effective rotation of the inal insertion sites; and (2) 4 months later, the
globe opposite the null angle and the subsequent same T&R procedure was performed on the four
innervation required to move the eyes back to vertical recti and four obliques.97 The fi rst stage
primary position (i.e., the same innervation that tested the efficacy of T&R on horizontal INS,
placed the eyes in the null position preopera- and the second, on SSN. The results were imme-
tively). Because the only surgery performed in diately obvious; there was a profound damp-
addition to the removal (resection) and move- ing of the horizontal INS over a broad range of
ment (recessions) of the muscle was the accom- gaze angles (stage 1) and the SSN was abolished
panying incision at its insertion (tenotomy) and (stage 2).97 Eye-movement recordings over the
reattachment, it was hypothesized that the teno- next 7 months verified the profound and persis-
tomy and reattachment alone was responsible for tent nystagmus damping. The dog also exhib-
the favorable INS changes.75 Initially, the proce- ited immediate behavioral improvements that
dure was simply called the tenotomy procedure, supported the prediction that the INS damping
despite its description that accurately described would increase his acuity.97

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As a result of the T&R hypothesis, based structures are probably related to afferent cen-
on analysis of human eye-movement data after tral nervous system input, and disruption of
Anderson-Kestenbaum procedures, and demon- them during surgery might influence postop-
stration that T&R damped the INS in a canine erative outcome. Using rabies toxin as an ana-
model of human INS, a clinical trial of this tomic tracer, it has been possible to show that
procedure under the support of the National an afferent group of ocular motor neurons (dis-
Eye Institute was performed.91,92 Pre- and post- tinct from the classic oculomotor, trochlear,
T&R eye movement data were recorded at the and abducens nuclei, and surrounding each of
Laboratory of Sensorimotor Research, NEI. them) innervates these enthesial fibers.107–109
The data were masked and analyzed by a sepa- The role of sensory receptors in eye muscles
rate expert ocular motor scientist at the Daroff- is not well understood, but there is physiologi-
Dell’Osso Ocular Motility Laboratory. The cal and clinical evidence for the presence of pro-
fi rst phase included 10 adults and the second, prioceptive signals in many areas of the central
5 children. After the data from up to 6 weeks after nervous system. It is unclear which structures
tenotomy for the fi rst five adult subjects were generate these sensory signals and which central
analyzed, they were unmasked to determine neural pathways are involved. Th ree different
whether phase 2 could be started. Preliminary types of receptors are associated with eye mus-
results of these data showed improved NAFX cles: (1) muscle spindles, (2) palisade endings,
scores and improved visual function. The and (3) Golgi tendon organs, but their occur-
NAFX values for all patients improved (average rence varies widely between species.108 A review
improvement was 48%).91,92 of their organization shows that each receptor is
The T&R procedure was tested on two mon- mainly confi ned to a morphologically separate
keys said to have “congenital nystagmus” with layer of the eye muscle. The palisade endings,
mixed results.98 However, closer examination of which are unique to eye muscles, are associated
the eye-movement data revealed the monkeys with the global layer; and they have been found
had FMN and NOT nystagmus (see Chapters 2 in all mammals studied so far.110,111 Their func-
and 3); they did not have IN. Thus far, no case tion is unknown. The muscle spindles, if they
of INS in monkeys has been confi rmed by eye- are present in a species, lie in the orbital layer, or
movement data. However, multiple studies of at its junction to the global layer. Golgi tendon
the T&R procedure have demonstrated positive organs appear to be unique to sheep and goats,
waveform and therapeutic results in confi rmed and so on. They lie in an outer distal marginal
cases of INS in dogs (achiasmatic Belgian sheep- layer of the eye muscle, called the “peripheral
dogs and Briards with Leber congenital amauro- patch layer” in sheep. The specific association
sis) and hundreds of human patients with either between palisade endings and the multiply
INS or acquired nystagmus.82,91,92,97,99–103 innervated type of muscle fibers of the global
Insight into the physiology of this response layer has led to the hypothesis that together
has renewed the interest of the ocular motor they may act as a sensory receptor and provide
basic-science community regarding ocular a source of central proprioceptive signals.
motor proprioception and its role in both invol- Thus, eye-muscle surgery may improve the
untary ocular oscillations and normal ocular nystagmus waveform, and vision/visual func-
motor control. 57,104 The tendino-scleral area tion in some patients, by altering a propriocep-
of the global portion of the extraocular mus- tive feedback pathway that normally calibrates
cle where surgery is carried out is now called the ocular motor system. It has been repeat-
its “enthesis.” Recently identified and studied edly shown since the late 1990s that surgi-
enthesial neurons by Hertle et al. and Butt ner- cal disruption of the enthesis (and associated
Ennever et al. have shown them to have propri- enthesial neuroanatomy) in patients with INS
oceptive anatomy and physiology.105,106 They results in long-standing beneficial effects on
probably provide feedback that assists with nystagmus and visual function. The neurophys-
alignment and stabilization of the eyes. These iological hypothesis for the “improvement”

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in the nystagmus is that there is a reduction of Relevant studies of INS surgery74,91,92,97,123–134 are
small-signal gain of the ocular motor plant by summarized in Table 7.3. Our approach to eye-
interfering with enthesial, neural propriocep- muscle surgery in patients with nystagmus devel-
tive tension control.112 Enthesial nerve signals oped as a result of a need to improve multiple
from palisade-type non-twitch fibers are likely preoperative ocular motor and/or visual system
involved in modulating the gain of sensory abnormalities in this patient population. These
feedback from the eye muscles analogous to the include, but may be limited to, nystagmus, anom-
gamma–efferent loop that controls the gain of alous head posturing, strabismus, deficient acuity,
proprioceptive feedback in skeletal muscles. stereopsis, motion processing, gaze dependent
Neuropeptides, neurotransmitters, and mem- vision, and visual reaction time. The nine-opera-
brane transport mechanisms may play an impor- tion system122,135 presented in Table 7.4 (see also
tant role in the neurochemical functioning of Chapter 2, Section 2.4.3) allows the clinician to
these enthesial endings’ membrane potential maximize surgical intervention in those patients
as it does in other sensory systems. Plasticity in in whom the primary indication for eye-muscle
the central ocular motor system may be modu- surgery is INS using one procedure with easily
lated as a result of the peripheral “trauma” to applicable clinical indications.
the enthesial area. Th is postt raumatic plasticity A few observations can be made as a result of
facilitates enthesial neuronal feedback to cen- using and analyzing this system. Most patients
tral ocular motor areas continuing to enhance with the infantile forms of nystagmus (91%)
the developmentally disturbed circuit, result- have strabismus and/or an anomalous head
ing in the improved ocular oscillation of INS. posture and will benefit from some removal or
repositioning of the extraocular muscles or ten-
dons and not only horizontal rectus tenotomy
7.2.2 Classification
with reattachment.122,136 The largest populations
The type of operation used for nystagmus has of patients have a combination of a head pos-
not been systematically classified until recently. ture (horizontal or vertical) and/or strabismus.
In 1953, Anderson and Kestenbaum independ- There is also a large population of patients who
ently suggested that an abnormal head posture benefit from surgical intervention for a chin-up
related to nystagmus could be alleviated by and chin-down head posture.122,136 In a study of
surgery.73,113 In the following year Goto made 224 patients with INS, Abadi et al. found that
similar suggestions.114 Anderson’s proposal was 73% had spatial nulls within1 ±10° of the pri-
for recession of the pair of yoke rectus mus- mary position, although 69% employed a com-
cles whose action was in the direction of the pensatory head posture.137 They found that
face turn. Goto suggested resection of the yoke patients with eccentric null zones at or beyond
antagonist muscles, and Kestenbaum favored 20° always adopted a head posture. Head shak-
surgery on all four horizontal recti muscles, ing was found in 27% and horizontal tropias
although he also suggested the two eyes should were found in 62.4%. There is some evidence
have sequential surgery. It is the Kestenbaum that the presence of a vertical head posture with
strategy, with modifications, that is most com- INS is more commonly associated with diagnos-
monly performed today, and his name tends to able diseases of the prechiasmal visual system,
be att ached to this surgical approach to nystag- that is, albinism, optic nerve hypoplasia, and
mus. A logical extension of these procedures retinal dystrophy.2,4,136,138 It may be that clini-
was applied by Dermot Pierse of England in cians have either not recognized these vertical
1959.76 He described two patients with nystag- null positions or there is less experience with
mus with the head held backward for maximum their treatment; either way, those patients with a
vision. He weakened both depressors (inferior chin-down or chin-up posture should be eligible
rectus and superior obliques). for surgical treatment in the same way, and for
Many authors subsequently have published the same reason, as those with horizontal head
their results with similar operations.74,77,78,115–122 postures.

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07_Hertle_Ch07.indd 219
Table 7.3 Summary of Interventional Treatment Trials for Infantile Nystagmus Syndrome

S U R G IC A L A N D
AU T HOR S YEAR T Y P E OF S T U DY P H A R M AC O L O G IC A L T R E A T M E N T S OU T C O M E S
Dell’Osso, Flynn 1979 Case series (N = 3) Kestenbaum surgery for horizontal AHP Null shift and broadening, VA
in all cases
Carruthers 1995 Case series (N = 4) Botox VA ↑ in 3/4
Gradstein, Reinecke, 1997 Case series (N = 9) Th ree prior Kestenbaum procedures, five Kestenbaum: VA unchanged
Wizov Congenital PAN recessions of horizontal recti, one had Baclofen Rec.: AHP & VA ↑ all cases
Baclofen: unsuccessful
Dell’Osso, Hertle, 1999 Case study (N = 1), Severed and reattached the tendons of the Immediate and persistent visible, behavioral, and
Williams, et al. Canine extraocular muscles EOG effects
Graf, Droutsas, 2000 Case series (N = 34) Kestenbaum surgery for horizontal AHP Long-term dose/response effect of 1.5°/mm
Kaufmann
Lee, Lee, Kim, et al. 2000 Case series (N = 63) Mod. Kestenbaum surgery (AHP), varying Mean preop AHP 32°
degrees, follow up > 5 m Mean postop AHP 5°
Graf 2002 Case series (N = 78) Kestenbaum (N = 31) AHP ↓ from 30° to 10°
Artificial divergence (N = 27) AHP ↓ from 30° to 5°
Combined (N = 20) AHP ↓ from 30° to 7°
Hertle, Maybodi, 2002 Case study (N = 1) Antianorexic drug (diethylproprionate) ↑ foveation broadened null zone
Mellow, et al. VA 20/70 to 20/50
Alio, Chipont, 2003 Case series (N = 42) Extensive recessions of the four horizontal AHP ↓ in all cases 21% ↑ by 0.2 logMAR
Mulet, et al. rectus muscles Consecutive XT three cases
Hertle, Dell’Osso, 2003 Case series (N = Tenotomy of all four horizontal recti with Mean foveation times ↑ in 9/9
et al. 10)* *one excluded reattachment at original insertion VA ↑ in 5/10 NEI-VFQ-25 ↑ in 9/10
from NAFX analysis Followed-up after 1 yr+
(continued)
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Table 7.3 (Continued)

S U R G IC A L A N D
AU T HOR S YEAR T Y P E OF S T U DY P H A R M AC O L O G IC A L T R E A T M E N T S OU T C O M E S
Kose, Egrilmez, 2003 Case series (N = 12) Retroequatorial recession of all four horizontal Intensity ↓ sig in all patients.
Uretmen, et al. recti. Follow-up ranged 6–26 months VA ↑ in 10/12 Improvements
Cao, Xin, Wang, 2004 Case series (N = 21) Parks shift of neutral zone Nystagmus ↓ VA ↑ 2–5 lines AHP ↓ in all cases
et al.
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Erbagci, Gungor, 2004 Case series (N = 7) Large recessions of four horizontal recti VA ↑ in 5/7, (5/5) AHP & (5/7) intensity ↓
Bekir
Hertle, Dell’Osso, 2004 Case series (N = 5) Tenotomy of all four horizontal recti with 1 yr postop, 2/3 had persistent significant ↑ in
FitzGibbon reattachment at original insertion NAFX and foveation times VA ↑ in 4/5
Hertle, Anninger, 2004 Case series (N = 15) Various surgery on all four horizontal recti VA ↑ ≥ 0.1 LogMAR in 14/15
Yang, et al. AHP ↓ Nystagmus ↓
Oleszczynska-Prost 2004 Case series (N = 32) Botox Amplitude ↓ in 29%–50%VA ↑ in all cases HT ↑

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Table 7.4 Nystagmus Operation Classification System (Based on 100 Patients)

Operation 1—Eccentric Horizontal Null Position Alone (22%)
Indication
Measurable or clinically observable eccentric gaze null with head posture in opposite direction
Preparation
Rule out aperiodic or periodic infantile subtype; no changing posture over 10 minutes of observation
Technique
A. Recess lateral rectus 10.0 mm in the abducted eye + medial rectus 7.0 mm in the adducted eye
with tenotomy and reattachment of the other horizontal recti for turns up to 20°
B. Recess lateral rectus 10.0 mm on the abducted eye + medial rectus 7.0 mm on the adducted eye
10.0 mm and resect the medial rectus 7.0 mm on the abducted eye + resect the lateral rectus 11.0
mm on the adducted eye for head turns greater than 20°
Operation 2—Chin-Down Head Posture (+/- Strabismus) (16%)
Indication
Chin-down head posture alone, nystagmus changes intensity in downgaze
Preparation
Rule out aperiodic or periodic infantile subtype, no changing posture over 10 minutes of observation
Technique
Bilateral inferior oblique myectomy plus bilateral superior rectus 5.0 mm recessions + recess or
resect one horizontal rectus on each eye for strabismus
Operation 3—Strabismus Alone (15%)
Indication
Nystagmus and horizontal strabismus with no head posture
Preparation
Treat refractive errors
Technique
Recess/resect on all four horizontal recti for the total deviation or bilateral recess for the total
deviation plus tenotomy and reattachment on the remaining two horizontal recti
Operation 4—Head Posture + Strabismus (10%)
Indication
Head posture plus strabismus
Preparation
Rule out aperiodic or periodic infantile subtype or esotropia with fusion maldevelopment and
adduction damping, that is, no changing posture over 10 minutes of observation; determine fi xing
eye (eye driving the head posture)
Technique
Straighten the head with prism correction over the fi xing eye, neutralize the resulting strabismic
deviation with prism over the nonfi xing (deviated) eye; perform bilateral recess/resect on each eye’s
respective measured prism correction or bilateral recess plus tenotomy and reatt achment on the
remaining two horizontal recti
(continued)

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Table 7.4 (Continued)

Operation 5—Chin-Up Head Posture (+/- Strabismus) (10%)
Indication
Chin-up head posture alone, nystagmus increased intensity in upgaze
Preparation
Rule out aperiodic or periodic infantile subtype; no changing posture over 10 minutes of observation
Technique
Bilateral superior oblique 5.0 mm tenectomy nasal to the superior rectus plus bilateral inferior rectus
5.0 mm recessions + recess or resect one horizontal recti on each eye for strabismus
Operation 6—Nystagmus Alone (About 7%–15% of Infantile Nystagmus Syndrome
Population) (9%)
Indication
Infantile nystagmus syndrome with or without periodicity and NO strabismus, static anomalous
head posture, or fusion with convergence damping
Preparation
Rule out strabismus, static head posture, or convergence damping
Technique
Bilateral horizontal recti tenotomy and reattachment
Operation 7—Multiplanar Head Posture (+/- Strabismus) (7%)
Indication
Combination chin-up/down and face turn
Preparation
Rule out aperiodic or periodic infantile subtype or esotropia with fusion maldevelopment and
adduction damping, that is, no changing head posture over 10 minutes of observation
Technique
Three muscles each eye; combine respective oblique plus vertical recti (above) for chin-up/down with
9.0–10.0 mm recess of lateral rectus of abducting eye and 7.0–8.0 mm recess of medial rectus of adducting
eye for face turn or recess or resect one horizontal rectus on each eye for strabismus with no face turn
Operation 8—Convergence Damping (Artificial Divergence) (6%)
Indication
Binocular function (stereopsis) with measurable improvement or observable convergence damping
Preparation
Prism adapt with 7 BO each eye, not Fresnell
Technique
Bilateral medial rectus recess 3.0 mm +/– bilateral lateral rectus tenotomy and reattachment
Operation 9—Torsional Head Posture Alone (5%)
Indication
Torsional head posture alone
Preparation
Rule out aperiodic or periodic infantile subtype; no changing head posture over 10 minutes of
observation
Technique
Horizontal transposition of vertical recti one full tendon width (hint: take the vertical recti off, move
the eyes in the direction of the head posture, reatt ach the vertical recti), that is, right head tilt, RSrec
nasal, RIrec temporal, LSrec temporal, LIrec nasal

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Strabismus surgeons are reluctant to operate classification of surgical procedures into nine
on the obliques without some obvious oblique separate but related types was necessary. Twenty
dysfunction due to the potential of creating percent had operation 1 (eccentric horizontal
cyclovertical motor and sensory complica- head position alone), 15% had operation 2 (chin-
tions. Unfortunately, nystagmus surgeons are down head posture +/- strabismus), 12% had
often required to operate on extraocular mus- operation 3 (strabismus alone), 12% had oper-
cles without obvious dysfunction, including the ation 4 (horizontal head posture + strabismus),
obliques. Th is is especially true for chin-up and 10% had operation 5 (chin-up head posture +/-
chin-down postures. The reason that we have strabismus), 11% had operation 6 (nystagmus
preferred bilateral oblique and recti operation alone, no head posture, vergence damping or
for chin-up and chin-down postures is that this strabismus), 8% had operation 7 (multiplanar
combination will prevent secondary alphabet head posture +/- strabismus), 8% had opera-
and cyclotorisonal deviations more than com- tion 8 (induced convergence alone), and 4% had
bined vertical rectus recession and resection operation 9 (torsional head posture alone). Each
procedures. The key to surgical success in this of the nine individual methods used to approach
group of patients is attention to detail with equal surgery on the extraocular muscles of both eyes
oblique and recti surgery on each eye. The only is diagrammed in the figures of Appendix C.
consequence of surgery is usually a 15%–20% The average changes in the visual acuities
comitant, limitation of vertical gaze with some of the patients undergoing each of the nine
lid retraction. operations are shown in Figure 7.4. As can
In our experience most patients (80%–85%) be seen from those circled, patients with the
with INS will have, in addition to their oscil- poorest preoperative acuities received the
lation, either a clinically significant head pos- most improvement, as was predicted by the
ture, strabismus, or vergence damping alone or NAFX versus percent improvement curve
in some combination. These facts require that shown in Chapter 2, Figure. 2.26. Because
the surgical approach to treatment incorporate measured acuities ref lect both sensory and
all the patient’s fi ndings. Thus, the rationale for motor deficits and posttherapy visual acuity

AVERAGE ACUITY COMPARISON PRE VS.POSTOP – ALL 9 OPERATIONS

PREOP POSTOP
Log MAR
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
VA1–N=22 VA2–N=16 VA3–N=15 VA4–N=10 VA5–N=10 VA6–N=9 VA7–N=7 VA8–N=6 VA9–N=5

P<.05 Group Means (0.68 pre vs. 0.45 post)

P>.10 Between Groups BUT
“TREND” = LOWER VA PREOP = MOST IMPROVED POSTOP

FIGURE 7.4 In 100 patients followed prospectively before and after eye-muscle surgery for infantile nys-
tagmus, the group comparison showed best-binocular acuity significantly improved after surgery. Circled
groups showed greatest improvements (see discussion in Section 7.2.2). The logMAR values shown reflect
the negative of the logarithm of the decimal acuity.

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is not a direct measure of that therapy, rela- one should perform to achieve a given amount
tive improvements cannot be used to compare of eye rotation in the Kestenbaum procedure.
the results of the different operations; only Flynn favored making equal amounts of reces-
NAFX values can do that accurately. However, sion and resection to place the eyes in a posi-
the longest foveation domain (LFD) meas- tion equal to but in the opposite direction of
ure translates directly into the range of gaze the null angle. Values taken from the published
angles with the highest acuity, regardless of curve74 are shown in Table 7.5 (see Chapter
whether there are associated sensory deficits. 2, Fig. 2.30 for curve). Parks favored unequal
Thus, the prediction of percent increase in amounts based on the difference in muscle
LFD (also shown in Chapter 2, Fig. 2.26) is strengths between the medial and lateral rec-
the actual percent broadening of the highest tus muscles (see Table 7.6). Significantly, both
acuity range of gaze angles. methods have been used with success in INS
To better appreciate the implications of the surgeries. Although the values shown in the fig-
NAFX and LFD plots in Chapter 2 and just ures in Appendix C reflect the Parks approach,
how much broadening, shift ing, and raising the the advantage of the Flynn approach is that it
NAFX peak improves the patient’s overall vis- retains homeostasis as much as possible. The
ual function, Figures 7.5 and 7.7–7.9 were con- reported success in INS treatment using several
structed to illustrate the difference between the different formulae to determine the amounts of
gaze angles with maximal, albeit perhaps still recession and resection needed suggested that
poor, acuity that further degrades at gaze angles the actual amounts were not as important as
lateral to the NAFX peak. Th is type of illus- doing the surgery. The demonstration that the
tration does not represent the perceived visual T&R portion of these surgeries was responsible
world; that perception is of uniform clarity (lim- for broadening the range of gaze angles with the
ited by peak visual acuity) just as normals per- patient’s highest acuity provides an explana-
ceive uniform clarity despite reduced acuity of tion for patient satisfaction and claims of being
targets lateral to the fovea. Instead, it illustrates able to “see better” despite different amounts of
the patient’s profound acuity degradation at dif- globe rotation, and even when no improvement
ferent gaze angles away from the peak gaze angle in peak acuity was measured.
while the head is held in primary position.
In Figure 7.5 the gaze-dependent acuity of Clinical Pearl: Determination of the amounts
a patient with a narrow, lateral (left ward) null of recession and resection needed to rotate
(sharp, lateral NAFX peak) appears with the the using bilateral recession and resection
head in primary position (top panel). To see of the horizontal recti (A-K procedure) may
objects/persons in primary position clearly, the be best accomplished by dividing the total
head must be moved to the right (middle panel), amount of surgery (indicated by the curve
and to see clearly in right gaze, the head must given in Dell’Osso and Flynn 1979) in two
be moved further to the right (bottom panel). and applying those equal amounts to the two
Th is is both stressful and time consuming in antagonist muscles.
real-world situations and is why broadening the
LFD is a prime goal in INS therapy; even normal The issue of the timing of nystagmus sur-
acuity (20/20) would not alleviate the visual gery, with or without an associated AHP, is not
function deficit of a narrow range of gaze angles sett led.139,140 It is our opinion that early surgery
with that high acuity. Th is has historically been (under 24 months of age) for INS may result in
unappreciated or underappreciated by both phy- a more profound effect on the nystagmus and
sicians and family members and is why multiple associated visual system development than later
visual acuity measurements must be made for all surgery (after 5–7 years of age);3 this is espe-
INS patients, before and after therapy. cially true for those INS patients with associated
There are two schools of thought regarding visual sensory deficits. We usually wait until the
the actual amounts of resection and recession children are on their feet (about 10–14 months

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FIGURE 7.5 Illustrations of the clarity of portions of the visual field in an infantile nystagmus syndrome
(INS) patient with a narrow, lateral, null (sharp, lateral eXpanded nystagmus acuity function [NAFX] peak)
and how gaze angle (+) affects an INS patient’s view of the world and the necessary head (H) shift s to main-
tain the same gaze angle and effectively move that lateral acuity peak across the visual field in order to see
each portion clearly.

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FIGURE 7.6 Plots of pre-tenotomy and reattachment (T&R) eXpanded nystagmus acuity function (NAFX)
peak versus percent increase (top left panel) or post-T&R NAFX (top right panel) and pre-T&R longest foveation
domain (LFD) versus percent increase (bottom left panel) or post-T&R LFD (bottom right panel). Colors of each
curve illustrate the areas where excellent (green), good (blue), and poor (red) improvement will result.

FIGURE 7.7 Illustrations of the clarity of portions of the visual field in an infantile nystagmus syndrome
patient with a narrow, central, null (sharp, central eXpanded nystagmus acuity function [NAFX] peak)
before and after tenotomy and reatt achment (T&R) surgery. As noted, this procedure can also be used in
cases where there are no nulls.

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Table 7.5 Nystagmus Operation–Modified Bilateral Horizontal Recess/Resect

LEFT NULL LEFT EYE R IG H T E Y E

A NGL E
R IG H T FAC E
TURN (R E C E S S L R ) (R E S E C T M R ) (R E C E S S M R ) (R E S E C T L R )
Flynn (for 10° <1 mm <1 mm <1 mm <1 mm
<10°, four- 15° 2.5 mm 2.5 mm 2.5 mm 2.5 mm
muscle 20° 6.5 mm 6.5 mm 6.5 mm 6.5 mm
T&R)
30° 8.5 mm 8.5 mm 8.5 mm 8.5 mm
45° 9.5 mm 9 mm 9 mm 9.5 mm
50° 10.5 mm 10 mm 10 mm 10.5 mm
LR, lateral rectus; MR, medial rectus; T&R, tenotomy and reatt achment.

of age) unless there is an associated infantile development of cortical visual motion process-
strabismus that requires surgery. Early eye-mus- ing, whereas later surgery is associated with
cle surgery for eye-movement disorders in not abnormal mVEPs. Shirabe et al. concluded that
a new idea. The results of Birch et al. suggest that early surgery in infantile esotropia is beneficial
early surgical alignment in those patients with to achieve binocular visual function, but it was
infantile esotropia is associated with better ster- necessary to confi rm a stable angle of deviation
eopsis and higher prevalence of fusion without with accurate preoperative evaluation.144 In the
adverse motor outcomes, because early surgery fi nal report of the early versus late infantile stra-
minimizes the duration of misalignment, not bismus surgery study, a controlled, prospective,
because alignment is achieved during an early multicenter study children operated early had
critical period of visual maturation.141–143 Drover better gross stereopsis at age 6 as compared to
found in a comparison clinical trial that fol- children operated late.145 Human and animal
lowing surgery a comparison group of patients studies conducted largely during the last 25 years
showed rapid development and possessed motor support both the clinical insights that early ocu-
skills comparable to those of normal children, lar motor treatment is preferred. Although there
suggesting that early surgery is beneficial to are data suggesting improved results in early
both visual and motor development.143 Early eye-muscle surgery (under 24 months of age) for
surgery for infantile esotropia promotes the nystagmus, the total picture is not clear.

Table 7.6 Nystagmus Operation–Traditional Bilateral Horizontal Recess/Resect

LEFT NULL LEFT EYE R IG H T E Y E

A NGL E
R IG H T
FAC E T U R N (R E C E S S L R ) (R E S E C T M R ) (R E C E S S M R ) (R E S E C T L R )
Classic < 20° 7 mm 6 mm 5 mm 8 mm
Parks 30° 9 mm 8 mm 6.5 mm 10 mm
(+) 40% 45° 10 mm 8.5 mm 7 mm 11 mm
(+) 60% 50° 11 mm 9.5 mm 8 mm 12.5 mm
LR, lateral rectus; MR, medial rectus.

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7.2.3 Preoperative Evaluation the strabismus should be measured as part of the

clinical exam. However, our analysis of thou-
7. 2.3.1 V I S U A L ACU I T Y sands of eye-movement records revealed that
Valid measurement of visual acuity is best per- often the strabismus is time varying as well as
formed with refraction in place both binocularly gaze-angle dependent. Th is has provided further
and monocularly using one of three methods: importance for the use of such data. By observing
the Teller Acuity Card (TAC) or Lea Symbols shifts in the alignments of the foveation periods
procedure in preverbal children, the amblyopia from each eye with the target position, the fi xat-
treatment study (ATS) ETDRS chart protocol ing eye can be identified along with the amount
(≥7 years of age), or the ATS single, surrounded, and stability of the strabismus angle.
HOTV optotype protocol (<7 years of age).146,147 As has been stated previously, both the nystag-
Measurements are obtained in the patient’s mus surgery and any necessary strabismus surgery
null position determined by the use of clinical should be performed in the same procedure. For
evaluation, head posture measuring system +/- instance, if an INS patient had an NAFX peak
eye-movement recordings. Due to the patient’s (nystagmus “null”) 20° to the right and a 19° left-
nystagmus, visual acuity is tested with the TAC’s eye esotropia when looking 20° to the right, the
held vertically so that the gratings are horizontally total left ward surgical shift (recession plus resec-
oriented.148 It is important to note that the ocular tion) of each eye for the nystagmus portion of the
motor oscillation of INS is almost uniformly hori- procedure, determined from Chapter 2, Figure
zontal, with horizontal intensity changes seen even 2.30, would be 11 mm (i.e., RLR: 5.5 mm reces-
in those patients with torsional and vertical head sion; RMR: 5.5 mm resection; LMR: 5.5 mm
postures, thus allowing the testing of acuity with recession; LLR: 5.5 mm resection). The strabis-
vertically held TAC valid for all these patients. mus portion would require 9.8 mm total to rotate
the deviated left eye to the left. Thus, the com-
bined surgery would be RLR: 5.5 mm recession;
7. 2.3. 2 O C U L A R M OT O R A N D
RMR: 5.5 mm resection; LMR: 5.5 + 4.9 = 10.4
S TA N D A R D C L I N I C A L E VA L U AT I O N S
mm recession; LLR: 5.5 + 4.9 = 10.4 mm resec-
Ocular motor examination includes a determina- tion. If, on the other hand, the patient had a 15°
tion of heterophoria/tropia at distance (3–6 m) left-eye exotropia, the combined surgery would
and near (33 cm) in all diagnostic positions of gaze. be RLR: 5.5 mm recession; RMR: 5.5 mm resec-
Sensory adaptations such as suppression, anoma- tion; LMR: 5.5 – 4.9 = 0.6 mm recession; LLR:
lous retinal correspondence, and varied levels of 5.5 – 4.9 = 0.6 mm resection. In this case, doing
fusion should be determined in standard fashion. the indicated recession and resection of the right
Cycloplegic refraction, tonometry, and exami- eye and simply performing a T&R procedure on
nation of the anterior and posterior segments the LMR and LLR would yield approximately
should be performed on all patients. Fundus pho- the same results. If the patient alternated the fi x-
tographs, electroretinography, and visual evoked ing eye, the total strabismus correction could be
potential testing are performed when retinal and/ split between the appropriate muscles of each eye
or optic nerve pathology are clinically suspected. (i.e., add 4.9 mm to the recessions of the RLR and
Evaluation of the ocular motor oscillations includes LMR for the esotropic example or subtract 4.9
measurement of any anomalous head posture and mm from the recessions of the RLR and LMR for
changes in the oscillation in primary position, the exotropic example). The broadening effects of
at near, and in diagnostic positions of gaze under the built-in T&Rs will overcome small deviations
monocular and binocular conditions. from the calculated numbers.

7. 2.3.3 S T R A B I S M US 7. 2.3. 4 E Y E- M OV E M E N T R ECO R D I N GS

Because of the prevalence of strabismus in patients The horizontal and vertical eye-movement
with INS, the type, amount, and comitance of recordings are most easily accomplished using

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an IR reflection method or digital video eye- is confi rmed by history, complete ophthalmic
movement system (see Appendix A). Key to evaluation, and eye-movement recordings show-
both accurate, repeatable diagnosis and wave- ing INS that changed in intensity commensu-
form and NAFX analysis of the fi xating eye is rate with head posturing or eye positioning. It
accurate calibration of each eye individually should be noted here that in patients with INS,
while the other is occluded. As described ear- an AHP is not the “abnormality” that needs
lier, it is also necessary for accurate, time-vari- to be treated. An AHP is an adaptive strategy
able strabismus analysis. While the careful use that is deliberately employed in the service of
of the clinical exam, history, and clinical motil- improved visual function; it is not a primary
ity tests can help identify some types of nystag- abnormality. If it were, surgery on the neck mus-
mus; only eye-movement data can reliably do so cles would be in order, not on the EOM. Also,
for all types. an AHP is under the direct control of the patient
One of the newest and most important and is, therefore, neither an accurate nor repeat-
uses of eye-movement data analysis (using the able measure of the real problem (or, especially
NAFX) is its unique ability to differentiate the postoperatively, of the “success” of a surgical
two components (sensory and motor) of meas- procedure)—the position of the INS waveforms
ured visual acuity. When one measures visual with the most well-developed foveation peri-
acuity in an INS patient, the resultant value ods is. The most precise method to determine
is due to both the sensory and motor deficits. the amount of EOM surgery needed to repo-
However, the percentage of each is unknown sition the gaze angle with the best foveation is
and that means that the potential for improve- through the use of data from eye-movement
ment is also unknown. All current therapies for recordings (e.g., NAFX function) plotted over
INS are aimed at improving the INS waveform, all gaze angles. Correction of the primary prob-
which would then improve acuity, both peak lem (i.e., the lateral position of the NAFX peak)
and gaze-angle acuity. However, one cannot pre- and broadening the NAFX peak will automati-
dict how much improvement in measured acuity cally negate the need for the patient to adopt an
is possible knowing only its measured value. In AHP postoperatively. Thus, accurate treatment
one patient, that value might be totally depen- of the primary abnormality removes the sec-
dent on a sensory deficit (i.e., when the INS ondary symptom of an AHP and prevents the
waveform was of the highest quality). In another subsequent development of structural abnor-
patient with the same measured acuity, it could malities in the neck. If neither NAFX analysis
be totally due to a poor INS waveform. In the (the best method) nor visual acuities at differ-
fi rst case, no improvement is possible with any ent gaze angles (an acceptable clinical method)
known INS therapy; in the second case, a high are available, measuring head position will yield
percentage improvement is possible, depending an approximate value upon which to base EOM
on the NAFX value. In most cases, there are both surgery. Measurement of the patient’s head pos-
sensory and motor deficits compromising visual ition using one of a number of head-posture
acuity, and significant improvement in visual measurement systems is best accomplished with
function is possible despite the sensory deficit. refraction in place during threshold visual acu-
The methodology available to estimate the ther- ity testing at distance and near.149 Head-posture
apeutic improvement possible regardless of the testing should be repeated at multiple intervals
relative percentages of sensory and motor defi- over a continuous 15-minute time frame to help
cits is discussed in Section 7.5. rule out APAN.
There is a strong caveat to using direct AHP
measurements (no matter how accurately the
7. 2.3.5 H E A D - P OS T U R E
measurement is accomplished) in either deter-
M E A S U R E M E N T S (“ N U L L ZO N E S ” )
mining the amount of surgery necessary or
Head posturing due to INS and not other cen- assessing the results of that surgery. Because
tral nervous system or vestibular abnormalities the AHP is both variable and under the direct

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control of the patient, it is inherently unrelia- 7. 2.3.6 L A B O R AT O R Y A N D S P EC I A L

ble and subject to bias, postoperatively. Th is TESTS
is especially problematic with children who
Those patients in whom systemic diseases or
“know” that the purpose of the surgery was to
associated ophthalmic abnormalities are sus-
“straighten their head” and that their parents
pected as a result of a thorough history and clini-
had spent a lot of money to do so. It is not sur-
cal evaluation may need serology, urine analysis,
prising to hear, in cases of insufficient surgical
neuroimaging, genetic testing, neurological and
rotation of the eyes, that immediately postoper-
ophthalmological electrophysiology, and con-
atively the patient’s AHP was gone but months
sultation by other specialists.
later it had “reappeared” at an intermediate pos-
ition. The myth of the reappearing null angle is
just that, a myth based on unreliable data. All 7.2.4 Results
accurate eye-movement data confi rm that the
7. 2. 4 .1 V IS U A L ACU I T Y
surgical rotation to center an eccentric null is
permanent (i.e., remains unchanged many years Multiple examples of level II- and III-based evidence
later) whether initially done correctly or under- suggest eye-muscle surgery improves nystagmus
corrected. However, there are three reasons that and visual function in patients with INS.79,84,92,97,102,1
22,128,136,150–153
an AHP may “reappear”: (1) there is a surgical Vision, if used as a secondary outcome
undercorrection; (2) a previous nondominant measure when reporting effects of eye-muscle sur-
(and clinically “silent”) multiplanar eccentric gery must be explicit and measured at multiple gaze
null position becomes clinically relevant (e.g., a angles straddling the angle of best acuity. The steps
“new” vertical AHP after treatment of a horizon- necessary to refract patients with nystagmus are
tal AHP); and (3) a new strabismus develops, summarized in Table 7.7,154,155 and the various signs
prompting a change in the INS compensation and symptoms of nystagmus amenable to refractive
mechanism. treatment are listed in Table 7.8.

