THE NEUROLOGY OF

EYE MOVEMENTS
THIRD EDITION
CONTEMPORARY NEUROLOGY SERIES AVAILABLE:
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55 THE NEUROLOGY OF EYE MOVEMENTS, EDITION 3
R.John Leigh, M.D., and David S. Zee, M.D.
(book and CD-ROM versions available)
THE NEUROLOGY OF
EYE MOVEMENTS
THIRD EDITION

R. John Leigh
Professor, Departments of Neurology, Neurosciences,
Otolaryngology, and Biomedical Engineering
Case Western Reserve University
University Hospitals and Department of
Veterans Affairs Medical Center
Cleveland, Ohio

David S. Zee
Professor of Neurology, Ophthalmology,
Otolaryngology and Head and
Neck Surgery, and Neuroscience
Director, Ocular Motor-Visual Testing Lab
Johns Hopkins University
Baltimore, Maryland

New York Oxford

OXFORD UNIVERSITY PRESS
1999
Oxford University Press
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Copyright © 1999 by Oxford University Press Inc.

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All right reserved. No part of this publication may be reproduced,
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Library of Congress Cataloging-in-Publication Data

Leigh, R.John.
The neurology of eye movements /
R.John Leigh, David S. Zee. — 3rd ed.
p. cm. — (Contemporary neurology series ; 55)
Includes bibliographical references and index.
ISBN 0-19-512972-5. — ISBN 0-19-512973-3 (book/CD package). — ISBN 0-19-512974-1 (CD ROM upgrade)
1. Eye—Movement disorders—Diagnosis. 2. Eye—Movements. 3. Diagnosis, Differential.
I. Zee, David S. II. Title. III. Series.
[DNLM: 1. Eye Movements—physiology. 2. Ocular Motility Disorders.
WlC'769Nv.55 1999] RE731.L44 1999 617.7'62—dc21
DNLM/DLC for Library of Congress 98-37880

The science of medicine is a rapidly changing field. As new research and clinical experience broaden our knowledge, changes
in treatment and drug therapy do occur. The author and the publisher of this work have checked with sources believed to be re-
liable in their efforts to provide information that is accurate and complete, and in accordance with the standards accepted at the
time of publication. However, in light of the possibility of human error or changes in the practice of medicine, neither the au-
thor, nor the publisher, nor any other party who has been involved in the preparation or publication of this work warrants that
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987654321
Printed in the United States of America
on acid-free paper.
 PREFACE TO
THE THIRD EDITION
As in the first two editions of The Neurology of Eye Movements, our main goal has
been to synthesize information discovered through basic research into a form that
is directly applicable to the interpretation of clinical disorders of eye movements.
A number of new concepts appear in this edition, such as three-dimensional
aspects of eye rotations, identification of cortical "eye fields" in humans by func-
tional imaging, and the development of treatments for nystagmus and other ab-
normal movements that impair vision. New findings have required us to revise
or modify our hypothetical schemes for several classes of eye movements. In
making these substantial revisions, we have abided with our effort to write for a
broad audience that includes neurologists, ophthalmologists, otolaryngologists,
optometrists, neurosurgeons, psychiatrists, and basic researchers working in
various aspects of neuroscience for whom eye movements are pertinent. We
have endeavored to provide up-to-date references but, since the current output
of scientific papers is large, have had to leave out some fine citations that ap-
peared in previous editions. The growth of the scientific and clinical literature
shows no signs of slowing down. Thus, the reader will inevitably turn to biblio-
graphic resources on the World Wide Web for the latest information. Nonethe-
less, we hope that the schemes we present here will provide a coherent way of
interpreting basic and clinical research for some years.
New to this edition, we have provided the option of accessing supplemen-
tary material on a CD-ROM, in conjunction with the conventional clothbound
book. Though the book can stand alone, the armchair reader can also choose to
move to the computer to read and print the text, to view color figures and more
than 60 videos referred to in the text, and to take advantage of the linking of
physiology and anatomy with clinical ocular motor syndromes and their differ-
ential diagnosis.
The new CD-ROM component has many advantages. First, the reader can
appreciate the dynamic characteristics of abnormal eye movements being dis-
cussed in the text, and relate these features to patients that they examine at the
bedside. Second, when reading about a clinical disorder, access to pertinent ba-
sic information can be readily accessed (or vice versa) via hypertext links. This is
facilitated by "displays," which summarize clinical syndromes and pertinent
anatomy, and serve as bridges between related basic and clinical sections and
videos. Case histories of illustrative patients, MR and CT scans, eye movement
records, and videos are also linked in this way. One trade-off has been the need
for us to make each heading and sub-heading specific, and the reader is asked
to bear with what might seem unnecessary repetition of the topic titles within
sections. Each video clip is quite short, to contain file size and facilitate real-time
video images. The reader might find it useful to play the clips continuously
while the legend is being read.
V
VI Preface

As is previous editions, we are indebted to many inidividuals who have con-

tributed their expertise and time to improve our book, any short-comings being
our own. The following individuals read substantial portions of the manuscript:
Lea Averbuch-Heller, Kanokwan Boonyapisit, Stephan Brandt, Vallabh Das,
Henry Kaminski, Phillip Kramer, Lloyd Minor, Lance Optican, Vivek Patel,
Grace Peng, Klaus Rottach, Mark Shelhamer, Heimo Steffen, John Stahl,
Ronald Tusa, and Mark Walker. Individuals who have provided reviews, fig-
ures, videos, or other contributions include Jean Biittner-Ennever, Patrick
Chinnery, Mark Cohen, Robert Daroff, Louis Dell'Osso, Joseph Demer, Susan
Herdman, Manabu Honda, Anja Horn, Henry Kaminski, Gregory Kosmorsky,
Richard Leigh, Hans Liiders, Vendetta Matthews, Lloyd Minor, Joel Miller, Neil
Miller, Adonis Moschovakis, Gary Paige, Robert Ruff, Scott Seidman, Robert
Spencer, Ki Bum Sung, David Waitzman, Shirley Wray, Stacy Yaniglos, and
Arthur Zinn. We are grateful to Bernice Wissler and Nancy Wolitzer for editor-
ial assistance, and to Kyle Bates and Kirk Pedrick for help in making the videos.
We thank Lauren Enck and her staff at Oxford University Press, Al Cecchini
and his colleagues at Libera, and Sid Gilman for his crucial role in facilitating
the publication of this edition. We are grateful for the continued support of our
work by the National Eye Institute, the National Institute of Deafness and Com-
municative Disorders, the National Space Biomedical Research Institute
(NASA), the Department of Veterans Affairs Medical Research Service, and the
Evenor Armington Fund. Finally, we thank Daniele Nuti for making it possible
for us to make a start on our writing in the inspiring atmosphere of the Certosa
of the University of Siena, Italy.

January 1999 R.J.L.

D.S.Z.
 CONTENTS
PART I THE PROPERTIES AND NEURAL SUBSTRATE OF
EYE MOVEMENTS

1. A SURVEY OF EYE MOVEMENTS: 3

CHARACTERISTICS AND TELEOLOGY

Why Study Eye Movements? 3

Visual Requirements of Eye Movements 5
Functional Classes of Eye Movements 5
Orbital Mechanics: Phasic and Tonic Innervation 6
Vestibular and Optokinetic Systems 8
Saccadic System 10
Smooth Pursuit and Visual Fixation 10
Combined Movements of the Eyes and Head 11
Vergence Eye Movements 12
Three-Dimensional Aspects of Eye Movements 12
Adaptive Control of Eye Movements 13
Voluntary Control of Eye Movements 13
Eye Movements and Spatial Localization 14
The Scientific Method Applied to the Study of 15
Eye Movements
Summary 15

2. THE VESTIBULAR-OPTOKINETIC SYSTEM 19

Function of the Vestibular-Optokinetic System 21

Anatomy and Physiology of the Peripheral Vestibular System 24
Brain Stem Elaboration of the Vestibulo-ocular Reflex 29
Neural Substrate for Optokinetic Responses 36
Quantitative Aspects of the Vestibular-Optokinetic System 37
Adaptive Properties of the Vestibulo-ocular Reflex 48
Vestibulocerebellar Influences on the Vestibulo-ocular Reflex 53
Vestibular Sensation 56
Clinical Examination of Vestibular and Optokinetic Function 57
Laboratory Evaluation of Vestibular and Optokinetic Function 63
Pathophysiology of Disorders of the Vestibular System 67
Summary 72

3. THE SACCADIC SYSTEM 90

The Purpose of Saccades 90

Behavior of the Saccadic System 91
Vii
Viii Contents

Neurophysiology of Saccadic Eye Movements 102

Saccades and Movements of the Eyelids 126
Examination of Saccades 128
Pathophysiology of Saccadic Abnormalities 130
Summary 134

4. SMOOTH PURSUIT AND VISUAL FIXATION 151

The Purpose of Smooth Pursuit 151

Visual Fixation 152
Stimulus for Smooth Pursuit 156
Quantitative Aspects of Smooth Pursuit 159
Neural Substrate for Smooth Pursuit 164
Models of Smooth Pursuit 174
Clinical Examination of Fixation and Smooth Pursuit 177
Laboratory Evaluation of Fixation and Smooth Pursuit 179
Abnormalities of Visual Fixation and Smooth Pursuit 180
Summary 186

5. GAZE HOLDING AND THE NEURAL INTEGRATOR 198

Neural Coding of the Ocular Motor Signal 199

Quantitative Aspects of Neural Integration 201
Neural Substrate for Gaze Holding 203
Clinical Evaluation of Gaze Holding 208
Abnormalities of the Neural Integrator 209
Summary 211

6. SYNTHESIS OF THE COMMAND FOR CONJUGATE 215

EYE MOVEMENTS

Brain Stem Connections for Horizontal Conjugate 215

Movements
Brain Stem Connections for Vertical and Torsional 221
Movements
Cerebellar Influences on Gaze 228
The Cerebral Hemispheres and Voluntary Control of 233
Eye Movements
Summary 250

7. EYE-HEAD MOVEMENTS 263

Stabilization of the Head 263

Voluntary Control of Eye-Head Movements 265
Examination of Eye-Head Movements 273
Laboratory Evaluation of Eye-Head Movements 273
Disorders of Eye-Head Movement 274
Summary 278
 Contents iX

8. VERGENCE EYE MOVEMENTS 286

Stimuli to Vergence Movements 287

Fusion or Disparity-Induced Vergence 287
Blur-Induced Vergence 290
The Near Triad 290
Interactions between Accommodation and Vergence 291
Dynamic Properties of Vergence Eye Movements 292
Neural Substrate of Vergence Movements 295
Conceptual Models of Supranuclear Control of Vergence 300
Adaptive Mechanisms to Maintain Ocular Alignment 302
Examination of Vergence Movements 306
Abnormalities of Vergence 307
Summary 310

PART II: THE DIAGNOSIS OF DISORDERS OF EYE MOVEMENTS

9. DIAGNOSIS OF PERIPHERAL OCULAR MOTOR 321

PALSIES AND STRABISMUS

Anatomy of the Orbital Fascia and the Extraocular Muscles 323

Structure and Function of Extraocular Muscle 327
Anatomy of Ocular Motor Nerves and Their Nuclei 331
Physiologic Basis for Conjugate Movements: 336
Yoke Muscle Pairs
Clinical Testing in Diplopia 337
Pathophysiology of Some Commonly Encountered Signs 344
in Strabismus
Clinical Features and Diagnosis of Concomitant Strabismus 348
Clinical Features of Ocular Nerve Palsies 350
Disorders of the Neuromuscular Junction 373
Chronic Progressive External Ophthalmoplegia and 379
Restrictive Ophthalmopathies

10. DIAGNOSIS OF CENTRAL DISORDERS OF 405

OCULAR MOTILITY

Diagnosis of Nystagmus and Saccadic Intrusions 407

Treatments for Nystagmus and Saccadic Intrusionsists 456
Skew Deviation and the Ocular Tilt Reaction (OTR) 463
Disease of the Vestibular Periphery 465
Oscillopsia 479
Ocular Motor Syndromes Caused by Lesions in 482
the Medulla
Ocular Motor Syndromes Caused by Disease of 487
the Cerebellum
X Contents

Ocular Motor Syndromes Caused by Disease of the Pons 497

Ocular Motor Syndromes Caused by Lesions of 511
the Mesencephalon
Ocular Motor Syndromes Caused by Lesions in the 526
Superior Colliculus
Ocular Motor Syndromes Caused by Lesions in 526
the Diencephalon
Ocular Motor Abnormalities and Disease of 528
the Basal Ganglia
Ocular Motor Syndromes Caused by Lesions in the 534
Cerebral Hemispheres
Abnormalities of Eye Movements in Patients 548
with Dementia
Eye Movement Disorders in Psychiatric Illnesses 550
Eye Movements in Stupor and Coma 551
Ocular Motor Dysfunction and Multiple Sclerosis 556
Ocular Motor Manifestations of Metabolic and 558
Deficiency Disorders
Effects of Drugs on Eye Movements 561

Appendix A 611
Appendix B 614
Index 617
CD-ROM Documentation 645
Part I

THE
PROPERTIES
AND NEURAL
SUBSTRATE
OF EYE
MOVEMENTS
This page intentionally left blank
Chapter 1
A SURVEY OF EYE MOVEMENTS:
CHARACTERISTICS
AND TELEOLOGY

WHY STUDY EYE MOVEMENTS? EYE MOVEMENTS AND SPATIAL

VISUAL REQUIREMENTS OF EYE LOCALIZATION
MOVEMENTS THE SCIENTIFIC METHOD APPLIED TO
FUNCTIONAL CLASSES OF EYE THE STUDY OF EYE MOVEMENTS
MOVEMENTS SUMMARY
ORBITAL MECHANICS: PHASIC AND
TONIC INNERVATION
VESTIBULAR AND OPTOKINETIC
SYSTEMS WHY STUDY EYE MOVEMENTS?
The Vestibulo-ocular Reflex: Responses to
Brief Angular and Linear Head Move- The study of eye movements is a source
ments of valuable information to both clinicians
Eye Movements in Response to Sustained and basic scientists. To neurologists and
Rotations: The Optokinetic System ophthalmologists, abnormalities of ocular
SACCADIC SYSTEM motility are frequently the clue to the lo-
Quick Phases calization of a disease process. To the neu-
Voluntary Saccades robiologist, the study of the control of eye
SMOOTH PURSUIT AND VISUAL movements presents a unique opportunity
FIXATION to understand the workings of the brain.
Smooth Pursuit Furthermore, the visual and perceptual
Visual Fixation consequences of eye movements are im-
Similarities and Differences between Fixa- portant to both clinicians and basic scien-
tion, Smooth-Pursuit, and Optokinetic tists, and information from the study of
Eye Movements eye movements may contribute to the
COMBINED MOVEMENTS OF THE EYES knowledge of motor control in general.52
AND HEAD The singular value of studying eye
VERGENCE EYE MOVEMENTS movements stems from certain advantages
THREE-DIMENSIONAL ASPECTS OF EYE that make them easier to interpret than
MOVEMENTS movements of the axial or limb muscula-
ADAPTIVE CONTROL OF EYE ture. The first is that eye movements are
MOVEMENTS essentially restricted to rotations in three
VOLUNTARY CONTROL OF EYE planes. This facilitates precise measure-
MOVEMENTS ment (Fig. 1-1 and Appendix B ), which is
3
4 The Properties and Neural Substrate of Eye Movements

Figure 1-1. A method for precise measurement of horizontal, vertical and torsional eye rotations. The subject is
wearing a silastic annulus embedded in which are two coils of wire, one wound in the frontal plane (to sense
horizontal and vertical movements), and the other wound in effectively the sagittal plane (to sense torsional eye
movements). When the subject sits in a magnetic field, voltages are induced in these search coils that can be
used to measure eye position (see Appendix B for details).

a prerequisite for quantitative analysis. A their anatomical substrates. Finally, many

second advantage is the apparent lack of a
classic, monosynaptic stretch reflex.32 This
is not unexpected since the eye muscles
move the globe against an unchanging
mechanical load. Third, different classes
of eye movements (Table 1-1) can be dis-
tinguished on the basis of how they aid
vision, their physiological properties, and
abnormalities of eye movements are dis-
tinctive and often point to a specific
pathophysiology, anatomical localization,
or pharmacological disturbance. This chap-
ter provides an overview of the normal be-
havior of eye movements, and introduces
the reader to some current concepts of the
underlying neural control. We start by ex-

Table 1-1. Functional Classes of Human Eye Movements

Class of Eye Movement Main Function

Vestibular Holds images of the seen world steady on the retina during brief head
rotations
Visual fixation Holds the image of a stationary object on the fovea
Optokinetic Holds images of the seen world steady on the retina during sustained
head rotation
Smooth pursuit Holds the image of a small moving target on the fovea; or holds the im-
age of a small near target on the retina during linear self-motion; with
optokinetic responses, aids gaze stabilization during sustained head
rotation
Nystagmus quick Reset the eyes during prolonged rotation and direct gaze toward the
phases oncoming visual scene
Saccades Bring images of objects of interest onto the fovea
Vergence Moves the eyes in opposite directions so that images of a single object
are placed or held simultaneously on both foveas
 A Survey of Eye Movements: Characteristics and Teleology
amining why the eyes need to move at
all—the raison d'etre of eye movements.51'67
VISUAL REQUIREMENTS OF
EYE MOVEMENTS
What visual needs must eye movements
satisfy? To answer this question, we must
first identify the prerequisites for a clear
and stable view of the environment. Sim-
ply stated, clear vision of an object re-
quires that its image be held fairly steadily
on the foveal region of the retina. Other-
wise visual acuity declines, and patients
may experience oscillopsia, or illusory
movement of the visual environment. Just
how steadily do images of the world have
to be held on the retina in order for vision
to remain clear and stable? The amount of
retinal image motion that can be tolerated
before vision deteriorates depends on
what is being viewed, and specifically, its
spatial frequency. For objects with higher
spatial frequencies, such as the Snellen op-
totypes used for conventional testing, reti-
nal image motion should be held below
about 5°/sec; above this threshold, visual
acuity declines in a logarithmic fashion.7'14
An exception to these general rules con-
cerns eye rotations about the line of
sight—torsional movements—when the
subject views a small object with the fovea;
in this case, geometry dictates that hori-
zontal and vertical components of retinal
image motion will remain relatively small.
For clearest vision of a single feature of
the world, its image must not only be held
fairly steady on the retina but also be
brought close to the center of the fovea,
where photoreceptor density is greatest.
Visual acuity declines steeply from the
fovea to the retinal periphery;14-30 for ex-
ample, at 2° from the center of the fovea,
visual acuity has declined by about 50%.
For best vision, the image of the object of
regard should be within 0.5° of the center
of the fovea.
Under normal circumstance, the angle
of gaze (which corresponds to eye position
in space) is held steadily enough that our
perception of the world is one that is clear
and stationary. The normal, small move-
5
Figure 1-2. Normal and abnormal eye movements
during attempted visual fixation of a stationary tar-
get. (A) One-second, representative record of the
gaze of a normal subject. (B) One-second record
from a 35-year-old woman with multiple sclerosis, in
whom acquired pendular-jerk nystagmus (see Chap-
ter 10) precluded steady fixation. Her main com-
plaints were that she could not see clearly and that
the world appeared to be moving (oscillopsia) in a di-
rection corresponding to that of her nystagmus (see
VIDEOS: "Acquired nystagmus impairing vision").
Measurements were made using the magnetic search
coil technique. RH, right horizontal; LH, left hori-
zontal; RV, right vertical; LV, left vertical; RT, right
torsional; LT, left torsional. Note that gaze positions
are relative, having been offset to aid the clarity of
the display, and that the scales differ by a factor of 10.
Polarity: positive-right, up, or clockwise.
ments of the eyes that occur as we fix upon
an object (Fig. 1-2A) do not interfere with
clear vision and may actually enhance it.14
However, when disease causes abnormal
oscillations of the eyes, such as nystagmus,
(Fig. 1-2B) the images of stationary ob-
jects move excessively on the retina and
patients report blurring of vision and os-
cillopsia (see VIDEO: "Acquired nystagmus
impairing vision").
FUNCTIONAL CLASSES OF
EYE MOVEMENTS
Since our eyes (and retinas) are attached
to our heads, the disturbances that are
most likely to affect vision are head per-
turbations, especially those that occur dur-
ing locomotion (Fig. 7-1, Chap. 7).26'43 If
we had no eye movements, images of the
6 The Properties and Neural Substrate of Eye Movements
visual world would "slip" on the retina
with every such head movement. This
would cause our vision to become blurred
and our ability to recognize and localize
objects to be impaired whenever we
moved through the environment. To this
end, two distinct mechanisms evolved to
stabilize images on the retina in general
and the fovea in particular during such
head perturbations. The first comprises
the vestibulo-ocular reflexes, which de-
pend on the ability of the labyrinthine
mechanoreceptors to sense head accelera-
tions. The second consists of visually me-
diated reflexes (optokinetic and smooth-
pursuit tracking), which depend on the
ability of the brain to determine the speed
of image drift on the retina. Together,
these reflexes stabilize the angle of gaze,
so that the foveas remain pointed at the
object of regard whenever the head is
moving.
With the evolution of the fovea, a sec-
ond requirement of eye movements also
arose: when a new object of interest ap-
pears in the visual periphery, we need to
point this central portion of the retina so
that the object can be seen best. This re-
quires a repertoire of eye movements to
change the angle of gaze. In animals with-
out a fovea, such as the rabbit, eye move-
ments are dominated by vestibular and
optokinetic stabilization. When such ani-
mals choose to change their center of vi-
sual attention, they must link a rapid eye
movement to a voluntary head movement
and so override or cancel vestibular and
optokinetic drives. With the emergence
of foveal vision, it became necessary to
change the line of sight independent of
head movements. In this way, images of
objects of interest could be brought to
and held on that portion of the retina pro-
viding best visual acuity. As animals as-
cended the evolutionary scale and de-
veloped frontal vision and binocularity,
disjunctive or vergence eye movements
also became necessary, so that images of
an object of interest could be placed on
both foveas simultaneously, and then held
there.
Thus eye movements are of two main
types: those that stabilize gaze, thus keeping
images steady on the retina, and those
that shift gaze, thus redirecting the line of
sight to a new object of interest.13'67 The
chief functional classes of eye movement
are summarized in Table 1-1. Each func-
tional class has properties suited to a spe-
cific purpose.22-51 Moreover, as detailed in
the following chapters, certain anatomical
structures and connections make distinc-
tive contributions to each functional class
of movements. An understanding of the
properties of each functional class of eye
movements will guide the physical exami-
nation; knowledge of the neural substrate
will aid topological diagnosis. Before
discussing each of these various classes
of eye movement, we must examine the
mechanical properties of the orbital con-
tents that the brain must deal with in pro-
graming fluent and accurate eye move-
ments.
ORBITAL MECHANICS: PHASIC
AND TONIC INNERVATION
The tissues supporting the eyeball impose
mechanical constraints on the control of
gaze. To move the eye, it is necessary to
overcome viscous drag and elastic restor-
ing forces imposed by the orbital support-
ing tissues. To overcome the viscous drag,
a powerful contraction of the extraocular
muscles is necessary. For rapid movements
(e.g., a saccade), this requires a phasic in-
crease or burst of neural activity in the oc-
ular motor nuclei*—the pulse of innervation
(Fig. 1-3). Once at its new position, the
eye must be held there against elastic
restoring forces that tend to return the
globe to its central position. To hold the
eye in an eccentric position, a steady con-
traction of the extraocular muscles is re-
quired, arising from a new tonic level of
neural activity—the step of innervation.
When this pulse-step of innervation is ap-
propriately programed, the eye is moved
*We use the term ocular motor to refer to the eye
movement control system as a whole, or the 3rd, 4th,
and 6th cranial nerves or their nuclei collectively,
and oculomotor to indicate the 3rd nerve or its nucleus
alone.
 A Survey of Eye Movements: Characteristics and Teleology 7

Figure 1-3. The neural signal for a saccade. At right is shown the eye movement: E is eye position in the orbit;
the abscissa scale represents time. At left is shown the neural signal sent to the extraocular muscles to produce
the saccade. The vertical lines indicate the occurrence of action potentials of an ocular motoneuron. The graph
above is a plot of the neuron's discharge rate (R) against time (firing frequency histogram). It shows the neu-
rally encoded pulse (velocity command) and step (position command).

rapidly to its new position and held there
steadily.
Some of the first studies of the discharge
characteristics of ocular motoneurons (see
Fig. 5-2, Chap. 5) in monkeys,49'53 and of
eye muscles in human beings (see Fig. 9-6,
Chap. 9),16 confirmed the presence of
both the pulse and step of innervation
during saccades.t
Without the pulse (velocity command),
the progress of the eye would be slow;
without the step (position command), the
eyes could never be maintained in an ec-
centric position in the orbit. Moreover, the
pulse and step must be correctly matched
to produce an accurate eye movement and
steady fixation following it. These con-
cepts are important for the interpretation
of clinical disorders of eye movements,
such as internuclear ophthalmoplegia (see
VIDEO: "Unilateral internuclear ophthal-
moplegia").
Although our discussion thus far has
concerned the generation of saccades, the
same considerations about mechanical
properties of the orbit apply to the com-
mands for all types of eye movement.
Studies of the activity of ocular motoneu-
rons in alert monkeys have shown that the
neural commands for all conjugate move-
tThe mechanical properties of the orbital contents
actually dictate a need for a more complicated ocular
motor command than a pulse and a step (see Fig.
3-5, Chap. 3).
ments (vestibular, optokinetic, saccadic,
and pursuit) and for vergence movements
have both velocity and position compo-
nents.24'41'49 How are the velocity and po-
sition components of the ocular motor
commands synthesized?
Neurophysiological evidence indicates
that the position command (e.g., for sac-
cades, the step) is generated from the ve-
locity command (e.g., for saccades, the
pulse) by the mathematical process of inte-
gration with respect to time. A neural net-
work integrates, in this mathematical
sense, velocity-coded signals into position-
coded signals; this network is referred to
as the neural integrator.2'5*1 When this pro-
cess is faulty, the eye is carried to its new
position by the pulse but cannot be
held there and drifts back to the central
position. This is evident clinically as gaze-
evoked nystagmus (see VIDEO: "Gaze-
evoked, rebound and downbeat nystag-
mus"). Since all types of conjugate eye
movements require both velocity-coded
and position-coded changes in innerva-
tion, all versional eye movement com-
mands need access to a common neural
integrator. Experimental lesions of struc-
tures vital for neural integration affect all
classes of conjugate eye movements.11'18
Furthermore, it appears that vergence eye
movements are also synthesized from ve-
locity and position commands, the latter
being derived from a vergence integra-
tor.23
8 The Properties and Neural Substrate of Eye Movements
VESTIBULAR AND
OPTOKINETIC SYSTEMS
The Vestibulo-ocular Reflex:
Responses to Brief Angular and
Linear Head Movements
The vestibular system stabilizes gaze and
ensures clear vision during head move-
ments, especially those that occur during
locomotion. Vestibular eye movements are
generated much more promptly (i.e., at
shorter latency) than visually mediated
eye movements. This is because the accel-
eration sensors of the labyrinth signal mo-
tion of the head much sooner than the vi-
sual system can detect motion of images
on the retina. Thus, the angular vestibulo-
ocular reflex (VOR) (Fig. 1-4) generates
eye movements to compensate for head
movements at a latency of <16 msec,40
whereas visually mediated eye movements
are initiated with latencies >70 msec.12
This difference becomes an important is-
sue during locomotion because the head
perturbations that occur with each footfall
are at frequencies ranging from 0.5 to 5.0
Hz.20 Only the short-latency VOR is fast
enough to generate eye movements to
compensate for head perturbations at
these frequencies. This becomes clinically
evident in patients who have lost lab-
yrinthine function, who complain, for ex-
ample, that they cannot read street signs
while they are in motion.29
Although the VOR acts independently
of visually mediated eye movements, the
brain continuously monitors its perfor-
mance by evaluating the clarity of vision
during head movements. Thus, an appro-
priately sized eye movement must be gen-
erated by the VOR in order for the angle
of gaze (eye position in space) to be held
steady and the image of the world to re-
main fairly stationary upon the retina
(Fig. 1-4). If it is not, the performance of
the VOR undergoes adaptive changes to
restore optimal visuomotor performance.
The vestibular system can respond to
movements that have angular (rotational)
or linear (translational) components.17
The angular VOR (Fig. 1-4) depends on
the semicircular canals, of which there are
Figure 1-4. The angular vestibulo-ocular reflex
(VOR). As the head is rapidly turned to the left, the
eyes move by a corresponding amount in the orbit to
the right. Below, head position in space and eye posi-
tion in the orbit are plotted against time. Because the
movements of head and eye in orbit are equal and
opposite, the sum, eye position in space (the angle of
gaze or "gaze"), remains zero (bottom equation). If
gaze is held steady, then images do not slip on the
retina and vision remains clear. During viewing of
targets at optical infinity, eye rotations are equal and
opposite to head rotations. During viewing of near
targets, eye rotations are greater than head rotation,
because the eyes do not lie in the center of the head
(see Chap. 2 and 7).
three in each inner ear (see Fig. 2-1,
Chap. 2). In health, the semicircular
canals work together to sense head rota-
tions in any plane. However, when disease
affects an individual semicircular canal,
spontaneous eye movements (nystagmus)
may occur in the plane of that canal, re-
flecting a common evolutionary relation-
ship between individual semicircular canals
and the pulling directions of the extraocu-
lar muscles.15'56 An appreciation of this
fundamental physiologic and anatomic
feature of vestibulo-ocular control helps
one interpret various patterns of nystag-
mus observed in vestibular disease (see
VIDEO: "Nystagmus with benign paroxys-
mal positional vertigo"). Because the eyes
are not at the center of rotation of the
 A Survey of Eye Movements: Characteristics and Teleology

The translational VOR (Fig. 1-5) depends

on the otolithic organs, the utricle and the
saccule (see Fig. 2-IE). Otolith-ocular re-
flexes become important if a subject views
a near object, when eye rotations are gen-
erated to compensate for translation of the
head.54 Natural head movements have
both rotational and translational compo-
nents; the eye rotations to compensate for
them may have horizontal and vertical
components and must be appropriate for
the viewing distance of the visual scene.

Eye Movements in Response

Figure 1-5. The translational VOR. Before the head
movement (left panel), the subject fixates both the
right eye (RE) and left eye (LE) on a stationary, near
target, which requires convergence. As the subject's
head translates to his left (arrow), a compensatory eye
rotation movement to the right is generated. After
the head movement (right panel), note that the right
eye has rotated through a larger angle (than the left
eye) because of the asymmetry of the geometric rela-
tionship between each eye and the target. Eye rota-
tions are only necessary to compensate for head
translations while viewing near targets.
head, but are situated eccentrically, in the
orbits, pure head rotations also produce
translations, or linear displacements, of
the eye. This geometry becomes impor-
tant if head rotations occur during view-
ing of a near object, when the brain must
independently adjust the size of move-
ments of each eye so that they can remain
pointed at the object of regard.
to Sustained Rotations:
The Optokinetic System
Although the labyrinthine semicircular
canals reliably signal transient head rota-
tions, their Achilles' heel is a sustained ro-
tation (i.e., at low frequency), which they
signal progressively less accurately be-
cause of the mechanical properties of the
semicircular canals. If a subject is rotated
in darkness at a constant velocity, the slow
phases of vestibular nystagmus, which are
initially compensatory, decline in velocity
and after about 45 sec, the eyes become
stationary (Fig. 1-6). Sustained rotation
may occur naturally as a component of a
prolonged chase, and the declining vestib-
ular responses, if acting alone, would lead
to degradation of vision, thus threatening
survival. Hence there is a need for alterna-
tive means of stabilizing retinal images to
supplant the fading vestibular response.

Figure 1-6. Record (D.C. electro-oculography) of the vestibulo-ocular response to sustained rotation. Horizon-
tal eye position is plotted against time. At the arrow, the subject starts to rotate clockwise, in darkness, at 50°/sec,
and this velocity is maintained throughout the record. Initially there is a brisk nystagmus consisting of vestibu-
lar slow phases that hold gaze steady during the head rotation, and quick-phases that not only reset the eyes to
prevent them from lodging at the corners of the orbit but move them into the direction of head rotation. After
about 30 seconds of rotation, the nystagmus (i.e., the vestibular response) dies away. Because of the mechanical
limitations of the semicircular canals, the motion detectors cannot accurately inform the brain about sustained
rotations. Eventually, nystagmus develops in the opposite direction (reversal phase); this represents the effect of
short-term vestibular adaptation, a phenomenon discussed in Chap. 2. Upward deflections indicate rightward
eye movements.
10 The Properties and Neural Substrate of Eye Movements
Visually mediated eye movements can
serve this function, because sustained re-
sponses do not require a short latency of
action. In afoveate animals, such as the
rabbit, visually mediated eye movements
can only be driven if the entire visual
scene moves—the optokinetic response.
However, in foveate, frontally eyed
animals, both behavioral and neurophysi-
ological evidence suggests that smooth-
pursuit eye movements are mainly re-
sponsible for holding gaze on an object
during self-motion.43 The supplementa-
tion of the VOR by visually mediated eye
movements is more than a summation of
responses that are generated indepen-
dently. For example, in the vestibular
nuclei of the monkey, some neurons
are driven by both visual (optokinetic)
and vestibular stimuli, implying a neural
symbiosis.50-66 As the labyrinthine signal
declines, visual drives take over and main-
tain compensatory slow-phase eye move-
ments during sustained rotation.
Visually mediated eye movements also
supplement the translational VOR, when
the visual scene is close to the subject.8 In
this case, smooth-pursuit eye movements
are important, since they allow steady fix-
ation of a small, near target, the position
of which changes with respect to the back-
ground, as the subject translates. If we
view distant objects, no eye movements
are needed to compensate for head trans-
lations, but no matter what the viewing
distance, eye movements are always needed
to compensate for head rotations.
SACCADIC SYSTEM
Quick Phases
Most head movements are brief and re-
quire only small compensatory eye move-
ments to maintain the stability of gaze.
Any sustained head rotation, however,
would cause the eyes to lodge at the cor-
ners of the orbits in extreme contraversive
deviation, where they no longer could
make appropriate movements. This is not
observed, except in certain pathologic
states (see VIDEO: "Congenital ocular mo-
tor apraxia"), because of corrective quick
phases (Fig. 1-6). These rapid eye move-
ments, the evolutionary forerunners of
voluntary saccades, have been likened to a
resetting mechanism for the eye. In fact,
they do more than this since, during head
rotation, quick phases move the eyes in
the orbit in the same anticompensatory di-
rection (Fig. 1-6) as that of head rotation
and thus enable perusal of the oncoming
visual scene.42 Quick phases of nystagmus
are rapid, with maximal velocities as high
as 500 /sec, repositioning the eye in the
shortest time possible. The anatomic sub-
strate of these rapid eye movements is in
the paramedian reticular formation of the
pons and mesencephalon, the same as that
for saccades.9
Voluntary Saccades
Foveate animals have developed the abil-
ity to redirect the line of sight even in the
absence of head movements: they have
both quick phases and voluntary saccades.
With the evolution of the fovea, it became
important to be able to direct this special-
ized area of the retina at the object of in-
terest. Saccades may be triggered in day-
to-day life by objects actually seen or
heard, from memory, or as part of an in-
voluntary natural strategy to scan the vi-
sual scene. There is usually a delay of
about 200 msec from the stimulus for a
saccade until its enactment, and this time
presumably includes neural processing in
the retinal, cerebral cortex, superior col-
liculus, and cerebellum. The final neural
instruction for voluntary saccades arises
from the same brain stem neurons in the
paramedian reticular formation that gen-
erate the quick phases of nystagmus.
SMOOTH PURSUIT AND
VISUAL FIXATION
Smooth Pursuit
With the evolution of a fovea, the need to
track a moving object smoothly also arose.
This is possible to only a limited degree
with saccadic movements, since, once cap-
 A Survey of Eye Movements: Characteristics and Teleology
tured on the fovea by a saccade, the image
of the moving target soon slides off again,
with a consequent decline in visual acuity.
The pursuit system, however, generates
smooth tracking movements of the eyes
that closely match the pace of the target.
To overcome the delays inherent in the vi-
sual system (the latency of responses,
which ranges between 70 and 120 msec),
predictive mechanisms can adjust the eye
movements when the motion of the target
can be anticipated. 4 It seems possible that
smooth-pursuit eye movements evolved in
response to the need to sustain foveal fixa-
tion on a near target during self-motion
(translation).43 In this case, to compensate
for movement of the head, the visual sys-
tem would need to generate eye move-
ments appropriate for the proximity of
the near target, and despite relative mo-
tion between the near target and back-
ground.
More than vision can be used to gener-
ate pursuit, as some normal subjects can
follow their own fingers in the dark. 59 The
brain relies on a number of sensory inputs
and its own motor efforts to determine the
motion of the target of interest. Impaired
smooth pursuit is a sensitive sign of neuro-
logic dysfunction but alone, does not allow
accurate localization. Recent studies of vi-
sual processing in cerebral cortex and the
effects of discrete lesions have clarified
much about the neural substrate of smooth
pursuit.31
Visual Fixation
Visual fixation of a stationary target may
represent a special case of smooth pur-
suit—suppression of image motion caused
by unwanted drifts of the eyes68—but it
might also be due to an independent vi-
sual fixation system.38 Such a mechanism
would reflect the ability of the visual sys-
tem to detect retinal image motion caused
by unwanted drifts of the eyes and pro-
gram corrective movements. Another as-
pect of steady fixation is the ability to sup-
press saccadic eye movements that turn
the fovea away from the object of interest.
Thus, certain neurons in the frontal eye
fields and superior colliculus seem impor-
11
tant for suppressing saccades when steady
fixation of a target (e.g., threading a nee-
dle) is necessary.61 The concept of a fixa-
tion system becomes important in certain
disease states. For example, after a periph-
eral vestibular lesion, the nystagmus is
"suppressed" if visual fixation of a station-
ary object is possible. On the other hand,
unwanted saccades may intrude on steady
fixation, for example, as opsoclonus (see
VIDEO: "Opsoclonus").
Similarities and Differences
between Fixation, Smooth-
Pursuit, and Optokinetic
Eye Movements
We have described three situations in
which smooth, sustained eye movements
may be made in response to motion of im-
ages across the retina. Such eye move-
ments produced in response to viewing
the whole visual scene during sustained
self-rotation are referred to as Optokinetic.
When they oppose drifts of the eyes di-
rected away from a stationary target, they
are called fixation. And when they are used
to smoothly follow a moving object or
maintain fixation on a near, stationary tar-
get during self-motion, they are termed
smooth pursuit. In each of these cases, areas
of cerebral cortex extract information
about the direction and speed of retinal
image slip from each eye, so that brain
stem and cerebellar circuits can program
an eye movement. The overlap and inter-
action among these types of eye move-
ments are discussed in later chapters.
Here, however, we present them as three
different functional classes of eye move-
ments; their different purposes and prop-
erties lead to distinct methods of testing
during clinical and laboratory examina-
tions.
COMBINED MOVEMENTS OF
THE EYES AND HEAD
The study of eye movements with the
head held stationary is useful for inves-
tigative purposes, but this kind of study
12 The Properties and Neural Substrate of Eye Movements
is artificial; during natural behavior, hu-
mans usually move their eyes and head to-
gether. We have already indicated how
vestibular responses compensate for head
perturbations due to locomotion. Such
vestibular drives, however, may become an
encumbrance when voluntary changes of
the angle of gaze (eye position in space),
using the eyes and head, are required. For
example, if we were smoothly tracking a
target moving to the right with a com-
bined movement of the eyes and head, the
eyes would continually be taken off target
to the left if the VOR went unchecked. In
fact, however, the eyes remain relatively
stationary in the orbit as if the VOR were
turned off. This implies an ability to over-
ride those vestibular drives invoked by
voluntary head movements made to track
a moving target. Current evidence sug-
gests that the VOR signal is mainly can-
celed by an equal but opposite smooth-
pursuit signal, but a direct adjustment of
the basic VOR response itself also takes
place.19'28
During rapid gaze changes, achieved
with the eyes and head, saccadic and ves-
tibular signals are appropriately combined
so that gaze is accurately redirected to-
ward the desired target; this may be
achieved by either adding the two oppo-
sitely-directed signals or by effectively
disconnecting the VOR.35 Which process
takes place may depend upon the size of
the gaze change;63 for larger movements
that exceed the ocular motor range, dis-
connecting the VOR may be the major
strategy.62
VERGENCE EYE MOVEMENTS
With the development of frontal vision, it
became possible to direct both foveas at
one object of interest. This requires dis-
junctive or vergence movements that, in
contrast to conjugate or versional move-
ments, move the eyes in opposite direc-
tions. There are two principal types of
vergence movement: fusional and accom-
modative. Fusional vergence movements oc-
cur in response to disparity between the
location of images on the retina of each
eye. This type of vergence eye movement
may be elicited at the bedside by placing a
wedge prism before one eye. Accommoda-
tive vergence is stimulated by loss of focus of
images (blur) on the retina and occurs in
association with accommodation of the
lens and pupillary constriction, as part
of the near triad. Accommodative effort
alone can produce vergence movements.
Thus, if one eye is covered and the other
eye suddenly changes fixation from a dis-
tant to a near target, then the eye under
cover responds by converging. The same
effect may be induced by placing a nega-
tive diopter (minus) lens in front of the
viewing eye. Other stimuli that are impor-
tant inputs for vergence, include the sense
of nearness of the object of interest and a
sense of motion of the target away from or
toward oneself (looming).
When vergence eye movements are per-
formed alone, they are characteristically
slow. Under natural conditions, however,
vergence movements are invariably ac-
companied by saccades, since the position
of most objects in our environment differs
in both the frontal plane (horizontal and
vertical) and in distance (depth). When
vergence movements are accompanied by
saccades, they appear to be much faster,69
and the nature of the interaction of these
two types of movements has received sub-
stantial recent investigation. In particular,
the degree to which the innervation to
each eye can be modified independently
of the other is a crucial question in ocular
motor control. Abnormalities of vergence
are responsible for many symptomatic oc-
ular motor disorders.
THREE-DIMENSIONAL
ASPECTS OF EYE MOVEMENTS
Conventionally, the eyes are described as
rotating about three axes, which intersect
at the center of the globe: X (parasagittal),
Z (vertical), and Y (transverse); these are
shown in Figure 9-3 in Chapter 9. The
choice of the coordinate system becomes
important when considering the implica-
tions of Listing's and Bonders' laws, which
 A Survey of Eye Movements: Characteristics and Teleology
describe the properties of 3-D eye rota-
tions. Listing's law states that all eccentric
eye positions are reached from the pri-
mary position* by a rotation about a single
axis that lies in the frontal or Listing's
plane (Fig. 9-3). Danders' law states that
the torsional orientation of the eye around
the line of sight that is associated with any
given horizontal and vertical displacement
from primary position is constant, regard-
less of the path by which the eye reached
that eccentric position. The actual angle of
torsion (i.e., the tilt of the eye ball with re-
spect to the earth-vertical axis) can be pre-
dicted from Listing's law.
There has been considerable interest in
the neural and mechanical factors that
control these aspects of 3-D rotations.
With the development of reliable method-
ology to measure torsion—the orientation
of the globe around its visual axis (Fig.
1-1)—it has been confirmed that Listing's
and Donders' laws are approximately
obeyed. The relative contributions made
by the mechanical and suspensory proper-
ties of the orbital tissues on the one hand,
and by neural factors on the other, in de-
termining Listing's law remain to be de-
termined; this is discussed further in
Chapter 9. Measurements of tilts and dis-
tortions of Listing's plane are providing a
new tool for clinicians to better under-
stand the underlying pathogenesis of ab-
normal eye movements, especially those
related to torsion. Even at the bedside, ob-
servation of 3-dimensional aspects of eye
movements may prove valuable. For ex-
ample, determination of how the axis of
rotation of nystagmus changes as the eye
is moved into lateral, up, or down gaze,
whether conforming to a head-fixed or an
eye-fixed coordinate system, may suggest
the pathogenesis of the disorder (see
Chap. 10).
+The term primary position is now defined with ref-
erence to Listing's law: it is the position from which
purely horizontal or purely vertical rotations of the
eye are unassociated with any torsion. In this book,
we use the term central position simply to denote that
the eye is pointing straight ahead (visual axis is paral-
lel to the midsagittal plane of the head).
13
ADAPTIVE CONTROL OF
EYE MOVEMENTS
In order to achieve clear, stable, single vi-
sion, the control of eye movements must be
accurate. One of the most impressive as-
pects of ocular motor control is the way in
which the brain constantly monitors its
performance and, in the face of disease and
aging, adjusts its strategies accordingly. For
example, the performance of the VOR can
be appropriately modified to new visual
circumstances (e.g., a change in spectacle
lens correction).10 Furthermore, inaccurate
saccades and deficient smooth pursuit
caused, for example, by abducens nerve
palsy, can be corrected.45 Even the yoking
of conjugate eye movements is under some
degree of adaptive control.3 The cerebel-
lum plays a central role in recalibrating oc-
ular motor reflexes for optimal visual per-
formance.47 Within the cerebellum are a
variety of neurons that appear to influence
eye movements. The vestibulocerebellum
(flocculus and nodulus) is particularly im-
portant in the control of smooth pursuit, in
vestibular eye movements, and in holding
positions of gaze. The dorsal vermis (lob-
ules V-VII) and underlying fastigial nu-
cleus enable both saccades and pursuit to
be accurate. Thus, disease affecting the
cerebellum may not only disrupt the con-
trol of eye movements but also impair the
individual's ability to correct them.
Recent research has shown that the
adaptive repertoire consists of many levels
of response to disease, from relatively
low-level adjustments in innervation to
higher-level strategies that may depend
upon the context in which they are
elicited.21'33'55 Thus patients may develop
different adaptive states that, based upon
the stimulus context, allow for different
innervational commands for the same
type of eye movement.
VOLUNTARY CONTROL OF
EYE MOVEMENTS
The control of eye movements ranges
from the most reflexive responses (e.g., a
14 The Properties and Neural Substrate of Eye Movements
quick-phase of vestibular nystagmus) to
eye movements that are willed without a
sensory stimulus (e.g., a saccade made to a
remembered or imagined location). Vol-
untary control of gaze depends upon a
number of areas in cerebral cortex; their
separate contributions have been eluci-
dated by electrophysiological and lesion
studies in monkeys. Homologous areas
have been suggested in humans, based on
studies of either the behavioral effects of
discrete lesions or functional imaging (see
Fig. 6-8).
From these cortical areas, parallel pro-
jections descend via the basal ganglion
and superior colliculus to the brain stem
and cerebellum. Certain neurons in these
pathways may encode mismatches be-
tween eye and target positions, which can
be used to program more than one type
of eye movement.34 There is some ap-
parent redundancy of these pathways,
so that lesions affecting one cortical area
tend not to produce a permanent defect
of voluntary gaze. Thus, independent
lesions of either the frontal or parietal
eye fields in monkeys produce subtle,
chronic defects of saccadic eye move-
ment control. However, combined lesions
of these structures cause more severe
and enduring limitation of ocular motil-
ity (see VIDEO: "Acquired ocular motor
apraxia").39
An important issue in the control of
voluntary eye movements is the way
that the brain transforms sensory sig-
nals into motor commands. Visual stimuli
are encoded in a place code, such as
the topographic map of the visual fields
in primary visual cortex, while ocular
motoneurons encode the properties of
an eye movement in their temporal dis-
charge characteristics (Fig. 1-3). Thus a
spatial-temporal transformation of neural
signals is required if, for example, a sac-
cade is to be made in response to a vi-
sual target. The site and mechanism
by which this transformation is achieved
are subjects of present research. Corti-
cal areas, the superior colliculus, cerebel-
lum, and brain stem reticular formation
may all contribute to this transforma-
tion.44
EYE MOVEMENTS AND
SPATIAL LOCALIZATION
Because the eyes, head, and body can all
move, the retinal location of an image can-
not specify the position of the object in
space. For this to occur, information is re-
quired concerning the direction of gaze
(eye in space), and this in turn must be
computed from information about the po-
sition of the eye in the orbit and the direc-
tion in which the head and body point.
Neurophysiological studies of the parietal
lobe have demonstrated neurons with vi-
sual responses that are influenced by the
direction of gaze and take into account the
direction in which the head points.6 Such
neuronal behavior is a prerequisite for en-
coding the location of objects in a head-
centered frame of reference.
The mechanism by which the brain de-
termines the position of the eyes in the
head is not settled. The most widely ac-
cepted mechanism is that the brain inter-
nally monitors its own motor commands
(efference copy or corollary discharge).5'58'65
Another possibility is proprioceptive in-
formation from the extraocular muscles.
Although there appears to be no stretch
reflex in the extraocular muscles,32 pro-
prioceptors do exist in extraocular mus-
cle,48'60 and they project to the brain stem
via the ophthalmic division of the trigemi-
nal nerve.46 If this nerve is cut, eye move-
ment control is not acutely affected; this
implies that proprioception is not impor-
tant in the planning of saccades, thus ef-
ference copy must provide information on
eye position.27 Recent studies, however,
indicate that extraocular proprioception
may be much more important than previ-
ously thought in recovery from ocular mo-
tor palsy,37 in phoria adaptation,25 deter-
mining saccadic accuracy when visual cues
are absent (such as for memory-guided
saccades),1 and in the control of eye posi-
tion in patients with misalignment of their
visual axes—strabismus.36 Proprioception
may also play a role in determining the
position of small visual targets in the ab-
sence of other background visual informa-
tion that can be used to reference the posi-
tion of the eye to the visual target.64
 A Survey of Eye Movements: Characteristics and Teleology
Finally, there is evidence that the brain
may estimate the direction of gaze on the
basis of visual cues. Thus, when normal
subjects make saccades to the remembered
locations of targets, their eye movements
are influenced by position of the visual
background on which a target light was
flashed.70
THE SCIENTIFIC METHOD
APPLIED TO THE STUDY OF
EYE MOVEMENTS
Our understanding of the way that the
brain controls eye movements has ad-
vanced conceptually because of the scien-
tific method of formulating and testing hy-
potheses, an approach championed in this
field by D.A. Robinson. A wealth of infor-
mation concerning the neural mecha-
nisms for control of eye movements has
been provided by electrophysiological and
lesion studies in trained monkeys; this in-
formation can be readily applied to un-
derstanding of the effects of human dis-
ease by developing testable hypotheses.
Conversely, the careful study of patients
with disorders of eye movements, with
these hypotheses in mind, has led to a bet-
ter understanding of how the normal
brain functions. In this regard, the study
of eye movements offers a further advan-
tage because it is relatively easy to con-
struct hypotheses that are quantitative
(mathematical models). The most useful
approaches have been the application of
control systems analysis to understanding
the effects of feedback and oscillations and
the use of neural networks to account for
the behavior of populations of neurons.
Not all clinicians will want to attempt
quantitative mathematical descriptions of
disturbed forms of eye movement, but an
understanding of certain simple principles
of control systems analysis may help in the
bedside interpretation of clinical signs.
For example, a mismatch of the pulse and
step is the cause of the adduction lag en-
countered in internuclear ophthalmople-
gia (see VIDEO: "Unilateral internuclear
ophthalmoplegia"). Furthermore, qualita-
15
tive tests of hypotheses concerning the
control of eye movements are often possi-
ble using careful clinical observations.
Throughout the remaining chapters, we
will refer to certain relatively basic princi-
ples of control systems analysis that have
direct clinical implications.
SUMMARY
1. Normal eye movements are a prereq-
uisite for clear, stable, single vision.
For best vision of objects, such as the
words of a book, the images must be
brought to the fovea of the retina and
held there with image drift of less
than about 5°/sec.
2. Eye movements can be best under-
stood by considering their functions.
Of the conjugate types of eye move-
ments, vestibular, optokinetic, and vi-
sual fixation systems act to hold im-
ages of the seen world steady on the
retina; their function is to hold gaze
steady. Saccades, smooth pursuit, and
vergence eye movements work to-
gether to acquire and hold images of
objects of interest on the fovea; their
function is to shift gaze. Vergence
movements have both gaze-holding
and gaze-shifting properties.
3. To move the eyes conjugately (for ex-
ample, as a saccade) requires a phasic-
tonic or pulse-step of innervation (Fig.
1-3). The pulse moves the eyes
rapidly against viscous forces and the
step holds the eyes steady against elas-
tic restoring forces. The pulse is a ve-
locity command; the step is a position
command. All eye movement com-
mands have velocity and position
components. Position components are
created from velocity components by a
process of mathematical integration,
performed by the nervous system.
4. Vestibular and visually mediated eye
movements work together to main-
tain clear vision during head move-
ments—both rotations (Fig. 1-4) and
translations (Fig. 1-5). The vestibulo-
ocular reflex promptly produces eye
movements to compensate for the
16 The Properties and Neural Substrate of Eye Movements
brief head perturbations that occur
during most natural activities. Dur-
ing sustained head rotations and
translations, visually mediated eye
movements supplement the vestibu-
lar response. If one fixes upon a near
object, there must also be an adjust-
ment for the translational compo-
nents of head motion.
5. With the evolution of the fovea and
frontal vision, saccadic, smooth pur-
suit, fixation, and vergence systems
became necessary. These gaze-shifting
movements are under voluntary con-
trol, thus it is possible to choose
which part of the visual scene one
wants to scrutinize using the fovea.
6. The performance of the ocular motor
system undergoes constant recalibra-
tion and readjustment to assure opti-
mal visual capabilities. The cerebel-
lum plays an important role in this
adaptive control of eye movements.
7. An understanding of the properties
of each functional class of eye move-
ments (Table 1-1) will guide the
physical examination. Knowledge of
the neural substrate of each class of
eye movements will aid topological
diagnosis. Knowledge of current hy-
potheses of the control of eye move-
ments aid the interpretation of dis-
orders of ocular motility and may
advance understanding of how the
brain controls movements of the eyes
in normal human beings.
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Chapter 2
THE VESTIBULAR-
OPTOKINETIC SYSTEM
FUNCTION OF THE
VESTIBULAR-OPTOKINETIC SYSTEM
Head Rotations and Translations
Head Tilt
Vestibular-Visual Symbiosis
ANATOMY AND PHYSIOLOGY OF THE
PERIPHERAL VESTIBULAR SYSTEM
Structure of the Labyrinth
Blood Supply and Innervation of the
Labyrinth
Mechanical Properties of the Semicircular
Canals and Otolith Organs
Neural Activity in Vestibular Afferents
BRAIN STEM ELABORATION OF THE
VESTIBULO-OCULAR REFLEX
Anatomic Organization of the
Vestibulo-ocular Reflex
Neurophysiology of the Vestibulo-ocular
Reflex
The Velocity-Storage Mechanism
NEURAL SUBSTRATE FOR OPTOKINETIC
RESPONSES
QUANTITATIVE ASPECTS OF THE
VESTIBULAR-OPTOKINETIC SYSTEM
VOR Gain and Phase: General
Characteristics
Three-Dimensional Aspects of the VOR
Optokinetic Nystagmus
Optokinetic After-Nystagmus
Cervico-ocular Reflex (COR)
ADAPTIVE PROPERTIES OF THE
VESTIBULO-OCULAR REFLEX
VOR Habituation
Short-Term VOR Adaptation that Produces
the Reversal Phases of Nystagmus
Visually Induced Adaptation of the VOR
Mechanisms of Recovery from Lesions in
the Labyrinth
VESTIBULOCEREBELLAR INFLUENCES
ON THE VESTIBULO-OCULAR REFLEX
Anatomical Pathways by which the Vestibu-
locerebellum Influences the VOR
Electrophysiological Aspects of Vestibulo-
cerebellar Control of the VOR
Effects of Vestibulocerebellar Lesions on the
VOR
Role of Cerebellum in VOR Adaptation
VESTIBULAR SENSATION
CLINICAL EXAMINATION OF
VESTIBULAR AND OPTOKINETIC
FUNCTION
General Principles for Evaluating Vestibular
Disorders
History-Taking in Patients with Vestibular
Disorders
Clinical Examination of Patients with
Vestibular Disorders
LABORATORY EVALUATION OF
VESTIBULAR AND OPTOKINETIC
FUNCTION
Quantitative Caloric Testing
Quantitative Rotational Testing
Optokinetic Testing
Testing Otolith-Ocular Responses
PATHOPHYSIOLOGY OF DISORDERS OF
THE VESTIBULAR SYSTEM
Pathophysiology of Acute Unilateral Disease
of the Labyrinth or Vestibular Nerve
Pathophysiology of Bilateral Loss of
Vestibular Function
Pathophysiology of Lesions of Central
Vestibular Connections
19
20 The Properties and Neural Substrate of Eye Movements

Pathophysiology of Disorders of the Historically, quantitative descriptions of

Optokinetic System
SUMMARY
This chapter deals with those ocular mo-
tor systems that hold images steady upon
the retina during movements of the head.
This ocular gyroscopic function guaran-
tees clear and stable vision during natural
activities that induce head perturbations,
such as locomotion (Fig. 7-1). To hold the
angle of gaze steady, the brain uses pri-
marily labyrinthine and visual cues, al-
though in disease, somatosensory infor-
mation from muscle spindles and joint
receptors may substitute for deficient ves-
tibular signals.
vestibular and optokinetic behavior long
preceded any knowledge of the substrate
for these reflexes. In 1796, Erasmus Dar-
win described how body rotation induced
movement of the eyes,113 and in 1819,
Purkinje reported how optokinetic nystag-
mus and sensations of movement were
produced while watching a cavalry pa-
rade.217 The mechanisms for these phe-
nomena were unknown and the prevailing
notion was that sensations of movement
emanated from cutaneous receptors that
detected displacement of the body fluids.
The important role of the vestibular organ
in initiating eye movements that compen-
sate for head movements was first demon-
strated by Flourens179 and later elaborated
upon by Ewald.164 These pioneers noted

Table 2-1. The Vestibular-Optokinetic System:

A Glossary of Terms and Abbreviations
Circularvection Illusion of self-rotation induced during optokinetic stimulation
Eccentric rotation Rotation around an earth-vertical axis with the head located away from
(usually in front of) the usual axis of rotation
Gain Ratio of output (e.g., eye velocity) to input (e.g., head velocity)
Ocular counterrolling Torsional rotations of the eyes induced by rolling the head, ear to shoul-
der. During rotation the response is generated by the r-VOR. When
the head is kept in the tilted position, the torsional response is driven
by a static otolith-ocular reflex.
OKN Optokinetic nystagmus
OKAN Optokinetic after-nystagmus (usually measured in darkness), which fol-
lows a period of optokinetic stimulation
Oscillopsia Illusory, to-and-fro movements of the environment
OVAR Off-vertical axis rotation. Rotation about an axis tilted from earth-
vertical
Phase Measure of the temporal synchrony between input (e.g., head velocity)
and output (e.g., eye velocity)
Time constant Time taken for slow-phase eye velocity to decline to 37% of its initial
value after the onset of a velocity-step stimulus
Velocity step stimulus Sudden acceleration ("impulse") to a constant velocity rotation
Velocity storage Central vestibular mechanism whereby the peripheral labyrinthine re-
sponse is prolonged or perseverated. Optokinetic after-nystagmus
(OKAN) is also generated by this mechanism
Vertigo Illusion of movement (usually turning) of self or environment
VOR Vestibulo-ocular reflex
r-VOR Rotational VOR, compensatory slow phase driven by the semicircular
canals in response to angular motion of the head
t-VOR Translational VOR, compensatory slow phase driven by the otolith or-
gans in response to linear motion of the head

that opening or applying pressure to the
lumen of the semicircular canals of ani-
mals produced movements of the head or
eyes in the plane of the canal being stud-
ied. Ewald also first emphasized that there
must be resting tone in the vestibular nu-
clei even when the head was still. This dis-
covery of the significance of the vestibular
organ led to systematic clinical study of
vestibular function. Barany41 formalized
aspects of rotational testing and intro-
duced positional and caloric stimulation of
the vestibular labyrinth. Mach237 and Ter
Braak463 predicted from human and ani-
mal studies that vestibular and visual in-
formation must interact centrally, a notion
that modern neurophysiologic research
has confirmed. Steinhausen448 developed
the mathematical equations to describe
how the cupula is able to transduce head
motion.
In this chapter, we will (1) identify the
functional demands made of the vestib-
ular-optokinetic system during natural
activities; (2) discuss its inner workings;
(3) summarize the quantitative perfor-
mance of this system in response to nat-
ural and laboratory stimuli; (4) describe
testing of patients with vestibular disease;
and (5) apply these principles to under-
stand the pathophysiology of vestibu-
lar disorders. A glossary of commonly
used terms and abbreviations appears in
Table 2-1.
FUNCTION OF THE
VESTIBULAR-OPTOKINETIC
SYSTEM
Head Rotations and Translations
The vestibular system must respond to
both the angular (rotational) and linear
(translational) components of head mo-
tion. To be more precise, eye rotations
must compensate for movements of the
orbits. Angular and linear motions of the
head are sensed by different structures.
The semicircular canals respond to angu-
lar acceleration, and the otoliths respond
to linear acceleration. Together, they pro-
vide the inputs for the vestibulo-ocular re-
The Vestibular-Optokinetic System 21
flex (VOR). The response to the rotational
(angular) component of head motion is
called the r-VOR, and the response to the
translational (linear) component of head
motion is called the t-VOR (see Figs. 1-4
and 1-5). A third type of VOR, called ocu-
lar counterrolling, is also mediated by the
otoliths and responds to linear accelera-
tion, but, in this case, the stimulus is a
change in the static orientation of the
head with respect to the pull of gravity. In
response to a sustained tilt of the head to
one side, there is a small change in static
torsion (counterrolling) of the eyes in the
opposite direction to the head tilt.
The r-VOR responds to the three possi-
ble directions of head rotation, producing
horizontal (around the rostral-caudal,
yaw, or z-axis), vertical (around the in-
teraural, pitch, or y-axis) and torsional
(around the naso-occipital, roll, or x-axis)
eye movements. The t-VOR responds to
three possible directions of head transla-
tion, producing horizontal (heave, along
the interaural axis), vertical (bob, along the
dorsal-ventral axis) and vergence (surge,
along the naso-occipital axis) eye move-
ments. Since the eyes are horizontally sep-
arated and the axis of rotation of the head
is usually behind the eyes, rotational head
movements invariably produce transla-
tions, or linear displacements, of the or-
bits. Even if the axis of rotation is centered
on one orbit, the other eye will still be
translated during rotation of the head.
The compensation for translation of the
orbits, during both rotations and pure
translations of the head, is a function of
the distance of the point of regard from
the head (the viewing distance}. The closer
the object of interest, the larger the com-
pensatory response must be to prevent
unwanted motion of images on the retina
(for an equation that approximately re-
lates these variables, see Laboratory Eval-
uation of Eye-Head Movements, Chap. 7).
Furthermore, depending upon the loca-
tions of the axis of rotation of the head rel-
ative to the two eyes (e.g., closer to one eye
than the other), and the location of the ob-
ject of interest relative to the location of
the two eyes (e.g., on the midline or off to
one side), the brain must adjust the move-
ments of each eye independently, so that
22 The Properties and Neural Substrate of Eye Movements
they can both remain pointed at the object
of regard during any pattern of head mo-
tion.
Most naturally occurring rotational
head perturbations are of high frequency
(0.5 to 5.0 cycles/sec), commonly due to vi-
brations from heel strike, which are trans-
mitted through the body to the head dur-
ing walking (see Chap. 7, Fig. 7-1). These
head movements are compensated for by
an oligosynaptic pathway consisting of
three or four neurons. This pathway, the
elementary VOR,454 extends from the
labyrinth to the extraocular muscles. The
r-VOR has a latency of action (i.e., time
from start of head turn to initiation of
compensatory eye rotation) that has been
reported to be in the range of 7 to 15 msec
depending on the sensitivity of the record-
ing system.196'267'314'455 No other sensory
mechanism that contributes to the genera-
tion of eye movements compensating for
head movements is so prompt in its action.
If the VOR fails due to disease, then vision
during locomotion is impaired. The ef-
fects of "living without a balancing mecha-
nism" were reported vividly by a physician
who had lost labyrinthine function after
receiving streptomycin.263 When walking
in the street, he could not recognize faces
or read signs unless he stood still. These
symptoms indicate that visual-following
reflexes, because of slow retinal process-
ing, cannot adequately substitute for the
VOR during natural head movements. In-
deed, the latency of visual-mediated eye
movements is >75 msec.197
It should be noted that head rotations
in roll (around the anterior-posterior axis
of the head) place different demands
upon the VOR than do head rotations in
yaw (horizontally) or in pitch (vertically).
This is because head movements in roll,
while the subject views straight ahead, do
not displace images from the fovea; only
in the periphery of the retina will appre-
ciable slip of images occur. Likewise, the
torsional compensatory responses to head
rotations in the roll plane need not be
modulated for viewing distance, as is the
case for the horizontal and vertical VOR.
So, from a visual standpoint, the torsional
VOR need not be as efficient as its hori-
zontal and vertical counterparts.
Head Tilt
The otolith organs provide an afferent sig-
nal by virtue of their sensitivity to linear
accelerations. During translation of the
head, their signals are transformed into
the t-VOR. But the otoliths also respond to
the pull of gravity, the most pervasive
form of linear acceleration. Hence, when
the static attitude of the otoliths is altered
relative to gravity, a tilt of the head is sig-
naled and a compensatory reorientation
of the eyes occurs. The action of this static
otolith-ocular reflex can be seen clearly
in afoveate, lateral-eyed animals such as
the rabbit. When the head is tilted later-
ally and kept there, the eyes are moved
and held in a compensatory position along
the horizontal meridian (one up and the
other down, in a physiological skew devia-
tion). When the head is pitched forwards
or backwards, the eyes counterroll and are
then held in their new position to keep the
retinas aligned with the horizontal merid-
ian. In human beings, if the head is
pitched forward (chin to chest), the object
of interest can be fixed upon using sac-
cades, so that static compensatory eye
movements to keep the retina aligned
along the horizontal meridian are unnec-
essary. When the head is tilted laterally,
a dynamic component, primarily medi-
ated by the semicircular canals, preserves
vision during the head movement. During
sustained lateral head tilts, however, we
still rely on the static otolith-ocular reflex
that produces ocular counterrolling, be-
cause we cannot make voluntary torsional
movements. Counterrolling of the eyes in
humans is vestigial and compensates for
only about 10% of the head tilt.19'124 This
paucity of response does not seem disad-
vantageous for vision because changes in
the torsional orientation of the retina have
little effect on foveal acuity. Nevertheless,
a fundamental question in vestibular
physiology is how, and to what degree, the
vestibular system resolves the inherent
ambiguity between translation and tilt.
The otolith organs respond in the same
way to linear accelerations of any type,
and their afferent discharge in itself does
not allow for a distinction between tilt and
translation.

Vcstibular-Visual Symbiosis
Both the translational and rotational
vestibulo-ocular reflexes (t-VOR and r-
VOR) perform optimally in response to
brief, high-frequency motion of the head.
Their ability to transduce reliably the mo-
tion of the head fades during sustained,
low-frequency head motion. Consequently,
other mechanisms must supplant the de-
clining vestibular response, and visual-
following reflexes assume the burden of
maintaining stability of images on the
retina during prolonged (low-frequency)
motion of the head.115'337'422 Specifically,
the optokinetic system appears to have
evolved to supplement the r-VOR. Its ac-
tion is best seen in lateral-eyed animals
(such as the rabbit) that do not have
foveae, and in which other forms of visual
tracking, such as smooth pursuit and ver-
gence, are rudimentary. Consider the rab-
bit as it moves in a large circle for 30 or 40
sec, a typical response when the animal is
being chased by predators. The rotational
component of this movement will have a
low frequency. Because of the mechanical
properties of the semicircular canals, the
r-VOR by itself can only hold the eyes
steady during the first few seconds of
turning (the cupula slowly returns toward
its initial position during a sustained rota-
tion). As the animal moves around the
circle, vestibulo-ocular compensation de-
clines and visual images of the seen world
increasingly slip across the retina. This is
the stimulus to the optokinetic system.
Consequently, vestibular compensation is
supplanted by optokinetic visual following
during sustained self-rotation.
When the optokinetic system is tested
artificially in the rabbit in isolation (for ex-
ample, using a drum rotating around the
animal to produce a sudden movement of
the visual surround at a constant velocity),
the optokinetic response slowly builds
(charges) over time until it reaches a veloc-
ity close to that of the stimulus. 121 Then, if
the lights are turned off, the optokinetic
system slowly discharges, producing an
optokinetic after-nystagmus (OKAN). This
charging and discharging behavior is just
the backup that is needed to supplant the
fading vestibular response during rotation
The Vestibular-Optokinetic System 23
in the light and to help suppress the inap-
propriate postrotatory vestibular nystag-
mus that occurs when the rabbit suddenly
stops its sustained rotation. These optoki-
netic responses are mediated centrally by
a velocity-storage mechanism (see below).
The t-VOR has similar limitations in its
ability to transduce low-frequency stimuli,
in this case, in response to linear motion of
the head. Translations of low frequency
are partially misinterpreted as tilts of the
head with respect to gravity. They pro-
duce both ocular counterroll and compen-
satory slow phases of vertical or horizontal
nystagmus.462 The actions of the t-VOR
are best seen in foveate animals. In lat-
eral eyed animals, the t-VOR and visual-
following responses are rudimentary; a
robust translational response in a lateral-
eyed animal could actually become a hin-
drance during forward motion in the en-
vironment by pinning the eyes onto the
visual scene behind the animal. The inher-
ently poor optokinetic response of lateral-
eyed animals to nasal-temporal-directed
motion could reflect the need to avoid
inappropriate visual stabilization during
forward locomotion.494
Once animals became foveate and frontal-
eyed, they evolved systems to focus their
lines of sight in a particular depth plane,
necessitating compensatory responses for
head translation that depend upon view-
ing distance.337 Like the t-VOR, the visual-
driven compensatory response for transla-
tion of the head depends upon the depth
plane of the target of interest. To maintain
fixation of objects of interest in that depth
plane, two mechanisms are required.
First, there must be a disjunctive mecha-
nism, vergence, for maintaining the align-
ment of eyes for the desired depth plane,
and second, there must be a conjugate
mechanism, pursuit, for keeping the line
of sight on the particular target of interest
within the desired depth plane. As might
be predicted, the frequency ranges in
which the t-VOR and pursuit function op-
timally are complementary.462
With the evolution of binocular, foveate
vision, circumstances arise when there
might be a conflict between the needs for
stabilization of images on the fovea and
for stabilization of images on the rest of
24 The Properties and Neural Substrate of Eye Movements
the retina. This might occur, for example,
when fixing upon a small object relatively
close to oneself, while walking. The more
distant background would move on the
retina in the opposite direction. In these
circumstances, the pursuit system, with its
attentional focus, dominates visual follow-
ing. A similar response can be seen when
foveate animals are subjected to artificial
movement of the visual environment, such
as within an optokinetic drum or with a
visual scene projected onto a tangent
screen. There is an immediate, almost in-
voluntary response, variously called the
direct, early, rapid, or immediate compo-
nent of optokinetic nystagmus (OKN) or,
more simply, the ocular-following response.3^
This response is likely mediated by pur-
suit pathways, but with a shorter latency
than seen with the onset of pursuit track-
ing of a small target. Perhaps with a full-
field stimulus, the time for the attentional
decision-making processes that are associ-
ated with voluntary pursuit of small ob-
jects can be circumvented. In humans,
optokinetic nystagmus is dominated by
smooth pursuit, blurring the distinction.
VOR suppression or cancellation of the VOR
refers to modulation of VOR responses
during combined eye-head tracking, when
the object of interest is not stationary. The
mechanism is related to smooth pursuit
and is discussed in Chapter 7.
ANATOMY AND PHYSIOLOGY
OF THE PERIPHERAL
VESTIBULAR SYSTEM
Structure of the Labyrinth
The membranous labyrinth lies within its
bony counterpart in the temporal bone,
cushioned by perilymph (Fig. 2-1A).240'505
It contains the cristae of the semicircular
canals, which sense head rotation, and the
maculae of the utricle and saccule, which
sense linear motion and static tilt of the
head. Both cristae and maculae contain
specialized hair cells of two forms (type I
and type II) that transduce mechani-
cal shearing forces into neural im-
pulses.126'200'240'312 The processes of each
hair cell consist of many stereocilia and one
kinocilium. The cilia are aligned so that
they react best to shearing forces applied
in a specific orientation. Deflection of the
stereocilia toward the kinocilium causes
depolarization (stimulation) of the hair
cell; deflection in the opposite direction
causes hyperpolarizationn (inhibition)315
(Fig. 2-1B). The processes of the hair cells
of the cristae are embedded in a gelati-
nous, sail-like structure, called the cupula.
One cupula lies in each of the ampullae
(regions of enlargement) of the three semi-
circular canals. Each turning movement of
the head causes the endolymph within the
semicircular canals to lag behind and to
bend the cupula and thus stimulate the
hair cells that lie at its base.
The hair cells of the maculae also have
their processes embedded in a gelatinous
membrane, but attached to this are cal-
cium carbonate crystals called otoconia
(Fig. 2-1C). The main stimulus to the
macula is linear acceleration of the head,
including the gravitational pull on the oto-
conia. The arrangement of the hair cells
on the macula, which is more complex
than that of the cristae, enables detection
of any linear motion permitted by three-
dimensionallspace. Hair cells of opposite
polarization tend to be aligned on either
side of a central stripe of hair cells called
the striola. The macula of the utricle lies
approximately in the horizontal plane and
the macula of the saccule approximately in
the parasagittal plane. They respond best
to linear accelerations in these planes, al-
though both are curved structures and re-
spond to some degree to linear accelera-
tion in any direction.
Blood Supply and Innervation
of the Labyrinth
The blood supply of the membranous
labyrinth is from the internal auditory or
labyrinthine artery.318 The labyrinthine
artery usually arises from the anterior in-
ferior cerebellar artery (AICA), but some-
times arises directly from the basilar
artery. After giving a branch to the eighth
nerve in the cerebellopontine angle, the
internal auditory artery traverses the in-
ternal auditory meatus. When it reaches

the labyrinth, it branches into (1) the ante-
rior vestibular artery, which supplies the an-
terior and lateral semicircular canals and
the utricular macula; (2) the vestibulo-
cochlear artery, also called the posterior ves-
tibular artery, which supplies the posterior
semicircular canal, the saccular macula,
and part of the cochlea; and (3) the
cochlear artery. The internal auditory
artery is an end artery; when it or its
source, the AICA, is occluded, inner ear
function is lost (see VIDEO: "Anterior infe-
rior cerebellar artery (AICA) distribution
infarction"). Selective occlusion of branches
of the internal auditory artery, such as
the anterior vestibular artery, may also
cause selective loss of labyrinthine func-
tion.177'206'360
Nerves from the cristae and maculae
pass through the perforations of the lam-
ina cribrosa to reach Scarpa's ganglion at
the lateral aspect of the internal auditory
canal. The vestibular nerve is divided into
two branches: the superior division, which
innervates the anterior and lateral semi-
circular canals and the utricle, and the in-
ferior division, which innervates the poste-
rior semicircular canal and saccule. The
superior branch runs with the facial nerve,
and the inferior branch runs with the
cochlear nerve. A small number of vestibu-
lar fibers may also run in the cochlear divi-
sion. The anterior vestibular artery sup-
plies the structures innervated by the
superior branch of the vestibular nerve,
and the posterior vestibular artery sup-
plies structures innervated by the inferior
branch. From Scarpa's ganglion, the ves-
tibular nerve passes medially, traversing
the cerebellopontine angle. It then lies
posterior to the cochlear nerve and below
the facial nerve, entering the brain stem
between the inferior cerebellar peduncle
and the spinal trigeminal tract, to synapse
in the vestibular nuclei.355
Mechanical Properties of
the Semicircular Canals and
Otolith Organs
The physical properties of the labyrinthine
motion sensors are important determi-
nants of the overall vestibular responses.
The Vestibular-Optokinetic System 25
The crista ampullaris is most sensitive to
brief head turns because of the proper-
ties of the cupula and surrounding en-
dolymph, which have been likened to
those of an overdamped torsion pendu-
lum.448'505 The internal diameter of the
semicircular canals is small relative to
their radius of curvature. Thus, given
the hydrodynamic properties of the en-
dolymph, the motion of endolymph, and
hence the change in the position of the
cupula, caused by a head rotation is ap-
proximately proportional to head veloc-
ity.139-505 Thus, the semicircular canals
mechanically integrate the angular head
acceleration that they sense, allowing
them to provide the brain with a head-
velocity signal. This has been confirmed
electrophysiologically by recordings from
semicircular canal afferents in the vestibu-
lar nerve.165'201 Another consequence of
these mechanical features is that only a
small amount of endolymph displacement
occurs, even with high-acceleration head
turns, and the cupula is not in danger of
being excessively displaced. With sus-
tained head rotations, the elastic proper-
ties of the cupula become important and
cause it to return to its resting position
with an exponentially decaying time
course. The time constant of return of the
cupula cannot be directly measured in hu-
mans, but it has been estimated to be
about 6 sec.115
The return of the cupula to its resting
position can be related to the decline in
nystagmus during velocity-step rotations
(an impulse of acceleration to some con-
stant velocity). This per-rotational nystag-
mus is greatest at the onset of the stimu-
lus, but then slow-phase velocity shows
an approximately exponential decline. If
the subject is suddenly stopped after sus-
tained, constant-velocity rotation, postro-
tational nystagmus will be produced. This
reflects displacement of the cupula in the
direction opposite to that when the rota-
tion began. In animals and probably in
humans, per-rotational nystagmus lasts
considerably longer than the time re-
quired for the cupula to drift back to its
starting position. This suggests that the
brain manipulates the canal signal so as to
prolong the time that motion of the head
can be perceived. This phenomenon is
26 The Properties and Neural Substrate of Eye Movements

Figure 2-1. (A) Schematic of the mammalian labyrinth. The crista of the lateral semicircular canal is shown but
not labeled. (B) Motion transduction by the vestibular hair cells. At rest there is a resting rate of action potential
discharge in the primary vestibular afferents (center). Shearing forces on the hair cells cause depolarization (left)
if the stereocilia are deflected toward the kinocilium (indicated by longest cilium, with beaded end), or hyper-
polarization (right) if the stereocilia are deflected away from the kinocilium. This modulates the discharge rate
in the vestibular nerve neuron. (C) Schematic drawing of a macula, showing how the cilia of the hair cells are
embedded in the gelatinous otolithic membrane, to which are attached calcium carbonate crystals, otoconia. (A
is redrawn after Wersall DJ, Bagger-Sjoback D. Morphology of the vestibular sense organs. In Kornhuber HH,
editors. Handbook of Sensory Physiology, Vol. VI/1, Vestibular System. New York: Springer; 1974; pp 123-170;
B is redrawn after Precht W. Vestibular mechanisms. Annu Rev Neurosci 1979;2:265-89; and C is adapted from
lurato S. Submicroscopic Structure of the Inner Ear. Oxford: Pergamon Press; 1967.)

mediated by the velocity-storage mecha-
nism, and is common to both vestibular
and optokinetic responses.
Flow of endolymph within each canal, in
one direction, produces excitation in its
ampullary nerve (increasing its discharge
rate) and, in the other direction, produces
inhibition. For the lateral (or horizontal)
canals, flow toward the ampulla (ampul-
lopetal flow) is excitatory. For the vertical
canals, flow away from the ampulla (am-
pullofugal flow) is excitatory. The semicir-
cular canals are arranged so that each ca-
nal on one side of the head is paired with
another on the opposite side, both lying in
nearly the same plane. Careful measure-
ments have shown that the relative planes
of the three canals vary among individu-
 The Vestibular-Optokinetic System 27

Figure 2-2. (A) Schematic summary of the ocular motor effects of stimulating individual semicircular canals and
combinations of canals. Stimulation of a single canal produces slow-phase movements of the eyes in a plane par-
allel to one in which the canal lies. As shown by the equations at the bottom, purely vertical nystagmus can only be
induced by simultaneous stimulation of the same canal on both sides. Purely torsional nystagmus can only be pro-
duced by stimulation of both vertical canals, but not the lateral canal, on one side. Thus, disease of the labyrinth
seldom produces purely vertical or purely torsional nystagmus. Combined involvement of all three canals on one
side causes a mixed horizontal-torsional nystagmus. (B) The effects of left utricular stimulation. Besides torsional
eye movements, there is a vertical deviation of the optic axes (skew deviation) and horizontal deviation away from
the side of stimulation. LAC, left anterior canal; LHC, left horizontal canal; LE, left eye; LPC, left posterior canal;
RAG, right anterior canal; RE, right eye; RHC, right horizontal canal; RFC, right posterior canal.

als,138 however, and complementary ca- ampullofugal flow of endolymph within

nals on opposite sides of the skull may not
be precisely aligned.457 Clearly, the brain
must make adjustments for such individ-
ual variations. Despite these small differ-
ences, the semicircular canals can be
thought of as working in pairs. Thus, an
the right anterior semicircular canal will
be accompanied by an ampullopetal flow
in the left posterior semicircular canal.
This push-pull arrangement stands the
organism in good stead in the event that
disease should destroy one labyrinth,
28 The Properties and Neural Substrate of Eye Movements
since the brain can then still use a (nor-
mal) decrease in activity from the intact
labyrinth to detect head rotation toward
the side of the lesion. The effects of stimu-
lating individual semicircular canals are
summarized in Figure 2-2A. Each canal
produces movements of the eyes in the
plane of that canal (Flourens' law). These
findings have important clinical signifi-
cance, which is discussed later in this
chapter in the section on disorders of the
vestibular-optokinetic system.
The physical properties of the otolith
maculae are more difficult to analyze than
those of the semicircular canals, but the
basic properties of the otolith organs are
well established.505 The utricular macula lies
on the floor of the utricle, approximately
in the plane of the lateral semicircular
canals. The saccular macula lies on the me-
dial wall of the saccule, nearly parasagittal
with respect to the head (i.e., in a plane
approximately orthogonal to the utricular
macula). The utricle is oriented to respond
best to lateral or fore-and-aft tilts, and
side-to-side translations of the head. The
saccule is oriented to respond best to up-
and-down translations of the head. Hence
these two otolith organs serve complemen-
tary roles in sensing gravitational and
other forces applied to the head. Because
the maculae are located eccentric to the
axes of rotation of the head, they are able
to sense both tangential and centrifugal
forces during head rotations.
The mechanism of action of the otoliths
is an inertia-generated shearing move-
ment of the otoconial layer, parallel to the
underlying surface of the sensory epithe-
lium. In this way, the otoliths can sense
both translational head movements (i.e.,
linear accelerations) and static tilts of the
head (with respect to the pull of gravity).
Electrical stimulation of the utricle and
saccule produces upward-torsional move-
ment of the ipsilateral eye and downward-
torsional movement of the contralateral
eye.133 Similar results are produced by
stimulation of the utricular nerve, al-
though there is also a horizontal compo-
nent452 (Fig. 2-2B). A behavioral study
suggested that the sacculus also can con-
tribute to ocular torsion, and perhaps to
disconjugate torsion.148 It must be reiter-
ated that the otolith maculae are curved,
not flat, structures and that both the sac-
cule and utricle can respond to some ex-
tent to linear accelerations in any direc-
tion.
Neural Activity in
Vestibular Affcrents
The discharge properties of the vestibular
nerve are distinguished by continuous
spontaneous activity or resting vestibular
tone.201 For semicircular canal afferents,
this resting discharge frequency is modu-
lated up or down during rotation of the
head. The modulation of vestibular activ-
ity by rotational stimuli has been exten-
sively studied in many species. Results
confirm that for the physiologic range of
head movements, the signal from the
semicircular canals is a representation of
head velocity, although head acceleration
is the stimulus that leads to excitation of
the hair-cell receptors. The integration
from acceleration to velocity is a mechani-
cal one, related to the physical properties
of the endolymph and semicircular canals,
as just discussed.
At high head velocities, however, when
the discharge of one set of canal afferents
is fully inhibited, the VOR will depend
upon the excitatory response from one
labyrinth alone. This asymmetry in re-
sponse at high velocities leads to one form
of Ewald's second law, which, in its generic
form, states that excitation is a relatively
better vestibular stimulus than is inhibi-
tion. Ewald's second law becomes particu-
larly evident when there is a loss of the
function of the labyrinth on one side.
The nonlinear effects of Ewald's second
law have important implications even in
normal behavior. The rotational VOR has
a gain, or ratio of output (eye velocity) to
input (head velocity), of 1.0 in normal sub-
jects for392 rotational velocities up to
400°/sec, even though vestibular affer-
ents are presumably driven into inhibitory
cutoff at velocities well below 200°/sec.165'201
Therefore, for high speeds of head rota-
tion there must be a mechanism to com-
pensate for the loss of the contribution of

the afferents (disinhibition) on the side
opposite rotation (when these afferents
are driven into inhibitory cutoff). Several
suggestions have been made as to how
central mechanisms ensure such a wide
range of linear responses. One hypothesis
is that when activity no longer comes from
the inhibited labyrinth, there is a central
disinhibition that increases the sensitivity
of the response to afferent activity emanat-
ing from the excited labyrinth. 514 Alterna-
tively, the presence of quick phases may
prevent vestibular neurons from being
driven into inhibitory cutoff and thus im-
prove their linear range of response.194-440
Another form of Ewald's second law may
apply to the acceleration and frequency
characteristics of head rotation (see Clini-
cal Findings with Dynamic Vestibular Im-
balance, below).
Vestibular nerve fibers have been classi-
fied as regular afferents or irregular afferents,
and both project to neurons within the
vestibular nuclei that mediate VOR re-
sponses.72-202'313'339 It seems that inputs
from the regular afferents dominate
the vestibular response during higher-
frequency vestibular stimulation.339 Their
inputs may also play a role in VOR adap-
tation.91 Regular afferents have tonic re-
sponse dynamics, resembling the displace-
ment of the cupula or of the otolithic
membrane, and have a low sensitivity to
head rotations or linear forces. The cal-
iber of their axons is medium to small and
they end as dimorphic units and bouton
units in intermediate and peripheral
zones of the cupula or macula. Irregular
afferents have phasic-tonic response dy-
namics, including a sensitivity to the veloc-
ity of cupula and otolithic membrane dis-
placement, and hence show acceleration
sensitivity. Their axons are medium to
large. Irregular afferents in the central
zone of the cristae and striolar regions
have low rotational sensitivities and termi-
nate as calyx endings onto type I hair cells.
Irregular afferents located away from the
center have high rotational sensitivities
and terminate as dimorphic endings onto
both type I and type II hair cells.
Certain otolith afferents show a sus-
tained modulation of discharge rate with
changes in static head position. Other
The Vestibular-Optokinetic System 29
fibers, however, are sensitive to velocity,
acceleration, or higher-order derivatives,
such as jerk.438 The irregular otolith affer-
ents may play a role in the generation of
off-vertical axis rotation (OVAR), possibly
through the velocity-storage mechanism,18
as well as viewing distance dependent
changes in the t-VOR.16a
The VOR inputs from irregular affer-
ents from the semicircular canals are can-
celled at the vestibular nuclei by central
polysynaptic pathways.107 They may, how-
ever, play a role in VOR adaptation; in
modulation of the VOR during eccentric
rotation, near viewing, or VOR cancel-
lation; in the generation of the low-
frequency, velocity-storage component of
the VOR; and perhaps in extending the
linear range of the VOR at high speeds
of head rotation.iv,io6b,io7,338a The neuro-
transmitter used by vestibular afferents
appears to be glutamate.144'149'326
Not all fibers within the vestibular nerve
are afferent. Some vestibular efferents
carry impulses to the labyrinth, but their
function in mammals is unknown. They
do not suppress unwanted vestibular re-
sponses during passively evoked com-
bined movements of head and eyes.98
What they might do during active com-
bined eye and head movements is not yet
known. Axon collaterals of vestibular ef-
ferents project to the cerebellar flocculus
and so might play some functional role in
the VOR.393
BRAIN STEM ELABORATION
OF THE VESTIBULO-OCULAR
REFLEX
Anatomic Organization of the
Vestibulo-ocular Reflex
How the brain stem fashions the precise
compensatory eye movements from the
raw vestibular signals has been extensively
investigated since Adrian first recorded
the activity of neurons within the vestibu-
lar nucleus.2 Of prime importance has
been the study of the three-neuron arc:
vestibular ganglion, vestibular nuclei, and
ocular motor nuclei. Although this ele-
30 The Properties and Neural Substrate of Eye Movements

Table 2-2. Direct Vestibulo-Ocular Projections as Determined by

Electrophysiologic and Anatomic Studies in Monkey,323-324 Cat,207'452
and Rabbit388-390

Receptor Effect Muscle Relay Nucleus Pathway Motor Nucleus

LC Excitation c-LR M/LVN MLF c-VI

i-MR M/LVN ATD i-III
Inhibition i-LR MVN MLF i-VI
c-MR — Poly c-III
AC Excitation i-SR M/LVN* MLF* c-III
c-IO M/LVN* MLF* c-III
Inhibition i-IR SVN MLF i-III
c-SO SVN MLF i-IV
PC Excitation c-IR M/LVN MLF c-III
i-SO M/LVN MLF c-IV
Inhibition c-SR SVN extra i-III
i-IO SVN extra i-III
U Excitation i-SO LVN MLF c-IV
i-SR LVN MLF c-III
i-MR LVN ATD i-III
c-IO LVN MLF c-III
c-IR LVN MLF c-III
c-LR LVN MLF c-VI
s Excitation y-group BC
Muscles: c, contralateral; i, ipsilateral; LR, lateral rectus muscle; MR, medial rectus muscle; SR, superior rec-
tus muscle; IO, inferior oblique muscle; IR, inferior rectus muscle; SO, superior oblique muscle. Relay nucleus:
M/LVN, medial and adjacent lateral vestibular nucleus; *, other nuclei and pathways are also probably in-
volved; see Fig. 2-3; MVN, medial vestibular nucleus; SVN, superior vestibular nucleus; LVN, lateral vestibular
nucleus. Pathway: MLF, medial longitudinal fasciculus; ATD, ascending tract of Deiters; poly, polysynaptic
pathway lying outside MLF; extra, extra-MLF pathway. Motor nucleus: VI, abducens nucleus; III, oculomotor
nucleus; IV, trochlear nucleus.

mentary vestibulo-ocular reflex arc454 is ular connections in primates,99'105'131'323'324

readily equated with the notion of a
rapidly acting reflex, parallel polysynaptic
projections are equally important for gen-
eration of an appropriate, compensatory
eye movement.309 The direct neuronal
pathways include both excitatory and in-
hibitory contributions.
Each semicircular canal directly influ-
ences a pair of extraocular muscles that
move the eyes approximately in the plane
of that canal, regardless of the initial posi-
tion of the eye in the orbit. Important to
the clinician is that disease selectively af-
fecting one semicircular canal may pro-
duce nystagmus that rotates the globe in a
plane parallel to that in which the canal
lies (see, for example, benign paroxysmal
positional vertigo (BPPV), in Chap. 10).
In summarizing pathways that mediate
the VOR (Table 2-2 and Fig. 2-3), we have
drawn largely on studies of central vestib-
but we also mention here pathways re-
ported in other species.105'472-473 The anat-
omy of the vestibular nuclei in humans
has been well characterized,451 and most
features are similar to those of non-human
primates and other mammalian species.99'355
In humans, the volume of the vestibular
nuclei is about 67 mm 3 and it contains
over 200,000 neurons. Vestibular nuclei
neurons receive projections from the ves-
tibular nerve that contains about 14,000 to
18,000 axons. As a generalization, larger
neurons in the vestibular nuclei receive
labyrinthine input from axons of a larger
caliber with an irregular discharge rate;
smaller neurons receive input from
smaller-caliber axons, with a regular dis-
charge rate.416 There are four major ves-
tibular nuclei: the medial vestibular nu-
cleus (MVN), lateral vestibular nucleus
(LVN), inferior or descending vestibular

nucleus (DVN), and superior vestibular
nucleus (SVN). In addition, there are sev-
eral smaller accessory subgroups, includ-
ing the interstitial nucleus (IN), with its
cells distributed among the vestibular
rootlets as they enter the brain stem, and
the y-group, near the superior cerebellar
peduncle. The MVN has the greatest vol-
ume and is the longest vestibular nucleus.
Its rostral portion is a major receiving
area for afferents from the semicircular
canals and its cells project to the III,
IV, and VI cranial nuclei, mediating
vestibulo-ocular reflexes. Its caudal por-
tion is reciprocally connected to the cervi-
cal region of the spinal cord, presumably
mediating vestibulocollic reflexes. The
caudal MVN is also reciprocally connected
to the cerebellum.
The rostroventral portion of the LVN
receives afferents from the cristae of the
semicircular canals and the macula of the
utricle. Like the rostral MVN, it partici-
pates in vestibulo-ocular reflexes, in part
through the ascending tract of Deiters
(ATD) to the oculomotor nucleus. The
LVN also has projections to the spinal
cord, mainly via the ipsilateral lateral
vestibulospinal tract but also through the
contralateral medial vestibulospinal tract.
In its most rostral aspect, the DVN also
projects to the ocular motor nuclei.
There is considerable divergence of sin-
gle primary afferents within the vestibular
nuclei (about 15 neurons per axon). A sin-
gle axon from a lateral semicircular canal
can impinge upon neurons in the central
part of the SVN, the rostral half of the
MVN, the medial-rostral part of the DVN,
and the ventromedial part of the LVN.
The primary vestibular afferents enter
the medulla at the level of the lateral ves-
tibular nucleus. Almost all bifurcate, giv-
ing a descending branch to terminate in
the MVN and DVN and an ascending
branch to the SVN, with a final destina-
tion in the cerebellum, especially the an-
terior vermis and the nodulus and
uvula.99-451 All canals and otoliths project
to zone 1, which lies around the borders of
ventromedial LVN, medial MVN, and
dorsomedial DVN. All canals also con-
verge on a small patch in the ventromedial
SVN. These two areas contain the sec-
The Vestibular-Optokinetic System 31
ondary vestibulo-ocular neurons that pro-
ject to the abducens, oculomotor, and
trochlear nuclei. Canal afferents also con-
verge on the IN of the vestibular nerve,
which projects to the flocculus. Utricular
afferents project to the rostral MVN and
saccular afferents project to the y-group.
Some projections from the utricle overlap
with those from the lateral semicircular ca-
nal, presumably reflecting their common
roles in detecting horizontal motion; and
some projections from the saccule, which
is involved in detecting vertical motion,
overlap with those from the vertical semi-
circular canals.14'155
For both the horizontal and vertical
VOR, many neurons in the vestibular nu-
clei that receive inputs from primary ves-
tibular afferents encode not only head ve-
locity but also eye position and varying
amounts of smooth pursuit and saccadic
signals.322'423 A common and important
cell type is the position-vestibular-pause
(PVP) neuron. It encodes head velocity and
eye position and becomes silent (pauses)
during saccades. Another cell type is the
floccular target neuron (FTN), which also re-
ceives a projection from the cerebellar
flocculus and may be important in VOR
adaptation.300 Additional cell types in-
clude those that show a sensitivity to eye
and head velocity—the EH neurons, to
head velocity alone, and to eye velocity
and eye position—the burst-position (BP)
neurons. 423 These secondary vestibular
neurons may also show changes depend-
ing upon the particular combination of
stimuli, including during VOR cancella-
tion and eccentric rotation.131'132'321'322'469
Vestibular nuclei neurons do not project
just to motoneurons; they also send axon
collaterals to the nucleus prepositus hy-
poglossi (NPH) and the nucleus of Roller
(see Table 5-1, Chap. 5) and to the cell
groups of the paramedian tracts (PMT)
(see Display 6-4, Chap. 6).100'101 The NPH
and adjacent medial vestibular nucleus
(the NPH-MVN region, see Chap. 5) have
a crucial role in holding gaze steady
(neural integration). The cell groups of
the PMT may be important for relaying an
internal or efference copy of eye move-
ment signals to the flocculus of the cere-
bellum.101 In addition, certain cells in
 The Vestibular-Optokinetic System 33

NPH that receive vestibular inputs project
to burst neurons in the paramedian pon-
tine reticular formation (PPRF) to trigger
quick phases of nystagmus.187'362 Finally,
many secondary vestibular axons have
dual projections, both rostrally as VOR
neurons and caudally as vestibulocollic
neurons.341
The main vestibulo-ocular projection
neurons lie in zone 1 and the center of
SVN. Zone 1 predominantly carries exci-
tatory PVP cells, and is also the origin of
the ascending tract of Deiters, which runs
lateral to the MLF to impinge upon the
medial rectus subdivision of the oculomo-
tor nucleus (see Fig. 2-3). Zone 1 is under
little direct cerebellar influence. In-
hibitory PVP cells also lie in rostral MVN.
The center zone in the SVN contains pre-
dominantly burst-position cells (neurons
that discharge with eye velocity and eye
position); most are related to vertical canal
inputs. These neurons, along with those in
the dorsal y-group, the marginal zone (be-
tween the MVN and nucleus prepositus),
and the rostral MVN, are under the influ-
ence of the flocculus. In general, the pe-
ripheral areas of the vestibular complex
are the source of intrinsic interconnec-
tions and commissural connections. They
also receive projections from the cerebel-
lar nodulus and the accessory optic nuclei.
Taken together, this pattern of connectiv-
ity suggests that they play a role in the ve-
locity-storage mechanism. The interstitial
nucleus of Cajal (INC) receives axon col-
laterals from all secondary vestibular af-
ferents that supply the oculomotor nu-
cleus and sends reciprocal projections,
predominantly ipsilateral, to the vestibu-
lar nuclei (see Display 6-6, Chap. 6).
For the vertical semicircular canals, sev-
eral important principles may be summa-
rized. First, the excitation of the anterior
semicircular canals produces upward and
torsional eye movements, and excitation
of the posterior semicircular canals pro-
duces downward and torsional eye move-
ments. Second, each vestibular nucleus
neuron concerned with the vertical VOR
contacts two motoneuron pools, one for
each eye.512 Third, excitatory projections
from the vestibular nuclei cross the mid-
line, but inhibitory connections do not.
Fourth, the pathways taken by axons con-
veying the upward and downward VOR
differ.
For the anterior canal system, excitatory
PVP cells in the MVN or adjacent ventral
lateral vestibular nucleus (VLVN) project
medially and dorsally, crossing the mid-
line caudally, differing from the projec-
tions of the posterior-canal PVP cells. Af-
ter crossing, they ascend in or just below
the medial longitudinal fasciculus (MLF)
to contact the superior rectus and inferior
oblique subdivisions of the oculomotor
complex. Axon collaterals of these fibers
project to the INC, to cell groups of the
PMT, and to the perihypoglossal nuclei,
including NPH. Recall that the projections
of the superior rectus subnucleus are
crossed, but those of the inferior oblique
subnucleus are uncrossed. Thus, this exci-
tatory pathway connects the anterior semi-
circular canal to the ipsilateral superior
rectus and contralateral inferior oblique
muscles (see Fig. 2-3).
Another cell group, described in the cat,
that may contribute excitatory inputs to
the anterior canal system lies in the SVN.
Their axons cross the midline in the ven-
tral tegmental tract, close to the medial
lemniscus, and then abruptly turn ros-
trally, passing through the decussation of
the superior cerebellar peduncle to termi-

Figure 2-3. Summary of probable direct connections of VOR, based on findings from a number of
species.26-99'104'105'207'241'260'323'324'361'388-390-397 Excitatory neurons are indicated by open circles, inhibitory neu-
rons by filled circles. Ill, oculomotor nuclear complex; IV, trochlear nucleus; VI, abducens nucleus; XII, hy-
poglossal nucleus; AC, anterior semicircular canal; ATD, ascending tract of Deiters; BC, brachium conjunc-
tivum; HC, horizontal or lateral semicircular canal; 1C, interstitial nucleus of Cajal; IO, inferior oblique muscle;
IR, inferior rectus muscle; LR, lateral rectus muscle; LV, lateral vestibular nucleus; MLF, medial longitudinal
fasciculus; MR, medial rectus muscle; MV, medial vestibular nucleus; PC, posterior semicircular canal; PH,
prepositus nucleus; SO, superior oblique muscle; SR, superior rectus muscle; SV, superior vestibular nucleus;
V, inferior vestibular nucleus; VTP, ventral tegmental pathway.
34 The Properties and Neural Substrate of Eye Movements
nate mainly on the superior rectus and in-
ferior oblique subdivisions of the oculo-
motor complex.104 Also, in some species,
the SVN projects rostrally, just near the
brachium conjunctivum, to the oculomo-
tor nuclei. Thus, more than one pathway
may contribute to the generation of eye
movements during stimulation of the an-
terior semicircular canal; the projections
in primates have not yet been completely
described.
Inhibitory neurons for the anterior ca-
nal system lie in the SVN. Their axons exit
from the rostromedial aspect of this nu-
cleus and course medially and rostrally in
the lateral wing of the ipsilateral MLF
to contact superior oblique motoneurons
in the trochlear nucleus and inferior rec-
tus neurons in the oculomotor nucleus.
Axon collaterals project to the NPH and to
cell groups of the PMT. The neurotrans-
mitter of these inhibitory vestibular neu-
rons may be gamma-aminobutyric acid
(GABA).144'149-326
For the posterior canal system, PVP cells
are also found at the junction of the
MVN and VLVN. These excitatory neu-
rons project rostrally, medially, and dor-
sally through MVN until, at the level of
the caudal abducens nucleus, they turn
medially and cross the midline beneath
the NPH and abducens nucleus, ventral
to the MLF. After crossing the midline,
they enter the MLF and project rostrally
to the trochlear nucleus and inferior rec-
tus subdivision of the oculomotor com-
plex. Axon collaterals also pass, via the
MLF, to the NPH and PMT cell groups
and to the INC. The projections of the
trochlear motoneurons are contralateral,
but those of the inferior rectus are ipsilat-
eral. Thus, this excitatory pathway con-
nects the posterior semicircular canal to
the ipsilateral superior oblique and con-
tralateral inferior rectus (Fig. 2-3). In ad-
dition, the posterior semicircular canal
also projects to the contralateral abducens
nucleus.
Inhibitory neurons subserving the pos-
terior semicircular canals are found in the
SVN and rostral MVN. Their axons pro-
ject through the pontine reticular forma-
tion to reach the ipsilateral MLF and thus
contact the superior rectus and inferior
oblique subdivisions of the oculomotor
complex. These neurons also contact PMT
cell groups and the INC. Like the in-
hibitory neurons of the anterior canal sys-
tem, these cells may use GABA as an in-
hibitory neurotransmitter.144'149'326
For the lateral (or horizontal) canals,
PVP neurons are located in the ventral
part of the MVN and adjacent VLVN.
Most of these excitatory neurons course
rostrally and medially through the MVN,
pass through or beneath the ipsilateral ab-
ducens nucleus or rostral NPH, and cross
the midline at the level -of the abducens
nucleus or slightly rostral to it. Soon after
crossing the midline, these axons give col-
laterals that either enter and terminate in
the abducens nucleus or project to the
NPH and PMT cell groups. Some PVP
neurons project rostromedially, passing
through the abducens nucleus, and run in
the ATD to terminate in the medial rectus
subdivision of the ipsilateral oculomotor
complex; some of these axons send collat-
erals to PMT cell groups. Thus, these exci-
tatory pathways connect the lateral semi-
circular canal to the ipsilateral medial
rectus and contralateral lateral rectus
muscles (Fig. 2-3). The functional signifi-
cance of the pathway through the ATD is
uncertain, but it may relate to vestibulo-
ocular responses associated with transla-
tion.106a
Inhibitory pathways for the lateral
canals pass from the MVN to the adjacent
abducens nucleus; these neurons may use
glycine as a neurotransmitter.326 The me-
dial rectus neurons are peculiar in having
no known disynaptic inhibitory input, al-
though a multisynaptic, extra-MLF path-
way may play a role.26'241
Central otolith projections have been
less well studied than those concerned
with the rotational VOR. Experimental
stimulation of the utricular nerve causes
eye movements that suggest contraction of
the ipsilateral superior oblique, superior
rectus, and medial rectus, and the con-
tralateral inferior oblique, inferior rectus,
and lateral rectus muscles452 (Fig. 2-2B).
Table 2-2 summarizes some of the direct
anatomic pathways involved.

Neurophysiology of the
Vestibulo-ocular Reflex
The functional organization of the
vestibulo-ocular responses is more compli-
cated than the elementary anatomic con-
nections suggest. For horizontal rotations,
neurons in the vestibular nuclei that en-
code head velocity can be divided into two
main types. Type I neurons increase their
discharge rate for ipsilateral rotations and
decrease their discharge rate during con-
tralateral rotations; type II neurons show
the converse. Thus, each vestibular nu-
clear complex monitors rotation in both
directions. This facility is aided by a vestib-
ular commissure,103 whereby ipsilateral
type I vestibular neurons drive contralat-
eral type II neurons. The organization of
this vestibular commissure is specific, so
that neurons in the right vestibular nu-
cleus that receive input from the right lat-
eral semicircular canal project to neurons
in the left vestibular nucleus that are dri-
ven by the left lateral semicircular canal. A
similar reciprocal connection is found for
vertical canals (e.g., the right anterior ca-
nal and the left posterior canal). The ves-
tibular commissure probably contributes
to the velocity-storage mechanism (see
next section).276'498 Its precise role in ves-
tibular compensation is unclear.106'174-276
A role for the vestibular commissure is
less certain for otolith-ocular reflexes. It
has been shown that the equivalent of a
push-pull relationship for saccular (and
possibly utricular) reflexes can be created
on just one side of the brain stem.473 This
can be achieved by combining on the same
vestibular nucleus neuron monosynaptic
excitatory inputs from one population of
saccule hair cells on one side of the striola
and disynaptic inhibitory inputs from an-
other population of saccule hair cells on
the other side of the striola.
Vestibular nucleus neurons encode a
range of sensory and motor signals: vestib-
ular, ocular motor, visual, and somatosen-
sory. Head velocity, the primary vestibular
signal, is still present, but eye position is
also neurally encoded. The presence of
eye position signals on vestibular nucleus
neurons reflects the crucial role played by
The Vestibular-Optokinetic System 35
the NPH-MVN region in gaze holding
(neural integration of velocity-coded to
position-coded signals); this role is dis-
cussed further in Chapter 5.
A neural-network approach has been
used to account for the diversity of signals
encountered in the vestibular nuclei.5 The
essence of this idea is that the central ner-
vous system adjusts the activity of an en-
semble of neurons for optimal vestibular
performance even though there can be
considerable variability amongst individ-
ual neurons as to exactly what signals they
carry and to which head rotations they re-
spond optimally.4 The attractive feature of
such a model is that it is able to predict
and account for the seemingly paradoxical
finding of individual neurons that carry
velocity signals for movement in one di-
rection and position signals for movement
in another. For discussion of how a neural
network could function as a neural inte-
grator, see Chapter 5.
The Velocity-Storage Mechanism
Vestibular neurons respond to sustained
rotational stimuli with an initial increment
in discharge rate that declines exponen-
tially with the same time constant as the
VOR (15 sec), not as the cupula or vestibu-
lar nerve (6 sec). So, as early in the path-
way as the vestibular nucleus, the perfor-
mance of the VOR has been improved.
This central phenomenon, by which the
raw vestibular signal is prolonged or
perseverated, is accomplished by the ve-
locity-storage mechanism. It improves the
ability of the VOR to transduce the low-
frequency components of head rota-
tion.399 During sustained (low-frequency)
rotations, the velocity-storage mechanism
also functions to realign the axis of eye ve-
locity with the direction of gravito-inertial
acceleration (which usually calls for
slow phases in a plane close to earth-
horizontal). This effect, while seen in
humans for small angles of lateral head
tilt, is much more pronounced in mon-
keys.9'12>140'17°'172' 199,400
The vestibular commissure seems to be
important for velocity storage; section of
36 The Properties and Neural Substrate of Eye Movements
this structure abolishes it.276 Presumably,
interruption of pathways connecting the
central portions of both MVN, the pu-
tative site for the generation of velocity
storage, is responsible. Optokinetic after-
nystagmus (OKAN), the decaying after-
response that is seen when a subject is
placed in darkness following sustained op-
tokinetic stimulation, the bias component
of off-vertical axis rotation (OVAR) (dis-
cussed below), and the modulation of the
direction and time constant of the angular
VOR with changes in head orientation
are also lost after section of the vestibu-
lar commissure.498 Thus, without velocity
storage, the VOR generates slow phases in
a head-coordinate system, regardless of
the direction of gravito-inertial accelera-
tion. Although achieved by central vestib-
ular connections, velocity storage depends
upon the tonic discharge of the vestibular
nerves;116 section of one vestibular nerve
decreases the time constant of the VOR.
Because optokinetic signals also are
processed in this same velocity-storage
mechanism, bilateral vestibular nerve sec-
tion abolishes OKAN.117'521 Visual fixation
of a full-field, earth-stationary surround
for even a few seconds largely discharges
or nulls activity within the velocity-storage
mechanism.115'488 Ablation of the nodulus
and uvula (see Display 10-18, Chap. 10) of
the cerebellum maximizes velocity stor-
age, except perhaps when torsion is stimu-
lated.7'485 The velocity-storage mechanism
can also be influenced by cervical in-
puts.271 The velocity-storage mechanism is
suppressed by baclofen, presumably by
mimicking the inhibitory, GABAergic ac-
tions of Purkinje cells from the nodulus on
the vestibular nuclei.114-485
Off-vertical axis rotation is the compen-
satory response induced when a subject's
body is rotated around an axis that it is
tilted away from the vertical. During a
constant-velocity rotation, there is an
initial response due to the rotational
VOR from stimulation of the semicircular
canals. As the response from the semicir-
cular canals dies away, it is replaced by an
otolith-mediated response consisting of a
steady-state velocity (bias component of
OVAR) and a component that changes
with the gravity vector (modulation com-
ponent of OVAR). The bias component
derives from the velocity-storage mecha-
nism, and the modulation component,
from the direct otolith signal.145-220'400'492
Because the changing orientation of the
head with respect to gravity imposes a
changing linear acceleration along the
naso-occipital axis, not only is there the
modulation component of slow-phase ve-
locity, but also a sinusoidal modulation of
the vergence angle as a function of head
position with respect to gravity.141 Discrete
lesions of vestibular nerve afferents abol-
ish continuous nystagmus during OVAR.116
Lesions of the nodulus affect the bias com-
ponent of OVAR by virtue of its influence
on the velocity-storage mechanism.8'497
NEURAL SUBSTRATE FOR
OPTOKINETIC RESPONSES
Both smooth-pursuit and optokinetic sys-
tems contribute to the stabilization of im-
ages of stationary objects during head
rotations. In humans, the optokinetic re-
sponse to a full-field, moving visual stimu-
lus has two stages. First, nystagmus is
promptly generated within 1 to 2 sec of
stimulus onset, with slow-phase velocity
approximating stimulus velocity. This ini-
tial response mainly reflects smooth pur-
suit. Second, there is a slower buildup of
stored neural activity. This activity is re-
vealed as OKAN when the subject is
placed in darkness.
In monkeys, vestibular nucleus neurons
that respond to head rotation also are dri-
ven by optokinetic stimuli (Fig. 2-4).71'238'486
Moreover, when the lights are turned off
after a period of optokinetic stimulation,
the vestibular nucleus neurons continue
discharging for some seconds;487 this is the
neurophysiological correlate for OKAN.
Vestibular nucleus neurons only respond
well to low-frequency visual stimuli, in
agreement with the demands made of the
optokinetic system in supplanting the
VOR during sustained rotation. Thus,
during combined vestibular and optoki-
netic stimulation, which occurs during the
natural situation of self-rotation, the opto-
kinetic input takes over as the vestibular
 The Vestibular-Optokinetic System 37

Figure 2-4. The response of a type I vestibular nucleus

neuron of the alert rhesus monkey to vestibular and opto-
kinetic stimulation. In each panel, instantaneous dis-
charge rate (left ordinate) is plotted against time (ab-
scissa). Below each panel, the direction and magnitude of
the stimulus is indicated (60;dg/sec). (A) The monkey is
rotated in darkness. The initial vestibular response de-
clines (to parallel the decline of per-rotatory nystagmus;
see Figs. 1-6 and 2-6). (B) The monkey is rotated in the
light. This time the neuron's response is sustained during
the period of rotation. (C) The monkey sits stationary
within a rotating optokinetic drum. This visual stimulus
causes a sustained response of the same vestibular nucleus
neuron. (Courtesy, Dr. Walter Waespe.)

drive declines and maintains a steady ves-
tibular discharge that continues to gener-
ate compensatory eye movements (Fig.
2-4B). Thus the importance of testing
OKAN is in allowing one to assay activity
within the vestibular nuclei without em-
ploying any motion of the head. The
neural substrate for OKN, and especially
the nucleus of the optic tract and acces-
sory optic pathway, are discussed further
in Chapter 4.
phase or time constant). We assume here
that, to a first approximation, the VOR can
be treated as a linear control system. In
this case, transient and sinusoidal stimuli
give rise to responses that are equivalent in
terms of the mathematical information
they reveal about the dynamic characteris-
tics of a particular system. There are, how-
ever, important nonlinearities in the VOR,
especially at high velocities and high accel-
erations. These have important clinical
and physiological implications.

QUANTITATIVE ASPECTS
OF THE VESTIBULAR-
OPTOKINETIC SYSTEM
A quantitative description of any type of
control system compares the output with a
known input. Here we compare induced
eye movements with head movements, us-
ing two important characteristics: (1) the
ratio of amplitudes of the output and input
(gain), and (2) the temporal synchrony be-
tween the output and input (described by
VOR Gain and Phase:
General Characteristics
The VOR gain is given by the ratio of am-
plitude of eye rotation to amplitude of
head rotation. For sine-wave stimuli (i.e.,
sinusoidal rotation of a subject in dark-
ness, Fig. 2-5A), gain is usually calculated
from peak slow-phase eye velocity divided
by peak head velocity (Fig. 2-5B). The
temporal difference between output and
 A

Sinusoidal oscillation in
the dark

INPUT OUTPUT

38
 The Vestibular-Optokinetic System 39

C
Figure 2-5. Quantitative evaluation of the VOR using sinusoidal rotation in darkness. (A) A typical record of
the VOR during sinusoidal rotation at 0.5 Hz. The subject is imagining the location of an earth-fixed target. (B)
Schematic summary of VOR during sinusoidal stimulation, as shown in A. The graph on the left shows charac-
teristics of the stimulus (head velocity) and the graph on the right shows the response (slow-phase eye velocity,
quick phases having been disregarded). R, right; L, left; t, time. In this case, VOR gain is 1.0 and the phase dif-
ference between eye velocity and head velocity is 180;dg (by convention, this is referred to as zero phase shift).
The dashed curve on the right represents head velocity. (C) A Bode diagram of the VOR showing the idealized
behavior of gain and phase with varying stimulus frequencies. Note that for the frequency range of most nat-
ural head rotations (0.5-5.0 Hz), gain is 1.0 and phase shift is 0°.

input is described by phase. Using sine-
wave stimuli, the phase of eye and head
movements may be compared (Fig. 2-5B);
the difference (or phase shift) is expressed
in degrees. For the frequencies of head ro-
tation that correspond to most natural
head rotations (0.5 to 5.0 cycles/sec), gain
is close to —1.0 and phase shift is close to
180°: equal-sized eye movements and
head movements occur synchronously in
opposite directions. By convention, the
gain of the VOR that perfectly compen-
sates for head rotations is assigned a value
of 1.0, and the phase that perfectly com-
pensates for head rotations is assigned a
value of 0°. For lower frequencies of rota-
tion (<0.01 cycle/sec), a shift in phase oc-
curs and gain falls; this reflects the inabil-
ity of the VOR to compensate for more
sustained head rotations that contain low-
frequency components. The ways that
gain and phase change with different stim-
ulus frequencies can be represented
graphically as a Bode plot (Fig. 2-5C).
For sustained, constant-velocity rotation
(also called velocity steps or impulsive
stimuli), gain is usually calculated from ini-
tial eye velocity divided by head velocity.
With such sustained rotations in darkness,
vestibular eye movements (slow phases of
nystagmus) progressively decline in veloc-
ity, and after about 30 sec, the eye move-
ments cease (see Fig. 1-6). The time
course of the decline of slow-phase velocity
is similar to a decaying exponential curve
that can be defined by a time constant (Fig.
40 The Properties and Neural Substrate of Eye Movements

Figure 2-6. Schematic summary of vestibular-optokinetic interaction occurring in response to velocity-step

(impulsive or constant-velocity) rotations. Graphs on the left show characteristics of the stimulus (head velocity
during rotation or drum velocity during optokinetic stimulation); graphs on the right show the responses (slow-
phase eye velocity, quick phases having been removed). R, right; L, left; t, time. In the top panel, constant-veloc-
ity rotation to the left in the dark produces slow-phase movements to the right (per-rotatory nystagmus, RN)
with initial eye velocities equal to head velocity (VOR gain = 1.0). Slow-phase velocity subsequently declines.
This decline may be approximated by a negative exponential with a time constant, TC, given by the time taken
for a 63% decline in eye velocity. When rotation stops, nystagmus starts in the opposite direction (postrotatory
nystagmus, PRN). In the middle panel, an optokinetic stimulus (drum rotation to the right) causes a sustained
optokinetic nystagmus (OKN), with slow phases to the right during the entire period of stimulation. When the
lights are turned off during stimulation, eye movements do not stop immediately but persist as optokinetic af-
ter-nystagmus (OKAN). In the lower panel, the subject is rotated in the light (natural situation of self-rotation).
This gives a combined vestibular and optokinetic stimulus. The response is a sustained nystagmus. When the
chair stops rotating, eye movements stop nearly completely: postrotatory nystagmus is suppressed by the oppo-
site-directed optokinetic after-nystagmus and by visual fixation of the stationary world.

2-6). After one time constant, eye velocity
declines to 37% of its initial value; after
three time constants, eye movements
nearly stop. The time constant is mathe-
matically related to the phase of the VOR
observed during low-frequency sinusoidal
stimulation: the larger the time constant,
the less the difference in phase between
the head and eye at a given frequency and,
hence, the better the compensation. The
latency of the r-VOR has already been dis-
cussed and is about 7 to 15 msec.
DETERMINANTS OF VOR GAIN:
ROTATIONAL VOR
Laboratory measurements of the gain and
time constant of the human VOR are influ-
enced by many factors, so normal ranges
vary considerably. Some published sets of
values are summarized in Figure 2-7. The
torsional VOR, in response to roll rota-
tion, has a lower mean gain value, typically
0.5, than the horizontal or vertical VOR to
yaw or pitch rotations.23.380,427,428,47o,47i The
 The Vestibular-Optokinetic System 41

Sinusoidal, passive, alert Pseudo random, passive, alert

Sinusoidal, passive, imagined target Sinusoidal, active, imagined target

Figure 2-7. Summary of reported values of gain of the VOR tested in darkness. The source of each set of data is
given by the numbers in brackets, which correspond to the references listed at the end of this chapter. Note that
scales differ from panel to panel. (Redrawn from Collewijn122.)

VOR measured in the light—the natural
circumstance—may have different charac-
teristics. The amplitude and variability of
gain, and the presence of inappropriate
off-axis components, may differ from re-
sponses in the dark.171
One related factor is that the gain of the
VOR is affected by the proximity of the vi-
sual scene being viewed during rotation or
the imagined location of the target of in-
terest. During viewing of a near target, the
brain must compensate not only for the
rotation of the head but also for the lateral
or vertical displacement (translation) of
the eyes. Consequently, VOR gain in-
creases during viewing of a near ob-
ject.6.128,244,367,477,479 This isSUC is disCUSSed
further below and also under Laboratory
Evaluation of Eye-Head Movements in
Chapter 7.
A second important determinant of VOR
gain, particularly when measured during
42 The Properties and Neural Substrate of Eye Movements
rotation in darkness, is the mental set or
imagined percept that the subject chooses
during rotation.47-267'292'344'345'503 jf t he
subject imagines fixation of an earth-fixed
visual scene during low-amplitude and
low-frequency sinusoidal rotation, VOR
gain increases to approximately 1.0. If, on
the other hand, the subject imagines a vi-
sual stimulus that moves with the head,
then VOR gain declines to about 0.1. Fi-
nally, if the subject makes no attempt to
imagine a visual stimulus but is distracted
by performing mental arithmetic, VOR
gain is intermediate between these two ex-
tremes.47 This voluntary control of the
VOR gain is most effective during lower-
frequency head rotations, but less so
during head rotations with frequencies
greater than 1.0 cycles/sec. If the subject
daydreams or closes the eyes, VOR gain is
variable and low; thus it is important to
keep the subject alert, such as by asking
the subject to vocalize during vestibular
testing.503 A third factor determining
VOR gains in humans is the effect that any
spectacle correction has upon the relation-
ship between eye movements and dis-
placement of images upon the retina; this
relationship is discussed below, under
Adaptive Properties of the Vestibulo-ocular
Reflex.
The VOR also changes with age. The el-
derly show a decrease in gain, predomi-
nantly at low frequencies of stimulation
and high speeds of rotation. This is associ-
ated with increasing phase lead.36'368'381'382
These findings are probably related to the
senescence of the velocity-storage mecha-
nism and age-related loss of neurons
within the vestibular system.33'308 Al-
though higher VOR gains have been re-
ported in normal children, OKN gains
were equivalent to those for adults.414
During natural activities such as loco-
motion, rotational head perturbation with
predominant frequencies >5.0 Hz may
occur.216 Only a few attempts have been
made to measure VOR gain with high-fre-
quency or transient stimuli; these have
suggested that VOR gain is slightly less
than 1.0 until frequencies of about 2 to 4
Hz and then rises to values of 1.0 or even
higher at higher frequencies.314'455
DETERMINANTS OF VOR GAIN:
TRANSLATIONALVOR
A number of investigators have measured
the t-VOR response of human subjects to
lateral motion on a linear sled.40'87'94-197'198'435
The results are largely in accord with find-
ings in monkeys.613'372'373'419'420'462 All stud-
ies show that compensatory slow phases
are a linear function of the reciprocal of
the viewing distance, although humans
tend to have a lower gain than monkeys
(i.e., the movements are not truly com-
pensatory). One possible explanation for
the difference in the gain between the two
species is that the various cues used to esti-
mate the distance of the target of interest
are weighted differently by monkeys and
humans. Vergence and accommodation
may be relatively more important for
monkeys; size and other cognitive cues
to distance, more important for hu-
mans.40'94'129'432'462 Vergence cues may also
be more important for adjusting the t-
VOR gain for distance when the fre-
quency of the stimulus is higher.370'462 Just
as for the angular VOR, mental set and
context probably play important roles in
preparing the anticipated response to
head translation. The relatively impover-
ished visual environments in which these
experiments are carried out and the un-
natural profile of imposed head motion
may also influence the results.
The translational VOR must produce
not only disconjugate eye movements (for
example, during horizontal translation
when the target of interest is off to the
side) but also disjunctive eye movements,
or convergence and divergence, during
naso-occipital translation.613'373'444 Disjunc-
tive movements also occur during off
vertical axis rotation (OVAR). The latency
of the t-VOR in humans is in the range of
35 to 75 msec, a value that may also be in-
fluenced by mental set and context, espe-
cially at lower frequencies.94'198 The com-
pensatory responses to vertical (bob,
up-down) linear accelerations are sub-
ject to viewing distance in a way similar
to the horizontal t-VOR.367 In monkeys,
the vertical t-VOR occurs with a latency
of about 16 to 18 msec,95 a value simi-
 The Vestibular-Optokinetic System 43

lar to the latency of the horizontal t-
VOR.420
Several important questions about how
otolith signals are processed to produce
responses to linear acceleration remain
unanswered. First, the brain must distin-
guish linear acceleration associated with
lateral tilt of the head, which calls for a sta-
tic change in torsion or ocular counterroll,
from linear acceleration associated with
translation of the head, which calls for
horizontal (to interaural translation) or
vertical (to dorsal-ventral translation)
slow phases. Inappropriate torsion occurs
during interaural translation,299 especially
at low frequencies of translation.462 Thus,
the frequency of the stimulus may be one
important cue, because in natural circum-
stances, relatively high-frequency stimu-
lation of the otoliths is usually asso-
ciated with translation, and relatively
low-frequency stimulation with head
tilt.10'373'462 A model incorporating this
idea is presented in Figure 2-8. There
may be other factors. The static orienta-
tion of the head relative to gravity, on
which an additional (translational) linear
acceleration is imposed, can also influence
whether inappropriate torsion occurs in
response to translation and whether it is
conjugate.331-333 Other contextual cues
(for example, if the vertical canals on one
side are stimulated in association with acti-
vation of the otoliths) may help the brain
to distinguish head translation from tilt.6b
A second issue relates to the role of the
smooth-pursuit system in the generation
of the t-VOR.40'198'297'370'435 It may be that
pursuit plays some role in generating the
slow phases in response to low-frequency
translations; the usual response to a nat-
ural low-frequency linear acceleration (tilt
of the head) is ocular counterroll. High-
frequency responses to linear acceleration
(translation) probably occur indepen-
dently of pursuit, as is the case for the
r-VOR during high frequencies of head
rotation.