Table 7.7 Refraction Steps in Patients with Nystagmus

S T E P S I N R E F R AC T ION OF PA T I E N T S W I T H N Y S TAG M U S
1. Acuity Measurement
a. PEDIG—ATS and ETDRS Protocols
b. Measure binocularly
c. Allow patients with anomalous head position to assume that position
2. Perform Subjective Refraction
a. Begin with retinoscopy obtained at distance (phoropter or trial lenses)
b. Do binocular refraction
c. Fog nontested eye with enough plus to decrease acuity by 1–3 lines
d. Perform routine subjective refraction (e.g., sphere, cylinder, etc.)
e. Repeat procedure on opposite eye
f. With best refraction in place, add up to 7 prism diopter base-out (if patient has fusion) with
additional 0.75 to 1.00 sphere to check for “convergence damping”
g. Check binocular acuity again (with AHP, if present)
3. Perform Objective Refraction
a. Forty minutes after 1% cyclogyl or 60 minutes after 1% atropine
b. Start with retinoscopic fi ndings in both eyes
c. Repeat steps C–F above (if patient is able)
d. Record differences in subjective and objective refraction

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Table 7.8 Refractive Treatment in greater. Eye-movement recordings also show

Patients with Nystagmus that surgical intervention increases the preva-
lence of favorable nystagmus waveforms. Even
S IG N S A N D S Y M P T O M S O F if the nystagmus were completely eliminated,
N Y S TA G M U S A M E N A B L E T O the integrity of the afferent system (optic nerve,
R E F R AC T I V E T R E A T M E N T retina, brain disease) and the age-related timing
of surgery may limit the acuity potential in any
S IG N S Y M P T O M E T IO L O G Y
specific patient with INS.
As a result of eye-muscle surgery improv-
Decreased vision Myopia ing their beat-to-beat nystagmus, these patients
Hyperopoia receive more useful vision per unit time and, as
Astigmatism a function of gaze, recognize objects faster, have
Anisometropia less head movement and better motion and con-
Amblyopia trast sensitivity; thus, they “function” better.
Anomalous head INS null or vestibular The common clinical misperception is that eye-
posture gaze damping muscle surgery only serves to either centralize
FMNS adduction the INS null position or reposition the eye(s)
damping in the orbit.156 In fact, what happens in patients
NBS with INS is a broadening and deepening of the
INS convergence null zone (more importantly, a broadening and
damping raising of the NAFX peak). In a more scientifi-
cally sound representation of this phenomenon,
Oscillopsia “Acquired”
this area is labeled “visual function space,” a
nystagmus
three-dimensional representation of visual func-
INS change (motor or tion. Data accumulated over the last 30 years
sensory status) show that many afferent and efferent visual sys-
Photophobia Retinal dystrophies tem measures improve as a result of eye-muscle
Albinism surgery on INS patients, regardless of the indi-
Hypoaccommodation Unknown cation (eccentric null, vergence damping, stra-
INS, infantile nystagmus syndrome; FMNS, fusioin
bismus, or nystagmus alone), suggesting that
maldevelopment nystagmus syndrome; NBS, nystagmus blockage neurovisual changes take place as a result of the
syndrome surgical procedure itself, unrelated to moving or
removing some of the extraocular muscle.75 The
current hypothesis is that surgical interference
There are at least five psychophysical meas- with peripheral extraocular muscle/tendon,
ures of acuity (e.g., detection, recognition, reso- “enthesial” proprioceptive nerve endings influ-
lution, hyperacuity, and localization). Variables ence central ocular motor pathways, resulting in
reported pre- and postoperatively in patients an improved INS oscillation. In a recent study
with INS include optotype and gaze-dependent of 100 patients with INS the average group mul-
acuity, contrast sensitivity, motion detection, tiple aspects of ocular motor as well as visual
null-zone characteristics, visual recognition sensory system function improved significantly
time, subjective visual function, and electro- after surgery.122
physiological characteristics. In 138 patients
from multiple studies who had their null zone 7. 2. 4 . 2 S T R A B IS M US
optotype best-corrected binocular vision tested
within 1 week and 4 to 6 weeks after eye-mus- The occurrence of strabismus with nystag-
cle surgery for INS grouped mean data showed mus, especially in infancy and childhood,
a significant improvement (p < .05) and, over- is very common, with reported incidence of
all, 75% improved 1–3 lines and 15% 3 lines or 20%–75%.122,157–161 In a report of 100 patients

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undergoing eye-muscle surgery for INS, there Excellent results were reported in another 38
was a significant improvement in the strabis- patients with a horizontal head turn, and fi ve
mic deviation of the 71 patients with associated with a vertical abnormal head posture who
strabismus.122 In patients with FMNS and stra- underwent horizontal nystagmus surgery.119
bismus, surgery of the eyes decreases the nystag- Kraft et al. reported a success rate of 78.3% of
mus intensity and may also improve binocular 23 INS patients having surgery for an AHP.165
visual acuity.162 Properly combined nystagmus Roberts et al. reported in 7 patients and Hertle
and strabismus surgeries should both improve et al. in 24 patients that rectus and oblique sur-
INS waveforms (i.e., breadth and height of the gery were effective surgical management of
NAFX peak) and reduce or eliminate the stra- vertical plane torticollis.166 Lee et al. reported
bismus (i.e., alignment of the two eyes). that 56 out of 63 patients (89%) achieved a
straight head position or a residual face turn of
10° or less after bilateral recession and resec-
7. 2. 4 .3 E Y E- M OV E M E N T R ECO R D I N GS
tion for INS and an AHP.126 Graf reported in
Postoperative eye-movement recordings have 78 patients with an AHP, aged 3 to 68 years,
always demonstrated the expected INS waveform that the AHP was reduced to 10° or less in 69
improvements that were based on the preopera- patients after one procedure.127 Chang et al.
tive recordings. Recordings made years later also reported that in the follow-up of an average
confi rmed the stationary nature of these thera- 33 months, 45 out of 51 patients (88.2%) who
peutic improvements. Usually plots of the post- underwent eye-muscle surgery for an AHP
operative NAFX values taken at different gaze resulted in an AHP less than 10°.167 Surgery on
angles are compared to those made preopera- the extraocular muscles in 19 patients aged less
tively. From such comparisons, improvements in than 2 years with INS resulted in a significant
peak NAFX and LFD can be made. Broadening improvement in those who had an AHP. 3
of the LFD is the most important therapeu- In 53 patients who had eye-muscle surgery
tic improvement to overall visual function and with a diagnosis of infantile periodic alternating
raising the peak NAFX translates directly into nystagmus and a dynamic “null” position, their
higher best-corrected visual acuity, regardless of PAN cycle, null period, and variability, duration,
whether there is an associated sensory deficit. and eccentricity of their AHP improved signifi-
cantly after eye-muscle surgery.168 In another
report in 70 patients with INS who had eye-mus-
7. 2. 4 . 4 H E A D - P OS T U R E
cle surgery and an AHP, the average change in
ME ASUREMENTS
posture improved significantly for all directions
Although the most accurate method of deter- (horizontal, vertical, and torsional).122 These
mining how to use eye-muscle surgery to and multiple other reports since 1959 confi rm
improve an AHP due to INS is the use of eye- that extraocular muscle surgery in the treatment
movement recordings (as mentioned earlier), of AHPs associated with nystagmus is a safe and
there is over 50 years of reported information effective therapy. Had the primary outcome
on the use of other methods of evaluation and measure been the NAFX peak (determined
treatment. It is worthwhile to briefly review from eye-movement data), the results could
some of this data. The extent of the head pos- have been better and should have been less var-
ture is usually dictated by the velocity dis- iable (i.e., would have better reflected the actual
tribution of the nystagmus slow phase, beat improvements).
direction, and the neutral zone, suggesting that
the surgical management of a head posture has
7.2.5 Complications
been based on the relocation of the minimum
intensity zone to the primary gaze position.163 Fortunately for those patients who undergo eye-
In a larger study, the net change in 38 patients muscle surgery, the overall incidence of surgical
after surgery of their head turn was 33.4°.164 complications is low (<3%–5%).169,170 Confusions

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involving incorrect procedures and patients can presents at the suture site as a localized, ele-
occur despite the Universal Protocol. vated, hyperemic mass that is less than 1 cm in
Unsatisfactory eye alignment (5%–20%) diameter. A conjunctival or Tenon’s inclusion
after surgery is the most common undesirable cyst (<1%) can present days to years after sur-
effect after surgery, but it should not be consid- gery.170 Conjunctival scarring can be a persis-
ered a “complication” in the true sense of the tent problem after surgery. Instead of returning
word, due to the generally unpredictable num- to the typical translucent white appearance,
ber of neurological and physiological factors that the conjunctiva can remain bulky and hypere-
contribute toward “perfect” ocular alignment in mic. Orbital tissue adherence (<1%) is usually
the fi rst place. Despite careful preoperative mea- seen after in conjunction with excessive bleed-
surements and utilization of common surgical ing into the orbital tissues or after infection.
dosage tables, a certain percentage of patients The orbital tissues and/or muscles produce
will have new deviations or be overcorrected a fibro-fatt y scar that is adherent to the muscle
or undercorrected after surgery.171 A change in and globe leading to a restrictive strabismus.
the refraction (<5%) can occur, especially if two A dellen (<1%) can occur on either the cornea
muscles are operated in the same eye. For exam- or sclera when thickened bulbar conjunctiva
ple, operating on two horizontal muscles can (either from scarring, hemorrhage, or swell-
induce a small with-the-rule astigmatism. Th is ing) prevents adequate and even lubrication of
change is typically temporary and resolves after the ocular surface.173
a few months.84 Diplopia (<5%) can occur, par- Anterior segment ischemia (ASI) (very rare)
ticularly in adult patients who are overcorrected. occurs when strabismus surgery creates impaired
Patients younger than age 10 years typically can blood flow to the anterior segment.174 Most of
suppress the deviated eye, but older patients may the blood supply to the anterior segment flows
not have suppression or, if suppression is present through the ciliary arteries within the four rectus
preoperatively, may not be able to shift the sup- muscles. Simultaneous surgery on three rectus
pression scotoma to cover an overcorrection.172 muscles in the same eye, or two rectus muscles
During surgery, scleral penetration or perfora- in a patient with compromised blood flow from
tion (< 9%) can occur from an inadvertent deep vascular disease are high-risk situations. Typical
pass of the suture needle or during dissection to fi ndings in ASI include iritis, corneal edema, folds
isolate and disinsert the muscle tendon. The risk in Descemet’s membrane, and, if severe, anterior
increases during a reoperation or on an eye with segment necrosis and phthisis of the operated
high myopia. In most cases, the penetration/ eye can occur. Eyelid malpositions (<5%) occur
perforation does not create a problem other than after eye-muscle surgery, most often on the ver-
a chorioretinal scar, but in some cases can trig- tical recti. The eyelid retractors, particularly in
ger endophthalmitis, vitreous hemorrhage, or the lower eyelid, are adherent to the intermuscu-
retinal detachment.170 lar septum and fascial tissue around the vertical
Postoperative infection (<1%) can occur, rectus muscles. Th is connection creates a shift
usually within the fi rst week after surgery. Most in eyelid position during standard recession or
infections occur around the initial surgical resection surgery of the vertical rectus muscles.
incision into the conjunctiva. Rarely, infections A lost or slipped muscle occurs (very rare) when
can penetrate deeper into the orbit with prop- the muscle slips free of the sutures or surgical
tosis, eyelid swelling, chemosis, and erythema. instruments during or after surgery.
As mentioned earlier, sometimes endophthal- Other rare complications that can lead to dis-
mitis can develop, either with or without a scle- ruption in vision include macular edema, burns,
ral perforation.170 Allergic reactions (<1%) can corneal erosion, diplopia, disruption of fusion,
occur in response to either the suture material dragged-fovea diplopia syndrome, and induced
or postoperative medications. A foreign body intraocular inflammation. Anesthetic compli-
granuloma (<1%) can develop, usually a few cations include malignant hyperthermia, too
weeks after surgery. The granuloma typically litt le anesthesia, globe penetration/perforation,

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orbital hemorrhage, and nausea and vomiting; patients with INS received a series of treatments
very rarely, asystole may occur as part of the consisting of two needles inserted into each ster-
oculocardiac reflex.170 nocleidomastoid, stimulated by tapping gently
every 5 minutes, for 20 minutes per session.180
Their eye movements were recorded using scle-
7.3 OTHER
ral search coils and changes in their INS wave-
forms analyzed at each point in the treatment.
7.3.1 Biofeedback
Changes in the stability and duration of fove-
Biofeedback has also been reported to help ation periods were examined. In four of the six
some patients with congenital nystagmus.175– patients, improved foveation was recorded at the
177
Auditory feedback of eye position and eye commencement of treatment; three maintained
motion was given to each subject to aid in con- this response throughout the treatment period
trolling the abnormal eye movement. Less than and after the needles were removed. In two, the
1 hour was needed for all the subjects to learn INS waveform itself was modified. Although
to use the auditory information. Reductions in not practical at the present time the acupunc-
eye-movement amplitude ranged from 41% to ture study suggests that afferent stimulation to
73%. Sensory functions like visual acuity and the neck and face stimulate projections to the
contrast sensitivity also improved under the reticular formation and vestibular nucleus and
auditory feedback condition. Auditory feedback may alter the behavior of the pathophysiologi-
of eye position in these patients was thought cal mechanism underlying INS.75 In the future
to have potential usefulness in improving INS. this information may support a pharmacologi-
In a related study using biofeedback, multiple cal method to access these pathways other than
subjects could voluntarily suppress nystagmus direct dermal stimulation.
and prolong foveation time. A damping of the
nystagmus amplitude, intensity, and frequency
7.3.3 Cutaneous Stimulation
was observed. On the average the intensity
decreased by about 40%, and the foveation time Cutaneous afferent stimulation (rubbing, vibra-
was prolonged by about 190%. After completion tion, or electricity) of the forehead or neck
of the training all the patients reported a subjec- damps INS in some individuals. Discussions
tive improvement in their vision when suppress- regarding possible mechanisms for the INS
ing their nystagmus.178 Sharma et al. studied damping produced by contact lenses led to the
10 patients with INS without null position who hypothesis that excitation of the ophthalmic
underwent six sessions (twice a week for 3 weeks) division of the trigeminal nerve by cutaneous
of auditory biofeedback.177 All patients could stimulation above one eye could affect the oscil-
reduce the nystagmus during the treatment ses- lation of INS.181 The stimulation resulted in a
sions. Mean amplitude (degrees) and intensity 50% diminution of the INS amplitude. Th is led
of nystagmus were reduced. Simultaneous eye- to studies of afferent stimulation using vibra-
movement recording shows significant reduction tion and electrical stimuli of the forehead and
of nystagmus amplitude and intensity because of the neck. Damping of INS is not necessary for
auditory biofeedback only during the treatment improved acuity; lengthening foveation periods
sessions; also, any objective effect on visual acu- and reducing their position variation are the
ity and contrast sensitivity was noted only dur- most important effects of therapy for functional
ing the therapy. The role of these treatments in vision improvement; however, amplitude reduc-
clinical practice has yet to be demonstrated. tion does result in cosmetic improvement.

7.3.2 Acupuncture 7.3.4 Gene-Transfer Therapy

The treatment of INS using acupuncture has As part of a larger study of gene-transfer ther-
been around for decades.179 In one study, six apy in RPE65-deficient canines, we completed

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a study to determine whether their nystagmus disappeared clinically after removing one of the
can be used as a motor indicator of restored cataracts and replacing it with an intraocular
retinal function.101,103 Treated and untreated lens.186 Finally, Rabiah et al. reported that the
canines were comfortably suspended in a cus- nystagmus (presumably INS) in 40% of child-
tom-built sling and encouraged to fi xate on ren with congenital cataracts was reduced or
distant targets at gaze angles varying between clinically eliminated after cataract surgery.187
+/–15° horizontally and +/–10° vertically. These reports, plus our fi ndings that gene ther-
Ocular motility recordings were made, using apy to alleviate canine LCA also resulted in the
two distinct methods: infrared reflection and clinical elimination of INS, provide strong evi-
high-speed video. The resultant recordings dence that, unlike the visual system, the ocular
from three untreated, four treated, and three motor system has no “sensitive” period after
pre- and postt reatment dogs were analyzed which deficits cannot be corrected. It appears
for using the NAFX.101,103 During fi xation, the that the necessity to constantly maintain accu-
untreated dogs exhibited large-amplitude, clas- rate and precise calibration of the ocular motor
sic INS waveforms, including pendular and subsystems throughout life also allows recali-
jerk in both the horizontal and vertical planes, bration when deficient visual input is improved.
which prevented them from keeping the targets Thus, future INS therapies that ameliorate or
within the area centralis (the region of highest eliminate an associated visual sensory deficit
receptor density, spanning +/–3° horizontally rather than the present therapies that are either
by +/–1.5° vertically, analogous to the fovea). peripheral (e.g., surgery or topical drugs applied
Some untreated dogs also had small-amplitude to the extraocular muscles) or central (e.g., sys-
(0.5°–1°), high-frequency (6–9 Hz) oscillations. temic drugs) may have substantial therapeutic
Under the same conditions, successfully treated benefits to visual function.
canines no longer exhibited clinically detectable
INS. Their IN was converted to waveforms with
7.3.5 Mind-Body Stress Reduction:
very low amplitudes that yielded higher NAFX
Mindfulness Meditation Techniques
values and allowed target images to remain well
within the area centralis. In this animal model, Half of the adults in the United States use com-
gene-transfer therapy that successfully restored plementary and alternative medicine with
retinal function also reduced the accompanying mind-body therapy being the most commonly
INS to such a great extent that it was not clini- used form. Mindfulness-based stress reduc-
cally detectable approximately 90% of the time tion (MBSR) has been used with patients with
in many of the dogs.101,103 Two research groups, a variety of conditions.188,189 Randomized con-
one in Philadelphia (Maguire et al.) another in trolled clinical trials and seven uncontrolled
London, England (Bainbridge et al.), recently clinical trials reported positive results, includ-
tested RPE65 replacement in two human ing improvements in mood, sleep quality, and
trials with a total of six LCA patients.182–184 reductions in stress.190 From a clinical view-
Remarkably, visual improvements were docu- point, MBSR has shown efficacy for many psy-
mented by ETDRS visual acuity measurements, chiatric and physical conditions and also for
pupillometry, nystagmus-frequency reduction, healthy subjects. Mindfulness-based cognitive
visual field measures, perimetry, and an obsta- therapy (MBCT) is mainly efficacious in reduc-
cle course. There were no local or systemic side ing relapses of depression in patients with three
effects, or improvements in ERG measures. or more episodes. Zen meditation significantly
In 1982, Cross et al. reported on a case reduces blood pressure and Vipassana medi-
of acquired periodic alternating nystagmus tation shows efficacy in reducing alcohol and
(PAN) that appeared following bilateral vitre- substance abuse in prisoners.191 Despite encour-
ous hemorrhages and which cleared after vit- aging fi ndings, several limitations affect current
rectomy.185 Jay et al. reported a case of acquired studies. Neurology patients, including those
PAN in a 60-year-old man with cataracts that with nystagmus, often turn to their physicians

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for insight into the effectiveness of the therapies 7.3.7 Educational Assistance
and resources to integrate them into their care.
Mind-body therapy application to general pain, The rate at which visual impairments occur
back and neck pain, carpal tunnel syndrome, in individuals under the age of 18 years is
headaches, fibromyalgia, multiple sclerosis, 12.2 per 1000. Severe visual impairments
epilepsy, muscular dysfunction, stroke, aging, (legally or totally blind) occur at a rate of .06
Parkinson disease, stroke, migraine headache, per 1000.195 Globally, more than 171 million
and attention-deficit/hyperactivity disorder people are visually impaired, of whom 134
are several conditions where there is evidence million people had low vision and 37 million
for mind-body therapies.188 Mind-body thera- were blind. Worldwide for each blind person,
pies for other neurology applications have lim- an average of 3.4 people have low vision, with
ited evidence, due mostly to small clinical trials country and regional variation ranging from
and inadequate control groups.191 The potential 2.4 to 5.5. Visual impairment is unequally
application of MBSR in the treatment of nystag- distributed across age groups. More than 82%
mus is an opportunity yet to be explored. of all people who are blind are 50 years of age
and older, although they represent only 19%
of the world’s population. Childhood blind-
7.3.6 Occupational and
ness is estimated at 1.4 million blind below
Vision Therapy
age 15 years. Available studies consistently
In addition to those medical and surgical thera- indicate that in every region of the world, and
pies discussed earlier, optical aids, vision ther- at all ages, females have a significantly higher
apy, and low-vision rehabilitation are available to risk of being visually impaired than males.196
nystagmus patients to improve visual function- Children and youth with low vision have
ing.192 These therapies improve visual function unique educational needs. Research docu-
in patients with INS by promoting binocularity, ments that these students often require direct
enhancing image quality and stabilization, build- instruction by a teacher for students with vis-
ing vergence and accommodation, and provid- ual impairments in areas that are not typically
ing novel orientation and mobility techniques to addressed for other students. All students
overcome a visually challenging environment.193 who meet the criteria for visual impairment
Vision therapy has been practiced since the late within their state should have a document
1800s to assist with binocular function. The goal that addresses their individual needs. This
of vision therapy for treating nystagmus is to try document, called an individualized education
to increase foveation time and promote binocu- plan (IEP), is used to place a child in the most
larity. Handheld magnifiers, credit-card style, appropriate educational setting. A thorough
full 8.5x11 magnifier pages, globes, and magni- assessment for students with visual impair-
fying rulers may be useful to many patients. ments is the key in creating an adequate IEP.
Handheld mini telescopes are useful for spot- And the assessment process is an essential com-
ting things far away, as are bioptics, which are ponent in developing appropriate goals and
tiny telescopes mounted on the top of glasses. objectives for the student. Parents may learn
Closed-circuit TVs can be portable or perma- that their child has vision impairment much
nent; these systems have large screens that will earlier than do parents of children with other
greatly magnify a page from a book or a cricket disabilities. Children with visual impairments
from the back yard. Computer soft ware such as should be assessed early in order to benefit
ZoomText (or similar soft ware) and accessibility from early intervention programs, when appli-
features in Windows and Macintosh comput- cable. Students with visual impairments may
ers can magnify what is shown on the computer need additional help with special equipment
screen. Screen-reading soft ware such as JAWS and modifications in the regular curriculum
will assist with interpretation of text displayed to emphasize listening skills, communication,
on the computer screen.194 orientation and mobility, vocation/career

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options, and daily living skills. Students who 7.4 ASSESSING THERAPEUTIC
have visual impairments combined with other OUTCOMES (POST-THERAPY )
types of disabilities have a greater need for an
interdisciplinary approach and may require 7.4.1 Direct Outcome Measures
greater emphasis on self-care and daily living (eXpanded Nystagmus Acuity
skills.197 Function, Longest Foveation Domain,
Information for parents of school child- and Target Acquisition Time)
ren with nystagmus is available through many
resources both online and via eye care societies; In assessing outcome measures for any ther-
particularly useful societies are the American apy, it is important to differentiate between a
Nystagmus Network (htt p://www.nystagmus. desired medical outcome that may, or may not,
org/entry.html) and the England Nystagmus be directly related to the actual changes brought
Network (http://www.nystagmusnet.org/). about by that therapy, and those actual changes
The student should be encouraged to explain (i.e., the direct outcome measures). An example
his or her visual needs; however, continual and would be the outcome measure for strabismus
undue attention to these should be avoided. surgery. While the restoration of binocularity is
Allow books/objects to be held close to the a highly desirable medical outcome, it does not
eyes, the head tilted, and any other body pos- directly result from aligning the two eyes and,
ture adopted if this enhances vision. Provide therefore, should not be used as an outcome
the students with their own book/worksheet. measure for the success or failure of the stra-
Sharing is impossible. Enlarging material will bismus surgery. In acquired nystagmus with
often help, although good contrast may suffice. oscillopsia, the diminution or elimination of the
Wall displays for reference should be placed perception of world motion is a highly desirable
at eye level and where the student can stand medical outcome; it does not directly result from
close. Ask the student where he or she would damping the nystagmus and, therefore, should
prefer to sit. It is oft en facing and near to the not be used as an outcome measure for the suc-
board; students should not sit to one side. He cess or failure of the nystagmus surgery, which
or she should be offered positions close to may have damped the nystagmus, as anticipated.
demonstrations during activities. Store visual Similarly, in nystagmus surgery (specifically
aids so that the student has easy access and can INS surgery), while improved peak acuity is also
use them when he or she judges that they will a highly desirable medical outcome, it does not
be helpful. Allow the use of prescribed tinted directly result from extraocular muscle surgery
glasses, cap, hat, or eyeshade to reduce the and, therefore, should not be used as an outcome
effects of glare. Read aloud when writing on measure for the success or failure of the nystag-
the board; describe diagrams. Allow sufficient mus surgery.
time to complete tasks and to examine mate- The only direct changes that can be brought
rials/objects. Good (though not necessarily about by nystagmus surgery are those that can be
bright) lighting is essential. The light should measured from ocular motor data (i.e., changes
be behind the student and directed onto the in INS waveforms that may improve visual func-
object being viewed. Matte surfaces for walls, tion). The direct ocular motor outcome meas-
boards, and paper prevent light reflection ures that affect visual function are as follows:
and glare. Use strong color contrast between the peak NAFX value, the LFD value, and the Lt
letters/fi gures/lines and background. These (target acquisition time) value. The peak NAFX
should be well spaced. To keep track of where improvement translates directly into improved
the pupil is up to when reading, a piece of dark acuity, the LFD improvement translates directly
card may be used or he or she can track with into the widening of the range of gaze angles
a fi nger. Exercise books with matte paper, dif- with the highest acuity, and the Lt improvement
ferent colors, and line spacing should be made translates directly into shortened target acquisi-
available. tion time.

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7. 4 .1.1 P OS T-T E N OT O M Y A N D cryogenically) without performing any tenotomies

R E AT TA C H M E N T (augmented tendon suture—sans tenotomy).
Some data have begun to be collected to test this
We assessed the therapeutic effects of the T&R
hypothesis.
procedure by measuring the postt herapy peak
NAFX, LFD, and Lt values and comparing them
to their respective pretherapy values; improve- 7. 4 .1. 2 P OS T- CO N V E R G E N C E /B I M E D I A L
ments were expressed as percentages. 3,4,82,83,91 R EC T US R EC E SS I O N S
,92,99,100,102,136,168
As Figure 7.6 (top left and right
panels) shows, for low pre-T&R peak NAFX val- Our research found that, for those binocular INS
ues, improvement is greatest and for high pre- patients whose IN damped with convergence,
T&R peak NAFX values, improvement is least. the improvements in peak NAFX and LFD were
The same applies for the LFD improvements, greater than for gaze-angle peaks.28 The visual
as is shown in Figure 7.6 (bottom left and right function improvements of convergence induced
panels). These improvements are in the motor by either base-out prisms or the bilateral medial
component of visual function and are independ- rectus muscle recession procedure are illus-
ent of any associated sensory deficits and were trated in Figure 7.8.
also independent of age. As Figure 7.7 illustrates,
the T&R procedure allows clearer vision over a
7. 4 .1.3 P OS T- K E S T E N B A U M O R
broader range of gaze angles.
A N D E R S O N P L US T E N OT O M Y A N D
It has been hypothesized that adding an extra
R E AT TA C H M E N T
suture or two to each tendon in the T&R proce-
dure (augmented T&R) might result in an even The beneficial effects of surgery of the extraocu-
greater diminution of the small-signal gain of lar muscles was fi rst demonstrated by eye-move-
the extraocular muscles.198 If that were found ment data analysis of patients who underwent
to be true, a further hypothesis was advanced the four-muscle Kestenbaum procedure.74,78
that the four-muscle T&R might be replaced These included translation of the eccentric null
by simply placing several sutures in the ten- to primary position, improvement of the null,
dons of each extraocular muscle (or manipulat- and broadening of the null. The latter gave rise to
ing them mechanically, pharmacologically, or the hypothesis that led to the T&R procedure.75

FIGURE 7.8 Illustrations of the clarity of portions of the visual field in an infantile nystagmus syndrome
(INS) patient with a narrow, central, null (sharp, central eXpanded nystagmus acuity function [NAFX]
peak) before and after either base-out prisms or bimedial recession surgery to broaden and shift the central
acuity peak.

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Figure 7.9 illustrates the multiple therapeu- 7. 4 .1.5 S Y S T E M I C A C E TA ZO L A M I D E

tic benefits of the four-muscle Kestenbaum A N D T O P I C A L B R I N ZO L A M I D E
procedure for these patients. The top left panel
Our most recent research has been into the thera-
shows the preoperative acuity field. The top
peutic effects of either systemic acetazolamide or
right panel illustrates the expected shift in clear
topical brinzolamide (i.e., eye drops) on INS.34,35
vision to primary and, prior to the Dell’Osso
Both produced both higher NAFX and LFD val-
and Flynn study,74 the absence of appreciable
ues and would, therefore, also result in the types
improvements in visual function. However, the
of improvements illustrated in Figures 7.7 and
bottom panel illustrates the actual visual func-
7.8 (see also Chapter 2, Fig. 2.26). As Figure 7.10
tion benefits measured after the Kestenbaum
shows, the brinzolamide eye drops improved the
surgery. Not only has the angle of clear vision
peak NAFX more than contact lenses and pro-
been shifted but also improved and, most
duced the same improvement in the LFD. The
important, broadened.
possible use of topical drugs, in the form of eye
drops, to treat INS is a new area of research whose
outcomes are yet to be determined.
7. 4 .1. 4 S O F T CO N TA C T L E N S E S
Studies of the therapeutic effects of soft contact
7.4.2 Indirect/Clinical Outcome
lenses on INS revealed some increases in peak
Measures
NAFX and significant broadening of the LFD.32,33
Thus, contact lenses would have the same broad- Improvement in those direct-outcome charac-
ening effect on the range of gaze angles with high- teristics of IN is reflected in clinical improve-
est acuity as the T&R or convergence therapies ments in visual function such as high-spatial
illustrated in Figures 7.7 and 7.8. frequency discrimination (e.g., visual acuity),

FIGURE 7.9 Illustrations of the clarity of portions of the visual field in an infantile nystagmus syndrome
patient with a narrow, lateral, null (sharp, lateral eXpanded nystagmus acuity function [NAFX] peak) before
and after Kestenbaum surgery to broaden and shift the lateral acuity peak to primary position. Also shown is
the expected effect of shift ing the lateral acuity peak with no other improvements.