Figure 2-8. A model of the translational VOR for lateral (IA, interaural) head acceleration. Pathways for the lin-
ear VOR (L-VOR) are shown. The tilt pathway contains a low-pass filter and scaling (G ilt) to produce ocular
counterroll. The translational pathway includes a mathematical integration (acceleration-to-velocity) and a
high-pass filter before splitting into two subpathways, one with a gain element (G2 trans ) that accounts for the re-
sponse at zero vergence (an offset term, since theoretically no t-VOR is required when viewing is at optical in-
finity and vergence is zero), and another with a gain element (Gl trans ) and a multiplier by which a vergence com-
mand signal is used to modulate response amplitude (which accounts for the slope of t-VOR gain as a function
of vergence (i.e., viewing distance). The summed output of these two subpathways (which is a velocity signal) is
passed to a second integrator (the classic velocity-to-position integrator for conjugate eye movements) that gen-
erates the signal to control eye position, e, eye position; e, eye velocity; h, head velocity; h1A, head acceleration
(interaural); h roll head tilt (or equivalent). (From Telford L, Seidman SH, Paige GD. J Neurophysiol
1997;78:1775-90, with permission.)
44 The Properties and Neural Substrate of Eye Movements
DETERMINANTS OF VOR GAIN:
ECCENTRIC ROTATION
Transient responses to linear acceleration
have also been investigated using a para-
digm in which the axis of head rotation is
placed eccentrically, combining linear and
angular components. Both the viewing
distance and the location of the axis of ro-
tation relative to the orbits must be taken
into account. Results in studies using
monkeys333'445-447'461'477 are similar to those
in human studies.6'86'128'129'333-479
Studies in the monkey of the compensa-
tory response to an abrupt rotation, with
the head positioned eccentrically to the
axis of rotation, have shown three adjust-
ments following the initial response, oc-
curring sequentially, for viewing distance
and the linear motion of the orbits.445 The
first 20 msec of the VOR response is inde-
pendent of viewing distance and the loca-
tion of the rotation axis. In the next 20
msec, an adjustment is made for viewing
distance. The next adjustment is for trans-
lation of the otoliths and occurs within 30
msec. The final adjustment, which occurs
within 100 msec, is for eye translation rel-
ative to the visual target and compensates
for the difference in the relative anatomic
locations of the otoliths and the orbits. Co-
incident with these adjustments is an im-
posed disconjugacy of the VOR, which
does not become evident until at least 10
msec after the VOR has begun. The ad-
justment of the VOR for vergence angle
appears to be on the basis of an efference
copy signal of vergence, since the change
in VOR anticipates the vergence change
by about 50 msec.447 The substrate for the
modulation of the VOR during eccentric
rotation may be, at least in part, in the
flocculus of the cerebellum.446
In humans, the pattern of response
to eccentric rotation appears roughly simi-
lar.128 There is a translation-independent
adjustment for target distance in the first
40 msec after the onset of rotation. In the
next 60 msec, an otolith-related adjust-
ment (relative to target distance and the
eccentricity of the head from the axis of
rotation) appears and eventually masks
the initial canal-related adjustment. Ad-
justments in the VOR during eccentric ro-
tation 12are also made during sinusoidal ro-
tation. 9,212,479
How are the various signals from the
labyrinth during eccentric rotation com-
bined centrally? In the monkey, the inter-
action between the angular and the linear
VOR has been studied using a variety of
combinations of linear and angular accel-
erations at different frequencies, ampli-
tudes, and head orientations.461 By plac-
ing the head in front of or behind the
center of rotation, the linear VOR can be
made to sum or subtract from the angular
VOR. Overall, these data are compatible
with the idea that the VOR during eccen-
tric rotation is accounted for by summa-
tion of the isolated response to a compara-
ble pure translation stimulus on a linear
sled, and the isolated angular VOR re-
sponse to rotation with the head centered
on the axis of rotation.
In humans, similar interactions between
angular (r-VOR) and linear (t-VOR) re-
sponses have been noted during eccentric
rotation, although there is some disagree-
ment as to how well the interactions can be
accounted for by simple summation of the
t-VOR and r-VOR. In one study, the linear
response associated with rotation was re-
ported to be higher than would be pre-
dicted from simple linear summation of
the t-VOR induced during pure transla-
tion and the r-VOR induced during head-
centered rotation.6 Likewise, the response
to stimulation of the semicircular canals
may inappropriately dominate the linear
response and the effect of viewing dis-
tance.86 In other studies of eccentric rota-
tion during yaw (horizontal) and pitch
(vertical) rotation, a linear model of canal
and otolith interaction could account for
the findings.129'479 The specifics of the
neuronal processing underlying these ca-
nal-otolith interactions remain to be dem-
onstrated.106a Several models have been
presented.14-331'400
To sum up, the amplitude and direction
of compensatory VOR responses must be
adjusted according to the rotational and
translational components of the head
movement, the point of regard (i.e., the
target of interest), and a knowledge of the
anatomic locations of the otolith organs
relative to both orbits. Finally, any im-

posed linear acceleration must be sepa-
rated into its gravitational and transla-
tional components. In addition, a number
of cognitive factors come into play, de-
pending upon context and anticipation.
Thus, the VOR is subject to a variety of in-
fluences, making it a far more complicated
reflex than previously thought.
DETERMINANTS OF VOR PHASE
AND TIME CONSTANT
The time constant of the human VOR, us-
ing velocity-step rotations, shows consid-
erable intersubject variation, with a range
typically between 10 and 15 sec.32'115'382 As
indicated above, these values are greater
than would be predicted from a knowl-
edge of the mechanical properties of the
semicircular canals. Thus, the nystagmus
outlasts the duration of the signal re-
corded from the vestibular nerve. The dif-
ference represents a prolongation or per-
severation of the raw vestibular signal by
the brain, and is accomplished by the
velocity-storage mechanism. Factors that
may cause the VOR time constant to de-
cline include repeated testing (habitua-
tion),30 peripheral vestibular disease,32-82'166
and visual deprivation in early life.436
Newborn babies have a VOR time con-
stant of about 6 sec, but adult values
are attained during the first few months
of life. This change probably reflects mat-
uration of visual pathways, which are
important for calibration of the VOR, in-
cluding the development of velocity stor-
age.437'504
Static head position can also influence
the time constant of the VOR. Tilting of
the head, forward or laterally, immedi-
ately following a head rotation, reduces
the duration of postrotational nystagmus,
probably by disengaging or dumping
activity in the velocity-storage mecha-
nism.170'172 During rotation around an
earth-vertical axis, if the head is held in a
tilted position, the time constant of the
VOR measured in the earth-horizontal
plane decreases in proportion to the de-
gree of head tilt. The compensatory re-
sponse has both horizontal and vertical
components of rotation with respect to the
orbit. The time constant of the two com-
The Vestibular-Optokinetic System 45
ponents may differ, leading to a change in
the axis of eye rotation.221'470
Vertical vestibular responses may be
asymmetric, often (but not always) favor-
ing upward rather than downward slow
phases.27'38'62'317'470 Some of these asymme-
tries probably arise in the velocity-storage
mechanism (which is relatively feeble for
the vertical VOR), so they may appear or
change direction during low-frequency
stimulation (the later part of a constant-
velocity rotation).233'470'471 In monkeys and
cats, there is a spontaneous downbeat nys-
tagmus in darkness; it may increase as the
head is tilted away from the upright posi-
tion.410 In humans, there is commonly a
vertical drift in the dark as well, although
in the head-upright position, it can be ei-
ther up or down.203 When the head is
placed prone, an upward bias is added to
the spontaneous drift present in the up-
right position. These findings may be re-
lated to biases in the processing of infor-
mation from the saccules (which are
optimized to detect superior-inferior lin-
ear acceleration of the head). Clinically,
pathologic vertical nystagmus is more
commonly down-beating, perhaps because
of an inherent upward bias in the otolith
system. Alternatively, there may be an in-
herent upward bias in canal pathways me-
diating the vertical VOR, at either a pe-
ripheral or central level.66'261
The time constant of the torsional VOR
during rotation about an earth-vertical
axis, with the subject's face supine or
prone, is typically 4 to 5 sec, suggesting
that there427is470
little velocity storage for the
roll VOR. '
Three-Dimensional Aspects
of the VOR
Traditionally, the VOR has been studied
by measuring eye and head rotations in
one plane (e.g., horizontal). But in normal
circumstances head motion is rarely con-
fined to the plane of one pair of semicircu-
lar canals and the line of sight is seldom
precisely in the plane of head rotation (for
yaw or pitch stimulation) or perpendicu-
lar to it (for roll stimulation). Yet compen-
46 The Properties and Neural Substrate of Eye Movements
satory eye movements occur in the appro-
priate plane, and vision remains clear. For
example, during rotation about an earth-
vertical axis, the gain of the horizontal
component of the VOR is attenuated by a
factor equal to the cosine of the angle be-
tween the optical axis and the plane of
head rotation.168'343 Thus, for a complete
understanding of how the VOR functions
in natural circumstances, it is essential
to measure the movement of the head
around all three axes of rotation—yaw
(horizontal), pitch (vertical), and roll (tor-
sion)—and along all three axes of trans-
lation—interaural (side-to-side or heave),
naso-occipital (front-to-back or surge),
and rostral-caudal (up-and-down or bob).
For example, during walking and run-
ning, a seemingly inadequate r-VOR may
actually be quite appropriate when the ef-
fect of translation of the head on gaze
stabilization is taken into account.127 The
consequent compensatory response, ro-
tations of each eye around its three axes
of rotation, must be measured. Techno-
logical advances have made this possi-
ble (see Appendix B). Such approaches
have both heuristic value for a com-
plete
1
understanding of vestibular func-
tion, 1,14,169,173,233,264,400,428,4473,471,508,509
clinical value for topical localization.19'130'
169,181,428 For example, considering all
three axes of eye rotation, a spontaneous
nystagmus often can be attributed to in-
volvement of just one or of several semi-
circular canals.67'167'503
Optokinetic Nystagmus
Optokinetic stimulation occurs naturally
during sustained self-rotation in the light.
In the laboratory, the optokinetic system is
usually stimulated by rotating a large pat-
terned drum around the stationary sub-
ject. The subject experiences a compelling
sensation of self-rotation called circularvec-
tion, even though there is no peripheral
vestibular stimulation.75 During optoki-
netic stimulation in humans (e.g., the
drum rotating at 607sec for 60 sec, see
Fig. 2-6, Chap. 2), both the smooth-
pursuit and optokinetic systems con-
tribute to this response. At the onset of the
stimulus, the smooth-pursuit system is
most important and causes eye velocity to
reach its maximum within a second or
two. Typically, for stimulus velocities
<60%ec, gain (eye velocity/stimulus veloc-
ity) is about O.8.178'467'475 Vertical optoki-
netic responses tend to be of lower gain
than horizontal responses, and most sub-
jects show a greater gain for upward stim-
ulus motion than for downward.62 This
difference may be related to an asymmetry
in saccular inputs.251 If the subject actively
looks at the moving stimulus, greater eye
velocities can be achieved than if the sub-
ject passively stares at the surround. This
difference may represent greater activa-
tion of smooth pursuit during the former
condition. Target luminance is also an im-
portant factor.495 Attention to the stimulus
may be as important as the area of retina
being stimulated in determining the opto-
kinetic response.1'96'108 The gain of vertical
optokinetic nystagmus (OKN) is influ-
enced by binocular disparity. This finding
supports the view that the optokinetic re-
sponse is optimized for viewing of objects
in the plane of regard.247'336 The effects of
attention and prediction on visual track-
ing are discussed further under Stimulus
an(j for Smooth Pursuit in Chapter 4. Like
pursuit, OKN gain declines with age, due
to a loss at both high frequencies and high
velocities.36'369 Curiously, circularvection,
or the illusion of self-rotation associated
with rotation of the visual surround,
may become enhanced with age, perhaps
reflecting greater dependence on visual
cues for orientation in the elderly, as
labyrinthine and proprioceptive sensa-
tions become blunted.369
Torsional OKN can be induced by a roll
stimulus. For example, watching a revolv-
ing disk directly in front of oneself
elicits such a response. The gain and
range of torsional OKN responses are
low. 109,110,124,248,348,482
Optokinetic After-Nystagmus
An important property of the optokinetic
system is a persistence of the response af-
ter the stimulus has ceased. During the
stimulation period, the optokinetic sy-

stem effectively acts through the velocity-
storage mechanism. After the lights are
turned out, nystagmus continues in the
same direction for some seconds, with a
declining slow-phase velocity; this is called
optokinetic after-nystagmus (OKAN). The
velocity-storage mechanism that causes
OKAN is probably the same one that
causes the time constant of the VOR to be
2 to 3 times greater than the time constant
of the cupula of the semicircular canals.
As can be seen in Figure 2-6, the optoki-
netic and vestibular systems temporally
complement each other during and fol-
lowing sustained rotation in the light.
Thus, during rotation, as the VOR de-
clines, optokinetic responses, supplemented
by the smooth-pursuit system, take over.
When the period of self-rotation ends,
OKAN is a mechanism by which postrota-
tional nystagmus can be counteracted.48
Overall, however, in foveate animals, vi-
sual fixation (and smooth pursuit) are
more important in nullifying postrota-
tional nystagmus.
In humans and monkeys, the properties
of the optokinetic system can only be sepa-
rated from those of smooth pursuit by
studying OKAN. Four separate measures
of OKAN are initial eye velocity, time con-
stant of slow-phase decline, cumulative
slow-phase eye position, and symmetry.
If all lights are turned out after a period
of optokinetic stimulation (e.g., 60° or
150°/sec for 60 sec), initial eye velocity re-
flects the persisting action of smooth
pursuit, but this is gone within a second,
and subsequently the initial value of
OKAN can be measured. (Typically it is
107sec.426'467) Maximal amounts of OKAN
are produced by relatively large values
of retinal slip, in the range of 30° to
100°/sec.178 By measuring the rate of de-
cline of slow-phase velocity and fitting this
with a negative exponential curve, the
time constant of OKAN can be deter-
mined; reported values range consider-
ably, from 5 to nearly 50 sec.178'286'426-467
Cumulative slow-phase eye position (the
sum in degrees of all the slow phases) is
another, less variable measure of OKAN.225
Most normal subjects show less than a
6°/sec difference between rightward and
leftward initial OKAN velocities.
The Vestibular-Optokinetic System 47
Because of considerable intrasubject vari-
ability in measurements of initial OKAN
eye velocity and time constant, it is neces-
sary to make as many as a dozen separate
measurements to obtain reliable results.467
One way of achieving this and avoiding
prolonged and tedious testing is to moni-
tor the buildup of slow-phase velocity of
OKAN during stimulation, by briefly turn-
ing out the lights at intervals.426 This pro-
cedure is detailed further in Laboratory
Evaluation of Vestibular and Optokinetic
Function, below.
The occurrence of OKAN declines with
age,439 and OKAN may be more promi-
nent in women.467 With the head upright,
OKAN in the vertical plane is usually ab-
sent and, when present, only occurs fol-
lowing upward stimulus motion.62'295'317'349
These asymmetries are affected by head
tilt 125 and space flight. 111 They are also
modified in the altered-gravity period
during parabolic flight, implicating otolith
(saccule) inputs in their genesis.501 There
are asymmetries in the illusions of motion
in response to vertically moving optoki-
netic stimuli that correspond to asymme-
tries in vertical optokinetic eye movement
responses.310 Similar to vestibular testing,
repeated optokinetic stimulation can lead
to reduced duration of OKAN.266 Tilting
the head forward, backward, or laterally
shortens the duration of OKAN, an effect
similar to that of head movements on
postrotational nystagmus. 500 Fixation of
a small, stationary target during optoki-
netic stimulation suppresses subsequent
OKAN.74'178 On the other hand, a brief pe-
riod of fixation of a stationary target fol-
lowing optokinetic stimulation has little ef-
fect on OKAN. 178 These results suggest
that fixation of a small target may act to
"switch off" visual inputs to the velocity
storage mechanism, but once the mecha-
nism is "charged," fixation has little influ-
ence on the course of OKAN.
Ccrvico-ocular Reflex
The cervico-ocular reflex (COR), when
tested in darkness using rotation of the
body underneath the stationary head, has
a low gain at frequencies corresponding to
48 The Properties and Neural Substrate of Eye Movements
most natural head rotations for normal
human subjects.268'417 Only in some in-
fants may a higher gain be seen.404 If
labyrinthine function is lost due to disease,
however, the COR may increase in gain
and assume greater importance in gener-
ating compensatory eye rotations during
natural head movements.90'236'273'421 In pa-
tients with bilateral loss of vestibular func-
tion, isolated stimulation of cervical affer-
ents during body rotation produces both
slow phases and catch-up saccades in the
same direction (i.e., opposite to relative
head motion) to aid gaze stabilization (see
Table 7-1, Chap. 7). If labyrinthine func-
tion recovers, the cervico-ocular reflex
may revert to its previous low gain.89 In
labyrinthine-defective patients, and even
in normal subjects, the COR can be en-
hanced when subjects are instructed to fix
upon a part of their trunk that is moving
relative to the stationary head, instead of
keeping their eyes focused on a stationary
position in space.250 The latter instruction
could act to cancel compensatory slow
phases, unless there was a perception of
the head moving in space. The COR
can be actively trained in labyrinthine-
deficient patients using magnifying and
reducing lenses in a similar way to adapta-
tion of the gain of the r-VOR.236 Again, the
mental set and the subject's perception of
the context in which the neck afferents are
being stimulated are critical in determin-
ing whether the COR should be enhanced
(if the head is perceived to be moving) or
decreased (if the head is perceived to
be still).236-421 Likewise, cervico-ocular re-
flexes contribute little to ocular counter-
roll (with lateral tilt of the head relative to
the body) in normal subjects, but in pa-
tients with bilateral labyrinthine loss, their
contribution can be considerable.59'147
Patients with bilateral labyrinthine loss
and coincident cerebellar disease may not
show enhancement of the COR, suggest-
ing a role for the cerebellum in this aspect
of vestibular adaptation90 (as is the case for
VOR adaptation). Cervical afferents may
influence the velocity-storage mechanism;
OKAN is made asymmetric during optoki-
netic stimulation with the head kept
turned relative to the body.271
ADAPTIVE PROPERTIES OF
THE VESTIBULO-OCULAR
REFLEX
The brain shows a remarkable ability to
adapt* the VOR to prevailing environ-
mental circumstances. The VOR can com-
pensate for the effects of disease and
trauma and the changes that occur with
growth and aging. From a profound loss
of labyrinthine function on one or both
sides to wearing a new spectacle prescrip-
tion, the VOR must detect errors in per-
formance and correct for them. Mecha-
nisms exist to maintain balanced levels of
tonic activity, i.e., to prevent spontaneous
nystagmus, and to ensure calibrated com-
pensatory responses to head motion, so
that slow phases are of the correct ampli-
tude, direction, and timing (phase). Other
mechanisms and strategies also help stabi-
lize the line of sight during head move-
ment; they become especially evident
when there is a loss of the peripheral ves-
tibular signal. In this section we will dis-
cuss habituation, the short-term adapta-
tion that produces the reversal phases of
nystagmus, calibration of the VOR in re-
sponse to imposed visual-vestibular mis-
matches, and recovery from unilateral loss
of labyrinthine function.
VOR Habituation
Although impaired vision during head
movements is the basis for many adaptive
changes in VOR performance, the VOR
also may habituate (i.e., show a reduction
of time constant and gain) to repetitive
stimuli in complete darkness. Habituation
is most evident after repeated constant-
velocity rotations or low-frequency contin-
*We will not make a rigid distinction here between
the terms adaptation and compensation. Usually, adap-
tation is used in a more restricted sense, to imply ad-
justment in the basic vestibulo-ocular reflex, whereas
compensation is used in a larger sense, to include the
entire repertoire of ways, including substitution, pre-
diction, and other cognitive strategies, by which pa-
tients recover from, and learn to live with, vestibular
disorders.

uous oscillations (stimuli outside the fre-
quency range of most natural head rota-
tions).30 The functional significance of ves-
tibular habituation is uncertain, although
it may contribute to eliminating the spon-
taneous nystagmus that follows a unilat-
eral labyrinthine lesion. Its relevance to
clinical testing is that patients previously
subjected to repetitive stimuli that contain
a low-frequency component (for example,
ice skaters who do long, high-speed spins),
may have seemingly abnormal, low VOR
time constants.
Short-Term VOR Adaptation that
Produces the Reversal Phases
of Nystagmus
Adaptive mechanisms are also engaged by
the presence of a persistent, unchanging
vestibular stimulus. Such a stimulus al-
most never occurs in natural circum-
stances except when there is a lesion that
creates an imbalance in vestibular tone be-
tween the two sides. This results in a spon-
taneous nystagmus. For example, with a
constant-velocity rotation, after the origi-
nal nystagmus dies out, a reversal phase of
nystagmus may develop with slow phases
in the opposite direction (i.e., the same di-
rection as head rotation) (see Fig. 1-6,
Chap. 1). This phenomenon probably re-
flects an adaptive mechanism, residing in
both the brain stem and the peripheral
vestibular apparatus, which has been acti-
vated by a persistent vestibular stimu-
lus.191'513 It has a time constant of action of
about 80 sec, so that its effect is completed
in minutes. One natural cause of such a
persisting vestibular signal is an imbalance
in the tonic levels of activity due to a
peripheral labyrinthine disturbance; the
adaptation mechanism could help to nul-
lify the pathologic spontaneous nystag-
mus. Such a mechanism, however, proba-
bly works best only for small degrees of
imbalance; after a unilateral loss of
labyrinthine function, it may take days for
vestibular tone to be brought back into
balance, eliminating the spontaneous nys-
tagmus. Prolonged optokinetic stimula-
The Vestibular-Optokinetic System 49
tion also may cause ocular motor and per-
ceptual aftereffects that are manifestations
of motion habituation.74 Like per-rotatory
or postrotatory nystagmus, optokinetic af-
ter-nystagmus may be followed by a rever-
sal phase (OKAN II).
The adaptation mechanism producing
the reversal phases of nystagmus is partic-
ularly prominent in infants.504 Its action
may also become particularly obvious in
patients with cerebellar lesions; it is re-
sponsible for the change in the direction
of the slow phase that characterizes peri-
odic alternating nystagmus (see VIDEO.
"Periodic alternating nystagmus").293 The
reversal phase of head shaking-induced
nystagmus is another manifestation of this
same mechanism. 222
Visually Induced Adaptation
of the VOR
The VOR functions in an inherently open-
loop manner. Because of the brief periods
and short latencies within which it must
operate, immediate visual inputs cannot
correct for most imperfections because of
the time taken in retinal processing. Con-
sequently, the brain must continuously
monitor the effectiveness of its VOR and
adjust it accordingly when it malfunctions.
Longer-term adaptive capabilities, based
upon visual error signals during head mo-
tion, must be used.
ADAPTATION TO REVERSING
PRISMS AND SPECTACLE LENSES
A dramatic example of the effects of
changed visual demands upon the VOR
are the consequences of viewing the world
through head-fixed optical devices such as
mirrors or prisms that laterally invert the
world, left to right.204'205'327 While wearing
such devices, head turns cause the envi-
ronment to appear to move in the same
direction as head turning. After just a few
minutes of head rotation during reversed
vision, VOR gain (measured during rota-
tion in darkness) declines, and this is not
the only change. Subjects adopt strategies
50 The Properties and Neural Substrate of Eye Movements
such as altering the pattern of head mo-
tion or using saccades to help stabilize
gaze in this altered visual environ-
ment.60'329 After removal of the optical de-
vice, gain rapidly returns to its previous
value. With longer periods of exposure to
visual inversion, changes in the VOR are
retained for a longer period, such as
overnight. In subjects who wear reversing
prisms for 3 to 4 weeks, large changes of
gain and phase occur that actually reverse
their VOR; head rotations cause eye
movements in the same direction. Thus,
the gain and phase of the VOR are
changed so that images are once again
stable upon the retina during head
movements. While these adaptive changes
are taking place, subjects report symp-
toms of motion sickness, reflecting the
conflict between vestibular and visual
cues.330
A less extreme and more common visual
demand on the VOR is wearing a specta-
cle correction. Spectacle lenses have a
prismatic effect called rotational magnifica-
tion, which is distinguished from the linear
magnification that produces clearly fo-
cused images. This means, for example,
that individuals who wear high-positive
lenses (e.g., for aphakic correction or hy-
peropia) must rotate their eyes more when
they attempt to change their line of sight
than when they are not wearing their
glasses. Similarly, they will be required to
rotate their eyes proportionally more dur-
ing head rotations in order to hold images
steady upon the retina than when they are
not wearing glasses. Nearsighted (myopic)
individuals who habitually wear negative
spectacle lenses have lower values for
VOR gain than farsighted (hyperopic) in-
dividuals, or patients who have had their
lenses removed and habitually wear posi-
tive-spectacle lenses.102 Individuals who
habitually wear contact lenses show no
such changes in VOR gain; because the
contact lenses rotate with the subject's
eyes, there is no rotational magnification
effect. Adaptation of the VOR to spectacle
correction occurs rapidly in normal sub-
jects. More than 50% of subjects show sig-
nificant changes in VOR gain after wear-
ing telescope lenses for 15 min.150 Older
subjects are capable of developing such
short-term adaptation, but the response is
diminished.368
Changes in VOR gain are achieved over
a broad frequency range and not just at
the testing frequency. With prolonged
training at one frequency of rotation,
however, adaptive gain changes are great-
est at the training frequency.302 If subjects
wear 2 X magnifying lenses for several
days during natural behavior, then an in-
crease in VOR gain is most evident for
testing frequencies of head rotation
greater than 2 cycles/sec.255 With shorter
periods of wearing the lenses, however,
adaptation may be greater for lower fre-
quencies.371 Amplitude nonlinearities, with
less adaptation at higher velocities, may
also become apparent.371'479a Critical to
understanding why there are such differ-
ences in adaptive responses is considera-
tion of an important principle of VOR,
and presumably, of many other types of
motor adaptation: the adaptive response
is tailored to the specific nature of the
adaptive stimulus. Differences in how sub-
jects move their heads during the training
period likely determine the adapted re-
sponse.
CROSS-AXIS ADAPTATION
OF THE VOR
A variety of paradigms have been used to
demonstrate the wide repertoire of VOR
adaptive responses, including the ability
to change the direction, phase (timing),
and amplitude of the VOR. For example,
if the head is rotated horizontally (in yaw)
while the visual display is synchronously
rotated vertically, after a training period,
horizontal rotations in darkness will pro-
duce eye movements that have a vertical
component.15'186'277'378'418 This cross-axis
plasticity is in accord with electrophysio-
logic evidence that secondary neurons in
the vestibular nucleus receive inputs from
one, two, or all three pairs of semicircular
canals.24 Furthermore, during cross-axis
training, neurons in the vestibular nuclei
that are normally maximally sensitive to
pitch axis (vertical) stimulation increase
their sensitivity to yaw axis (horizontal)
rotation,395 providing a neurophysiologic
substrate for the change in direction of the

VOR. Similar considerations apply to the
fact that wearing left-right reversing
prisms calls for a change in the torsional
(roll) but not vertical (pitch) VOR gain.
Such a selective change in the VOR takes
place even though both torsional and ver-
tical signals are carried on the same vestib-
ular afferents.49'54'55
D.A. Robinson has presented a matrix
analysis of the problem of producing slow
phases in a direction orthogonal to head
motion, or producing a change in tor-
sional gain alone.408'409 One matrix rep-
resents the vectors of the semicircular
canals, a second matrix represents the
pulling actions of the extraocular muscles,
and a third matrix represents the strength
of central connections between vestibular
neurons and ocular motoneurons. When
head movements are artificially dissoci-
ated from apparent motion of the visual
environment, as described above, then a
change in the central matrix must occur so
that, for example, vertical eye rotations
are coupled to horizontal head rotations,
or the torsional VOR gain is selectively en-
hanced or depressed.
OTHER FORMS OF
VOR ADAPTATION
Other examples of VOR adaptive capabili-
ties include changes in dynamic character-
istics160such as the phase (timing) of the
VOR. >282,283,386,402 Disconjugate adapta-
tion of the VOR may occur in response to
a unilateral muscle palsy,478 for example,
or to wearing prisms in front of one eye.365
Such a capability is especially important
for a correct compensation to the transla-
tional component of head (orbit) motion,
because the eyes must rotate by different
amounts whenever the point of regard is
near to the subject and away from the
midline.
Otolith-ocular reflexes are also subject
to adaptive control. VOR learning ac-
quired with training during upright
(yaw axis) rotation is transferred to the
otolith-derived modulation component of
OVAR.28°,493 Similarly, there is (inappro-
priate) transfer to otolith-mediated slow-
phase compensation during orthogonally
directed rotations (head-over-heels).385
The Vestibular-Optokinetic System 51
Prolonged centrifugation can also lead to
changes in the roll (torsional) angular
VOR,215 although 2 hr of static lateral
head tilt (up to 34°) in monkeys induced
no change in ocular counterrolling.453 A
few studies have suggested that the t-VOR
is also subject to adaptive control.3752'429'518
In contrast to the r-VOR, however, we
know much less about adaptive control of
otolith-ocular reflexes.
Although a visual stimulus (motion of
images on the retina) is the main determi-
nant of the pattern of these adaptive
changes of the VOR, even imagination of
a visual stimulus can be enough to bring
about plastic changes in VOR gain, al-
though at about half the rate that occurs
when visual stimuli are used.328 An after-
image placed on the retina (which does
not allow for retinal image motion) can
also be used to stimulate VOR adap-
tation.433 There are also perceptual con-
comitants of VOR adaptation that accord
nicely with the ocular motor responses
measured in darkness. 61
Probably one of the more critical aspects
of successful vestibular compensation in
natural circumstances is a capability for
VOR adaptive responses to be expressed
on the basis of context. The attitude of the
head relative to gravity, the position of the
eye in the orbit, and the frequency content
and pattern of the head movement have
been shown to be potent contextual cues
for gating of different vestibular re-
sponses.25'282'387'434'468 For example, the
horizontal r-VOR or t-VOR can be made
to have an increased gain when the verti-
cal eye position is up in the orbit, and a
decreased gain when the eye is down in
the orbit3753'434 (Fig. 2-9), or the horizon-
tal r-VOR can be selectively adapted for
different viewing distances.112 In other
words, the brain has mechanisms to enlist
different learned vestibular responses de-
pending upon the circumstances in which
they must occur.
Mechanisms of Recovery from
Lesions in the Labyrinth
Thus far, we have discussed adaptive re-
sponses that affect the VOR gain symmet-
52 The Properties and Neural Substrate of Eye Movements

Figure 2-9. Context-driven VOR adaptation in a subject who had been trained to have a higher horizontal
VOR gain in upgaze (Xl.7 viewing, optokinetic drum moves opposite the head) and a lower horizontal VOR
gain in downgaze (XO viewing, optokinetic drum moves with the head). The subject was trained for 2 hrs, with
vertical eye position (and the appropriate horizontal visual-vestibular conflict stimulus) being alternated every
10 min. After the training period, the horizontal VOR gain, measured in darkness, was different depending on
whether gaze was up or down. (Reprinted from Journal of Vestibular Research, volume 2, Shelhamer M,
Robinson DA, Tan HS. Context-specific adaptation of the gain of the vestibulo-ocular reflex in humans, pages
89-96, 1992, with permission from Elsevier Science.)

rically. But a common and important clini-
cal problem is how the brain compensates
for unilateral labyrinthine lesions (see Dis-
play 10-15, Chap. 10). What factors influ-
ence the rate and pattern of recovery from
a peripheral vestibular lesion?136'137-156'441-443
Here we will highlight some key features
based upon a study of experimental, uni-
lateral labyrinthectomy in monkeys, which
illustrates how different parts of the recov-
ery process depend upon visual or nonvi-
sual factors.174-176 In the first 24 hr follow-
ing labyrinthectomy, there is a head tilt
and turn towards the side of the lesion.
With the head stationary, spontaneous
nystagmus, with slow phases directed to-
wards the side of the lesion, is present in
light and darkness. The nystagmus indi-
cates a static vestibular imbalance. The
slow-phase velocity in the dark (20° to
607sec) is much greater than in the light
(up to 4°/sec), illustrating that visual fixa-
tion suppresses this nystagmus. The ve-
locity of the slow phases of nystagmus
declines during the next few days, irre-
spective of whether the monkeys are kept
in a dark or an illuminated environment.
Moreover, in monkeys that have previ-
ously undergone bilateral occipital lobec-
tomy, resolution of spontaneous nystag-
mus occurs at a similar rate. Thus,
recovery from the static imbalance that
follows a unilateral labyrinthine lesion
does not depend upon vision. Recovery of
static balance from unilateral labyrinthine
loss in humans may never be complete; in
darkness, some patients show spontaneous
nystagmus years after their lesion. The ba-
sis of the resolution of the spontaneous
nystagmus after a unilateral loss of func-
tion is largely a restoration of activity on
the side of the lesion.441 Other factors may
also supervene early in the compensation
process, including, for example, suppres-
sion of activity on the intact side.319'406
Later during compensation, subjects may
also employ strategies apart from chang-
ing the gain of the slow-phase response.

An additional finding after recovery
from labyrinthectomy in monkeys is an in-
creased response to cold caloric stimula-
tion of the normal ear. Similar findings
have been reported in humans. 249 The
change in caloric responses may represent
an adaptive increase in vestibular nucleus
sensitivity on the intact side.
Recovery from the dynamic vestibu-
lar imbalance that follows unilateral
labyrinthectomy depends on visual inputs;
VOR gain does not increase in monkeys
kept in darkness. Moreover, monkeys that
have undergone bilateral occipital lobec-
tomy prior to labyrinthectomy show only a
partial recovery, with little compensation
for high-velocity stimuli. This finding sug-
gests that both striate and extrastriate vi-
sual pathways play a role in the recovery
of dynamic vestibular responses following
unilateral labyrinthectomy. These findings
contrast with the recovery from static ves-
tibular imbalance, which does not depend
upon visual factors.
Especially at high speeds and accelera-
tions of the head toward the side of the le-
sion, patients with unilateral as well as bi-
lateral loss of labyrinthine function may
also employ preprograming of saccades in
the direction in which slow phases are in-
adequate.273,379,425
Recovery from peripheral vestibular
lesions depends in part upon the degree
to which peripheral function is spared.
Plugging of individual semicircular canals
has shown that compensation can be
partly restored by using information from
the remaining intact canals. The spatial
tuning of information from the intact ca-
nal (as a function of the plane of rota-
tion) is readjusted centrally so that it can
provide a better signal of rotation in a
plane close to that of the plugged Ca-
nal 13,16,63,68,508
VOR adaptation and compensation de-
pend upon the integrity of a number of
structures, including the cerebellum and
perhaps the vestibular commissure. After
destruction of one labyrinth, vestibular
nucleus neurons ipsilateral to the lesion
are driven exclusively by the contralateral
vestibular nucleus, through the vestibular
commissure; this finding led to the sug-
gestion that this structure is important in
The Vestibular-Optokinetic System 53
compensation from peripheral vestibular
lesions. A change of neural tone in the
vestibular nucleus, however, independent
of changes in commissural gain, could
achieve the same effect.106'174 Such a
change of neural tone might be achieved
by the deep cerebellar nuclei or by intrin-
sic factors within the vestibular nuclei.
Compensation for a bilateral loss of
labyrinthine function includes a number
of compensatory responses and strategies,
which are discussed in Pathophysiology of
Bilateral Loss of Labyrinthine Function,
below.
VESTIBULOCEREBELLAR
INFLUENCES ON THE
VESTIBULO-OCULAR REFLEX
Anatomical Pathways by which the
Vestibulocerebellum Influences
the VOR
The vestibulocerebellum consists of the
flocculus, nodulus, ventral uvula, and ven-
tral paraflocculus.481 The flocculi and ad-
jacent paraflocculi share anatomic con-
nections and physiologic properties. The
flocculus receives bilateral, mossy fiber in-
puts, primarily from the vestibular nuclei
and nucleus prepositus hypoglossi (NPH),
but also from the pontine nuclei and nu-
cleus reticularis tegmenti pontis. The
climbing fiber inputs to the flocculus are
from the dorsal cap of the contralateral in-
ferior olivary nucleus.84'288 Another input
to the flocculus is from the cell groups of
the paramedian tracts (PMT), which may
relay an efference copy of eye move-
ment.101 Thus, the flocculus receives ves-
tibular, visual, and ocular motor signals.
In primates, the flocculus probably re-
ceives relatively few direct vestibular
nerve afferents, although the nodulus is
more richly innervated directly from the
vestibular nerve.288'353 The flocculus pro-
jects to the ipsilateral vestibular nuclei, y-
group, and the basal interstitial nucleus of
the cerebellum.287 Particularly important
are the floccular target neurons (FTN) in
the vestibular nuclei, which probably play
a role in vestibular adaptation. These ana-
54 The Properties and Neural Substrate of Eye Movements
tomical connections are summarized in
Display 6-10 in Chapter 6.
Electrophysiological Aspects
of Vestibulocerebellum Control
oftheVOR
Recordings from the flocculus of alert,
trained monkeys have revealed a particu-
lar group of Purkinje cells that do not
modulate their discharge during either
vestibularly induced eye movements in
darkness or head rotation while fixating a
stationary target. Their discharge modu-
lates in relation to gaze velocity (velocity of
the eye in space) during pursuit of a mov-
ing target with the head still or during
combined eye-head tracking.285 The role
of these gaze-velocity Purkinje cells in the
control of eye movements is not settled;
they may play a role in the on-line modu-
lation of the VOR using visual-following
reflexes and in the long-term changes in
the VOR related to adaptation partly via
the y-group (see Display 6-8).242'284>304>374>402a
They may also participate in adjusting the
gain of the r-VOR or the t-VOR, when
subjects view targets that are close to the
head.446
Effects of Vestibulocerebellar
Lesions on the VOR
Experimental lesions of the primate floc-
culus and paraflocculus produce relatively
small changes in vestibular responses; the
VOR gain may be slightly higher or
lower.118'484'520 On the other hand, the
ability to adapt VOR gain in response to
visual demands is abolished.303'418 Human
patients with cerebellar disease may also
show abnormalities in VOR adapta-
tion;188'411'507 these deficits are likely due
to floccular involvement. Optokinetic nys-
tagmus and the velocity-storage mecha-
nism are relatively preserved after floc-
culectomy, but smooth tracking, either
with the head still or moving, is im-
paired.484'520 The output of the integrator,
the step of innervation, cannot be main-
tained when the eye is put into an eccen-
tric position, producing gaze-evoked nys-
tagmus. The step is also not matched cor-
rectly to the amplitude of the velocity
command that moved the eye to its new
position, producing postsaccadic drift (glis-
sades). These deficits are summarized in
Display 10-17, in Chapter 10.
Experimental lesions of the nodulus
and ventral uvula of monkeys (Display
10-18) maximize horizontal velocity stor-
age, which increases the time constant of
the horizontal VOR. The lesion also pre-
vents habituation of the VOR, impairs tilt-
suppression of postrotatory nystagmus,
disturbs the reorientation of the velocity-
storage mechanism to earth-horizontal
with head tilt, alters vertical OKAN, and
causes periodic alternating nystagmus in
darkness.118'243-485'499 In monkeys, but pre-
sumably not in humans (who show little
torsional velocity storage),427'428 ablation
of the nodulus and ventral uvula de-
creases the time constant of the roll (tor-
sional) VOR.7
Role of Cerebellum in
VOR Adaptation
What is the neural substrate for the adap-
tive properties of the VOR that flocculec-
tomy abolishes? Ito proposed that the er-
ror signal for an inadequate VOR, drift of
images on the retina, is relayed, via the in-
ferior olivary nucleus and climbing fibers,
to Purkinje cells in the flocculus.256'257 On
the basis of this visual information and
vestibular inputs relayed by mossy fibers
and the parallel fibers of granule cells,
Purkinje cells are able to make appropri-
ate changes in the VOR via their projec-
tions to the vestibular nucleus (Fig. 2-10).
Thus, it was proposed that the vestibulo-
cerebellum is the site of a form of mo-
tor learning, on account of modifiable
synapses between parallel fibers and Purk-
inje cells. Ito has proposed that this learn-
ing is due to a long-term depression
(LTD) of synaptic transmission from par-
allel fibers to the Purkinje cell.258'259 This
synaptic change depends upon calcium
ions and glutamate receptors, and is in-
duced by the nearly simultaneous arrival
 The Vestibular-Optokinetic System 55

Figure 2-10. Hypothetical scheme to account for vestibulo-ocular adaptation. Head velocity (H) is transduced
by the semicircular canals (SCC) and sent to the vestibular nuclei (VN) to be relayed via a three-neuron arc to
the motoneurons (MN) to create an equal but opposite eye velocity (E). The canal signal is relayed to the floccu-
lus on mossy fibers (mf) that are axon collaterals of either first- or second-order vestibular neurons via granule
cells (gc) and their parallel-T fibers to Purkinje cells (Pc). Retinal image motion is sensed by direction-selective
cells in the retina, relayed through the nucleus of the optic tract (NOT), to the inferior olivary nucleus (IO),
and thence to the PCS on climbing fibers (cf). The PC project to a subset of second- or third-order cells (not
shown) in the VN called floccular target neurons (FTN), which also receive an axon collateral from the cfs. The
PCS are also thought to receive a copy of the eye velocity signal (E). According to Ito, the error signal is carried
by cfs, and the modifiable synapses are on PC dendrites at site 1*. According to Lisberger and colleagues, the PC
carry the error signal and the main modifiable synapses are on FTNs at site 2*. (Redrawn from Luebke and
Robinson311.)

of signals from climbing fibers and parallel
fibers on Purkinje cells.
Although Ito's flocculus hypothesis has
many attractive features, it does not ac-
count for all the experimental data in
primates, including the behavior of the
so-called gaze velocity Purkinje cells previ-
ously discussed.161'301'307'338 The flocculus
hypothesis does not completely account
for the effects on VOR adaptation of si-
lencing the climbing fibers of the inferior
olivary nucleus with a local anesthetic, or
experimentally stimulating climbing fibers
to produce "floccular shutdown."151'311
Furthermore, a critical issue in VOR
learning that is not yet adequately ex-
plained is how the correct relative timing
between the arrival of signals conveying
information about motion of the head and
those conveying information about mo-
tion of images on the retina (the error sig-
nal) is achieved on floccular Purkinje
cells.30i,402,402a There is also evidence for
differential regulation of VOR gain and
dynamics. Low-frequency training stimuli
tend to produce frequency-specific changes
in gain; high-frequency training stimuli
tend to produce changes in gain that
are relatively frequency-independent.402
It has been suggested that the frequency-
specific changes are mediated by calcium
channels and the frequency-independent
changes by calcium-activated potassium
channels.159 One source of the discrep-
ancy between Ito's work and the results
described in primates may be disagree-
ment about what the flocculus is. Parts of
what has traditionally been called the floc-
culus are probably part of the ventral
paraflocculus, which may be associated
with pursuit rather than with VOR adap-
tation.258,352,354
An alternative explanation is that the
flocculus, rather than being the sole site of
VOR learning, serves other functions in
VOR adaptation.300'304~306>374'375'394a'402a'403
It could provide an error correction signal
to certain neurons in the vestibular nu-
cleus called the flocculus target neurons
(FTN), which would be one site of motor
56 The Properties and Neural Substrate of Eye Movements
learning for VOR adaptation (Fig. 2-10).
Perhaps adaptive changes in the ampli-
tude of the VOR are mediated by this
mechanism. The flocculus, however, could
still be a site of learning for other types of
vestibular adaptation (e.g., the response to
low-frequency training stimuli, the re-
sponses that require a change in the tim-
ing or dynamic response of the VOR, or in
context-driven VOR learning). The cere-
bellar flocculus, with its rich sources of af-
ferent information and internal copies of
motor commands, would be ideally poised
to gate different VOR responses based
on the circumstances in which they are
needed.
The flocculus also plays a role in recov-
ery of function after unilateral labyrinthine
loss. Although restoration of relatively
small degrees of imbalance between the
vestibular nuclei can probably take place
independently of the flocculus,219 large
amounts of spontaneous nystagmus and
the recovery of amplitude and symmetry
of gain during head movement probably
require it.279
Of course, a number of other adaptive
strategies are used to compensate for a
vestibular loss, apart from adjusting the
gain of slow phase of the VOR. They in-
cluding preprograming of compensatory
eye movements.273'379 Whether the cere-
bellum is involved in these "higher-level"
strategies is not known. It has been shown,
however, that when a rabbit is exposed
to sustained sinusoidal oscillation of the
head, some climbing fibers in the nodulus
of the rabbit discharge in a sinusoidal fash-
ion after the animal stops rotating.43 This
finding is compatible with the idea that
the cerebellum can learn patterns of ves-
tibular stimulation and generate them
even after the actual stimulus has ceased.
Many neurotransmitters and neuropep-
tides have been implicated in the pro-
cess of vestibular adaptation.143'159-384'442'443
In the vestibulocerebellum, nitric ox-
ide, NMDA receptors, acetylcholine, and
catecholamines appear to be impor-
tant.278'298'325'326'476
Numerous computational models have
been proposed to account for many as-
pects of VOR learning including adapta-
tion of the phase and gain of the VOR,
and restoration of dynamic balance after
unilateral lesions. Many such models in-
clude a potential role for the cerebel-
lum-208,283,300,383,384,394,394a,396,401,402a,502 per.
haps the plethora of models reflects the
lack of critical experimental data with
which they can be confirmed or refuted.
VESTIBULAR SENSATION
Inputs from the labyrinth constitute the
basis for a "sixth sense."79 Thus, rotation
in the dark at a constant velocity produces
a sensation of turning that declines, as do
the vestibularly induced eye movements.
Similarly, one can detect and identify static
tilts of the head. Vestibular sensations are
usually accompanied by congruent visual
and somatosensory inputs; when conflict
arises, discomfort and motion sickness re-
sult. During natural activities, it is neces-
sary to distinguish between sensations due
to self-motion and those due to movement
of objects in the environment. One insight
into how this is achieved is the observation
that real or perceived thresholds for de-
tecting motion of objects in the environ-
ment are elevated during locomotion.391
Such a change in perceptual thresholds
may contribute to the ability to maintain a
sense of a stable world during locomotion,
and it may also be an adaptive strategy in
patients with vestibular loss and oscillop-
s i a> 93,158a,210,269,335,356
The vestibular system also plays an im-
portant role in the perception of the posi-
tion of the head on the body, the body in
space, and how sensory conflicts might be
resolved.246'272'334 Evaluation of percep-
tion, including the sense of where the
head is pointing in darkness, and the atti-
tude of the visual or body vertical may
also be valuable in detecting lesions in
various parts of the vestibular system,
from the labyrinth to the cerebral cor-
j-ex_58,79,81,185,252,253,269,356,421
Vestibulocortical projections are ex-
tensive and now reasonably well de-
fined.52'69'185'290'464 They presumably carry
information for spatial orientation, but
they could also be involved in other
aspects of vestibulo-ocular control, includ-
ing adaptation, perhaps related to con-

text. The vestibular nuclei project dif-
fusely to the lateral and inferior portion of
the ventroposterior lateral (VPL) thalamic
nucleus, where activity related to head ro-
tation in darkness can be recorded.97
Thalamic neurons appear to receive their
major inputs from excitatory rather than
inhibitory secondary vestibular neurons,
although the inhibitory neurons are
clearly important for the VOR itself.316
Stimulation of the human thalamus dur-
ing operations for intractable pain or
movement disorders produces sensations
of movement.234 In monkeys, projections
from the VPL pass rostrally to parietal,
parieto-insular, and frontal cortex.3 These
several regions of vestibular cortex in-
clude area 2v at the anterior tip of the in-
traparietal sulcus, area 3av in the lateral
sulcus, area MST, and the parieto-insular-
vestibular cortex (PIVC) deep in the Syl-
vian sulcus posterior to the insular cortex.
In this last area, most of the cells are mul-
timodal, often responding to labyrinthine,
visual (optokinetic), proprioceptive (usu-
ally from the neck), or somatosensory in-
puts from the skin. Neurons can be
excited for ipsilateral (type I) or contralat-
eral (type II) rotation, as is the case for
neurons in the vestibular nuclei. Optoki-
netic and labyrinthine inputs can be syn-
ergistic (excited for opposite directions, as
occurs during natural head rotation) or
antagonistic (excited for the same direc-
tion). Neurons that carry inputs from the
neck and labyrinth also may be synergistic
or antagonistic. The three cortical vestibu-
lar areas, 2v, 3a, PIVC, are strongly inter-
connected with each other and with the
opposite hemisphere. Area PIVC, in par-
ticular, seems to be a nexus for spatial ori-
entation, as it also receives projections
from areas 3aH (hand), 6pa, 7a,b, 8a, cin-
gulate gyrus, and a visual temporal Syl-
vian area. In addition, there are monosy-
naptic cortical projections from most of
these same areas to the vestibular nuclei
(some ipsilateral, some contralateral), and
these pathways may mediate cortical influ-
ences upon the VOR.185'218
In humans, evidence suggests that mul-
tiple cortical areas receive vestibular sig-
nals.290 The temporal lobes have been
thought to mediate a vestibular sense; this
The Vestibular-Optokinetic System 57
is based on Penfield's observation that
stimulation of the superior temporal gyrus
of awake patients caused sensations of
bodily displacement.377 He and others also
reported focal seizures, vestibular or "tor-
nado" epilepsy, starting in this area, with
auras consisting of sensations of rotation.
Similar seizures, sometimes with epileptic
nystagmus, have subsequently been re-
ported in association with focal dis-
charges in frontal, parietal, or temporal
lobes.190'270'449 PET and fMRI studies have
also identified cortical areas responding to
caloric, optokinetic or galvanic stimulation
in humans. The results largely agree with
the anatomic and physiological studies
described above (see Fig. 6-8).69'70'93a'156a'
183,480 jce water produces predominantly
contralateral activation. In addition to
the "vestibular" cortical areas described
above, the anterior cingulate cortex, in-
sula, and putamen are activated during
caloric stimulation. Humans with lesions
in the cerebral cortex (probably in a re-
gion homologous to PIVC and nearby
parietal cortex) show altered perceptions
of the subjective visual vertical79'81 and dis-
turbances of circularvection.235'450 They
may occasionally have rotational vertigo.80
Lesions in the PIVC also produce deficits
in generating memory-guided saccades to
a previously seen target after the head is
displaced to a new position in the dark.254
CLINICAL EXAMINATION
OF VESTIBULAR AND
OPTOKINETIC FUNCTION
General Principles for Evaluating
Vestibular Disorders
Here we apply the basic principles already
discussed to the clinical and laboratory
evaluation of patients with vestibular dis-
ease (see Appendix A for a summary). A
more systematic treatment of specific ves-
tibular disorders is given under Disease of
the Vestibular Periphery in Chapter 10.
The reader is referred to neurotologic
texts for details on otoscopy, audiometry,
and vestibulospinal testing.29 We will be-
gin by recapitulating certain important
58 The Properties and Neural Substrate of Eye Movements
physiologic properties that will guide the
examination.
First, to maintain steady gaze during
head rotation, the VOR produces eye
movements that compensate for head ro-
tations. VOR gain (eye velocity/head ve-
locity) and phase (temporal relationship
between input and output during sinu-
soidal stimuli) are used to quantify this re-
flex. Phase relationships during sinusoidal
rotations and measurements of the time
course of decay of the response to con-
stant-velocity stimuli (velocity steps) pro-
vide a measure of the time constant of the
VOR, which is a function of both periph-
eral vestibular properties and central ve-
locity storage.
Second, when the head of a healthy sub-
ject is stationary, the left and right vestibu-
lar nerves and nuclei show resting dis-
charge rates (vestibular tone) that are
balanced. If disease causes a static imbal-
ance of vestibular tone, a spontaneous
nystagmus results (see Display 10-1,
Chap. 10). This imbalance causes slow
phases with horizontal components di-
rected toward the side with lower tonic ac-
tivity (quick phases away from the side of
the lesion). In addition, a dynamic imbal-
ance may occur during head rotation.
This is similar to the directional prepon-
derance of caloric testing (discussed later)
and causes a VOR gain greater for head
turns away from the side of the lesion than
for head turns toward it.
Static otolith-ocular reflexes are vesti-
gial in human beings, and ocular counter-
rolling and responses to translation can-
not be readily tested at the bedside.
Nevertheless, disturbances of otolith path-
ways cause characteristic symptoms and
signs including disturbances of the subjec-
tive visual vertical, and skew deviation, oc-
ular counterroll, and head tilt.76'77>79a>213
Both the optokinetic and smooth-pur-
suit systems supplement the VOR during
sustained rotations in the light so that
compensatory eye movements can be
maintained as vestibular input decays. To
evaluate the optokinetic system alone, in-
dependent of pursuit, it is necessary to
study optokinetic after-nystagmus (OKAN)
in darkness.
History-Taking in Patients with
Vestibular Disorders
Patients with vestibular disease may com-
plain of dysequilibrium, unsteadiness, or
vertigo, which often reflect imbalance of
vestibular tone. Vertigo is a distressing, illu-
sory sensation of motion (literally, turn-
ing) of self or of the environment. In con-
trast to one's perception of self-motion
during natural locomotion, vertigo is
linked to impaired perception of a station-
ary environment. The mismatch between
the actual multisensory inputs and the ex-
pected pattern of sensory stimulation with
the head stationary causes vertigo. The
nature of the vertigo may differ according
to disturbances of the semicircular canals
and the otoliths. Rotational vertigo con-
notes disturbance of the semicircular canals
or their central projections, whereas sen-
sations of body tilt or impulsion (e.g., lat-
eropulsion, levitation, translation) imply a
disturbance in the otolith system.
Patients with rotational vertigo due to
acute, peripheral vestibular lesions are of-
ten uncertain of the direction of their ver-
tiginous illusions. This is because their
vestibular sense indicates self-rotation in
one direction, but their eye movements
(the slow phases of vestibular nystagmus)
cause visual image movements that, when
self-referred, connote self-rotation to the
opposite side. It is worthwhile to evaluate
the vestibular sense alone by asking specif-
ically about the perceived direction of
self-rotation with the eyes closed, thus
eliminating possible confounding visual
stimuli. On the other hand, with the eyes
open, one should ask about the direction
of image motion, from which one can de-
duce the direction of the nystagmus. The
direction of the slow phase of nystagmus is
opposite the direction of apparent motion
of the visual world.
Complaints of tilts of the perceived
world or body are often encountered in
patients who have suffered Wallenberg's
syndrome (lateral medullary infarction).
Such patients may describe, for example,
a 180° rotation of the environment, so that
they see the floor where the ceiling should
be; these complaints should not be dis-

missed as fanciful. Again, one should elim-
inate conflicting visual stimuli by asking
about the perception of the body when the
eyes are closed.
Oscillopsia is an illusory, side-to-side or
up-and-down movement of the seen envi-
ronment. When brought on or accentu-
ated by head movement, it is usually of
vestibular origin and reflects an inappro-
priate VOR gain or phase. Vision becomes
blurred to the extent that, for example,
fine print on grocery items can only be de-
tected if the patient stands still in the store
aisle. In the most severe cases, even the
transmitted pulsations of the heart may
interfere with vision.263
Clinical Examination of Patients
with Vestibular Disorders
Our strategy here will be (1) to determine if
any static or dynamic vestibular imbalance
is present; (2) to determine if a change in
head position or other maneuvers will in-
duce an imbalance; (3) to estimate the gain
of the VOR; (4) to elicit vestibular nystag-
mus by rotating the patient; and (5) to per-
form caloric testing. In patients with un-
diagnosed vestibular symptoms, each of
these clinical tests should be performed;
they are summarized in Table 2-3.515
CLINICAL FINDINGS WITH STATIC
VESTIBULAR IMBALANCE
Initially, inspect the eyes as the patient
keeps the head stationary and fixes upon a
distant point. Nystagmus may be present,
particularly with acute vestibular imbal-
ance. The hallmark of vestibular nystag-
mus is that it is initiated or accentuated
when fixation is removed (see Display
10-1, Chap. 10). For example, during
gentle eye closure, nystagmus may be seen
as the lid ripples with each quick phase, or
it may be palpated through the lids. A
steady-state deviation of the eyes under
closed lids may be inferred from the ap-
pearance of a corrective saccade back
to central position when the eyes are
opened. Sometimes, horizontal vestibular
The Vestibular-Optokinetic System 59
Table 2-3. Clinical Tests of
Vestibular Function
Tests of Vestibular Balance
Static imbalance
Gaze stability during fixation, during ophthal-
moscopy, or behind Frenzel goggles
Dynamic imbalance
Nystagmus following head-shaking
Gaze stability with rapid head turns
Positionally induced imbalance
Positional nystagmus
Imbalance induced by other measures
Tragal pressure
Valsalva maneuver
Hyperventilation
Mastoid vibration
Sounds
Tests for Abnormalities of VOR Gain
Comparison of visual acuity with head station-
ary and during head shaking at above 2 Hz
Ophthalmoscopic examination during head
shaking at about 2 Hz
Testing Vestibular Nystagmus
After sustained rotation for about 45 sec, ob-
servation of postrotational nystagmus, be-
hind Frenzel goggles
Bedside Caloric Testing
Minimal ice water caloric stimulation, with
Frenzel goggles
nystagmus is induced during vertical
smooth pursuit, perhaps because a sepa-
rate fixation mechanism is turned off. In
some patients, vestibular nystagmus is
most apparent on upward gaze, perhaps
because steady fixation is more difficult.
The effect of fixation on nystagmus
can also be observed during ophthal-
moscopy.511 First, the patient fixes on a
distant target with one eye while the ex-
aminer observes the optic disc of the
other. Any drift of the optic nerve head is
noted; then the fixing eye is covered for a
few seconds in order to compare drift ve-
locity with and without fixation. In inter-
preting the findings during the ophthal-
60 The Properties and Neural Substrate of Eye Movementsmoscopic
examination of eye movements,
it is sometimes easier to detect nystagmus
by observing the slow-phase drifts, be-
cause the quick phases may be infrequent.
Also, because the optic nerve head is be-
hind the center of rotation of the eye, the
direction of horizontal and vertical move-
ment is the opposite of that seen when
viewing the front of the eye during simple
inspection. Torsional nystagmus may be
detected during ophthalmoscopy if move-
ment of the vessels around both sides of
the macula is observed; on one side, quick
phases will be directed upward, and on
the other, they will be directed downward.
Frenzel goggles are also used to study
eye movements in the absence of fixation.
This is the equivalent of Romberg's sign
for impaired balance when the eyes are
closed. The commercially available illumi-
nated goggles are best, but they are ex-
pensive; an alternative is +20 diopter
lenses mounted in a spectacle frame and
fitted with side-blinkers. The room lights
should be turned off and the lights of the
goggles or a pen light (illuminating one
eye behind the goggles) used to illuminate
the eyes. The patient should not fix on the
illuminating light bulbs, lest nystagmus be
spuriously created by the retinal afterim-
ages that they produce.57
CLINICAL FINDINGS WITH
DYNAMIC VESTIBULAR
IMBALANCE
In patients with vestibular symptoms, it is
also important to attempt to demonstrate
a dynamic vestibular imbalance using two
maneuvers: vigorous, sustained head shak-
ing, and single, rapid head turns.
Clinical testing for head-shaking nystag-
mus is a useful method of detecting
asymmetry of velocity storage that occurs
after peripheral or central vestibular le-
sions.175'222'224 While wearing Frenzel gog-
gles, the patient is instructed to vigorously
shake the head for 10 to 15 sec in the hori-
zontal plane, and the eyes are then ob-
served for development of a transient
nystagmus (see VIDEO: "Head-shaking nys-
tagmus"). The procedure is then repeated
for vertical head shaking. With unilateral,
peripheral, vestibular lesions, asymmetry
of velocity storage can be revealed by in-
ducing differences in the level of vestibular
activity coming from the labyrinths when
the head rotates toward the intact side ver-
sus toward the paretic side. (One form of
Ewald's second law dictates that at high
speeds the intact labyrinth will not be able
to decrease its discharge below zero for
head rotations toward the paretic side.) Af-
ter horizontal head shaking, patients with
unilateral peripheral lesions may show hor-
izontal nystagmus, initially with slow
phases directed toward the side of the le-
sion (contralateral quick phases). After ver-
tical head shaking, they may show a rela-
tively less prominent nystagmus with
horizontal slow phases directed away from
the side of the lesion (ipsilateral quick
phases). This "cross-coupled" response
probably reflects an asymmetry in the con-
tribution that the posterior semicircular ca-
nal normally makes to the horizontal VOR
during vertical head shaking.222 It is im-
portant to remember that with a loss of
labyrinthine function on one side, a hori-
zontal or vertical head shaking-induced
nystagmus will only occur when there is an
intact velocity-storage mechanism. Velocity
storage may be so impaired in some pa-
tients with an acute complete loss of vestib-
ular function on one side or with additional
involvement on the other side that they do
not show head-shaking nystagmus.175 Fol-
lowing circular head shaking (the patient
rotates the head in a circle [up and left,
then down and right]), normal subjects
produce a predominantly torsional nystag-
mus, which is probably a postrotatory nys-
tagmus rather than a nystagmus arising
from the velocity-storage mechanism.
Hence the absence of circular head-shak-
ing nystagmus can be used to infer bilateral
loss of vertical canal function.224'23213
Central vestibular lesions may cause in-
appropriate cross-coupling of nystagmus,
usually a prominent vertical nystagmus
(especially downbeat) after horizontal
head shaking. Central lesions also may
produce an asymmetry in the velocity-
storage mechanism, which itself can pro-
duce horizontal head-shaking nystagmus
even though the peripheral vestibular in-
puts are balanced. (In this case, the asym-
metry of velocity storage can be revealed

by finding different time constants for sus-
tained head rotations in opposite direc-
tions.)
Certain individuals with peripheral le-
sions may show head-shaking nystagmus
with ipsilateral quick phases. The mecha-
nism may be related to recovery nystag-
mus,320 which usually refers to a change in
direction of spontaneous nystagmus when
prior adaptive rebalancing suddenly be-
comes inappropriately excessive, as pe-
ripheral function recovers (see below).
Similarly, a recovery in dynamic function,
or gain, could make prior adaptive
changes inappropriate, thus causing an
asymmetry in inputs to the velocity-stor-
age mechanism during head shaking. This
would cause head-shaking nystagmus in a
direction opposite that usually seen with a
peripheral lesion.
A single rapid head turn, the head
thrust maneuver, is another effective
method for detecting dynamic vestibular
imbalance (see VIDEO: "Anterior inferior
cerebellar artery (AICA) distribution in-
farction").229 The patient is asked to fix
upon a target while the examiner briskly
turns the head horizontally or vertically.
The rotation should not be large (<20°),
but should be of high acceleration. If the
VOR is working normally, gaze will be
held steady; if not, a corrective saccade
will be needed at the end of the head
movement to bring the image of the target
back to the fovea. The test is another
manifestation of Ewald's second law. In
this case, high-acceleration and/or high-
frequency head motion is not transduced
as well when the nerve is being inhibited
as when it is being excited. Hence, in the
absence of one-half of a push-pull pair of
canals, the response is defective when the
head is rotated toward the side of the le-
sion. Such rotation is easily accomplished
for the horizontal canals; an individual
pair of vertical canals can also be stimu-
lated by rotating the head with a com-
bined vertical-roll motion130 or by turning
the head (but not the trunk) to the right or
left by 45° and then rotating the head in
the pitch plane relative to the body (i.e.,
up and down). Just as for the horizontal
canals, an Ewald's law for high-frequency,
high-acceleration stimuli can be used to
The Vestibular-Optokinetic System 61
identify loss of function of a single vertical
canal. For example, with the head turned
to the right on the body, the left anterior
and right posterior semicircular canals
(SCC) will be maximally excited with a
pitch (relative to the body) stimulus.
Thus, with a complete unilateral loss of
labyrinthine function on the left side, a
corrective saccade will be present with
rapid rotation of the head downwards.
Conversely, if the head is turned to the
left, the left posterior and right anterior
SCC will be maximally excited with the
pitch stimulus and a corrective saccade
will be present with rapid rotation of the
head upwards.
POSITIONAL TESTING IN
PATIENTS WITH VESTIBULAR
DISORDERS
This is an important part of the vestibular
examination, particularly in patients who
complain of vertigo with a change in head
position. A distinction should be made be-
tween a paroxysm of nystagmus induced
by rapidly placing the patient in specific
head-hanging positions (positioning nys-
tagmus) and nystagmus that persists while
the patient is held in a static position (posi-
tional nystagmus).
First, the Dix-Hallpike maneuver is
used, as follows. With the patient sitting,
the head is turned about 45° toward one
shoulder. The examiner stands in front of
the patient and grasps the head at the
temples. After informing the patient of the
nature of the test, the head, neck, and
trunk are briskly moved en bloc to a head-
hanging position (see Fig. 10-19, Chap.
10), about 30° below the horizontal. The
eye movements in central position and
on left and right gaze should be noted. Af-
ter about 45 sec, the patient is returned to
the upright position and the eye move-
ments are again observed. The whole pro-
cedure is repeated with the head rotated
45° toward the other shoulder. Transient
mixed vertical-torsional nystagmus in-
duced by these maneuvers is usually diag-
nostic of benign, paroxysmal, positional
vertigo (BPPV) emanating from the poste-
rior semicircular canal (see VIDEO: "Nys-
tagmus with benign paroxysmal positional
63 The Properties and Neural Substrate of Eye Movements
vertigo"). The clinical features of BPPV
are discussed in Chapter 10.
Testing for nystagmus with static
changes in head position (e.g., with the
subject lying supine, with the head turned
to the right, and with the head turned to
the left) is useful in eliciting the horizontal
nystagmus associated with the lateral canal
variant of BPPV. This nystagmus usually
changes direction with lateral head turn
(direction-changing nystagmus), such that
it is either always beating toward the
earth (geotropic) or always beating away
from the earth (apogeotropic). Direction-
changing nystagmus may be encountered
with either peripheral or central vestibu-
lar lesions,31'35-496 but the lateral canal vari-
ant of BPPV is probably the most common
cause. Some normal subjects show a weak
horizontal nystagmus with positional test-
ing in darkness. It is usually in the same
direction with respect to the head (di-
rection-fixed nystagmus), regardless of
whether the head is turned to the left or to
the right.
OTHER TECHNIQUES FOR
TESTING PATIENTS WITH
VESTIBULAR SYMPTOMS
Several other clinical maneuvers may be
used to induce an inappropriate nystag-
mus. Tragal compression can be used to
test for a fistula or for abnormalities of the
ossicular chain and its connection to the
oval window. The Valsalva maneuver
(tested against both the closed glottis and
against pinched nostrils) may make
Arnold-Chiari malformations or fistulae
symptomatic. Hyperventilation may pre-
cipitate nystagmus in patients with a
variety of lesions including compen-
sated peripheral lesions,415 fistulas, and
compressive lesions on the vestibular
nerve,403-340 including tumors (see Chap.
10, Case History: Hyperventilation-in-
duced Nystagmus, and VIDEO: "Hyperven-
tilation-induced nystagmus"). Central
lesions such as abnormalities at the cranio-
cervical junction, demyelination or cere-
bellar degeneration may also produce
hyperventilation-induced nystagmus. Hy-
perventilation may, of course, also bring
out manifestations of an anxiety syn-
drome, but without nystagmus. An au-
diometer can also be used to look for
sound-induced nystagmus (the Tullio phe-
nomenon; see VIDEO: "Tullio phenome-
non").342 Vibration, applied to the mastoid
tip, may also bring out nystagmus in
patients with Tullio's phenomenon and
other vestibular pathologies. These tests
are best performed with the patient wear-
ing Frenzel goggles. The ability to per-
form VOR suppression using visual fixa-
tion, either during caloric stimulation or
combined eyehead tracking of a moving
target (cancellation of the VOR), is a test of
smooth pursuit (see Chap. 7). Note that
patients who have intact VOR cancellation
but impaired smooth pursuit may have a
decreased VOR response (and hence have
nothing to cancel when they track a target
moving with their head).
Vestibular nystagmus can be elicited by
rotating the patient in a swivel chair at
an approximately constant velocity (per-
rotatory nystagmus). The head can be po-
sitioned to induce nystagmus that is hor-
izontal (head upright), vertical (head
turned to one shoulder), torsional (look-
ing up at the ceiling), or mixed
vertical-torsional from a push-pull pair of
vertical canals (head turned 45° to the
right and then pitched back by 90°). If ro-
tation is maintained for about 45 sec, at
one revolution every 3 sec, and the chair is
then suddenly brought to a halt, postrota-
tional nystagmus will be induced. If the
patient wears Frenzel goggles to abolish
visual references, the duration of postrota-
tional nystagmus can be estimated in each
plane. The normal presence of quick
phases also can be confirmed.
CLINICAL TESTS
OF VESTIBULAR GAIN
Disturbances of vestibular gain are most
satisfactorily tested by quantitative meth-
ods. Nevertheless, a simple assessment is
possible by measuring dynamic visual acu-
ity during head rotations. The patient is
asked to read the optotypes of a visual
acuity card while the examiner passively
rotates the head (horizontally and then
vertically) at a frequency of about 2 cycles
per second. The patient is encouraged not

to stop at the turnaround points, prevent-
ing vision of the chart as the head slows
down. If vestibular gain is abnormal, vi-
sual acuity will deteriorate by several lines,
compared with what the patient can read
with the head still. Note that roll move-
ments of the head do not usually lead to a
significant decrease in visual acuity when
labyrinthine function is lost, because
foveal acuity is relatively independent of
rotation of the eye around its visual axis.
Thus, patients with factitious symptoms
may report a marked decrease in visual
acuity during roll as well as horizontal and
vertical rotation of the head.
In some patients who have an abnormal
VOR gain, it may be possible to detect cor-
rective saccades during sinusoidal head
rotation at a variety of frequencies (e.g.,
0.5 to 2.0 Hz) during attempted fixation
upon a target; these saccades may be more
apparent during fixation of a near target
(e.g., at 15 cm). If the gain is too low, sac-
cades will be directed opposite the move-
ment of the head; if the gain is too high,
the converse occurs.
A more sensitive bedside assessment of
VOR gain can be made using the ophthal-
moscope.511 While the examiner views one
optic nerve head and vessels, the patient is
asked to view a distant target and shake
the head from side to side. At frequencies
greater than about 2 cycles per second,
the pursuit system alone is unable to hold
images stable upon the retina; conse-
quently, at this frequency, gaze stability de-
pends solely upon the VOR. The fixing
eye can also be covered during head shak-
ing to eliminate visual cues to pursuit. Re-
call that because the optic nerve head is
behind the center of rotation of the eye,
the direction of horizontal or vertical
movement is opposite that of what is seen
when viewing the front of the eye. If the
VOR gain is unity, then eye position with
respect to the observer (eye in space) is
stable, since eye movement in the orbit is
equal and opposite to head movement in
space: the optic-nerve head and retinal
vessels appear stationary. If the vessels or
disc appear to move opposite to the direc-
tion of the head, then the reflex is hypoac-
tive (gain <1.0); if they move in the same
direction, then the reflex is hyperactive
The Vestibular-Optokinetic System 63
(gain > 1.0). If the nerve head drifts in the
same direction regardless of the direction
of head movement, there is a directional
preponderance caused by vestibular im-
balance. In the unresponsive patient, vi-
sual systems are in abeyance, and once
again the vestibular system can be studied
in isolation, using the ophthalmoscope
test. Recall that patients who habitually
wear a spectacle correction may adaptively
change their VOR gain. The results of the
ophthalmoscope test must be interpreted
accordingly: the gain goes up with a hy-
peropic correction, and down with a my-
opic correction. Finally, patients with es-
sential head tremor and vestibular failure
may show abnormal oscillations during
ophthalmoscopy.88
BEDSIDE CALORIC TESTING
Caloric testing is often valuable in deter-
mining the side of a peripheral vestibular
lesion. After verifying that the tympanic
membrane is intact and that wax is absent,
the minimal ice-water caloric test may be
performed.357 The patient's head should
be elevated 30° relative to earth-horizontal
to place the lateral semicircular canal in a
vertical position. This ensures that ther-
mally induced changes in the density of
the endolymph lead to a maximal deflec-
tion of the cupula. Ideally, eye movements
should be observed behind Frenzel gog-
gles or recorded in darkness to avoid the
effects of visual fixation. A normal re-
sponse can be elicited with as little as 0.2
ml of ice-cold water. The caloric test is a
sensitive indicator of loss of unilateral ves-
tibular function. Because it uses essentially
a low-frequency stimulus, caloric testing
detects vestibular impairment that may
not be apparent during higher-frequency
head rotation.32
LABORATORY EVALUATION OF
VESTIBULAR AND
OPTOKINETIC FUNCTION
By recording movements of the eyes, it is
possible to quantify the vestibulo-ocular
and optokinetic responses. Some methods
64 The Properties and Neural Substrate of Eye Movements
available for testing vestibular and optoki-
netic responses are listed in Table 2-4;
methods for recording eye movements are
summarized in Appendix B.
In quantifying the performance of the
VOR, the goals of testing are to determine
VOR gain, phase and imbalance. A static
vestibular imbalance is manifest by sponta-
neous nystagmus and is best detected by
recording eye movements in the absence
of fixation (see Display 10-1, Chap. 10).
Such nystagmus may follow Alexander's
law and can be classified as first degree
(present only when looking in the direc-
tion of quick phases), second degree (also
present in central position), and third de-
gree (present in all directions of gaze). In
some patients, the nystagmus may reverse
direction between right and left gaze. The
effects of different gaze positions upon
vestibular nystagmus probably relate to in-
Table 2-4. Laboratory Evaluation of
Vestibular Function
VOR (Semicircular Canals)
Quantitative caloric testing
Rotational testing
Passive rotation
Sinusoidal
Velocity steps
Pseudo-random
Accuracy of "gaze-adjusting" saccades
Active head shaking: sinusoidal or sudden
head turns (position steps)
Optokinetic System
Measurement of OKAN, in darkness, following
varying periods of full-field optokinetic
stimulation
Otolithic-Ocular Reflexes
Linear acceleration on moving platform
Human centrifuge
Passive change in tilt (roll) (up to 360°)
Rotation about an axis tilted from earth-verti-
cal (e.g., OVAR or "barbecue-spit")
Rotation of body about earth-vertical axis with
head positioned eccentrically (e.g., forward
or to side of the axis of rotation)
Parallel swing
Linear carts
Subjective visual vertical (and horizontal)
teractions between a vestibular imbalance
and the gaze-holding network (neural in-
tegrator).
Quantitative Caloric Testing
Laboratory caloric testing is most useful for
detecting loss of peripheral vestibular func-
tion.189 Introduced by Barany, the method
was modified and popularized by Fitzger-
ald and Hallpike. The caloric response is
due to two separate effects of the thermal
stimulus: convection currents induced in
the endolymph, and a direct effect of the
temperature change on the discharge rate
of the vestibular nerve; the convection cur-
rents are more important.366
Caloric responses are best tested with
the subject in complete darkness or wear-
ing Frenzel goggles in a dark room. It is
important to maintain the state of arousal
of the subject with an alerting stimulus
such as vocalization.491'503 The head of the
supine subject is tilted upwards by 30°;
thermal gradients then principally stimu-
late the lateral semicircular canals, since
the canals are approximately vertical in
this head position. Traditionally, water is
infused into the external auditory meatus
at temperatures of 30° and 44°C, although
air also may be used. After checking that
the tympanic membranes are intact, the
procedure typically consists of first infus-
ing 250 ml of water at 44°C for 40 sec into
one ear and recording the ensuing nystag-
mus. After a recovery period of 5 min, the
same stimulus is repeated for the opposite
ear. Then each ear is stimulated in turn
with water at 30°C. Shorter versions of the
test have been advocated, often using si-
multaneous bilateral stimulation or bither-
mal stimulation (hot immediately followed
by cold or vice versa).44 In analyzing the
nystagmus induced by caloric stimulation,
maximum horizontal slow-phase velocity
is considered the most reliable index of
peripheral vestibular function. Each labo-
ratory should establish its own range of
normal values because the conditions of
testing are partly responsible for the vari-
ability of results, which also are influenced
by other factors such as age.
If both warm and cold stimuli produce
less response in one ear than in the other,

and this asymmetry is 25% or greater, then
a unilateral peripheral vestibular distur-
bance (often called canal paresis} is likely.
When caloric stimuli cause a greater ocu-
lar response in one direction (e.g., greater
slow-phase velocities—to the left—from
warm water in the right ear and cold wa-
ter in the left ear, than slow-phase veloci-
ties—to the right—produced by the op-
posite stimuli), there is a directional
preponderance of the vestibular system. If
the asymmetry of leftward and rightward
slow phases exceeds 30%, then the direc-
tional preponderance is likely to be signifi-
cant. Directional preponderance occurs
with both peripheral and central vestibu-
lar lesions; by itself, it has no localizing
value. Some normal subjects and patients
with vestibular symptoms may show a ver-
tical (usually downbeating) component to
their caloric-induced nystagmus. Provided
that there is a horizontal component (so
that the nystagmus is oblique), this ap-
pearance is not necessarily abnormal.42
Quantitative Rotational Testing
Rotational tests give more accurate and re-
producible results than do caloric tests, al-
though, of course, they have the disadvan-
tage of not being able to stimulate a single
labyrinth alone.189 The alertness and men-
tal state of the patient while in darkness
may influence the results. Testing should
be performed with the eyes open, in dark-
ness;491 if this is not possible, patients
should gently vocalize (e.g., count aloud)
while their eyes are closed.503 VOR gain
may be obtained by measuring the peak
eye velocity in response to a velocity step
(e.g., sudden sustained rotation at 50° or
100°/sec). VOR gain also can be measured
during sinusoidal rotation; consideration
should be given to the distance at which a
visual (or remembered) target is fixated,
since this will affect gain (see Laboratory
Evaluation of Eye-Head Movements in
Chap. 7). Rotational testing also can reveal
asymmetry (or directional preponder-
ance), in which the VOR gain is greater in
one direction than in the other.195
The time constant of the VOR can be es-
timated from the phase shift at low fre-
quencies of sinusoidal rotation. When the
The Vestibular-Optokinetic System 65
phase shift is 45°, the time constant is equal
to the reciprocal of the frequency, ex-
pressed in radians per second. For veloc-
ity-step stimuli, the time constant can be
estimated in several ways, assuming
the decay is a simple exponential. One
method is to use the logarithm of slow-
phase velocity as a function of time. As a
rough approximation, the time constant of
the VOR can be estimated from the time
that it takes slow-phase velocity to drop to
37% of its initial value (Fig. 2-6). Alterna-
tively, one can measure cumulative slow-
phase eye position (by adding up all the
slow phases of the response) and then com-
pute the time constant of the VOR from
the ratio of cumulative slow-phase eye po-
sition to the initial value of slow-phase ve-
locity (at the onset of the response).
At low frequencies (<0.01 Hz) of passive
rotation in a vestibular chair, gain and
phase relationships can be used to glean
information about peripheral vestibular
disease. The time constant is often de-
creased in such patients (to values <10
sec), but low-frequency stimuli can them-
selves shorten the VOR time constant be-
cause they habituate the response. Never-
theless, low-frequency stimuli are useful
for revealing evidence of peripheral ves-
tibular loss.32-351
An asymmetry of the vestibular re-
sponses due to unilateral labyrinthine dis-
ease (even involving just one semicircular
canal) is more easily demonstrated with ei-
ther head accelerations exceeding 20007
sec/sec,20-23-130 or head velocities exceed-
ing 100°/sec.34 It is generally easier to ap-
ply such stimuli with a manual or motor
driven head turn than with a vestibular
chair.4563 By recording the rotation of the
eye around all three axes (horizontal, ver-
tical, and torsional) in response to differ-
ent patterns of head rotation that maxi-
mally stimulate different pairs of canals,
the function of individual canals can be
evaluated and pathology can be more
precisely localized to an individual
semicircular canal or a combination of
canals.21'130'181
Pseudorandom (white noise) chair rota-
tions offer a broad bandwidth of stimulus
frequencies and short testing time. They
require substantial instrumentation and
analysis programs, however.
66 The Properties and Neural Substrate of Eye Movements
Another simple way to test the VOR that
does not require precise measurement of
slow-phase eye movements has been de-
scribed.424 The patient views an earth-sta-
tionary target; then the lights are turned
off and the chair is briefly turned. The pa-
tient is required to keep looking at the re-
membered target location. Normal sub-
jects show a combination of a vestibular
slow phase and a gaze-adjusting saccade.
The lights are then turned on and any in-
adequacy of the combined vestibular-sac-
cadic response that occurred in darkness
is revealed by a corrective, foveating sac-
cade. Although the response during this
test is the sum of a slow phase and a sac-
cade, vestibular and other sensory inputs
are essential in programing the size of the
saccade. The test may be a sensitive way of
detecting vestibular imbalance.425 A simi-
lar strategy can be used to assay otolith
function during translation of the body.53
Active head rotation is a convenient way
to test for unilateral labyrinthine le-
sions. i90a,232a,359 Caution is required, how-
ever, in equating eye movements gener-
ated during active head rotation with the
passively induced VOR.291 Especially in
patients with bilateral vestibular loss, ac-
tive head rotation tests not only the VOR
but also preprogramed eye movements
and the contribution of the cervico-ocular
reflex. Abnormalities of gain and phase
during high-frequency (2 to 6 Hz), active
head movements have been reported 412 to be
at least as sensitive as caloric testing in
detecting unilateral vestibular hypofunc-
tion,364 or abnormalities in Meniere's syn-
drome.245'358 Such active head rotations
have also been used to monitor the prog-
ress of patients undergoing physical ther-
apy for vestibular loss due to ototoxicity.363
Other ways to test the VOR that have
not reached frequent clinical use include
galvanic stimulation37'346 and recording of
vestibular evoked potentials.162
Optokinetic Testing
Optokinetic testing requires a stimulus
that fills the field of vision. A common
method is for the patient to sit inside a
large, patterned optokinetic drum. Virtual
reality (VR) technology has been used to
overcome the cumbersome nature of large
mechanical rotating drums.281 Another
method is to rotate the patient at a con-
stant velocity for more than a minute with
the eyes open in a lighted room; as the
labyrinthine signal dies away, the sus-
tained nystagmus is due to purely visual
drives. Small hand-held optokinetic drums
or tapes primarily test the pursuit system.
The optokinetic response is judged by
both the nystagmus during visual stimula-
tion (which in primates consists of pursuit
and optokinetic components) and the op-
tokinetic after-nystagmus (OKAN) that oc-
curs after the lights are turned out (see
Fig. 2-6). The instructions to the patient
determine the pattern of nystagmus quick
phases during optokinetic stimulation. If
the patient is asked to follow the stripes,
there are prolonged slow phases with
large corrective saccades (look nystag-
mus). If the patient is asked to stare
straight ahead as the stripes pass by, quick
phases are smaller and more frequent
(stare nystagmus).
The velocity-storage component of the
optokinetic system is best evaluated by
measuring OKAN. The initial slow-phase
velocity of OKAN, after a 60-sec period of
stimulation, ranges from 6° to 20°/sec, and
right-left asymmetry does not exceed
6°/sec.467 As previously discussed, the ini-
tial velocity of OKAN and its time constant
vary considerably, so several measure-
ments should be made for each patient.
A convenient method is to sample the
buildup of the slow-phase velocity of
OKAN during frequent, 2-sec periods
of darkness during stimulation.178'426'467
These periods are too short to discharge
the velocity-storage mechanism. It is im-
portant to discard data from the first sec-
ond of each of these 2-sec epochs to pre-
vent contamination by the influences of
the pursuit system.
Testing Otolith-Ocular Responses
Testing of otolith-ocular function in hu-
mans has traditionally been relegated to a
few sophisticated laboratories because it
usually requires elaborate equipment such

as moving platforms or swings that impose
linear acceleration, human centrifuges, or
special chairs that rotate the subject
around the roll axis (to test ocular coun-
terroll).40'209'211'376 Recently, however, sev-
eral more practical tests of otolith function
have been introduced.211'213 Measures of
the subjective visual vertical or subjec-
tive visual horizontal can be used to infer
the torsional position of the eye, and
hence imbalance in otolith-ocular re-
flexes.51'64-134'158'456 The functional in-
tegrity of the saccule and of its afferents
carried in the inferior division of the ves-
tibular nerve can be tested using clicks or
head vibration (with a reflex hammer) as
the stimulus and measuring the response
in the surface electromyographic (EMG)
activity of the sternocleidomastoid, called
a sacculocollic re//^5'119'120'228'232'407 For
example, patients with vestibular neuro-
labyrinthitis who develop BPPV have a
normal click-evoked neck EMG, confirm-
ing sparing of the inferior division of the
vestibular nerve.350
Tilt-suppression of postrotatory nystag-
mus (the subject's static head position is
reoriented with respect to gravity at the
beginning of postrotatory nystagmus) is a
test of the ability of the nodulus to modu-
late the velocity-storage mechanism. It
uses a change in otolith activity to signal a
change in orientation of the head with re-
spect to gravity.170'172 Tilt-suppression is
abnormal with nodulus lesions (Display
10-18),227 and theoretically, with selective
bilateral otolith lesions.
It may be possible to identify the side of
an acute utricular lesion by measurement
of the asymmetry of torsional eye move-
ments (ocular counterrolling) during lat-
eral head tilt,154 or changes in torsion or in
the perception of tilt of a light-bar (oculo-
gravic illusion) during imposed linear ac-
celeration in a human centrifuge.135'142
The translational VOR can also be mea-
sured on a linear sled cart, and, at least
with acute unilateral lesions, it may be
asymmetric.296 This finding probably re-
flects a form of Ewald's second law for the
otoliths. The effect of otolith stimulation
also can be measured during sustained ro-
tation about an axis tilted from earth-ver-
tical (OVAR), which in the extreme case is
The Vestibular-Optokinetic System 67
about an earth-horizontal axis and is
called barbecue-spit rota^on.6a>146>153'192'376
Another method is to rotate the subject
about an earth-vertical axis with the head
positioned in front of the center of rota-
tion of the chair in which the subject sits
(eccentric rotation);129'212'479 such a stimu-
lus causes the gain of compensatory eye
movements to increase, especially if the
subject views or imagines a near target. In
some patients, this enhancement of gain
with eccentric head position has been
found to be absent; in others, asymmetries
appeared that were not evident with the
head centered. Eccentric rotation can also
be performed with the head displaced lat-
erally from the axis of rotation, and so
stimulate only one otolith at a time.
Otolith function can also be tested on a
parallel swing, which consists of a plat-
form suspended from the ceiling in such a
way that it can only be displaced along one
axis. Swing displacement along the inter-
aural axis induces primarily horizontal
movements, whereas swing displacement
along the longitudinal (up and down) axis
causes vertical eye movements. The re-
sponses are influenced by viewing or
imagining a stationary target. Patients
with cerebellar disorders may show abnor-
malities on a parallel swing.40
PATHOPHYSIOLOGY OF
DISORDERS OF THE
VESTIBULAR SYSTEM
Disorders of the peripheral or central ves-
tibular system disrupt eye movements, fol-
lowing pathophysiologic principles sum-
marized in Table 2-5. In Chapter 10, we
discuss these abnormalities from a view-
point of topological diagnosis (see Display
10-15).
Pathophysiology of Acute
Unilateral Disease of the Labyrinth
or Vestibular Nerve
Acute, unilateral vestibulopathy causes a
static imbalance of vestibular tone; the dif-
ference in neural activity of the left and
68 The Properties and Neural Substrate of Eye Movements

Table 2-5. Disorders of the Vestibular-Optokinetic System

Type of Disorder Features

Unilateral peripheral
vestibular disorders
Bilateral peripheral
vestibular disorders
Central vestibular
disorders
Optokinetic disorders
Static imbalance of canal inputs causing
spontaneous nystagmus
Dynamic imbalance with lower gain for hori-
zontal head rotations, at high velocity or high
accelerations, towards the side of the lesion
Loss of velocity storage causing reduced VOR
time constant
Imbalance of otolithic inputs causing skew
deviation; positional nystagmus
Severest impairment of gain is for low-frequency
stimuli
VOR time constant decreased to less than 6 sec
LossofOKAN
Imbalance of canal connections causing nystag-
mus that is often purely vertical or torsional
Imbalance of otolithic connections causing skew
deviation
Increased or decreased VOR gain
Prolonged or shortened VOR time constant
Loss of OKAN with peripheral vestibular lesions
Slow buildup of OKN with lesion affecting vari-
ous parts of the visual pathways
Asymmetric, monocular OKN in individuals
who have not developed binocularity

right vestibular nuclei causes spontaneous
nystagmus (see Display 10-1). For exam-
ple, unilateral loss of an entire labyrinth or
destruction of the vestibular nerve causes
a mixed horizontal-torsional nystagmus,
with slow phases directed toward the side
of the lesion. The pattern of nystagmus re-
flects the summed influence of individual
semicircular canals on one side (see Fig.
2-2A). Disease restricted to a single canal
or its immediate projections causes nystag-
mus in the plane of that canal, indepen-
dent of the position of the eye in the orbit.
So, for example, irritation of the left pos-
terior semicircular canal, as in benign
paroxysmal positional vertigo (BPPV),
causes a nystagmus that appears more ver-
tical with the patient looking to the right
and more torsional looking to the left; the
eyeball rotates approximately in the same
plane in the head, irrespective of the di-
rection of the line of sight.1713 This pattern
of nystagmus is commonly encountered in
benign paroxysmal positional vertigo (see
VIDEO: "Nystagmus with benign paroxys-
mal positional vertigo"). Disease of the su-
perior division of the vestibular nerve,
which is usually due to viral infections,
also produces a distinctive pattern of nys-
tagmus. Patients show a mixture of hori-
zontal, vertical (slow phase downward),
and torsional nystagmus that is compatible
with involvement of the anterior and lat-
eral semicircular canals.167 Rarely, the slow
phases of spontaneous nystagmus are di-
rected away from the side of the lesion; in
some cases, this may represent a compen-
satory mechanism and has been called re-
covery nystagmus (see below).
A dynamic vestibular imbalance of the
VOR, affecting gain and time constant,
is also produced by a unilateral loss
of labyrinthine function. In labyrinthec-
tomized monkeys, the VOR gain initially
falls from a preoperative value of about
1.0 to approximately 0.5 and the time con-
stant of the VOR declines from 35 sec to
about 7 sec.174 The decline in the time

constant represents loss of velocity stor-
age, which is also evident from a loss of
OKAN, particularly following optokinetic
drum rotations toward the side of the in-
tact ear. In addition, the VOR is asymmet-
ric (directional preponderance), partly
owing to the spontaneous nystagmus.
When correction is made for the sponta-
neous nystagmus, however, VOR gain is
still lower for high-speed head rotations
toward the side of the lesion. This finding
is consistent with Ewald's second law. Sim-
ilar changes are found in humans with
unilateral labyrinthine loss,82'83'226-460 al-
though even at lower head velocities there
may be some asymmetry of response.275
Some recovery of these dynamic distur-
bances occurs if monkeys are kept in an il-
luminated environment: VOR gain in-
creases towards a value of 1.0 and the time
constant of the VOR rises slightly (to
about 9 sec). At higher head velocities,
however, VOR gain remains lower than
preoperative gain (approximately 0.8) and
is asymmetric, being lower for head
rotations toward the side of the lesion. A
similar course of recovery has been re-
ported in humans who suffer unilate-
ral labyrinthine loss,33'92-166'175'239 although
with high acceleration the recovery is
much more limited.20-22-130'136 Other find-
ings with unilateral loss are hypometria of
gaze-adjusting saccades following ipsilat-
eral head turns,425 and a delay, up to 40
msec, in the slow phase response to ipsilat-
eral head turns.4563
If the other labyrinth is destroyed after
recovery from a unilateral labyrinthine
lesion, a deficit occurs as if the original
damaged labyrinth were left intact. This
Bechterew's phenomenon reflects the re-
balancing of central vestibular tone follow-
ing the first lesion. The second lesion then
creates a new imbalance.274'517
Unilateral disease of the vestibular or-
gan may also cause imbalance of otolith
function. 213 Sometimes there is a promi-
nent ipsilateral head tilt and an ocular
skew deviation in which the eye ipsilat-
eral to the lesion is lower and extorted;
the contralateral eye is higher and in-
torted. This is the ocular tilt reac-
tion.19,76,193,230,405,413 The torsion can a l so
be detected objectively, or by measure-
The Vestibular-Optokinetic System 69
ments of the subjective visual vertical or
horizontal.51'64'65'134'135'262'456 This patho-
logical skew and torsion is quite different
from that produced physiologically by
static head tilt in normals.19'56'124'483 Patho-
logical skew resembles the otolith im-
balance produced by experimental stimu-
lation of the utricle in lower animals (see
Fig. 2-2B). In lateral-eyed animals, a skew
deviation of the eyes is the appropriate re-
sponse to a lateral head tilt. Even in nor-
mal humans19'264 and in monkeys,430 a
small amount of dynamic skewing may be
associated with rolling of the head. The
amount of skewing is influenced by the lo-
cation of the point of regard.
Otolith inputs may also interact centrally
with the connections of the semicircular
canals. For example, it has been suggested
that the reason that patients with an acute
labyrinthine lesion often lie with the af-
fected ear up is to use otolith inputs to de-
crease the imbalance between the canals,
and so reduce nystagmus and discom-
fort.180 Likewise, otolith imbalance might
lead to positional nystagmus on lateral
head tilt. The cause may be a misinterpreta-
tion of a change in the attitude of the head
with respect to gravity (which calls for ocu-
lar counterroll) as a translation of the head
(which calls for a horizontal nystagmus).
A dynamic otolith imbalance following
experimental unilateral otolith lesions
has been demonstrated in monkeys.459
Acutely, the increase in gain of the VOR
that is normally produced if the animal's
head is positioned in front of the axis of
rotation is no longer present. Recovery oc-
curs in weeks. In humans with unilateral
lesions, during off-vertical axis rotation
(OVAR) with the body and axis of rotation
tilted together away from upright (includ-
ing earth-horizontal or barbecue-spit rota-
tion), there is an abnormally low-ampli-
tude or even inappropriately directed bias
component when the head is rotated to-
ward the lesioned side.146-192'376 The mod-
ulation component is intact. When tested
on a linear sled, patients with a recent (1
week) unilateral loss of labyrinthine func-
tion show a decreased response when
translated toward the abnormal side.296
This may reflect the equivalent of an
Ewald's law for the otolith response. Pa-
70 The Properties and Neural Substrate of Eye Movements
tients with more chronic lesions, however,
usually show little asymmetry in the trans-
lational VOR.87
Pathophysiology of Bilateral Loss
of Vestibular Function
Bilateral labyrinthine loss presents a sen-
sory deficit to which the brain cannot so
readily adapt. In the acute phase of loss
of labyrinthine function, the inadequate
VOR causes visual images to move on the
retina with every head movement; this
causes oscillopsia and impairment of vi-
sion. Some clinical causes of bilateral ves-
tibular loss are included in Table 10-11 in
Chapter 10. Patients with partial, bilateral
vestibular loss tend to show preferential
sparing of the VOR for high-frequency
stimuli;32 testing with lower-frequency ro-
tations or caloric stimuli are more likely to
demonstrate the deficit. With time, a num-
ber of strategies may be developed to com-
pensate for this deficit (see Table 7-1,
Chap. 7).273 These include potentiation of
the cervico-ocular reflex, preprograming
of compensatory eye movements, substitu-
tion of small saccades and quick phases in
the direction opposite head rotation to
augment inadequate vestibular slow phases,
improvement of smooth pursuit, restric-
tion of head movement, and perceptual
threshold changes to ignore oscillop-
sia.214,231,335,347,466 Beamse Qf these adap.
tive mechanisms, the gain of compensa-
tory eye movements may be near normal
during active head rotation. During less
predictable head motions, however, such
as those occurring during walking, it is
harder to compensate for the deficit, and
gaze instability causes impaired vision and
sometimes oscillopsia. Like unilateral ves-
tibular lesions, bilateral disease causes loss
of velocity storage with a consequent
shortening of the time constant of the
VOR,32 and of OKAN.117'223'521
Pathophysiology of Lesions of
Central Vestibular Connections
Disturbance within central vestibular
structures may also produce disturbances
of balance, gain, and phase (time constant)
of the VOR. These can be divided into
those that affect the different planes of ro-
tation (roll, yaw, and pitch), which in turn
have topographical diagnostic use.78 Addi-
tionally, imbalance of otolith inputs and
disturbance of optokinetic nystagmus may
occur. Moreover, disturbance of gaze-
holding function may be impaired because
the medial vestibular nucleus is an impor-
tant contributor to the neural substrate for
gaze-holding (see Chap. 5).
Imbalance of central vestibular tone
leads to spontaneous nystagmus that is
usually present in primary position. Ex-
amples are downbeat, (see Display 10-2),
upbeat (see Display 10-3), and torsional
nystagmus (see Display 10-4). Some cases
of horizontal nystagmus also may repre-
sent imbalance of central vestibular con-
nections. A number of hypotheses have
been proposed to explain the pathogene-
sis of central vestibular nystagmus; these
are discussed in Chapter 10. Experimental
ablation of the flocculus and parafloccu-
lus (Display 10-17) invariably produces
downbeat nystagmus, perhaps because
these structures inhibit the VOR in an
asymmetric pattern. 520 Purkinje cells send
inhibitory projections to the central con-
nections of the anterior canal but not to
those of the posterior canal.261 Downbeat
nystagmus (see VIDEO: "Downbeat nystag-
mus") is commonly present in patients
with the Arnold-Chiari malformation.
Experimental ablation of the nodulus
and uvula in monkeys (Display 10-18)
causes prolongation of velocity storage
and a loss of the normal ability to reduce
postrotational nystagmus by pitching the
head forward when postrotational nystag-
mus begins.485 Humans with midline cere-
bellar tumors show a similar finding. 227 In
addition, monkeys with nodulus lesions
show downbeat nystagmus and defects in
generating the bias component of OVAR.8
They also develop periodic alternating
nystagmus when in darkness (Display
10-5);485 this nystagmus is discussed in
Chapter 10 (see VIDEO: "Periodic alternat-
ing nystagmus").
Experimental unilateral lesions of the
vestibular nuclei in monkeys do not pro-
duce purely vertical or horizontal nys-
tagmus; it is either mixed horizontal-

torsional, mixed vertical-torsional, or pure
torsional.474 With lesions of the vestibular
nerve root and caudal lateral parts of the
vestibular nucleus, the horizontal compo-
nent of slow phases is directed toward the
lesion. When the superior vestibular or
rostral medial vestibular nuclei are le-
sioned, the horizontal component of the
slow phases is directed away from the le-
sion. Nystagmus with vestibular nucleus le-
sions is more persistent than that caused by
labyrinthectomy. Some patients with such
central lesions may manifest nystagmus
that corresponds to the effects of stimulat-
ing one semicircular canal. Wallenberg's
syndrome (lateral medullary infarction)
may cause mixed horizontal- torsional nys-
tagmus with slow phases directed towards
the side of the lesion. Experimental lesions
of the medial vestibular nuclei and nucleus
prepositus hypoglossi, which are essential
elements of the gaze-holding mechanism
(neural integrator), cause a combination of
deficits of gaze holding and vestibular im-
balance. These interactions and their rela-
tionship to Alexander's law of nystagmus
are discussed in Chapter 5.
Lesions of the cerebral hemispheres,
such as hemidecortication, cause some dy-
namic imbalance of the VOR.163 During
rotation in darkness, a mild asymmetry of
VOR gain is present, with greater values
being obtained for eye movements away
from the side of the lesion. This asymme-
try is greater if the patient either imagines
or views a stationary target,431 but it is ab-
sent for higher frequency rotations (see
Enduring Disturbances of Gaze Caused by
Unilateral Hemispheric Lesions in Chap.
10). Central lesions may affect the vestibu-
lar nerve as it courses through the brain
stem or in the medial vestibular nuclei it-
self, causing a unilateral caloric paresis,
but not usually a complete paralysis.182
The gain of the VOR is variably de-
creased or increased with central lesions.
For example, disease affecting the vestibular
nucleus at the root entry zone may cause
loss of vestibular function similar to that
from a more peripheral lesion in the
labyrinth. Thus, with an occlusion of the an-
terior inferior cerebellar artery (AICA), the
vestibular disturbance can be due to a com-
bination of central vestibular and peripheral
labyrinthine dysfunction (see VIDEO: "Ante-
The Vestibular-Optokinetic System 71
rior inferior cerebellar artery (AICA) distri-
bution infarction"). Lesions involving the
flocculus and paraflocculus may cause ei-
ther an increase or decrease in vestibular
gain.520 Patients with cerebellar disease may
show inappropriately directed slow phases
or vestibular hyper-responsiveness (VOR
gain greater than 1.0), which also causes os-
cillopsia with head movements.28'465'516 Le-
sions of the vestibulocerebellum cause an in-
ability to adapt the gain of the VOR in
response to new visual demands.303
Disturbances of the phase and the time
constant of the VOR may occur with
disease affecting a variety of central struc-
tures. Bilateral lesions of the medial longi-
tudinal fasciculus (MLF) (bilateral inter-
nuclear ophthalmoplegia (INO)) cause
reduced gain of the vertical VOR; in addi-
tion, slow-phase eye velocity lags head ve-
locity.398 The torsional VOR may also be
affected.19 Lesions of the MLF also impair
the horizontal VOR because of weakness
of the ipsilateral medial rectus muscle.
The consequence of these disturbances of
phase and gain are impaired vision and
oscillopsia with head movements. The in-
terstitial nucleus of Cajal may influence
the phase relationships of both the vertical
and torsional VOR,184 but quantitative
studies of the effects of restricted lesions of
this nucleus in humans are lacking.
Unilateral lesions of central otolith con-
nections cause skew deviation and the
ocular tilt reaction.19'78'793 With lateral
medullary lesions affecting the vestibular
nuclei, such as Wallenberg's syndrome
(lateral medullary infarction) (Table 10-3),
the head is typically tilted (i.e., rolled ear-
to-shoulder) toward the side of the lesion,
and there is a skew deviation with hy-
potropia and excyclotropia of the ipsilat-
eral eye (see VIDEOS: "Skew deviation"
and "Wallenberg's syndrome").157 Certain
complaints of these patients, such as per-
ceived tilts of the environment, probably
also represent central disturbance of
otolith inputs.4683 Unilateral MLF or mid-
brain lesions may cause a contralat-
eral head tilt and ipsilateral hyper-
tropia,76'78'158 consistent with interruption
of the crossed pathways that subserve
otolith inputs (see Table 2-2). Abnormali-
ties of the torsional VOR may also occur in
such patients.19
72 The Properties and Neural Substrate of Eye Movements
Disturbance of visual inputs, whether
due to immaturity of the visual path-
ways,504 albinism,152 or blindness,436 may
affect the time constant and gain of the
VOR. It seems likely that such visual infor-
mation is passed to the cerebellum, be-
cause cerebellar lesions cause similar
deficits of ocular motility.294'519
Pathophysiology of Disorders
of the Optokinetic System
Abnormalities of the optokinetic responses
(see Table 2-5) are caused by peripheral
and central vestibular disease and by le-
sions affecting the visual pathways.39 In
primates, optokinetic nystagmus (OKN)
represents the responses of both smooth-
pursuit and optokinetic systems. The per-
formance of the velocity-storage compo-
nent of the optokinetic response is most
reliably evaluated by studying optokinetic
after-nystagmus (OKAN) in the dark.
Unilateral peripheral vestibular disease
(see Display 10-15, Chap. 10), particularly
during the acute phase, may also cause a
directional preponderance of OKN, with
increased slow-phase velocity toward the
side of the lesion.73 Unilateral labyrinthine
lesions reduce OKAN to both sides but
more so with visual stimuli moving toward
the intact side.83 Patients who have bilat-
eral labyrinthine loss show normal nystag-
mus during the period of optokinetic
stimulation, but afterward show no OKAN
in darkness.510'521 This finding supports
the notion that OKAN in humans, as in
other species, depends on normal central
vestibular tone. Disease of central vestibu-
lar connections that impairs velocity stor-
age may abolish OKAN.
SUMMARY
1. During head perturbations, such as
those caused by natural activities,
the vestibulo-ocular, optokinetic, and
smootji-pursuit systems work to-
gether to generate compensatory eye
movements and thus maintain clear
vision of the environment. The rota-
tional vestibulo-ocular reflex (r-
VOR), relying on inputs from the
semicircular canals, generates com-
pensatory slow-phase eye movements
at short latency during brief (high-
frequency) head turns (Fig. 1-4). The
translational vestibulo-ocular reflex
(t-VOR), relying on inputs from the
otolith organs, generates compensa-
tory slow-phase eye movements at
short latency during brief (high-
frequency) head translations (Fig.
1-5). During both translation and ro-
tation, the VOR must be adjusted for
the viewing distance of the target of
interest; the gain (amplitude) of the
VOR must increase for viewing near
targets.
2. The VOR functions less well at lower
frequencies of rotation, thus the op-
tokinetic system and smooth pursuit
supplement the VOR during sus-
tained rotations or translations (Fig.
2-6). Otolith inputs, responding to
the pull of gravity, also generate a
change in the static torsional align-
ment of the eyes (ocular counter-
rolling) in response to sustained lat-
eral tilt of the head. Inputs from the
semicircular canals, otolith organs, vi-
sual system, and somatosensors are
combined centrally in the vestibular
nuclei to give the brain's best estimate
of head movement.
3. Stimulation of any one semicircular
canal causes compensatory eye move-
ments in a plane parallel to that of
the canal (Fig. 2-2). The semicircular
canals are arranged in three pairs,
one half of each pair on either side.
The vestibular nerve shows a resting
discharge rate that is modulated up
or down according to head rotation.
This organization maximizes vestibu-
lar sensitivity and provides the sys-
tem with an opportunity to cope with
the effects of unilateral disease.
4. The VOR is capable of adaptation of
its properties in response to visual
demands. This is a form of motor
learning that depends upon connec-
tions between the vestibulocerebel-
lum and the vestibular nuclei (Fig.
2-10).

5. Testing of the VOR requires mea-
surement of symmetry (balance), gain
(ratio of eye movement to head rota-
tion), direction of the eye movement
relative to the head movement, and
the temporal synchrony between
head and eye movements (reflected
by phase or time constant). A number
of factors influence VOR gain. These
include mental set, viewing distance
of a target, and habitual wearing of a
spectacle refraction. Testing of the
optokinetic system entails measure-
ment of optokinetic after-nystagmus
(OKAN). Testing of otolith function
requires linear acceleration of the
subject's head, rotation about an axis
tilted from the gravitational vertical,
or measurement of ocular counter-
roll to sustained head tilt. A useful
clinical test of otolithic function is
measurement of the percept of sub-
jective visual vertical.
6. Disorders of the VOR cause changes
in gain, phase, direction and balance.
Disorders of the optokinetic system
are characterized by abnormalities of
OKAN; they occur in diseases that af-
fect the peripheral or central vestibu-
lar system. Otolith disorders produce
static tilts of the head, ocular torsion,
and skew deviation—the ocular tilt
reaction.
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Chapter 3
THE SACCADIC SYSTEM
THE PURPOSE OF SACCADES
BEHAVIOR OF THE SACCADIC SYSTEM
Saccadic Velocity and Duration
Saccadic Waveform
Saccadic Trajectory
Saccadic Initiation Time (Latency)
Saccadic Accuracy
Quantitative Aspects of Quick Phases of
Nystagmus
Ballistic Nature of Saccadic Movements
Saccades during Visual Search and Reading
Visual Consequences of Saccades
NEUROPHYSIOLOGY OF SACCADIC EYE
MOVEMENTS
Brain Stem Pathways for Saccades
Models for Saccadic Pulse Generation
Higher-Level Control of the Saccadic Pulse
Generator
Superior Colliculus
Role of the Frontal Lobe in Saccade
Generation
Role of the Parietal Lobe in Saccade
Generation
Role of the Thalamus in Saccade Generation
Role of the Basal Ganglia in Saccade
Generation
Cerebellar Contribution to Saccades
Adaptive Control of Saccadic Accuracy
SACCADES AND MOVEMENTS OF THE
EYELIDS
EXAMINATION OF SACCADES
Clinical Examination of Saccades
Measurement of Saccadic Eye Movements
PATHOPHYSIOLOGY OF SACCADIC
ABNORMALITIES
Disorders of Saccadic Velocity
Disorders of Saccadic Accuracy
Disorders of Saccadic Initiation
90
Inappropriate Saccades (Saccadic
Intrusions)
SUMMARY
Saccades, the fastest of eye movements,
enable us to rapidly redirect our line of
sight. They include both voluntary and in-
voluntary changes of fixation, the quick
phases of vestibular and optokinetic nys-
tagmus, and the rapid eye movements that
occur during rapid eye movement (REM)
sleep.465 The term saccade is French in ori-
gin, referring to the jerking of a horse's
head by a tug on the reins or to the flick-
ing of a sail in a gust of wind. Javal203 and
Landolt228 first used the word saccade to
describe the rapid eye movements associ-
ated with reading or voluntary changes of
gaze. Abnormalities of saccades are often
distinctive, and thus, diagnostically impor-
tant.
THE PURPOSE OF SACCADES
In the early twentieth century, Dodge,94
along with J.J. Cogan, was the first to dis-
tinguish saccades clearly from other types
of eye movements. He explicitly stated
their function: "to move the eyes so that
the point of interest will be seen with the
visual center of the retina." The function
of voluntary saccades in primates is di-
rectly linked to the presence of a fovea, be-
cause images are best seen if located there.
Animals without a fovea, such as the rab-
 The Vestibular-Optokinetic System 91

bit, do make voluntary saccades, but only BEHAVIOR OF THE

in association with head movements.72'139
They also produce quick phases of nys-
tagmus during passive head movements
so that the slow phases of vestibular
and optokinetic nystagmus do not drive
the eyes into an extreme orbital position
and the oncoming visual scene can be pe-
rused.
Saccadic eye movements consist of a hi-
erarchy of behavior, from the most rudi-
mentary of all saccades, quick phases of
vestibular nystagmus during passive ro-
tation in darkness, to reflexive saccades
made in response to the sudden appear-
ance of a novel visual stimulus, to higher-
level volitional behavior such as saccades
directed toward the remembered location
of a visual target (Table 3-1). This orga-
nization can be applied in the clinical
neuro-ophthalmologic examination. For
example, if voluntary saccades cannot be
generated, then it is useful to test progres-
sively more reflexive types of saccades
right down to the quick phases of nystag-
mus. A comparable approach is used in
the neurologic localization of motor disor-
ders of all types.
SACCADIC SYSTEM
We will discuss here the main characteris-
tics of saccades: velocity, duration, wave-
form, trajectory, latency, and accuracy.
Saccadic Velocity and Duration
Saccades show a unique feature: they have
a consistent relationship between their
peak velocity and the size of the move-
ment. The bigger the eye movement, the
greater its top speed. Large saccades (80°)
may have peak velocities of over 500°/sec.
The relationship between the amplitude
and peak velocity of saccades (Fig. 3-1)
has been called the main sequence,1'7'3'7
which can be used to identify unknown
types of eye movements as saccades. For
saccades that are smaller than about 20°,
there is a linear relationship between am-
plitude and peak velocity; above 20°, peak
velocity shows a progressive saturation
with asymptotic values of about 5007sec.
Therefore, a commonly used equation to

Table 3-1. Classification of Saccades

Classification Definition

Volitional saccades Elective saccades made as part of purposeful behavior

Predictive, anticipatory Saccades generated in anticipation of or in search of the appearance
of a target at a particular location
Memory-guided Saccades generated to a location in which a target has been previously
present
Antisaccades Saccades generated in the opposite direction to the sudden appear-
ance of a target (after being instructed to do so)
To command Saccades generated on cue
Reflexive saccades Saccades generated to novel stimuli (visual, auditory or tactile) that
unexpectedly occur within the environment
Express saccades Very short latency saccades that can be elicited when the novel stimu-
lus is presented after the fixation stimulus has disappeared (gap
stimulus)
Spontaneous saccades Seemingly random saccades that occur when the subject is not re-
quired to perform any particular behavioral task
Quick phases Quick phases of nystagmus generated during vestibular or optoki-
netic stimulation or as automatic resetting movements in the pres-
ence of spontaneous drift of the eyes
92 The Properties and Neural Substrate of Eye Movements
Figure 3-1. The relationship of saccadic amplitude
to peak velocity (V) and duration (D) is illustrated.
Dashed lines indicate standard deviation of velocity.
(Adapted from Zee DS, Robinson DA. Velocity char-
acteristics of normal human saccades, In: Topics in
Neuro-ophthalmology, Edited by Thompson HS,
Daroff R, Glaser JS, and Sanders MD, Baltimore,
Williams and Wilkins, 1979, with permission.)
describe the main sequence relationship
is:
peak velocity = Vmax * (1 - e-AmPlitude/c)
where Vmax is the asymptotic peak velocity
and C is a constant. Using regression
analysis, it is possible to define 95% confi-
dence limits for a group of normal subjects
using such an equation and thereby iden-
tify patients whose saccades are slowed
because of disease affecting the saccade-
generating mechanisms. Other equations
have been used to describe the main se-
quence for smaller saccades.231 The appli-
cation of this and other equations describ-
ing the main sequence relationship to the
laboratory evaluation of saccades is de-
scribed below (Measurement of Saccadic
Eye Movements). The durations of sac-
cades are approximately linearly related
to their amplitudes for movements from
1° to 50°. A 30° saccade typically lasts
about 100 msec (Fig. 3-1). Acceleration
and its derivative, jerk, is greater than for
other types of eye movement and can be
used to identify saccades.4543
Saccadic speed and duration cannot be
voluntarily controlled. However, there is
some variability in the peak velocity and
duration of saccades of similar size, even
for the same individual, from day to day.38
Other factors have predictable effects on
saccadic velocity. Thus, saccades are about
10% slower when made in complete dark-
ness (for example, to auditory targets or
to the remembered locations of visual
stimuli); when made in anticipation of tar-
gets moving in a predictable fashion;424
and when made in the opposite direction
of a visual stimulus (the antisaccade
task).27-43'391-392 When repetitive saccades
are made to visual targets at a high fre-
quency (e.g., >1 Hz), their peak velocities
are greater than when made at a lower fre-
quency (e.g., <0.2 Hz). 237 Saccadic veloc-
ity also increases when saccades are made
in association with manual tasks,115 or if
the fixation target is turned off before the
stimulus for the saccade appears (gap
stimulus). 321
Saccade velocity also depends upon the
direction of the movement and the initial
and final orbital position.2'73'74'307 Cen-
tripetally directed (toward the center) sac-
cades tend to be faster than centrifu-
gally directed saccades. Upward saccades
made in the upper portion of the ocular
motor range are slower than upward sac-
cades made in the lower portion of the
ocular motor range.74 It is not settled
whether saccadic velocity declines with
a g e _ 198,318,384,395 Saccades of normal veloc-
ity can be made by young infants if they
are suitably aroused.388
Saccadic Waveform
The shape of the temporal waveform of
the saccade, and the velocity profile in
particular, is another way to characterize
saccades (Fig. 3-2). The skewness, or
asymmetry, of the waveform can be esti-
mated from the ratio of the time to reach
 The Vestibular-Optokinetic System 93

maximum velocity (the acceleration phase)

to the total duration of the saccade.73'431
This skewness ratio is about 0.5 for small
saccades (acceleration and deceleration
phases are equal in duration) and falls to
values of about 0.2 for the largest saccades
(peak velocity is reached earlier relative to
the end of the saccade). Skewness also in-
creases for antisaccades, saccades made to
remembered targets, and saccades made
under fatigue or decreased vigilance.392
Another useful way to analyze saccades is
by examining phase-plane plots of eye po-
sition versus eye velocity or acceleration.
Large saccades, especially those moving
downward, may show abrupt changes in
the velocity profile (so-called discrete de-
celerations).5'74 Taken together, these re-
ports indicate that under different stimu-
lus conditions, the premotor saccadic eye
movement commands are not identical for
saccades of a given amplitude and de-
pend, at least in part, on the behavioral
context.
During saccades, the eyes do not move
perfectly together.73'74 For horizontal re-
fixations, the saccades of the abducting
eye tend to be larger, faster, and more
skewed than the concomitant saccades of
the adducting eye. This disconjugacy be-
tween the two eyes leads to a transient in-
trasaccadic divergence. For vertical refixa-
tions, the eyes are better yoked, although
idiosyncratic horizontal vergence move-
ments may occur.no,427a,459
Following a horizontal saccade there is
usually some postsaccadic drift that has
both disjunctive (vergence) and conjugate
(version) components. The disjunctive
component of the drift is convergent while
the conjugate component is onward, in
the direction of the movement. The dis-
junctive component may compensate for
divergence during saccades, while the
conjugate component may compensate for
the tendency for most saccades to slightly
undershoot the target. Such postsaccadic
drift has been called a glissade,449 and has
been attributed to a mismatch between the
sizes of the phasic (pulse) and tonic (step) Figure 3-2. Search-coil recording of a rightward 10°
components of the innervational change saccade in a normal human subject showing position,
velocity, and acceleration traces. Data were collected
that creates saccades (see Fig. 1-3, Chap. at a 250-Hz sampling rate with digital filtering of the
1). The eye drifts in a glissade because or- velocity (0-100 Hz) and acceleration (0-50 Hz)
bital elastic forces pull the eye to a position traces.
94 The Properties and Neural Substrate of Eye Movements
in the orbit corresponding to the new step
level of innervation. Glissades occur more
frequently in fatigued subjects.19
At the end of a saccade, a postsaccadic
movement in the opposite direction occa-
sionally occurs and appears to be as fast as
a small saccade (1/4 to 1/2 degree). Such
small saccades have been called dynamic
overshoots, which can occur after saccades
of all sizes but are more conspicuous after
small saccades and may be conjugate
or more prominent in the abducting
eye 39,212,425 Dynamic overshoots also oc-
cur with large saccades if subjects blink
with the eye movement. Dynamic over-
shoots have been attributed to brief rever-
sals of the central saccadic command.16
Such a reversal of saccadic innervation
would normally bring the eye to an abrupt
stop but, if too large, would lead to a dy-
namic overshoot. Alternatively, dynamic
overshoot might arise from the mechani-
cal properties of orbital tissues rather than
a central reversal of innervation;335 mea-
surements of the forces generated by ex-
traocular muscles support this interpreta-
tion.257
Saccadic Trajectory
When humans make saccades in oblique
directions, the horizontal and vertical
components show minor slowing com-
pared with purely vertical or purely hori-
zontal saccades of similar size.30'348 For di-
agonal saccades (45° inclination), the
horizontal and the vertical components
are similar and the trajectory is nearly
straight (Fig. 3-3A). For oblique saccades
made at angles other than 45° inclination,
a smaller component that stayed on the
main sequence would not last as long as
the larger component,18'157 and the trajec-
tory of the saccade would be curved. How-
ever, the trajectories of oblique saccades
are usually approximately straight be-
cause the duration of the smaller compo-
nent is stretched.323 When the brain stem
mechanism generating either the horizon-
tal or vertical components of oblique sac-
cades is impaired, oblique saccades have
strongly curved trajectories that are evi-
dent at the bedside (Fig. 3-3B). The sig-
nificance of the trajectories of oblique sac-
cades is discussed further under Models
for Saccadic Pulse Generation and Patho-
physiology of Saccadic Abnormalities,
below.
Saccadic Initiation Time (Latency)
The interval between target presentation
and when the eye starts to move in a sac-
cade (conventionally identified by when
eye speed exceeds some threshold, such as
30°/sec) has received intensive study be-
cause it reflects various aspects of visual
processing, target selection, and motor
programing. Saccadic initiation time is
highly dependent upon the nature of the
stimulus—both its modality and the tem-
poral properties of target presentation.
SACCADES MADE TO
DISPLACEMENTS OF A
VISIBLE TARGET
When a visual target jumps from one
point to another, normal subjects generate
a saccade within about 200 msec. The in-
dividual values for a number of such trials
are not distributed normally (in the statis-
tical sense) but are skewed, with more val-
ues having higher latencies. If, however,
the reciprocal of latency is plotted as a
measure of promptness, the distribution
of values is closer to a normal one.59 It has
been suggested that the variability in sac-
cadic initiation time shown by any subject
reflects the time needed to decide whether
a target is in fact present.60
Aside from the motivational and atten-
tive state of the subject,155 a number of
properties concerning the stimulus influ-
ence saccadic initiation time. These in-
clude stimulus luminance, size, contrast,
and complexity;86'96'97'155'300'469 whether the
target is visual or auditory;457 the size of
the intended eye movement and orbital
position from which it starts;140 the pre-
dictability of the target's motion;346'367
the presence of distracting stimuli;445 the
handedness of the patient and the lateral-
ity of the target;199 and the patient's
agei61,198,265b,318,384,388
 The Vestibular-Optokinetic System 95

Figure 3-3. Trajectories of oblique saccades. (A) Comparison of trajectories of oblique saccades made to and
from four target positions starting at primary position in a normal subject and (B) in a patient with Niemann-
Pick type C disease,348 who showed a selective slowing of vertical saccades. Arrowheads in B indicate the direc-
tion of eye movement. The trajectory of the target jump is shown as a dotted line. The trajectories of the pa-
tient's saccades are strongly curved, reflecting the initial, faster, horizontal component and the later, slower,
vertical component. (C) Time plot comparing horizontal and vertical components of an oblique saccade (up
and rightward) made by the patient with Niemann-Pick type C disease. Horizontal oscillations occurred after
the horizontal component had ended but while the vertical component was still going on.

GAP AND OVERLAP STIMULI
Often, the stimulus for a saccade is the ap-
pearance of a novel object in the visual
scene. In the laboratory, this type of stimu-
lus is conveniently created by turning on a
peripherally located, small target light in a
darkened room, and turning off the fixa-
tion light that the subject is currently
viewing with the fovea. The temporal rela-
tionship between when the fixation light is
extinguished and the target light is illumi-
nated also influences saccade latency. La-
tencies are less when the fixation light is
turned off 100 to 400 msec before the
peripheral target appears (the gap stimu-
lus) and greater when the fixation light
remains illuminated after the periph-
eral target appears (the overlap stimu-
lus).207'328'329 In the gap paradigm, human
96 The Properties and Neural Substrate of Eye Movements
subjects generate some saccades with short
reaction times, or express saccades; laten-
cies are as low as 100 msec.126-129'247 This
facility improves with practice128 and is
performed best for the target positions
used during training,302 suggesting that
express saccades reflect a predictive mech-
anism. However, express saccades are still
generated even if gap and overlap stimuli
are randomly presented in a block of tri-
als.447
Express saccades can be generated if the
gap stimulus is used during fixation or
smooth pursuit;225'4160 this implies that in
the case of the gap stimulus, fixation may
be defined more in terms of keeping the
fovea pointed towards a visual object than
suppression of an eye movement. How-
ever, the shortened latency achieved with
the gap stimulus applies much more to
saccades than to pursuit or vergence.224'415
Thus, it appears that the gap stimulus
mainly releases a fixation mechanism for
saccadic gaze shifts. No equivalent change
in latency can be achieved in response to
auditory stimuli.382
Evidence reviewed below suggests that
the rostral pole of the superior colliculus
may play an important role in such release
of fixation.98'99 In monkeys, the occur-
rence of express saccades is completely
eliminated with lesions of the superior col-
liculus but not with those of the frontal
lobes.355 Thus, express saccades provide a
way of testing collicular function in hu-
mans. The so-called spasm of fixation, in
which a patient cannot change gaze until
the fixation target is removed, may be an
extreme case of the retarding influence of
a persistent fixation target (overlap par-
adigm) upon saccade latency. However,
caution is required in interpreting in-
creased saccadic latency as being collicular
in origin, since it may also be due to de-
fects in the ability to disengage, shift, and
re-engage visual attention.155'275'325 Cau-
tion is also required in accounting for the
finding that some individuals with devel-
opmental dyslexia can generate express
saccades even in response to the overlap
stimulus, and do so without training.62
Overall, the ability to generate express
saccades is probably related to an ability to
turn off the fixation mechanism, a process
that is influenced by directed visual atten-
tion.448
ANTISACCADES
In order to investigate the control of vol-
untary (as opposed to reflexive) saccades,
a special test paradigm called the antisac-
cade task has been developed (see Fig.
10-31, Chap. 10).117b'162 In this task, the
subject is required to suppress a saccade
(the prosaccade) towards a stimulus that
appears in the periphery of vision and in-
stead generate a voluntary saccade of
equal size towards the opposite side (the
"antisaccade"). After time for the antisac-
cade to be made, a target light is turned on
at the correct location, to check the accu-
racy of the movement. The simplest mea-
sure of the response to this test concerns
the direction of the initial saccade, ex-
pressed as the ratio of antisaccades to
prosaccades; this can be tested at the bed-
side.81 Normal subjects initially make fre-
quent errors on this task, but with a brief
period of practice, error rates fall to below
15%. Antisaccades are less accurate,2233
slower, and made at longer latency than
prosaccades. When the fixation point is
turned off before the peripheral target is
presented (gap stimulus), antisaccades are
generated at a latency of about 175 msec
and with errors on about 15% of trials; er-
ror rates increase if targets are more ec-
centric.130 Children develop the ability to
make antisaccades by adolescence.265b In
adults, the latency to generate antisac-
cades increases with age.291 Patients with a
variety of cerebral lesions, especially ones
involving the eye fields of the frontal
lobes, show abnormalities on the antisac-
cade task. They are unable to suppress a
reflexive saccade towards the visual target
and have difficulty generating a voluntary
saccade towards an imagined location. In
addition, individuals who make unusually
frequent express saccades, such as those
with developmental dyslexia, make exces-
sive prosaccade errors on the antisaccade
task.35 Such a deficit could be due to an
impaired ability by the rostral pole of the
superior colliculus to suppress reflexive
saccades. Study of the properties of anti-
saccades and prosaccades made in re-

sponse to more complex stimuli may pro-
vide further insights into the mechanisms
of normal and abnormal saccadic pro-
graming. 130a,447a
Saccadic Accuracy
ACCURACY OF VISUALLY
GUIDED SACCADES
The ideal ocular motor response to the
sudden appearance of a target of interest
in the visual periphery is an eye move-
ment that rapidly reaches, and abruptly
stops at, the target. Such saccades need to
be accurate regardless of whether the tar-
get is stationary or moving.343 Saccades
may be inaccurate or dysmetric in two
general ways; according to whether the
size of the rapid, pulse portion of the sac-
cade is inappropriate (called saccadic pulse
dysmetria), and whether the eyes drift at the
end of the saccade (called postsaccadic drift
or a glissade).221'296 Postsaccadic drift is of-
ten attributed to a mismatch between the
two major components of saccadic inner-
vation, the pulse and the step, producing
pulse-step mismatch dysmetria. Often it is
necessary to record the movements of
both eyes, to determine whether the post-
saccadic drift is conjugate or disjunctive.
For example, in internuclear ophthalmo-
plegia, the slow adducting saccade results
from the inability of the demyelinated me-
dial longitudinal fasciculus to conduct the
high-frequency discharge of the pulse, and
it is the step that mainly carries the eye, in
a glissade, towards the target (see VIDEO:
"Unilateral internuclear ophthalmople-
gia"). In this section, we will mainly deal
with features of pulse dysmetria. Saccadic
step dysmetria will be discussed in Adap-
tive Control of Saccadic Accuracy, below.
Normal individuals frequently show
small degrees of saccadic pulse dysme-
tria—most commonly undershooting (hy-
pometria) of the target. The degree of dys-
metria is usually relatively small, about
10% of the amplitude of the saccade
for nonpredictable visual targets,27-419 and
more accurate still for small saccades.223
For oblique saccades, the net trajectory of
the movement is more accurate than the
The Vestibular-Optokinetic System 97
initial direction.116 Hypometria is usually
more prominent for centrifugally directed
saccades (that is, those directed toward the
periphery) and for saccades of larger am-
plitude. Normal individuals occasionally
make hypermetric (overshooting) saccades
when the saccade is small or directed cen-
tripetally (toward the center) and espe-
cially downward. 74 Fatigue and age may
also influence saccade accuracy. Tired sub-
jects may make two small, closely spaced
saccades rather than a single saccade, and
elderly subjects tend to make more hypo-
metric saccades.4'198 Infants frequently
make several small saccades, instead of
one large saccade, to an eccentric target.388
The amount of saccadic pulse dysmetria
is also influenced by the particular task.
Saccades to targets already present are con-
siderably more accurate than saccades to
suddenly appearing targets.235 Dysmetria
at the end of the primary saccade is greater
along the axis between the two targets (so-
called amplitude dysmetria) than away
from the axis between the two targets (di-
rection dysmetria).432 There is also a range
effect such that if the size of the target dis-
placement is suddenly above or below the
range of previous target displacements, the
next saccade will be correspondingly hypo-
metric or hypermetric.209'211
Saccadic accuracy can also be influenced
by the background near the target (the
"global" effect). Also, if two targets are
presented simultaneously and not too far
apart, the saccade will often take the eye to
a position between them; these saccades
are called averaging saccades.125'266^00 As
the distance between the targets increases,
the proportion of averaging saccades de-
creases and the eye more commonly lands
on one of the two targets. If the target con-
sists of a word, the eye usually lands close
to its center26 (see Saccades during Visual
Search and Reading, below). Changing
the size or luminance of one of two targets
will cause the saccade to bring the eye
closer to the larger or brighter target.86
ACCURACY OF MEMORY-
GUIDED SACCADES
It has proven useful to study the accuracy
of saccades made to remembered target
98 The Properties and Neural Substrate of Eye Movements
locations, especially in patients with le-
sions affecting the frontal lobes and basal
ganglia that might impair working mem-
ory. When normal subjects attempt to
make saccades to the remembered loca-
tion of a target that they viewed a few sec-
onds before, they do so with an accuracy
only slightly less than if the target were
visible.27'452'470 Furthermore, the accuracy
of memory-guided saccades is similar re-
gardless of whether normal subjects main-
tain steady fixation or shift gaze using
smooth pursuit or an eye-head movement
during the memory period (i.e., from the
time of target presentation until they are
required to make the memory-guided sac-
cade in darkness).36-202'287'363'470 This im-
plies that the brain takes into account the
gaze shift that has occurred during the
memory period. Although the brain might
monitor such gaze shifts by monitoring
neural signals of eye movements, such as
efference copy, visual estimates of the direc-
tion of gaze may assume greater impor-
tance, when they are available.470 The ac-
curacy of memory-guided saccades is
affected by lesions at a variety of sites, but
especially with those located in the dorso-
lateral prefontal cortex (see Display
10-36, Chap. 10).
CORRECTIVE SACCADES
When normal individuals undershoot the
target, they usually make a corrective sac-
cade with a latency of 100 to 130 msec.27
Such corrective movements can occur
even when the target is extinguished
before the initial saccade is completed.
Therefore, a nonvisual or extraretinal
signal can provide information about
whether the first movement is accurate, so
that a corrective saccade can be triggered
if necessary. Such nonvisual information is
most likely based upon monitoring of ef-
ferent ocular motor commands or effer-
ence copy ("effort of will"; see Chap. 1).
Vision, however, is still important. The
probability of occurrence of a corrective
saccade and its accuracy increase and the
latency to the corrective saccade decreases
if a visual signal is available at the end of
the initial saccade.90'320 Furthermore, vi-
sual information may be used during the
deceleration phase of a saccade to trig-
ger a corrective movement.108 Nonvisual
mechanisms for generating corrective sac-
cades are also apparent when subjects
make saccades in complete darkness to re-
membered locations of targets.470 If a sac-
cade made in darkness brings the eye to a
position more than about 5° away from the
location of the previously seen target,
an accurate corrective saccade is usually
made.290
Quantitative Aspects of Quick
Phases of Nystagmus
The quick phases of vestibular and optoki-
netic nystagmus can also be characterized
by their velocity, amplitude, and timing.
When elicited naturally, such as during a
smooth rotation of the head, quick phases
fall on the same main sequence as for sac-
cades made in the dark.383 The size and
frequency of quick phases are such that
they tend to bring the eye into the anti-
compensatory direction (i.e., the direction
opposite to that of the slow phase).255'385a
An exception occurs when a subject, sit-
ting inside a revolving, striped, optoki-
netic drum, is specifically instructed to fol-
low a stripe as it moves from one side to
the other and then to make a saccade in
the other direction to acquire another
stripe (look nystagmus). In this case, vol-
untary saccades, rather than reflexive
quick phases, are probably being elicited.
On the other hand, if the subject is asked
to stare straight ahead as the stripes pass
by, quick phases are smaller and more fre-
quent (stare nystagmus). Despite these
general properties, quick phases of nys-
tagmus have a randomness to them.385 An
algorithm using the speed of the slow
phase and the position of the eye in the or-
bit can describe the probability of their oc-
currence.64'65 In some patients, the timing
and amplitude of quick phases may be ab-
normal, just as the latency and amplitude
of voluntary saccades may be abnormal.
An example is patients with congenital
ocular motor apraxia, who may show a
defect in the initiation of quick phases
during passive head rotation; the eyes
 The Vestibular-Optokinetic System 99

intermittently deviate tonically in the
compensatory (slow phase) direction
(see VIDEO: "Congenital ocular motor
apraxia").464
Ballistic Nature of
Saccadic Movements
The duration of most saccades is <70
msec, so visual information does not have
time to influence these movements once
they begin. Saccades are not truly ballistic,
however, because they can be modified in
mid-flight by factors presented before the
eye starts to move. The first ideas on how
the central nervous system processes vi-
sual information for saccades were devel-
oped by Westheimer,450 who showed that if
a target jumped to a new location and
then promptly (<100 msec) returned to
the origin, a sequence termed double-step
stimulus motion, the subject would still
make a saccade away from the current lo-
cation of the target (Fig. 3-4 ). Then, after
a fairly constant interval (150 to 200
msec), the subject would make another
saccade back to the original position of the
target. The interval between saccades was
relatively independent of the interval be-
tween the target jumps away from and
back to the initial position. These findings
suggested that (1) the saccadic system can
react to only one stimulus at a time, and
(2) there is a refractory period during
which a second saccade cannot be initiated
after the first.
Young and Stark456 recognized that the
type of behavior shown in Westheimer's
experiments was compatible with what
control systems engineers call a sampled
data system. They hypothesized that a
"snapshot" of the visual information, at a
given instant, is sampled by the saccadic
system. If an object of interest is observed
in the periphery of this snapshot, a deci-
sion is made to generate a saccade that will
bring the image of the target onto the
fovea. On the basis of the retinal error (the
distance between the retinal location of an
image and the fovea), the size, direction,
and duration of the upcoming saccade are
calculated and an irrevocable decision to
generate the saccade is made. A prepro-
gramed saccadic command is then gener-

Figure 3-4. Saccadic eye movement responses to double-step target jumps. Horizontal position is on the ordi-
nate scale. Note that the intersaccadic interval remains constant in spite of the different durations (compare A
and B) between the two target jumps. (Reproduced, with permission, from Westheimer G. Archives of Ophthal-
mology, 1954, volume 52, pages 932-941, Copyright, 1954, American Medical Association.)
100 The Properties and Neural Substrate of Eye Movements
ated, based upon the visual information
that was acquired during the initial snap-
shot. Once the saccade is completed, the
visual world is again sampled to deter-
mine if another saccade is still needed to
bring the target of interest onto the fovea.
Westheimer's results could then be inter-
preted by assuming that the return of the
target to its initial position was not actually
"seen" by the saccadic system until after
the first saccade was made. Therefore, a
normal saccadic latency, determined by
the interval between snapshots, was re-
quired before making a second saccade to
bring the eyes back to the target.
Although the sampled-data model ac-
counts for many aspects of saccadic eye
tracking, such a scheme does not explain
all of the responses that normal individu-
als make. If Westheimer's experimental
paradigm is expanded to include target
jumps of different sizes and directions,
and if large numbers of responses are ana-
lyzed, it can be shown that visual informa-
tion can be continuously acquired and
used to modify the initial saccadic re-
sponse until about 70 msec before the
movement begins.13'20'27 This is approxi-
mately the time it takes visual information
to traverse the retina and central visual
pathways and reach the brain stem ocular
motor mechanisms.
Furthermore, the saccadic system does
not have an obligatory refractory period;
two saccades may occur with virtually no
intersaccadic interval in response to the
appropriate sequence of double-step mo-
tion of the stimulus.29'153 Slow saccades,
which occur in certain neurologic dis-
eases, can be interrupted in mid-flight
when the target position is changed, even
after the eye has already begun to
move.461 When presented with two-
dimensional, double-step stimuli, normal
subjects make a single curved saccade
rather than two successive straight sac-
cades, indicating that the saccade trajec-
tory has been modified in flight.426 The
earliest responses to such two-dimensional,
double-step stimuli suggest that direction
and amplitude may be programed sepa-
rately.147 Thus, the central nervous system
appears able to change saccades at any
stage, and even to overlap some presac-
cadic planning. Normal saccades only ap-
pear to be ballistic because of their high
velocities and brief durations.
Saccades during Visual Search
and Reading
The idiosyncratic pattern of eye move-
ments made when viewing a pictorial dis-
play is called a scan path.1283 It has been
shown that during manual tasks such as
copying a design, frequent eye movements
are used to scan the display for informa-
tion, rather than committing that informa-
tion to working memory.21'114 Such pat-
terns may be severely disrupted in
patients with neurologic lesions that cre-
ate visual neglect or simultagnosia, but
on occasion may be surprisingly nor-
mal.239-331'332 Saccades made during visual
search for targets embedded in an array of
stimuli are not random and such behavior
can be quantified and used to study visual
attention.2653
Interpretation of ocular motor behavior
during reading remains a controversial is-
sue and is certainly difficult to interpret in
the context of the known control of sac-
cades. For example, there is disagreement
as to whether the spaces between words,
or the words themselves, serve to guide
saccades.111"113'327'438 It is suggested that
when subjects read music, the pattern of
saccades reflects not the visual stimulus or
the manual response but the flow of infor-
mation from the musical score to perfor-
mance.220
There has been substantial research ef-
fort to determine whether developmental
dyslexia is due to abnormal control of sac-
cadic eye movements. The lack of consen-
sus may, in part, reflect the heterogeneity
of patients with dyslexia. In some patients,
the underlying cause of the reading dis-
ability may be auditory-linguistic defects,
and in others, visuospatial defects. Thus,
shifts of attention are important in read-
ing,201 and they may be disturbed in
dyslexia. Cytoarchitectonic abnormalities
in the cerebral hemispheres and in the
thalamus of dyslexic patients have been
reported,142-143 and EEC and evoked po-

tential asymmetries have been noted.102-103
Defects in interhemispheric transfer of in-
formation have also been implicated in
dyslexia.178
One reproducible finding is that dyslexic
children often show impairment of steady
fixation,34'107 with excessive numbers of
square-wave jerks.80 The presence of this
fixation abnormality in dyslexics during
non-reading tasks indicates that the un-
derlying abnormality is not caused by lan-
guage problems alone.107 Some individu-
als with developmental dyslexia show an
ability to generate express saccades, even
during the overlap stimulus (see Saccadic
Initiation Time (Latency), above).62 It is
suggested that their excessive distractibil-
ity for visual stimuli may reflect impaired
"fixation" behavior, perhaps involving cor-
tical projections to the rostral pole of the
superior colliculus.35
Although the relationship between eye
movement abnormalities and childhood
dyslexia is not clear, patients with certain
types of acquired ocular motor abnormali-
ties do have difficulty reading.67 This ef-
fect is seen in patients with slow saccades,
ocular motor apraxia, saccadic oscillations,
and various forms of nystagmus. 166 Fur-
thermore, homonymous hemianopia may
disrupt reading eye movements, especially
when it is due to damage of the occipital
white matter.467
Visual Consequences of Saccades
An important perceptual problem is how
the brain can correctly interpret motion of
images on the retina as being due to
movement of the eyes rather than of the
visual scene. It is possible to identify two
components of this problem: the percep-
tion of motion during the eye movement,
and correct localization of an object in
space following a gaze shift.
VISUAL STABILITY
DURING SACCADES
We appear not to see during saccadic eye
movements. Even though the seen world
is rapidly sweeping across the retina, there
The Vestibular-Optokinetic System 101
is no sense of motion or a blurred image.
One proposed explanation for this is that
the clear perceptions before and after a
saccade would mask the gray-out due to
image motion on the retina at speeds up
to 500°/sec, and both behavioral and elec-
trophysiological findings suggest that this
may be part of the explanation.58'2583
However, if subjects attempt to view a
moving stimulus, it is still possible to see
the lower spatial frequencies in an image
when it moves across the retina at speeds
of up to 800°/sec.50 The situation is differ-
ent if vision is tested during saccades:
there is a selective suppression of vision
for lower spatial frequencies.49 It has been
suggested that this saccadic suppression
selectively affects the magnocellular path-
way, which is mainly responsible for "mo-
tion vision." The mechanism of this sup-
pression is presently unknown, but might
occur as early as the lateral geniculate nu-
cleus.344 Functional imaging studies have
demonstrated decreased regional cerebral
blood flow in striate cortex during repeti-
tive saccades made in darkness, which is
consistent with the notion of saccadic sup-
pression of visual inputs. 306
SPATIAL CONSTANCY FOLLOWING
SACCADIC GAZE SHIFTS
While every saccadic eye movement causes
the entire visual world to be shifted upon
the retina, we are still able to maintain an
appropriate sense of straight-ahead. How
do we ensure such spatial constancy? The
classic explanation is that our central ner-
vous system monitors the effort of will (ef-
ference copy) and then sends this motor
information (as a corollary discharge) to
sensory systems.172 In this way, our per-
ceptual sense knows and adjusts for the
shift of images upon the retina using
an egocentric frame of reference. It is
also possible that extraocular propriocep-
tion could serve this function, but avail-
able evidence suggests that such inputs
are more important for long-term adap-
tive changes in the ocular motor sys-
tems.145-160'236
Other evidence suggests that the brain
estimates the location of objects in space
with reference to other objects in the
102 The Properties and Neural Substrate of Eye Movements
visual scene; these are called egocentric
cues.83'308 For example, if visual targets are
flashed just prior to or during a saccade,
they are incorrectly localized as judged by
subsequent saccades or finger point-
ing.57'83'193'256 If efference copy were the
mechanism by which spatial constancy was
maintained, then there should be no dif-
ference in spatial localization of targets
presented just before or after a saccade.
The changes in visual responses to targets
flashed just before a saccade may reflect
changes in apparent visual direction and a
compression of visual space that antici-
pates the consequences of the upcoming
saccade.259'345
What relative reliance does the brain
place on visual and extraretinal estimates
of the direction of gaze? It seems that
visual estimates are more important, if
they are available. Thus, a classic line of
evidence to support the role of efference
copy in spatial localization is that, in
darkness, normal subjects perceive a
small afterimage, induced by a photo-
flash, as moving with the eye.244 The af-
terimage is stationary on the retina,
and its apparent movement in space is
probably due to efference copy signaling
movement of the eye. However, if a large
afterimage of a complex scene is in-
duced, it does not seem to move as the
eye drifts in darkness.308 Thus, a large vi-
sual afterimage appears to override non-
visual cues about eye movements. Other
experiments have shown that visual esti-
mates of the direction of gaze are given
preference over efference copy, even if
the visual information is corrupted by il-
lusory stimuli. 470 During saccades, visual
inputs become less reliable, but the brain
still puts more reliance on visual than on
extraretinal information. Thus, if a vi-
sual target is displaced during a saccadic
eye movement, its movement may go un-
noticed.89 If, however, the target is only
shown in its new position 100 msec after
the saccade ends, then its displacement
to a new position is detected. Thus, it
seems that the brain weighs visual and
extraretinal estimates of the direction of
gaze,213 putting more reliance on the vi-
sual estimates except when visual factors
are not available.
NEUROPHYSIOLOGY OF
SACCADIC EYE MOVEMENTS
In this section we review the neural ma-
chinery by which saccades shift the line of
sight so that an image detected in the reti-
nal periphery is brought to the fovea,
where it can be seen best. In primary visual
cortex (Brodmann area 17, VI) the loca-
tion of a visual stimulus is represented by
the distribution of activity across a "place"
map. Thus, different parts of this map cor-
respond to different locations on the
retina. The neural representation of the
motor command for the saccadic response
is quite different. The ocular motoneurons
encode the characteristics of the saccade in
terms of their temporal discharge; the size
of the saccade is proportional to the total
number of discharge spikes. The ocular
motoneurons lie in the third, fourth, and
sixth cranial nerves and cause the extraoc-
ular muscles to move the eyes with respect
to the head, in craniotopic coordinates.
This means that the brain must transform
the stimulus, which is encoded in terms of
the location of active neurons within visual
cortex (i.e., place-coded), into the saccadic
command on ocular motoneurons, which
is encoded in terms of discharge frequency
and duration (i.e., temporally-coded). Fur-
thermore, a transformation from retinal
coordinates into craniotopic coordinates is
necessary. The retinal coordinates are two-
dimensional, whereas the eye rotates about
three axes.79 We will return to these issues
in the following section, Brain Stem Path-
ways for Saccades, and in our discussion of
the cortical and subcortical structures that
project to these pathways.
Brain Stem Pathways for Saccades
FINAL SACCADIC COMMAND FROM
OCULAR MOTONEURONS
Electrophysiologic studies of extraocular
muscle activity in humans, and of ocular
motoneurons in animals, have delineated
the innervational changes that accompany
saccadic eye movements (see Fig. 1-3,
Chap. 1). During a saccade, a high-
frequency burst of phasic activity can be
 The Vestibular-Optokinetic System 103

recorded from the agonist ocular muscle

and, as shown in experimental animals,
from the corresponding ocular motoneu-
rons. This burst of activity, the saccadic
pulse of innervation, starts about 8 msec
before the eye movement425 and generates
the forces necessary to overcome orbital
viscous drag so that the eye will quickly
move from one position to another. Fol-
lowing a saccade, the agonist eye muscle
and its ocular motoneurons assume a new,
higher level of tonic innervation, the sac-
cadic step of innervation, which holds the
eye in its new position against orbital elas-
tic restoring forces. The transition be-
tween the end of the pulse of innervation
and the beginning of the step of innerva-
tion is not abrupt but gradual, taking up to
several hundred msec. This is the slide of
innervation. Hence the change in innerva-
tion accounting for saccades is actually a
pulse-slide-step (Fig. 3-5).294'335 If one
records from the antagonist muscle or
its motoneurons, one finds the reciprocal
innervational changes.390 The antagonist
muscle is silenced during the saccade by an
inhibitory, off-pulse of innervation; at the
end of the saccade, the antagonist assumes
a new, lower level of tonic innervation, the
off-step. Measurement of muscle forces
generated by extraocular muscles indi-
cates that the eye comes to rest at the end
of a saccade owing to the viscous forces of
the orbital tissues rather to than any "ac-
tive braking" by the antagonist muscle.257
Figure 3-5. Pulse-step-slide of innervation during a
20° leftward saccade in the rhesus monkey. (Top trace)
BRAIN STEM SACCADIC Eye movement recording from left eye. (Bottom trace)
PULSE GENERATOR Single unit activity from a neuron in the left ab-
ducens nucleus showing the pulse, slide (horizontal
Two types of neurons are critically impor- bar), and step change in innervation. (Courtesy of H.
tant in the generation of saccades: burst P. Goldstein.)
cells* and omnipause cells.52'173'215'399 Fol-

lowing the saccade, the eye is held in posi-

*In burst cell nomenclature, cells in the brain stem
reticular formation that burst (discharge) for sac-
cades are of two main types: medium-lead units that
begin their discharge about 12 msec before saccades,
and long-lead units that begin their discharge over
40 msec before saccades. Hereafter, we will call
medium-lead cells premotor burst neurons or simply
burst neurons. Long-lead burst neurons will be re-
ferred to by their initials, LLBN. There are also cells
that burst for saccades in the superior colliculus,
called collicular burst neurons. Burst neurons are of
two types: excitatory and inhibitory.
tion by a tonic, step command that is gen-
erated by the neural integrator (see Chap.
5 and Fig. 1-3, Chap. 1). A century of clin-
ical experience has demonstrated that the
caudal pons is important for horizontal
saccades and the rostral mesencephalon
for vertical saccades.132'403 For horizontal
saccades, burst neurons within the para-
median pontine reticular formation (PPRF)
are essential (see Display 6-3, Fig. 6-1,
104 The Properties and Neural Substrate of Eye Movements
and Fig. 6-2, Chap. 6). For vertical and
torsional saccades, burst neurons lying in
the rostral interstitial nucleus of the me-
dial longitudinal fasciculus (riMLF) play
the equivalent role (see Display 6-5, Fig.
6-3, and Fig. 6-4). Omnipause neurons lie
in the nucleus raphe interpositus, in the
midline of the pons (see Display 6-3 and
Fig. 6-2).
PREMOTOR BURST NEURONS
Pontomedullary Burst Cells
Excitatory burst neurons (EBN) in the
TPRF lie rostral to the abducens nucleus,
corresponding to dorsomedial nucleus
reticularis pontis caudalis.195 These EBN
begin discharging at a high frequency,
about 12 msec prior to, and time-locked
with, the horizontal component of all
types of rapid eye movements, including
quick phases.176-407'425 Recent evidence
suggests that some EBN in the PPRF en-
code saccades monocularly (i.e., for move-
ments of one eye or the other).2473'466 The
EBN discharge preferentially for ipsilat-
eral saccades and they appear to create
the immediate premotor command that
generates the pulse of activity for horizon-
tal saccades. Three pieces of evidence sup-
port this hypothesis. First, during sac-
cades, the instantaneous burst cell firing
rate of EBN is closely correlated with in-
stantaneous eye velocity,175'425 and the to-
tal number of spikes in the burst of activity
(the integral of the discharge rate) is pro-
portional to the amplitude of the ipsilat-
eral, horizontal component of the sac-
cades. Second, stimulation of the PPRF
elicits ipsilateral saccades.69 Third, a uni-
lateral lesion within the PPRF abolishes
the ability to generate ipsilateral sac-
cades.174 It should be noted, however, that
EBN in the PPRF also discharge during
vertical and oblique saccades,323'425 and bi-
lateral PPRF lesions not only abolish hori-
zontal saccades but also cause slowing of
vertical saccades.165'174
EBN project directly to the ipsilateral
abducens nucleus to contact both ab-
ducens motoneurons and internuclear
neurons. The latter project up the con-
tralateral MLF to contact the medial rec-
tus subgroup of the contralateral oculo-
motor nucleus. EBN also project to ipsilat-
eral inhibitory burst neurons, to the
perihypoglossal and vestibular nuclei, to
the reticular formation adjacent to the ab-
ducens nucleus, and to the cell groups of
the paramedian tracts (see Display 6-4,
Chap. 6). Thus, for horizontal saccades,
the excitatory pulse reaches the ocular
motoneurons from the EBN in the ipsilat-
eral PPRF. As discussed in Chapter 5 (Fig.
5-3), the step of innervation that is re-
quired to hold the eye steady at the end
of the saccade arises from the neural in-
tegrator, for which the nucleus prepositus-
medial vestibular nucleus complex (NPH-
MVN region) is most important.
Inhibitory burst neurons (IBN) for hor-
izontal saccades have been identified just
caudal to the abducens nucleus in the
nucleus paragigantocellularis dorsalis of
the dorsomedial portion of the rostral me-
dulla.195'374'408 The IBN send their axons
across the midline to the contralateral ab-
ducens nucleus to inhibit contralateral ab-
ducens motoneurons and interneurons
during ipsilateral saccades. The IBN also
project to the vestibular nuclei, nucleus
prepositus, and portions of the pontine
reticular formation.408 Thus, the role of
IBN is to silence activity in the antagonist
muscle during horizontal saccades.
Midbrain Burst Cells
The EBN in the riMLF encode the vertical
and the torsional components of saccades,
just as EBN in the PPRF encode the hori-
zontal component.51'219'435 Excitatory and
inhibitory EBN for upward and for down-
ward saccades appear to be intermingled
in the riMLF, although their projection
pathways show some differences.264'265 The
EBN discharge most vigorously for rapid
eye movements that rotate the globe in a
plane parallel to that of a pair of recipro-
cally acting vertical semicircular canals
(for example, right anterior and left poste-
rior). Hence, EBN in one riMLF increase
their discharge when the eye on the same
side extorts and the eye on the opposite
side intorts. While the direction of torsion

is fixed for EBN on each side, the direc-
tion of vertical rotation is upward in some
and downward in others. Thus, unilateral
lesions have only mild effects on vertical
saccades, but abolish ipsilateral torsion.
For example, with a lesion of the right
riMLF, torsional quick phases, clockwise
from the point of view of the subject, (ex-
torsion of the right eye and intorsion of
the left eye) are lost.413 Bilateral lesions in
riMLF abolish all vertical and torsional
saccades.413
Vertical EBN project directly to vertical
ocular motoneurons in the CN III and CN
IV nuclei and send axon collaterals to the
interstitial nucleus of Cajal (see Fig. 6-4,
and Display 6-6).264'265 The latter struc-
ture is an important component of the ve-
locity-to-position integrator for vertical
and torsional eye movements. Thus, for a
vertical or torsional saccade, the pulse
reaches the ocular motoneurons from the
riMLF, whereas the step of innervation
comes mainly from the interstitial nucleus
of Cajal. This scheme is supported by the
results of pharmacologically inactivating
the interstitial nucleus of Cajal; verti-
cal and torsional saccades can still be
made, but there is centripetal postsaccadic
drift.78
OMNIPAUSE NEURONS
Omnipause cells lie in the nucleus raphe
interpositus, which is located in the mid-
line between the rootlets of the abducens
nerves (see Fig. 6-2, Chap. 6).53>229 These
neurons utilize glycine as their neuro-
transmitter,196 which is consistent with
their inhibitory function. A number of
structures project to the omnipause cell
region, including the rostral pole ("fixa-
tion zone") of the superior colliculus,55'144
the frontal eye fields,404 the supplemen-
tary eye fields,386 the central mesen-
cephalic reticular formation, the long-lead
burst neurons in the rostral pons and mid-
brain, and the fastigial nucleus.53'375 Om-
nipause cells send inhibitory projections
to EBN in the pons, to IBN in the me-
dulla, and to the riMLF.53>196'276'286'406
Omnipause neurons discharge continu-
ously except immediately prior to and
The Vestibular-Optokinetic System 105
during saccades, when they pause. Omni-
pause cells cease discharging during sac-
cades in any direction, hence their name.
Omnipause cells also cease discharging
during blinks.176 When omnipause cells
are experimentally stimulated in the mon-
key, the animal is unable to make saccades
or quick phases in any direction, although
other types of movements, such as vestibu-
lar slow phases, can still be elicited.451 If
omnipause cells are stimulated during a
saccade, the eye movement is aborted in
mid-flight. 216
On the basis of these findings, it has
been hypothesized that omnipause cells
tonically inhibit all burst cells (Fig. 3-6),
and when a saccade is called for, the omni-
pause cells themselves must be inhibited
to permit the burst cells to discharge. By
acting as an inhibitory gate, omnipause
cells help maintain the necessary synchro-
nization of the activity of premotor sac-
cadic burst neurons to drive the eyes
rapidly during the saccade and to keep the
eyes still when the saccade is over. Experi-
mental lesions with excitotoxins in the om-
nipause region have the predominant ef-
fect of making horizontal and vertical
saccades slow.208 This effect may be be-
cause the omnipause neurons normally
synchronize the onset and offset of burst
neuron discharge and, after such lesions,
the activity of the burst neurons is no
longer coordinated. However, it also re-
mains possible that these experimental le-
sions also affected the nearby EBN in the
PPRF.
LONG-LEAD BURST NEURONS
AND THE CENTRAL
MESENCEPHALIC
RETICULAR FORMATION
Neurons that start to discharge 40 msec or
more before saccades are found through-
out the brain stem. Some long-lead burst
neurons (LLBN) lie in the midbrain and
receive projections from the superior col-
liculus.375 They project to pontine EBN,
medullary IBN, and omnipause neurons;
they also project to the nucleus reticularis
tegmenti pontis (NRTP). These mesen-
cephalic LLBN discharge before and dur-
106 The Properties and Neural Substrate of Eye Movements

Figure 3-6. The relationship among omnipause cells (P), burst cells (B), and the cells of the neural integrator
(NI), in the generation of the saccadic pulse and step. Omnipause cells cease discharging just before each sac-
cade, allowing the burst cells to generate the pulse. The pulse is integrated by the neural integrator (NI) to pro-
duce the step. The pulse and step combine to produce the innervational change on the ocular motoneurons
(OMN) that produces the saccadic eye movement (E). Vertical lines represent individual discharges of neurons.
Underneath the schematized neural (spike) discharge is a plot of discharge rate versus time.

ing saccades to their movement field. The
portion of the mesencephalic reticular for-
mation that lies just lateral to the CN III
nucleus (central mesencephalic reticular
formation, cMRF) 70 contains neurons that
have reciprocal connections with the supe-
rior colliculus,263 and it has been postu-
lated that they may serve in a feedback
loop, perhaps acting as a resettable inte-
grator for saccades (see Models for Sac-
cadic Pulse Generation, below).442 How-
ever, since these neurons also receive
projections from the supplementary eye
fields and fastigial nucleus, project to the
PPRF, and start to discharge more than 40
msec before saccades,163 they may also
serve a long-lead function, perhaps trans-
forming spatially coded to temporally
coded commands.175 Experimental lesions
of the cMRF cause hypermetria of con-
tralateral and upward saccades and hy-
pometria of ipsilateral and downward sac-
cades.441 More rostral inactivation of the
MRF impairs vertical saccades.443
Other LLBN lie in NRTP and project
mainly to the cerebellum via the middle
peduncle; some of these cells project to
the PPRF.376 Thus, it seems that LLBN
may serve more than one function. While
those LLBN that receive input from the
superior colliculus may play a crucial role
in a spatial-to-temporal transformation of
saccadic commands, other LLBN may syn-
chronize the onset and end of saccades, by
virtue of their projections to omnipause
neurons. 175 ' 375
Models for Saccadic
Pulse Generation
MODELS FOR
HORIZONTAL SACCADES
Early hypotheses for the generation of sac-
cades proposed that the duration of the
pulse of activity that creates saccades was
predetermined or preprogramed accord-

ing to desired saccadic amplitude. Studies
of patients with slow saccades, however,
led to an alternative hypothesis suggesting
that saccades are generated by a mecha-
nism that drives the eyes to a particular
orbital position rather than moving the
eyes a specified distance.461 By continu-
ously comparing desired eye position and
actual eye position (the latter is probably
based on monitoring an internal efference
copy of the eye position command), the
neurons that generate the saccadic pulse
are driven until the eye reaches the target,
when they automatically cease discharg-
ing. This is the original local-feedback
model for saccades proposed by D.A.
Robinson334'461 (Fig. 3-7A). It has the ad-
vantage of automatically generating the
main-sequence relationship of saccades.
The model also accounts for slow but ac-
curate saccades made both by some pa-
tients with neurological disease and by
normal subjects taking various sedative or
hypnotic medications.206 It can also pro-
duce saccadic oscillations such as flutter if
the omnipause neurons malfunction or
are inhibited.462 Although the notion of
local feedback has sometimes been called
into question,208 the evidence to support it
remains substantial. Thus, inactivation of
the PPRF causes slow, usually orthometric
saccades, indicating that local feedback
sustains the reduced discharge of premo-
tor burst neurons until the error signal is
zero.401 Perhaps the most compelling evi-
dence is that if a saccade is arrested in
mid-flight by briefly stimulating the omni-
pause neurons, a new saccade is generated
to get the eye on target within 70 msec,
which is shorter than could have been
achieved by responding to the visual con-
sequences of the arrested movement.216
More recent physiological studies have
called for modifications of the original
Robinson model, while retaining the no-
tion of local feedback control of saccade
generation. One important revision is that
the command signal is a desired change
in eye position206 (Fig. 3-7B). This signal
would be compared continuously with an
efference copy of the actual change in eye
position in order to determine when to
terminate the saccade. Inherent in this
modification of the local-feedback model
The Vestibular-Optokinetic System 107
is the idea of separate integrators—one
common neural integrator for conversion
of eye velocity to eye position commands
(for all types of conjugate eye movements)
and a separate resettable neural inte-
grator that operates on saccadic velocity
commands in the feedback loop that
controls the duration of the saccadic
pulse.1'206'226'278-396'399'400 However, the na-
ture of a separate resettable integrator for
saccades is not yet settled.153'359
What presently remains unresolved is
the anatomical basis for the local feedback
mechanism. One proposal is that the feed-
back may involve LLBN rather than pre-
motor burst neurons (Fig. 3-7C).371 In this
model, LLBN are also the proposed site
for the second, saccade-specific integra-
tion. However, this model is not consistent
with the anatomical projections of the su-
perior colliculus,55 cannot simulate the
staircase of saccades that occurs with sus-
tained stimulation of the superior collicu-
lus,42 and does not account for saccadic
oscillations. Another suggestion is that
feedback control of saccades and the sac-
cadic integrator involve the superior col-
liculus.440 The electrophysiological evi-
dence to support this concept is discussed
below in the section Superior Colliculus.
Third, it has been proposed that local
feedback occurs via a cerebellar loop.232a'322
This proposal is consistent with the
anatomical connections between the pre-
motor burst neurons, dorsal vermis and
fastigial nucleus, which are reviewed below
(Effects of Total Cerebellectomy on Sac-
cades). Further, hypermetria is a cardinal
sign of fastigial nucleus lesions, and it is ar-
gued that this structure serves an impor-
tant role in the feedback control of sac-
cades.2323'322 Inactivation with muscimol of
premotor burst neurons to which the fasti-
gial nucleus projects causes both slowing
and hypometria of saccades.372 More ex-
perimental tests of these hypotheses are
needed.
MODELS FOR OBLIQUE SACCADES
The ocular motoneurons innervate ex-
traocular muscles that rotate the eyes ap-
proximately in Cartesian coordinates (e.g.,
the medial and lateral rectus rotate the
Figure 3-7. Models of the saccadic pulse generator. (A) Model after Robinson.334 A desired eye position signal
(Ed) excites burst neurons (EBN), which in turn project to the ocular motoneurons (OMN), to the neural inte-
grator (NI), and to the inhibitory burst neurons (IBM). Omnipause neurons (OPN) have a tonic level of dis-
charge (TONE) but are inhibited by a trigger signal (TRIG) when a saccade is desired. During the saccade,
OPN are kept silent by IBN. The output of the NI is fed back as an efference copy of eye position to EBN via an
inhibitory interneuron (UN). When this signal becomes equal to Ed, the burst neurons cease discharging and
the saccade is over. (B) Model after Jiirgens and colleagues.206 The input to the burst neurons is now a desired
change in eye position (EA). This signal is compared with an efference copy of eye position, which is now de-
rived from a separate, resettable neural integrator (RI) specific to the saccadic system. (C) Model modified from
Scudder.371 Long-lead burst neurons (LLBN) receive excitatory signals from the superior colliculus (SC) and
are the site for the saccade-specific integration of velocity to position signals. The saccade is terminated by com-
paring the integral of an efference copy of saccade velocity (via IBN) and the integral of the input from the su-
perior colliculus.

108

globe a specified distance horizontally).
However, the premotor burst neurons dis-
charge for oblique movements, and so one
aspect of modeling saccades is whether
they encode the saccadic command in po-
lar coordinates. In other words, how inde-
pendent are the two populations in the
PPRF and riMLF? This becomes an issue
during programing of oblique saccades,
when the activity of the two separate popu-
lations of neurons need to be coordinated.
In one view of the way that oblique sac-
cades are programed, the common source
saccadic model, the command from the
burst neurons is specified in polar coordi-
nates: an oblique (radial) velocity at angle
0 427 Then, neural circuitry converts this
into a signal multiplied by cosine G for the
horizontal motoneurons and a signal mul-
tiplied by sine 6 for the vertical motoneu-
rons. This model predicts that (7) the du-
ration of the horizontal and vertical
components of oblique saccades may differ
from those produced when similar-sized
movements are made as purely horizontal
or vertical saccades; (2) the horizontal and
vertical components will have synchronous
onset and offset; and (3) the trajectory of
the oblique saccade will be straight. An al-
ternative hypothesis, the Cartesian coordi-
nate model, proposes that the central com-
mand for the oblique saccade is broken
down into horizontal and vertical compo-
nents before being sent to the horizontal
and vertical burst neurons.30'157 The criti-
cal predictions of this model are the fol-
lowing: (1) the horizontal and vertical sac-
cadic components of oblique saccades will
have the same duration as when made as
purely horizontal or vertical saccades; (2)
although the horizontal and vertical com-
ponents of oblique saccades will have a
synchronous onset, they may end at differ-
ent times; (3) the trajectory of oblique sac-
cades could be curved.
Normal human saccades are brief, and
it is often difficult to confirm these predic-
tions. However, oblique saccades that have
dissimilar horizontal and vertical compo-
nents appear curved,18 and have different
times of offset of the two components.157
Studies of patients with selective slowing
of the vertical or horizontal components
provide further evidence to support a
Cartesian model.461 Thus, patients with
The Vestibular-Optokinetic System 109
selective slowing of vertical saccades due
to Niemann-Pick type C disease show
markedly curved oblique saccades (Fig.
3-3B).348 The initial movement was mainly
horizontal and most of the vertical compo-
nent occurred after the horizontal compo-
nent ended. After completion of the hori-
zontal component of an oblique saccade,
the eyes oscillated horizontally at 10-20
Hz until the vertical component ended
(Fig. 3-3C). These horizontal oscillations
may occur because the omnipause neu-
rons are silent until the vertical compo-
nent is complete, and the normal horizon-
tal burst neurons oscillate until the whole
saccade is over. Additional support for in-
dependence of the horizontal and vertical
premotor burst neurons comes from elec-
trically stimulating the superior colliculus
during oblique saccades.279 To resolve the
issue of how oblique saccades may have a
straight trajectory in monkeys, it is pro-
posed that prolongation of the smaller
component is achieved down-stream from
the colliculus, by "cross-coupling" be-
tween the horizontal and vertical burst
neurons.30-157'279 However, such models do
not take account of the neurophysiological
finding that some premotor burst neurons
discharge maximally for directions tilted
from their cardinal direction (e.g., hori-
zontal for the PPRF). A model that incor-
porates such variations within a distrib-
uted network of neurons is able to
simulate several characteristics of oblique
saccades, with no cross-coupling.323
MODELS FOR THREE-
DIMENSIONAL SACCADES
The development of reliable methods to
measure 3-D eye rotations has led to the
development of models to account for ro-
tations of the eye in three planes during
saccades. In fact, eye rotations are essen-
tially restricted to rotation about axes that
lie in the frontal plane (Listing's plane; see
Fig. 9-3, Chap. 9), and so three degrees of
freedom are reduced to two. What remains
to be settled is the mechanism that imposes
Listing's law, and the relative contributions
made by the mechanical and suspensory
properties of the orbital tissues on the one
hand,84'295-324-326'370 and by neural factors
on the other.420a'421 At present, models as-
110 The Properties and Neural Substrate of Eye Movements
cribing more responsibility to central
neural factors, for which there is electro-
physiological evidence,430 or to the con-
straints imposed by the orbital mechanics,
are being tested experimentally.253'412
Higher-Level Control of the
Saccadic Pulse Generator
It is now clear that several distinct cortical
areas are involved in the voluntary control
of saccades. The anatomical connections of
these areas and the way that they project
to the brain stem saccadic pulse generator
are summarized in the text and displays of
Chapter 6 and in Figure 3-8. Direct pro-
jections from the cortical eye fields to the
PPRF and riMLF appear meager com-
pared with those to the superior colliculus
or to the cerebellum via NRTP.405 Thus,
recent research has emphasized the role of
the superior colliculus, which receives in-
puts from all the cortical eye fields and
may coordinate the discharge of burst and
omnipause neurons. Although pharmaco-
logical inactivation of the superior colliculi
disrupts normal saccadic programing,232
destructive lesions here do not perma-
nently abolish voluntary saccades,9 and so
the cortical projection to NRTP and the
cerebellum also seems important. How-
ever, the latter pathway is also not essential
because saccades can still be made after
frontal eye field lesions. A crucial finding is
that bilateral lesions of the frontal eye
fields and the superior colliculus cause an
enduring, severe deficit of voluntary sac-
cades.355 A similar defect occurs with com-
bined bilateral lesions of the frontal and
parietal eye fields.241 Thus, parallel de-
scending pathways are involved in gener-
ating voluntary saccades, and it appears
that each is capable of performing spatial-
to-temporal and retinotopic-to-craniotopic
transformations of neural signals.
Superior Colliculus
VISUAL AND MOTOR LAYERS OF
THE SUPERIOR COLLICULUS
Anatomically, the superior colliculus con-
sists of seven layers.262'263'338-396'454 Early
studies established that the dorsal layers
of the superior colliculus are "visual" in
terms of their properties and that the
more ventral or "intermediate" layers are
"motor."6'12 The dorsal layers contain an
orderly retinal projection such that the vi-
sual field can be mapped onto its surface
(Fig. 3-9A).82 These layers receive visual
inputs directly from the retina and from
the striate cortex and send efferents to the
pretectal nuclei, lateral geniculate body,
and pulvinar. The ventral layers contain a
"motor map" (Fig. 3-9B), which has been
defined by the eye movements that are
produced by electrical stimulation.333 Al-
though there are connections between
the dorsal visual and the ventral motor
layers,261-262 in primates, cortical projec-
tions to the ventral superior colliculus
seem to be more important. Furthermore,
visually induced activity in the dorsal lay-
ers does not necessarily lead to movement
activity in ventral layers, and conversely,
movement activity in ventral layers may
occur without visual activity in the dorsal
layers.248'454 Thus, the rest of this section
deals with the connections and properties
of the ventral layers of the superior col-
liculus.243
Important projections to the ventral lay-
ers arise from striate, extrastriate, and
parietal cortex, and from the frontal lobes
(Fig. 3-8). Thus, the frontal eye field, sup-
plementary eye field, and dorsolateral pre-
frontal cortex project to the superior col-
liculus; some of these pathways are direct
and some are via the basal ganglia, includ-
ing the caudate nucleus and the pars retic-
ulata of the substantia nigra. The superior
colliculus has reciprocal connections with
the central mesencephalic reticular forma-
tion263 and receives inputs from the nu-
cleus prepositus hypoglossi.167 The ros-
tral pole receives an input from the
cerebellar fastigial nucleus.246 Serotonin,
acetylcholine, and GABA have all been
identified as transmitters in the ventral
layers.
The ventral layers project to critical
structures in the brain stem that generate
the premotor commands for saccades.
These include the PPRF and riMLF, the
nucleus prepositus hypoglossi, the nucleus
reticularis tegmenti pontis (NRTP), the
central mesencephalic reticular formation,
 The Vestibular-Optokinetic Ill

Figure 3-8. A block diagram of the major structures that project to the brain stem saccade generator (premotor
burst neurons in PPRF and riMLF). Also shown are projections from cortical eye fields to superior colliculus.
FEF, frontal eye fields; SEF, supplementary eye fields; DLPC, dorsolateral prefrontal cortex; IML, intramedul-
lary lamina of thalamus; PEF, parietal eye fields (LIP); PPG, posterior parietal cortex; SNpr, substantia nigra,
pars reticulata. Not shown are the pulvinar, which has connections with the superior colliculus and both the
frontal and parietal lobes, and certain projections, such as that from the superior colliculus to nucleus reticu-
laris tegmenti ponds (NRTP).

and the vestibular nuclei. The ventral lay-
ers also send ascending projections to the
central thalamus.366 Descending outputs
from the ventral layers of the superior col-
liculus are carried via an ipsilateral tecto-
pontine pathway and a contralateral tec-
toreticular pathway. The latter crosses in
the dorsal tegmental decussation of Meyn-
ert and, as the predorsal bundle, lying
ventral to the MLF, carries descending
branches destined for the pontine and
medullary reticular formation and ascend-
ing branches destined for the rostral mid-
brain.262'263 The functional anatomy of the
superior colliculus has been elucidated by
the technique of microstimulation.
Figure 3-9. The topography of maps in the superior colliculus. (A) Representation of the visual field on the sur-
face of the right colliculus. The stippled area represents the part of the contralateral visual field within 5° of the
fovea. Stippled and striped areas combined represent the part of the contralateral visual field within 10° of the
fovea. (From Cynader M., and Burman, N., Receptive field organization of monkey superior colliculus, Journal
of Neurophysiology, 1972, volume 35, page 187-201, with permission.) (B) The motor map of the ventral layers
of the left superior colliculus, based on stimulation studies. On the left, arrows indicate the direction and ampli-
tude of saccades produced by stimulation. On the right are smoothed contours of the motor map. Isoamplitude
lines (2°-50°) run from medial to lateral, and isodirection lines (-60°-;+ 60°) run from anterior to posterior.
(From Vision Research, volume 12, Robinson DA. Eye movements evoked by collicular stimulation in the alert
monkey, 1795-1808, 1972 with permission from Elsevier Science.)

112

FUNCTIONAL ANATOMY OF THE
SUPERIOR COLLICULUS
REVEALED BY STIMULATION
Saccades can be produced by electrical
stimulation throughout the superior col-
liculus, but in the ventral layers this is
possible at low-current thresholds.333'356
Within these ventral layers, the direction
and size of the saccade are mainly func-
tions of the site of stimulation rather than
the strength of the stimulus or current
position of the eye. Thus, once threshold
has been reached, saccades occur in an
all-or-none fashion, although the effects
of stimulation are influenced by whether
the animal is actively fixating a target.398
The smallest saccades are elicited ros-
trally, the largest, caudally. Saccades with
upward components occur with more me-
dial stimulation, those with downward
components, with more lateral stimula-
tion. Purely vertical saccades only occur
with bilateral simultaneous stimulation of
corresponding points. This motor map in
polar coordinates (Fig. 3-9B) lacks three-
dimensional (i.e., torsional) informa-
tion.428 Saccades of similar size (isoampli-
tude) correspond to lines running
medial-to-lateral (largest with stimulation
caudally), and saccades of similar direc-
tion (isodirection) correspond to lines
running anterior to posterior (0° corre-
sponding to a pure, horizontal, contralat-
eral saccade). Stimulation of the rostral
pole of the motor map suppresses sac-
cades; this "fixation zone" of the superior
colliculus sends a monosynaptic excita-
tory projection to omnipause neurons, 144
thereby suppressing saccades. Stimulation
more caudally induces saccades at laten-
cies that imply disynaptic connections
with premotor burst neurons; it is sug-
gested that the long-lead burst neurons
are interposed.258 Stimulation in the cau-
dal third of the ventral motor map pro-
duces combined eye-head gaze shifts;
both eye and head movements are di-
rected contralateral to the side stimu-
lated.76 Consistent with these studies is
the finding that the rostral pole of the su-
perior colliculus projects to the omni-
pause region (nucleus raphe interposi-
tus), whereas more caudal portions
project to the premotor burst neurons. 55
The Vestibular-Optokinetic System 113
NEURAL ACTIVITY OF THE
SUPERIOR COLLICULUS DURING
SACCADE GENERATION
The first studies of the activity of single
neurons in the ventral layers of the supe-
rior colliculus in monkeys trained to make
saccades to visual targets revealed a vari-
ety of cell types that showed responses re-
lated to either the visual stimulus or the
saccadic movement or to both.397 Some
neurons that respond to visual stimuli do
so in anticipation of a saccade that will
bring a target into their receptive field444
or show activity related to the selection of
a target for a saccade.25'149 Another type of
neuron, quasivisual cells, hold in spatial
register the amplitude and the direction
of the upcoming required saccade (i.e.,
they encode the motor error signal neces-
sary to acquire the target).402
Three populations of saccade-related
cells have been defined in the ventral lay-
ers: fixation neurons and buildup neu-
rons, which lie more ventrally, and col-
licular-burst neurons, which lie more
dorsally.243'453 The activity of collicular-
burst neurons during a saccade is in accor-
dance with the motor map demonstrated
by microstimulation. Thus, it is the loca-
tion of the active population of collicular-
burst neurons that encodes the size and
direction of the saccade, not the rate of
discharge.270'271 The site of maximum ac-
tivity on the collicular motor map deter-
mines the desired change in eye position.
During the course of a saccade, the site of
maximum activity of collicular-burst neu-
rons does not change, but their discharge
rate declines as the eye approaches its tar-
get. Although it has been postulated that
the temporal discharge of collicular-burst
neurons might encode motor error (the
difference between current and desired
eye position), current evidence suggests
that they are more likely to encode desired
change in eye position.106'267 Their dis-
charge is also influenced by current eye
position.429 Collicular-burst neurons lo-
cated in the caudal part of the superior
colliculus appear to encode a gaze dis-
placement signal for a combined eye-head
saccade.133
Fixation neurons lie at the rostral pole
of the motor map and probably suppress
114 The Properties and Neural Substrate of Eye Movements
saccades via their projections to omni-
pause neurons;144-268-269 they may also
inhibit collicular-burst neurons.266a Build-
up neurons start to discharge when a vi-
sual stimulus becomes the target for a sac-
cade.271 Like collicular-burst neurons, the
location of build-up cell activity initially
occurs at a site on the motor map related
to the amplitude and direction of the up-
coming saccade. However, unlike the loca-
tion of discharging collicular-burst cells,
which remains constant throughout the
eye movement, there appears to be a ros-
tral spread of activity of buildup neurons
(a moving wave or hill) towards the fixa-
tion zone. This spread of activity among
the buildup neurons population may con-
tribute to the spatial-temporal transfor-
mation of signals that is needed to provide
the reticular burst neurons with the sac-
cadic command. When the spreading wave
of activity reaches the fixation neurons at
the rostral pole, the saccade ends.271 Not
all studies, however, support this hypothe-
sis.113 During the antisaccade task, pre-
stimulus activity of build-up neurons is
predictive of an error (prosaccade).117a
Cells in the ventral layers of the superior
colliculus also have auditory204'205-238 as well
as somatosensory receptive fields,154 which
are generally in register.446 The spatial map
of auditory responses in the superior col-
liculus is dynamic, being a function of the
initial position of the eye in the orbit. In this
way, saccades made to auditory targets are
still governed by the same retinotopically
coded, change-in-position movement fields
that underlie visually driven saccades.
Studies in humans support this idea.238
THE EFFECTS OF
PHARMACOLOGICAL
INACTIVATION AND LESIONS OF
THE SUPERIOR COLLICULUS
Insight into the role of the ventral layers
of the superior colliculus in saccade gener-
ation has been gained by local injection
of the GABA agonist muscimol, which in-
creases normal GABA inhibition and
thereby decreases neuronal activity; and
the GABA antagonist bicuculline, which
increases neuron activity by decreasing
normal GABA inhibition. Injection of
muscimol into the rostral pole of the SC
reduces saccadic latency, causing express
saccades and disruption of steady fixation
by saccadic intrusions. Conversely, bicu-
culline injected into this fixation zone in-
creased saccadic latency and sometimes
saccades were not generated. Injection of
these same agents into more caudal re-
gions of the superior colliculus has the
opposite effect. Thus, inactivation with
muscimol (or lidocaine) causes impaired
initiation of saccades, which are hypomet-
ric and slow.188'190-232 Bicuculline injections
cause fixation instability, with saccadic in-
trusions. These findings support the sug-
gestion that the fixation neurons at the
rostral pole of the superior colliculus sup-
press saccades both through excitation
of omnipause neurons55 and by inhibiting
collicular burst neurons.453 However, in-
puts from structures other than the supe-
rior colliculus also influence omnipause
neurons and the timing of saccadic on-
set.118 If muscimol is injected locally into
the superior colliculus at a point corre-
sponding to small saccades (Fig. 3-9B),
and the monkey makes large saccades, the
eye gets on target but by a curved trajec-
tory.7 This finding supports the hypothesis
that during saccades, activity in the
buildup cell layer sweeps forward but has
to circumvent the area that has been phar-
macologically inactivated.7
Conventional lesion studies have been
less revealing than acute pharmacological
inactivation, in part because of the effects
of recovery and adaptation. However, cer-
tain persistent defects are noted with
chronic lesions of the superior colliculus.9
Saccadic accuracy is mildly impaired with
a small degree of hypometria. The fre-
quency of spontaneous saccades is dimin-
ished during scanning of a visual scene but
not in complete darkness. During fixation
of a stationary target, the monkey without
a superior colliculus is less easily distracted
by peripheral stimuli and makes fewer sac-
cades away from the fixation target. Most
notably, the ability to generate express sac-
cades is abolished after collicular le-
sions.355 When lesions of the superior
colliculus are combined with lesions of
the caudal medial thalamus10 or with the
frontal eye field (see The Role of the

Frontal Eye Field in Saccade Generation,
in the following section), more long-lasting
ocular motor abnormalities are produced.
Lesions restricted to the superior colli-
culi are rare in humans. One patient who
had undergone removal of an angioma
from the right superior colliculus showed
evidence of dorsal midbrain syndrome.179
Spontaneous horizontal saccades to the
left occurred less frequently and were
more commonly followed by corrective
saccades; saccadic latency was normal. An-
other patient with a hematoma largely re-
stricted to the right superior colliculus
showed defects in latency and accuracy for
contralateral saccades and increased num-
bers of inappropriate saccades (prosac-
cades) in the antisaccade task.317
Role of the Frontal Lobe in
Saccade Generation
The frontal eye field has been implicated
in ocular motor control ever since Ferrier
stimulated the premotor cortical area 8
of monkeys and elicited contralateral eye
movements. 124 In humans, electrical stim-
ulation (experimental or epileptic) elicits
contraversive deviation of the eyes.151'309
The location of the homologue of the
frontal eye field in humans has been re-
cently defined by functional imaging stud-
ies.305 Two other areas, the supplementary
eye field and dorsolateral prefrontal
cortex, have been shown to contribute
to the voluntary control of saccades. The
anatomical location and connections of
these three areas are described in Chapter
6 and summarized in Figure 6-8, Display
6-19, Display 6-20, and Display 6-21.
Here we summarize results of electrophys-
iological and lesion studies that have
helped define the role that each area
plays.
ROLE OF THE FRONTAL EYE
FIELD IN SACCADE GENERATION
Effects of Microstimulation of the
Frontal Eye Field
Microstimulation studies in the rhesus
monkey have been crucial in defining the
The Vestibular-Optokinetic System 115
extent of the frontal eye field (FEF) (along
the posterior portion of the arcuate sulcus,
part of Brodmann area 8)46 and have also
given insights into FEF function. Stimula-
tion at any site on the FEF elicits a saccade
of a specific direction and amplitude. The
latency from FEF stimulation to the onset
of a saccade is about 30-45 msec, similar
to that for stimulation in the superior col-
liculus. Usually, the movement is oblique,
with a contralateral horizontal compo-
nent; bilateral stimulation is required to
elicit a purely vertical saccade. A motor
map is present with larger saccades
evoked from stimulation of the dorsome-
dial portion of the FEF and with smaller
saccades from stimulation of the ventrolat-
eral part.46 Stimulation of first one FEF
and then the other elicits two successive
saccades that take the eye to a position
corresponding to single stimulation of the
second site.137a Microstimulation can also
suppress saccades if it is timed to coincide
with the visual stimulus for the eye move-
ment; this occurs at thresholds lower than
those evoking saccades.47 Such suppres-
sion of saccades occurs when stimulation is
applied deep within the anterior bank,
close to the representation for small sac-
cades, a region that projects to the fixation
region at the rostral pole of the superior
colliculus and to omnipause neurons in
the pons.47'405 Stimulation of one FEF af-
fects the activity of cells in the other con-
sistent with coordination between the two
eye fields.358
Activity of Frontal Eye Field Neurons
Only occasional FEF neurons discharge
before spontaneous saccades made in
complete darkness, although many neu-
rons discharge after such movements. The
most useful information about the activity
of single neurons in the FEF has been
gained from experiments in which mon-
keys were trained to perform a variety of
saccadic tasks for reward. 45 - 152 Different
subpopulations of FEF neurons encode
the visual stimulus, the planned saccadic
movement, or both. As in the superior col-
liculus and parietal eye fields, some cells
with visual responsiveness anticipate the
visual consequences of planned sac-
116 The Properties and Neural Substrate of Eye Movements
cades.422 Although the discharge of FEF
neurons is related to the amplitude and
direction of voluntary saccades, their dis-
charge during saccades does not dynami-
cally encode signals such as motor error
(the difference between current and de-
sired eye position).377 The FEF neurons
also discharge for visual and motor aspects
of memory-guided saccades.134 When
monkeys perform a double-step task, in
which two target lights are flashed in suc-
cession before the eye has time to move,
most units discharge not in relation to the
retinal location of the second target but ac-
cording to the saccade needed to acquire
it.152 Such cells behave similarly to quasivi-
sual cells of the superior colliculus—their
activity encodes the desired change in eye
position. Neurons that appear to be con-
cerned with disengaging fixation prior to
a saccade increase their discharge when
the fixation light is turned out, even be-
fore the new target becomes visible.92
Some FEF neurons show properties indi-
cating that they contribute to selection of
the target to which a saccade will be
made,352 the decision whether to look at it
or not,164 and the process of visual scan-
ning of a complex visual scene.48
Effects of Frontal Eye Field Lesions
on Saccade Generation
Acute destructive lesions of the FEF in
monkeys produce an increase in latency
for contralateral saccades and a decrease
in latency for ipsilateral movements, i.e.,
an increase in express saccades ipsilateral
to the side of the lesion.353 Acute phar-
macological inactivation with muscimol
causes a contralateral ocular motor scotoma
with abolition of all reflex, visual, and vol-
untary saccades with sizes and directions
corresponding to the injection site.93 Inac-
tivation with lidocaine principally impairs
contralateral saccades made to targets that
are no longer visible.394 With muscimol in-
activation of FEF, during attempted fixa-
tion there is a gaze shift towards the side
of the lesion. In contrast, bicuculline pro-
duces irrepressible saccades.93 Thus, these
results are similar to the effects of inject-
ing these agents into the superior collicu-
lus; inactivation of either structure causes
substantial defects in reflex visual and vol-
untary saccades.
More subtle changes in the generation
of visually guided saccades are present
with chronic experimental lesions of the
FEF, including decreased frequency and
size of movements,357 and defects of sac-
cades made to paired or multiple targets
that are presented asynchronously.353a
Saccadic deficits after chronic FEF lesions
in humans are relatively minor, consisting
of increased latency and inaccuracy of vi-
sual and memory-guided saccades (see
Display 10-36, Chap. 10).
ROLE OF THE SUPPLEMENTARY
EYE FIELD IN
SACCADE GENERATION
The supplementary eye field (SEF) lies
just anterior to the supplementary motor
cortex, in the dorsal medial portion of the
frontal lobe.362 Like the FEF, the SEF con-
tains neurons that discharge prior to vol-
untary saccades. Stimulation in the SEF
elicits saccades at low thresholds, though
at a slightly longer latency than in the
frontal eye fields.362 Initial studies using
microstimulation seemed to indicate that
the eye was driven to a specific orbital po-
sition.361 This was unlike the results of
stimulation of the FEF, which produced an
eye movement of specific size and direc-
tion, determined by the site stimulated.
Thus, it was postulated that neurons in
the SEF encoded saccadic eye movements
in craniotopic rather than oculocentric
(retinal) coordinates.361>416d Other studies
have questioned this conclusion, however,
and indicate that neurons in both the SEF
and FEF encode visual targets and sac-
cades retinotopically.349 This raises the
question of what special contribution, if
any, the SEF makes to the control of sac-
cades. Neurons in the SEF show different
activity than FEF neurons when monkeys
are trained to make a learned sequence of
saccades,63 a combined eye-arm task,274
or are required to cancel planned sac-
cades.304 Neurons in the SEF also show
different discharge characteristics before
antisaccades,364 and cerebral event-related
potentials recorded from the scalp of hu-
man subjects correlate with correct and-

saccade responses.119 This notion that the
SEF is concerned with eye movements that
are programed as part of learned, com-
plex behaviors is supported by functional
imaging studies in humans which have
demonstrated increased activation during
a series of memory-guided saccades.310
Studies of patients with lesions involving
the SEF also indicate that the behavioral
defect concerns the ability to make a re-
membered sequence of saccades to an ar-
ray of visible targets.146 The effects of SEF
on human eye movements are summa-
rized in Display 10-36.
ROLE OF DORSOLATERAL
PREFRONTAL CORTEX IN
SACCADE GENERATION
Although not a conventional eye field (as
defined by low threshold for stimulation
of saccades), neurons in the prefrontal
cortex of monkey in the posterior third of
the principal sulcus (see Fig. 6-8, Chap.
6), which lies on the dorsolateral convexity
of the frontal lobe, corresponding to
Walker's area 46, show an ability to hold in
memory the location of a visual target to
which a saccade is to be made (Display
6-21).141'168 Pharmacological inactivation
of dorsolateral prefrontal cortex (DLPC)
impairs the accuracy of monkeys to make
contralateral memory-guided saccades.351
In humans, there is activation of DLPC
when subjects make memory-guided sac-
cades or antisaccades.284'414 Lesions af-
fecting DLPC impair both of these sac-
cadic functions.158'313 Repetitive transcranial
magnetic stimulation over DLPC in nor-
mal subjects also impairs the accuracy of
memory-guided saccades.41 Cingulate cor-
tex and the hippocampus both appear to
contribute to programing of single or mul-
tiple memory guided saccades; they are
discussed further in Chapter 6.
Role of the Parietal Lobe in
Saccade Generation
The parietal lobe appears to influence the
control of saccades in at least two ways.
First, the posterior parietal cortex is im-
The Vestibular-Optokinetic System 117
portant for shifts of visual attention, which
may be accompanied by saccades. Second,
the parietal eye fields (PEF) are directly
involved in programing saccades to visual
targets.
ROLE OF POSTERIOR PARIETAL
CORTEX IN SACCADE
GENERATION
In monkeys, area 7a of the inferior pari-
etal lobule contains populations of neu-
rons that respond to visual stimuli and dis-
charge mainly after saccades have been
made (Fig. 6-8).22 It appears that the ac-
tivity of some of these neurons is influ-
enced not just by visual stimuli but also by
eye and head position.11-44 This finding
has led to the hypothesis that a neural net-
work of such cells could encode a visual
target in spatial or craniotopic coordi-
nates.11 Such a transformation of signals
would seem to be essential for programing
saccadic gaze shifts towards selected tar-
gets.
In humans, unilateral posterior parietal
lesions, especially acute right-sided le-
sions, cause contralateral inattention and
may restrict saccades to the ipsilateral
hemirange of gaze (see Display 10-35,
Chap. 10).260 Chronic lesions cause in-
creased latency of visually guided sac-
cades;242 in humans this is especially the
case with right-sided lesions.314 In addi-
tion, memory-guided saccades are inaccu-
rate, possibly because posterior parietal
cortex projects to DLPC.313 In normal hu-
man subjects, a defect of memory-guided
saccades is produced if transcranial mag-
netic stimulation is applied to the poste-
rior parietal area early during the mem-
ory period.273-301 Antisaccades are also
delayed by transcranial magnetic stimula-
tion over parietal cortex; a similar effect is
possible over frontal cortex if the stimulus
is delivered later, suggesting flow of infor-
mation from posterior to anterior during
presaccadic processing.4166 Bilateral poste-
rior parietal lesions cause Balint's syn-
drome,312 features of which include diffi-
culty initiating voluntary saccades to visual
targets, and visual scanning.240 These
deficits may reflect disruption of the nor-
mal mechanisms by which posterior pari-
118 The Properties and Neural Substrate of Eye Movements
etal cortex transforms visual signals into
spatial coordinates.
ROLE OF THE PARIETAL EYE
FIELD IN SACCADE GENERATION
In rhesus monkeys, the PEF lies adjacent
to area 7a, in the caudal third of the lateral
bank of the intraparietal sulcus, an area
called LIP (Fig. 6-8). Electrical stimula-
tion on the lateral wall of the intraparietal
sulcus produces saccades of similar direc-
tion irrespective of the starting position of
the eye.417 However, if the floor of the in-
traparietal sulcus and its underlying white
matter are stimulated, the direction of the
resulting eye movements appears to de-
pend on starting eye position. Thus, the
summed output of the PEF may be con-
cerned with making saccades to specified
targets in spatial coordinates.417
Unlike area 7a, LIP neurons discharge
prior to saccades.22'23 Like cells in area 7a,
the response of LIP neurons is influenced
by eye position.11 These cells in the LIP
also show a shift of their visual response
field that anticipates the consequence of
the upcoming gaze shift. 104 Another im-
portant property of LIP neurons is their
ability to remain active while the mon-
key is required to withhold eye move-
ments and remember the desired target
location.23'303 Thus, the activity of these
neurons corresponds to the size and direc-
tion of the required eye movement, a
memory of motor error, and is similar to
that of certain quasivisual cells found in
the superior colliculus and frontal lobe.
Furthermore, LIP neurons appear to
encode not only the intended saccade
but also reflect changes in the planned
movement and other cognitive fac-
tors.40'71-249'319'337
In humans, lesions of the PEF, which is
located in cortex adjacent to the horizon-
tal portion of the intraparietal sulcus,272
cause prolonged latency of visually guided
saccades during gap or overlap stimuli
(see Display 10-35, Chap. 10).314 These
changes are more pronounced with right-
sided lesions. A similar effect results in
normal subjects if transcranial magnetic
stimulation is applied to the PEF re-
gion.109 It has been suggested that the
greater latency resulting when the fixation
light is left on indicates that the PEF is im-
portant for disengagement of fixation
prior to generating a saccade.315 Parietal
lesions impair the ability to make two sac-
cades to two targets flashed in quick suc-
cession. In response to this double-step
stimulus, the brain must take into account
not only the retinal location of both targets
but also the effect of the eye move-
ments.105'169 Patients with right parietal le-
sions show errors when the first target ap-
pears in the left hemifield an'd the second
target appears in the right; the first sac-
cade may be accurate, but the second is
not. This deficit may be present even
though there is no inattention or difficulty
responding to the reverse order of presen-
tation or of making single saccades to left-
sided targets. It appears that there has
been disruption of the ability to monitor
the size of the first saccade using efference
copy.105'169
To summarize, the influence of frontal
and parietal cortex on the control of sac-
cades appears to be via two parallel de-
scending pathways (Fig. 3-8). One path-
way is via the frontal eye field to the
superior colliculus (directly and indirectly
via the basal ganglia). This pathway
appears to be more concerned with self-
generated changes in gaze related to re-
membered, anticipated, or learned behav-
ior. The other pathway is directly from
posterior parietal cortex to the superior
colliculus. This pathway is more concerned
with reorienting gaze to novel visual stim-
uli and in particular with shifting visual at-
tention to the location of new targets ap-
pearing in extrapersonal space. However,
there are strong interconnections between,
and common projection sites of, the pari-
etal and the frontal lobes, which precludes
a strict separation of function between the
two pathways.623-378 Thus, for example, le-
sions of both posterior parietal cortex and
DLPC may impair memory-guided sac-
cades.313
Role of the Thalamus in
Saccade Generation
On the basis of animal experiments, it is
clear that at least two parts of the thala-
mus contribute to the programing of sac-

cades: the central nuclei of the internal
medullary lamina and the pulvinar.
ROLE OF THE INTERNAL
MEDULLARY LAMINA IN
SACCADE GENERATION
Neurons scattered throughout the inter-
nal medullary lamina (IML), which is the
fiber pathway separating the medial from
the lateral thalamic mass, show saccade-
related properties.360'365'366 Electrical stim-
ulation in the region of the IML elicits
contralaterally directed saccades that may
either be of fixed size and direction or di-
rected to an orbital position. Neurons in
the IML discharge in relation to sponta-
neous and visually guided, contralateral
saccades. Consistent with the effects of
stimulation is the observation that some
units appear to encode saccades in cran-
iotopic rather than retinotopic coordi-
nates. Yet, other types of neurons in IML
stop discharging during saccades but show
a strong postsaccadic increase in activity,
discharge in relation to eye position, or
discharge during steady fixation.
In humans, functional imaging has con-
firmed activation of the thalamus during
voluntary saccades.311 Because IML neu-
rons receive inputs from cortical and brain
stem structures concerned with eye move-
ments but project only to the cortex and
basal ganglia, it has been suggested that
they might be a source of efference copy
information to the cortical eye fields.366 In
support of this hypothesis is the report
that patients with lesions affecting the
intralaminar nuclei show inaccuracy of
memory-guided saccades only if gaze is
perturbed during the memory period.146a
ROLE OF THE PULVINAR IN
SACCADE GENERATION
Two separate parts of the pulvinar appear
to each make distinctive contributions to
saccades. Neurons in the inferior-lateral
portions of the pulvinar respond to retinal
image motion when it is produced by a
moving stimulus, but much less so if it is
due to a saccade.339 Thus, this region
might contribute to the process of sac-
cadic suppression. In the dorsomedial
pulvinar, visually responsive neurons are
The Vestibular-Optokinetic System 119
not retinotopically organized and seem
more important for shifts of attention to-
wards salient features in the environ-
ment.32'292,336 i n j ec tion of GABA antago-
nists and agonists into the dorsal medial
portion of the lateral pulvinar facilitates or
retards, respectively, the ability of an ani-
mal to shift its attention toward the con-
tralateral visual field.340 Electrolytic le-
sions in the pulvinar of monkeys cause a
paucity of saccades towards blank portions
of the visual field, and gaze appears to
be "captured" by visual stimuli.423 Other
studies, however, have revealed relatively
normal patterns of visual search after pul-
vinar lesions.31 Furthermore, after kainic
acid lesions in the pulvinar, the latency
and amplitude of saccades to single- and
double-step targets are normal. Thus, the
abnormalities that appear after electrolytic
lesions of the pulvinar might be related to
interruption of fibers of passage.
In humans, functional imaging sup-
ports the idea that the pulvinar is im-
portant for directing visual attention. 227
Nonetheless, reports of the effects of le-
sions restricted to the pulvinar on sac-
cades are rare. A patient with a left
pulvinar lesion showed a paucity of spon-
taneous saccades into the contralateral
field (there was hemispheric extension,
but no visual field defect); latencies were
increased for all saccades, but especially
those directed into the contralateral field.468
Another patient had damage to the left
pulvinar and showed a paucity of sponta-
neous eye movements and defective visual
scanning into the contralateral field.285 A
group of patients who underwent ventro-
lateral thalamotomy showed contralateral
hemi-inattention.437 Taken together, these
experimental and clinical results suggest
that the predominant effect of pulvinar le-
sions in humans is a defect of the ability to
shift visual attention. The effects of pulv-
inar lesions on saccadic suppression have
yet to be evaluated.
Role of the Basal Ganglia in
Saccade Generation
Although the frontal lobe "eye fields" pro-
ject directly to the superior colliculus, they
120 The Properties and Neural Substrate of Eye Movements
also contact the tectum indirectly through
a pathway that mainly involves the cau-
date nucleus and the substantia nigra pars
reticulata (SNpr) (Fig. 3-8). In essence,
the SNpr maintains a tonic inhibition of
collicular-burst neurons. Thus, for a sac-
cade to be initiated by this pathway, the
caudate nucleus must disinhibit the SNpr.
In turn, the caudate depends on cortical
inputs to signal the need to suppress the
tonic inhibition of the superior colliculus
by SNpr. In considering what role this
pathway could play in the control of sac-
cades, we will first examine the properties
of the caudate nucleus.
ROLE OF THE CAUDATE NUCLEUS
IN SACCADE GENERATION
The caudate (and parts of the putamen)
receives inputs from the FEF, SEF, DLPC,
IML region of the thalamus, and from the
substantia nigra, pars compacta (the
dopaminergic portion). The caudate pro-
jects primarily to the SNpr and to the
globus pallidus. Neurons lying in the cen-
tral longitudinal zone of the caudate have
a low rate of tonic discharge that increases
prior to saccades.181'182 Significantly, this
presaccadic activity is related more to the
behavioral nature of the saccade than to
its size and direction. Specifically, the ac-
tivity of these caudate neurons shows a
strong dependency on memory, expecta-
tion, attention, and reward.183'2143 Thus,
the caudate nucleus seems to be con-
cerned with complex aspects of ocular
motor behavior that are necessary, for
example, in predicting environmental
changes.183 Consistent with this is the find-
ing from functional imaging in humans
demonstrating activation of the putamen
and substantia nigra during memory-
guided saccades.299
Experimental, unilateral dopamine de-
pletion of the caudate and adjacent puta-
men causes impairment of contralaterally
directed saccades.214 The major deficit is
for memory-guided saccades, which be-
come hypometric and slow, and are initi-
ated at increased latency.222 Similarly, pa-
tients with chronic lesions involving the
putamen show deficits in saccades made to
remembered locations and in anticipation
of predictable target motion; visually
guided saccades are intact.433
ROLE OF SUBSTANTIA NIGRA
PARS RETICULATA IN
SACCADE GENERATION
The saccade-related cells in SNpr lie in its
lateral portion (near the cerebral pedun-
cle) and project to the intermediate layers
of the superior colliculus. Neurons in the
SNpr have high tonic discharge rates that
decrease prior to voluntary saccades that
are either visually guided or are made to
remembered target locations.184-187 These
"fixation" neurons are more dependent
on the presence or absence of a visual tar-
get than are saccade-related neurons in
the caudate nucleus. Neurons with similar
properties are reported in the subthalamic
nucleus.245
Stimulation of caudate neurons pro-
duces suppression or facilitation of SNpr
neurons, the latter possibly due to a multi-
synaptic pathway.180 However, neurons in
the SNpr that seem important for mem-
ory-guided saccades are usually inhibited
by stimulation of the caudate. The SNpr
sends inhibitory projections to the su-
perior colliculus, which are probably
GABAergic. Injection of muscimol (a GABA
agonist) into SNpr has an effect similar to
that of injection of bicuculline (a GABA
antagonist) into the superior colliculus:
repetitive, irrepressible saccades occur,
which are directed contralaterally to the
side of the injection.189 These saccadic in-
trusions appear to occur from loss of the
normal suppressive effect of SNpr on col-
licular-burst neurons rather than from
any effect on the fixation neurons at the
rostral pole of the superior colliculus.268
Thus, a simplified view of this basal gan-
glia pathway is that it is composed of two
serial, inhibitory links: a caudonigral inhi-
bition that is only phasically active and a
nigrocollicular inhibition that is tonically
active. In this way, the basal ganglia ap-
pear to facilitate the initiation of more vol-
untary, self-generated types of saccades
made in the context of learned behavior,
such as that which might occur during
tasks involving prediction or memory.
Conversely, the basal ganglia could aid

steady fixation by preventing unwanted
reflexive saccades to stimuli which, at that
particular moment, would be disruptive.
The means by which the frontal eye fields
influence the superior colliculus is com-
plex and might produce difficulties in ei-
ther initiating or suppressing saccades.
For example, both deficits have been de-
scribed in patients with disorders affecting
the basal ganglia, such as Huntington's
disease.230
Ccrebellar Contribution
to Saccades
A major projection from the cortical eye
fields is to the cerebellum, via the pontine
nuclei (Fig. 3-8). In addition, several im-
portant saccade-related structures in the
brain stem project to the cerebellum. A
role for the cerebellum in the control
of saccades has been suspected since
Hitzig191 and Ferrier124 elicited eye move-
ments by electrical stimulation. And clini-
cians since Holmes192 and Cogan68 have
associated saccadic dysmetria and gaze-
evoked nystagmus with cerebellar lesions.
Although more than one cerebellar area
contributes to the programing of saccades,
the dorsal vermis and caudal fastigial nu-
cleus play key roles. The cerebellar hemi-
spheres may also contribute to the control
of saccades (Fig. 3-10), but their role has
yet to be defined; the same is true of the
basal interstitial nucleus.416b Before re-
viewing these areas, we will first examine
the role of a pontine nucleus that is a ma-
jor relay for saccadic commands to the
cerebellum.
NUCLEUS RETICULARIS
TEGMENTI PONTIS
The NRTP, which lies ventral to the rostral
PPRF (see Fig. 6-3), contains neurons that
discharge in relation to a variety of
eye movements, including saccades.77 Its
medial portion receives inputs from
the frontal and supplementary eye
fields.387-404 The caudal part of NRTP re-
ceives inputs from the superior collicu-
lus.148 Portions of the NRTP project to
The Vestibular-Optokinetic System 121
Figure 3-10. Activity of the cerebellum during a sac-
cadic task as revealed by functional magnetic reso-
nance imaging (fMRI). The subject was making vol-
untary, self-paced saccades between two visible
targets. There is increased metabolic activity in the
midline cerebellum (dorsal vermis and underlying
fastigial nuclei) and also in the cerebellar hemi-
spheres. Similar activation occurred if saccades were
made in darkness between remembered target loca-
tions. (Courtesy Dr. Manabu Honda of Kyoto,
Japan.)
the dorsal vermis and caudal fastigial nu-
cleus.282'455 The NRTP contains long-lead
burst neurons, which project to the cere-
bellum and PPRF.375 Neurons in the cau-
dal NRTP show similarities to collicular
burst neurons, encoding the size and di-
rection of saccades. However, unlike col-
licular neurons, they encode the three-
dimensional eye displacement vectors.430
Neurons in NRTP differ from those in
riMLF by encoding both directions of tor-
sional movement on each side of the brain
stem. Microstimulation in NRTP elicits
movements with an ipsilateral component
that has a fixed torsional component. In-
activation of NRTP with muscimol caused
torsional "errors," implying that NRTP
normally ensures that saccadic eye move-
ments obey Listing's law.430 The influence
of NRTP on the three-dimensional control
of eye movements may depend on its cere-
bellar projections.389 The medial portion
of the NRTP contains cells that discharge
in relation to vergence movements (see
Chap. 8). The rostral portion of the NRTP
122 The Properties and Neural Substrate of Eye Movements
contains neurons with pursuit-related ac-
tivity (see Chap. 4).
ROLE OF THE DORSAL VERMIS IN
SACCADE GENERATION
The ocular motor vermis consists of lob-
ules VI and VII (parts of the declive,
folium, tuber, and pyramis); its anatomical
connections are summarized in Display
6-12.455 Purkinje cells in the dorsal vermis
discharge about 15 msec before saccades
in a preferred direction.170-289 Stimulation
of the vermis produces saccades with an
ipsilateral component;342 with currents
near to threshold, a topographic organiza-
tion is evident.280 Stimulation of vermal
lobule V evokes saccades that range from
upward to horizontal, whereas stimulation
of lobules VI and VII evokes saccades that
range from horizontal to downward. The
vertical component of the elicited saccade
is larger when stimulation is more medial.
Saccadic direction is largely dictated by
the anatomic location of stimulation in the
cerebellum, just as it is in the frontal eye
fields and in the superior colliculus. In
contrast to the latter structures, however,
saccades evoked by cerebellar stimulation
are graded in amplitude and, to a minor
extent, direction, as a function of stimulus
intensity. Furthermore, the amplitude of
the elicited saccade and the amount of
postsaccadic drift depend upon the initial
position of the eye in the orbit.
If the vermis is stimulated while the
monkey is making a naturally occurring
saccade, the saccade trajectory is modified
more than if stimulation is applied during
fixation.217 This implies that the cerebel-
lum may be directly involved in modulat-
ing, on-line, the amplitude of an individ-
ual saccade. Furthermore, if an animal's
eyes are perturbed by cerebellar stimula-
tion just prior to the generation of a vol-
untary saccade to a visual target, the ensu-
ing saccade does not land on target.150-281
This is unlike the corrective movements
that occur when the frontal eye field354 or
the superior colliculus398 are stimulated
just prior to a saccade.
Unilateral pharmacological decortica-
tion of the dorsal vermis with bicuculline
causes marked ipsilateral hypometria and
mild contralateral hypermetria, with a
gaze deviation away from the side of the
inactivation (see Display 10-19).35° Abla-
tive lesions of the dorsal vermis also cause
saccadic dysmetria that is mainly hypome-
tria.416 The dysmetria concerns the sac-
cadic pulse, and there is no postsaccadic
drift, as is seen after ablation of the cere-
bellar flocculus and paraflocculus463 or to-
tal cerebellectomy.296 Symmetrical lesions
cause bilateral hypometria of horizontal
saccades, with a slight increase in saccadic
latency. Asymmetrical lesions cause hy-
pometria and increased latency of ipsilat-
eral saccades, so that express and anticipa-
tory saccades are abolished. Centrifugal
movements tend to be smaller and made
at longer latency than centripetal move-
ments. The dynamic characteristics of sac-
cades are also affected, with abnormal
waveforms and decreased speed during
both the acceleration and deceleration
phases; these changes are not dependent
on the starting position of the eye in the
orbit. Finally, the ability to adapt saccades
to visual demands is impaired by lesions of
the dorsal vermis.416'4163 These defects can
be better understood by considering the
role of the fastigial nucleus, to which
Purkinje cells from the dorsal vermis pro-
ject.
ROLE OF THE FASTIGIAL
NUCLEUS IN
SACCADE GENERATION
In addition to receiving inputs from Purk-
inje cells of the dorsal vermis, the caudal
part of the fastigial nucleus, the fastigial
oculomotor region (FOR), also receives a
copy of the saccadic commands, which are
relayed by NRTP from the frontal eye
fields and superior colliculus.282 The main
projection from the fastigial nucleus
crosses within the cerebellum and enters
via the uncinate fasciculus, which runs in
the dorsolateral border of the brachium
conjunctivum, to reach the brain stem.
The main projections of the caudal fasti-
gial nucleus are the omnipause neurons;
burst neurons in the medulla, pons and
midbrain, and the mesencephalic reticular
formation; and the rostral pole of the su-
perior colliculus.246 Some of these connec-
 The Vestibular-Optokinetic System 123

tions are summarized in Display 6-13 and
in Figure 3-11.
Neurons in the caudal fastigial nucleus
discharge about 8 msec prior to onset of
saccades with contralateral components,
but generally toward the end of saccades
with ipsilateral components.137'171'288 These
neurons modulate their discharge accord-
ing to horizontal, vertical, and torsional
components of saccades.389 Most such
units show a burst duration that is corre-
lated with saccade size, but not with eye
position at the onset of the saccade. Under
normal circumstances, the fastigial nu-
cleus might influence saccades by provid-
ing an early drive to burst neurons during
contralateral saccades and a late brake or
choke during ipsilateral ones.137 These
ideas are summarized in Figure 3-11.
Fastigial nucleus lesions produce marked
hypermetria of saccades.379'380 Destructive
lesions tend to be bilateral because axons
destined for the brain stem cross within
the fastigial nucleus itself. A more effective
way of demonstrating the contribution of
the fastigial nucleus to saccade generation
has been to use muscimol to pharmacolog-
ically inactivate the caudal fastigial nu-
cleus on one side (see Display 10-19,
Chap. 10).341 A unilateral injection causes
hypermetria of ipsilateral saccades (typical
gain 1.3) and hypometria of contralateral
saccades (typical gain of 0.7). The acceler-
ation of ipsilateral saccades is increased
and that of contralateral saccades is de-
creased. Hypermetria is slightly greater
for centripetal (centering) saccades than
centrifugal saccades. With bilateral injec-

Figure 3-11. Hypothetical scheme for the role of the cerebellum in the generation of saccades. The superior col-
liculus (and probably the frontal eye field) provides a neural signal representing desired change in eye position
(AE), which is compared with an efference copy of current eye position (Eeff), to give motor error, the signal that
drives the premotor burst neurons (EBN). The superior colliculus (rostral pole) also provides the trigger signal
to initiate the saccade, which inhibits omnipause neurons (OPN), which then stop inhibiting EBN. The EBN
project to inhibitory burst neurons (IBN), which act as a latch circuit to stop OPN from discharging until the
end of the saccade (when motor error is zero). The output of EBN and IBN constitute the saccadic command,
which projects to ocular motoneurons. To generate Eeff, the output of EBN (and IBN, not shown) must be inte-
grated (Resettable NI) and adjusted to account for non-linearities due to the orbital contents ("Plant"). The dor-
sal vermis and fastigial ocular motor region (FOR) receive inputs from the pontine nuclei, such as NRTP, and
climbing fiber inputs from the inferior olive (not shown). The dorsal vermis inhibits the FOR, which projects to
several elements of the brain stem saccade generator (broken lines), including EBN, IBN, and OPN. In an alter-
native scheme, the dorsal vermis and FOR could lie within the saccadic feedback loop.
124 The Properties and Neural Substrate of Eye Movements
tions, all saccades, both horizontal and
vertical, become hypermetric. 341 Vertical
saccades show ipsipulsion with unilateral
fastigial nucleus lesions and contrapulsion
with unilateral vermal lesions.
The findings after unilateral fastigial
nucleus inactivation are similar to the lat-
eropulsion encountered in Wallenberg's
syndrome (lateral medullary infarction)
(see VIDEO: "Wallenberg's syndrome"). It
has been postulated that in that disorder,
interruption of olivocerebellar climbing
fibers within the lateral medulla causes in-
creased activity of Purkinje cells in the
contralateral dorsal vermis which in turn
inhibit the underlying fastigial nucleus.439
EFFECTS OF TOTAL
CEREBELLECTOMY ON SACCADES
Complete cerebellectomy in trained mon-
keys creates an enduring saccadic pulse
dysmetria.296 In this case, all saccades
overshoot, although the degree of over-
shoot is greatest for centripetally directed
movements. The degree of saccadic hy-
permetria may be so great that the animal
shows repetitive hypermetric saccades about
the position of the target, a form of
macrosaccadic oscillations. Monkeys with
a complete removal of the cerebellum also
show postsaccadic drift, implying pulse-
step mismatch dysmetria. At the end of the
rapid, pulse portion of the saccade, the
eyes drift on as a glissade for a few hun-
dred milliseconds toward the final eye po-
sition. As noted above, saccadic pulse dys-
metria can be attributed to involvement of
the dorsal vermis and fastigial nuclei
whereas postsaccadic drift reflects involve-
ment of the vestibulocerebellum (flocculus
and paraflocculus). 298 Thus, the dorsal
cerebellar vermis and underlying fastigial
nuclei appear to function in controlling
the size of the saccadic pulse, while the
flocculus and paraflocculus seem to be re-
sponsible for appropriately matching the
saccadic step to the pulse.
In sum, the cerebellum appears to be
important for the control of saccadic accu-
racy, dynamics and trajectory and possi-
bly in correcting for position-dependent
changes in the mechanical properties of
the eye muscles and orbital tissues. This
capability appears to function both in an
on-line fashion, since cerebellar dysmetria
is apparent immediately after inactivating
the fastigial nuclei, as well as in the long
term, as part of the process of adaptive
control of saccade accuracy. A hypothetical
scheme of the role of the cerebellum in the
control of saccades is presented in Figure
3-11. The FOR is shown to project to and
control the activity of burst neurons, om-
nipause neurons, and the local saccadic
feedback loop. An alternative scheme is
that the cerebellum actually lies in the
feedback loop that controls the discharge
of premotor burst neurons and con-
tributes to the resettable integrator.2323'322
This pivotal role of the cerebellum in the
control of saccades is supported by find-
ings that neither frontal eye field nor su-
perior colliculus lesions alone cause en-
during changes in saccadic metrics; in
each case, another area must be comput-
ing the size and dynamics of saccades, and
the cerebellum seems the likely candidate.
Adaptive Control of
Saccadic Accuracy
SACCADIC ADAPTATION
FOLLOWING OCULAR
MOTOR PALSY
The first reports of adaptation in the sac-
cadic system concerned patients with par-
tial abducens nerve palsies who preferred
to view objects using their paretic eye for
fixation because it had better vision.221
With the affected eye viewing, saccades
made by the paretic eye were accurate (or-
thometric) even in the direction of the
muscle weakness. The saccades of the non-
paretic eye, on the other hand, were much
larger and had postsaccadic drift. With the
paretic eye covered and the "normal" eye
viewing, the saccades of the nonparetic
eye both overshot the target and showed
postsaccadic drift. In other words, sac-
cadic innervation had been readjusted (to
both eyes, which is consistent with Her-
ing's law of equal innervation) in an at-
tempt to improve the performance of the
habitually fixating but paretic eye. Both
the pulse amplitude and the pulse-step

match dysmetria created by the palsy had
been repaired. The investigators then
patched the paretic eye of their patients
continuously, requiring them to use their
nonparetic eye. When examined after 3
days, the patients had readjusted the am-
plitude of the saccadic pulse and the
pulse-step match so that saccades made by
the nonparetic eye became orthometric.
In other words, the central nervous sys-
tem changed saccadic innervation in order
to meet best the visual needs of the habitu-
ally viewing eye.
It was subsequently shown that the
change in saccadic amplitude was accom-
plished by prolonging the duration of the
saccadic pulse alone, without an increase
in its height.3-200 If pulse height had in-
creased, the peak velocity of saccades
made by the normal eye would have in-
creased; but it did not. Moreover, the
adaptive changes were specifically tailored
to the mechanical needs dictated by the
particular orbital positions from and to
which the saccade was to be made.297 An-
other clinical example of this adaptive ca-
pability concerns patients with internu-
clear ophthalmoplegia, who often show
saccadic overshoot and backward postsac-
cadic drift in the abducting eye. This ab-
duction nystagmus may be accounted for
in some patients by the same mechanism
that adjusts innervation conjugately in re-
sponse to a peripheral muscle palsy.101'460
Further discussion on saccadic changes in
paralytic strabismus is given in Chapter 9.
EXPERIMENTALLY INDUCED
SACCADIC ADAPTATION
In normal subjects, saccadic pulse dysme-
tria can be simulated by changing the po-
sition of the target just before the eye
reaches it, forcing the subject to make a
corrective saccade after every target jump.
After as few as 150 such trials, subjects au-
tomatically make saccades that are bigger
or smaller, depending on the particular
nature of the induced dysmetria.8'91'381'409
This is the case even though subjects may
not perceive the small movements of the
target that are made during each saccade
(see Spatial Constancy Following Saccadic
Gaze Shifts, above). Such adaptation is
The Vestibular-Optokinetic System 125
specific to the stimulus conditions; adapta-
tion for movements in one direction does
not automatically lead to adaptation in an-
other.85 When adaptation is required for
just one size of saccade, movements of
other sizes are much less adapted. 411
Moreover, if saccades are adapted with
one type of stimulus, the modified sac-
cadic behavior may not be present with
another. It is not the visual features of the
stimulus, such as color, that influence the
learning process, but the nature of the
saccadic response.88 Thus, saccadic gain
adaptation induced by step movements of
a single target does not transfer to sac-
cades made during scanning of an array of
targets or to remembered locations of sin-
gle targets.87 On the other hand, adapta-
tion achieved during scanning an array of
targets transfers to memory-guided sac-
cades, but not to step movements of a sin-
gle target.87 Furthermore, adaptation of
memory-guided saccades does not trans-
fer to saccades during scanning or to sin-
gle-target jumps. Saccades induced by
electrical stimulation of the superior col-
liculus in monkeys can be adapted if a vi-
sual stimulus is presented at a location dif-
ferent from where the eye movement
ended.254 This adaptation shows incom-
plete transfer to normal visually guided
saccades, suggesting the need for involve-
ment of cortical areas in normal adapta-
tion of saccades to single-target jumps.
How can these properties of saccadic
adaptation be explained? Although results
from adaptation experiments in monkeys
may differ,136-373 the transfer of adaptation
from one type of saccade in human is spe-
cific and has suggested a hypothesis based
on current notions of the control of
saccades.88 Thus, memory-guided saccadic
adaptation may depend on dorsolat-
eral prefrontal cortex, scanning saccades
adaptation on the frontal eye field, and
saccades to target jumps on the parietal
eye field and superior colliculus. This hy-
pothesis could be tested by studying sac-
cadic adaptation in patients with discrete
cortical lesions and provides a new tool for
clinicians to investigate the cerebral con-
trol of saccades.87 A model accounting for
the way that the superior colliculus con-
tributes to saccadic adaptation, by changes
126 The Properties and Neural Substrate of Eye Movements
in the nature of the spreading of activa-
tion, has also been proposed.156
A pulse-step match dysmetria can be
simulated by making a large, projected vi-
sual stimulus drift briefly after every sac-
cade. Both humans and monkeys soon
learn to preprogram a postsaccadic drift
of the eyes, by creating a pulse-step mis-
match, that nearly matches the artificial
motion of the visual scene.210'294
Other aspects of saccadic adaptation
that occur following abducens nerve palsy
are discussed in Adaptive Changes of Eye-
Head Saccades in Chapter 7, Disconjugate
Adaptation in Chapter 8, and Saccades in
Paralytic Strabismus in Chapter 9.
NEURAL SUBSTRATE FOR
SACCADIC ADAPTATION
Which structures in the central nervous
system participate in the adaptive control
of saccadic accuracy? This has been stud-
ied experimentally in monkeys who have
extraocular muscle weakness created by
surgical tenectomy or section of an ocular
motor nerve. Experimental cerebellectomy
completely abolishes the adaptive capabil-
ity—for both the pulse size and the pulse-
step match.296 Monkeys with lesions re-
stricted to the dorsal cerebellar vermis
cannot adapt the size of the saccadic pulse;
they have pulse-size dysmetria.416'416a On
the other hand, monkeys with floccular le-
sions cannot match the saccadic step to the
pulse to eliminate pulse-step mismatch
dysmetria.298 This evidence suggests that
the repair of conjugate saccadic dysmetria
is mediated by two different cerebellar
structures: the dorsal cerebellar vermis
and the fastigial nuclei control pulse size,
and the flocculus and paraflocculus control
the pulse-step match. Does the cerebellar
contribution to saccadic adaptation extend
to all types of saccades? One patient with
a midline cerebellar hemangioblastoma
showed greater hypermetria for saccades
made to single-target presentations than
during saccadic scanning of a display of
targets.410 Further work is required to de-
termine whether the cerebellum is more
concerned with adaptation of externally
cued than internally generated saccades.
The dorsal vermis and fastigial nucleus
may also participate in the repair of dis-
conjugate saccadic dysmetria, since pa-
tients with cerebellar disease show discon-
jugacy of saccades,434 and experimental
inactivation by cooling of the fastigial nu-
cleus causes disconjugate dysmetria.436 Al-
though visual signals are probably most
important in providing the error signal
that drives disconjugate saccadic adapta-
tion, extraocular proprioception also con-
tributes. Thus, monkeys deprived of pro-
prioceptive information by section of the
ophthalmic branch of the trigeminal nerve
show abnormalities in disconjugate adap-
tation after surgically induced CN IV
palsy.236
SACCADES AND MOVEMENTS
OF THE EYELIDS
The study of eyelid movements is a bur-
geoning field, and the reader is referred
to recent reviews of normal and abnormal
control.14'120'369 Here we focus on two as-
pects: the coordination of vertical saccades
and eyelid movements, and the effects of
blinks on saccades. The interaction of four
separate forces determines the position
of the eyelids. Upward forces are mainly
due to the levator palpebrae superioris
(LPS),117 with Miiller's smooth muscle,
which bridges the LPS and its tendon,
making a minor contribution. Downward
forces are due to stretching of tendons
and ligaments connected to the LPS, and
the orbicularis oculi muscle.117
The eyelids closely follow vertical gaze
shifts, including saccades. Thus, eye and
lid saccades show similar dynamic proper-
ties.28'123-159 Upward lid saccades are due
to a burst of activity in the LPS muscle and
its motoneurons,135 which lie in the un-
paired, central caudal nucleus of the ocu-
lomotor nuclear complex (see Fig. 9-9,
Chap. 9). Downward lid saccades are due
entirely to elastic forces, which close the
eye when the LPS relaxes. The orbicularis
oculi muscle is electrically silent except
during blinks or voluntary lid closure.
Thus, neural coordination of vertical gaze
and lid position is due to a synkinesis
between the vertically acting extraocu-
lar muscles and the LPS. How is this
achieved? The main elevator of the eye,
 The Vestibular-Optokinetic System 127

the superior rectus, has a common embry-
ology to LPS and these two muscles are
connected by a common sheath of inter-
muscular fascia. However, the muscles are
structurally different, and their motoneu-
rons lie in distinct subnuclei of the ocu-
lomotor nucleus. It appears that a key
structure in the coordination of vertical
saccades is the M-group of neurons, which
lie adjacent, medial, and caudal to riMLF,
and project to both the elevator subnuclei
of the eye (superior rectus and infe-
rior oblique) and the motoneurons of
Lps.54,56,i96a The M-group receives inputs
from the riMLF and superior colliculus
and has reciprocal connections with the
nucleus of the posterior commissure.
Thus, in patients who have dissociation of
lid-eye movement during vertical saccades
(i.e., impaired lid saccades in the presence
of preserved eye saccades), the M-group
or the nucleus of the posterior commis-
sure is likely to be involved.
Blinks typically occur 20 times per
minute. During a blink, a burst of activity
occurs in the normally quiescent orbicu-
laris oculi muscle, while at the same time,
tonic activity in the levator palpebrae
ceases.121 How do they affect eye move-
ments? If blinks are made during fixation

Figure 3-12. Effect of blinks on rightward saccades from one normal subject. Position records are shown above
and corresponding velocity traces below. Note that peak velocities are smaller, for similar sized saccades, when
the subject blinks with the saccade. Also note that dynamic overshoots, opposite-directed (DO) postsaccadic
movements, occur more frequently with blinks. LH, left horizontal position; LHV, left horizontal velocity; RH,
right horizontal position; RHV, right horizontal velocity. (Courtesy of Klaus G. Rottach.)
128 The Properties and Neural Substrate of Eye Movements
of a stationary target, the eyes transiently
move down and toward the nose;75 such
movements are slower than saccades and
are due to a cocontraction of all extraocu-
lar muscles except the superior oblique
muscle.122 Blinks are often made with sac-
cades; the probability of a blink oc-
curring increases with the size of the
gaze shift. 122 - 123 Blinks cause substantial
changes in the dynamic properties of hor-
izontal saccades, decreasing peak velocity
and increasing duration.347 These changes
are unlikely to be due to a summation of
the down-and-inward movement pro-
duced by blinking and the saccade, since
there is no direction preponderance in
the slowing of saccades. Furthermore, sac-
cades made with blinks show an increased
incidence of dynamic overshoots (Fig.
3-12).347 One possible explanation for this
finding is that omnipause neurons are
silent during both blinks and saccades,
and if the blink outlasts the saccade, the
eyes might briefly oscillate around the
new eye position as a dynamic overshoot.
Patients with opsoclonus or ocular flutter
may show oscillations during blinks161'177
or during eyelid closure (see VIDEO: "Op-
soclonus"). Another, paradoxical finding
is that blinks may speed up abnormally
slow saccades in patients with degenera-
tive or other diseases.458 In this case, the
blink may cause a more synchronized and
complete inhibition of the omnipause
neurons, thus allowing the burst neurons
a better chance to discharge. This may
also be the mechanism that patients with
ocular motor apraxia employ (along with
a head movement) to initiate a saccade
(see VIDEO: "Acquired ocular motor
apraxia"). Whatever the mechanism, it is
clear that studies of saccades must take
into account the occurrence of blinks,
which may substantially affect these eye
movements.
EXAMINATION OF SACCADES
Clinical Examination of Saccades
Saccadic eye movements are best exam-
ined at the bedside by instructing the pa-
tient to fixate alternately upon two targets,
such as the tip of a pen and the examiner's
nose. Saccades in each direction can be ex-
amined in each field of gaze in both the
horizontal and vertical planes. The exam-
iner should determine the following: Are
saccades of normal velocity? Are they
promptly initiated? Are they accurate? Do
the eyes move together? (see Appendix A
for a summary).
Saccadic slowing, such as the lag of the
adducting eye in internuclear ophthalmo-
plegia, can be best appreciated when the
patient is instructed to rapidly refixate be-
tween two widely spaced targets (see
VIDEO: "Unilateral internuclear ophthal-
moplegia"). Another useful technique to
detect slow adduction is with a hand-held
optokinetic drum or tape.393 Quick phases
made by the affected eye are smaller and
slower. If slowing of saccades occurs in
only one plane of movement, it can be eas-
ily appreciated when the patient makes
saccades between obliquely placed targets.
The rapid, normal component is com-
pleted before the slower, orthogonally di-
rected component, so that the saccade tra-
jectory is strongly curved (Fig. 3-3B).
Saccade latencies can be appreciated by
noting the time it takes the patient to initi-
ate the saccade. Saccadic dysmetria can be
inferred by the direction and size of cor-
rective saccades made to acquire the fixa-
tion target (see VIDEO: "Saccadic hyperme-
tria"). Since small saccades (as little as Vz
degree) can be detected by careful obser-
vation, saccadic dysmetria can be easily
observed clinically at the bedside. Normal
individuals may undershoot the target by
a few degrees when refixations are large,
and saccadic overshoot may occur nor-
mally for centripetal and especially down-
ward saccades. This tendency toward
downward overshoot in normals may also
appear when making horizontal refixa-
tions, when a slight downward compo-
nents necessitates an upward corrective
saccade. The dysmetria should disappear
with repetitive refixations between the
same targets.
If a saccade abnormality is detected, the
strategy is to localize the disturbance
within the hierarchical organization of
the saccadic eye movement system (Table
3-1). First, establish whether more reflex-

ive types of saccades are affected by the
disease process. Quick phases can be ex-
amined by spinning the patient in a swivel
chair to elicit vestibular nystagmus or by
using an optokinetic drum to elicit optoki-
netic nystagmus. Loss of quick phases usu-
ally points to a brain stem process af-
fecting premotor burst neurons. Next,
examine the ability of the patient to make
a saccade to a suddenly appearing visual
target. Determine if saccades can be made
without a visual target or in response to
auditory targets, or by asking the patient
to refixate under closed lids or behind
Frenzel goggles. Loss of voluntary sac-
cades with preservation of reflexive sac-
cades and quick phases is characteristic of
acquired ocular motor apraxia. One can
also test the ability to make more volitional
types of saccades by asking the patient to
make saccades rapidly, back and forth, be-
tween two stationary targets. Likewise, the
ability to make predictive saccades can be
assessed by asking the patient to change
fixation when the examiner holds both
hands up and then, with predictable tim-
ing, moves first a finger on one hand as a
signal to make a saccade and then a finger
on the other. By occasionally not moving
one finger, the examiner can determine if
the patient makes the predictive saccade
without a visual stimulus. Defects of pre-
dictive saccadic control are common in
Parkinson's disease. One can even elicit
antisaccades at the bedside. The examiner
holds both hands up and asks the patient
to look to the finger that does not move.81
Errors on the antisaccade task, with sac-
cades toward the visual stimulus, are en-
countered with disease affecting the pre-
frontal cortex.
If saccade initiation seems impaired, ob-
serve gaze changes when the patient makes
a combined eye-head movement to see if
an accompanying head movement can fa-
cilitate the production of a saccade. This
strategy is employed by some patients with
ocular motor apraxia. The effect of blinks
should also be noted since they may fa-
cilitate the ability to initiate saccades,234
speed up slow saccades,458 or induce sac-
cadic oscillations.161'177 Finally, the effects
of fatigue upon saccadic eye movements,
for example, in myasthenia gravis, may be
The Vestibular-Optokinetic System 129
tested by asking the patient to repetitively
refixate between two targets.
During attempted steady fixation, ex-
traneous saccadic eye movements (saccadic
intrusions, which imply impaired ability to
suppress saccades) should be noted. Sub-
tle degrees of abnormal fixation behavior
can be best appreciated during ophthal-
moscopy. The motion of the optic nerve
head of one eye is observed as the patient
attempts to fixate a target with the other.
Measurement of Saccadic
Eye Movements
While many abnormalities of saccadic ve-
locity, initiation, and accuracy can be easily
appreciated at the bedside, more subtle
changes can be detected only by analysis
of eye movement recordings. To obtain re-
liable recordings of saccade trajectories,
one needs to have a measuring system
with a high bandwidth (preferably >100
Hz, which requires a digitization rate of at
least 200 Hz) and which reproduces faith-
fully the saccade trajectory. The search
coil and corneal reflection techniques usu-
ally meet these requirements (see Appen-
dix B). Electro-oculography (EOG), how-
ever, induces a number of artifacts in the
eye movement trace due to movement of
the lid, movement of the opposite eye, and
a muscle action potential spike at the onset
of the saccade.95 With EOG, the speed of
abducting saccades appears to be lower
than that of adducting saccades, although
recordings with search-coil and infrared
reflection techniques indicate that the op-
posite is actually the case. EOG is unreli-
able for measurement of vertical saccades.
Saccadic gain (saccade amplitude/target
amplitude) is the usual measure of sac-
cadic accuracy. Saccadic amplitude is usu-
ally defined by the position of the eye at
the start of the saccade and the position of
the eye when the saccadic pulse is fin-
ished. (Conventionally, saccade onset is
defined by the rise of eye velocity to some
arbitrary value, often 30°/sec, and saccade
pulse offset is defined by the dropping of
eye velocity below that value.) Saccadic
gain should be tested using both station-
130 The Properties and Neural Substrate of Eye Movements
ary and moving targets since lesions in the
posterior cerebral hemisphere may pro-
duce a specific deficit in saccade accuracy
for moving targets.277 The most common
measurements of saccadic dynamics are
peak velocity and duration; both are con-
ventionally plotted as a function of ampli-
tude (Fig. 3-1). In addition, the skewness
of the trajectory—the ratio of time-to-peak
velocity to total saccadic duration—is
sometimes helpful. Postsaccadic drift, the
unusual waveforms observed in myasthe-
nia gravis, and some types of ocular oscil-
lations are examples of saccadic abnor-
malities that are best detected with eye
movement recordings. Recordings of eye
movements are essential if one wants to
analyze carefully quick phases of vestibu-
lar nystagmus induced in darkness, sac-
cades made to auditory targets, and sac-
cades made in combination with head
movements. Comparison of latencies of
saccades made in different behavioral con-
texts (e.g., antisaccades, predictive sac-
cades, saccades on command) also re-
quires quantitative measurements of eye
movements.
Even though certain properties of sac-
cades, such as peak velocity, are relatively
machine-like, such measures are influ-
enced by a number of experimental fac-
tors and possibly by the age of the patient.
It is therefore essential to compare mea-
surements in any patient with 95% confi-
dence limits defined by an age-matched
control group during similar testing in
that laboratory.
PATHOPHYSIOLOGY OF
SACCADIC ABNORMALITIES
The clinical disorders that cause saccadic
abnormalities are described in Chapter
10. Here our review aims to apply current
knowledge about the normal generation
of saccades to present a scheme for think-
ing about saccadic abnormalities. From a
pathophysiological point of view, abnor-
malities of saccades can be classified as sac-
cadic pulse dysmetria, saccadic step dys-
metria, or saccadic pulse-step mismatch
(Fig. 3-13). For example, a change in the
amplitude (size; approximately, width
times height) of the saccadic pulse creates
overshoot or undershoot (saccadic dysme-
tria); a decrease in the height of the sac-
cadic pulse, which reflects discharge fre-
quency, causes slow saccades; a mismatch
between the saccadic pulse and step cre-
ates postsaccadic drift or glissades; and if
the saccadic step cannot be sustained, the
eye drifts toward the central position at
the end of each eccentric saccade, creat-
ing gaze-evoked nystagmus. In addition,
there may be disturbance of the voluntary
initiation or suppression of saccades.
Disorders of Saccadic Velocity
Saccades are usually defined as being
too slow or too fast if their peak velocities
fall outside the normal peak velocity-
amplitude relationship (main sequence).
Small-amplitude saccades that appear to
be too fast usually occur when a saccade is
interrupted in mid-flight, such that its fi-
nal intended position is not reached.
These are characteristic of myasthenia
gravis (see VIDEO: "Myasthenia gravis").24'293
Thus the saccade, rather than being too
fast, is actually too small; this, in effect, in-
creases its peak velocity-amplitude rela-
tionship. Abnormalities in the orbit, such
as tumors, that restrict the motion of the
globe in certain orbital positions can also
lead to these seemingly fast saccades. Sac-
cades that are faster than normal have
been reported in some patients with sac-
cadic oscillations such as flutter and opso-
clonus (see VIDEO: "Opsoclonus")33 and in
some patients who are stutterers.100
Slow saccades of restricted amplitude
usually reflect abnormalities in the ocular
motor periphery, such as an ocular muscle
or ocular motor nerve paresis, or in the
MLF, such as the slow adduction of in-
ternuclear ophthalmoplegia (see VIDEO:
"Unilateral internuclear ophthalmople-
gia"). Slow saccades occurring when the
ocular motor range is full are usually
caused by central neurologic disorders,
which are summarized in Table 10-15 (see
VIDEO: "Slow horizontal saccades"). Possi-
bilities include direct disruption in the
brain stem neural networks generating
 The Vestibular-Optokinetic System 131

Figure 3-13. Disorders of the saccadic pulse and step. Innervation patterns are shown on the left, eye move-
ments on the right. Dashed lines indicate the normal response. (A) Normal saccade. (B) Hypometric saccade:
pulse amplitude (width X height) is too small but pulse and step are matched appropriately. (C) Slow saccade:
decreased pulse height with normal pulse amplitude and normal pulse-step match. (D) Gaze-evoked nystag-
mus: normal pulse, poorly sustained step. (E) Pulse-step mismatch (glissade): step is relatively smaller than
pulse. (F) Pulse-step mismatch due to internuclear ophthalmoplegia (INO): the step is larger than the pulse,
and so the eye drifts onward after the initial rapid movement.

the saccadic pulse, because of either in-
trinsic disturbances of burst neurons or
failure to recruit a portion of burst cells.
This latter problem could arise from a loss
of higher-level excitatory inputs to burst
cells or an abnormality in inhibition of
omnipause cells. If the omnipause cells
are at fault, slow saccades can be ex-
plained by desynchronization of the dis-
charge of burst neurons or by failure to
recruit a certain proportion of burst neu-
rons during the saccade. Thus, while it
was originally believed that slow saccades
due to central disorders were pathog-
nomonic of burst cell dysfunction, it
has become apparent that disturbances
of higher-level structures, including the
cerebral hemispheres420 and superior col-
liculus,188 can lead to saccade slowing.
Nonetheless, selective slowing of horizon-
tal saccades usually indicates pontine dis-
ease (PPRF), whereas slowing of vertical
saccades suggests upper midbrain dys-
function (riMLF; see VIDEO: "Vertical sac-
132 The Properties and Neural Substrate of Eye Movements
cadic palsy"). In patients with selective
slowing of horizontal or vertical saccades,
diagonal saccades often show a character-
istically curved trajectory (Fig. 3-3B).
Some patients with slow vertical saccades
show curved trajectories even during ver-
tical refixations (see VIDEO: "Niemann-
Pick type C disease"); this might be an
adaptive strategy that employs a normal
horizontal component to completely in-
hibit omnipause neurons and thus maxi-
mize the vertical component. In Gaucher's
disease, a similar curved trajectory loop-
ing upwards is seen in association with
slow horizontal saccades. Finally, it must
be remembered that saccadic velocities
may be lower in drowsy, inattentive, or
drug-intoxicated patients.206'368'418
Disorders of Saccadic Accuracy
Saccadic pulse dysmetria, especially hy-
permetria, is the hallmark of cerebellar
disease (see VIDEO: "Saccadic hyperme-
tria"). It also occurs in Wallenberg's syn-
drome as lateropulsion, or hypermetria of
ipsilateral saccades and hypometria of
contralateral saccades (see VIDEO: "Wallen-
berg's syndrome"). This pattern of dysme-
tria may be due to interruption of olivo-
cerebellar climbing fibers within the
inferior cerebellar peduncle, causing in-
creased activity of Purkinje cells in the ip-
silateral dorsal vermis which in turn in-
hibit the underlying fastigial nucleus.439
Thus, the ipsipulsion that characterizes
lateral medullary infarction may be equiv-
alent to a lesion of the ipsilateral fastigial
nucleus. In contrast, lesions of the supe-
rior cerebellar peduncle cause contrapul-
sion—hypermetria of contralateral sac-
cades and hypometria of ipsilateral
saccades. In this case, it is the crossed out-
put of the fastigial nucleus that is responsi-
ble. These findings are summarized in
Display 10-19 in Chapter 10.
Patients with extreme degrees of sac-
cadic hypermetria may show macrosac-
cadic oscillations, a series of hypermetric
saccades made about the position of the
target (see VIDEO: "Macrosaccadic oscilla-
tions"). Occasionally, saccadic hypermetria
reflects an adaptive response to a periph-
eral ocular motor deficit221'293 or occurs af-
ter edrophonium is given to a myasthenic
(see VIDEO: "Myasthenia gravis"). Saccadic
hypometria occurs with a variety of cere-
bellar and brain stem disorders. Postsac-
cadic drift, reflecting pulse-step match
dysmetria, has been reported in patients
with both central and peripheral ocular
motor disorders. Visual defects may also
lead to saccadic dysmetria. For example,
patients with hemianopia may make hy-
permetric and hypometric saccades (de-
pending on direction) to keep the target
within the intact part of the visual
field.250'252 Patients with lesions in poste-
rior parietal-temporal cortex may show
saccadic dysmetria specifically for moving
targets.233 Cerebral lesions may also di-
rectly affect saccade metrics. Unilateral
hemispheric lesions may lead to a biasing
of vertical saccades toward the side of the
lesion420 and patients with neglect, with or
without hemianopia, may make hypomet-
ric saccades away from the side of the le-
sion. 251
Disorders of Saccadic Initiation
Disorders of saccade initiation vary from
slight increases in saccadic reaction time,
which are not perceptible at the bedside,
to latencies greater than several seconds.
The variability of response may also be in-
creased. Allowances must be made for the
patient's age, state of consciousness, and
level of attention. Saccadic latencies are in-
creased in the presence of visual abnor-
malities66 and may also be increased due
to disorders of directing visual attention.
Patients with focal hemispheric lesions, es-
pecially those affecting the cortical eye
fields may show increased latencies. Bilat-
eral frontoparietal lesions produce a se-
vere defect of saccade initiation called ocu-
lar motor apraxia (see VIDEO: "Acquired
ocular motor apraxia"). Such patients may
be alert and cooperative but have im-
paired or delayed initiation of voluntary
saccades, despite normal frequency of ran-
dom saccades and quick phases of nys-
tagmus.
Patients with basal ganglionic disease
such as Huntington's disease show a char-

acteristic abnormality of saccadic initiation
(see Display 10-32, Chap. 10). Single sac-
cades made in response to the sudden ap-
pearance of a visual target, or reflexive
saccades, are performed relatively nor-
mally with appropriate latencies and
amplitudes. More volitional saccades,
however, are impaired. Patients with
Huntington's disease show a greater in-
crease in latency for initiating saccades on
command than for more reflexive sac-
cades to novel visual stimuli.230
Patients with diffuse hemispheric dis-
ease may show impaired ability to antici-
pate the location of a target moving in a
predictable fashion.218 Some patients, for
example, with Alzheimer's disease or
schizophrenia may show excessive antici-
pation when the location but not the tim-
ing of the target is predictable.197 Finally,
in certain circumstances, saccadic latencies
may actually be decreased, for example,
in progressive supranuclear palsy (PSP),
in which the superior colliculus and
brain stem reticular formation may be in-
volved.316
Inappropriate Saccades
(Saccadic Intrusions)
Saccades are inappropriate if they inter-
fere with foveal fixation of an object of in-
terest. Normally, subjects can suppress
saccades during steady fixation. Saccadic
intrusions are inappropriate saccades that
take the eye away from the target during
attempted fixation (see Display 10-14 and
Fig. 10-15, Chap. 10). They occur sponta-
neously, without the appearance of a novel
visual stimulus. They should be differenti-
ated from excessive distractibility, in which
novel visual targets that are behaviorally
irrelevant evoke inappropriate saccades.
Excessive distractibility can be demon-
strated in the antisaccade task. When in-
structed to make a saccade in the direction
opposite that of a visual stimulus, patients
with Huntington's disease, Alzheimer's
disease, schizophrenia, and frontal lobe le-
sions make an inappropriate saccade to
the visual target (see Fig. 10-31, Chap.
10) 131,138,158,230,315
The Vestibular-Optokinetic System 133
Several types of saccadic intrusions are
recognized (Display 10-36, Chap. 10). At
one end of the spectrum are square-wave
jerks, or involuntary saccades that take the
eyes off the target and are followed after a
nearly normal intersaccadic interval (130
to 200 msec) by a corrective saccade that
brings the eyes back to the target (see
VIDEO: "Square-wave jerks"). They may
occur in normal individuals but also in a
variety of neurologic disorders, most
prominently, cerebellar disorders and
progressive supranuclear palsy. In these
disorders, it is possible that the normal fix-
ation mechanism, which may exert its ef-
fect through the rostral pole of the supe-
rior colliculus, is at fault. In this context, it
is relevant that the fastigial nucleus pro-
jects to the rostral superior colliculus246
and that the superior colliculus is often in-
volved by progressive supranuclear palsy.
Another form of saccadic intrusion is
macrosaccadic oscillations (see VIDEO:
"Macrosaccadic oscillations"). These may
be an extreme form of saccadic hyperme-
tria and are encountered in cerebellar dis-
ease that involves the fastigial nucleus or
its output, 380 but they are also reported
with discrete pontine lesions that involved
the region of the omnipause neurons. 15
At the other end of the spectrum of sac-
cadic intrusions are back-to-back horizon-
tal saccades without an intersaccadic inter-
val. If such oscillations occur only in the
horizontal plane, they are termed ocular
flutter; if they occur in all directions, the
oscillation is called opsoclonus (see VIDEO:
"Opsoclonus"). Some normal individuals
can generate brief bursts of horizontal sac-
cadic oscillations (voluntary nystagmus;
see VIDEO: "Voluntary nystagmus"). Dis-
eases associated with flutter and opso-
clonus also often cause brain stem and
cerebellar findings. Such oscillations prob-
ably reflect an inappropriate, repetitive,
alternating discharge pattern of different
groups of burst neurons. It was originally
proposed that three factors contributed to
saccadic oscillations without an intersac-
cadic interval: (1) the inherent, extremely
high discharge rates (gain) of saccadic
burst neurons, even for very small sac-
cades, (2) the existence of central process-
ing delays that make a system susceptible
134 The Properties and Neural Substrate of Eye Movements
to oscillations, and (3) abnormalities of the
brain stem omnipause cells (or their in-
puts), which normally inhibit burst neu-
rons during fixation.462 Contrary to the
hypothesis that omnipause cell dysfunc-
tion is the cause of opsoclonus or flutter is
the finding that at autopsy, some patients
who had had opsoclonus showed no ab-
normalities in the region in which omni-
pause cells are located,330 although other
investigators have found abnormalities in
this region.194 Experimentally induced le-
sions of the omnipause cell region in mon-
keys produce slow saccades,208 not oscilla-
tions, although these lesions may have also
affected burst cells.
Alternatively, the inputs to omnipause
cells, rather than the omnipause cells
themselves, may be abnormal: either a loss
of the tonic excitation that maintains om-
nipause cell discharge during fixation or
an increase in the phasic inputs that in-
hibit omnipause cells when a normal sac-
cade is to be produced. Another possible
cause might be abnormalities in the inputs
that drive burst neurons, either those
from the adjacent reticular formation,
perhaps LLBN, or from more remote
structures such as the superior colliculus
or the cerebellum. Any extraneous input
that can directly modulate activity in the
various classes of burst cells could, by
virtue of the feedback loops inherent in
the saccade pulse generator, inhibit omni-
pause cells, and potentially lead to sac-
cadic oscillations. (Fig. 3-6). In this re-
gard, abnormally fast saccades (which
could reflect an increase in the gain of the
saccadic burst neurons making the sac-
cadic pulse generator even more suscepti-
ble to oscillations) have been reported in
some patients with opsoclonus (see VIDEO:
"Opsoclonus").33
Apart from any changes in burst or om-
nipause cell activity, an increase in the in-
herent delays within the pulse generator
could make it more susceptible to instabil-
ity. Furthermore, the delay determines the
frequency and hence, the amplitude of os-
cillation. The larger the feedback delay,
the lower the frequency and the larger the
amplitude of the oscillation will be.462
Thus, it is the combination of the intrinsic
delay time and the patterns of burst and
omnipause cell activity that determines
the propensity to develop the properties
of saccadic oscillations.
Finally, normal subjects and some pa-
tients may also show transient saccadic os-
cillations in association with blinks, which
turn off omnipause cells.161'177 In this case,
the saccadic pulse generator is susceptible
to oscillations that do not appear until the
omnipause cells are turned off.
SUMMARY
1. Saccades are rapid eye movements
that change foveal fixation. They
comprise both voluntary refixations
and the quick phases of vestibular
and optokinetic nystagmus. Saccades
are characterized by a relatively in-
variant relationship between their
amplitude and peak velocity (Fig.
3-1). The velocity of large saccades
may exceed 500°/sec.
2. Saccades have many characteristics
that suggest that they are under
open-loop or ballistic control. How-
ever, the saccadic system can acquire
and use visual information to modify
the amplitude and the direction of
the impending saccade.
3. The main innervational change un-
derlying saccadic eye movements is a
pulse-step: the pulse is a saccadic eye
velocity command that overcomes or-
bital viscous drag; the step is an eye
position command that holds the eye
in position against orbital elasticity
(Fig. 1-3).
4. Excitatory burst neurons, within the
pontine and mesencephalic reticular
formation, generate the premotor
commands for the horizontal and
vertical components of saccades, re-
spectively. Inhibitory burst neurons,
located in the rostral medulla for
horizontal saccades, assure reciprocal
innervation by suppressing activity in
motoneurons of antagonist muscles
and help to stop the saccade. Burst
neurons are tonically inhibited by
omnipause neurons except when a
saccade is required. The duration of
burst cell discharge is controlled by

internal feedback loops (Fig. 3-6 and
Fig. 3-7).
5. The cerebral hemispheres can trigger
saccades via parallel descending path-
ways (Fig. 3-8) to the superior collicu-
lus and from there to the brain stem
reticular formation. More volitional
saccades (Table 3-1), made in the
context of learned or remembered
behavior, depend upon the frontal
eye fields, which project both directly
and indirectly (via the basal gan-
glia) to the superior colliculus. More
reflexive saccades to the locations
of novel targets suddenly appear-
ing in the external world depend
more upon direct projections from
the parietal cortex to the superior
colliculus. When the superior collicu-
lus is damaged, recovery is probably
mediated by direct projections from
the frontal eye fields to the brain
stem.
6. The basal ganglia, via serial, in-
hibitory projections from the caudate
nucleus to the substantia nigra pars
reticulata and from the substantia ni-
gra pars reticulata to the rostral pole
of the superior colliculus serve to in-
hibit extraneous reflexive saccades
during attempted fixation and to fa-
cilitate volitional saccades in the con-
text of remembered and learned be-
havior.
7. The cerebellum (Fig. 3-11) calibrates
saccadic amplitude (dorsal vermis
and fastigial nucleus) and the sac-
cadic pulse-step match (flocculus) for
optimal visuo-ocular motor behavior.
The cerebellum also influences the
dynamics and the initiation (latency)
of saccades.
8. Disorders of saccades consist of ab-
normalities of initiation, velocity,
accuracy, and the presence of sac-
cadic intrusions. Saccadic disorders
can be classified according to whether
the saccadic pulse, the saccadic step,
or the pulse-step match is inappro-
priate (Fig. 3-13). Dysfunction of
specific cell types within the brain
stem reticular formation may account
for various types of saccadic disor-
ders.
The Vestibular-Optokinetic System 135
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Chapter 4
SMOOTH PURSUIT AND
VISUAL FIXATION
THE PURPOSE OF SMOOTH PURSUIT
VISUAL FIXATION
Gaze Stability with and without Visual Fixa-
tion
Evidence for and against an Independent
Fixation System
STIMULUS FOR SMOOTH PURSUIT
Effects of the Size and Retinal Location of
the Stimulus on Smooth Pursuit
Influence of Dynamic Properties of the
Stimulus on Smooth Pursuit
Pursuit Response to Nonvisual Stimuli
Smooth Pursuit to Predictable Target Mo-
tion
QUANTITATIVE ASPECTS OF SMOOTH
PURSUIT
Onset of Pursuit
Smooth-Pursuit Responses during Sus-
tained Tracking
NEURAL SUBSTRATE FOR SMOOTH
PURSUIT
Primary Visual Cortex and Smooth Pursuit
Contributions of the Middle Temporal Visual
Area to Smooth Pursuit
Contributions of the Medial Superior Tem-
poral Visual Area to Smooth Pursuit
Contributions of Posterior Parietal Cortex
to Smooth Pursuit
Contributions of the Frontal and Supple-
mentary Eye Fields to Smooth Pursuit
Descending Pursuit Pathways to the Pons
Cerebellar Contribution to Smooth Pursuit
Nucleus of the Optic Tract and Accessory
Optic Pathway
Summary of Pursuit Pathway
MODELS OF SMOOTH PURSUIT
CLINICAL EXAMINATION OF FIXATION
AND SMOOTH PURSUIT
Examining Fixation
Examining Smooth Pursuit
LABORATORY EVALUATION OF FIXATION
AND SMOOTH PURSUIT
ABNORMALITIES OF VISUAL FIXATION
AND SMOOTH PURSUIT
Abnormalities of Visual Fixation
Abnormalities of Smooth Pursuit
Smooth Pursuit, Visual Fixation, and Latent
Nystagmus
Smooth Pursuit in Patients with Congenital
Nystagmus
SUMMARY
THE PURPOSE OF
SMOOTH PURSUIT
Smooth-pursuit eye movements allow con-
tinuous, clear vision of objects moving
within the visual environment, such as
when we watch an eagle soaring in front of
cliffs. Dodge80 pointed out that this ability
depends upon the generation of continu-
ous eye movements that "keep the line of
regard congruent with the line of inter-
est." He demonstrated that the velocity of
smooth-pursuit eye movements matched
the velocity of the target, that pursuit had
"the character of habitual movements,"
151
152 The Properties and Neural Substrate of Eye Movements
that it was continuous in nature with no
"periods of rest," and that vision remained
clear throughout the movement. To achieve
this last attribute, the image of a moving
object must be attended to and kept on the
fovea. Smeared images of the stationary
background that move across the rest of
the retina because of the eye movement
must be relatively ignored.119
Although most research on smooth pur-
suit embodies Dodge's concept of eye
movements that follow moving targets,
F.A. Miles has suggested that this system
evolved to keep the fovea pointed at a sta-
tionary target during self-motion.212'213 As
we walk through our environment, we in-
duce an optic flow of images on the retina.
The optic flow provides important infor-
mation about the three-dimensional lay-
out of the environment and our direction
of heading.16 Recall, however, that exces-
sive slip of images on the retina degrades
vision. Without eye movements, such slip
will occur on the fovea if the object of re-
gard is not located in the direction of
heading but lies, for example, on the
ground just ahead. To resolve this conflict,
smooth pursuit reduces image slip of an
object of interest on the fovea, while optic
flow still occurs on other parts of the
retina. In other words, smooth-pursuit
movements must be generated in re-
sponse to local optic flow. Furthermore,
other visually mediated eye movements,
such as the optokinetic responses to reti-
nal image motion caused by head rota-
tions and translations, must be sup-
pressed. The implication is that smooth
pursuit depends on an ability to filter out
visual motion inputs save for those at the
focus of attention. Once evolved, this
mechanism could also be used to pursue
a small object moving across a com-
plex background, and it could help to
hold the image of a stationary object on
the fovea when the observer was station-
ary, visual fixation. Finally, there is evi-
dence that the neural signals for smooth
pursuit can be used to cancel the
vestibulo-ocular reflex during combined
eye-head tracking; this is discussed in the
section Smooth Tracking with Eyes and
Head in Chapter 7.
VISUAL FIXATION
Gaze Stability with and without
Visual Fixation
In order to see a stationary object best, its
image must be held steady upon the fovea.
As discussed in Chapter 1, either motion
of the image or displacement of it from the
center of the fovea will influence visual
acuity. For clear vision of higher spatial
frequencies (e.g., a 20/20 Snellen opto-
type), motion of the image should be less
than about 5°/sec and the image should lie
within 0.5°of the center of the fovea.46'52'140
During natural activities, the major
threat to steady fixation comes from
perturbations of the head.115'281 Even if the
subject's head is stabilized, however, gaze is
still disrupted by unwanted eye movements,
or ocular motor noise.89'164'165'271'287'288 An
example is shown in Figure 4-1. This
Figure 4-1. Gaze stability during fixation in a normal
subject. The subject was viewing a small, stationary
cross at a viewing distance of 1.2 meters in normal
room illumination, with head stabilized. Three-di-
mensional rotations of both eyes were measured us-
ing the magnetic search coil technique. Gaze posi-
tions are relative, having been offset for clarity of
display. RH, right horizontal; LH, left horizontal;
RV, right vertical; LV, left vertical; RT, right torsional;
LT, left torsional. Positive deflections indicate right-
ward, upward, and clockwise rotations, from the
point of view of the subject. Note that small saccades
and drifts occur; the drifts are greater in the tor-
sional plane.

noise is more prominent in the torsional
than the horizontal or vertical planes.91'245
It has three main components: a high-fre-
quency, low-amplitude tremor, small sac-
cades, and slow drifts. The amplitude of
the tremor is <0.01°—so small that it is
unlikely to interfere with vision, since it
corresponds to less than the size of one
photoreceptor.165'288 The small saccades
(microsaccades, which are typically <0.1°
in amplitude) can be suppressed during
visual tasks that demand steady fixation,
such as threading a needle. Thus, one as-
pect of fixation is the suppression of sac-
cades, an attribute that depends partly on
regions of the frontal eye field and supe-
rior colliculus and which is lost with dis-
ease states that either cause inappropriate
saccades or disrupt the ability to focus vi-
sual attention (e.g. Alzheimer's disease).
The slow drifts that occur during at-
tempted fixation—and the image motion
that they produce—is small (standard devi-
ation of position is typically <0.1° and of
velocity is <0.25°/sec). (When the eyes
move away from the central to an eccentric
position in the orbit, stability of gaze be-
comes susceptible to elastic-restoring forces
because of passive properties of the orbital
contents, and gaze-evoked nystagmus may
develop. See The Need for a Neural Inte-
grator of Ocular Motor Signals, Chap. 5.)
When a subject sits in darkness and at-
tempts to view the remembered location of
a target, the velocity of slow drifts increases
about fourfold (Fig. 4-2). This implies that
during vision of the stationary target, any
slip of images on the retina due to ocular
drifts stimulates the brain to generate eye
movements that will counter the drifts and
hold gaze steady. This response to drift of
images upon the retina caused by instabil-
ity of gaze during active fixation has been
called slow-control, or a field-holding re-
/kx:.90-227 It appears that this mechanism is
enhanced in the wake of a saccade, proba-
bly to minimize postsaccadic drifts.107'215
One issue of debate is whether it is the
smooth-pursuit system or a separate visual
fixation system that reduces ocular drifts
when subjects view, rather than imagine, a
visual target. What is the evidence for an
independent visual fixation system?
Smooth Pursuit and Visual Fixation 153
Figure 4-2. Comparison of gaze stability during fixa-
tion of a small red target light in a dark room and
during attempted fixation of the remembered target
location after it had been turned out (indicated by ar-
row). The subject had been instructed to suppress
saccades. Note that increased drift occurs, especially
horizontally, after the light is turned out. Conven-
tions are as in Figure 4-1.
Evidence for and Against an
Independent Fixation System
Perhaps the strongest evidence that fixa-
tion differs from smooth pursuit comes
from electrophysiological studies. Certain
parietal lobe neurons discharge during
steady fixation but not during smooth
pursuit of a moving target.201 In monkeys,
microstimulation of neurons in the pur-
suit pathway—the medial superior tempo-
ral visual area,161 the dorsolateral pontine
nucleus,206 or the posterior vermis174 (see
Fig. 6-7, Chap. 6)—produces changes in
smooth eye velocity only if the monkey is
already engaged in smooth pursuit; it
does not produce pursuit if the object of
regard is stationary. There is also electro-
physiological evidence for a mechanism to
suppress saccades during attempted fixa-
tion. Thus, microstimulation of parts of
the frontal eye fields45 and of the rostral
pole of the superior colliculus226 will sup-
press or delay the initiation of a visually
triggered saccade. Thus, the electrophysi-
ological properties of both the saccadic
154 The Properties and Neural Substrate of Eye Movements

Figure 4-3. Initiation of smooth pursuit. Indi-

vidual position (A, C) and velocity (B, D) re-
sponses to 157sec and 30° step-ramps (Rash-
bass stimuli). In velocity records, saccades
have been removed. Note how in (A) and (B)
the target (T) initially steps 1.8° to the left
(thereby creating a position error on the
retina) and then immediately commences a
smooth movement to the right at 15°/sec (cre-
ating a velocity error on the fovea). If the
main response of the pursuit system were to
the position stimulus, then the initial move-
ment would be in the direction of the initial
target step (to the left). In fact, the eye (E)
commences a smooth pursuit movement in re-
sponse to the smooth movement of the target
(to the right). B and D show target velocity (T)
and eye velocity (E) records corresponding to
position records A and C, respectively. After a
latency of about 120 msec, the eye accelerates
to peak values (maximum slopes) of 140 and
200°/sec/sec, respectively. Eye velocity initially
overshoots target velocity; thereafter, eye ve-
locity oscillates ("rings") at a frequency of 2 to
3 Hz. E and F show the response to a ramp
stimulus at 15°/sec that comes to an unex-
pected halt. When the target stops, the eye de-
celerates with a time course that approximates
a negative exponential with a time constant of
90 msec.
Continued on following page

and the pursuit systems are changed dur-
ing active fixation of a stationary target,
suggesting the influence of an indepen-
dent, visual fixation system.
There is also evidence from behavioral
studies that visual fixation differs from
smooth pursuit. Most such studies have fo-
cussed on differences between smooth
pursuit of a moving target and the eye
movements that occur just after the target
comes to a halt. In the latter case, retinal
image slip is due to eye motion rather

than target motion and may therefore rep-
resent visual fixation. Several studies have
confirmed Robinson's original observation
that during smooth pursuit of a moving
target and especially at the onset, small oc-
ular oscillations may occur (Fig. 4-3).261
Smooth Pursuit and Visual Fixation 155
These oscillations are usually absent or
minor after the target for pursuit comes to
a halt (Fig. 4-3F),135'i73,i77,2oo,263 suggest.
ing that different mechanisms are in-
volved in fixation than in pursuit. How-
ever, these differences might be due to
156 The Properties and Neural Substrate of Eye Movements
other experimental factors. For example,
these oscillations occur after the target
stops if there is uncertainty about whether
it will stop or speed up.177 Thus, the oscil-
lations that occur during smooth pursuit
may be because the brain is placing
greater reliance on visual inputs, and may
not be related to whether retinal slip is
due to target or eye motion.177 In any case,
it is not the percept of an earth-fixed tar-
get that is the unique stimulus for visual
fixation since the oscillations are present
when patients who have lost vestibular
function attempt to view a stationary tar-
get while they are rotated at constant
speed in a chair.185
Other attempts to identify an indepen-
dent fixation system have involved com-
parisons of the dynamic properties of visu-
ally mediated eye movements when the
eyes are either stationary or engaged in
pursuit. First, the latency to onset of ex-
press saccades using the gap paradigm, in
which the fixation light is turned off be-
fore the new target is displayed, is approx-
imately the same whether the target is
stationary (fixation) or moving (smooth
pursuit). Thus, the trigger for these sac-
cades does not recognize the difference
between fixation and pursuit.32-176 Second,
comparison of the ability to visually track a
target that vibrates in place (fixation) or
follow similar vibrations that are superim-
posed upon ramp motion of the target
(pursuit) shows no difference in humans, 69
although monkeys do better during pur-
suit.110 A final line of evidence that sup-
ports an independent pursuit system is
that patients have been reported who
show normal fixation of a stationary target
but whose eyes break into oscillations of
the type seen in congenital nystagmus
when they try to pursue a moving tar-
get.152
In summary, a fixation mechanism has
been demonstrated for the suppression of
saccades; this depends on known struc-
tures, such as the rostral pole of the supe-
rior colliculus, and is discussed further in
Chapter 3. On the other hand, whether
reduction of retinal image motion is ef-
fected by fixation when the target is sta-
tionary and by smooth pursuit when the
target is moving remains unproven. How-
ever, it has been shown that the shortest
latency responses to moving visual stimuli
occur for images in the plane of fixation,
i.e., for binocular images that lack dispar-
ity.213 Thus, in this sense, the depth plane
of fixation may define a separate set of oc-
ular following properties.
STIMULUS FOR
SMOOTH PURSUIT
In this section, we first examine attributes
of the stimulus that are important in influ-
encing the pursuit response, especially its
size, retinal location, and dynamic proper-
ties. We then discuss how smooth pursuit
can be sustained without visual stimuli. Fi-
nally, we review the role of stimulus pre-
dictability in generating the pursuit re-
sponse.
Effects of the Size and Retinal
Location of the Stimulus on
Smooth Pursuit
The usual stimulus for smooth pursuit is
movement of an image upon the retina.
The image of the target may not cover
the fovea (it may be smaller); indeed, it
may not lie on the fovea,328'334 and such
parafoveal tracking may be preferred if
ambient light is poor, at which time rods
are more efficient photoreceptors than
cones. Pursuit tracking can also be trig-
gered by objects moving in the far visual
periphery and can begin before a saccade
can be programed. Nevertheless, foveal le-
sions impair smooth pursuit of small tar-
gets.260
Experimentally, the responses to stimu-
lation of various parts of the field of vision
have been mapped by measuring the ini-
tial eye acceleration to targets that are
projected onto specific portions of the
retina.51'309 Each trial starts during fixa-
tion of a stationary target so that the reti-
nal location of the moving stimulus can be
controlled. Since it takes about 100 msec
for a pursuit eye movement to be initiated
after the presentation of the stimulus, it
follows that the first 100 msec of the pur-

suit movement will be due to stimulation
of the selected portion of the retina. This
technique is a sensitive way of measuring
the open-loop response of pursuit that oc-
curs before visual feedback is possible.
The initial acceleration of the eye in re-
sponse to horizontal, transient target mo-
tion is greater in the central than in the
peripheral field and is greater for targets
moving towards the fovea than for targets
moving away from the fovea. For verti-
cal target motions, eye accelerations are
greater for stimulus motion in the lower
visual field, irrespective of whether the
target is moving towards or away from the
fovea. Bright targets elicit greater eye ac-
celerations, at shorter latencies, than do
dim targets. Quantitative aspects of these
responses are dealt with in the next sec-
tion.
Another technique used to determine
the relative influence of different parts of
the retina (visual field) upon smooth pur-
suit is artificial stabilization of images upon
the retina using electronic feedback.82'331
For example, if a target is stabilized at the
fovea and optokinetic stimuli are pre-
sented to the peripheral visual field, the
optokinetic response is partially sup-
pressed.253 However, the response to such
stimuli are affected not only by the visual
stimulus but also by the subject's mental
set 9,62,67,82,315 Furthermore, because the
moving stimuli are presented to one part
of the eccentric retina, there is a displace-
ment or position-error component to the
stimulus. Pursuit responses to target dis-
placements are discussed in the next sec-
tion.
When a subject pursues a larger stimu-
lus, such as one that almost fills the visual
field, the pursuit response is usually en-
hanced. This may be due in part to stimu-
lation of a larger area of retina, but an-
other factor that improves tracking is the
freedom to select and attend to any fea-
ture of the visual stimulus. 314 When a full-
field visual stimulus is used, the central
5°-10° of the visual field still dominates
the response.317 With sudden movement
of full-field visual stimuli, humans gener-
ate smooth eye movements at latencies as
short as 70 msec.107 This short-latency re-
sponse may represent a visual back-up
Smooth Pursuit and Visual Fixation 157
to the translational vestibulo-ocular reflex
(see Fig. 1-5, Chap. I). 212
In natural conditions, we pursue objects
that move across a background provided
by the stationary environment. Under
these conditions, slip of images of the sta-
tionary background occurs on the retina.
Thus, a mechanism must exist to at least
partly ignore the slip of images of the sta-
tionary background and focus attention
on the relatively stable image of the mov-
ing target. When the moving target and
the textured background lie in the same
depth plane, there is a 10%-20% decre-
ment in pursuit gain compared with track-
ing the same target in the absence of a
background.61-146'340 This effect is more
pronounced for the onset of pursuit than
during its maintenance,151 and is influ-
enced by the physical characteristics of the
target and background.126a>33° The effect
of the background is still present even if it
is excluded from the path taken by the tar-
get or seen only by one eye while the
other sees only the moving target.155 If,
however, the target moves in a plane that
is closer than the background (corre-
sponding to natural conditions), pursuit
is improved.133'155 Taken together, these
findings suggest that under natural condi-
tions, the smooth pursuit response de-
pends on binocular visual inputs to gener-
ate a response appropriate to keep the
eyes on a target moving through the envi-
ronment.
If the background on which a small vi-
sual stimulus is projected moves—a rare
event outside of the laboratory—there is a
percept that the small target projected
onto it moves in the opposite direction
(the Duncker illusion).86 Furthermore, if a
small target moves vertically over a hori-
zontally moving background, subjects ex-
perience a strong illusion that the trajec-
tory of the target is diagonal, but smooth
pursuit follows the vertical target mo-
tion.352 This finding illustrates the closed-
loop nature of smooth pursuit, which is
discussed in the section Models of Smooth
Pursuit, below. If complex visual stimuli
such as two-dimensional plaids are pre-
sented, the ocular tracking response is not
along the direction of either component
but rather along the resultant, indicating
158 The Properties and Neural Substrate of Eye Movements
that the response is due to higher-level
cortical processing that could extract the
complex stimulus motion.342
Influence of Dynamic Properties
of the Stimulus on
Smooth Pursuit
What information about the movement of
an image of a target does the pursuit sys-
tem use? Is it target position (where) or
target motion (at what speed)? In support
of the importance of target motion, Rash-
bass,255 and later Robinson,261 showed that
if a target abruptly jumps (steps) to one
side of the fovea and then immediately
commences a smooth movement in the
opposite direction (a step-ramp stimulus;
Fig. 4-3A), the subject makes a smooth eye
movement in the direction of the ramp,
but no saccade in the direction of the tar-
get step. In other words, the pursuit sys-
tem responds to the ramp and the step
appropriately, taking into account the mo-
tion of the ramp, which brings the target
back to the fovea, thus making a saccade
unnecessary.265 In fact, cortical areas that
abstract visual information about target
motion project to both pursuit- and sac-
cade-generating mechanisms; this is dis-
cussed further in the section Neural Sub-
strate for Smooth Pursuit, below.
More recent studies indicate that the
smooth-pursuit system may respond to
both position and velocity errors,51'177-251
but the rate of image motion on the retina
is probably more important, particularly
in initiating pursuit. Thus, an after-image
placed just outside the fovea can stimulate
pursuit. 129 The acceleration of the target's
image upon the retina also serves as a
stimulus to pursuit. 194
Pursuit Response to
Nonvisual Stimuli
Image motion on the retina is not the
only stimulus capable of eliciting smooth-
pursuit movements. Some subjects can
smoothly track their own outstretched fin-
ger while in darkness, probably using
knowledge of the motor command to the
limb (efference) and the consequent pro-
prioceptive input (reafference).104'204'285'286
Certain patients with acquired blindness
can do the same.189
Few individuals can generate smooth
eye movements without any perception,
or short-term memory, of a moving stimu-
lus.129'143 However, most can do so in re-
sponse to certain visual stimuli in which
no image motion has actually occurred in
the direction of the eye movement (i.e.,
displacement of luminance-defined con-
tours). Examples of such stimuli are the
motion of the imaginary center of a rolling
wheel285 and the apparent motion of
sigma and phi phenomena.28'29'47'60'94'316
Further evidence is that patients with cor-
tical lesions causing simultagnosia can still
generate smooth pursuit at a time that
they could not report seeing the target.258
Thus, in addition to direct information
about image motion from the retina, the
brain can generate pursuit movements by
using information about target motion
from other sensory systems, by monitor-
ing motor commands and by using
higher-level perceptual representations of
target motion.
Smooth Pursuit to Predictable
Target Motion
Another feature of the stimulus that
greatly influences smooth-pursuit perfor-
mance is the predictability of the target
motion. In nature, both unpredictable
movements (e.g., of a predator) and pre-
dictable motions (e.g., generated by the
subject's hands) occur and must be pur-
sued. One example of predictive behavior
is that the eye will start to move in antici-
pation of the onset of target motion. These
anticipatory drifts are small (<1.0°/sec) if
the time of onset and the direction of tar-
get motion are unknown.27'33'167-170 When
the target light is kept on throughout the
testing, then real or apparent motion of
the target is necessary to evoke anticipa-
tory eye movements. If the target light is
extinguished at the onset of a trial, follow-
ing several prior, predictable, target mo-

tions, anticipatory drifts may increase to
over 5°/sec.27'33 They may be even faster
and of short latency if subjects move the
target with their own hands.81'190 Once the
target starts to move, a predictive accelera-
tion of the eye occurs. For example, if on
some trials of a predictable and repetitive
nature the target light is extinguished just
at the time that it would start to move, the
eye may still accelerate.27 If the target ve-
locity is unexpectedly reduced, eye veloc-
ity may exceed it.143 This behavior cannot
depend upon actual motion of the target
because that visual information has not yet
reached the ocular motoneurons (due to
the time taken for visual processing—over
70 msec). Thus, these anticipatory drifts
and early accelerations of the eye depend
upon previous tracking experience, a
form of memory that depends upon per-
ceived motion.33'34'3243 There is similar an-
ticipation of the target stopping,263 and of
reversal of direction.35
After pursuit is initiated, subjects may
be able to match almost perfectly the mo-
tion of a target moving in a regular wave-
form, such as a sine wave.68'80'211 As dis-
cussed below in Models of Smooth Pursuit,
this behavior defies explanation by simple
models of smooth pursuit that incorporate
a delay due to visual processing. This pre-
dictive response is established rapidly—
within a quarter cycle after the onset of si-
nusoidal target motion. Certain unusual
waveforms (such as a cubic function or
sum of several different sine waves) also
can be smoothly tracked, following a train-
ing period.11'153'208 Other studies have
shown that predictive features of smooth
pursuit can be related to performance on
the preceding trials.18'19-21'143 This has
led to the suggestion that prediction in
smooth pursuit is due to the storing of
memories of eye movements, which are
referred to during tracking. 10 - 21 ' 76 How-
ever, simply viewing repeated, predictable
target motions can promote anticipatory
smooth eye movements. 22
A second possible mechanism, however,
is an extrapolation of target behavior
based on the current stimulus to the pur-
suit system. This is evident if subjects track
targets moving at constant speed and, at
an unpredictable time, the target light is
Smooth Pursuit and Visual Fixation 159
turned off.27 Eye velocity falls about 200
msec after the target disappears, but not
to zero; the eye continues to move at about
60% of target velocity for periods of up to
4 sec. Because the amplitude of this resid-
ual velocity depends upon the previous
target velocity, a process of extrapolation
seems likely.27 Although more than one
predictive mechanism may aid smooth
pursuit, there seems to be a basic dif-
ference between those subserving pursuit
and predictive mechanisms underlying
saccadic tracking. Thus, predictive mecha-
nisms for pursuit are quickly established,
whereas observation of several cycles of
target jumps is generally required before
predictive saccades can be generated.351
QUANTITATIVE ASPECTS OF
SMOOTH PURSUIT
Smooth-pursuit performance varies con-
siderably among individuals and is af-
fected by many factors such as the proper-
ties of the stimulus, attention, and age.
Smooth-pursuit eye movements are sensi-
tive to the effects of many medications (see
Table 10-21, Chap. 10). Conventionally,
pursuit is measured during tracking of
predictable, sinusoidal target motion. There
are advantages, however, to measuring the
initiation of smooth pursuit, and we will
start by summarizing the properties of
normal responses to such stimuli.
Onset of Pursuit
The initiation of smooth pursuit is most
conveniently studied by measuring eye
position and velocity in the first second
following presentation of a either a ramp
or a step-ramp (Rashbass) stimulus (Fig.
4_3).5i,263,309,332 The latency to onset of
smooth pursuit in response to a ramp tar-
get motion is about 100 msec,51 and it is
not influenced by turning off a fixation
target before a pursuit target appears in
the way that saccades are; that is, there
does not appear to be any express smooth
pursuit. 175 ' 218 If the ramp is proceeded by
a step displacement in the opposite direc-
160 The Properties and Neural Substrate of Eye Movements
tion, the latency is greater, close to 150
msec, because the pursuit system is af-
fected by the step.51 Nevertheless, such
step-ramp stimuli do have an advantage
over pure ramp stimuli because they are
less likely to stimulate saccades that often
contaminate pursuit responses to ramp
stimuli.
Eye acceleration during the initial 40
msec of the pursuit response to a step-
ramp stimulus is largely unrelated to the
speed of the target, its brightness, or its
position in the visual field.173'309 Typical
values for this initial eye acceleration are
40 to 1007sec/sec, varying from subject to
subject.51'309 Thereafter, eye acceleration is
a function of the velocity of image motion
on the retina and is decreased if the target
is dimmer or if it stimulates more periph-
eral retina.198'309 As target velocity is pro-
gressively increased, eye acceleration does
not increase by the same amount; this has
been called an acceleration saturation.194'26^
Thus, the relationship between peak eye
acceleration and target velocity is a mea-
sure of smooth-pursuit initiation. Latency
to onset, but not eye acceleration, is influ-
enced by the presence of a distracter, re-
flecting the process of target selection.92
The initial acceleration, but not latency, of
pursuit onset is reduced if targets move
across a textured background.151'155
Elderly subjects show a decrease in ini-
tial acceleration but no change in the la-
tency to onset of pursuit. 221 ' 289 Infants less
than 12 weeks of age do show pursuit re-
sponses, but they are small and intermit-
tent.139'278 By 4 months of age, smooth
pursuit responses improve and are more
related to target velocity.249-321
The initiation of smooth pursuit may
show larger eye accelerations for vertical
pursuit than for horizontal pursuit (the
opposite of the case for predictable pur-
suit, as discussed in the next section); this
difference may be evident during diagonal
tracking (Fig. 4-4).266 In the horizontal
plane, pursuit accelerations are higher
when the target moves towards the mid-
line. In the vertical plane, responses are
greater during stimulation of the inferior
visual hemifield, irrespective of the direc-
tion of target movement. Initial accelera-
tion is unaffected by whether the eye starts
in a central or eccentric position.203 If
the target motion is toward the subject,
and the trajectory is aligned with one
eye, disjunctive smooth-pursuit move-
ments are generated, and it appears that
these are distinct from any vergence re-
sponse.156
The early phase of the response
also shows damped pursuit oscillations—
so-called ringing—at a frequency of 3 to 4
Hz and often, an initial velocity overshoot
of the target (Fig. 4-3B, D, F); these find-
ings are present in both horizontal and
vertical planes (Fig. 4-4).266 Velocity over-
shoot and ringing during pursuit onset,
however, are not present in every subject
and are influenced by test conditions such
as luminance of the target and back-
ground. Moreover, the offset of smooth
pursuit in response to cessation of target
motion (Fig. 4—3E, F) is usually different
from the onset: after a latency slightly
smaller than the onset, eye velocity de-
clines exponentially to zero with a time
constant of about 90 msec.177'200'216 As dis-
cussed above, the lack of any sustained
ringing during cessation of pursuit has
been used as evidence that visual fixation
is due to a different mechanism than
smooth pursuit.
Although the onset of smooth pursuit is
an open-loop, preprogramed response,
learning is possible, similar to that of sac-
cades. This was first noted in patients with
extraocular muscle palsies who viewed the
world with their paretic eye,244 but it can
also be induced in normal subjects.102'241
In monkeys, it has been shown that such
learning (a form of pursuit adaptation)
may occur selectively for eye movements,
but not image motion, in a specific direc-
tion.142
Smooth-Pursuit Responses during
Sustained Tracking
Two types of stimuli are commonly used to
test smooth pursuit: sine-wave and con-
stant-velocity movements (ramps or saw-
tooth waveforms). In addition, pseudo-
random stimulus motion is sometimes
used.
 Smooth Pursuit and Visual Fixation 161

Figure 4-4. Comparison of horizontal and vertical components of the smooth-pursuit response to a diagonal
(in 45° direction) step-ramp stimulus. Note that the velocity of the vertical eye component increases faster
(higher acceleration of smooth pursuit initiation), although the horizontal component has a greater maximal
velocity. Also note that both horizontal and vertical velocity components overshoot the target velocity and show
transient oscillations. Positive values correspond to rightward and upward movements. (From Vision Research,
volume 36, Rottach KG, Zivotofsky AZ, Das VE, Averbuch-Heller L, DiScenna AO, Poonyathalang A, Leigh RJ,
pages 2189-95, 1996, with permission from Elsevier Science.)

During smooth pursuit of a sinusoidal so that an increase in target frequency is

target motion, performance convention-
ally is evaluated by measuring gain (peak
eye velocity/peak target velocity) and
phase. Phase is a measure of the temporal
synchrony between the target and the eye.
During ideal pursuit tracking, the gain is
close to 1.0 and the eye does not lag be-
hind the target (i.e., phase shift is small).
Breakdown in smooth pursuit of a sinu-
soidal stimulus is indicated by a decrease
in gain and by the appearance of a phase
lag of the eye with respect to the target at
higher frequencies. Although gain and
phase may be plotted as functions of fre-
quency (as a Bode plot, see Fig. 2-5C,
Chap. 2), deterioration of smooth pursuit
may also be related to increasing target
acceleration.194'197 Under usual circum-
stances, target amplitude is kept constant
also accompanied by an increase in peak
acceleration and in peak velocity. If, on
the other hand, stimulus frequency is held
constant, pursuit also declines if the am-
plitude of the target motion increases. A
demonstration of this is shown in Figure
4-5A. The subject is able to pursue a tar-
get moving at a frequency of 1.0 Hz if its
amplitude is small (5°, peak-to-peak). If
the frequency of the target movement is
held at 1.0 Hz but its amplitude is in-
creased, then smooth pursuit deteriorates.
Evidence to show that such deterioration
is not due to target velocity is provided by
the observation that, with constant-veloc-
ity targets (ramps), pursuit gain does not
significantly deteriorate until target veloc-
ity exceeds about 100°/sec (Fig. 4-5B).210
Up to this velocity saturation, gain is typi-
Figure 4-5. Quantitative aspects of smooth pursuit to predictable target motion. (A) Comparison of smooth
pursuit at 1.0 Hz with target peak-to-peak amplitude of either 5° (left) or 30° (right). During tracking of the
smaller amplitude movements, pursuit gain (peak eye velocity/peak target velocity) is greater than 0.8, but dur-
ing tracking of the larger amplitude target, it falls to less than 0.5, and tracking is largely saccadic because of ac-
celeration or velocity saturation. TPOS, target position; EPOS, eye position; EVEL, eye velocity. Upward de-
flections indicate rightward eye or target movements. (B) Demonstration in a normal subject of pursuit velocity
saturation, which becomes evident with target velocities above 93°/sec; below this, mean pursuit gain (eye veloc-
ity/target velocity) was 0.86 (From Vision Research, volume 25, Meyer CH, Lasker AG, Robinson DA. The up-
per limit of smooth pursuit velocity, pages 561-3, 1985, with permission from Elsevier Science.)

162
 Smooth Pursuit and Visual Fixation 163

cally less than 1.0, but is fairly constant.
Therefore, it is important to study pursuit
responses with both constant velocity
and with sinusoidal target motions. From
the responses to constant-velocity stimuli,
steady-state pursuit gain and the thresh-
old of the velocity saturation of pursuit
can be determined. From responses to si-
nusoidal stimuli, the acceleration satu-
ration of smooth pursuit to predictable
target motion can be determined. By ana-
lyzing the responses in this way, a number
of characteristic pursuit deficits due to
specific disorders have been defined (com-
pare upper and lower panels of Fig. 4-6);
these are discussed in the final section of
this chapter.
Generally, smooth pursuit of pre-
dictable target motions is superior to
that of nonpredictable motions such as
step-ramps. For example, values of
peak eye acceleration in response to pre-
dictable sinusoidal stimuli may exceed
1000°/sec/sec.194 Horizontal smooth pur-
suit is usually superior to vertical smooth
pursuit for sustained responses to pre-
dictable target motions;15'266 in some sub-
jects, this is the opposite of what is found
during the onset of pursuit (Fig. 4-4),
which suggests different mechanisms. An
important characteristic of the pursuit re-
sponses to predictable target motions is
their variability. Even normal, young sub-
jects show considerable intersubject vari-
ability. For example, for target motion at a
constant velocity of 30°/sec, gain ranges
from below 0.8 to about 1.0.i8°,i93,269 Some
of the variability of such reports reflects
differences in testing protocols and analy-
sis procedures; thus it is important for
each laboratory to determine its normal
range of responses. Smooth pursuit gain is
reduced if pursuit is performed with the
eye in an eccentric position in the orbit;
this cannot be ascribed to the effects of or-
bital mechanics, since pursuit initiation is
not similarly affected.203
A number of studies have measured the
deterioration of smooth pursuit that oc-
curs with age.146'247'277'282-344 The main

Figure 4-6. Comparison of smooth pursuit of a target moving in a triangular waveform by a normal subject (top
panel) and a patient with cerebellar disease (bottom panel). In each panel, the calibration marks on the top line are
seconds, the top trace shows horizontal eye position, and the bottom trace shows movement of the target (a small
laser spot). The normal subject generates tracking eye movements that consist mainly of smooth pursuit move-
ments with occasional small saccades. The patient with cerebellar disease can generate some smooth following
movements, but their velocity (i.e., the slope of the position trace) is much less than that of the target. Conse-
quently, the patient has to make catch-up saccades to place the image of the target on the fovea. L: left; R: right.
164 The Properties and Neural Substrate of Eye Movements
change is a decrease of the steady-state
gain for ramp target stimuli. With sinu-
soidal stimuli, there is a further decline in
gain with high target accelerations (above
about 400°/sec/sec).344 These changes
should be kept in mind when evaluating
elderly patients. Some technical points
about how to make the different pursuit
measurements are reviewed below, in
Laboratory Evaluation of Fixation and
Smooth Pursuit. Smooth pursuit may also
be tested with less predictable pseudoran-
dom or sum-of-sine waves stimuli.20'23'61'339
With such stimuli, pursuit tracking is opti-
mized (minimal phase shift) at some fre-
quency, at the expense of poorer tracking
(larger phase shifts) at lower frequencies.
Similar results have been reported for op-
tokinetic responses.333 How much these
stimuli are able to test pursuit perfor-
mance without the effects of predictive
mechanisms is controversial.23'339
NEURAL SUBSTRATE FOR
SMOOTH PURSUIT
Here we present a hypothetical scheme
for the generation of smooth-pursuit eye
movements using information from both
humans and monkeys. As we have stated
elsewhere, caution is required in extrapo-
lating results from different species and in
linking behavioral deficits to neuronal ac-
tivity that is monitored by electrophysio-
logical measures or functional imaging.
Nonetheless, the present scheme, summa-
rized in Figure 4-7 and Figure 6-7 has,
with modifications, grown in acceptance
since it was included in the second edition
of this text. An important, though still de-
bated, principle is that there are two func-
tional divisions of the visual system.199'318
One is primarily concerned with the
analysis of moving stimuli and starts with
retinal ganglion cells that project via the
magnocellular layers of the lateral genicu-
late nucleus to layer 4Ca of primary visual
(striate) cortex. A second subdivision is
primarily concerned with feature analysis
(e.g., color) and projects via parvocellular
layers of the lateral geniculate nucleus to
layer 4CP of primary visual cortex. The la-
tency of neurons in layer 4C(3 to flashing
spots of light is about 20 msec longer than
those in layer 4Ca.240 Chemical lesions of
the magnocellular pathway in the lateral
geniculate nucleus impair but do not abol-
ish smooth pursuit. 246 Thus, both mag-
nocellular and parvocellular pathways
probably contribute to the generation of
smooth pursuit, but the former seem to be
more important.
Primary Visual Cortex and
Smooth Pursuit
Primary visual cortex (VI, Brodmann
area 17, striate cortex) contains neurons
that respond to moving visual stim-
uli.134'225 Such complex cells, however,
have small visual fields and a narrow
range of preferred target speeds. Using
step-ramp stimuli, it has been shown that
unilateral lesions of striate cortex abolish
smooth pursuit of targets moving in the
defective hemifield, contralateral to the
side of the lesion,272 but pursuit remains
intact for stimuli moving in any direction
that are presented into the normal hemi-
field. During tracking of predictable target
motion, smooth pursuit is usually normal
on account of the predictable properties of
smooth pursuit and the sparing of the
macular projection.131
Contributions of the Middle
Temporal Visual Area to
Smooth Pursuit
Striate cortex projects to the middle tem-
poral visual area (MT or V5) which, in
rhesus monkey, lies in the superior tempo-
ral sulcus (see Fig. 6-8, Chap. 6).78'310'349
The projections from striate cortex to MT
depend on arcuate, subcortical fiber bun-
dles;307 there is a direct pathway and an
indirect pathway via prestriate cortex.
The projections from striate cortex to MT
are retinotopic and entirely ipsilateral.
Most neurons in MT encode the speed
and direction of moving visual stimuli;
preferred stimulus velocity is typically
30°/sec.205 Neurons in MT have larger re-
Figure 4-7. A hypothetical anatomic scheme for smooth pursuit eye movements. Signals encoding retinal im-
age motion pass via the lateral geniculate nucleus (LGN) to striate cortex (VI), and extrastriate areas. MT (V5),
middle temporal visual area; MST, medial superior temporal visual area; PP, posterior parietal cortex; FEF,
frontal eye fields; SEF, supplementary eye fields. The nucleus of the optic tract (NOT) and accessory optic sys-
tem (AOS) receive visual motion signals from the retina but also from extrastriate cortical areas. Cortical areas
concerned with smooth pursuit project to the cerebellum via pontine nuclei, including the dorsolateral pontine
nuclei (DLPN). The cerebellar areas concerned with smooth pursuit project to ocular motoneurons via fastigial,
vestibular, and y-group nuclei; the pursuit pathway for fastigial nucleus efferents has not yet been defined. The
NOT projects back to LGN. The NOT and AOS may influence smooth pursuit through their projections to the
pontine nuclei, and indirectly, via the inferior olive.