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FIGURE 7.10 Plots of % eXpanded nystagmus acuity function (NAFX) improvement versus gaze angle
for contact lenses, topical brinzolamide, and convergence showing the large increases resulting from all
treatments at lateral gaze angles. The longest foveation domain (LFD) values for each curve are shown.

broader range of gaze angles where acuity is near where only the LFD is broadened (i.e., little or
peak values, and faster target acquisition and no increase in peak NAFX), large improvements
recognition. These direct outcome measures are in visual acuity across the field of gaze result and
reflected in therapeutic improvements in peak thereby improve visual function leading to patient
visual acuity and broadening of the gaze-angle satisfaction. The large improvements in acuity for
range of high acuity. three different therapies are illustrated in Figure
7.11. Regardless of whether peak acuity (at primary
position) is increased, each increases acuity by
7. 4 . 2.1 V I S U A L ACU I T Y AT D I F F E R E N T
large amounts at lateral gaze angles. Such increases
GA ZE ANGLES
result in overall increases in visual function that
Visual acuity measurements taken at five or more can be documented by pre- and posttherapy acuity
gaze angles can be used to determine the most measurements at different gaze angles.
effective therapy and as an outcome measure
(especially the LFD) if eye-movement recordings
7.5 ESTIMATING THERAPEUTIC
are unavailable. In cases with no associated sen-
OUTCOMES (PRE-THERAPY )
sory deficits, the NAFX values translate directly
into best-corrected visual acuities. In cases with
7.5.1 Direct Outcome Measures
associated sensory deficits, the actual measured
(eXpanded Nystagmus Acuity
visual acuities would be less than predicted by
Function, Longest Foveation Domain,
the NAFX values. However, the percent improve-
and Target Acquisition Time)
ments in NAFX values would be equally reflected
in measured acuities. The percent improvements When pretherapy values of the NAFX function
in LFD values would be directly translated into are low or medium, posttherapy values are higher.
ranges of gaze angles with improved acuities for They also remain near peak values at gaze angles
both patient populations. lateral to the peak (LFD or peak broadening).
It is important to understand that plots of Also, the long pretherapy latencies before target
NAFX versus gaze angle demonstrate the drastic acquisition are shortened after therapy. These
decrements in visual acuity lateral to the NAFX direct outcome measures, unlike measured acu-
peak, wherever it is located. Thus, even in cases ities, are measures of the motor components of

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FIGURE 7.11 Plots of % eXpanded nystagmus acuity function (NAFX) improvement versus gaze angle
for contact lenses, systemic acetazolamide, and convergence showing the large increases resulting from all
treatments at lateral gaze angles.

visual acuity. Because of that, they can be used to in the same increases in visual acuity. The curves
provide per-therapy estimates of percent improve- shown in Figure 7.6 were plotted from the results
ments in measured peak acuities and range of gaze of evaluating the T&R procedure in patients from
angles with high acuity. These estimations are not several studies.100 It then became possible to use
dependent on the presence, absence, or severity those curves to estimate both NAFX and LFD
of associated sensory deficits. For the first time, it improvements before application of the therapy.
became possible not only to determine the most The following example illustrates how both
appropriate therapy for individual INS patients the improvements in peak NAFX and LFD can
and have a direct measure of that therapy but be estimated for an 8-year-old INS patient who
also be able to use pretherapy data to estimate the has no associated afferent deficits and a meas-
improvements that would result from the therapy. ured pre-T&R NAFX peak of 0.30. Using either
Such estimates provide the physician and patient of the curves in Figure 7.12, the 0.30 value is
with realistic expectations and also are useful in located on the x-axis and the corresponding
determining the efficacy of the therapy. estimated improvement (0.48 or 60%) is read
off the y-axis. Then using the curve in Figure
7.13, the pre-T&R point is plotted (fi lled cir-
7.5.1.1 T E N OT O M Y A N D R E AT TA CH M E N T
cle at: calculated pre-NAFX = 0.30, measured
( I N FA N T I L E N Y S TA G M US S Y N D R O M E
preacuity = 20/70); allowing for measure-
WITHOUT AFFERENT VISUAL DEFICITS)
ment errors, that point should lie on or near
For INS patients with no afferent deficits, the the age-dependent NAFX versus acuity line.
NAFX values measured from eye-movement data The estimated post-T&R value is then plotted
are correlated with the patient’s best-corrected on the NAFX versus acuity line (open circle)
visual acuity.181 Thus, both the pre- and post- and estimated best-corrected visual acuity
therapy values have visual acuity equivalents, and read from the y-axis, here 20/40. Note that
specific measured increases in the NAFX result if it is known that the patient has no afferent

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FIGURE 7.12 Plots of estimated improvements in eXpanded nystagmus acuity function (NAFX) (left
panel) or NAFX percentage (right panel) versus pre- tenotomy and reatt achment (T&R) value. Example
shows the improvements for a pre-T&R value of 0.30.

sensory deficits and eye-movement data to cal- needed to estimate NAFX, and LFD therapeu-
culate the NAFX are not available, measured tic improvements, see Appendix D, Figs. D.6
pre-T&R visual acuity, expressed as a decimal, and D.7). To calculate the estimated improve-
may be used with the curves in Figure 7.12 to ments in the LFD value, the curves in Figure
obtain the estimated improvements in visual 7.14 are used. The pre-T&R value (for this
acuity, but only in such cases. For patients out- example, 15°) is located on the x-axis and the
side this age range, conversion between NAFX corresponding estimated improvement (>31°
value and visual acuity is obtained from lines of or >110%) is read off the y-axis. Worksheets
the age-appropriate slope (for printable graphs useful in making these estimations are shown

FIGURE 7.13 Plot of visual acuity versus eXpanded nystagmus acuity function (NAFX) for an infantile
nystagmus syndrome patient (age range 6–12 years or >60 years) with no afferent visual sensory deficits.
Shown are the pre-tenotomy and reatt achment (T&R) (solid circle) and estimated post-T&R (open circle)
values and their respective best-corrected visual acuity values.

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FIGURE 7.14 Plots of estimated improvements in LFD (left panel) or LFD percentage (right panel) versus
pre- tenotomy and reatt achment (T&R) value. Example shows the improvements for a pre-T&R value of 15°.

in Appendix D and may be copied and printed Finally, plot and the estimated post-T&R point
from Appendix F.3. on the new line (open circle) and read off the
estimated visual acuity (here, 20/70). Note that
in this example, the sensory deficit alone (i.e., no
7.5.1. 2 T E N OT O M Y A N D R E AT TA CH M E N T
IN and NAFX = 1.0) would have only reduced
( I N FA N T I L E N Y S TA G M US S Y N D R O M E
visual acuity to 20/25, the bulk of the acuity def-
WITH AFFERENT VISUAL DEFICITS)
icit being att ributable to the INS waveform. In
Many INS patients also have associated afferent other cases the situation could well be reversed
sensory deficits. Fortunately, because the NAFX with a higher NAFX and equally low, or lower,
and LFD measures are only dependent on the measured pre-T&R acuity. To calculate the esti-
motor components of visual function, the afore- mated improvements in the LFD value, the pre-
mentioned method may be modified to also esti- T&R value (for this example, 15°) is located on
mate the measured improvements of the T&R the x-axis in Figure 7.14 and the corresponding
procedure in this larger subset of INS patients. estimated improvement (>31° or >110%) is read
To estimate the improvement in peak NAFX, off the y-axis. Note that the LFD improvement
the same steps outlined earlier for INS patients is calculated in exactly the same way regardless
with no afferent visual sensory deficits are fol- of the presence or absence of afferent visual sen-
lowed using Figure 7.12. Let us assume that sory deficits and that the percent improvements
instead of 20/70, the pre-T&R measured acu- in both NAFX and LFD are also independent of
ity is 20/200. As in the example for INS with no such deficits.
associated visual sensory deficits, the pre- and
post-T&R points are plotted as follows. First, 7.5.1.3 P R IS M S/B I M E D I A L R EC T US
plot the pre-T&R point (obtained from Fig. 7.12) R EC E SS I O N S
at the measured previsual acuity point (fi lled
circle at: calculated pre-NAFX = 0.30, measured Research has shown that, in binocular (i.e., no
preacuity = 20/200), as is shown in Figure 7.15; strabismus) INS patients whose IN damps with
due to the sensory deficit, it should lie well below convergence, the therapeutic improvements
the age-determined NAFX versus acuity line. resulting from convergence are greater than
Then, plot a line through that point that is par- from using the gaze angle with peak NAFX (i.e.,
allel to the age-specific NAFX versus acuity line. the “null”).28 Thus, for this subset of patients

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 OUP UNCORRECTED PROOF – REVISES, 09/11/12, NEWGEN

FIGURE 7.15 Plot of visual acuity versus eXpanded nystagmus acuity function (NAFX) for an infantile
nystagmus syndrome patient (age range 6–12 years, or >60 years) with an afferent visual sensory deficit.
Shown are the pre-tenotomy and reatt achment (T&R) (solid circle) and estimated post-T&R (open circle)
values and their respective best-corrected visual acuity values.

either base-out prisms or a bimedial rectus reces- a patient has no afferent visual sensory deficits
sion operation is indicated. The estimated null associated with his or her INS, the direct rela-
broadening and increase in peak NAFX should tionship between the waveform quality measure,
exceed those values determined from the T&R NAFX, and visual acuity can be used in both the
estimation curves of Figure 7.6. estimation of the post-T&R therapeutic improve-
ment and measuring that post-T&R improve-
ment. However, when such afferent deficits are
7.5.1. 4 S O F T CO N TAC T L E NS E S
present, both become problematic because the
Research has shown that, in INS patients whose proportion of measured acuity att ributable to
IN damps with soft contact lenses, the therapeu- either the afferent deficit or the INS waveform
tic improvements resulting from their use are is unknown.
similar to those from the T&R procedure. 32,33
Thus, for this subset of patients, the estimated
7.5.2.1 V I S U A L ACU I T Y AT D I F F E R E N T
null broadening should equal and the increase
GA ZE ANGLES
in peak NAFX might be less than those values
determined from the T&R estimation curves of Measuring visual acuity at different gaze angles
Figure 7.6. does provide a method to estimate the LFD
improvement in all INS patients (as the above
examples show) and the peak NAFX in some.
7.5.2 Indirect/Clinical Outcome
At one end of the spectrum, where the measured
Measures
visual acuity is high, one can presume the INS
Although it is obvious that accurate and repeat- waveform component is paramount and substi-
able diagnoses, identification of appropriate tute age-determined NAFX values for visual acu-
therapeutic options, measurements of direct ity measurements. At the other end, where visual
outcome measures, and estimation of therapeu- acuity is very poor and the INS appears to be
tic improvements can only be made using eye- slight, one can presume that afferent visual sen-
movement data, they are not always available. As sory deficits are paramount; as Figure 7.6 shows,
mentioned earlier, if one is absolutely sure that the probability for therapeutic improvement

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 OUP UNCORRECTED PROOF – REVISES, 09/11/12, NEWGEN

as a result of INS therapy is low in such cases. concepts of physiology and pharmacology. Ann
That does not mean that all, or even most, cases Neurol 1994;36(2):129–141.
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to the fi nal stage of Schopenhauer’s three stages 1997;48:1178–1184.
of truth recognition (see epigraph). 13. Stahl JS, Averbuch-Heller L, Leigh RJ.
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nystagmus surgery using extended hang responses. Invest Ophthalmol Vis Sci
back recession of the four horizontal 2008;49(8):3432–3437.
rectus muscles. Eur J Ophthalmol 141. Birch EE, Stager DR, Berry P, Everett
2003;13(5):415–423. ME. Prospective assessment of acuity and
130. Kose S, Egrilmez DG, Uretmen O, Celebisoy stereopsis in amblyopic infantile esotropes
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131. Cao GL, Xin HR, Wang D, Wang SX, Zhang surgery for infantile esotropia. J AAPOS
M, Liu B. Stereoacuity before and after 2006;10(5):409–413.
operation of Parks shift of neutral zone 143. Drover JR, Stager DR, Sr., Morale SE,
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[in Chinese]. Zhonghua Yan Ke Za Zhi development following surgery for infantile
2004;40(2):101–103. esotropia. J AAPOS 2008;12(2):136–140.
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infantile esotropia: results and influence Gaze-dependent and time-restricted visual
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effects on cortical motion visual evoked “Sensory” and “motor” nystagmus:

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erroneous and misleading terminology augmented modified Kestenbaum surgery

based on misinterpretation of David protocols for abnormal head postures in
Cogan’s observations. Arch Ophthalmol infantile nystagmus. Binocul Vis Strabismus Q
2007;125(11):1559–1561. 2007;22(4):235–241.
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184. Bainbridge JW, Tan MH, Ali RR. Gene Jones LA, Raasch TW, Bullimore MA.
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8
summary and conclusions
One of the most important functions in science is to reward those who disprove our most closely held
beliefs.
—Carl Sagan (1934–1996)

IN THIS text, we have presented a synopsis of To paraphrase the magician, “the (patient’s) eye
the past 50 years of our and many others’ ocu- is quicker than the (physician’s) eye.”
lar motor research relevant to the diagnosis Recently discovered peripheral afferent neu-
and treatment of infants, children, and adults roanatomy with its central ocular motor connec-
with infantile nystagmus syndrome (INS) and tions may be the mechanism by which peripheral
other benign types of nystagmus of infancy. disruptions initiate central changes. Plasticity
Analogous to the assessment of afferent visual following peripheral nerve transection has been
system function with the use of the electroreti- demonstrated throughout the neuroaxis in ani-
nogram (retinal level) and visual evoked poten- mal models of nerve injury. Human brain imag-
tial (prechiasmal and postchiasmal levels), ing studies have corroborated the fi ndings from
defi nitive diagnostic ocular motility criteria have animal models with the identification of altered
now been established for all types of nystagmus functional magnetic resonance imaging activa-
appearing in infancy. The purely clinical signs of tion maps due to spinal cord injury, amputation,
these types of nystagmus, albeit indispensable, toe-to-thumb transfer, and in patients with car-
are often ambiguous and reliance on them for pel tunnel syndrome. There is functional plastic-
fi nal diagnosis and treatment without quantita- ity in several cortical areas following upper limb
tive motility data will continue to cause diagnos- peripheral nerve transection and surgical repair.
tic errors that may be compounded by poor or Until recently, most neuroscientists believed that
inaccurate choices for therapeutic intervention. the adult brain is hard-wired and largely incapa-
In many cases, both afferent and efferent visual ble of reorganization. The only areas of the brain
function can be improved by the correct therapy where some reorganization might occur would
applied in a timely manner. Unfortunately, only be those involved in learning and skill acquisi-
in selected centers of ophthalmological or neu- tion. However, over the past two decades, it has
ro-ophthalmological research are ocular motil- been conclusively established that even primary
ity recordings now routinely available as part of sensory areas of the brain are capable of reorgan-
the evaluation of nystagmus patients. Decades ization in response to injuries or changes in pat-
ago, cardiologists realized that they could not terns of peripheral stimulation. The mechanisms
rely solely on their fi ngers and ears to accurately that facilitate functional plasticity are thought
diagnose complex disorders of cardiac function. to include the immediate unmasking of preex-
Clinical observation alone is no longer a valid or isting projections from adjacent cortical and
reliable way to evaluate ocular motor disorders. subcortical levels, and long-term sprouting of

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axons at multiple levels of the neuroaxis, includ- measured in at least five gaze angles to document
ing the primary somatosensory cortex. There is the sharpness of the off-peak, pretherapy decre-
accumulating evidence that EOM propriocep- ment of visual acuity and its broadening after
tive afferent signals are not only available to ocu- therapy; therein lies the most important meas-
lar motor and visual control structures, but they ure of improved visual function. Also, a broader
influence the processing of information in these range of highest acuity will diminish the need
structures and may be involved in modifying for an anomalous head position and make up for
visuomotor behavior after eye-muscle surgery as slight errors in surgical corrections. After ther-
well as oral and topical medications. apy, peak acuity may not improve significantly
The patient’s complete diagnosis must and nystagmus amplitude or frequency may not
include the motility diagnosis in addition to the decline; the latter factors affect cosmesis but are
afferent-system diagnosis, as must the therapeu- not tightly correlated to visual function.
tic plan. No longer can visual scientists or cli- The strides made in the understanding,
nicians ignore the complex interrelationship of diagnoses, analyses, and treatment of the nys-
the developing visual afferent and visual motor tagmus found in infants and children began
systems and, as a consequence, need to evaluate in the 1960s and are based on accurate eye-
both if there is a developmental disorder in either. movement data and application of the con-
Most, if not all, of the technologies for evalua- trol-system approach to understanding the
tion of the afferent visual system are feasible for relevant ocular motor system mechanisms. In
clinical use. Th is includes behavioral testing of the ensuing fi ve decades, the key observations
acuity in infants, visual evoked responses, elec- and hypotheses that followed were as follows:
troretinography, color, contrast sensitivity, and (1) the recognition that IN does not cause the
visual field testing. There is now also important eyes to oscillate across the target (as the med-
information to be obtained from optical coher- ical texts claimed) but rather they move away
ence tomography. The complex combination of from and back to the target with each cycle;
structural and developmental visual sensory and (2) as the eyes approach the target, they slow
visual motor abnormalities in infants and child- down and maintain foveation for an extended
ren with nystagmus results in varied and multi- period of time; (3) the resulting foveation peri-
ple effects on visual system functioning; these ods can be very accurate from one cycle to the
include decreased spatial acuity, contrast sensi- next despite variations in the nystagmus wave-
tivity, color, motion perception, dark adaptation, forms and direction; (4) the IN waveform char-
functional visual field/space, visual recognition acteristics that determine visual acuity are the
time, and a high incidence of ametropia, binoc- duration of the foveation periods and their pos-
ular dysfunction, and amblyopia. There may be ition and velocity variations—all other portions
a form of amblyopia unique to the developing of the IN waveform are essentially noncontrib-
visual system of eyes in constant motion we have utory; (5) there are a range of secondary ther-
labeled “motion amblyopia,” the complete visual apeutic benefits to extraocular muscle surgery
consequences of which are yet to be described. for INS—broadening the range of gaze angles
The importance of how treating the developing with highest acuity and improving visual rec-
system affects both the afferent and efferent sys- ognition time; (6) in INS patients with neither
tems was shown in an animal model of develop- gaze-angle or convergence “nulls,” simply per-
mental retinal disease, with associated infantile forming a tenotomy and reatt achment (T&R)
nystagmus, when, after treating the sensory of each of the four horizontal rectus muscles
system with gene-transfer therapy, the ocular duplicates the broadening benefits and improves
motor system was also improved. The addition visual function significantly; (7) a mathemati-
of eye-movement recordings in the clinical set- cal function applied to eye-movement data that
ting to augment tests of the afferent visual sen- was based on only the statistics of foveation
sory system is now a clinical necessity. Also, periods (e.g., the eXpanded Nystagmus Acuity
best-corrected binocular visual acuity must be Function—NAFX) provides a measure of the

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motor component (independent of the sensory appearing in infancy. Unfortunately, the Greek
component) of best-corrected visual acuity; origin of the word may also be related to the
(8) eye-movement data provide the most accu- “tragedy” that still exists today—the failure to
rate and unbiased (i.e., not under the patient’s adequately treat patients and improve their vis-
control, as is anomalous head position) method ual function despite the proven therapies pre-
of determining the amount of surgical correc- sented in this volume. Th is failure on the part
tion necessary; (9) when the NAFX is com- of the medical community has relegated many
bined with measured, best-corrected visual children and adults with INS to a second-class
acuity, it provides, for the fi rst time, a prethera- life, unable to realize their full potential, pro-
peutic estimate of the amount of visual func- fessionally or personally. Fortunately for future
tion improvement that would result from the patients, the overwhelming amount and verac-
proposed therapy; and (10) the use of computer ity of the data gathered and analyzed in the
modeling to encapsulate top-down hypotheses, twentieth century are slowly bringing the field
in the form of behavioral ocular motor system of pediatric vision care out of the nineteenth
models, is of paramount importance in under- and into the twenty-fi rst century, where diag-
standing the underlying mechanisms of differ- nosis, therapy, and measured outcomes are data
ent types of nystagmus present in infancy and driven.
in predicting the effects of therapy on target We have striven to cite all relevant, scientifi-
acquisition time for stationary and moving tar- cally sound research in the various chapters and
gets. Additionally, the development and use of hope that those studies cited (and the citations
the “Eyeballs 3D” program to illustrate in real that each contain) have not left many we unin-
time the motion of the eyes and the waveforms tentionally omitted. The serious student of INS
producing that motion has been of immense should also read the many excellent papers ema-
pedagogical value, both to us and to others. nating from the laboratories of Richard Abadi
Th is body of ocular motor research into INS and Harold Bedell; there is a wealth of relevant
has resulted in new approaches to its diagnosis psychophysics in that literature. Unfortunately,
and therapy. They are presented in Chapters 5–7 because of the persistence of the ophthalmic
and include clinical guidelines to examination mythology surrounding nystagmus, the litera-
and diagnosis as well as the development of sur- ture (past and present) contains many studies
gical techniques (e.g., the nine operations) and that are not of the same quality of those we cited.
other therapies (e.g., contact lenses or base-out As pointed out in Chapter 2, many of them have
prisms) based on our eye-movement fi ndings. been reviewed as part of six literature reviews of
The net result is a level of accuracy and predict- nystagmus and saccadic intrusions and oscilla-
ability that supercedes past practices, which tions published during 1980–1991 and were not
were based on clinical examination alone and included in this volume. Finally, a small num-
mistaken premises; the net results are greater ber of papers have made it into the literature
improvement for more patients and a higher despite the false and plagiarized material they
degree of patient satisfaction. contained, and the unethical behavior of some
As pointed out in Chapter 2, the roots of the of their authors. That is an unfortunate and irre-
word nystagmus are Greek, which may partially versible pollution of the literature. To cite such
explain the extensive mythology that had been papers would denigrate the honest, objective sci-
built up around this eye sign (see Appendix B, ence that comprises the majority of research in
Section B.5). Early in our research, the absence this area; therefore, they were not cited herein.
of accurate, quantitative eye-movement data was In Appendix A, we have provided eye-move-
recognized as the main reason for the misstate- ment recording methodology, analysis method-
ments of fact and contradictions present in the ology, calibration techniques; in Appendix B,
literature as well as the simplistic presumptions clinical examination forms, clinical pearls, and
regarding the possible causes and underlying ophthalmological myths and facts; in Appendix
mechanisms of the different types of nystagmus C, illustrative cases and treatment; and in

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Appendix D, diagnosis and treatment flow- and treated without eye-movement data?” The
charts and graphs useful for INS analysis. On answer is, “Yes, but not always correctly or opti-
Companion Website, we provided in Appendix mally and only with variable or unpredictable out-
E, “Eyeballs 3D,” canine, and patient videos and comes.” Difficult, and some not-so-difficult, cases
in Appendix F, OMLAB reports, patient hand- require eye-movement data to avoid problematic
outs, physician/scientist worksheets, analysis outcomes; the less difficult cases will also bene-
soft ware, and modeling soft ware. fit from the more accurate and repeatable diag-
In the fi nal analysis, we must answer this noses and predictable, measurable therapeutic
question, “Can nystagmus patients be diagnosed improvements based on eye-movement data.

256 • SUM M A RY A ND CONCLUSIONS

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epilogue
Science is unlike democracy; a good hypothesis neither requires nor becomes more accurate by scientific
consensus. In fact, many of the most scientifically far-reaching hypotheses suffered both the skepticism and
hostility of contemporary scientists.
—Louis F. Dell’Osso (1941)

THE SCIENTIFIC research that is the basis blind, people see my eyes as genetic mutations.
for this book and for the diagnostic and thera- If that is so, this mutation has proven to be the
peutic advances that resulted has been both our best life lesson.
driving force and source of great personal sat- Th roughout my life, it has always been my goal
isfaction. There is litt le that compares with the to turn my disability into an ability. Whether it
exhilaration of making new discoveries, of being be through playing varsity basketball for seven
the only person who knows of them (albeit, until years, maintaining above average grades, or dis-
publication of the fi ndings), or of making the proving the stereotype that “albinos” are anti-
critical connections that transform new knowl- social, by surrounding myself with an endless
edge into successful therapeutic applications. group of friends and by holding countless lead-
However, the essay that follows, submitted by ership roles, through student council, public
a prospective medical student whose visual speaking, and mentor programs.
function is limited by both albinism and infan- “Just wear your glasses and adapt,” is the typi-
tile nystagmus syndrome, provides an elegant cal response I would receive when I would seek
painting for which our work is but a frame. help from my eye doctors. I’ve been adapting my
entire life in order to survive in this world that
Freshman Applicant Prompt 2 was made for perfect sight—Charles Darwin
Tell us about a personal quality, talent, would be proud. But, as independent as I have
accomplishment, contribution, or experience worked so hard to become, I was still not happy
that is important to you. What about this with having to hide my wandering eyes.
quality or accomplishment makes you proud, “I want to be a doctor.” Whenever people
and how does it relate to the person you are? hear what my dream career is their faces cringe
with doubt. I don’t blame them. I am very aware
that becoming a doctor is a very challenging
BEHIND THESE BLUE EYES
task for anyone, but for someone who’s visu-
I HATE fi rst impressions. When people fi rst ally impaired, it’s nearly impossible. Despite
meet me, they stare bewilderingly into my blue the doubt others may have, I have no second
eyes, not able keep up with the rapid movement thoughts. If anything, I think this is one aspect
of my nystagmus, automatically writing me off of my life in which my disability can benefit me.
as handicapped, blind, and useless. Having been Doctors can prescribe medicines and perform
born with Albinism, and been labeled as legally procedures that can alleviate the short-term

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pain of patients that have been diagnosed with the piercing stares that have made fi rst impres-
an illness that will affect the rest of their life. But sions so unbearable. Th is was the boost I was
as for the long-term pain, how many doctors can looking for. Today, my nystagmus has decreased
give advice on how to put a disability on the back to the point where I can actually feel comforta-
burner and live their lives to the fullest, all based ble enough to look you in the eyes and give my
on personal experience? fi rst genuine impression.
If there is anything I take pride in, it is my abil- My name is Kaila Uniacke; look me in the
ity to overcome obstacles. I am looking forward to eyes and you may see a girl with a disability.
spending the rest of my life helping others, physi- Take a closer look, and you will see that behind
cally and mentally, to overcome their illnesses, but these blue eyes, lies anything but. I am a stu-
in order to do this, I must first have 100% confi- dent, not just of textbooks, but of life, a lifelong
dence in myself. I need to be able to look the world learner, taking each of my life lessons to heart.
in the eyes and make a good first impression. I live not to cover up my flaws, but to express
So I took the initiative, and did some research. myself, to stand out, to make a difference. If you
I spent months looking for my “confidence could see the world through my eyes, you would
booster.” I was referred to Dr. David Granet, an realize that I may not have sight, but I know
ophthalmologist from UC San Diego. He offered I have vision; the vision to take pride in every-
me a life changing surgery that would dramat- thing I do, whether I succeed or fail, whether
ically decrease my nystagmus and increase my my dreams come true or fall short. I will always
vision. With this new source of hope, I con- be proud of who I am, imperfections and all.
fronted my parents and doctors about the sur- I am a girl with many passions in life: a passion
gery. Before I knew it, I was at UCSD, lying on for laughter, a passion for medicine, a passion to
the operating table, a place where most people continually prove to the world that my disability
feel anxiety and fear; I felt only hopeful anticipa- has not won.
tion of waking up to a more lucid world, free of —It’s nice to meet you.

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appendix a

eye-movement recording
systems and criteria
A.1 RECORDING METHODS 263 A.3 CLINICAL CRITERIA 268
A.1.1 Contact Electrooculography 263 A.4 CALIBRATION TECHNIQUES 268
A.1.2 Infrared Reflection 264 A.4.1 Adults and Children 268
A.1.3 Scleral Search Coil 265 A.4.1.1 Infantile Nystagmus 269
A.1.4 High-Speed Video Oculography A.4.1.2 Fusion Maldevelopment
266 Nystagmus 269
A.2 RESEARCH CRITERIA 268 A.4.2 Infants 269

THE STUDY of ocular motor mechanisms eye—inhomogeneous. Visual acuity in the cen-
(normal or abnormal) for the diagnosis and tral 1° of the visual field is maximal, but it falls
treatment of ocular motor disorders requires off rapidly as one moves toward the periphery.
accurate recording of eye movements. Th is What keeps us from ever being aware of this is
includes a reliable, easy-to-use recording system; the nearly incessant motion of our eyes, con-
accurate monocular calibration and linearization trolled by the interconnected control systems
paradigms; and, in subjects with nystagmus or that direct our gaze to an object of interest and
other ocular motor oscillations, knowledge of keep it fi xated in the face of target and body
the foveation portions of the eye-movement movement. Massive processing in the visual
waveforms. We describe the historical develop- areas of the brain integrates the discontinuous
ment of eye-movement recording systems, the flow of visual images along with efference copy
advantages and disadvantages of those com- of motor commands to the extraocular muscles,
monly used today, the requirements for accu- into the clear, stable perception of the world
rate calibration of those systems, and the use experienced by both normals and those with
of eye-movement recordings in basic research, some ocular motor oscillations.
including clinical sett ings. What follows are descriptions of the more
Despite the fact that human hearing is infe- common eye-movement recording technolo-
rior to that of the owl, and the human sense of gies used in the past and present. Technical
smell is far poorer than a dog’s, our visual acu- descriptions, engineering, and physics of these
ity is excelled by few other species. However, and other methods will not be discussed in this
if we processed our entire visual field simulta- volume (see also Abel and Dell’Osso1). Rather,
neously at our maximal resolution, we would emphasis will be on the abilities of different
need so many optic nerve fibers to carry visual types of systems and the calibration require-
information back to the brain that there would ments to provide accurate eye-movement data in
be room for litt le else. Evolution has solved both the basic and clinical research sett ings.
this problem by making the resolution of the Historically, the instrumentation for record-
retina—the light-sensitive neural layer of the ing all types of eye movements was used

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originally to record vestibular nystagmus. tape or “kymograph”8 (Fig. A.2). The technique
Purkinje noted eye movements by visual obser- further improved when small cups resembling
vation in 1825 and E. Darwin by palpations of contact lenses were attached to the cornea. In
the eyes in 1794.2 Studies of eye movements by 1899, Orschansky fi xed a small mirror to the cup
visual observation were described by Java1 in on the eye and used a beam of light to project the
1879. 3 The experimenter stood behind the sub- reflected eye movements onto a screen.9,10 The
ject and observed the movement of the eyes in method of recording eye movement by reflected
a mirror. Specially designed optical instruments light was further advanced with the use of spe-
were used to magnify the mirrored images that cial contact lenses. Unfortunately, this method
then could be studied in detail. More accu- could injure the eye and was too heavy to meas-
rate descriptions, based on the observation of ure the large accelerations occurring during sac-
afterimages, were also made at the end of the cades. To overcome this problem, Javal recorded
eighteenth century. Using this method, Wells the reflection of a light beam from a litt le mirror
described the slow and fast phases of vestibular attached to the conjunctiva, a method that was
nystagmus.4 The occurrence of saccades during not successfully applied before von Romberg
reading was fi rst reported by Javal and Lamare, and Ohm used it to measure ocular torsion. Th is
who used a rubber tube connected to the con- technique was, however, still too invasive.11
junctiva and both ears. 3 With this device, each Photographic analysis of nystagmus was
eye movement caused a sound that was heard. introduced by Dodge and Cline in 1901 and
Hering used a similar acoustic device in combi-
nation with the technique of afterimages. 5
The earliest mechanical methods of recording
eye movements were proposed by Raehlmann
in 1878, who used one end of a lever attached
to the globe and with the other end of the lever,
recorded the transmitted eye motions, on a mov-
ing smoked drum (Fig. A.1).2–4,6,7 The lever tech-
nique was modified by Gradenigo in l909, by Buys
and Coppez in 1909, and Ohm in 1914. In their
studies, one polished end of the lever touched the
anesthetized cornea, while the other end of the
moving lever made the record on a moving paper

FIGURE A.2 Model of Kymograph of the type

used to record eye movements. Time recordings of
physiological phenomena became possible when
a galvanometer’s needle was put into contact with
a loop of paper coated with a thin layer of smoke
black and stretched over a metal drum. A precise
mechanical clockwork allows the drum to be rotated
at a calibrated speed, and the movements of the
galvanometer’s pen scratch out the smoke black,
leaving a record of amplitude as a function of time.
Mechanical phenomena, such as eye movements,
could be recorded along time, by rigging levers, axes,
membranes, springs, and strings. The time axis was
FIGURE A.1 Lever device to document horizon- calibrated and measured by using electromagnetic
tal eye movements during reading. tuning forks att ached to inscribing pens.

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1903. 3 In 1913 Coppez used early cinematogra- rotation information (Fig. A.5). These IR devices
phy. Electrical recording of eye movements was measure the intensity of these reflections by pho-
fi rst reported by Schott in 1922 by modifying tosensitive elements placed at different locations
electrocardiography.12 Schott and Meyers meas- in front the eye. The fi rst system was developed
ured electrical potentials with skin electrodes by Torok et al.15
attached near the eye.12 Mowrer et al. discov- Video-based eye trackers typically use one or
ered that the electrical potential is primarily multiple Purkinje images and the center of the
caused by the electrical dipole between cornea pupil as features to track eye movement over
and retina, which moves with the eye. Th is tech- time. These optical methods, particularly those
nique has been the basis of modern electrony- based on video recording, are now widely used
stagmography (ENG) or electrooculography and are favored for eye-movement analysis. They
(EOG)13 (Fig. A.3). The eyes are the origin of are especially useful in infants and children,
a steady electric potential field, which can also being noninvasive and inexpensive (Fig. A.6).
be detected in total darkness and if the eyes are These so-called double Purkinje image (DPI)
closed. The electric signal that can be derived eye trackers reach high resolution, accuracy,
using two pairs of contact electrodes placed on and bandwidth. The high accuracy of the DPI
the skin around each eye with a ground or ref- eye tracker during steady fi xation is due to the
erence electrode placed on the forehead. Jung fact that it uses the angular differences between
applied this method to record horizontal and light reflections that are insensitive to small
vertical components of the eye position simul- translations between the eye and the tracker.
taneously14 (Fig. A.4). Previously, recording Videooculography (VOG), defi ned as the use
techniques had been restricted to one move- of these methods for dynamic measure of eye
ment direction only. Moreover, the EOG allows movements, became feasible with the rapid
recording of eye movements while the eyes are development computer-based automatic image
closed, of particular interest for sleep research. processing. Th is progress is mainly reflected in
Noncontact optical methods are currently the the frame rates being processed online and in
most popular. The use of infrared light reflected the robustness and the accuracy of the marker
(IR) from the eye, which is sensed by specially detection algorithms. Both improve with the
designed optical sensors remains common. increase in computational power. Since the
A voltage is generated from the difference in measurement of two-dimensional gaze direc-
reflection between the sclera and iris as the eye tion in VOG is primarily based on the locali-
moves and is the basic output to extract eye zation of the pupil, the two-dimensional VOG

+
+ –

FIGURE A.3 The eye acts as a dipole in which the FIGURE A.4 Electrode placement for contact
anterior pole is positive and the posterior pole is neg- oculography. Pairs of electrodes are placed to the
ative (arrow). The cornea (relative positive charge) left and right and top and bottom of each eye. If the
approaches one canthal electrode while moving eye is moved from the center position toward one
away from the other canthal electrode to which the electrode, this electrode “sees” the positive side (the
retina moves near (relative negative charge), result- cornea) and the opposite electrode “sees” the nega-
ing in recordable changes in the potentials between tive side (the retina). Consequently, a potential dif-
the two electrodes. ference occurs between the electrodes.

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FIGURE A.6 Remote video-based, eye-movement

recording system. Th is method is based on tracking
of the position of eye-fi xed markers in a two-dimen-
IR Emitter
sional image.

IR Detector
and torsional eye movements simultaneously.
Vertical and horizontal movement components
could be quantified by the EOG, IR, or the DPI
tracker, but these devices cannot measure ocu-
FIGURE A.5 Principle of infrared-reflectance
(IR), eye-movement recording. A voltage is gener- lar torsion. Von Romberg and Ohm measured
ated as the eye moves in front of an infrared detec- pure ocular torsion in primary position with
tor due to the difference in reflectance between the their mirror system.16 By the nineteenth cen-
sclera and iris as the eye moves. Th is signal from tury, the technique of afterimages had provided
the detector as a result of the measured difference important fi ndings about ocular torsion during
in reflectance is amplified and fi ltered to produce fi xation. Th is field of research became of increas-
the eye-movement recording. Standard push-pull- ing interest when the magnetic search-coil tech-
connected detectors (top panel) and single detector nique, developed by Robinson and Collewijn
(bottom panel). et al., was extended by Collewijn et al. and
Kasper and Hess to cover three-dimensional
movements.17,18 The method is based on the volt-
works reliably in head-mounted systems and ages induced in coils by two or three orthogo-
with stabilized head positions. To compute the nal, rapidly alternating magnetic fields. The coils
three-dimensional eye position, the orientation are embedded in a soft silicone annulus that
of the iris signature can be used. Th is signature adheres elastically to the eyeball. One coil is suf-
must be scanned along a circular path close to ficient to measure gaze direction (Fig. A.7). Two
the limbus, in order to be insensitive to changes coils with different orientations must be molded
of the pupil diameter. Direct polar cross-corre- in the annulus to measure gaze direction and
lation of the iris signature at the actual eye posi- ocular torsion simultaneously. The search-coil
tion with that of a reference position can be used method combines high spatial and temporal res-
to measure ocular torsion. Th is works well while olution and is so far the most precise method for
gaze is pointing straight ahead, but geometric measuring ocular torsion.
distortions of the iris occurring at eccentric gaze Like other methods based on contact lenses,
positions lead to large errors. the search-coil technique has the main disad-
None of the recording methods mentioned vantage of being invasive (Fig. A.8). Therefore,
thus far are able to quantify horizontal, vertical, considerable effort was made to evaluate the

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FIGURE A.7 Scleral search coil. The coils are

embedded in a soft silicone annulus that adheres FIGURE A.8 Scleral search coil. The silicone
elastically to the eyeball. annulus rests on the eye at the corneo-scleral limbus
on the conjunctiva similar to the older “scleral” con-
tact lenses.
three-dimensional eye position on the basis
of photographic images of the eye. All photo-
graphic methods are based on the detection and small differences between the electrical poten-
localization of eye-fi xed markers (pupil, limbus, tial at the skin surface next to the eye depending
iris signatures, episcleral blood vessels) in image on eye position. A rightward eye movement will
coordinates. The eye position with respect to the increase the surface potential at the temporal
head can be computed from these image coordi- canthus and decrease it at the nasal canthus of
nates if the camera is fi rmly attached to the head. the right eye (Fig. A.4). The potential differences
Otherwise, head-fi xed markers can be used to can be measured with a contact electrode con-
compensate for relative translations between figuration. The voltages are usually referenced to
head and camera. Howard and Evans described a third electrode that is generally placed at the
a method for computing three-dimensional forehead or one of the mastoid processes or on
angular eye positions from the image coordi- the earlobe.2,20–22 To simultaneously record ver-
nates of the markers.19 tical eye movements, two additional electrodes
must be placed below and above the eye. Vertical
EOG signals are less reliable than horizontal sig-
A.1 RECORDING METHODS
nals due to lid artifacts.
The resolution of both horizontal and vertical
A.1.1 Contact Electrooculography
EOG signals is limited by electromagnetic field
The simplest method for measuring human noise in the environment, thermal noise gener-
eye movements is based on the feature that the ated by the input resistance of the amplifier and
human eye is an electrical dipole. The axis of the contact resistance of the skin electrodes,
this dipole and the optical axis of the human eye and capacitive noise due to electrical activity
are roughly collinear. The retina is more nega- of muscles and neurons.2,20–22 To lower the con-
tive than the cornea. The potential difference of tact resistance, the skin should be cleaned with
about 0.4–1.0 millivolts results from the electri- alcohol. Electrodes should be made of relatively
cal activity of photoreceptors and neurons in the nonpolarizeable material such as silver-silver
retina. Changes of this potential induced by sud- chloride or gold and applied with a conductive
den light stimulus have been used for decades paste. Subjects should be instructed to avoid any
to monitor the electrical activity of the retina movements except eye movements. Changes of
(electroretinogram [ERG]). However, the EOG the dark adaptation level induce slow drift s of the
measures the eye dipole as it rotates. Th is causes corneo-retinal potential that are superimposed

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on the EOG signal. Since both the EOG and

ERG measure the corneo-retinal potential, the
standards of ERG recordings are also recom-
mended for EOG recordings. The spatial resolu-
tion of EOG is ~1°, temporal resolution ~40 Hz,
vertical recording is confounded by blink arti-
fact, noise is 1° or more, setup is slow, calibration
is needed, and cost is ~$500.00.

A.1.2 Infrared Reflection

These devices measure the differences in inten-
FIGURE A.10 Infrared reflectance eye-movement
sity of infrared light reflected from across the
recording system embedded in a goggle system spe-
surface of the eye at a fi xed location from the
cially designed for use in infants.
eye.2,23–26 Light intensity is measured with photo
diodes that have a high temporal resolution
(Figs. A.9 and A.10). The distance between eye the device is not properly adjusted in front of
and photoreceptors is in the range of 24 mm. At the eye. Lid artifacts are more pronounced for
such small distances, the differences in the inten- vertical than for horizontal eye movements.
sity between the different photodiodes depend Moreover, the position of the photodiodes is also
mainly on the position of iris and pupil, which critical for the system linearity. Due to these fea-
reflect less light than the surrounding sclera. IR tures, optimal adjustment of the device requires
devices are very sensitive to relative translations that the experimenter carefully controls the eye-
of the photodiodes and the eye because they position signal of the IR device and compares it
do not evaluate the angle, but only the inten- with the eye movements (Figs. A.11 and A.12).
sity of the reflection. For an eye radius of 1.25 The spatial resolution is ~0.1°, temporal reso-
cm, a translational error of 1 mm will lead to lution is 100–500 Hz, and vertical recording is
an eye-position error of almost 5°. The system confounded by blink artifact and the intrinsic
must therefore be fi rmly attached to the head. IR difficulty in distinguishing lid movement from
devices have a much lower noise level than EOG, eye movement. Setup is fast but calibration is
but they suffer from eyelid artifacts that criti- necessary. Linearity is a problem with nonline-
cally depend on the position of the photodiodes. arity occurring at 15°–20° and cost is moderate,
These lid artifacts may increase dramatically if ~ $4000.

FIGURE A.9 Infrared reflectance eye movement FIGURE A.11 Children positioned in head and
recording system embedded in a goggle system. Th is chin rest with infrared goggles in place and a view-
shows the combination of vertical and horizontal ing stimulus screen for accurate calibration (side
detectors for each eye. view).

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FIGURE A.12 Children positioned in head and FIGURE A.13 Th ree-foot scleral search-coil, mag-
chin rest with infrared goggles in place and a view- netic field system with dichoptic stimuli apparatus
ing stimulus screen for accurate calibration (front (monocular stimulus screens and mirrors). Around
view). the head of the subject an alternating horizontal and
vertical magnetic field (spatially and temporally in
quadrature) is generated and consequently an alter-
IR systems are second only to EOG in their nating voltage will be induced in the scleral contact
range of applications. Because they can resolve lens with embedded coil.
fi ne detail with low noise, they are excellent
for conditions where subtle features of the eye
The voltage induced by one of the magnetic
movement are important. IR systems were the
fields in the scleral search coil is proportional to
key to the accurate analyses of saccadic trajecto-
the projection of the coil vector (defi ned as the
ries and the analysis of small corrective saccades
vector orthogonal to the effective coil plane)
within nystagmus waveforms. Also, being non-
onto the magnetic field vector. Thus, the three
invasive, they provided a major advantage for
voltages induced by three orthogonal magnetic
the study of patients and children.
fields form the vector components of the coil
vector expressed in field coordinates. A dual
A.1.3 Scleral Search Coil search coil for recording three-dimensional eye
orientation provides six voltages, correspond-
The scleral search-coil system measures the
ing to the two three-dimensional coil vectors of
voltages in one or two coils induced by two or
the directional and the torsional coil (Fig. A.14).
three rapidly oscillating magnetic fields2,17,18,27–31
Methods to compute the three-dimensional
(Fig. A.13). The coils are molded in a soft con-
eye orientations from these six signals are then
tact annulus that is att ached to the eyeball.
Th ree pairs of large coils, mounted in a cubic
frame, generate the magnetic fields. The sub-
ject’s head is positioned at its center. The field
coils should be large, because the homogeneity
of the magnetic field is crucial for the precision
of the measurement. With pairs of square-
shaped coils, arranged in a cubic configuration,
the inhomogeneity inside of a central test cube
stays below 5% when the edge length of the test FIGURE A.14 Torsional coil on eye. The principle
cube approaches one-fi ft h of the edge length of of the scleral search-coil technique is based upon the
the field coil. Th is means that when using field magnetic induction of a small coil embedded in a
coils with an edge length of 1.5 m, subjects flexible ring of silicone rubber, which adheres to the
should not move by more than 7 cm. limbus of the human eye concentric with the cornea.

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employed. Search-coil recordings require a cal- with a modified exit point that minimized the
ibration procedure that is often based on mul- contact between wire and eyelids. Other disad-
tiple alignments to targets at various positions. vantages of the scleral search coil are that wear-
The calibration parameters are computed by ing the coil may lead to drying, and temporal
minimizing the errors between the calibrated deformations of the cornea, and reduced visual
gaze vector and target vectors. 2,17,18,27–31 Systems acuity in the eye with the search coil. Therefore,
with three magnetic fields can be objectively the manufacturer of the search coil limits wear-
calibrated, that is, their calibration does not rely ing time to 30 minutes.
on accurate fi xation of targets at different posi- The coil spatial resolution is ~0.01°; temporal
tions, as most other recording techniques. Only resolution is at least 1000 Hz. Vertical and tor-
a single fi xation target is needed in order to deter- sional recordings are also possible and linearity
mine the orientation of the coil with respect to is good, although setup is slow and calibration is
the eye. Another important advantage of three- needed. A reasonable coil system can be bought
field systems over two-field systems is that the for about $15,000; each eye coil costs about $100.
orientation of the coil vector can be determined A typical eye coil lasts for two subjects. There is
without knowledge of the actual inductance of a small risk of a corneal abrasion from the con-
the scleral search coil. Th is is because changes tact lens. The estimate of the risk is about 1/400
in inductance will have the same proportional subjects. There is also a small risk of transmitt ing
effect on all three voltages and can easily be very serious diseases if the lab reuses lens between
eliminated by normalization. 2,17,18,27–31 patients. Certain biologic agents (prions—such
With the search-coil technique, the inher- as found in “Mad Cow”) are very difficult to kill.
ent system noise of horizontal and vertical eye Th is risk can be avoided if the lab simply uses
position has been estimated to be on the order a new scleral contact lens rather than “recycling”
of 0.5 min of arc (0.0083°). The system reso- them. Only about 30 minutes of continuous
lution is a very important parameter; it deter- recording is usually possible at one sett ing. Eye-
mines the smallest eye movement that can be coil systems are usually research tools. To use
detected. However, to compare the metrics of an eye-coil system subjects must sign a consent
eye movements between different subjects or form because of the risk of corneal abrasion. Th is
with a stimulus-defi ned requirement the accu- technology is certainly the most expensive of all,
racy is more important than the system noise. because of the cost of the eye coils.
The system accuracy of search coils depends
mainly on the quality of the calibration. Due to
A.1.4 High-Speed Video Oculography
its large signal-to-noise ratio and reliability, the
search-coil technique has been the generally Video-based, eye-movement recordings have
accepted reference standard for eye movement become more and more popular because of
recordings for 30 years. However, the disadvan- the rapid progress made in electronic data
tages, connected with the invasiveness of the processing.21,24,34–39 High-speed video oculogra-
method, have also been recognized. The search phy (VOG) has become affordable, the robust-
coil not only measures eye movements but also ness of the algorithms improved, and the range
affects them. Some authors have found that of applications expanded (Fig. A.15). Nowadays,
saccades last longer (by about 8%) and become commercial companies produce VOG devices
slower (by about 5%) when subjects wear search that can be used in a functional magnetic res-
coils in both eyes than when they do not. 32,33 It onance imaging scanner (MeyeTrack R , SMI R ,
was also shown that the eye torsion, when evalu- Berlin, Germany). Most fundamental VOG
ated with the search coil, depends on the orien- techniques are based on tracking of the posi-
tation of exit point of the connecting line from tion of eye-fi xed markers in a two-dimensional
the search coil and, with the nasal exiting orien- image. These positions have to be expressed in
tation of a commercial eye coil (Skalar), ocular head-fi xed coordinates. Since head-fi xed mark-
torsion depended more on eye elevation than ers are difficult to obtain with high precision, one

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of about 12°–15° the reflection reaches the edge

of the cornea and can no longer be used for com-
pensation. Moreover, this approach relies on the
topography of the cornea, which varies between
subjects. Therefore, it seems to be useful when
compensating for large translations, but it may
be unable to provide very high accuracy. Since
the pupil position is detected and evaluated in
image coordinates, the nonlinearity of the VOG
(in contrast to IR) systems is well defi ned by the
geometry of the image projection. With parallel
projection, the angular eccentricity of the eye can
be approximated by the inverse sinus of the ratio
FIGURE A.15 Video-based, eye-movement
system showing programming computer interface
of the eccentricity of the pupil center and the eye
displaying calibration parameters and actual pupil radius, both expressed in image coordinates. The
location within the camera system. main aim of the VOG calibration is therefore to
determine the location of the center of rotation
of the eye and the radius of the eyeball. The res-
strategy of VOG systems is to attach the video olution of the two-dimensional VOG defi ned by
camera as fi rmly as possible to the head. As long the standard deviation of system noise measured
as the system is not compensated for relative with an artificial eye is about 0.01°. The VOG of
translation between camera and head, the accu- two-dimensional measurements of ocular tor-
racy of VOG has a problem very similar to that of sion also reach accuracy values that are similar
IR. A translation of 1 mm will result in an error to those of coil measurements. The spatial res-
of about 5°. Head-fi xed devices cause a problem olution is 1 part in 1024 and now with high-
under head free conditions, because the stabil- speed cameras, temporal resolution is as high as
ity of the head mount is not sufficient. Because 1000 Hz. VOG can record vertical and torsion
of this problem, actual VOG systems can make movements.21,24,34–39 Setup is rapid and calibra-
highly accurate measurements of eye position, tion may be less difficult. Goggles effectively
only as long as the head is stable in space. black out vision, so maintaining a “light-tight”
A VOG method of compensating for head lab is not crucial; this may be important in some
translation uses the relative position of the cor- applications and for some systems. Systems cost
neal reflex of an infrared LED (Eyelink II R , SR from $18, 000 to $50,000.
Research, Osgode, Canada) (Fig. A.16). One dif- As Figure A.17 illustrates, in addition to the
ficulty with this method is that using the corneal study of humans with nystagmus, we have used
reflection adds more noise. For eye movements both IR and video systems successfully to study
canine eye movements in both normal dogs and
those with nystagmus. The dog on the left was
(a) (b) an achiasmatic Belgian sheepdog with infantile
and seesaw nystagmus; the dog on the right was
a Briard with Leber congenital amaurosis; and
the dog at the bottom was a normal Brittany,
highly trained for upland bird hunting.
Eizenman and his students have devel-
FIGURE A.16 Head-mounted eye trackers: oped new algorithms for video-based systems
(a) SMI EyeLink I and (b) Arrington Research that may make patient-cooperative calibration
ViewPoint PC-60 BS007. The shutter-glasses have unnecessary.40,41, 42 Th is promises to be a major
been att ached to the head-mount and the cameras improvement in the ability to obtain accurate eye-
are recording the eyes from below. movement data from infants and uncooperative

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FIGURE A.17 Use of infrared (eyeglass-frame type, top left panel and goggle type, top right panel) and
high-speed digital video (bottom panel) systems to study canine eye movements.

children in the clinic. Its accuracy in patients with invasive for studying most patients and child-
nystagmus is yet to be tested. ren. Accurate differential diagnoses of nystag-
mus and detection of fi xating-eye changes due
to strabismus require accurate, monocular cal-
A.2 RESEARCH CRITERIA
ibration and zeroing.
At present, IR, search-coil, and digital video sys-
tems meet the criteria for accurate eye-move-
ment data. Each has its own set of advantages
A.4 CALIBRATION TECHNIQUES
and limitations, and a well-equipped laboratory
usually has several of the systems available that
A.4.1 Adults and Children
can be tailored to each study. In all systems, For both adults and children each eye must be
accurate, monocular calibration and zeroing is calibrated at several target positions while the
a necessity. other eye is occluded; for search coils, each eye
must be zeroed while the other is occluded (each
eye coil will have been precalibrated on a pro-
A.3 CLINICAL CRITERIA
tractor jig before inserting it into the eye). The
In the clinic or clinical laboratory, IR, search- calibration and zeroing values can then be used
coil, and digital video systems have also been post hoc on the data collected to ensure accu-
used, but the search-coil system is usually too racy and linearity.

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A . 4 .1.1 I N FA N T I L E N Y S TA G M US 5. Kennedy EA, Bonivtch AR, Manoogian SJ,

Stitzel JD, Herring IP, Duma SM. The effects
For infantile nystagmus syndrome (INS) patients, of extraocular muscles on static displacements
monocular calibration allows analysis of the fi x- of the human eye. Biomed Sci Instrum
ating eye for foveation quality and detection of 2006;42:372–377.
microstrabismus, both static and time varying. 6. Wade NJ. Porterfield and Wells on the motions
Application of foveation-quality formulae like the of our eyes. Perception 2000;29(2):221–239.
7. Huey E. Preliminary experiments in the
NAFX require that the data being analyzed come
physiology and psychology of reading.
from the fi xating eye only; data from a deviated eye Am J Psychol 1898;9:575–586.
would be meaningless in the determination of best- 8. De Leo A. The origin of graphic recording of
possible acuity. psycho-physiological phenomena in Germany.
Physis Riv Int Stor Sci 2006;43(1–2):345–362.
9. Hoff HE, Geddes LA, Guillemin R. The
A . 4 .1. 2 F US I O N M A L D E V E L O P M E N T anemograph of Ons-en-Bray: an early
N Y S TA G M US self-registering predecessor of the kymograph
with translations of original description and a
For fusion maldevelopment nystagmus (FMNS) biography of the inventor. J Hist Med Allied Sci
patients, monocular calibration is necessary for 1957;12(4):424–448.
the same reasons as for INS patients. In these 10. Ono H. On Wells’s (1792) law of
patients, switching from one fi xating eye to the visual direction. Percept Psychophys
other varies with both gaze angle and time; with- 1981;30(4):403–406.
out an accurate method of determining which eye 11. Aust W. Der Nachbildablauf bei Schielamblyopen
is fi xating at any particular instant, analysis would am Ohm-Rombergschen Gerat. [The
afterimage process in squint amblyopia with the
become hopelessly confounded.
Ohm-Romberg apparatus]. Albrecht Von Graefes
Arch Klin Exp Ophthalmol 1966;170(2):175–200.
A.4.2 Infants 12. Hobson JA, Pace-Schott EF, Stickgold
R, Kahn D. To dream or not to dream?
For infants with either INS or FMNS, the diffi- Relevant data from new neuroimaging and
culties in calibration may, in some cases, preclude electrophysiological studies. Curr Opin
acquiring accurate data. This is usually a problem Neurobiol 1998;8(2):239–244.
13. Smith CR. Measurement of nystagmus using
in children between the ages of 2 to 4 years old
electronystagmography (ENG). J Speech Hear
who may be uncooperative. For this group, a non- Disord 1967;32(2):133–138.
invasive, self-calibrating system would be invalu- 14. Jung R. Cerebral control of eye movements
able (see earlier discussion of recently developed and motion perception. Introduction. Bibl
soft ware algorithms that may solve this problem). Ophthalmol 1972;82:1–6.
15. Torok N. Measuring eye movements. Science
1960;131(3404):940.
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1. Abel LA, Dell’Osso LF. Ocular motility Geburtstag am 5. November 1965. [Ernst von
recording and nystagmus. In: Webster J, Romberg; on the 100th anniversary of his birth
ed. Encyclopedia of Medical Devices and on November 5, 1965]. Munch Med Wochenschr
Instrumentation. 2nd ed. Hoboken, NJ: John 1965;107(53):2683–2686.
Wiley and Sons; 2006:137–149. 17. Robinson DA. A method of measuring eye
2. Eggert T. Eye movement recordings: methods. movement using a scleral search coil in
Dev Ophthalmol 2007;40:15–34. a magnetic field. IEEE Trans Biomed Eng
3. Wade NJ, Tatler BW, Heller D. Dodge-ing 1963;10:137–145.
the issue: Dodge, Javal, Hering, and the 18. Ferman L, Collewijn H, Van den Berg AV. A
measurement of saccades in eye-movement direct test of Listing’s law—II. Human ocular
research. Perception 2003;32(7):793–804. torsion measured under dynamic conditions.
4. Wade NJ. William Charles Wells (1757–1817) Vision Res 1987;27(6):939–951.
and vestibular research before Purkinje and 19. Howard IP, Evans JA. The measurement of eye
Flourens. J Vestib Res 2000;10(3):127–137. torsion. Vision Res 1963;61:447–455.

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20. Hoff HE, Geddes LA. Graphic registration 32. Bergamin O, Zee DS, Roberts DC,
before Ludwig; the antecedents of the Landau K, Lasker AG, Straumann D.
kymograph. Isis 1959;50(159):5–21. Three-dimensional Hess screen test with
21. Henn V, Straumann D. Th ree-dimensional eye binocular dual search coils in a three-field
movement recording for clinical application. magnetic system. Invest Ophthalmol Vis Sci
J Vestib Res 1999;9(3):157–162. 2001;42(3):660–667.
22. Rubin AM, Zafar SS. The assessment and 33. Bergamin O, Ramat S, Straumann D, Zee
management of the dizzy patient. Otolaryngol DS. Influence of orientation of exiting
Clin North Am 2002;35(2):255–273. wire of search coil annulus on torsion
23. Ciuff reda KJ, Bahill AT, Kenyon RV, Stark L. aft er saccades. Invest Ophthalmol Vis Sci
Eye movements during reading: case reports. 2004;45(1):131–137.
Am J Optom Physiol Opt 1976;53(8):389–395. 34. Allum JH, Honegger F, Troescher M.
24. Ukai K, Saida S, Ishikawa N. Use of infrared Principles underlying real-time nystagmus
TV cameras built into head-mounted display analysis of horizontal and vertical eye
to measure torsional eye movements. Jpn J movements recorded with electro-, infra-
Ophthalmol 2001;45(1):5–12. red-, or video-oculographic techniques. J Vestib
25. Traisk F, Bolzani R, Ygge J. A comparison Res 1998;8(6):449–463.
between the magnetic scleral search coil and 35. Eckert AM, Gizzi M. Video-oculography
infrared reflection methods for saccadic eye as part of the ENG battery. Br J Audiol
movement analysis. Graefes Arch Clin Exp 1998;32(6):411–416.
Ophthalmol 2005;243(8):791–797. 36. Zhu D, Moore ST, Raphan T. Robust
26. De Luca M, Spinelli D, Zoccolott i P, Zeri F. pupil center detection using a curvature
Measuring fi xation disparity with infrared algorithm. Comput Methods Programs Biomed
eye-trackers. J Biomed Opt 2009;14(1):014013. 1999;59(3):145–157.
27. Ferman L, Collewijn H, Jansen TC, Van 37. Geisler C, Bergenius J, Brantberg K.
den Berg AV. Human gaze stability in the Nystagmus fi ndings in healthy subjects
horizontal, vertical and torsional direction examined with infrared videonystagmoscopy.
during voluntary head movements, evaluated ORL J Otorhinolaryngol Relat Spec
with a three-dimensional scleral induction coil 2000;62(5):266–269.
technique. Vision Res 1987;27(5):811–828. 38. van der Geest JN, Frens MA. Recording
28. Quinn KJ, Rude SA, Brett ler SC, Baker JF. eye movements with video-oculography
Chronic recording of the vestibulo-ocular and scleral search coils: a direct comparison
reflex in the restrained rat using a permanently of two methods. J Neurosci Methods
implanted scleral search coil. J Neurosci 2002;114(2):185–195.
Methods 1998;80(2):201–208. 39. Schreiber K, Haslwanter T. Improving
29. Stahl JS, van Alphen AM, De Zeeuw CI. A calibration of 3-D video oculography systems.
comparison of video and magnetic search coil IEEE Trans Biomed Eng 2004;51(4):676–679.
recordings of mouse eye movements. J Neurosci 40. Guestrin ED, Eizenman M. General theory of
Methods 2000;99(1–2):101–110. remote gaze estimation using the pupil center
30. Foeller P, Tychsen L. Eye movement training and corneal reflections. IEEE Trans Biomed Eng
and recording in alert macaque monkeys: 1. 2006;53(6):1124–1133.
Operant visual conditioning; 2. Magnetic 41. Kang JJ, Eizenman M, Guestrin ED, Eizenman
search coil and head restraint surgical E. Investigation of the cross-ratios method for
implantation; 3. Calibration and recording. point-of-gaze estimation. IEEE Trans Biomed
Strabismus 2002;10(1):5–22. Eng 2008;55(9):2293–2302.
31. Houben MM, Goumans J, van der Steen J. 42. Model D, Eizenman M. An automatic personal
Recording three-dimensional eye movements: calibration procedure for advanced gaze
scleral search coils versus video oculography. estimation systems. IEEE Trans Biomed Eng
Invest Ophthalmol Vis Sci 2006;47(1):179–187. 2010;57(5):1031–1039.

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appendix b

clinical ex amination
B.1 GENERA L CLINICAL EXAMINATION B.4 CLINICAL PEARLS 277
FORM 272 B.5 OPHTHALMOLOGICAL MYTHS AND
B.2 STRA BISMUS EXAMINATION FACTS 279
FORM 276
B.3 NYSTAGMUS EXAMINATION
FORM 277

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B.1 GENERAL CLINICAL EXAMINATION FORM

Outpatient Pediatric Ophthalmology
Medical Record

New Annual Follow up Urgent Consult

Referring Physician: Unknown PCP: Unknown

Chief Complaint: Time Patient in Office:

HPI: (Location, Duration, Frequency, Severity, Associated Sign and Symptoms, Modifying Factors)

Ocular HX: (Mark X if positive HX, -- if no HX) PMH: (Mark X if positive HX, -- if no HX)
Cataracts Diabetes
Glaucoma Arthritis
Strabismus Cancer
Visual Delay Thyroid
Retinopathy of Prematurity Cerebral Palsy
Amblyopia Autism
Nystagmus Hearing Deficit
Retinal Disease Hydrocephalus
Corneal Disease Craniofacial Disease
Refractive Error Childhood Heart Condition
Other Other

Review of Systems: (Normal mark X; Abnormal mark numerically the give description below) Medications: None (Mark X if none) Allergies: None (Mark X if
none)
__Constitutional (fever, wt loss/gain) __Gastrointestinal (diarrhea, constipation) __________________________ ________________________
__Neurological (siezures, headache) __EENT (infections, blurriness, deafness) __________________
________ ________________________
__Musculoskeletal (weakness, pain) __Endocrine (diabetic, thyroid) __________________________ ________________________
__Hematologic (sickle cell, clotting) __Respiratory (couch, SOB) __________________________ ________________________
__Cardiovascular (palpitation, angina)__Genitourinary (frequency, stones) __________________________ ________________________
__Psychiatric (depression, bipolar) __Integumentary (rashes, lesions) __________________________ ________________________
Description:

Family HX: (Mark X if positive HX & note patient relation, --if no HX) Social HX: (Mark X if positive HX, -- if no HX)
Retinal Detachment Substance Use
Glaucoma Sexual Activity
Lazy Eye Grade Level
Diabetes Guardian – Relation
Childhood Cataracts Sports
Nystagmus Other
Thyroid
Cancer
Other

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Outpatient Pediatric Ophthalmology

Medical Record

Exam: (Mark X if Positive)

Appropriate for ag e Developmentally Delayed Cooperative Uncooperative Unresponsive/Sleeping
Stereopsis: External: (Mark X if Normal)
Worth 4 Dot: Head Posture
Color: Head/Face
Visual Field: Brows
Near Point of Covergence: Lids
Near Point of Accommodation: Lashes
Fusional Amplitude: Lacrimal System
Accommodative Amplit ude: Levator Function
Exophthalmetry: Margin Reflex Distance
Direct Ophthalmoscopy:
Dynamic Retinoscopy:

/ /
HOTV
Snellen
Glasses Distance Vision OU Vision - Animal
Single
Glasses / No Glasses Glasses / No Glasses Crowd
Line

Near Vision /
Glasses/ Bifocal / No Glasses
IOP / @ Pupils /
Afferent Pupillary Defect________
__

Motility:
Distance Near
Glasses No Glasses Bifocal Glasses No Glasses

Versions/Ductions: Full (Mark X if normal)

Fixation Preference Fixation Preference

OD / OS OD / OS

Nystagmus: (Mark X if postive) Diagram:

Jerk R in R / L Jerk Up in Up / Down
Jerk L in R / L Jerk Down in Up / Down
Pendular Decreases with Convergence
Rotary Head Oscillation
Latent/ Manifest Latent Iris Transillumination
Seesaw Null Position

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Outpatient Pediatric Ophthalmology

Medical Record

Refraction / Retinoscopy / Keratometry Diagnostic Medications Given:

Time: (Mark X if used)
__Mydriacyl 1% OD / OS

Keratometry / __Cyclogyl 1%
__Phenylephrine 2.5%
__Fluress 0.25%
OD / OS
OD / OS
OD / OS

AutoRef / Vision / OU -
__T etracaine 0.5%
__Cyclogyl 2%
__Pilocarpine 1%
OD / OS
OD / OS
OD / OS
__Goniosoft 2.5% OD / OS

MRef / Vision / OU -
__Pilocarpine 2%
__Atropine 1%
Administered By:
OD / OS
OD / OS

CRef / Vision / OU -

/ /
(Signature)

CRet Vision OU -

Slit Lamp Exam: (Mark X if normal for each eye listed)

OD OS
Lids & Lashes
Conjunctiva
Cornea
ANT Chamber
Iris
Lens

Fundus Exam: (Mark X if normal for each eye listed)

OD OS
Vitreous
Optic Nerve
Vessels
Macula/Fovea
Periph. Retina

Cup / Disc_______ Cup / Disc______

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Outpatient Pediatric Ophthalmology

Medical Record

Impression/Diagnosis: Plan/Treatment:

Follow Up:

Eyeglasses Given:
__ AutoRef __CRef __CRet __MRef

Sphere Cylinder Axis Add/Prism

OD: _________ + _________ X ________ ______________

OS: _________ + _________ X ________ ______________

Orders:
Fundus Photos Optical Coherence Tomography
Optic Nerve Macula EUA RNFL Macula Optic Nerve
Humphrey Visual Fields Electroretinography
24 -2 30 -2 Peripheral Screen Standard EUA
Visual Evoked Potentials CT -Scan MRI
Swee p Flash Pattern contrast without contrast 1mm 5 mm
Color D -15 Preferential Looking Tests

Sensorimotor Examination Eye Movement Recording

A -Scan B -Scan

Letter: (Mark X for all that apply) Signatures:

Dictated to Referring Physician
Technician
cc:
Resident

Physician

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B.2 STRABISMUS EXAMINATION FORM

276 • CLINICA L EX A M INATION

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B.3 NYSTAGMUS EXAMINATION FORM

.3 NYSTAGMUS EXAMINATION FORM

OCULAR MOTILITY CHART

Near

cAdd

W -4-Dot Dist____________ Near______________ Stereo______________

Saccades_______________Pursuit_______________VOR_______________

Forced Ductions_________________________________________________

Forced Generations_______________________________________________
DIST ANCE NEAR
ConvergenceAmplitude __________ ________
Divergence Amplitude __________ ________
Torsion __________ ________
Accommod Amplitude __________ ________
Anomalous Head Posture __________ _________

Ocular Oscillations YES NO

Characteristics:

B.4 CLINICAL PEARLS Chapter 2

Following are the clinical pearls presented 2.1. 2.6
throughout this volume along with the chapter
Clinical Pearl: Based on the research of the past 50
and section in which they appeared.
years, the INS in all patients is directly caused by

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instability in smooth pursuit damping plus a varia- 2. 4

ble amount of tonic imbalance in the visual-vestib-
Clinical Pearl: INS therapy is not contraindicated
ular system. Thus, INS is a motor oscillation with
in patients with associated visual sensory deficits;
known motor causes, making the adjective “motor”
in fact, these patients have the greatest chances for
(e.g., motor nystagmus or congenital motor nystag-
significant (i.e., life-changing) improvements in
mus) redundant. Similarly, the terms “sensory” and
their visual function.
“idiopathic” are both incorrect and misleading. None
of these terms should be used in describing INS.
2. 4 . 2. 2
2.1.3.1 Clinical Pearl: Contact lenses are not contraindicated
in INS and can provide better acuity than spectacles
Clinical Pearl: Patients with INS and two static (or
in patients whose nystagmus damps with afferent
multiple) head postures should be examined for a
stimulation. Plano soft contact lenses can be used if no
latent component, FMNS or APAN.
refractive correction is required. Four advantages of
contacts in the INS patient are better optical quality,
2.1. 4 .1 improvement in nystagmus foveation, move with eye
to utilize eccentric gaze null, and ability to decrease
Clinical Pearl: Occlude the nonpreferred eye and
light sensitivity/interference via tinting or painting.
examine the preferred eye with the head straight
and gaze in primary position over at least 5–7
minutes. A regular or irregular changing oscillation Chapter 3
intensity and/or direction indicates APAN.
3. 2.3
Clinical Pearl: To distinguish between benign
2.1. 4 .1
(non-neurologically threatening), infantile, pri-
Clinical Pearl: Patients with INS whose measured mary-position, jerk nystagmus, and that which is
visual acuity changes from one office visit to the next neurologically threatening, first verify that there is
may have short periods when the nystagmus stops and no periodic alternation in direction and then per-
acuity peaks; this is an exaggerated form of APAN. form bilateral, sequential, cover-uncover testing.
If the cover test causes a reversal in the nystagmus
direction consistent with FMNS, the nystagmus is
2.1.5
benign (FMNS or INS with a latent component).
Clinical Pearl: Patients who (taking advantage of If not, attempt to rule out INS (by history, clinical
their null) move their heads word to word across the signs [see Table 2.1], and waveforms).
line while reading (even those with high acuity) may
have INS with a narrow range of gaze angles where
3. 2.3
their acuity is highest.
Clinical Pearl: If the results of an alternate-cover test
indicate a benign, infantile, primary-position, jerk
2.1.6
nystagmus (i.e., it causes a reversal in the nystagmus
Clinical Pearl: Patients with INS whose near visual direction consistent with FMNS or INS with a latent
acuity is greater than distant may have INS that component), perform the test again but in far adduc-
damps with convergence. tion of the fixating eye (e.g., far left gaze when the left
eye is occluded). If the nystagmus again reverses (i.e.,
becomes jerk left in left gaze with left eye occluded),
2.1. 8
it is INS with a latent component. Repeat the test in
Clinical Pearl: Point out the head tremor to the adduction of the other eye fixating. If the nystagmus
patient. If it stops, the nystagmus is that of INS; if it remains in the direction of the fixating eye, it may be
persists, both are more likely acquired. either FMNS or INS with a large latent component.