165
166
 Smooth Pursuit and Visual Fixation 167

Figure 4-8.—continued. Effects of a lesion located at the temporo-occipital junction upon visual tracking. (A)
Magnetic resonance images demonstrating the location of the left-hemisphere infarct (indicated by arrows), the
cortical involvement of which primarily affects Brodmann areas 37 and 19. (B) Typical responses of this patient
to foveafugal step-ramps (left), foveapetal step-ramps (middle) and steps (right). Target motions are indicated by
dotted lines and eye movement responses by solid lines. When step-ramps are presented in the right visual
hemifield, pursuit initiation is impaired and saccades are inaccurate, compared with corresponding responses
to targets presented in the left visual hemifield. By contrast, saccades made to steps are equally accurate in the
right or the left visual hemifield. This tracking deficit is similar to that occurring after experimental lesions of
the middle temporal visual area (MT) in monkey. R, right; L, left. (Reproduced from Thurston SE, Leigh RJ,
Crawford T, Thompson A, Kennard C. Two distinct deficits of visual tracking caused by unilateral lesions of
cerebral cortex in humans, Ann Neurol 1988;23:266-73, with permission of Lippincott Williams and Wilkins.

ceptive fields than those in striate cortex
and, if complex visual stimuli such as two-
dimensional plaids are presented, some
neurons respond not to the direction of ei-
ther component but to the resultant global
direction of the stimulus.224-256 Microstim-
ulation in MT during tracking of a
smoothly moving target increases smooth-
pursuit eye velocity and may induce
smooth eye movements even if the target
is stationary.114
In monkeys, discrete chemical lesions of
those portions of MT that encode visual
inputs from the extrafoveal (peripheral)
visual field cause a scotoma for motion,
and these animals cannot estimate the
speed of a moving target. Consequently,
the initiation of smooth pursuit is de-
creased and the amplitude of saccades to
moving targets are dysmetric for stimuli
presented in the affected portion of the vi-
sual field.237 In contrast, saccades made to
targets that are stationary within the af-
fected field are normal. Thus, the deficit
caused by a lesion of extrafoveal MT is one
of visual processing of moving stimuli,
rather than of pursuit per se. Moreover,
this visual defect is accompanied by a se-
lective loss of motion perception.236
On the basis of functional imaging stud-
ies, the probable homologue of MT in hu-
mans is located posterior to the superior
temporal sulcus, at the junction of Brod-
mann areas 19, 37, and 39, close to the in-
tersection of the ascending limb of the in-
ferior temporal sulcus and the lateral
occipital sulcus (see Fig. 6-7, Chap. 6).324>350
Patients with selective lesions at this site
have defects of motion perception (akine-
topsia)279 and impairment of smooth pur-
suit184'301 similar to those described in
monkeys with MT lesions (Fig. 4-8).
Contributions of the Medial
Superior Temporal Visual Area to
Smooth Pursuit
Area MT in rhesus monkeys projects to
the medial superior temporal visual area
(MST), which lies adjacent to MT in the
168 The Properties and Neural Substrate of Eye Movements
superior temporal sulcus (see Fig. 6-8,
Chap. 6).78'311 In addition, area MT pro-
jects by the major forceps and splenium of
the corpus callosum to areas MT and MST
of the contralateral hemisphere.307
In rhesus monkeys, area MST lies in the
superior temporal sulcus (STS), and has
been subdivided into three subareas:159'310
a dorsal region (MSTd), a ventrolateral
portion (MST1), and an area located on
the floor of the STS (FST). The neurons in
MST1 respond best to motion of small
spots of light and seem concerned with
smooth pursuit.161 Their responses are
also influenced by visual stimuli presented
in the region surrounding their receptive
field.88a The neurons in MSTd seem par-
ticularly suited to analysis of the optic
flow.85'106 They have large receptive fields,
and they respond at short latencies to ro-
tations and expansions of visual stimuli
and to speed gradients across the visual
field.84'147 The response of individual neu-
rons in MSTd to moving stimuli is influ-
enced by the disparity between the loca-
tion of images of the same target on the
two retina;268 such motion disparity infor-
mation provides information about self-
motion and the layout of the environment.
Vergence angle also influences their re-
sponses.13621 Further, MSTd neurons sense
the direction of heading,83 and seem able
to contribute to spatial orientation on the
basis of motion parallax information. 84
Like MT neurons, the activity of those in
MST can be linked to perceptions of mo-
tion.53
Neurons in MST may differ from those
in area MT by taking into account the
effects of eye movements.37'159'160'238'283
Thus, it seems possible that an efference
copy of the eye movement command is
sent to these neurons. Availability of an
eye movement signal is important if the
direction of heading is to be estimated
while the eyes pursue a moving target.37
In addition, a neural signal encoding head
movement reaches some MST neurons.299
Eye and head movement signals would
seem to be important to enable smooth
pursuit of a small target moving across a
textured background while the subject is
moving the head or walking. Thus, certain
neurons in MST respond to large-field
stimuli moving in the opposite direction to
that preferred by these same neurons
during pursuit of small targets.160 Thus,
MST may play an important role during
smooth pursuit of a small target across a
textured background or fixation of a sta-
tionary target during self-motion.160 This
summation of a visual signal and an effer-
ence copy of eye movement is similar to
that proposed in certain models of smooth
pursuit (Fig. 4-9B). Because these MST
neurons combine visual and eye move-
ment signals, they may encode the motion
of the moving visual stimulus in a cran-
iotopic-coordinates (head-centered) rather
than a retinotopic (eye-centered) frame of
reference.
The human homologues of MT and
MST probably lie adjacent to each other
at the occipitotemporoparetial junction.
Thus, when subjects smoothly pursue a
small target, there is activation of the lat-
eral occipitotemporal cortex, an area close
to the homologue of MT.26 However, there
is no activation in this area when subjects
view a large moving stimulus with the eyes
still; this finding implies that extraretinal
signals, which are possibly related to eye
movements, are reaching this area, which
might be the human homologue of MST.26
If pursuit becomes unpredictable, addi-
tional activation occurs in the superior
parietal lobule, intraparietal sulcus, poste-
rior superior temporal sulcus, and pari-
eto-insular cortex.38 When human sub-
jects view visual displays that simulate the
optic flow, functional imaging detects in-
creased activity in the region of the right
superior parietal lobe and dorsal cuneus
(the probable homologue of V3 in mon-
key) and bilaterally, on the ventral surface
of the brain in the occipital-temporal
(fusiform) gyrus.44'70 Thus, multiple poste-
rior cortical areas contribute to the gener-
ation of smooth-pursuit eye movements
during natural activities, such as locomo-
tion. Nonetheless, bilateral lesions of MT
cause a profound akinetopsia.279
Experimental lesions of MST1 in mon-
keys produce a unidirectional deficit of
horizontal smooth pursuit for targets mov-
ing toward the side of the lesion, irrespec-
tive of the visual hemifield into which the
stimulus falls.87 In addition, a retinotopic

deficit for motion detection, similar to that
with MT lesions, occurs for targets pre-
sented in the contralateral visual field. Le-
sions of the adjacent foveal representation
of MT may produce a similar deficit.88-161
Consistent with the effects of lesions is the
finding that activation of MST1 (or foveal
MT) by microstimulation during smooth
pursuit increases eye velocity during
tracking towards the side of stimulation
and decreases eye velocity during tracking
away from the side of stimulation.161 Dur-
ing steady fixation, electrical stimulation
produces lower eye velocity than that pro-
duced by stimulation during smooth pur-
suit.161 Combined experimental lesions of
MT and MST produce more permanent
deficits.337 Unilateral, posterior cerebral
lesions in humans that may involve the
homologue of MST produce a tracking
deficit similar to that in monkey, with im-
pairment of ipsilateral pursuit and a de-
fect of motion processing affecting the
contralateral visual hemifield. 25 > 184 ' 220 ' 301
Bilateral lesions involving MST are re-
ported to cause inability to suppress image
motion of the background during smooth-
pursuit movements. 119
Contributions of Posterior Parietal
Cortex to Smooth Pursuit
In rhesus monkeys, both MT and MST
project via arcuate fiber bundles to poste-
rior parietal cortex (area 7a) lying ventral
to the intraparietal sulcus (see Fig. 6-8).307
In addition, posterior parietal cortex has
reciprocal connections with MST. Neurons
in posterior parietal cortex that modulate
their activity during smooth-pursuit eye
movements seem less concerned with the
speed and direction of pursuit and more
with the nature of the target being pur-
sued (e.g., a scrap of food). 201 Thus, the
pursuit-related activity of these posterior
parietal neurons probably relates more to
attention of a small moving target than to
eye movements per se. This contrasts with
neurons in areas MT and MST, which play
an important role in processing motion
signals but do not seem to contribute sub-
stantially to target selection.93 The re-
Smooth Pursuit and Visual Fixation 169
sponses of visually sensitive neurons in
posterior parietal cortex are influenced by
current eye position, and thus may encode
the location of the visual stimulus in cran-
iotopic coordinates.5'40 This is consistent
with the finding that unilateral posterior
parietal lesions, especially right-sided
ones, cause contralateral inattention and
may contribute to ipsilateral gaze devia-
tion or preference and partially restrict
smooth pursuit and saccades to the ipsilat-
eral hemirange of gaze.31'217
Although unidirectional pursuit deficits,
including poorer pursuit when the target
moves towards the side of the lesion, have
been ascribed to parietal lesions, these are
probably due to involvement of other ar-
eas, such as MST, FEF, or their projec-
tions. It seems more likely that parietal le-
sions impair the ability to attend to the
image of the moving target and "ignore"
the smeared images of the stationary back-
ground consequent to the eye movement.
Thus, patients with lesions affecting Brod-
mann area 40 show impaired smooth pur-
suit when the target moves across a struc-
tured background compared with pursuit
across a dark background. 182 Impairment
of the same mechanism may explain why
patients with parietal lesions show rela-
tively preserved responses to full-field vi-
sual stimuli, which demand less selective
visual attention. 13
Contributions of the Frontal and
Supplementary Eye Fields to
Smooth Pursuit
Visual areas MT, MST, and posterior pari-
etal cortex have reciprocal connections
with the frontal eye field (FEF; Brod-
mann area 8) in monkeys (see Fig.
6_8). 183,284,307,311 within a circumscribed
part of the ventral (inferior) FEF, in the
arcuate fundus and posterior bank, is a
population of neurons that discharge for
smooth pursuit, but not for saccades.112
Microstimulation in this region produces
smooth eye movements, usually with an
ipsilateral component; such movements
can be elicited even during attempted fix-
ation.111 Individual neurons increase their
170 The Properties and Neural Substrate of Eye Movements
activity during pursuit in a preferred di-
rection, and generally increase their dis-
charge rate with eye velocity.112 Typically,
the onset of neuronal activity occurs 100
msec after target motion and 20 msec be-
fore the eye starts to move.112 In humans,
functional imaging indicates that a por-
tion of the FEF concerned with smooth
pursuit also lies in the inferior lateral as-
pect of the FEE 248 Lesions of the FEF in
monkeys and humans cause a predomi-
nantly ipsidirectional defect of smooth
pursuit that involves predictive aspects of
the pursuit response.202,222,257,278a Although
the pursuit may be impaired in both direc-
tion, optokinetic responses may be pre-
served.148'149
The supplementary eye field (SEF),
which lies in the dorsomedial frontal lobe,
also receives inputs from MST, the poste-
rior parietal lobe, and the FEF.136 The SEF
contains neurons that discharge during
smooth pursuit. 124 Microstimulation in the
SEF may produce smooth eye movements
if delivered during fixation.302 Electro-
physiological and clinical evidence sug-
gests that the SEF is involved with predic-
tive aspects of smooth pursuit.122-123'126'191
Thus, current evidence suggests that both
FEF and SEF make important contribu-
tions to predictive aspects of smooth pur-
suit.
Descending Pursuit Pathways to
the Pons
The posterior part of the descending pur-
suit pathway (Fig. 6-7) in monkeys runs
ipsilaterally from areas MT and MST
through the internal sagittal stratum, the
retrolenticular portion of the internal cap-
sule, and the cerebral peduncle. The tar-
gets of this projection are the dorsolateral
and lateral pontine nuclei.36'43'108'307-312
The projections from MT and MST to the
nucleus of the optic tract and accessory
optic system are discussed in a separate
section below.
In the human brain, the descending
pathway is thought to originate in the
parieto-temporo-occipital cortex; it runs
along the lateral surface of the lateral
ventricle (internal sagittal stratum), turns
medially above the temporal horn, and
then toward the posterior limb of the in-
ternal capsule.219-307 A clinical lesion of
the internal sagittal stratum that did not
impair smooth pursuit was probably lo-
cated posterior to the critical part of this
pathway.274'307 At a more caudal level in
the pathway, an ipsilateral pursuit deficit
has been reported with lesions affecting
the posterior thalamus and adjacent
retrolenticular portion of the internal
capsule41 and with lesions of the dorsal
midbrain. 343
In monkeys, the terminations are scat-
tered throughout several pontine nuclei
including the dorsolateral pontine nu-
clei (DLPN) and the rostral portion of
the nucleus reticularis tegmenti pontis
(NRTP).36'99'108'136'150'183'296 Pursuit-related
neurons in these nuclei encode a variety of
visual and ocular motor signals.228'294-300
Many neurons modulate their discharge
during smooth pursuit of a small target in
an otherwise dark room and show direc-
tional selectivity, with either ipsilateral or
contralateral target motion. Some of these
neurons continue to discharge if the target
light is briefly turned off while pursuit
continues; this property implies that a
nonvisual signal (probably efference copy)
encoding eye movement is reaching these
neurons. This property is similar to that
shown by some MST neurons. 238 Micros-
timulation in the DLPN does not cause
smooth eye movements during fixation
but accelerates the eye if the monkey is en-
gaged in smooth pursuit; 150 this result is
similar to stimulation in MST.161 Micros-
timulation in rostral NRTP produces pre-
dominantly upward eye movements.336
Discrete chemical lesions of DLPN pro-
duce a deficit of smooth pursuit that is
predominantly for ipsidirectional target
motion.207 An accompanying saccadic deficit
to moving stimuli is directional, unlike the
retinotopic defect that occurs following
MT lesions.207 The major projections of
the pontine nuclei are to the vestibulo-
cerebellar paraflocculus and flocculus,
and the dorsal vermis of the cerebellum.
There is also evidence that the cerebellar
hemispheres may contribute to smooth
pursuit. 290

Cerebellar Contribution to
Smooth Pursuit
THE VESTIBULOCEREBELLUM
AND SMOOTH PURSUIT
A major projection of the pontine nuclei is
to the vestibulocerebellum (paraflocculus
and flocculus (see Fig. 6-6, Chap. 6)).109'234
These structures also receive mossy fiber
inputs from the vestibular nucleus, nu-
cleus prepositus hypoglossi, cell groups
of the paramedian tracts,50 and climbing
fiber inputs from the contralateral inferior
olive. The main efferent pathways of the
paraflocculus and flocculus are to the ipsi-
lateral superior and medial vestibular nu-
clei and to the y-group.181 The parafloc-
culus may also project to the posterior
interpositus and dentate nuclei.235 The
major anatomical connections are summa-
rized in Display 6-10, in Chapter 6.
It appears that the paraflocculus is more
important for the control of smooth pur-
suit, and the flocculus, for controlling the
vestibulo-ocular reflex. 234 Purkinje cells in
the paraflocculus and flocculus modulate
their discharge according to gaze velocity
during smooth pursuit or eye-head track-
ing (cancellation of the vestibulo-ocular
reflex).195'196'214 If the monkey fixates a
stationary target during passive head rota-
tion, no significant modulation of these
neurons occurs, which is consistent with
gaze velocity remaining at zero. Some of
these neurons modulate their activity with
ipsilateral, horizontal pursuit movements;
others discharge preferentially for down-
ward movements. Some neurons show
transient overshoots of activity that might
help initiate pursuit.17'2 Microstimulation
of the flocculus produces smooth eye
movements, even during attempted fixa-
tion.30 Typically the initial eye movement
is upward and contralateral to the side of
stimulation.
Bilateral experimental lesions of the
flocculus and paraflocculus greatly impair
smooth pursuit. 348 Unilateral lesions cause
ipsilateral pursuit deficits (see Display
10-17, Chap. 10). The deficit following le-
sions of the flocculus and paraflocculus is
a low pursuit gain, differing from that fol-
lowing total cerebellectomy, which totally
Smooth Pursuit and Visual Fixation 171
abolishes smooth pursuit.325'326 This dif-
ference confirms that other areas of the
cerebellum also contribute to smooth pur-
suit. Lesion studies suggest that the uvula
may influence pursuit responses, although
most of its neurons respond to large-field
(optokinetic) rather than small moving vi-
sual stimuli.125 Two other cerebellar re-
gions contain neurons that discharge for
smooth pursuit: the dorsal vermis and the
caudal fastigial nucleus.
THE DORSAL VERMIS AND
SMOOTH PURSUIT
Lobules VI and VII of the dorsal vermis
also receive inputs from the pontine nu-
clei; other inputs are from the parame-
dian pontine reticular formation (PPRF)
and vestibular and prepositus hypoglossi
nuclei.335 These anatomical connections
are summarized in Display 6-12 in Chap-
ter 6. Purkinje neurons in the dorsal ver-
mis encode gaze velocity during smooth
pursuit or combined eye-head track-
ing. 292 - 293 However, they differ from Purk-
inje cells in the vestibulocerebellum by
also responding to retinal slip velocity
during deficient pursuit. Thus, vermal
Purkinje cells encode the sum of gaze ve-
locity and retinal image velocity: target
velocity in space.144'295 Microstimulation
evokes changes in smooth eye movement
only during pursuit, not during fixa-
tion.174 In humans, transcranial magnetic
stimulation over the posterior cerebellum
accelerates ipsilateral smooth pursuit. 2413
Experimental lesions of the posterior
vermis cause a partial, mainly ipsidirec-
tional defect of smooth pursuit (see Dis-
play 10-19, Chap. 10).150'296a Cerebellar
infarction that involves the posterior ver-
mis impairs smooth pursuit, more so ipsi-
laterally with unilateral lesions.313
THE FASTIGIAL NUCLEUS AND
SMOOTH PURSUIT
The caudal fastigial nucleus (the fasti-
gial oculomotor region—FOR), which is
known to be important in the control of
saccades, also contributes to smooth pur-
suit.101 It receives inputs from the Purk-
inje cells of the dorsal vermis and also
172 The Properties and Neural Substrate of Eye Movements
axon collaterals from pontine nuclei (see
Display 6-13, Chap. 6).239 Neurons in the
caudal fastigial nucleus discharge most
vigorously during the acceleration phase
of smooth pursuit onset; they sustain a
lower firing rate during the subsequent,
steady-state pursuit movement. 101 Al-
though these neurons modulate their dis-
charge during head movements, they do
not encode gaze velocity. Their pattern of
discharge at pursuit onset suggests that
these neurons may help accelerate the eye
during contralateral pursuit. 239 Thus, this
pattern is similar to the effects of the cau-
dal fastigial nucleus on saccades.
Unilateral inactivation with muscimol
decreases the acceleration of contralateral
pursuit onset and increases the accelera-
tion of ipsilateral pursuit onset; sustained
pursuit was impaired in all directions, but
it was impaired most for horizontal, con-
tralateral pursuit (see Display 10-19).264
This pattern of pursuit asymmetry is sim-
ilar to that reported in Wallenberg's
syndrome (lateral medullary infarction),
where lateral medullary infarction inter-
rupts olivary inputs to the cerebellar
cortex, possibly leading to excessive inhi-
bition of one fastigial nucleus.323 Para-
doxically, bilateral fastigial inactivation
causes little net effect on eye acceleration
during pursuit onset, but impairs sus-
tained pursuit responses in all direc-
tions.264 There is little effect on pursuit
latency. Patients with bilateral lesions
affecting the fastigial nucleus may appear
to show preservation of pursuit. 48
Thus, it seems likely that the caudal fasti-
gial nucleus contributes to smooth pursuit,
especially at its onset. However, the vestibu-
locerebellum may be more important dur-
ing steady-state pursuit. What is not known
is how this is achieved. Although the pro-
jections from the caudal fastigial nucleus to
saccade related structures are known, it is
not clear how signals related to smooth
pursuit reach ocular motoneurons.101
Nucleus of the Optic Tract and
Accessory Optic Pathway
In humans, the pathway that runs from
extrastriate areas MT and MST and the
frontal eye fields to the pontine nuclei and
cerebellum appears to play the major role
in generating smooth-pursuit eye move-
ments. However, there is another pathway
by which visual inputs can lead to smooth
eye movements; this is via the accessory
optic system (AOS) and the nucleus of the
optic tract (NOT).49'98'100'130'231
The AOS comprises a group of mid-
brain nuclei that receive mainly contralat-
eral retinal inputs via the accessory optic
tract: the dorsal terminal nucleus (DTN),
the lateral terminal nucleus (LTN), the
medial terminal nucleus (MTN), and the
interstitial terminal nucleus (ITN).231 The
retinal afferents to the AOS encode retinal
slip: neurons in the DTN respond to hori-
zontal stimulus motion, and neurons in
the LTN and MTN respond better to ver-
tical motion. The AOS projects to the
dorsal cap of the inferior olive and to
the nucleus prepositus hypoglossi—medial
vestibular nucleus (NPH-MVN) region.
Although neurons in the LTN respond to
moving visual fields, their responses satu-
rate above 157sec.100'229 Thus, the AOS
may be more concerned with visual adap-
tation of the vestibulo-ocular reflex than
with generation of smooth-pursuit or op-
tokinetic eye movements per se.
The NOT is a pretectal nucleus that lies
in the brachium of the superior colliculus,
from which it receives its retinal inputs. It
projects to the pontine nuclei, including
DLPN and NRTP, and the inferior olive,
but only weakly to the NPH-MVN region
(Fig. 4-7).49 The NOT also sends substan-
tial projections to the magnocellular layers
of the lateral geniculate nucleus, the
pregeniculate nucleus, thalamic nuclei
(including pulvinar), the mesencephalic
reticular formation, and the superior col-
liculus. Retinal slip information is mainly
provided to NOT by projections from MT,
MST, and striate cortex.130 An important
aspect of the projections to NOT is that
whereas neurons in MST variously show
preferences for ipsilateral or contralateral
stimulus motion, neurons in NOT re-
spond only to ipsilateral stimuli.100'230 This
rectification of the output from cortical vi-
sual areas has been demonstrated to de-
pend on crossing, callosal projections of
neurons showing contralateral, but not ip-
silateral, responses as they pass from MST

to NOT.130 A similar organization of other
cortical areas, such as FEF, may explain
why there appears to be no predominance
of preferred direction based on neuronal
activity, but lesions cause predominantly
ipsilateral pursuit deficits. Thus, stimula-
tion in NOT produces nystagmus with ip-
silateral slow phases.57 Most NOT units re-
spond preferentially to movement of a
large-field visual stimulus toward the side
of recording; they respond to visual stim-
uli of up to 60°/sec.137>230 Lesioning the
NOT abolishes or impairs slow phases of
optokinetic nystagmus directed towards
the side of the lesion.145 In sum, NOT ap-
pears to play an important role in the gen-
eration of eye movements to large, moving
visual stimuli, such as the early and late
components of optokinetic nystagmus.
Along with adjacent pretectal neurons, 232
it may also play a "switching" function,
possibly contributing to saccadic suppres-
sion, or the initiation of smooth pursuit.
Recent studies have indicated that when
binocular vision does not develop nor-
mally, the responses of NOT neurons are
affected, which may contribute to the syn-
drome of latent nystagmus (see Smooth
Pursuit, Visual Fixation, and Latent Nys-
tagmus, below).
Since NOT and DTN receive visual in-
puts from both retina and cortical visual
areas, what are the relative contributions
of each input to the optokinetic response?
Bilateral occipital lobotomies in monkeys
impair the optokinetic responses in three
ways:347 (1) the initial high-acceleration,
pursuit component of the response to a
constant velocity stimulus is abolished;56
(2) the velocity-storage component is poor
(low and variable gain) for high retinal-
slip velocities; and (3) monocular optoki-
netic response is better when the stimulus
moves temporal—nasally than nasal-
temporally, a nasal-temporal asymmetry.
These optokinetic properties are similar
to those shown by the normal rabbit.58
Unilateral hemisphere lesions, such as
hemidecortication or localized destruction
of area MST, cause deficits 1 and 2 above,
but not 3.87
How much does the accessory optic
pathway contribute to the optokinetic re-
sponses in humans? In newborn babies, in
whom pathways to the cerebral visual
Smooth Pursuit and Visual Fixation 173
areas remain immature, optokinetic re-
sponses show certain similarities to those
obtained in the rabbit;58 for example,
monocular optokinetic responses show
temporal-nasal asymmetry.7'270 Disap-
pearance of this temporal-nasal asymme-
try between 2 and 6 months of life implies
that pathways from retina to NOT and
AOS are functioning in humans at birth,
but that with the maturation of the cortical
visual pathways, projections via extrastri-
ate areas MT and MST to the brain stem
supercede. However, when amblyopia or
strabismus prevents normal development
of binocular vision, nasal-temporal asym-
metry of the optokinetic responses per-
sists.308
Patients with bilateral occipital-lobe le-
sions that cause cortical blindness usually
lack optokinetic responses; this is our ex-
perience and that reported by others.42-320
One patient was reported to show a slow
buildup of optokinetic nystagmus in one
direction, with full-field stimulation, but
there was some sparing of visual cortex
when his brain was examined post-
mortem.297 Thus, although the NOT and
AOS may contribute to visually induced
eye movements, the transcortical pathway
for optokinetic nystagmus is most impor-
tant once binocular visual mechanisms are
developed. One reason why the transcorti-
cal optokinetic mechanism has come to
eclipse the brain stem optokinetic pathway
in humans may be the evolution of frontal
vision and the consequent changes in op-
tic flow that occur during locomotion.212
The normally developed cortical contribu-
tion to OKN in humans provides a direc-
tional^ symmetrical monocular response,
achieves stabilization of images in one
depth plane during movement, and en-
sures that vergence mechanisms are pro-
vided with stable retinal images.133'212
Summary of Pursuit Pathway
Figure 4-7 summarizes important path-
ways for smooth pursuit. Retinal informa-
tion on the speed and direction of a mov-
ing target is abstracted in visual cortex,
especially areas MT and MST. Such pro-
cessing takes into account current eye
movements, encodes the direction and
174 The Properties and Neural Substrate of Eye Movements
speed of complex moving stimuli, and al-
lows for the effects of relative motion of
the background during pursuit (including
the case of fixating a stationary target dur-
ing self-motion). These signals are passed
on to frontal areas, which may contribute
predictive properties to the pursuit re-
sponse. The frontal and extrastriate visual
areas project to pontine nuclei, especially
the dorsolateral pontine nuclei (DLPN),
which contains cells encoding a mixture of
eye movement signals and visual infor-
mation. The NOT, which receives inputs
from areas MT and MST, may be impor-
tant in the initiation of pursuit by virtue of
its projections to the pontine nuclei and
the superior colliculus. The pontine nuclei
project to the paraflocculus, flocculus, and
dorsal vermis of the cerebellum. The cere-
bellum plays a critical role in synthesizing
the pursuit signal from visual and ocular
motor inputs. The dorsal vermis and fasti-
gial nucleus may contribute mainly to the
onset of pursuit, whereas the parafloccu-
lus and flocculus mainly sustain the pur-
suit response. The output of the flocculus
and paraflocculus is primarily through the
vestibular nuclei and y-group (for vertical
responses), but it remains unclear how the
fastigial nucleus effects its pursuit outputs.
Further details of the anatomical pathways
involved in smooth pursuit may be found
in Figure 6-7 in Chapter 6.
MODELS OF SMOOTH PURSUIT
Quantitative hypotheses, or models, have
played an important role in advancing our
understanding of how the brain programs
smooth-pursuit eye movements. Visually
mediated eye movements, such as smooth
pursuit, have traditionally been described
as negative feedback control systems. What
does this mean? Let us assume that, to
start with, the eye is stationary, and a tar-
get of interest starts to move at velocity T
(Fig. 4-9A). Thus, the stimulus to pursuit
is the velocity of motion, or slip, of the vi-
sual image of the target as it moves away
from the fovea, across the retina. In this
case, the error signal, which is called reti-
nal error velocity (REV in Fig. 4-9A) is equal
to target velocity. Retinal error velocity is
the signal used by the pursuit system to
generate an eye velocity command, E.
Note that as soon as the eye starts to move,
retinal error velocity is no longer equal to
target velocity. Now, retinal error velocity
is the difference between target velocity
and eye velocity. This subtraction of eye
velocity (via the visual feedback loop) from
target velocity to produce retinal-error ve-
locity is represented by the summing junc-
tion in Figure 4-9A. This subtraction re-
flects the physical fact that the retina is
attached to the eye. The calculation of
retinal error velocity is performed by the
visual system based on the rate of image
movement across the retina. The retinal
error signal is amplified by the brain to
generate an eye movement that will catch
up with the target. This model, therefore,
uses negative feedback with a central am-
plification; it is a simple velocity servo.
Ideally, we would want eye velocity (E in
Fig. 4-9A) to increase until it matched tar-
get velocity (T) so that the image of the
moving target would be held steady on the
fovea. However, the model shown in Fig-
ure 4-9A would not achieve this because if
the retinal error velocity were reduced to
zero, then the stimulus for the eye move-
ment would disappear, and the eye would
slow down and fall behind the target.
What could be achieved by this model is a
steady state in which a constant, small reti-
nal error velocity remains in order to sus-
tain tracking. Intuitively, it is apparent
that if the internal amplification factor (or
open-loop gain, GOL) is large, then small
amounts of retinal slip will still drive an
eye movement. A convenient measure of
the overall tracking performance is the
overall or closed-loop gain, GCL, which is
given by the ratio eye velocity/target veloc-
ity. An equation relating GQL and GCL is
given in Figure 4-9A. It can be seen that
for eye speed to be close to target speed
(GCL close to 1.0), the value of GOL must be
large.
Negative feedback is widely used in
physiologic control systems. It offers cer-
tain advantages: a prompt and accurate
response to stimuli and a relative insensi-
tivity to changes in internal parameters.
Consider, for example, the effects of a de-
cline in the value of the internal amplifica-
 Smooth Pursuit and Visual Fixation 175

Figure 4-9. Models for smooth pursuit. (A) Negative feedback hypothesis. The target velocity (T) and the eye
velocity (E) are compared at the retina indicated by the summing junction. The difference is the retinal image
motion—the error velocity signal (REV)—which stimulates the pursuit system. GOL is the open-loop gain or am-
plification factor. It determines the velocity of the resulting pursuit eye movement (E). The time delay repre-
sents the time taken for neural processing. G CL is the closed-loop gain. CNS, central nervous system. (B) A pur-
suit model similar to that proposed by Yasui and Young.338 In this scheme it is not the retinal error signal but an
internal representation of the motion of the target in space, (T), that drives the pursuit system. This internal
representation of target velocity is constructed by combining retinal error velocity (REV), after the delay due to
visual processing (TR), with an internal signal or efference copy of eye-velocity smooth-pursuit command (£"SP)
at an internal summing junction. (T 1 ) is subject to central processing delays (T,), and a low pass filter with time
constant T, (s is the Laplace operator) and drives the pursuit response according to a nonlinear gain (the equiv-
alent of GOL, an acceleration saturation). G is the gain of the internal feedback loop, which also takes into ac-
count the mechanical properties of the orbital tissues ("Eyeball"), and the delay due to visual processing ("TR").
An extension of the model would include the effects of retinal image acceleration.171-177

don factor or GOL. Such a decline might
occur with disease. From the equation in
Figure 4-9A, a decline in GOL from 9.0 to
4.0 would cause GCL to drop only from 0.9
to 0.8. So, a >50% reduction of GOT would
cause only a small effect on overall smooth
pursuit gain. Negative feedback also car-
ries a potential risk: oscillations caused by
instability. Instability is more likely if the
gain, GQL, is high and if there are time de-
lays in the system.
Although the model in Figure 4-9 is an
oversimplified representation of smooth
pursuit, it does make an interesting pre-
176 The Properties and Neural Substrate of Eye Movements
diction. If normal closed-loop gain is close
to 1.0 (near-perfect tracking), then GQL
must be large. This prediction can be
tested experimentally by using a number
of techniques to artificially open the visual
feedback loop, i.e., dissociate retinal error
velocity from the effects of eye movements
that it stimulates. For example, the visual
feedback loop is opened when one eye is
immobilized and a moving stimulus is pre-
sented to it. In this case, the velocity at
which images drift across the retina can no
longer be affected by eye movements. The
response to this open-loop stimulation can
be studied by measuring the movements
of the other eye, which is mobile but cov-
ered (to prevent visual feedback). Ter
Braak was among the first to perform this
experiment (an English translation of his
paper can be found as an appendix to the
monograph by Collewijn).58 He used opto-
kinetic stimulation in the rabbit and found
that the open-loop gain, GQL, was indeed
high: the covered eye moved many times
faster than the stimulus. Similar results
have been reported in monkeys.158 Pa-
tients with a complete unilateral ophthal-
moplegia and with preservation of vision
provide conditions suitable for measur-
ing the open-loop gain.113-116'186'291 Similar
large values have been found for the
open-loop gain from these studies, partic-
ularly for low-stimulus velocities. During
chronic exposure to such an open-loop sit-
uation, plastic adaptive changes, for ex-
ample, in the vestibulo-ocular reflex, are
also stimulated.291
The feedback loop also can be opened
in normal subjects by artificially stabilizing
stimuli on the retina using electronic feed-
back systems.82'331 Another method is to
use photoflash afterimages placed close to
the fovea.129 All these methods suffer from
the drawback that during this open-loop
condition, the mental state of the sub-
ject may considerably influence the re-
sults.9'67'186'315 Because there is a time
delay in the pursuit response of approxi-
mately 100 msec, another method of
studying the open-loop pursuit response
is to measure the movement of the eye
that occurs prior to the response of the vi-
sual system to that eye movement. This
technique measures the initial eye acceler-
ation using step-ramp stimuli (discussed
in the section Onset of Pursuit, above).
Since feedback tends to "protect" the
closed-loop gain of the system, measuring
the open-loop response directly is a more
sensitive way of determining if there has
been a change in the internal workings of
the system.
The model of Figure 4-9A incorporates
a time delay, which is about 100 msec, and
is largely due to delays in the visual sys-
tem. This delay has an important potential
consequence: if the gain GOL is large (high
amplification), this negative feedback sys-
tem would become unstable, with oscilla-
tions. Although damped oscillations (ring-
ing) occur during smooth pursuit, their
magnitude is small and, overall, tracking
is relatively stable, thus implying that a
simple negative feedback model does not
account for normal behavior. This discrep-
ancy led Young and colleagues338 to postu-
late that the stimulus to the pursuit system
is not retinal error velocity per se, but an
internal representation of the motion of
the target in space (Fig. 4-9B). This inter-
nal representation of target velocity is ob-
tained by combining retinal error velocity
with an eye velocity signal, which is proba-
bly based on monitoring of motor com-
mands (efference copy or corollary dis-
charge). The effect of adding this positive,
internal feedback loop is to cancel the
outer, negative, visual feedback loop; the
effective model is therefore open-loop.
However, if the efference copy loop did
not exactly match the visual feedback loop
(a plausible possibility, since the former
depends on the performance of neurons,
but the latter on physics), then certain fea-
tures of pursuit onset, such as the oscil-
lations at onset (Fig. 4-3), could be
explained.177'252 This model has been ex-
tended further to account for dynamic as-
pects of pursuit onset,77'263 the effects of
pursuit adaptation that occur, for exam-
ple, after extraocular muscle palsies,244'263
and the finding that acceleration of im-
ages on the retina also drives smooth-
pursuit onset.171'1733
The model shown in Figure 4-9B has
also been extended to account for the ces-
sation of smooth pursuit, which may be
equivalent to visual fixation.8'135'185 One
 Smooth Pursuit and Visual Fixation 177

manifestation of an abnormal fixation

mechanism is abnormal drifts, which lead
to nystagmus (see A Pathophysiological
Approach to the Diagnosis of Nystagmus
in Chap. 10). In patients with nystagmus
who also have disease affecting the visual
pathways, such as demyelination in optic
neuritis, prolongation of the delay due to
visual feedback beyond 100 msec might be
the cause of oscillations (Fig. 4-10A).24 In
normal subjects, it is possible to induce
spontaneous ocular oscillations by experi-
mentally increasing the latency of visual
feedback during fixation (Fig. 4-1 OB). 329
However, the frequency of these induced
oscillations is <2.5 Hz, which is lower than
that in most patients who have acquired
pendular nystagmus in association with
optic nerve demyelination. Furthermore,
when this experimental technique is ap-
plied to patients with acquired pendular
nystagmus, it does not change the char-
acteristics of the nystagmus, but instead,
superimposes lower-frequency oscillations
similar to those induced in normal sub-
jects (Fig. 4-1OC). Thus, disturbance of vi-
sual fixation due to visual delays cannot
account for the high-frequency oscillations
that often characterize acquired pendular Figure 4-10. Effect of electronically delaying the vi-
nystagmus. sual consequences of horizontal eye movements dur-
During steady-state smooth pursuit of ing attempted fixation; details of the methodology
predictable target motion (such as a sine are described elsewhere.8 (A) Acquired pendular
nystagmus during attempted fixation of a stationary
wave), many normal subjects can generate target in a patient with multiple sclerosis. The fre-
eye movements that match target move- quency of these quasisinusoidal oscillations is over 6
ment with a gain of 1.0 and no phase Hz. (B) Effect of electronically delaying visual feed-
shift.68'351 Models such as those in Figure back by 480 msec in a normal subject, starting at time
4-9 cannot account for this behavior. The zero. The subject developed spontaneous ocular os-
cillations at about 1.0 Hz. (C) Effect of electronically
same problem occurs when such models delaying visual feedback by 480 msec in the patient
are used to account for sustained visual whose nystagmus is shown in (A). The oscillations of
fixation: the dynamic properties are better her nystagmus (essentially unchanged) were super-
than what could be accounted for given imposed upon growing oscillations at about 0.67 Hz,
which were induced by the electronic manipulation.
the delays in the system, especially that Positive rotations are rightward.
due to visual processing.8'135'177'329 The
conclusion from this discrepancy between
model predictions and observed behavior
is that both sustained smooth pursuit of a CLINICAL EXAMINATION
moving target and fixation of a stationary OF FIXATION AND
one require a predictor mechanism. Sev- SMOOTH PURSUIT
eral such models have been proposed, 21 ' 154
with different topology and underlying as- Examining Fixation
sumptions. These models suggest experi-
ments that are likely to produce new in- First examine the patient's eyes while they
sights into how the brain generates are in primary position. This should be
visually mediated eye movements. performed as the patient views an object
178 The Properties and Neural Substrate of Eye Movements
located across the room, and which re-
quires a visual discrimination, such as an
optotype of a visual acuity chart. (Evalua-
tion of the stability of fixation during ec-
centric gaze-holding is discussed in Chap.
5.) Next, occlude one eye and observe the
other eye to see if any abnormalities—
particularly latent nystagmus—develop.
Switch the cover and repeat this proce-
dure for the other eye.
The most sensitive clinical method to
evaluate fixation is with the ophthalmo-
scope: the patient fixates with one eye
while the optic disc of the other is viewed
by the examiner. Look for any drifts, nys-
tagmus, or saccadic intrusions. If nystag-
mus is observed, examine one eye with the
ophthalmoscope and transiently occlude
the other, to determine if the nystagmus
increases as fixation is prevented.
In evaluating visual fixation, the exam-
iner should keep in mind that gaze is less
steady in preschool children,166 and it may
be disrupted by saccadic intrusions in
some normal individuals, particularly the
elderly. 128,273
Examining Smooth Pursuit
Ask the patient to track a small target with
the head still, such as a pencil tip held a
meter or more before the eyes. Initially,
move the target at a low, uniform speed.
Pursuit movements that do not match the
target velocity necessitate corrective sac-
cades. If these are catch-up saccades, then
the pursuit gain is low. If pursuit gain is
too high (for example, because of super-
imposed slow phases of nystagmus), then
backup saccades are seen. During a series
of regular to-and-fro movements of the
test object, suddenly stop the target mo-
tion at a turnaround point and look for a
brief continuation of pursuit; this tests the
ability of the patient to use a predictive
strategy (see Appendix A for a summary).
In evaluating smooth pursuit, recall that
these movements depend upon the sub-
ject's ability to direct visual attention and
are particularly susceptible to the influ-
ence of medications. Moreover, "normal"
smooth pursuit depends upon the sub-
ject's age. It is not well developed in young
infants178>249,267,28o,32i and is more variable
in preschool children than in adults.4-166
Smooth-pursuit performance progres-
sively deteriorates in old age.247'344 In eval-
uating smooth pursuit, recall that some
normal subjects may show directional
asymmetries, usually in the vertical plane
and sometimes worse during downward
tracking.15 With these qualifications, it is
usually possible, with experience, to deter-
mine clinically if pursuit is abnormal, or at
least if it warrants quantitative evaluation.
Certain special techniques are often use-
ful for the clinical evaluation of pursuit.
Uncooperative or inattentive patients, small
children, or those thought to have hysteri-
cal blindness may be tested by slowly rotat-
ing a mirror held before their eyes; a large
mirror that fills most of the visual field is a
compelling stimulus for visual tracking.
Hand-held optokinetic drums or tapes do
not adequately test the optokinetic system
but do stimulate pursuit. These are useful
tools for demonstrating pursuit asymme-
tries (e.g., with cerebral hemispheric dis-
ease) and "reversed pursuit" seen in some
patients with congenital nystagmus. Al-
though the corrective quick phases are
most evident at the bedside, it is the direc-
tion and nature of the slow phases that
should be analyzed. For example, a pa-
tient with a right posterior cerebral lesion
may show fewer corrective quick phases
when the drum is rotated to the right side.
This is in part because the pursuit gain is
lower to the right, and, because the eyes
deviate more slowly from the primary po-
sition, fewer quick phases are needed.
In some patients, it will be difficult to
test smooth pursuit because of sponta-
neous nystagmus. Sometimes this nystag-
mus is less prominent in the central posi-
tion or at some null point. In these
patients, pursuit function can be inferred
by testing cancellation or suppression of
the vestibulo-ocular reflex with the eyes
held in this orbital position (see Smooth
Tracking with Eyes and Head in Chap.
7) 79,345 Patients often do this best by fixat-
ing their thumb nail with an arm out-
stretched while they rotate their heads.
Those who have muscle weakness can be
rotated in a wheelchair while fixating the
examiner's pointer (which rotates with the

chair). As with pursuit, the rotation should
be gentle at first. With inadequate cancel-
lation, the eyes will be continually taken
off target by the slow phase of the
vestibulo-ocular reflex and corrective sac-
cades will be made. An asymmetrical
deficit may imply a pursuit imbalance; for
example, deficient cancellation of the
VOR on rotation to the right corresponds
to a low pursuit gain to the right. When
there is a clear discrepancy between the
performance of smooth pursuit and can-
cellation of the VOR (e.g., poor pursuit
but good cancellation), then one should
suspect an inadequate or asymmetrical
VOR.
LABORATORY EVALUATION
OF FIXATION AND
SMOOTH PURSUIT
A prerequisite for smooth-pursuit testing
is to maintain the alertness and attention
of the subject or patient; recording ses-
sions should be kept as short as possible.
The most commonly used stimulus for
smooth pursuit is a small, bright spot of
light, typically from a Helium-Neon laser,
projected onto a dark or featureless
screen. The position of the target light is
usually controlled by mirror galvanome-
ters that lie in the ray's path. A correction
for the tangent error inherent in project-
ing the stimulus onto a flat screen is neces-
sary for larger target movements; another
solution is to project the target onto an arc
at the center of which the subject sits. An
alternative to a projected stimulus is a
bright spot on a video screen. This
method allows more precise control over
the stimulus but the range of movement is
usually less than the requisite ±20° useful
for clinical testing. Alternatively, a video
image may be projected onto a large
screen.
To investigate the onset of smooth pur-
suit, step-ramp or ramp stimuli of various
velocities (typically 5° to 30°/sec) are used
(Fig. 4-3). Several advantages are offered
by nonpredictable, step-ramp stimuli. (7)
The initial response of smooth pursuit can
be directly related to the stimulus, as there
Smooth Pursuit and Visual Fixation 179
has not been time for any eye movement
to influence the visual stimulus (the re-
sponse is open-loop). (2) Because visual
feedback tends to compensate for the sys-
tem's inadequacies, it follows that the
open-loop response to a step-ramp stimu-
lus is a more sensitive index of dysfunction
than the closed-loop response that occurs
during maintenance of pursuit. (3) Using
step-ramp stimuli, it is possible to stimu-
late selected portions of the extrafoveal vi-
sual field, a useful facility in studying, for
example, patients with focal cerebral le-
sions who may have a retinotopic tracking
deficit. The response to step-ramp stimuli
may be analyzed to determine latency to
onset of pursuit; average eye acceleration
in the first 100 msec (open-loop response);
peak eye acceleration and the time taken
to reach it and the velocity at that time;
peak velocity of the first overshoot and the
time to reach it; frequency of ringing; and
steady-state gain.263 The relationship be-
tween peak eye acceleration and target ve-
locity is one measure of the initiation of
smooth pursuit. In some studies, interac-
tive computer programs have been used
to identify valid trials, remove saccades,
and average the responses to several trials.
Averaging programs, however, may hide
some of the dynamic features of the re-
sponse because of trial-to-trial variations.
Maintenance of smooth pursuit is usu-
ally tested with predictable waveforms
such as constant-velocity (ramp) and sinu-
soidal target motion. During smooth pur-
suit of a constant-velocity target, the most
useful measurement is gain (eye velocity/
target velocity). Eye velocity may be esti-
mated either from maximum smooth eye
velocity for each trial269 or from eye veloc-
ity as the eye passes through central po-
sition. For constant-velocity waveforms,
gain should be estimated for each of sev-
eral trials at the same target velocity; then
mean gain can be calculated. This should
be done for several different target speeds
(e.g., 5°-507sec) and directions. These
measurements are most easily accom-
plished by computer programs. Our expe-
rience is that interactive approaches,
which allow the investigator to exclude
saccades or blinks, are more reliable than
automated methods.
180 The Properties and Neural Substrate of Eye Movements
For sinusoidal target motions, gain may
be estimated from peak eye velocity/peak
target velocity. The dependence of gain on
peak target acceleration is a useful mea-
sure of the pursuit performance (see Mod-
els of Smooth Pursuit, above). Alterna-
tively, using digitized data, it is possible to
remove saccades and perform a Fourier
transform of target and eye signals and
thereby compute gain and phase.
A variety of indirect methods are com-
monly used to measure smooth-pursuit
performance.3 Attempts to quantify smooth
pursuit by measuring frequency and num-
ber of saccades are prone to error, since
saccadic abnormalities (e.g., square wave
jerks) may disrupt overall tracking but not
necessarily imply impaired pursuit (i.e.,
pursuit gain may be normal): Similarly,
power spectral measurements (e.g., nat-
ural logarithm of ratio of the power at tar-
get frequency to power at higher frequen-
cies) or root-mean-square error values are
estimates of overall tracking, not just
smooth pursuit. Finally, qualitative rating
scales of pursuit as relatively "normal" or
"deviant" are of little value in determining
the nature of the deficit.3 For quantitative
aspects of smooth eye-head tracking, see
the Evaluation of Eye-Head Movements in
Chapter 7.
ABNORMALITIES OF
VISUAL FIXATION AND
SMOOTH PURSUIT
Here we discuss the pathological physiol-
ogy of disordered fixation and smooth
pursuit. In Chapter 10, these abnormali-
ties are approached from the viewpoint of
topological diagnosis.
Abnormalities of Visual Fixation
Steady fixation may be disrupted by slow
drifts, nystagmus, or involuntary saccades.
Since normal subjects show miniature
movements of all three types (Fig. 4-1),
determination of abnormal fixation be-
havior is sometimes dependent on statisti-
cal analysis of measured eye movements.
One specific example of the problem of
determining what is abnormal concerns
square-wave jerks (Fig. 10-16A, Chap.
10). These are small saccades (typically
0.5-5.0 deg) that take the eye away from
the fixation point and after a period of
about 200 msec, return it to the starting
position. Many normal subjects show
square-wave jerks when they attempt
steady fixation.128'273 The frequency of
these saccadic intrusions upon fixation is
greater in older subjects. In some elderly
subjects, the frequency of square-wave
jerks is as great as that occurring in cer-
tain neurological conditions, notably pro-
gressive supranuclear palsy, Friedreich's
ataxia, and focal cerebral lesions.275 Thus,
such disruption of fixation is only sugges-
tive of an underlying neurological condi-
tion. Square-wave jerks are discussed fur-
ther in the section Saccadic Intrusions in
Chapter 10.
Detection of nystagmus during at-
tempted steady fixation is abnormal. If the
slow-phase velocity or intensity of such
nystagmus is similar both during fixation
and when fixation is prevented (e.g., by
Frenzel goggles or in darkness), then a
disorder of the fixation system is inferred.
If slow-phase velocity is reduced during
attempted fixation, then the fixation sys-
tem is at least partially functioning and an-
other ocular motor disorder (e.g., imbal-
ance of vestibular drives) is present. A
variety of conditions may lead to nystag-
mus during attempted fixation and are
discussed under A Pathophysiological Ap-
proach to Nystagmus in Chapter 10.
Disorders of the visual system lead to in-
stability of gaze; the extreme example is
blindness (see Fig. 10-10, Chap. 10).189
Monocular loss of vision may lead to un-
stable gaze in the affected eye, which is
predominantly due to slow, low-frequency
vertical drifts. 187 These movements may
reflect disturbance of a monocular fixation
system or, perhaps, vergence.341 Binocular
loss of vision causes loss of gaze stability
and a continuous horizontal and verti-
cal nystagmus develops (see VIDEO: "Eye
movements with complete blindness").
This nystagmus characteristically changes
direction over the course of seconds
and minutes, a feature also encountered

following experimental cerebellectomy.262
Thus, the nystagmus that follows bilateral
visual loss reflects a gaze-holding mecha-
nism that has never been calibrated by vi-
sual inputs. Acquired lesions of the cere-
bellum without specific involvement of the
visual pathways may disrupt fixation with
saccadic intrusions and with slow drifts,
especially in the vertical plane, that lead to
nystagmus.13'2'242 These abnormalities may
reflect the important role of the cere-
bellum in optimizing fixation to provide
clearest vision.
As discussed in Models of Smooth Pur-
suit, the pathogenesis of pendular oscilla-
tions in association with visual loss is unde-
termined. Experimental deprivation of
information on retinal slip velocity during
development causes a 4- to 5-Hz pendular
nystagmus.64'209 When pendular nystag-
mus occurs in association with optic nerve
demyelination due to multiple sclerosis,
the size of the oscillations tends to be
greatest in the eye with worse vision.24
However, experimental studies (Fig. 4-10)
indicate that visual delays cannot be the
cause of their nystagmus. 8
Abnormal maturation of binocular vi-
sual mechanisms may be responsible for
disruption of steady fixation by latent nys-
tagmus and, in some cases, by congenital
nystagmus; these conditions are discussed
below.
Abnormalities of Smooth Pursuit
ABNORMALITIES OF
PURSUIT INITIATION
Here we will discuss disorders of smooth
pursuit in terms of abnormalities of initia-
tion, gain, and symmetry. The issue of dis-
turbance of pursuit in latent and congeni-
tal nystagmus will also be reviewed. Like
fixation, smooth pursuit can be disrupted
by saccadic intrusions and, often, disease
affecting the pursuit system also causes
square-wave jerks and other saccadic ab-
normalities.
The advantages of studying the onset of
pursuit were discussed above; in the case
of cortical lesions, step-ramp stimuli are
particularly valuable because they provide
Smooth Pursuit and Visual Fixation 181
a method of controlling the location of the
visual stimulus on the retina (i.e., in the vi-
sual field). Because of the latency of the
pursuit system (approximately 100 msec),
the initial 100 msec of the response will re-
flect stimulation of the selected portion of
retina. Thus, using step-ramp stimuli, it
has been shown that experimental, unilat-
eral lesions of striate cortex cause a loss of
smooth pursuit for targets moving in the
blind visual field; 272 this deficit is not evi-
dent during pursuit of a predictably mov-
ing target partly because of preserved
macular vision.131 In humans, bilateral oc-
cipital lobe lesions abolish or prevent the
development of smooth pursuit. 259
More important, it has been possible to
identify distinct disturbances of ocular
tracking due to lesions of secondary visual
areas.220'301 One such disturbance was ex-
emplified by a patient who complained of
difficulties in seeing moving, but not sta-
tionary, objects in his right visual hemi-
field following a stroke (Fig. 4-8).184'301
Routine perimetric testing of his visual
fields was normal. Furthermore, testing of
pursuit with predictable, sinusoidal stim-
uli showed little abnormality. Neverthe-
less, with step-ramp stimuli, his ocular
motor deficits reflected a loss of the ability
to estimate the speed of moving objects in
the right visual hemifield. Specifically, the
initiation of pursuit and planning of sac-
cades to targets moving to right or left
within the right visual hemifield were im-
paired. In contrast, saccades made to static
target displacements were normal (Fig.
4-8). Thus, these deficits are similar to
those described in monkeys after lesions of
the middle temporal visual area (MT): a
retinotopic defect for the perception of
motion. The lesion lay at the junction of
temporo-occipital cortex (Fig. 4-8), sug-
gesting it might involve the human homo-
logue of area MT.
A second type of tracking deficit occur-
ring with unilateral cerebral lesions con-
sists of a directional pursuit deficit in
which horizontal pursuit directed towards
the side of the lesion is impaired com-
pared with contralateral pursuit (Fig.
4-1 IB). Using step-ramp stimuli and mea-
suring the onset of smooth pursuit, it has
been demonstrated that this unidirec-
182 The Properties and Neural Substrate of Eye Movements

tional deficit occurs irrespective of the

visual hemifield into which the stimulus
falls (Fig. 4-11C).220'301 A retinotopic deficit
such as that occurring with lesions of MT
may or may not coexist. The unidirec-
tional deficit may occur with lesions affect-
ing posterior cortical areas and underly-
ing white matter (Fig. 4-11A); this may be
due to damage to the medial superior
temporal visual area (MST) or its projec-
tions. In addition, a unidirectional defect
of smooth pursuit may occur following le-
sions of the frontal lobes that affect the
frontal eye field222 or of the supplemen-
tary eye field.122'191
The initiation of pursuit has also been
investigated in patients with latent nystag-
mus.308 By presenting step-ramp stimuli
monocularly, it was possible to demon-
strate a nasal-temporal asymmetry such
that nasally directed target motion evoked
a more vigorous onset of pursuit. This
finding is evidence for maldevelopment of
visual motion processing in patients with
latent nystagmus and is discussed further
below.
Another advantage offered by studying
the initiation of smooth pursuit is that it
measures the open-loop gain of the pur-
suit system; this is a sensitive index of
smooth pursuit dysfunction. Three exam-
ples of how this strategy has proven effec-
tive are in studying adaptive changes oc-
curring following extraocular muscle
palsy, identifying pursuit abnormalities in Figure 4-11. Asymmetric impairment of horizontal
some cases of congenital nystagmus, and smooth pursuit due to unilateral lesions of the cere-
in confirming a disorder of pursuit in bral hemispheres. (A) Computer-generated three-di-
mensional reconstruction of the zones of lesion con-
schizophrenia. Each example is discussed fluence associated with asymmetric reduction of
further below. It seems likely that in the pursuit gain in eight patients; ipsilateral pursuit ve-
future, the initiation of smooth pursuit will locities were consistently lower than contralateral ve-
be tested in a variety of clinical conditions. locities. The affected cortical areas included Brod-
mann 19 and the adjacent ventrocaudal aspect of
area 39. (From Morrow MJ, Sharpe JA. Cerebral
ABNORMALITIES OF PURSUIT TO hemispheric localization of smooth pursuit asymme-
try. Neurology 1990;40:284-292, with permission of
SUSTAINED TARGET MOTION Lippincott Williams and Wilkins.)
Low gain pursuit is a common ocular mo- Continued on following page
tor abnormality. Recent attempts have
been made to differentiate between a low gain occurs with a variety of conditions,
steady-state pursuit gain in response to including old age,247>282'344 Parkinson's dis-
constant-velocity target motions (i.e., re- ease,327 progressive supranuclear palsy,303
duced gain at both low and high target ve- and following large cerebral lesions.304 Im-
locities, termed velocity saturation) and a re- pairment of smooth pursuit due to an ab-
duction of pursuit gain with accelerating normal acceleration saturation is seen with
targets (e.g., sine waves), so-called acceler- posterior cortical lesions,188'219 Alzheimer's
ation saturation. Low steady-state pursuit disease,96 and schizophrenia.193
Figure 4-11.—continued (B) An example of asymmetric smooth pursuit in a patient with a porencephalic cyst of
the right cerebral hemisphere. Note how smooth pursuit to the right (upward) is impaired, but corrective sac-
cades are accurate. During tracking to the left, eye velocity exceeds target velocity, and back-up saccades are
made. (C) Step-ramp responses to same patient as in B. Pursuit initiation in response to rightward ramps is im-
paired compared with leftward ramps, regardless of the visual hemifield stimulated. In addition to this unidi-
rectional pursuit deficit, saccades made to targets in the left visual hemifield are hypometric or delayed, sug-
gesting a defect of motion processing in that hemifield. Thus this deficit is similar to that described after
experimental lesions of the medial superior temporal visual area (MST) or the descending pursuit pathway in
monkey. R, right; L, left. (Reproduced from Thurston SE, Leigh RJ, Crawford T, Thompson A, Kennard C.
Two distinct deficits of visual tracking caused by unilateral lesions of cerebral cortex in humans. Ann Neurol
1988;23:266-73, with permission of Lippincott Williams and Wilkin 183
184 The Properties and Neural Substrate of Eye Movements
Studies of the effects of predictive as-
pects of smooth pursuit have shown im-
pairment in schizophrenia193 but preser-
vation in patients with Alzheimer's disease96
who have otherwise poor tracking. Large
lesions of the cerebral hemispheres caus-
ing predominantly ipsilateral tracking
deficits have been reported to impair,39
but not abolish,192 predictive aspects of
smooth pursuit. Frontal lesions impair
smooth pursuit more than posterior le-
sions.122 Smooth anticipatory eye drifts
that precede predictable target stepping
are absent in patients with cerebellar dis-
ease who have impaired smooth pur-
suit.223
Excessively high pursuit gain may re-
flect adaptive changes due to extraocular
muscle palsy. If, for example, a patient
with partial left abducens palsy is forced to
use that eye (by patching the normal, right
eye), increased innervation is sent to the
weak muscle.244 If, after several days, the
patch is switched so that the normal eye
views again, smooth-pursuit gain of the
right eye to the left is increased and track-
ing is unstable with pendular oscillations;
the latter were most evident when the ini-
tiation of pursuit was studied using step-
ramp stimuli. These findings imply that
pursuit adaptation, rather than simple
negative feedback, is used to optimize
smooth-tracking performance.
An asymmetry of horizontal smooth
pursuit is seen with lesions of certain por-
tions of the pathway for smooth pursuit
(Fig. 4-1 IB). Thus, some patients with
unilateral, lesions of the cerebral hemi-
spheres show impaired tracking of targets
moving towards the side of the lesion.
This has been most commonly reported
with lesions restricted to posterior corti-
cal areas and underlying white matter
(Fig. 4-11A),219'301 but it also occurs with
frontal lobe lesions191'222 and is invariable
with large lesions such as hemidecortica-
tion. 276 > 304 Clinically, this pursuit deficit is
often brought out with hand-held opto-
kinetic drums or tapes.17'55'65'97-163 This
impairment of smooth pursuit is inde-
pendent of homonymous hemianopia or
visual neglect.301 Use of step-ramp stimuli
(Fig. 4-11C) has demonstrated that in pa-
tients with intact visual fields, this direc-
tional deficit is present for visual stimuli
presented in either visual hemifield.184'220
After an acute large hemispheric lesion,
there may be a defect of pursuit in cran-
iotopic coordinates, with difficulty moving
the eyes in the contralateral orbital hemi-
range. There may also be contralateral ne-
glect, especially with right-sided lesions.
However, within the remaining field of
movement, pursuit responses to stimulus
motion towards the intact hemisphere are
greater.217
In some patients with unilateral lesions
of the cerebral hemispheres, pursuit away
from the side of the lesion may also have
reduced gain, though not usually so much
as ipsilaterally.191'219 In other patients,
particularly those with large lesions such
as hemidecortication or involvement of
the posterior internal capsule,253 pursuit
eye movements away from the side of the
lesion may be faster than the target (i.e.,
smooth pursuit gain exceeds 1.0). An ex-
ample is shown in Figure 4-1 IB. One con-
sequence of such increased gain for con-
tralateral pursuit is that the moving target
is held in the visual hemifield ipsilateral to
the side of the lesion, where the ability to
estimate target speed is likely to be nor-
mal;184 responses to moving stimuli pre-
sented into the visual hemifield contralat-
eral to the side of the lesion may be
impaired.
An ipsilateral pursuit deficit similar to
that due to hemispheric disease may be
encountered with unilateral lesions at
lower points in the descending pursuit
pathway (Fig. 4-7), such as in the thala-
mus,41 midbrain tegmentum,343 dorsolat-
eral pontine nucleus,105'298 and cerebel-
lum.326 However, because of the double
decussation of the smooth-pursuit path-
way (see Fig. 6-7, Chap. 6), lesions involv-
ing the vestibular nucleus or pontine pro-
jections to the cerebellum may cause a
greater impairment of either ipsilateral322
or contralateral smooth pursuit. 14 - 103 ' 141
Disturbance of vertical smooth pursuit
occurs with bilateral internuclear ophthal-
moplegia (INO).254 Lesions affecting the
brachium conjunctivum, which conveys
pursuit signals from the y-group nucleus
to the oculomotor nucleus, may also im-
pair smooth pursuit.54'250 It has also been

reported that projections from the pon-
tine nuclei to the cerebellum may affect
vertical smooth pursuit. In three patients
with cavernous angiomas involving the
middle cerebellar peduncle, torsional nys-
tagmus developed during vertical pursuit.
This finding suggests that pursuit signals
might be encoded in the same planes as
the labyrinthine semicircular canals, per-
haps during cerebellar processing.95 Le-
sions restricted to either the paramedian
pontine or mesencephalic reticular forma-
tion impair saccades but spare horizontal
and vertical smooth pursuit. 121 - 127
In some patients with asymmetry of
pursuit, nystagmus is present during fixa-
tion with the eyes near to central position.
Thus, horizontal nystagmus is reported in
some patients with unilateral cerebral le-
sions, particularly those with increased
gain of contralateral pursuit. 276 This nys-
tagmus is low amplitude, with slow phases
drifting away from the side of the lesion at
a few degrees per second. Such nystagmus
has been hypothesized to indicate an im-
balance of pursuit tone. Another circum-
stance in which an imbalance of pursuit
drives has been postulated as a cause of
nystagmus is with cerebellar or brain stem
lesions.2'346 The nystagmus is present with
the eyes close to primary position and may
be downbeat, upbeat, or horizontal (see
Fig. 10-7, Chap. 10). In such patients, the
slow-phase velocity is unchanged in dark-
ness and smooth pursuit is impaired. The
more likely cause for nystagmus with cere-
bellar or brain stem disease is now
thought to be an imbalance of central ves-
tibular connections.12
Smooth Pursuit, Visual Fixation,
and Latent Nystagmus
Individuals with latent nystagmus, 73 a
congenital form of nystagmus (see VIDEO:
"Latent nystagmus"), show abnormalities
of smooth pursuit. This conjugate nystag-
mus is brought out or exaggerated by cov-
ering one eye (hence, "latent" nystagmus).
The slow phases of this conjugate nystag-
mus are directed such that the viewing eye
rotates towards the nose. Latent nystag-
Smooth Pursuit and Visual Fixation 185
mus is probably always associated with
strabismus and lack of development of
normal binocular vision.
Monkeys that are binocularly deprived
of pattern vision early in life may develop
latent nystagmus.306 A similar nystagmus
can be produced in monkeys by surgically
creating strabismus in the first 2 months of
life.157 Such monkeys also show an asym-
metry of smooth pursuit and optokinetic
movements, with stronger responses for
nasally than temporally directed target
motion.305 In humans, the asymmetry of
pursuit is more marked at the onset than
during maintenance.308 Furthermore, if
moving stimuli are briefly presented after
pursuit is underway, nasally and tempo-
rally directed image motion is equally ef-
fective in modulating eye velocity.157 This
suggests that the defect is more related to
pursuit initiation than maintenance. Elec-
trophysiological studies have shown that
neurons in MT in strabismic monkeys
have normal responses but are rarely dri-
ven binocularly.157 In NOT, neurons nor-
mally respond to visual stimuli presented
to either eye,100 but in binocularly de-
prived monkeys, neurons are driven ex-
clusively or mainly by the contralateral
e y e 233,305 This contralateral eye domi-
nance seems to be relevant to the patho-
genesis of LN. For example, during
monocular viewing through the right eye,
the left NOT will be activated preferen-
tially, thus producing leftward smooth
movements (slow phases of nystagmus).
Support for this hypothesis comes from
the finding that inactivation of the NOT
abolishes LN in monkeys who have been
deprived of binocular vision.233 Further-
more, lesioning the NOT abolishes flash
nystagmus, which occurs during monocu-
lar stimulation with repetitive flashes of
light and has similarities to latent nystag-
mus. 319
Whether binocular deprivation of vision
affects other brain stem targets of areas
MT and MST, such as the pontine nuclei,
remains unknown. It also seems likely that
other factors, such as abnormal extraoc-
ular proprioception138 or disturbance of
either directed visual attention or ego-
centric localization, play a role in the
pathogenesis of LN.72'162 Thus, some sub-
186 The Properties and Neural Substrate of Eye Movements
jects can change direction of their nystag-
mus by "attempting" to view with one or
the other eye, without change in visual in-
puts. Further discussion may be found in
the section on latent nystagmus in Chap-
ter 10.
Smooth Pursuit in Patients with
Congenital Nystagmus
Some individuals with congenital nystag-
mus (see VIDEO: "Congenital nystagmus")
maintain adequate foveation periods (peri-
ods when the image of the target is close to
the fovea and eye velocity is similar to tar-
get velocity) during smooth pursuit. 74
Other individuals pursue visual targets
poorly, probably because of associated vi-
sual defects rather than the congenital nys-
tagmus per se. Finally, some affected indi-
viduals appear to respond to a step-ramp
pursuit stimulus with a reversal of their
nystagmus slow phase that is in the direc-
tion opposite to the target ramp.152 Some
individuals with congenital nystagmus
seem to show an "inversion of smooth-pur-
suit or optokinetic responses."120 For ex-
ample, when they watch a hand-held opto-
kinetic drum, the quick phases are
directed to the same side as that to which
the drum rotates. It has been shown, how-
ever, that the velocity of the moving opto-
kinetic stimulus does not influence the
slow-phase velocity of the nystagmus.1 One
interpretation of this last phenomenon is
that smooth pursuit causes the nystagmus
null point (i.e., orbital eye position at
which eye velocity is zero) to shift to some
other point.71'179 An alternative explana-
tion is that in some individuals, velocity
signals are processed incorrectly with an
inversion of sign, leading to a wrongly-di-
rected smooth-pursuit command.243
"Inversion of optokinetic responses" has
also been found in albino rabbits when
stimulation was limited to the anterior vi-
sual field (temporal retina). 63 Such ani-
mals showed a spontaneous nystagmus
when their posterior visual fields were
covered. A variety of albino species show
anomalies of their visual pathways.117-118
Evidence for abnormal decussation of tem-
poral retinal fibers has been found in pa-
tients with ocular albinism.66 Congenital
nystagmus is a cardinal feature of human
albinism.59 Absence of crossing of nasal
fibers in achiasmatic patients6 or mutant
sheep dogs75 is associated with congenital
seesaw nystagmus. The relationship be-
tween these misroutings of the visual
pathways and congenital nystagmus has
yet to be determined.
SUMMARY
1. Smooth-pursuit eye movements en-
able continuous clear vision of ob-
jects moving within the environment.
Smooth pursuit may have evolved to
provide continuous foveal vision of a
stationary object during self-motion.
There is evidence for separate neural
mechanisms that are more concerned
with either visual fixation of a station-
ary target or smooth pursuit of a tar-
get that moves.
2. The principal stimulus for pursuit
eye movements is the motion of the
image of a target across the retina
and especially the foveal and peri-
foveal region. In certain circum-
stances, the perception of image mo-
tion may be sufficient, and even
nonvisual stimuli such as propriocep-
tion can generate smooth tracking
movements. Smooth-pursuit responses
are greatly influenced by the pre-
dictability of target motion.
3. Smooth pursuit can be quantified by
measuring its onset and its mainte-
nance. Step-ramp stimuli, presented
in a nonpredictable sequence, can be
used to measure the onset of smooth
pursuit and especially the open-loop
response, which is a sensitive index of
pursuit malfunction. Step-ramp stim-
uli also permit one to assay the con-
tribution of a specified portion of the
retina (visual field) to the genera-
tion of the pursuit response. During
maintenance of smooth pursuit, gain
(eye velocity/target velocity) is the
most useful measurement. If sinu-
soidal stimuli are used, the effects
upon gain of increasing peak velocity

and peak acceleration of the stimulus
can be determined.
4. The pursuit pathway (Fig. 6-7) be-
gins with a visual subsystem for ana-
lyzing movement; it starts at the
retina and runs to the magnocellular
portion of the lateral geniculate nu-
cleus, the striate cortex, secondary vi-
sual areas (MT and MST), the dorso-
lateral pontine nucleus, cerebellum,
vestibular nuclei, brain stem reticular
formation, and the ocular motor nu-
clei. Study of discrete lesions along
this pathway has provided insight
into visual processing of moving tar-
gets. Unilateral lesions along this
pathway produce a predominantly
ipsilateral deficit of smooth pursuit.
The frontal and supplementary eye
fields also contribute to smooth pur-
suit and may be important in gener-
ating responses to predictable target
motions. An accessory optic system
and the nucleus of the optic tract may
play a role in activating the transcor-
tical-pontine-cerebellar pursuit path-
way (Fig. 4-7).
5. The pursuit response shows consid-
erable intersubject variability. Pursuit
is influenced by alertness and by a va-
riety of drugs, and it declines in old
age. Impaired pursuit (reduced gain)
is a nonspecific finding of many dif-
fuse neurologic disorders. Cortical le-
sions cause distinct deficits of smooth
pursuit (Fig. 4-11). Adaptive in-
creases in pursuit gain may occur if it
becomes necessary to track moving
targets with a paretic eye. Abnormali-
ties of smooth pursuit may be en-
countered in some individuals with
congenital forms of nystagmus.
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Chapter 0 5
GAZE HOLDING AND THE
NEURAL INTEGRATOR
NEURAL CODING OF THE OCULAR
MOTOR SIGNAL
The Need for a Neural Integrator of Ocular
Motor Signals
Special Demands on the Neural Integrator
QUANTITATIVE ASPECTS OF NEURAL
INTEGRATION
NEURAL SUBSTRATE FOR GAZE
HOLDING
Contribution of the Nucleus Prepositus
Hypoglossi and Medial Vestibular Nucleus
to Gaze Holding
The Interstitial Nucleus of Cajal and Vertical
Gaze Holding
Contribution of the Cerebellum to Gaze
Holding
How a Network of Neurons Could Function
as the Neural Integrator
CLINICAL EVALUATION OF GAZE
HOLDING
ABNORMALITIES OF THE NEURAL
INTEGRATOR
Pathogenesis of Deficient Neural
Integration
Pathogenesis of Centripetal Nystagmus and
Rebound Nystagmus
SUMMARY
This chapter deals with the neural mecha-
nism that holds gaze steady when the eyes
are turned away from the central position.
Clinicians traditionally test the stability of
gaze with the patient's eyes at the limits of
the horizontal or vertical range. Holding
198
the eyes steady under such circumstances
calls upon more than visual fixation (dis-
cussed in Chap. 4), since eccentric gaze re-
mains relatively steady in darkness.5'74 In
Chapter 1, we pointed out that the orbital
contents impose elastic restoring forces
that tend to pull the eyes back to central
position. To counteract these forces and
hold the eyes steady in an eccentric posi-
tion in the orbit, the extraocular muscles
must contract tonically. Such a tonic con-
traction is achieved by a sustained rate of
discharge of the ocular motoneurons.
The mechanical forces that act on the
eye are illustrated in the experiment
shown in Figure 5-1.76 The subject viewed
a stationary visual target with one eye
while vision from the other eye was oc-
cluded with a sheet of opaque paper at a
distance of about 5 cm. After applying top-
ical anesthetic to the nonfixating eye, it
was mechanically displaced, using oph-
thalmic forceps, into eccentric positions of
(^4) intorsion, (B) extorsion, or (C) hori-
zontal abduction. After the eye was sud-
denly released from each of these eccen-
tric positions, it sprang back to a "central"
position of rest. The time course of this re-
turn was determined by the mechanical
forces acting on the eye, which differed ac-
cording to the prior direction in which it
had been displaced. The brain must take
into account these mechanical forces in
programing all types of eye movements.
Our approach in this chapter will be
first, to explore what neural signals the oc-
 Gaze Holding and the Neural Integrator 199

Figure 5-1. Experimental data from a normal human subject to show the time course of the return to resting
position after the eye was mechanically displaced into an eccentric position in the orbit and then suddenly re-
leased. If the time course of return were fit by a single exponential function, the time constants would be (A)
323 msec after release from intorsion; (B) 58 msec after release from extorsion; and (C) 183 msec after release
from abduction. The asterisk in C indicates a blink. (Adapted from Vision Research, volume 35, Seidman SH,
Leigh RJ, Tomsak RL, Grant MP, Dell'Osso LF. Dynamic properties of the human vestibulo-ocular reflex dur-
ing head rotations in roll, page 679-89, 1995, with permission from Elsevier Science.)

ular motoneurons must generate to hold NEURAL CODING OF THE

the eye in an eccentric position; second, to
outline quantitative aspects of this gaze
holding function; third, to identify what
anatomical pathways are important for
normal gaze holding; fourth, to apply
these principles to the clinical examina-
tion; and finally, to review clinical disor-
ders that impair the ability to hold steady,
eccentric gaze.
OCULAR MOTOR SIGNAL
The Need for a Neural Integrator
of Ocular Motor Signals
To understand the neural basis for the
gaze-holding mechanism, it is helpful to
consider the way that brain stem neurons
200 The Properties and Neural Substrate of Eye Movements

encode eye movement signals. The activity
of any single neuron is represented by its
frequency of spike discharges. Although
differences exist between the physiological
properties of each member of the pool of
ocular motoneurons,9'20'26'80 it is possible
to make some general statements. The dis-
charge frequency of neurons within the
ocular motor nuclei varies quite linearly
with eye position during fixation (Fig.
5-2A and B).33 In addition, during conju-
gate movements, these ocular motoneu-
rons modulate their discharge in propor-
tion to eye velocity (Fig. 5-2C and D). This
combination of velocity and position infor-
mation is necessary to compensate for the
restrictions imposed upon eye movements
by the mechanical properties of the orbital
contents. The viscous drag of the orbital
contents slows down eye movements; the
elastic restoring forces tend to pull the eye
back towards its central position in the
orbit.
Consider the neural signal required to
program a saccade (see Fig. 1-3, Chap. 1).
A pulse of innervation (velocity command)
causes a phasic contraction of the extraoc-
ular muscles, which overcomes the viscous
drag of the orbit and moves the eye
rapidly towards its destination. At the end
of the saccade, a step of innervation (posi-
tion command) causes a tonic contraction
of the extraocular muscles, which resists
the elastic restoring forces of the orbit
and holds the eye steady at its new posi-
tion. Hence ocular motoneurons carry in-
formation about both eye position and ve-
locity. Although we have presented a
scheme for saccades as our example here,
ocular motoneurons encode velocity and
position commands for all types of eye
movements.

Figure 5-2. Discharge properties of ocular motoneurons during fixation and smooth pursuit. (A) The neuron
discharges at a steady rate during fixation. (B) The discharge rate (R) of four ocular motoneurons is compared
with eye position (E) during fixation. For each neuron, this relationship is approximately linear, although the
slope (k) varies from unit to unit, as does the threshold (given by the intercept ET). Typical means and standard
deviations (bars) of R are shown for cell b. (C) During smooth pursuit, the eye passes through the same position
at times 1 and 2, but the discharge rate of the neuron is different because the velocity of the eye is different at
the two times. (D) The relationship between eye velocity (dE/dt) and neuron discharge rate is shown. Its slope is
r. These relationships are expressed by the equation at the bottom, which describes how ocular motoneurons
discharge according to both eye position and velocity. (From Robinson DA, Keller EL. The behavior of eye
movement motoneurons in the alert monkey, Biblitheca Ophthalmologica, volume 82, pages 7-16, 1972, re-
produced with permission of S. Karger AG, Basel.)

In contrast to the combined velocity and
position commands encoded by ocular
motoneurons, the raw sensory or premo-
tor inputs, from which the final ocular
motor command is assembled, primarily
encode velocity signals. Thus, vestibular
afferents24 and secondary vestibular neu-
rons88 carry information on head velocity.
Saccadic burst cells discharge at rates that
reflect saccadic eye velocity.86 For the pur-
suit system, cells within cortical visual
areas,46 brain stem nuclei,63 and cerebel-
lum61 encode combinations of retinal er-
ror velocity and eye velocity signals. More-
over, during combined movements of the
head and eyes, it is gaze velocity (i.e., eye
velocity in space) that is encoded, for ex-
ample, by Purkinje cells of the cerebel-
lum.61 Yet an eye position signal clearly is
required in order to hold gaze steady.
Therefore, a mathematical integration is
necessary to convert velocity-coded infor-
mation to position-coded signals. Theoret-
ical and experimental evidence suggests
a common neural network that inte-
grates all conjugate eye movement com-
mands;30'72 this is referred to as the neural
integrator. A similar integration of vergence
signals also occurs, and is discussed in
Chapter 8.
Special Demands on the
Neural Integrator
The concept of a velocity-position neural
signal (such as the saccadic pulse-step
shown in Fig. 1-3) that moves the eye
against the viscous and elastic forces of
the orbit is valuable in interpreting gaze-
holding abnormalities at the bedside. In
fact, the orbital mechanics are more com-
plicated than this description. This is evi-
dent, for example, in the different cen-
tripetal drifts that occur after the eye is
pulled to different eccentric positions and
suddenly released (compare the curves in
Fig. 5-1). The mechanical properties of
the orbit are nonlinear, especially as the
eye moves out toward the extremes of
gaze. Furthermore, as discussed in Chap-
ter 3, the brain must actually program a
pulse-slide-step in order to avoid drift at
Gaze Holding and the Neural Integrator 201
the end of the saccade (see Fig. 3-5, Chap.
3).64 For gaze to be held steady and vision
to remain clear, the neural integrator must
take these factors into account.
Also, certain neural signals need more
integration than others. Thus, for the hor-
izontal vestibulo-ocular reflex, more than
one integration occurs between vestibular
afferents and the ocular motoneurons.79
This further integration of the vestibular
signal is called the velocity-storage mecha-
nism69'70 and represents a perseveration or
prolongation of the signal from the semi-
circular canals, which is important during
sustained rotations of the head and body.
Most evidence suggests that the neural in-
tegrator and the velocity-storage mecha-
nism depend upon separate anatomical
connections; the neural substrate for ve-
locity storage is reviewed in Chapter 2.
When we view and follow the move-
ments of a near target, it becomes necessary
to move the eyes by different amounts.
Electrophysiological studies suggest that
neurons contributing to the neural integra-
tor network reflect these differences, and
some cells may encode the position of a sin-
gle eye.55 This aspect of interaction be-
tween conjugate and vergence eye move-
ments is discussed in Saccade-Vergence
Interactions in Chapter 8.
QUANTITATIVE ASPECTS OF
NEURAL INTEGRATION
If the performance of the neural integra-
tor is perfect, then eye velocity commands
(e.g., a saccadic pulse) are converted into
appropriate and sustained position com-
mands (e.g., a step, shown in Fig. 5-3A). If
the integrator does not function perfectly,
the eye position signal decays with time
and the integrator is said to be "leaky"
(just as water might leak from a hole at the
bottom of a bucket). The elastic restoring
forces of the orbit pull the eye back toward
the central position with a time course that
approximates a negative (decreasing) ex-
ponential (Fig. 5-3B). The rate of this cen-
tripetal drift of the eyes indicates the time
constant of the neural integrator (Fig.
5-3C). Specifically, 63% of the drift back to
202 The Properties and Neural Substrate of Eye Movements

Figure 5-3. The neural integrator. (A) For saccades, the input to the neural integrator is a pulse, which may be
thought of as an eye velocity signal. If neural integration is perfect, then the output will be a step, which may be
thought of as an eye position signal. (B) If the integration of eye velocity signals is imperfect (i.e., if the neural
integrator is leaky), then the eye position signal will be a decaying exponential. Thus, the eye will drift back to-
ward the midline until a corrective quick phase puts the eye back on target. This causes gaze-evoked nystagmus.
(C) The centripetal drift of the eyes that occurs with a leaky integrator can be described by its time constant (Tc),
given by the time at which the eye has drifted 63% of the way back to the midline. Thus, the leakier the integra-
tor, the shorter the time constant. A convenient way of calculating the time constant is from the ratio of the ini-
tial displacement of the eye from midline (E) to the initial velocity of eye drift (E).

the midline occurs during an interval
equal to one time constant; so, for exam-
ple, if it takes 2 sec to drift back 63%, the
time constant would be 2 sec. The time
constant, therefore, is a quantitative mea-
sure of the fidelity of integration: the
longer the time constant, the better the in-
tegration. When a leaky integrator causes
centripetal drift of the eye, corrective sac-
cades are required to carry the eye back to
the desired eccentric position in the orbit.
A convenient, approximate method to
measure the time constant of the neural
integrator is to measure the ratio of eye
displacement from the midline immedi-
ately after an eccentrically directed sac-
cade to the initial velocity of the cen-
tripetal drift after that saccade (Fig. 5-3C).
Normal subjects do not have "perfect"
neural integrators. In darkness, when vi-
sion cannot be used for ocular stabiliza-
tion, healthy individuals show a drift of
the eyes back from eccentric gaze to cen-
tral position with a time constant of be-
tween 20 and 70 sec;5-39 the rate of this
drift is influenced by the mental percept
of the subject.74 If disease or drugs impair
the process of neural integration, the time
constant may become much smaller. In
darkness, centripetal drifts due to defi-
cient integration are corrected by quick
phases of nystagmus;39 in the light, visual

fixation can also help to suppress any
spontaneous drift (see Chap. 4).
The way in which the brain is able to
hold the eyes still, the neural integrator func-
tion, has been conceptualized in a num-
ber of different ways.1'42'72'77'85 Recent at-
tempts to model the neural integrator
have simulated the behavior of networks
of neurons. 3 We will review these studies
after discussing the anatomical pathways
involved in gaze holding.
NEURAL SUBSTRATE FOR
GAZE HOLDING
The neural integrator depends upon con-
nections between a number of structures
in the brain stem and cerebellum. Collec-
tively, these circuits perform mathematical
integration of vestibular, optokinetic, sac-
cadic, and pursuit eye velocity commands.
For horizontal, conjugate eye movements,
the nucleus prepositus hypoglossi and the
adjacent medial vestibular nucleus are
most important. The interstitial nucleus of
Cajal plays an important role in vertical
and torsional conjugate movements. The
cerebellum also contributes to normal
gaze holding, and for this purpose, it may
receive important inputs from the cell
groups of the paramedian tracts (PMT)
(see Display 6-4, Chap. 6). The parame-
dian pontine reticular formation (PPRF) is
no longer thought to contribute to neural
integration because lesions there spare the
ability to hold eccentric gaze.36
Contribution of the Nucleus
Prepositus Hypoglossi and Medial
Vestibular Nucleus to
Gaze Holding
The nucleus prepositus hypoglossi (NPH)
is one member of the perihypoglossal
complex of nuclei and lies just medial to
the vestibular nuclei and caudal to the ab-
ducens nucleus (see Fig. 6-1). Other peri-
hypoglossal nuclei are the nucleus interca-
latus and the nucleus of Roller, which may
also contribute to the control of eye move-
Gaze Holding and the Neural Integrator 203
ments. The main afferent and efferent
connections of the NPH are summarized
in Table 5-1.6,8,35,48,56 The NPH receives
projections from every structure that pro-
jects to the abducens nucleus.6 Both the
NPH and adjacent medial vestibular nu-
cleus (MVN) contain neurons that en-
code eye position.53'58 Acetylcholine ap-
pears to be a neurotransmitter in the
projections of NPH to the abducens nu-
cleus.57 Vestibular inputs to NPH may uti-
lize nitric oxide, and inputs more con-
cerned with eye position appear to utilize
gamma-aminobutyric acid (GABA).62 The
NPH sends a strong projection to the ab-
ducens nucleus via its rostrolateral "mar-
ginal" zone,48 where it abuts the medial
vestibular nucleus.28
Studies in monkeys of the effects of le-
sions induced by excitotoxins have de-
fined the crucial role of the NPH-MVN
region in neural integration of ocular mo-
tor signals.13'16'31 At the beginning of the
experimental session (Fig. 5-4A), the
monkey holds steady horizontal gaze dur-
ing fixation or in darkness. Following uni-
lateral injection of excitotoxin, a unilateral
lesion produces an acute, partial failure
of both ipsilateral and contralateral gaze
holding (Fig. 5-4B and C), and a shift of
the null or neutral point (the eye position
where eye velocity is zero) toward the side
of the lesion. Bilateral excitotoxin lesions
of NPH and MVN abolish neural inte-
gration for all horizontal, conjugate eye
movements. Horizontal saccades are still
possible and are of normal velocity, but
the eye cannot be held at its new position
and drifts rapidly back to central position
with a time constant of about 200 msec, a
value close to that determined by the me-
chanical properties of the orbital tissues
(Fig. 5-4D). Besides saccades, horizon-
tal vestibular, optokinetic, and smooth-
pursuit (Fig. 5-5) eye movements are also
affected. Neurotoxic lesions confined to
NPH and sparing MVN cause milder de-
fects of neural integration.43 Pharmaco-
logical inactivation, achieved by discrete
injections of muscimol, which increases
normal GABA inhibition and thereby de-
creases neuronal activity, has largely con-
firmed that the NPH and adjacent central
204 The Properties and Neural Substrate of Eye Movements
Table 5-1. Principal Connections of the Nucleus Prepositus
Hypoglossi (NPH)6.35
Structure
Inputs
Vestibular nuclei
Contralateral NPH
Brain stem reticular formation
Medullary reticular formation
PPRF
RiMLF
Interstitial nucleus of Cajal
Mesencephalic reticular
formation
Ocular motor nuclei
Cerebellar fastigial nuclei
Others
Outputs
Ocular motor nuclei
Vestibular nuclei
Cerebellum
Interstitial nucleus of Cajal
Brain stem reticular formation
Superior colliculus
Others
PPRF, paramedian pontine reticular formation; riMLF, rostral interstitial nucleus of
the medial longitudinal fasciculus.
portion of the MVN are key anatomical
structures for the horizontal neural inte-
grator.60'81 Local injection of NMDA ago-
nists and antagonists into this region
also cause partial integrator failure, but
glycine and strychnine do not.59'73 Injec-
tions of either the GABA antagonist bicu-
culline81 or the GABA agonist muscimol73
into the more lateral parts of the medial
vestibular nucleus may cause instability of
gaze holding, in which the eye drifts away
from the central position with increasing
velocity. Electrolytic lesions in the midline
of the pons, just caudal to the abducens
nuclei, disable the horizontal neural inte-
Characteristics
Bilateral projections, especially from the
medial and ventral lateral nuclei
Mainly contralateral
Mainly ipsilateral
Mainly ipsilateral
Bilateral
Bilateral
Bilateral, including oculomotor inter-
nuclear neurons
Bilateral
Raphe nuclei, nucleus of the optic tract
Abducens and trochlear nuclei, bilater-
ally; oculomotor nucleus, mainly
ipsilaterally
Bilaterally, heavy to medial nucleus, but
also to other nuclei, including y-group
Bilateral, to cortex of vestibulocerebel-
lum and posterior vermis
Bilateral
Medullary and pontine reticular forma-
tion
Contralateral
Dorsal cap of inferior olive; raphe nuclei
grator; this effect may be due to interrup-
tion of commissural connections between
the right and left NPH-MVN regions.3
Vertical gaze holding is also impaired fol-
lowing bilateral NPH-MVN lesions; fol-
lowing vertical saccades, centripetal drift
has a time constant of about 2.5 sec.13 This
result implies that other structures and
pathways are important for vertical gaze
holding, such as the interstitial nucleus of
Cajal. A clinical lesion involving the nu-
cleus intercalatus was reported to cause
upbeat nystagmus, suggesting that this
structure may relay vertical eye position
signals to the cerebellum.40
 Gaze Holding and the Neural Integrator 205

Figure 5-4. Saccadic eye movements before and after injection of an excitotoxin (ibotenate) into the medial ves-
tibular nucleus and adjacent nucleus prepositus hypoglossi, first on the right and then the left side. (A) Target-
directed and spontaneous saccades recorded from a normal monkey. In the first half of the record, the fixation
light was alternated between right and left 20°. For the second half, spontaneous eye movements were recorded
in total darkness. Notice that even in total darkness, horizontal gaze holding is steady. The upward drift in
darkness is a form of downbeat nystagmus found in many normal rhesus monkeys. (B-D) Each panel shows
spontaneous saccades recorded in total darkness from the same monkey as in A at various times after the injec-
tion of 30 /j.g of ibotenate, as indicated. The records in D (following bilateral lesions) are two excerpts from a
continuous record to demonstrate that eye position drifts centripetally after both leftward and rightward sac-
cades. The time constant of the horizontal drift decreases progressively from 2 to 0.6 to 0.2 in B-D. A-D were
recorded at the same time scale as indicated. R, right; L, left; U, up; D, down. (Reproduced from Cannon SC
and Robinson DA. Loss of the neural integrator of the oculomotor system from brain stem lesions in monkey, J
Neurophysiol 1987;57:1383-409, with permission.)

The Interstitial Nucleus of Cajal (combined horizontal and vertical dis-

and Vertical Gaze Holding
The anatomical connections of the intersti-
tial nucleus of Cajal (INC) are summarized
in Figure 6-5 and Display 6-6. The INC
receives vertical and torsional saccadic in-
puts from the rostral interstitial nucleus of
the medial longitudinal fasciculus (riMLF)
and vestibular inputs via the medial lon-
gitudinal fasciculus (MLF) and other as-
cending pathways. It contains neurons that
encode burst-tonic (velocity-position) sig-
nals.19'27-29'44 Projections of the INC to ocu-
lar motoneurons may be exclusively via the
posterior commissure.45 Pharmacological
inactivation of the INC with muscimol pro-
duces failure of vertical and torsional gaze
holding that is most evident after saccades
that take the eye to a tertiary eye position
placement from primary position).18-19 The
eye drifts toward a central position with a
time constant of about 200 msec. The tor-
sional drifts are clockwise with left INC in-
activation and counterclockwise with right
INC inactivation.19 Thus, the INC appears
to play a crucial role for holding vertical
and torsional gaze steady after saccades.
The INC may contribute less to the inte-
gration of vertical vestibular signals, how-
ever.28'353 Torsional vestibular signals ap-
pear to be a special case in which little
neural integration normally occurs. For
example, when normal subjects rotate
their head in roll to a new position, the
eyes counterroll, but then drift back to-
wards a central position with a time con-
stant of 2 to 3 sec.76 Experimental inactiva-
tion or lesions of the posterior commissure,
206 The Properties and Neural Substrate of Eye Movements
Figure 5-5. Pursuit eye movements before and after
bilateral injection of excitotoxin (kainic acid) into the
NPH-MVN region. (A) Eye position (E), eye velocity
(£), and target position (T) recorded in a normal
monkey during smooth pursuit of a small target
moving in a triangular waveform. (B) Eye move-
ments recorded during smooth pursuit in the same
task 22 hr after injection of kainic acid. Null point is
close to zero. When the eyes move centrifugally,
catch-up saccades are needed (filled circles); when
centripetal, backup saccades occur (arrows). (Repro-
duced from Cannon SC, Robinson DA. Loss of the
neural integrator of the oculomotor system from
brain stem lesions in monkey, J Neurophysiol 1987;
57:1383-409, with permission.)
which contains INC projections, disable
the vertical neural integrator.66
Contribution of the Cerebellum to
Gaze Holding
Lesions of the cerebellum,15'32'71'89 espe-
cially the flocculus and paraflocculus,82'87'93
make the neural integrator deficient. The
centripetal drift following a saccade to an
eccentric horizontal position typically has
a time constant of 1.5 sec. It has been sug-
gested that a function of the cerebellum is
to improve the performance of an inher-
ently leaky neural integrator in the brain
stem.42'71'91 One way in which the cerebel-
lum could perform this function is shown
in Figure 5-6. Although hypothetical, this
scheme may help clinicians interpret nys-
tagmus with exponential slow-phase wave-
forms. The effects of the cerebellum on
neural integration are represented, in this
scheme, by a gain, K, in a positive feed-
back loop between the cerebellum and
brain stem. Anatomical evidence for such
a pathway exists; the NPH-MVN region
has reciprocal connections with the
vestibulocerebellum, and the flocculus re-
ceives inputs from the cell groups of the
paramedian tracts (PMT),11 which relay
ocular motor signals from a variety of
brain stem structures (see Fig. 6-3 and
Display 6-4, Chap. 6). Such a feedback
loop implies that neurons excite them-
selves and so perseverate their own activ-
ity, an action that is, in effect, integration.
Figure 5-6. A hypothesis of the cerebellar influence
on the brain stem neural integrator. A positive feed-
back loop with a gain of K improves the time con-
stant of an inherently leaky brain stem neural inte-
grator. The effects of varying the value of K are
shown below. If K is appropriate, neural integration
is perfect and the eyes are held steady in their new
position in the orbit after an eye movement. If K is
too small, the integration becomes imperfect (leaky)
and the eyes drift back, with a negative exponential
time course, toward the central position; gaze-
evoked nystagmus results. If K is too large, the
neural integrator becomes unstable and the eyes
drift away from the central position with a positive
exponential time course (increasing velocity) also
causing nystagmus. 91

If the value of K is appropriate, integra-
tion is nearly perfect. If the value of K
falls, the integrator becomes leaky, with
exponentially decaying drifts of the eyes
back to the neutral position. This is the
waveform of gaze-evoked nystagmus. If K
rises above the appropriate value, then
the integrator becomes unstable, with ex-
ponentially increasing drifts of the eyes
away from the midline. This last waveform
has been reported in patients with down-
beating nystagmus (see VIDEO: "Downbeat
nystagmus"),91 upbeating nystagmus (see
Fig. 10-4, Chap. 10), and in monkeys with
floccular lesions.93 The time constant of
the neural integrator has been shown to
be under adaptive control;47 the cerebellar
flocculus may play a key role in this adap-
tation.
How a Network of Neurons Could
Function as the Neural Integrator
The simple scheme shown in Figure 5-6
does not account for some of the ac-
tual properties of the gaze-holding net-
work.3-12'14 For example, relatively small
changes in the feedback loop gain, K,
would cause the network to become leaky
or unstable, but in reality, the gaze-holding
network is quite stable. A second factor is
that neurons that carry an eye-velocity sig-
nal to the neural integrator have a back-
ground discharge rate; it is modulation
about this background discharge that
encodes eye velocity. The properties of
gaze holding indicate that although the
modulated signal is integrated, the back-
ground activity is not. Third, cells in
the NPH-MVN region encode not just eye
position but also, to varying extents, eye
velocity, which the scheme in Figure 5-6
would not predict. Fourth, the integrator
must be relatively robust to the effects of
lesions; some integration must still be pos-
sible after loss of a proportion of its con-
stituent neurons. 12 Fifth, the properties of
the neural integrator can be changed,
such as during adaptation to novel vi-
sual-vestibular demands.83 A neural net-
work approach has been able to address
some of these problems and also to repre-
Gaze Holding and the Neural Integrator 207
sent the anatomical way that the neural in-
tegrator is distributed.
A network of neurons in which cells ex-
cite themselves through connections with
other cells can sustain its activity after ini-
tial stimulation without further input.
This integrating network is conceptually
similar to Lorente de No's "system of re-
verberating collaterals."3'54'77 In practice,
if each neuron inhibits its neighbors and is
in turn inhibited by them, the overall ef-
fect is a positive feedback loop.12'14 Such a
model, unlike the model shown in Figure
5-6, integrates velocity modulated signals,
but not the background activity.14 Because
the inhibition is distributed over many
cells and synapses, the network is robust
to the effect of lesions and also accounts
for some of the subtle differences in wave-
forms of gaze-evoked nystagmus in pa-
tients with various neurologic diseases,
such as an initial rapid centripetal drift
(smaller time constant) followed by a
slower drift (larger time constant). 1 ' 14 It
has proved possible to "train" a network of
neurons to simulate normal gaze-holding
behavior using a Hebbian learning rule, in
which correlated activity between pre-
and postsynaptic neurons strengthens the
synapse between them, whereas uncorre-
lated activity weakens the synapse.3 When
such a network has been trained, each
unit carries a weighted combination of eye
position and velocity. The trained network
is capable of simulating adaptation to new
visual-vestibular demands. Furthermore,
if the model is arranged into left and right
sides, the synaptic development that oc-
curs during training leads to the forma-
tion of an inhibitory commissure. "Lesion-
ing" this commissure in the model disables
the neural integrator in much the same
way that a midline lesion in the pons, just
caudal to the abducens nucleus, does.3
One unresolved aspect of neural inte-
gration of ocular motor signals concerns
three-dimensional aspects of eye move-
ments. When a sphere rotates first in one
direction and then in another, the final
eye position is not the same if the rotations
were performed in the reverse order. This
noncommutative property of the rotation
of spheres also means that in a vectorial
sense, eye position is not the exact integral
208 The Properties and Neural Substrate of Eye Movements
of eye velocity. This geometric property
has led to the hypothesis that the brain
uses a noncommutative operator to con-
vert eye velocity to eye position.85 How-
ever, given the demonstration of pulleys
(see Fig. 9-1, Chap. 9) that limit move-
ment of the tendons of extraocular mus-
cle,21 it has been proposed that for most
eye movements (<40° amplitude), three
simple integrators, one for each direction,
will account for observed behavior.75 The
issue remains unsettled65'68-84 and its clini-
cal significance is unknown. However, if
networks of neurons are accurate repre-
sentations of how the brain integrates ocu-
lar motor signals, then three independent
networks could be trained to carry out the
necessary operation in which the transfor-
mation from an eye-velocity command to a
change in eye position depends on eye po-
sition itself.3
CLINICAL EVALUATION OF
GAZE HOLDING
The fidelity of the neural integrator is
tested at the bedside by noting the patient's
ability to hold the eyes in an eccentric posi-
tion in the orbit (see Appendix A for a sum-
mary). When the integrator is leaky (i.e.,
has a low time constant) the eyes will drift
back toward the central position; this ne-
cessitates corrective saccades, and gaze-
evoked nystagmus will result (see VIDEO:
"Gaze-evoked, rebound and downbeat nys-
tagmus"). (The term gaze-paretic nystagmus,
although in common use, is probably best
avoided because it implies a paresis of
gaze, which may or may not accompany
nystagmus with centripetal drifts.)
Before testing gaze stability in eccentric
positions, examine the eyes during fixa-
tion in the central position and note any
nystagmus. An ophthalmoscopic examina-
tion will often help to determine the pres-
ence and nature of any drift of the eyes,
both with and without fixation (if the fixat-
ing eye is covered for a short period).
Next, examine the eye movements as the
patient fixates to the right, left, up, and
down. Repeat this examination behind
Frenzel goggles to exclude the effects of
visual fixation. If gaze-evoked nystagmus
occurs, is it only present at extremes of
gaze and is it symmetrical on looking
right, left, up, and down? With sustained
efforts at eccentric gaze, does the nystag-
mus diminish? On returning the eyes to
central position, does transient nystagmus
occur with slow phases toward the direc-
tion of prior gaze? (This phenomenon,
called rebound nystagmus, is discussed below
in the section Pathogenesis of Centripetal
and Rebound Nystagmus.) The presence
of gaze-evoked nystagmus in the light of-
ten implies more than just a leaky integra-
tor: the visual fixation and stabilization re-
flexes are probably impaired, and hence
smooth pursuit and cancellation of the
vestibulo-ocular reflex may be abnormal.
They require testing.
Recording of eye movements helps es-
tablish the nature of the slow-phase com-
ponent during attempted eccentric fixa-
tion in both light and darkness. The time
constant of drift (see Fig. 5-3), when mea-
sured in normal subjects in darkness,
varies considerably but is typically 20 to 70
sec.5'23'39'74 Some normal subjects show
a unidirectional drift.39 Centripetal drift
caused by an inadequate (leaky) integra-
tor due to disease typically has a time con-
stant of a few seconds. Rarely, disease
of the gaze-holding mechanism causes
nystagmus with an increasing-velocity
slow-phase waveform that is evident
clinically (see VIDEO: "Downbeat nystag-
mus").
The centripetal drifts of gaze-evoked
nystagmus may appear to have a linear
rather than a decaying exponential wave-
form (compare Fig. 10-1A and B, Chap.
10). This nystagmus may still be due to a
deficient neural integrator; exponential
decay may not be obvious if the integrator
is only slightly leaky or if visual-following
reflexes reduce the drift. In addition,
lesions affecting the vestibular nuclei
that impair gaze holding may also cause
a vestibular imbalance leading to nystag-
mus with more linear slow-phases (see
Alexander's law, below). In practice, the
best way to show that slow phases of nys-
tagmus have a negative exponential wave-

form is to record eye movements in dark-
ness.
ABNORMALITIES OF THE
NEURAL INTEGRATOR
Disease affecting the neural integrator
causes an inadequately sustained eye posi-
tion signal. This is manifest by drift of the
eyes back from an eccentric position to
the central position and corrective quick
phases that produce gaze-evoked nystag-
mus. As noted previously, even normal
subjects do not have a perfect neural inte-
grator; most individuals will show some
centripetal drift when in darkness. Some
normal subjects show deficient gaze hold-
ing even when fixating a visual target.
This physiological or end-point nystag-
mus usually occurs when such individ-
uals are in extreme lateral gaze or
upgaze.2'23'78 Certain normal subjects,
however, develop gaze-evoked nystagmus
even with modest eye deviations, such as
at 20° eccentricity.2 End-point nystagmus
usually comes on soon after turning the
eyes to an eccentric position,78 and may
damp after several seconds. It may be
asymmetric (e.g., present on looking to
the right but not to the left) and be of
greater amplitude in the abducting eye.78
Important points in differentiating physi-
ological nystagmus from the effects of dis-
ease are low amplitude (slower drift) and
the absence of other ocular motor abnor-
malities (see Display 10-8, Chap. 10).10
End-point nystagmus increases when the
subject imagines a target location in dark-
ness, rather than viewing it.23 Prolonged
attempts to maintain extreme lateral gaze
lead to fatigue nystagmus in some normal
subjects,2-23 but this probably represents a
different mechanism than the more com-
mon finding of nystagmus that develops
soon after the eye reaches its eccentric po-
sition.
Although a leaky neural integrator pro-
duces gaze-evoked nystagmus, this does not
produce great functional disability, since the
eyes are used mostly near the central posi-
tion. When the eyes are held in an eccentric
position in the orbit, each quick phase (sac-
Gaze Holding and the Neural Integrator 209
cade) resets the level of activity of the neural
integrator so that the eye position is cor-
rected before the eye drifts far off target.
Only if the velocity of centripetal drifts is
high will vision be noticeably degraded.
Pathogencsis of Deficient
Neural Integration
In the clinic, the most common cause of
gaze-evoked nystagmus is medication, in-
cluding sedatives, tranquilizers, or anti-
convulsants (see Table 10-21, Chap. 10).
Such nystagmus may occur in the horizon-
tal or vertical plane. Although the exact
site of action of such agents is not always
known, it seems likely that either the cere-
bellum or the vestibular nuclei may be af-
fected.57
A variety of abnormalities affecting the
cerebellum cause gaze-evoked nystagmus
and usually reflect involvement of the
vestibulocerebellum (flocculo-nodular lobe)
or its connections (see Display 10-17,
Chap. 10). Other abnormalities of eye
movements, especially impaired smooth
pursuit, usually co-exist.10 Brain stem le-
sions affecting the NPH and MVN, which
are essential for neural integration, impair
gaze holding. Loss of neurons from
the medial vestibular and prepositus hy-
poglossi nuclei has been reported in a pa-
tient who suffered from lithium intoxica-
tion.17 Prior to her death from respiratory
failure, she lost voluntary and reflexive
eye movements, except for what may have
been saccades followed by a rapid cen-
tripetal drift.
When a vestibular imbalance occurs that
is due to either a peripheral or central le-
sion, gaze-evoked nystagmus is often su-
perimposed. Such interaction of vestibular
nystagmus and gaze-evoked nystagmus is
the basis for Alexander's law: nystagmus
due to a vestibular lesion is more intense
when the patient looks in the direction of
the quick phases.38'74 In other words, slow-
phase velocity is greatest when the eye is
turned away from the direction of drift.
The effect of deficient gaze holding is
small during natural behavior of the VOR,
but is evident during sustained stimula-
210 The Properties and Neural Substrate of Eye Movements
tion (rotational or caloric) and especially
with imbalance due to lesions.22'74 It has
been postulated that, faced with a persist-
ing vestibular imbalance (i.e., a false sig-
nal), the nervous system disables the
neural integrator and the time constant
of centripetal drift falls.37'74 In this way,
centripetal drift due to a leaky neural inte-
grator can be used to counteract the ves-
tibular nystagmus in one field of gaze. The
negative-exponential waveforms that char-
acterize a leaky neural integrator are diffi-
cult to discern in patients when a vestibu-
lar imbalance is also present.74 However, if
the slow-phase velocity of a unidirectional
nystagmus varies with orbital position, im-
paired integration can be inferred. Such
waveforms have been identified following
experimental lesions of the peripheral
vestibular organ or nerve in monkeys.25
Vertical gaze-evoked nystagmus is caused
by medications and by brain stem and cere-
bellar lesions that also disrupt horizontal
gaze holding. Other causes of vertical gaze-
evoked nystagmus include bilateral inter-
nuclear ophthalmoplegia50 and lesions af-
fecting the posterior commissure.66'67 Both
the medial longitudinal fasciculus and the
posterior commissure convey signals that
encode vertical eye position.
Sometimes, disease involving the neural
integrator causes nystagmus with expo-
nentially increasing slow phases. This
finding is indicative of an unstable rather
than a leaky neural integrator. Nystagmus
with increasing-velocity waveforms is most
commonly encountered in the horizontal
plane as a feature of congenital nystag-
mus. It also occurs in some patients with
cerebellar disease, who show horizontal or
vertical nystagmus that is made worse by
looking in the direction of the slow phases
(see VIDEO: "Downbeat nystagmus").4'91
We have attempted to interpret this find-
ing by the simple integrator model in Fig-
ure 5-6. Nystagmus with slow phases that
variably increase or decrease in velocity
and have a variable neutral point has been
reported in blind individuals (see VIDEO:
"Eye movements with complete blind-
ness")51-52 and following experimental oc-
cipital lobectomy.92 In such cases, it seems
that deprivation of visual or vestibular in-
puts can cause the neural integrator to be-
come uncalibrated, with a variable, inap-
propriate performance. Similar drifts of
the eyes are reported following experi-
mental cerebellectomy.71
Pathogencsis of Centripetal
Nystagmus and
Rebound Nystagmus
Persistent effort at maintaining eccentric
gaze usually reduces the intensity of gaze-
evoked nystagmus and may actually cause
a reversal of direction, so-called cen-
tripetal nystagmus (Display 10-7, Chap.
10).49 If the patient then returns the eyes
to the central position, a transient nystag-
mus may be observed with slow phases oc-
curring in the direction of former gaze;
this is called rebound nystagmus (see VIDEO:
"Gaze-evoked, rebound and downbeat
nystagmus"). 41 Rebound nystagmus oc-
curs in normal subjects after prolonged,
eccentric gaze.78 In normals, rebound nys-
tagmus partly reflects the development of
a drift (velocity bias) to counter the cen-
tripetal drifts of the eyes; in addition, the
time constant of the neural integrator may
be shortened.34 Clinicians most frequently
encounter rebound nystagmus in patients
with cerebellar disease (Fig. 10-9),7-41 but
it has been reported in monkeys with bilat-
eral lesions restricted to the NPH and
MVN.13 On the other hand, rebound nys-
tagmus in one patient who had a choroid
plexus papilloma involving the flocculus
and nodulus disappeared when the vestib-
ular nucleus was invaded by tumor.90
Since rebound nystagmus can occur fol-
lowing eccentric gaze holding in the dark,
it cannot simply be a response to reti-
nal slip.34 Moreover, rebound nystagmus
occurs in patients who have impaired pur-
suit,7 so abnormalities of the pursuit system
are unlikely to be primarily responsible for
it. More likely, the generation of rebound
nystagmus depends upon the ability to in-
ternally monitor eye movement signals
(i.e., efference copy or proprioception) and
activate compensatory eye drifts. Rebound
nystagmus only occurred during the recov-
ery phase following lesions of the NPH and
MVN, indicating that some neural integra-

tor function may be necessary for its gener-
ation.13
SUMMARY
1. For normal conjugate eye move-
ments, the ocular motoneurons carry
a neural signal that contains velocity
and position components. Such a sig-
nal is necessary to hold the eyes
steady at an eccentric position in the
orbit (see Fig. 1-3, Chap. 1). The po-
sition-coded ocular motor signal is
obtained from the velocity-coded
signal by a process of mathematical
integration. Electrophysiological evi-
dence indicates that a common
neural network integrates all conju-
gate eye movement commands; this
network is called the neural integrator.
2. For horizontal, conjugate eye move-
ments, the nucleus prepositus hy-
poglossi and medial vestibular nuclei
are of prime importance for holding
steady, eccentric gaze. Unilateral le-
sions of this NPH-MVN region cause
partial, bilateral loss of gaze holding;
bilateral lesions abolish the horizon-
tal neural integrator. For vertical eye
movements, midbrain structures, es-
pecially the interstitial nucleus of
Cajal, contribute to neural integra-
tion. The vestibulocerebellum also
contributes to the integration of ocu-
lar motor signals, and this role may
depend on feedback of eye move-
ment signals by the cell groups of the
paramedian tracts. Thus, mathemati-
cal integration of ocular motor sig-
nals may be achieved by a network of
interconnected neurons.
3. Inadequate neural integration causes
a rapid decay in the eye-position sig-
nal and consequent negative expo-
nential drift of the eyes back from an
eccentric to a neutral position (see
Fig. 5-3B). Clinically, this is manifest
as gaze-evoked nystagmus. Such im-
paired integration is a common side
effect of medications and is caused by
disease affecting the vestibulocerebel-
lum and brain stem. Deficient neural
integration also impairs vestibular,
Gaze Holding and the Neural Integrator 211
optokinetic, and pursuit eye move-
ments. Vestibular lesions lead to a de-
ficient neural integrator, in addition
to causing a tonic vestibular imbal-
ance. This combination of deficits can
be seen in Alexander's law—nystagmus
with a slow-phase velocity that in-
creases when the eyes are brought to
a position in the orbit in the direction
of the quick phases.
4. The nervous system can partially
compensate for deficient integrator
function by programing opposite-
directed, adaptive drifts of the eyes
that are apparent as rebound nys-
tagmus. If the nervous system is
deprived of vision (blindness), the
neural integrator loses its calibration
and is unable to hold gaze steady.
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Chapter 6 6
SYNTHESIS OF THE COMMAND FOR
CONJUGATE EYE MOVEMENTS
BRAIN STEM CONNECTIONS FOR
HORIZONTAL
CONJUGATE MOVEMENTS
Interpretation of the Effects of Discrete
Lesions on Pathways for Horizontal Gaze
BRAIN STEM CONNECTIONS FOR
VERTICAL AND TORSIONAL
MOVEMENTS
CEREBELLAR INFLUENCES ON GAZE
Contributions of the Vestibulocerebellum to
Gaze Control
Contributions of the Dorsal Vermis and
Fastigial Nucleus to Gaze Control
THE CEREBRAL HEMISPHERES AND
VOLUNTARY CONTROL OF EYE
MOVEMENTS
Approaches to Studying the Cerebral
Control of Eye Movements in Humans
Contributions of Posterior Cortical Areas to
Gaze Control
Contributions of the Temporal Lobe to Gaze
Control
Contributions of the Parietal Lobe to Gaze
Control
Contributions of the Pulvinar to Gaze Control
Contributions of the Frontal Lobe to Gaze
Control
Descending, Parallel Pathways that Control
Voluntary Gaze
SUMMARY
This chapter provides an anatomic scheme
for the synthesis of neural commands for
conjugate eye movements. We present a hy-
pothesis to account for the way that neural
signals for vestibular, optokinetic, saccadic,
and pursuit eye movements and the gaze-
holding mechanism (neural integrator) pro-
ject to ocular motoneurons. At the outset,
the reader should realize that we draw on
findings from studies of both humans and
monkeys to forge our hypothesis. Although
such an approach carries the risk of making
inaccurate suppositions, it also enhances the
opportunities for experimental tests.
Our approach is from the bottom up.
First, we discuss the brain stem machinery
responsible for all conjugate eye move-
ments—reflex or voluntary. Second, we
summarize the role of the cerebellum. Fi-
nally, we review the pathways responsible
for voluntary eye movements. Although
most of our account concerns anatomy, we
will recapitulate important neurophysio-
logic points and summarize what is cur-
rently known about the neurotransmitters
for these pathways. We will also outline
the effects of certain well-defined lesions
and lay out an anatomic basis for the topo-
logical diagnosis of clinical conditions that
are discussed in Chapter 10.
BRAIN STEM CONNECTIONS
FOR HORIZONTAL
CONJUGATE MOVEMENTS
The tegmentum of the pons contains the
neural machinery that ultimately controls
215
216 The Properties and Neural Substrate of Eye Movements

horizontal conjugate eye movements (Fig.
6-1). The most important structure is the
abducens nucleus, which controls conju-
gate movements of both the ipsilateral lat-
eral rectus and the contralateral medial
rectus muscles (Display 6-1); thus it may
be regarded as the horizontal gaze center.
The abducens nucleus houses abducens
motoneurons, which innervate the lateral
rectus muscle, as well as abducens inter-
nuclear neurons, which project up the
contralateral medial longitudinal fascicu-
lus (MLF) (Display 6-2) to contact medial
rectus motoneurons of the oculomotor
nucleus (Fig. 6-1).$0,127 Thus, the axons of
the abducens nerve, together with those of
the abducens internuclear neurons that
course in the MLF, encode conjugate hor-
izontal eye movements.157'261 Abducens
motoneurons and internuclear neurons
are partially intermingled but show some
morphologic differences.192 Abducens mo-
toneurons have no axon collaterals, but
the internuclear neurons send collaterals

Figure 6-1. Anatomic scheme for the synthesis of signals for horizontal eye movements. The abducens nucleus
(CN VI) contains abducens motoneurons that innervate the ipsilateral lateral rectus muscle (LR) and abducens
internuclear neurons that send an ascending projection in the contralateral medial longitudinal fasciculus
(MLF) to contact medial rectus (MR) motoneurons in the contralateral third nerve nucleus (CN III). From the
horizontal semicircular canal, primary afferents on the vestibular nerve project mainly to the medial vestibular
nucleus (MVN), where they synapse and then send an excitatory connection to the contralateral abducens nu-
cleus and an inhibitory projection to the ipsilateral abducens nucleus. Saccadic inputs reach the abducens nu-
cleus from ipsilateral excitatory burst neurons (EBN) and contralateral inhibitory burst neurons (IBN). Eye po-
sition information (the output of the neural integrator) reaches the abducens nucleus from neurons within the
nucleus prepositus hypoglossi (NPH) and adjacent MVN. The medial rectus motoneurons in CN III also re-
ceive a command for vergence eye movements. Putative neurotransmitters for each pathway are shown: Ach,
acetylcholine; asp, aspartate; glu, glutamate; gly, glycine. The anatomic sections on the right correspond to the
level of the arrowheads on the schematic on the left. Abd. nucl., abducens nucleus; ATD: ascending tract of
Deiters; CN VI, abducens nerve; CN VII, facial nerve; CTT, central tegmental tract; ICP, inferior cerebellar pe-
duncle; IVN, inferior vestibular nucleus; Inf. olivary nucl., inferior olivary nucleus; MRF, medullary reticular
formation; SVN, superior vestibular nucleus. (Transverse sections redrawn from Carpenter MB. Human Neu-
roanatomy, 7th ed. Baltimore: Williams & Wilkins; 1976.)
 Synthesis of the Commands for Conjugate Eye Movements 217

Display 6-1: Abducens Nucleus

• The conjugate, horizontal gaze center that houses abducens motoneu-
rons and abducens internuclear neurons

• Axons of abducens motoneurons project in the sixth cranial nerve to

innervate the ipsilateral lateral rectus muscle

• Axons of abducens internuclear neurons cross the midline to ascend

in the medial longitudinal fasciculus to contact contralateral medial
rectus motoneurons in the oculomotor nucleus

(For related clinical disorders, see Display 10-20 in Chap. 10.)

to the cell groups of the paramedian tracts
(PMT cell groups), which lie in the mid-
line of the brain stem and, in turn, pro-
ject to the cerebellum.47'192 Abducens mo-
toneurons and internuclear neurons are
pharmacologically distinct: the motoneu-
rons use acetylcholine, and the inter-
nuclear neurons use glutamate.53'194'304
Although both populations of neurons
show qualitatively similar electrophysio-
logic properties, internuclear neurons show
a lower sensitivity for eye position and a
higher sensitivity for eye velocity.96
How do signals for each functional class
of eye movement reach the abducens
nucleus? Figure 6-1 summarizes monosy-
naptic excitatory and inhibitory projec-
tions to the abducens nucleus and indi-
cates neurotransmitters that have been
postulated for these projections.194 Vestib-
ular and optokinetic inputs reach the ab-
ducens nucleus from the vestibular nuclei;
some of these axons pass through the ipsi-
lateral abducens nucleus en route to the
contralateral abducens nucleus.193 Excita-
tory saccadic commands originate from
burst neurons that lie in the ipsilateral
paramedian pontine reticular formation
(PPRF) (Fig. 6-2; Display 6-3), rostral to
the abducens nucleus.140'141'313 Excitatory
burst neurons may be separated into two
populations, projecting either to abducens

Display 6-2: Medial Longitudinal Fasciculus (MLF)

• Conveys axons from neurons concerned with horizontal, vertical, and
torsional conjugate gaze

• For horizontal gaze: Axons from abducens internuclear neurons,

which carry the conjugate eye movement command, project to medial
rectus motoneurons in the contralateral oculomotor nucleus

• For vertical gaze: Axons from vestibular nuclei, which carry signals
contributing to smooth pursuit, the vestibulo-ocular and otolith-
ocular reflexes, and gaze holding project to the oculomotor and troch-
lear nuclei, and the interstitial nucleus of Cajal

(For related clinical disorders, see Display 10-22 in Chap. 10.)

218 The Properties and Neural Substrate of Eye Movements

Figure 6-2. Human brain stem section showing pontine tegmentum at the level of the abducens nucleus
(N.VI). The close relationship between the medial longitudinal fasciculus (F.lo.m), nucleus reticularis pontis
caudalis (Po.c), which houses excitatory saccadic burst neurons, and nucleus raphe interpositus (rip), which is
the location of omnipause neurons, is evident. VI, abducens nerve; VII, facial nerve; Gc, nucleus gigantocellu-
laris; Le.m, medial lemniscus; PC, nucleus parvocellularis; Scoe.v, nucleus subcoeruleus, subnucleus ventralis;
Spg, nucleus suprageniculatus; St.gl, stratum gliosum subependymale; Tr, nucleus trapezoidalis. (From
Olszewski J, Baxter D. Cytoarchitecture of the human brain stem, second edition, 1982, reproduced with per-
mission of Basel: S. Karger AG.)

motoneurons or to internuclear neu- which contributes to the control of conju-

rons. i89a,354 Inhibitory saccadic commands
originate from burst neurons located con-
tralaterally, in the paramedian reticular
formation caudal to the abducens nucleus,
at the pontomedullary junction.140'314 In-
hibitory burst neurons are driven by
monosynaptic projections from ipsilateral
excitatory burst neurons (see Chap. 3).
Pursuit signals are relayed from the cere-
bellum, in part via the vestibular nu-
clei.95'169 The output of the gaze-holding
network (neural integrator) reaches the
abducens nucleus from the nucleus
prepositus hypoglossi (NPH) and adjacent
medial vestibular nucleus (MVN). 17 > 169 In
addition, the abducens nucleus receives a
projection from the contralateral medial
rectus subdivision of the oculomotor com-
plex (oculomotor internuclear neurons),
gate gaze.60'169
In addition to inputs via the MLF, me-
dial rectus motoneurons receive direct
projections from neurons in the ipsilateral
vestibular nucleus via the ascending tract
of Deiters (see Fig. 2-3, Chap. 2),193'268
which runs lateral to the MLF and may
play a role in adjusting the vestibular re-
sponses during near-viewing.573 Medial
rectus motoneurons also receive inputs for
vergence eye movements from neurons in
the mesencephalic reticular formation,
which lie dorsolateral to the oculomotor
nucleus.41'190
All the neurons that project to the ab-
ducens nucleus also send axon collaterals
to a continuum of cell clusters that lie close
to the MLF and other paramedian tracts
in the caudal pons and medulla; these
 Synthesis of the Commands for Conjugate Eye Movements 219

Display 6-3: Paramedian Pontine Reticular Formation

(PPRF)
• A physiologically defined entity that houses the vital machinery for
horizontal saccades, including excitatory and inhibitory burst neurons
and omnipause neurons

• Excitatory burst neurons lie in the dorsomedial nucleus reticularis

pontis caudalis (NRPC), rostral to the level of the abducens nucleus,
receive inhibitory inputs from omnipause neurons, and project mono-
synaptically to the ipsilateral abducens nucleus

• Inhibitory burst neurons lie in the medial portion of the nucleus

paragigantocellularis dorsalis (PGD), caudal to the abducens nucleus
(rostral medulla), receive inhibitory inputs from omnipause neurons
and excitatory inputs from ipsilateral excitatory burst neurons, and
project monosynaptically to the contralateral abducens nucleus

• Omnipause neurons lie in the nucleus raphe interpositus (RIP), close

to the midline, at the level of the abducens nucleus, receive inputs
from long-lead burst neurons, the rostral pole (fixation zone) of the
superior colliculus, and fastigial nucleus, and project to excitatory and
inhibitory burst neurons for horizontal and vertical saccades

(For related clinical disorders, see Display 10-21 in Chap. 10.)

have been called the cell groups of the para-
median tracts (PMT) (see Display 6-4 and
Fig. 6-3).43'47 One of these cell groups lies
at the rostral end of the abducens nucleus.
The PMT cell groups, in turn, project to
the cerebellar flocculus, paraflocculus,
and vermis of the cerebellum.39'43 In this
way, the cerebellum may receive feedback
about all motor signals flowing to the ab-
ducens nucleus. The possible role of the

Display 6-4: Cell Groups of the Paramedian Tracts (PMT)

• Clusters of neurons scattered along the midline fiber tracts in the pons
and medulla

• Receive inputs from essentially all structures that project to ocular

motoneurons

• Project to the flocculus, paraflocculus and vermis of the cerebellum

• May provide the flocculus with an efference copy of eye movement

commands for gaze-holding or more long-term adaptation

(For possible clinical significance, see Pathogenesis of Central Vestibular

Nystagmus and Pathogenesis of Nystagmus Occurring With Visual System
Disorders in Chap. 10.)
220 The Properties and Neural Substrate of Eye Movements

Figure 6-3. A sagittal section of the monkey brain stem showing the location of the rostral interstitial nucleus of
the medial longitudinal fasciculus (rostral iMLF) and other structures important in the control of vertical and
horizontal gaze. The shaded areas indicate the mesencephalic reticular formation (MRF), paramedian pontine
reticular formation (PPRF), and medullary reticular formation (Med RF). The asterisks indicate the location of
cell groups of the paramedian tracts, which project to the flocculus. Ill, oculomotor nucleus; IV, trochlear nu-
cleus; VI, abducens nucleus; eg, central gray; h, habenular complex; iC, interstitial nucleus of Cajal; mb, mam-
millary body; MT, mammillothalamic tract; N III, rootlets of the oculomotor nerve; N IV, trochlear nerve; N
VI, rootlets of the abducens nerve; nD, nucleus of Darkschewitsch; nrtp, nucleus reticularis tegmenti pontis;
PC, posterior commissure; ppH, nucleus prepositus hypoglossi; sc, superior colliculus; t, thalamus; TR, tractus
retroflexus. The arrow refers to the Horsley-Clarke plane of section. (Adapted from Biittner-Ennever JA, Horn
AKE. Pathways from cell groups of the paramedian tracts to the floccular region. Ann NY Acad Sci
1996;781:532-40, with permission.)

PMT pathway is discussed further in Cere- 10).2i,52,i95,209 Vcrgence is spared, since

bellar Influences on Gaze, below.
jections that pass directly to medial rectus
Interpretation of the Effects of
Discrete Lesions on Pathways for
Horizontal Gaze
A test of the validity of the anatomic
scheme shown in Figure 6-1 is its ability to
account for the effects of discrete lesions on
horizontal eye movements. Lesions of the
abducens nucleus produce paralysis of
both the ipsilateral lateral rectus and con-
tralateral medial rectus for all conjugate
eye movements (see Display 10-20, Chap.
these movements mainly depend on pro-
motoneurons. Saccadic, pursuit, optoki-
netic, and vestibular movements are still
present in the contralateral hemifield, but
are impaired when directed toward the
side of the lesion. Contraversive saccades
are preserved because they depend on the
intact abducens nucleus, which receives
projections from excitatory burst neurons
in the ipsilateral PPRF. Saccades directed
toward the side of the lesion are also pres-
ent in the contralateral hemifield of move-
ment, but they are slow. This is because
they must now depend solely on projec-
tions to the intact abducens nucleus from
 Synthesis of the Commands for Conjugate Eye Movements
the inhibitory burst neurons of the con-
tralateral medullary reticular formation,
and saccadic peak velocity is now a func-
tion of antagonist muscle relaxation rather
than agonist contraction. Another finding
with abducens nerve palsies is horizontal
gaze-evoked nystagmus on looking con-
tralaterally. This nystagmus is probably
due to involvement of fibers of passage
from the medial vestibular nucleus, which
provide an eye position signal to the con-
tralateral abducens nucleus.209 This expla-
nation is supported by the report of a dis-
crete experimental lesion made between
the abducens nuclei, which caused pro-
found bilateral gaze-holding failure.3 Alter-
natively, it might be due to involvement of
the PMT cell group that lies at the rostral
pole of the abducens nucleus and possibly
contributes to horizontal gaze-holding via
its projections to the cerebellum.47'209
Lesions of the medial longitudinal fasci-
culus produce internuclear ophthalmo-
plegia (INO) (see Display 10-22, Chap.
10), which is characterized by paresis of
adduction for conjugate movements on
the side of the lesion (see VIDEO: "Unilat-
eral internuclear ophthalmoplegia").54'85'100
Adduction is still possible with conver-
gence because of direct vergence inputs to
medial rectus motoneurons (see Fig. 6-1;
VIDEO: "Bilateral internuclear ophthalmo-
plegia"). Thus, when INO is produced
experimentally by lidocaine blockade of
the MLF between the levels of the
trochlear and abducens nuclei, the ver-
gence response is preserved or even in-
creased.100 More rostral lesions of the
MLF may impair vergence if the medial
rectus motoneurons or their vergence
inputs are involved. With complete, ex-
perimental lesions of the MLF, the eye
does not adduct across the midline with
any conjugate movements, implying that
extra-MLF pathways, such as the as-
cending tract of Deiters, can only play a
minor role in the horizontal VOR. A com-
bined lesion of one MLF and the ab-
ducens nucleus on the same side produces
paralysis of all conjugate movements
save for abduction of the eye contralat-
eral to the side of the lesion; this is
known as one-and-a-half syndrome (see Dis-
play 10-23).90'250
221
Discrete lesions of the paramedian pon-
tine reticular formation (PPRF) cause loss
of saccades and quick phases of nystagmus
to the side of the lesion (see Display
10-21).108'161 Experimental lesions in the
PPRF, using excitotoxins that spare fibers
of passage, leave smooth pursuit, the
vestibulo-ocular reflex, and gaze-holding
ability intact;125 similar sparing is some-
times encountered with clinical lesions.118-161
Often, however, lesions of the pons that af-
fect the PPRF also involve axons convey-
ing vestibular and pursuit inputs to the
abducens nucleus.252 Furthermore, lesions
that affect the excitatory burst neurons
may also affect omnipause neurons, which
lie in the nucleus raphe interpositus, close
to the midline at the level of the abducens
nerve (Fig. 6-2),42>142'230 and which inhibit
all burst neurons except during saccades.
Involvement of omnipause neurons might
account for the slowing of vertical as well
as horizontal saccades that is sometimes
reported after bilateral pontine lesions.118'125
Unilateral lesions affecting the vestibu-
lar nuclei, such as in Wallenberg's syn-
drome (lateral medullary infarction) (see
Display 10-16), may produce an ocular
motor imbalance manifest by spontaneous
nystagmus, skew deviation and the ocular
tilt reaction. An additional finding, lat-
eropulsion of saccades (see VIDEO: "Wal-
lenberg's syndrome"), may reflect inter-
ruption of axons running in the restiform
body from the inferior olivary nucleus to
the cerebellum.340 Bilateral, experimental
lesions of the nucleus prepositus hypoglos-
si-medial vestibular complex, the NPH-
MVN region, abolish the gaze-holding
mechanism (neural integrator) for eye
movements in the horizontal plane.49'197
BRAIN STEM CONNECTIONS
FOR VERTICAL AND
TORSIONAL MOVEMENTS
The ocular motoneurons concerned with
vertical and torsional eye movements lie in
the oculomotor nucleus and trochlear nu-
cleus. How do these motoneurons receive
signals for each functional class of eye
movement? A partial dichotomy is evi-
222 The Properties and Neural Substrate of Eye Movements

Display 6-5: Rostral Interstitial Nucleus of the Medial

Longitudinal Fasciculus (riMLF)
• A wing-shaped structure that lies dorsomedial to red nucleus, rostral
to INC, and caudal to the posterior branch of the thalamosubthalamic
paramedian artery

• Houses most burst neurons for vertical and torsional saccades; those
for clockwise movements (right eye extorts, left eye intorts) lie in the
right riMLF; those for counterclockwise movements lie in the left
riMLF

• Receives inputs from omnipause neurons in the pontine nucleus

raphe interpositus, superior colliculus, nucleus of the posterior com-
missure, long-lead burst neurons of midbrain and rostral PPRF, cere-
bellar fastigial nucleus, and contralateral riMLF via the ventral com-
missure

• Projects predominantly to the ipsilateral oculomotor and trochlear

nuclei, each burst neuron sending axon collaterals to motoneurons
supplying yoke muscle pairs (Hering's law for vertical movements);
projections to motoneurons innervating the superior rectus and infe-
rior oblique are bilateral, crossing within the oculomotor nuclear com-
plex

• Also projects to the ipsilateral interstitial nucleus of Cajal, to cell

groups of the paramedian tracts, and to the spinal cord (for head
movements)

(For related clinical disorders, see Display 10-25 in Chap. 10.)

dent, with vertical saccadic commands and
gaze-holding (neural integrator) innerva-
tion being generated in the midbrain, and
vestibular and pursuit signals arising from
the lower brain stem.
Vertical and torsional saccades are gen-
erated in the rostral interstitial nucleus of
the medial longitudinal fasciculus (riMLF),
a region of the rostral mesencephalon in
the prerubral fields, rostral to the tractus
retroflexus and caudal to the mammil-
lothalamic tract (see Display 6-5, Fig. 6-3,
and Fig. 6-4).38'40'139 In the past, this struc-
ture has also been called the nucleus of
the prerubral fields and the nucleus of the
fields of Forel. Although the riMLF lies ad-
jacent to other mesencephalic reticular
nuclei, particularly the interstitial nucleus
of Cajal, its physiologic properties and
anatomic connections make it a distinct
functional entity. It contains both excita-
tory and inhibitory burst neurons for
vertical and torsional saccades and quick
phases. 37 '206,208,2i7 Each riMLF contains
neurons that burst for upward and down-
ward eye movements, but for torsional
quick phases in only one direction. Thus,
the right riMLF discharges for quick
phases that are directed clockwise with re-
spect to the subject;37'38'155'337 that is, the
top pole of the right eye rotates tempo-
rally, and the top pole of the left eye
rotates nasally. Electrophysiologic and an-
atomic studies suggest that although exci-
tatory and inhibitory burst units are inter-
mingled, neurons projecting to muscles
that depress the eye (inferior rectus and
superior oblique) may be located more
 Synthesis of the Commands for Conjugate Eye Movements
rostrally, whereas projections to muscles
that elevate the eye (superior rectus and
inferior oblique) lie more caudally.163'344
The postulated projections of the riMLF
and the associated neurotransmitters are
summarized in Figure 6-5. Each riMLF
projects predominantly to the ipsilateral
oculomotor and trochlear nuclei; how-
ever, projections to motoneurons inner-
vating the elevator muscles appear to be
bilateral, with axon collaterals probably
crossing to the opposite side at the level of
the motoneurons, and not in the posterior
commissure.207 Furthermore, each burst
neuron in the riMLF appears to send axon
collaterals to motoneurons supplying yoke
muscle pairs; this appears to be part of the
neural substrate for Hering's law of equal
innervation in the vertical plane.202'205 Ax-
ons from the riMLF neurons also send col-
laterals to the interstitial nucleus of Cajal
(bilaterally for upward burst neurons) and
to the PMT cell groups, 47 which project to
the cerebellum. The riMLF receives an as-
cending projection from omnipause neu-
rons in the pons. 218
Unilateral, experimental lesions of the
riMLF using excitotoxins that spare fibers
of passage cause a mild defect in vertical
movements, consisting of slowing of down-
ward saccades (see Display 10-25).318 This
slowing probably occurs because each nu-
cleus contains burst neurons for both up-
ward and downward movements; however
projections to motoneurons innervating
depression are ipsilateral, whereas those
innervating the elevators may be bilat-
eral.207 At the same time, a severe, specific
defect of torsional quick phases is pro-
duced.318 For example, with a lesion of the
right riMLF, torsional quick phases clock-
wise from the point of view of the subject
(extorsion of the right eye and intorsion of
the left eye) are lost; in addition, there is a
static, contralesional torsional deviation
(equivalent to a shift of Listing's plane),
with torsional nystagmus beating contrale-
sionally.123 Similarly, a lesion of the left
riMLF impairs counterclockwise quick
phases. Unilateral riMLF lesions in hu-
mans are reported to produce similar but
generally more severe defects, probably
because of involvement of adjacent struc-
tures.176 Bilateral experimental lesions of
223
the riMLF in monkeys abolish vertical and
torsional saccades,318 but vertical gaze-
holding, vestibular eye movements, and
pursuit are preserved, as are horizontal
saccades. Patients with discrete, bilateral
infarction in the region of the riMLF show
deficits of either downward saccades (see
VIDEO: "Vertical saccadic palsy") or both
upward and downward saccades.40'249
A critical structure for vertical gaze-
holding (the neural integrator) is the in-
terstitial nucleus of Cajal (INC) (Display
6-6). This nucleus contains at least two
distinct populations of neurons.357 In the
monkey, some neurons in the INC encode
the complete, vertical, burst-tonic, ocular
motor signal.156 The INC receives inputs
from the vestibular nuclei, y-group, and
axon collaterals from burst neurons in the
riMLF.158'159 Pharmacological inactivation
of the INC with muscimol causes impaired
vertical and torsional gaze-holding after
a saccade carries the eye to a tertiary
(oblique) position.68-69 The gaze-holding
signal following a vestibular eye move-
ment may also depend on ascending sig-
nals from the nucleus prepositus hypoglossi.
The INC projects to vertical motoneurons
in the oculomotor and trochlear subnuclei
on the contralateral side of the brain stem
via the posterior commissure (Display
6-7).159 Experimental inactivation of the
posterior commissure with lidocaine causes
failure of vertical gaze-holding function,
with centripetal drifts of the eyes following
vertical saccades.237 Larger destructive le-
sions severely limit vertical eye move-
ments, especially upward; 240 ' 241 it is possi-
ble that such lesions also affect other
structures, such as the nucleus of the pos-
terior commissure, which normally con-
tribute to upward gaze.
The INC also contains neurons that
project to motoneurons of the neck and
trunk muscles and appears to coordinate
combined eye-head movements in tor-
sional and vertical planes. Stimulation
near the INC in the monkey produces an
ocular tilt reaction (see Fig. 10-18) that
consists of an ipsilateral head tilt and a syn-
kinetic ocular reaction: depression and
extorsion of the eye ipsilateral to the stim-
ulation and elevation and intorsion of the
contralateral eye;346 similar findings have
224
 Synthesis of the Commands for Conjugate Eye Movements 225

Figure 6-5. Anatomic schemes for the synthesis of upward, downward, and torsional eye movements. From the
vertical semicircular canals, primary afferents on the vestibular nerve (vn) synapse in the vestibular nuclei (VN)
and ascend into the medial longitudinal fasciculus (MLF) and brachium conjunctivum (not shown) to contact
neurons in the trochlear nucleus (CN IV), oculomotor nucleus (CN III), and the interstitial nucleus of Cajal
(INC). (For clarity, only excitatory vestibular projections are shown; more details about inhibitory vestibular pro-
jections may be found in Fig. 2-3 and Table 2-2 of Chap. 2.). The rostral interstitial nucleus of the medial longi-
tudinal fasciculus (riMLF), which lies in the prerubral fields, contains saccadic burst neurons. It receives an in-
hibitory input from omnipause neurons of the nucleus raphe interpositus (rip), which lie in the pons (for clarity,
this projection is only shown for upward movements). Excitatory burst neurons in riMLF project to the mo-
toneurons of CN III and CN IV and send an axon collateral to INC. Each riMLF neuron sends axon collaterals
to yoke-pair muscles (Hering's law). Projections to the elevator subnuclei (innervating the superior rectus and in-
ferior oblique muscles) may be bilateral because of axon collaterals crossing at the level of the CN III nucleus.
Projections of inhibitory burst neurons are less well understood, and are not shown here. The INC provides a
gaze-holding signal, and projects to vertical motoneurons via the posterior commissure. Signals contributing to
vertical smooth pursuit and eye-head tracking reach CN III from the y-group via the brachium conjunctivum
and a crossing ventral tegmental tract. Neurotransmitters: asp, aspartate; glu, glutamate; gly, glycine.

been reported in a human patient.180 Ex-
perimental, unilateral lesions of the INC
also cause an ocular tilt reaction with con-
tmlateral head tilt, skew deviation with hy-
pertropia of the ipsilateral eye, extorsion
of the contralateral eye, and intorsion of
the ipsilateral eye. This pattern of ocular
tilt reaction is similar to that produced by
stimulation of the contralateral utricular
nerve317 and is encountered clinically with
a variety of brain stem lesions that involve
central otolithic pathways.28 Bilateral inac-

Figure 6-4. Transverse section of rostral mesencephalon of human brain stem showing structures important for
vertical gaze. (A) Schematic showing location of riMLF with respect to the rostral pole of the red nucleus (rn),
substantia nigra (sn), H-fields of Forel (H) , habenular (hb), centromedian nucleus of the thalamus (cm), nu-
cleus dorsalis of thalamus (nd), mammillary body (mb), and the tractus retroflexus (TR), which separates the
riMLF from the more caudal interstitial nucleus of Cajal (iC). (B) Nissl-stained section showing riMLF, which is
bordered by the posterior thalamo-subthalamic paramedian artery (star). (C, D) photomicrographs immunocy-
tochemically labeled with PAV antibodies.139 The iC is highlighted by its PAV content and forms a compact nu-
cleus; the inset shows that iC neurons are round and densely packed. The riMLF contains elongated neurons
(presumed burst neurons) that are oriented parallel to the mediolateral axis of the riMLF. Scale bar: 500 (Jim
(B-D); 30 (Jim (insets of C, D) (Courtesy of A.K.E. Horn, Munich, Germany.)
226 The Properties and Neural Substrate of Eye Movements

Display 6-6: Interstitial Nucleus of Cajal (INC)

• Contains two populations of neurons: one set makes a major contribu-
tion to the neural integrator (gaze-holding mechanism) for vertical
and torsional gaze; the other contributes to eye-head coordination in
the roll plane

• Receives inputs from burst neurons in the riMLF, the vestibular nu-
clei, and the y-group

• Projections are contralateral (via the posterior commissure) to ocular

motoneurons of CN III and CN IV and to the opposite INC

• Ascending projections are to mesencephalic reticular formation, zona

incerta, riMLF, and nuclei of the central thalamus

• Descending projections are to nucleus gigantocellularis of pontine

reticular formation (for head movements), vestibular nuclei, PMT cell
groups in medulla, and cervical cord

(For related clinical disorders, see Display 10-26 in Chap. 10.)

tivation or lesions of INC restrict the verti-
cal ocular motor range, and cause upbeat
nystagmus and neck retroflexion. 97 > 123a
The neural signals necessary for vertical
vestibular and smooth pursuit eye move-
ments and for contributions to the vertical
gaze-holding command ascend from the
medulla and pons to the midbrain. The
MLF is the most important route for these
projections, but the brachium conjunc-
tivum (superior cerebellar peduncle) and
other pathways are also involved. Details
of ascending vestibular projections are
summarized in Figure 2-3 and Table 2-2
in Chapter 2. The ascending axons con-
cerned with vertical eye movements arise
from vestibular nucleus neurons that have
been calledposition-vestibular-pause cells.326'353
They carry an eye position signal and a
head velocity signal and cease discharging
during vertical saccades. These fibers also
convey an eye velocity signal during verti-
cal smooth pursuit, but during combined
eye-head tracking (see Chap. 7), when the
eyes may be nearly stationary in the orbits,
a head velocity signal is still present on

Display 6-7: Posterior Commissure

• Contains axons from INC projecting to contralateral CN III, CN IV,
and INC

• Also contains axons from the nucleus of the posterior commissure

projecting to contralateral riMLF and INC, which may be important
for up-gaze; and to the "M" group, which may be important for coor-
dination of vertical eye and lid movements

(For related clinical disorders, see Display 10-2*7 in Chap. 10.)