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Chapter 4 Myth: Nystagmus causes the eyes to oscillate across

the intended line of regard (i.e., fixation direction).
4 . 2.1.3 Facts: Nystagmus slow phases take the eyes
“Cultured” Clinical Pearl: Based on the obser- away from the intended line of regard (target
vation that head nodding is compensatory in the being fi xated) and the eyes are returned by either
SNS, if further research on the eye movements of a foveating saccade (for pendular waveforms) or
the “SN-like” nystagmus associated with brain- a foveating fast phase (for jerk waveforms).
stem gliomas demonstrates that no head nodding is Myth: Extraocular muscle surgery to correct
exhibited by these patients, the presence of deliber- anomalous head positions does not improve the
ate, compensatory head nodding is an indication of nystagmus or visual acuity.
SNS and is benign. Facts: Nystagmus surgery of the extraocular
muscles to center eccentric INS “nulls” not only
corrects anomalous head positions but also
Chapter 5 broadens the range of gaze angles with high-
5.1.1. 2 est acuities, may increase the peak acuity, and
shortens the target acquisition time; all of which
Clinical Pearl: When the preferred fi xating eye is improve visual function.
kept in abduction, the nystagmus is most probably Myth: If there is no anomalous head position or
IN, not FMN. Caveat: It might still be FMN if the no nystagmus damping with convergence, nothing
patient has exotropia or an angle kappa. can be done to improve the nystagmus.
Facts: Improvement of INS waveforms, and
Chapter 7 therefore, visual function, is possible by the
tenotomy and reattachment procedure, which
7. 2.1 broadens the range of gaze angles with high-
Clinical Pearl: When performing simultaneous est acuities, may increase the peak acuity, and
nystagmus and strabismus surgery, the procedure is shortens the target acquisition time; all of which
determined by a combination of moving the eccen- improve visual function.
tric null (straightening the head) using the preferred Myth: Patients with afferent visual sensory defi-
eye and correcting the remaining strabismus using cits and nystagmus cannot be helped by nystagmus
the nonpreferred eye. surgery.
Facts: All INS patients can profit from the
therapeutic improvements in visual function
7. 2. 2 resulting from the proper extraocular muscle
Clinical Pearl: Determination of the amounts of surgery, and those with the poorest acuities may
recession and resection needed to rotate the eyes profit the most (i.e., receive the largest percent
using bilateral recession and resection of the horizon- increases in the direct outcome measures affect-
tal recti (A-K procedure) may be best accomplished ing visual function).
by dividing the total amount of surgery (indicated Myth: After surgery to correct anomalous head
by the curve given in Dell’Osso and Flynn, 1979) position by centering an eccentric nystagmus null,
in two and applying those equal amounts to the two the null often returns at some intermediate lateral
antagonist muscles. gaze angle.
Facts: Eye-movement data verify that ade-
quate surgery, determined by that data, per-
B.5 OPHTHALMOLOGICAL MYTHS manently repositions an eccentric INS null to
AND FACTS primary position. However, insufficient surgery,
Listed next are ophthalmological myths that were determined by measurement of the anomalous
prevalent in the literature and, in some cases, still head position, can result in the patient using the
taught, repeated, or even published. The factual partially centered null by adopting a head turn
data contradicting each are also listed. that is less than preoperatively.

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appendix c

illustrative cases and

treatment
C.1 INFANTILE NYSTAGMUS C.1.4.2 Four-Muscle Tenotomy and
SYNDROME 281 Reattachment 283
C.1.1 Gaze-Angle Null Only 281 C.1.4.2.1 Tenotomy and Reattachment
C.1.1.1 Version Prisms 281 with Augmented Tendon Suture 284
C.1.1.2 Soft Contact Lenses 281 C.1.4.2.2 Augmented Tendon Suture
C.1.1.3 Four-Muscle Resection, Procedure sans Tenotomy and
Recession, and Tenotomy and Reattachment 284
Reattachment 281 C.1.4.3 Faden 284
C.1.1.3.1 Fine Tuning with Prisms 281 C.2 INFANTILE NYSTAGMUS PLUS
C.1.1.3.2 Soft Contact Lenses 281 STRA BISMUS 284
C.1.2 Convergence Null Only 281 C.2.1 Gaze-Angle Null Only 284
C.1.2.1 Vergence Prisms with Negative C.2.1.1 Four-Muscle Resection,
Spheres 282 Recession, and Tenotomy and
C.1.2.2 Soft Contact Lenses 282 Reattachment 284
C.1.2.3 Bimedial Recession 282 C.2.2 Vertical and Torsional Nulls 284
C.1.3 Both Gaze-Angle and Convergence C.2.3 No Nulls 286
Nulls 282 C.2.3.1 Four-Muscle Tenotomy and
C.1.3.1 Convergence > Gaze-Angle 282 Reattachment and Strabismus 286
C.1.3.1.1 Composite Prisms and C.3 FUSION MALDEVELOPMENT
Negative Spheres 282 NYSTAGMUS SYNDROME 286
C.1.3.1.2 Base-Out Prisms and C.3.1 Uniocular Fixation 286
Negative Spheres 283 C.3.2 Alternating Fixation 286
C.1.3.1.3 Soft Contact Lenses 283 C.3.3 Alexander’s Law Th reshold 286
C.1.3.1.4 Bimedial Recession 283 C.4 NYSTAGMUS BLOCKAGE
C.1.3.2 Gaze-Angle > Convergence 283 SYNDROME 287
C.1.3.2.1 Version Prisms 283 C.4.1 Bimedial Recession (Plus Tenotomy
C.1.3.2.2 Soft Contact Lenses 283 and Reattachment) 287
C.1.3.2.3 Four-Muscle Resection, C.4.2 Recession and Resection Plus
Recession, and Tenotomy and Tenotomy and Reattachment 287
Reattachment 283 C.4.3 Four-Muscle Tenotomy and
C.1.4 No Nulls 283 Reattachment 287
C.1.4.1 Soft ContacWt Lenses 283

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C.1 INFANTILE NYSTAGMUS In the example shown in Figure C.1, the null
SYNDROME is >20° to the right and the four-muscle resection
and recess procedure is used.
Th is section contains examples of optical and In the example shown in Figure C.2, the null
surgical nystagmus therapies for patients with is <20° to the right and the two-muscle recession
infantile nystagmus syndrome (INS) whose plus two-muscle T&R procedure is used to cen-
characteristics determine which is the most ter and broaden the null.
effective therapy.
C.1.1.3.1 Fine Tuning with Prisms. It used
C.1.1 Gaze-Angle Null Only to be thought that if the surgery to center the
null was insufficient, postoperative fi ne-tuning
The therapeutic options for an INS patient with with the use of version prisms could achieve the
a gaze-angle null (i.e., an eccentric eXpanded desired result. However, the use of eye-move-
nystagmus acuity function [NAFX] peak) ment data (to determine the surgical rotation
depend on three things: the eccentricity, the needed) plus documentation of the null-broad-
depth, and the breadth of the null, as discussed ening effects of the surgery itself have precluded
in Chapter 2. If nystagmus surgery is indicated, the need for postoperative prisms in most cases.
the amount necessary is determined by the
eccentricity. C.1.1.3.2 Soft Contact Lenses. Just as soft
contact lenses improve INS before surgery, they
C .1.1.1 V E R S I O N P R I S M S can be used postoperatively in lieu of eyeglasses.
The extent of further improvement has not been
If the null is close to primary position (e.g., < studied and may be idiosyncratic.
5° = 8.75 PD) and is broad (e.g., > 25°), version
prisms may be used to center it, however. At
larger eccentricities, the required prism would C.1.2 Convergence Null Only
be too great, causing both chromatic aberration The therapeutic options for an INS patient
and diminished acuity. At narrower breadths, a with a convergence null (i.e., an NAFX peak at
therapy that broadens the null (version prisms
do not) is more suitable.

C .1.1. 2 S O F T CO N TA C T L E N S E S
If the null is in primary position and is narrow,
soft contact lenses may be used to improve the
range of gaze angles with best-corrected visual
acuity (i.e., broaden the null); they may also
improve the peak acuity.

C .1.1.3 F O U R- M US C L E R E S EC T I O N ,
R EC E SS I O N , A N D T E N OT O M Y A N D
R E AT TA C H M E N T
FIGURE C.1 Operation 1—Bilateral horizontal
If the null is at any eccentricity >10° and is of any rectus recession and resection to improve a horizon-
breadth, the four-muscle resection and reces- tal head posture and the nystagmus associated with a
sion procedure or the two-muscle recession plus moderate to large horizontal eccentric-gaze null. The
tenotomy and reattachment (T&R) of the other percentage indicates the incidence of this procedure.
two muscles may be used. These nystagmus sur- The operation number reflects the order of these inci-
geries both center and broaden the null. dences. LR, lateral rectus; MR, medial rectus.

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C.1.2.2 Soft Contact Lenses

Soft contact lenses can also be used to broaden
the null when the base-out prisms are not in use,
such as for some sports where eyeglasses would
interfere, or socially if preferred by the patient.

C.1.2.3 Bimedial Recession

The bimedial recession operation is the most
therapeutically powerful nystagmus surgery
for INS. Originally, the addition of bilateral lat-
eral rectus T&R to the bimedial recessions was
advocated to achieve the maximal benefits of
FIGURE C.2 Operation 1B—Bilateral hori-
zontal rectus recession and tenotomy + reatt ach-
four-muscle T&R. However, research has shown
ment to improve a horizontal head posture and that convergence alone (e.g., fi xation on a near
the nystagmus associated with a small horizontal target or through the use of base-out prisms)
eccentric-gaze null. The percentage indicates the achieves the maximal improvements in NAFX
incidence of this procedure. The operation number values and negates the need for the addition of
reflects the order of these incidences. LR, lateral rec- the T&R of the lateral rectus muscles. Th is is
tus; MR, medial rectus. the only nystagmus surgery where operating on
two muscles will provide foveation improve-
ments that are equivalent to operating on all
near) depend on only one thing: the absence four. Because the bimedial recession nystagmus
of strabismus. Whether through the use of surgery for binocular INS patients induces con-
base-out prisms or bilateral medial rectus vergence, it has different therapeutic benefits
recessions, convergence-induced foveation than the same strabismus surgery for esotropic
improvement and null broadening is the most patients, where it does not induce convergence.
therapeutically beneficial method currently The patient in Figure C.3 has INS that damps
available. When both gaze-angle and conver- with convergence and has no strabismus. The
gence nulls are present, the latter is almost artificial divergence produced by the bimedial
always greater. recessions induces the convergence necessary to
improve the INS foveation quality at distance.
C.1.2.1 Vergence Prisms with
Negative Spheres C.1.3 Both Gaze-Angle and
Although the NAFX continues to increase as
Convergence Nulls
the eyes converge by as much as 60 PD, the use Some INS patients exhibit both gaze-angle
of base-out prisms to improve the foveation and convergence nulls. Th is allows for several
quality at distance is accomplished by 7 PD approaches, although one is the most effective.
base-out OU (i.e., a total of 14 PD of conver-
gence) with the addition of –1.0 S OU to negate
the vergence-induced accommodation in
C.1.3.1 Convergence > Gaze-Angle
children and young adults. Th is allows for fur- C.1.3.1.1 Composite Prisms and Negative
ther convergence at middle-distance and near Spheres. It used to be thought that in cases with
targets without loss of fusion and the result- both types of nulls, a combination of version
ing diplopia. At the onset of presbyopia, these and vergence prisms (i.e., composite prisms)
added negative spheres must be removed from would provide the greatest improvement in fove-
the prescription. ation quality. However, research has shown that

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these cases, the same therapies recommended

for gaze-angle-only cases apply.

C.1.3.2.1 Version Prisms. If the null is close

to primary position (e.g., < 5° = 8.75 PD) and is
broad (e.g., > 25°), version prisms may be used
to center it. At larger eccentricities, the required
prism would be too great, causing both chro-
matic aberration and diminished acuity. At nar-
rower breadths, a therapy that broadens the null
is more suitable.
FIGURE C.3 Operation 8—Bilateral medial rec- C.1.3.2.2 Soft Contact Lenses. If the null is
tus recession with bilateral horizontal rectus teno-
in primary position and is narrow, soft contact
tomy and reatt achment (T&R) to induce vergence
lenses may be used to improve the range of gaze
and improve the nystagmus. Subsequent research
indicates that the addition of the bilateral T&R is angles with best-corrected visual acuity and may
unnecessary. The percentage indicates the incidence improve peak acuity.
of this procedure. The operation number reflects the
order of these incidences. LR, lateral rectus; MR, C.1.3.2.3 Four-Muscle Resection, Recession,
medial rectus. and Tenotomy and Reattachment. If the null is
at any eccentricity >10° and is of any breadth, the
four-muscle resection and recession procedure or
because of the large broadening of the gaze-angle the two-muscle recession plus T&R of the other
range of highest NAFX caused by the conver- two muscles may be used to center and broaden
gence, gaze angle becomes inconsequential and the null. In these rare cases, the bimedial recession
the need for composite prisms is negated. The nystagmus surgery may be combined with this
negative spheres are still required for pre-presby- surgery in an attempt to maximize the foveation
opic patients (e.g., children and young adults). improvements.

C.1.3.1.2 Base-Out Prisms and Negative

C.1.4 No Nulls
Spheres. Because of the aforementioned fi nd-
ings, the same base-out prisms with negative There are some patients with INS who have no
spheres are used in these cases as in those with null or whose null is in primary position. Prior to
only convergence damping. the discovery of the beneficial effects of the four-
muscle T&R nystagmus surgery, these patients
C.1.3.1.3 Soft Contact Lenses. As in the had no therapy available to improve their fove-
aforementioned cases, soft contact lenses can ation quality.
also be used to broaden the null when the base-
out prisms are not in use.
C.1.4.1 Soft Contact Lenses
C.1.3.1.4 Bimedial Recession. The bimedial As in the aforementioned cases, soft contact
recession nystagmus procedure described ear- lenses can also be used to further damp the INS.
lier is the recommended therapy for these cases.
C.1.4.2 Four-Muscle Tenotomy and
C.1.3.2 Gaze-Angle > Convergence Reattachment
There are very rare cases where eye-movement The patient in Figure C.4 had no INS nulls. The
data show that the gaze-angle improvements in therapy of choice was the four-muscle T&R
foveation may exceed those of convergence. For procedure.

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C.2 INFANTILE NYSTAGMUS PLUS

STRABISMUS

C.2.1 Gaze-Angle Null Only

Many INS patients also have strabismus. Their
treatment mimics those described earlier with
the additional recessions or resections needed
to correct the strabismus.

C.2.1.1 Four-Muscle Resection,

FIGURE C.4 Operation 6—Bilateral horizontal
Recession, and Tenotomy and
rectus tenotomy and reatt achment alone to improve
Reattachment
the nystagmus. The percentage indicates the inci- Many patients have strabismus and nystagmus
dence of this procedure. The operation number with an eccentric gaze null (i.e., either INS or
reflects the order of these incidences. FMNS). The operation shown in Figure C.5 cor-
rects the strabismus and improves the nystagmus.
C.1.4.2.1 Tenotomy and Reatt achment The INS patient in Figure C.6 had a left ward
with Augmented Tendon Suture. It has been null position and an esotropia. The nystagmus
hypothesized that adding a suture or two to plus strabismus surgical procedure employed
each tendon undergoing a T&R might result combined the necessary recessions and resec-
in greater improvement. These additional tions to improve both the INS foveation quality
sutures are placed in the tendons alone, not and the ocular alignment.
to the globe. If the data confi rm this hypothe-
sis, the augmented suture technique would be C.2.2 Vertical and Torsional Nulls
recommended.
Many INS patients have nulls in the verti-
C.1.4.2.2 Augmented Tendon Suture cal or torsional plane, despite the horizontal
Procedure sans Tenotomy and Reattachment.
A related hypothesis has also been advanced.
Simply placing a suture or two to each tendon
(again, not to the globe) without perform-
ing a T&R might also result in improvement,
greater than or equal to the T&R. Again, if the
data confirm this, the augmented suture tech-
nique sans T&R would be recommended; it
is both simpler and safer than suturing to the
globe.

C.1.4.3 Faden
FIGURE C.5 Operation 3—Bilateral horizontal
The Faden procedure has not been studied using
rectus (BLR) and bimedial horizontal rectus (BMR)
the eye-movement, data-based analysis tech- recession (RES), resection (REC), or tenotomy (T)
niques described in Chapter 2; therefore, its to improve the strabismus, anomalous head posture,
potential benefits as a nystagmus surgery used and the nystagmus associated with an eccentric-gaze
instead of, or in concert with, the surgeries pre- null. The percentage indicates the incidence of this
sented in this appendix cannot be assessed at procedure. The operation number reflects the order
this time. of these incidences.

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strabismus. A bilateral superior rectus recession

and bilateral inferior oblique myectomy is used
to center the vertical null plus either a bilateral
medial or lateral rectus T&R (if no strabismus)
or a bilateral medial or lateral rectus recession (if
strabismus).
Patients like the one in Figure C.8 have a ver-
tical null (in downgaze) with or without stra-
bismus. The surgical procedure combines the
necessary recessions and resections to improve
both the INS foveation quality and eye align-
ment, if strabismus is present.
FIGURE C.6 Operation 4—Bilateral horizontal Patients like the one in Figure C.9 have a mul-
rectus recession and resection to improve the stra- tiplanar null position (here, torsionally coun-
bismus and the nystagmus associated with a primary
terclockwise and to the left); they may or may
position null. The percentage indicates the incidence
of this procedure. The operation number reflects the
not have strabismus. The surgical procedure
order of these incidences. ET, esotropia; LE, left eye; combines the necessary nystagmus surgery to
LR, lateral rectus; MR, medial rectus. improve the INS foveation quality and addition
of strabismus surgery to improve eye alignment,
if strabismus is present.
predominance of the nystagmus. The same prin- Patients like the one in Figure C.10 have a
ciples embodied in nystagmus surgery of the torsional null position; the patient has a coun-
horizontal rectus muscles must be applied to the terclockwise INS null. The nystagmus surgical
vertical rectus and oblique muscles. procedure corrects the torsional null.
Patients like the one in the Figure C.7 have
a vertical null (in upgaze) with or without

FIGUR E C.8 Operation 5—Bilateral inferior

FIGURE C.7 Operation 2—Bilateral superior rectus recession and superior oblique tenectomy
rectus recession and inferior oblique myectomy with bilateral single horizontal recti tenotomy
with bilateral single horizontal recti tenotomy with with reattachment or recession to improve a
reatt achment or recession to improve a chin-down chin-up head posture and the nystagmus +/- stra-
head posture and the nystagmus +/- strabismus bismus associated with a vertically downward
associated with a vertically upward eccentric-gaze eccentric-gaze null. The percentage indicates
null. The percentage indicates the incidence of this the incidence of this procedure. The operation
procedure. The operation number reflects the order number ref lects the order of these incidences. BI,
of these incidences. BIO, bilateral inferior oblique; bilateral inferior rectus; BSO, bilateral superior
BS, bilateral superior rectus. oblique.

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surgery with the addition of whatever recessions

or resections are needed to correct the misalign-
ment of the eyes.

C.3 FUSION MALDEVELOPMENT

NYSTAGMUS SYNDROME
Patients with fusion maldevelopment nystag-
mus syndrome (FMNS) all have strabismus.
Their surgical therapy will require strabis-
mus surgery (to correct eye alignment) and
may also require the T&R nystagmus sur-
FIGURE C.9 Operation 7—Bilateral horizontal gery applied to horizontal rectus muscles not
rectus muscle transposition with or without associ- recessed or resected (to improve nystagmus
ated resection/recession to improve a multiplanar foveation).
head posture, the nystagmus +/- strabismus associ-
ated with multiplanar eccentric-gaze null. The per-
centage indicates the incidence of this procedure. C.3.1 Uniocular Fixation
The operation number reflects the order of these
incidences. LR, lateral rectus; MR, medial rectus; Some FMNS patients always fixate with their
REC, resection; RES, recession; TR, transposition. preferred eye, regardless of gaze angle. For
them, eye-muscle surgery combines operat-
ing on the nonpreferred eye plus T&R of the
C.2.3 No Nulls remaining horizontal rectus muscles. This
may produce fusion damping in addition to
C.2.3.1 Four-Muscle Tenotomy and the nystagmus damping from the surgery
Reattachment and Strabismus itself.
INS patients with no nulls plus strabismus
require the four-muscle T&R nystagmus C.3.2 Alternating Fixation
Some FMNS patients alternate their fixating
eye, depending on gaze angle. In these cases,
recessions of the two medial rectus mus-
cles and T&R of the two lateral rectus mus-
cles is recommended for small deviations.
For exotropia, recessions of the two lateral
rectus muscles and T&R of the two medial
rectus muscles is recommended (again for
small deviations). For large deviations, reces-
sions and resections of all four horizontal
rectus muscles sufficient to align the eyes is
recommended.

FIGURE C.10 Operation 9—Bilateral vertical C.3.3 Alexander’s Law Threshold

rectus muscle transposition to improve a torsional/
tilt head posture and the nystagmus associated with The amount and type of eye-muscle surgery
a torsional gaze null. The percentage indicates the may be affected by the preoperative intensity of
incidence of this procedure. The operation number the Alexander’s law threshold and slope (i.e., the
reflects the order of these incidences. IR, inferior gaze angles at which the FMN begins to increase
rectus; SR, superior rectus; TRA NS, transposition. and the rate of that increase).

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C.4 NYSTAGMUS BLOCKAGE the maximum esotropia plus a T&R of the two lat-
SYNDROME eral rectus muscles is recommended to improve
both convergence and baseline foveation.
Nystagmus surgery for patients with the nystag-
mus blockage syndrome (NBS) is determined
by the characteristics of the baseline INS (i.e., C.4.2 Recession and Resection Plus
null angle depth and breadth) with no purpos- Tenotomy and Reattachment
ive esotropia. The variable esotropia with either If the purposive esotropia added to improve
eye fi xing is amenable to surgical correction, foveation, and is always in one eye, a head turn
although the procedure is less well defi ned. The toward that eye results. In these cases, recession
suggestions that follow apply to both types of the and resection to move the adopted eccentric
NBS (see Chapter 4). However, eye-movement position to primary position plus a T&R of the
data that could confi rm the efficacy of these sug- horizontal rectus muscles of the other eye may
gestions are lacking. improve both foveation quality and reduce/
eliminate the head turn. The preferred eye drives
C.4.1 Bimedial Recession (Plus the head.
Tenotomy and Reattachment)
If there is good binocular function, bimedial C.4.3 Four-Muscle Tenotomy and
recession will result in improved baseline fove- Reattachment
ation due to convergence. If the eyes are aligned before the purposive
If there is a static esotropia to which the pur- esotropia is added to improve foveation and there
posive esotropia is added to improve foveation, is poor binocular fusion, a four-muscle T&R is
a bimedial recession strabismus surgery to correct recommended to improve baseline foveation.

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appendix d

diagnosis and treatment

flowcharts
D.1 WAVEFORM-BASED DIAGNOSES 288 D.4 THERA PEUTICALLY EXPLOITABLE
D.2 THERA PEUTICALLY EXPOITABLE CLINICAL CHARACTERISTICS 288
WAVEFORM CHARACTERISTICS 288 D.5 ANALYSIS GRA PHS 293
D.3 CLINICALLY BASED DIAGNOSES
AND LIMITATIONS 288

D.1 WAVEFORM-BASED Using the flowchart below (Fig. D.2),

DIAGNOSES eye-movement data provide the answers
along each path to a therapeutically appro-
Using eye-movement recordings, accurate,
priate therapy.
repeatable diagnoses can be made of infantile nys-
tagmus syndrome (INS), fusion maldevelopment
nystagmus syndrome (FMNS), the nystagmus D.3 CLINICALLY BASED
blockage syndrome (NBS), the pendular nystag- DIAGNOSES AND LIMITATIONS
mus of the nucleus of the optic tract (NOT) asso-
Although it is possible to accurately diag-
ciated with either INS or FMNS, and the spasmus
nose and treat some cases of INS or FMNS
nutans syndrome (SNS). If none can be identified,
based on clinical signs and examination
the nystagmus will be either vestibular nystag-
alone, other cases the correct diagnosis will
mus (VN) or another type of acquired nystagmus
be problematic. Using the flowchart in Figure
(AN). The flowcharts in this Appendix reflect the
D.3, some diagnoses may be presumed while
differential diagnosis material in Chapter 5 and
others remain doubtful.
the therapeutic material in Chapter 7.
Nystagmus diagnosis from clinical exam-
Using the flowchart in this chapter (Fig. D.1),
ination alone is highly problematic and may
eye-movement data provide the answers along
result in the choice of an ineffective therapy.
each path to a nystagmus diagnosis.

D.4 THERAPEUTICALLY
D.2 THERAPEUTICALLY EXPLOITABLE CLINICAL
EXPOITABLE WAVEFORM CHARACTERISTICS
CHARACTERISTICS
Some of the INS characteristics may be
Using eye-movement recordings, the therapeuti- determined clinically to provide an indica-
cally exploitable characteristics of INS, FMNS, tion of the therapy best suited for a patient
NBS, the pendular nystagmus of the nucleus of (see Fig. D.4).
the NOT associated with either INS or FMNS, Unlike the case when using waveform
and SNS may be determined. analysis, the improvements resulting from

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FIGURE D.1 Flowchart demonstrating how eye-movement data are used to arrive at a repeatable, definitive
nystagmus diagnosis. AN, acquired nystagmus; FMNS, fusion maldevelopment nystagmus syndrome; INS,
infantile nystagmus syndrome; NBS, nystagmus blockage syndrome; NOT, nucleus of the optic tract; SNS,
the spasmus nutans syndrome; VN, vestibular nystagmus.

FIGURE D.2 Flowchart demonstrating how eye-movement data are used to determine therapeutically
exploitable characteristics of infantile nystagmus syndrome (INS). The relevant therapies may be surgical or
nonsurgical. Note that when the eXpanded nystagmus acuity function (NAFX) peak is high and the longest
foveation domain (LFD) is broad, their values cannot be significantly increased and, therefore, no wave-
form foveation improvements are possible; only under these simultaneous conditions is nystagmus therapy
precluded. BMR, bimedial recession; m, muscle; Rec, recession; R&R, recess and resect; Strab, strabismus;
T&R, tenotomy and reatt achment.

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FIGURE D.3 Flowchart demonstrating how clinical observations and tests may be used to arrive at a
nystagmus diagnosis. Note that, unlike when using waveform analysis, all paths do not lead to a defi nitive
diagnosis and there is no reliable path to acquired nystagmus. AN, acquired nystagmus; FMNS, fusion
maldevelopment nystagmus syndrome; INS, infantile nystagmus syndrome; NBS, nystagmus blockage syn-
drome; SNS, the spasmus nutans syndrome; VN, vestibular nystagmus.

FIGURE D.4 Flowchart demonstrating how clinical observations and tests may be used to determine ther-
apeutically exploitable characteristics of infantile nystagmus syndrome (INS). The relevant therapies may be
surgical or nonsurgical. Note that when the peak is high and the range of high-visual acuity (Hi VA) gaze angles
is broad, their values cannot be significantly increased and, therefore, no waveform foveation improvements are
possible; only under these simultaneous conditions is nystagmus therapy precluded. BMR, bimedial recession;
m, muscle; Rec, recession; R&R, recess and resect; Strab, strabismus; T&R, tenotomy and reattachment.

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FIGURE D.5 Plot of total millimeters of extraocular muscle surgery (recession plus resection) required to
achieve the required amount of null (eXpanded nystagmus acuity function [NAFX] peak) shift ing in infan-
tile nystagmus syndrome.

FIGURE D.6 Plot of the estimated postt herapeutic improvement in the eXpanded nystagmus acuity func-
tion (NAFX) peak based on the pretherapeutic NAFX peak value.

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FIGURE D.7 Plot of the estimated postt herapeutic improvement in the longest foveation domain (LFD)
based on the pretherapeutic LFD value.

FIGURE D.8 Plot of the eXpanded nystagmus acuity function (NAFX) versus best-corrected visual
acuity for patients of different ages.

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the indicated therapies cannot be estimated and resections, pretherapeutic estimation of

prior to therapy because acuity measures may therapeutic improvements, postt herapeutic
not be correlated with INS foveation quality measurement of therapeutic improvements, and
alone. Therapies chosen based solely on clinical differentiation of the motor and sensory com-
observations and tests may not provide improve- ponents of visual acuity. Individual work sheets
ments in visual function. may be copied and printed from the Companion
Website (Appendix F, Section F.3) or down-
D.5 ANALYSIS GRAPHS loaded from www.omlab.org.