 Synthesis of the Commands for Conjugate Eye Movements 227

Display 6-8: y-Group

• A small collection of cells that cap the inferior cerebellar peduncle. Re-
ceives afferents from flocculus Purkinje cells, and projects to the ocu-
lomotor and trochlear nuclei via the brachium conjunctivum and a
crossing ventral tegmental tract

• Dorsal y-group cells increase their discharge during upward smooth

pursuit, optokinetic following, and combined eye-head tracking (VOR
suppression), but show no consistent modulation during VOR in
darkness

• Along with flocculus, may contribute to adaptation of the vertical VOR

(For functional significance, see Neural Substrate for Eye-Head Pursuit

in Chap. 7 and Electrophysiological Aspects of Vestibulocerebellar Control
of the VOR in Chap. 2.)

these axons. This vestibular signal must be
canceled by another equal and opposite
signal, which also projects to the oculomo-
tor and trochlear nuclei. One mechanism
that might make possible such cancellation
of the VOR during vertical eye-head
tracking is a gaze velocity signal that as-
cends from the dorsal portion of the
y-group (Display 6-8), a small collection of
cells that cap the inferior cerebellar pe-
duncle.51>59'238,239,282,307 Tne y-group re-
ceives afferents from flocculus Purkinje
cells and projects to the oculomotor and
trochlear nuclei via the brachium conjunc-
tivum and a crossing ventral tegmental
tract.
Consistent with these projections is the
finding that bilateral lesions of the medial
longitudinal fasciculus cause bilateral INO
and impair vertical vestibular and smooth-
pursuit movements, but they spare verti-
cal saccades (see Display 10-22).85'266 In
addition, partial loss of the vertical eye po-
sition signal causes vertical gaze-evoked
nystagmus. Other cell groups in the mes-
encephalon may contribute to the control
of vertical gaze. The nucleus of the poste-
rior commissure (nPC) contains neurons
that burst for upward saccades206'207 and
project through the posterior commissure
to contact the riMLF, INC, and the in-
tralaminar thalamic nuclei.39 The central
mesencephalic reticular formation (cMRF)
(Display 6-9), which contains the nucleus
subcuneiformis, seems to play an impor-
tant role in the control of horizontal and
vertical saccades.62'117'342 It receives inputs
from the PPRF, nucleus of the posterior
commissure, fastigial nucleus, and cortical
eye fields, and has reciprocal connections
with the superior colliculus. Its other pro-
jections are to the omnipause neurons
and nucleus reticularis tegmenti pontis
(NRTP).61'117'342 Experimental lesions of
the cMRF cause hypermetria of contralat-
eral and upward saccades and hypometria
of ipsilateral and downward saccades.341
In addition, fixation is disrupted by sac-
cadic intrusions directed away from the
side of inactivation (see Display 10-28).
The periaqueductal gray matter is known
to contain neurons with vertical burst-
tonic or saccadic pause properties.149 An
important structure in the coordination of
vertical saccades and eyelid movements is
the M-group of neurons, which lie adja-
cent, medial, and caudal to the riMLF and
project to both the elevator subnuclei of
the eye (superior rectus and inferior
oblique) and the motoneurons of the leva-
tor palpebrae superioris in the central
caudal subdivision of the oculomotor nu-
cleus.44-48'292 The M-group also has recip-
rocal connections with the nucleus of the
posterior commissure, and lesions affect-
ing either structure may disrupt lid-eye
228 The Properties and Neural Substrate of Eye Movements

Display 6-9: Central Mesencephalic Reticular

Formation (cMRF)
• Extending rostral and caudal to the posterior commissure; in coronal
section, a line extending laterally from the aqueduct divides into
dorsal (nucleus cuneiformis) and ventral segment (nucleus sub-
cuneiformis)
• Reciprocal, topographically arranged connections with ventral layers
of superior colliculus; receives projections from PPRF, nucleus of pos-
terior commissure, fastigial nucleus, and cortical eye fields
• Projects to nucleus reticularis tegmenti ponds (NRTP) and omnipause
neurons in nucleus raphe interpositus in the pons
• May contribute to programing of both horizontal and vertical saccades
through reciprocal connections with superior colliculus and brain
stem nuclei
(For related clinical disorders, see Display 10-28 in Chap. 10.)

coordination during vertical saccades.48
The nucleus of Darkschewitsch does not
seem to be involved in the control of eye
movements.39
CEREBELLAR INFLUENCES
ON GAZE
The cerebellum (Fig. 6-6) optimizes eye
movements so that they are calibrated to
ensure clearest vision. Two main subdivi-
sions of the cerebellum play an important
role in the control of eye movements: (1)
the vestibulocerebellum (flocculus, parafloc-
culus, nodulus, and ventral uvula), and
(2) the dorsal vermis of the posterior lobe
and the fastigial nucleus.
Contributions of the
Vestibulocerebellum to
Gaze Control
Theflocculi are paired structures which, in
human brain, lie adjacent to the tonsils
(paraflocculi), ventral to the inferior cere-
bellar peduncle, and next to the eighth
cranial nerve (Display 6-10). In primates,
the caudal five folia of the flocculus re-
ceive mossy fiber inputs mainly from the
vestibular nucleus and nerve, the nucleus
prepositus hypoglossi (NPH), the nucleus
reticularis tegmenti pontis, and the mes-
encephalic reticular formation. The adja-
cent paraflocculi receive inputs mainly
from the contralateral pontine nuclei.
Both the flocculi and paraflocculi receive
climbing fiber inputs from the contralat-
eral inferior olivary nucleus (Fig. 6-1),
which might provide information impor-
tant for adaptive ocular motor con-
tro l.i7,io5,i68,2i5,223a Qn the basis of this pat-
tern of inputs, it is suggested that the
flocculus is more important for controlling
the vestibulo-ocular reflex, whereas the
paraflocculus mainly contributes to smooth
pursuit. 215
One further important input to the floc-
culus is from the cell groups of the para-
median tracts (PMT), which receive inputs
from essentially all premotor structures
that project to ocular motoneurons (Dis-
play 6-4).43>47 The PMT cell groups are,
numerically, a larger projection to the floc-
culus than are the vestibular nuclei, but
only recently have they been defined and
studied. One PMT cell group in the me-
dulla, the nucleus pararaphales, receives
 Synthesis of the Commands for Conjugate Eye Movements 229

Figure 6-6. Gross anatomy of the human cerebellum. (A) Inferior surface, after removal from brain stem by
transection of cerebellar peduncles. (B) View of sagittally sectioned cerebellum showing lobules of the cerebel-
lar vermis.

inputs from the INC and projects via the
ventrolateral surface of the medulla and
inferior cerebellar peduncle to the floccu-
lus and ventral paraflocculus.43 Neurons
in another probable PMT cell group, the
nucleus incertus, have been shown to con-
tain burst-tonic neurons,58 and so it seems
possible that the PMT cell groups send an
efference copy of eye movement com-
mands to the flocculus.47 Such a signal
could be important for normal function of
the gaze-holding (neural integrator) net-
work or for the adaptive control of eye
movements. The main efferent pathways
230 The Properties and Neural Substrate of Eye Movements

Display 6-10: Vestibulocerebellum: Flocculus and

Paraflocculus
• Main floccular inputs are from the vestibular nuclei, nucleus preposi-
tus hypoglossi, inferior olivary nucleus, and cells group of the para-
median tracts (PMT)

• Dorsal and ventral paraflocculus receive main inputs from pontine

nuclei

• Main outputs are to ipsilateral superior and medial vestibular nuclei,

and y-group

• Important for stabilizing the eyes with respect to a visual scene or

object. Contribute to visual-vestibular interactions, gaze-holding,
smooth-pursuit or combined eye-head tracking, and to plasticity of
the VOR, by providing the brain stem with signals necessary for adap-
tive changes

(For related clinical disorders, see Display 10-17 in Chap. 10.)

of the flocculus and paraflocculus are to important deficit caused by floccular-

the ipsilateral superior and medial vestib-
ular nuclei and to the y-group.167'216
The flocculus Purkinje cells may supple-
ment vestibular nucleus neurons in gener-
ating compensatory eye movements dur-
ing self-rotation,339 regulate the phase of
the VOR,74'306 and contribute to the trans-
formation of vestibular and visual signals
into a common frame of reference.164 In
addition, the floccular Purkinje cells play
an important role in the adaptive control
of the VOR.178 Parafloccular and floccular
Purkinje cells discharge during smooth
pursuit and combined eye-head tracking
to encode gaze velocity.177'198
Experimental lesions of the flocculus
and paraflocculus in monkeys produce a
characteristic syndrome that is similar to
that encountered clinically in patients
with the Arnold-Chiari malformation (see
Table 10-12).35° This includes impaired
smooth pursuit and eye-head tracking, as
well as impaired gaze holding (deficient
neural integrator). The gaze-holding deficit
probably reflects loss of the cerebellum's
contribution to the fidelity of the brain
stem neural integrator, which lies in
the medial vestibular nuclei and the nu-
cleus prepositus hypoglossi.49'197 Another
parafloccular lesions is loss of ability to
adapt the properties of the VOR in re-
sponse to visual demands.178
The nodulus, which is the midline por-
tion of the flocculonodular lobe, lying im-
mediately caudal to the inferior medullary
velum, and the adjacent ventral uvula, re-
ceive afferents from the vestibular nuclei,
nucleus prepositus hypoglossi, inferior
olivary nucleus, and vestibular nerve (Dis-
play 6-11).278'281'343 The nodulus and ven-
tral uvula project to the vestibular nuclei
and control the velocity-storage mecha-
nism of the VOR, by which the response of
this reflex to low-frequency stimuli is en-
hanced.302'338 The effects of velocity stor-
age are best illustrated by considering the
duration of nystagmus that ensues follow-
ing the onset of a sustained, constant-
velocity rotation: this nystagmus lasts two
or three times longer than can be ac-
counted for by the mechanical properties
of the cupula and endolymph. In mon-
keys, lesions of the nodulus and uvula
maximize the velocity-storage effect; ma-
neuvers that will usually reduce it, such as
pitching the head forward during postro-
tational nystagmus, are abolished.338 Simi-
lar effects are seen in patients with midline
 Synthesis of the Commands for Conjugate Eye Movements 231

Display 6-11: Vestibulocerebellum: Nodulus and

Ventral Uvula
• Main afferents are from medial and inferior vestibular nuclei, nucleus
prepositus hypoglossi, inferior olivary nucleus, and vestibular nerve

• Main projections are to the vestibular nuclei

• Controls velocity-storage mechanism of the VOR, by which responses

of secondary vestibular neurons are prolonged beyond those in pri-
mary vestibular neurons

(For related clinical disorders, see Display 10-75 in Chap. 10.)

cerebellar tumors that involve the nodu-
lus.116 In addition, when monkeys that
have nodular lesions are placed in dark-
ness, they may develop periodic alternat-
ing nystagmus.338 Evidence from patients
with periodic alternating nystagmus sup-
ports a causative role of lesions of the
nodulus and ventral uvula.
Contributions of the Dorsal
Vermis and Fastigial Nucleus to
Gaze Control
Lobules VI and VII of the vermis (parts of
the declive, folium, tuber, and pyramis)
(Display 6-12) receive mossy fiber inputs
from the paramedian pontine reticular for-
mation (PPRF), nucleus reticularis tegmenti
pontis (NRTP), dorsolateral and dorsome-
dial pontine nuclei, vestibular nuclei, and
nucleus prepositus hypoglossi, as well as
climbing fiber inputs from the inferior oli-
vary nucleus.30'321'348 The projection from
the NRTP may relay information neces-
sary for the planning of saccades from the
frontal eye field to the cerebellum,67'144'174
whereas those from the dorsolateral pon-
tine nuclei seem more concerned with
smooth pursuit. 154 ' 321
Purkinje cells in the dorsal vermis dis-
charge before saccades122'227 and encode
target velocity during smooth pursuit and
combined eye-head tracking.316 Stimula-
tion of the vermis produces saccades.277

Display 6-12: Cerebellar Dorsal Vermis (Lobules VI and VII)

• Receives mossy fiber inputs from nucleus reticularis tegmenti pontis
(NRTP), PPRF, dorsolateral and dorsomedial pontine nuclei, vestibu-
lar nuclei, nucleus prepositus hypoglossi, and inferior olivary nucleus

• Main projection is to underlying caudal fastigial nucleus

• Purkinje cells in the dorsal vermis discharge before saccades and en-
code gaze velocity during smooth-pursuit and combined eye-head
tracking. Microstimulation produces contralaterally directed saccades
and pursuit

(For related clinical disorders, see Display 10-19 in Chap. 10.)

232 The Properties and Neural Substrate of Eye Movements

With currents near to threshold, a topo-
graphic organization is evident: upward
saccades are evoked from the anterior
part, downward saccades from the poste-
rior part, and ipsilateral, horizontal sac-
cades from the lateral part.222 Lesions of
the dorsal vermis produce saccadic dysme-
tria. Unilateral pharmacological decorti-
cation with bicuculline typically causes
marked ipsilateral hypometria and mild
contralateral hypermetria, with a gaze de-
viation away from the side of the inactiva-
tion.280 Lesions of the posterior vermis
also impair smooth pursuit, predomi-
nantly towards the side of the lesion.332
The main projection of the Purkinje
cells of the dorsal vermis is to the caudal
part of the fastigial nucleus—the most me-
dial of the deep cerebellar nuclei (Display
6-13).348 This fastigial oculomotor region
(FOR) also receives climbing fiber inputs
from the inferior olivary nucleus and axon
collaterals from mossy fibers projecting to
the dorsal vermis from pontine nuclei, es-
pecially NRTP.111'223'348 Thus, the fastigial
nucleus receives a "copy" of the saccadic
commands, which are relayed by NRTP
from the frontal eye fields and superior
colliculus.223 The main projection from
the fastigial nucleus crosses through the
other fastigial nucleus and enters the unci-
nate fasciculus, which runs in the dorsolat-
eral border of the brachium conjunc-
tivum, to reach the brain stem. The main
targets of the caudal fastigial nucleus are
the omnipause neurons and burst neu-
rons in the medulla, pons, and midbrain.
In addition, the nucleus of the posterior
commissure, the mesencephalic reticular
formation, and the rostral pole of the su-
perior colliculus receive inputs from the
fastigial nucleus.189'223 Smaller projections
to other structures—NRTP, the dorso-
lateral pontine nuclei, vestibular nuclei,
the superior colliculus, and the nucleus
prepositus hypoglossi—have been re-
ported.16-17'111
Neurons in the caudal fastigial nucleus
also discharge in relation to saccades94'124'226
and smooth pursuit. 95 Fastigial nucleus le-
sions are well known to produce marked
hypermetria of saccades.298 Destructive le-
sions tend to be bilateral because of the
crossing of axons destined for the brain
stem within the fastigial nucleus itself. The
nature of the defect has been clarified us-
ing muscimol to induce pharmacological
inactivation of one side of the caudal fasti-
gial nucleus. The main effect is markedly
hypermetric ipsilateral saccades and hypo-
metric contralateral saccades. Addition-
ally, there is a tonic gaze deviation toward
the side of inactivation, and smooth pur-
suit is impaired for targets moving con-

Display 6-13: Fastigial Nucleus

• Receives inputs from the dorsal vermis, inferior olivary nucleus, and
axon collaterals from mossy fibers projecting to the dorsal vermis
from pontine nuclei

• Main projection from the fastigial nucleus crosses and runs in unci-
nate fasciculus of the brachium conjunctivum to reach PPRF, riMLF,
nucleus of the posterior commissure, the mesencephalic reticular for-
mation, superior colliculus, and omnipause neurons

• Neurons in the caudal fastigial nucleus (FOR) discharge prior to and

during saccades and smooth pursuit; earlier discharge occurs for
movements contralaterally

(For related clinical disorders, see Display 10-19 in Chap. 10.)

 Synthesis of the Commands for Conjugate Eye Movements
tralaterally. These findings are similar to
the lateropulsion encountered in Wallen-
berg's syndrome (lateral medullary infarc-
tion) (see VIDEO: "Wallenberg's syndrome").
In that disorder, interruption of olivocere-
bellar climbing fibers within the restiform
body is postulated to cause increased ac-
tivity of Purkinje cells in the ipsilateral
dorsal vermis, which, in turn, inhibits the
underlying fastigial nucleus.340
THE CEREBRAL HEMISPHERES
AND VOLUNTARY CONTROL OF
EYE MOVEMENTS
Approaches to Studying the
Cerebral Control of Eye
Movements in Humans
In developing a hypothetical scheme for
the voluntary control of eye movements in
humans, we have drawn on several differ-
ent lines of evidence, each of which has
inherent strengths and weaknesses. Ana-
tomic and electrophysiologic studies in
monkeys have contributed substantial in-
sights, but caution is required in extrapo-
lating hypotheses from these data to ac-
count for pathways and behavior in
humans. 334 Functional scanning, includ-
ing proton emission tomography (PET)
and functional magnetic resonance imag-
ing (fMRI), have held the promise of iden-
tifying cortical areas homologous to those
that have been well defined in monkeys.333
However, such studies have often yielded
discrepant results, partly reflecting the
use of different test paradigms. Another
pitfall of functional imaging is that in-
ferred local changes in cerebral metabo-
lism may represent excitation or inhibi-
tion. Furthermore, there is evidence that
just thinking about eye movements, with-
out actually making them, may cause
metabolic changes in areas such as the
frontal eye field.23'166 Direct electrical
stimulation of cerebral cortex during or
before operations has limited availability.
The noninvasive technique of transcranial
magnetic stimulation (TMS), which tran-
siently perturbs local cortical activity, will
233
not induce eye movements, but it has pro-
vided information on the sequence of pro-
graming that takes place in different corti-
cal areas. Of abiding importance are
studies of the behavioral effects of discrete
lesions, using paradigms that test specific
aspects of the voluntary control of eye
movements. Most useful are the behav-
ioral changes that occur with acute lesions
or pharmacological inactivation. However,
the effects of adaptation and recovery
may modify or abolish acute behavioral
deficits.
Interpretation of studies of the role of
the cerebral hemispheres in the control of
eye movements requires consideration of
several special factors. First, it is important
to test a range of behaviors from pure re-
flex to most voluntary, since all may be af-
fected by hemispheric lesions. For exam-
ple, rapid eye movements include reflex
quick phases of nystagmus, saccades that
respond to the changing highlights of the
environment, and premeditated saccadic
refixations (see Table 3-1, Chap. 3). Sec-
ond, voluntary eye movements depend on
attentional factors, and electrophysiologic
evidence has linked increased attention
with enhanced neural performance.64'305
Thus, smooth ocular tracking of a large
moving target, such as a mirror rotated in
front of a subject's face, may seem almost
reflexive, but tracking of a small target
moving across a textured background
requires focused visual attention. Third,
association areas that receive disparate
sensory signals (e.g., visual or vestibular)
must transform these signals so that they
are synchronized and in similar coordi-
nates. These areas must also take into ac-
count the current position of eye, head,
and body in space. Finally, although our
scheme is presented as a series of opera-
tions by different cortical and subcortical
centers, parallel-distributed processing of
retinal, ocular motor, and limbic inputs
may be necessary to achieve the extensive
repertoire of voluntary eye movements.
Our approach here will be (1) to sum-
marize the contributions of visual and ves-
tibular cortical areas; (2) to review the role
played by parietal cortex and the pulv-
inar; (3) to examine the properties of neu-
234 The Properties and Neural Substrate of Eye Movements
rons in several frontal areas and the thala-
mic nuclei to which they are connected;
and (4) to discuss the parallel, descending
pathways by which volition controls eye
movements.
Contributions of Posterior Cortical
Areas to Gaze Control
PRIMARY VISUAL CORTEX AND
GAZE CONTROL
Striate cortex (visual area VI, Brodmann
area 17; Fig. 6-7 and Fig. 6-8) is of funda-
mental importance in the control of visu-
ally guided eye movements (Display 6-14).
In monkeys, experimental, unilateral le-
sions of striate cortex impair eye move-
ments because of the lack of visual input;
saccadic and pursuit eye movements can
still be made if the visual stimulus falls in
the intact visual hemifield.296 If moving
targets are presented in the visual hemi-
field contralateral to the lesion, however,
saccades are inaccurate and no smooth
pursuit is generated. Although monkeys
tend to show some recovery from bilateral
occipital lobe lesions, so they eventually re-
gain some smooth-pursuit function,349 hu-
man beings with occipital lobe lesions show
limited recovery.12 The deficit is greater
with larger lesions, and smooth pursuit is
impaired more than saccades.270 Complete,
bilateral lesions of the occipital lobes that
produce cortical blindness probably abol-
ish optokinetic nystagmus in humans.335
CONTRIBUTIONS OF
PERISTRIATE CORTEX TO
GAZE CONTROL
A separate visual pathway for the percep-
tion of motion has been demonstrated,
starting in retinal ganglion cells that pro-
ject via the magnocellular layers of the lat-
eral geniculate nucleus to layer 4Ca of
striate cortex.179 Some neurons in striate
cortex respond to moving visual stimuli,
but these cells have small receptive fields,
respond only to motion in the frontal
plane, and cannot encode higher image
velocities. Further information processing
is necessary before a pursuit or saccadic
eye movement can be programed; this is
largely performed in the middle temporal
visual area (MT or V5) and the medial su-
perior temporal visual area (MST) (Dis-
play 6-14 and Fig. 6-8).73'87'351 Striate cor-
tex projects both directly and indirectly to
MT;328 in addition, MT receives inputs
that bypass striate cortex,88 perhaps via
the superior colliculus and pulvinar.275
Neurons in area MT have larger receptive
fields than those in striate cortex and en-
code the speed and direction of target
movements in three dimensions,73'160'187
and contribute to stereopsis.71a Experi-
mental lesions in MT corresponding to
extrafoveal retina cause a scotoma for mo-
tion in the contralateral visual field: sta-
tionary objects are perceived appropri-
ately but motion perception is disrupted.220
The consequences of lesions of extrafoveal
MT for eye movements are that saccades
can still be made accurately to stationary
targets in the affected visual field, but
moving stimuli cannot be tracked accu-
rately by saccades or smooth pursuit. 83
Functional imaging studies have demon-
strated the human homologue of area MT
is located at the temporo-parieto-occipital
junction, posterior to the superior tempo-
ral sulcus, at the junction of Brodmann ar-
eas 19, 37 and 39, close to the intersection
of the ascending limb of the inferior tem-
poral sulcus and the lateral occipital sul-
cus.327-352 Patients with cortical lesions
have been described who appear to have
perceptual11'13'356 or ocular motor200'323
deficits similar to those reported with MT
lesions in monkeys.83'220
Visual area MT, in turn, projects to area
MST,73'87 which contains neurons that not
only encode moving visual stimuli but also
appear to carry an eye movement sig-
nal.221 Area MST seems to be important
for analyzing the optic flow that occurs
during locomotion.78'114 Area MST is also
important for the generation of smooth-
pursuit eye movements; lesions here or in
the foveal representation of MT cause a
deficit primarily of horizontal smooth pur-
suit for targets moving towards the side
of the lesion. In addition, a retinotopic
deficit for motion detection, similar to that
with extrafoveal lesions of MT, is present
for targets presented in the contralateral
Figure 6-7. A hypothetical scheme for horizontal smooth pursuit. Primary visual cortex (VI) projects to the ho-
mologue of the middle temporal visual area (MT) that in humans lies at the temporal-occipital-parietal junc-
tion. MT projects to the homologue of the medial superior temporal visual area (MST) and also to the frontal
eye field (FEF). MST also receives inputs from its contralateral counterpart. MST projects through the retro-
lenticular portion of the internal capsule and the posterior portion of the cerebral peduncle to the dorsolateral
pontine nucleus (DLPN). The DLPN also receives inputs important for pursuit from the frontal eye field; these
inputs descend in the medial portion of the cerebral peduncle. The DLPN projects, mainly contralaterally, to
the flocculus, paraflocculus, and ventral uvula of the cerebellum; projections also pass to the dorsal vermis. The
flocculus projects to the ipsilateral vestibular nuclei (VN), which in turn project to the contralateral abducens
nucleus. Note that the sections of brain stem are in different planes from those of the cerebral hemispheres.

235
236 The Properties and Neural Substrate of Eye Movements

Figure 6-8. Probable location of cortical areas important for eye movements in rhesus monkey (A) and human
brain (B). al, lateral arcuate sulcus; as, superior arcuate sulcus; cs, central sulcus; FEF, frontal eye field; FST,
fundus of the superior temporal area; ip, intraparietal sulcus; L, large saccade region of FEF; LIP, lateral intra-
parietal area; Ml, primary motor cortex; MST, medial superior temporal visual area; MT, middle temporal vi-
sual area; ps, principal sulcus; PSR, principal sulcus region; S, small saccade region of FEF; SI, primary sensory
cortex; SEF, supplementary eye field; SMA, supplementary motor area; SP, smooth pursuit region of FEF; STP,
superior temporal polysensory area; sts, superior temporal sulcus; VI, primary visual cortex; V3A, parietal vi-
sual area V3a; VIP, ventral intraparietal area; 5, area 5; 7, area 7; numbers refer to Brodmann's areas. In hu-
mans, MT and MST may form a contiguous cortical area. (A reproduced from Biittner-Ennever JA, Horn AKE.
Anatomical substrates of oculomotor control. Curr Opinion Neurobiol 1997;7:872-9, with permission of Cur-
rent Biology Ltd publications)

visual hemifield.83 Thus, experimental le- tribute to processing of moving visual

sions of MT produce a tracking deficit that
resembles the effects of certain posterior
cerebral lesions in patients.200'323 The hu-
man homologue of area MST may lie adja-
cent to MT14 Other cortical regions, such
as the superior temporal polysensory
area,232 visual area 3a, and the superior
parietal occipital region27 may also con-
stimuli and directing visuospatial atten-
tion, but their homologous areas and con-
tributions to human eye movements re-
main to be determined.
Cortical areas MT and MST are both
important components of the neural sub-
strate for smooth pursuit (Fig. 6-7),328
which projects ipsilaterally through the
 Synthesis of the Commands for Conjugate Eye Movements 237

Display 6-14: Posterior Cortical Areas

PRIMARY VISUAL CORTEX (STRIATE CORTEX, VI)
• Important for control of visually guided eye movements, but receptive
fields are small and unable to analyze complex visual stimuli

MIDDLE TEMPORAL VISUAL AREA (MT, V5)

• Human homologue lies at occipito-temporo-parietal junction, at junc-
tion of Brodmann areas 19, 37, and 39

• Receives inputs from primary visual cortex (VI)

• Projects to FEF, MST, other cortical areas concerned with visual mo-
tion, and to dorsolateral pontine nuclei

• Encodes speed and direction of visual stimuli in three dimensions

MEDIAL SUPERIOR TEMPORAL VISUAL AREA (MST)

• Human homologue lies close to MT at occipito-temporo-parietal junc-
tion

• Receives visual inputs from area MT and from vestibular and ocular
motor signals

• Projects to FEF and other cortical areas concerned with visual motion
and to dorsolateral pontine nuclei

• Encodes moving visual stimuli and may also carry an eye movement
signal
(For related clinical disorders, see Display 10-34 in Chap. 10.)

retrolenticular portion of the internal cap-
sule200 and the posterior portion of the
cerebral peduncle to reach the dorsolat-
eral pontine nuclei (DLPN). 104 > 188 > 214 The
pontine nuclei also receive inputs related
to smooth pursuit from the frontal eye
field. The dorsolateral pontine nuclei pro-
ject to the dorsal paraflocculus105 and the
dorsal vermis of the cerebellum.30 These
cerebellar areas project in turn to the
brain stem via the vestibular and fastigial
nuclei.95'167 The effects of lesions at vari-
ous points along this pursuit pathway are
discussed in Chapter 4.
It has also been shown that areas MT
and MST are important for mediating op-
tokinetic nystagmus.83 Although a subcor-
tical visual pathway exists in human
brain,92 and MT and MST project to nu-
clei in it,328 its functional capacity in adult
humans with normal, binocular vision is
uncertain. It may be important in the
pathogenesis of latent nystagmus.
Contributions of the Temporal
Lobe to Gaze Control
Localization of the site of human vestibu-
lar cortex175 in the posterior aspect of
the superior temporal gyrus, the parieto-
insular-vestibular cortex (PIVC) (Fig.
6-8), has been achieved using functional
238 The Properties and Neural Substrate of Eye Movements

Display 6-15: Posterior Temporal Lobe (Vestibular Cortex)

• In humans, one component of vestibular cortex corresponds to the
posterior aspect of the superior temporal gyrus, the parieto-insular-
vestibular cortex (PIVC)

• Clinical lesions cause contralateral tilts of subjective visual vertical,

abolish circularvection, and cause memory-guided saccades to become
inaccurate if the subject is rotated during the memory period

(For related clinical disorders, see Display 10-34 in Chap. 10; for vestib-
ular sensation see Chap. 2.)

imaging during vestibular and optokinetic in extrapolating these results to parietal

stimulation,25'273'343'763'93 and by studying
the effects of cortical lesions (Display
6_l5).28,29,i46,i75 This localization confirms
the stimulation studies of Penfield.243 Clin-
ical lesions affecting this area of temporal
cortex cause contraversive tilts of the sub-
jective visual vertical,29 abolish the sense
of self-rotation (circularvection) that nor-
mally occurs with optokinetic stimula-
tion,315 and impair memory-guided sac-
cades if patients are rotated to a new
position during the memory period.146 It
seems likely that, as in monkey, other cor-
tical areas also receive vestibular inputs, so
more than one vestibular area may ex-
ist.25'175 Reported effects of parietotempo-
ral lesions on fixation-suppression of ves-
tibular eye movements (such as those
induced by caloric stimulation) probably
reflect impaired smooth pursuit due to in-
volvement of secondary visual areas, such
as MT and MST.
Contributions of the Parietal Lobe
to Gaze Control
The parietal lobe has an important influ-
ence on all classes of eye movements by
virtue of its role in directing visual atten-
tion to objects in extrapersonal space. In
addition, the parietal eye field (PEF) has a
direct role in programing saccades. Sub-
stantial progress has been achieved in un-
derstanding parietal lobe contributions to
the control of eye movements in the rhe-
sus monkey. However, caution is necessary
lobe function in humans, because differ-
ences in anatomy exist between the two
species,333 and humans have developed
right hemisphere dominance for directing
spatial attention. In general, the parietal
lobes are important in programing sac-
cades concerned with reflexive explo-
ration of the visual environment.
CONTRIBUTIONS OF THE
POSTERIOR PARIETAL CORTEX
TO GAZE CONTROL
The inferior parietal lobule of the mon-
key, specifically the caudomedial portion
that has been called area 7a or PG,4'5'9'185
contains populations of neurons that re-
spond to visual stimuli and discharge dur-
ing a range of eye movements (see Fig.
6-8A and Display 6-16). In monkeys,
these neurons receive inputs from sec-
ondary visual areas, such as MST, the
pulvinar, superior colliculus, cingulate
cortex, and the intralaminar thalamic
nuclei.5'55'219 Parietal area 7a projects to
dorsolateral prefrontal cortex and to the
cingulate gyrus, but only weakly to the
frontal eye field.5 A homologous area in
the human brain, corresponding to por-
tions of Brodmann areas 39 and 40, may
lie in the inferior parietal lobule (see Fig.
6-8B). Functional imaging studies suggest
that the adjacent superior parietal lobule
is also important for shifting attention in
humans. 65
Area 7a contains a variety of neurons
that discharge during active visual fixa-
 Synthesis of the Commands for Conjugate Eye Movements 239

Display 6-16: Posterior Parietal Cortex

• The human homologue of area 7a in the rhesus monkey may lie in the
inferior parietal lobule, corresponding to portions of Brodmann areas
39 and 40
• In monkey, area 7a receives inputs from secondary visual areas, such
as MST, and from the pulvinar, superior colliculus, cingulate cortex,
and the intralaminar thalamic nuclei
• Area 7a projects to dorsolateral prefrontal cortex and to the cingulate
gyrus, but only weakly to the frontal eye field
• Important for directing visual attention in extrapersonal space; to this
end, visually responsive neurons modulate their discharge according
to eye position
(For related clinical disorders, see Display 10-35 in Chap. 10.)

tion, in relation to saccades, or during
smooth pursuit.9 The visual receptive
fields of neurons in area 7a are large and
often cross the midline. Neurons that re-
spond to moving stimuli in the periphery
of vision may be important for processing
the optic flow that occurs during locomo-
tion.312 Neurons that discharge in rela-
tionship to saccades usually do so after the
eye movement is made.9 Furthermore,
cells that are active during smooth pursuit
seem more concerned with directing at-
tention to the visual stimulus than with re-
cording its dynamic properties.185 Thus, it
seems that posterior parietal cortex is
more concerned with shifts of attention
than with eye movements per se.311 In
fact, eye movements are not necessary to
shift the focus of attention.262 On the other
hand, difficulties in initiating saccades
may occur if attention cannot be shifted
from one location to another.263 For poste-
rior parietal cortex to be able to synthesize
a signal that can direct visual attention to-
wards an object in extrapersonal space,
one must take account of not only the reti-
nal coordinates of the stimulus but also
the direction of gaze (eye position in
space). Thus, an important finding is that
the discharge of some neurons in area 7a
is influenced not just by visual stimuli but
also by eye and head position.6'31 Area 7a
has been shown to receive vestibular in-
puts,86 and eye position could be signaled
by efference copy. It has been postulated
that a neural network of such cells could
encode a visual target in spatial or head-
centered coordinates.6
Similar properties have been demon-
strate in another subdivision of the pari-
etal lobe, the ventral intraparietal area
(VIP), which lies in the fundus of the in-
traparietal sulcus in monkeys (Fig. 6-8A).
Some neurons here encode the location of
visual stimuli in a head-centered frame of
reference79 and respond to somatosensory
stimuli. Thus, VIP may be important for
building an internal, multisensory repre-
sentation of extrapersonal space.81
Clinically, unilateral posterior parietal
lesions, especially right-sided ones, cause
contralateral inattention and may produce
ipsilateral gaze deviation or preference
and partially restrict saccades and smooth
pursuit to the ipsilateral hemirange of
gaze.24'199 Even after the acute phase, la-
tency of visually guided saccades remains
bilaterally increased, especially with right-
sided lesions.184'256 In addition, memory-
guided saccades are inaccurate.255 A simi-
lar defect of memory-guided saccades is
produced in normal subjects if TMS is
applied to the posterior parietal area
early during the memory period.212-234
240 The Properties and Neural Substrate of Eye Movements
Unilateral parietal lesions have also been
thought to cause greater impairment of
pursuit when the target moves towards the
side of the lesion, but such deficits are
probably due to involvement of other ar-
eas, such as MT and MST. A more specific
defect for parietal lobe lesions, especially
when Brodmann's area 40 is involved, is
impaired smooth pursuit when the target
moves across a structured background,
compared with pursuit across a dark back-
ground.171 This defect may be due to an
impaired ability to attend to the image of
the moving target and "ignore" the smeared
images of the stationary background con-
sequent to the eye movement.
Bilateral posterior parietal lesions cause
Balint's syndrome,253 features of which
are disturbance of visual attention (simul-
tanagnosia), inaccurate arm pointing (optic
ataxia), and difficulty initiating voluntary
saccades (ocular motor apraxia). These
deficits, which are discussed further in
Chapter 10, could be partly due to disrup-
tion of the normal mechanisms by which
posterior parietal cortex encodes visual
targets in spatial coordinates.
CONTRIBUTIONS OF THE
PARIETAL EYE FIELD TO
GAZE CONTROL
In rhesus monkeys, the parietal eye field
(PEF) lies adjacent to area 7a, in the cau-
dal third of the lateral bank of the intra-
parietal sulcus, an area called the lateral in-
terparietal area (LIP) (Display 6-17). The
homologue of the PEF in humans may lie
within or close to the horizontal portion of
the intraparietal sulcus, corresponding to
adjacent parts of the superior part of the
angular gyrus and the supramarginal
gyrus, bordering Brodmann areas 39 and
40.210 Area LIP receives inputs from sec-
ondary visual areas and projects strongly
to the frontal eye field and the superior
colliculus.5'22'183 Neurons here respond to
visually salient stimuli112 and discharge
prior to saccades,9'10'63 and they take into
account the position of the target in three-
dimensional space.106 As in area 7a, the re-
sponse of LIP neurons is influenced by
eye position.6 These cells also show a shirt
in their visual response field that antici-
pates the consequence of the upcoming
gaze shift.80 Another important property
of LIP neurons is their ability to remain
active while the monkey is required to
withhold eye movements and remember
the desired target location.10'235 Thus, the
activity of these neurons corresponds to
the size and direction of the required eye
movement—a memory of motor error—
and is similar to that of certain quasivisual
cells found in the superior colliculus and
dorsolateral prefrontal cortex. Further-
more, LIP neurons appear not only to en-
code the intended saccade but also to re-
flect changes in the planned movement26'191
and other cognitive factors,63'260 such as
attention. 272 Electrical stimulation of the
lateral wall of the intraparietal sulcus pro-
duces saccades of similar direction irre-
spective of the starting position of the
eye.322 However, stimulation in the floor of
the intraparietal sulcus and underlying
white matter produced saccades with a di-
rection that depended on starting eye po-
sition, with a tendency for the end-points
to be a goal zone. This finding has been
interpreted as indicating that the summed
output of the PEF is concerned with mak-
ing saccades in craniotopic coordinates,
rather than in a retinotopic mapping.322
Functional imaging of the PEF in hu-
mans has demonstrated activation during
voluntary, visually guided saccades.210
Unilateral lesions of the PEF cause bilat-
eral prolongation of latency to visually
guided saccades if the fixation light is
turned off before the target light is turned
on ("gap" stimulus), 256 and even more so if
it is left on throughout the trial.257 These
changes are more pronounced with right-
sided lesions. A similar effect is seen in
normal subjects if TMS is applied to the
PEF region.84 Parietal lesions impair the
ability to make two saccades to two targets
flashed in quick succession. In response to
this double-step stimulus, the brain must
take into account not only the retinal loca-
tion of the two targets but also the effect of
the eye movements.82'119 Thus, patients
with right parietal lesions show errors
when the first target appears in the left
hemifield and the second in the right; the
first saccade may be accurate, but the sec-
ond is not. Such a deficit may be present
 Synthesis of the Commands for Conjugate Eye Movements 241

Display 6-17: Parietal Eye Field (PEF)

•The human PEF lies surrounding the horizontal portion of the intra-
parietal sulcus, in adjacent parts of the superior part of the angular
gyrus and the supramarginal gyrus, corresponding to Brodmann ar-
eas 39 and 40

• Receives inputs from secondary visual areas

• Projects to the frontal eye field and the superior colliculus

• Important for triggering visually guided saccades to reflexively ex-

plore the visual environment

(For related clinical disorders, see Display 10-35 in Chap. 10.)

even though there is no inattention or dif-
ficulty responding to the reverse order of
presentation or of making single saccades
to left-sided targets. It has been inter-
preted as being due to disruption of the
ability to monitor the size of the first sac-
cade using efference copy.82'119
Contributions of the Pulvinar to
Gaze Control
The pulvinar is the posterior and largest
portion of the thalamus (Display 6-18). It
has reciprocal connections with striate,
peristriate, parietal, and frontal cor-
tex.56,70,144,244,273,274,276,331 The pulvinar re-
ceives inputs from the retina and superior
colliculus, but inputs from the cortex seem
most important.18'66'147 Indeed, the evolu-
tion of the pulvinar appears to have paral-
leled that of association cortex. Three re-
gions of the pulvinar contain neurons that
show visual responses: inferior, lateral,
and dorsomedial. Neurons in the first
two regions are retinotopically organized.
They send a projection to visual area
MT275 Neurophysiologic evidence sug-
gests that these two regions may be impor-

Display 6-18: Pulvinar

• Posterior, largest part of thalamus

• Receives inputs from striate, peristriate, parietal, and frontal cortex;

smaller inputs from retina and superior colliculus

• Projects to striate, peristriate, parietal, and frontal cortex

• Inferior and lateral pulvinar project to visual area MT and may be im-
portant in dealing with the visual effects of eye movements

• Dorsomedial pulvinar projects to parietal lobe and seems concerned

with shifts of attention

(For related clinical disorders, see Display 10-30 in Chap. 10.)

242 The Properties and Neural Substrate of Eye Movements
tant in dealing with the visual effects of
eye movements (for example, the visual
blur produced by a saccade), because neu-
rons here respond to moving visual stim-
uli, but they respond much less if the mo-
tion of images on the retina is caused by
an eye movement. 273 Visually responsive
cells in the dorsomedial pulvinar are not
retinotopically organized and have large
receptive fields; some show sensitivity to
visual features such as color.20-186 They re-
spond vigorously if the visual stimulus is a
cue for active behavior, such as a saccade.
Like neurons in the inferior parietal lobe,
to which they project, these pulvinar neu-
rons seem more concerned with shifts of
attention than with eye movements per se.
Other neurons in the dorsomedial pulvi-
nar discharge for saccades and quick
phases, even in the dark, but these neu-
rons do not encode the amplitude and di-
rection of such movements and so are
probably signaling that an eye movement
has occurred, a form of efference copy.
Pharmacological manipulation of cells in
dorsomedial pulvinar, using microinjec-
tion of GABA-related drugs, has con-
firmed that this region is involved in shifts
in spatial attention towards salient fea-
tures.228'271'274 Functional imaging studies
in humans support the notion that the
pulvinar is important for directing visual
attention.165 Pulvinar lesions in monkeys
and in humans are reported to cause a
characteristic prolongation of fixation, dif-
ficulties in shifting gaze into the contralat-
eral hemifield,225'331'355 and perhaps loss of
stereoacuity.320
Contributions of the Frontal Lobe
to Gaze Control
The frontal lobes contain several areas im-
portant in the voluntary control of eye
movements, especially saccades, but smooth
pursuit and vergence as well. These areas
include the frontal eye field (FEF), the
supplementary eye field (SEF), and the
dorsolateral prefrontal cortex (DLPC). In
addition, cingulate cortex and the in-
tralaminar thalamic nuclei, with which the
frontal and supplementary eye fields have
reciprocal connections, may contribute to
the control of gaze.
CONTRIBUTIONS OF THE
FRONTAL EYE FIELD TO
GAZE CONTROL
Although the FEF is well known to con-
tribute to the voluntary control of gaze,138
a clear definition of its role has required
the application of modern electrophysio-
logic and anatomic studies, and novel test
paradigms to demonstrate defects in pa-
tients (Display 6-19). In rhesus monkeys,
the FEF has been precisely located by di-
rect microstimulation and has been shown
to lie in a circumscribed zone along the
posterior portion of the arcuate sulcus
(part of Brodmann area 8).33 In humans,
localization of the FEF is based on studies
of regional cerebral blood flow during
saccadic tasks and the effects of electrical
stimulation. Although there is some inter-
subject variability in the medial-lateral lo-
cation, the FEF lies around the lateral part
of the precentral sulcus, extending superi-
orly to its junction with the superior
frontal sulcus, involving adjacent areas of
the precentral gyrus, the middle frontal
gyrus, and the superior frontal gyrus,
and corresponding to confluent portions
of Brodmann areas 6 and 4, but not
8.71,91,107,181,196,242,245-247,319 TllUS the FEF
lies about 2 cm lateral, 1 cm ventral, and 1
cm anterior to the area of motor cortex ac-
tivated by hand movements.319 The FEF
receives inputs from posterior visual corti-
cal areas, inferior parietal cortex (PEF),
contralateral FEF, supplementary eye
field, prefrontal cortex, central thalamic
nuclei, substantia nigra pars reticulata, su-
perior colliculus, and cerebellar dentate
nucleus.145'308"310 The projections of the
FEF are discussed further in the section
Descending Parallel Pathways that Control
Saccades, below. Important targets in-
clude the caudate and putamen, superior
colliculus, nucleus reticularis tegmenti
pontis (NRTP), and the omnipause neu-
rons of the pontine raphe.144'174-310 The
FEF also projects to the claustrum and
subthalamic nuclei, but the role of these
structures in the control of eye movements
is unknown.
 Synthesis of the Commands for Conjugate Eye Movements 243

Display 6-19: The Frontal Eye Field (FEF)

• In humans, the FEF is located around the lateral part of the precen-
tral sulcus, involving adjacent areas of the precentral gyrus, the mid-
dle frontal gyrus, and the superior frontal gyrus, and corresponding
to confluent portions of Brodmann areas 6 and 4, but not 8

• Receives inputs from posterior visual cortical areas, inferior parietal

cortex, contralateral FEF, SEF, DLPC, intralaminar thalamic nuclei,
substantia nigra pars reticulata, superior colliculus, and cerebellar
dentate nucleus

• Projects to contralateral FEF, SEF, and posterior visual cortical areas;

superior colliculus (both directly and via caudate and substantia nigra
pars reticulata); nucleus reticularis tegmenti pontis; and nucleus
raphe interpositus (pontine omnipause neurons)

• FEF probably contributes to all voluntary and visually guided sac-

cades, to smooth pursuit and vergence

(For related clinical disorders, see Display 10-36 in Chap. 10.)

Neurons in the FEF do not become ac-
tive before every saccade, only those made
purposively.32 A topographic motor map
has been defined, with larger saccades be-
ing evoked from stimulation of the dorso-
medial portion of the FEF and smaller sac-
cades from stimulation of the ventrolateral
part.33 Different subpopulations of FEF
neurons encode the visual stimulus, the
planned saccadic movement, or both. 109
Cells with visual responsiveness anticipate
the visual consequences of planned sac-
cades.330 A second role for the FEF is a
contribution made by its inferior portion
to smooth-pursuit eye movements.113'324'325
Neurons that discharge during pursuit
project to the ipsilateral dorsolateral pon-
tine nuclei (see Fig. 6-7). Some neurons
also appear to be concerned with disen-
gaging fixation prior to a saccade; their
discharge increases when the fixation light
is turned out, even before the new target
becomes visible.75 Other neurons appear
to promote fixation; if microstimulation of
these neurons is timed to coincide with
the visual stimulus for a saccade, the eye
movement may be suppressed.35 In hu-
mans, functional imaging demonstrates
activation of the FEF area during active
fixation of a stationary target.248 Finally,
some FEF neurons show properties indi-
cating that they contribute to selection of
the target to which a saccade will be
made284 and to the process of visual scan-
ning of a complex visual scene.36 The FEF
may also play a role in vergence.
Functional imaging studies in humans
have demonstrated increased FEF activa-
tion during all visually guided saccades, be
they reflex or voluntary,7'77'319 during re-
petitive saccades made in darkness,246-247
and during memory-guided saccades.233'319
In addition, activation of the right FEF is
reported during antisaccades.224'319 Anti-
saccades are delayed by TMS over frontal
cortex; the same effect can be achieved if
the stimulus is delivered earlier over pari-
etal cortex, suggesting flow of information
from posterior to anterior during presac-
cadic processing.321a During smooth pur-
suit, the inferior lateral aspect of the FEF
is activated.245
The influence of the FEF on eye move-
ments has been demonstrated using the
technique of pharmacological inactiva-
tion.76 Muscimol injection causes a con-
tralateral ocular motor scotoma with aboli-
tion of all reflex visual and voluntary
244 The Properties and Neural Substrate of Eye Movements
saccades with sizes and directions corre-
sponding to the injection site on the FEF
map. In addition, during fixation, there is
a gaze shift toward the side of the lesion.
Acute destructive lesions of the FEF in
monkeys produce an increase in latency
for contralateral saccades and a decrease
in latency for ipsilateral movements (that
is, an increase in express saccades ipsi-
lateral to the side of the lesion).285 Re-
covery from acute FEF lesions is rapid
but incomplete, with enduring effects
on the latency and accuracy of visual
and memory-guided saccades,269 espe-
cially when directed contralaterally. In ad-
dition, ipsilateral smooth pursuit is im-
paired, but optokinetic responses may be
preserved.120'151'153'201
CONTRIBUTIONS OF THE
SUPPLEMENTARY EYE FIELD TO
GAZE CONTROL
The dorsomedial frontal lobe of monkeys
contains neurons that discharge before
contralateral saccades; this region has
been designated the supplementary eye field
(SEF) (Display 6-20).289 On the basis of
functional imaging studies, the SEF in hu-
mans lies on the dorsomedial surface of
the hemisphere in the posteromedial por-
tion of the superior frontal gyrus, 7 mm
anterior to the area of supplementary cor-
tex activated by hand movements, cor-
responding to the medial portion of
Brodmann area 6.246'247'319 The SEF has
reciprocal connections with the FEF, dor-
solateral prefrontal cortex, cortex sur-
rounding the cingulate, intraparietal and
superior temporal sulci, the thalamus, and
the claustrum.15'299'301 Like the FEF, the
SEF projects to the caudate and puta-
men, superior colliculus, nucleus reticu-
laris tegmenti pontis, and other pontine
nuclei, including the pontine omnipause
neurons in the nucleus raphe interposi-
tus.143'299'300 Convergence of projections
from the FEF and SEF occurs in the cau-
date nucleus.236 The SEF has more exten-
sive connections with prefrontal and skele-
tomotor areas and fewer connections with
vision-related structures than the FEE143
Saccade-related neurons in the monkey
SEF have many properties similar to those
in FEF,279 but they also show certain dif-
ferences, such as their function during
learned eye movement tasks57 or during
combined eye-arm movements.213 Like
the FEF, some units in the SEF dis-
charge in relation to smooth pursuit.121'324
Functional imaging studies in humans
have demonstrated increased SEF activa-
tion during single memory-guided sac-
cades7'233-319 or a series of them 246 and dur-
ing antisaccades.224'319 Activation during
visually guided saccades may occur if the
task involves predictable behavior.91
Studies of patients with lesions involv-
ing the SEF suggest that left-sided lesions
are more likely to impair the ability to
make a sequence of saccades to an array of
visible targets in the order that they were
turned on.101'102 Single, memory-guided
saccades are probably impaired only if the
eye moves during the memory period.254
Taken together, the evidence suggests a
role for the SEF in the planning of sac-
cades—to both visual and nonvisual
cues—as part of complex or learned be-
haviors. However, a deficit in the ability to
remember a sequence of saccades has also
been reported in patients with lesions af-
fecting the hippocampus,211 and it seems
likely that cerebral regions other than the
SEF are important for normal perfor-
mance on such tasks. Predictive aspects
of smooth pursuit may also be impaired
when lesions involve the SEE 120
CONTRIBUTIONS OF THE
DORSOLATERAL PREFRONTAL
CORTEX TO GAZE CONTROL
In monkeys, neurons in the posterior
third of the principal sulcus (Fig. 6-8),
which lies on the dorsolateral convexity
of the frontal lobe, corresponding to
Walker's area 46, show an ability to hold in
memory the location of a visual target to
which a saccade is to be made (Display
6-21).98'99 In humans, the homologue of
the DLPC lies on the dorsolateral surface
of the frontal lobe, anterior to the FEF, oc-
cupying approximately the middle third
of the middle frontal gyrus and adjacent
cortex, corresponding to Brodmann's ar-
eas 46 and 9.264'265 The DLPC has recipro-
cal connections with the FEF, SEF, pos-
 Synthesis of the Commands for Conjugate Eye Movements 245

Display 6-20: Supplementary Eye Field (SEF)

• In humans, the SEF lies on the dorsomedial surface of the hemi-
sphere, in the posteriomedial portion of the superior frontal gyrus

• Receives inputs from FEF, prefrontal, cingulate, parietal, and tempo-

ral cortex; thalamus; and claustrum

• Projects to FEF; prefrontal, cingulate, parietal, and temporal cortex;

thalamus; claustrum; caudate nucleus; superior colliculus; nucleus
reticularis tegmenti pontis; and pontine omnipause neurons

• SEF seems important for programing saccades as part of learned or

complex behaviors

(For related clinical disorders, see Display 10-36 in Chap. 10.)

terior parietal cortex, and limbic cortex
(including parahippocampal and cingu-
late cortex). It also receives inputs from
the thalamus and medial pulvinar, and
projects to the caudate, putamen, claus-
trum, thalamic nuclei, superior colliculus,
and PPRF.55'297
Human subjects show activation of the
DLPC when they make memory-guided
saccades or antisaccades;209a'233>319 these
results are consistent with properties of
neurons in monkey DLPC." Pharmaco-
logical inactivation of DLPC with Dl-
dopamine antagonists impairs the accu-
racy of monkeys in making contralateral
memory-guided saccades.283 Patients with
lesions affecting this area show defects of
both memory-guided saccades and anti-
saccades.115'255 When TMS is applied over
the DLPC in normal subjects during the
memory period, memory-guided saccades
become inaccurate. 212
The DLPC receives inputs from the an-
terior cingulate cortex, which has been re-
ported to show changes in regional cere-
bral blood flow during memory-guided
saccades and antisaccades.7'319 This find-
ing might reflect the cingulate's contribu-

Display 6-21: Dorsolateral Prefrontal Cortex (DLPC)

• In humans, lies on the dorsolateral surface of the frontal lobe, occupy-
ing the middle frontal gyrus and adjacent cortex, corresponding to
Brodmann areas 46 and 9

• Receives inputs from FEF, SEF, posterior parietal cortex and limbic
cortex (including parahippocampal and cingulate cortex), thalamus,
and medial pulvinar .

• Projects to the FEF, SEF, posterior parietal and limbic cortex, caudate
and putamen, superior colliculus, and PPRF

• DLPC is important for programing saccades to remembered locations

(For related clinical disorders, see Display 10-36 in Chap. 10.)

246 The Properties and Neural Substrate of Eye Movements

Display 6-22: Intralaminar Thalamic Nuclei

• Portion of thalamus lying near the upper wing of the internal
medullary lamina (IML), the fiber pathway that separates the medial
and lateral thalamic masses
• Receive inputs from FEF, SEF, PEF, PPRF, cerebellum, superior col-
liculus, and pretectum
• Project to the striatum, FEF SEF, PEF, and cingulate gyri, but not to
brain stem structures concerned with eye movements
• Might be a source of efference copy information for cortical areas
(For related clinical disorders, see Display 10-30 in Chap. 10.)

tion to spatial information processing and
suppressing reflexive saccades during the
antisaccade task.15'319 Units located in the
posterior cingulate cortex are reported to
discharge during or after eye move-
ments. 229 In humans, small posterior le-
sions of the right cingulate cortex have
been reported to impair memory-guided
saccades, antisaccades, and sequences of
memory-guided saccades.lola
CONTRIBUTIONS OF THE
INTRALAMINAR THALAMIC
NUCLEI TO GAZE CONTROL
The FEF, SEF, and PEF all have reciprocal
connections with thalamic neurons lying
near the upper wing of the internal
medullary lamina (IML, the fiber pathway
that separates the medial from the lateral
thalamic mass; see Display 6-22).288>290>291
These saccade-related neurons are scat-
tered throughout adjacent portions of the
central lateral, superior central lateral,
and dorsomedial nuclei. In addition to
frontal cortical areas, the intralaminar
thalamic nuclei also receive inputs from
the pontine reticular formation, cerebel-
lum, tectum, and pretectum. However, the
intralaminar nuclei do not project to brain
stem structures concerned with eye move-
ments.111'288'291 These thalamic neurons
are variously active in relation to sponta-
neous and visually guided saccades and to
fixation. Functional imaging has shown
that human thalamus shows activation
when subjects make voluntary saccades.247
Because of their widespread projections
and variety of properties, it has been sug-
gested that these cells are concerned with
controlling the onset and offset of saccadic
and fixation behaviors and are an impor-
tant source of efference copy to the corti-
cal eye fields.291 In support of this hypoth-
esis is the report that patients with lesions
affecting the intralaminar nuclei show in-
accuracy of memory-guided saccades only
if gaze is perturbed during the memory
period.103
Descending, Parallel Pathways
that Control Voluntary Gaze
Here we will first describe the descending
pathways from the several eye fields of
cerebral cortex and then discuss the influ-
ence that each may have on the genera-
tion of saccades. No direct projection ex-
ists from cortical neurons to ocular
motorkeurons;148 instead, several interme-
diate structures play important roles, in-
cluding the caudate and putamen, sub-
stantia nigra pars reticulata, superior
colliculus, and brain stem reticular forma-
tion. The descending pathway for smooth
pursuit is summarized in Figure 6-7.
Refinement of the definition of the FEF
in monkeys, using microstimulation tech-
 Synthesis of the Commands for Conjugate Eye Movements 247

niques, has led to a revision of the projec-
tions of the FEE309-310 Each FEE projects
to its counterpart and also to other cortical
areas concerned with visual processing,
such as inferior parietal cortex.145 The de-
scending projections of the FEF initially
run in the anterior limb of the internal
capsule; clinical lesions here and in the ad-
jacent deep frontal region are reported to
increase saccadic latency.258
Below the level of the internal capsule,
several separate pathways can be dis-
cerned (Figure 6-9; Fig. 3-8, Chap.
3) 173,174 One projection, via the anterior
limb of the internal capsule, goes to the
caudate and adjacent putamen, which in
turn project, via the pars reticulata of the
substantia nigra (SNpr), to the superior
colliculus. A transthalamic pathway starts
in the anterior limb of the internal capsule
and projects to the dorsomedial and in-
tralaminar thalamic nuclei, to the ipsilat-
eral superior colliculus and perhaps to
certain midbrain reticular nuclei such as
the riMLF.174 A pedunculopontine path-
way runs from the internal capsule in the

Figure 6-9. Projections from prefrontal cortex to ocular motor structures in the monkey. From prefrontal cor-
tex (PFC.frontal eye field and caudal sulcus principalis), a unified projection runs in the anterior limb of the in-
ternal capsule and then divides into a dorsal prefrontofugal system (D, transthalamic pathway) and a ventral
prefrontofugal system (V, classic pedunculo-tegmental pathway). The transthalamic pathway traverses and pro-
jects to the dorsomedial (MD) and intralaminar thalamic nuclei and the superior colliculus (SC). The peduncu-
lotegmental pathway descends in the most medial portion of the cerebral peduncle, decussating partially in the
upper pons and contacting neurons in the nucleus reticularis tegmenti pontis and in the nucleus raphe inter-
positus of the paramedian pontine reticular formation (PPRF). An intermediate prefrontofugal system (I, pre-
frontal oculomotor bundle) becomes evident at the border of the diencephalon and mesencephalon and con-
tacts cell groups adjacent to the oculomotor nuclear complex, which may include the nucleus of the posterior
commissure and the rostral interstitial nucleus of the medial longitudinal fasciculus. A, anterior thalamic nu-
cleus; ac, anterior commissure; f, fornix; III, oculomotor nerve; iv, trochlear nerve; MB, mammillary body; mlf,
medial longitudinal fasciculus; pc, posterior commissure. (Reproduced from Journal of the Neurological Sci-
ences, volume 49, Leichnetz GR. The prefrontal cortico-oculomotor trajectories in the monkey. A possible ex-
planation for the effects of stimulation/lesion experiments on eye movement, pages 387-96, 1981, with permis-
sion from Elsevier Science.)
248 The Properties and Neural Substrate of Eye Movements
most medial aspect of the cerebral pedun-
cle.173 Its main projection is to the nucleus
reticularis tegmenti pontis (NRTP) (Fig.
6-3), which in turn projects to the cerebel-
lum. The PPRF and especially the midline
pontine raphe nuclei that house saccadic
omnipause cells also receive projections
from the FEE174'293 A partial ocular motor
decussation, first defined on the basis of
stimulation studies,19'34 may occur be-
tween the levels of the trochlear and ab-
ducens nuclei.173
The SEE also projects to the caudate,
putamen, superior colliculus, nucleus
reticularis tegmenti pontis, and pon-
tine omnipause neurons.143'300 The DLPC
projects to parts of the caudate and
putamen the superior colliculus, and
PPRF.8,173,297 Tne PEE projects to the su-
perior colliculus.5'183 How do these multi-
ple projections from frontal and parietal
cortex to the caudate nucleus, superior
colliculus, and pontine nuclei (see Fig.
3-8) differ in the influence they exert on
the voluntary control of saccades?
CONTRIBUTIONS OF THE
STRIATAL-NIGRAL-COLLICULAR
PATHWAY TO GAZE CONTROL
A pathway through the caudate and adja-
cent putamen seems to be important for
execution of saccades, especially when
made to remembered target locations.
The caudate and putamen receive inputs
from the FEF,310 SEF,143 and DLPC.8 Most
neurons within the caudate nucleus that
discharge for eye movements do so for
memory-guided saccades,129 and the gen-
eral properties of these cells suggests that
they are concerned with complex aspects
of ocular motor behavior that are neces-
sary, for example, in predicting environ-
mental changes130'131 and the potential for
reward.1503 Functional imaging studies in
humans have demonstrated activation of
the putamen and substantia nigra during
memory-guided saccades.233 Experimen-
tal lesions of the caudate and putamen
produced ipsilateral gaze deviation and
impairment of contralateral spontaneous,
visually mediated, and memory-guided
saccades.150'162 Patients with chronic le-
sions affecting the putamen (and globus
pallidus) show deficits in saccades made to
remembered locations and in anticipation
of predictable target motion; visually
guided saccades are unaffected.336
The caudate and putamen send projec-
tions to the nondopaminergic substantia
nigra pars reticulata (SNpr); these projec-
tions are probably GABAergic. Neurons in
the SNpr have high tonic discharge rates
that decrease before voluntary saccades
that are either visually guided or made to
remembered target locations.132"135 The
SNpr, in turn, sends inhibitory projections
to the superior colliculus; these projec-
tions are also GABAergic. A simplified
view of this basal ganglia pathway is that it
is composed of two serial, inhibitory links:
a caudonigral inhibition, which is only
phasically active, and a nigrocollicular in-
hibition, which is tonically active. If frontal
cortex causes caudate neurons to fire,
then the nigrocollicular inhibition is re-
moved and the superior colliculus is able
to activate a saccade. Studies of the effects
of pharmacologically inactivating136-137 or
chemically lesioning150'162 the nuclei in
this pathway have supported this hypothe-
sis. However, stimulation of caudate neu-
rons produces suppression or facilitation
of SNpr neurons; the facilitation may be
due to a multisynaptic pathway.128 Thus,
the means by which the frontal eye field
influences the superior colliculus is com-
plex and might produce difficulties in ei-
ther initiating or suppressing saccades.
Both deficits have been described in pa-
tients with disorders affecting the basal
ganglia, such as Huntington's disease.170
DESCENDING PATHWAYS TO THE
SUPERIOR COLLICULUS FOR
GAZE CONTROL
The FEF, SEF, PEF, and DLPC all pro-
ject directly to the superior collicu-
lus. 143,183,295,297,310 In addition, the frontal
areas also project indirectly to the supe-
rior colliculus via the basal ganglia. The
superior colliculus has superficial, inter-
mediate, and deep layers.203'204'303 The su-
perficial layers receive inputs from both
the optic tract and visual cortical areas;
these inputs are in register, so that a re-
gion receiving direct input from a specific
 Synthesis of the Commands for Conjugate Eye Movements
retinal area also receives indirect input
from visual cortex that processes informa-
tion about that same area of retina. The
superficial layers of the superior colliculus
contain neurons that enhance their activ-
ity when the visual stimulus to which they
respond is to be the target for a saccadic
eye movement.110 The more ventral layers
of the superior colliculus contain neurons
that, when stimulated, elicit saccadic eye
movements. The direction and size of
these elicited saccades is a function of the
site of stimulation, indicating organization
into a motor map.231'347 Neurons at the
rostral pole of this motor map appear to
be important for maintaining steady fixa-
tion and they project to omnipause neu-
rons; more caudally located neurons pro-
ject to burst neurons in the PPRF.46
Hypothetical schemes to account for how
the superior colliculus might contribute to
programing of saccades were reviewed in
Chapter 3. An important point here is that
the command by the superior colliculus to
enact a saccade is influenced by several in-
puts—directly from the FEF, SEF, and
PEF, and indirectly via the basal ganglia.
CORTICOPONTINE PROJECTIONS
FOR GAZE CONTROL
A direct pathway has been defined from
the FEF to the PPRF, probably to long-
lead burst neurons and to the omnipause
neurons that lie in the nucleus raphe
interpositus (see Fig. 6-2).293'294>310 This
pathway may explain why monkeys are
still able to initiate saccades after ablation
of the superior colliculus. However, this
projection is small compared with that go-
ing via the nucleus reticularis tegmenti
pontis (NRTP) to the cerebellum. Al-
though this latter pathway is probably im-
portant in optimizing saccadic metrics, it is
not essential for the initiation of saccades,
which persist even after total cerebellec-
tomy.345
RELATIVE IMPORTANCE OF
DESCENDING PATHWAYS FOR
GAZE CONTROL
Studies of the effects of restricted, experi-
mental lesions have provided insights into
249
the relative roles of the descending path-
ways for saccades. In monkeys, pharmaco-
logical inactivation of the superior collicu-
lus substantially impairs the ability to
make saccades,172 but chronic lesions are
associated with relatively minor deficits:
an increase in saccadic latency, mild sac-
cadic hypometria, reduced frequency of
spontaneous saccades, and less distractibil-
ity on a fixation task.1 Collicular lesions
also abolish short-latency or "express" sac-
cades that occur if the fixation light is
turned out prior to the appearance of a
peripheral visual target.286 In normal cir-
cumstances, disappearance of the fixation
light presumably releases the superior col-
liculus from inhibitory inputs so the ap-
pearance of the visual target can then elicit
a short-latency saccade.89 If damage ex-
tends to the pretectum and adjacent pos-
terior thalamus (possibly also affecting
descending pathways for saccades), the
deficit consists of an enduring hypometria
without corrective saccades, suggesting
that the correct motor error signal re-
quired to initiate a saccade no longer
reaches the superior colliculus.2
Similarly, acute pharmacological inacti-
vation of the FEF substantially impairs
saccades, but chronic lesions cause minor
deficits that affect visual search and sac-
cades to remembered targets.72 In con-
trast, combined lesions of the FEFs and
superior colliculi produce a severe and en-
during deficit of eye movements, with
a greatly restricted range of move-
ment. 286 ' 287 Acute, reversible lesions of the
FEF and superior colliculus also cause
marked hypometria of saccades and a re-
stricted range of movement. 152 Severe
deficits of saccadic and pursuit eye move-
ments also follow combined, bilateral
lesions of parietal-occipital and frontal
cortex in monkeys.182 With unilateral,
combined parietofrontal lesions, saccades
to visual targets in contralateral hemispace
are impaired; 184 with hemidecortication,
the deficit is more enduring. 329
In humans, the relative importance of
the descending ocular motor pathways is
less well defined. Functional imaging has
not yet been able to document increased
blood flow in the superior colliculi during
saccadic tasks, but with increased resolu-
250 The Properties and Neural Substrate of Eye Movements
tion in the future, it may be possible to de-
fine their role. Isolated lesions of the supe-
rior colliculus are reported to cause in-
creased latency and inaccuracy of visually
guided saccades259 and a paucity of spon-
taneous saccades contralateral to the side
of the lesion.126 As previously summa-
rized, frontal lobe lesions in humans cause
hypometria of visually guided and mem-
ory-guided saccades contralateral to the
lesion and impairment of smooth pursuit
of targets moving towards the side of the
lesion. No reports exist of combined le-
sions of the frontal eye fields and superior
colliculi in humans. However, combined
lesions of frontal and parietal cortex cause
loss of ability to make voluntary saccades,
or ocular motor apraxia (see VIDEO: "Ac-
quired ocular motor apraxia").251 Overall,
it seems likely that during normal ocular
motor behavior, the frontal and parietal
lobes of humans complement each other.
The FEFs direct the eyes towards an ob-
ject or a location of behavioral interest,
while the parietal lobes are more con-
cerned with reflexively induced saccades.
Finally, although the contributions of the
FEF, parietal lobes and superior colliculus
have been defined best for saccades, it
seems likely that each of these areas influ-
ences all types of eye movements.
SUMMARY
1. The abducens nucleus is the center
for conjugate, horizontal eye move-
ments and receives inputs for each
functional class of eye movement (Fig.
6-1). The abducens nucleus contains
two groups of neurons: motoneurons
that send axons to the ipsilateral lat-
eral rectus muscle, and internuclear
neurons that project, via the con-
tralateral medial longitudinal fascicu-
lus, to synapse in the oculomotor nu-
cleus on medial rectus motoneurons.
The abducens motoneurons and in-
ternuclear neurons receive inputs for
horizontal saccades from the PPRF,
vestibular and pursuit inputs from the
vestibular nuclei, and the gaze-hold-
ing signal from the prepositus-medial
vestibular nuclear complex.
2. The oculomotor and trochlear nuclei
receive inputs for vertical saccades
from the rostral interstitial nucleus of
the medial longitudinal fasciculus
(riMLF), which lies in the prerubral
fields (Fig. 6-5). The interstitial nu-
cleus of Cajal (INC) is important for
vertical gaze holding. Vertical vestib-
ular and pursuit signals ascend to
the oculomotor and trochlear nuclei
from the lower brain stem.
3. The cerebellum (Fig. 6-6) ensures
that all classes of eye movements and
gaze holding are calibrated to pro-
vide clearest vision. The vestibulo-
cerebellum, which consists of the floc-
culus, paraflocculus, and nodulus, is
important for steady gaze holding,
smooth ocular tracking, and optimal
performance of the vestibulo-ocular
reflex. The dorsal vermis and under-
lying fastigial nucleus have an impor-
tant role in programing accurate sac-
cades and smooth pursuit.
4. Primary visual cortex is essential for
accurate saccades and for generating
smooth pursuit and optokinetic eye
movements. The parietal-occipital-
temporal lobe junction contains sec-
ondary visual areas important for de-
tecting the speed and direction of
moving targets and generating an
eye-tracking response. This area of
posterior cortex gives rise to an ipsi-
lateral pathway to brain stem and
cerebellum, which is important for
smooth-pursuit eye movements (Fig.
6-7).
5. Parietal cortical areas contribute to
shifting visual attention and also to
initiating saccades (Fig. 6-8). The vi-
sual responses of some neurons in
parietal cortex are influenced by the
current direction of gaze. The dorso-
medial pulvinar projects to parietal
cortex and contributes to shifts of
attention.
6. Frontal cortex contains three areas
that contribute to programing of sac-
cades (Fig. 6-8). The frontal eye field
(FEF) contains neurons that dis-
charge before visually guided and
memory-guided saccades. The dorso-
medial, supplementary motor area
 Synthesis of the Commands for Conjugate Eye Movements
appears to be important for control
of learned ocular motor behaviors.
Dorsolateral prefrontal cortex (DLPC)
probably contributes to programing
of saccades to remembered target
locations.
7. The eye fields of the frontal lobes
project in parallel descending path-
ways to the superior colliculus, the
brain stem reticular formation, and,
via pontine nuclei, to the cerebellum
(Fig. 6-9). Indirect pathways involve
the caudate nuclei and the pars retic-
ulata of the substantia nigra (SNpr).
Combined lesions of the frontal eye
fields and the parietal eye fields, or of
the frontal eye fields and the superior
colliculi, cause profound and endur-
ing ocular motor deficits.
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Chapter i 7
EYE-HEAD MOVEMENTS
STABILIZATION OF THE HEAD
VOLUNTARY CONTROL OF EYE-HEAD
MOVEMENTS
Rapid Gaze Shifts Achieved by Combined
Eye-Head Movements
Smooth Tracking with Head and Eyes
EXAMINATION OF EYE-HEAD
MOVEMENTS
LABORATORY EVALUATION OF EYE-
HEAD MOVEMENTS
DISORDERS OF EYE-HEAD MOVEMENT
Disorders of Head and Gaze Stabilization
Disorders of Voluntary Head and Gaze
Control
SUMMARY
When most animals visually track or ac-
quire targets, they use a combination of
eye and head movements. Likewise, in re-
sponse to perturbations of the body, both
eye and head movements are used to re-
flexively stabilize the line of sight. This be-
havioral cooperation is reflected in the
anatomic and physiologic similarities be-
tween the head (cephalomotor) and the
eye (ocular motor) control systems. With
the evolution of a fovea and a large ocular
motor range, however, it became advanta-
geous to be able to move the eyes with the
head still. Therefore, primates in general
and humans in particular have evolved a
high degree of independent control of the
head and eyes. Even so, we frequently
move our eyes and head together,503 and
an analysis of the effects of disease on eye
movements must consider the interactions
between the ocular motor and cephalomo-
tor control systems. Rotations of the head
are usually described as having compo-
nents in one or more of three planes: hor-
izontal (yaw, rotation about the Z or verti-
cal axis), sagittal (pitch, rotation about the
Y or interaural axis), and torsional or
frontal (roll, rotation about the X or nasal-
occipital axis). Likewise, displacements or
translations of the head are described as hav-
ing components along one or more of
three axes: bob (vertical), surge (anterior-
posterior), and heave (lateral).
STABILIZATION OF THE HEAD
Head perturbations that occur during lo-
comotion are a major threat to clear vi-
sion. Although the vestibulo-ocular reflex
(VOR) can compensate for head rotations
by producing compensatory eye rotations,
its ability to do so is limited; for example,
when head velocities exceed approxi-
mately 350°/sec, saturation is reached and
the reflex no longer works adequately.130
Stabilization of the head in space reduces
demands made of the VOR. How well is
the head stabilized during locomotion?
Measurement of the rotational perturba-
tions of the head during walking or run-
ning in place indicates that angular head
velocity usually does not exceed 1007sec,
even during running (Fig. 7-1A).44.71'72'95'128
The predominant frequencies of head
perturbations principally lie in the range
0.5-5.0 Hz (Fig. 7-1B), although some
harmonic frequencies may be as high as 20
263
264 The Properties and Neural Substrate of Eye Movements

Figure 7-1. Summary of the ranges of (A) maximum velocity and (B) frequency of rotational head perturba-
tions occurring during walking or running in place. Distribution of data from 20 normal subjects are displayed
as Tukey box graphs, which show selected percentiles of the data. All values beyond the 10th and 90th per-
centiles are graphed individually as points. (From King OS, Seidman SH, Leigh RJ. Control of head stability
and gaze during locomotion in normal subjects and patients with deficient vestibular function. In Berthoz A,
Graf W, Vidal PP, editors. Second Symposium on Head-Neck Sensory-Motor System. New York: Oxford Uni-
versity Press; 1990; 91, p. 568-70, with permission.)

Hz. The predominant frequency of verti-
cal head perturbations (i.e., pitch rota-
tions) is usually twice that of horizontal
perturbations (i.e., yaw rotations).71 The
reason for this is that the head is per-
turbed vertically (up and down) with each
heel strike, but rotates horizontally (right
and left) with each successive pair of steps.
During locomotion, the angle of head ori-
entation in the sagittal plane with respect
to gravity is held quite constant (standard
deviation of 3°).128 It has been hypothe-
sized that this head orientation is neces-
sary to optimize the sensitivity of the

otolithic organs of the labyrinth, which
sense linear accelerations. During run-
ning, the head may bob as much as 6 cm,
and this becomes important if subjects view
near targets.35'72 Normal subjects show a
synchronization of head translations and
rotations, so that when the head bobs up,
it pitches down, and as it heaves laterally,
it rotates medially.35'128
What mechanisms operate to hold the
head as a relatively stable platform during
locomotion? Four main factors have been
studied in humans: (1) mechanical forces
due to the inertial mass of the head and
the muscles and tissues that support it;
(2) the vestibulocollic reflex (VCR), 20 ' 118 by
which vestibular inputs activate neck mus-
cles to stabilize the head with respect to
space; (3) the cervicocollic reflex (CCR),
the stretch reflex of the neck muscles,
which acts to stabilize the position with re-
spect to the trunk; 85 - 123 and (4) voluntary
control of the neck muscles.
For most head rotations occurring dur-
ing natural activities, the inertial mass of
the head and passive viscoelastic proper-
ties of the neck play a major role in main-
taining stability.67'73 Although the mass of
the head tends to make it resistant to per-
turbations, its eccentric carriage on the
series of joints that form the neck pre-
disposes it to oscillations, especially in
pitch. 62 ' 67 - 123 ' 172 During pitch motion of
the head, caused by linear body motion,
head stability is determined by both pas-
sive viscoelastic properties and active tone
in the neck muscles.68
The contributions of the VCR and CCR
are difficult to assess experimentally in
normal human subjects, but they appear
to play more of a role when the subject
views or imagines an earth-fixed tar-
get.73-92'93 Based on measurements of head
stability and neck muscle electromyogra-
phy, these reflexes may be more active
at frequencies of body rotation between
1 and 2 Hz, more so in the vertical
plane.92'93 The purpose of the VCR and
CCR is not entirely clear. During head
perturbations, the VCR and CCR work to-
gether to stabilize the head in space. How-
ever, during body perturbations, the CCR
detracts from the ability of the VCR to
hold the head steady in space. An alterna-
tive explanation is that the purpose of
Eye-Head Movements 265
these reflexes is to prevent oscillations of
the head.123 Head perturbations induced
by sudden, passive body rotations in pa-
tients who have lost one vestibular labyrinth
cause increased head oscillations when
they are rotated towards the lesioned
side.124 To stop the head from oscillating,
the VCR and CCR may adjust the ratio of
viscosity to elasticity of the neck muscles
and connective tissues.67'92
VOLUNTARY CONTROL OF
EYE-HEAD MOVEMENTS
During natural activities, we commonly
use a combined eye-head saccade to shift
gaze towards a novel visual target or scan
the environment.98 However, head move-
ments occur during a variety of behaviors
besides gaze-shifts, such as during com-
munication and eating. Thus, indepen-
dent control of eye and head movements
is to be expected. Just how independent
eye and head movements are during vol-
untary gaze shifts is debated. In cats, they
seem to be closely coupled,74 but care is re-
quired in extrapolating such findings to
primates, who have a larger ocular motor
range and may use eye-head movements
independently for more complex behav-
iors. In discussing gaze shifts achieved by
combined movements of eye and head, it
is necessary to distinguish between eye po-
sition in the head (eye position) and eye
position in space (the angle of gaze or, sim-
ply, gaze). During viewing of distant tar-
gets, gaze is the sum of eye position and
head position. During viewing of a near
target, a correction is necessary to account
for the eyes not being at the center of rota-
tion of the head (see Laboratory Evalua-
tion of Eye-Head Movements, below).
Rapid Gaze Shifts Achieved by
Combined Eye-Head Movements
Rapid gaze shifts that are achieved by
combined, rapid eye-head movements
(eye-head saccades or gaze saccades) serve
two related, but separate functions: (1)
they bring the image of an object, detected
in the retinal periphery, to the fovea,
266 The Properties and Neural Substrate of Eye Movements
where it can be seen best; and (2) they re-
orient the head and eyes in space so that a
new part of the visual scene can be viewed
using ocular saccades.100 The second type
of rapid gaze change is the only one made
by afoveate animals,32 and it assumes par-
ticular importance in animals with a lim-
ited ocular motor range. Note also that
quick phases of nystagmus, which occur
during vestibular stimulation, do not
bring a specific object to the fovea. The
purpose of quick phases is to keep the eyes
within the working ocular motor range
(i.e., prevent the eyes reaching the me-
chanical limits of the orbits). During self-
rotation, quick phases reorient the eyes to-
wards the oncoming visual scene.
During natural activities, most ocular
saccades occurring without head move-
ments are < 15°,5 and eye-head movements
are used to make larger gaze shifts. The
tendency to make an eye-head saccade,
rather than a purely ocular saccade, is
partly determined by the ocular motor
range, which in humans is about ±50°. If
targets are presented outside this range,
then an eye-head saccade is necessary to ac-
quire it. However, if visual targets are pre-
sented within the current ocular motor
range, the tendency to make an eye-head
saccade is influenced by how eccentric the
eye would be in the orbit at the end of the
gaze shift.144 Some individuals (head-
movers) are more prone to make eye-head
saccades while others (non-movers) tend
not to,53 but for any individual, the propen-
sity to make a head movement is fairly con-
stant,144 unless visual demands change.113
These idiosyncratic differences are gener-
ally preserved regardless of whether the
target is visual or auditory, a finding that
has suggested that the propensity to make
a eye-head saccade is determined in a com-
mon reference framework for these two
sensory modalities.54-61
EYE-HEAD SACCADES TO
UNEXPECTED AND EXPECTED
TARGET PRESENTATIONS
Examples of eye-head saccades are shown
in Figure 7-2. When the movement is to-
wards a target that unexpectedly appears
in the periphery, the saccadic eye move-
ment usually starts 200 msec after the
target appears and precedes the head
movement by about 20-50 msec (Fig.
7-2A).66-158'164 During eye-head saccades,
the velocity of the head increases with the
amplitude of the head movement; this
main sequence of head movements differs
from the main sequence of eye saccades
in that the former shows no saturation
for larger movements and is more vari-
able.8'145'154'175 Centrifugal head rotations
may be faster than centripetal rotations.126
Like eye saccades, these movements have
a ballistic, preprogramed nature 15 that is
capable of adaptive changes in response to
increases in head inertia or visual de-
mands.56 When eye-head saccades with
horizontal and vertical components are
made in response to diagonal target
jumps, the trajectories of eye and head dif-
fer, suggesting independent control mech-
anisms.157 During such gaze shifts, ocular
torsion stays near zero.157a If two visual
targets are briefly presented in succession,
the ocular response to this double-step
stimulus is towards the second target
whereas the head moves towards the
first.134
A different pattern of eye-head coordi-
nation appears when the subject can antic-
ipate the time and location of the next vi-
sual stimulus.14 In this "predictive" mode
of tracking, the head begins to move sev-
eral hundred milliseconds before the sac-
cade (Fig. 7-2B), and both begin before
the stimulus moves. When self-paced and
repetitive gaze shifts are required, eye and
head components are more closely syn-
chronized98 than in response to nonpre-
dictable target jumps.126 During tracking
of a visual stimulus moving predictably in
an illusory trajectory, eye and head com-
ponents are similar affected, tracking the
illusion rather than actual target mo-
tion.180 When subjects use combined eye-
head movements during manual tasks, the
latency and velocity of the eye movement
are influenced by both gaze shift and hand
movements.143 Thus, the evidence for a
common control signal governing eye and
head components of eye-head saccades is
only supported by behavior during repeti-
tive, predictable tasks.
 Eye-Head Movements 267

Figure 7-2. (A) A combined, eye-head saccade in response to the unexpected appearance of a visual target.
About 200 msec after the appearance of the target, the eye commences a saccade. A head movement follows and
causes the eye to rotate back, on account of the vestibulo-ocular reflex. The sum of the eye and head move-
ments is a saccadic gaze shift. The latter is followed by a corrective saccade, indicated by an arrow. L, left; R,
right. Time mark at top indicates 1 sec. (B) Combined eye-head saccadic refixations between two stationary tar-
gets. Note the smooth, slow, predictive pattern of head motion rather than the ballistic pattern shown in A that
is associated with a suddenly appearing target. Eye, eye position in the orbit; Head, head position in space;
Gaze, Eye + Head, eye position in space. Note inversion of head position axis. (From Zee DS. Disorders of eye-
head coordination. In Brooks BA, Bajandas FJ, editors. Eye Movements. New York: Plenum Press; 1977; p.
9-39, with permission.)

INTERACTION BETWEEN THE command interacts with the mechanisms

SACCADIC COMMAND AND
VESTIBULO-OCULAR REFLEX
During rapid gaze shifts achieved by com-
bined eye-head movements, the saccadic
that act to hold gaze steady. In normal
subjects, the VOR is of prime importance
in holding gaze steady. The cervico-ocular
reflex (COR), which depends on proprio-
ceptive afferents from neck muscles to the
268 The Properties and Neural Substrate of Eye Movements

vestibular nucleus,50'94-151 makes little con-

tribution to the stabilization of gaze in hu-
mans,7'11'89'137 unless vestibular function
has been lost.23'29-90 Information from cer-
vical afferents, however, may contribute to
the sensation of head position.18
What is the nature of the interaction be-
tween the saccadic command and the
VOR during eye-head saccades? Bizzi and
colleagues14'115 initially proposed that dur-
ing eye-head saccades of up to 40° ampli-
tude, there is a linear summation of the
saccadic command and the VOR. One
prediction of this hypothesis is that the
speed and accuracy of eye-head saccades
would be independent of the head move-
ment. This is not the case for large eye-
head gaze shifts. In both humans and
monkeys, during large eye-head saccades,
gaze velocity and duration are clearly in-
fluenced by head velocity (Fig. 7-3);10° if
the subject deliberately moves the head
slower, gaze velocity is reduced. This is
strong evidence against the linear summa-
tion hypothesis. Further, if the head is per-
turbed during large eye-head saccades,
the eye movements produced indicate that
the VOR is partially disabled.75'100'122'149-155
For smaller eye-head saccades (i.e., within
the ocular motor range), however, linear
addition of the saccadic command and
the VOR probably does occur.75'122-153 Figure 7-3. Demonstration of how the duration of an
Such gaze shifts might concern foveation eye-head saccade can be influenced by the speed of
the head movement. The behavior of eye (E), head
of an object that has already been seen (H), and gaze (G), are shown during eye-head sac-
(i.e., is within the current ocular motor cades between targets 205° apart. In B, the subject
range), and thus represents a different deliberately moved his head more slowly than in A.
class of eye movement than large eye-head In A, the duration (vertical dashed lines) was 250
msec; in B, 380 msec. (From Laurutis VP, Robinson
saccades. DA. The vestibulo-ocular reflex during human sac-
Although there is some independence cadic eye movements. J Physiol (Lond) 1986;373:
of eye and head contributions to large 209-33, with permission.)
gaze shifts,126 and the VOR may be discon-
nected,1343 some mechanism appears to
monitor head movements so that the accu- tion of several different models for eye-
racy of the eye-head saccade is guaran- head saccades.39.75'100'122,126.153
teed.100-122'138'153 So, for example, if the Like ocular saccades, rapid gaze shifts
head is unexpectedly braked during an achieved by a combined eye-head move-
eye-head saccade, gaze still lands on the ment are also capable of adaptation. Thus,
target. This finding has lead to the pro- if subjects wear goggles with an aperture
posal that head velocity information, al- that restricts the effective ocular motor
though disconnected from the conven- range to a few degrees, they adapt by
tional VOR, is still available to control the making more use of head movements that
duration of the saccadic burst neurons via are specific for the residual ocular motor
a vestibulosaccadic reflex,100 a notion that range.36'113 Adaptive changes of eye-head
has received electrophysiological support.171 saccades to new visual demands partly
These findings have led to the formula- transfer to eye-only saccades, which sug-

gests that the substrate for adaptation lies
upstream of the site where separate eye
and head command are programed.125
NEURAL SUBSTRATE FOR RAPID
EYE-HEAD GAZE SHIFTS
Electromyographic studies during eye-
head saccades demonstrate a burst of ac-
tivity in the agonist muscles of both the
eye and neck and inhibition in the corre-
sponding antagonists.14 Although extraoc-
ular and neck muscles may be activated al-
most synchronously, the head has a higher
moment of inertia and does not begin to
move until about 20 to 50 msec after the
eye.176 In trying to understand how eye
and head movements are coordinated
during eye-head saccades, a useful "bot-
tom-up" approach is to compare struc-
tures projecting to ocular motoneurons
with those projecting to motoneurons in
the cervical spinal cord that control volun-
tary head movements.132 Such anatomical
studies indicate that the major projections
to the cervical cord are from the reticular
formation, including the gigantocellular
head-movement region (see next section),
the paramedian pontine reticular forma-
tion (PPRF), the mesencephalic reticular
formation adjacent to the interstitial nu-
cleus of Cajal, and the rostral interstitial
nucleus of the medial longitudinal fascicu-
lus (riMLF) (see Fig. 6-3, Chap. 6). In ad-
dition, vestibular and fastigial nuclei (see
Display 6-13) project to these cervical ar-
eas, but the superior colliculus does not
directly.132 Projections from motor cortex
to cervical cord in humans have been
studied by percutaneous scalp stimula-
tion which evokes electromyographic re-
sponses in the contralateral sternocleido-
mastoid, trapezius and splenius capitis
muscles at short (6-12 msec) latency.55 Be-
low, we review possible contributions of
each of these regions to the generation of
eye-head saccades.
The Gigantocellular
Head-Movement Region
Anatomical and electrophysiological stud-
ies in monkeys have defined neurons
within the nucleus reticularis gigantocel-
lularis (see Fig. 6-2, Chap. 6) to be impor-
Eye-Head Movements 269
tant for generating head movements dur-
ing eye-head gaze shifts.33'34'132 This region
lies in the rostral medulla, between the
posterior aspect of the abducens nucleus
rostrally and the rostral third of the hy-
poglossal nucleus caudally. It lies caudal
and ventral to the physiologically defined
PPRF. Electrical stimulation here evokes
head movements at a latency of about 30
msec. These evoked movements are usu-
ally ipsilaterally directed horizontal (yaw)
rotations; sometimes pitch or roll move-
ments are evoked. Electrical stimulation
in the gigantocellular head-movement
region does not produce saccadic eye
movements, although vestibular eye move-
ments occur during evoked head move-
ment and hold gaze steady. Neurotoxic
damage to this area in cats abolishes spon-
taneous head movements.147
The gigantocellular head-movement re-
gion receives a major input from the pos-
terior part of the superior colliculus, from
the mesencephalic reticular formation
surrounding the riMLF and interstitial
nucleus of Cajal, from the medial pontine
reticular formation, and from the fastigial
and vestibular nuclei (see Fig. 6-3, Chap.
6). It projects to the upper cervical cord,
via the anterolateral funiculus and the me-
dial longitudinal fasciculus, to terminate
in lateral parts of the ventral horn. Here
axons contact cervical interneurons that
also receive vestibulospinal inputs. These
interneurons project to motoneurons that
innervate rectus capitis, obliquus capitis,
and splenius capitis muscles. It has been
suggested that the gigantocellular head-
movement region contributes to a variety
of behaviors, such as feeding, as well as
eye-head gaze shifts. Since electrical stim-
ulation here does not produce gaze shifts,
it appears that prenuclear inputs must
synchronize movements of eyes and head.
The frontal eye fields do not appear to
project directly to the gigantocellular pre-
motor area, and thus, inputs from the
superior colliculus seem to be crucial for
programing eye-head gaze saccades.
Role of the PPRF in
Eye-Head Saccades
Two classes of burst neurons in the PPRF
of alert monkeys have been defined: those
270 The Properties and Neural Substrate of Eye Movements
with discharge activity related to the size
of the eye-in-orbit movement (ocular burst
neurons) and others that discharge in re-
lation to the size of the eye-in-space move-
ment (gaze burst neurons). 171 These two
classes of bursts cells are intermingled, but
differences in their anatomical connec-
tions have not yet been defined. It has
been suggested that the different proper-
ties of these two classes of neurons reflect
the effects of vestibular (head velocity)
projections to ocular, but not gaze, burst
neurons.153 Thus, even though the VOR
itself appears to be disconnected during
large eye-head saccades,134a the vestibular
head velocity signal is available to burst
neurons so that an accurate gaze shift can
be achieved. Alternatively, gaze burst neu-
rons might inhibit the VOR during eye-
head saccades.126
In cat, the PPRF contains a class of burst
neurons that project to both the abducens
nucleus and the spinal cord.64-65 These
neurons, which lie rostral-ventral to
the abducens nucleus, also project to the
prepositus, vestibular, and facial nuclei
and other reticular nuclei. These cells dif-
fer from classic saccadic burst neurons in
that the burst is followed by a prolonged
discharge; in addition, these neurons be-
come silent if the eyes deviate into the
contralateral ocular motor range. These
eye-neck reticulospinal (EN-RS) neurons
receive monosynaptic projections from the
contralateral superior colliculus. Thus,
EN-RS neurons may be important in gen-
erating combined orientating movements
of the eyes and head.
In humans, individual motor unit activ-
ity in the splenius muscle has shown that
units increase their activity when gaze is
shifted ipsilaterally, even though the sub-
jects' heads were fixed and they were in-
structed to look just with their eyes.3 This
evidence supports the concept of coupling
of eye and neck muscles, perhaps by mech-
anisms such as brain stem EN-RS neurons.
The Mesencephalic Reticular
Formation, Rostral Interstitial
Nucleus of the Medial Longitudinal
Fasciculus, and Eye-Head Saccades
Several parts of the mesencephalic reticu-
lar formation project to the cervical cord
region. One is the area ventrolateral to the
interstitial nucleus of Cajal, and stimu-
lation in this area may induce the ocular
tilt reaction.169 The central mesencephalic
reticular formation (cMRF), which has
reciprocal connections with the superior
colliculus, may contribute to both horizon-
tal and vertical gaze.163 In addition, cells
within the riMLF project to the cervical
cord,132 and, like the pontine reticular for-
mation for horizontal eye-head saccades,
may coordinate vertical movements.
The Caudal Superior Colliculus and
Eye-Head Saccades
In the monkey, electrical stimulation of
the intermediate layers of the rostral two-
thirds of the superior colliculus evokes
purely saccadic eye movements (see Fig.
3-9, Chap. 3). Stimulation in the caudal
superior colliculus produces combined
eye-head gaze shifts at an average latency
of 40 msec; both eye and head movements
are directed contralaterally to the side
stimulated.33 However, the relationship
between the timing and size of eye and
head components of these electrically
evoked gaze shifts is not tight. Thus, the
suggestion that the caudal portion of the
superior colliculus generates a single sig-
nal related to the gaze shift may not ap-
ply to primates.33 Nonetheless, this cau-
dal collicular region does project to both
the PPRF and the gigantocellular head-
movement region, so it could help to coor-
dinate eye-head gaze shifts.
The Frontal Eye Field and
Eye-Head Saccades
The FEF (see Fig. 6-8, Chap. 6) contains a
class of neurons that discharge in relation
to head movements.16 Stimulation of the
cerebral cortex in monkeys, with the head
free, may elicit contralateral movements of
both eyes and head.110 Experimental le-
sions of the FEF acutely cause a contralat-
eral neglect during which the monkey
tends not to look at targets in the con-
tralateral hemifield, and when it does, it
generates eye-head saccades that are hy-
pometric.160 Effects of FEF lesions on eye
saccades are summarized in Chapter 3; no
changes in the timing of eye and head
 Eye-Head Movements 271

contributions to eye-head saccades have

been reported. With recovery, the contri-
bution of head movements to eye-head
saccades tends to increase.160
The descending pathway from the FEF
for eye-head saccades is probably similar
to that for eye saccades (see Fig. 6-9,
Chap. 6) and differs from the pathways
mediating voluntary control of the limbs.
Stimulation within the brain stem also elic-
its head movements and, as for eye move-
ments, there appears to be a midbrain de-
cussation for the direction of elicited head
movement. 13

Smooth Tracking with

Head and Eyes
We may choose to visually track a
smoothly moving target with the eyes
alone (i.e., with the head stationary, as in
smooth pursuit) or using a combination of
eye and head movements, as in gaze pur-
suit. In general, normal subjects track
equally well under either condition.9'102
During combined eye-head tracking, the
VOR must be nulled for gaze to smoothly
follow the movement of the target. Behav-
ioral studies suggest that two separate
mechanisms contribute to negation of the
VOR during eye-head tracking: cancella-
tion of the VOR by a smooth-pursuit sig-
nal, and a partial reduction of VOR gain
(VOR suppression).
One experimental strategy to determine
whether the VOR is still operating during Figure 7-4. The head brake experiment. Typical re-
eye-head tracking is to perturb the sub- sponses from a normal subject (top) and a patient
who had lost vestibular function (bottom). G, gaze; H,
ject's head and measure the short-latency head; T, target. At the beginning of each record, the
(<15 msec) vestibulo-ocular response be- subject is visually tracking a head-fixed target that
fore visually mediated eye movements moves with the vestibular chair in which he is sitting
have time to act (>80 msec). This is the ba- (eye-head tracking). At the arrow, the chair is sud-
sis for the head-brake experiment, in denly and unexpectedly stopped (head brake) while
the visual target continues to move. The normal sub-
which the head is suddenly stopped dur- ject continues to generate a smooth tracking eye
ing eye-head pursuit (Fig. 7-4).so,99 jn movement, implying that the smooth-pursuit system
normal subjects, ocular smooth pursuit is was already active during the prior eye-head track-
initiated too promptly for it to be in re- ing. In contrast, after the onset of the head brake, the
patient with no VOR temporarily stopped tracking
sponse to target motion after the head the target: G fell behind T, and only recommenced
stops. Since there is insufficient time to tracking with saccades and pursuit after about 200
initiate pursuit after the head is braked, it msec. This implied that the smooth-pursuit system
follows that the smooth pursuit system was not active during the prior combined eye-head
must have been operative during com- tracking. Also note that the patient, but not the nor-
mal subject, showed superior eye-head tracking to
bined eye-head tracking, and it seems smooth pursuit.
likely that this signal is being used to can-
272 The Properties and Neural Substrate of Eye Movements
eel the VOR. If the head-brake experi-
ment is performed in patients who have
lost their vestibular function (Fig. 7-4,
bottom), smooth pursuit does not com-
mence promptly after their heads stop but
takes about 100 msec to be generated. An
explanation for this result is that patients
who have lost their vestibular function
have no VOR to cancel during eye-head
pursuit; therefore an ocular smooth pur-
suit signal is not needed. Some of these
patients show better performance during
eye-head tracking than during smooth
pursuit with the head stationary (Fig. 7-4,
bottom), and this result could be because,
with no VOR to cancel, fewer demands
are made of the pursuit system.102 Cancel-
lation by a smooth-pursuit signal appears
to be the main mechanism by which the
VOR is negated during eye-head track-
ing, especially when head movements are
made actively12'165 or if the subject is in
motion.43
Several lines of evidence suggest that a
second mechanism, reduction of VOR
gain or VOR suppression, may contribute
to smooth eye-head pursuit. For example,
by visually fixing upon a head-fixed target
during head roll rotations (around the
naso-occipital axis), it is possible to cancel
the torsional VOR, and yet there is no tor-
sional smooth pursuit and only a weak tor-
sional optokinetic response.101 Studies of
the way that the VOR and smooth pursuit
obey Listing's law during three-dimen-
sional head rotations indicate that VOR
gain is reduced if subjects fixate a target
that moves with the head.112 Certain pa-
tients with cerebellar or brain stem disor-
ders may show disparate defects of smooth
pursuit and combined eye-head tracking
(Fig. 7-5).28,63,131 Barbiturate drugs impair
cancellation of the VOR more profoundly
than smooth pursuit. 105 Whether normal
subjects show differences between smooth
pursuit and combined eye-head tracking
during passive rotation in the horizontal
plane is disputed;10'108 however, perfor-
mance during head-free gaze tracking is
probably similar to that of smooth pursuit
(Fig. 7-4, top).9'12-165 Finally, the ability to
visually "enhance" the VOR when the tar-
get is stationary and the head moves also
appears to depend on more than a simple
summation of vestibular and visual sig-
nals.42 Behavioral evidence is suggestive of
more than one mechanism to negate the
VOR during eye-head pursuit. Firmer evi-
dence comes from electrophysiological
studies.
NEURAL SUBSTRATE FOR
EYE-HEAD PURSUIT
Once again, insights into the mechanism
for combined eye-head tracking have been
gained from electrophysiological studies
that have applied a bottom-up approach
comparing the properties of cells that pro-
ject to ocular motoneurons during ocular
pursuit, eye-head pursuit, and the VOR.
For horizontal movements, the relevant
cells mainly lie in the vestibular nuclei and
nucleus prepositus hypoglossi.
First-order vestibular neurons that re-
spond to passive horizontal head rotation
show no modulation of this discharge if a
monkey views a target that moves with
the head (i.e., no electrophysiological evi-
dence of VOR suppression).40 Second-
order vestibular neurons (PVP cells),
which project to abducens motoneurons,
modulate their discharge during VOR
suppression, but with an amplitude that is
only about 70% of that during the VOR. If
the monkey's head is perturbed during
eye-head pursuit, a reduced response is
evident at a latency of 30 msec, indicating
a reduction of vestibular responses rather
than any visually mediated mechanism.
Thus, during passive eye-head pursuit,
the vestibular responses are reduced.40
How this reduction of sensitivity in PVP
cells during eye-head pursuit is achieved
remains unknown, but the short latency
of action has led to the suggestion that
vestibular inhibitory connections might
switch in a copy of the head velocity signal
with an opposite sign.40 Nonetheless, a
second mechanism is still required to can-
cel the persisting head velocity signal that
PVP cells deliver to ocular motoneurons
during the VOR suppression paradigm.
Studies of abducens motoneurons and
neurons in the vestibular and prepositus
nuclei that project to them indicate that
this second mechanism consists of can-
cellation of the residual vestibular signal

by an oppositely-directed ocular smooth-
pursuit signal.38 Thus, certain cells in the
medial vestibular and prepositus nuclei
consistently modulate their discharge dur-
ing smooth pursuit and eye-head tracking,
but not during the VOR. Such neurons
might receive a pursuit signal from the
vestibulocerebellum, where Purkinje cells
are known to carry a gaze velocity signal
during ocular and eye-head pursuit, but
not to modulate their discharge during
the VOR.111 In the vertical plane, the
y-group (see Display 6-8) may play a key
role by relaying a gaze-velocity signal from
the vestibulocerebellum to ocular motoneu-
rons; this signal could then cancel the
head velocity signal that projects from ver-
tical PVP neurons to ocular motoneurons
in the oculomotor and trochlear nu-
clei.30'121'156-179 Thus, the electrophysiolog-
ical evidence is consistent with the results
of behavioral studies in monkeys37'104 and
humans, 80 indicating that two mechanisms
help to negate the VOR during combined
eye-head tracking.
EXAMINATION OF EYE-
HEAD MOVEMENTS
Head movements can be examined at the
bedside using an approach similar to that
used for eye movements. First note any
spontaneous head tilt, turn, tremor or
other adventitious movement when the
patient is at rest and when walking. Then
instruct the patient to rapidly move the
head from one target to another on com-
mand, so that the velocity, accuracy, and
latency of head saccades can be noted.
During eye-head saccades, note if the eye
movement continues after the head move-
ment is complete—a finding in some pa-
tients with slow saccades.
To assess head pursuit, instruct the pa-
tient to track a slowly moving target using
both the head and eyes. A useful clinical
test is to rotate the patient's head during
fixation upon a head-fixed target.49'178 In
this way, the eye is held near to primary
position and smooth tracking can be eval-
uated without contamination from gaze-
evoked nystagmus. Patients who have
muscle weakness can be rotated in a
wheelchair while fixating a pointer that
Eye-Head Movements 273
rotates with the chair. The rotation of the
chair should be gentle at first. If eye-head
pursuit is inadequate (impaired cancel-
lation of the VOR), the eyes will be contin-
ually taken off target by slow phases of
the VOR and corrective saccades will
be made. For example, deficient smooth
pursuit to the right will usually be accom-
panied by deficient cancellation of the
VOR on rotation to the right. In patients
in whom smooth pursuit is impaired
(lower tracking gain) compared with com-
bined eye-head tracking, one should sus-
pect an inadequate VOR.
Head nystagmus (the vestibulo-collic re-
flex) can be detected by rotating the pa-
tient in an office chair with the head
free to move.118 Some normal individuals,
mainly children, may show head nys-
tagmus during low-frequency sinusoidal
body rotation in either the dark or light.
In the latter case, head nystagmus reflects
a combined vestibular and visual (optoki-
netic) input.
LABORATORY EVALUATION OF
EYE-HEAD MOVEMENTS
In many laboratories, routine testing of
combined, eye-head movements consists
of measurement of cancellation of the
VOR during passive rotation in a vestibu-
lar chair to which a fixation light is at-
tached. Measurement of VOR suppression
offers the means to test visually mediated
tracking eye movements in patients in
whom either a limited ocular motor range
or gaze-evoked nystagmus prevents reli-
able measurement of smooth pursuit with
the head stationary. When the intent is to
compare smooth ocular pursuit and com-
bined eye-head tracking, it is essential to
test the VOR (Fig. 7-5).
Either sinusoidal or velocity-step stimuli
(e.g., sudden onset of rotation at 20°/sec)
can be used. For each stimulus, the peak
eye velocity is measured (Ec). The proce-
dure may then be repeated in darkness to
obtain the peak velocity of unsuppressed
vestibular eye movements (Ev). Compari-
son of the two (1 — [EC/EV]) enables calcu-
lation of the gain of VOR cancellation.
Some normal subjects may show greater
gain values for VOR cancellation during
274 The Properties and Neural Substrate of Eye Movements
passive rotation than for smooth pursuit
with the head stationary.96'108 Like smooth
pursuit, combined eye-head tracking
changes during development and ag-
ing,63-119'162 and each laboratory should es-
tablish its range of normal values.
Fixation suppression of calorically in-
duced nystagmus is a less precise measure
of the ability to use visual signals to modu-
late vestibular responses. The amount of
suppression depends on whether a small
or large-field visual target is viewed.78
When fixation suppression is severely im-
paired, it points to the presence of cen-
tral nervous system disease,77'78-91 espe-
cially pathways mediating smooth pursuit,
such as the vestibulocerebellum.150 The
properties of visual fixation are discussed
in the first part of Chapter 4.
Although not routinely tested, eye-head
saccades may also provide useful infor-
mation, especially in patients with ocular
motor apraxia (see VIDEOS: "Acquired ocu-
lar motor apraxia," "Congenital ocular
motor apraxia"), or slow saccades due to
degenerative conditions (see Table 10-15,
Chap. 10).
Quantitative testing of active eye-head
movements can be achieved by a number
of simple methods. Head movements can
be measured using a light, snugly fitting
helmet attached to a potentiometer, angu-
lar rate sensor, or accelerometer. The best
results are probably obtained using the
magnetic search coil method (see Appen-
dix B). Eye movements can be measured
using electro-oculography or the search
coil method; infrared reflection tech-
niques are not well suited because of their
limited range of linear operation.
Stability of the head and gaze during
perturbations of the body can be tested by
rotating the subject in a vestibular chair.
The stimuli should ideally be of high fre-
quency (0.5-5.0 Hz) and be nonpre-
dictable (either pseudorandom or nonpre-
dictable transient rotations) to simulate
the perturbations that occur during loco-
motion (Fig. 7-1). Eye-head saccades or
smooth pursuit can be tested with visual
stimuli similar to those used to test ocular
saccades (Chap. 3) and measure smooth
pursuit (Chap. 4).
During testing of combined eye-head
movements, it is important to remember
that changes in gaze must be related to the
proximity of the target being viewed. If
the subject fixates upon a distant target,
then changes in gaze (eye in space) are
simply the sum of the eye-in-orbit and
head rotations. For near targets, however,
the relationship is more complicated be-
cause the eyes are not located at the center
of rotation of the head; they lie about 10
cm in front of the axis of head rotation. As
an example, consider a head rotation dur-
ing fixation of a near, earth-fixed target;
during this head rotation, the eyes are dis-
placed (translated) laterally and either an-
teriorly or posteriorly. Consequently, an
additional rotation of the globes is re-
quired above what is needed to compen-
sate for the head rotation if the line of
sight is to be held upon the target. Thus,
the gain of the VOR should ideally be 1.0
when viewing distant targets, but greater
than 1.0 when viewing near targets. (The
situation is even more complicated if both
eyes are considered, because they are sep-
arated from each other and must there-
fore rotate by different amounts.) The
geometric solution of this problem has
been discussed by several authors.17'81'82'161
Neglecting the separation between the
eyes and assuming head rotations are rela-
tively small, an equation that approxi-
mately relates eye and head rotations, and
the viewing distance of the target is:
E = (1+R/D) * –
where EQ — eye rotation in orbit, H —
head rotation (the negative sign indicates
that eye and head rotations are in differ-
ent directions), R = radius of rotation of
eyes in head (i.e., distance from center of
rotation of head to the eyes, typically
about 10 cm), and D = distance from cen-
ter of rotation of head to target.
DISORDERS OF
EYE-HEAD MOVEMENT
In this section, we will first deal with con-
ditions that disrupt stability of head and

gaze and then discuss disordered volun-
tary control of eye-head movements.
Disorders of Head and
Gaze Stabilization
EFFECTS OF VESTIBULAR
DISTURBANCES ON
EYE-HEAD STABILITY
Abnormalities of head posture and gaze
are commonly caused by disturbance of
vestibular function. Individuals who have
bilateral loss of vestibular function fre-
quently complain of disturbed vision and
oscillopsia (illusory movement of the vi-
sual world) during head movements—
particularly those movements that occur
during locomotion51'86 or riding in an au-
tomobile.31 These visual symptoms corre-
spond to head perturbation (rotations or
translations) above about 1.5 Hz, when vi-
sually mediated eye movements cannot
compensate for head perturbations.70'103
Patients who have a head tremor and defi-
cient VOR may complain of oscillopsia
and be mistakenly diagnosed as having
nystagmus. 21 Oscillopsia brought on by
head movements may also be caused by
disease of the central nervous system. Pa-
tients who have deficient peripheral ves-
tibular function lose the ability to sustain a
steady angle of head orientation in the
sagittal (pitch) plane.129 However, dynamic
head stability in the horizontal plane is
only mildly impaired in patients with de-
ficient vestibular function, perhaps be-
cause the effective viscoelastic properties
of the neck change in relation to the de-
ficiency.44'67 In patients with unilateral
labyrinthine loss, sudden perturbations of
the trunk (applied by rotating the chair in
which they sit) cause greater head oscilla-
tions and diminished head stability in
space when they are rotated towards the
lesioned side.124
A number of adaptive strategies are
available to labyrinthine-defective patients
so they can stabilize gaze in the absence of
a functioning VOR. These are summa-
rized in Table 7-1. Coexistent disease of
the central nervous system, such as multi-
Eye-Head Movements 275
Table 7-1. Summary of Adaptive
Strategies to Compensate
for Loss of Vestibular
Function23'24'47'48'69'72*-90'116'148'159
Substitution of small saccades and quick
phases in the direction opposite head rota-
tion to compensate for inadequate slow
phases
Potentiation of the cervico-ocular reflex
Preprograming of compensatory slow eye
movements in anticipation of a head move-
ment
Decreased saccadic gain (saccade amplitude/
target amplitude) during active, combined
eye-head movements, to prevent gaze over-
shoot
Extension of the range of frequencies over
which the visual-following reflexes (pursuit)
perform adequately
Perceptual adaptations so that oscillopsia can
be ignored
Restriction of movement of the head so as not
to challenge an inadequate vestibulo-ocular
reflex.
Use of the effort of spatial localization to in-
crease the gain of compensatory slow
phases.
system atrophy, may limit the develop-
ment of adaptive strategies, such as poten-
tiation of the cervico-ocular reflex.25'167
One patient with a cerebellar tumor, how-
ever, was reported to show an increase in
the normal low gain of the cervico-ocular
reflex.22
Loss of otolithic inputs is most evident
clinically when it occurs unilaterally.76 The
result is an ipsilateral head tilt; in addi-
tion, a skew deviation and cyclotorsion of
the eyes may occur (with hyperdeviation
and extorsion of the eye ipsilateral to the
lesion)—the ocular tilt reaction. Head tilt
due to either unilateral loss or unilat-
eral increase in otolithic input (as occurs
paroxysmally in the Tullio phenomenon)
is accompanied by a disturbance in the
perception of gravitational vertical.19'41
Lesions affecting the central otolithic
pathways, in either the vestibular nuclei,
medial longitudinal fasciculus, or intersti-
tial nucleus of Cajal, may cause the ocular
276 The Properties and Neural Substrate of Eye Movements
tilt reaction. These clinical findings are
compatible with results of experimental
lesions52 or stimulation studies169 and are
discussed in Chapter 10.
CENTRAL NEUROLOGIC
DISORDERS AFFECTING
HEAD STABILITY
Tremors of the head due to essential
tremor or Parkinson's disease seldom in-
terfere with steady gaze, because an ade-
quate VOR is maintained. However, cere-
bellar disease causing titubation also
frequently involves central vestibular con-
nections and disturbs gaze either due to
spontaneous ocular oscillations or to an
abnormal VOR. Observation with an oph-
thalmoscope is a useful clinical method of
evaluating the stability of gaze during
head tremor.
Patients with Parkinson's disease and
progressive supranuclear palsy frequently
show rigidity of the neck;67 in Parkinson's
disease, muscle tone may be reduced by
levodopa so that compensatory head move-
ments increase during rotational perturba-
tions of the body.168 The vestibulo-collic re-
flex, which is vestigial in normal subjects,118
may become clinically evident in patients
with certain degenerative disorders. For
example, patients with progressive su-
pranuclear palsy and some patients with
dementia87 lose the corrective phase of
head nystagmus during whole-body rota-
tion with the head free. The vestibulo-collic
reflex elicits a slow phase of head nystag-
mus in an attempt to stabilize the position
of the head in space, but no corrective
quick phase is made to maintain head
alignment on the body. As a result, the head
tonically deviates in the direction opposite
that of body rotation. If the quick phase of
eye nystagmus is also absent, the eyes also
tonically deviate (in the orbit) in the direc-
tion opposite to that of body rotation.
Several studies have addressed the rela-
tionship between spasmodic torticollis and
a possible underlying vestibular imbal-
ance. In response to head rotations in roll,
both increases and decreases of the gain of
counterrolling have been demonstrated,
without directional asymmetries or tor-
sional nystagmus. 4 - 46 Other studies have
investigated horizontal vestibular responses
in darkness and demonstrated asymme-
tries26 and hyperactivity of responses.83
Whether vestibular abnormalities are the
root cause or simply a secondary effect of
spasmodic torticollis, due, for example, to
reduced neck motion, has not been set-
tled,27'83'146 and there might be a subgroup
of patients in whom spasmodic torticollis
is precipitated by vestibular disease.27 In
any case, patients with spasmodic torti-
collis show changes in their perceptions
of the subjective visual vertical and of
straight ahead. 1 - 2
Patients with Wallenberg's syndrome (lat-
eral medullary infarction) occasionally show
abnormal eye-head coordination.97 Their
head and eyes may tonically deviate towards
the side of the lesion, and occasionally they
have spontaneous head nystagmus. These
abnormalities probably reflect lesions in
vestibulospinal and reticulospinal projec-
tions to cervical motoneurons.
CONGENITAL DISORDERS
Two infantile disorders characterized by
head tremor and disturbance of gaze are
spasmus nutans (see Display 10-13) and
congenital nystagmus (Display 10-11);
both conditions are discussed in Chapter
10. Children with the bobble-head doll
syndrome45'60'88'120-136 show arrhythmic,
to-and-fro, flexion-extension, bobbing of
the head and occasionally of the trunk. In
one patient, electromyography of the neck
extensor muscle showed contractions at
2-3 Hz.136 These patients usually have a
slowly growing mass near or in the ante-
rior part of the third ventricle or aqueduc-
tal stenosis. The mechanism for this oscil-
lation is unknown, but the movements
cease following treatment of the hydro-
cephalus.
Disorders of Voluntary Head and
Gaze Control
PARALYSIS OF VOLUNTARY
HEAD TURNING
Paresis of voluntary head turning occurs
as a component of conjugate gaze paresis

following an acute lesion of one cerebral
hemisphere: the head and eyes are turned
toward the side of the lesion (see Display
10-33). Head turning probably depends
on both the sternocleidomastoid muscle
(SCM) and the splenius capitis muscle.
The splenius capitis receives contralateral
cortical innervation, but the SCM appears
to receive both contralateral and ipsilat-
eral input. 55 Patients who have suffered a
unilateral cerebral lesion often show some
weakness of the SCM ipsilateral to the side
of the cerebral lesion (recall that the SCM
turns the head to the contralateral side).
Thus, a right hemispheric lesion might
produce a gaze palsy to the left, involving
head and eye movements; the right SCM
would be weak, but there would be a left
hemiplegia, with involvement of the left
trapezius muscle. This finding suggests
that the descending pathways to SCM are
either uncrossed6 or undergo a double de-
cussation.57 In support of the latter hy-
pothesis, it has been reported that brain
stem lesions may cause SCM weakness and
hemiparesis on the same side,107 presum-
ably because the lesions are below the first
decussation for SCM but above the sec-
ond. The site of the second decussation
for SCM is unknown. It might occur in the
high cord, because (7) hemicord section at
Cl, on the right, causes a flaccid right
hemiparesis that spares the right SCM but
causes left SCM weakness,84 and (2) lesions
at C4 may cause paralysis of the trapezius
and quadriparesis but spare the SCM.106'114
It seems likely that the brain stem path-
ways to the SCM and perhaps to the sple-
nius capitis muscle lie in the tegmentum,
because ventral pontine infarction that
causes quadriparesis and trapezius weak-
ness may spare the SCM.106 An important
consequence of this is that patients who
are in the locked-in or de-efferented state
due to ventral pontine infarction often re-
cover voluntary eye and head movements,
which may be important for communi-
cation.135
HEAD TURNING AS A FEATURE
OF EPILEPSY
Involuntary head turning is a common
feature of focal motor epileptic seizures.
Eye-Head Movements 277
Head-turning away from the side of the
seizure focus is called adversive or con-
tralateral versive; head turning towards
the side of the seizure focus is called ip-
siversive. Although both adversive and ip-
siversive head turning may occur with
seizures, certain associated features may
help with localization of the seizure focus.
If the patient remains conscious during
the attack, then head turning at the onset
is generally, but not always, away from the
side of the seizure focus, which is usually
frontal.109'152'173'174 A contralateral focus is
also likely in patients who show marked,
sustained, and unnatural lateral posi-
tioning of their head and eyes.173'174 In
patients who are unconscious, whose
seizures generalize, or who show milder
deviations of the head and eyes, about half
manifest ipsiversive movements of the
head.58'117 The site of the seizure focus
may be in any lobe, but frontal and tempo-
ral are the most common. Contraversive
eye deviation often accompanies the head
turning and may be followed by nystag-
mus; this issue is discussed further in Eye
Movements During Epileptic Seizures in
Chapter 10.
EYE-HEAD STRATEGIES
IN PATIENTS WITH
ABNORMAL SACCADES
Disordered Eye-Head Coordination
in Ocular Motor Apraxia
This term is commonly applied to patients
who show an impaired ability to generate
saccades on command. However, apraxia
is often defined as the lack of skilled move-
ments despite an intact, innate neurophys-
iological substrate for performing such
movements. Ocular motor apraxia, there-
fore, should refer to a condition in which
voluntary eye movements are impaired
but reflexively induced saccades and quick
phases are intact. In fact, the term has
been applied to deficits of voluntary sac-
cades that either spare140 or involve127 sac-
cades made reflexively to visual targets.
Quick phases of vestibular nystagmus are
preserved. An important general feature
of ocular motor apraxia is that, with the
head free, patients are more easily able to
278 The Properties and Neural Substrate of Eye Movements
voluntarily shift their gaze (see VIDEO: "Ac-
quired ocular motor apraxia"). This pat-
tern of behavior is similar to that of
afoveate animals, who are unable to make
voluntary gaze shifts without a head move-
ment. Acquired ocular motor apraxia oc-
curs with bilateral parietofrontal lesions. A
number of disorders lead to ocular motor
apraxia in children, including idiopathic
congenital ocular motor apraxia, which is
characterized by prominent head thrusts
(see VIDEO: "Congenital ocular motor
apraxia"). These disorders are discussed
further in Chapter 10.
Eye-Head Movements in Patients
with Slow or Inaccurate Saccades
In patients with slow ocular saccades (see
Table 10-15), the saccadic eye movements
may outlast the head movements, even if
saccadic latency is not prolonged. The ac-
curacy of head movements may be affected
by cerebellar disease.142'177 In such pa-
tients, eye-head saccades may also be dys-
metric. The pattern of saccadic dysmetria
may vary, however, depending on whether
the gaze change is accompanied by a head
movement. Pharmacological inactivation
of the cerebellar fastigial nucleus (see Dis-
play 10-19, Chap. 10) causes ipsilateral hy-
permetria and contralateral hypometria of
eye-head gaze shifts.59>121a These findings
are similar to the pattern of dysmetria of
eye saccades following fastigial inac-
tivation.133 Patients with Parkinson's disease
may show delayed, small, and slow head
movements during head-free tracking of
step displacements of targets.170
Eye-Head Movements in Patients
with Restricted Ocular Motor Range
Patients with ocular motor palsies or dis-
ease of the neuromuscular junction or of
the extraocular muscles may all show an
increased range of head movements to
compensate for their ocular deficit. Such
adaptive strategies are determined by the
nature of the ocular motor restriction;36
these are discussed under Head Turns
and Tilts in Chapter 9.
DISORDERS OF SMOOTH
EYE-HEAD TRACKING
As a general rule, disorders that impair
smooth ocular pursuit, including drugs
such as sedatives (see Table 10-21, Chap.
10), also affect eye-head tracking. When
there is a disparity, eye-head pursuit is
usually superior,63 perhaps reflecting the
two mechanisms by which the VOR is
negated during eye-head pursuit (see
Smooth Tracking with Head and Eyes,
above). So, for example, unilateral lesions
affecting secondary visual areas concerned
with motion analysis impair both smooth
ocular pursuit and eye-head tracking as
the patient follows targets moving toward
the side of the lesion;28'141 in some pa-
tients, eye-head pursuit is superior.79
Other disorders that impair smooth pur-
suit, such as cerebellar disease, multiple
sclerosis,139 Parkinson's disease,170 and pro-
gressive supranuclear palsy, frequently af-
fect eye-head tracking evaluated during
passive chair rotation.
When smooth ocular pursuit and head-
free eye-head pursuit deficits are com-
pared in patients with brain stem and cere-
bellar disease, in the horizontal and
sagittal planes, combined eye-head track-
ing is usually, but not always, superior
(Fig. 7-5).63'166 In the torsional (roll) plane,
in which optokinetic responses are weak in
both normals and patients, combined eye-
head tracking is invariably better. In pa-
tients who have bilateral loss of vestibular
function, combined eye-head tracking is
often superior to smooth pursuit (Fig. 7-4,
bottom),102 perhaps because these patients
have little VOR to cancel during combined
eye-head tracking. Similarly, patients with
deficient vestibular function can more ac-
curately fixate upon a head-fixed target
during locomotion than normal subjects.44
Conversely, patients with an increased
VOR gain (due, for example, to cerebellar
disease) may show better smooth pursuit
than eye-head tracking (Fig. 7-5A).
SUMMARY
1. During natural behavior, eye and
head movements usually occur to-
 Eye-Head Movements 279

Figure 7-5. Comparison of smooth ocular pursuit and eye-head tracking (A) in the horizontal plane in a patient
with cerebellar degeneration, and (B) in the vertical plane in a patient with progressive supranuclear palsy
(PSP). The cerebellar patient shows better smooth pursuit (gain 0.38) than eye-head tracking (gain 0.29); the
difference is partly explained by her visually assisted VOR, which was hyperactive (gain 1.11), necessitating
back-up saccades (indicated by arrows). The patient with PSP showed superior combined eye-head tracking to
that during smooth pursuit. Some of the difference reflected the inability to generate vertical catchup saccades
to foveate the moving target; such saccades were less necessary during combined eye-head tracking. However,
preservation of the mechanism by which VOR gain is reduced during combined eye-head tracking may account
for the difference. TARG, target.

gether—a linkage reflected in a num- steady, with velocities generally below

ber of behavioral, anatomic, and
physiologic similarities between the
cephalomotor and ocular motor con-
trol systems. Primates have evolved a
high degree of independent volun-
tary control over both eye and head
movements.
2. During natural activities such as loco-
motion, the head is held relatively
100°/sec (Fig. 7-1). The frequency
range of rotational head perturba-
tions that occur during locomotion
ranges between 0.5 and 5.0 Hz. The
stability of the head during such per-
turbations is mainly due to the mass
of the head and the viscoelastic prop-
erties of the neck. The vestibulocollic
and cervicocollic reflexes may pre-
280 The Properties and Neural Substrate of Eye Movements
vent head oscillations in pitch and
roll while subjects are in motion.
3. During large gaze shifts to reorient
the head and eyes in space (eye-head
or gaze saccades; Fig. 7-2), the
vestibulo-ocular reflex is in part dis-
connected. During smaller eye-head
saccades in response to visual stimuli
within the field of vision, a linear ad-
dition of the saccade command and
the vestibulo-ocular reflex may occur.
4. During combined, smooth eye-head
tracking (Fig. 7-4), the vestibulo-ocu-
lar reflex is probably cancelled by an
internal smooth pursuit signal. In ad-
dition, the VOR gain may be reduced
during smooth eye-head tracking.
5. Disorders of eye-head coordination
may be conceptualized as abnormali-
ties of head stability or posture, and
abnormalities of gaze shifting by ei-
ther eye-head saccades or smooth
eye-head tracking. Proper evaluation
of disorders of eye-head tracking
requires separate evaluation of the
vestibulo-ocular reflex (Fig. 7-5).
Certain patterns of head movements
observed in patients with impaired
VOR, ocular saccades, or smooth
pursuit are adaptive and help stabi-
lize or change gaze as necessary.
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Chapter 8 8
VERGENCE EYE MOVEMENTS
STIMULI TO VERGENCE MOVEMENTS
FUSION OR DISPARITY-INDUCED
VERGENCE
Horizontal Vergence
Vertical Vergence and Cyclovergence
BLUR-INDUCED VERGENCE
THE NEAR TRIAD
INTERACTIONS BETWEEN
ACCOMMODATION AND VERGENCE
DYNAMIC PROPERTIES OF VERGENCE
EYE MOVEMENTS
Pure Vergence
Saccade-Vergence Interactions
NEURAL SUBSTRATE OF VERGENCE
MOVEMENTS
Anatomic Substrate for Vergence
Motor Commands for Vergence
Premotor Commands for Vergence
Cerebellar Control of Vergence
Cerebral Control of Vergence
Visual Physiology of Disparity-Induced
Vergence
CONCEPTUAL MODELS OF
SUPRANUCLEAR CONTROL
OF VERGENCE
Vergence Integrator
Commands for Saccadic Vergence
Movements
Commands for Pursuit Vergence
Movements
ADAPTIVE MECHANISMS TO MAINTAIN
OCULAR ALIGNMENT
Phoria Adaptation
Disconjugate Adaptation
EXAMINATION OF VERGENCE
MOVEMENTS
ABNORMALITIES OF VERGENCE
Convergence and Nystagmus
286
Vergence Oscillations
Convergence Spasm
Divergence Weakness
SUMMARY
In previous chapters, we have discussed
the control of ocular movements as if the
brain were directing a single eye. This
chapter and the next will discuss how
binocular movements are coordinated.
In some lower species (e.g., the
chameleon), the two eyes may be aimed in-
dependently, although reflex eye move-
ments (vestibular, optokinetic) remain con-
jugate. In primates, who have foveae and
frontally directed eyes, all eye movements
are binocularly coordinated. The reasons
for this uniform motion of our eyes were
already appreciated by Porterfield in his
1759 Treatise on the Eye:
The final cause is ... that the sight might
thence be rendered more strong and perfect:
for since each eye apart impresses the mind
with an idea of the same object, the impression
must be more strong and lively when both eyes
concur, than when only one: and consequently
the mind must receive a strong, lively and per-
fect idea of the object in view, as is agreeable to
experience: and that both may concur it is nec-
essary that they move uniformly. . . . A second
advantage that we reap from the uniform mo-
tion of our eyes, which is yet more considerable
than the former, consists in our being thereby
enabled to judge with more certainty of the
distance of objects. There is yet another advan-
tage . . . that is thought to arise from the uni-

form motion of our eyes, and that is, the single
appearance of objects seen with both eyes.180
Although monocular cues such as mo-
tion parallax and overlay of contours can
be used to derive a sense of an object's dis-
tance, stereoscopic vision is necessary for
an accurate perception of the third dimen-
sion, especially in the space around us in
which we use our hands. Both stereopsis
and bifoveal fixation of a single object
of interest require precise alignment of
the visual axes. This onus falls upon the
vergence system; unless we are viewing
objects located at a great distance (opti-
cal infinity), disjunctive (opposite-directed)
components must be incorporated into
all normal eye movements. Otherwise, we
would experience diplopia.
Because of the horizontal separation of
the orbits, each eye receives a slightly dif-
ferent image of an object. These dissimilar
retinal images allow creation of a three-
dimensional percept, stereopsis. For sin-
gle vision to be derived from the inputs of
the two eyes, however, the images of an
object of interest must fall on correspond-
ing retinal points, allowing sensory fusion,
the perception of an object seen by both
eyes as single, to take place.235'236 The de-
gree to which images can be separated and
still be perceived as one is called Panum's
area. Such corresponding retinal elements
also allow a subjective sense of visual di-
rection, based on the concept of an imagi-
nary, third, cyclopean eye.41'76'78'172 If the
two images of an object fall on noncorre-
sponding retinal areas in each eye, then
that object is simultaneously localized in
two separate visual directions, causing
double vision, or diplopia. Alternatively,
two different objects may be localized to
the same position in space and appear to
overlap, causing visual confusion. Under
normal circumstances, because of our hor-
izontal vergence system, foveal retinal dis-
parity is short-lived, and we seldom expe-
rience diplopia or visual confusion.
Some terms commonly used to describe
aspects of vergence movements and binoc-
ular vision are summarized in Table 8-1.
For more detailed treatment of binocular
vision, stereopsis and accommodation, the
reader is referred to textbooks by Regan,185
Vergence Eye Movements 287
Howard and Rogers,87 and Schor and
Ciuffreda.203
STIMULI TO VERGENCE
MOVEMENTS
There are two primary stimuli to disjunc-
tive eye movements: the disparity between
the location of images on the two retinas,
which produces diplopia and leads to
fusional vergence movements, and reti-
nal blur (defocused images), which leads to
a loss of sharpness of perceived images
and accommodation-linked vergence move-
ments. Other cues, such as awareness
of the proximity of targets249 (based on
cues such as perspective),40 changes in size
(looming),145 and monocular cues derived
from motion22'186'187 may evoke vergence.
Voluntary, attentional factors can modu-
late vergence movements by influencing
which of many disparities from a complex
visual scene are selected to provide the
stimulus for depth. 46 - 226 There is also an
underlying resting level of vergence tone,
called tonic vergence, about which changes
in vergence induced by new sensory cues
take place.176 Vergence movements are
under a degree of voluntary control; this
can be aided by biofeedback.220 Horizon-
tal, but not vertical vergence can be in-
fluenced by instruction. 226 However, ver-
gence movements are mainly performed
without our being aware of them, in much
the same way that we unconsciously shift
our line of sight across the visual field.
In natural circumstances, retinal blur,
retinal disparity, and other stimuli that act
as clues to the distance of a target interact
to elicit appropriate vergence eye move-
ments. It is useful, however, to consider
the effects of each stimulus alone on ver-
gence eye movements.
FUSION OR DISPARITY-
INDUCED VERGENCE
Horizontal Vergence
Fusional or disparity-induced vergence
may be studied independently of the ef-
288 The Properties and Neural Substrate of Eye Movements

Table 8-1. Glossary of Terms Used to Describe Aspects of Vergence

Eye Movements

Term Definition

AC/A ratio The synkinetic relationship between accommodative-linked conver-

gence and accommodation which is expressed in prism diopters/
sphere diopters (see text: Interactions Between Accommodation and
Vergence and measurement by the heterophoria method).
Accommodation The process by which the refractive power of the lens of the eye is al-
tered to diminish retinal blur and to obtain clear vision of a near ob-
ject. Accommodation is measured in sphere diopters (D). (See text:
the Near Triad)
CA/C ratio The synkinetic relation between convergence-linked accommodation
and convergence which is expressed in sphere diopters/prism
diopters (see AC/A ratio).
Corresponding retinal Those points of the two retinas that, during binocular vision, give rise
elements to localization of seen objects in the same subjective visual direction.
If images from a single object do not fall upon corresponding retinal
elements, retinal disparity is present and serves as the stimulus to fu-
sional vergence and stereopsis.
Depth perception A sense of an object's distance that depends upon stereopsis and
monocular cues (e.g., motion parallax, overlay of contours).
Fusion A cortical phenomenon, wherein the two retinal images are perceived
as one.
Near triad The synkinesis of accommodation, convergence, and pupillary con-
striction. (See text: the Near Triad)
Phoria The relative deviation of the visual axes during monocular viewing of
a single target. This is usually a latent ocular misalignment, since fu-
sional vergence mechanisms maintain alignment during binocular
viewing.
Prism diopter (A) One prism diopter is the strength of a prism that deviates a light ray 1
cm, measured tangentially at 1 m; 1 prism diopter (A) corresponds
to approximately 1/2 degree.
Sphere diopter (D) One sphere diopter is the amount of accommodation that occurs when
the fixation distance (d) is 1 m. (In general, D = 1/d.)
Stereopsis The ability to visually perceive the third dimension, which depends on
each eye receiving a slightly different image of the same object.
Tropia The relative deviation of the visual axes during binocular viewing of a
single target. This is a manifest ocular misalignment, which fusional
vergence cannot correct: Exotropia (deviation out), Esotropia (devi-
ation in), Hypertropia (vertical deviation—e.g., right hypertropia =
right eye higher).
Vergence or disjunctive Movements that rotate the eyes simultaneously in opposite directions:
movements Convergence, Divergence, Incyclovergence (upper poles to nose),
Excyclovergence (lower poles to nose). The two main types of ver-
gence movements are fusional (disparity) and accommodative (blur).
Versions or conjugate Movements that rotate the eyes in the same direction by the same
movements amount. (Movements are disconjugate if they do not rotate the eyes
in the same direction by the same amount.)

fects of retinal blur and its attendant ac-
commodation if the subject views the test
object through optical pinholes. This pro-
cedure ensures a large depth of focus so
that the image is sharp on the retina, irre-
spective of the lens power of the eye or the
distance of the object. One can then study
disparity-driven vergence alone by, for ex-
ample, placing a wedge prism before one
eye. This shifts the position of the image on

the retina of that eye and thereby induces a
retinal disparity that can serve as a stimu-
lus for vergence. The change in disparity
may be large and abrupt, as would occur
when changing one's line of sight from
near to far. In this case, a single, relatively
rapid vergence movement is made, which
in some ways, is analogous to the rapid
shift of conjugate gaze that occurs with a
saccade. The change in disparity, however,
may be smooth and slow, as would occur
with a target moving slowly in depth. In
this case, a smooth vergence movement is
made, which in some ways, is analogous to
the smooth change of conjugate gaze dur-
ing tracking of a target with pursuit.
The motor response to an abrupt
change in retinal disparity occurs with a
latency of about 160 msec when the task is
to change fixation from one depth to an-
other. Much shorter latencies are reported
(<100 msec) when the visual stimulus is
full-field in size and the disparity small in
amplitude 14 or in response to radial optic
flow.14a These early responses need not be
accompanied by a sense of depth percep-
tion and are best elicited in the wake of a
saccade, which is when they would be
needed most to restore clear vision after a
change in fixation. Vergence latencies are
decreased by manipulation of the timing
of offset of the fixation target relative to
the appearance of a new target at a differ-
ent depth (gap effect), but not to the same
degree as are saccade latencies (a decrease
of 17 msec for vergence compared with 41
msec for saccades when the fixation target
is extinguished 75 to 200 msec early).227
Unlike saccades, however, there does not
appear to be a distinct class of express ver-
gence. For smooth vergence tracking, la-
tency decreases when the motion of the
target is predictable.49'116
If the change in retinal disparity is rela-
tively large, the vergence response can be
separated into two components: initia-
tion and completion.96'248 Initiation re-
flects a coarse, transient, trigger mecha-
nism, which can respond to large retinal
disparities of images that can be quite
dissimilar.87 Completion reflects a slower,
feature-sensitive, fusion-lock mechanism,
which sustains vergence at the level nec-
essary for fusion. It responds well only
to small disparities and requires that
Vergence Eye Movements 289
the images seen by each eye have many
features in common. These two types of
motor vergence responses—initiation and
completion—may reflect separate physio-
logic mechanisms that underlie coarse and
fine stereopsis. These, in turn, may be re-
lated to the various classes of disparity-
sensitive neurons that can be identified in
visual cortex (see Visual Physiology of Dis-
parity-Induced Vergence, below).
The stimulus necessary for a sensation
of motion in depth (stereomotion) is not
always the same as that which elicits ver-
gence eye movements.11'14'22'186 The sensa-
tion of motion in depth requires a change
in the relative disparity of one target with
respect to another, but neither target need
be at the fixation point. A change in ab-
solute disparity (the disparity of an object
point with respect to the fixation point)
need not elicit a sense of motion in depth,
but it can induce a change in vergence (for
example, a single target moving on a fea-
tureless background). As a general rule,
relative disparities provide the basis for
stereovision and binocular function; ab-
solute disparities are used for control of
vergence eye movements.
The horizontal fusional vergence system
maintains correspondence of images on
the retina with precision, but not perfec-
tion. The remaining disparity is known as
fixation disparity.^ This residual disparity
leads to a steady-state vergence error that
is presumably the feedback signal re-
quired by the fusional vergence system to
sustain its motor command. The smallest
range of disparities that can be fused is at
the fovea, where horizontal retinal dispari-
ties of more than 10 min of arc, depending
on the nature of the stimulus, may cause
diplopia. This range is called Panum's area
of single binocular vision. Panum's area is
under some degree of dynamic control, so
somewhat larger disparities, such as those
that occur during head movements, can be
tolerated without diplopia.27
Vertical Vergence
and Cyclovergence
Vertical and torsional fusional movements
are also possible, but their properties
290 The Properties and Neural Substrate of Eye Movements
differ from those of the horizontal sys-
tem, primarily in their slow speed and
restricted range of amplitudes.84'85'113'218
Vertical fusional movements to a step of
disparity, for example, take seconds for
completion and usually cannot overcome
disparities of more than a degree or two.
They are more robust for near viewing.75
In some patients with a vertical muscle im-
balance, however, the vertical fusional
range may be strikingly increased,158 and
in normal adults, the vertical fusional
range can be increased with training.68
Cyclodisparities elicit torsional fusional
movements called cyclovergence, but just as
for vertical vergence, they are slow and
of limited range.88-113'241 During fixation,
cyclovergence is more tightly controlled
than the torsional position of each eye
alone (i.e., cycloversion).242 This finding
suggests that the relative alignment of the
two eyes around the visual axis plays a role
in certain types of depth perception, such
as determining the slant of objects toward
or away from the subject.86 So, for exam-
ple, disturbances of the perception of slant
accompany the cyclodeviation of superior
oblique palsy and can be used as a diag-
nostic test.130 For a vertical bar, the top will
appear closer to the subject. For a hori-
zontal bar, the two images will be slanted
with respect to each other, with the appar-
ent intersection of the lines pointing to-
ward the side of the affected, excylodevi-
ated eye. Changes in the relative torsional
alignment of the eyes also occur in normal
subjects with near viewing; there is rela-
tive intorsion on upgaze and extorsion on
downgaze.147'153'240 This finding can also
be related to the orientation of Listing's
plane.225a'225b With convergence, there is
a relative temporal rotation of Listing's
plane in each eye. In patients with inter-
mittent exotropia, the added convergence
needed to overcome the inherent exopho-
ria is also associated with an increased
temporal rotation of Listing's plane.238
The functional consequences of such
changes in relative eye orientation with
vergence are not yet settled.22513'234
Most infants can make appropriate ver-
gence movements within the first 3 months
of life, although appropriate accommoda-
tive responses to blur occur later.74'231 Rel-
atively little is known about the effect of
aging on vergence capabilities. Because of
presbyopia, elderly subjects show diminu-
tion in convergence associated with a
given accommodative stimulus. This leads
to some compensatory adaptation in the
linkage between convergence and accom-
modation.191'192 Many elderly individuals
have poor convergence with simple bed-
side testing.
BLUR-INDUCED VERGENCE
Accommodative vergence responses may
be studied independently of the effects of
retinal disparity by covering one eye. In
the classic experiment by Miiller,159 when
the seeing eye changed fixation from a
distant to a near target along the visual
axis of that eye, the eye under cover con-
verged. The seeing eye seemed not to
move, although sensitive recording meth-
ods show that it is not always perfectly still;
in some trials it makes small vergence
movements with corrective saccades (Fig.
8-1 ).3i,44,io8 when stimulus motion is
unanticipated, the reaction time for blur-
driven vergence movements is about 200
msec.
Fusional vergence movements reduce
the stimulus that produces them, retinal
disparity, to a minimum; that is, they use
negative visual feedback. However, the
vergence movements associated with ac-
commodation have no direct effect upon
the retinal blur stimulus that evokes them.
They are open-loop responses. Thus, in
the Miiller experiment, once accommo-
dation is adequate and retinal blur is
quelled, accommodative vergence tone is
held steady irrespective of whether or not
the eye under cover points at the target.
(Of course, under normal binocular view-
ing conditions, fusional vergence move-
ments will precisely direct the lines of
sight.)
THE NEAR TRIAD
Vergence is one part of the near triad.214 A
second component is a change in the
shape of the lens of the eye, accommodation.
When the lens is focused to view objects at
optical infinity, the lens is stretched by its
 Vergence Eye Movements 291

Figure 8-1. Accommodative vergence movements induced in a manner similar to the classic experiment by
Miiller. On the left, the experimental conditions are shown; on the right, the corresponding eye movements are
presented. Movements of the right eye were recorded using the magnetic search coil method; movements of
the left eye were recorded by electro-oculography. The time scale at the top is in seconds. In each condition, A
and B, the subject changed fixation from a far target (F) to a near target (N), aligned along the line of sight of
the viewing eye. (A) With the left eye viewing and the right eye under cover, both eyes began to converge to-
ward the target, but the amplitude of the right eye's movement was larger. The left eye was taken off target by
the convergent movement and a corrective saccade was made. (B) With the right eye viewing and the left eye
under cover, the vergence movements of the right eye are evident at the higher sensitivity of recording (note
different calibration setting). A saccade enabled the right eye to reacquire the target.

attachments. To focus on close objects, the
ciliary muscle contracts to reduce the ten-
sion on the suspensory ligaments of the
lens. The lens then becomes more spheri-
cal and is accommodated for near vision.
Accommodation is measured in sphere
diopters (D), which are related to the reci-
procal of the viewing distance (Table 8-1).
The third component of the near triad is
pupillary constriction. Although it probably
plays only a minor role in focusing near
objects, the degree of pupillary constric-
tion is a useful clinical sign.
INTERACTIONS BETWEEN
ACCOMMODATION
AND VERGENCE
The synkinetic relationship between ac-
commodation (A) of the lens and accom-
292 The Properties and Neural Substrate of Eye Movements
modation-linked convergence (AC) can be
expressed as a ratio (AC/A, expressed in
prism diopters/sphere diopters). This ra-
tio would be close to 6.0 (the average in-
terpupillary distance in centimeters) if the
amount of vergence linked to accommoda-
tion were equal to that required for binoc-
ular fixation at all viewing distances. In
fact, the AC/A ratio is usually smaller
(about 3.5). Hence, during binocular view-
ing of near objects, disparity-induced ver-
gence must also be enlisted to align the
visual axes correctly. Not only is conver-
gence (C) causally linked to accommo-
dation, but likewise, accommodation is
linked to vergence (convergence-linked
accommodation [CA]). The CA/C ratio—
the amount of accommodation in sphere
diopters induced per prism diopter of
convergence—is typically about 0.1 to
0.15, being higher in younger sub-
jects.50'112'152 This ratio should be about
0.16 if the amount of convergence-linked
accommodation were just equal to that
required for clear vision at all viewing
distances.
Under normal conditions of binocular
viewing, accommodative and fusional dri-
ves work together to enable clear, single
vision of close or distant objects. Mad-
dox131 believed that the accommodative
stimulus was the main contributor to ver-
gence and that disparity-induced fusional
vergence was a supplement. Current evi-
dence, however, suggests that fusional ver-
gence is the more important contributor
to ocular alignment.98 In other words, ac-
commodation of the lens is more strongly
linked to disparity (vergence) than ver-
gence to blur (accommodation).31'50'149'152
According to this view, the role of blur is
to serve as the stimulus for the fine-tuning
of accommodation. Some of the other
stimuli that contribute to a sense of near-
ness, including size, texture, and looming,
may also be important for stimulating ver-
gence under conditions of natural view-
ing. The interactions between vergence
and accommodation have been addressed
in models that explicitly incorporate
cross-coupling between accommodation
and vergence (see Adaptive Mechanisms
to Maintain Ocular Alignment and Phoria
Adaptation, below).91'195'202
DYNAMIC PROPERTIES OF
VERGENCE EYE MOVEMENTS
Pure Vergence
The waveform of an isolated vergence
movement, stimulated by a sudden (step)
change in retinal disparity or in blur, ap-
proximates a negative exponential with a
time constant in the range of the orbital
plant (about 150 to 200 msec) (see Fig.
5-1, Chap. 5). This might suggest that the
command signal for pure vergence move-
ments is approximately a step (or tonic)
change in innervation to the extraocular
muscles.188 It has been shown, however,
that during vergence movements, ocular
motoneurons also receive a phasic com-
mand that is proportional to the velocity
of the movement (see Motor Commands
for Vergence, below).60 Analysis of ver-
gence waveforms, using, for example, the
phase plane plot (eye position versus eye
velocity), shows that there is an initial fast,
open-loop or preprogramed response,
usually complete within several hundred
milliseconds, which is followed by a slower
response that completes the vergence
movement and brings the image of the
target to both foveae.216 Occasionally, two
rapid vergence responses will occur to a
single disparity, the second response being
similar to a corrective saccade strategy in
the conjugate system.3 Vergence move-
ments to ramp stimuli may also show what
appear to be two types of vergence re-
sponses: step-like to large disparities and
ramp-like to small disparities.215 Whether
these reflect different control modes com-
parable to saccadic and pursuit vergence
or processing of disparity of different sizes
by different channels is debatable.178 Par-
ticularly confusing in the literature is the
use of the terms fast vergence and slow ver-
gence to describe both the early and late
components of a response to a step of dis-
parity and the fast and slow responses
during tracking of a ramp of disparity.
There is still no proof that these distinct
characteristics of vergence derive from
identical mechanisms.
The peak velocity of vergence can be re-
lated to its amplitude in the same way as

the peak velocity of saccades is related to
its amplitude, using a main sequence plot.
The dynamic properties of vergence re-
sponses have been reported to be more
variable than those of saccades. However,
once the presence or absence of associated
saccades (including vertical saccades) and
blinks are taken into account and the
analysis is restricted to the early pre-
programed component of the vergence
response, much of the variability disap-
pears.90 The two eyes often show dynamic
asymmetries during a pure vergence move-
ment.823 In most studies, convergence has
been reported to be faster than diver-
gence.92'253 Finally, the relationship be-
tween vergence amplitude and disparity
amplitude is under adaptive control.45
This can be shown by artificially altering
the position of the target, using visual
feedback, to make each initial vergence
movement of an incorrect amplitude. Af-
ter a training period, the vergence re-
sponse is adjusted to correct for the artifi-
cially induced dysmetria.213
When targets are slightly displaced from
the midline, and the task is to look from
far to near, some subjects can make asym-
metric, smooth adducting movements,
with the dynamic properties of slow ver-
gence. This brings both eyes to the target
without requiring a saccade to change the
conjugate position of the eyes.44 This type
of response is akin to the asymmetric
movements of the eyes recorded during
pursuit of targets moving toward and
away from the subject on an axis aligned
with one eye.114 Both of these responses
question the validity of an important
corollary of Hering's Law of equal inner-
vation. Hering's Law itself states that the
yoking of the eyes arises because both eyes
get their innervation from a single conju-
gate command. The corollary is that seem-
ingly independent movements of the eyes
are produced by summation of a pure ver-
gence (disjunctive) command and a pure
versional (conjugate) command. In con-
trast to convergence, when a pure diver-
gence is called for it is usually accompa-
nied by a saccade that initially brings one
eye (usually the dominant one) closer to
the target.24'42'44'238a>253 Such a strategy
would allow rapid identification (albeit
Vergence Eye Movements 293
primarily based on information from one
eye) of an object suddenly appearing in
the visual field beyond a near point of
regard.
Saccade-Vcrgcnce Interactions
Vergence eye movements have been con-
ventionally taught as being slow, taking as
long as a second for completion.184'188 This
is the case when vergence movements are
tested in a laboratory setting, such as by
presenting isolated disparity stimuli un-
der dichoptic viewing conditions (each eye
sees a different image). Vergence move-
ments seem much faster when tested un-
der more natural conditions, using real
targets or having the subject move toward
a stationary target.49
Perhaps the most important circum-
stance in which the velocity of the ver-
gence change is increased is when the tar-
get of interest changes its position across
the visual field as well as in depth. A com-
bined version and horizontal vergence
movement is required, and the vergence
component is several times faster when
conjoined with a horizontal or even a ver-
tical saccade (Fig. 8-2).39'238a In other
words, much more of a change in align-
ment is accomplished when saccades and
vergence are combined than when ver-
gence is made alone.48 The degree to
which the change in alignment appears to
be incorporated into the saccade depends
on the distance of the target239 and the size
of the change in alignment; smaller dis-
parities can be overcome entirely during
the saccade.15 Also important is whether
the change in gaze is self-generated to
fixed targets, in which case the conjugate
and disconjugate components of the change
in alignment usually begin synchronously,
or if the change in gaze is in response to
an externally presented target, in which
case some of the change in alignment
usually precedes the onset of the saccade
as a slow vergence movement. Curiously,
accommodation, like vergence, is also
speeded up when it occurs in association
with saccades.208
The mechanism for facilitation of ver-
gence by saccades and blinks is not settled.
294 The Properties and Neural Substrate of Eye Movements

Figure 8-2. Vergence changes with or without an accompanying saccade, shown using binocular search coil re-
cordings in a rhesus monkey. LE, left eye; RE, right eye; VERG, vergence change. Vergence traces (obtained by
subtracting the right and left eye position signals) are offset for clarity. Convergence is negative. Note the in-
crease in vergence speed when a saccade is conjoined with vergence. The facilitation is greater for divergence,
probably because of the inherent divergence associated with horizontal saccades.

One hypothesis suggests that the same
pontine neurons (pause cells) that gate ac-
tivity of saccadic burst neurons also gate
vergence activity.253 During the time that
pause-cell inhibition is lifted, not only can
saccades occur but vergence would also be
facilitated (Fig. 8-3). There is electrophys-
iological support for this hypothesis; stim-
Figure 8-3. Model of saccade-vergence interaction.
Omnidirectional pause neurons (OPN) partially in-
hibit the activity of vergence velocity neurons (VVN)
so that during a saccade, when OPN inhibition is
completely removed, the gain of VVN increases from
1.0 to k + 1.0. This facilitates the vergence-driven
change of alignment that occurs during the saccade.
SEN, saccade burst neurons; CME, conjugate motor
error; VME, vergence motor error; VVC, vergence
velocity command; CVC, conjugate velocity co
mand; RE, right eye; LE, left eye. (From Zee DS,
FitzGibbon EJ, Optican LM. Saccade-vergence inter-
actions in humans. Journal of Neurophysiology
1992;68:1624-41, with permision.)
ulation of pause neurons slows ongoing
vergence.138 Pause cells also cease dis-
charging during blinks, and this too would
account for facilitation of vergence by
blinks.173'177 Other hypotheses to explain
saccade-vergence interaction, which are
not necessarily mutually exclusive, include
programing of saccades of different sizes
in each eye15'25-42-239 and nonlinear interac-
tions between version and vergence at the
level of the ocular motoneurons or in the
eye muscles themselves.109 Indeed, neuro-
physiological evidence suggests that at the
level of premotor commands (for exam-
ple, in saccade burst neurons) there is a
higher degree of separation of activity into
right eye-related and left eye-related neu-
rons than previously thought.259'260
Other findings that must be considered
in interpreting saccade-vergence interac-
tion include the transient change in ver-
gence (usually divergence in adults)
that occurs even when saccades are made
between targets on an isovergence ar-
ray (calling for no change in ver-
gence).23'104'133'238a'253 In contrast, children
younger than 10 years of age usually show
a transient convergence during saccades.52
It has been suggested that these changes

in alignment during and immediately af-
ter saccades in normal subjects are a
byproduct of inherent asymmetries in the
mechanical characteristics of the ocular
plant (muscles and orbital tissues) and of
the adaptive processes that attempt to
compensate for them. 52 Finally, saccades
not only influence vergence but vergence
influences saccades. Saccades associated
with vergence are slower than saccades
made without vergence, except in the eye
that is abducting and diverging.24'25'238a
Whether the images seen by the two
eyes are processed in the same or different
cerebral hemispheres also influences how
saccades and vergence are combined.51
When the images of the targets seen by the
left eye and the right eye are in the same
hemifield and processed by the same
hemisphere, the resulting averaging sac-
cade is made to a position nearly between
the two targets (global effect). When the
images are in opposite hemifields and
processed by opposite hemispheres, how-
ever, the saccade is directed to just one of
the targets. Saccade latencies are also in-
fluenced by hemispheric localization. If in
the same hemisphere, saccade latency in-
creases by about 2.5 msec per degree of
disparity, with a baseline of 215 msec. If in
opposite hemispheres, there is a different
relationship. Latency is about 260 msec,
with no dependence on disparity. Because
of the relatively small distance between
the pupils, most naturally occurring sac-
cades will be to targets seen by the same
hemisphere. Hence it has been argued
that the global averaging effect on sac-
cades, when they are combined with ver-
gence, would allow for a symmetric
vergence movement to complete any nec-
essary change in alignment when the cy-
clopean (average between the two eyes)
saccade was completed.51
Because the eyes are horizontally sepa-
rated, they must also rotate by different
amounts when making vertical saccades
between near targets that are separated
vertically and off to one side (i.e., closer to
one eye than the other). Even saccades
made in darkness to the remembered lo-
cations of vertically displaced targets are
disconjugate to nearly the same degree as
if the visual targets were actually pres-
Vergence Eye Movements 295
ent.251 When vertical disparities are in-
duced artificially with a prism or dichoptic
display, the vertical saccades become more
disconjugate when the stimuli appear to
be close.239'251 When a subject is asked to
wear a vertically oriented prism in front of
just one part of the visual field of one eye
(for example, the lower field) for a day,
there is an adaptive change in the vertical
yoking of the eyes such that the degree of
disconjugacy is appropriate to the visual
demands created by the prism.251 These
findings suggest that the brain develops a
three-dimensional map (horizontal, verti-
cal, depth) for vertical saccade yoking.
This map is used to preprogram automati-
cally the relative excursions of the eyes
during vertical saccades according to the
point of regard before and after the
change in gaze. Other factors related to
the relative pulling directions of the verti-
cal muscles in the orbit may also con-
tribute to this automatic disconjugacy,36'43
but central mechanisms, which are subject
to adaptive modification, are clearly im-
portant.251 A facilitation of vertical ver-
gence by horizontal saccades does not con-
sistently occur in normal subjects,251 but it
has been shown in a patient with the syn-
drome 222of dissociated vertical deviation
(DVD).
NEURAL SUBSTRATE OF
VERGENCE MOVEMENTS
Anatomic Substrate for Vergence
Studies of the oculomotor nucleus have
shown that medial rectus motoneurons do
not lie in one discrete location; the cells
are distinctly segregated into different
groups. Three distinct aggregates of me-
dial rectus motoneurons have been iden-
tified: subgroup A, located ventral and
rostral; subgroup B, located dorsal and
caudal; and subgroup C, located dorsome-
dial and rostral (see Fig. 9-9B, Chap. 9).
Subgroup C consists of the smallest cell
bodies and can be labeled independently
of the other subgroups by selective injec-
tions of radioactive tracer into the outer
(orbital) layer of the medial rectus muscle.
296 The Properties and Neural Substrate of Eye Movements

Because the outer layer of the ocular mus-
cles contains smaller muscle fibers, which
are more likely to be involved in generat-
ing slower eye movements, it is tempting
to speculate that the neurons in subgroup
C have a selective function, perhaps in
vergence.16 Nevertheless, there is as yet no
physiologic evidence to support this hy-
pothesis.
Motor Commands for Vergence
Neurophysiologic studies in monkeys
have shown that almost all oculomotoneu-
rons subserving the medial rectus and
most neurons in the abducens nucleus dis-
charge for both conjugate (version) and
disjunctive (vergence) eye movements (Fig.
8-4). 106,107,140 Ocular motoneurons show a
velocity-position (phasic-tonic) change in
discharge rate during vergence, as is the
case for conjugate movements.60 Even
though most of the motoneurons subserv-
ing the lateral and medial recti carry both
version and vergence signals, the sensitiv-
ity of individual neurons to changes in eye
position varies according to whether the
eye position is reached by a version or a
vergence movement. In other words,
there is evidence that different neurons
play relatively smaller or larger roles
in conjugate versus vergence eye move-
ments.
Premotor Commands for Vergence
Neurons involved specifically in the con-
trol of vergence139 and presumably pro-
jecting to ocular motoneurons 257 have
been found in the mesencephalic reticular
formation, 1 to 2 mm dorsal and dorsolat-
eral to the oculomotor nucleus.99'137-141
Three main types of neurons can be
found: those that discharge in relation to
vergence angle (vergence tonic cells), to
vergence velocity (vergence burst cells),
and to both vergence angle and velocity
(vergence burst-tonic cells). Many of these
neurons also discharge with accommo-
dation, although when vergence and ac-
commodation are experimentally dissoci-
ated and pitted against each other, some
remain predominantly related to ver-
gence.99^

Figure 8-4. Neural activity of a medial rectus motoneuron during convergence and during a rightward sac-
cade. During convergence (A), the neuron discharges in relation to both the eye velocity (HLV, horizontal left
eye velocity) and the vergence angle (VA). Likewise, during saccades (B) the discharge frequency is propor-
tional to both eye velocity and (conjugate) eye position. HR, horizontal position of right eye; HL, horizontal po-
sition of left eye. (Courtesy of L.E. Mays and based upon Gamlin, PDR, and Mays LE. Dynamic properties of
medial rectus motoneurons during vergence eye movements, J Neurophysiol 1992;67:64-74, reproduced with
permission.)
 Vergence Eye Movements 297

Most vergence tonic cells increase their
discharge directly in relation to the angle
of convergence; they change their firing
rate 10 to 30 msec before any detectable
eye movements. A second, smaller group
of cells increases the rate of discharge with
divergence. The activity of both of these
types of cells is unaffected by the direction
of conjugate gaze.
Before and during vergence, vergence
burst cells exhibit a burst of activity that is
linearly related to the velocity of the ver-
gence movement (Fig. 8-5).141 For most of
these cells, the number of spikes within
each burst (i.e., the integral of the rate of
discharge) is correlated with the ampli-
tude of the movement. These vergence
burst neurons are analogous to the sac-
cadic burst neurons that discharge in rela-
tion to saccade velocity. There are both
convergence and divergence burst neu-
rons, with convergence neurons being
more abundant.
Vergence burst-tonic cells combine ver-
gence position and vergence velocity in-
formation in their output: the burst is re-
lated to vergence velocity and the tonic
firing rate to vergence angle. Most of these
cells are located next to the dorsolateral
portion of the oculomotor nucleus.
The role of abducens internuclear neu-
rons (see Display 6-1 and Fig. 6-1, Chap.
6) and oculomotor internuclear neurons
in generating the vergence command is
not well understood. Each of these in-
terneurons has projections to the other
nucleus, presumably via the medial longi-
tudinal fasciculus (MLF). Clinically, lesions

Figure 8-5. Vergence burst neuron. The neuron only discharges (bursts) during convergence (A), and its fre-
quency of discharge (bottom trace) can be correlated with vergence velocity. (B) Divergence; (C) rightward sac-
cade; (D) leftward saccade. VL, vertical position of left eye; HR, horizontal position of right eye; HL, horizontal
position of left eye; VA, vergence angle. (From Mays LE, Porter JD, Gamlin PDR, Tello C. Neural control of ver-
gence eye movements: neurons encoding vergence velocity. J Neurophysiol 1986;56:1007-21, with permis-
sion.)
298 The Properties and Neural Substrate of Eye Movements
in the MLF (internuclear ophthalmople-
gia [INO]; see Display 10-22, Chap. 10)
do not impair the ability to make vergence
movements. The MLF, however, carries
activity related to vergence.58 Further-
more, monkeys with an acute lidocaine-in-
duced internuclear ophthalmoplegia show
an increased AC/A ratio, implying that
the MLF carries signals that inhibit ver-
gence.19'59 The source of additional ver-
gence inputs to the abducens nucleus is
not certain, but there are cells close by in
the pons that discharge with vergence in a
way similar to that of the midbrain premo-
tor vergence neurons.64 Commands to the
abducens nuclei for changes in vergence
may also be mediated in association with
conjugate signals. Theoretical considera-
tions, with some experimental support,
suggest that vergence signals must be car-
ried on neurons that also provide premo-
tor conjugate commands, such as neurons
in the vestibular nuclei or nucleus preposi-
tus hypoglossi.30'144
Cerebellar Control of Vergence
Historically, two observations have impli-
cated the cerebellum in the control of ver-
gence. Holmes81 described a weakness of
convergence in patients with acute cere-
bellar lesions. Westheimer and Blair247
showed that acute ablation of the cerebel-
lum in the monkey leads to a transient
paralysis of vergence. Paralysis of conver-
gence, to both accommodative and dispar-
ity stimuli, has been reported in a single
patient with a lesion involving the right
cerebellum.169 Disorders of ocular align-
ment, including esodeviations (eyes turned
inward) at distance viewing, and vertical
skew deviations that sometimes alternate
on right and left horizontal gaze, have also
been reported in patients with cerebellar
lesions.156'243'252 By and large, however,
careful studies of vergence capabilities in
humans with either focal or diffuse cere-
bellar lesions are lacking.
Studies in nonhuman primates also
suggest that particular portions of the
cerebellum have a role in vergence. The
cerebellar flocculus has neurons that dis-
charge in relation to the vergence angle.151
Whether these cells relate to vestibular
function (e.g., adjusting the gain of the
VOR as a function of target distance)151'225
or to some other aspect of vergence
(e.g., vergence gaze holding, ocular align-
ment, or phoria adaptation) is not known.
Nevertheless, monkeys with floccular le-
sions still are able to undergo adaptive
changes in ocular alignment and the AC/A
ratio.97
The posterior interposed nucleus, cor-
responding to the globose and embo-
liform nuclei in humans, and the posterior
portion of the fastigial nucleus (FOR or
fastigial oculomotor region) have cells that
discharge in relation to vergence (and ac-
commodation).255'256 Those in the poste-
rior interposed nucleus appear to be re-
lated to a far response (divergence), and
those in the FOR to a near response (con-
vergence). Inactivation of the FOR inter-
feres with convergence.63 The FOR and
posterior interposed nucleus have recip-
rocal anatomic connections with the mid-
brain areas containing neurons that con-
vey premotor vergence commands to the
oculomotor nuclei.136 The projection from
the deep nuclei is predominantly con-
tralateral, whereas the projection to them
is predominantly ipsilateral. Some neu-
rons within the medial portion of the nu-
cleus reticularis tegmenti pontis (NRTP)
discharge in relation to either conver-
gence (near response) or divergence (far
response); stimulation in this region can
produce convergence or divergence.57 In-
activation here leads to impaired holding
of angles of convergence.61 These ver-
gence-related cells lie close to other neu-
rons in the NRTP that discharge with sac-
cades (see NRTP in Chap. 3). Electrical
stimulation sometimes produces saccades
combined with vergence. Hence, some as-
pects of saccade-vergence interactions
may be mediated by this area. The NRTP
projects to the oculomotor vermis of the
cerebellum (lobules VI and VII), the in-
terposed and fastigial nuclei, and the cere-
bellar flocculus, and hence could be a
source of vergence (and disparity) infor-
mation to the cerebellum. The NRTP re-
ceives projections from many structures,
including the frontal lobes; this may be
one source of premotor vergence com-

mands to the NRTP and cerebellum (see
next section).62 The cerebellar cortex
overlying the FOR and posterior inter-
posed nucleus may also play a role in ver-
gence. As expected, lesions in the oculo-
motor vermis produce the reciprocal of
those in the FOR. Monkeys develop an
esodeviation after vermal ablations.229
Positron emission tomography (PET) shows
an increase in activity in the cerebellar
vermis in humans performing a binocular-
ity discrimination task.72 The effects of
cerebellar lesions on vergence responses
in humans have not been quantified (see
also Phoria Adaptation, below).
Cerebral Control of Vergence
Information about the role of cortical
structures in vergence is relatively sparse.
In alert cats, stimulation in area LS (lateral
suprasylvian), an extrastriate area roughly
comparable to areas MT (middle tempo-
ral) and MST (medial superior temporal)
in the monkey (see Display 6-14 and Fig.
6-8, Chap. 6), produces various compo-
nents of the near response.7'232 Single-unit
recordings in this region have revealed
some neurons that discharge with ver-
gence; lesions here interfere with ver-
gence eye movements. 228
Some neurons in area LIP (see Display
6-17) on the lateral bank of the intrapari-
etal sulcus discharge not only in relation to
saccades but also when the saccade is com-
bined with a vergence movement to take
the eyes to a particular depth plane.65 In
the frontal lobes (area 8), there is a region
in the prearcuate cortex, just in front of
the saccade-related area in the anterior
bank of the arcuate sulcus, in which neu-
rons discharge with the near or far re-
sponse and also with the tonic angle of
vergence.62 These neurons may be one
source of vergence premotor commands
to the brain stem and cerebellum.
Finally, one wonders if the organization
of the cerebral control of vergence is com-
parable to that for saccades (see Higher-
Level Control of the Saccadic Pulse Gen-
erator, Chap. 3), with more reflexive,
stimulus-bound movements being gener-
ated by the posterior hemispheres and
Vergence Eye Movements 299
more volitional, self-initiated movements
by the frontal lobes.62
Visual Physiology of Disparity-
Induced Vergence
What is known about the sensory stimuli
that drive vergence eye movements? In a
number of areas of the visual cortex of the
monkey, cells have been identified that are
sensitive to binocular stimulation.179 Some
of these neurons show a binocular re-
sponse over a narrow depth range about
the fixation point (called tuned-zero neurons
or near-zero neurons). These cells may be in-
volved in fine stereopsis. They may also
play a role in the generation of the ultra-
short-latency (60-85 msec) vergence re-
sponses to small disparities in a large field
of view.14'150 Such movements could help
stabilize the visual scene during self-
motion. Other cells (called tuned-far and
near cells) respond to binocular stimuli that
are nearer or farther than the fixation
point. These cells may participate in
coarse stereopsis. They may provide sen-
sory input for fusional vergence move-
ments to large disparities associated with
voluntary changes in the depth plane of
focus. The activity of some disparity-
sensitive cells in the primary visual cortex
(VI) changes as a function of target dis-
tance (and vergence angle), even though
the disparity stimulus on the retina is the
same.233 These cells could be calculating
the distance of an object from the ob-
server.182 Extraretinal signals, either pro-
prioceptive or corollary discharge based
on monitoring of internal commands,
help to shape the activity of these neurons,
allowing them to signal the actual depth of
the target. In spite of extensive psy-
chophysical and neurophysiological inves-
tigations and theorizing, however, there is
still no consensus on the physiological un-
derpinnings of stereopsis and depth per-
ception.171'179'183'246
Other areas in monkey cerebral cortex
also have neurons that discharge in rela-
tion to disparity. They include the MT
(middle temporal) and MST (medial supe-
rior temporal) areas in the superior tern-
300 The Properties and Neural Substrate of Eye Movements
poral sulcus.35a>132'196 In area MST, the
cells seem more likely to participate in
coarse stereopsis and may function in sig-
naling self motion and/or initiation of ver-
gence. In another region in the caudal
part of the lateral bank and fundus of the
intraparietal cortex, there are neurons
that discharge in relationship to the three-
dimensional orientation of objects221 or
to objects moving toward an animal.21
Whether neural activity in these various
cortical areas is used to trigger activity in
the premotor staging areas for vergence
commands (and if so, exactly how) is un-
known. As discussed above, however, le-
sions in homologous regions in the cat
lead to abnormalities of vergence. An
attractive hypothesis is that area MST,
shown to be so important for generating
pursuit movement, also commands track-
ing eye movements in three dimensions.
In this way it could drive both pursuit
and vergence premotoneurons within the
brain stem and cerebellum and thus en-
sure that images of targets moving across
the visual field and in depth are kept sta-
ble on the fovea.
The widely distributed nature of process-
ing of information about three-dimensional
space is reflected in PET studies of hu-
mans performing a binocular disparity
discrimination. There are increases in
blood flow in the polar striate and neigh-
boring peristriate cortex, the parietal lobe,
the dorsal lateral and mesial prefrontal
cortex, and the cerebellar vermis.72 Im-
pairment of stereopsis (tested with ran-
dom-dot stereograms) can be induced by
repetitive magnetic stimulation of occipi-
tal cortex in humans. 230
Westheimer and Mitchell248 studied ver-
gence movements in a split-brain patient
who had undergone section of the corpus
callosum and anterior commissure. A
near-target light located on either side of
the sagittal plane induced vergence eye
movements, but a near target located ex-
actly in the midsagittal plane did not. In
this latter circumstance, images lay on the
temporal retina of each eye, and therefore
did not gain access to the same cerebral
hemisphere. This evidence suggests that
fusional vergence movements require that
visual information from each eye reach
the same hemisphere.
CONCEPTUAL MODELS OF
SUPRANUCLEAR CONTROL
OF VERGENCE
The organization of vergence premo-
toneurons has many parallels with that of
the saccadic system. Thus it will be useful
to compare the functional roles of these
various types of neurons in the generation
of saccadic and vergence movements.
Likewise, smooth tracking of targets mov-
ing slowly in depth is in some ways compa-
rable to smooth pursuit of targets moving
across the visual field. Accordingly, we
will use a conceptual framework for the
supranuclear control of vergence analo-
gous to current ideas about the control
of saccades and pursuit. Although this
scheme is speculative, we believe it useful
for understanding vergence.
Vergence Integrator
Both the saccadic system and the vergence
system must provide the appropriate posi-
tion-coded information to hold the eyes
steady at the end of each movement. This
involves maintaining the eyes in a particu-
lar orbital position after saccades and at a
particular vergence angle after vergence.
Because the eyes are held in position rea-
sonably well even in darkness, immediate
visual feedback cannot account for the
perseveration of tonic activity in the dark.
One way to obtain the necessary position
information is to integrate (in the mathe-
matical sense) the prior velocity command
that brought the eyes to their present po-
sition. Models for generating conjugate
eye movements incorporate such a velocity
to-position integrator (see The Need for a
Neural Integrator of Ocular Motor Sig-
nals, Chap. 5). Models of the vergence sys-
tem have also incorporated an integrator
to explain vergence input-output rela-
tionships.118 This vergence position inte-
grator is presumably distinct from the

conjugate position integrator, although hy-
pothetical constructs suggest some com-
monality.30'144 It has yet to be established
experimentally, however, that the premo-
toneurons that carry eye position signals
during conjugate movements also carry
eye position signals during pure vergence.
Commands for Saccadic
Vergence Movements
The source of input to the vergence inte-
grator may be the output of vergence
burst cells.141 The vergence tonic cells may
then carry the output of the vergence
integrator. The vergence burst-tonic cells
seem to combine both vergence velocity
and vergence position information. A par-
simonious interpretation of these observa-
tions is that the vergence system uses a
direct (velocity) pathway from vergence
burst neurons, in parallel with a vergence
integrator (position) pathway; the com-
bined signal may be the input to the ocu-
lar motoneurons. The finding that ocular
motoneurons discharge not only in rela-
tion to the angle of vergence but also to
the velocity of vergence is consistent with
this idea.60
Finally, one may ask what determines
the moment when vergence burst neurons
cease discharging. A scheme analogous to
that for saccades (see Fig. 3-7, Chap. 3)
using internal signals proportional to de-
sired vergence position, actual vergence
position (based on efference copy), and
vergence motor error has been proposed.254
Vergence motor error would serve as the
necessary error signal to drive the ver-
gence burst neurons to provide the appro-
priate vergence velocity command for the
correct duration. A similar scheme has
been used to account for the interaction
between saccades and vergence during
combined shifts of gaze that move the
point of regard both across the visual field
and in depth.253 It is not settled whether a
desired vergence position or a desired
change in vergence position (analogous to
the change in eye position signals that dri-
ves saccades) is the critical input signal to
the premotor vergence generator.121
Vergence Eye Movements 301
When both saccades and vergence are
commanded together, the relationship
between their latencies of initiation and
target selection suggests common signal
processing, probably in the cerebral hemi-
spheres, at an early stage of saccade and
vergence initiation.18^227 Downstream, how-
ever, their trigger signals must diverge,
since each can be influenced separately by
the conditions of fixation (see, for exam-
ple, the gap effect discussed above).
Commands for Pursuit
Vergence Movements
One can also propose a scheme, analogous
to models of smooth pursuit (see Chap. 4),
for pursuit vergence tracking of slower,
smoothly moving stimuli. In this case,
a desired vergence velocity would be re-
created and used to generate a vergence
velocity error signal and, in turn, a ver-
gence acceleration command. Thus, we
speculate that there may be separate ver-
gence premotor networks for generating
saccadic and pursuit vergence. One can
envision that both systems work in con-
cert, just as they do for pursuit and sac-
cades in the conjugate system. One move-
ment brings images to the fovea, and the
other attempts to keep them there. In fact,
such a combination of saccadic and pur-
suit vergence has been reported when
the velocity of the disparity change is
high.215
One implication of this scheme for ver-
gence is that it may be possible to classify
vergence disorders in a way similar to that
for disorders of saccades, pursuit, and
conjugate gaze-holding. For example,
holding of positions of convergence may
be impaired, perhaps with consequent di-
vergent drift. This would be analogous to
the impaired holding of eccentric posi-
tions of conjugate gaze after saccades, with
consequent centripetal drift. Instability of
the conjugate integrator leads to slow
phases with an increasing velocity wave-
form. Similarly, the vergence integrator
might become unstable, leading to exces-
sive convergence and convergence spasm
(see Abnormalities of Vergence, below).
302 The Properties and Neural Substrate of Eye Movements
ADAPTIVE MECHANISMS TO
MAINTAIN OCULAR ALIGNMENT
As has been emphasized in previous chap-
ters dealing with the conjugate eye move-
ment systems, a robust and versatile adap-
tive capability is essential if an organism is
to maintain optimal visuomotor function
throughout its life. Most research has fo-
cused on conjugate adaptive mechanisms,
especially those of the saccade and ves-
tibular systems. Usually, however, muscle
weakness is unilateral and asymmetric, so
that many of the needed adaptive correc-
tions are disconjugate and may have to
vary with the position of the eye in the or-
bit. Such a capability implies that Hering's
Law of equal innervation is not im-
mutable, although the exact mechanisms
by which this adaptation takes place are
unknown.
Phoria Adaptation
Phoria is the relative deviation of the visual
axes when a single target is viewed with
one eye. If a disparity is introduced by
placing a wedge prism in front of one eye,
the subject's phoria changes by an amount
equal to the strength of the prism. Tropia,
the relative deviation of the visual axes
when the target is viewed binocularly, does
not occur if the new disparity is within the
range in which fusional mechanisms can
cope, but the residual fixation disparity, or
steady-state vergence error during binoc-
ular viewing, is increased. In seconds to
minutes, however, the subject undergoes
phoria or prism adaptation, so both the
phoria and the fixation disparity (mea-
sured with the prism on) revert to their
preprism values. Thus, there has been a
resetting of the alignment of the two visual
axes by an amount equivalent to the pris-
matic demand. 17,28,122,149,167,168,200,202,217
It has been suggested that the reduction
in fixation disparity after prolonged wear-
ing of a prism is accomplished by a slow
fusional adaptive mechanism.168'200'202 The
output of the slow fusional mechanism re-
sets the level of tonic vergence so as to re-
duce fixation disparity. This relieves the
stress from the increased disparity de-
mands of the prism on the fast fusional
mechanism (or what we commonly think
of as disparity-induced vergence).
There are important practical implica-
tions of such a phoria adaptation mecha-
nism.28 Short-term phoria adaptation
influences measures of the range of diver-
gence and convergence as tested with base-
in or base-out prisms; this influence varies
with viewing distance.167'194 Conversely, to
fully appreciate the baseline phoria in a
symptomatic patient, one must eliminate
binocular cues for hours to days, allowing
phoria adaptation to dissipate.82'161 Normal
subjects also commonly show a change in
phoria after prolonged monocular occlu-
sion, often in the pattern of an oblique mus-
cle imbalance.128'160 Rarely, a symptomatic
tropia may emerge after prolonged occlu-
sion, requiring treatment with prisms or
even surgery.13 A robust phoria adaptation
mechanism might act to limit the efficacy of
prismatic therapy for ocular motor imbal-
ance. These patients "eat up the prism," as
their phoria adaptation overcomes the ef-
fect of the prism and defeats its purpose.
Elderly individuals show decreased phoria
adaptation, but this has the advantage that
they often accept a prismatic correction
more readily than younger patients.250
An adaptive mechanism has also been
demonstrated for accommodation. By open-
ing the visual feedback loop, one can mea-
sure the tonic level of accommodation
(i.e., the accommodative phoria). Using
appropriate lenses, one can demonstrate
that the tonic level of accommodation can
be adaptively readjusted, independent of
a change in disparity.146'165'193
Using these findings, models for phoria
adaptation that incorporate both accom-
modation and vergence have been devel-
oped (Fig. 8-6).91'202 The fast fusional sys-
tem uses retinal image disparity, and the
slow fusional adaptive system uses the mo-
tor output of the fast fusional system as its
error signal. The fast fusional vergence
system appears to use a slightly imperfect,
leaky integrator with a time constant of 10
to 15 sec. This is the vergence position in-
tegrator previously described. The slow
fusional adaptive system also uses a leaky
integrator but with a much longer time
 Vergence Eye Movements 303

Figure 8-6. Model of vergence-accommodation interaction. Note the cross-links producing accommodation-
linked convergence (AC/A) and convergence-linked accommodation (CA/C). The fast system provides the im-
mediate (hundreds of milliseconds), phasic response to a change in disparity (angle) or blur (diopters). The
tonic adaptation (slow) system uses the motor output of the fast system to provide a slower (seconds) adjustment
in tonic level of accommodation or vergence. (Adapted from Schor CM. Influence of accommodative and ver-
gence adaptation on binocular motor disorders. Optometry andVision Science 1988;65:464-475, with permis-
sion of Lippincott, Williams and Wilkins.)

constant (minutes or more). In fact, there
are probably multiple mechanisms that
subserve phoria adaptation, with different
capabilities, degrees of permanency, and
time courses of action. In time, the slow
fusional mechanism takes over much of
the load of keeping the eyes aligned, by
resetting the level of tonic vergence. Thus,
phoria adaptation resets the resting posi-
tion of the eyes toward the original phoria
and thereby restores the dynamic range
(or fusional reserve) in which fast fusional
vergence can function. Similar considera-
tions apply to the accommodation system.
The fast accommodative system uses reti-
nal blur and the slow accommodative sys-
tem adjusts tonic accommodation using
the output of the fast system as its error
signal. One unresolved issue is the stage of
central processing at which voluntary ver-
gence and accommodation interject their
influences on phoria adaptation.37'146
One may ask if the AC/A or CA/C ratios
are genetically fixed or if they can be mod-
ified by environmental factors. If subjects
wear periscopic spectacles to simulate an
increase in the interocular separation,
both the AC/A and the CA/C ratios
may change.10'53'100-152 Such a mechanism
would be necessary, for example, to opti-
mize visual function as the interpupillary
distance increased during growth or to as-
sure an accurate response when accom-
modation or vergence fatigues.149 Some
disorders of binocular ocular motor func-
tion (e.g., vergence excess or vergence in-
sufficiency) may have their basis in alter-
ations in the strength of the cross-linkages
between accommodation and convergence
and/or in the sensitivity of the slow adap-
tive mechanisms for vergence and accom-
modation (see Abnormalities of Vergence).
The anatomic substrate underlying pho-
ria adaptation is not known. Physiological
recordings indicate that some but not all of
the phoria adaptation signal is carried by
midbrain vergence-related neurons.155 Pa-
tients with cerebellar lesions occasionally
show a decrease in phoria adaptation,148
but in most cases it is normal.73 Monkeys
with floccular lesions can still undergo
phoria adaptation.97 The deep cerebellar
nuclei may be the critical cerebellar struc-
ture influencing phoria adaptation.
304 The Properties and Neural Substrate of Eye Movements
Disconjugate Adaptation
A special case of phoria adaptation is illus-
trated by the response to wearing an ani-
sometropic spectacle correction.77'217 Ani-
sometropia is a difference in the anterior-
posterior dimensions of the two eyes and
requires a corrective lens of a different
power for each eye. Corrective spectacle
lenses have a prismatic effect that results
in the relative displacement of an image of
an object from its actual position. This is
also known as the rotational magnification
effect because it changes the amount the
eye must rotate to fix upon a target lo-
cated at a given point in space. (The linear
magnification effect, on the other hand, de-
scribes the relative size of an image of
an object. Contact lenses have a linear but
not a rotational magnification effect.) The
prismatic effect of a spectacle lens is
roughly proportional to both its power
and the distance from its optical center.
This effect will increase continuously to-
ward the lens periphery. With an ani-
sometropic correction, the prismatic effect
of each spectacle lens is different. There-
fore, the retinal disparity between the im-
ages of a given object will change as a
function of gaze position. Accordingly, oc-
ular alignment must undergo disconju-
gate adaptation to produce a new pattern
of innervation, as a function of orbital po-
sition. When subjects begin wearing an
anisometropic spectacle correction, their
phoria (as measured while wearing their
spectacle correction) soon reverts to the
preadaptation state in all positions of gaze
(i.e., the resting ocular alignment appro-
priately varies as a function of orbital po-
sition).77 This is the way to assure con-
comitancy while wearing glasses; ocular
alignment becomes correct in all or-
bital positions. However, to achieve fusion
promptly upon changing gaze, a subject
wearing an anisometropic spectacle cor-
rection must also be able to change the
alignment of the visual axes during the
saccade.
The most frequent circumstance to
which a disconjugate adaptive mecha-
nism must respond is asymmetry in the
strengths of the eye muscles themselves.
This may occur either during natural de-
velopment and aging or after trauma or
disease of the ocular motor nerves or or-
bital contents. Such asymmetries lead to a
noncomitant deviation and consequent
diplopia if the disparity-driven fusional
mechanisms cannot overcome it. It is due
to this visuomotor problem that our dis-
conjugate adaptation mechanisms evolved,
certainly not from a need to wear correc-
tive spectacles!
Disconjugate adaptation has been ex-
tensively investigated using a number
of techniques and covering time frames
of adaptation ranging from minutes to
days.26 These paradigms include having
anisometropic subjects wear newly fit-
ted corrective spectacles47'125'175 or having
emmetropic subjects wear optical devices
that simulate a spectacle-corrected ani-
sometropia, such as a contact lens-spectacle
combination77'254 or an afocal magni-
fier.124'206 Other techniques used to elicit
disconjugate adaptation include wearing
displacing prisms in front of one eye in
just one part of the visual field,5'174'251'254
presenting different-sized images (ani-
seikonia) of a target to each eye,102-103'239
and dissociating the images seen by each
eye at the end of a saccade.2'38'103'206
In experimental animals, surgically or
botulinum-induced asymmetrical muscle
weakness elicits disconjugate adapta-
tion.94'244 Human patients with strabismus
have also been a model group for studying
disconjugate adaptation.i2,93,ioo a ,ioi,i27a
What have we learned from these many
experiments? First, clinical experience in-
dicates that the degree to which the inner-
vation to the two eyes can be selectively
adjusted to overcome a noncomitant devi-
ation is limited. If the relative degree of
weakness is large, disconjugate mecha-
nisms may be overwhelmed. Another fac-
tor may the degree of ocular dominance.
Patients who strongly prefer to fix with
one eye (even with both eyes viewing) may
undergo no adaptation at all if the pre-
ferred eye is the strong one. If the pre-
ferred eye is the weak one, they may un-
dergo conjugate adaptation, which increases
the innervation to both eyes.
Second, in some individuals, especially
some patients with a long-standing re-
quirement for a disconjugate correction,

disconjugate adaptation can be remark-
ably robust. As an example, consider the
recordings shown from a subject who had
been wearing spectacles to correct a large
degree of anisometropia (Fig. 8-7). It is
important to note that the intrasaccadic
and postsaccadic changes in alignment oc-
curred under both binocular and monoc-
ular viewing conditions. In other words,
the subject learned to preprogram in-
trasaccadic and postsaccadic disconjugate
movements independent of any immedi-
ate disparity cues.
Third, and even more remarkable, is
the finding that subjects may have more
than one motor program of disconjugate
innervation, which can be gated in and
out on the basis of context.175 Both the
phoria and the yoking of the eyes can be
trained to specific combinations of eye po-
sitions, both across the visual field and in
depth.18'209'210-251 Even the angle of head
Figure 8-7. Search coil recordings showing dis-
conjugate adaptation to spectacle-corrected ani-
sometropia.175 The subject habitually wore a specta-
cle correction of about -10 diopters (myopic
correction) in front of the left eye and -0.5 diopters
in front of the right eye. (This correction calls for di-
vergence on right gaze and convergence on left
gaze.) For this recording only the right eye was view-
ing the target (i.e., there were no disparity cues).
Note the change in vergence during the saccade and
the corresponding change in phoria at the end of the
saccade. RE, right eye position; LE, left eye position;
VERG, vergence angle; obtained by subtracting the
right and left eye position traces.
Vergence Eye Movements 305
tilt can be a contextual clue for gating in
different adaptive changes in phoria.134'135
The degree of context specificity does
have some limits. If two different eye posi-
tions used as contextual cues are too close
to each other, adaptation at each will inter-
fere with adaptation at the other.174'206
These types of interactions can be success-
fully simulated using neural network
models.142'143 Disconjugate adaptation also
can be made selective to one type of conju-
gate eye movement (e.g., pursuit) and not
to another (e.g., saccades).204 Disconjugate
pursuit adaptation and phoria adaptation
can be trained together, leaving saccade
conjugacy unchanged.205 This last finding
suggests that the velocity (pulse) and posi-
tion (step) components of conjugate in-
nervation to each eye may be differentially
adapted.
The exact mechanisms underlying
both the static and dynamic changes in
ocular alignment that occur with dis-
conjugate adaptation are not presently
known.5'3*'102'124'125'174'175'205'239 Presumably,
the retinal disparity that occurs at the end
of conjugate eye movements, or per-
haps the disparity-driven vergence effort
to overcome it, is the necessary error sig-
nal used to readjust the relative innerva-
tion to the eyes during and after eye
movements. Afferent cues from orbital
proprioceptors may also be important. 127
Patients with microstrabismus and lack of
bifoveal fixation can still undergo discon-
jugate adaptation, but only if some degree
of binocular function is present.12'101 The
beneficial effect of corrective surgery in
childhood strabismus is aided by disconju-
gate adaptive mechanisms that may come
into play once some binocular function is
restored.93
With respect to the motor learning it-
self, there could be an adjustment of the
innervation to the two eyes independently,
or it could perhaps reflect a modification
of the normal interaction between saccade
and vergence eye movements.5 Recall
that even under normal circumstances,
changes in ocular alignment are facilitated
when vergence movements are combined
with an ongoing saccade (see Fig. 8-2).
Whatever the precise mechanisms, such a
disconjugate adaptive capability is exceed-
306 The Properties and Neural Substrate of Eye Movements
ingly important. It will make adjustments
not only for acquired abnormalities but
also for the small, inherent asymmetries in
ocular muscle strength and in other or-
bital mechanical properties that exist in all
humans.
EXAMINATION OF
VERGENCE MOVEMENTS
As with the interpretation of all ocular mo-
tor function, it is important to measure
the corrected visual acuity of each eye, for
both near and far viewing. In addition, it
is useful to measure stereopsis as a pre-
lude to evaluating vergence. Appendix A
contains a summary of the examination.
Conventionally, the examiner tests fu-
sional and accommodative vergence to-
gether by asking the patient to fix upon an
accommodative target (one that requires
bringing its image into focus) as it is slowly
brought in along the sagittal plane to the
bridge of the nose. More quantitative esti-
mates of a near point of convergence can
be made using both objective and subjec-
tive tests. Such measurements are helpful
in evaluating patients with visual fatigue
(asthenopia) or horizontal diplopia due to
convergence insufficiency. The neurolo-
gist should always keep in mind that pres-
byopia, the loss of accommodation that be-
comes symptomatic when humans reach
their early forties, is often the cause of a
number of visual complaints. These in-
clude episodic diplopia, visual fatigue, and
difficulty with reading.
Testing the vergence responses to pure
fusional or pure accommodative stimuli
usually requires use of prisms and lenses,
and in some cases, laboratory facilities.
Nevertheless, if the patient has a phoria
but not a tropia, one can infer that fu-
sional vergence mechanisms are working.
The fusional vergence system may be
tested directly by asking the patient to fix
upon a distant target. Insertion of a hori-
zontal prism before one eye will then in-
duce a fusional vergence movement, often
in combination with a saccade. By slowly
and progressively increasing the ampli-
tude of the prism (for example, using a ro-
tary prism) until diplopia occurs (the
break point of vergence), one can gain a
measure of the range of fusional ampli-
tudes for both convergence and diver-
gence. Fusional capabilities depend upon
the stimulus. For example, disparities seen
in the periphery aid fusion of central tar-
gets.96 Measures of fusional vergence am-
plitudes can only be properly interpreted
if the patient's underlying phoria is
known. The recovery point of vergence
(when fusion is restored as the prism
strength is decreased) is also an important
measure, and may be different from the
break point in patients with, for example,
intermittent deviations (see Von Noor-
den245 for a discussion of these testing
techniques).
The accommodative vergence system
may be tested using the procedure of the
Miiller experiment (the heterophoria
method). One eye is covered and the
other eye changes fixation from a far to a
near target, both of which lie along the vi-
sual axis of the viewing eye. (Alternatively
a plus or a minus lens may be placed in
front of the viewing eye to change the
depth of focus.) The vergence movement
of the covered eye is recorded or mea-
sured using prisms when the occluder is
switched to the other, uncovered eye.
This procedure is often used to measure
the AC/A (accommodative convergence/ac-
commodation) ratio. Conventionally, mea
surements of the phoria are made when
viewing a distant target and one at 33 cm.
Then, the AC/A ratio is given by the equa-
tion
AC/A =IPD +(phoria[n] -phoria[d])/d
where IPD is the interpupillary distance
(cm); phoria[n] is the phoria in prism
diopters (exodeviations are negative, es-
odeviations are positive) when viewing the
near target; phoriafd] is the phoria when
viewing the distant target, and d is the fix-
ation distance of the near target in sphere
diopters (in this case, 3.0).
The dynamic aspects of vergence eye
movements can be judged at the bedside
by asking the patient to change fixation
abruptly between near and far targets
aligned along the midsagittal plane (sac-

cadic vergence) and to follow a target mov-
ing slowly in depth (pursuit vergence).
The dynamic responses of vergence move-
ments elicited by pure disparity or pure
accommodation stimuli can be elicited
with prisms and lenses, as already de-
scribed.
Vergence movements, which are charac-
teristically slow, should be differentiated
from abnormal rapid disjunctive move-
ments, such as the quick phases of conver-
gent or divergent nystagmus. Eye move-
ment recordings can often help make the
distinction.
ABNORMALITIES
OF VERGENCE
Inborn defects of the vergence mech-
anisms are common. Abnormalities of
the accommodative-convergence synkine-
sis (high AC/A ratio) accompany some
forms of childhood strabismus (see Diag-
nosis of Concomitant Strabismus, Chap.
9).245 Common disorders of binocular
function include convergence insuffi-
ciency, convergence excess, divergence in-
sufficiency, and divergence excess.189 In
these conditions, "excess" refers to a high
AC/A ratio, and "insufficiency" refers to a
low ratio; "convergence" and "divergence"
refer to the viewing distance (near or far)
at which the largest phoria exists.
The cause of these disorders may be re-
lated to an inability to adjust correctly the
level of tonic vergence and tonic accom-
modation, as well as the values of the
cross-links between accommodation and
convergence, as reflected in the AC/A and
CA/C ratios. 166,201,207 Specifically, patients
with unusually high AC/A ratios (vergence
excess) usually have a poor ability to adap-
tively adjust their level of tonic accommo-
dation. Patients with unusually low AC/A
ratios (vergence insufficiency) usually
have a poor ability to adaptively adjust
their level of tonic vergence. High AC/A
ratios are associated with low CA/C
ratios, and vice versa. Orthoptic exer-
cises designed to restore normal vergence-
accommodation interactions might be
therapeutic.71
Vergence Eye Movements 307
The neurologist is sometimes asked to
evaluate patients with diplopia due to con-
vergence insufficiency. This is a common
disorder among teenagers and college stu-
dents (often those with an increased visual
workload and stress), the elderly, and indi-
viduals who have suffered even mild head
trauma. 120 Convergence insufficiency is
usually treated by orthoptic exercises,70
although prisms may be necessary. Occa-
sionally, acquired cerebral lesions (espe-
cially of the nondominant cerebral hemi-
sphere and probably the parietal lobe)
may lead to both impaired stereopsis and
poor fusional vergence.8'55'170'237 Anecdo-
tal reports attest to the efficacy of orthop-
tic exercises in treating disorders of fu-
sional convergence following head trauma
and cerebral ischemia.110'111
Many acquired neurologic disorders
cause disturbances of vergence often associ-
ated with abnormalities of vertical gaze. In
some of these conditions, such as Parkin-
son's disease or progressive supranuclear
palsy, vergence is impaired or absent. In
others, such as tumors of the pineal region
and infarction of the rostral midbrain and
thalamus, excessive disjunctive eye move-
ments appear as convergence-retraction
nystagmus and spasm of convergence.
Convergence and Nystagmus
Convergence-retraction nystagmus is dis-
cussed in detail in Chapter 10 (see VIDEO:
"Convergence-retraction nystagmus"). It is
primarily a disorder of saccades and occurs
as part of the dorsal midbrain syndrome.
In these patients, excessive convergence
drives may also appear during horizontal
saccades; the abducting eye moves slower
than the adducting eye. This has been
called pseudoabducens palsy,34 and it often
leads patients with pretectal lesions to com-
plain of difficulty in reading because of the
break of fusion that occurs when changing
lines. Pretectal pseudobobbing, another
disorder of saccades associated with lesions
in the midbrain, is nonrhythmic and rapid
and has combined downward and adduct-
ing movements, often preceded by a blink;
each movement is followed by a slow re-
turn toward the midline.105
308 The Properties and Neural Substrate of Eye Movements
Convergence-retraction nystagmus should
be differentiated from convergence-
induced nystagmus. Voluntary nystagmus,
a form of saccadic oscillation in normal in-
dividuals, can often be produced only in
association with convergence (see VIDEO:
"Voluntary nystagmus"; see Chap. 10). Al-
though convergence usually clamps or
stops congenital nystagmus, sometimes
the opposite occurs. Rarely, acquired con-
vergent-divergent pendular nystagmus
may be induced by convergence (for ex-
ample, in patients with multiple sclerosis).219
Lid nystagmus may be affected by conver-
gence tone. Thus, a patient with lateral
medullary infarction (Wallenberg's syn-
drome) showed synchronous lid and ocu-
lar nystagmus that was suppressed by con-
vergence.35 Pure lid nystagmus, which is
induced by convergence, has also been de-
scribed.198 Downbeat nystagmus charac-
teristically is brought out or accentuated
by convergence, but in some cases, con-
vergence lessens or changes the direc-
tion of downbeat or upbeat nystagmus
(Chap. 10).
Vergence Oscillations
Divergence nystagmus (nystagmus with
divergent quick phases) may occur in
patients with hindbrain anomalies (e.g.,
Arnold-Chiari malformation) who also
have downbeat nystagmus.6 Upbeat nys-
tagmus may also have a divergent compo-
nent (see Fig. 10-6, Chap. 10). These pa-
tients have slow phases of nystagmus that
are directed upward or downward, and
inward. Divergent nystagmus may be an
inappropriate manifestation of an otolithic
response; normal individuals may show it
during forward linear acceleration of the
head.224 In the rabbit, the projections
from the flocculus to the vestibular nuclei
inhibit only the adduction component of
the horizontal vestibulo-ocular reflex.95 A
flocculus lesion might then lead to exces-
sive adduction and divergence nystagmus.
Repetitive divergence has been re-
ported in a patient comatose because of
hepatic encephalopathy.164 The eyes slowly
diverged to extreme bilateral abduction
and then rapidly returned to the primary
position. A similar abnormality was re-
ported in a neonate in association with ab-
normalities of the electroencephalogram
that were perhaps related to seizures.162
Another type of vergence oscillation oc-
curs in association with contractions of the
masticatory muscles. This is called oculo-
masticatory myorhythmia.211 The ocular oscil-
lations (see VIDEO: "Whipple's disease")
are characterized by smooth, pendular,
convergent-divergent movements occur-
ring at a frequency of 0.8 to 1.2 Hz. This
abnormality has only been reported in pa-
tients with Whipple's disease involving the
central nervous system; it may be pathog-
nomonic for this disease. Such patients
also have a vertical saccade palsy. Somno-
lence and intellectual deterioration are as-
sociated features.
Convergence Spasm
Spasm of convergence (or spasm of the
near triad) may be a sign of an organic le-
sion or of a functional disorder. Cogan20
has described convergence spasm, elicited
by extending the neck, in a patient who had
downbeat nystagmus. Other causes of in-
creased or sustained convergence include
disease at the diencephalic-mesencephalic
junction (thalamic esotropia,67'80 occurring
with thalamic hemorrhage or pineal tu-
mors), encephalitis, Wernicke-Korsakoff
syndrome,79 occipitoatlantal instability with
vertebrobasilar ischemia,29 Chiari malfor-
mations and other posterior fossa le-
sions,33 multiple sclerosis,181 metabolic dis-
turbances,157 and phenytoin intoxication.713
Spasm of the near triad has been confused
with myasthenia gravis.190 The mechanism
underlying organic convergence spasm is
not known. One possibility is that it reflects
an instability in the neurons that create
tonic vergence premotor commands (i.e.,
the vergence integrator). Convergence
spasm must also be distinguished from sub-
stitution of vergence for versional move-
ments in patients with horizontal gaze
palsies (see Chap. 9).197
Organic causes of spasm of convergence
are rare and must be differentiated
from the more common, functional spasm
of convergence. Functional convergence

spasm consists of voluntary convergence
accompanied by pupillary constriction
and accommodation; its features are illus-
trated in the following case history.
CASE HISTORY: Functional
Convergence Spasm
A 20-year-old woman presented to the emer-
gency room complaining of headache and
diplopia. Her headache had come on suddenly
the previous evening. It had been getting
worse, and on direct questioning, she agreed
that it was the worst headache of her life.
Despite her pain, she remained alert and ori-
ented. Her vital signs were normal. In the
emergency room, she developed a "noticeable
esotropia. . . . her eye movements [were] full,
but not conjugate." The patient's neck was sup-
ple, and her neurologic examination was oth-
erwise normal.
She was thought to have had a subarachnoid
hemorrhage, and so computed tomography
and a spinal tap were performed; both test re-
sults were normal.
Her headache persisted and the nursing staff
noted that she was "unable to focus her eyes
well."
When seen in consultation, she was emotion-
ally upset. Her corrected near visual acuity was
20/30 when each eye was tested separately. Oc-
ular ductions (movements with one eye view-
ing) were full. With both eyes viewing (ver-
sions), there was a characteristic limitation in
movement of the abducting eye: as it crossed
the midline there were shimmering, small to-
and-fro movements associated with varying
constriction of the pupils.
It eventually emerged that the patient had
been summarily dismissed from her job the af-
ternoon before admission.
Comment: This case history illustrates fea-
tures typical of spasm of the near triad.66 It is
frequently misdiagnosed as bilateral sixth
nerve palsy (leading to inappropriate tests and
procedures).20'69'199 Careful examination of the
eye movements allows the diagnosis to be
made. There is often a full range of movements
and less pupillary constriction with only one
eye viewing.163 With both eyes viewing, the pa-
tient limits abduction by imposing a strong
convergence command (voluntary vergence)
that causes accommodation and, most impor-
Vergence Eye Movements 309
tantly, miosis. On lateral gaze, there may be
dissociated nystagmus that is greater in the ab-
ducting eye.117 Convergence spasms typically
come and go, but some patients can sustain
them for long periods. They may cause ocular
pain. Rapid, passive head-turns (the doll's-
head maneuver) elicit a full range of eye move-
ments. Treatment is best directed toward
the underlying psychological factors,199'212 al-
though cycloplegic eye drops and refractive
measures (positive or negative lenses) may be
effective.199'223
Divergence Weakness
Abnormalities of divergence (divergence in-
sufficiency and divergence paralysis) should
be differentiated from bilateral sixth nerve
palsy. Bielschowsky9 defined the diagnosti
criteria for divergence paralysis: an es-
otropia with uncrossed diplopia during fix-
ation of a distant object; single vision dur-
ing fixation of objects located at about 10 to
20 inches; crossed diplopia with fixation
closer than about 10 to 20 inches (due to as-
sociated convergence insufficiency); hori-
zontal motion of the eyes that may be nor-
mal; and diplopia that is unchanged or may
even disappear on lateral gaze. To these
should be added another criterion: normal
amplitude and speed of horizontal sac-
cades.
Divergence paralysis has been reported
with a variety of neurologic diseases, in-
cluding conditions raising the intracranial
pressure (such as tumor, pseudotumor, in-
tracranial hematoma, or head trauma), 119
and with tumors in the midbrain. 123 It
may also occur as the initial sign of the
Miller Fisher syndrome,56 in association
with diazepam,4 and with intracranial hy-
potension (the low-pressure syndrome).83'154
Some patients with divergence paralysis
have developed frank abducens palsies.32
These patients may show markedly de-
creased saccadic velocities of the abduct-
ing eye, even though the range of motion
is full. 115 They commonly have increased
intracranial pressure. Divergence paraly-
sis, with esotropia greater at distance, has
been associated with cerebellar lesions,
including craniocervical-junction anom-
alies.1'89'126'243 When there are no associ-
310 The Properties and Neural Substrate of Eye Movements
ated neurologic deficits, saccade velocities
are usually normal in divergence paralysis
(i.e., abducens nerve palsies are not the
cause).129 If necessary, such cases can be
treated successfully with bilateral surgical
resection of the lateral rectus muscles.
SUMMARY
1. Vergence movements rotate the eyes
in opposite directions to enable binoc-
ular fixation of a single object. Ver-
gence movements occur in response
to several distinct stimuli. Fusional
(disparity) vergence movements are
stimulated when images from one ob-
ject fall on noncorresponding retinal
elements in the two eyes. Accom-
modative vergence movements are
stimulated by retinal blur. Another
important stimulus for vergence is
the sense of nearness (proximal ver-
gence), which may be abstracted from
cues such as size and motion. These
stimulus-induced changes of ver-
gence are superimposed upon an un-
derlying level of vergence tone (tonic
vergence). Vergence is also under a
degree of voluntary control. Under
normal circumstances, fusional and
accommodative vergence are tightly
coupled, each affecting the other
through neural cross-linkage. Ver-
gence movements occur synkineti-
cally with accommodation of the lens
and pupillary constriction (the near
triad).
2. When performed without accompa-
nying saccades, vergence movements
are slow and show an approximately
negative exponential waveform. Un-
der most natural circumstances, how
ever, vergence movements are used
in combination with saccades to place
the images of an object on both
foveae, or with pursuit to keep the
images of a moving object on both
foveae. When vergence is conjoined
with saccades, the change in relative
alignment is much faster than with
vergence movements made alone
(Fig- 8-2).
3. During a vergence movement from a
far to a near target, ocular motoneu-
rons show a phasic-tonic (velocity-
position) change in innervation (Fig.
8-4). Premotor vergence neurons of
three major types lie in the midbrain,
dorsal and lateral to the oculomotor
nuclei. They encode vergence veloc-
ity, vergence position, or a combina-
tion of both signals.
4. The maintenance of both static and
dynamic ocular alignment is under
long-term adaptive control to ensure
that with every change of gaze, the
lines of sight of both eyes are
promptly brought to the fixation tar-
get and kept there (Fig. 8-7).
5. Abnormal vergence eye movements
should be differentiated from disor-
ders of conjugate eye movements
induced by convergence. Conver-
gence-retraction nystagmus, which is
common with midbrain lesions, is pri-
marily a disorder of saccades in which
attempted upgaze elicits rapid, bilat-
eral, nearly simultaneous phasic ad-
duction with contraction. Divergence
nystagmus (slow phases convergent,
quick phases divergent) may be a sign
of lesions at the craniocervical junc-
tion. Bilateral sixth nerve palsies must
be differentiated from divergence
palsy and from voluntary spasm of the
near reflex, which is recognized by
the accompanying miosis and full
range of movement during monocu-
lar viewing or vestibulo-ocular testing.
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Part II

The Diagnosis
of Disorders of
Eye Movements
This page intentionally left blank
Chapter \)
DIAGNOSIS OF PERIPHERAL
OCULAR MOTOR PALSIES
AND STRABISMUS
ANATOMY OF THE ORBITAL FASCIA AND
THE EXTRAOCULAR MUSCLES
The Pulling Directions of the Extraocular
Muscles and the Planes of Rotation of
the Eye
STRUCTURE AND FUNCTION OF
EXTRAOCULAR MUSCLE
Unique Characteristics of Extraocular Muscle
Structure and Function of Extraocular
Muscle Fiber Types
Extraocular Proprioception
ANATOMY OF OCULAR MOTOR NERVES
AND THEIR NUCLEI
Anatomy of the Abducens Nerve
Anatomy of the Trochlear Nerve
Anatomy of the Oculomotor Nerve
PHYSIOLOGIC BASIS FOR CONJUGATE
MOVEMENTS: YOKE MUSCLE PAIRS
Law of Reciprocal Innervation
Law of Motor Correspondence
Deviations of the Visual Axes
CLINICAL TESTING IN DIPLOPIA
History: The symptomatology of strabismus
The Examination in Strabismus
PATHOPHYSIOLOGY OF SOME
COMMONLY ENCOUNTERED SIGNS IN
STRABISMUS
Primary and Secondary Deviation
Past-pointing and Disturbance of
Egocentric Localization
Head Tilts and Turns
Dynamic Properties of Eye Movements in
Paralytic Strabismus
CLINICAL FEATURES AND DIAGNOSIS
OF CONCOMITANT STRABISMUS
CLINICAL FEATURES OF OCULAR NERVE
PALSIES
Abducens Nerve Palsy
Trochlear Nerve Palsy
Oculomotor Nerve Palsy
Multiple Ocular Motor Nerve Palsies
DISORDERS OF THE NEUROMUSCULAR
JUNCTION
Botulism
The Lambert-Eaton Myasthenic Syndrome
Myasthenia Gravis
CHRONIC PROGRESSIVE EXTERNAL
OPHTHALMOPLEGIA AND
RESTRICTIVE OPHTHALMOPATHIES
Involvement of the Extraocular Muscles in
Muscular Dystrophies
Kearns-Sayre Syndrome and Disorders of
Mitochondrial DNA
Thyroid Ophthalmopathy
Restrictive Ophthalmopathy and Congenital
Fibrosis of the Extraocular Muscles
The most common symptom caused by ab-
normal eye movements is double vision
(diplopia). Diplopia is usually due to mis-
alignment of the visual axes—strabismus
(Table 9-1). The clinical evaluation of
diplopia or strabismus may be challeng-
ing, especially in young or uncooperative
321
Table 9-1. A Glossary of Terms Related to Strabismus
Term Definition
Cardinal or diagnostic positions Primary, secondary, and tertiary positions, which are denned
of gaze separately, below (total of nine)
Central position The position of the eye when looking straight ahead; the visual axis
is parallel to the midsagittal plane of the head
Concomitant deviation Misalignment of the visual axes that does not change in different
positions of gaze with either eye fixating (for diagnosis, see text)
Crossed diplopia Double vision caused by exotropia. The false image is displaced to the
side opposite to the paralyzed eye (e.g., due to medial rectus palsy)
Cyclodeviation Misalignment of the eyes in the torsional plane (eye rotations
around the visual axis). With both eyes viewing, such misalign-
ment causes a cyclodisparity, which stimulates cyclovergence. In-
cyclodeviation: relative intorsion of the eyes (increased separation
of lower poles of eyes). Excyclodeviation: relative extorsion of the
eyes (increased separation of upper poles of eyes)
Duction Rotation of one eye while it alone is viewing: adduction (horizontally
toward the nose); abduction (horizontally away from the nose);
supraduction or sursumduction (elevation); infraduction or deorsum-
duction (depression); incycloduction (intorsion, upper pole nasal-
ward); excycloduction (extorsion, upper pole templeward)
Nonconcomitant deviation Misalignment of the visual axes that varies with position of gaze
and changes according to which eye is fixating. Most noncon-
comitant deviations are paralytic in origin
Orthophoria Alignment of the visual axes while viewing a distant target with
one eye
Orthotropia Alignment of the visual axes while viewing a distant target with
both eyes
Paralytic strabismus Nonconcomitant deviation due to extraocular muscle weakness
Phoria (or heterophoria] The relative deviation of the visual axes during monocular viewing
of a single target. This is a latent ocular misalignment, since fu-
sional vergence mechanisms maintain alignment during binocu-
lar viewing
Primary deviation The deviation of the paretic eye under cover while the normal eye
is fixating. (For mechanism of primary and secondary deviation
see text)
Primary position The position of the eye from which pure horizontal or vertical rota-
tions will be associated with zero torsional component. (See List-
ing's law in text)
Secondary deviation The deviation of the normal eye under cover while the paretic eye
is fixating. (For mechanism of primary and secondary deviation
see text)
Secondary position The position of the eye in adduction, abduction, elevation, or de-
pression
Strabismus A misalignment or deviation of the visual axes
Tertiary position The position of the eye after combined horizontal and vertical
movement away from the central position (e.g., adduction and el-
evation)
Tropia (or heterotropia) The relative deviation of the visual axes during binocular viewing
of a single target. This is a manifest ocular misalignment, which
fusional vergence cannot correct: exotropia (deviation out),
esotropia (deviation in), hypertropia (vertical deviation—e.g.,
right hypertropia = right eye higher)
Continued on following page

322
Table 9-1.—continued

Term Definition

Uncrossed diplopia Double vision caused by esotropia. The false image is displaced on
the same side as the paralyzed eye (e.g., due to lateral rectus
palsy)
Vergence Movements that rotate the eyes simultaneously in opposite direc-
tions: Convergence, divergence, incyclovergence (upper poles to
nose), excyclovergence (lower poles to nose). The two main types of
vergence movements arefusional (disparity) and accommodative
(blur)
Version Movements that rotate the eyes in the same direction by the same
amount: dextroversion, levoversion, sursumversion (elevation), deor-
sumversion (depression), dextrocycloversion (upper poles to subject's
right), levocycloversion (upper poles to subject's left)
Visual axis The line connecting the fovea with the fixation point

patients, and requires an organized and
systematic approach. Recognizing this prob-
lem, Alfred Bielschowsky (1871-1940)
commented: "In examining and treating
motor anomalies (of the eyes), one never
loses an uneasy feeling of incompetence
until he has become thoroughly familiar
with the physiologic fundamentals from
which the signs and symptoms of those
anomalies are to be derived."52
Those physiologic fundamentals had
been established by the 19th-century mas-
ters. One pioneer worthy of special note
was Ewald Hering (1834-1918), who
taught Bielschowsky. When Hering pub-
lished his Theory of Binocular Vision in
1868,250 it was widely held that coordinated
movement of the eyes was an acquired skill.
Hering challenged this view in his treatise,
stating that "one and the same impulse of
will drives both eyes simultaneously as we
can direct a pair of horses with single
reins." Although recent research has ques-
tioned the mechanisms by which equal in-
nervation reaches each eye,715 the idea that
the brain controls the globes as a single or-
gan—"the Double Eye"—still forms the ba-
sis for our understanding of diplopia.
ANATOMY OF THE ORBITAL
FASCIA AND THE
EXTRAOCULAR MUSCLES
The eyeball is suspended in the cone-
shaped orbit by a fibrous sac of fascia called
Tenons capsule, which is attached anteriorly
to the conjunctiva behind the corneal lim-
bus and posteriorly to the orbital fat sur-
rounding the optic nerve. Tenon's capsule
has a tough peripheral part, which is pene-
trated by the rectus extraocular muscles,
and a thin, delicate central region, which is
penetrated by the optic nerve, posterior
ciliary nerves, and ciliary vessels. The at-
tachments of Tenon's capsule, between the
anterior circumference of the eyeball (be-
hind the corneal limbus) and the orbital
rim, effectively suspend the eye in a
"drumhead" that mechanically governs its
freedom of rotation (Fig. 9-1).142 The thin,
central part of Tenon's capsule allows the
optic nerve and the ciliary vessels and
nerves to move with the eye. One other im-
portant fascial connection is between the
superior surface of the superior rectus
muscle sheath and the lower surface of the
levator palpebrae superioris.666
Each eye is rotated by six muscles: four
rectus muscles and two oblique muscles
(Fig. 9-1 and Table 9-2). The four recti and
the superior oblique arise from the apex of
the orbit (the annulus of Zinn, Fig. 9-2). The
inferior oblique muscle arises from the infe-
rior nasal aspect of the orbit. The four rec-
tus muscles insert into the sclera anterior to
the equator of the globe: the medial rectus
muscle on the nasal side, the lateral rectus
muscle on the temporal side, the superior
rectus muscle on the superior side and the
inferior rectus muscle on the inferior side.
The superior and inferior oblique muscles
approach the globe from its anterior and
medial aspect and insert posterior to the
equator of the globe. The superior oblique
muscle first passes through the trochlea (a fi-
brous, cartilaginous, U-shaped ring that
324 The Diagnosis of Disorders of Eye Movements

Figure 9-1. Schematic representation of orbital connective tissues. IR, inferior rectus; LPS, levator palpebrae su-
perioris; LR, lateral rectus; M, medial rectus; SO, superior oblique; SR, superior rectus; tndn: tendon. The three
coronal views correspond to the levels indicated by arrows in the horizontal section. In the horizontal section,
note the attachment of the globe to the orbit by the anterior part of Tenon's capsule (collagen and elastin)
through which the extraocular muscles pass in sleeves, which serve as pulleys. (Courtesy of Joel M. Miller and
Joseph L. Demer.)

lies just inside the superior medial orbital
rim) before inserting on the superior side
of the globe. The inferior oblique inserts on
the temporal side.
An important new discovery is that the
tendons of the rectus extraocular muscles
pass through sleeve-like pulleys that lie
within peripheral Tenon's capsule.142'506
These pulleys lie several millimeters poste-
rior to the equator of the globe (Fig. 9-1),
approximately 10 mm posterior to the in-
sertion sites of the muscles. The pulleys
contain not just fibrous tissue but also
smooth muscle, which is innervated by sev-
eral neurotransmitters—catecholamines,
acetylcholine, and nitric oxide.143 The func-

Table 9-2. Actions of the Extraocular Muscles with the Eye in

Central Position

Muscle Primary Action Secondary Action Tertiary Action

Medial rectus Adduction — —

Lateral rectus Abduction — —
Superior rectus Elevation Intorsion Adduction
Inferior rectus Depression Extorsion Adduction
Superior oblique Intorsion Depression Abduction
Inferior oblique Extorsion Elevation Abduction
 Diagnosis of Diplopia and Strabismus 325

Figure 9-2. Posterior aspect of the left orbit showing the relationship of the sites of extraocular muscle attach-
ment, which define the annulus of Zinn (schematically represented by the elipse) and adjacent neurovascular
structures. (Redrawn from von Noorden.666)

tional importance of the fibromuscular pul-

leys is that they limit side-slip movement of
the rectus muscles during eye rotations, a
factor that had confounded prior attempts
to mathematically model the properties of
the orbit. Furthermore, the pulleys effec-
tively change the point of origin of the rec-
tus muscles, just as the trochlea changes the
functional point of origin of the superior
oblique muscle. Confirmation of the func-
tion of the pulleys comes from magnetic
resonance imaging (MRI), which shows
that the paths of rectus muscles remain
fixed even during large eye rotations.105'141

The Pulling Directions of the

Extraocular Muscles and the
Planes of Rotation of the Eye
The eyes rotate about three axes (Fig.
9-3); one current convention refers to
these axes as X (parasagittal), Y (trans-
verse), and Z (vertical). All axes pass
through the center of rotation of the
globe. Translations (linear movements) of
the globe are small, owing to the proper-
ties of Tenon's capsule, which suspends
the eyeball. The pulling actions of the ex-
traocular muscles are summarized in
Table 9-2. The primary action of the mus- Figure 9-3. Axes of rotation of the eye (X, Y, Z) and
cle refers to the axis about which the eye Listing's plane.
326 The Diagnosis of Disorders of Eye Movements
principally rotates when that muscle con-
tracts; the secondary and tertiary actions
refer to the axes about which there are
lesser rotations. The horizontal recti ro-
tate the eye horizontally about the Z axis,
more or less irrespective of the vertical po-
sition of the globe. The superior recti are
the main elevators of the eyes, and the in-
ferior recti are the main depressors; these
muscles also have smaller torsional and
horizontal actions. The pulling actions of
the oblique muscles are mainly torsional,
but because they approach the eye from its
medial aspect, their direction of pull is
substantially affected by the horizontal po-
sition of gaze. For example, the superior
oblique acts mainly as a depressor when
the eye is adducted and mainly as an in-
torter when the eye is abducted (Fig. 9-4).
The tertiary action of the oblique muscles
is to abduct the eye.
Although in theory the eye could rotate
about axes lying in any plane, in fact, the
axes of rotation are confined to the equa-
torial or Listing's plane, which is perpendic-
ular to the fixation line in primary position
(Fig. 9-3). Thus, Listing's law states that
any eye position can be reached from the
primary position by rotation of the eye
about a single axis lying in the equatorial
plane. One consequence of this scheme is
that the vertical meridian of the eye,
which is earth-vertical and parasagittal
with the eye in the primary position, re-
Figure 9-4. Pulling directions of the right superior oblique muscle, viewed from above. (A) When the eye
is fully adducted, its depressing action is maximized. (B) When the eye is fully abducted, its action is mainly
intorsion.
mains vertical when the eye rotates to a
secondary position but systematically tilts
with respect to gravity in any tertiary posi-
tion. Danders' law states that the angle of
tilt in any tertiary position of gaze de-
pends upon the horizontal and vertical
gaze angles, irrespective of how the eye
reached that position of gaze. Both Bon-
ders' and Listing's laws have been shown
to apply approximately to saccadic and
smooth-pursuit eye movements.176'177'616
Because the globe is suspended in the
"drumhead" of fascia provided by Tenon's
capsule, and the fibromuscular pulleys en-
sure relatively fixed pulling directions of
the extraocular muscles, it has been sug-
gested that Listing's and Bonders' laws
are partially effected by these mechanical
properties of the orbital tissues.415 Bevia-
tions from Listing's law do, however, occur
for vestibular eye movements induced by
head rotations in roll,421 for the eye move-
ments occurring during sleep, and after
ingesting alcohol.179'415 In one patient with
alternating strabismus, the orientation of
Listing's plane depended on which eye the
subject chose to view with.411 Thus, it ap-
pears that orbital mechanics cannot be the
sole factor that ensures that saccadic and
pursuit eye movements obey Listing's law,
but changes in smooth muscle pulley tone
could mediate these central effects. Fur-
thermore, electrophysiological evidence
supports the view that the brain takes into

account deviations from Listing's law and
corrects them.650 However, mathematical
models suggest that orbital factors are
more important than neural programing
in constraining axes of eye rotations to
Listing's plane.475 The functional signifi-
cance of Listing's law or its changes with
vergence are not clear. Various sugges-
tions have been made though none is to-
tally satisfactory. They include a relative
simplicity of neural computation since
patterns of innervation for a given posi-
tion of gaze are reduced from three de-
grees of freedom to two (torsion is
automatically specified—Donders' law);
economy of work since the eyes take the
straightest path to a new orbital position;
and sensory considerations, to keep tor-
sional disparity constant no matter what
the viewing distance.641a
STRUCTURE AND FUNCTION
OF EXTRAOCULAR MUSCLE
Unique Characteristics of
Extraocular Muscle
Extraocular muscles differ anatomically,
physiologically, and immunologically from
limb muscle.499'501 Eye muscle fibers are
smaller, more variable in size, and more
richly innervated than limb muscle fibers.
Some extraocular muscle fibers are amongst
the fastest contracting and yet remain fa-
tigue resistant.189 Motor unit size is the
lowest known, being about 10 muscle
fibers per motoneuron. Like limb muscles,
the extraocular muscles contain twitch
fibers that have a single endplate per fiber
and can generate an all-or-none propagat-
ing response (action potential). In addition,
there are nontwitch fibers that cannot gen-
erate action potentials and show graded
contractions to trains of electrical pulse
stimuli; these are similar to the tonic fibers
found in amphibians.430'563 Fibers with in-
termediate properties also exist; they have
multiple nerve terminals on individual
fibers but still generate slow action poten-
tials.430
Another difference from limb muscles is
that extraocular muscles preserve their
Diagnosis of Diplopia and Strabismus 327
embryonic myosin in the proximal and
distal portions of muscle fibers in the or-
bital layers (see following section).502 This
preservation of embryonic myosin may
partly account for the remarkable capacity
of extraocular muscles to adapt to changes
in innervation and disease states. Fibers
with single and multiple nerve endplates
have different antigens.461 One factor in
this antigenic difference may lie in the
structure of the acetylcholine receptor.
Both the embryonic c^P^S type and adult
a2pe5 isoforms of the acetylcholine recep-
tor are present on multiply innervated,
and some singly innervated, adult ex-
traocular muscle fibers. Adult skeletal
muscle and the levator of the eyelid pos-
sess only the adult isoform.257'286'287
Extraocular muscle is more susceptible
to some disease processes (e.g., myasthe-
nia gravis)289'499 and more resistant to
others (e.g., Duchenne's dystrophy)285-316
than skeletal muscles. Furthermore, when
disease does involve extraocular muscle,
the histopathologic changes may be quite
unlike those observed in skeletal muscle
affected by a similar condition. For exam-
ple, experimental denervation of the ex-
traocular muscles causes little muscle
atrophy but with a mononuclear infil-
trate.499'503 Some of these findings would
suggest a myopathic process if encoun-
tered in limb muscle.
Structure and Function of
Extraocular Muscle Fiber Types
Each extraocular muscle has two distinct
layers. Near the origin of each muscle,
these lie in two concentric zones, but as
the muscle is traced anteriorly, two paral-
lel zones or layers are formed: a central
global layer and a peripheral orbital layer.
Each layer contains fibers more suited for
either sustained contraction or brief rapid
contraction. However, the orbital zone
contains many fatigue-resistant twitch
fibers. Using modern methods, six types
of fibers have been defined in the extra-
ocular muscles (Fig. 9_5).502.596-598
In the orbital layer, about 80% are singly
innervated fibers, which have fast-type my-
328 The Diagnosis of Disorders of Eye Movements

ofibrillar ATPase and high oxidative activ-
ity (with numerous mitochondria in dense
clusters); these very fatigue-resistant fibers
are not found in skeletal muscle or the
eyelid. They alone show long-term effects
after injection of botulinum toxin.595 The
remaining 20% of orbital fibers are multi-
ply innervated. They have twitch capacity
near the center of the fiber and nontwitch
activity proximal and distal to the end-
plate band.
In the global layer, about 33% of fibers
are singly innervated, fast twitch, and fa-
tigue resistant. About 33% are pale, singly
innervated fibers with fast-twitch proper-
ties but low fatigue resistance. About 25%
are singly innervated fibers with fast-
twitch properties, numerous mitochon-
dria, and an intermediate level of fatigue
resistance. The remaining 10% are multiply
innervated fibers, with synaptic endplate
along their entire length, as well as at the
myotendinous junction, where there are
palisade organ proprioceptors. Like am-
phibian muscle, these fibers show tonic
properties, with slow, graded, nonpropa-
gated responses to neural or pharmaco-
logical activation. Recent evidence sug
gests that these muscle fibers receive
innervation from a separate group of mo-
toneurons, which lie just outside the con-
fines of the abducens and trochlear nuclei
and include the C subgroup of the oculo-
motor nucleus.85a
The levator palpebrae superioris contains
the three singly innervated muscle types
encountered in the global layer of the ex-
traocular muscles, plus a true slow-twitch
fiber type. The multiply innervated fiber
types and the fatigue-resistant singly in-
nervated type seen in the orbital layer are
absent.
Although direct electrophysiological
confirmation of the contribution of each
fiber type to different types of eye move-
ment is lacking, electromyographic studies

Figure 9-5. Trichrome-stamed cross section of a rat lateral rectus muscle. The section shows the junction be-
tween the orbital region on the left and the global region toward the right. In the orbital layer are smde inner
vated, fatigue-resistant fibers (1) and multi-innervated fibers (2). The "global layer, at rigj con^nsfndy ?i-
nervated fatigue-resistant fibers (3). Two singly innervated, fatigable fibers are presentT(4 L and 5
flobal
^^^^™^^^^ d^Ctf - ^ «*** ^i-innlervatej'fibe:. |££
nification 400X). (Courtesy, Dr.Henry J.Kaminski.)

by Scott and Collins, using miniature elec-
trode needles with multiple recording
sites, established a division of labor be-
tween global and orbital layers of extraoc-
ular muscle (Fig. 9-6).551 They found that
orbital fibers are active throughout nearly
the entire range of movement, but during
fixation, global fibers are recruited only as
the eye is called into the field of action of
that muscle. It seems likely, therefore, that
the singly innervated, fatigue-resistant or-
bital fibers play a key role in sustaining
eye position and maintaining extraocular
muscle "tone" in any eye position. During
saccades, both global and orbital fibers are
activated, but the activity of global fibers
subsequently may fall, whereas that of or-
bital fibers is sustained. These findings are
consistent with the presence of more fa-
tigue-resistant fibers in the orbital layers.
Further, it has been shown experimentally
that "fast-fatigable" muscle fibers are the
strongest,563 so such global fibers may be
best able to generate rapid eye move-
ments. Thus, the order of recruitment of
fibers appears to reflect mainly their fati-
gability; the less fatigue-resistant fibers of
the global layers may only be activated
during saccades.
These findings might suggest that the
properties of muscle fiber types differ
from those of the ocular motoneurons,
which appear to discharge for all types of
eye movements, version or vergence.523
However, an alternative interpretation is
that although each fiber can potentially
contribute to all classes of eye movement,
orbital, fatigue-resistant twitch fibers are
most important for holding the eye in
steady fixation, whereas global, pale,
twitch fibers only become active when the
eye is moved rapidly to a new orbital posi-
tion. One special exception might be the
multiply innervated tonic fibers, which do
not generate action potentials and thus
cannot be monitored by electromyo-
graphic activity. They appear to have mo-
toneurons lying outside the oculomotor,
trochlear and abducens nuclei,85a and may
contribute to proprioception.
Diagnosis of Diplopia and Strabismus 329
Extraocular Proprioception
Although human extraocular muscles
contain muscle spindles,384'535 the pali-
sade tendon organs seem most important
for ocular proprioception.518'610 Afferents
from these proprioceptors project via the
ophthalmic branch of the trigeminal nerve
and the Gasserian ganglion to the spinal
trigeminal nucleus (pars interpolaris and
pars caudalis).498 Proprioceptive inputs
may also project centrally via the ocular
motor nerves.204 From the trigeminal nu-
cleus, proprioceptive information is dis-
tributed widely to structures involved in
ocular motor control—the superior col-
liculus, vestibular nuclei, nucleus preposi-
tus hypoglossi, cerebellum, and frontal
eye fields—as well as to structures in-
volved in visual processing—the lateral
geniculate body, pulvinar, and visual cor-
tex. The palisade endings are mainly asso-
ciated with distal myotendinous junctions
of the global, multiply innervated fiber
type. This fiber type, which only accounts
for about 10% of global fibers and is absent
from the eyelid, might function similarly
to the intrafusal fibers of skeletal muscle.
What purpose could proprioception
play in the normal control of eye move-
ments? After all, vision provides continu-
ous sensory feedback by which the brain
can monitor the precision of gaze. Fur-
thermore, no external loads are applied to
the extraocular muscles (as they may be
to skeletal muscles), and the extraocular
muscles appear to lack a stretch reflex.312
After the trigeminal proprioceptors are
severed, monkeys can still aim their eyes
accurately after they are perturbed by
electrical stimulation while in darkness.226
This evidence suggests that the brain
monitors an efference copy or corollary
discharge of ocular motor commands
rather than relying on proprioception.
However, other evidence suggests that
extraocular proprioception may play a role
in programing eye movements when visual
cues are impoverished.12'654'655 If one eye is
artificially displaced with a suction contact
lens and the subject views with the other
eye, spatial localization is perturbed in the
direction of forced eye rotation.199 Spatial
localization is also impaired in patients who
330
 Diagnosis of Diplopia and Strabismus 331

have undergone trigeminal nerve thermo-
coagulation for tic douloureux.656 Studies
of a patient with a congenital oculomotor-
trigeminal nerve synkinesis, who could
adduct one eye by moving her jaw, also
provide evidence that extraocular proprio-
ception could contribute to spatial localiza-
tion.373 Thus, when this patient viewed
with her normal eye, but adducted her cov-
ered, abnormal eye by moving her jaw, she
mislocalized targets opposite to the direc-
tion of eye rotation, consistent with the ef-
fects of active contraction of the left medial
rectus on palisade tendon organs. Proprio-
ception may also play a role in maintaining
correct ocular alignment.200'366 If trochlear
nerve palsy is induced experimentally in
m.onkeys, proprioceptive deafferentation
of the paretic eye produces gradual wors-
ening of both static alignment and saccadic
conjugacy.374 Finally, there is evidence that
proprioception plays a role in the normal
development of binocularity.79
ANATOMY OF OCULAR MOTOR
NERVES AND THEIR NUCLEI
The ocular motor nuclei are located in the
brain stem, close to the midline.597 They
lie adjacent to the medial longitudinal fas-
ciculus and reticular formation, ventral to
the aqueduct of Sylvius and fourth ventri-
cle. The intracranial courses of the ocular
motor nerves are shown in Figure 9-7.
Anatomy of the Abducens Nerve
of cells: motoneurons, which innervate the
lateral rectus muscle, and internuclear
neurons, which innervate contralateral
medial rectus motoneurons via the medial
longitudinal fasciculus. Thus, the neurons
of the abducens nucleus contain all the
neural signals responsible for conjugate
horizontal eye movements. From the me-
dial aspect of the nucleus, fibers destined
for the ipsilateral lateral rectus muscle
course ventrally, laterally, and caudally,
passing through the pontine tegmentum
and medial lemniscus, to emerge at the
caudal border of the pons. Here the ab-
ducens nerve lies close to the anterior in-
ferior cerebellar artery. In some individu-
als, the nerve consists of several trunks
that eventually fuse within the cavernous
sinus.448 The nerve then courses nearly
vertically along the clivus, through the
prepontine cistern, and close to the infe-
rior petrosal sinus. It then rises to the
petrous crest, where it bends acutely for-
ward to penetrate the dura,645'647 medial
to the trigeminal nerve, and passes under
the petroclinoid ligament in Dorello's ca-
nal. It courses forward in the body of the
cavernous sinus, where it lies lateral to the
internal carotid artery and medial to the
ophthalmic division of the trigeminal
nerve (Fig. 9-8). For a few millimeters,
pupillosympathetic fibers run with the
sixth nerve as they leave the carotid artery
to reach the first division of the trigeminal
nerve.386-482 The abducens nerve then en-
ters the orbit through the superior orbital
fissure449 and passes through the annulus
of Zinn to innervate the lateral rectus on
the inner surface of the muscle.

The abducens nucleus lies in the floor of

the fourth ventricle, in the lower pons (see Anatomy of the Trochlear Nerve
Fig. 6-1, Chap. 6). It is capped by the
genu of the facial nerve. The abducens The trochlear nerve is the longest and
nucleus contains two distinct populations thinnest of all cranial nerves, which makes

Figure 9-6. The relationship between discharge rate of extraocular muscle fibers and eye movements in human
subjects. A miniature multielectrode enabled simultaneous sampling of different fiber layers of the same mus-
cle. (A) The relative contributions of orbital and global fibers of the left medial rectus muscle (LMR) are shown
as the eye is held in various positions in the orbit. The orbital fibers progressively increase their activity as the
fixation point is moved to the right. The global fibers, however, appear to saturate as the medial rectus is called
upon to sustain stronger contractions during fixation into the far right field. (B) The integrated electromyo-
graphic activity in outer orbital and inner global layers of the left medial rectus muscle is sampled during a sac-
cade from primary position to 50° to the right (5OR). The global fibers are maximally innervated during the
saccade, but their activity falls when the eye reaches extreme rightward gaze. The orbital fibers, however, main-
tain their new level of activity to hold the eye in its new position. (From Collins,113 with permission.)

it susceptible to trauma. Each trochlear
nucleus sends axons to supply the con-
tralateral superior oblique muscle. The
trochlear nucleus lies at the ventral border
of the central, periaqueductal gray matter,
dorsal to the medial longitudinal fascicu-
lus, at the level of the inferior colliculus.
Its fibers pass dorsolaterally and caudally
around the central gray matter and decus-
sate completely in the anterior medullary
velum (the roof of the aqueduct). The
trochlear nerve emerges, as one or more
rootlets,447 from the dorsal aspect of the
brain stem, caudal to the inferior collicu-
lus and close to the tentorium cerebelli.
The nerve passes laterally around the up-
per pons, lying between the superior cere-
bellar and posterior cerebral arteries, to
reach the prepontine cistern. During its
cisternal course, the trochlear nerve re-
ceives its blood supply from branches of
the superior cerebellar artery.389 It then
runs forward on the free edge of the ten-
torium for 1 to 2 cm before penetrating
the dura of the tentorial attachment and
entering the cavernous sinus. Within the
lateral wall of the sinus (Fig. 9-8), the
fourth nerve lies below the third nerve
and above the ophthalmic division of the
fifth nerve, with which it shares a con-
nective tissue coat. It then crosses over
the oculomotor nerve to enter the supe-
rior orbital fissure above the annulus of
Zinn,449 passing to the medial aspect of
the orbit to supply the superior oblique
muscle.536
Anatomy of the Oculomotor Nerve
The oculomotor nucleus is a paired struc-
ture that lies at the ventral border of the
periaqueductal gray matter; it extends
rostrally to the level of the posterior com-
missure and caudally to the trochlear nu-
cleus (Fig. 9-9). It sends efferent fibers to
the medial rectus, superior rectus, inferior
rectus, and inferior oblique muscles; the
levator palpebrae superioris; the pupillary
Figure 9-7. The intracranial courses of the third, fourth, and sixth cranial nerves. (Top) Parasagittal view.
(Bottom) Superior view. Lig. of Gruber: petroclinoid ligament. (From Wolff's Anatomy of the Eye and Orbit, Edition
8, edited by Bron AJ, Tripathi RC, Tripathi BC, pages 181 and 192, Edward Arnold, London, 1997, with per-
mission.)
Diagnosis of Diplopia and Strabismus\ 333
Figure 9-8. Diagram of transverse section of the cav-
ernous sinus, showing superficial and deep layers
and the relationships of the oculomotor (III),
trochlear (IV), abducens (VI), and ophthalmic divi-
sion of the trigeminal nerve (Vj). (Redrawn from
Umansky and Nathan. 646 )
constrictor muscle; and the ciliary body.
Warwick's anatomic scheme678 for the ocu-
lomotor nucleus of the rhesus monkey is
shown in Figure 9-9A. More recent stud-
ies have revised Warwick's scheme,81'84'85
and demonstrated that the neurons sup-
plying the medial rectus muscle are dis-
tributed into three areas of the oculomo-
tor nucleus, designated A, B, and C (Fig.
9-9B). Neurons from area C receive pre-
tectal inputs,85 and their axons mainly in-
nervate the orbital layers of the medial
rectus muscle; orbital fibers seem most
suited to sustained contraction, such as
during convergence. Neurons from all
three of these locations receive inputs
from the contralateral abducens nucleus
via the medial longitudinal fasciculus (Fig.
9-9B). The neurons innervating each su-
perior rectus muscle lie next to each other,
and their axons decussate in the caudal
portion of this nucleus.53 The caudal nu-
cleus, supplying both levator palpebrae
superioris muscles, is a single structure.
All projections from the oculomotor nu-
cleus are ipsilateral save for those to the
superior rectus, which are totally crossed,
334 The Diagnosis of Disorders of Eye Movements

Figure 9-9. The anatomy of the oculomotor complex in the rhesus monkey. (A) Warwick's scheme, based on
retrograde denervation studies. CCN, caudal central nucleus; DN, dorsal nucleus; 1C, intermediate nucleus;
IV, trochlear nucleus; VN, ventral nucleus; R, right; L, left. (From Warwick, R., Representation of the extraoc-
ular muscles in the oculomotor nuclei of the monkey, Journal of Comparative Neurology, volume 98, pages
449-503, copyright 1953, with permission of John Wiley and Sons, Inc.) (B) Scheme of Biittner-Ennever and
Akert, based on radioactive tracer techniques. Top: The medial rectus (MR) motoneurons, identified by inject-
ing isotope into medial rectus muscle, lie in three groups, A, B, and C. IO, inferior oblique; IR, inferior rectus;
SR, superior rectus. Bottom: These same three areas also receive inputs from abducens internuclear neurons as
demonstrated by injecting isotope into the contralateral sixth nerve nucleus. (From Biittner-Ennever JA, Akert
K. Medial rectus subgroups of the oculomotor nucleus and their abducens internuclear input in monkey. J
Comparative Neurol volume 197, pages 17-27, copyright 1981, with permission of John Wiley and Sons, Inc.)
Continued on following page

and those to the levator palpebrae superi-
oris, which are both crossed and un-
crossed. Parasympathetic innervation for
the pupil originates in the Edinger-West-
phal nucleus.338
The fascicles of the oculomotor nerve
originate from the entire rostral-caudal
extent of the nucleus and pass ventrally
through the medial longitudinal fascicu-
lus, the red nucleus, the substantia nigra,
and the medial part of the cerebral pe-
duncle. As they pass through the red nu-
cleus, the fascicles fan out to converge
again before exiting the midbrain. At-

Figure 9-9.—continued
tempts have been made to identify the
topographic organization of the oculomo-
tor fascicles, based on clinicoradiologic
and clinicopathologic findings. One scheme
proposes that from lateral to medial, the
order is inferior oblique, superior rectus,
medial rectus and levator palpebrae, infe-
rior rectus, and pupil.96'198 However, se-
lective involvement of the levator and su-
perior rectus with some ventral midbrain
lesions has suggested that, even at this
stage, the organization corresponds to
the superior and inferior branching of
the oculomotor nerve that occurs in the
orbit.344
The third nerve emerges from the in-
terpeduncular fossa as several rootlets
which then fuse to form a single trunk.
The nerve then runs between the poste-
rior cerebral artery and superior cerebel-
lar artery, passing forward, downward,
and laterally through the basal cistern. It
passes lateral to the posterior communi-
cating artery and below the temporal lobe
uncus, where it runs over the petroclinoid
ligament, medial to the trochlear nerve
and just lateral to the posterior clinoid
Diagnosis of Diplopia and Strabismus 335
process. During its subarachnoid course,
parasympathetic pupillary fibers lie pe-
ripherally in the dorsomedial part of the
nerve.314'619 Segregation of libers into
those that will supply superior and infe-
rior branches of the oculomotor nerve in
the orbit may already have occurred.229 As
the oculomotor nerve pierces the dura, it
lies close to the free edge of the tento-
rium cerebelli. Within the cavernous si-
nus, the third nerve lies initially above the
trochlear nerve, and here it receives sym-
pathetic fibers from the carotid artery
(Fig. 9-8). As it leaves the cavernous sinus,
it is crossed superiorly by the trochlear
and abducens nerves and divides into a
superior and inferior ramus. These pass
through the superior orbital fissure,449
and enter the orbit within the annulus of
Zinn (Fig. 9-2). The superior oculomotor
ramus or division runs lateral to the optic
nerve and ophthalmic artery and supplies
the superior rectus and levator palpebrae
muscles. The larger inferior oculomotor
ramus or division branches in the poste-
rior orbit and supplies the medial rectus,
inferior rectus, and inferior oblique mus-
336 The Diagnosis of Disorders of Eye Movements
cles, and the ciliary ganglion.536 The blood
supply of the intracranial portion of the
oculomotor nerve from its emergence
from the brain stem until it passes the pos-
terior cerebral artery originates from thal-
amoperforating branches.86 From this
point until the nerve enters the cavernous
sinus, it receives no nutrient arterioles
from adjacent arteries. The part of the
oculomotor nerve within the cavernous si-
nus receives branches from the inferior
cavernous sinus artery and from a tentor-
ial artery arising from the meningohy-
pophyseal trunk.
PHYSIOLOGIC BASIS FOR
CONJUGATE MOVEMENTS:
YOKE MUSCLE PAIRS
Law of Reciprocal Innervation
Sherrington determined that whenever an
agonist muscle (e.g., the lateral rectus) re-
ceives a neural impulse to contract, an
equivalent inhibitory impulse is sent to the
motoneurons supplying the antagonist
muscle of the same eye (e.g., the medial
rectus) so that it will relax—the law of recip-
rocal innervation.b&1 In other words, the ex-
traocular muscles do not cocontract during
conjugate eye movements, although they
do so during blinks168 and vergence.197
Sherrington postulated that this reciprocal
innervation was due to a stretch reflex in
extraocular muscle.567 Although, as re-
viewed above, the extraocular muscles do
possess proprioceptors, neurophysiologic
evidence in monkeys argues against the ex-
istence of a classic stretch reflex. When a
trained monkey fixates a target with one
eye, perturbation of the other, covered
eye, using a suction contact lens, produces
no change in the discharge of neurons in
the abducens nucleus corresponding to
the perturbed eye.312 Moreover, bilateral
section of the ophthalmic division of the
trigeminal nerve, which conveys extraocu-
lar proprioceptive inputs,504 does not af-
fect the ability of the brain to program sac-
cadic eye movements accurately.226 Thus,
at present, the weight of evidence suggests
that the law of reciprocal innervation de-
pends upon the organization of brain stem
connections. For example, the saccadic sys-
tem is organized in a push-pull fashion
that involves excitatory and inhibitory
burst neurons (see Chap. 3).
Law of Motor Correspondence
A second physiological principle is that for
the eyes to move together requires a coor-
dination or yoking of pairs of muscles, one
from each eye. For example, to produce a
horizontal movement to the left requires
that the left lateral rectus and right medial
rectus muscles contract together. These
muscles are a yoke pair, as are the left me-
dial rectus and right lateral rectus, which
relax during the same movement. Implicit
in the concept of a yoke pair is that corre-
sponding muscles of each eye (e.g., left lat-
eral rectus and right medial rectus) re-
ceive equal innervation so that the eyes
move together. This is the simplest state-
ment of Bering's law of motor correspon-
dence.250 Conventionally, vertically acting
muscles are also conceptualized as being
arranged in yoke pairs (e.g., the right su-
perior rectus and the left inferior oblique),
a concept that has received experimental
support.435 In fact, the way in which the
extraocular muscles interact is compli-
cated and all the extraocular muscles
probably contribute force during even a
simple horizontal movement. Further-
more, recent studies indicate that some
premotoneurons may encode monocular
eye movement signals.715 Nonetheless, the
concept of yoke muscle pairs is valuable in
interpreting the results of clinical testing.
Deviations of the Visual Axes
Many normal subjects develop a deviation
of the visual axes when sensory fusional
mechanisms are temporarily interrupted
by covering one eye. This is a phoria or la-
tent deviation of the visual axes (Table
9-1). The deviation is usually constant in
all directions of gaze and is called concomi-
tant (or comitant). If, on the other hand,
the amount of deviation changes accord-
ing to the direction of gaze, it is called non-

concomitant and may be due to extraocular
muscle weakness or mechanical hindrance.
During saccadic eye movements made
by normal subjects, the eyes do not move
exactly together.112 In addition, the yok-
ing mechanism is not fixed, but can un-
dergo some limited, adaptive changes to
partially compensate for mild degrees of
extraocular muscle weakness.472 This ca-
pability can also be shown to adjust the
relative innervation to the eyes in re-
sponse to wearing spectacles in which the
strength of the correction is different be-
tween the eyes.473
CLINICAL TESTING
IN DIPLOPIA
The prerequisite for accurate diagnosis of
diplopia and strabismus is a clear under-
standing of underlying anatomy and phys-
iology. One should also record the results
of each part of the examination, heeding
Darwin's advice that "it is a fatal fault to
reason while observing, though so nec-
essary beforehand and so useful after-
wards."
History: The symptomatology
of strabismus
Misalignment of the visual axes—strabis-
mus—causes the two images of a seen ob-
ject to fall on noncorresponding areas of
the two retinas (Fig. 9-10). This usually
causes diplopia—the sensation of seeing an
object at two different locations in space.
In addition, the two foveae are simultane-
ously presented different images, so occa-
sionally two different objects are perceived
at the same point in space. This is called
visual confusion.
At an early point in the evaluation, it
should be determined whether the
diplopia is binocular or monocular. The
distinction can be made by covering one
eye. Monocular diplopia is most com-
monly caused by astigmatism or spherical
refractive errors,107-692 incipient cataract,
corneal irregularity,252 lens dislocation, or
eye trauma. Such patients may report that
Diagnosis of Diplopia and Strabismus 337
Figure 9-10. Disparate retinal images. The image of
a distant object lies on the fovea of the left eye but,
because of an esotropia in the right eye (due to a
right lateral rectus weakness, for instance), the image
lies medial to the fovea. Each retinal element corre-
sponds to a specific subjective visual direction. Con-
sequently, the subject localizes the same object in two
different directions and experiences diplopia. The
broken line indicates the perceived direction of the
false image.
the two images differ in brightness or that
there are more than two images. Monocu-
lar diplopia caused by lens or corneal ab-
normality can be overcome by pinhole vi-
sion. Slitlamp examination or retinoscopy
may be necessary to make the diagnosis.
In some patients, monocular diplopia is a
psychiatric symptom. Rarely, it is due to
retinal detachment or to cerebral disor-
ders.404'538
Patients who complain of little or no vi-
sual disturbance despite an obvious ocular
misalignment usually have had their stra-
bismus from early in life, though this is
not always the case. Thus, it is important
to inquire about any history of strabismus,
eye patching, or abnormal head posture;
old photographs may be of help. It is
also worthwhile asking about prior visits
to ophthalmologists and optometrists. On
occasion, patients with strabismus (espe-
cially children) present with an abnormal
338 The Diagnosis of Disorders of Eye Movements
head posture but without any visual com-
plaints.88
Ask about the type of diplopia (horizon-
tal, vertical, torsional), in what direction of
gaze it is most marked, if it is worse for
near or distant viewing, and if it is affected
by head posture. For example, a lateral
rectus weakness leads to horizontal diplopi
that is typically worse on looking ipsilater-
ally and at distant objects and is less trou-
blesome if the head is turned toward the
side of the palsy.
Other symptoms caused by misalign-
ment of the visual axes include blurred vi-
sion, vertigo, and oscillopsia; the last two
complaints relate to inadequate compen-
satory movements of the eyes during head
rotation.165-688 Patients with diplopia tend
to close one eye.676 This may be the clue to
an ocular misalignment in confused or le-
thargic patients who do not complain of
diplopia.
The Examination in Strabismus
Certain essential preliminaries should
precede ocular motor testing. These are
measurement of corrected visual acuity in
each eye, tests for binocularity, and a sim-
ple confrontation assessment of the cen-
tral and the peripheral visual fields. In
certain patients, particularly children and
some young adults, refraction is necessary.
Any abnormal head posture should also be
noted. These observations completed, the
examination consists of four parts: assess-
ment of range of eye movements, subjec-
tive diplopia testing, cover testing, and,
with vertical deviations, the Bielschowsky
head-tilt test. Appendix A contains a sum-
mary of this testing.
RANGE OF EYE MOVEMENTS
Ask the patient to follow a small target
through the full range of movement, in-
cluding the nine cardinal or diagnostic po-
sitions of gaze (Table 9-1). First test one
eye at a time with the other covered—
ductions. Then test both eyes together—
versions. Note any limitation of eye
movement that persists despite vigorous
encouragement. A simple, approximate
method to evaluate ocular alignment dur-
ing versional movements is to ask the pa-
tient to fixate on a penlight and to note
the position of the corneal reflection of the
light in the nine cardinal positions. Rather
than moving the penlight, move the pa-
tient's head so that the examiner's eye
stays aligned with the penlight. If the im-
ages from the two corneas appear cen-
tered, then the visual axes are usually cor-
rectly aligned. This method is especially
valuable when facial asymmetries, such as
hypertelorism, ptosis, or epicanthic folds,
give the false impression of strabismus.
Epicanthic folds simulate esotropia in
young children.
When the range of movement is limited,
it is important to determine whether the
limitation is due to muscle weakness or
mechanical restriction. For this purpose, a
forced duction test may be of value. After ap-
plying topical anesthesia, an attempt is
made to move the eye into the direction of
action of the paretic muscle. This can be
done using ophthalmic forceps or by sim-
ply pressing a cotton-tipped applicator
against the limbus of the cornea. First ask
the patient to attempt to look in the direc-
tion of action of the weak muscle. If it is
possible for the examiner to move the eye
into the paretic field, this implies weak-
ness of that muscle. Restriction to passive
movement constitutes a positive passive
forced duction test and indicates mechani-
cal restriction. Second, ask the patient to
attempt to look in the direction of action
of the paretic muscle while this movement
is actively opposed by the examiner's for-
ceps. Resistance to the forceps constitutes
a positive active forced duction test and
suggests that muscle strength is intact and
that the loss of ocular motility is due to
mechanical restriction. Modern MRI tech-
niques often allow precise diagnosis in
such patients.
In any patient with a reduced range of
voluntary eye movements, it is important
to exclude myasthenia gravis; usually an
edrophonium (Tensilon) test is performed
(see below).
SUBJECTIVE DIPLOPIA TESTING
When the patient is cooperative, subjec-
tive tests of diplopia may reliably indicate
the disparity between retinal images.