The graphs in Figures D.5 through D.8 are use-

ful in the determination of surgical recessions

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appendix e

online access videos

E.1 “EYEBALLS 3D” EYE-MOTION AND MV10 Infantile Nystagmus Syndrome

WAVEFORM VIDEOS 296 (Pseudo Pendular with Foveating
MV1 Infantile Nystagmus Syndrome Saccades) 1/2-Speed Ocular Motor
(Pseudo Pendular with Foveating System Model Ramp and Step-Ramp
Saccades) 1 Cycle 1/20-Speed Illustrating Responses 297
Foveation Period 296 MV11 Fusion Maldevelopment Nystagmus
MV2 Infantile Nystagmus Syndrome (Jerk Syndrome Gaze-Angle Effect Ocular
with Extended Foveation) 4 Cycles 1/3- Motor System Model 297
Speed with Phase Plane 296 MV12 Fusion Maldevelopment Nystagmus
MV3 Infantile Nystagmus Syndrome Syndrome 1/2-Speed Alternate Cover
(Pseudo Pendular with Foveating Test Ocular Motor System Model 298
Saccades) 3 Cycles 1/2-Speed Illustrating MV13 Fusion Maldevelopment Nystagmus
Well-Developed Foveation 296 Syndrome Adducting Eye Fixation Ocular
MV4 Infantile Nystagmus Syndrome Motor System Model 298
(Pseudo Pendular with Foveating MV14 Infantile Nystagmus Syndrome
Saccades) 3 Cycles 1/5-Speed with Phase Damping with Rapid Convergence 298
Plane 297 MV15 Infantile Nystagmus Syndrome
MV5 Infantile Nystagmus Syndrome 1/2-Speed Pre-Tenotomy and
(Pseudo Pendular with Foveating Reattachment 298
Saccades) 1/2-Speed Th ree-Dimensional MV16 Infantile Nystagmus Syndrome
Motion with Subclinical Seesaw 1/2-Speed Post-Tenotomy and
Nystagmus 297 Reattachment 298
MV6 Infantile Nystagmus Syndrome 1/5- MV17 Infantile Nystagmus Syndrome 1/2-
Speed Subclinical Seesaw Nystagmus Speed RPE65-Deficient Canine Pre-Gene
Motion Amplified 297 Therapy 298
MV7 Infantile Nystagmus Syndrome MV18 Infantile Nystagmus Syndrome 1/2-
(Pseudo Pendular with Foveating Speed RPE65-Deficient Canine Post-
Saccades) 1/2-Speed from Ocular Motor Gene-Therapy Scan Path 298
System Model and Patient 297 MV19 Infantile Nystagmus Syndrome 1/2-
MV8 Infantile Nystagmus Syndrome Speed RPE65-Deficient Canine Post-
(Pendular with Foveating Saccades) Gene-Therapy 298
Step Responses Ocular Motor System MV20 Infantile Nystagmus Syndrome
Model 297 1/2-Speed RPE65-Deficient Canine Post-
MV9 Infantile Nystagmus Syndrome Gene-Therapy Scan Path 298
(Pseudo Pendular with Foveating MV21 Oscillopsia Simulation 298
Saccades) 1/2-Speed Pulse Responses MV22 Uniocular Acquired Pendular
Ocular Motor System Model 297 Nystagmus Pre- and Post-Therapy 298

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MV23 Infantile Nystagmus Syndrome PV8 Infant with Opsoclonus (Ocular

(Alternating Jerk) Ocular Motor System Flutter—“Saccadomania”) 302
Model 299 PV9 Acquired Saccadic Oscillations-1 302
MV24 Flutter 299 PV10 Acquired Saccadic Oscillations-2 302
MV25 Flutter in a Blind Patient 299 PV11Acquired Saccadic Oscillations-3 302
MV26 Psychogenic Flutter 299 PV12 Acquired Nystagmus Plus Saccadic
MV27 Square-Wave Jerks 299 Oscillations 302
MV28 Opsoclonus 299 PV13 Acquired Upbeat Nystagmus with
KeyNote and PowerPoint Files 299 Wiernecke’s Encephalopathy 302
E.1.1 Infantile Nystagmus Syndrome PV14 Acquired Vertical Pendular
Dynamic Visual Acuity 299 Nystagmus 303
E.1.2 Infantile Nystagmus Syndrome PV15 Fusion Maldevelopment
Latency 299 Nystagmus-1 303
E.1.3 Infantile Nystagmus Syndrome PV16 Fusion Maldevelopment
Latency Poster 299 Nystagmus-2 303
E.1.4 Infantile Nystagmus Syndrome Model PV17 Down Syndrome and Infantile
Poster 300 Nystagmus 303
E.2 CANINE VIDEOS (PLUS PV18 Achiasma Plus Seesaw Nystagmus Plus
OTHERS) 300 Infantile Nystagmus 303
CV1 Normal Brittany 300 PV19 Octogenarian with Infantile
CV2 Achiasmatic Belgian Sheepdog: Pre- Nystagmus 303
Tenotomy and Reattachment 300 PV20 Infantile Nystagmus: Aperiodically
CV3 Achiasmatic Belgian Sheepdog: Post- Changing Intensity (Not Direction) 303
Tenotomy and Reattachment 300 PV21 Infantile Nystagmus: Aperiodically
CV4 RPE65-Deficient Canine: Pre-Gene- Changing Direction (Not Intensity) 303
Therapy Behavior 300 PV22 Infantile Nystagmus: Unequal-1 304
CV5 RPE65-Deficient Canine: Post-Gene- PV23 Infantile Nystagmus: Unequal-2 304
Therapy Behavior 300 PV24 Infantile Nystagmus: Unequal-3 304
CV6 RPE65-Deficient Canine: Pre-Gene- PV25 Infantile Nystagmus: Jerk with
Therapy Eye Movements 301 Extended Foveation 304
CV7 RPE65-Deficient Canine: Post-Gene- PV26 Infantile Plus Nucleus of the Optic
Therapy Eye Movements 301 Tract Nystagmus: Dual Jerk 304
CV8 Cat with Infantile Nystagmus 301 PV27 Infantile Nystagmus: Pre- and
CV9 Goat with Seesaw Nystagmus 301 Postoperative 304
KeyNote and PowerPoint Files 301 PV28 Optic Nerve Dysplasia and Infantile
E.3 PATIENT VIDEOS 301 Nystagmus: Multiplanar 304
PV1 Saccadic Initiation Failure 301 PV29 Infantile Nystagmus: Jerk with
PV2 Brainstem Tumor: Tonic Gaze Extended Foveation 305
Deviation 301 PV30 Infantile Nystagmus: Unequal with a
PV3 Acquired Downbeat Nystagmus 301 “Latent Component” 305
PV4 Acquired Gaze-Evoked (Gaze-Holding PV31 Albinism and Infantile
Failure) Nystagmus 301 Nystagmus 305
PV5 Acquired Unidirectional Gaze-Evoked PV32 Optic Nerve Dysplasia and Infantile
(Gaze-Holding Failure) Nystagmus 301 Nystagmus: Multiplanar 305
PV6 Ocular Motor Neuromyotonia of PV33 Albinism, Upgaze Null, and Infantile
Cranial Nerve III 301 Nystagmus: Equal 305
PV7 Ocular Motor Neuromyotonia of PV34 Retinal Dystrophy and Infantile
Cranial Nerve VI 302 Nystagmus: Multiplanar 305

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PV35 Albinism and Infantile Nystagmus: PV42 “Vertical” Infantile Nystagmus-1 306
Pre- and Postoperative Horizontal PV43 Retinal Dystrophy and “Vertical”
Null 305 Infantile Nystagmus-2 307
PV36 Albinism and Infantile Nystagmus: PV44 Spasmus Nutans Nystagmus-1 307
Multiplanar 306 PV45 Spasmus Nutans Nystagmus-2 307
PV37 Infantile Nystagmus: Periodic PV46 Voluntary Ocular Flutter 307
Alternating 306 E.4 HISTORICAL 307
PV38 Infantile Nystagmus: Asymmetric E.4.1 Demonstration of Bias and Bias Shift in
Aperiodic Alternating 306 Infantile Nystagmus Waveforms 307
PV39 Albinism and Infantile Nystagmus: E.4.2 Demonstration That Cutaneous
Pre- and Postoperative Vertical Null Stimulation Damps Infantile
306 Nystagmus 307
PV40 Albinism, Upgaze Null, and Infantile E.4.3 First Canine Eye-Movement
Nystagmus 306 Recording 307
PV41 Albinism and Infantile E.4.4 First Tenotomy and Reattachment
Nystagmus 306 Surgery for Infantile Nystagmus 308

THE VIDEO files in this appendix may be viewed MV1 Infantile Nystagmus Syndrome
or copied. Many were originally presented as parts (Pseudo Pendular with Foveating
of papers or posters at various scientific meetings. Saccades) 1 Cycle 1/20-Speed
Illustrating Foveation Period
Note the flattened foveation period at 0°.
E.1 “EYEBALLS 3D” EYE-MOTION
AND WAVEFORM VIDEOS
MV2 Infantile Nystagmus Syndrome
This appendix contains videos made from patient (Jerk with Extended Foveation) 4
data, the OMS behavioral model, and patients, Cycles 1/3-Speed with Phase Plane
canines, and other animals with nystagmus. In
many of the “Eyeballs 3D” videos a yellow fi xation Note the flattened foveation periods at 0° imme-
target is superimposed on the eyeballs and the tar- diately following the foveating left ward fast
get position (usually at 0°) is shown, surrounded phases; all fall within the foveal area. In the
by the foveal area (±0.5°, shown as a dot-dashed phase plane, they fall within the foveation win-
line). In phase planes, the foveation window (±0.5° dow where there is a discernable pause in the tra-
by ±4°/sec) is shown as a rectangular box. These jectory of the phase plane.
additions help us appreciate the foveation periods
in INS waveforms. Eyeballs 3D videos may be MV3 Infantile Nystagmus
viewed individually or using E1_Eyeballs 3D.ppt Syndrome (Pseudo Pendular with
(Mac users may prefer to use E1_Eyeballs 3D.key). Foveating Saccades) 3 Cycles 1/2-
It is best to view the videos in the continuous- Speed Illustrating Well-Developed
loop mode (CMD-L command). These and other Foveation
PowerPoint and KeyNote presentations are in their
respective folders. It is best to view the videos in the Note the accuracy of each successive foveation
continuous-loop mode (CMD-L command). period.

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MV4 Infantile Nystagmus Syndrome MV8 Infantile Nystagmus Syndrome

(Pseudo Pendular with Foveating (Pendular with Foveating Saccades)
Saccades) 3 Cycles 1/5-Speed with Step Responses Ocular Motor System
Phase Plane Model
Note the accuracy of each successive fove- Behavioral OMS model simulations of INS dur-
ation period, especially in the phase plane ing small (5°) and large (30°) saccades. Note the
where they overlap despite cycle-to-cycle oveation accuracy within 1–3 cycles after the
variation throughout the rest of the cycles. voluntary saccade.
Also, the pause within the foveation window
is discernable.
MV9 Infantile Nystagmus Syndrome
(Pseudo Pendular with Foveating
MV5 Infantile Nystagmus Syndrome Saccades) 1/2-Speed Pulse
(Pseudo Pendular with Foveating Responses Ocular Motor System
Saccades) 1/2-Speed Three- Model
Dimensional Motion with Subclinical
Behavioral OMS model simulations of INS dur-
Seesaw Nystagmus
ing short (50 ms) and longer (100 ms°) pulses.
Th is video illustrates that even in so-called Note the normal behavior of ignoring short tar-
horizontal IN, there is an appreciable torsional get pulses is duplicated despite the INS. Again
component and a hidden (subclinical) seesaw note the foveation accuracy.
component. The red markers on the eyeballs
help to appreciate the torsional motion.
MV10 Infantile Nystagmus Syndrome
(Pseudo Pendular with Foveating
MV6 Infantile Nystagmus Syndrome Saccades) 1/2-Speed Ocular Motor
1/5-Speed Subclinical Seesaw System Model Ramp and Step-Ramp
Nystagmus Motion Amplified Responses
In this video, the horizontal and torsional Behavioral OMS model simulations of INS dur-
motion has been turned off and the vertical has ing ramp and step-ramp responses. Note the nor-
been amplified. By focusing on a spot between mal behavior of accounting for the target step in
the eyes, the subclinical seesaw component of the latter response is duplicated despite the INS.
INS can be appreciated. Again note the foveation accuracy.

MV7 Infantile Nystagmus MV11 Fusion Maldevelopment

Syndrome (Pseudo Pendular Nystagmus Syndrome Gaze-Angle
with Foveating Saccades) Effect Ocular Motor System Model
1/2-Speed from Ocular Motor
Behavioral OMS model simulations of FMNS
System Model and Patient
demonstrating the small (left simulation)
Th is video demonstrates the ability of the behav- Alexander’s law variation of the jerk-right FMN
ioral OMS model to simulate even the most with gaze angle and the switch from a linear jerk-
complex INS waveform (PPfs). Note the same right nystagmus whose corrective fast phases fove-
accuracy of successive foveation periods in the ate the target to a rightward saccadic pulse train
model (left) as in the patient (right). whose initiating saccades defoveate the target,

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allowing sustained foveation at the ends of the procedure. Note the improved foveation quality
decelerating, corrective slow phases. In the right and better eye alignment.
simulation, the large Alexander’s law variation
results in the rightward saccadic pulse train at 0°
MV17 Infantile Nystagmus Syndrome
transforming into a jerk-right FMN in left gaze.
1/2-Speed RPE65-Deficient Canine
Pre-Gene Therapy
MV12 Fusion Maldevelopment
Multiplanar INS in an RPE65-deficient Briard
Nystagmus Syndrome 1/2-Speed
dog prior to gene transfer therapy. Note both the
Alternate Cover Test Ocular Motor
uncontrolled nystagmus and eye drift ing.
System Model
Behavioral OMS model simulations of the alter-
MV18 Infantile Nystagmus Syndrome
nate cover test in FMNS demonstrating the
1/2-Speed RPE65-Deficient Canine
changes in FMN direction as the fi xating eye is
Post-Gene Transfer-Therapy Scan Path
changed.
Left- and right-eye scan paths of the above RPE65-
deficient Briard dog prior to gene therapy. Note
MV13 Fusion Maldevelopment
that neither eye can foveate the target.
Nystagmus Syndrome Adducting Eye
Fixation Ocular Motor System Model
MV19 Infantile Nystagmus Syndrome
Behavioral OMS model simulations of change in
1/2-Speed RPE65-Deficient Canine
FMN direction and fi xating eye as gaze is changed.
Post-Gene Transfer-Therapy
In left and center gaze, the right eye is fi xating with
the left being esotropic; and in right gaze, the left Multiplanar INS in an RPE65-deficient Briard
eye is fi xating with the right being esotropic. dog after gene therapy. Note both the nystagmus
and eye drift ing are markedly diminished (dif-
ferent scale from MV17).
MV14 Infantile Nystagmus Syndrome
Damping with Rapid Convergence
MV20 Infantile Nystagmus Syndrome
Demonstration of INS damping with rapid con-
1/2-Speed RPE65-Deficient Canine
vergence followed by an increase when distance
Post-Gene Transfer-Therapy Scan
fi xation is resumed.
Path
Left- and right-eye scan paths of the above RPE65-
MV15 Infantile Nystagmus Syndrome
deficient Briard dog after gene therapy. Note that
1/2-Speed Pre-Tenotomy and
both eyes continuously foveate the target.
Reattachment
INS of a patient with a right esotropia before
MV21 Oscillopsia Simulation
treatment with a bilateral horizontal rectus
muscle T&R plus strabismus procedure. Note An illustration of the perception of oscillopsia sec-
the large variability and failure to achieve good, ondary to horizontal acquired nystagmus. Note
repeatable foveation. that as you stare at the scene, in addition to the visual
problems, there may be a sense of disequilibrium.
MV16 Infantile Nystagmus Syndrome
1/2-Speed Post-Tenotomy and MV22 Uniocular Acquired Pendular
Reattachment Nystagmus Pre- and Post-Therapy
INS of a patient after treatment with a bilat- Note the reduction in the nystagmus (5° p-p to
eral horizontal muscle T&R plus strabismus <1° p-p).

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MV23 Infantile Nystagmus Syndrome INS4_Ramp Response Eye Switching

(Alternating Jerk) Ocular Motor Switching the fi xating eye during pursuit
System Model results in poor pursuit and long target-acquisi-
tion latency.
Behavioral OMS model simulation of alternat- INS5_Ramp Response Post T&R
ing direction jerk INS. Note that despite the Post T&R, target motion near INS fast phase
cycle-to-cycle direction changes, foveation still results in poor pursuit and long target-
quality is maintained. acquisition latency; also there is a steady-state
position error.
MV24 Flutter INS6_Water Trial
Demonstration of post-therapy ability to
Typical flutter seen in neurological disease. track and shoot a flying bird during a water trial
for hunting dogs.
MV25 Flutter in a Blind Patient INS7_Hunting
Demonstration of post-therapy ability to
High-frequency flutter recorded from a blind track and shoot a flying bird during upland game
patient. hunting.
INS8_Activities
MV26 Psychogenic (Voluntary) Flutter Photos of possible normal-life-style activities
after INS treatment.
A party trick incorrectly called voluntary
“nystagmus.”
E.1.2 Infantile Nystagmus Syndrome
Latency
MV27 Square-Wave Jerks
L1_INS Step Response
Typical square-wave jerks often seen in normal Despite normal saccadic latency, the target
individuals. acquisition time (before target foveation) in
INS is longer.
MV28 Opsoclonus L2_INS Step Response Different Timings
In INS, the target acquisition time is deter-
Typical multivectorial opsoclonus. mined by the timing of the target step; near
intrinsic INS saccades it is longer than during
KeyNote and PowerPoint Files the slow phase.
L3_INS Step Response Preprogrammed
Fast Phase
Individuals with INS respond to target steps
E.1.1 Infantile Nystagmus Syndrome
in different ways; here a preprogrammed fast
Dynamic Visual Acuity
phase is elongated to reposition the eyes; it is fol-
INS1_Ramp Response Bad Timing lowed by another saccade to reach the target.
Target motion near INS fast phase results in
poor pursuit and long target-acquisition latency.
E.1.3 Infantile Nystagmus Syndrome
INS2_Ramp Response Good Timing
Latency Poster
Target motion during INS slow phase results
in good pursuit and shorter target-acquisition Each of the following poster panels is self-
latency. explanatory.
INS3_Ramp Response Poor Gain LP1_Abstract
Target motion in opposite direction in same LP2_Latency T&R Procedure
patient results in poor pursuit and long target- LP3_Latency Background
acquisition latency. LP4_Latency Questions

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LP5_Latency Hypotheses MP20_INS Model Outputs Sharp Null

LP6_Latency Methods 1 MP21_INS Model Medium NAFX Peak
LP7_Latency Methods 2 MP22_INS Model Sharp NAFX Peak
LP8_Latency Model MP23_INS Model Broad NAFX Peak
LP9_Latency Model Predictions 1 MP24_INS Mode Results
LP10_Latency Model Predictions 2 MP25_INS Model Conclusions
LP11_Latency Results 1
LP12_Latency Results 2
E.2 CANINE VIDEOS (PLUS OTHERS)
LP13_Latency Results 3
LP14_Latency Results 4 Canine videos may be viewed individually or
LP15_Latency Results 5 using E2_Canine Videos.ppt (Mac users may
LP16_Latency Results 6 prefer to use E2_Canine Videos.key). It is best
LP17_Latency Results Preprogrammed Fast to view the videos in the continuous-loop mode
Phase (CMD-L command).
LP18_Latency Results Riding Slow Phase
LP19_Latency Results Anticipation
CV1 Normal Brittany
LP20_Latency Results Altered Fast Phase
LP21_Latency Results Waveform Change Gaze changes on command with no head motion
LP22_Latency Results Hypometria exhibited and recorded from a well-trained,
LP23_Latency Results Riding Slow Phases Brittany upland game dog (Copper the wonder
LP24_Latency Results Direction Change dog).
LP25_Latency Conclusions 1
LP26_Latency Conclusions 2
CV2 Achiasmatic Belgian Sheepdog:
LP27_Latency Conclusions 3
Pre-Tenotomy and Reattachment
The INS of an achiasmatic Belgian sheepdog
E.1.4 Infantile Nystagmus Syndrome
before any treatment. Note both horizontal INS
Model Poster
and SSN.
Each of the following poster panels is self-
explanatory.
CV3 Achiasmatic Belgian Sheepdog:
MP1_Abstract
Post-Tenotomy and Reattachment
MP2_INS Models
MP3_INS Model Behavior The INS of an achiasmatic Belgian sheepdog
MP4_INS Model Questions after a two-stage (horizontal and vertical) four-
MP5_INS Model Hypotheses muscle T&R treatment. Note the damping of the
MP6_INS Model Methods horizontal INS and elimination of the SSN.
MP7_INS Model Block Diagram
MP8_INS Model
CV4 RPE65-Deficient Canine: Pre-
MP9_INS Model AL Gain Modulation
Gene Transfer-Therapy Behavior
MP10_INS Model Internal Monitor
MP11_INS Model Methods 2 The inability of an RPE65-deficient Briard to
MP12_INS Model Alexander’s Law navigate around obstacles.
MP13_INS Model Predictions Sharp AL
MP14_INS Model Predictions Medium AL
CV5 RPE65-Deficient Canine: Post-
MP15_INS Model Predictions Broad AL
Gene Transfer-Therapy Behavior
MP16_INS Model Outputs Sharp Null
MP17_INS Model Outputs Sharp Nulls The remarkably improved ability of an RPE65-
MP18_INS Model Outputs Medium Nulls deficient Briard to navigate around obstacles
MP19_INS Model Outputs Broad Nulls after gene-therapy treatment.

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CV6 RPE65-Deficient Canine: illustrates periodic fast vertical eye movements

Pre-Gene Transfer-Therapy Eye on a background of saccadic oscillations. On the
Movements figure: up, up; down, down; OD, right eye; OS,
left eye; Sec, seconds.
Eye movements of an RPE65-deficient Briard prior
to treatment. Note the multiplanar nystagmus.
PV3 Acquired Downbeat Nystagmus
CV7 RPE65-Deficient Canine: Eye-movement video and recording showing
Post-Gene Transfer-Therapy Eye a patient with acquired downbeat nystagmus.
Movements The recording illustrates a continuous jerk down
oscillation with linear and occasional decreasing
Eye movements of an RPE65-deficient Briard velocity slow phases, worse in lateral and down
after gene-therapy treatment. Note the absence gaze. On the figure: up, up; down, down; OS, left
of clinically visible multiplanar nystagmus. eye; Sec, seconds.

CV8 Cat with Infantile Nystagmus PV4 Acquired Gaze-Evoked (Gaze-

A Siamese (albinotic) cat with INS. Holding Failure) Nystagmus
Eye-movement video and recording showing
a patient with gaze-holding failure nystagmus.
CV9 Goat with Seesaw Nystagmus
The recording illustrates horizontal, jerk oscil-
A dwarf goat with SSN. lations with linear slow phases, increasing in
intensity and changing direction from jerk right
in right gaze to jerk left in left gaze and jerk right
KeyNote and PowerPoint Files in right gaze. On the figure: up, right; down, left;
OD, right eye; OS, left eye; Sec, seconds.
E.3 PATIENT VIDEOS
PV5 Acquired Unidirectional Gaze-
Patient videos may be viewed individually tog-
Evoked (Gaze-Holding Failure)
ether with the accompanying eye-movement
Nystagmus
figure.
Eye-movement video and recording showing a
patient with gaze-holding failure nystagmus in
PV1 Saccadic Initiation Failure
left gaze and associated saccadic oscillations due
Eye-movement video and recording showing a to cerebellar disease. The recording illustrates
patient with saccadic initiation failure (ocular horizontal, jerk oscillations with linear slow
motor apraxia). The recording illustrates severe phases, increasing in intensity in left gaze with
hypometria during attempted horizontal gaze associated saccadic oscillations in primary pos-
with unequal involvement of right and left eyes. ition. On the figure: up, right; down, left; OD,
The left eye shows an almost total inability to gen- right eye; Sec, seconds.
erate a saccade. On the figure: up, right; down,
left; OD, right eye; OS, left eye; Sec, seconds.
PV6 Ocular Motor Neuromyotonia of
Cranial Nerve III
PV2 Brainstem Tumor: Tonic Gaze
Eye-movement video and recording showing
Deviation
a patient with ocular motor neuromyotonia
Eye-movement video and recording showing affecting the right medial rectus (inferior divi-
a patient with a brainstem tumor and involun- sion of CN III) by “spasm” of convergence and
tary tonic vertical gaze deviation. The recording esotropia after prolonged adduction of the right

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eye (medial rectus stimulation). The recording oscillations associated with cerebellar disease.
illustrates a slow saccadic response of abducting The recording illustrates horizontal, constant,
right eye after prolonged adduction. On the fig- conjugate, back-to-back saccades both with an
ure: up, up; down, down; OD, right eye; OS, left intersaccadic interval. On the figure: up, right;
eye; Sec, seconds. down, left; OD, right eye; OS, left eye; Sec, sec-
onds; the two top traces are position and the
bottom traces are velocity.
PV7 Ocular Motor Neuromyotonia of
Cranial Nerve VI
PV11 Acquired Saccadic Oscillations-3
Eye-movement video and recording showing a
patient with ocular motor neuromyotonia affect- Eye-movement video and recording showing a
ing the right lateral rectus (CN VI) by “spasm” patient with constant, conjugate, horizontal ocu-
of divergence and exotropia after prolonged lar oscillations typical of saccadic oscillations
abduction of the right eye (lateral rectus stim- associated with cerebellar disease. The recording
ulation). The recording illustrates a slow sac- illustrates horizontal, constant, conjugate, back-
cadic response of the adducting right eye after to-back saccades with an intersaccadic interval
prolonged abduction and an associated pendu- interrupting low-gain smooth pursuit. On the
lar nystagmus of the left eye. On the figure: up, figure: up, right; down, left; OD, right eye; OS,
up; down, down; OD, right eye; OS, left eye; Sec, left eye; Sec, seconds; the two top traces are pos-
seconds. ition and the bottom traces are velocity.

PV8 Infant with Opsoclonus (Ocular PV12 Acquired Nystagmus Plus

Flutter—“Saccadomania”) Saccadic Oscillations
Eye-movement video and recording showing Eye-movement video and recording from a
an infant with irregular, mulitplanar, conju- patient with a brainstem tumor showing a
gate, symmetric, saccadic oscillations typical of mulitplanar constant, conjugate, oscillation
opsoclonus. The recording illustrates the typical that is predominantly vertical. The record-
conjugate, saccadic, and multiplanar compo- ing illustrates both (separated by the horizon-
nents (broken into horizontal and vertical by tal and vertical recording channels) a vertical,
the recording technique) of the oscillation. On upbeat jerk oscillation with linear slow phases
the figure: up, right; down, left; OD, right eye; and a constant, horizontal saccadic oscillation
OS, left eye. with an intersaccadic interval. On the figure:
up, either right (horizontal trace) or up (verti-
cal trace); down, either left (horizontal trace)
PV9 Acquired Saccadic Oscillations-1
or down (vertical trace); OD, right eye; OS, left
Eye-movement video and recording showing a eye; Sec, seconds.
patient with constant, conjugate, horizontal ocu-
lar oscillations typical of saccadic oscillations.
PV13 Acquired Upbeat Nystagmus
The recording illustrates constant, conjugate,
with Wiernecke’s Encephalopathy
back-to-back saccades both with (square-wave
jerks) and without an intersaccadic interval. On Eye-movement video and recording from a
the figure: up, right; down, left . patient with malnutrition-induced Wiernecke’s
encephalopathy, upbeat nystagmus, conver-
gence spasm, and resolving CN VI palsy. The
PV10 Acquired Saccadic Oscillations-2
recording from the right eye illustrates typical
Eye-movement video and recording showing jerk-up nystagmus with linear and decreasing
a patient with constant, conjugate, horizontal velocity slow phases, worse in upgaze. On the
ocular oscillations typical of macro saccadic figure: up, up; down, down.

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PV14 Acquired Vertical Pendular recording illustrates pendular and unequal mixed
Nystagmus INS waveforms. On the figure: up, right; down,
left; OD, right eye; OS, left eye; Sec, seconds.
Eye-movement video and recording from a
patient with vertical, pendular nystagmus con-
sequent to a brainstem hemorrhage and cere- PV18 Achiasma Plus Seesaw
brovascular accident. The recording illustrates Nystagmus Plus Infantile Nystagmus
conjugate, in-phase, pendular nystagmus that Eye-movement video and recording from a
occasionally changes to upbeat with a pendular patient with achiasma showing the horizon-
slow phase. On the figure: up, up; down, down; tal (faster) and vertical (slower) oscillations of
Sec, seconds. INS and SSN, respectively. The recording from
the vertical channel illustrates the 180° out-of-
PV15 Fusion Maldevelopment phase, slower vertical oscillation superimposed
Nystagmus-1 on a symmetric, smaller amplitude, jerk, INS
waveform. On the figure: up (U), up; down (D),
Eye-movement video and recording from a down; OD, right eye; OS, left eye; Sec, seconds.
patient with amblyopia OD and a small-angle
strabismus. He has a change in both nystagmus
intensity and direction with monocular cover. PV19 Octogenarian with Infantile
The recording illustrates a conjugate, variable-in- Nystagmus
tensity, and changing direction (jerk in the direc- Eye-movement video and recording from an
tion of the viewing eye) oscillation with linear 86-year-old patient with albinism and INS.
(nystagmus) and decreasing velocity (saccadic The recording illustrates conjugate, jerk with
pulse trains) slow phases, typical of FMNS with extended foveation waveforms. Notice that after
a monocular preference. In this patient, the left the 2-sec mark the nystagmus improves due to a
eye is preferred. On the figure: up, right; down, null position in immediate left gaze. On the fig-
left; OD, right eye; OS, left eye; Sec, seconds. ure: up, right; down, left; OD, right eye; OS, left
eye; Sec, seconds.
PV16 Fusion Maldevelopment
Nystagmus-2 PV20 Infantile Nystagmus:
Eye-movement video and recording from a
Aperiodically Changing Intensity (Not
patient with amblyopia OS and a small-angle
Direction)
strabismus. She has a change in both nystagmus Eye-movement video and recording from a
intensity and direction with monocular cover. patient with strabismus and INS. The recording
The recording illustrates a conjugate, variable-in- illustrates conjugate, pseudopendular with fove-
tensity, and changing direction (jerk in the direc- ating saccades and jerk with extended foveation
tion of the viewing eye) oscillation with linear waveforms. The bottom trace shows how the nys-
(nystagmus) and decreasing velocity (saccadic tagmus spontaneously changes over time while
pulse trains) slow phases, typical of FMNS with the patient remains visually stimulated and in the
a monocular preference. In this patient the right same mental state (aperiodicity). On the figure:
eye is preferred. On the figure: up, right; down, up, right; down, left; OD, right eye; OS, left eye.
left; OD, right eye; OS, left eye; Sec, seconds.
PV21 Infantile Nystagmus:
PV17 Down Syndrome and Infantile Aperiodically Changing Direction (Not
Nystagmus Intensity)
Eye-movement video and recording showing a Eye-movement video and recording from a patient
patient with Down syndrome and nystagmus. The with INS. The recording illustrates conjugate, jerk

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with extended foveation waveforms. The trace foveation waveforms. The recording illustrates
shows how the nystagmus spontaneously changes pure, conjugate, jerk with extended foveation
direction over time while the patient remains vis- waveforms. The intensity of both eyes is equal
ually stimulated and in the same mental state during this 2-second data collection and the
(aperiodicity). There is no change in eye position binocular acuity of this patient is 20/25. On the
or spontaneous change in fi xation between the figure: up, right; down, left; OD, right eye; OS,
eyes that would diagnose INS with a “latent com- left eye.
ponent” rather than aperiodicity. On the figure:
up, right; down, left; OD, right eye; OS, left eye.
PV26 Infantile Plus Nucleus of the
Optic Tract Nystagmus: Dual Jerk
PV22 Infantile Nystagmus: Unequal-1
Eye-movement video and recording from a
Eye-movement video and recording from a patient patient with INS and dual-jerk waveforms.
with and A-pattern strabismus and INS. The The recording illustrates pure, conjugate,
recording illustrates in-phase, unequal, jerk with dual jerk with extended foveation waveforms.
extended foveation waveforms with the fi xing eye The intensity of both eyes is equal during this
(predominantly right eye in this segment of the 10-second data collection and the binocular
recording) and saccadic oscillations in nonfi xing acuity of this patient is 20/25. On the fig-
eye (predominantly the left eye in this segment ure: up, right; down, left; OD, right eye; OS,
of the recording). On the figure: up, right; down, left eye.
left; OD, right eye; OS, left eye; Sec, seconds.
PV27 Infantile Nystagmus: Pre- and
PV23 Infantile Nystagmus: Unequal-2 Postoperative
Eye-movement video and recording from a Eye-movement video and recording from a
patient with INS. The recording illustrates in- patient with INS before and after eye-muscle
phase, unequal, jerk with extended foveation surgery. The 11-second recording illustrates,
waveforms. The intensity of the visually pre- in-phase, INS with unequal pendular and
ferred left eye is obviously less that the right. On pseudocycloid waveforms. The improvement
the figure: up, right; down, left; OD, right eye; in intensity of the nystagmus illustrated in
OS, left eye; Sec, seconds. the bottom figures illustrates what happens
after surgery. On the figure: up, right; down,
left; OD, right eye; OS, left eye.
PV24 Infantile Nystagmus: Unequal-3
Eye-movement video and recording from a
PV28 Optic Nerve Dysplasia and
patient with INS. The recording illustrates in-
Infantile Nystagmus: Multiplanar
phase, unequal, jerk with extended foveation
waveforms and breaking saccades. The visually Eye-movement video and recording from a
preferred left eye is due to better foveation and patient with a large-angle exotropia, optic
not overall intensity as shown by analysis of fove- nerve dysplasia and INS. This 8-second
ation using the expanded nystagmus acuity func- recording from his preferred right eye illus-
tion (NAFX). On the figure: up, right; down, left; trates both the horizontal (red) and vertical
OD, right eye; OS, left eye; Sec, seconds. (yellow) components of a conjugate, jerk with
extended foveation INS. The fast phases are
artificially separated into right and down by
PV25 Infantile Nystagmus: Jerk with
the recording methodology, but the clinical
Extended Foveation
appearance is an “oblique” nystagmus. On the
Eye-movement video and recording from figure: up, right; down, left; OD, right eye;
a patient with INS and jerk with extended OS, left eye.

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PV29 Infantile Nystagmus: Jerk with “oblique” nystagmus. On the figure: up, right
Extended Foveation and up; down, left and down; OD, right eye; OS,
left eye.
Eye-movement video and recording from a
patient with X-linked (FRMD7) INS jerk wave-
forms. The recording illustrates pure, conjugate, PV33 Albinism, Upgaze Null, and
jerk with extended foveation waveforms. The Infantile Nystagmus: Equal
intensity of both eyes is equal during this 9-sec- Eye-movement video and recording from a
ond data collection and the binocular acuity of patient with INS, albinism, and chin-down
this patient is 20/50. On the figure: up, right; head posture. The recording illustrates conju-
down, left; OD, right eye; OS, left eye. gate, jerk with extended foveation waveforms.
The intensity of both eyes is equal during this
PV30 Infantile Nystagmus: Unequal 7-second, upgaze data collection (his best
with a “Latent Component” nystagmus characteristics). On the figure:
up, right; down, left; OD, right eye; OS, left
Eye-movement video and recording from a eye.
patient with INS, esotropia, high myopia, ambly-
opia, and a history of retinopathy of prematurity.
The recording illustrates in-phase, unequal, jerk PV34 Retinal Dystrophy and Infantile
right with the right eye viewing and jerk left with Nystagmus: Multiplanar
the left eye viewing both with extended fove- Eye-movement video and recording from a
ation waveforms. The intensity of the nystagmus patient with a stationary rod-cone dystrophy
and quality of foveation is better with the pre- and INS. Th is 24-second binocular record-
ferred right eye. On the figure: up, right; down, ing illustrates both the horizontal and vertical
left; OD, right eye; OS, left eye; Deg, degrees. components of a conjugate, jerk waveform INS.
The fast phases are artificially separated into
right and down by the recording methodology,
PV31 Albinism and Infantile
but the clinical appearance is a “vertical” nys-
Nystagmus
tagmus. On the figure: up, right and up; down,
Eye-movement video and recording from a left and down; OD, right eye; OS, left eye; Sec,
patient with INS and albinism. The recording seconds.
illustrates pure, conjugate, jerk with extended
foveation waveforms. The intensity of both eyes
is equal during this 12-second data collection
PV35 Albinism and Infantile
and the binocular acuity of this patient is 20/60.
Nystagmus: Pre- and Postoperative
On the figure: up, right; down, left; OD, right
Horizontal Null
eye; OS, left eye. Eye-movement video after, and recording
from a patient before and aft er eye-muscle sur-
gery with INS and albinism. The two record-
PV32 Optic Nerve Dysplasia and ings illustrate, conjugate, jerk, and jerk with
Infantile Nystagmus: Multiplanar extended foveation (plus one pseudopendu-
Eye-movement video and recording from a lar with a foveating saccade—right panel)
patient with strabismus, optic nerve dysplasia, INS waveforms. The improvement in this
and INS. Th is 6-second binocular recording patient’s nystagmus intensity illustrates a
illustrates both the horizontal and vertical com- marked improvement in foveation with a small
ponents of a conjugate, jerk, dual-jerk, and une- decrease in frequency, giving the clinical illu-
qual pendular INS. The fast phases are artificially sion that there was no effect of the operation.
separated into right and down by the recording On the fi gure: up, right; down, left; OD, right
methodology, but the clinical appearance is an eye; OS, left eye.

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PV36 Albinism and Infantile position (chin-down head posture), before and
Nystagmus: Multiplanar after eye-muscle surgery. The two videos show
the significant improvements in clinical head
Eye-movement video and recording from a patient position and nystagmus prior to (a) and after
with albinsim, strabismus, optic nerve dysplasia, (b) eye-muscle surgery. The 50-second record-
and INS. This 15-second binocular recording ing illustrates, in-phase, unequal, INS with jerk
illustrates both the horizontal and vertical com- waveforms. The improvement in intensity of the
ponents of a horizontally conjugate and vertically nystagmus illustrated in the bottom four figures
out-of-phase, unequal pendular INS. The wave- illustrates what happens after surgery. On the
forms are artificially separated into horizontal and figure: up, right; down, left; OD, right eye; OS,
vertical by the recording methodology, but the left eye; PRE-OP, preoperatively; POST-OP,
clinical appearance is an “elliptical” (sometimes postoperatively; Sec, seconds.
diagonal) nystagmus (note the subclinical see-
saw component). On the figure: up, right and up;
down, left and down; OD, right eye; OS, left eye. PV40 Albinism, Upgaze Null, and
Infantile Nystagmus
PV37 Infantile Nystagmus: Periodic Eye-movement video and recording from a
Alternating patient with INS, exotropia, albinism, and chin-
down head posture. The recording illustrates
Eye-movement video and recording from a conjugate jerk and pendular waveforms. The
patient with pure periodic INS. Eye-movement intensity of both eyes is equal during this 7-sec-
recording performed under binocular condi- ond, upgaze data collection (his best nystagmus
tions showing velocity data only from the pre- characteristics). On the figure: up, right; down,
ferred right eye over 800 seconds illustrating left; OD, right eye; OS, left eye.
a typical periodic rhythm. On the figure: up,
right; down, left; OU, both eyes open.
PV41 Albinism and Infantile
Nystagmus
PV38 Infantile Nystagmus:
Asymmetric Aperiodic Alternating Eye-movement video and recording from a
patient with INS and albinism. The recording
Eye-movement video and recording data of OS illustrates pure, conjugate, jerk with extended
from patient with X-linked (FRMD7) asymmetric foveation waveforms. The intensity of both eyes
aperiodic alternating INS performed under binoc- is equal during this 12-second data collection
ular conditions using data from the left eye illus- and the binocular acuity of this patient is 20/40.
trating asymmetry during an aperiodic, rhythmic On the figure: up, right; down, left; OD, right
cycle with changes in the waveforms evident when eye; OS, left eye.
the fast phase is to the left (pure jerk left waveform)
and to the right (jerk right with extended fove-
ation). It is easy to see how this patient has better PV42 “Vertical” Infantile Nystagmus-1
vision and visual function during the jerk-right Eye-movement video and recording from a rare
phase of the cycle. OS, left eye; up, right (R); down, patient with predominant vertical INS. The
left (L); upper trace, position; lower trace, velocity. recording illustrates pure, vertical, conjugate,
pendular waveforms. Complete neurological
and ophthalmological investigations were oth-
PV39 Albinism and Infantile erwise normal. The intensity of both eyes is
Nystagmus: Pre- and Postoperative equal during this 12-second data collection and
Vertical Null the binocular acuity of this patient is 20/50. On
Eye-movement video and recording from a the figure: up, up; down, down; OD, right eye;
patient with INS and an upgaze, eccentric null OS, left eye; Sec, seconds.

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PV43 Retinal Dystrophy and voluntary, familial oscillation. The recording

“Vertical” Infantile Nystagmus-2 illustrates dysconjugate (unequal and out of
phase), high-frequency (7–10 Hz) flutter wave-
Eye-movement video and recording from a rare forms. Complete neurological and ophthalmo-
patient with strabismus and a predominant ver- logical investigations were otherwise normal.
tical INS. The recording illustrates vertical, On the figure: up, right; down, left; OD, right
conjugate, jerk waveforms. The gross, vertic- eye; OS, left eye; Sec, seconds.
ally, dysconjugate movements of the two eyes
every 5 seconds is occurring during horizon-
tal refi xation showing a changing hypertropia. E.4 HISTORICAL
Complete neurological and ophthalmological
investigations showed a stationary rod-cone E.4.1 Demonstration of Bias and
dystrophy. The intensity of both eyes is equal Bias Shift in Infantile Nystagmus
during this 50-second data collection and the Waveforms
binocular acuity of this patient is 20/70. On the The fi rst defi nitive evidence (1972) supporting
figure: up, up; down, down; OD, right eye; OS, the hypothesis that those with INS oscillate
left eye; Sec, seconds. away from and back to the target came from a
fundus fi lm that was made while the subject was
PV44 Spasmus Nutans Nystagmus-1 fi xating the low-level laser aiming spot in a laser
photocoagulation apparatus. The fovea could be
Eye-movement video and recording from a seen oscillating to one side of the spot and then
2-year-old patient with barely visible nystagmus shift ing to the other. In the same year, the fi rst
that improved over the last 6 months according eye-movement data confi rmation was made that
to maternal history. The recording illustrates both eyes of a person with INS oscillate to one
dysconjugate (unequal and 180° out of phase), side of the target, coming to rest on the target
high-frequency (7–10 Hz) pendular waveforms. and thereby allowing good visual acuity. Figure
Complete neurological and ophthalmological E.4.1 shows the two eyes oscillating to the right
investigations were otherwise normal. On the of the target at 10° right gaze and then (at arrow)
figure: up, right; down, left; OD, right eye; OS, simultaneously shift ing to the left . Subsequent
left eye. eye-movement data confi rmed that the same
applied for all nontransient INS waveforms.
PV45 Spasmus Nutans Nystagmus-2
Eye-movement video and recording from an E.4.2 Demonstration That Cutaneous
8-month-old patient with a head oscillation and Stimulation Damps Infantile
dysconjugate, unequal nystagmus that had been Nystagmus
previously diagnosed as congenital nystagmus. It was fi rst demonstrated in 1994 that cutane-
The recording illustrates dysconjugate (unequal ous stimulation could damp INS via exterocep-
and 180° out of phase), high-frequency (7–10 Hz) tive signals from the ophthalmic division of
pendular waveforms. Complete neurological and the trigeminal nerve. In Video E.4.2, note the
ophthalmological investigations were otherwise damping of the INS during stimulation of the
normal. On the figure: up, right; down, left; OD, forehead and its reappearance after stimulation
right eye; OS, left eye; Sec, seconds. ceased.

PV46 Voluntary Ocular Flutter E.4.3 First Canine Eye-Movement

Recording
Eye-movement video and recording from a
10-year-old patient with an intermittent, high- Canine eye-movement recordings were fi rst
frequency, small-amplitude, dysconjugate, made in 1993 at the University of Tennessee,

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on an achiasmatic Belgian sheepdog, by L. F. T&R procedures were performed on all of his

Dell’Osso and J. B. Jacobs. Figure E.4.3a shows extraocular muscles.
a dog calmly suspended in a sling while hav-
ing his eye movements recorded by an infrared
E.4.4 First Tenotomy and
method. Figure E.4.3b shows several methods
Reattachment Surgery for Infantile
(infrared, top two; and digital video, bottom)
Nystagmus
of recording canine eye movements. Figure
E.4.3c shows a dog calmly suspended in a sling Performed in 1997 on an achiasmatic Belgian
while having his eye movements recorded by a sheepdog, by R. W. Hertle and assisted by L. F.
digital video method. Figure E.4.3d shows an Dell’Osso—believed to be the fi rst time a per-
achiasmatic Belgian sheepdog with INS and the son with INS assisted in a surgery for INS (see
dramatic difference in the dog’s demeanor after Figs. E.4.4a and E.4.4b).

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appendix f

online access

F.1 OMLAB REPORTS 309 F.2.3 Tenotomy and Reattachment 310

F.1.1 #011105 Recording and Calibrating F.2.4 INS and Acuity 310
the Eye Movements of Nystagmus F.2.5 INS Miscellaneous 310
Subjects 310 F.3 PHYSICIAN/RESEARCH SCIENTIST
F.1.2 #111005 Using the NAFX for Eye- WORKSHEETS 310
Movement Fixation Data Analysis and F.3.1 Recession and Resection Surgical
Display 310 Calculation 310
F.1.3 #111905 Nystagmus Therapies: Types, F.3.2 Estimating Improvement in Peak
Sites, and Measures 310 NAFX 311
F.1.4 #090506 Original Ocular Motor F.3.3 Estimating Improvement in LFD
Analysis of the First Human with 311
Achiasma: Documentation of Work Done F.3.4 NAFX versus Visual Acuity (Motor
in 1994 310 and Sensory Components) 311
F.1.5 #123007 The Benefits of Extraocular F.4 CLINICAL EXAMINATION
Muscle Surgery in INS 310 FORMS 311
F.1.6 #030509 How Someone “Sees” the F.4.1 General Clinical Examination
World and How to Clinically Assess Form 311
Therapeutic Improvements in Visual F.4.2 Strabismus Examination Form 311
Function 310 F.4.3 Nystagmus Examination Form 311
F.2 PATIENT HANDOUTS 310 F.5 ANALYSIS SOFTWARE 311
F.2.1 INS Information 310 F.5.1 OMtools 311
F.2.2 INS Treatments 310 F.5.2 OMS Model GUI User Guide 311

THE R EPORT, figure, and video fi les in this F.1 OMLAB REPORTS
appendix may be copied, viewed, or printed.
Both PDF and HTML forms of the OMlAB
Many of the Omlab Reports, Patient Handouts,
reports described below may be found in the F.1
Physician Worksheets, and Soft ware were origi-
OMLAB REPORTS folder.
nally made available at htt p://www.omlab.org.

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F.1.1 #011105 Recording and F.2.1 INS Information

Calibrating the Eye Movements of
Handout F.2.1 answers common general ques-
Nystagmus Subjects
tions that INS patients or their parents may
OMLAB Report #011105 describes the methods have.
used to obtain accurately calibrated eye-move-
ment data in subjects with ocular oscillations.
F.2.2 INS Treatments
Handout F.2.2 answers more specific questions
F.1.2 #111005 Using the NAFX for Eye-
(including those about surgery and strabismus)
Movement Fixation Data Analysis and
that INS patients or their parents may have.
Display
OMLAB Report #111005 describes the proper
F.2.3 Tenotomy and Reattachment
use of the NAFX soft ware to assess the foveation
quality of nystagmus waveforms. Handout F.2.3 provides illustrations of the
world seen through the eyes of someone with
INS and helps both INS patients and their
F.1.4 #090506 Original Ocular Motor
parents to better appreciate the types of visual
Analysis of the First Human with
function limitations produced by INS; a similar
Achiasma: Documentation of Work
post-T&R illustration demonstrates the type of
Done in 1994
improvement possible. In addition, several com-
OMLAB Report #090506 presents the fi rst ocu- mon questions regarding the T&R procedure
lar motor analysis of a human with achiasma. are answered.

F.1.5 #123007 The Benefits of F.2.4 INS and Acuity

Extraocular Muscle Surgery in INS
Handout F.2.4 answers common questions that
OMLAB Report #123007 describes the often- about INS waveforms and their relation to visual
unappreciated beneficial effects of extraocular acuity that patients or their parents may have.
muscle surgery in patients with INS.
F.2.5 INS Miscellaneous
F.1.6 #030509 How Someone “Sees”
Handout F.2.5 answers additional questions
the World and How to Clinically
that INS patients or their parents may have.
Assess Therapeutic Improvements in
Visual Function
F.3 PHYSICIAN/RESEARCH
OMLAB Report #030509 presents a visual pic-
SCIENTIST WORKSHEETS
ture of how the world appears to a person with
INS and the methods to assess therapeutic Both PDF and HTML forms of the patient
improvements. handouts described below may be found in the
F.3 PHYSICIAN RESEARCH SCIENTIST
HANDOUTS folder.
F.2 PATIENT HANDOUTS
Both PDF and HTML forms of the patient
F.3.1 Recession and Resection
handouts described below may be found in the
Surgical Calculation
F.2 PATIENT HANDOUTS folder. They are
written in lay terms so that they may be easily Figure F.3.1 is a plot of the required null shift
understood by patients. versus the total surgical rotation required; that

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is, the sum of the amounts of recession and resec- F.4.1 General Clinical Examination
tion required in each eye. Form
Forms F.4.1.1–F.4.1.4 are general ophthalmo-
F.3.2 Estimating Improvement in Peak logical examination forms.
NAFX
Figure F.3.2 is a plot of the pre-T&R NAFX ver- F.4.2 Strabismus Examination Form
sus the estimated post-T&R percent increase in
Form F.4.2 is a strabismus examination form.
peak NAFX.

F.4.3 Nystagmus Examination Form

F.3.3 Estimating Improvement in LFD
Form F.4.3 is a nystagmus examination form.
Figure F.3.4 is a plot of the pre-T&R LFD ver-
sus the estimated post-T&R percent increase
in LFD. F.5 ANALYSIS SOFTWARE
Both PDF and HTML forms of the patient
F.3.4 NAFX versus Visual Acuity handouts described below may be found in the
(Motor and Sensory Components) F.5 ANALYSIS SOFTWARE folder.

Figure F.3.4 contains plots of the pre-T&R LFD

versus visual acuity for several age groups. By F.5.1 OMtools
choosing the proper line based on the patient’s The OMtools folder and its subfolders and fi les
age, one can use this plot to make a pre-T&R should be placed in the MATLAB folder along
estimate of the post-T&R improvement in visual with the proper paths. These fi les contain the
acuity for both INS patients with and without soft ware we developed during 20 years of ocular
associated visual sensory deficits. motor research and evaluation of INS.

F.4 CLINICAL EXAMINATION F.5.2 OMS Model GUI User Guide

FORMS The PDF in the F.5.2 OMS USER GUIDE 1.5
Both PDF and HTML forms of the patient folder explains the use of this GUI with current
handouts described below may be found in the versions of the behavioral ocular motor system
F.4 CLINICAL EXAMINATION FORMS model and outlines how additional GUI func-
folder. tions may be included in the model and the GUI.

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index

abducens nerve, 7, 11 FMN intensity and, 145

acetazolamide, 80, 207, 213, 239, 241 FMNS and, 118
achiasma, 57, 58, 60, 62, 65, 67, 71, 86, 163, 216 INS and, 136
achromatopsia, 25, 68, 130, 138, 145, 149 NBS and, 129
acquired nystagmus, 28, 43, 55, 68, 79, 148, 150, 206, 207, 209, threshold, 286
210, 217, 231, 237, 288–290, 295, 298, 301 alternate cover test, 111, 117–118, 141, 298
oscillopsia suppression and, 55 APAN and, 278
acquired pendular nystagmus (APN), 87, 158–159, 207, 208, 214, benign vs. neurologically threatening nystagmus and,
294, 298 278–279
acupuncture, 57, 78, 207, 215, 234 FMNS and, 147
afferent stimulation, 56–57, 78–79, 234 INS and, 142, 144, 145
afferent system, 12–15, 140 nystagmus reversal and, 278
afferent system function testing, 185 amblyopia, 50, 73, 114, 118, 129, 148, 185, 189, 206, 228, 231,
in diagnosis, 254 303, 305
objective, 194–202 FMNS and, 115
subjective, 185–194 motion, 254
afferent visual pathway dysfunction, 138 amblyopia treatment study (ATS), 187, 228, 230
afterimages, 51, 56, 260–262 American Nystagmus Network, 237
AHP. See anomalous head posture ametropia, 118, 148, 185, 207, 211, 254
albinism, 24, 25, 42–44, 51, 62, 63, 65–67, 71, 77, 138, 141, 145, correction, 212–213
198, 201, 202, 206, 212, 213, 218, 231, 257, 303, 305, 306 analysis graphs, 293
APAN and, 43 Anderson+Goto procedure, 84–85
living with, 257–258 Anderson-Kestenbaum procedure, 49, 84–85, 216, 217, 279
oculocutaneous, 43, 44, 201, 202 Anderson procedure, 75, 85–87, 218, 238–239
PAN and, 155 anesthesia, 156, 199, 202, 233
visual acuity and, 53 angle kappa, 141, 145, 279
alcohol, 130, 137, 155, 207, 214, 235, 263 aniridia, 25, 68, 138, 213
Alexander’s law, 28, 40, 47, 68–70, 112, 114, 123, 124, 127, 141, anisometropia, 206, 212–213, 231
145, 151, 155, 297, 298, 300 annulus of Zinn, 2

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anomalous head posture (AHP), 43, 44, 47, 85, 112, 119, 129, 139, gliomas, 131, 279
192, 206, 209, 212, 216, 219, 220, 222, 224, 231, 278, 284 horizontal saccades and, 11
absence of, 279 sagitt al section of, 151
measuring, 229–230 vertical saccades and, 12
post surgery, 232 Briards, 60, 217, 237, 298, 300, 301
strabismus and, 139 brinzolamide, 80, 239, 240
surgery, 279 burst neurons, 9, 10, 165, 172
anterior segment ischemia (ASI), 233
AP. See waveforms café au lait spots, 130, 149
APAN. See asymmetric, (a)periodic alternating nystagmus CAI. See carbonic anhydrase inhibitor
APN. See acquired pendular nystagmus canine nystagmus, 57–60, 71–73, 81–83, 163, 216, 217, 219, 234,
Arnold-Chiari malformation, 26, 162 235, 245, 267, 298, 300, 301
ASI. See anterior segment ischemia cannabis, 207, 214
association cortex, 14 carbamazepine, 213, 214
asymmetric, (a)periodic alternating nystagmus (APAN), 40, carbonic anhydrase inhibitor (CAI), 80
42–44, 47, 58, 62, 86, 142, 143, 155, 156, 206, 229 central myelin diseases, 158–160, 214
albinism and, 43 cerebellum, 11–12, 15, 17, 27, 63, 90, 142, 155, 157, 160, 161, 163,
alternate cover test and, 278 165, 173, 213
as compared to PAN, 143 PAN and, 155, 156
congenital, 154, 155 sagitt al section of, 151
direction of, 42 Chiari malformation, 26, 155, 162, 172
rhythmic component of, 50 chiasmal disorders, 65
visual acuity changes and, 278 chromosome 6p12, 62
waveforms, 44 clinical examinations, 70, 193, 197, 255, 272, 311
asymmetric pendular (AP). See waveforms diagnosis from, 288–290
ATS. See amblyopia treatment study flow chart, 290
attention, SWJ and, 166 therapeutically exploitable characteristics of, 290
augmented suture procedure, 284 clonazepam, 207, 213, 214
CNS glioma, 149
baclofen, 156, 206, 213–214 color-vision testing, 190–191, 191
Bardet Biedl syndrome, 130, 149 computed tomography (CT), 4, 154, 155
BDJ. See waveforms cones, 12, 13
Belgian sheepdogs, 57–60, 62, 65, 163, 216, 217 congenital channelopathy, 62
betahistine, 213 congenital stationary night blindness, 68, 80, 130, 138, 149, 198
bias reversals, 47 conjugate signals, 16
bidirectional jerk (BDJ); See waveforms conjunctival scarring, 233
bilateral abducens paralysis, 147 contact lenses, 54, 57, 78–80, 87, 208, 210–211, 215, 234, 241,
bilateral horizontal rectus recession and resection with chin- 255, 260, 262, 263
down posture (operation 2), 285 convergence and, 79, 80, 240, 241
bilateral horizontal rectus recession and resection with chin-up direct outcome measures of, 239
posture (operation 5), 285 INS and, 278
bilateral horizontal rectus recession and resection with INS with convergence and gaze angle nulls and, 283, 283
multiplanar head posture (operation 7), 286 INS with convergence null only and, 282
bilateral horizontal rectus recession and resection with INS with gaze-angle null only and, 281
strabismus alone (operation 3), 284 outcome estimates, 244
bilateral horizontal rectus recession and resection with outcomes, 240
strabismus and head posture (operation 4), 285 post-operative, 281
bilateral horizontal rectus recession and resection with torsional tinted, 211–212
head posture (operation 9), 286 contrast-sensitivity testing (CST), 191–192, 192
bilateral horizontal rectus recession + T&R (operation 1A,B), 84, control-systems approach, 26
85, 281, 282 convergence, 15, 16, 27, 53, 79, 122, 124, 154, 164, 173, 175,
bilateral horizontal rectus T&R (operation 6), 86, 284 301, 302
bilateral medial rectus recession procedure (operation 8), 86, contact lenses and, 79, 80, 240, 241
238, 283 damping of, 33, 48–49, 81, 87, 123, 124, 126, 136, 147, 148,
NBS and, 287 159, 161, 162, 192, 206, 209–212, 222–223, 230, 231,
bimedial recession, 86, 238, 243–244 238–241, 243, 278, 282, 283, 287, 298
INS with convergence and gaze angle nulls and, 283 effects on waveforms of, 33, 36
INS with convergence null only and, 282 NAFX and, 44, 70, 71, 80, 282, 283
NBS and, 287 null, with gaze angle null, 53, 54, 58, 78, 141, 280, 282–283
binocularity nulls, 27, 48–50, 78, 86, 126, 141, 254, 281–282
FMNS and, 117, 145, 147 convergence-evoked nystagmus, 137, 160–161
stereo testing and, 187–190 convergence nystagmus, 131, 137, 160–161
biofeedback, 57, 78, 81, 234 convergence-retraction “nystagmus,” 160, 163, 171–172
blindness, 158–159, 236 cranial nerve II. See optic nerve
botulinum, 208, 214–215 cranial nerve III. See oculomotor nerve
brain stem cranial nerve IV. See trochlear nerve
control of eye movements, 8, 10 cranial nerve V. See trigeminal nerve

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cranial nerve VI. See abducens nerve electronystamography (ENG), 261

CST. See contrast-sensitivity testing electrooculography (EOG), 24, 261, 263–264
CT. See computed tomography electroretinography (ERG), 67, 197–200, 198, 199, 200, 253
cutaneous stimulation, 57, 234, 307 EMG. See electromyography
cycloplegic refraction, 212, 228 ENG. See electronystamography
engineering, 22–23
damping, 32, 57, 87, 113, 236 England Nystagmus Network, 237
control feedback loop, 28, 108 enthesis, 217
of convergence, 33, 36, 48–50, 77, 81, 86, 126, 136, 206, 212, EOG. See electrooculography
222, 223, 230, 231, 278, 283, 286, 298 EOM surgery. See extraocular muscle surgery
FMNS, 114, 119, 123, 221, 222, 231 episcleral space, 6
INS, 47, 53, 58, 60, 66, 78, 79, 81, 122–124, 126, 129, 211, 216, episodic ataxia type 2, 62
234, 300, 307 EPN. See physiological end-point nystagmus
prisms and, 53, 78, 209, 211 ERG. See electroretinography
smooth-pursuit, 37, 39, 63, 68–70, 115, 277–278 esotropia, 40, 41, 107
darkness, 26, 158, 161, 165, 166, 167, 169, 261 INS with latent component and, 126, 127
FMN and, 106, 107, 108, 114, 116 NBS and, 147
INS and, 25, 26 purposive, 123–124, 126, 127, 129, 147, 148, 206, 287
SNS and, 130 SNS and, 130
DBN. See downbeat nystagmus willed, 122–123, 148
decreased vision, 206, 231 EUA. See exam under anesthesia
deep muscle stimulation, 57 examination forms, general clinical, 272–277
diagnostic tests, 66 exam under anesthesia (EUA), 199, 199
diplopia, 162, 174, 214, 233, 282 excitatory burst neurons (EBNs), 10
FMNS and, 104 excyclotorsion, 4
oscillating, 147 exotropia, 40, 41, 107
disparate differentiation, 1–2 eXpanded Nystagmus Acuity Function (NAFX), 28, 36, 41,
dissociated ocular oscillations, 172 53–54, 69, 79, 83, 85, 89, 114, 143, 225, 226, 254–255, 281,
dissociated vertical deviation/divergence (DVD), 103, 113–114, 289, 304
116 alternatives to, 54
divergence mechanisms, 15–16, 49, 160, 301 contact lenses and, 79–80, 87, 211
DJ. See waveforms convergence and, 71, 79, 80
DLPN. See dorsolateral pontine nuclei direct outcome measures, 237–239
dorsal stream, 14 FMN and, 114
dorsal vermis, 12 foveation and, 53
dorsolateral pontine nuclei (DLPN), 15 gaze angle and, 71
double Purkinje image (DPI) eye trackers, 261, 262 gaze angle curve vs., 47, 48, 240
downbeat nystagmus (DBN), 62, 87, 154, 155, 160, 161–162, 172, implications of, 224
174, 206, 208, 213, 301 LFD and, 70–73
Down’s syndrome, 116, 303 NBS and, 126–127
DP. See waveforms outputs, 71
DPfs. See waveforms preoperative, 228–229
DPI eye trackers. See double Purkinje image eye trackers before therapy estimation, 240–244
drugs, 80, 158, 213–214, 235, 239 after surgery, 88, 232
topical, 57, 78, 80, 207, 214, 235, 239, 240, 254 after therapies, 80, 291
dual jerk (DJ). See waveforms therapies and, 54
dual pendular (DP). See waveforms therapy goals and, 77–78
dual pendular with foveating saccades (DPfs). See waveforms T&R procedure and, 71–73, 87
Duane syndrome, Type I, 123–124 visual acuity and, 53, 73
DVD. See dissociated vertical deviation visual acuity line vs., 71, 241–242, 243, 292
dynamic overshoots, 30, 104, 105, 109, 164, 166 extraocular muscle pulleys, 4–5, 5
dysmetria, 12, 164–165, 169, 172, 173. See also flutter dysmetria extraocular muscles, 1–4
anatomy, 6
EBNs. See excitatory burst neurons functions of, 4
educational assistance, 236–237 insertional anatomy of, 3
E-ETDRS. See Electronic-Early Treatment of Diabetic proprioceptive feedback from, 7–8, 15, 42, 49, 58, 87,
Retinopathy Study 217–218
efference copy, 7–8, 23, 37–39, 56, 58, 157, 167, 168, 259 sensory innervation of, 7–8
FMNS and, 114–115, 127 extraocular muscle (EOM) surgery, 54, 58, 75, 84, 214, 223, 229,
modeling and, 56, 60, 168 232, 237, 254, 279, 310. See also surgery
NBS and, 127 amount of, 291
oscillopsia suppression and, 56, 114, 127 visual acuity following, 77
efferent system, 15–17, 140, 254 eyeball rotations
egocentric direction confusion, 115, 116–118 peripheral vestibular nystagmus and, 150–151
electromyography (EMG), 47–48 waveforms with, 31
Electronic-Early Treatment of Diabetic Retinopathy Study Eyeballs 3D program, 255–256, 296
(E-ETDRS), 188 eyelid position, 26, 233

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eye-movement recordings, 26, 51, 255 NBS and, 287

calibration techniques, 40, 67, 229, 255, 259, 264, 265, 266, results, 84
267, 268–269 strabismus and, 286
canine, 72, 82, 83, 235, 267, 268, 294, 295, 296, 298, 300, 301, fovea, 1, 13, 14, 31, 44, 46, 51, 52, 68, 73, 162, 202, 215, 224, 233,
307, 308 235, 300
clinical criteria, 268 foveal hypoplasia, 68
contact, 261 foveation. See also longest foveation domain
diagnosis from, 289 accuracy, 35–36, 34, 111–112, 123
differential diagnosis of INS and, 142–145 dynamics, 55
electrical, 260–261, 261 extended, 31, 139
with gaze angles, 152 during fi xation, 52–53
head-mounted, 267 FMN and, 114
history of, 259–261 FMNS and, 114–115
infrared, 262, 264–265 instability, 55
mechanical, 260, 260, 260 NAFX and, 53
methods, 263–268 NBS and, 126–128
noncontact, 261 pursuit during, 46
photographic, 260–261 target, 108, 123
post-surgery, 232 T&R procedure and, 90
preoperative evaluation of, 228–229 visual acuity and, 52–54
research criteria, 268 window, 36, 37, 53–55, 70, 71, 87, 88, 108, 109, 114,
surgery principles and, 215 296, 297
therapeutically exploitable characteristics of, 289 foveation periods, 25, 27, 28, 30, 31, 33, 35–37, 39, 45, 51–56, 58,
velocity trace from, 154 59, 71, 73, 79, 88, 108, 111, 112, 114, 126, 148, 211, 215, 228,
eye movements 234, 254–255, 296, 297
brain stem control of, 10, 8 INS waveforms and, 139
classes of, 16 ocular stabilization system and, 51
curve, 84 VOR and, 46
orbital structures controlling, 2 FPL. See forced-preferential looking
torsional, 35 FRMD7 mutation, 62–63
visual observation of, 260 frontal eye field (FEF), 8–9, 16
eye muscle surgery. See surgery functional plasticity, 253–254
eye position, 7–8, 233 fundus photography, 202, 201, 202
fusion maldevelopment nystagmus (FMN), 22, 61, 71, 103, 104,
Faden procedure, 129, 284 115, 118, 119, 123, 124, 126, 127, 129, 141–143, 147, 148,
fastigial nuclei, 12 217, 278, 279, 303
FD. See flutter dysmetria amplitude, gaze angle and, 113, 141, 303
FEF. See frontal eye field comparative characteristics of, 144
fi xation conjugate, 106, 303
adducting, 114 darkness and, 106, 107, 108, 116
alternating, 87, 89, 111, 148, 286 dual-mode fast phases of, 108
attempt, 25–26, 27, 32, 39, 40, 60, 104 with dynamic overshoots, 104, 105, 109
FMNS and, 104, 105–108, 105 fast phase of, 104, 105, 109
during foveation, 52–53, 111 foveation and, 114
foveation window and, 36 intensity of, 145, 303
inhibition, 27 latent, 117, 144, 145, 146
INS and, 30, 31–32 manifest, 109, 110, 141–145, 145–146
INS modulation and, 39 monocular occlusion and, 106, 110, 111, 303
mechanisms, 38, 65, 158 NAFX and, 114
preference, 118, 129 pure, 144, 145, 146
reflexes, 52 slow phase of, 104–105, 109, 144
surgery, 129 visual acuity and, 114
SWJ and, 165–167 fusion maldevelopment nystagmus syndrome (FMNS), 22, 27,
T&R procedure and, 58 48, 55, 61, 62, 66, 103–104, 118, 122, 123, 124, 126, 131,
uniocular, 286 138, 139, 145–147, 148, 149, 150, 152, 171, 185, 187, 206,
flocculus, 12 215, 269, 286, 288
flutter dysmetria (FD), 173 Alexander’s law and, 47, 118, 123, 128
FMN. See fusion maldevelopment nystagmus Alexander’s law threshold and, 286
FMNS. See fusion maldevelopment nystagmus syndrome alternate cover test and, 147, 278
forced-preferential looking (FPL), 185–186 alternating fi xation and, 148, 286
four-muscle resection and recession procedure (operation 1), amblyopia and, 115
84–85, 281–282 binocularity and, 117, 147
amounts of, 85 characteristics of, 104–112
INS with convergence and gaze angle nulls and, 283 diagnosis of, 146, 288, 289, 290
INS with gaze-angle null only and, 281 differential diagnosis of, 146, 288, 289, 290
INS with no nulls and, 283 differentiated from INS, 142, 143
INS with strabismus and, 284 diplopia and, 104

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efference copy and, 114–115 gaze palsies, vii, 1

egocentric direction confusion and, 116–118 Gegenrucke. See square-wave jerks
etiology of, 115–118 GEN. See gaze-evoke nystagmus
fi xation and, 105–108, 105 genetics, 25, 26, 60, 61–64, 68, 130, 140, 155, 230, 257. See also
fi xation preference and, 118 heredity
foveation accuracy with, 111–112 FMNS and, 115–116
foveation and, 55, 56, 114–115 loci of INS, 63
gaze-angle cover test, 147 sensory defects and, 66
gaze angles and, 112, 152 SNS and, 130
genetics and, 115 gene-transfer therapy, 80–81, 234–235
head position and, 112–114 AAB2-mediated, 60
inattention and, 104 RPE65 deficiency and, 82, 83
infantile strabismus and, 67 geniculostriate, 14
INS plus, 40, 117, 146–147 gliomas
INS with latent component vs., 40, 142, 144, 278 brain stem, 279
mechanisms, 104–112 CNS, 149
misdiagnosis of, 40, 149 SNS-like, 130, 131, 132, 149, 279
modeling, 104–112, 297–298 global stereopsis, 67
monocular calibration and, 269 globes, excursions of, 4
not a null gaze angle and, 47, 141, 209 Goldmann test, 194
NOT plus, 28, 32–33, 39, 104–112, 106 Golgi tendon organs, 217
oscillopsia and, 55, 57, 114–115 Goto procedure, 84–85, 218
strabismus and, 67, 104, 115, 145
symptoms, 145–146 head nodding, SNS and, 130–131, 132, 149, 278
theories, 115 head position, 86, 129, 151, 215, 216, 223, 262
therapies, 118–119, 208, 231, 232, 284, 286 FMNS and, 123
types, 104–112 INS and, 111, 138, 142, 187, 229, 232, 306
uniocular fi xation and, 286 NBS and, 124
waveforms, 104–112 null zone and, 138
PAN and, 156
GABA. See gamma-amino-butyric acid head posture, 51–52. See also anomalous head posture
gabapentin, 80, 214 infantile strabismus and, 67
gamma-amino-butyric acid (GABA), 156 measures of, 75
Ganzfeld, 199 multiplanar, 286
gaze-angle cover test multiple, 278
FMNS and, 147 post surgery, 232
INS and, 2, 144, 145 preoperative evaluation of, 229–230
gaze angles, 27, 27, 156–157, 206, 209, 216, 228, 235 torsional, 286
curves, NAFX vs., 47, 48, 78, 79, 240, 241 VOR and, 51–52
eye-movement recordings with, 152 hemichiasma, 58, 67, 216
FMN amplitude and, 113 heredity, 46, 49, 60, 61–63, 66, 137, 155, 162.
FMNS and, 40, 112, 113, 116, 118, 128, 141, 142, 145, 150, See also genetics
269, 286, 297 Hermansky-Pudlak syndrome (HPS), 43
infantile strabismus and, 67 high-gain instability, 26
INS and, 32–33, 33, 36, 39, 40, 45, 46, 55, 90, 141, 150, 216 high spatial frequency vision, 187
kappa, 141, 145, 279 high-speed digital video systems, 35
NAFX and, 53, 70, 69, 71, 75, 88, 142, 143, 193, 232, 240, 243, horizontal grating stimulus, 67
283 HOTV test, 189
NFF and, 53 HPS. See Hermansky-Pudlak syndrome
null, 42, 43, 47, 52, 79, 86, 141–143, 279, 280, 281, 284 hydrocephalus, 149
null, with convergence null, 40, 48–49, 48, 50, 78, 86, 238, hyperacuity, 187, 231
282–283 hypermetria, 169, 172
reading and, 278 hyperopia, 206, 212, 213, 231
restricted, 70 hyperphoria, 103
shift s, 225, 229 hypertropia, 162, 307
testing, 192–193
T&R procedure and, 90, 224, 238 IEP. See individualized education plan
visual acuity at different, 40, 47, 67, 70, 73, 77, 78, 84, 147, 187, image-stabilization systems, 207–209, 209
192, 193, 211, 224, 225, 229, 230, 237, 239, 239, 240, 241, image-stabilizing reflexes, 12
244–245, 254, 278, 283, 290 IN. See infantile nystagmus
waveforms and, 47, 34, 61, 63, 69, 69, 113, 143, 152, 152, 211 INC. See interstitial nucleus of Cajal
gaze-dependent acuity, 184, 224, 231 incyclotorsion, 4
testing, 192–193 individualized education plan (IEP), 236–237
gaze-evoke nystagmus (GEN), 156–157 infantile nystagmus (IN), 22, 25, 27, 43–44, 49–50, 123, 127,
gaze holding, 51 136, 143, 144, 147, 190, 223, 254, 301, 303–308
gaze-holding deficiency nystagmus, 156–157 comparative characteristics of, 144
gaze instability, 157–158 reversal, 142