When strabismus is due to extraocular
muscle weakness (nonconcomitant or par-
alytic strabismus), the patient can view, with
the fovea of the nonparetic eye, targets in
all directions of gaze. The eye with the
paretic muscle, however, will not be able to
bring to the fovea the image of a target lo-
cated in the field of weakened action; con-
sequently, the image will be projected onto
extrafoveal retina (Fig. 9-10). In other
words, the patient will interpret the object
to be displaced in the direction of the
paralysis (or opposite to the direction of
the deviation). When the image is on the
nasal retina, the patient thinks the object
is in the temporal field of vision. This is
uncrossed diplopia and is typical of esotropia
(e.g., due to lateral rectus palsy). When
the image is projected onto the temporal
retina, the patient thinks the object is lo-
cated nasally. This is crossed diplopia and is
typical of exotropia (e.g., due to medial
rectus palsy).
Two further principles are important in
this type of diplopia testing: (1) the two
images are maximally separated when the
patient looks into the direction of action of
the paretic muscle, and (2) the target seen
by the paretic eye is usually projected
more peripherally, particularly as the pa-
tient looks into the paretic field. One can
determine which image comes from the
paretic eye by transiently occluding either
eye and asking the patient to report to
which eye the most remotely located im-
age belongs.
The use of a red glass or Maddox rod
(Fig. 9-11) usually aids examination. A
Maddox rod consists of small glass rods
with a red filter; it may be oriented ac-
cording to the desired plane of testing—
horizontal or vertical. When the Maddox
rod is held before the right eye and a pen-
light is viewed with both eyes, the patient
sees a white spot of light with the left eye
and, through the Maddox rod, a red line.
Since the Maddox rod can be rotated 90°,
the horizontal and vertical components of
diplopia can be evaluated separately. Ask
the patient to follow the penlight as the
eyes are taken into the nine cardinal posi-
tions. For each position, the patient re-
ports how far the white light and red line
are separated and where the white light is
located in relation to the red line. The im-
Diagnosis of Diplopia and Strabismus 339
Figure 9-11. The Maddox rod test. Because the
Maddox rod breaks fusional vergence, it tests for
both phorias and tropias. (See text for explanation.)
This patient has a left superior oblique weakness.
The separation of images is greatest when the patient
looks down and to the right.
age from the eye with the weakened mus-
cle (whether it be the white light or the red
line) will be projected furthest into the
paretic field of gaze. Note that the Mad-
dox rod prevents fusional vergence be-
cause the images are so dissimilar. There-
fore, it primarily tests for phorias and
latent palsies that may not be apparent
under binocular viewing conditions. Nor-
mal individuals commonly have a phoria,
so small, concomitant deviations detected
during Maddox rod testing may be nor-
mal. If a phoria is nonconcomitant, how-
ever, an extraocular muscle may be weak
or restricted. Two Maddox rods (one
white, one red) can be used to evaluate
torsional disparity between the two eyes,
although careful interpretation of the re-
sults is necessary, and other methods (such
as fundus photography) are sometimes in-
dicated.665
Other subjective tests that dissociate the
images seen by the two eyes include the
Hess screen test and the Lancaster
red-green test.^54 In the Lancaster test, the
patient wears goggles with a red filter in
front of the right eye and a green filter in
front of the left. Thus, the patient can see
the image of a red light with one eye and
the image of a green light with the other.
340 The Diagnosis of Disorders of Eye Movements

The test prevents fusional vergence. The

examiner holds one flashlight and the pa-
tient holds the other. The separation of
the red and green images on a screen, in
each of the nine cardinal positions of gaze,
is measured and represents the deviation
of the visual axes. An alternative method is
to measure the separation of red and
green lights at various points on the hori-
zontal and vertical meridians; 713 the in-
ferred positions of the right and left eyes
can then be plotted on a graph. The devia-
tion of such a curve from the line for or-
thophoria can be used to compare relative
strengths of yoke muscles and to deter-
mine whether the deviation is concomitan
or non-concomitant (paralytic). The Lan-
caster red-green test can be performed
with simple, inexpensive portable equip-
ment.605

COVER TESTS
Cover tests demand less cooperation on
the part of the patient than do the red
glass and Maddox rod tests, so they are
more suitable for examining young or
inattentive patients. Moreover, cover tests
can be used in patients without binocular
vision, provided they can fixate foveally.
Cover tests depend upon the principle
that, when one eye is required to fix upon
an object, it will do so with the fovea. (Cer-
tain exceptions to this rule, due to eccen-
tric fixation and anomalous retinal corre-
spondence, occur in some patients with
congenital strabismus).666 If the principal
visual axis is not directed toward the ob- Figure 9-12. The cover test. (A) Initially, with both
ject, then an eye movement (saccade) will eyes viewing, there is an esotropia (right eye turned
be necessary to move the image of the ob- in). (B) When the cover is placed before the nonfixat-
ing right eye, no movement occurs; nor does it occur
ject onto the fovea. It is the detection and when (C) the cover is removed. (D) When the left eye
estimation of the size of this corrective sac is covered, the right eye must fixate the target and a
cade (movement of redress) that provides movement of redress occurs. Note that the deviation
the clinician with an indication of mis- of the sound eye under cover (the secondary devia-
tion—a) is greater than that of the paretic eye under
alignment of the visual axes. cover (primary deviation—b). When the cover is re-
The cover test (Fig. 9-12) reveals het- moved, either (E) the left eye again takes up fixation,
erotropia (or tropia)—a misalignment of the or (F) the paretic eye continues to fixate, if the pa-
visual axes when both eyes are viewing a tient is an "alternate fixator."
single target. A target that requires visual
discrimination (e.g., an "E") must be used is also necessary. First with the eyes in the
to ensure a fixed accommodative state. central position (Fig. 9-12A), cover the
This fixation target should ideally be at a right eye and look for any movement of
distance of 6 m (20 feet). Sometimes, test- the uncovered left eye—the movement of re-
ing with a near target at 35 cm (14 inches) dress. If no movement of the left eye is de-
 Diagnosis of Diplopia and Strabismus 341

tected (Fig. 9-12B), remove the cover

(Fig. 9-12C) and then cover the left eye,
looking for a movement of redress of the
right eye (Fig. 9-12D) (see VIDEO: "Oculo-
motor nerve palsy"). Repeat this test with
the eyes brought to the nine cardinal posi-
tions of gaze by rotating the patient's head
while the eyes fix upon the same target.
The test can then be repeated with a near
target to determine the effect of vergence
and accommodation upon any ocular de-
viation.
Note that during the cover test only the
uncovered eye is observed. When the
cover is removed from the other eye, it
may also rotate to reacquire the target if it
is the preferred eye for fixation (Fig.
9-12E). If, however, neither eye is pre-
ferred (alternate fixation), then no move-
ment occurs when the cover is removed
(Fig. 9-12F). Movements of an eye that oc-
cur when the cover is removed from it—
the cover-uncover test—may indicate either
heterotropia or heterophoria (or pho-
ria)—misalignment of the visual axes
when only one eye is viewing. Therefore,
the cover test must first be performed to
determine if a tropia is present; if it is not,
then movement of the eye when the cover
Figure 9-13. The alternate cover test. This test pre-
is removed indicates a phoria. Use of a vents fusional vergence and thus tests for phorias
translucent occluder, which is opaque to and tropias. Any movement of the eyes, as the cover
the patient but transparent to the exam- is quickly transferred (to prevent binocular vision), is
iner, allows movements of the eye under noted. In this example, there is an esodeviation
caused by a right lateral rectus weakness. The sec-
cover to be observed.600 ondary deviation (a) of the sound, left eye under
In order to bring out the maximal devi- cover (shown in B) is greater than the primary devia-
ation—whether tropia or phoria—the al- tion (b) of the paretic, right eye under cover (shown
ternate cover test should be used. As the in A and C).
occluder is quickly transferred from one
eye to the other (to prevent binocular tion of the paretic eye under cover while
viewing), any movement of redress is noted the normal eye is fixating is referred to as
(see VIDEO: "Oculomotor nerve palsy"). the primary deviation; the deviation of the
Each eye must be covered for about 2 sec- normal eye under cover while the paretic
onds to allow the eyes to acquire their eye is fixating is called the secondary devia-
new resting position before switching the tion. The secondary deviation is always
cover. An example of the use of the alter- greater than the primary deviation (see
nate cover test in diagnosing a right sixth below). When the cover is moved from the
nerve palsy is shown in Figure 9-13. Be- paretic eye to the normal eye, the differ-
cause the deviation varies according to the ence between the primary and secondary
direction of gaze, the strabismus is non- deviations can be observed (see Fig. 9-12
concomitant and probably paralytic. Dur- and Fig. 9-13). With concomitant strabis-
ing the alternate cover test, the detection mus, however, the movement of redress is
of a larger movement of redress in one eye equal in both eyes. It is often helpful to
than the other also helps identify the weak perform the alternate cover test during
member of a yoke muscle pair. The devia- fixation of both near and far targets; sixth
342 The Diagnosis of Disorders of Eye Movements
nerve palsy may only become evident
while viewing far targets.
Performing the alternate cover test with
prisms is the most convenient way to mea-
sure the deviation. Place a prism before
the viewing eye and then alternate the
cover to establish whether there is any
change in the size of the movement of re-
dress. For esodeviations, the prism should
be placed base out; for exodeviations, base
in; for left hyperdeviation, base down in
front of the left eye; and for right hyper-
deviation, base down in front of the right
eye. (Generally, this may be stated, "The
prism points toward the deviation.") The
strength of the prism is increased until the
movement of redress is absent or just re-
verses (e.g., esotropia becomes exotropia).
The prism strength at this point then indi-
cates the magnitude of the deviation. This
procedure is simple (it may be performed
at the bedside) and often aids in the diag-
nosis and documentation of a change in
the strabismus.
DIAGNOSIS OF VERTICAL OCULAR
MOTOR DEVIATION: THE
BIELSCHOWSKY HEAD-TILT TEST
Testing of a vertical deviation is best per-
formed as a four-stage procedure: First,
determine the side of the hypertropia.
Second, determine whether the deviation
is greater in right or left gaze. Third, de-
termine whether the deviation is greater
in up or down gaze. Finally, measure the
size of the deviation with head tilt to the
right or left shoulder (the Bielschowsky
head-tilt test).
Consider a patient with an acute left su-
perior oblique weakness (Fig. 9-14). First,
with the eyes in central position, use the
cover-uncover test to reveal the tropia.
The alternate cover test confirms a left hy-
perdeviation (Fig. 9-14A). (By conven-
tion, all vertical deviations are described
as hyperdeviations.) This means that ei-
ther the depressors of the left eye or eleva-
tors of the right eye are weak. Second, ask
the patient to look to the right and to the
left and in both positions use the alternate
cover test to determine the effect on the
vertical deviation. In our particular pa-
tient, the left hyperdeviation is more
marked on gaze to the right (Fig. 9-14B).
In this position of gaze, the oblique mus-
cles become more important for control of
the vertical position of the left eye and the
vertical recti become more important for
the right eye. Thus, either the left supe-
rior oblique or the right superior rectus
must be weak. Third, ask the patient to
look up and down in right gaze (Fig.
9-14C). The left hyperdeviation will be
more marked in gaze down (the field of
action of the left superior oblique), pin-
pointing the weakness to the left superior
oblique muscle. Finally, the head is tilted
first to the left and then to the right,
performing the alternate cover test in
each position (Fig. 9-14D) (see VIDEOS:
"Trochlear nerve palsy"). It is important
to maintain the eyes close to central posi-
tion during this part of the testing. With a
left superior oblique palsy, the left hyper-
deviation becomes more marked on tilt of
the head to the left shoulder (positive
Bielschowsky head-tilt test). The reason
for this is that normally a small (about 5°)
counterrolling movement about the visual
axis occurs when the head is tilted 45°
to either shoulder. This ocular counter-
rolling reflex is accomplished by the con-
certed action of the superior rectus and
superior oblique of one eye and by the in-
ferior rectus and inferior oblique of the
other eye. When the action of the superior
oblique muscle is lacking on one side, only
the superior rectus will contract on that
side, and it elevates and intorts the eye. In
some patients with fourth nerve palsy, dy-
namic head rolling may induce vertical
nystagmus rather than the torsional nys-
tagmus that normally occurs.326
With an acute muscle palsy, the first
three tests usually give the diagnosis. With
time, deviations that were originally para-
lytic in type tend to become equal in all di-
rections of gaze (so-called spread of concomi-
tance}. In long-standing superior oblique
palsy, the deviation may even become
greater on up gaze. This may be due to a
change in innervational pattern as well as
due to mechanical factors. Occluding
one eye for 24 to 48 hours—diagnostic
occlusion—may bring out the maximum
deviation. Alternatively, when a muscle
paresis affects a strongly dominant eye,
 Diagnosis of Diplopia and Strabismus 343

Figure 9-14. The diagnosis of vertical ocular deviation. The steps in the diagnosis of a left superior oblique
palsy are shown. (A) In primary position there is a left hypertropia. This could be due to weakness of elevators
of the right eye or depressors of the left eye. (B) The deviation becomes worse on gaze to the right. This implies
weakness of the right superior rectus or the left superior oblique. (C) With the eyes in right gaze, the deviation
is more marked on looking down. This implies weakness of the left superior oblique muscle. (D) The
Bielschowsky head-tilt test. With a rightward head tilt, there is no detectable vertical deviation of the eyes. (This
would be the patient's preferred head position.) With the head tilted to the left, there is an exaggeration of the
left hypertropia.

the innervation to the other eye may ap-
pear to be affected. Consider a patient
with a left superior oblique palsy who ha-
bitually fixates with the left eye. To elevate
the adducted left eye requires less inner-
vation for the left inferior oblique muscle.
By Hering's law, the innervation to the
right superior rectus (to which the left in-
ferior oblique is yoked) will also be less
and so the depressed right eye may falsely
suggest a paresis of the right superior rec-
tus muscle.147'665 This may make steps 1
and 2 inconclusive,483 but step 3 will still
show that the deviation is greater in down
gaze and the Bielschowsky head-tilt test
results usually will be positive, the left
hypertropia being maximized on left
head tilt.
The head-tilt test results are positive in
most cases of oblique muscle palsies, and
the vertical deviation often increases with
time.576 The test results are positive less
frequently with palsies of the vertical recti,
inferior oblique, or restrictive ophthal-
mopathy.348 Bielschowsky thought that a
vertical deviation combined with a nega-
tive head-tilt test result usually indicated a
vertical rectus palsy.52
The physiologic basis of the head-tilt test
rests with the pattern of innervation to the
extraocular muscles during a head tilt to
either shoulder, when stimulation of the
vestibular otoliths induces ocular counter-
rolling. In this situation, the vertical eye
muscles no longer are driven in their usu-
ally yoked pairs. Instead, the otolithic re-
344 The Diagnosis of Disorders of Eye Movements
flex causes compensatory cyclorotation of
the eyes by co-innervation of the ipsilat-
eral (to the side of the tilt) superior
oblique and superior rectus muscles, pro-
ducing intorsion, and of the contralateral
inferior oblique and inferior rectus mus-
cles, producing extorsion. Weakness of
any one of these muscles leads to both a
cyclodeviation and a vertical deviation of
the eyes. Nevertheless, the deviation that
occurs following superior oblique palsy is
often larger than can be accounted for
simply by weakness of this muscle. Quanti-
tative analysis indicates that such devia-
tions must be due to overaction of the su-
perior rectus of the same eye.522 This
increase in the deviation, which tends to
become greater with time, may be due to
an increase in the gain (i.e., hyperactivity)
of ocular counterrolling,328'576 or to a
"tight" or contracted superior rectus.
PATHOPHYSIOLOGY OF SOME
COMMONLY ENCOUNTERED
SIGNS IN STRABISMUS
Primary and Secondary Deviation
Testing of the movements of each eye
viewing alone (ductions) may not reveal
minimal muscle weakness that the patient
can overcome by effort. Observing the
movements of both eyes at the same time
(versions), however, will often reveal a sub-
tle muscle paresis. The hallmark of stra-
bismus due to muscle paresis is incomi-
tance—the deviation varies as a function
of the angle of gaze. During alternate
cover testing, the deviations of the two
eyes (as judged by the movement of re-
dress) may differ. Most patients normally
fixate with their good eye, and the paretic
eye deviates a certain amount from the
line of sight: This is the primary deviation.
If, by briefly covering the good eye, the
weak eye is forced to fixate a target located
within its paretic field of action, then a
larger deviation of the good eye under
cover occurs: the secondary deviation
(Fig. 9-12 and Fig. 9-13) (see VIDEO:
"Oculomotor nerve palsy"). The discrep-
ancy between the size of the primary and
secondary deviations forms the basis of a
widely accepted clinical dictum used to
differentiate paralytic from nonparalytic
strabismus. The secondary deviation (the
angle between the visual axes of the eyes
when the paretic eye fixates a given target)
is greater than the primary deviation (the
angle between the visual axes when the
normal eye fixates the same target).
The explanation of this phenomenon is
mainly related to the change in the posi-
tion of the eyes within the orbits when ei-
ther one eye or the other takes up fixation
of the same target. When a single given
muscle is paretic, the deviation between
the two eyes is proportional to the differ-
ence between the forces generated by the
paretic muscle and its normal yoke mus-
cle. Furthermore, the amount of force
contributed by a given muscle to holding
the eye in a given orbital position in-
creases as the eye is moved into the direc-
tion of action of that muscle. Therefore, as
the eyes move in the direction of action of
the paretic muscle, the difference in forces
generated by the normal and paretic yoke
muscles increases, thus increasing the de-
viation between the two eyes—the hall-
mark of a paralytic or nonconcomitant stra-
bismus.
Why is secondary deviation evident
when the paretic eye is fixating? In this
case, the affected eye is held in an orbital
position farther in the direction of action of
the paretic muscle than when the non-
paretic eye is fixating the same target (Fig.
9-12 and Fig. 9-13). Therefore, the sec-
ondary deviation is greater than the pri-
mary deviation, mainly because of the
change in the positions of both eyes toward
the direction of action of the paretic mus-
cle. In addition, if the paretic eye is unable
to foveate a target that lies in its paretic
field of action, then the inability to de-
crease the retinal error (difference between
the location of the image of the target on
the retina and the fovea) precludes nor-
mal, negative feedback (see Chap. 4). This
open-loop stimulation leads to an increase in
the innervation sent to the extraocular
muscle and the secondary deviation is
made even larger. The fundamental reason

for the phenomenon, however, relates to
where both eyes are located in the orbits.
Past-pointing and Disturbance of
Egocentric Localization
Patients who have an acute paralytic stra-
bismus may mislocalize objects (e.g., an
examiner's finger) when rapidly reaching
in the direction of the field of action of the
paretic extraocular muscle. The phenom-
enon is more easily demonstrated if the
patient's pointing arm is hidden from his
or her view by, for example, being held
under a table. Alternatively, the patient is
asked to look at the target and then point
with the eyes closed. For example, a pa-
tient with a left lateral rectus palsy, when
viewing with the left eye and reaching into
the left field, will tend to past-point to the
left of the target. Although past-pointing is
usually thought of as a sign of paralytic
strabismus, it has been encountered occa-
sionally with concomitant deviations when
sight, long deprived from one eye, is sud-
denly restored.13
The explanation of past-pointing is con-
troversial. It could occur because, for ex-
ample, with a left lateral rectus palsy, the
image of the examiner's finger lies nasal to
the fovea of the paretic eye, and hence the
patient incorrectly localizes the object in
the temporal field. This explanation, how-
ever, does not account for the persistence
of past-pointing after the image of the tar-
get has been brought to the fovea of the
paretic eye.486'667 Another explanation for
past-pointing is that it reflects what
Helmholtz called the "intensity of the ef-
fort of will,"248 or efference copy, which is
sent to the paretic muscle (as evidenced by
the large deviation of the normal eye un-
der cover).
It has also been suggested that a mis-
match between extraocular propriocep-
tion and the neural signal being sent to
these muscles may contribute to the phe-
nomenon of past-pointing. Recall that the
important extraocular proprioceptors are
the palisade organs that lie at the musculo-
tendinous junctions. It is reported that
Diagnosis of Diplopia and Strabismus 345
if patients who have undergone correc-
tion of strabismus are tested the instant
the bandage is removed from their oper-
ated eye, they pointed accurately to targets
provided that the musculotendinous junc-
tion was not involved in the operation. If,
however, surgery has disrupted the mus-
culotendinous junction, pointing is in-
accurate.611'612 These results have not al-
ways been confirmed, however.63 Other
evidence to support a role for propriocep-
tion comes from the report that patients
with herpes zoster ophthalmicus,89 or
those who have undergone thermocoagu-
lation of the trigeminal nerve,656 may show
past-pointing. This may be due to dysfunc-
tion of the proprioceptive inputs that run
in the first division of the trigeminal nerve.
Experimental proprioceptive denervation
of the extraocular muscles in monkeys
does not impair pointing accuracy.3722 Fi-
nally, enucleation in infancy may lead to
esotropia of the remaining eye,249 im-
plying that afferent information from a
blind eye is important for the alignment of
the fellow eye. Although the relative roles
of inflow and outflow in past-pointing in
patients with strabismus have yet to be
agreed upon, this common clinical sign re-
mains an important method for studying
the ways that the brain constructs an accu-
rate internal map of extrapersonal space.
Head Tilts and Turns
Commonly, patients with strabismus turn
or tilt their heads to minimize diplopia.
Indeed, these findings suggest a paralytic
deviation of the eyes.88 Head turns are fre-
quently associated with paresis of the hori-
zontal extraocular muscles, most typically
lateral rectus palsy, in which case the head
is turned toward the side of the weakness.
They also occur in patients with congenital
nystagmus, when the nystagmus is reduced
by keeping the eyes in an eccentric (null)
position in the orbit. Rarely, a continu-
ous change of horizontal head position
occurs—-periodic alternating nystagmus (see
Chap. 10).
Patients with weakness of the vertical
recti may carry their heads flexed or ex-
346 The Diagnosis of Disorders of Eye Movements
tended to keep the eye out of the field of
action of the paretic muscle. Similarly, pa-
tients whose horizontal diplopia is made
worse in elevation or depression of the
eyes—A- pattern and V- pattern—may ele-
vate or depress their chin (see Clinical
Features and Diagnosis of Concomitant
Strabismus, below).
Head tilts (ear to shoulder) are most
common with paresis of the oblique mus-
cles but also occur with restrictive ophthal-
mopathy. With a superior oblique palsy, the
head is characteristically turned and tilted
away from the side of the weakness and
the chin may be depressed. The tilted pos-
ture of the head with a superior oblique
palsy is usually adopted to lessen diplopia.
In some patients, the head is habitually
tilted toward the side of the lesion; in this
situation, the deviation is actually greater,
but presumably this makes it easier for the
patient to ignore one image. In general,
however, patients adopt abnormal head
postures that keep the eye out of the field
of action of the paretic muscle. Compensa-
tory ocular head tilt should be differenti-
ated from the ocular tilt reaction, and
from spasmodic torticollis of other cause.
Dynamic Properties of
Eye Movements in
Paralytic Strabismus
Clinical testing of strabismus emphasizes
examination of static deviations of the eyes,
since these are relatively easy to quantify
and compare. Nonetheless, paralytic stra-
bismus invariably leads to changes in dy-
namic properties of the various classes of
eye movement.
Three different types of abnormalities
are encountered in patients with paralytic
strabismus. First, weakness of an extraoc-
ular muscle causes slowing and restriction
of all classes of eye movements made into
the field of action of that muscle, although
the specific pattern of weakness will de-
pend upon the innervational command
(see below). Second, if the patient views
with the paretic eye but the movements of
the covered, normal eye are measured,
then as the patient persists in attempts to
look at a target in the paretic field of ac-
tion, larger movements of the normal eye
will occur. This latter effect is referred to
as an open-loop response since the paretic
eye is not able to foveate the desired target
and the inability to decrease the retinal er-
ror precludes normal negative feedback.
(For discussion, see Chap. 4.) This phe-
nomenon is, in part, responsible for sec-
ondary deviation. Third, if the patient
chooses to habitually view with the paretic
eye (for example, by patching the normal
eye), then plastic-adaptive changes will oc-
cur; specifically, the brain will increase in-
nervation conjugately in an attempt to im-
prove the accuracy of movements of the
paretic eye. These adaptive changes af-
fect saccades,4'330'476 smooth pursuit, 476 the
vestibulo-ocular reflex,660 and even the
yoking mechanism itself. The last is only
amenable to a relatively small range of
adaptive change, which may nevertheless
be adequate to compensate for partial
muscle palsies.472 A fuller discussion of
these adaptive changes may be found in
chapters dealing with each class of eye
movements, but here findings from a pa-
tient are presented to illustrate key points.
The patient was a 70-year-old diabetic
man who suffered a left abducens palsy
1 month previously. At the time of eye
movement recording, the patient had
been habitually fixating with his normal,
right eye. With the sound eye covered, the
patient was able to look about 8° left into
the field of action of the paretic lateral rec-
tus muscle.
SACCADES IN
PARALYTIC STRABISMUS
With the sound eye viewing, the patient was
asked to alternately refixate targets lo-
cated 8° to the right and to the left of the
midline in the horizontal plane (Fig.
9-15A). Leftward saccades, made by the
paretic eye, were slow and hypometric,
with onward postsaccadic drifts that
slowed as the eye moved into the left field
of gaze. The initial part of these saccades,
from right gaze to the central position,
was faster because of the elastic restoring
forces, which helped the eye to the mid-
line. Rightward saccades, made by the left

eye, were, in contrast, rapid and only
mildly hypometric. The saccades of the
normal, right eye showed only mild hy-
pometria.
With the paretic eye viewing, a series of
slow, leftward saccades occurred in that
eye as the patient attempted to foveate the
leftward target. During refixations from
the target located at right 8° to that at left
8°, an initial saccadic command for a
movement of about 16° was sent out. This
is revealed by the movements of the sound
eye under cover, which reflect the neural
command sent to both eyes (Hering's law).
The paretic eye, however, fell short of the
target, and the persistent retinal error
stimulated a corrective saccadic command.
In this way, the paretic eye made a series
of saccades until the target was placed on
the fovea. When this was achieved, the
sound eye under cover was deviated to the
left of the desired eye position, a sec-
ondary deviation.
By contrast, rightward saccades made
by the viewing, paretic eye were rapid,
though hypometric. Each of these right-
ward saccades was followed by backward
drift of the eye, which necessitated small
corrective saccades. The corresponding
movements of the sound eye under cover
consisted of an initial rightward saccade of
about 14°, followed by a series of smaller
saccades.
The drifts of the paretic eye that follow
saccades can be attributed to at least three
factors. First, although the two horizontal
extraocular muscles in each eye contribute
reciprocally to eye movements, the rela-
tive contributions of each depend upon
orbital position. Second, the amount by
which the force of the agonist increases
and antagonist decreases can be related to
the pulse-step innervation program for
saccades (see Fig. 1-3 of Chap. 1). Sac-
cades need much larger agonist forces
than do slower movements such as pur-
suit. Relaxation of antagonist forces can
contribute relatively little to the pulse por-
tion of saccades, since incremental forces
in the agonist must be so much higher
compared to the possible forces from a
decrement in activity in the antagonist.
The step portion of saccades, however,
does depend upon contributions from a
Diagnosis of Diplopia and Strabismus 347
muscle both when it is acting as the ago-
nist (an increase in force) and as the antag-
onist (a decrease in force). Hence, sac-
cades made by the affected eye, in the
direction of action of the paretic muscle,
usually show a postsaccadic drift in the di-
rection of the movement, owing to the
decrement in antagonist forces. Third, the
backward drift following saccades made
into the normal field of movement by the
paretic eye may reflect a loss of the decre-
ment in antagonist forces of the weak eye
for the step of innervation (i.e., the paretic
muscle cannot be normally relaxed). Alter-
natively, these backward drifts that follow
saccades made into the normal field of
movement by the paretic eye may reflect a
central misrepresentation of the position
of the paretic eye by the gaze-holding net-
work (neural integrator). This would be a
consequence of the series of saccades re-
quired to attain leftward gaze.714
SMOOTH PURSUIT IN
PARALYTIC STRABISMUS
With the sound eye viewing, tracking by the
right eye was probably normal for the pa-
tient's age, with some catchup saccades ev-
ident (Fig. 9-15B). The paretic eye, under
cover, made similar movements through
a smaller range, due to the lateral rectus
weakness. With the paretic eye viewing, the
left eye appeared to make smooth follow-
ing movements, especially to the right.
The movements of the sound eye, under
cover, however, showed that the patient
was tracking target movement to the left
mainly with a series of small saccades. The
total amplitude of the movements in the
right eye was much greater than those in
the left (partly because of open-loop stim-
ulation—see Chap. 4).
VESTIBULAR RESPONSES IN
PARALYTIC STRABISMUS
Sinusoidal rotation during fixation of a
stationary target by the sound eye, or in
darkness, demonstrated a slightly asymmet-
ric reflex caused by the left lateral rectus
weakness (Fig. 9-15C). This reduced
range of vestibular eye movements proba-
bly accounts for the complaints of oscillop-
348 The Diagnosis of Disorders of Eye Movements

Figure 9-15. Abnormalities of versional eye movements in a patient with a left sixth nerve palsy. Eye move-
ments were recorded by infrared oculography. (A) Saccades between two targets located 8° to the right and left
of the midline. With the sound right eye viewing, leftward saccades made by the right eye were of normal veloc-
ity and only mildly hypometric, whereas leftward saccades made by the left eye were slow and hypometric. With
the paretic left eye viewing, leftward saccades made by the left eye were slow and hypometric, whereas leftward
saccade made by the right eye were hypermetric, reflecting the neural command sent to both eyes. (B) Smooth
pursuit. With the sound right eye viewing, the right eye made smooth pursuit with some catch-up saccades;
corresponding movements in the left eye were of smaller amplitude. With the paretic left eye viewing, the left
eye appeared to make smooth following movements. The right eye, however, showed a series of small saccades,
especially when tracking to the left, and a larger range of tracking movements, indicating the neural commands
being sent to both eyes. (C) Vestibulo-ocular reflex. During rotation in darkness, asymmetry of movements was
evident in the left eye due to the lateral rectus paresis; similar findings occurred during visual fixation with the
sound right eye. During fixation with the paretic left eye, the range of movements in the covered right eye in-
creased, due partly to saccades, reflecting the neural signals being sent to both eyes. CV, chair (head) velocity;
LEP, left eye position; LEV, left eye velocity; REP, right eye position; REV, right eye velocity; TP, target position.
Time marks at top are in seconds. Upward deflections indicate rightward movements.

sia, vertigo, or "dizziness" by some pa-
tients with paralytic strabismus.615'688 With
the paretic eye viewing, the amplitude of
movements of the sound right eye under
cover were increased, owing partly to sac-
cades.
CLINICAL FEATURES
AND DIAGNOSIS OF
CONCOMITANT STRABISMUS
A common diagnostic problem for the
neurologist is to determine whether or not
strabismus is paralytic. Sometimes a his-
tory of strabismus since childhood will set-
tle the matter; lack of diplopia in such pa-
tients is due to suppression of images from
one eye. In other patients, the demon-
stration of associated findings such as the
lack of stereoacuity or the presence of
latent nystagmus (see Display 10-12,
Chap. 10) help identify a longstanding
strabismus. Occasionally adults with a
history of strabismus since childhood will
develop diplopia if a new pair of specta-
cles encourages fixation with their nondom-
inant eye.349 This fixation switch diplopia
can be remedied with refraction that
encourages fixation with their dominant
eye.
 Diagnosis of Diplopia and Strabismus 349

Figure 9-15.—continued

Most nonparalytic horizontal deviations
of the optic axes are relatively concomi-
tant; that is, the deviation remains ap-
proximately the same for all fields of gaze,
whichever eye is fixating. Many individu-
als have small concomitant phorias when
the fusional mechanism is interrupted
by covering one eye. Concomitant tropias
(deviations that the fusional mechanism
cannot correct) or "strabismus" is asso-
350 The Diagnosis of Disorders of Eye Movements
dated with a variety of factors.666 These
include refractive errors (especially hyper-
metropia) and abnormalities of the accom-
modation-convergence synkinesis (see Ab-
normalities of Vergence in Chap. 8).
The acute onset of strabismus and
diplopia later in life need not be paralytic;
sometimes nonspecific illness, head injury,
or eye injury disrupts the fusional mecha-
nisms that maintain orthotropia. These
may present as convergence insufficiency
or divergence weakness (see Chap. 8). If,
however, the acute onset of a concomitant
tropia occurs without history of previous
strabismus, monocular visual loss, or my-
opia, and if nystagmus or other neurologi-
cal abnormalities are present, imaging
studies are warranted. 260 Thus, certain ac-
quired, central, neurologic problems such
as tumors or the Arnold-Chiari malforma-
tion occasionally present with onset or
worsening of strabismus.213'575-686
In some nonparalytic forms of horizon-
tal strabismus, the deviation is vertically
nonconcomitant; that is, the horizontal
deviation of the visual axes varies accord-
ing to the vertical position of the eyes.
These have been called A-pattern (e.g., es-
otropia that increases in upward gaze, or
exotropia that increases in downward
gaze) and V-pattern (e.g., esotropia that
increases in downward gaze, or exotropia
that increases in upward gaze). Such pat-
terns are encountered in patients with
craniosynostosis with hypertelorism.100 Oc-
casionally these patterns are encountered
in paralytic strabismus, the best example
being a V-pattern esotropia in bilateral
trochlear nerve palsy. V-patterns also oc-
cur in craniofacial anomalies and with le-
sions of the dorsal midbrain.446
Asymptomatic vertical phorias may oc-
cur in some normal individuals in the pe-
riphery of gaze.584 A commonly encoun-
tered, nonconcomitant, nonparalytic form
of strabismus is dissociated vertical deviation
(DVD], also called alternating sursumduction.
It is characterized by upward deviation of
whichever eye is under cover.651 In some
patients it manifests without covering one
eye. The phenomenon is unexplained, 70
but usually coexists with estropia and latent
nystagmus, and might represent a mecha-
nism to suppress the latter.2323 The latter is
a conjugate jerk nystagmus, accentuated
by covering one eye; both eyes drift to the
side of the covered eye, with oppositely di-
rected quick phases (see Display 10-12,
Chap. 10).137 Another nonparalytic verti-
cal deviation is so-called overactivity of the
inferior oblique muscle. This causes a hyper-
deviation of whichever eye is adducted
(also called upshoot in adduction or unilateral
sursumduction), but no deviation in central
position.577 Differentiation from fourth
nerve palsy depends upon demonstrating
that the deviation is greatest in up gaze
rather than in down gaze, though the two
may coexist. Skew deviation is a vertical
tropia that may vary in right and left gaze,
and is due to disturbance of prenuclear,
otolithic inputs. It is usually part of the oc-
ular tilt reaction and is associated with
other signs of brain stem dysfunction (see
Chap. 10).
When strabismus is associated with ei-
ther amblyopia or acquired visual loss, ab-
normal dynamic properties of eye move-
ments may coexist. During attempted
fixation, gaze is unstable in the eye with
poor vision (Fig. 10-lOB).104'363'604 This is
evident as low-frequency, bidirectional
drifts that are more prominent vertically,
and unidirectional drifts with nystagmus
that are more evident horizontally; the lat-
ter often conform to the pattern of latent
nystagmus. 137 Instability of gaze is proba-
bly due to the poor vision rather than stra-
bismus. Saccades in patients with poor vi-
sion in one eye are disconjugate, with
postsaccadic drifts, implying that normal
vision is required to calibrate the yoking
mechanism.268'363'400 Saccadic latency is in-
creased if the visual stimulus is presented
to the amblyopic eye.103 Amblyopia may be
associated with temporal-nasal asymmetry
of monocular optokinetic responses in the
nucleus of the optic tract—issues that are
discussed in Chap. 4.
CLINICAL FEATURES OF
OCULAR NERVE PALSIES
Our approach in discussing palsies of the
ocular motor nerves will be (1} to review
the typical clinical features; (2) to com-

Table 9-3. Laboratory Evaluation of
Palsies of CN III, IV, VI
Complete blood count with differential
Erythrocyte sedimentation rate
Tests for diabetes, thyroid disorder, syphilis,
Lyme disease
Acetylcholine receptor antibodies
Chest x-ray
Nasopharyngeal examination*
Consider CT, MRI with gadolinium enhance-
ment, MRA
Consider spinal tap
Edrophonium (Tensilon) test for painless and
subtle deficits
*Especially with abducens palsy and facial pain.
ment on the differential diagnosis; (3) to
discuss features that aid in topological di-
agnosis; and (4) to summarize the clinical
management. Some laboratory tests that
often aid the evaluation of palsies of the
ocular motor nerves are summarized in
Table 9-3. The differential diagnosis of
palsies of CN III, IV, and VI are summa-
Table 9-4. Differential Diagnosis of
Ocular Motor Nerve Palsies
Concomitant strabismus, with or without a his-
tory of eye muscle surgery
Disorders of vergence, especially spasm of the
near triad
Brain stem disorders causing abnormal
prenuclear inputs (e.g., skew deviation and
internuclear ophthalmoplegia)
Miller Fisher syndrome
Myasthenia gravis
Botulism
Restrictive ophthalmopathies (e.g., Brown's
superior oblique tendon syndrome)
Trauma (e.g., blowout fracture of the orbit)
Ophthalmic Graves' disease
Orbital metastases
Orbital pseudotumor
Orbital infections (e.g., trichinosis)
Disease affecting extraocular muscle (e.g., ocu-
lopharyngeal dystrophy)
Kearns-Sayre syndrome
Diagnosis of Diplopia and Strabismus 351
rized in Table 9-4. Diagnosis has been
aided by magnetic resonance imaging
(MRI) and magnetic resonance angiogra-
phy (MRA) of the head and by the applica-
tion of surface coils to visualize individual
extraocular muscles, orbital vessels, and
nerves.58'953'139'140'166'406'568 Nonetheless, even
with modern imaging and laboratory test-
ing, the cause of ocular nerve palsy is
not determined in 20% to 35% of pa-
tients.43'50'517'629
Abducens Nerve Palsy
CLINICAL FEATURES OF
ABDUCENS NERVE PALSY
Abducens nerve palsy is the most common
ocular motor paralysis. It causes horizon-
tal diplopia, which is greatest when view-
ing distant objects and when looking ipsi-
laterally; the two images are uncrossed.
Abduction is restricted or slowed (see
VIDEO: "Abducens nerve palsy"), and there
is an esotropia (or in mild cases, only an
esophoria) that is greatest on looking to-
ward the side of the lesion (Fig. 9-12 and
Fig. 9-13). With the Maddox rod, some
patients may show small, associated, verti-
cal deviations.579
Abducens palsy should be differentiated
from other causes of impaired abduction
(Table 9-4). Differentiation from long-
standing esotropia can sometimes be diffi-
cult, but old photographs often will help.
Stereopsis, impaired in strabismus, is usu-
ally preserved in patients with acquired
abducens palsy. Duane's syndrome is asso-
ciated with retraction of the globe on ad-
duction. Functional convergence spasm
is sometimes confused with sixth nerve
palsy, but careful observation of the pupils
and of ductions (range of movement with
one eye covered) will help identify this
psychogenic cause of reduced abduction.
Restrictive ophthalmopathies, such as that
due to thyroid ophthalmopathy, are iden-
tified by a forced duction test. Myasthenia
gravis can usually be diagnosed by the
edrophonium (Tensilon) test. Causes of
abducens palsy are summarized in Table
9-5.
352 The Diagnosis of Disorders of Eye Movements
Table 9-5. Etiology of Abduccns Nerve Palsy50'195'296'324'517'542'629
Nuclear (characterized by horizontal gaze palsy)
Mobius syndrome93-340-377-416-484
Other congenital or hereditary gaze
palsies343'564'700
Duane's syndrome (most cases)144'259'419-440
Infarction 47 ' 443
Tumor408
Wernicke-Korsakoff syndrome109
Trauma117
Histiocytosis X492
Fascicular (nucleus to exit from brain stem)
Infarction155'190'296'311
Demyelination296'436
Tumor*296
Inflammation 394
Wernicke-Korsakoff syndrome 109
Subarachnoid
Compression by arteriosclerotic or anomalous
vessels or aneurysm (anterior inferior cere-
bellar artery, posterior inferior cerebellar
artery, or basilar artery)62'123'466
Subarachnoid hemorrhage*296
Trauma296
Meningitis (infectious—including syphilis and
Lyme disease),32-297-453'583'612* neoplastic,507
and in association with AIDS49'303
Wegener's granulomatosis454
Clivus tumor239'664
Cerebellopontine angle tumors296
Trigeminal schwannoma
Abducens nerve tumors 468
Neurosurgical complication2423-703
Petrous
Infection of mastoid or tip of petrous bone131
Thrombosis of inferior petrosal sinus621
Trauma15'368'444
"Common causes of bilateral abducens palsy.
tMay cause paresis by involvement of nerve, or extraocular muscle.
DISORDERS AFFECTING THE
ABDUCENS NUCLEUS
Acquired Horizontal Gaze Palsies
Sixth nerve palsy should be differentiated
from the effects of lesions of the abducens
nucleus (see Display 10-20, in Chap. 10).
Petrous—continued
Downward displacement of brain stem by
supratentorial mass (e.g., tumor, pseudo-
tumor cerebri)530
Following lumbar puncture, myelography,
spinal or epidural anesthesia, or ventriculo-
atrial shunt 46 ' 164
Spontaneous intracranial hypotension 256
Aneurysm, arteriovenous malformation, or
persistent trigeminal artery43i.538a,64i
Cavernous Sinus and Superior Orbital Fissure
Carotid aneurysm 2 ' 227 or dissection546
Cavernous sinus thrombosis152'672
Carotid-cavernous fistula: direct and
dural245'313'336'372'559
Tumor: pituitary adenoma, nasopha-
ryngeal carcinoma, meningioma,
other102'122'240'267'382'450
Dental anesthesia388
Sphenoid sinus mucocele441
Tolosa-Hunt syndrome87
Herpes zoster17
Nerve infarction
Orbital*
Tumor, and other infiltrates
Following arterial ligation for epistaxis115'275
Localization Uncertain
Nerve infarction (associated with diabetes, hy-
pertension, or arteritis)553
Migraine485
In association with viral and other infections,
immunization, and the idiopathic form of
childhood55-65'111'675'682'716
Transient palsy in newborns 192 ' 371
Toxic side effect of drugs474-618-657
The latter contains abducens motoneu-
rons that supply the lateral rectus muscle
and abducens internuclear neurons that
project, via the medial longitudinal fasci-
culus, to the medial rectus subdivision of
contralateral oculomotor nucleus (see Fig
6-1, Chap. 6). Thus, lesions of the ab-
ducens nucleus cause an ipsilateral, conju-

gate gaze palsy (i.e., defective abduction in
the ipsilateral eye and defective adduction
in the contralateral eye.)47'408'443'492 An ip-
silateral, peripheral facial nerve palsy is an
almost invariable accompaniment because
of the proximity of the fascicles of this
nerve to the abducens nucleus. Larger le-
sions may also affect the ventral pons and
pyramidal tracts; for example, Foville's syn-
drome consists of an ipsilateral, horizontal
gaze palsy, ipsilateral facial palsy, and con-
tralateral hemiparesis.
Mobius Syndrome and Failure
of Development of the
Abducens Nucleus
The abducens nucleus is susceptible to ab-
normalities of development or injury in
early life. Mobius syndrome consists of a
congenital disturbance of conjugate hori-
zontal gaze and facial diplegia.93'416 It may
be accompanied by atrophy of the tongue,
deformities of the head and face, endo-
crine abnormalities, and malformations of
the chest, great vessels, and extremities.
Present evidence suggests that either ge-
netic disorder340-484 or hypoxic-ischemic
insult to the fetus 377 may cause the syn-
drome.93
Congenital paralysis of horizontal gaze
that is probably due to abnormal develop-
ment of the abducens nucleus has also
been described with mild or absent facial
weakness;343'717 some of these palsies are
familial,564'700 and scoliosis may be pres-
ent. Vertical eye movements may be nor-
mal or show deficient smooth pursuit.
Some patients show pendular nystagmus.
It is possible that some of these reported
cases are similar to congenital fibrosis of
the extraocular muscles, in which there is
failure of development of the oculomotor
nucleus. 162 In others, MR findings suggest
absent abducens nuclei.17a
Patients with congenital absence of hori-
zontal, conjugate eye movements may
adopt several adaptive strategies to com-
pensate for their deficit. They substitute
rapid head movements (head saccades) for
eye saccades to change gaze rapidly.547
When the head is restrained, they may use
their intact vergence system to move both
eyes into adduction and then cross-fixate,
Diagnosis of Diplopia and Strabismus 353
using the right eye to view objects seen on
the left and vice versa. Such substitution of
vergence for versional movements also has
been reported in patients with a variety of
gaze and muscle palsies.82'83-684 In some
patients, retraction of the nonfixing eye
occurs during such vergence movements.717
Duane's Syndrome
Failure to develop normal innervation of
the lateral rectus muscle is the cause of
most cases of Duane's retraction syn-
drome.144 This syndrome occurs in three
forms,666 each of which is characterized by
a narrowing of the palpebral fissure on
adduction secondary to retraction of the
eye. Type I, the most common, is charac-
terized by limitation of abduction but full
adduction. In type II, the eye abducts well
but adduction is incomplete. Type III pa-
tients show limitation of both abduction
and adduction.
The key to clinical diagnosis of Duane's
syndrome is identification of retraction of
the eyeball, evident as narrowing of the
palpebral fissure, on adduction. This phe-
nomenon is brought out during horizon-
tal saccades (see VIDEO: "Duane's syn-
drome") or by observing the affected eye
from the side during nystagmus induced
by optokinetic stimulation. In addition to
limitation of horizontal movement (usu-
ally abduction), there may also be abnor-
mal "upshoot" or "downshoot" movements
as the patient attempts to shift horizontal
gaze.59 Duane's syndrome is more com-
mon in female patients, affects the left
eye more than the right, and may be bilat-
eral. It may be familial,253'484 and a num-
ber of associated congenital abnormalities
have been reported.144'405'565 Patients with
Duane's syndrome seldom complain of
diplopia; in fact, they usually have binocu-
lar, single vision with good stereopsis and
fusion when the eyes are in the field of in-
tact movement.637 Occasionally, diplopia
may develop later in life, making differen-
tial diagnosis from abducens palsy diffi-
cult. In such patients, ocular retraction
during adduction provides a useful diag-
nostic clue.
Most cases of Duane's syndrome are due
to a congenital anomaly of innervation.
354 The Diagnosis of Disorders of Eye Movements
This view was initially based on elec-
tromyographic evidence262'264-391 and has
been confirmed by clinicopathologic stud-
ies. Neuropathologic examination of one
patient with a unilateral left-sided type I
Duane's syndrome showed an absent left
abducens nerve; the left lateral rectus was
innervated by aberrant branches from
the inferior division of the oculomotor
nerve.419 The brain stem of this patient
showed a normal right abducens nucleus
but the left abducens nucleus contained
less than half as many neurons as the
right; these remaining cells were thought
to be abducens internuclear neurons since
the medial longitudinal fasciculi were in-
tact. These findings are in accord with the
observation that adducting saccades in the
normal eye of patients with a unilateral
type I Duane's syndrome usually have
normal velocities or only slight slow-
ing.218'698 Similar autopsy findings were
reported in a patient with familial, unilat-
eral Duane's type III syndrome.440 An-
other patient who had bilateral type III
Duane's syndrome lacked both abducens
nuclei and nerves.259 Thus, the limitation
of horizontal movement in most cases of
Duane's syndrome can be ascribed to an
agenesis of abducens motoneurons (see
Fig. 6—1, Chap. 6). Failure of abduction is
due to lack of innervation of the lateral
rectus by the abducens nerve. Absence of
the abducens nerve can sometimes be con-
firmed by MRI.483a Retraction of the globe
on adduction is brought about by cocon-
traction of the horizontal recti, which is
the consequence of aberrant innervation
of the lateral rectus muscle by the oculo-
motor nerve. When there is limited ad-
duction of the eye, this could also be due
to cocontraction of the lateral and medial
recti. The upshoot and downshoot of the
eye that occurs during horizontal move-
ments in Duane's syndrome may be be-
cause of side-slip of the horizontal recti
brought about by weakening of the hori-
zontal recti due to chronic cocontrac-
tion.142 Alternatively, certain patients may
have anomalous innervation of vertically
acting muscles.
Although most cases of Duane's syn-
drome are congenital, a similar clinical
syndrome can occur with acquired disease
of the extraocular muscles or of the orbit
(e.g., fibrosis or inflammation of muscle or
fascia).210'607'666 The occurrence of Duane's
syndrome in patients with thalidomide
embryopathy suggests that the distur-
bance in development occurs between
about 21 and 26 days.417 Although there is
presently no genetic model of Duane's
syndrome, a mutant mouse has been de-
scribed that fails to develop oculomotor
and trochlear motoneurons and shows
aberrant innervation of extraocular mus-
cles with the abducens nerve.499'500 Re-
ports of patients also suggest other forms
of congenital anomalous innervation of
extraocular muscles, such as abduction
twitch on attempted up gaze (Fig. 9-16)327
or synkinesis of the levator and lateral rec-
tus with eyelid elevation occurring on at-
tempted abduction.442 Another reported
anomaly is restricted up gaze and ex-
otropia in up gaze due to the persistence
of a retractor bulbi muscle, which, in ro-
dents, retracts the globe.649 Congenital fi-
Figure 9-16. Probable congenital synkinesis of supe-
rior rectus and lateral rectus, causing abduction with
upward movements. The patient was a 27-year-old
woman who had no visual complaints but was noted to
have a diagonal trajectory for upward, but not down-
ward, saccades. This difference was more marked
when she made vertical saccades in right gaze. Rapid
vestibular movements were similarly affected. OD,
movements of right eye; OS, movements of left eye.
The arrow indicates the direction of upward saccades
in the left eye. H: horizontal; V: vertical.

brosis of the extraocular muscles, dis-
cussed at the end of this chapter, has also
been shown to be a genetic disorder char-
acterized by failure of development of oc-
ular motoneurons; in this case, the supe-
rior division of the oculomotor nerve is
affected.162
DISORDERS AFFECTING THE
ABDUCENS FASCICLES
As the abducens nerve fascicles course
through the medial pons to gain the ven-
tral surface, they pass next to the pyrami-
dal tract. Hence, infarction of the ventral
paramedian pons may produce ipsilateral
abducens palsy, contralateral hemiplegia,
and ipsilateral facial weakness, Millard-
Gubler syndrome. Sixth nerve palsy accom-
panied only by contralateral hemiplegia,
constitutes Raymond's syndrome. Other im-
portant causes of nuclear and fascicular
sixth nerve lesions include both pontine
and cerebellar tumors, Wernicke's en-
cephalopathy, and multiple sclerosis.6263
Demyelination causes bilateral sixth nerve
palsy as commonly as unilateral. Rarely,
isolated sixth nerve palsy may be due to a
fascicular lesion.155
DISORDERS AFFECTING THE
SUBARACHNOID PORTION OF THE
ABDUCENS NERVE
After emerging from the brain stern, the
nerve may fall prey to infectious or neo-
plastic meningitis and may be compressed
by vascular structures such as an enlarged
ectatic basilar artery. As the nerve ascends
to the petrous ridge, it may be compressed
by clivus tumor, such as chordoma or
meningioma; such tumors may produce
bilateral, isolated sixth nerve palsy. The
abducens nerve is fixed where it pierces
the dura, so any downward displacement
of the brain stem caused by a supratentor-
ial mass lesion may produce either unilat-
eral or bilateral sixth nerve palsy. Al-
though oculomotor nerve palsy is a more
useful diagnostic sign of acute transtentor-
ial herniation, abducens palsy is more
common when such a process evolves
slowly. Diplopia caused by lateral rectus
weakness sometimes develops after other-
Diagnosis of Diplopia and Strabismus 355
wise uncomplicated lumbar puncture with
or without accompanying increased in-
tracranial pressure, after halopelvic trac-
tion for neck injury, and with intracranial
hypotension. In such cases, traction on the
subarachnoid portion of the abducens
nerve seems the likely mechanism.
DISORDERS AFFECTING THE
PETROUS PORTION OF THE
ABDUCENS NERVE
After leaving the subarachnoid space, the
nerve rests upon the petrous bone and its
crest. Here it is susceptible to trauma
(temporal bone fractures) and spread of
infections from the underlying mastoid
process. These infections can cause pet-
rositis or thrombosis of the inferior pet-
rosal sinus, both of which may affect func-
tion in the adjacent fifth and sixth cranial
nerves, with consequent diplopia and fa-
cial (usually supraorbital) pain. The com-
bination of pain in the distribution of the
first trigeminal division and impaired ab-
duction (often accompanied by deafness)
constitutes Gradenigo's syndrome. This syn-
drome is now more commonly due to tu-
mor than to infection.
DISORDERS AFFECTING THE
CAVERNOUS PORTION OF THE
ABDUCENS NERVE
After the sixth nerve passes forward into
the cavernous sinus, it lies lateral to the in-
ternal carotid artery, where the oculosym-
pathetic fibers are located (Fig. 9-8).
Aneurysms of the internal carotid artery
and tumors or infection in the cavernous
sinus may cause weakness of the ipsilateral
lateral rectus muscle and, rarely, an associ-
ated ipsilateral Horner's syndrome. 2 ' 227 ' 617
Tumor, inflammation, or carotid-cavernous
fistula may compromise the abducens
nerve as it passes through the cavernous
sinus and superior orbital fissure. Tumor
arising from the base of the skull, partic-
ularly nasopharyngeal carcinoma, may
compress the sixth nerve. This occurs be-
cause most nasopharyngeal tumors arise
in the fossa of Rosenmuller, immediately
beneath the foramen lacerum. Extension
of the tumor up through the foramen
356 The Diagnosis of Disorders of Eye Movements
lacerum brings it into contact with the
fifth and sixth cranial nerves.527 Thus, the
combination of facial pain and diplopia is
a common presentation of nasopharyn-
geal carcinoma. Serous otitis media is
a frequent accompaniment because of
blockage of the eustachian tube. Infarc-
tion of the abducens nerve, in association
with diabetes or hypertension, may also
occur within its cavernous portion.
BILATERAL ABDUCENS
NERVE PALSY
Compared with unilateral palsies, bilateral
abducens nerve palsy more commonly oc-
curs with tumors, demyelination, sub-
arachnoid hemorrhage, meningitis, Wer-
nicke's encephalopathy, and increased
intracranial pressure. 296 Associated abnor-
malities, such as other cranial nerve
deficits and long tract signs, usually help
make the diagnosis. Bilateral abducens
palsy must be differentiated from func-
tional convergence spasm and divergence
paresis; these entities are discussed in
Chap. 8.
ABDUCENS NERVE PALSY
IN CHILDREN
Sixth nerve palsy in children up to age 3
years seldom causes a complaint of double
vision; a head turn to the involved side
is the most prominent finding. Certain
childhood disorders commonly cause ab-
ducens palsy.242'309'324 Thus, abduction
weakness may be the first sign of tumor of
the posterior fossa. In these cases, a coex-
istent horizontal gaze palsy may suggest
a pontine glioma. Coexistent cerebellar
signs usually indicate astrocytoma, ependy-
moma, or medulloblastoma. Less com-
monly, supratentorial mass lesions present
with lateral rectus weakness, usually with
papilledema. Sixth nerve palsy in child-
hood may also occur in association with vi-
ral illness or vaccination (see VIDEO: "Ab-
ducens nerve palsy").65'111'682 If diplopia is
the only symptom, and imaging studies,
spinal fluid examination, and myasthenia
gravis test results are normal, the child
usually recovers and corrective surgery is
only occasionally necessary. Gradenigo's
syndrome may be due to middle ear infec-
tion, though if hearing is preserved, a tu-
mor may be the cause.
In infants, sixth nerve palsy must be dif-
ferentiated from Duane's syndrome and
congenital esotropia with cross-fixation.
The latter may occur in association with
latent nystagmus (nystagmus blockage
syndrome) as part of the infantile squint
syndrome.136 In a patient who cross-fix-
ates, the lateral rectus can be shown to be
intact by the doll's head maneuver or by
patching one eye for several days. Patch-
ing forces the child to abduct the eye to
see laterally. Any child who suddenly de-
velops an ocular deviation must be care-
fully evaluated for loss of vision in the de-
viating eye, which may be due to tumors
in the retina or anterior visual pathways.
MANAGEMENT OF ABDUCENS
NERVE PALSY
Patients presenting with abduction weak-
ness may have a variety of disorders other
than sixth nerve palsy (Table 9-4). After
these differential diagnoses are excluded,
certain routine tests are usually indicated
to identify the site and cause of the palsy
(Table 9-3). Most patients have abducens
palsy in association with diabetes or hy-
pertension ("medical sixth") and although
some initial worsening is the rule, 273 over
75% show some recovery within 6
months. 317 These patients usually require
little workup at the time of their presen-
tation. However, young adults, children,
and older individuals who do not have
diabetes or hypertension merit fuller in-
vestigation, including brain imaging. Ab-
ducens nerve palsy that persists for more
than 6 months and is unaccompanied by
other symptoms or signs may sometimes
be due to intracavernous aneurysms, tu-
mors such as meningioma, or metasta-
ses 195,317 Although sixth nerve palsy asso-
ciated with diabetes usually resolves, it
may not in patients in whom hypertension
is implicated or if no other cause is found.
If no resolution of abduction paresis is evi-
dent after 3 to 6 months, repeat MRI and
nasopharyngeal examination are usually
indicated.

Trochlear Nerve Palsy
CLINICAL FEATURES OF
TROCHLEAR NERVE PALSY
Trochlear nerve palsy accounts for most
cases of acquired vertical strabismus. Most
patients with unilateral trochlear nerve
palsy complain of vertical and torsional
diplopia that is typically worse when look-
ing down, such as when descending a
flight of stairs. Disturbances of the percep-
tion of slant also occur, due to the cyclode-
viation.376 If the patient views a vertical
bar, the top will appear closer. When view-
ing a horizontal bar, the two images will be
slanted with respect to each other, with the
apparent intersection of the lines pointing
toward the side of the affected, excyclo-
deviated eye.
Trochlear nerve palsy causes a hyper-
tropia of the affected eye, which is in-
creased during adduction and depression.
A common finding is head tilt away from
the side of the lesion. The most reliable
clinical test to diagnose fourth nerve palsy
is the head-tilt test (Fig. 9-14) (see VIDEOS:
"Trochlear nerve palsy"). The hypertropia
is maximized as the head is tilted toward
the side of the lesion and minimized on
contralateral head tilt. It may also increase
on attempted down gaze and with ipsilat-
eral head turn (contralateral gaze). In a
patient who has a third nerve palsy and
who is unable to adduct, the action of the
superior oblique muscle can be best evalu-
ated by looking for intorsion of the ab-
ducted eye on attempted downward gaze.
Clinical features of bilateral trochlear
nerve palsy are summarized in the case
history below. Measurement of eye move-
ments in patients with trochlear nerve
palsy has shown that vertical saccadic
velocities may be normal, but downward
saccades are hypometric;2913'608'628 muscle
surgery may improve conjugacy.375
The main differential diagnoses of
trochlear nerve palsy are skew deviation,
thyroid and other restrictive ophthal-
mopathies, and overaction of the inferior
oblique muscle. With skew deviation, the
head-tilt test is usually negative. Accom-
panying brain stem findings, such as in-
ternuclear ophthalmoplegia, are common
Diagnosis of Diplopia and Strabismus 357
with skew deviation but rare with
trochlear nerve palsy.652 Typically, the hy-
pertropic eye in fourth nerve palsy is ex-
torted, whereas with skew deviation it is
intorted; these differences are relatively
small, however, and may fall within the
range shown by normal subjects.149 Re-
strictive ophthalmopathies are diagnosed
by a forced duction test and imaging of
the orbit. Certain patients with nonparetic
strabismus since childhood may have clini-
cal findings that mimic fourth nerve
palsy;577 these have been referred to by
the terms upshoot in adduction or unilat-
eral sursumduction. Since the deviation is
greatest in adduction and up gaze, overac-
tion of the inferior oblique muscle may be
the mechanism. Such patients show large
vertical fusional abilities that have been
developed to compensate for their muscle
weakness. Old photographs showing a
long-standing head tilt may help make the
diagnosis. In diagnosing fourth nerve
palsy, it should be noted that some normal
individuals may show small hyperdevia-
tions, as revealed with the Maddox rod.584
Causes of trochlear palsy are summarized
in Table 9-6. Of all the extraocular mus-
cles, the superior oblique is perhaps most
amenable to MRI, using surface coils, to
demonstrate size and contractility.140
DISORDERS AFFECTING
THE TROCHLEAR NUCLEUS
AND FASCICLES
The trochlear nucleus may be congenitally
absent or hypoplastic. In addition, it may
be damaged by brain stem infarction,
hemorrhage, trauma, or tumor. Since the
fascicles of the trochlear nerve lie so close
to the nucleus, it is usually impossible to
differentiate nuclear from fascicular le-
sions. When fourth nerve palsy is associ-
ated with a Horner's syndrome on the side
opposite to the palsy, however, a brain
stem location affecting fibers prior to their
decussation may be present. 231
TROCHLEAR NERVE PALSY DUE
TO HEAD TRAUMA
The most frequently diagnosed cause of
fourth nerve palsy is head trauma, espe-
358 The Diagnosis of Disorders of Eye Movements
Table 9-6. Etiology of Trochlear Nerve Palsy50'304'324'387-517'629'669
Nuclear and Fascicular
Aplasia93
Mesencephalic hemorrhage or infarc-
tion69'623'652
Tumor and other mass lesion300'341-465
Arteriovenous malformation 231
Trauma300
Demyelination 704
Neurosurgical complication304
Subarachnoid
Trauma276'304-368
Tumor: pineal tumors, tentorial meningioma,
ependymoma, metastases, trochlear nerve
tumors, others205-271'304'539'543'590
Aneurysm of the superior cerebellar artery8 or
posterior communicating artery5673
Hydrocephalus 232
Neurosurgical complication 277 ' 703
Meningitis (infectious and neoplastic)95'304'507
Superficial siderosis569
*More commonly accompanied by other ocular motor nerve palsies (see Table 9-9).
t
May cause paresis by involvement of nerve, tendon, trochlea, or extraocular muscle.
daily blunt frontal injury (e.g., that caused
by motorcycle accidents). Occasionally,
mild head trauma may cause a superior
oblique weakness, especially if there is an
underlying disorder, such as an arterio-
venous malformation.276 With bilateral
trochlear nerve palsies, the lesions are
likely to be in the anterior medullary
velum, where the nerves emerge together.
Contrecoup forces transmitted to the
brain stem by the free tentorial edge may
injure the nerves at this site. The following
case is typical.
CASE HISTORY: Bilateral trochlear
nerve palsy
A 35-year-old man, who had just been released
from jail, drank a large quantity of beer and
decided to spend his first evening of freedom
sleeping on the roof of a garage "underneath
the stars." He awoke the next morning lying on
the ground with a headache and double vision.
When evaluated in the emergency room he
complained of vertical diplopia. With the red
glass before his right eye, in central position,
Subarachnoid—continued
Following lumbar puncture or spinal
anesthesia318
Cavernous Sinus and Superior Orbital Fissure
Tumor321'578
Tolosa-Hunt syndrome*
Herpes zoster17'357'516
Internal carotid aneurysm 18 or dissection546
Carotid-cavernous sinus dural fistula 557
Orbitf
Trauma
Tumor and other infiltrates437'532
Localization Uncertain
Nerve infarction (associated with diabetes or
hypertension) 517
Congenital21'243'324
Idiopathic517
Tetanus477
In association with familial periodic ataxia28
he reported the white light to be above the red
one. On looking down and to the left, the im-
ages separated further, but the white light was
still above the red one. On looking down and
to the right, the images were also separated,
but now the white light was below the red one.
Cover testing revealed right hypertropia and
a small esotropia in the central position. The
right hypertropia increased on left lateral gaze
and reversed to a left hypertropia on right
gaze. On tilting the head to the right, there was
a right hypertropia; on tilting the head to the
left, there was a left hypertropia. The impres-
sion was that the patient had a bilateral fourth
nerve palsy secondary to trauma.
Comment: This case illustrates the cardinal
diagnostic features of a bilateral superior
oblique paresis: an alternating hyperdeviation
depending on the direction of horizontal gaze
and, in asymmetric cases, tilt of the head. Both
subjective and objective tests of superior
oblique function in the diagnostic positions of
gaze, and the head-tilt test, brought out the bi-
lateral weakness of the superior oblique mus-
cles. Other features of bilateral superior
oblique palsy include a large degree of excy-

clotropia that may be evident during ophthal-
moscopy (elevated position of the disc in rela-
tion to the macula) and a V-pattern esotropia
(i.e., esotropia that is worse on looking
down).358'496'665'669 It is important to differenti-
ate fourth nerve palsy secondary to head
trauma from orbital blow-out fracture (see be-
low).
OTHER COMMON CAUSES OF
TROCHLEAR NERVE PALSY
The second-most-commonly diagnosed
cause of trochlear palsy is ischemic neu-
ropathy, often associated with diabetes
("medical fourth"). Unlike third nerve
palsy, no clinicopathologic correlation of
this process has been made. The prognosis
of such palsies is much better than the prog-
nosis of palsy caused by trauma. Pressure
from hydrocephalus or from adjacent dis-
eased vascular structures may cause fourth
nerve palsy. When an intracavernous ca-
rotid aneurysm compresses the trochlear
nerve, the oculomotor nerve is usually
also affected. Certain tumors (Table 9-6)
and neurosurgical procedures may cause
trochlear palsy, as may hydrocephalus. Her-
pes zoster ophthalmicus may affect any of
the ocular motor nerves.17 Fourth nerve
palsy may be associated with herpes zoster
because the ophthalmic trigeminal division
and the trochlear nerve share the same
connective tissue sheath. When only the
trochlear nerve is involved, the palsy may
be caused by a local granulomatous angiitis,
which originates in the ophthalmic division
and spreads upward; postmortem exami-
nation in one patient with total, unilateral
ophthalmoplegia revealed inflammation
and demyelination of the trochlear nerve
within the cavernous sinus.357 Orbital dis-
ease may cause weakness of the superior
oblique muscle, but in most of these cases,
damage to the muscle, the trochlea, or the
tendon is more likely than a lesion of the
fourth cranial nerve.
MANAGEMENT OF TROCHLEAR
NERVE PALSY
Patients presenting with vertical diplopia
usually have trochlear nerve palsy or skew
Diagnosis of Diplopia and Strabismus 359
deviation,72 but consideration should be
given to other disorders that are summa-
rized in Table 9-4. Some patients may
have congenital palsies that have decom-
pensated later in life and cause vertical
diplopia. Consideration should also be
given to the syndrome of overaction of the
inferior oblique.577'666 In patients who lack
a history of head trauma, MRI may show
relevant brain stem lesions, and gadolin-
ium enhancement usually demonstrates
infiltrative or inflammatory processes in-
volving the long course of the fourth
nerve.205 Often the cause of fourth nerve
palsy cannot be ascertained.517 Isolated su-
perior oblique palsy with no apparent
cause is only rarely caused by tumor or
aneurysm. If the results of imaging of the
head and orbit are normal, and test results
for diabetes and myasthenia are negative,
then the outcome is usually favorable.
BROWN'S SYNDROME
Brown's syndrome is characterized by lim-
ited elevation of the adducted eye because
the movements of the superior oblique
tendon are restricted in the trochlea.191
When congenital, the superior oblique
tendon may be short or tethered.235'562
When acquired, the tendon may be pre-
vented from passing through the trochlea
by tendosynovitis, adhesions, metasta-
ses,582 or trauma, 29 ' 412 which may cause
the muscle itself to become entrapped in
the roof of the orbit.33 Paradoxically,
sometimes trauma to the trochlea leads to
hypertropia rather than impaired eleva-
tion in adduction. 361 When Brown's syn-
drome occurs in association with rheuma-
tological disorders, antiinflammatory drugs
are usually effective.191
SUPERIOR OBLIQUE MYOKYMIA
Another syndrome peculiar to the supe-
rior oblique muscle is superior oblique
myokymia. Affected patients typically com-
plain of brief, recurrent episodes of
monocular blurring of vision, or tremu-
lous sensations in one eye.73'261'365 Some
also report vertical or torsional diplopia or
oscillopsia. Attacks usually last less than 10
seconds, but they may occur many times
360 The Diagnosis of Disorders of Eye Movements

per day. The attacks may be brought on

by looking downward, by tilting the head
toward the side of the affected eye, or
by blinking. Most patients with superior
oblique myokymia have no underly-
ing disease, though cases have been re-
ported following trochlear nerve palsy,
head injury, possible demyelination or
brain 261stem stroke, and with cerebellar
tumor. '433-62?
The eye movements of superior oblique
myokymia are often difficult to appreciate
on gross examination, but the spasms of
torsional-vertical rotations can sometimes
be detected by looking for the movement
of a conjunctival vessel as the patient
announces the onset of symptoms (see
VIDEO: "Superior oblique myokymia").
They are more easily detected during ex-
amination with an ophthalmoscope or slit
lamp. Measurement of the movements
of superior oblique myokymia using the
magnetic search coil technique has dem-
onstrated an initial intorsion and depres-
sion of the affected eye, followed by irreg-
ular oscillations of small amplitude (Fig.
9-17).365'433>627 The frequency of these os-
cillations is variable; some resemble jerk
nystagmus at frequencies of 2 to 6 Hz, but
superimposed upon these oscillations are
low-amplitude, irregular oscillations with
frequencies ranging up to 50 Hz.
Electromyographic recordings from su-
perior oblique muscles affected by the dis-
order have revealed abnormal discharge Figure 9-17. Superior oblique myokymia (see VIDEO:
from some muscle fibers, either sponta- "Superior oblique myokymia"). A shows a typical at-
neous or following contraction of the mus- tack affecting the right eye, which the patient in-
duced by blinking (b). The affected right eye de-
cle.261'325'331 These discharge abnormalities pressed and intorted, and high frequency oscillations
include prolonged duration, increased were superimposed. B compares the torsional posi-
amplitude, and polyphasic pattern, with a tion of the right eye and left; note that the high fre-
spontaneous discharge rate of approxi- quency oscillations of superior oblique myokymia are
only present in the right eye; the left eye shows some
mately 45 Hz. Spontaneous activity is only drift and nystagmus that is typical in the torsional
absent with large saccades in the "off" plane for normal subjects during fixation. LT, left
(upward) direction. Those fibers having torsional; RH, right horizontal; RV, right vertical; RT,
an irregular discharge following muscle right torsional. Upward deflections indicate right-
contraction subside to a regular discharge ward, upward, or clockwise rotations, from the point
of view of the subject. Eye position is relative, individ-
of about 35 Hz. These findings have been ual records having been offset to aid clarity of display.
interpreted as indicating neuronal dam-
age and subsequent regeneration, leading
to desynchronized contraction of mus- ons to hold the total constant.266'671 Pa-
cle fibers. Experimental lesions of the tients with superior oblique myokymia
trochlear nerve have demonstrated regen- usually do not report a prior episode of
erative capacities such that the remaining diplopia, but MRI studies sometimes show
motoneurons increase their number of ax- atrophy of the superior oblique muscle,406

and it seems possible that mild dam-
age to the trochlear nerve could trigger
the regeneration mechanism for main-
taining a constant number of axons in
the nerve;360'365 some of these cases
might be predisposed to superior oblique
myokymia.
No treatments for superior oblique
myokymia are consistently effective, but
individual patients may respond to car-
bamazepine, baclofen, and systemically
or topically administered beta block-
ers. In some patients, superior oblique
myokymia spontaneously resolves,73 but
in others the symptoms are so trouble-
some that surgical treatment is consid-
ered, and a modification of the Harada-Ito
procedure—nasal transposition of the ante-
rior portion of the superior oblique ten-
don, to weaken cyclorotation—has been
beneficial.335
Oculomotor Nerve Palsy
CLINICAL FEATURES OF
OCULOMOTOR NERVE PALSY
The third cranial nerve supplies four ex-
traocular muscles (medial, superior and
inferior recti, and inferior oblique) and
the levator of the lid and contains
parasympathetic fibers that supply the
sphincter of the pupil and the ciliary body.
A complete, peripheral third nerve palsy
is easily recognized by ptosis; a fixed, di-
lated pupil; and a resting eye position that
is "down and out" (see VIDEOS: "Oculomo-
tor nerve palsy"). Incomplete third nerve
palsies, however, are more common, and
characteristic patterns of loss of function
can be correlated with lesions at various
sites along the course of the nerve from
nucleus to muscle. It is necessary to differ-
entiate such patterns of muscle weakness
from a variety of restrictive ophthal-
mopathies, and from myasthenia gravis
(Table 9-4).
Accurate diagnosis of the site and
cause of oculomotor palsy is impor-
tant, since some underlying conditions—
notably aneurysms—require prompt ther-
apy (Table 9-7). An MRI often helps to
confirm the underlying cause.56
Diagnosis of Diplopia and Strabismus 361
NUCLEAR OCULOMOTOR
NERVE PALSY
Lesions of the nucleus of the third nerve
are rare. When they occur, they usually in-
volve adjacent structures important for
vertical conjugate gaze. Based on current
knowledge of the anatomic organization of
the oculomotor nucleus (Fig. 9-9), it is
possible to set certain criteria for diagnosis
of nuclear third nerve palsy;124 these are
summarized in Table 9-8. However, it is
important to recognize that in this small
area of the midbrain, the nuclei and fasci-
cles of the oculomotor nerve lie in close
proximity, and both may be affected to
varying degrees. At present, MRI findings
may not provide sufficient resolution to
differentiate between nuclear and fascicu-
lar lesions.67'378-509
When nuclear lesions affect the superior
rectus subnucleus, elevation of both eyes is
impaired.78'203 This is because axons from
one superior rectus subnucleus cross and
pass through the fellow subnucleus of the
opposite side.53'711 Thus, a lesion of one
superior rectus subnucleus is effectively a
bilateral lesion. It follows that in those case
reports when only one superior rectus
muscle—either ipsilateral or contralateral
to the side of the lesion—is involved, the
lesion must have involved the superior
rectus nerve fascicles (i.e., axons after they
have left the nucleus).
Similarly, when lesions affect the central
caudal nucleus, the result is bilateral pto-
sis. This is because of the unpaired nature
of the central caudal subnucleus that sup-
plies the levator muscle (Fig. 9-9). Since
the central caudal nucleus sits at the bot-
tom of the oculomotor nuclear complex, it
may be selectively affected and bilateral
ptosis may be the only manifestation of the
nuclear palsy. The "plus-minus" lid syn-
drome of unilateral ptosis and contralat-
eral eyelid retraction has been reported in
association with nuclear third lesions.202 If
raising the ptotic lid does not abolish the
contralateral lid retraction (which would
be expected according to Hering's law of
the eyelids),24 and if the lesion is acute
(i.e., there has not been time for aberrant
reinnervation), then the eyelid retraction
in such cases is most probably due to loss
362 The Diagnosis of Disorders of Eye Movements
Table 9-7. Etiology of Oculomotor Nerve Palsy50'324'517-629
Nuclear
Congenital hypoplasia234'269'508
Infarction or hemorrhage202'203-322'339
Tumor307'510
Trauma630
Infection16-554'636
Fascicular
Infarction96-344'438
Hemorrhage183'301'344
Demyelination 193 ' 643
Syphilis663
Trauma30-305
Subarachnoid
Aneurysm (typically posterior communicat
ing artery; occasionally basilar
artery) 220 ' 22 J ,306,434,653,673,690
Meningitis (infectious, syphilitic, granuloma-
tous, Lyme, and neoplastic)44'241'282'418-507'541'636
Nerve infarction (associated with diabetes)680
Tumors of the oculomotor nerve3'491-515'697
Neurosurgical complication418'703
Trauma305
At the Tentorial Edge
Uncal herniation 495 ' 526
Pseudotumor cerebri402
Hydrocephalus 534
Trauma342
Cavernous Sinus and Superior Orbital Fissure
Aneurysm of internal carotid artery37'319'459
Carotid-cavernous fistula7'313'347'422
*May cause paresis by involvement of nerve or extraocular muscle.
of inhibition of the levator. The origin of
this inhibition is undetermined, but it ap-
pears to emanate from the nucleus of the
posterior commissure, which synapses in
the M-group of neurons before reaching
the central caudal nucleus. Since ptosis is
unilateral, the lesion cannot be localized to
the central caudal nucleus (even though
other parts of the oculomotor nucleus
are), and the ptosis is fascicular in origin.
The medial rectus neurons lie at three
locations within the nucleus, so it would
seem unlikely for medial rectus paralysis
(unilateral or bilateral) to be the sole man-
ifestation of a nuclear third nerve palsy.
Cavernous Sinus and Superior Orbital
Fissure—continued
Cavernous sinus thrombosis672
Internal carotid artery stenosis,31 or
dissection546
Tumor: pituitary adenoma, meningioma,
nasopharyngeal carcinoma, metastases,
angioma, other1'76'194-295.321'458'463
Pituitary infarction (apoplexy)414'514-529
Nerve infarction (associated with diabetes,
hypertension, or arteritis)19'157'528'625 or
hemorrhage 423
Sphenoid sinusitis and mucocele280
Herpes zoster17
Tolosa-Hunt syndrome 22
In association with monoclonal gammopathy
and Waldenstrom's macroglobulinemia68'353
Orbit*
Trauma368
Mucormycosis and other fungal infections512
Tumor and other infiltrates566
Frontal or sphenoidal sinus mucocele159'560'609
Localization Uncertain
In association with viral and other infections,
and following immunization97'309'556
In association with cancer chemotherapy 591 or
cocaine413
Nerve infarction129'236
Migraine479'613-691
Following dental488 or retrobulbar
anesthesia 132
Similarly, because the visceral nuclei are
spread throughout the rostral half of the
nucleus, unilateral internal ophthalmople-
gia is unlikely to be the sole manifestation
of a lesion of the oculomotor nucleus. In-
volvement of the pupil with midbrain
third nerve lesion suggests a rostral site in
the nucleus.537
The third-nerve nucleus also houses
oculomotor internuclear neurons, which
project to the contralateral abducens nu-
cleus. Experimental studies indicate that
they play a role in coordinating conjugate
eye movements and that pharmacological
inactivation of these internuclear neurons

Table 9-8. Diagnosis of Nuclear
Oculomotor Nerve Palsy*i24,203
Obligatory Lesions
Unilateral third nerve palsy with contralateral
superior rectus paresis and bilateral partial
ptosis
Bilateral third nerve palsy associated with
spared levator function (internal ophthalmo-
plegia may be present or absent)
Possible Nuclear Lesions
Bilateral total third nerve palsy
Bilateral ptosis
An isolated weakness of any single muscle ex-
cept the levator, superior rectus, and medial
rectus muscles
Conditions That Cannot Be Due to Nuclear Lesions
Unilateral third nerve palsy, with or without
internal involvement, associated with normal
contralateral superior rectus function
Unilateral internal ophthalmoplegia
Unilateral ptosis
Isolated unilateral or bilateral medial rectus
weakness
*In the absence of pupillary involvement, ocular
myasthenia must always be ruled out.
with lidocaine causes a contralateral ab-
duction weakness.106 We have observed
abduction weakness in the eye contralat-
eral to a midbrain lesion that caused a
third nerve palsy.
Paralysis of the inferior rectus and infe-
rior oblique muscles in isolation is theoret-
ically possible but is usually associated
with conjugate vertical gaze disorders. Pa-
tients reported to have impaired depres-
sion of one eye associated with impaired
elevation of the other with or without ad-
duction paresis of the higher eye133'167'677
most probably had skew deviation rather
than nuclear oculomotor palsy.586 Disrup-
tion of saccadic inputs from the riMLF
have sometimes been invoked to account
for vertical disconjugacy in patients with
lesions involving the oculomotor nucleus.
However, the demonstration of axon col-
laterals from saccadic burst neurons in the
riMLF (see Fig. 6-5), which contact yoke
muscle pairs in the oculomotor and
trochlear nuclei,435 means that violations
of Hering's law for vertical saccades must
reflect lesions within or close to the mo-
Diagnosis of Diplopia and Strabismus 363
toneurons. This issue is discussed further
in Chap. 10 (see Display 10-25).
CONGENITAL OCULOMOTOR
NERVE PALSY
Congenital palsies of the third nerve are
usually incomplete and unilateral; aber-
rant reinnervation is a common associated
finding (see below).34'234 The location of
the lesion is variable and may be associ-
ated with other developmental anom-
alies.214'234 Rarely, congenital oculomotor
weakness may alternate with periodic
spasms of third nerve overactivity such as
esotropia or miosis; this is called oculomotor
palsy with cyclic spasms.186'381 This syndrome
sometimes occurs with acquired oculomo-
tor palsies;329'640 its pathogenesis is un-
known.
Ophthalmoplegic migraine usually has its
onset in childhood. 27 The oculomotor
palsy is usually complete, but rarely just
the superior ramus is affected.293 The
palsy typically lasts for days or weeks after
the headache has resolved. Rarely, pa-
tients are reported with congenital limita-
tion of ocular motility that suggests anom-
alous innervation of muscles normally
supplied by the oculomotor nerve. One
example is a syndrome of congenital, uni-
lateral adduction palsy; when the patient
attempts to look into the field of action of
the weak medial rectus muscle, the af-
fected eye abducts rather than adducts
(synergistic divergence). Electromyographic
studies suggest a pattern of anomalous in-
nervation which is analogous to the abnor-
mality in Duane's retraction syndrome
(see above).119-670 Slowly progressive third
nerve palsy in childhood may, in some
cases, be due to schwannoma of the nerve
sheath that can be detected with imaging
studies,3 but in others no cause can be
found. 324 ' 424
DISORDERS AFFECTING THE
FASCICLES OF THE
OCULOMOTOR NERVE
As the fascicles of the oculomotor nerve
traverse the midbrain, they pass through
important structures that enable precise
localization of third nerve palsies.379 If the
oculomotor nerve is involved as it tra-
364 The Diagnosis of Disorders of Eye Movements
verses the cerebral peduncle, a contralat-
eral hemiparesis will result, called Weber's
syndrome.574 Involvement of the oculomo-
tor fascicles, red nucleus, and superior
cerebellar peduncle causes Claude's syn-
drome: oculomotor palsy, contralateral
ataxia, asynergy, and dysdiadochokinesis.
More extensive lesions may affect the
third nerve fascicles, cerebral peduncle,
and adjacent red nucleus and substantia
nigra, causing Benedikt's syndrome: oculo-
motor palsy, contralateral hemiparesis,
and contralateral involuntary movements
or tremor. Dorsal midbrain lesions that
involve the oculomotor nucleus and
produce a combination of nuclear and
supranuclear gaze limitation with ataxia
have been called Nothnagel's syndrome.379
The third nerve may also be affected by
hemorrhages caused by downward herni-
ation of the brain stem. Small midbrain le-
sions may selectively involve the fasci-
cles of the oculomotor nerve, causing
paresis of one or more of the extraocular
muscles with no associated neurologic
deficits.96-198-263'344'345'470* Thg pattern
involvement of the third nerve has been
used to advance theories for the topo-
graphic organization of the oculomotor
fascicles (see Anatomy of the Oculomotor
Nerve, above).
DISORDERS AFFECTING THE
SUBARACHNOID PORTION OF
THE OCULOMOTOR NERVE
After its exit from the brain stem, the third
nerve runs in the subarachnoid space and
is susceptible to meningeal processes (in-
fection, tumor, blood) and compression by
arterial aneurysm. Basilar artery aneurysms
can cause oculomotor nerve palsy,639 but
the internal carotid-posterior communi-
cating arterial junction is the more com-
mon site. With these aneurysms, it is un-
usual for the pupil to be affected alone;
ptosis and external ophthalmoplegia usu-
ally coexist. With posterior communicat-
ing aneurysms, third nerve palsy may
occur in the setting of subarachnoid hem-
orrhage, but another presentation is of
acute diplopia with facial or orbital pain
but without subarachnoid hemorrhage.
Occasionally, minor head trauma may pre-
cipitate oculomotor nerve palsy due to
aneurysms or tumors.673 A common clini-
cal challenge is to differentiate third nerve
compression due to aneurysm from nerve
infarction in association with diabetes or
hypertension (see below), in which cere-
bral arteriography is not indicated. The
presence of pupillary involvement can be
relied on to identify those patients that
harbor an aneurysm. Initially, however,
the pupil may be spared,37'319'459 so pupil-
sparing third nerve palsy requires careful
observation for a week before a decision
can be made about arteriography. After
a week, third nerve palsy with com-
plete pupillary sparing is rarely due to
aneurysm.298 Cases of complete extra-
ocular palsy with normal pupils due to
aneurysm are rare.385 Partial pupillary in-
volvement may be grounds for an arteri-
ogram,320 although mild involvement of
the pupil may occur with noncompressive
processes.60 Pleocytosis in the cerebrospinal
fluid may occur with aneurysm.306 Sponta-
neous resolution of an oculomotor paresis
Qf does not necessarily mean that aneurysm
is excluded.220 Another factor that should
be weighed when considering arteriogra-
phy for acute oculomotor palsy is the pa-
tient's age: Individuals between 20 and 50
years of age are more likely to have an
aneurysm, 638 whereas children younger
than 11 years almost never do.690 MRI and
angiography often help to differentiate
nerve infarction from compressive or
brain stem lesions,56 and gadolinium en-
hancement of the cisternal portion of the
oculomotor nerve is a sensitive index of
neoplastic or inflammatory processes, in-
cluding migraine.613
COMPRESSION OF THE
OCULOMOTOR NERVE AT
THE TENTORIAL EDGE
The third nerve may also be compressed
against the tentorial edge, the petroclinoid
ligament, or clivus by the uncus of the
temporal lobe during transtentorial herni-
ation.495 Alternatively, the third nerve may
be stretched by displacement of the mid-
brain.526 Classically, the pupillary fibers
are affected first and mydriasis results.
When the pupil becomes fixed, extraocu-

lar muscle weakness also appears. Rarely,
upward herniation of a posterior fossa
mass lesion may cause a third nerve palsy.
DISORDERS AFFECTING THE
CAVERNOUS PORTION OF THE
OCULOMOTOR NERVE
Within the cavernous sinus (Fig. 9-8), the
oculomotor nerve may be compressed by
aneurysm or tumor. Intracavernous (in-
fraclinoid) aneurysms are less common
than posterior communicating (supra-
clinoid) aneurysms and seldom rupture.
The typical presentation of intracavernous
aneurysms is progressive ophthalmople-
gia and ptosis, often with signs of aberrant
reinnervation.390 About half of all patients
suffer pain in the face. Often the abducens
and trochlear nerves are also affected.
Symptoms are usually slowly progressive
and may suggest tumor. Sparing of the
pupil is more common with aneurysms in-
volving the cavernous sinus than with pos-
terior communicating aneurysms, proba-
bly because the inferior division of the
oculomotor nerve, which contains the
pupillomotor fibers, is less frequently in-
volved in the former.638 An alternative ex-
planation is that sympathetic paresis and
parasympathetic paresis coexist. Rarely,
the aneurysm ruptures and creates a ca-
rotid-cavernous fistula (see below).
Tumors arising near the cavernous sinus,
including meningioma, pituitary adeno-
mas, and lymphomas, may cause third
nerve palsy; usually other nerves in the
cavernous sinus are also affected. Typically,
the tumors grow slowly without producing
any pain. Sometimes, the diagnosis only
becomes evident with serial MRIs. Occa-
sionally, hemorrhage occurs into a pituitary
tumor, causing the syndrome of pituitary
apoplexy as in the following case history.
CASE HISTORY: Pituitary apoplexy
A 56-year-old man suddenly developed nausea
and vomiting, which lasted for 24 hours and
then resolved. The next day, he noticed a mild
headache; several hours later, he suddenly de-
veloped diplopia and a left, partial ptosis. On
examination, he had normal visual acuity and
Diagnosis of Diplopia and Strabismus 365
full visual fields. His left pupil diameter was 6
mm and his right was 5 mm. There was a left
exotropia and hypotropia; testing showed
weakness of all extraocular muscles supplied
by the left oculomotor nerve but sparing of the
lateral rectus and superior oblique (see VIDEOS:
"Oculomotor nerve palsy"). He was hyperten-
sive but had no neck stiffness, and results of the
general neurologic examination were normal.
A CT showed possible enlargement of the sella
turcica. A carotid arteriogram showed no
aneurysm. A spinal tap revealed a protein of
57 mg/dL, glucose of 54 mg/dL, 200 red cells/
mm3, and 4 white cells/mm3. An MRI showed a
pituitary tumor that extended laterally on the
left to compress the oculomotor nerve (Fig.
9-18). The patient was treated with cortico-
steroids and underwent a successful trans-
sphenoidal resection of his tumor. Histologi-
cal examination demonstrated hemorrhage in
a chromophobe adenoma.
Comment: This case illustrates several fea-
tures of pituitary apoplexy: sudden onset of
headache (usually severe), variable degrees of
ophthalmoparesis (which may be bilateral and
complete), and subarachnoid hemorrhage. Vi-
sual loss and endocrine insufficiency may also
occur. A CT or MRI confirms the diagnosis.
Prompt transsphenoidal neurosurgical inter-
vention, preceded by massive corticosteroid
administration, is usually required.487'514'681
Septic thrombosis of the cavernous sinus is
now rare,152 but low-grade inflammatory
processes may cause oculomotor nerve
palsy as part of the Tolosa-Hunt syndrome
(see below).
INFARCTION OF THE
OCULOMOTOR NERVE
Solitary third nerve palsy may be due to
infarction, usually in association with dia-
betes or hypertension ("medical third"). It
is also reported in association with colla-
gen vascular disease or giant cell arteri-
tis.129 The pupil is usually spared or only
minimally involved,2733 though it may oc-
casionally be fixed to light.209 Patients of-
ten complain of facial or orbital pain that
usually precedes the muscle palsy and dis-
appears when diplopia or ptosis develops.
366 The Diagnosis of Disorders of Eye Movements

Figure 9-18. Magnetic resonance images of a patient who presented with a left third nerve palsy due to infarc-
men± C^ ^^ ^^ ""^ ^'^ ^^ f°r details -) <A> Coronal ™w ^holing encroach-
ment on left cavernous sinus by the tumor (arrow). (B) Sagittal view, showing tumor (arrow).

The onset of diplopia is sudden but the
muscle paresis may evolve for up to 2
weeks.274 Recovery is usually the rule
within 3 months.90 Although it generally
occurs in diabetic patients who already
have evidence of small-vessel disease in
other organs, third nerve palsy may be the
presenting feature of the disease and it
has been reported in children with dia-
betes.225 Pathologic examination of the
third nerve in diabetic patients has shown
infarction of the nerve in the intracav-
ernous19'157 or subarachnoid portions.680
The core of the nerve is most severely in-
volved, thus sparing the peripherally lo-
cated pupillary fibers. The oculomotor
nerves of diabetics who have not suffered
third nerve palsy show microfasciculation

Figure 9-18.—continued
of edge fibers and changes in the distribu-
tion of fiber size.585 Other studies, how-
ever, suggest that a common site of nerve
infarction in diabetics is within the brain
stem.255 Coexistent involvement of the
oculomotor nerve and the trochlear nerve
or of all three ocular motor nerves and
the ophthalmic division of the trigemi-
nal nerve probably implies occlusion of
branches of the inferolateral trunk that
arises from the intracavernous carotid
artery.356 Mucormycosis must always be
considered in the diabetic patient who de-
velops ocular muscle palsies.
OCULOMOTOR NERVE PALSY DUE
TO TRAUMA
In most large series of patients with oculo-
motor nerve palsy, trauma is an important
cause. The head injury usually causes frac-
Diagnosis of Diplopia and Strabismus 367
ture or loss of consciousness; only rarely
does palsy follow mild trauma, and then
other diagnoses, such as tumors at the
base of the skull, should be considered.170
The third nerve may be injured as it
emerges from the brain stem (root avul-
sion) in its subarachnoid course as it at-
taches to the dura, or by fractures at the
supraorbital fissure. Penetrating injuries
to the orbit or brain may also cause third
nerve palsy.305
ABERRANT REGENERATION OF
THE OCULOMOTOR NERVE
A common sequel of oculomotor nerve
palsy is aberrant regeneration. Ramon y
Cajal first showed that after experimental
transection of the oculomotor nerve, the
regenerating fibers no longer follow their
previous paths but innervate different
368 The Diagnosis of Disorders of Eye Movements
muscles supplied by the third nerve.511
Other studies have confirmed such mis-
routing of axons.178'572-573 This cannot be
the mechanism in every case, however,
since anomalous synkinesis can occur
transiently after an acute third nerve
palsy.369'572-573
The clinical signs of aberrant regenera-
tion include abnormal lid movements.
Most commonly the lid elevates during
adduction or depression of the eye. Other
common patterns include depression of
the lid on abduction, and pupillary con-
striction on adduction or depression of
the eye, but absent direct pupillary light
reaction. All these combined movements
are due to cocontraction of muscles inner-
vated by the third nerve. Rarely, the lid of
the other eye may be affected with elevation
on down gaze.228 Acquired oculomotor-
abducens synkinesis has been reported.281
Aberrant reinnervation of the oculo-
motor nerve may occur after trauma,552
aneurysm,580'653 congenital third nerve
palsy,34 migraine,54 or as a complication of
neurosurgery.270 If aberrant regeneration
is encountered without a history of pre-
ceding oculomotor palsy, then slowly
growing intracavernous meningioma66'545
or carotid aneurysm 116 is likely, though
sometimes no cause can be found.351 Aber-
rant regeneration almost never occurs
with diabetic third nerve palsy. Aberrant
regeneration in which misdirected fibers
of the abducens nerve came to innervate
the pupil has been proposed as the expla-
nation of miosis with abduction in a pa-
tient who suffered palsies of CN III, IV,
and VI following head trauma. 489
PARTIAL OCULOMOTOR
NERVE PALSY
As the oculomotor nerve passes through
the cavernous sinus, it divides into supe-
rior and inferior rami or divisions. The su-
perior oculomotor division supplies the
superior rectus and levator palpebrae su-
perioris; the inferior oculomotor divi-
sion supplies the other extraocular mus-
cles, the pupil, and the ciliary body.
Isolated lesions of these branches oc-
cur. 74,120,161,464,540,609 Tne pattern of weak-
ness encountered with a superior division
lesion can be produced, however, by le-
sions located in the more proximal por-
tions of the nerve,229'230 or even within the
brain stem.344 Less commonly, individual
muscles supplied by the third cranial nerve
may be paralyzed.96'439'510'668 In patients
with isolated ptosis or paralysis of individ-
ual muscles, myasthenia gravis should be
considered. Rarely, double-elevator palsy,
with no tropia in central position, is due to
a brain stem lesion (see Chap. 10).
MANAGEMENT OF OCULOMOTOR
NERVE PALSY
Complete oculomotor palsy is easily diag-
nosed, but with partial involvement, con-
sideration should be given to whether the
patient has another condition (Table 9-4).
In adults, a common challenge is to deter-
mine whether the palsy is due to nerve
infarction in association with diabetes or
hypertension, or is due to a compressive
lesion such as arterial aneurysm. If the
pupil is completely fixed to light, the
chance of aneurysm is high, and angiogra-
phy is usually indicated. Patients with par-
tial involvement of the pupil and complete
involvement of the extraocular muscles
and lid should undergo MRI-MRA and be
closely observed. An MRA will reveal some
but not all aneurysms compressing CN
III. It is wise to closely observe all patients
who have developed a third nerve palsy
for several days, since their signs may
evolve and cerebral angiography may be-
come indicated. Anisocoria of greater than
2 mm may be considered grounds for an
arteriogram.638a An MRI may also demon-
strate brain stem infarction or hemor-
rhage, and gadolinium enhancement may
demonstrate inflammation or infiltration
affecting the oculomotor nerve through-
out its course.56 Oculomotor nerve palsy
in children is less likely to be due to
aneurysm, but if there has been no an-
tecedent trauma, cerebral tumors should
be sought with MRI. 324
Multiple Ocular Motor
Nerve Palsies
The principal culprits causing combined
third, fourth, and sixth nerve palsies are

brain stem stroke, lesions within the cav-
ernous sinus or superior orbital fissure
(where the three nerves lie near each
other), trauma, and generalized neurop-
athies (Table 9-9). Any of these processes
can lead to complete ophthalmoplegia.299
Other causes to be considered in the pa-
tient with complete ophthalmoplegia in-
clude neuromuscular disorders (myasthe-
nia gravis, Miller Fisher syndrome, and
botulism), drug intoxications (see Table
10-21), and Wernicke's encephalopathy.
BRAIN STEM LESIONS CAUSING
OPHTHALMOPLEGIA
Infarction or hemorrhage of the brain
stem may limit horizontal and vertical eye
movements;299'693 diagnostic features are
described in Chap. 10. A combination of
ocular motor nerve palsies, with brain
stem lesions, is encountered in some pa-
tients with acquired immune deficiency
syndrome (AIDS).237'303 The nuclei of the
ocular motor nerves are usually spared in
amyotrophic lateral sclerosis (ALS), with
only rare pathologic reports of involve-
Table 9-9. Etiology of Multiple Ocular Motor Nerve Palsies50'299'324'368'517'629
Brain stem
Tumor534
Infarction or hemorrhage299'632'693
Encephalitis215
Subarachnoid
Meningitis (infectious and neoplastic)380-507
Trauma302'368
Clivus tumor
Aneurysm and dolichoectasia158
Cavernous Sinus and Superior Orbital Fissure
Aneurysm of internal carotid artery182-390
Occlusion of internal carotid artery 201 ' 687
Tumor: meningioma, pituitary adenoma
with apoplexy, cavernous angioma or
hemangiopericytoma, nasopharyngeal
carcinoma, lymphoma, myeloma,
Waldenstrom's macroglobulinemia,
Other20' 138 > 25 1,352,383,401,445,497,514,558,620
Pseudotumor cerebri355
Cavernous sinus thrombosis152'672
*May cause paresis by involvement of nerve or extraocular muscle.
Diagnosis of Diplopia and Strabismus 369
ment in advanced cases,425'469 although
other brain stem nuclei may be involved.23
This rarity of involvement has been re-
lated to the peculiarly low concentrations
of glycinergic and muscarinic cholinergic
receptors of these nuclei, when compared
with other cranial nerve nuclei or the
spinal cord.683 Abnormalities of eye move-
ments in ALS are discussed in Chap. 10.
Limitation of eye movements has been de-
scribed in some forms of spinal muscular
atrophy.224-480
CAVERNOUS SINUS AND
SUPERIOR ORBITAL
FISSURE SYNDROMES
Within the cavernous sinus (Fig. 9-8), a
variety of disease processes may affect the
ocular motor nerves. To differentiate cav-
ernous sinus from orbital apex lesions, as-
sociated findings are helpful. 71 Involve-
ment of the first two sensory divisions of
the trigeminal nerve suggests disease of
the cavernous sinus; if all three divisions
are involved, a retrocavernous process
may be present. If trigeminal function is
Cavernous Sinus and Superior Orbital
Fissure—continued
Tolosa-Hunt syndrome 87 ' 212 - 265 ' 631
Neurosurgical complication703
Herpes zoster 17
Nerve infarction (associated with diabetes or
arteritis) 128 ' 337 ' 410
Carotid-cavernous fistula217'313'372
Orbital*
Mucormycosis and other infec-
tions121'279'362'512'710
Trauma399
Tumor and other infiltrates 332
Localization Uncertain
Generalized neuropathies, especially post-
inflammatory type (Guillain-Barre and
Miller Fisher syndromes) 181 - 409
Sjogren's syndrome396
Toxins622
Behget's disease460
370 The Diagnosis of Disorders of Eye Movements
normal but vision is impaired, then the
process is probably in the orbit. The ocu-
lar motor deficit may be complete if dis-
ease occurs in either the cavernous sinus
or orbit, but with a more anterior location,
the pupil and muscles supplied by the in-
ferior division of the oculomotor nerve
tend to be spared.639 Tumors (particularly
meningioma, pituitary adenoma, and na-
sopharyngeal carcinoma) are common
causes of combined ophthalmoparesis.
Meningioma and pituitary adenoma are
slow growing, but hemorrhage into a pitu-
itary adenoma, as already discussed, pro-
duces the distinctive clinical syndrome of
pituitary apoplexy. Combined ocular mo-
tor palsies may also be due to nerve infarc-
tion in the cavernous sinus.356
CAROTID-CAVERNOUS FISTULA
This abnormal communication between
the carotid arterial system and the cav-
ernous sinus is of two types: direct and
dural. Direct fistulae are caused by tears in
the intracavernous portion of the internal
carotid artery arising from severe head
trauma or from rupture of a preexisting
aneurysm. These are high-flow fistulae,
characterized by sudden onset of pulsatile
proptosis, bruit, and impaired vision; they
lie anteriorly in the cavernous sinus and
drain forward into the orbit.372 Dural fis-
tulae are due to rupture of thin-walled
meningeal branches of the internal or ex-
ternal carotid arteries within the cav-
ernous sinus; such rupture may occur
spontaneously, especially in elderly, hy-
pertensive patients, and following minor
head trauma or straining. These low-flow
fistulae present more subtly, with subjec-
tive bruit, mild proptosis, chemosis, con-
junctival redness, and glaucoma; they lie
posteriorly in the cavernous sinus and
tend to drain posteriorly to the inferior
petrosal sinus rather than into the supe-
rior ophthalmic vein. Sometimes they are
evident on MRA.642a Occasionally, the pre-
sentation is one of painful ophthalmo-
plegia without chemosis or exophthal-
mos.7'245'336 Thrombosis of the superior
ophthalmic vein may produce temporary
worsening followed by spontaneous remis-
sion.559
Diplopia is common with both direct
and dural fistulae; abduction weakness is
frequent and all eye movements may be
affected. It is thought that while all three
ocular motor nerves may be affected, a
more common cause of the restricted ocu-
lar motility is hypoxic, congested extraoc-
ular muscles.367 Embolization is an effec-
tive treatment for many patients with
carotid-cavernous fistula.313-347'372'420 Some
dural shunts spontaneously resolve.
TOLOSA-HUNT SYNDROME AND
PAINFUL OPHTHALMOPLEGIA
Almost any process causing ophthalmo-
plegia can be painful, with the possible ex-
ceptions of myasthenia gravis and chronic
progressive external ophthalmoplegia.22
The physician should always be concerned
about infections and tumors. However,
there are patients who present with pain-
ful, combined ophthalmoplegia due to a
granulomatous inflammatory process that
affects the cavernous sinus, extending for-
ward to the superior orbital fissure and
orbital apex. Called the Tolosa-Hunt syn-
drome, this is usually a disease of middle or
later life that may spontaneously remit
and relapse. The presenting complaints
are steady, retro-orbital pain and diplopia.
The third, fourth, or sixth nerves or a
combination of ocular motor nerves may
be affected. Visual impairment occurs in
some patients.265'631 There is some overlap
with orbital pseudotumor. Sensation sup-
plied by the ophthalmic and maxillary
trigeminal divisions may be impaired. The
pupil may be constricted if the sympa-
thetic innervation is involved or dilated if
parasympathetic innervation is affected.
Pathologic examination has shown a low-
grade, noncaseating, granulomatous, in-
flammatory response in the cavernous si-
nus encroaching on the carotid artery and
nerves of passage.87'212
Diagnosis is by imaging, which demon-
strates soft-tissue infiltration in the cav-
ernous sinus, sometimes with extension
into the orbital apex, but without erosion
of bone.216 The infiltrate is either hy-
pointense on Tl-weighted images and
isointense on T2-weighted images, or hy-
perintense on Tl-weighted and interme-

diate-weighted images.216 Angiography may
show narrowing of the carotid siphon, oc-
clusion of the superior orbital vein, and
nonvisualization of the cavernous sinus.
It has been suggested that the Tolosa-
Hunt syndrome is a variant of a larger
syndrome of recurrent multiple cranial
neuropathies.35'283-648 There is also an as-
sociation with other forms of vasculitis,
such as lupus or Wegener's granulomato-
sis.128'427 Patients with the Tolosa-Hunt
syndrome usually respond promptly to
corticosteroid treatment. However, cau-
tion is required in attributing diagnos-
tic value to a positive response, because
tumors in the cavernous region may
respond similarly to steroids594 or even
resolve spontaneously.194 Thus, serial
MRIs to monitor such patients are advis-
able 216,350,452,626,705
The differential diagnosis of Tolosa-
Hunt syndrome includes the entities de-
scribed in Table 9-9. Orbital myositis may
usually be distinguished by swelling and
erythema of the eyes.80'426'581'603 The com-
bination of painful palsies of the ocular
motor nerves associated with Horner's
syndrome is called Raeder's paratrigeminal
syndrome2'2'2- and often reflects coexistent in-
volvement of the oculosympathetic fibers
in the cavernous sinus, usually due to
mass lesions. Ophthalmoplegic migraine is re-
ported to affect each of the ocular motor
nerves and sometimes is difficult to distin-
guish from Tolosa-Hunt syndrome.126-614
HEAD TRAUMA AND
OPHTHALMOPLEGIA
Multiple ocular motor nerve palsies occur-
ring with trauma are usually due to severe
head injury, with fractures of the orbital,
sphenoid, or petrous temporal bones.
Blowout fracture of the orbit may be confused
with ocular motor palsies. It is caused by a
blunt impact to the globe or infraorbital
rim that fractures the orbital floor.315'555'689
Prolapse of the inferior rectus muscle
through the bony defect mechanically re-
stricts upward gaze. There may also be
enophthalmos, and injury to the globe
may seriously disturb vision and pupillary
reactions. Diagnosis is suggested by a his-
tory of painful vertical diplopia following
Diagnosis of Diplopia and Strabismus 371
trauma and is confirmed by resistance to
forced duction of the eye, and by CT,
which shows herniation of soft tissue
through the fracture. 399
NEUROPATHIES CAUSING
OPHTHALMOPLEGIA
Guillain-Barre Syndrome
The oculomotor, abducens, and trochlear
nerves may be involved, in varying de-
gree, by this disorder. Manifestations
range from minor changes in saccadic tra-
jectory to complete external and internal
ophthalmoplegia.173 Occasionally, the ex-
traocular muscles are involved first; 57
sometimes ptosis is the only sign.524 The
eye movement abnormalities may resem-
ble those of myasthenia gravis (see below).
Prior infection with Campylobacter jejuni
can be demonstrated in some patients
with Guillain-Barre syndrome. Such pa-
tients may show raised antibodies against
GM1 ganglioside, an issue that has rele-
vance to those cases in which there is selec-
tive involvement of the eyes (see below).
Miller Fisher Syndrome
Miller Fisher syndrome comprises oph-
thalmoplegia (external and sometimes in-
ternal), areflexia, and ataxia of the limbs
or gait.181 It is probably a variant of Guil-
lain-Barre syndrome.51'456 The degree of
ophthalmoparesis varies, but certain pat-
terns might suggest involvement of the
central nervous system.10'407 For example,
the ophthalmoplegia may resemble a hori-
zontal or vertical gaze palsy or internu-
clear ophthalmoplegia. Ptosis is often ab-
sent even in the presence of significant
ophthalmoparesis. Bell's phenomenon may
also be preserved even when vertical eye
movements are otherwise absent. Re-
bound nystagmus, impairment of smooth
pursuit, optokinetic nystagmus, and sup-
pression (cancellation) of the vestibulo-
ocular reflex point to cerebellar dysfunc-
tion.712 As with myasthenia gravis, some of
these findings might be due the effects of
central adaptation to peripheral weakness.
Other findings, however, such as the con-
fusion that some patients suffer, the disso-
372 The Diagnosis of Disorders of Eye Movements
elated involvement of the levator palpe-
brae superioris and superior rectus, and
the MRI findings in some cases, point
to central involvement—an encephalitic
component.56'525'623a'712 Fisher himself was
impressed by the symmetry of the ocular
motor deficit and by ataxia unaccom-
panied by sensory loss, and "reluctantly
interpreted" the clinical signs "as mani-
festations of an unusual and unique dis-
turbance of peripheral neurons."181
Immunological evidence has clarified
the relationship of Miller Fisher syndrome
to Guillain-Barre syndrome and involve-
ment of the central nervous system. First,
anti-GQlb antibodies have been detected
in over 90% of patients with Miller Fisher
syndrome.101 Antibodies against the gan-
glioside GQlb have also been detected in
those patients with Guillain-Barre syn-
drome who have involvement of their eye
movements, and also in patients with the
Bickerstaff's brain stem encephalitis.9 The
latter is characterized by ophthalmoplegia
and ataxia, but also by pyramidal and sen-
sory tract findings and cerebrospinal fluid
pleocytosis.708 Consistent with this im-
munopathologic hypothesis, plasmaphere-
sis is reported to improve both Bicker-
staff's encephalitis and Miller Fisher
syndrome.456'706 Neuropathologic exami-
nation of two patients with Miller Fisher
syndrome showed a normal central ner-
vous system.134'490 Autopsy of a patient
who had Bickerstaff's encephalitis in asso-
ciation with Guillain-Barre syndrome and
anti-GQlb antibodies showed a normal
brain stem but demyelination of the ocular
motor and spinal nerves.709 Other studies
have shown staining of the molecular layer
of the cerebellum by anti-GQlb antibod-
ies, which is evidence for a central origin
of the ataxia—and probably some of the
eye movement disorders—in Miller Fisher
syndrome.333
Thus, evidence suggests that anti-GQlb
antibodies play a key role in producing
the disturbance of eye movements in
Miller Fisher syndrome, Guillain-Barre
syndrome, and Bickerstaff's encephali-
tis.456 As in Guillain-Barre syndrome, C.je-
juni may be the responsible trigger, since
anti-GQlb antibodies bind to surface epi-
topes on this organism.272 Patients pre-
senting with unexplained ophthalmopare-
sis may benefit from testing for anti-GQlb
antibodies.707
Recurrent Neuropathies
Causing Ophthalmoplegia
Certain patients with chronic relapsing neu-
ropathies may have involvement of the ex-
traocular muscles. Ocular palsies may pre-
cede the development of the neuropathy
by weeks.154-184 Motor symptoms may be
slight291 and some patients appear to have
"relapsing Fisher's syndrome."544'662 In
the future, immunological studies are
likely to clarify these entities. Rarely, re-
current ocular motor palsies may be part
of a familial disorder that is characterized
principally by recurrent Bell's palsy.11
OCULAR NEUROMYOTONIA
This rare disorder is characterized by epi-
sodes of diplopia that are usually precipi-
tated by holding the eyes in eccentric gaze,
often sustained adduction.171'187'455'701 In
most cases, these episodes of diplopia are
caused by involuntary, sometimes painful,
contraction of one or more muscles inner-
vated by one oculomotor nerve. One pa-
tient with bilateral oculomotor nerve in-
volvement has been described,432 and
another with involvement of the lateral
rectus muscle.36 Most reported patients
have undergone radiation therapy to the
parasellar region, but idiopathic cases
have also been reported.187
One reported patient showed ocular
neuromyotonia in the muscles supplied by
his right oculomotor nerve.187 There was
no diplopia or misalignment of the visual
axes in primary gaze. Following sustained
left gaze, he developed horizontal diplopia
and an esotropia (see VIDEO: "Ocular Neu-
romyotonia"), but following sustained
right gaze, no diplopia or deviation oc-
curred. Following sustained down gaze,
he developed diplopia and left hyper-
tropia, and following sustained up gaze,
he developed diplopia and a right hyper-
tropia. The metrics of his saccades indi-

cated a defect of both relaxation and max-
imal contraction of affected muscles.
The mechanism responsible for ocular
neuromyotonia is unknown. Both ephap-
tic neural transmission and changes in the
pattern of neuronal transmission follow-
ing denervation have been suggested,187
because spontaneous activity has been ob-
served in the ocular electromyograph of
affected patients.481'519 Axonal hyperex-
citability due to dysfunction of potassium
channels has also been implicated by anal-
ogy with systemic neuromyotonia. 171 ' 457
The episodic nature of the diplopia of-
ten suggests myasthenia gravis, but anti-
cholinergic medicines are ineffective. Car-
bamazepine, however, is often effective
treatment. Other differential diagnoses
are superior oblique myokymia, thyroid
ophthalmopathy, cyclic oculomotor palsy,
and rippling muscle disease.334 The spe-
cific relationship of the onset symptoms
following sustained attempts to hold ec-
centric gaze points to the diagnosis, and
this should be specifically looked for dur-
ing the examination of patients with
evanescent, unexplained diplopia.
DISORDERS OF THE
NEUROMUSCULAR JUNCTION
Several diseases affecting the neuromus-
cular junction at either presynaptic or
postsynaptic sites may cause abnormalities
of eye movements. Cholinergic crisis in
myasthenia and acute poisoning with
organophosphate anticholinesterases (in-
secticides) can also cause ophthalmopare-
sis and ptosis as part of a picture of gener-
alized weakness.392
Botulism
The neurotoxin of Clostridium botulinum
blocks release of acetylcholine from nerve
terminals. Botulism may be caused by in-
gested toxin in contaminated food, intesti-
nal production of toxin in infants, wound
infection, and in subcutaneous heroin
abuse.246'247'393'513'635 In any of these forms,
Diagnosis of Diplopia and Strabismus 373
varying degrees of internal and external
ophthalmoplegia may occur. In patients
with complete ophthalmoplegia, the dif-
ferential diagnosis includes brain stem
stroke, drug intoxications (see Table 10-21
in Chap. 10), Wernicke's encephalopathy,
pituitary apoplexy, myasthenia gravis, and
Guillain-Barre and Miller Fisher syn-
dromes.299
Residual eye movements in two patients
with systemic botulism were reported
to show hypometric, multistep saccades.
These saccades were followed by back-
ward drifts that gave the appearance of
quivering movements similar to those
encountered in myasthenia gravis (see
VIDEO: "Myasthenia gravis").247 This find-
ing might reflect a greater sensitivity of
the orbital, singly innervated muscle fibers
to botulinum toxin.595 These fibers are
continuously active and appear to be im-
portant for holding the eye steady after a
saccade has ended.502 Another patient
who was studied 6 days after mild systemic
botulism showed slow horizontal and ver-
tical saccades with centripetal postsaccadic
drift (Fig. 9-19) (see VIDEO: "Eye move-
ments in botulism"). 606 Edrophonium
(Tensilon) may produce some improve-
ment of saccadic velocity and increased
range of movement. 25
Alan B. Scott introduced botulinum A
toxin as therapy for strabismus.550 It is a
helpful adjunct in the management of
childhood strabismus403'599 and some cases
of paralytic strabismus.6'359 Botulinum A
toxin has also been used to reduce or abol-
ish acquired nystagmus by injecting it ei-
ther into selected extraocular muscles or
into the retrobulbar space (see Fig. 10-17
in Chap. 10).364'634 Botulinum toxin is an
effective treatment for facial spasms and
blepharospasm;288 occasionally, transient
diplopia may occur after such therapy.696
The Lambert-Eaton
Myasthenic Syndrome
Lambert-Eaton myasthenic syndrome (LEMS)
is due to impaired release of acetylcholine
secondary to an autoimmune disorder af-
374 The Diagnosis of Disorders of Eye Movements
Figure 9-19. Slow saccades due to botulism (see
VIDEO: "Eye movements in botulism"). Eye move-
ments of a 39-year-old man with botulism. Measure-
ments of his horizontal eye movements made on day
6 of his illness show slow saccades. Note also that ab-
ducting saccades are slower than adducting saccades,
causing a transient convergence at the end of each
horizontal gaze shift. The top two traces are position
plots and the bottom two traces are corresponding
velocity plots for the right eye (OD) and left eye (OS).
(Courtesy Dr. John S. Stahl)
fecting voltage-gated calcium channels.219
The LEMS is usually associated with carci-
noma, which may be occult. Typical symp-
toms are weakness and fatigability of the
proximal limb muscles, along with auto-
nomic dysfunction. Symptoms or signs of
extraocular involvement, if present, are
usually mild, although ophthalmoparesis
occasionally occurs.531 Nevertheless, mea-
surements of saccades are likely to demon-
strate characteristic hypometria with closely
spaced saccades.118'135 Some patients also
show slow saccades. The characteristic fa-
cilitation of muscle power with repeated
efforts can sometimes be observed as hy-
pometria gives way to hypermetria during
repetitive saccades. Occasionally, the edro-
phonium (Tensilon) test may be positive,
causing saccadic hypermetria.135
Myasthenia Gravis
CLINICAL FEATURES OF
MYASTHENIA GRAVIS
Myasthenia gravis is a disease of nicotinic
acetylcholine receptors that is character-
ized by fatigable muscle weakness.456 It
commonly affects the extraocular muscles.
Half of all patients present with ocular
symptoms and more than 90% eventually
develop eye movement abnormalities.588
Of those patients who present with ocular
symptoms, half persist with purely ocular
myasthenia. Of those who generalize,
most do so within 2 years of the onset of
the disease. Younger patients tend to have
a more benign course, though relapses
may occur.45 A congenital or familial myas-
thenic syndrome usually has a benign course,
with onset in childhood, and often in-
volves the extraocular muscles.160 Rarely,
ocular myasthenia occurs as a reversible
complication of penicillamine therapy.294
Muscle fatigue is the hallmark of myas-
thenia gravis and may affect the lids, eye
movements, or both. Lid abnormalities in-
clude progressive and often asymmetric
ptosis, brought out by attempting sus-
tained upward gaze. If there is a small,
asymmetric ptosis, instruct the patient to
fix upon an object with the eye showing
less ptosis and observe the ptotic eye be-
hind a cover; over the course of a minute,
worsening of the ptosis may become evi-
dent. Ptosis in myasthenia may be im-
proved by applying an ice pack over the
closed eye for 2 minutes.561 Transient eye-
lid retraction occurs during refixations
from down to straight ahead, called Co-
gan's eyelid twitch sign.108 This sign is not
pathognomonic, however, and may occur
with brain stem or oculomotor disor-
ders.428 Attempted eyelid closure may be
impaired. Ptosis is often relieved after a
short nap ("sleep test" for ocular myas-
thenia).462
The more common abnormalities of
myasthenia are summarized in Table

9-10. Myasthenia gravis characteristically
causes intermittent diplopia due to vari-
able extraocular muscle weakness. Such
weakness is often asymmetric and may
mimic third, fourth, or sixth nerve palsy,
gaze paresis, internuclear ophthalmople-
gia, one-and-a-half syndrome (see Ocular
Motor Syndromes Caused by Disease of
the Pons in Chap. 10) or strabismus. The
pseudo-internuclear ophthalmoplegia of
myasthenia gravis is sometimes associated
with depression or downshoot of the ad-
ducting eye.278 Fatigue, during sustained
attempts to hold lateral or upward gaze, is
manifest as centripetal drift or increasing
fatigue nystagmus (Fig. 9-20A), which
may be followed by rebound nystagmus.
Perhaps the earliest and most sensitive
signs of extraocular involvement are ab-
normalities of saccades and quick phases
of nystagmus. Examples are shown in Fig-
ure 9-20. Large saccades may be hypo-
metric and small saccades may be hyper-
metric. For large saccades, the eye may
start off rapidly but slow in midflight and
creep up to the desired eye position. A
characteristic quiver movement consists of
an initial, small saccadic movement fol-
lowed by a rapid drift backward (Fig.
9-20B). The relationship between the
peak velocity and amplitude of saccades
(the main-sequence relationship) is more vari-
Table 9-10. Ocular Manifestations of
Myasthenia Gravis
Ptosis
Peekaboo sign: prolonged eyelid closure lead-
ing to eye opening
Lid twitch 108
Gaze-evoked centripetal drift 478 or nystagmus180
Diplopia: due to single or multiple extraocular
muscle weaknesses, which may simulate ocu-
lomotor, trochlear,533 abducens, or combined
palsies; internuclear ophthalmoplegia; 211 ' 493
gaze palsy; one-and-a-half syndrome 130 ' 602
Saccades: hypometria of large saccades,
hypermetria of small saccades, quiver
movements, and "hyperfast" SaC-
^^es 110 > 173 ' 471 > 548 ' 549 ' 587 > 593 > 699 ' 702
After edrophonium: saccadic hypermetria,
macrosaccadic oscillations
Diagnosis of Diplopia and Strabismus 375
able than that of normal subjects.42 During
prolonged optokinetic nystagmus, quick
phases may become slow. Injection of
edrophonium (Tensilon) often reverses
extraocular muscle weakness and causes
saccades to become hypermetric. Some-
times the patient is not able to hold steady
fixation because of repetitive hypermetric
saccades that overshoot the target in both
directions—macrosaccadic oscillations (see
VIDEO: "Myasthenia gravis"). The duration
of saccades is decreased41 and the velocity
of larger saccades may be increased.40
PATHOPHYSIOLOGYOF
OCULAR MOTOR FINDINGS IN
MYASTHENIA GRAVIS
Two separate factors account for the vari-
ous ocular motor findings in myasthenia
gravis: failure of neuromuscular transmis-
sion and central adaptive mechanisms.
Failure of Neuromuscular
Transmission
During repetitive activation of motor
nerves, the amount of acetylcholine re-
leased at the nerve terminals declines to a
plateau value that depends upon the
firing frequency. In myasthenia, neuro-
muscular transmission is tenuous, since
the number of functioning postsynaptic
acetylcholine receptors is reduced. A small
decrease in the amount of released neuro-
transmitter reduces the probability that an
endplate potential will be generated and
so predisposes to failure of neuromuscular
transmission. Factors that may predispose
the extraocular muscles to frequent in-
volvement in myasthenia gravis include
their higher discharge rates, chemical dif-
ferences in the nature of the receptors,
and the lack of action potentials in the
tonic fibers.284'286'290 Though failure of
neuromuscular transmission affects both
global and orbital extraocular muscle
fibers, the more constant activity of the
latter makes them more susceptible to
fatigue.
The fundamental process in myasthe-
nia gravis is an autoimmune response
against the acetylcholine receptor.284'588
376 The Diagnosis of Disorders of Eye Movements

Figure 9-20. Myasthenia gravis. Fatigue of extraocular muscles causing eye movement abnormalities in myas-
thenia gravis. (A) Development of gaze-evoked nystagmus during attempts to sustain lateral gaze. After about
15 seconds, the patient developed a centripetal drift, more marked in the adducting, left eye, and gaze-evoked
nystagmus. Arrow indicates artifact. (B) Two quiver movements (see VIDEO: "Myasthenia gravis") and one slow
saccade prior to edrophonium. (C) Effects of edrophonium. The patient is asked to make saccades between
fixed target lights located at 0° and 5° to the right and left. However, as the effects of the edrophonium become
manifest, he finds this impossible to do and begins to develop oscillations about the target located at 0° (indi-
cated at arrow). These square wave oscillations reflect the increase in saccadic gain due to central adaptive
changes and the effects of edrophonium (see VIDEO: "Myasthenia gravis"). LEP, left eye position; REP, right eye
position; POS, position; VEL, velocity.

Thus, over 80% of patients with general-
ized myasthenia and about 65% with
the pure ocular form have anti-acetyl-
choline-receptor antibodies in their sera.
It has been suggested that antibodies spe-
cifically directed against the fetal form of
the acetylcholine receptor, which may be
found at synapses on extraocular but not
skeletal muscles, may be an important
factor that predisposes the extraocular

muscles to involvement by myasthe-
nia 286,289,290 However, myasthenia also af-
fects the levator of the lids, which does not
have synaptic fetal acetylcholine recep-
tors.287 This fact and the report that a pa-
tient with antibodies directed against fetal
acetylcholine receptors did not manifest
ocular myasthenia (even though her baby
developed transplacental, neonatal myas-
thenia) indicate the complexity of the
issue.456'661
Saccades that start off at high velocities
but slow in midflight and creep up to the
target (Fig. 9-20B) probably reflect in-
trasaccadic fatigue; muscle fibers are un-
able to sustain the vigorous muscular con-
traction required for the duration of the
saccadic pulse of innervation. The sac-
cadic step of innervation then carries the
eye slowly to its final position. The peak
velocity of such saccades may be normal
but the duration is prolonged. Early in the
disease, subtle changes in the waveform of
saccades, best detected in velocity traces,
may be noted with a characteristic deceler-
ation that varies from saccade to saccade.
Normal subjects only show these changes
for large saccades.5
Later in the disease, patients with little
residual ocular motility may seem to make
superfast saccades within their limited
range of motion. The peak velocity of
these movements is often greater than
would be expected for the size of the sac-
cade.471 Though central adaptive changes
may be partly responsible (see below), this
cannot be the whole explanation; adaptive
increases in saccadic innervation that oc-
cur in other types of muscle palsies do not
produce superfast saccades.476 A more
likely explanation is that the global (pre-
dominantly fast-twitch) fibers of the ago-
nist muscle, which are relatively inactive
and rested during fixation, can start the
saccade with a normal pulse of activity. So
tenuous is neuromuscular transmission,
however, that fatigue develops rapidly,
aborting the pulse. Since the orbital (pre-
dominantly tonic) fibers may also become
fatigued during the saccade, the eye stops
and may even begin to drift backward.
When the tonic fibers are completely fa-
tigued, the step is absent. Then the me-
chanical forces of the orbit pull the eye
Diagnosis of Diplopia and Strabismus 377
rapidly back toward the central position,
causing a glissade. The combination of the
aborted saccade and oppositely directed
glissade constitutes the quiver movement
(Fig. 9-20B). The presence of such rapid
movements in patients with restricted ocu-
lar motility should always suggest myas-
thenia; such movements are absent in
patients who have slow or restricted move-
ments due to disease of the central ner-
vous system. Occasionally, a quiver-like
movement may be followed by a slow con-
tinuation of the saccade; presumably the
fatigued pulse is followed, after a brief pe-
riod of electrical silence, by either a re-
newed step from tonic fibers or another
corrective saccadic pulse.
The ability to hold the eye steady after a
saccade may be affected by postsaccadic fa-
tigue. Depending upon whether the pulse
or step is more affected, the resulting
pulse-step mismatch causes onward or
backward postsaccadic drift. Often sus-
tained eccentric gaze will bring out nystag-
mus (Fig. 9-20A), with slow-phase wave-
forms that follow a linear or negative
exponential time course. This has been
called fatigue nystagmus and muscle-paretic
nystagmus549 and probably occurs when the
orbital fibers are fatigued. This nystagmus
differs from gaze-evoked nystagmus due
to cerebellar disease, which often dimin-
ishes with sustained effort. The global
fibers are relatively spared, since they only
discharge vigorously during saccades or
quick phases. Occasionally, when nystag-
mus develops with sustained eccentric
gaze, the amplitude (as well as the veloc-
ity) is more marked in the abducting eye.
This dissociated nystagmus mimics inter-
nuclear ophthalmoplegia.602
Adaptation and the Effects of
Edrophonium in Myasthenia Gravis
Not all features of myasthenic eye move-
ments can be ascribed to neuromuscular
block. As discussed in Chap. 3, the brain
monitors the accuracy of saccades and
makes adaptive changes of innervation to
optimize ocular motor performance (see
Chap. 3). When myasthenia causes paretic
saccades, central adaptation is stimulated
if the patient habitually views with the
378 The Diagnosis of Disorders of Eye Movements
paretic eye. These mechanisms can be ap-
plied to the pulse-step pattern of innerva-
tion that normally produces fast, accurate
saccades. Large saccades often fall short of
the target; they are hypometric. Smaller
saccades, however, made around the cen-
tral position, are often orthometric or
even overshoot the target. Why should
saccades become hypermetric in myasthe-
nia gravis? The answer is apparent from
the observation of the effects of edropho-
nium (Tensilon). During the edropho-
nium test, saccade size increases. Many
saccades become too large, and occasion-
ally an extreme degree of hypermetria
produces continuous, to-and-fro saccadic
movements about the target known as
macrosaccadic oscillations (Fig. 9-20C) (see
VIDEO: "Myasthenia gravis"). Saccade hy-
permetria occurs because the central ner-
vous system has adaptively increased the
size of the saccadic pulse in an attempt to
overcome the myasthenic weakness. The
central changes are revealed by edropho-
nium, which transiently removes the pe-
ripheral neuromuscular blockade, expos-
ing the increased saccadic innervation. If
the brain had been standing idly by, edro-
phonium would merely have caused refix-
ations to become orthometric.
EYE MOVEMENTS AND
THE DIAGNOSIS OF
MYASTHENIA GRAVIS
When ocular motility is minimally af-
fected, careful study of eye movements—
preferably measurements of saccades—
before and during the edrophonium
(Tensilon) test or the neostigmine test may
be particularly useful. Before edropho-
nium, an early finding is variability of sac-
cadic trajectory and main-sequence rela-
tionships.42 Edrophonium is best given in
small (0.2 mg) increments to avoid missing
a positive response owing to cholinergic
excess. Neostigmine (0.5 mg, given intra-
muscularly with atropine, 0.5 mg) is also
useful, because it allows more time to
make both clinical observations and quan-
titative measurements. We examine and
record at 15- to 20-minute intervals for
about 45 minutes to look for a positive re-
sponse, which includes changes in sac-
cadic accuracy and especially the produc-
tion of hypermetria. Such effects are prob-
ably diagnostic of myasthenia gravis. The
duration of saccades, especially larger
movements, tends to shorten.40 The veloc-
ity, especially of larger saccades, tends to
increase.40 In contrast, normal subjects or
patients with ocular motor palsies show in-
creased duration and slowing of saccades
after edrophonium.40'41 These changes in
normal subjects and in patients with non-
myasthenic strabismus illustrate the dan-
gers in not measuring the nature of the
changes produced by edrophonium. Fur-
thermore, some nonmyasthenic ocular de-
viations get worse after edrophonium if
one muscle is more susceptible to the ef-
fects of the drug than the others. In par-
ticular, subjective tests such as the red
glass, Maddox rod, or Lancaster red-
green test must be interpreted cautiously,
as they may give misleading results. Only
the direct observation of a weak muscle
becoming stronger after edrophonium is
reliable evidence of myasthenia.125 Even
then, the diagnosis depends on the full
clinical picture; false-positive test results
have been reported with central structural
lesions, and myasthenia can coexist with
intracranial lesions.150'428 If the Tensilon
test is negative, the longer-acting agent
neostigmine (given with atropine) may
help make the diagnosis. Neostigmine has
the advantage of giving the examiner
more time to detect a change in ocular
alignment or saccade metrics but has the
disadvantage that its rate of absorption af-
ter intramuscular injection varies.
In patients with purely ocular manifes-
tations, single-fiber EMG of the superior
rectus and levator muscles may contribute
to the diagnosis by showing jitter.521 Sin-
gle-fiber studies of the facial muscles are
useful, too, but may not differentiate mi-
tochondrial myopathy or oculopharyngeal
dystrophy from myasthenia.644
Late in the course of myasthenia gravis,
all ocular motility may become restricted
and the patient may be refractory to edro-
phonium or neostigmine testing. Imaging
studies show atrophied extraocular mus-
cles.470 If a clear history is unavailable, dif-

ferentiation from the syndrome of chronic
progressive external ophthalmoplegia may
be difficult.
TREATMENT OF
OCULAR MYASTHENIA
Anticholinesterase drugs such as pyri-
dostigmine are less effective for the treat-
ment of diplopia and ptosis than for other
symptoms. 169 Because of the variability of
ocular deviations, prisms are not usually
helpful and surgery is only considered if
there is troublesome diplopia in patients
who are otherwise in remission.467 Treat-
ment with a short course of prednisone
and long-term azathioprine is reported to
reduce the risk and severity of generalized
symptoms and to promote remission of
the disease.589 Thymectomy, prompted by
abnormal appearances on chest CT, is re-
ported to provide no advantage over med-
ical treatment for ocular symptoms. 589
Simple measures such as dark glasses to
reduce the discomfort of diplopia, prisms
to correct for stable ocular deviations, and
"lid-crutches" for ptosis are often appreci-
ated by selected patients.588
CHRONIC PROGRESSIVE
EXTERNAL OPHTHALMO-
PLEGIA AND RESTRICTIVE
OPHTHALMOPATHIES
Progressive limitation of ocular motility,
accompanied by ptosis but usually without
diplopia, occurs in many disease states
(Table 9-11). Such chronic progressive exter-
nal ophthalmoplegia (CPEO) usually spares
the pupils but involves the orbicularis
oculi. Saccades in CPEO are slow through-
out their movements, unlike those in
myasthenia, in which initial saccadic veloc-
ity is often normal. Imaging of the orbit
with MR may show small extraocular
muscles.92
The peculiar histological features of the
extraocular muscles and their unusual re-
sponses to disease have complicated at-
tempts to identify separate disease entities
(see section on Structure and Function of
Diagnosis of Diplopia and Strabismus 379
Table 9-11. Differential Diagnosis of
Chronic Progressive Ophthalmoplegia
Oculopharyngeal dystrophy
Mitochondrial cytopathies: Kearns-Sayre syn-
drome, CPEO* (sporadic), CPEO (domi-
nant), MELASt
Myotubular myopathy
Stephens syndrome (CPEO, ataxia, peripheral
neuropathy)
Myotonic dystrophy
Bassen-Kornzweig syndrome (abetalipopro-
teinemia)
Refsum's disease
Endocrine ophthalmoparesis (ophthalmic
Graves disease)
Congenital extraocular fibrosis or adherence
syndromes
Orbital pseudotumor
Myasthenia gravis
Limited ocular motility owing to brain stem
disease (e.g., Mobius syndrome, spinal mus-
cular atrophy, progressive supranuclear
palsy)
*CPEO = chronic progressive external ophthal-
moplegia.
i^MELAS = mitochondrial encephalopathy, lactic
acidosis, and stroke.
Extraocular Muscle). Because of this diffi-
culty in reliably discerning distinct noso-
logic entities, the term ophthalmoplegia plus
has been used to describe CPEO accompa-
nied by a variety of other findings. 156
However, modern genetic techniques
have defined distinct defects of nuclear or
mitochondrial DNA in some of these dis-
orders.346
Involvement of the Extraocular
Muscles in Muscular Dystrophies
DUCHENNE'S DYSTROPHY
Duchenne's and Becker's dystrophies, which
are due to allelic abnormalities of genetic
expression of the protein dystrophin, lead
to severe weakness of the limbs and trunk
but, remarkably, spare the extraocular
muscles. Thus, for example, patients with
advanced disease have normal-velocity
380 The Diagnosis of Disorders of Eye Movements
saccades.285 Immunohistochemical studies
have confirmed that the extraocular mus-
cles are preserved,316 and this led to the
speculation that they are better able to
manage the massive calcium influx that ac-
companies the dystrophin defect.499 Alter-
natively, the extraocular muscles may be
protected by endogenous upregulation
of a dystrophin analog, utrophin. 506a Eye
movements are also reported to be normal
in patients with fascioscapulohumeral dys-
trophy.658
MYOTONIC DYSTROPHY
Myotonic dystrophy, an autosomal dominant
condition due to trinucleotide repeats, has
widespread manifestations including pto-
sis and defects in ocular motility that are
usually mild, but occasionally conform to
the syndrome of CPEO.370 Saccades may
be slow, hypometric, and made at in-
creased latency.14'323'624'6583 Both smooth
pursuit and suppression of the vestibulo-
ocular reflex during eye-head tracking
are impaired, but the vestibulo-ocular re-
flex is normal.14 There is debate as to
whether these defects in eye movements
can be ascribed to central involvement by
the disease process or involvement of
the extraocular muscles by the myotonic
process. Impaired suppression of the
vestibulo-ocular reflex suggests central in-
volvement, since the eyes need not move
much in the orbits during this task.14
However, there is some evidence for my-
otonia of the extraocular muscles during
saccades. Thus, if saccades are tested after
a rest period with the eyes closed, their
amplitude and peak velocity progressively
increase ("warm-up" effect).238 Further,
administration of drugs such as to-
cainamide, which stabilizes muscle mem-
branes, normalize the initial saccadic size
and speed after a rest period. There is a
need for structural studies of the extraoc-
ular muscles in myotonic dystrophy using
modern techniques.
OCULOPHARYNGEAL DYSTROPHY
Autosomal dominant oculopharyngeal dystrophy
has been described in several ethnic
groups.61'451'659 The symptoms usually be-
gin after age 40 years; they consist of pto-
sis, limitation and slowing of saccadic eye
movements, weakness of the facial and
proximal limb muscles, and dysphagia.
Pharyngeal symptoms are most promi-
nent and bulbar dysfunction may lead to
the death of the patient. Surgical treat-
ment (cricopharyngeal myotomy) is re-
ported to help.153 Ptosis is generally more
prominent than restricted ocular motility.
Weakness of neck or limb muscles may de-
velop but is usually mild. Biopsy of limb
muscles has shown characteristic red-
rimmed vacuoles and nuclear inclu-
sions.61'153'633 The onset of symptoms is
earlier, and the findings are more severe,
in patients who are homozygous for the
disorder.61
CONGENITAL MYOPATHIES
Myotubular myopathy (or centronuclear my-
opathy} is a rare congenital disorder char-
acterized by ptosis, progressive limitation
of ocular motility, and weakness of facial
muscles, neck flexors, and the limbs.64'601
Limb muscle biopsy shows small type I
fibers and the presence of central nu-
clei.520 Extraocular muscles in this condi-
tion also have central nuclei, but there is
no significant alteration of fiber type dis-
tribution. 520 Nemaline myopathy also may
rarely present with ptosis and limitation of
eye movements.695 Ptosis and impaired
range of eye movements may be present in
patients with central core myopathy and
multicore disease.64'346
Kearns-Sayre Syndrome and
Disorders of Mitochondrial DNA
It has been established that one cause
of chronic progressive ophthalmoplegia,
Kearns-Sayre syndrome,127'308 is due, in most
cases, to deletions or duplications of mito-
chondrial ONA.77'188'429'570-685 Rare cases
are reported in which there appears to be
a defect of communication between nu-
clear and mitochondrial genomes.94'571
This multisystem disorder is characterized
by progressive ophthalmoparesis begin-
ning in childhood or adolescence, atypical

pigmentary degeneration of the retina,
and heart block. Both the cardiac and en-
docrine complications of Kearns-Sayre
syndrome may be life-threatening. The as-
sociated abnormalities are summarized in
Table 9-12. The involvement of the eye
muscles in mitochondrial myopathies
probably reflects their high oxidative
stress as functionally compromised mito-
chondria accumulate.505
Some patients show clinical features that
overlap Kearns-Sayre syndrome and other
mitochondrially inherited disorders, in-
cluding ME LAS (mitochondrial encephalopa-
thy, lactic acidosis, and stroke), and MERRF
(myoclonic epilepsy and ragged red fibers) .98 An
uneven distribution of deletions of mito-
chondrial DNA in different tissues may
account for the different phenotypic ex-
pressions. Pathologically, both limb and
extraocular muscles often show ragged-
red fibers with trichrome stains; this ap-
Table 9-12. Features of Kearns-Sayre
Syndrome48'127'145'196'223'258'308
Chronic progressive ophthalmoplegia*
Retinal pigmentary deposition
Heart block*
Small stature
Hearing loss (vestibular disturbance)
Cerebellar ataxia
Pendular nystagmus
Corticospinal tract signs
Impaired intellect
Cranial muscle weakness (face, palate, neck)
Peripheral neuropathy
"Myopathy" affecting skeletal muscles (ragged-
red fibers)
Corneal clouding
Scrotal tongue
Spinal fluid abnormalities (elevated protein)
Basal ganglion calcification
Slowed electroencephalogram
Endocrine abnormalities (hypopara-
thyroidism; diabetes; hypogonadism)
Elevated serum glutamic oxaloacetic trans-
aminase, creatinine phosphokinase, lactic
dehydrogenase, altered lactate-pyruvate
metabolism
*For diagnosis of Kearns-Sayre syndrome, these
features should be present before 20 years of age.
Diagnosis of Diplopia and Strabismus 381
pearance is due to increased numbers of
abnormal sarcolemmal mitochondria. The
brain shows a spongy degeneration that
results in cerebral and cerebellar atro-
phy.77'127'694 Therapy with Coenzyme Q10
aims to improve respiratory chain activ-
ity,75 but its clinical efficacy is unproven.
Thyroid Ophthalmopathy
Thyroid disease is an important cause of
restrictive ophthalmopathy.38 Orbital ab-
normalities encountered in patients with
thyroid disorders include chemosis, peri-
orbital congestion, lid retraction and lid
lag, proptosis (exophthalmos), ophthal-
moparesis, and optic neuropathy.38-39 Ex-
ophthalmos and periorbital edema usually
precede the development of impaired oc-
ular motility, though diplopia may be the
first symptom. Patients with thyroid oph-
thalmopathy often complain of diplopia,
unlike most forms of CPEO. In contrast to
myasthenia, symptoms are usually worse
in the morning. Lid retraction and lid lag
on downward gaze are common signs.
The most common abnormalities of eye
movements are impaired elevation, and ex-
torsion of the abducted eye. Abduction
and downward movements may also be
impaired. Thus, the limitation of move-
ment reflects a restrictive ophthalmopathy,
which can usually be confirmed by the
forced duction test. The velocity and ampli-
tude of saccadic eye movements is reduced
in some patients,693a and the development
of these abnormalities may correlate with
progression of orbital disease.174'398
The disturbances of eye movements in
Graves' disease have been ascribed to the
effects of increased tissue volume within
the orbit.175 Enlargement of the extraocu-
lar muscles is due to abnormal accumula-
tion of glycoaminoglycans in the connec-
tive tissue of the endomysium and in the
orbital fat. The primary process underly-
ing Graves' ophthalmopathy appears to be
due to an immune attack on orbital fibro-
blasts.26 Whether the extraocular muscles
are targeted by the disease process itself or
are affected secondary to increased in-
traocular pressure is debated.175'499 The
ligament of Lockwood, to which the infe-
382 The Diagnosis of Disorders of Eye Movements

rior rectus and inferior oblique muscles
are attached, is involved by the inflamma-
tory changes and contributes to impaired
upward movements.
In many patients with thyroid ophthal-
mopathy, symptoms and signs are minimal
and diagnosis may sometimes be diffi-
cult.592 As many as 20% of patients are eu-
thyroid. In this group, a thyrotropin re-
leasing hormone (TRH) stimulation test
or antibody studies (antithyroglobulin and
antimicrosomal antibodies) may help con-
firm the diagnosis. Also of great value is
orbital imaging and ultrasound, which can
provide evidence of extraocular muscle
enlargement (Fig. 9-21) and provide a re-

Figure 9-21. CT of the orbits showing enlarged extraocular muscles in a 76-year-old woman with Graves oph-
thalmopathy and myasthenia gravis. On examination she had bilateral ptosis, worse on the left. Horizontal
range of motion was moderately restricted, and forced duction tests of the right eye indicated restriction of the
inferior rectus. (Courtesy Dr. Henry J. Kaminski.)