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infantile nystagmus syndrome (INS), 22, 22–23, 136–145 static deficits, 70–73
Alexander’s law and, 136 static neutral zone and, 39–40
alternate cover test and, 142, 144, 145 strabismus and, 140–141, 284–286
ancient descriptions and theories of, 24–25 symptoms, 141–142
characteristics of, 23–60 target acquisition time and, 36, 299
clinical, 75–77 therapies, 33, 36, 40, 47, 54, 57, 58, 60, 63, 67, 70, 75–87, 90,
clinical features of, 136–142 193, 207–245, 253–256, 278, 279, 281–286, 288–293,
contact lenses and, 278, 281–283 298–300, 310
with convergence and gaze angle nulls, 33, 54, 58, 78, 141, 280, therapy goals, 77–78, 81, 215
282–283 treatment, 30, 44, 50, 60, 63, 67, 71, 73, 77–90, 206–245,
with convergence null, 27, 48–50, 78, 86, 128, 141, 254, 253–256, 281–286, 288–293, 298–301, 309, 310
281–282 variable strabismus and, 126, 128, 147, 229
damping, 47, 53, 58, 60, 66, 78, 79, 81, 122–124, 126, 128, 211, visual sensory deficits and, 25, 65, 138
216, 234, 300, 307 VOR and, 35, 36, 45, 46, 49, 50, 51–52, 61, 131
development of, 65, 140 waveforms, 25, 26–39, 61, 139. See also waveforms
diagnostic criteria of, 23, 68, 215 infantile visual deprivation, 68
differential diagnosis of, 142–144 infants, monocular calibration and, 269
direct causes of, 37, 51, 61–64, 65, 68–70, 115 infection, post-operative, 233
directional components of, 59 infrared (IR) systems, 35, 264–265, 262, 263
dynamic deficits, 73–75 INS. See infantile nystagmus syndrome
dynamic neutral zone and, 40–46 International Society for Clinical Electrophysiology of Vision
ERG and, 197–198 (ISCEV), 194
etiology of, 60–70 internuclear ophthalmoplegia, 170, 172, 207
familial, 61–64 interocular phase, variable, 131
fi xation and, 30, 31–32, 39 interstitial nucleus of Cajal (INC), 10
fi xation attempt and, 25–26, 27, 32, 39, 40, 60, 104 interventional treatment trials, for INS, 219
FMNS differentiated from, 142–144 intraocular lenses, 213
FMNS plus, 40, 117, 146–147 IR systems. See infrared systems
foveation accuracy and, 34, 35–36, 111–112, 123 isoniazid, 214
foveation period and, 25, 27, 28, 30, 31, 33, 35–37, 39, 45,
51–56, 58, 59, 71, 73, 79, 88, 108, 111, 112, 114, 126, 148, jerk (J). See waveforms
211, 215, 228, 234, 254–255, 296, 297 jerk with extended foveation (Jef). See waveforms
gaze-angle cover test and, 142–144, 145 Joubert syndrome, 167, 168, 169, 170
with gaze-angle null only, 47, 42, 43, 52, 79, 86, 141, 142, 279, Jef. See waveforms
280, 281, 284
genetic loci of, 63 Kestenbaum null, 47–48
head position and, 138, 141–142 Kestenbaum procedure, 58, 84–85, 218, 224, 238–239, 239
head posturing and, 51–52 Kymograph, 260
history of, 24–26
inattention and, 27, 32, 33 lab tests, 230
interventional treatment trials for, 219 Lang Test, 57
with latent component, 27, 39, 40, 41, 49, 50, 62, 104, 117, 118, laser systems, 213
126, 127, 141–144, 187, 278, 304, 305 latent/manifest latent nystagmus (LMLN), 22, 103, 114, 115,
measurements of, 70–77 145
mechanisms, 25–39, 63, 64, 67, 68, 254–255 latent nystagmus (LN), 103, 104, 145, 148
misdiagnosis of, 22, 40, 123, 146 lateral geniculate nucleus (LGN), 14
modeling, 23, 26–39, 46, 51, 56–58, 60, 61, 62, 67, 68, 70, lateral occipital complex, 14
73–75, 81, 140, 216, 217, 235, 255, 256, 294–300 lateral rectus muscles, 4
modulation, 27, 39, 107–108, 218 LCA. See Leber congenital amaurosis
monocular calibration and, 40, 67, 259, 268–269 Lea Symbols, 228
“motor,” 65 Leber congenital amaurosis (LCA), 60, 80–81, 234–235
with no nulls, 283–284 Leicerstershire nystagmus survey, 136
null zones and, 46–48, 49–50, 141 Leigh disease, 130, 149
onset of, 25, 52, 60, 61, 67, 68, 138 LFD. See longest foveation domain
oscillopsia suppression and, 27, 35, 39, 45, 54–56, 60, 128, LGN. See lateral geniculate nucleus
185 lid nystagmus, 163–164
physiological investigation of, 26 line of regard, 279
recognition of, 27, 43 literature, 255
research, 22–102, 123, 238, 239, 243, 244, 253, 255, 257, 268, LLBNs. See long-lead burst neurons
277, 282, 283, 311 LMLN. See latent/manifest latent nystagmus
saccades and, 27–32, 34, 35, 37, 50–51, 61, 64, 69, 73–75, 77, LN. See latent nystagmus
90, 104, 111, 128, 136, 216, 265, 279, 296, 297, 299, 303, longest foveation domain (LFD), 75, 79, 142, 289
304, 305 direct outcome measures, 237–239
“sensory,” 65 implications of, 224
sensory defects and, 63–64, 138 improvement estimates, 240–245, 243, 292, 311
smooth pursuit system and, 22, 28–30, 32, 35, 36–39, 40, measures, 70–73
42, 44–46, 49, 50–51, 61, 63, 64, 65, 67, 68, 74–75, 87, 90, NAFX and, 70–73
107–108, 115, 136, 141, 143, 215, 278, 299 post-surgical changes in, 86, 87, 223–224, 226, 232, 237–238

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after therapies, 80, 81, 240, 292 nucleus prepositus hypoglossi (NPH), 10
therapy goals and, 77–78 null regions/zones, 36, 39, 43, 45, 46–48, 49–50, 58, 81, 86, 192,
T&R procedure and, 87 208, 216, 218, 229
long-lead burst neurons (LLBNs), 10 broadening, 84–85
Lt. See target acquisition time factors affecting, 50
luminance fl ash paradigm, 66 four-muscle resection and recession procedure and, 84
macro saccadic oscillations (MSO), 167–169 head position and, 138–139
magnetic resonance imaging (MRI), 4 INS and, 46–48, 49–50, 141–143
magnocellular (M) ganglion cells, 14 post-surgical return of, 279
MBCT. See mindfulness-based cognitive therapy preoperative, 229–230
MBSR. See mindfulness-based stress reduction pursuit responses and, 45
M cells. See magnocellular ganglion cells shift s, 40
medial rectus muscles, 4, 147 static, 141
medial superior temporal visual area (MST), 16 NYS1 locus, 62
medial vestibular nucleus (MVN), 10 nystagmus. See also specifi c nystagmus types
meditation, 235–236 AHP and, 139
memantine, 80, 156, 214 benign, 61, 136–150
Meniere’s disease, 213 benign vs. neurologically threatening, 117, 278–279
migraine auras, 56 clinically-based diagnoses of, 288
mindfulness-based cognitive therapy (MBCT), 235 gaze-evoked, 27
mindfulness-based stress reduction (MBSR), 235–236 gaze-modulated, 27
modeling history of, 24
animal, 197, 216 horizontal-torsional, 37–39
bottom-up, 23 intensity of, 28
canine, 57, 58, 60, 80, 217, 234 intervention summary, 208
computer, 255, 256 leaky integrator, 27
efference copy and, 56 literature, 255
FMNS, 104–117 manifest latent, 103
INS, 26–39, 46, 50, 51, 56, 61 62, 67, 68, 70, 73–75, 140, medical treatment for, 44, 207
297–300 positional, 150, 153
OMS, 23, 33–34, 38, 167, 255, 296, 311 prevalence of, 136
PAN, 156 reversal, 278
SSI, 167–169, 170, 179 simultaneous surgery, with strabismus, 279
top-down, 23, 255 SN-like, 130, 131, 132, 149, 279
monocular calibration, 268–269 strabismus and, 150
monocular occlusion, 75 symptomatic, 150–164
FMN and, 106 types, 137
motion detection thresholds, 55 waveform variation with, 152
motor nystagmus, 25 nystagmus acuity function (NAF), 53, 53–54, 70
MRI. See magnetic resonance imaging nystagmus acuity function for position only (NAFP),
MSO. See macro saccadic oscillations 57, 70
MST. See medial superior temporal visual area nystagmus blockage syndrome (NBS), 61, 122–129, 124, 125,
multiple-gaze-angle monocular calibration records, 40 142, 143, 147–148, 231, 287, 288–290
muscle spindles, 7, 15, 217 Alexander’s law and, 129
musculo-orbital coupling, 4–5 bilateral medial rectus recession procedure and, 287
musculo-orbital tissue connections, 2 bimedial recession and, 287
MVN. See medial vestibular nucleus characteristics of, 123–127
myoclonus, 159–160, 173 differential diagnosis of, 148
myopia, 53, 206, 210, 211, 231, 233, 305 efference copy and, 127
esotropia and, 147
NAF. See nystagmus acuity function four-muscle resection and recession procedure and, 287
NAFP. See nystagmus acuity function for position only foveation and, 126–128
NAFX. See eXpanded Nystagmus Acuity Function head position and, 124
nasotemporal asymmetry, 116 mechanisms, 123
NBS. See nystagmus blockage syndrome NAFX and, 126–127
neurofi bromatosis, 149 oscillopsia and, 127
neutral zone, 33, 34, 47, 69, 144, 220, 232 during smooth pursuit, 125
dynamic, 40–46 strabismus and, 148
shift s, 45–46, 144 surgery, 127–129
static, 39–40 symptoms of, 147
NFF. See nystagmus foveation function therapies, 127–129
nodulus, 12 T&R procedure and, 287
NOT nystagmus. See nucleus of the optic tract nystagmus Type I, 124–127, 148
NPH. See nucleus prepositus hypoglossi Type II, 124–127, 148
nucleus of the optic tract (NOT) nystagmus, 30–31, 39, 137, 288, types of, 123
289, 304 visual acuity and, 126–127
FMNS plus, 28, 104–115, 106, 116, 117, 217 waveforms, 123
waveforms of, 30, 31, 32–33 nystagmus foveation function (NFF), 53

Index • 319

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oblique muscles orbital tissues, 6

inferior, 4 orbit nerve anatomy, 6
superior, 3–4 orthophoria, 144–145
surgery and, 223 oscillopsia, 23, 35, 37, 38, 55, 60, 151, 153, 155, 162, 173, 206,
occupational therapy, 236 298
OCT. See optical coherence tomography efference copy and, 56, 60, 114, 115, 128, 185, 207–209, 208,
ocular bobbing, 174 211, 213, 214, 231, 237
atypical, 175 FMNS and, 114–115
monocular, 175 INS and, 27, 35, 37–39, 45, 46
reverse, 175 NBS and, 127
typical, 175 proprioceptive tension control loop and, 60
ocular dipping, 175 PSN and, 37–39
ocular flutter, 172–173 suppression, 55, 56, 185
ocular motility, 166, 253, 254 temporal sampling and, 55–56
recordings, 66 otoliths, 17
ocular motor system (OMS), 1, 22, 23, 36, 39, 45, 47, 128, 138, outcomes, 36, 47, 54, 67, 70, 73, 75, 76, 77, 84, 215, 217, 219–220,
140, 148, 163, 218, 254 255, 256, 279
calibration, 61, 64, 140, 158, 217, 235 acetazolamide, 80, 239, 241
control, 2, 7–10, 12–15, 23–28, 37, 47, 49, 58, 60, 61, 63, 87, assessing, 237–240
108, 115, 118, 151, 156, 158, 159, 217, 218, 254, 259 base-out prisms, 238
developmental disturbance of, 61, 64–68 bimedial recession, 238
modeling, 23, 26, 28, 33–35, 38, 39, 56, 58, 65, 68, 70, 73–75, brinzolamide, 80, 239, 240
108, 111–114, 156, 167–169, 171, 255, 296–299, 311 contact lenses, 240
plasticity, 218 direct measures of, 232, 237–239
preoperative evaluation of, 228 estimates, direct measures of, 240–244
proprioception, 14–15, 58 estimates, indirect measures of, 244–245
recalibration, 81 estimating, pre-therapy, 240–245
ocular neuromyotonia, 174 indirect measures of, 230, 239–240
ocular oscillations, 185, 279 Kestenbaum procedure, 239
ocular stabilization system surgery, 223
foveation period and, 51 T&R procedure, 226, 226
theories, 61 oxcarbamazepine, 213
oculography, 27
torsional, 35 palisade endings, 7–8, 15, 217
oculomotor nerve, 6, 2 PAN. See periodic alternating nystagmus
oculopalatal tremor, 159–160 paramedian pontine reticular formation (PPRF), 9
OKN. See optokinetic nystagmus horizontal saccades and, 11
omnipause neurons (OPNs), 9, 10, 165, 167, 172 saccade direction and, 10
OMS. See ocular motor system saccade system and, 15
operation 1. See four-muscle resection and recession procedure parvocellular (P) ganglion cells, 14
operation 1A. See two-muscle recession procedure P. See waveforms
operation 1B. See bilateral medial rectus recession + T&R P cells. See parvocellular ganglion cells
operation 2. See bilateral horizontal rectus recession and PC. See waveforms
resection with chin-down posture Pelizaeus-Merzbacher disease, 130, 149
operation 3. See bilateral horizontal rectus recession and pendular nystagmus (P). See also Waveforms
resection with strabismus alone central myelin diseases and, 158–159
operation 4. See bilateral horizontal rectus recession and perimetry testing
resection with strabismus and head posture arc, 193
operation 5. See bilateral horizontal rectus recession and automated, 194
resection with chin-up posture hemispheric, 193
operation 6. See tenotomy and reatt achment procedure periodic alternating gaze deviation, 156
operation 7. See bilateral horizontal rectus recession and periodic alternating nystagmus (PAN), 42, 43, 49, 50, 142, 143,
resection with multiplanar head posture 151, 154–156, 219, 232
operation 8. See bilateral medial rectus recession procedure acquired, 41, 42, 142, 143, 154–156, 157, 235
operation 9. See bilateral horizontal rectus recession and albinism and, 154
resection with torsional head posture baclofen and, 208, 213–214
operation classification system, 223, 221, 222 as compared to APAN, 143
ophthalmological mythology, 279 gene transfer therapy and, 235
OPNs. See omnipause neurons head position and, 156, 232
opsoclonus, 173, 176, 214 symmetric infantile, 154
opsoclonus-myoclonus syndrome, 173 peripheral afferent neuroanatomy, 253–254
optical coherence tomography (OCT), 200–202, 200, 254 phase-plane analysis, 36, 51
optic atrophy, 130, 149 phase variation, with SNS, 131, 149
optic nerve, 13–14, 13 phenytoin intoxication, 155
defects, 68 photoreceptors, 13
optokinetic asymmetry, 116 physiological end-point nystagmus (EPN), 157
optokinetic nystagmus (OKN), 44–46 Pick’s sign, 164
quick phases of, 15 PL. See preferential looking

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Polaroid Vectograph test, 187–188 dysmetric, 172

posterior parietal cortex, 8 foveating, 35
PP. See waveforms frontal eye fields and, 8–9
PPfs. See waveforms horizontal, 11
PPRF. See paramedian pontine reticular formation hypometric, 50–51
preferential looking (PL), 185–186 INS and, 50–51
preoperative evaluation, 228–230 pseudopendular with foveating, 37, 69, 69
primary visual cortex (V1), 14 reflexive, 9–10
prisms, 78, 80 system, 15
base-out, 53, 211, 238, 283 vertical, 12
bilateral, 210 voluntary, 9
composite, 282–283 saccadic commands, 165
fi ne tuning with, 281 saccadic instabilities, 167
outcome estimates for, 243–244 saccadic intrusions/oscillations, 164–176, 168, 171, 169, 165,
Risley, 209 214
vergence, 209–210, 282 saccadic pulses (SP), 169–171
version, 209, 281, 283 saccadic pulse trains (SPT), 169–171
proprioception, 57, 80, 115, 217, 231, 254 SC. See superior colliculus
feedback, 7–8, 42, 49, 58, 217 Scarpa’s ganglion, 10
INS therapies and, 86, 87, 90, 118, 119, 218 scleral search coils, 35, 113, 262, 263, 264, 265–266
ocular motor, 14–15, 79 SD-OCT. See spectral domain optical coherence tomography
proprioceptive tension control loop, 58–60, 87, 218 seesaw nystagmus (SSN), 58, 162–163, 216
influence of, 254 SEF. See supplementary eye field
oscillopsia and, 60 sensory defects, 63–64
T&R procedure and, 87 genetics and, 66
pseudoabducens paralysis, 147 INS and, 65–66, 138
pseudocycloid (PC). See waveforms OMS development and, 64–68
pseudojerk (PJ). See wavefroms sensory nystagmus, 24–25
pseudo-isochromatic plate tests, 190–191 sensory receptors, 217
pseudopendular (PP). See waveforms sensory system development, 64, 140
pseudopendular with foveating saccades (PPfs). simulations
See waveforms ramp response, 74, 75
PSN. See pursuit system nystagmus step response, 74
psychogenic flutter, 160, 175–176 smooth pursuit system, 15
Purkinje images, 261 calibration of, 61
pursuit responses, 44–46. See also smooth pursuit system damping, 68–70
foveation during, 46 damping-control feedback loop in, 28
null zones and, 45 foveation window and, 36
pursuit system nystagmus (PSN), 30–31, 37, 30 INS and, 36–39, 50–51
modulation of, 39 instability, 30–31, 37–39, 277–278
oscillopsia and, 37–39 NBS and, 125
pyramidal tract fi bers, 7 SNS. See spasmus nutans syndrome
SOM. See superior oblique myokymia
ramp response simulations, 74, 75 SP. See saccadic pulses
random-dot E test, 190 spasmus nutans syndrome (SNS), 22, 61, 122, 129–133, 148–150
reading, gaze angles and, 278 characteristics of, 129–132, 160
rectus muscles, 2–3 differential diagnosis of, 149–150, 288, 289, 290
global layer of, 5 genetics and, 130
orbital layer of, 5 head nodding and, 130–131, 132, 149, 279
sheaths of, 6 mechanisms, 130–132
refractive therapy, 212–213, 230 strabismus and, 148, 206
retina, 12–13, 13, 198, 259 symptoms, 149
retinal dystrophy, 68 therapies, 132, 133
retinal image stabilization, 56 variable interocular phase and, 130, 132
rods, 13 VOR and, 131–132
rostral interstitial nucleus of the medial longitudinal fasciculus spectral domain optical coherence tomography (SD-OCT),
(riMLF), 9 202
saccade direction and, 10 spiral of Tillaux, 2–3
saccadic system and, 15 SPT. See saccadic pulse trains
rostral midbrain, 10 square-wave jerks (SWJ), 165–167
RPE65 deficiency, 60, 80–81, 82, 83, 234–235 square-wave oscillations (SWO), 166–167
square-wave pulses (SWP), 167, 168, 169, 170
saccades SSI. See staircase saccadic intrusions
brain stem and, 10 SSN. See seesaw nystagmus
braking, 35, 61 staircase saccadic intrusions (SSI), 167–169
defoveating, 108 stereopsis, 187–190, 189
direction of, 10 stereo testing, 187–190
dual pendular with foveating, 31 strabismic deviation, 212

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strabismus, 44, 67, 212, 231, 276, 289, 311 for moving targets, 73–75, 87, 90, 255
AHP and, 136–138, 139, 206, 230 for static targets, 73, 90, 255
APAN and, 44 T&R procedure and, 90, 279
FMNS and, 48, 103, 104, 105–106, 115, 116, 117, 123, 141, 142, target reconstruction, 37, 42, 74, 115, 168
145, 146, 206, 286, 303, 310 TD-OCT. See time domain optical coherence tomography
four-muscle resection and recession procedure and, 286, 287 Teller acuity cards (TAC), 185–187, 186, 228
infantile, 67 temporal sampling, 55–56
INS and, 140–142, 144, 145, 163, 206, 243, 284–286, 303, 304, Tenon’s capsule, 6
306, 307 tenotomy and reatt achment (T&R) procedure, 57, 75, 78–81,
latent, 146 86–90, 118, 119, 221, 222, 224, 227, 228, 245, 254, 279, 282,
NBS and, 147 283, 285–290, 294–296, 298, 300, 308, 310, 311
nystagmus and, 150, 215–216, 231–232, 268–269 with afferent visual deficits, 243, 244
post-surgery, 231–232, 233 without afferent visual deficits, 241–243, 242
preoperative evaluation of, 228–229, 237, 283–286 Anderson procedure and, 85
prevalence of, 150 with augmented tendon suture, 284
simultaneous surgery, with nystagmus, 87, 118–119, 128–129, bilateral, 284
228, 232, 279, 298 canine, 58–60, 71
SNS and, 148, 206 direct outcome measures of, 238, 238–239
surgery, 81, 218–223, 227, 282 estimated improvements, 242, 243
variable, 126, 128, 228 fi xation and, 58
stress, 75, 215 foveation and, 90
biofeedback and, 81 gaze angle and, 90
INS modulation and, 39 history of, 216–217
MBSR and, 235–236 INS with gaze-angle null only and, 281
striate cortex, layer IV, 14 INS with strabismus and, 284
substantia nigra, 9 LFD and, 87
superior colliculus (SC), 9–10, 15, 9 NAFX and, 71–73, 87
lesions of, 8–9 NBS and, 287
saccade-related activity of, 8 outcomes, 226, 226
superior oblique myokymia (SOM), 174, 214 proprioceptive tension control loop and, 87
supplementary eye field (SEF), 16 results, 89
supranuclear disorders, 1 target acquisition time and, 90
supranuclear ocular motor anatomy, 8–12 terminology, 22
supranuclear ophthalmoplegia, vii thalamus, 7
suprasellar tumors, 130, 149 therapies. See also gene transfer therapy; outcomes; surgery
surgery, 81–90, 88, 118–119. See also specific surgical procedures drug, 80
AHP, 278–279, 279 FMNS, 118–119
amount of, 224, 291 goals, 77–78, 215
classification, 218–227 INS, 78
complications, 232–234 intervention points for, 76
EOM, 75, 77, 223, 291 LFD after, 80, 292
eye muscle, 118–119, 215–234 medical, 206–215
fi xation, 129 NAFX after, 80, 291
general principles, 215–218 NAFX and, 54
indications for, 218 NBS, 127
INS, 81–90, 88 nonsurgical, 78–81, 80
modified bilateral horizontal recess/resect, 227 occupational, 236
NBS, 129 optical, 207–213
outcomes, 223 pharmacological, 213–214
preoperative evaluation, 228–230 refractive, 212–213, 230
refractive, 213 summary of, 208
results, 230–232 surgical, 81–90, 88, 118–119
simultaneous nystagmus and strabismus, 279 types, 77–90
strabismus, 218–223 vision, 236
testing for, 215 time-dependent acuity testing, 192–193
timing of, 224–227 time domain optical coherence tomography (TD-OCT),
traditional bilateral horizontal recess/resect, 227 200–201
visual sensory deficits and, 279 Titmus test, 188
SWJ. See square-wave jerks tonic imbalance, of visual-vestibular subsystem, 26–27
SWO. See square-wave oscillations torsional nulls, 284–285
SWP. See square-wave pulses torsional nystagmus, 37, 103, 105, 150, 153, 155, 158, 162
syndromes, 22 triangular (T). See waveforms
trigeminal nerve, 6–7
T. See waveforms cutaneous stimulation of, 57, 78–79
TAC. See Teller acuity cards motor nucleus of, 6–7
target acquisition time (Lt) sensory nucleus of, 7
direct outcome measures, 237, 239–240 trochlea, 3
INS and, 36, 299 trochlear nerve, 6

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T&R procedure. See tenotomy and reatt achment procedure dynamic, 73–75
two-muscle recession procedure (operation 1A), 85. See also static, 70–73
Anderson procedure visual function space, 231
visual sensory deficits
UBN. See upbeat nystagmus INS and, 25, 65, 138
upbeat nystagmus (UBN), 160, 161, 162, 163, 208, 213, 302 non-vectorial, 68
nystagmus surgery and, 279
V1. See primary visual cortex visual-vestibular subsystem, tonic imbalance of, 26–27, 70
valproate, 214 visual vestibular system nystagmus (VVSN), 29, 30, 70
velocity trace, 154 VOG. See video oculography
ventral stream, 14 VOR. See vestibuloocular reflex
VEP. See visual evoked potentials VVSN. See visual vestibular system nystagmus
vergence, 15–16
prisms, 209–210, 282 waveforms, 162, 231, 259, 265, 307
system, 15–16 amplitude of, 28
vergence nystagmus, 131, 160–161, 172 AP, 27–28, 29, 129, 149
vertical nulls, 284–285 APAN, 40, 42–44, 46, 47, 50, 58, 62, 86, 142, 143, 155, 156,
vestibular nuclei, 10, 10–11 206, 229, 278
vestibular nystagmus, 150–156, 153, 162 bidirectional jerk, 39, 43, 68, 146, 153
central, 153 BDJ, 27–28, 29, 31
central vs. peripheral, 153 central vestibular nystagmus and, 153, 154
peripheral, 137, 150–153 diagnoses from, 288
quick phases of, 15 DPfs, 31
visual observation of, 260 DJ, 27–28, 30, 34–35, 30, 68, 304
vestibular paroxysmia, 213 DP, 27–28, 30, 31
vestibuloocular reflex (VOR), 11, 44–46 DPfs, 30
foveation period and, 46 effects of convergence on, 33
foveation window and, 36 with eyeball rotations, 31
head posture and, 51–52 FMNS, 104–112, 114–117, 121, 123–125, 143, 144, 146–148,
nodulus and, 11 150, 152, 171
peripheral vestibular nystagmus and, 151 FMNS diagnosis and, 146
SNS and, 131–132 gaze angle and, 47, 34
vestibuloocular system, 16–17 heredity and, 49
video oculography (VOG), 261–262, 266–268, 262, 267 during inattention, 32
vision loss, 158 INS and, 22, 24, 25, 26–39, 40, 43, 45–47, 49, 51–58, 60, 61,
vision-loss nystagmus, 158 62–64, 67–70, 73, 75, 77–81, 84, 86, 87, 116, 117, 122–126,
vision therapy, 236 139, 141–144, 146–148, 150, 152, 171, 210, 211, 215, 216,
visual acuity 229, 232, 234, 235, 237, 254, 255, 279, 296, 303, 307, 310
albinism and, 53 INS vs. FMNS, 146–147
best-corrected binocular, 254 J, 27–28, 29, 68, 143, 279, 305–307
changes, 278 Jef, 27–28, 29, 31, 32, 34, 39, 141, 303–306
at different gaze angles, 77, 240, 244–245 major, 112
FMN and, 114 multiple, 141
following EOM surgery, 77 NBS, 123
foveation and, 52–54 of NOT nystagmus, 32–33
line, NAFX vs., 71, 241–242, 243, 292 P, 27–28, 28, 29, 58, 68, 279, 304, 306, 307
to measure INS, 75 PAN, 42, 43, 142, 143, 154, 155–156, 213, 214, 219, 232, 235
NAFX and, 53, 73 PC, 27–28, 29, 34, 43, 161, 304
NBS and, 126–127 PJ, 27–28, 29
peak, 77 Pfs, 27–28, 29, 30, 31, 297
post-surgical changes in, 223–224, 230–231 PP, 27–28, 29
preoperative, 228 PPfs, 27–28, 29, 33, 34, 37, 69, 69, 70, 74, 74, 75, 296, 297, 303,
psychophysical measures of, 231 305
testing, 187, 189 saw-toothed, 28
visual association cortex, 14 SNS, 130–132, 149
visual evoked potentials (VEP), 66–67, 194–197, 253 therapeutically exploitable, 288
fl ash, 196–197, 196 types, 27–35, 146
pattern reversal, 196, 197 T, 27–28, 29, 43, 68
specialized, 198 unidirectional jerk, 29
waveforms, 195–196 variations, 152
visual feedback, 51 VEP, 195–196
visual field testing, 193–194, 194, 195, 225 Whipple’s disease, 160
visual function deficits, 70–77
afferent, 243, 244 X-linked irregular dominant transmission, 62

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 LOUIS STOKES CLEVELAND DEPARTMENT OF VETERANS AFFAIRS MEDICAL CENTER
LOUIS STOKES CLEVELAND DEPARTMENT OF VETERANS AFFAIRS MEDICAL CENTER
CASE School of Medicine
CASE School of Medicine

Nov. 28, 2012 Nov. 28, 2012

Nystagmus in Infancy and Childhood. Current Nystagmus in Infancy and Childhood. Current
Concepts in Mechanisms, Diagnoses, and Concepts in Mechanisms, Diagnoses, and
Management. Management.
Richard W. Hertle and Louis F. Dell’Osso Richard W. Hertle and Louis F. Dell’Osso

[Errata, First Printing] [Errata, First Printing]

Page xxi, left column, MV18, line 2: “Post-“ should be “Pre-“ Page xxi, left column, MV18, line 2: “Post-“ should be “Pre-“

Page 140, Figure legend 5.3, line 6: “ocularmotor” should be “ocular Page 140, Figure legend 5.3, line 6: “ocularmotor” should be “ocular
motor” motor”

Page 310, left column, before “F.1.4 #090506 ….” Insert: Page 310, left column, before “F.1.4 #090506 ….” Insert:
F.1.3 #111905 Nystagmus Therapies: Types, F.1.3 #111905 Nystagmus Therapies: Types,
Sites, and Measures Sites, and Measures
OMLAB Report #111905 describes the current OMLAB Report #111905 describes the current
therapies by their types and sites of application therapies by their types and sites of application
along with the direct measurements for each. along with the direct measurements for each.

L.F. Dell’Osso, Ph.D., Director Emeritus, L.F. Dell’Osso, Ph.D., Director Emeritus,
Daroff-Dell’Osso Ocular Motility Laboratory Daroff-Dell’Osso Ocular Motility Laboratory
Louis Stokes Cleveland Veterans Affairs Medical Center Louis Stokes Cleveland Veterans Affairs Medical Center
and CASE School of Medicine and CASE School of Medicine
Professor Emeritus, Department of Neurology Professor Emeritus, Department of Neurology
Case Western Reserve University Case Western Reserve University
 Hertle • Dell’Osso
“Nystagmus, particularly the infantile forms, has had relatively few researchers devoting much
attention to it, resulting in an excess of misinformation and the consequence that many patients
never receive the care they should. This book should go far to remedy this, having been written by
the top collaborative team of clinician and scientist researchers. The extensive, detailed focus on
clinical management—always backed by solid science—means that this book belongs on the shelf

N y s t a g m u s i n In fa n c y
of any clinician who cares how their patients’ eyes move.”

Larry Alan Abel, MD, Senior Lecturer, Department of Optometry & Vision Sciences, The University
of Melbourne, Melbourne, Australia

and Childhood

Nystagmus in Infancy and Childhood

This timely volume outlines the understanding, evaluation, and treatments of nystagmus in infancy and
childhood. Aligning this condition with advanced concepts of developmental brain-eye diseases and
summarizing novel treatment paradigms, the authors provide an authoritative resource for both clinicians
Current Concepts in Mechanisms, Diagnoses, and Management
and scientists in the care of infants and children with nystagmus.

The chapters comprised here offer valuable coverage in all relevant areas related to nystagmus:

• algorithms for examination

• descriptions of diagnostic techniques

• medical, surgical, and alternative treatments of the visual system in infants and children

• methodologies for investigation, including analysis software, models of the ocular motor system,
and current hypotheses on the pathophysiology of ocular motor oscillations

Unlike earlier works on this topic, emphasis is placed on the motor mechanisms that cause the various types
of nystagmus rather than the diagnosis or treatment of the afferent visual deficits that may accompany them.
The study of each type of nystagmus using accurate eye-movement recordings serves as the foundation for
differential diagnosis and treatment options. Each chapter summarizes the results
of ocular motor research in a narrative manner, identifying the important ideas and observations that
point to underlying neurophysiological mechanisms.

Based on insights from the authors’ combined 75 years of clinical experience, Nystagmus in Infancy and
Childhood is a valuable clinical reference for ophthalmologists, neurologists, and other specialists in the
treatment of this condition.
Richard W. Hertle and Louis F. Dell’Osso
Richard W. Hertle MD, FACS, FAAO, FAAP, is Director of the Children’s Vision Center and Chief of
Pediatric Ophthalmology at Children’s Hospital Medical Center of Akron. He is also Professor of Surgery
in Ophthalmology at the Northeast Ohio Medical University in Rootstown, Ohio.

Louis F. Dell'Osso, PhD, is Professor Emeritus in the Department of Neurology at Case Western Reserve
University and Director Emeritus of the Daroff-Dell’Osso Ocular Motility Laboratory.
               

1 ISBN 978-0-19-985700-5

Ë|xHSKBTJy8570 5zv*:+:!:+:!
2

www.oup.com

COVER IMAGES From the collection of Louis F. Dell’Osso, Ph.D.

JACKET DESIGN Ciano Design

Hertle_Nystagmus_9857005_PPC_R1.indd 1 9/26/12 2:32 PM