liable index of the presence and progres-
sion of disease233'679 In patients with small
tropias due to thyroid ophthalmopathy,
prisms may alleviate diplopia. Many pa-
tients benefit from systemic corticosteroid
therapy. Sometimes surgery is performed;
this is best attempted during the quiescent
phase of the disease. With chronic tropias,
surgical recessions may be successful in
restoring single, binocular vision in cen-
tral and reading positions,666 but a nor-
mal, conjugate range of eye movements is
seldom achieved.
Restrictive Ophthalmopathy and
Congenital Fibrosis of the
Extraocular Muscles
A variety of other conditions are reported
to restrict eye movements. In some, ex-
traocular muscles appear enlarged on
computed tomography; these include
metastatic tumor deposits,91'99'146-172'185'244
amyloid, 254 sarcoid, 114 parasites,292 ca-
rotid-cavernous fistula (see above), orbital
myositis, and orbital pseudotumor.206'426'674
Some patients with giant-cell arteritis or
Wegener's granulomatosis develop nearly
complete ophthalmoplegia due to muscle
ischemia.151'494
Rarely, reduced ocular motility is due to
congenital (sometimes familial) disorders
in which there is failure of development
and fibrosis of one or more of the extraoc-
ular rnuscles.208'310'395'397'441a'470'484'623b'642'666
Occasionally, affected muscles are en-
larged rather than atrophic. 148 A new im-
petus has been given to understanding
these disorders by the demonstration of
linkage of an autosomal dominant form of
congenital fibrosis of the extraocular mus-
cles type 1, to chromosome 12163 and by
careful postmortem analysis of one case.162
This analysis revealed absence of the supe-
rior division of the oculomotor nerves and
the corresponding motoneurons and atro-
phy of the levator and superior rectus
muscles, which contained connective tis-
sue and fat. Affected family members show
a chin-up head posture, with ptosis and
the eyes fixed in down gaze. Eye move-
ments are limited, especially vertically,
with substitution of vergence for versional
Diagnosis of Diplopia and Strabismus 383
movements, convergence on up gaze, and
the appearance of pendular nystagmus
and ocular retraction during attempted
gaze shifts. Those patients with the sever-
est limitation may completely substitute
head movements for eye movements.207
Strabismus is the rule, but diplopia is ab-
sent due to the ability to suppress images
from either eye. Associated defects, in-
cluding mild facial diplegia, may be pres-
ent. Congenital fibrosis of the extraocular
muscles type 2, which maps to chromo-
some 1 Iql3, is characterized from birth by
bilateral ptosis, with the eyes fixed in ex-
treme abduction.676a
What remains unexplained about such
patients is the absence of aberrant inner-
vation to the superior rectus and levator
palpebrae superioris from the intact ab-
ducens nucleus, unlike the situation in
Duane's syndrome, in which the lateral
rectus gains some innervation from the
oculomotor nerve. Development of ge-
netic models for this group of disorders is
likely to clarify how the normal embryol-
ogy of the extraocular muscles can go
awry.500-502
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Chapter 10
DIAGNOSIS OF CENTRAL
DISORDERS OF OCULAR MOTILITY
DIAGNOSIS OF NYSTAGMUS AND
SACCADIC INTRUSIONS
The Nature and Visual Consequences of
Abnormal Eye Movements that Prevent
Steady Fixation
Clinical and Laboratory Methods for
Evaluating Nystagmus and Saccadic
Intrusions
A Pathophysiological Approach to the
Diagnosis of Nystagmus
Nystagmus due to Vestibular Imbalance
Periodic Alternating Nystagmus
Seesaw and Hemi-seesaw Nystagmus
Nystagmus Occurring When the Eyes Are in
Eccentric Gaze
Nystagmus Occurring in Association with
Disease of the Visual System
Convergent-Divergent Forms of Nystagmus
Congenital Forms of Nystagmus
Lid Nystagmus
Saccadic Intrusions
TREATMENTS FOR NYSTAGMUS AND
SACCADIC INTRUSIONS
Rational Basis for Therapy of Abnormal Eye
Movements
Pharmacological Treatments of Abnormal
Eye Movements
Optical Treatments of Abnormal Eye
Movements
Procedures to Weaken the Extraocular
Muscles
Application of Somatosensory or Auditory
Stimuli to Suppress Nystagmus
SKEW DEVIATION AND THE OCULAR
TILT REACTION (OTR)
Clinical Features of Skew Deviation and
OTR
Topologic Diagnosis of Skew Deviation and
the OTR
DISEASE OF THE VESTIBULAR
PERIPHERY
Vertigo and Dizziness
Clinical Features of Acute Peripheral
Vestibulopathy
Acute Vertigo
Recurrent Vertigo
Posturally-Induced Vertigo
Treatment of Vertigo
OSCILLOPSIA
Oscillopsia due to an Abnormal VOR
Oscillopsia due to Paresis of Extraocular
Muscles
Oscillopsia due to Nystagmus and other
Abnormal Eye Movements
OCULAR MOTOR SYNDROMES CAUSED
BY LESIONS IN THE MEDULLA
Medullary Lesions Impairing Gaze Holding
Effects of Disease involving the Inferior
Olivary Nucleus
Effects of Disease Restricted to the
Vestibular Nuclei
Wallenberg's Syndrome (Lateral Medullary
Infarction)
OCULAR MOTOR SYNDROMES CAUSED
BY DISEASE OF THE CEREBELLUM
Three Principal Cerebellar Syndromes
Other Disorders of Eye Movements
Attributed to Cerebellar Disease
Developmental Anomalies of the Hindbrain
and Cerebellum
405
406 The Diagnosis of Disorders of Eye Movements
Ocular Motor Findings in the Hereditary
Ataxias
Cerebellar Infarction
Cerebellar Mass Lesions
OCULAR MOTOR SYNDROMES CAUSED
BY DISEASE OF THE PONS
Lesions of the Abducens Nucleus
Lesions of the Paramedian Pontine
Reticular Formation (PPRF)
Lesions of the Medial Longitudinal
Fasciculus: Internuclear
Ophthalmoplegia (INO)
Combined Unilateral Conjugate Gaze Palsy
and INO: "One-and-a-half Syndrome" and
Other Variants
Selective Cell Vulnerability in the Pons
OCULAR MOTOR SYNDROMES CAUSED
BY LESIONS OF THE
MESENCEPHALON
Modern Concepts of Vertical Gaze Palsies
Lesions of the riMLF and Vertical Saccadic
Palsy
Lesions of the Interstitial Nucleus of Cajal
(INC)
Effects of Lesions of the Posterior
Commissure and Nucleus of the Posterior
Commissure
Clinical Manifestations of Other
Mesencephalic Lesions
Selective Cell Vulnerability in the
Mesencephalon
OCULAR MOTOR SYNDROMES CAUSED
BY LESIONS IN THE SUPERIOR
COLLICULUS
OCULAR MOTOR SYNDROMES CAUSED
BY LESIONS IN THE DIENCEPHALON
Effects of Thalamic Lesions on Eye
Movements
Effects of Pulvinar Lesions on Eye
Movements
OCULAR MOTOR ABNORMALITIES AND
DISEASE OF THE BASAL GANGLIA
Parkinson's Disease and Conditions Causing
Parkinsonism
Huntington's Disease (HD)
Other Diseases of Basal Ganglia
OCULAR MOTOR SYNDROMES CAUSED
BY LESIONS IN THE CEREBRAL
HEMISPHERES
Disturbances of Gaze With Acute
Hemispheric Lesions
Enduring Disturbances of Gaze Caused by
Unilateral Hemispheric Lesions
Effects of Focal Hemispheric Lesions on
Gaze
Ocular Motor Apraxia
Eye Movements During Epileptic Seizures
ABNORMALITIES OF EYE MOVEMENTS
IN PATIENTS WITH DEMENTIA
Alzheimer's Disease
Creutzfeldt-Jakob Disease
AIDS and Dementia
EYE MOVEMENT DISORDERS IN
PSYCHIATRIC ILLNESSES
EYE MOVEMENTS IN STUPOR AND COMA
Resting Position of the Eyes in Unconscious
Patients
Spontaneous Eye Movements in
Unconscious Patients
Reflex Eye Movements in Unconscious
Patients
OCULAR MOTOR DYSFUNCTION AND
MULTIPLE SCLEROSIS
OCULAR MOTOR MANIFESTATIONS OF
METABOLIC AND DEFICIENCY
DISORDERS
EFFECTS OF DRUGS ON EYE
MOVEMENTS
In this chapter, we describe the clinical
features of central disorders of ocular
motility, presenting video clips of the
more common conditions. In each case,
we draw on the anatomic and physiologic
principles developed in previous chapters
to provide a pathophysiological explana-
tion for the disorder. The reader should
be aware that, at the bedside, these patho-
physiologic hypotheses may fall short of
explaining clinical findings. When they do
so, we hope that they may encourage a
reevaluation of the assumptions that are
used in clinical diagnosis. The advantage
of this strategy was commented upon
by William James697 who noted "how
few facts 'experience' will discover unless
some prior interest, born of theory, is
already awakened in the mind." First,
we will discuss abnormal eye movements
that occur during attempted fixation—
nystagmus and saccadic intrusions. Then
we will discuss disease of the vestibular pe-
riphery, skew deviation, vertigo, and oscil-
lopsia. The rest of this chapter deals with
 Diagnosis of Central Disorders of Ocular Motility
the topological diagnosis of eye move-
ments caused by disease of the brain, start-
ing at the medulla and progressing ros-
trally to cerebral cortex, with special
mention given to certain multifocal disor-
ders and the effects of drugs.
DIAGNOSIS OF NYSTAGMUS
AND SACCADIC INTRUSIONS
The Nature and Visual
Consequences of Abnormal Eye
Movements That Prevent
Steady Fixation
A common clinical problem is the diag-
nosis of abnormal eye movements—often
oscillations—that disrupt steady fixation.
Such movements may interfere with vi-
sion. Recall the visual requirements of eye
movements: To see an object best, its image
must be held steadily over the foveal re-
gion of the retina. Excessive motion of im-
ages on the retina causes vision to decline
and may lead to the illusion of motion of
the seen world (oscillopsia). Furthermore,
if the image of the object is moved away
from the fovea to peripheral retina, it will
be seen less clearly. Abnormal eye move-
ments that prevent steady fixation are of
two main types: pathological nystagmus*
and saccadic intrusions. The essential dif-
ference between nystagmus and saccadic
intrusions lies in the initial eye movement
that takes the line of sight away from the
object of regard. For nystagmus, it is a
slow drift (or "slow-phase") as opposed to
an inappropriate saccadic movement that
intrudes on steady fixation. After the ini-
tial movement, corrective or other abnor-
mal eye movements may follow. Thus, a
definition of nystagmus is repetitive, to-
and-fro movement of the eyes that is initi-
ated by slow phases. Nystagmus may con-
sist mainly of sinusoidal slow-phase
oscillations (pendular nystagmus) or, more
*The word nystagmus derives from a comparison
with nodding of the head (slow downward drift and
sudden upward jerk) during drowsiness.
407
commonly, of an alternation of slow drift
and corrective quick phase (jerk nystag-
mus). Although nystagmus is often de-
scribed by the direction of its quick phases
(e.g., downbeat nystagmus), it is the slow
phase that reflects the underlying disor-
der. Saccadic intrusions are rapid move-
ments that take the eye away from the tar-
get and comprise a spectrum ranging
from single saccades to sustained saccadic
oscillations.
Not all nystagmus is pathological. Nor-
mally, physiological nystagmus acts to
preserve clear vision during self-rotation
when the vestibulo-ocular and optokinetic
responses prevent excessive slip of images
on the retina and quick phases reset the
eyes into their working range. Thus, both
vestibular and optokinetic nystagmus act
to hold retinal images steady. The oppo-
site is true of pathologic nystagmus, which
causes excessive drift of images of station-
ary objects on the retina and so degrades
vision.3923
Clinical and Laboratory Methods
for Evaluating Nystagmus and
Saccadic Intrusions
HISTORY-TAKING IN PATIENTS
WITH ABNORMAL EYE
MOVEMENTS THAT
DISRUPT FIXATION
The diagnosis of nystagmus and saccadic
intrusions is often possible on the basis of
a careful history and systematic examina-
tion. Inquire about the duration of the
nystagmus, whether it is accompanied by
other neurologic symptoms, and whether
it interferes with vision and causes oscil-
lopsia. Determine if nystagmus or associ-
ated visual symptoms are worse when
viewing far or near objects or when
the patient is in motion, or if they are
affected by different gaze angles (e.g.,
worse on right gaze). Ask about "jump-
ing eyes," strabismus, or eye operations
since childhood. Document current med-
ications. If the patient habitually tilts or
turns the head, determine whether these
findings are evident on old photographs.
408 The Diagnosis of Disorders of Eye Movements
EXAMINATION OF ABNORMAL
EYE MOVEMENTS THAT
DISRUPT FIXATION
Before examining eye movements, check
the visual system (including color vi-
sion) looking for signs of optic nerve de-
myelination or malformation or ocular
albinism, which often suggests the diagno-
sis. Then examine the stability of fixation
with the eyes close to central position,
viewing near or far targets, and at eccen-
tric gaze angles. For each eye, note the
planes in which the nystagmus occurs
(horizontal, vertical, torsional, mixed).
Compare the oscillations of each eye and
note whether the direction or amplitude
differs and whether there is an asyn-
chrony (i.e., a phase shift between the two
eyes), which may lead to movements that
sometimes are in opposite directions.
When the size of the oscillations differs in
each eye, it is referred to as dissociated nys-
tagmus. When the direction of the oscilla-
tions in each eye differs, it is called discon-
jugate nystagmus or disjunctive nystagmus. It
is often useful to make a note of the direc-
tion and amplitude of nystagmus for each
of the cardinal gaze positions. If the pa-
tient has a head turn or tilt, the eyes
should be observed in various directions
of gaze when the head is in that position as
well as when the head is held straight.
During fixation, occlude each eye in turn
to check for latent nystagmus. Some nys-
tagmus is intermittent and requires sus-
tained observation over 2 to 3 minutes.
Low amplitude nystagmus may only be
detected while viewing the patient's retina
with an ophthalmoscope.1526 (Note that
the direction of horizontal or vertical nys-
tagmus is inverted when viewed through
the ophthalmoscope.)
Always examine the effect on nystagmus
of removing fixation; nystagmus due to
peripheral vestibular imbalance may only
be apparent under these circumstances.
Removal of fixation can be achieved by
eyelid closure; nystagmus is then detected
by recording eye movements, by observ-
ing movement of the corneal bulge, or by
palpating the globes. Because lid closure
itself may affect nystagmus, it is better to
examine the effects of removing fixation
with the eyes open; two clinical methods
are available. The first is to observe the
nystagmus behind Frenzel goggles, which
prevent fixation of objects and also pro-
vide the examiner with a magnified, illu-
minated view of the patient's eyes. The
second technique consists of transiently
covering the fixating eye during ophthal-
moscopy in an otherwise dark room and
noting the effects on retinal motion in the
eye being viewed. Evaluation of nystag-
mus is incomplete without a systematic
examination of each functional class of eye
movements—vestibular, smooth-pursuit,
saccades, and vergence (see Appendix A);
selective defects may indicate the nature
of the underlying disorder.
At the bedside, a complete description
of nystagmus, separating it into horizon-
tal, vertical, and torsional components,
depends upon the coordinate system in
which the observer couches his or her ob-
servations. This, in turn, may be influ-
enced by the vantage point of the observer
relative to the direction in which the pa-
tient is looking, i.e., the patient's line of
sight, and also by the position of the eye of
the patient in the orbit. Consider a patient
with the head still who has a spontaneous
jerk nystagmus that appears horizontal in
the straight-ahead position of gaze, i.e.,
the eyes are rotating around the rostral-
caudal (yaw) axis relative to the head. If
the patient looks far up, and if the eyes
continue to rotate around the same (yaw)
axis relative to the head (which is typical
for a nystagmus of vestibular origin), then
the nystagmus would appear to have a de-
veloped a torsional component if the line
of sight of the observer is moved upward
to coincide with that of the eye of the pa-
tient. In this case, the observer, by moving
the vantage point to match the axis along
which the patient is looking, will be de-
scribing the nystagmus in an eye-fixed co-
ordinate system. However, the nystagmus
may still be rotating the eye around the
same head-fixed (yaw) axis even though
the nystagmus has acquired a torsional
component. The nystagmus has appeared
to change direction when described in an
eye-fixed but not when described in a
head-fixed coordinate system. If on up-
ward gaze the nystagmus still appears
 Diagnosis of Central Disorders of Ocular Motility
"horizontal" to the observer, when viewed
in an eye-fixed coordinate system, the axis
of rotation around which the eye was ro-
tating, relative to the head, must have
changed.T
Similar considerations apply to a cen-
tral position vertical nystagmus, such as
"downbeat" nystagmus, in which the eyes
are rotating around the interaural (pitch)
axis. If the patient looks far to the right,
and if the nystagmus continues to rotate
the eyes around the same (pitch) axis rela-
tive to head, then the nystagmus would
appear to have a developed a torsional
component if the nystagmus is described
in an eye-fixed coordinate system. Again,
the nystagmus may still be rotating the eye
around the same head-fixed (pitch) axis,
even though the nystagmus has acquired a
torsional component. The nystagmus has
appeared to change direction when de-
scribed in an eye-fixed but not when de-
scribed in a head-fixed coordinate system.
However, if on lateral gaze the nystagmus
still appears "vertical" to the observer,
when viewed in an eye-fixed coordinate
system, the axis of rotation around which
the eye was rotating, relative to the head,
must have moved. Of course, once cog-
nizant of these frame-of-reference issues,
the observer can perform the necessary
mental transformation to determine the
axis of rotation of nystagmus no matter
what the direction of gaze of the patient or
what the position of the examiner relative
to the patient's line of sight. These distinc-
tions about which axis the eye rotates
when the eyes move eccentrically may be
important in determine the etiology of
nystagmus, since the axis of rotation of
nystagmus of vestibular origin (peripheral
or central) usually remains constant, no
matter what the direction of gaze, in a
head-fixed coordinate system, whereas
other forms of central nystagmus may
change their axis of rotation with the posi-
tion of gaze.
tNote that when the eyes are directed straight
ahead, the eye and head frames of reference coin-
cide. One must examine the eyes in an eccentric rota-
tion to determine the effect of eye position on the
axis of rotation, and hence in what framework a par-
ticular nystagmus is organized.
409
MEASUREMENT OF ABNORMAL
EYE MOVEMENTS THAT
DISRUPT FIXATION
It is often helpful to measure the abnor-
mal eye movements because analysis of
their dynamic properties will usually iden-
tify the nature of the oscillation. First,
measurements will differentiate between
nystagmus and saccadic intrusions, which
may be difficult to do on a clinical basis.
Second, characterization of the nystagmus
waveform—especially the slow phase (Fig.
10-1)—often provides a pathophysiologi-
cal "signature" of the underlying disorder.
Conventionally, nystagmus is measured in
terms of its amplitude and frequency and
their product—intensity. However, the vi-
sual symptoms due to nystagmus usually
correlate best with the speed of the slow
phase and the displacement from the
fovea of the image of the object of re-
gard.235'827'836
Although many different methods for
recording eye movements are now avail-
able (Appendix B),236-396'437 the best ap-
proach for patients with nystagmus is the
magnetic search coil technique (see Fig.
1-1, Chap. 1). This method is preferable
because many patients with ocular oscilla-
tions cannot accurately point their eyes at
visual targets to allow a reliable calibra-
tion; however, the contact lens that the pa-
tient wears can be precalibrated on a pro-
tractor device. Furthermore, this is the
only technique that allows precise mea-
surement of horizontal, vertical, and tor-
sional oscillations over an extended range
of amplitudes and frequencies. Although
originally introduced as a research tool,
the technique is now widely used to evalu-
ate clinical disorders of eye movements;
we have studied over 500 patients with
this method.
A Pathophysiological Approach to
the Diagnosis of Nystagmus
Although nystagmus can be classified us-
ing descriptive features, our approach will
be to identify the pathophysiology of the
underlying disorder and therefore the eti-
ology of the oscillation. In health, three
410 The Diagnosis of Disorders of Eye Movements
Figure 10-1. Four common slow-phase waveforms of
nystagmus. (A) Constant velocity drift of the eyes.
This occurs in nystagmus caused by peripheral or
central vestibular disease and also with lesions of the
cerebral hemispheres. The added quick phases give a
"sawtooth" appearance. (B) Drift of the eyes back
from an eccentric orbital position toward the midline
(gaze-evoked nystagmus). The drift shows a negative
exponential time course, with decreasing velocity.
This waveform reflects an unsustained eye position
signal caused by an impaired neural integrator. (C)
Drift of the eyes away from the central position with a
positive exponential time course (increasing veloc-
ity). This waveform suggests an unstable neural inte-
grator and is encountered in the horizontal plane in
congenital nystagmus and in the vertical plane in
cerebellar disease. (D) Pendular nystagmus, which is
encountered as a type of congenital nystagmus and
with acquired disease.
separate mechanisms collaborate to pre-
vent deviation of the line of sight from the
object of regard. The first mechanism is
the vestibulo-ocular reflex, by which eye
movements compensate for head pertur-
bations at short latency, and so maintain
clear vision during natural activities, espe-
cially locomotion. The second mechanism
is the brain's ability to hold the eye at an
eccentric position in the orbit against the
elastic pull of the globe's suspensory liga-
ments and muscles, which tend to return
it toward central position. The third
mechanism is "fixation," which has two
distinct components: the visual system's
ability to detect retinal image drift and
program corrective eye movements, and
the suppression of unwanted saccades that
would take the eye away from the target.
For all three gaze-holding mechanisms to
work effectively, their performance must
be honed. This requires continuous "re-
calibration" by adaptive mechanisms,
which monitor the visual consequences of
eye movements.
Disorders of these mechanisms disrupt
steady gaze and lead to nystagmus; often
the characteristics of the slow-phase drift
indicate the ocular motor subsystem that is
at fault. For example, imbalance of vestib-
ular drives may cause constant velocity
drifts (see Fig. 10-1A). If the gaze-holding
mechanism is deficient, the eyes cannot be
held steadily in an eccentric orbital po-
sition but drift back to the midline with
a decreasing-velocity waveform (gaze-
evoked nystagmus—Fig. 10-1B). Because
the gaze-holding mechanism depends, in
part, upon the vestibular nuclei, nystag-
mus due to brain stem lesions often mani-
fests the properties of both vestibular
imbalance and disturbed gaze holding. In-
stability in the gaze-holding mechanism
may lead to a slow-phase drift that in-
creases in velocity (Fig. 10-1C). Disor-
ders of the visual pathways may interfere
with the ability to suppress nystagmus
(of vestibular origin, for example) dur-
ing fixation, and also lead to drifts of the
eyes—including pendular oscillations (Fig.
10-ID)—because adaptive mechanisms
cannot null such imbalances if deprived of
visual inputs.
Thus, disorders of the vestibular system,
the gaze-holding mechanism, and visual
stabilization may each lead to nystagmus.
First, we will discuss nystagmus due to
each of these disorders in turn. We will
then consider other forms of nystagmus
that are either due to different causes or
 Diagnosis of Central Disorders of Ocular Motility 411

for which no satisfactory pathophysiologic in the vestibular nuclei. If labyrinthine

basis is known. Finally, we will discuss sac-
cadic abnormalities that disrupt steady
gaze and are frequently mistaken for nys-
tagmus.
Nystagmus due to
Vestibular Imbalance
NYSTAGMUS CAUSED
BY PERIPHERAL
VESTIBULAR IMBALANCE
Disease affecting the vestibular labyrinth
or nerve (including the root entry zone)
causes nystagmus with linear slow-phase
drifts (Display 10-1). The alternation of
linear slow phases and corrective quick
phases creates a "saw-tooth" pattern of
nystagmus (see Fig. 10-1 A). Such unidi-
rectional slow-phase drifts reflect an im-
balance in the level of tonic neural activity
disease leads to reduced activity in, for ex-
ample, the right vestibular nuclei, then
the left vestibular nuclei will drive the
eyes, in a slow phase, to the right. In this
example, quick phases will be directed to
the left—away from the side of the lesion.
Such imbalance of vestibular tone also
causes vertigo and a tendency to fall and
"past-point" toward the side of the lesion.
Paradoxically, some patients will show nys-
tagmus beating toward the side of the le-
sion; this may be recovery nystagmus that
represent the effects of vestibular adapta-
tion.919 Two features are helpful in identi-
fying nystagmus as being of peripheral
vestibular origin: its trajectory (direction)
and whether it is suppressed by visual fix-
ation.
The trajectory of nystagmus can be re-
lated to the geometric relationships of the
semicircular canals and to the finding that
experimental stimulation of an individual

Display 10-1: Clinical Features of Peripheral

Vestibular Nystagmus
• Mixed horizontal-torsional trajectory; usually beats away from the
side of the lesion

• Linear ("constant velocity") slow phases

• Nystagmus increases when eyes are turned in the direction of the

quick phases (Alexander's law)

• Suppressed by visual fixation; increased when fixation is removed

• Horizontal component diminished when patient lies with intact ear

down; exacerbated with affected ear down

• Increased or precipitated by changes in head position, vigorous head-

shaking, hyperventilation, mastoid vibration, or Valsalva maneuver

• Bedside caloric stimulation: unilaterally impaired ability to modulate

spontaneous nystagmus

• Saccades and smooth pursuit are relatively preserved

See also Pathophysiology of Disorders of the Vestibular System, in Chap. 2. For a schematic
of the nystagmus waveform, see Figure 10-lAin Chap. 10. (Related VIDEOS: "Hyperventila-
tion-induced nystagmus" and "Head-shaking nystagmus.")
412 The Diagnosis of Disorders of Eye Movements
canal produces nystagmus in the plane
of that canal. Thus, complete unilateral
labyrinthine destruction leads to a mixed
horizontal-torsional nystagmus (the sum
of canal directions from one ear—see Fig.
2-2). In benign paroxysmal positional ver-
tigo, a mixed upbeat-torsional nystagmus
reflects posterior semicircular canal stimu-
lation (see VIDEO: "Nystagmus with benign
paroxysmal positional vertigo"). Pure ver-
tical or pure torsional nystagmus, how-
ever, almost never occurs with peripheral
vestibular disease because this would re-
quire selective lesions of individual canals
from both ears, an unlikely event.
Nystagmus due to disease of the vestibu-
lar periphery is more prominent, or may
only become more apparent, when visual
fixation is prevented. The reason for this
is that visually mediated eye movements
are working normally and will slow or stop
the eyes from drifting due to vestibular
imbalance. Fixation suppresses the hori-
zontal and vertical components of nystag-
mus more than the torsional component.
The effects of visual fixation on nystagmus
can be evaluated at the bedside with Fren-
zel goggles or during ophthalmoscopy, if
the fixating eye is transiently covered.1526
Another common, but not specific, fea-
ture of nystagmus caused by disease of the
vestibular periphery is that its intensity in-
creases when the eyes are turned in the di-
rection of the quick phase—Alexander's
/aw. 24 ' 622 - 1159 This phenomenon implies an
adaptive mechanism developed to coun-
teract the drift of the vestibular nystagmus
and so establish an orbital position, in the
direction of the slow phases, at which the
eyes are quiet and vision is clear. Because
the vestibular nuclei contribute to the
gaze-holding network (neural integrator),
peripheral or central lesions can cause
both imbalance of the vestibular nuclei
and impairment of gaze holding. Alexan-
der's law provides the basis for a common
classification of unidirectional nystagmus.
First-degree nystagmus is present only on
looking in the direction of the quick
phases; second-degree nystagmus is also pres-
ent in the central position; third-degree nys-
tagmus is present on looking in all di-
rections of gaze. In some patients, a
horizontal vestibular nystagmus may be-
come evident in up gaze, with conver-
gence, or during vertical smooth pursuit
movements.
Several bedside maneuvers can be em-
ployed to bring out nystagmus in patients
with peripheral vestibular disease. First, a
change of head position may exacerbate
nystagmus or induce it in the syndrome of
benign paroxysmal positional vertigo (see
VIDEO: "Nystagmus with benign parox-
ysmal positional vertigo"). Second, in pa-
tients who have symptomatically recov-
ered from a unilateral, peripheral,
vestibular lesion, nystagmus can usually
be induced following a period of vigorous
head shaking in the horizontal or the ver-
tical plane for 15 to 20 seconds.567'1353 Af-
ter horizontal head shaking, patients may
show horizontal nystagmus with quick
phases directed away from the side of the
lesion (see VIDEO: "Head-shaking nystag-
mus"). After vertical head shaking, pa-
tients with unilateral peripheral vestibular
lesions may show less prominent nystag-
mus with horizontal quick phases directed
toward the side of the lesion. Develop-
ment of vertical nystagmus following hori-
zontal head shaking suggests a central, not
a peripheral, cause. Third, a Valsalva ma-
neuver may induce nystagmus. Fourth, vi-
bration of the mastoid bone may induce
nystagmus in patients with perilymph fis-
tula, superior canal dehiscence, unilateral
loss of labyrinthine function, and with
some central lesions, including cerebellar
degeneration. Fifth, hyperventilation may
precipitate an acute vestibular imbal-
ance.91a>947a with nystagmus, as the follow-
ing case illustrates.
CASE HISTORY: Hyperventilation-
induced nystagmus
A freshman college student developed hemifa-
cial spasms and dizziness precipitated by exer-
cise. On examination, the sole findings were a
minimal right facial paresis, as reflected in a
decreased spontaneous blink, and strong hy-
perventilation-induced nystagmus with slow
phases directed toward the left and clockwise
(see VIDEO: "Hyperventilation-induced nystag-
mus"). Laboratory tests initially showed a
slightly decreased caloric response on the right
 Diagnosis of Central Disorders of Ocular Motility 413

side, but hearing was normal. Computed
tomography, angiography, and electroen-
cephalography were normal. The patient's
symptoms progressed over several years to a
considerable loss of hearing on the right side,
absent caloric responses on the right side, and
moderate right facial paresis with aberrant re-
generation. The hyperventilation-induced nys-
tagmus, however, resolved. A CT, repeated
with magnification views of the petrous bone,
revealed a lytic lesion that proved to be a con-
genital epidermoid tumor (Fig. 10-2).
Comment: The unusual feature of this pa-
tient's clinical examination was his hyperventi-
lation-induced nystagmus with slow phases di-
rected away from the side of the lesion (an
excitatory nystagmus). We considered four
possible explanations. Two of these, seizures
and ischemia (due to decreased cerebral blood
flow), seemed improbable. More plausible were
a perilymph fistula and a recovery nystagmus.
The former could have occurred because of
erosion of the tumor through the bony
labyrinth and into the subarachnoid space.
Changes in cerebrospinal fluid pressure (as oc-
cur with hyperventilation) can be transmitted
via the cochlear aqueduct to the perilymph
space or directly via the destroyed petrous
bone. If this was the mechanism, a Valsalva ma-
neuver should have produced nystagmus. Un-
fortunately, this maneuver was not attempted.
Alternatively, hyperventilation, by virtue of
its effects upon serum pH and free calcium
concentration, is known to improve nerve con-
duction in marginally functional, often de-
myelinated, fibers, as found in multiple sclero-
sis. In our patient, hyperventilation may have

Figure 10-2. Computed tomography showing a lytic lesion (indicated by arrowhead) in the right petrous bone
of a patient who presented with hyperventilation-induced vertigo. The lesion was a congenital epidermoid tu-
mor. See Case History: Hyperventilation-induced nystagmus for details (see VIDEO: "Hyperventilation-induced
nystagmus").
414 The Diagnosis of Disorders of Eye Movements

improved nerve conduction and thereby in- Hyperventilation-induced nystagmus also

creased the level of tonic discharge emanating
from the right peripheral labyrinth. Because of
a moderate degree of vestibular loss on the
right side (which was reflected in the caloric re-
sponse), central adaptation had occurred be-
forehand to rebalance the level of activity
within the vestibular nuclei. Now, with the im-
proved peripheral function due to the hyper-
ventilation, central adaptation became inap-
propriate (excessive) and a recovery nystagmus
ensued with slow phases directed away from
the lesioned side. Changes of serum pH may
also affect central adaptive mechanisms1206 or
calcium channel function.1452
occurs in patients with acoustic schwan-
noma and after vestibular neuritis. The nys-
tagmus may be directed with slow phases
away from the side of the lesion, and a tor-
sional component is often prominent.1206
Rarely, noises induce peripheral vestib-
ular nystagmus—the Tullio phenomenon
(Fig. 10-3) (see VIDEO: "Tullio phenome-
non").947-1188 Auditory stimulation of the
vestibular organ occurs when there is a
leak of perilymph due to a breach in the
bony labyrinth (e.g., the roof of the ante-
rior canal, the oval or round windows) or
pathologic transduction of sound by the
ossicular chain.392

Figure 10-3. The Tullio phenomenon during fixation of a stationary target.1188 As soon as the acoustic stimula-
tion starts, conjugate horizontal right-beating and torsional clockwise-beating nystagmus commenced. Note the
absence of any spontaneous nystagmus prior to this sound stimulation and the absence of vertical nystagmus
during it. The single-position traces are offset for convenience of display; upward deflections indicate right-
ward (horizontal), upward (vertical), or clockwise (torsional) eye rotations, with respect to the patient. The
sound signal is only displayed for timing information. RH, right horizontal; LH, left horizontal; RV, right verti-
cal; LV, left vertical; RT, right torsional; LT, left torsional. (For another example of the Tullio phenomenon, see
VIDEO: "Tullio phenomenon.")

Whether or not an imbalance of propri-
oceptive inputs from neck muscles can
produce a cervical nystagmus akin to that
from peripheral vestibular disease is un-
certain. In normal human subjects, cervi-
cal proprioception—the COR—plays little
role in the stabilization of gaze during nat-
ural head movements.190'1223 Although the
COR does assume more importance in in-
dividuals who have lost vestibular func-
tion,191'724'1501 the evidence that cervical
disease can induce nystagmus and vertigo
is sparse. In human subjects, injection of
local anesthetic into the neck has failed
to produce nystagmus although slight
gait instability or ataxia results.333'393 How-
ever, patients who have undergone rad-
ical neck surgery may show reduced
vestibular responses.705 Vibration of the
neck may induce nystagmus in patients
with labyrinthine disease.1501 Conversely, a
cerebellar lesion has been reported to
cause an increase in the COR.189
NYSTAGMUS CAUSED
BY CENTRAL
VESTIBULAR IMBALANCE
Here we discuss three forms of nystagmus
thought to be caused by central vestibu-
lar imbalance: downbeat, upbeat, and tor-
sional nystagmus. We also discuss how
central lesions may rarely produce nystag-
mus with trajectories that are horizontal,
or in the plane of a single semicircular ca-
nal. After describing the clinical features
of each form of nystagmus, we summarize
possible pathogenesis. Although periodic
alternating nystagmus and seesaw nystag-
mus may also be viewed as forms of central
vestibular nystagmus, they will be dealt
with separately, below.
Clinical Features of
Downbeat Nystagmus
Table 10-1 summarizes some of the clin-
ical disorders with which downbeat nys-
tagmus has been reported. Commonly it
occurs with degenerations affecting the
vestibulocerebellum, lesion near the cran-
iocervical junction, and with drug intox-
ication. Downbeat nystagmus is usually
Diagnosis of Central Disorders of Ocular Motility 415
Table 10-1. Etiology of Downbeat
Nystagmus86'193'580'1506
Cerebellar Degeneration,86'193'580 including
Familial Episodic Ataxia,175'1524 and Paraneo-
plastic Degeneration36'1452'1534
Craniocervical Anomalies, including Arnold-
Chiari Malformation, Paget's Disease, Basi-
lar Imagination11'1073'1313'1508
Infarction of Brain Stem or Cerebellum86'1294
Dolichoectasia of the Vertebrobasilar
Artery628'694 or Compression of the Vertebral
Artery 1176
Multiple Sclerosis86'193'912
Cerebellar Tumor, Including Hemangioblas-
toma 1230
Syringobulbia1095
Encephalitis 631
Head Trauma86
Increased Intracranial Pressure and Hydro-
cephalus1077-1294
Toxic-Metabolic
Anticonvulsant medication26'121'250'671'1134
Lithium intoxication 295 ' 577 ' 1488
Alcohol intoxication 1174 and induced cere-
bellar degeneration 1523
Wernicke's encephalopathy 297 ' 819
Magnesium depletion 1219
Amiodarone45a
Vitamin B ]2 deficiency916
Toluene abuse901
Tetanus1048
Congenital139'185
Transient Finding in Infants 659 ' 1467
present with the eyes in central position,
although its amplitude may be so small
that it is only detected during ophthal-
moscopy (Display 10-2). A low-velocity
upward drift of the eyes (downward drift
of the optic disc) may occasionally be seen
during ophthalmoscopy in normal sub-
jects, but it is not present with a fixation
target. Downbeat nystagmus may occur in-
termittently and, in some patients, only
becomes evident during convergence or in
lateral gaze (see VIDEO: "Gaze-evoked, re-
bound, and downbeat nystagmus"). In
most patients with downbeat nystagmus,
Alexander's law is obeyed and slow-phase
416 The Diagnosis of Disorders of Eye Movements

Display 10-2: Clinical Features of Downbeat Nystagmus

• Best evoked on looking down and laterally; often in association with
horizontal gaze-evoked nystagmus, and so may appear oblique on lat-
eral gaze

• Slow phases may have linear-, increasing-, or decreasing-velocity

waveforms

• Poorly suppressed by fixation of a visual target

• May be precipitated or exacerbated or changed in direction, by alter-

ing head position, vigorous head shaking (horizontal or vertical), hy-
perventilation, or mastoid bone vibration

• Convergence may increase, suppress, or convert to upbeat nystagmus

• Associated with other signs of vestibulocerebellar involvement

See also Pathogenesis of Central Vestibular Nystagmus. For a recorded example, see Figure
10-4 in Chap. 10. For etiologies, see Table 10-1. (Related VIDEOS: '"Downbeat nystagmus"
and "Gaze-evoked, rebound, and downbeat nystagmus.")

velocity (and nystagmus intensity) is great- accentuated or brought on by placing the

est in down gaze and least in up gaze.
Hence, asking patients to look down and
laterally is often the best way to bring out
downbeat nystagmus. In some patients,
however, downbeat nystagmus is greatest
on up gaze. In these cases, the slow phases
may not be linear but are, instead, increas-
ing in velocity (see Figure 10-1C and Fig-
ure 10-4) (see VIDEO: "Downbeat nystag-
mus");11'1534 this finding indicates an
instability of the vertical gaze-holding net-
work. A similar pattern of downbeat nys-
tagmus has also been observed following
removal of the vestibulocerebellum (floc-
culus and paraflocculus) in monkeys.1538
Downbeat nystagmus is occasionally dis-
junctive, being more vertical in one eye
and torsional in the other. In these cir-
cumstances, it may be accompanied by in-
ternuclear ophthalmoplegia.501'1024 Some
patients may show combined divergent-
downbeat nystagmus. 1509
In most patients, removal of fixation
(e.g., by Frenzel goggles) does not sub-
stantially influence slow-phase velocity, al-
though quick-phase frequency may dimin-
ish. Downbeat nystagmus may also be
patient in a head-hanging position or by
convergence. In some patients, downbeat
nystagmus is converted to upbeat nystag-
mus by convergence, or vice versa.297-435
A variety of ocular motor abnormalities
often accompanies downbeat nystagmus
and usually reflects coincident cerebellar
involvement. Vertical smooth pursuit and
the vertical vestibulo-ocular reflex are
usually abnormal in patients with down-
beat nystagmus. There is impaired ability
to generate downward pursuit eye move-
ments, which cannot simply be attributed
to superimposed nystagmus. 86 Often the
gain of the vestibulo-ocular reflex for up-
ward eye movements exceeds l.O. 1532 Im-
pairment of horizontal gaze holding,
smooth pursuit, and combined eye-head
tracking (vestibulo-ocular cancellation) also
commonly coexist. The consequences of
retinal slip produced by the slow phases
are oscillopsia, postural instability, and an
increased threshold for egocentric detec-
tion of object motion.210'392a Some patients
with downbeat nystagmus also report
diplopia, perhaps reflecting coexistent skew
deviation.
 Diagnosis of Central Disorders of Ocular Motility 417

Figure 10-4. Downbeat nystagmus with increasing velocity waveforms in a patient with paraneoplastic cerebel-
lar degeneration.1534 The waveform was also evident on clinical examination (see VIDEO: "Downbeat nystag-
mus") and may represent the consequences of an unstable vertical integrator. Horizontal eye position is shown
in the top record and vertical in the lower. The arrow indicates a blink. (From Zee DS, Leigh RJ, Mathieu-Mil-
laire F. Cerebellar control of ocular gaze stability. Annals of Neurology 1980;7:37-40, with permission of Lip-
pincott Williams and Wilkins.)

Clinical Features of tion usually follows Alexander's law, be-

Upbeat Nystagmus
Upbeat nystagmus that is present with the
eyes close to the central position may be re-
garded as a form of central vestibular nys-
tagmus (Display 10-3). The more common
disorders with which it is associated are
summarized in Table 10-2. Upbeat nystag-
mus is less well localized than downbeat
nystagmus, being reported with lesions
from the medulla to midbrain. Upbeat nys-
tagmus with the eyes close to central posi-
tion should be differentiated from nystag-
mus evoked exclusively on up gaze, which
occurs in general gaze-holding failure, with
peripheral ocular motor disorders includ-
ing myasthenia gravis, and in some normal
subjects. It should also be differentiated
from the transient, mixed upbeat-torsional
nystagmus that is induced by positional
testing in patients with benign paroxysmal
positional vertigo of the posterior canal
type (see VIDEO: "Nystagmus with benign
paroxysmal positional vertigo"). Upbeat
nystagmus that is present in central posi-
coming greatest in up gaze. Sometimes,
however, the nystagmus is accentuated on
looking down, and then the slow phase is
more likely to be increasing velocity rather
than linear (Fig. 10-5). Unlike downbeat
nystagmus, upbeat nystagmus usually does
not increase on lateral gaze. Removal of vi-
sual fixation may alter the frequency of
quick phases, but it does not influence
slow-phase velocity. Convergence enhances
the nystagmus in some patients, suppresses
it in others, and occasionally converts it to
downbeat nystagmus.297'435 Placing the pa-
tient in a head-hanging position increases
the nystagmus in some individuals. The
vertical vestibulo-ocular reflex (VOR) and
smooth pursuit are usually abnormal.
Some patients show a combined upbeat-di-
vergent form of nystagmus (Fig. 10-6) (see
VIDEO: "Upbeat nystagmus"). Other pa-
tients may show quick phases that have
small horizontal components that alternate
to the right or left; these trajectories
create the pattern of a bow-tie nystagmus
(Fig.lO-5D).1470
418
Figure 10-5. Upbeat nystagmus. The patient was a 50-year-old man who had a posterior fossa meningioma re-
moved in 1943 by Dr. Walter Dandy. His complaints were that in recent months his walking had become more
unsteady and his vision was not always clear. He admitted to a large alcohol intake. (A) A CT demonstrated a
large posterior fossa lucency thought to be due to a postoperative cyst. (B and C) Eye movements were recorded
by the magnetic search coil method; the upper trace in each pair of records is horizontal eye position, the lower
vertical. D, down; L, left; R, right; U, up. There was an upbeat nystagmus more marked on downward gaze (B).
At times, the slow-phase showed an approximately exponential increasing velocity (C). Note that although each
slow phase is directed downward, quick phases are directed obliquely upward alternately to the right or left, be-
cause of the changing direction of each horizontal component. This creates a trajectory (D) called bow-tie nys-
tagmus; 1470 quick phases are shown as solid lines and slow phases as dashed lines.

Figure 10-6. Upbeat nystagmus with an associated di-

vergent component in a 45-year-old woman with mul-
tiple sclerosis (see VIDEO: "Upbeat nystagmus"). Not
apparent on the video, but evident on this representa-
tive record, is that the predominant vertical compo-
nent and small torsional component are conjugate, but
the horizontal movements are disjunctive, having di-
vergent quick phases. The single-position traces are
offset for convenience of display; upward deflections
indicate rightward (horizontal), upward (vertical) or
clockwise (torsional) eye rotations, with respect to the
patient. RH, right horizontal; LH, left horizontal; RV,
right vertical; LV, left vertical; RT, right torsional; LT,
left torsional.

419
420 The Diagnosis of Disorders of Eye Movements

Display 10-3: Clinical Features of Upbeat Nystagmus

• Present in primary position; usually increases on looking up

• Slow phases may have linear-, increasing-, or decreasing-velocity

waveforms

• Poorly suppressed by visual fixation of a distant target

• Convergence may increase, suppress, or convert to downbeat nystag-

mus

• Associated with abnormal vertical vestibular and smooth-pursuit re-

sponses, and saccadic intrusions (square-wave jerks) that produce a
bow-tie nystagmus

See also Pathogenesis of Central Vestibular Nystagmus. For recorded examples, see Figure
10-5 and Figure 10-6 in Chap. 10. For etiologies, see Table 10-2. (Related VIDEO: "Upbeat
nystagmus.")

Clinical Features of eral gaze, when described in an eye-fixed

Torsional Nystagmus
Although peripheral vestibular, congeni-
tal, and seesaw nystagmus may all have
torsional components—especially on lat-
Table 10-2. 86Etiology of Upbeat
Nystagmus -446
Cerebellar degenerations and atrophies493'494
Multiple sclerosis446'1036
Infarction of medulla86'221'630'754'981 or cerebel-
115
lum and superior cerebellar peduncle
446 514
Tumors of the medulla, - cerebel-
lum, 419 ' 1390 or midbrain996'1396
Wernicke'sencephalopathy 297 - 446 ' 1550
Brain stem encephalitis488
Behget's syndrome678
Meningitis640
Leber's congenital amaurosis and other con-
genital disorders of the anterior visual path-
ways529-662
Thalamic arteriovenous malformation1023
Congenital1303
Organophosphate poisoning701
Tobacco1285
Associated with middle ear disease552
Transient finding in infants659
coordinate system—nystagmus that is
purely torsional in central position (like
purely vertical nystagmus) bespeaks dis-
ease affecting central vestibular connec-
tions (Display 10-4). Often it is difficult to
detect except by careful observation of
conjunctival vessels or by noting the direc-
tion of retinal movement on either side of
the fovea. This rarer form of central ves-
tibular nystagmus is usually associated
with medullary lesions, such as syringo-
bulbia and Wallenberg's syndrome (lateral
medullary infarction) (Table 10-3). Tor-
sional nystagmus may show features simi-
lar to downbeat and upbeat nystagmus, in-
cluding modulation by head rotations,
variable slow-phase waveforms, and sup-
pression by convergence.1021 It is probably
a common finding in patients with the oc-
ular tilt reaction,60 including those with in-
ternuclear ophthalmoplegia.343 Torsional
nystagmus has also been described during
vertical smooth pursuit in patients with le-
sions involving the middle cerebellar pe-
duncle;461 this phenomenon is discussed
further in the section on Ocular Motor
Syndromes Caused by Disease of the Cere-
bellum. Nonrhythmic but continuous tor-
sional eye movements have been reported
as a possible paraneoplastic phenome-

non 1178 Episodes of torsional nystagmus,
initiated by quick phases that rotated the
upper poles of each eye towards the side
of a mesodiencephalic lesion, might be
due to activation of the ipsilateral riMLF.H6a
Horizontal Nystagmus Due to
Central Vestibular Imbalance
Most predominantly horizontal nystagmus
is congenital or peripheral vestibular in
origin. However, central vestibular distur-
bances sometimes cause nystagmus that is
horizontal (when the eyes are close to cen-
tral position); often the underlying disor-
der is an Arnold-Chiari malformation
(Fig. 10-7).102 The slow-phase waveform
may be increasing velocity, making distinc-
tion from congenital nystagmus poten-
tially difficult. However, patients may re-
port recent onset of visual symptoms such
as oscillopsia, and measurements may
demonstrate an associated vertical compo-
nent, which is usually absent in congenital
nystagmus. Patients with horizontal nys-
tagmus that is present in the central posi-
tion should always be observed for a pe-
riod of 2 minutes to exclude the possibility
of periodic alternating nystagmus.
Perverted Vestibular Nystagmus
Patients with disease affecting central ves-
tibular connections, including the vestibulo-
cerebellum, sometimes develop nystagmus
in a plane other than that being stimulated
by either caloric stimulation or head rota-
tion. For example, after horizontal head
shaking, downbeat nystagmus may occur—an
inappropriate cross-coupling of vestibular
nystagmus. Following experimental lesions
of the vestibular nuclei, unilateral caloric
stimulation sometimes induced vertical re-
sponses ("perverted nystagmus").1407 This
last finding is not a reliable sign of vestibu-
lar nucleus disease, however, because a
small vertical component may also be pres-
ent in normal subjects.94
Pathogenesis of Central
Vestibular Nystagmus
Better understanding of the pathogenesis
of central forms of vestibular nystagmus
Diagnosis of Central Disorders of Ocular Motility 421
has been gained from clinicopathological
correlation, the development of animal
models, and application of modern anat-
omy and physiology. Downbeat nystagmus
is usually associated with lesions of the
vestibulocerebellum (flocculus, parafloccu-
lus, nodulus, and uvula) and underlying
medulla.86 Upbeat nystagmus is most com-
monly reported with medullary le-
sions,322'446'514'754'981 which variably involve
the perihypoglossal nuclei and adjacent
medial vestibular nucleus (structures im-
portant for gaze holding), nucleus interca-
latus,630'700a and the ventral tegmentum,
which contains projections from the vestib-
ular nuclei that receive inputs from the an-
terior semicircular canals.1121 Upbeat nys-
tagmus is also reported with lesions
involving the anterior vermis of the cere-
bellum 322 or the adjacent brachium con-
junctivum and midbrain.115'730'996 This evi-
dence suggests that lesions at several
distinct sites can cause upbeat and down-
beat nystagmus. However, it is possible to
account for these findings by considering
the fundamental anatomic fact that, unlike
the horizontal vestibular system, which is
right-left symmetric, the connections for
vertical vestibular responses are dissimilar
for upward and downward eye move-
ments. Furthermore, the anatomical ori-
entation of the semicircular canals may be
right- left symmetric, but it lacks symme-
try in a craniocaudal direction.160 These
up-down asymmetries involve connections
subserving (1} the vertical vestibulo-ocular
reflex, (2) the otolith-ocular reflexes, (3)
the vestibulocerebellum, (4) the network
for eccentric gaze holding (neural integra-
tor), and (5} the smooth-pursuit system.
Excitatory projections for the vertical
vestibulo-ocular reflex (see Fig. 2-3) from
the posterior semicircular canals, which
mediate downward eye movements,
synapse in the medial vestibular nucleus
and then cross dorsally in the medulla, be-
neath the nucleus prepositus hypoglossi to
reach the contralateral medial longitudi-
nal fasciculus. Experimental lesions that
presumably involve this pathway cause
upward eye drifts and downbeat nystag-
mus.86 It appears, however, that excita-
tory connections from the anterior semi-
circular canals, which mediate upward
422 The Diagnosis of Disorders of Eye Movements

Display 10-4: Clinical Features of Torsional Nystagmus

• Torsional jerk nystagmus (minimal vertical or horizontal components)
present with eye close to central position

• Slow phases may have linear-, increasing-, or decreasing-velocity

waveforms

• Poorly suppressed by visual fixation of a distant target

• Exacerbated by changes in head position or vigorous head shaking

• May be suppressed by convergence

• Often occurs in association with ocular tilt reaction or unilateral inter-

nuclear ophthalmoplegia

• May be precipitated or modulated by vertical smooth pursuit move-

ments

See also Pathogenesis of Central Vestibular Nystagmus, in Chap. 10. For a recorded exam-
ple, see Figure 10-17G, in Chap. 10. For etiologies, see Table 10-3.

eye movements, take different routes, be precipitated or exacerbated by a change

and more than one pathway may con-
tribute.922,923
It has also been suggested that a central
imbalance of otolithic inputs (see Table 2-2)
may contribute to vertical nystagmus.551
This hypothesis is based on the observation
that downbeat or upbeat nystagmus may
Table 10-3. Etiology of Torsional
Nystagmus*877
Syringobulbia, with or without syringomyelia
and Arnold-Chiari malformation1470
Brain stem stroke (e.g., Wallenberg's syn-
drome)960
Arteriovenous malformation in the brain
stem960'1021 or middle cerebellar peduncle461
Brain stem tumor877
Multiple sclerosis877
Oculopalatal tremor ("myoclonus")64
Head trauma 877
Congential
*Often occurs in association with the ocular tilt re-
action60'1331 and unilateral internuclear ophthalmo-
plegia.343
in head position (e.g., head-hanging posi-
tion). Furthermore, normal humans and
other species may develop vertical drifts
in darkness when their heads are not
erect.524-1193 While otolithic inputs (includ-
ing tilt of the head and imposed linear ac-
celerations) can influence vertical nystag-
mus, there is some debate as to whether
an otolithic imbalance is the primary dis-
turbance. For example, in some patients,
head tilt does not influence the nystag-
mus.551 Nevertheless, in one patient with
upbeat nystagmus due to a hemorrhage
affecting the left brachium conjunctivum
and anterior cerebellum, a leftward head
tilt suppressed the nystagmus.730 Further-
more, an otolithic influence on vertical
nystagmus offers perhaps the only plausi-
ble explanation for the effects of conver-
gence. It has been shown that viewing a
near target increases the gain of the VOR
and that the otoliths influence this modu-
lation. 1432
The case for the cerebellar flocculus (see
Display 6-10) rests on the finding that
Purkinje cells send inhibitory projections
to the central connections of the anterior
Figure 10-7. Horizontal nystagmus caused by the
Arnold-Chiari malformation. The patient was a 40-
year-old man who for 12 years had noticed slight im-
balance on making turns or negotiating stairs. For the
past 3 years, he had experienced episodes of severe
vertigo and nausea, which lasted for a few minutes
and were precipitated by straining or laughing. (A)
CT of his cranio-cervical junction, using metrizamide
contrast, showed descent of the cerebellar tonsils, con-
sistent with a diagnosis of Arnold-Chiari malforma-
tion. (B) Eye movements were recorded by electro-
oculography. The top trace shows a horizontal
nystagmus, more marked in left gaze. The lower two
traces show asymmetric smooth pursuit, worse during
tracking of target motion to the left. The time scale, at
top, is in seconds. His vestibulo-ocular reflex was pre-
served in both directions. Cancellation of the
vestibulo-ocular reflex was asymmetrical, consistent
with his pursuit deficit. L: left; R: right.
423
424 The Diagnosis of Disorders of Eye Movements
canal but not of the posterior canal.84-684
This asymmetry of inhibitory projections
accounts for the finding that experimental
flocculectomy causes downbeat nystag-
mus;1538 this lesion disinhibits anterior ca-
nal (but not posterior canal) projections
and so causes the eyes to drift up, produc-
ing downbeat nystagmus. The develop-
ment of an animal model makes this the
strongest hypothesis for downbeat nys-
tagmus.
A neural network that includes the nu-
cleus prepositus hypoglossi and adjacent
medial vestibular nuclei (NPH-MVN re-
gion) and the vestibulocerebellum is im-
portant for the mechanism for holding the
eyes steady in eccentric gaze. Consistent
with this, a patient with lithium intoxica-
tion and downbeat nystagmus had lesions
in the nucleus prepositus hypoglossi.295
Disease of the vestibulocerebellum may
cause instability of this network (Fig. 5-6),
causing the eyes to drift at increasing ve-
locity away from central position in the
vertical or horizontal planes (see VIDEO:
"Downbeat nystagmus").11'102'1534 The cell
groups of the paramedian tracts (PMT)
(see Display 6-4) also may contribute to
neural integrator function by relaying eye
movement signals to the vestibulocerebel-
lum.217 One component of the PMT cell
groups is the medullary nucleus parara-
phales, which receives vertical eye position
signals from the interstitial nucleus of Ca-
jal. Thus, medullary lesions that affect this
nucleus might lead to upbeat nys-
tagmus.221
Finally, based on the observation that
the slow-phase velocity of downbeat nys-
tagmus is unaffected by visual fixation,
and vertical smooth pursuit is impaired, it
was proposed that the characteristics of
downbeat nystagmus could be best ex-
plained by a central imbalance in smooth-
pursuit tone with cerebellar lesions.1532 Al-
though subsequent studies have made it
more likely that vestibular or gaze-holding
disturbances rather than pursuit imbal-
ance are primarily responsible, the origi-
nal observation remains valid and thus
might reflect coexistent impairment of the
smooth pursuit pathway either as it passes
through the cerebellum or in the vestibu-
lar and prepositus nuclei (see Fig. 6-7).
Resolution of upbeat or downbeat nystag-
mus after the first few months of life, in
otherwise normal infants,659 may reflect
"calibration" of pursuit or gaze-holding
mechanisms as the visual system becomes
fully myelinated.
Periodic Alternating Nystagmus
Acquired periodic alternating nystagmus
(PAN) is a spontaneous horizontal nystag-
mus, present in primary gaze, that re-
verses direction approximately every 2
minutes (Display 10-5) (see VIDEO: "Peri-
odic alternating nystagmus"). Because the
period of oscillation is about 4 minutes,
the disorder may be missed unless the ex-
aminer observes the nystagmus for several
minutes. As the nystagmus finishes one
half-cycle (e.g., of right-beating nystag-
mus), a brief transition period occurs dur-
ing which there may be upbeating or
downbeating nystagmus or square-wave
jerks before the next half cycle (e.g., of
left-beating nystagmus) starts. Although
rare, acquired PAN is perhaps the best un-
derstood of all forms of nystagmus and
was the first for which an effective treat-
ment was identified.579'835-1447
Several other disorders are character-
ized by periodic reversals of spontaneous,
abnormal eye movements. A congenital
form of PAN is usually much less regular
in the timing of reversal of direction and
shows slow-phase waveforms typical of
congenital nystagmus.7'542 PAN should be
differentiated from ping-pong gaze, which
is encountered in unconscious patients
with large bihemispheric lesions and con-
sists of ocular deviations that reverse di-
rection over the course of a few seconds.676
Certain patients with acquired PAN show
a "short cycle" of 20 to 30 seconds, and it
is uncertain whether their underlying
pathophysiology differs from classic ac-
quired PAN.
In most patients with acquired PAN, the
nystagmus has the same characteristics in
light or in darkness. Some patients, espe-
cially children, also show periodic head
rotations in the direction of the quick
phases, using Alexander's law to partially
or completely null the nystagmus.521'758'1318
 Diagnosis of Central Disorders of Ocular Motility 425

Display 10-5: Clinical Features of Acquired Periodic

Alternating Nystagmus
• Horizontal nystagmus reverses direction approximately every 90-120
seconds

• May be associated with periodic alternating head turns—the head

turns in the direction of the quick phase, and the eyes are moved into
a position in the orbit that is the same as the direction of the slow
phase—so minimizing the nystagmus by Alexander's law

• Nystagmus cycle is usually little affected by visual fixation

• Vestibular stimuli, such as head rotations, can change or transiently

stop nystagmus

• Downbeat nystagmus and square-wave jerks may become more obvi-

ous in the brief null period when the horizontal nystagmus wanes and
then reverses

For pathophysiology, see Effects of Vestibulocerebellar Lesions on the VOR, in Chap. 2. For
etiologies, see Table 10-4. (Related VIDEO: "Periodic alternating nystagmus.")

Smooth pursuit and optokinetic nystag- duration (velocity storage) of rotationally

mus are usually impaired.835 Vestibular
stimuli are able to "reset" the oscillations,
and critically timed rotational stimuli can
stop PAN for several minutes.492'835
Acquired PAN has been reported in
association with a number of conditions
(Table 10-4), many of which involve the
cerebellum. If the neurologic disorder
also involves the brain stem mechanism
for generating quick phases, patients may
progress to periodic alternating gaze devi-
ation.58'544 It has also been reported that
PAN develops following visual loss due to
vitreous hemorrhage 305 or cataract702 and
is abolished when vision is restored. The
GABAB-ergic drug baclofen abolishes ac-
quired PAN in most patients. 579
Insight into the pathogenesis of PAN
has come from experimental studies. Ab-
lation of the cerebellar nodulus and uvula
in monkeys causes PAN when they are in
darkness; baclofen abolishes this nystag-
mus.1447 One function of the nodulus and
uvula is to control the time course of rota-
tionally induced nystagmus—the so-called
velocity-storage mechanism.276 Thus, follow-
ing ablation of the nodulus and uvula, the
induced nystagmus is prolonged exces-
sively, and it is postulated that normal ves-
tibular "repair mechanisms" act to reverse
the direction of this nystagmus, so pro-
Table 10-4. Etiology of Periodic
Alternating Nystagmus492'791'835
Arnold-Chiari malformation and other hind-
brain anomalies492'835'934
Multiple sclerosis736'791
Cerebellar degenerations492-534'865
Cerebellar tumor, abscess, cyst, and other mass
lesion758-835
Creutzfeldt-Jakob disease544
Ataxia telangiectasia1327
Brain stem infarction492
Anticonvulsant medications228-1246
Infections affecting cerebellum, including
syphilis791'835
Hepatic encephalopathy58
Trauma791
Following visual loss (due to vitreous hemor-
rhage or cataract)305'702
Congenital nystagmus7
426 The Diagnosis of Disorders of Eye Movements
ducing the oscillations of PAN.492'791'835
These oscillations would ordinarily be
blocked by visual stabilization mechanisms
that tend to suppress nystagmus, but dis-
ease of the cerebellum that causes PAN
usually also impairs these mechanisms; in
rare cases, eye disease (cataract or retinal
detachment) prevents fixation and allows
PAN to develop.305-702 Finally, pharmaco-
logical evidence suggests that the nodulus
and uvula maintain inhibitory control on
the vestibular rotational responses by us-
ing GABA.276 Thus, the GABA agonist ba-
clofen is able to abolish PAN caused by ei-
ther experimental or clinical lesions of the
nodulus and uvula. 276
Two other unusual disorders may be re-
lated to PAN. The first is a variation
of PAN—alternating windmill nystagmus—
which consists of oscillations in both the
horizontal and vertical planes, 90° out of
phase.1212 This phenomenon occurred in
a blind patient. The second is a patient
with paroxysms of mixed torsional-hori-
zontal-vertical nystagmus that occurred
every 2 minutes in association with nau-
sea.821 In this patient, the initial mecha-
nism was probably paroxysmal hyperactiv-
ity in one vestibular nucleus complex,
unlike PAN, in which prolongation of the
vestibular response is the initial mecha-
nism. However, in both, an "adaptive
mechanism" appeared to influence the
nystagmus every 2 minutes; this is per-
haps the most direct evidence that activa-
tion of the ocular motor "recalibration
mechanism" can lead to nystagmus.
Seesaw and Hemi-seesaw
Nystagmus
In these forms of nystagmus, one half cy-
cle consists of elevation and intorsion of
one eye and synchronous depression and
extorsion of the other eye; during the
next half cycle, the vertical and torsional
movements reverse (Fig. 10-8, Display
10-6). The waveform may be pendu-
lar,318,402,406,994 or j^ in which case the
slow phase corresponds to one half-cycle
(hemi-seesaw nystagmus}.^1 A seesaw compo-
nent is present in many central forms of
nystagmus. Seesaw nystagmus has been re-
ported in association with a variety of dis-
orders (Table 10-5) and may present as a
form of congenital nystagmus (see VIDEO:
"Seesaw nystagmus").318'842'1229 One pa-
tient with congenital seesaw nystagmus
was reported to show the opposite pattern
of vertical-torsional synchrony seen with
acquired cases, so elevation occurred with
extorsion and depression with intorsion.318
Measurement of horizontal, vertical,
and torsional components of these oscilla-
tions using the magnetic search coil tech-
nique has clarified the characteristics and
pathogenesis of hemi-seesaw and seesaw
nystagmus. Jerk seesaw nystagmus (hemi-
seesaw nystagmus) occurs in patients with
lesions in the region of the interstitial nu-
cleus of Cajal (INC—see Display 6-6).
Such patients often have a contralateral
ocular tilt reaction; with a left INC lesion;
this would cause right head tilt, skew devi-
ation (left hypertopia), tonic intorsion of
the left and extorsion of the right eye, and
the misperception that earth-vertical is
tilted to the right.172'571 Rarely, the ocular
tilt reaction is paroxysmal in form, in
which case it is ipsilateral to the INC le-
sion; some such patients also show cor-
responding paroxysms of jerk seesaw
nystagmus. 571 The ocular tilt reaction rep-
resents an imbalance of central otolithic
projections from vestibular nuclei to the
INC. 172a Stimulation in the region of INC
in monkeys produces an ocular tilt reac-
tion1478 consisting of extorsion and de-
pression of the eye on the stimulated side
and intorsion and elevation of the other
eye; somewhat similar results are reported
in humans. 885 - 1215 Thus, the various forms
of the ocular tilt reaction are similar to the
slow phases of jerk seesaw nystagmus. The
presence of corrective, ipsilesional quick
phases may occur if the adjacent rostral
interstitial nucleus of the medial longitu-
dinal fasciculus (riMLF) (see Display 6-5)
is intact; if the riMLF is also involved, ei-
ther no quick phases571 or contralesional
quick phases608 may be observed. (Recall
that each riMLF contributes to upward
and downward saccades but only to ipsi-
laterally directed torsional quick phases,
with top poles rotating toward the ipsilat-
eral side—see Display 6-5.)
 Diagnosis of Central Disorders of Ocular Motility 427

Figure 10-8. Seesaw nystagmus. (A) Schematic of the

oscillation showing that during one half-cycle the right
eye rises and intorts, and the left falls and extorts
(top); during the next half-cycle, the opposite move-
ments occur (bottom). (B) Record of 39-year-old
woman with congenital seesaw nystagmus shown in the
video (see VIDEO: "Seesaw nystagmus"). The horizontal
component has a conjugate "pseudocycloid" waveform
typical for congenital nystagmus. There is a disconju-
gate vertical component and a large conjugate tor-
sional component. Note that as either eye goes up, it
intorts, and as it goes down, it extorts. The single posi-
tion traces are offset for convenience of display; up-
ward deflections indicate rightward (horizontal), up-
ward (vertical), or clockwise (torsional) eye rotations
with respect to the patient. RH, right horizontal; LH,
left horizontal; RV, right vertical; LV, left vertical; RT,
right torsional; LT, left torsional.

Pendular seesaw nystagmus has most
frequently been described with large
parasellar tumors, so these oscillations
have been attributed to either secondary
midbrain compression or to the effects of
commonly associated visual field defects.
Pendular seesaw nystagmus has been re-
ported with visual loss123 and has been
documented to develop in a patient who
progressively lost vision due to retinitis
pigmentosa.915 It is also reported in pa-
tients who have congenital abnormalities
of their optic chiasm.40'842 Thus, it is possi-
ble that visual loss inactivates the "recali-
428 The Diagnosis of Disorders of Eye Movements

Display 10-6: Clinical Features of Seesaw and Hemi-Seesaw

Nystagmus
• One half-cycle consists of elevation and intorsion of one eye and syn-
chronous depression and extorsion of the other eye; during the next
half-cycle, the vertical and torsional movements reverse

• Waveform may be pendular (seesaw) or jerk (hemi-seesaw), in which

the slow phase corresponds to one half-cycle

• Hemi-seesaw form associated with ocular tilt reaction and other mani-
festations of otolithic imbalance

• Pendular seesaw form associated with bitemporal hemianopia, chias-

mal disorders, visual loss

• Reversed congenital form—elevation and extorsion—may be related

to dissociated vertical deviation

For pathophysiology, see Disease Affecting the Optic Chiasm and Nystagmus and Skew Devi-
ation and the Ocular Tilt Reaction (OTR). For schematics and a recorded example, see Fig-
ure 10-8 and Figure 10-18 in Chap. 10. For etiologies, see Table 10-5. (Related VIDEO: "See-
saw nystagmus.")

bration" mechanism for eye movements
that compensate for head rotations in roll
(ear-to-shoulder). If the subject looks at an
object located off the midsagittal plane
during head roll, a seesaw rotation of the
eyes is the geometrically appropriate com-
pensation.1253 It seems that normal cali-
bration of this response, which would re-
quire that motion-visual information be
sent to the cerebellum, could be impaired
Table 10-5. Etiology of Seesaw and
Hemi-Seesaw Nystagmus571
Mesodiencephalic disease, such as stroke571'719
Parasellar masses318'402-406
Lack or loss of crossing fibers in the optic
chiasm (e.g., achiasma and septo-optic
dysplasia)40'326
Multiple sclerosis1208
Arnold-Chiari malformation1547
Syringobulbia433
Progressive visual loss (e.g., due to retinitis
pigmentosa)123'915
Head trauma479'741'1215
Congenital318'351'662'1229
with parasellar lesions, leading to the
pendular variant of seesaw nystagmus.994
Thus, the two variants of seesaw nystag-
mus probably arise from either imbalance
or miscalibration of vestibular responses
that normally function to optimize gaze
during head rotations in roll. Finally,
dissociated vertical deviation (DVD),1415 a
form of congenital vertical strabismus in
which the covered eye elevates and ex-
torts, is similar to one half-cycle of the
variant of congenital seesaw nystagmus
described by Daroff,318 and suggests a re-
lationship between these two disorders.
Nystagmus Occurring When the
Eyes Are in Eccentric Gaze
GAZE-EVOKED NYSTAGMUS
Nystagmus induced by moving the eye to
an eccentric position in the orbit is called
gaze-evoked nystagmus (Display 10-7). It is
the commonest form of nystagmus en-
countered in clinical practice. The term
gaze-paretic nystagmus is only accurate in
those cases with associated paresis of gaze
 Diagnosis of Central Disorders of Ocular Motility 429

Display 10-7: Clinical Features of Gaze-Evoked, Centripetal,

and Rebound Nystagmus
• Gaze-evoked nystagmus is induced by moving the eye into lateral or
up gaze; quick phases are directed away from central position

• With sustained attempts to look eccentrically, gaze-evoked nystagmus

declines and may reverse direction—centripetal nystagmus

• After the eyes are then returned to the central position, a short-lived
nystagmus with quick phases opposite to the direction of the prior ec-
centric gaze occurs—rebound nystagmus

For pathophysiology, see Abnormalities of the Neural Integrator, in Chap. 5. For a recorded
example, see Figure 10-9 in Chap. 10. For drug etiologies, see Table 10-21. (Related VIDEOS:
"Gaze-evoked, rebound, and downbeat nystagmus.")

due, for example, to a cerebral or brain In order to understand how gaze-

stem process, or to weakness of extraocular
muscles. Usually gaze-evoked nystagmus
occurs on lateral or upward gaze—seldom
on looking down. If fixation is impaired or
prevented (e.g., in darkness), the slow
phases consist of centripetal drifts that may
have an exponentially decaying waveform
(see Figure 10-1B and Figure 10-9). If vi-
sual fixation is possible, however, the slow
phases have a more linear profile.
Figure 10-9. Gaze-evoked and rebound nystagmus.
The eye movement recording is taken from a patient
with familial cerebellar degeneration. On looking to
the far left, gaze-evoked nystagmus commences, with
some individual slow phases showing declining ve-
locity. After 35 sec of this sustained effort at maintain-
ing eccentric gaze, the slow-phase drift velocity is re-
duced. When the eyes are returned to the central
position, the nystagmus reverses direction (rebound
nystagmus) (see VIDEOS: "Gaze-evoked, rebound,
and downbeat nystagmus"). (From Zee DS, Yee RD,
Cogan DG, Robinson DA, Engel WK. Ocular mo-
tor abnormalities in hereditary cerebellar ataxia.
Brain 1976;99:207-34, copyright, Oxford University
Press.)
evoked nystagmus arises, consider the
neural command required to hold the eye
steadily at an eccentric position in the or-
bit (see Fig. 1-3, Chap. 1). When the eye is
turned toward a corner of the orbit, the
tissues that suspend the eye exert an elas-
tic force to return it toward central posi-
tion. A tonic contraction of the extraocular
muscles is required to overcome this elas-
tic, restoring force. This is achieved by a
"step" eye position command from the oc-
ular motoneurons, which is generated by a
gaze-holding network (the neural integra-
tor). Gaze-evoked nystagmus is due to a
deficient eye position signal: The eyes can-
not be maintained at an eccentric orbital
position and they are pulled back toward
the central position by the elastic forces of
the orbital fascia. Then corrective quick
phases move the eyes back toward the de-
sired position in the orbit. Frequently, le-
sions that produce gaze-evoked nystag-
mus also impair visual fixation and
smooth pursuit. Crucial structures for
horizontal gaze holding are the nucleus
prepositus hypoglossi and medial vestibu-
lar nucleus (the NPH-MVN region); for
vertical gaze holding the interstitial nu-
cleus of Cajal (INC) (see Display 6-6) plays
an important role. In addition, the vestibu-
locerebellum contributes to this gaze-
holding function. The mechanism for gaze
holding is discussed further in Chap. 5.
430 The Diagnosis of Disorders of Eye Movements

Most commonly, gaze-evoked nystag-
mus is a side effect of medications, includ-
ing sedatives and anticonvulsants,616-1129'1308
or is due to intoxications with drugs, espe-
cially alcohol. Gaze-evoked nystagmus
may also be caused by structural lesions
that involve the gaze-holding neural
network. Experimental lesions of the
NPH-MVN region effectively abolish hor-
izontal gaze-holding function 230 ' 943 and
partially impair vertical gaze holding as
well. Experimental inactivation of the in-
terstitial nucleus of Cajal impairs vertical
gaze holding.298 Complete loss of gaze-
holding function was described in a pa-
tient with lithium intoxication and lesions
in the nucleus prepositus hypoglossi.295
Experimental flocculectomy greatly, but
not completely, impairs horizontal gaze
holding,1538 besides causing downbeat nys-
tagmus. Disease affecting the vestibulo-
cerebellum commonly causes gaze-evoked
nystagmus, often with a downbeating
component (see VIDEOS: "Gaze-evoked, re-
bound, and downbeat nystagmus"). Pa-
tients with cerebellar atrophy develop
gaze-evoked nystagmus with lower serum
concentrations of anticonvulsants than do
patients with a normal cerebellum.1308
Gaze-evoked nystagmus is a feature offa-
milial episodic vertigo and ataxia type 2 (EA-2),
which is a calcium channelopathy that is
responsive to acetazolamide.85'90'175'1524
Rarely, cerebellar lesions cause the gaze-
holding mechanism to become unstable
(i.e., hyperactive), so the eyes drift with
increasing velocity away from central
position either vertically1534 (see VIDEO:
"Downbeat nystagmus") or horizontally.102
Such gaze-instability nystagmus often violates
Alexander's law. Horizontal gaze nystag-
mus in which the quick phases of the ad-
ducting eye are slower than those of the
abducting eye—a form of dissociated nys-
tagmus—is characteristic of internuclear
ophthalmoplegia (see VIDEOS: "Unilateral
internuclear ophthalmoplegia").
DIFFERENCES BETWEEN
PHYSIOLOGIC "END-POINT"
NYSTAGMUS AND PATHOLOGIC
GAZE-EVOKED NYSTGAMUS
Gaze-evoked nystagmus is commonly en-
countered in normal subjects, when it is
often called end-point nystagmus (Display
10-8).10>415>1260 Typically it occurs on look-
ing far laterally or up, and is poorly sus-
tained. On lateral gaze, the nystagmus is
primarily horizontal. It may be asymmet-

Display 10-8: Clinical Features that Distinguish "End-Point"

Nystagmus from Pathological Gaze-Evoked
Nystagmus
• Low amplitude and frequency

• Horizontal on far lateral gaze; upbeating on far upgaze

• Unsustained

• On lateral gaze, nystagmus is horizontal without vertical component

• Rebound nystagmus is transient or absent

• Ocular motor examination is otherwise normal

For physiological mechanisms, see Abnormalities of the Neural Integrator, in Chap. 5. (Re-
lated VIDEOS: "Gaze-evoked, rebound, and downbeat nystagmus.")
 Diagnosis of Central Disorders of Ocular Motility
ric—for example, more prominent on
looking to the right than to the left.1260
Nonetheless, in some normal individuals,
the nystagmus is sustained, occurs with
less than full deviations of the eye, and
may be slightly dissociated or have a small
torsional component. A strong downbeat-
ing component on lateral gaze, however,
implies dysfunction of central vestibular
connections (see VIDEOS: "Gaze-evoked,
rebound, and downbeat nystagmus"). In
such individuals, gaze-evoked nystagmus
can usually be differentiated from nystag-
mus caused by disease; the gaze-evoked
nystagmus has lower intensity (i.e., slower
drift), and, most important, is not accom-
panied by other ocular motor abnormali-
ties. Usually, pathologic gaze-evoked nys-
tagmus is accompanied by other defects of
eye movements, such as impaired smooth
pursuit. 220
Another form of gaze-evoked nystag-
mus in normal subjects is induced by sus-
tained eccentric gaze for a minute or more
(fatigue nystagmus}.1® Often the nystagmus
is of greater amplitude in the abduct-
ing eye, similar to the dissociated nystag-
mus of internuclear ophthalmoplegia.
These findings probably represent the ef-
fects of fatigue and may therefore be simi-
lar to the gaze-evoked nystagmus seen
with myasthenia gravis (see Fig. 9-20A),
which also increases with prolonged fixa-
tion.1228
BRUNS' NYSTAGMUS
Tumors of the cerebellopontine angle
(e.g., Schwann cell tumors of the eighth
nerve) may produce a combination of low-
frequency, large-amplitude horizontal nys-
tagmus on looking ipsilaterally, due to de-
fective gaze holding, with high-frequency,
small-amplitude nystagmus on looking
contralaterally, due to vestibular imbal-
ance.80'1004 This is called Bruns' nystag-
mus.200 Even in patients in whom an
acoustic schwannoma had been resected
years previously, nystagmus in darkness
shows a summation of the effects of vestib-
ular imbalance and gaze-evoked nystag-
mus. It has been proposed that, faced with
a vestibular imbalance, the brain deliber-
431
ately makes the gaze-holding network
leaky so that gaze-evoked nystagmus can
be used to counteract the vestibular imbal-
ance.1159 In this way there would be at
least one position in the orbit in which the
eyes would not drift.
CENTRIPETAL AND
REBOUND NYSTAGMUS
If patients with gaze-evoked nystagmus
sustain their attempt to look eccentrically,
the nystagmus may begin to quiet down
and may even reverse direction, so the eye
begins to drift centrifugally ("centripetal
nystagmus").824 If the eyes are then re-
turned to the central position, a short-lived
nystagmus with slow drifts in the direction
of the prior eccentric gaze occurs, called re-
bound nystagmus (Display 10-7) (Fig. 10-9)
(see VIDEOS: "Gaze-evoked, rebound, and
downbeat nystagmus").155'645 Both cen-
tripetal and rebound nystagmus may re-
flect an attempt by brain stem or cerebellar
mechanisms to correct for the centripetal
drift of gaze-evoked nystagmus. Rebound
nystagmus typically occurs in patients with
cerebellar syndromes, but it has been re-
ported following experimental lesions of
the NPH-MVN region230 and in normal
subjects who show gaze-evoked nystag-
mus.1260 Torsional rebound nystagmus has
been described in association with vestibu-
locerebellar disease.1337 Extreme gaze de-
viation away from the side of the lesion in
one patient with a lateral medullary infarc-
tion was reported to cause paroxysmal nys-
tagmus and vertigo lasting about a
minute. 224 Such a phenomenon could be
explained by a sustained eye position sig-
nal causing an imbalance of central vestib-
ular mechanisms. The structures critical
for rebound nystagmus remain undeter-
mined. One patient with a tumor confined
to the flocculus was reported to show gaze-
evoked nystagmus and rebound nystag-
mus,1504 but when the tumor spread to in-
volve the vestibular nuclei, the rebound
nystagmus disappeared, even though the
gaze-evoked nystagmus persisted. Thus,
the vestibular nuclei or surrounding me-
dulla may be important for generating re-
bound nystagmus.155'644'1504
432 The Diagnosis of Disorders of Eye Movements

Nystagmus Occurring in Visually mediated eye movements such

Association With Disease of the
Visual System
PATHOGENESIS OF NYSTAGMUS
jects attempt to fixate on the remembered
OCCURRING WITH VISUAL
SYSTEM DISORDERS
Disorders of the visual pathways are often
associated with nystagmus (Display 10-9).
The most obvious example is the nystag-
mus that invariably accompanies complete
blindness (see VIDEO: "Eye movements with
complete blindness").841 What is the mecha-
nism? At least two separate effects of visual
loss can be identified: (1) an inability to gen-
erate eye movements to correct for drifts of
the eyes and (2) loss of the "error signal"
that drives ocular motor adaptation and
tunes eye movements to visual demands.
as smooth pursuit and "fixation" stop the
eyes from drifting away from a stationary
object of regard (see Visual Fixation, in
Chap. 4). So, for example, if normal sub-
location of a target while in darkness, the
eye drifts off target several times faster
than if the subject actually views the tar-
get.1325 Uncorrected drifts are eventually
remedied by a saccade that places the im-
age back on the fovea. The fixation mech-
anism that generates smooth eye move-
ments to correct for drifts of the eyes
depends upon the motion-vision system,
which is inherently slow. Thus, a response
time of over 70 msec encumbers all visu-
ally mediated eye movements, including
fixation, smooth pursuit, and optokinetic
responses. If the response time is delayed

Display 10-9: Clinical Features of Nystagmus Associated with

Disease of the Visual Pathways
LESIONS OF THE EYE OR OPTIC NERVE
• Bilateral visual loss causes continuous jerk nystagmus, with horizon-
tal, vertical, and torsional components, and a drifting "null" position

• Monocular visual loss causes slow vertical oscillations and low-ampli-

tude horizontal nystagmus mainly in the blind eye; in children, espe-
cially, pendular nystagmus of the blind eye

LESIONS AT THE OPTIC CHIASM

• Seesaw nystagmus with bitemporal visual field loss

LESIONS AFFECTING POSTERIOR CORTICAL AREAS

• Low-amplitude horizontal nystagmus beating towards the side of the
lesion

LESIONS AFFECTING CORTICAL-PONTINE-CEREBELLAR OR

OLIVOCEREBELLAR PROJECTION

• May be responsible for some forms of acquired pendular nystagmus

For pathophysiology, see Abnormalities of Visual Fixation, in Chap. 4. For recorded exam-
ples, see Figure 10-8 in Chap. 10. (Related VIDEO: "Eye movements with complete blind-
ness.")

further by disease of the visual system,
then the brain's attempts at correcting eye
drifts may actually add to the retinal error
rather than reducing it, leading to ocular
oscillations.63 This issue is discussed fur-
ther in the section on Models of Smooth
Pursuit in Chap. 4. Another aspect of fix-
ation—the suppression of saccades—is
dealt with under Saccadic Intrusions.
In addition, vision is needed for recali-
brating and optimizing all types of eye
movements. This optimization depends
on visual projections to the cerebellum—
the "ocular motor repair-shop."1158 Thus,
signals from secondary visual areas con-
cerned with motion-vision project to the
cerebellum via the pontine nuclei and
middle cerebellar peduncle (Fig. 6-8);
neurons in both the dorsolateral pontine
nuclei and Purkinje cells in the cerebellar
flocculus encode visual-motion signals.756
Visual signals for recalibration may also
pass via the inferior olivary nucleus, which
sends climbing fibers to the cerebel-
lum.683'1131 If the ocular motor system is to
be recalibrated, visual signals need to be
compared with eye movement commands.
One candidate for this function is the cell
groups of the paramedian tracts (PMT)
(see Display 6-4), which receive inputs
from all premotor structures that project
to ocular motoneurons and which project
to the cerebellar flocculus. 217 Alternatively,
pathways that coordinate conjugate and
vergence movements involving connec-
tions between the nucleus reticularis
tegmenti pontis and cerebellar nucleus in-
terpositus (discussed in Chap. 8) might be
involved.500 Thus, lesions at any part of
this visual-motor "recalibration" pathway
might deprive the brain of signals that are
essential to hold each of the eyes on the
object of regard; the result would be drifts
of the eyes away from the target, leading
to nystagmus.
CLINICAL FEATURES OF
NYSTAGMUS IN ASSOCIATION
WITH VISUAL SYSTEM DISEASE
Disease affecting various parts of the vi-
sual system, from retina to cortical visual
areas, and interrupting visual projections
to pons and cerebellum, has been associ-
Diagnosis of Central Disorders of Ocular Motility 433
ated with nystagmus. First, we review the
features of nystagmus reported with dis-
ease localized to the different sites in this
pathway. Second, we discuss the features
of acquired pendular nystagmus, which
may be associated with disease affecting
the visual system and its brain stem-cere-
bellar projections.
Nystagmus Associated with Disease
of the Retina and Ocular Media
Retinal disorders causing blindness, such
as Leber's congenital amaurosis, lead to
continuous jerk nystagmus with compo-
nents in all three planes, which changes
in direction over the course of seconds
or minutes (Fig. 10-10A) (see VIDEO:
"Eye movements with complete blind-
ness." The drifting null point—the eye po-
sition at which nystagmus changes direc-
tion—probably reflects an inability to
"calibrate" the ocular motor system, and it
has also been reported after experimental
cerebellectomy.824'1157 Nystagmus has been
reported in association with a variety of
hereditary retinal disorders; 536,712,1465,1507
some, but not all, show the increasing-
velocity waveform (Fig. 10-1C) that was
thought to be characteristic for congenital
nystagmus. Loss of vision later in life also
causes nystagmus, and seesaw nystagmus
has been reported to develop in a patient
who progressively lost vision due to retini-
tis pigmentosa
Disease Affecting the Optic Nerves
and Nystagmus
Optic nerve disease is commonly associ-
ated with pendular forms of nystagmus.
With unilateral disease of the optic nerve,
such as tumors or trauma, nystagmus
largely affects the abnormal eye (monocu-
lar nystagmus), with low-frequency, bidirec-
tional drifts that are more prominent
vertically and unidirectional drifts with
quick phases that occur horizontally (Fig.
10-10B).86'838'1111 Such nystagmus that
predominantly affects an eye with poor vi-
sion is called the Heimann-Bielschowsky phe-
nomenon;1^ it is not confined to primary
optic nerve disease, however, and also
Figure 10-10. Nystagmus associated with visual loss. (A) Horizontal and vertical movements of both eyes of a
25-year-old patient bilaterally blind since birth due to Leber's congenital amaurosis. In the horizontal plane,
there is a wandering null point and changes in direction of the quick phases evident in the velocity channels.
Slow-phase waveforms are variably linear, decreasing velocity, or, especially in the vertical plane, increasing ve-
locity (see VIDEO: "Eye movements with complete blindness"). (B) Horizontal and vertical eye movements of a
patient with loss of vision (20/200) in his left eye secondary to trauma, 2 years previously; he had normal (20/20)
vision in his right eye. During binocular viewing, steady gaze of the left eye is disrupted by slow disconjugate
drifts that are more prominent vertically. RHP, horizontal gaze position of right eye; RHV, horizontal gaze ve-
locity of right eye; LHP, horizontal gaze position of left eye; LHV, horizontal gaze velocity of left eye; RVP, verti-
cal gaze position of right eye; RVV, vertical gaze velocity of right eye; LVP, vertical gaze position of left eye; LVV,
vertical gaze velocity of left eye. Upward pen deflections indicate rightward or upward gaze movements. Mea-
surements were made using the magnetic search coil technique. (From Leigh RJ, Thurston SE, Tomsak RL,
Grossman GE, Lanska DJ. Effect of monocular visual loss upon stability of gaze. Investigative Ophthalmology
and Visual Science 1989;30:288-92, with permission of the copyright holder, Association for Research in Vision
and Ophthalmology.)
Continued on following page

434
 Diagnosis of Central Disorders of Ocular Motility
Figure 10-10.—continued
occurs in patients with profound ambly-
opia.86'838'1111
When disease such as demyelination af-
fects both optic nerves, the amplitude of
nystagmus is often greater in the eye with
poorer vision.101 Oscillations may also oc-
cur after development of a dense cataract
or high myopia in childhood; when vision
is restored they may disappear or they may
persist, leading to oscillopsia.1108'1499 Those
patients in whom nystagmus declines after
restoration of vision support the con-
tention that these ocular oscillations may
be primarily caused by the lack of visual in-
puts required for "calibration" rather than
by any primary disorder of the ocular mo-
tor system. The origin of vertical drifts that
occur in a blind eye is unknown but has
been attributed to disturbance of either
the vertical vergence mechanism86 or a
monocular visual stabilization system.838
In infants, the appearance of monocu-
lar, vertical pendular nystagmus raises the
possibility of an optic nerve tumor, and
imaging studies are indicated.430'530'818
However, monocular oscillations in chil-
dren are sometimes due to spasmus nu-
43
tans,1466 which spontaneously resolves.
Monocular visual impairment, such as am-
blyopia, also leads to horizontal nystag-
mus, and if present from birth, the fea-
tures are those of latent nystagmus.
Disease Affecting the Optic Chiasm
and Nystagmus
Parasellar lesions such as pituitary tumors
have traditionally been associated with
seesaw nystagmus (Display 10-6). As al-
ready discussed, seesaw nystagmus is a
form of pendular nystagmus in which one
half-cycle consists of elevation and intor-
sion of one eye and synchronous depres-
sion and extorsion of the other eye, with
the vertical and torsional movements re-
versing during the next half cycle (see Fig.
10-8) (see VIDEO: "Seesaw nystagmus").
However, many such cases were described
before the era of modern imaging, and the
tumors may have compressed the mid-
brain. Hemi-seesaw nystagmus has been
attributed to disease affecting the intersti-
tial nucleus of Cajal or its connections.571
Congenital seesaw nystagmus, however,
has been reported in a mutant strain of
dogs that lacks an optic chiasm372 and in
patients in whom imaging and visual
evoked studies suggested a similar devel-
opmental defect.40'842 Seesaw nystagmus
has also been documented to develop in a
patient with progressive visual loss due to
retinitis pigmentosa.915 Thus, it remains
possible that visual inputs—especially
crossed inputs—are important for opti-
mizing vertical-torsional eye movements.
Under natural conditions, seesaw eye
movements occur when subjects view a tar-
get located off the midsagittal plane dur-
ing ear-to-shoulder head roll.1253 Visual
inputs are presumably necessary to keep
this response calibrated and, if removed,
might lead to seesaw oscillations.56'100
Disease Affecting the Postchiasmal
Visual System and Nystagmus
Horizontal nystagmus occurs in patients
with unilateral disease of the cerebral hemi-
spheres, especially when the lesion is large
and posterior.1270 Such patients show a con-
stant-velocity drift of the eyes toward the in-
43 The Diagnosis of Disorders of Eye Movements
tact hemisphere (i.e., quick phases directed
toward the side of the lesion). The nystag-
mus is often low amplitude, and sometimes
is only appreciated on ophthalmoscopy.
Such patients usually also show asymmetry
of horizontal smooth pursuit (impaired to-
ward the side of the lesion). The asymmetry
is brought out at the bedside using a hand-
held optokinetic drum or tape;793 the re-
sponse is reduced when the stripes move to-
ward the side of the lesion. This asymmetry
of visual tracking has led to the suggestion
that nystagmus in such patients is caused by
an imbalance of pursuit "tone."1270 As dis-
cussed below, a congenital form of nystag-
mus—latent nystagmus—has been attrib-
uted to an abnormality of such cortical
motion-vision processing.
Sometimes, intermittent nystagmus is
due to seizure activity affecting cortical ar-
eas responsible for generating smooth-
pursuit movements; 721 this is discussed be-
low in the section Eye Movements During
Epileptic Seizures.
ACQUIRED PENDULAR
NYSTAGMUS AND ITS
RELATIONSHIP TO DISEASE OF
THE VISUAL PATHWAYS
Acquired pendular nystagmus (Fig. 10-11)
is one of the more common types of nystag-
mus and is often associated with distressing
visual symptoms (see VIDEOS: "Acquired nys-
Figure 10-11. Acquired pendular nystagmus. (A) A 2-sec record from a patient with multiple sclerosis who
showed elliptical nystagmus. (B) Trajectory of nystagmus shown in A, which is quasi-elliptical. HOR, horizontal
component; VER, vertical component. In A, upward deflections indicate rightward and upward eye rotations.
tagmus impairing vision"). Its pathogenesis
remains unclear, and more than one mech-
anism may be responsible. It is encountered
in a variety of conditions (Table 10-6), in-
cluding several disorders of myelin, the syn-
drome of oculopalatal tremor, and in associ-
ation with Whipple's disease. We will first
describe the common features of the nystag-
mus and then discuss characteristics pecu-
liar to the three major types separately.
Clinical Characteristics of Acquired
Pendular Nystagmus
Acquired pendular nystagmus usually has
horizontal, vertical, and torsional compo-
nents, although one may predominate
(Display 10-10). (In congenital pen-
dular nystagmus, usually the oscillation
is predominantly horizontal, with small
torsional and negligible vertical compo-
nents.) The horizontal, vertical, and tor-
sional components of each eye's oscilla-
tions usually have the same frequency. If
the horizontal and vertical oscillatory
components are in phase, the trajectory of
the nystagmus is oblique. If the horizontal
and vertical oscillatory components are
out of phase, the trajectory will be ellipti-
cal (Fig. 10-11). A special case is a phase
difference of 90° and equal amplitude of
the horizontal and vertical components,
when the trajectory is circular. When the
oscillations of each eye are compared, the
 Diagnosis of Central Disorders of Ocular Motility
Table 10-6. Etiology of
Pendular Nystagmus
Visual Loss (including unilateral disease of the
optic nerve)430'838
Disorders of Central Myelin
Multiple sclerosis63'101-879
Pelizaeus-Merzbacher disease1393
Cockayne's syndrome 280 ' 925
Peroxisomal disorders790
Toluene abuse891
Syndrome of Oculopalatal "Myoclonus" or
Tremor, developing after brain stem
stroke63'993 or as a degenerative1311 or famil-
ial disorder658
Acute Brain Stem Stroke747
Whipple's Disease1248
Spinocerebellar Degenerations62'534
Hypoxic Encephalopathy 62
Congenital Nystagmus 356
nystagmus may be conjugate, but often
the trajectories are dissimilar (i.e., discon-
jugate), and the size of oscillations is dif-
ferent (i.e., dissociated). Sometimes the
nystagmus appears monocular, and there
may be an asynchrony of timing (phase
shift), which may reach 180°, in which case
the oscillations may be regarded as a form
of convergent-divergent nystagmus. 64
The waveform of acquired pendular nys-
tagmus may approximate a sine wave, but
often it is more complex.64 The frequency of
oscillations of acquired pendular nystagmus
ranges from 1 to 8 Hz, with a typical value
of 3.5 Hz;555 for any particular patient, the
frequency tends to remain fairly constant.
Only rarely is the frequency of oscillations
different in the two eyes." In some patients,
the nystagmus stops momentarily after a
saccade (postsaccadic suppression).48 The nys-
tagmus may be suppressed or brought out
by eyelid closure.485'691 In some patients,
smooth pursuit may be intact, so despite the
oscillations, tracking eye movements occur
with nystagmus superimposed.555
Acquired Pendular Nystagmus With
Demyelinative Disease
Acquired pendular nystagmus is a com-
mon feature of a variety of disorders of
437
central myelin, including multiple scle-
rosis (MS), congenital disorders such
Pelizaeus-Merzbacher disease (see VIDEOS:
"Pelizaeus-Merzbacher disease"),1393 and
toluene abuse.891 Since concurrent optic
neuritis often coexists in patients with MS
who have pendular nystagmus, prolonged
response time of the visual processing
might be responsible for the ocular oscilla-
tions. Evidence to support this notion
comes from the observation that oscilla-
tions are larger in the eye with evidence of
more severe optic nerve demyelination. 101
However, the nystagmus often remains
unchanged in darkness (when visual in-
puts have no influence on eye move-
ments). As discussed in the section on
Models of Smooth Pursuit, in Chap. 4,
spontaneous ocular oscillations can be in-
duced in normal subjects by experimen-
tally delaying the latency of visual feed-
back during fixation (see Fig. 4-10);
however, the frequency of these induced
oscillations is less than 2.5 Hz, which
is lower than in most patients with pen-
dular nystagmus. 63 Furthermore, when
this experimental technique was ap-
plied to patients with acquired pendu-
lar nystagmus, it did not change the
characteristics of the nystagmus but in-
stead superimposed lower-frequency oscil-
lations similar to those induced in normal
subjects. Thus, disturbance of visual fixa-
tion due to visual delays cannot account
for the high-frequency oscillations that of-
ten characterize acquired pendular nys-
tagmus.
A more likely possibility is that visual
projections to the cerebellum are im-
paired, leading to instability in the recip-
rocal connections between brain stem nu-
clei and cerebellum that are important for
recalibration. Thus, it may be relevant
that internuclear ophthalmoplegia is com-
mon in these patients, suggesting involve-
ment of brain stem regions close to the cell
groups of the paramedian tracts (PMT)
(see Display 6-4).217'221 In patients in
whom the oscillations are predominantly
convergent-divergent, it is possible that in-
stability arises in connections between
the nucleus reticularis tegmenti pontis
and the cerebellar nucleus interpositus,
which both contribute to vergence move-
ments.64'500
 Display 10-10: Clinical Features of Acquired
Pendular Nystagmus
COMMON FEATURES
• May have horizontal, vertical, and torsional components; their ampli-
tude-and-phase relationship determines the trajectory of the nystag-
mus in each eye

• Phase shift between the eyes is common (horizontally and torsionally;

seldom vertically)—may reach 180°, so the nystagmus becomes con-
vergent-divergent or cyclovergent

• Amplitudes often differ, and nystagmus may appear monocular

• Trajectories may be conjugate, but more often are dissimilar

• Oscillations sometimes suppressed momentarily in the wake of a saccade

IN ASSOCIATION WITH DEMYELINATING DISEASES

• Frequency 2-8 Hz (typically 3-4 Hz)

• Generally greater amplitude in the eye with poorer vision

• Internuclear ophthalmoplegia commonly associated

• May have an associated upbeat component

SYNDROME OF OCULOPALATAL TREMOR

• Frequency 1-3 Hz (typically 2 Hz)

• May be vertical (with bilateral lesions) or disconjugate vertical-tor-

sional

• Accentuated by eyelid closure

• Movements of palate and other branchial muscles may be synchronized

WHIPPLE'S DISEASE
• Frequency typically about 1 Hz

• Usually convergence-divergence, occasionally vertical; sometimes with

associated oscillatory movements of the jaw, face, or limbs (oculomasti-
catory myorhythmia)

• Vertical gaze palsy similar to the clinical picture of progressive

supranuclear palsy is usually also present

For pathophysiology, see Models of Smooth Pursuit, in Chap. 4. For recorded examples, see
Figure 10-11 and Figure 10-12 of Chap. 10. For etiologies, see Table 10-6. (Related VIDEOS:
"Acquired nystagmus impairing vision," "Oculopalatal tremor," "Pelizaeus-Merzbacher dis-
ease," and "Whipple's disease.")

438
 Diagnosis of Central Disorders of Ocular Motility
Oculopalatal Tremor (Myoclonus)
Acquired pendular nystagmus may be
one component of the syndrome of
oculopalatal (pharyngolaryngodiaphrag-
matic) tremor (see VIDEO: "Oculopalatal
tremor").561'993 This condition usually de-
velops several months after brain stem or
cerebellar infarction (Fig. 10-12), though
it may not be recognized until years after
the stroke. Oculopalatal tremor also oc-
curs with degenerative conditions.64'1311
The term tremor is more accurate than my-
oclonus, since the movements of affected
muscles are to and fro and are approxi-
mately synchronized, typically at a rate of
about 2 cycles per second. The palate is
most often affected, but the eyes, facial
muscles, pharynx, tongue, larynx, dia-
phragm, mouth of the eustachian tube,
neck, trunk, and extremities may also
move, in synchrony. Essential rhythmic pala-
tal myoclonus is an idiopathic disorder in
which ocular oscillations do not accom-
pany palatal movements, unlike the symp-
tomatic variety, but in which auditory
clicking is common.381 Pendular vertical
oscillations of the eyes may occur acutely
with pontine infarctions that cause hori-
zontal gaze palsy;747 associated palatal
movements usually do not develop for sev-
eral months.
The ocular movements, present in most
cases, consist of pendular oscillations that
are often vertical but may have a horizon-
tal or torsional component. If the palatal
tremor is unilateral, the pendular oscilla-
tions consist of a mixed vertical-torsional
movement, with the eye on the side of the
palatal tremor intorting as it rises and ex-
torting as it falls. The opposite eye extorts
as it rises and intorts as it falls. The move-
ments may be disconjugate, with some or-
bital position dependency,555'993 and some
patients may show cyclovergence (tor-
sional vergence) oscillations.64 Occasion-
ally, following brain stem infarction, pa-
tients develop the eye oscillations without
movements of the palate. Eyelid closure
may bring out the vertical ocular oscilla-
tions.691 The nystagmus sometimes disap-
pears with sleep, but the palatal move-
ments usually persist. Once established,
the condition is usually intractable, and
spontaneous remission is uncommon. 693
439
The main pathologic finding with pala-
tal tremor is hypertrophy of the inferior
olivary nucleus; this may be evident by
MRI. 1311 There may also be destruction of
the contralateral dentate nucleus.561 His-
tologically, the olivary nucleus has en-
larged, vacuolated neurons with enlarged
astrocytes. The hypertrophic neurons and
their dendrites contain increased acetyl-
choline esterase reaction products.777 Func-
tional scanning has demonstrated in-
creased glucose metabolism.407 Guillain
and Mollaret proposed that disruption of
connections between the dentate nucleus
and the contralateral inferior olivary nu-
cleus, which run via the red nucleus and
central tegmental tract, is responsible for
the syndrome. 561 However, the red nu-
cleus is not known to have a role in the
control of eye movements. It has also been
postulated that the nystagmus is due to an
instability in the projections from the infe-
rior olive to the flocculus, which is thought
to be important in the adaptive control of
the vestibulo-ocular reflex.993 It is also
possible that projections from the PMT
cell groups (see Display 6-4), which feed
back ocular motor signals to the cerebel-
lum, 217 are impaired or delayed, leading
to oscillations.63
Convergent-Divergent Forms
of Nystagmus
Convergent forms of nystagmus are often
small in amplitude and may be missed
without reliable records to document the
phase relationship between each eye.
Comparatively few reports exist of conver-
gent or divergent forms, and not much is
known about their pathogenesis. More
than one mechanism is likely, and an oscil-
lation that emanates from the vergence
mechanism itself is probably rare. Here,
we discuss disjunctive forms of pendular
nystagmus, vertical jerk nystagmus that
has disjunctive horizontal components,
and convergence-retraction nystagmus,
which is properly classified as a disorder
of saccades.
Convergence-divergence forms of nys-
tagmus should be differentiated from
conjugate nystagmus that is evoked or
Figure 10-12. Syndrome of oculopalatal tremor following brain stem stroke. The patient was a 25 year-old man
who developed this syndrome following brain stem hemorrhage from an arteriovenous malformation. (A) An
MRI showing brain stem hematoma and a vein draining superiorly from the malformation. (B) The effects of
gabapentin on oscillations of his right eye are shown. The horizontal (hor) and torsional (tor) records have been
offset from the vertical (ver) records, which are aligned about zero for clarity of display; thus eye positions are
relative rather than absolute. Upward deflections indicate rightward, upward, or clockwise eye rotations, with
respect to the patient. Gabapentin substantially reduced this patient's nystagmus, as is also evident on the
videos (see VIDEO: "Oculopalatal tremor").
440

changed by convergence.1041'1268 Thus, in
some patients with acquired pendular nys-
tagmus 63 or central vestibular forms of
nystagmus (downbeat, upbeat, torsional),
convergence variably suppresses, increases,
or changes the form of the oscilla-
tions.297'435'1021 Further, congenital nystag-
mus is often suppressed by convergence, a
factor that has therapeutic significance.827
CONVERGENT-DIVERGENT
PENDULAR OSCILLATIONS
This form of nystagmus has been de-
scribed in patients with multiple sclero-
sis,64 brain stem stroke,555 and cerebral
Whipple's disease (see VIDEO: "Whipple's
disease").1248 In the last case, the abnormal
eye movements have been ascribed to os-
cillations of the vergence system—hence
the term pendular vergence oscillations.1248
This nystagmus typically has a frequency
of about 1.0 Hz and is accompanied by
concurrent contractions of the masticatory
muscles (oculomasticatory myorhythmia). In
addition, paralysis of vertical gaze occurs
and may mimic the paralysis of progres-
sive supranuclear palsy.881'1119
Using reliable methods of measuring
eye movements, other patients have been
reported with pendular oscillations that
were about 180° out of phase in the hori-
zontal and torsional planes but had conju-
gate vertical components.64 In certain pa-
tients, the torsional oscillations are the
greatest in amplitude (cyclovergence nystag-
mus). The convergent-divergent nature of
the nystagmus might be explained in two
possible ways: a phase shift between the
eyes, produced by dysfunction in the nor-
mal yoking mechanisms; or an oscillation
affecting the vergence system itself. The
latter is a more likely explanation, since
studied patients showed no phase shift
(i.e., were conjugate) vertically, and the re-
lationship between the horizontal and tor-
sional components was similar to that
occurring during normal vergence move-
ments (excyclovergence with horizontal
convergence).64 Under experimental con-
ditions, the vergence system has been
made to oscillate at frequencies of up to
2.5 Hz,1158 lower than the frequency re-
ported in patients with conditions other
than Whipple's disease. To account for
Diagnosis of Central Disorders of Ocular Motility 441
these higher-frequency oscillations, it
seems necessary to postulate instability
within the brain stem-cerebellar connec-
tions of the vergence system, such as be-
tween nucleus reticularis tegmenti pontis
and the cerebellar posterior interposed
nuclei (discussed in Chap. 8).64
VERTICAL NYSTAGMUS WITH A
CONVERGENT-DIVERGENT
HORIZONTAL COMPONENT
Like pendular nystagmus, some forms of
jerk nystagmus have a convergent or di-
vergent component. For example, the up-
beat nystagmus shown in Figure 10-6 in a
patient with multiple sclerosis (see VIDEO:
"Upbeat nystagmus") has convergent slow
phases. Only occasionally are the horizon-
tal, disjunctive components of the nystag-
mus large enough to be clinically appar-
ent. Divergence nystagmus has been
reported with cerebellar diseases such as
Arnold-Chiari malformation, when com-
bined divergent and downbeat nystagmus
produces slow phases that are directed up-
ward and inward.264'1509 These forms of
nystagmus might reflect an otolithic im-
balance, since geometric factors require
that the normal, translational vestibulo-oc-
ular reflex (see Fig. 1-5) during vertical
(bob) or fore and aft (surge) translational
head movements combines conjugate ver-
tical and disconjugate horizontal move-
ments if the subject looks at a near object
above or below eye level or off to one side.
Future studies of the three-dimensional
properties of vertical nystagmus are
needed to clarify these issues.
CONVERGENCE-RETRACTION
NYSTAGMUS
This is not truly a form of nystagmus,
since each cycle of the oscillation is initi-
ated by a disjunctive saccade (or quick
phase) that converges and retracts the
eyes (see VIDEO: "Convergence-retraction
nystagmus"). It is caused by lesions of the
mesencephalon that involve the region
of the posterior commissure, classically
pineal tumors (see Ocular Motor Syn-
dromes Caused by Lesions of the Mesen-
cephalon, below).264'1029 Convergence nys-
tagmus has also been described in patients
442 The Diagnosis of Disorders of Eye Movements
with Arnold-Chiari malformation. 972 Dur-
ing horizontal saccades, the abnormal
pattern of convergent innervation mani-
fests itself as slowing of the abducting eye:
pseudo-abducens palsy.*19 Convergence-
retraction nystagmus is elicited either by
asking the patient to make an upward sac-
cade, or by using a hand-held optokinetic
drum or tape, moving the stripes down
(see VIDEO: "Convergence-retraction nys-
tagmus"). With the optokinetic stimulus,
slow, downward, following eye movements
occur, but the upward quick phases are re-
placed by rapid convergent or retractory
movements, or both. Convergence-retrac-
tion nystagmus is usually intermittent, be-
ing determined by saccadic activity, and so
can be differentiated from other, more
continuous forms of disjunctive nystag-
mus such as acquired pendular nystagmus
and the oculomasticatory myorhythmia
that is characteristic of Whipple's dis-
ease. Pretectal pseudobobbing consists of
nonrhythmic, rapid movements which
carry the eyes down and medially, and
which are followed by a slow return to
midline; each movement may be preceded
by a blink. 745 This disorder is reported in
patients with acute obstructive hydro-
cephalus and is probably a variant of con-
vergence nystagmus.
Normal subjects show small, transient
disjunctive movements during vertical
saccades: often there is convergence with
downward movements and divergence
with upward, 1529 which is the opposite of
the pattern occurring in convergence-
retraction nystagmus (see saccade-vergence
interactions, in Chap. 8). Further, the re-
traction makes it likely that cocontraction
of the extraocular muscles is occurring
with each saccade. What structure or con-
nections in the dorsal midbrain are re-
sponsible for this mis-programing of sac-
cades has yet to be elucidated.
Congenital Forms of Nystagmus
THE NATURE OF CONGENITAL
OCULAR OSCILLATIONS
Progress in understanding the pathogene-
sis of congenital nystagmus has been ad-
vanced by the development of an animal
model in normal monkeys that are de-
prived of binocular vision during early
life1400 and the identification of congenital
forms of nystagmus in mutant dogs
with abnormal anatomy of the visual sys-
tem.372'373 However, although some pa-
tients with congenital nystagmus show vi-
sual abnormalities, others with similar
ocular oscillations do not. Furthermore,
the presence of any one type of wave-
form—such as pendular (see Fig. 10-ID)
or jerk (Fig. 10-1 A)—does not suggest a
specific pathogenesis or indicate whether
the congenital nystagmus is associated
with visual system anomalies.356 Thus,
the underlying mechanisms are not fully
understood. Three distinct syndromes
are currently recognized: congenital nys-
tagmus, latent nystagmus, and spasmus
nutans.
CONGENITAL NYSTAGMUS
Clinical Features of
Congenital Nystagmus
Congenital nystagmus may be present
at birth but usually develops during in-
fancy.537 It occasionally presents during
adult life,476'553 when it may create a diag-
nostic problem, especially if the patient
has other symptoms such as headaches or
dizziness. Although variable in form, cer-
tain clinical features usually differentiate
congenital nystagmus from other ocular
oscillations (Display 10-11) (see VIDEO:
"Congenital nystagmus"). It is almost al-
ways conjugate and mainly horizontal,
even on up or down gaze. A torsional com-
ponent to the nystagmus is probably com-
mon, but is usually too small to identify
clinically.3 Less commonly, congenital nys-
tagmus is mainly seesaw (see VIDEO: "See-
saw nystagmus"), and such patients may
have underlying disease of the retina,536'538
visual pathways,40'351 or cerebellum. Con-
genital nystagmus that is conjugately ver-
tical is rare.139'1303
Congenital nystagmus is usually accen-
tuated by the attempt to fixate an ob-
ject, and by attention or anxiety. Eyelid
closure1281 and convergence usually sup-
press it,386 but occasionally congenital nys-
tagmus is evoked by viewing a near
target.1268'1520 Its intensity may also be in-
 Diagnosis of Central Disorders of Ocular Motility 443

Display 10-11: Clinical Features of Congenital Nystagmus

• Present since infancy

• Usually conjugate, horizontal; smaller torsional or vertical compo-

nents

• Pendular or increasing-velocity waveforms punctuated by foveation

periods, during which eyes are transiently still and aimed at the object
of interest

• Suppressed on convergence or with eyelid closure

• Accentuated by visual attention or arousal

• Often minimal when the eyes are near one particular orbital position
(null zone)

• Accompanied by head shaking or head turn

For pathophysiology, see Smooth Pursuit in Patients With Congenital Nystagmus, in Chap.
4. For a recorded example, see Figure 10-13 in Chap. 10. (Related VIDEO: "Congenital nys-
tagmus.")

fluenced by viewing the vertical lines of an
optokinetic tape.320 Often, nystagmus de-
creases when the eyes are moved into a
particular position in the orbit; this is
called the null point or zone, and corre-
sponds to the range of eye position within
which slow-phase eye velocity is at a mini-
mum. In some patients, the nystagmus
periodically reverses direction, but this
reversal seldom occurs in the regular
manner seen in the acquired form of pe-
riodic alternating nystagmus.7'356'542 In
some patients, the direction of the nystag-
mus is influenced by which eye is viewing,
the nystagmus beating away from the cov-
ered eye. This is similar to what happens
in latent nystagmus, which is discussed
next.
The most distinctive feature of congeni-
tal nystagmus is its waveforms; the com-
monest are increasing-velocity (see Fig.
10-1C) and pendular (Fig. 10-1D). Fre-
quently superimposed on these wave-
forms, which may be combined, are
foveation periods, the "signature" of con-
genital nystagmus (Fig. 10-13).U,io8,356,362
During each cycle—usually after a quick
phase—there is a brief period when the
eye is still and is pointed at the object of
regard. With jerk waveforms, the quick
phases (saccades) may "brake" the oscilla-
tion,357 or bring the eye to the target. With
pendular waveforms, the oscillation is
"flattened" by a foveation period when the
eye is closest to the target (Fig. 10-13B).
Foveation periods are probably one rea-
son why most patients with congenital nys-
tagmus do not complain of oscillopsia,
in spite of otherwise nearly continuous
movement of their eyes,355'362'523'829 and
why many have normal visual acu-
ity.252-1279 Foveation periods are not invari-
able in congenital nystagmus, however.
When they are absent or poorly de-
veloped, visual acuity is usually im-
paired.107'362 Foveation periods are only
rarely reported in acquired forms of nys-
tagmus, however.355'1314 The waveform
also depends upon the child's age, being
large-amplitude "triangular" in the first
few months of life, then pendular, and fi-
nally jerk as the patient reaches about a
year of age.1133 These waveforms are so
characteristic of congenital nystagmus that
444 The Diagnosis of Disorders of Eye Movements
Figure 10-13. Congenital nystagmus. Examples of
(A) horizontal jerk waveform, with slow phases that
drift away from the fixation position with increasing
velocity waveforms (evident on lower, magnified
scale), (see VIDEO: "Congenital nystagmus") and (B) a
pendular type of waveform with superimposed quick
phases. Note that both subjects show foveation peri-
ods, following quick phases, when the eye is close to
the desired fixation point and eye velocity is low.
POS, position; VEL, velocity.
reliable records of eye position and veloc-
ity will often secure the diagnosis.
Up to 30% of patients with congenital
nystagmus have strabismus.350 A com-
monly described associated finding is "in-
version of smooth-pursuit or optokinetic
responses."576 Thus, with a hand-held op-
tokinetic drum or tape, quick phases are
directed in the same direction as the drum
rotates. In fact, the phenomenon can be
explained in terms of shifts in the position
of the null point of the nystagmus induced
by the pursuit or optokinetic stimuli. Mea-
surement of tracking during foveation pe-
riods has shown that smooth pursuit and
optokinetic eye movements are preserved
in at least some individuals.369-801 Simi-
larly, the higher-frequency vestibular re-
sponses have generally been found to be
normal in patients with congenital nystag-
mus and, if judged from retinal image sta-
bility during the foveation period, perfor-
mance is normal and allows a similar view
of the world while the patient is stationary
or in motion.234'370 However, patients with
congenital nystagmus may show increased
thresholds for motion perception.12583 Es-
pecially in those patients with associated
visual disorders such as albinism, vestibu-
lar responses to lower frequencies of head
rotations and optokinetic responses (i.e.,
the velocity-storage mechanism} may be im-
paired.379'550 Occasional patients exhibit
their congenital nystagmus only during
attempted smooth tracking, 757 and others
can voluntarily release or inhibit their
congenital nystagmus, suggesting that the
fixation mechanism plays some role in
their oscillations.1402 Congenital nystag-
mus associated with congenital gaze-hold-
ing failure (i.e., leaky neural integrator] has
been reported in one kindred. 371
Head turns are common in congenital
nystagmus and are used to bring the eye
in the orbit close to the null point or zone,
at which nystagmus is minimal. The pres-
ence of such head turns in childhood pho-
tographs is often useful evidence in di-
agnosing congenital nystagmus. Another
strategy used by patients with either con-
genital or latent nystagmus is to purposely
induce an esotropia (nystagmus blockage syn-
drome] in order to suppress the nystagmus;
such an esotropia requires a head turn to
direct the viewing eye at the object of in-
terest.359'1440
Some patients with congenital nystag-
mus also show head oscillations.234'358'557'11193
Such head movements could not act as an
adaptive strategy to improve vision unless
the vestibulo-ocular reflex were negated.
In most patients with congenital nystag-
mus, head movements are not compensa-
tory and tend to increase when the indi-
vidual attends to an object, an effort that
also increases the nystagmus. It seems pos-
sible, therefore, that the head tremor and
ocular oscillations represent the output of
a common neural mechanism.358'11193
Pathogenesis of
Congenital Nystagmus
As noted above, nystagmus developing
early in life and showing some of the
waveform characteristic of congenital nys-
tagmus in humans occurs in mutant dogs
 Diagnosis of Central Disorders of Ocular Motility
who lack any decussation of their visual
pathway,372 as well as in normal monkeys
who undergo a form of monocular visual
deprivation in infancy.1400 Nystagmus is
also associated with a variety of visual
system disorders, including ocular and
oculocutaneous albinism,5'284'1032 achro-
matopsia, cone dystrophy, optic nerve hy-
poplasia, Leber's congenital amaurosis,
colobomata, aniridia, corectopia, congeni-
tal stationary night-blindness, Chediak-
Higashi syndrome, Joubert's syndrome,
and peroxisomal disorders.536'538'1465 Nys-
tagmus that is present at birth, but re-
solves by 6 months of age, has been associ-
ated with delayed visual maturation. 130a
Failure to develop a normal optic chiasm
may predispose to congenital seesaw nys-
tagmus.40 Nystagmus associated with the
above-mentioned conditions may not
show the classic features of congenital nys-
tagmus. Because of the many diagnostic
possibilities, a complete ophthalmologic
evaluation and an electroretinogram are
necessary in patients with nystagmus asso-
ciated with decreased visual acuity or vi-
sual dysfunction.254-528'809'1465 Congenital
nystagmus, either with or without associ-
ated visual system abnormalities, may be
familial.361'371'762 Several modes of inheri-
tance have been reported; in X-linked
forms, the mothers may show subtle ocu-
lar motor abnormalities. Congenital nys-
tagmus has been reported in monozygotic
twins,4-6 and a gene for an autosomal
dominant form has been described.761'762
However, the waveforms or other char-
acteristics of the nystagmus may differ
considerably between twins or other rela-
tives.6'350'361
The known anatomical variations of the
anterior visual system in individuals with
congenital nystagmus, such as excessive
crossing at the chiasm in association with
albinism,562'918 or absent crossing of nasal
fibers in achiasmatic subjects with congen-
ital seesaw nystagmus,40'372 have led to de-
velopment of models for congenital nys-
tagmus based on "miswiring" of visual
pathways. 1047 ' 1402 These ideas about the
pathogenesis of congenital nystagmus are
discussed further in Chap. 4, under
Smooth Pursuit in Patients With Congeni-
tal Nystagmus.
445
LATENT (OCCLUSION)
NYSTAGMUS
Clinical Features of
Latent Nystagmus
True latent nystagmus is a jerk nystagmus
that is absent when both eyes are viewing
but appears when one eye is covered:
quick phases of both eyes beat away from
the covered eye (Display 10-12) (see
VIDEO: "Latent nystagmus"). In most pa-
tients, nystagmus (which may be of low
amplitude) is present when both eyes are
uncovered (manifest latent nystagmus}; how-
ever, only one eye is fixating, and vision
from the other eye (which may be devi-
ated, e.g., esotropic) is suppressed.365'559
Usually, the nystagmus reverses direction
upon covering of either eye; in some pa-
tients, nystagmus is present when one par-
ticular eye is covered but is absent when
the other is occluded. Occasional patients
can control their latent nystagmus at
will.788 Latent nystagmus is usually asso-
ciated with strabismus, typically es-
otropia.366'1235 Amblyopia is frequent,
whereas binocular vision with normal
stereopsis is rare. Like strabismus, latent
nystagmus sometimes occurs in individu-
als who have no other evidence of neuro-
logic dysfunction, but it is more common
in patients with disorders of cerebral de-
velopment, such as Down's syndrome. 53
The slow phase of latent nystagmus
shows a linear- or decaying-velocity wave-
form (Fig. 10-1), in contrast to the increas-
ing-velocity waveform of congenital nys-
tagmus.559 Recent studies have suggested
that foveation may occur during the slow-
est part of the drift if the amplitude of
the nystagmus is large and immediately af-
ter the quick phase if the amplitude is
small.363'4223 Latent nystagmus usually fol-
lows Alexander's law, the nystagmus being
greatest on looking in the direction of the
quick phases, away from the covered eye.
Some patients turn their head to keep
their viewing eye in an adducted position,
where nystagmus is minimal;784 this and
other strategies to reduce latent or con-
genital nystagmus have been called nystag-
mus blockage syndrome.S59'l548a Occasionally,
congenital and latent nystagmus coexist
and the waveforms may be more compli-
446 The Diagnosis of Disorders of Eye Movements

Display 10-12: Clinical Features of Latent Nystagmus

• Present since infancy; associated with strabismus and lack of binocular
vision

• Evoked or enhanced by covering one eye

• Conjugate, horizontal nystagmus beating away from covered eye

• May have an associated torsional component (pendular or jerk) and

vertical upbeating component

• Slow phases may have linear- or decreasing-velocity waveforms

• Smooth pursuit asymmetry, depending on viewing eye and ongoing

nystagmus

• Associated with dissociated vertical deviation (eye under cover devi-

ates up)

For pathophysiology, see Smooth Pursuit, Visual Fixation, and Latent Nystagmus, in Chap.
4. (Related VIDEO: "Latent nystagmus.")

cated. Rarely, if vision is clearer with the Pathogenesis of Latent Nystagmus

latent nystagmus waveforms than with the
congenital nystagmus waveforms, such pa-
tients may switch from congenital to latent
nystagmus as one eye becomes esotropic
and the other takes up fixation.359 In addi-
tion to strabismus, upward deviation of
the covered eye (called alternating sursum-
duction or dissociated vertical deviation) and a
torsional component to the nystagmus are
frequently associated.35>565a'1415 Individuals
with latent nystagmus show asymmetry of
monocular smooth pursuit, optokinetic
nystagmus, and the cortical visual-evoked
response (VEP) to motion stimuli; the sig-
nificance of these findings is discussed in
the next section and under Smooth Pur-
suit, Visual Fixation, and Latent Nystag-
mus, in Chap. 4.197a'787'1235-1404 Latent nys-
tagmus is quite a common disorder, and
accurate diagnosis is important to avoid
inappropriate investigations. It should be
differentiated from gaze-evoked nystag-
mus in association with strabismus, and es-
pecially from abducting nystagmus occur-
ring with internuclear ophthalmoplegia,
in which an exotropia may be present but
adducting saccades are slow.
Latent nystagmus can be induced experi-
mentally in monkeys by depriving them of
binocular vision early in life, either by
patching one eye1400 or by surgically creat-
ing strabismus.768 The cortical areas that
extract motion information from visual
stimuli—such as V5 or area MT (see Fig.
6-8, in Chap. 6)—in such monkeys have
normal responses but are rarely driven
binocularly.768 Changes are also found in
the nucleus of the optic tract (NOT), to
which V5 projects, where neurons nor-
mally respond to visual stimuli presented
to either eye. In monkeys with latent nys-
tagmus, these neurons are driven mainly
by the contralateral eye.986 Thus, for ex-
ample, during monocular viewing through
the right eye, the left NOT will be acti-
vated preferentially, producing leftward
slow phases of nystagmus. Furthermore,
inactivation of NOT with muscimol abol-
ishes latent nystagmus in monkeys who
have been deprived of binocular vision.986
Latent nystagmus occurs in some, but
not all, patients who have congenital
uniocular visual loss, suggesting that addi-
 Diagnosis of Central Disorders of Ocular Motility 447

tional factors beyond visual deprivation
are responsible for the development of
nystagmus. 802 ' 1274 Such factors may in-
clude disturbance of directed visual atten-
tion or egocentric localization. Thus, some
patients can change the direction of their
nystagmus by "attempting" to view from
one eye or the other, without a change of
visual inputs.354-788 It is also possible that
abnormality of extraocular propriocep-
tion predisposes to latent nystagmus,677
because extraocular proprioception has
been shown to be important for the nor-
mal development of binocularity.207 Now
that animal models have been developed
for latent nystagmus, the relative contri-
bution of each of these factors is amenable
to investigation.
SPASMUS NUTANS
Clinical Features ofSpasmus Nutans
This disorder is characterized by the triad
of nystagmus, head nodding, and anom-
alous head positions, such as torticollis
(Display 10-13) (see VIDEO: "Spasmus Nu-
tans").1020 Its onset is usually in the first
year of life. Neurologic abnormalities are
absent, although strabismus or amblyopia
may coexist.1517 The syndrome is some-
times familial and has been reported in
monozygotic twins.660 Spasmus nutans
spontaneously remits, usually within 1 to 2
years after onset, although it may persist
for over 8 years.539
The most consistent feature of spasmus
nutans is the nystagmus, although head
nodding may be the first abnormality to
be noticed.539'549'554'1466 The nystagmus is
usually intermittent, small amplitude, and
with a high-frequency (3-11 Hz, "shim-
mering"), pendular waveform; it is easily
missed. It may be more evident in the ab-
ducting eye during lateral gaze. Charac-
teristically, the nystagmus differs in the
two eyes, and sometimes it is uniocular.
Another distinguishing feature of these os-
cillations is the variability of the amplitude
in each eye and the phase relationship be-
tween the two eyes. Consequently, even
over the course of a few seconds or min-
utes, the oscillations might variably be
conjugate, disconjugate, disjunctive, or
purely monocular (Fig. 10-14). The plane
of the nystagmus is predominantly hori-

Display 10-13: Clinical Feature ofSpasmus Nutans

• Characterized by nystagmus, head nodding, and abnormal head posi-
tions, developing during first year of life

• Nystagmus is intermittent, small amplitude, high-frequency ("shim-

mering"), variably disconjugate or disjunctive, greater in the abduct-
ing eye, may have a vertical component, more evident during conver-
gence

• Head nodding is irregular, with horizontal or vertical components

• Strabismus and amblyopia may coexist

• Normal ophthalmoscopic examination and normal MRI or CT of vi-

sual pathways are required to rule out structural lesions

• Spontaneously remits in 2-8 years

See also Pathogenesis of Spasmus Nutans. For a recorded example, see Figure 10-14 in
Chap. 10). (Related VIDEO: "Spasmus Nutans.")
448 The Diagnosis of Disorders of Eye Movements

Figure 10-14. Spasmus nutans. Examples of spasmus nutans from one child during one recording session. In A
(left), there are binocular oscillations with no phase difference between the eyes; in B (middle), there are binoc-
ular oscillations with approximately 180;dg phase difference between the eyes; in C (right), there are uniocular
oscillations of the left eye. LE, left eye; RE, right eye; POS, position; VEL, velocity. Timing marks at top are sec-
onds. (Reproduced from Weissman et al.1466)

zontal but it may have vertical or torsional
components. It may sometimes be brought
out by evoking the near response.249
The head nodding is irregular, at a fre-
quency of about 3 Hz, with horizontal or
vertical components. It is usually more
prominent when the child attempts to in-
spect something of interest. About two-
thirds of the patients have an additional
head tilt or turn. In some patients, the
head nodding appears to turn off the nys-
tagmus.549'554 However, it remains unclear
whether head nodding, turning, or tilting
is always an adaptive strategy adopted to
reduce the nystagmus, or instead reflects
the underlying abnormality in spasmus
nutans.
Two important clinical judgments have
to be made in children with eye and head
oscillations. The first judgment is whether
the nystagmus reflects a tumor of the optic
nerve, chiasm, retina, or more posterior
visual pathways.430'538-808'818 A careful oph-
thalmologic evaluation should be per-
formed in all such children; if there is any
doubt about the diagnosis, imaging stud-
ies should be performed. The second
judgment is whether the child has spas-
mus nutans, which resolves, or congenital
nystagmus, which does not. Spasmus nu-
tans can be differentiated from congenital
and latent nystagmus by its intermittency,
high frequency, vertical component, and
dissociated characteristics; if the child will
cooperate, eye movement records often
help make the distinction.1466
Pathogenesis of Spasmus Nutans
The underlying abnormality in spasmus
nutans is unknown. Although the ocular
oscillations are of high frequency, their
disconjugate vertical component makes
saccadic oscillations unlikely, since the
eyes are tightly yoked during normal ver-
tical saccades. The reported ability of the

active head nodding,549'554 but not passive
rotation in a chair,1466 to stop the ocular
oscillations implies the importance of a
voluntary effort. Further, affected chil-
dren are reported to suppress their nys-
tagmus with a head turn, even though
changing eye position in the orbit had no
effect.251 Thus, voluntary head move-
ments or positions seem essential for re-
turning stability to gaze. Finally, the reso-
lution of spasmus nutans with age might
reflect either structural maturation of the
nervous system or "full calibration" of eye
movements.
Lid Nystagmus
Reflecting the anatomic and physiological
links between vertical eye and lid move-
ments, upward movements of the eyelids
frequently accompany upward movements
of vertical nystagmus. An important struc-
ture in the coordination of vertical sac-
cades is the M-group of neurons, which
lies adjacent, medial, and caudal to riMLF
(see Fig. 6-3 and Fig. 6-4) and projects to
both the elevator subnuclei of the eye (su-
perior rectus and inferior oblique) and the
motoneurons of levator palpebrae superi-
oris in the central caudal subnucleus of
the oculomotor nucleus.218-219 The M-
group also has reciprocal connections with
the nucleus of the posterior commissure.
Thus, in patients who have dissociation of
lid-eye movement during vertical sac-
cades (i.e., impaired lid saccades in the
presence of preserved eye saccades), the
M-group or the nucleus of the posterior
commissure is likely to be involved. Simi-
larly, lid nystagmus unaccompanied by
vertical eye nystagmus may also reflect
midbrain lesions.186-202 Patients with long-
standing compression of the central cau-
dal nucleus causing "midbrain ptosis" may
develop lid nystagmus. 186
Twitches of the eyelid may also accom-
pany horizontal nystagmus. This phenom-
enon has been described in a patient with
Wallenberg's syndrome (lateral medullary
infarction), in whom lid nystagmus was in-
hibited by convergence.321 The opposite—
eyelid nystagmus that is evoked by con-
vergence (Pick's sign)—is reported with
Diagnosis of Central Disorders of Ocular Motility 449
medullary and cerebellar lesions.657'1202-1213
The association of lid nystagmus with con-
vergence may reflect the normal synki-
netic lid retraction that occurs during an
effort to view a near target. Thus, conver-
gence effort increases innervation to the
lids and so may amplify any lid nystagmus.
Saccadic Intrusions
THE SPECTRUM OF
SACCADIC INTRUSIONS
Several types of inappropriate saccadic
movements may intrude upon steady fixa-
tion (Display 10-14); these are schema-
tized in Figure 10-15 and actual recorded
examples are shown in Figure 10-16. Sac-
cadic intrusions should be differentiated
from nystagmus, in which a drift of the
eyes from the desired position of gaze is
the primary abnormality. They should
also be differentiated from saccadic dys-
metria (see VIDEO: "Saccadic hyperme-
tria") (Fig. 10-15A), in which the eye over-
shoots or undershoots, sometimes several
times, before landing on target.162'1254 Be-
cause saccadic intrusions are rapid and
brief, it is usually necessary to measure eye
and target position and eye velocity in or-
der to identify accurately the saccadic ab-
normality. We first describe the character-
istics of each type of saccadic intrusion and
then consider their mechanisms of patho-
genesis.
SQUARE-WAVE JERKS
A common finding in healthy subjects,
particularly the elderly, is square-wave
jerks, also called Gegenrucke.6l7'lZ5g-l2ei
On eye movement records—see Figure
10-15C and Figure 10-16A—they have a
profile that earned them their name. They
are small, conjugate saccades, ranging
from 0.5° to 5.0° in size, which take the eye
away from the fixation position and then
return it there after a period of about 200
msec. They are often more prominent
during smooth pursuit and most easily de-
tected during ophthalmoscopy. They are
also present in darkness. In certain cere-
bellar syndromes,1117 progressive supranu-
 Display 10-14. Clinical Features of Saccadic Oscillations
and Intrusions
SQUARE-WAVE JERKS
• Pairs of small horizontal saccades (typically <2°) that take the eye away
from the target and then return it within 200 msec; often occur in a se-
ries

MACROSQUARE-WAVE JERKS
• Large (5-15°) saccadic intrusions that take the eye away from the tar-
get and return it within 70-150 msec

MACROSACCADIC OSCILLATIONS
• Oscillations (hypermetric saccades) around the fixation point that wax
and wane, with an intersaccadic interval of about 200 msec

SACCADIC PULSES
• Brief, usually small movements away from the fixation point (saccadic
pulse), followed by rapid drift back (due to lack of saccadic step)

OCULAR FLUTTER
• Intermittent bursts of conjugate horizontal saccades without an inter-
saccadic interval; may be small amplitude and only visible with an
ophthalmoscope (microflutter)

OPSOCLONUS
• Combined multidirectional, horizontal, vertical, and torsional sac-
cadic oscillations, without an intersaccadic interval

VOLUNTARY "NYSTAGMUS" OR FLUTTER

• High-frequency (15-25 Hz), conjugate horizontal oscillations

• Unsustained for more than about 30 seconds; often precipitated by

convergence

For pathophysiology, see Inappropriate Saccades (Saccadic Intrusions), in Chap. 3. For

schematic and recorded examples, see Figure 10-15 and Figure 10-16 in Chap. 10. For eti-
ologies of flutter and opsoclonus, see Table 10-7. (Related VIDEOS: "Macrosaccadic oscilla-
tions," "Opsoclonus," "Square-wave jerks," and "Voluntary nystagmus.")

450
 Diagnosis of Central Disorders of Ocular Motility
Figure 10-15. Schematic of saccadic intrusions and
oscillations. (A) Dysmetria: inaccurate saccades. (B)
Macrosaccadic oscillations: hypermetric saccades
about the position of the target; (C) Square-wave
jerks: small, uncalled-for saccades away from and
back to the position of the target; (D) Macrosquare-
wave jerks: large, uncalled-for saccades away from
and back to the position of the target; (E) Ocular flut-
ter: to-and-fro, back-to-back saccades without an in-
tersaccadic interval.
clear palsy1128-1394 (see VIDEO: "Square-
wave jerks"), and cerebral hemispheric
disease,1267 they occur frequently (but not
at more than 2 Hz) and have been called
square-wave oscillations.12 These may be
mistaken for nystagmus. Cigarette smok-
ing increases the frequency of square-
wave jerks. 1287 They are reported to
develop following pallidotomy in parkin-
sonian patients.603 In patients with de-
451
mentia, fixation is disrupted by large sac-
cadic intrusions that are usually due to in-
creased distractibility (see section on Alz-
heimer's Disease).
MACROSQUARE-WAVE JERKS
These oscillations are often large (typically
greater than 5°) and occur at a frequency
of about 2 to 3 Hz. After taking the eye off
the target, they return it with a latency of
about 80 msec (Fig. 10-15D).368 They oc-
cur in light or darkness but occasionally
are suppressed during monocular fixa-
tion.353 Macrosquare-wave jerks occur in
bursts and vary in amplitude. They are
encountered in multiple sclerosis.
MACROSACCADIC OSCILLATIONS
These oscillations usually consist of hori-
zontal saccades that occur in bursts, build-
ing up and then decreasing in amplitude,
with intersaccadic intervals of about 200
msec (Fig. 10-15B). Described originally
in patients with cerebellar disorders,1255
macrosaccadic oscillations reflect saccadic
dysmetria when a patient's saccades are so
hypermetric that they overshoot the target
continuously in both directions and so os-
cillate around the fixation point. They are
usually induced by a gaze shift but may oc-
cur during attempted fixation or even in
darkness.55 They may have vertical or tor-
sional components and occasionally the
former may be prominent clinically.483
Macrosaccadic oscillations have been de-
scribed in a patient with a discrete pontine
lesion that may have compromised the
action of the omnipause neurons (Fig.
10-16C) (see VIDEO: "Macrosaccadic oscil-
lations").55
SACCADIC PULSES, OCULAR
FLUTTER AND OPSOCLONUS
Saccadic pulses are brief intrusions upon
steady fixation. The eye movement is a
saccade away from the fixation position,
with a rapid drift back. They occur if the
saccadic pulse has not been integrated to a
step. Saccadic pulses may occur in series
or as double saccadic pulses. They are oc-
casionally encountered in normal subjects
452 The Diagnosis of Disorders of Eye Movements

Figure 10-16. Records of saccadic intrusions and oscillations; note different amplitude and times scales. (A)
Square-wave jerks—small saccades that repeatedly moved the image of regard off the fovea; the patient had
progressive supranuclear palsy (see VIDEO: "Square-wave jerks"). (B) Diagonal microsaccadic flutter, which was
detectable only with an ophthalmoscope but, because of its high frequency, caused oscillopsia and impaired vi-
sion in this patient, who was otherwise well. (C) Macrosaccadic oscillations from the right eye of a patient with a
pontine infarction. 55 Fixation is interrupted by bursts of saccadic intrusions, which are time-locked in the hori-
zontal, vertical, and torsional planes. The return saccade usually overshoots the central fixation point. Tor-
sional and vertical tracings have been offset for convenience of display. Upward deflections correspond to right-
ward, upward, or clockwise eye rotations, with respect to the patient (see VIDEO: "Macrosaccadic oscillations").
(D) Opsoclonus. The patient was a 51-year-old woman who had developed tremors, unsteadiness, and dis-
turbed vision over the course of a month. No cause could be found for her condition. Movements of the right
eye were recorded by the magnetic search coil technique. The patient showed conjugate saccadic oscillations,
without any intersaccadic interval, occurring in both horizontal and vertical planes. The top two and bottom
two traces are continuous. The variable difference in amplitude of the horizontal and vertical components ac-
counted for the bizarre trajectories taken by the eyes. Note that the eye position and time scales differ between
panels.
Continued on following page

but are also reported in patients with in-
ternuclearoophthalmoplegia.618
There is a continuum between saccadic
pulses and saccadic oscillations without an in-
tersaccadic interval.118'15^ The latter may
occur in one direction, usually the hori-
zontal plane (called ocular flutter, Fig.
10-15E), or may consist of saccadic oscilla-
tions with horizontal, vertical, and tor-
sional components, called opsoclonus or sac-
cadomania (Fig. 10-16D). The frequency of
oscillations is usually high, typically 10 to
15 cycles per second, being higher with
smaller-size movements. Ocular flutter
may be intermittent and is mainly associ-
ated with voluntary saccades (flutter dys-
metria). Occasionally, the amplitude is
very small (microflutter, see Fig.lO-16B)
and the oscillations can only be detected
with an ophthalmoscope or eye movement
recordings, even though visual symptoms
such as oscillopsia are produced.49 Some-
 Diagnosis of Central Disorders of Ocular M
Figure 10-16.—continued
times such microflutter may have compo-
nents in all three planes. Sustained opso-
clonus is a striking finding, in which multi-
directional conjugate saccades, usually of
large amplitude, interfere with steady fix-
ation, smooth pursuit, or convergence,
and usually persist during eyelid clo-
sure or sleep (see VIDEO: "Opsoclonus").
These oscillations are often accompanied
by myoclonus (brief, jerky involuntary
limb movements), hence the term opso-
clonus-myoclonus; in children, this syn-
drome has been called "dancing eyes
and dancing feet" (see VIDEO: "Opso-
clonus").411'1275 Ataxia and encephalopa-
thy may also accompany opsoclonus.
There are many reported causes of opso-
clonus and flutter (Table 10-7), but most
patients conform to four clinical settings:
parainfectious brain stem encephalitis,
paraneoplastic syndromes, metabolic-toxic
states, or without evident cause.243'395'1104'1105
453
Benign encephalitis with ocular oscilla-
tions and truncal ataxia may follow a pro-
drome of malaise and mild fever (see
VIDEO: "Opsoclonus").268'374'584'798'1298 Ver-
tigo may be the presenting neurologic
symptom. Such patients develop ocular
flutter or opsoclonus and shivering move-
ments of the head and body. Cerebellar
and long-tract signs also occur, but the
sensorium usually remains clear, apart
from emotional lability. Spinal fluid pro-
tein and cell count may be elevated. The
illness usually resolves in a few weeks or
months, although sometimes the course is
protracted and recovery incomplete. Op-
soclonus under closed eyelids is often the
last manifestation to resolve. Intravenous
immunoglobulin may hasten recovery.1097
Opsoclonus occurs in association with
cancer in both adults and children. In
children, about half of the cases are associ-
ated with tumors of neural crest origin,
454 The Diagnosis of Disorders of Eye Movements
Table 10-7. Etiology of Ocular
Flutter and Opsoclonus*
Parainfectiousencephalitis374'395'584'595'798'1486
Paraneoplastic effect of neuroblastoma and
other neural crest tumors (in chil-
dren)1'949'1104
Paraneoplastic effects of other tumors (in
adults) 17 ' 648 ' 792 ' 1100
Meningitis1153
Intracranial tumors 753
Hydrocephalus1280
Thalamic hemorrhage742
Multiple sclerosis473'556
Hyperosmolar coma913'1468
In association with systemic disease: viral hep-
atitis,1167 sarcoid,1207 AIDS688-715
Side effects of drugs: lithium, 279 amitripty-
line,50 cocaine,417'1225 phenytoin with di-
azepam,345 phenelzine with imipramine 453
Toxins: chlordecone,1359 thallium,893 strych-
nine, 141 toluene,822 and organophos-
phates1115
As a transient phenomenon of normal in-
fants663
*Not all case reports have documented the abnor-
mality with eye movement recordings.
tAs a component of the syndrome of myoclonic en-
cephalopathy of infants ("dancing eyes and dancing
feet").411'767
such as neuroblastoma. In adults, opso-
clonus occurs in association with lung,
breast, or ovarian cancer. The electroen-
cephalogram is usually normal, but the
cerebrospinal fluid (CSF) may show pleo-
cytosis with or without elevated protein,
and oligoclonal bands. In children with
opsoclonus-myoclonus, low CSF concen-
trations of 5-hydroxyindolacetic acid (5-
HIAA) and homovanillic acid (HVA) were
demonstrated.1106 Abnormalities in CSF
may occur in opsoclonus associated both
with tumor and encephalitis421 and there-
fore do not help to distinguish between
the infectious and paraneoplastic etiolo-
gies. In two patients with presumably
viral opsoclonus-myoclonus, MRI dem-
onstrated pontine tegmental lesions.595
Children with paraneoplastic opsoclonus
generally have a better oncologic progno-
sis than those without the neurologic syn-
drome, irrespective of disease stage. A bet-
ter course is associated with the single
copy of the N-myc oncogene; those chil-
dren with amplification of this oncogene
do not present with the neurologic disor-
der and carry a poor prognosis.421'1100-1102
Regardless of the tumor, neurologic out-
come is unpredictable; cure from cancer
may be associated with severe neurologic
sequela, or vice versa, in both children
and adults.
Various autoantibodies have been de-
scribed in sera of opsoclonus pa-
tients.289-1100'1101 Of these, anti-Ri antibody
has been most consistently associated with
opsoclonus. It is reported in association
with cancer of the breast or pelvic organs,
and less commonly in patients with small-
cell lung and bladder cancer; sometimes
no tumor can be found.239'405'648 Anti-Ri is
an RNA-binding, polyclonal IgG antibody
which reacts only with neurons of the cen-
tral nervous system. The concentration of
the antibody is higher in the CSF than in
serum, suggesting intrathecal synthesis. A
second antibody, anti-Hu, has been re-
ported with opsoclonus in children with
neuroblastoma and an adult with small-
cell lung cancer.456'1100'1437 This is an an-
tineuronal antibody that binds nuclear
RNA; it is usually associated with paraneo-
plastic sensory neuropathy, cerebellar de-
generation, and limbic encephalitis. Anti-
Hu is histochemically identical to anti-Ri
but recognizes different protein bands on
cortical neurons analyzed with Western
blot. Unlike anti-Ri, it reacts with neurons
of both the central and peripheral nervous
systems. A third type of antibody directed
against neurofilaments was found in a
child with paraneoplastic opsoclonus.1017
Paraneoplastic opsoclonus-myoclonus dif-
fers from other paraneoplastic syndromes
in that spontaneous remissions may occur
regardless of the status of the underlying
tumor.1100'1102
Flutter and opsoclonus are also re-
ported secondary to drug intoxications,
toxic chemicals, and hyperosmolar coma.
Some patients present with saccadic oscil-
lations, especially microsaccadic flutter,49
without apparent cause.395-1104 Their only
complaint may be oscillopsia and de-
graded vision due to the abnormal eye
movements. Such patients warrant a care-

ful evaluation for an occult neoplasm, and
long-term follow-up. It has been argued
that some of the "idiopathic" cases arise as
paraneoplastic but that the tumor subse-
quently undergoes spontaneous regres-
sion.1100'1102
Opsoclonus also occurs as a transient
phenomenon in otherwise normal in-
fants.663 Finally, recordings of saccades
made in association with a blink show that
some normal subjects show transient oscil-
lations, such as dynamic overshoot.570'1185
VOLUNTARY SACCADIC
OSCILLATIONS OR
VOLUNTARY NYSTAGMUS
Some normal subjects possess or can de-
velop the ability to voluntarily induce sac-
cadic oscillations; this has been called
voluntary or psychogenic flutter or voluntary
nystagmus.652 The oscillations are conju-
gate, with frequency and amplitude simi-
lar to those encountered in ocular flutter
and opsoclonus (see VIDEO: "Voluntary
nystagmus"). Although usually confined to
horizontal oscillations, voluntary nystag-
mus can have vertical or torsional com-
ponents, 1512 can be superimposed on
smooth-tracking eye movements, 255 and
may be accompanied by a head tremor.823
The oscillations cause oscillopsia due to
excessive retinal image motion. Voluntary
nystagmus presents a diagnostic challenge
when patients present with visual or ocu-
lar complaints due to these oscillations.
Distinguishing features of psychogenic
flutter are that it is usually not sustained
and is often accompanied by convergence
effort, facial grimacing, or eyelid flutter.
Pathologic flutter and opsoclonus are
more sustained, irrespective of the pa-
tient's vergence state.
PATHOGENESIS OF
SACCADIC INTRUSIONS
Pathogenesis ofSaccadic Intrusions
and Oscillations With
Intersaccadic Intervals
During visual fixation, the threshold for
electrical stimulation of saccades in either
the frontal eye field or the superior col-
Diagnosis of Central Disorders of Ocular Motility 455
liculus is elevated.199'980 These reports are
consistent with populations of neurons at
both sites that discharge during fixation.
Pharmacological inactivation at either site,
however, leads to disruption of fixation by
saccadic intrusions but not by flutter or
opsoclonus.384'980 Saccadic intrusions are
also induced if the mesencephalic reticu-
lar formation, which has reciprocal con-
nections with the superior colliculus (see
Display 6-9), is inactivated.1451 Each of
these areas may, via direct or indirect pro-
jections, affect the discharge of omnipause
neurons, which gate the onset of saccades.
Thus, square-wave intrusions (Fig. 16A)
are a feature of disease affecting the cere-
bral hemispheres 1267 and brain stem, espe-
cially progressive supranuclear palsy, in
which the mesencephalic reticular forma-
tion and superior colliculus are both in-
volved.288 Square-wave jerks are reported
to develop or increase following pallido-
tomy in parkinsonian patients.60a Finally, a
patient with a discrete lesion affecting the
omnipause region of the pons was re-
ported to have persistent macrosaccadic
oscillations (Fig 10-16C) (see VIDEO:
"Macrosaccadic oscillations").55
Pathogenesis of Ocular Flutter
and Opsoclonus
The pathogenesis of saccadic oscillations
without an intersaccadic interval—opso-
clonus and flutter—remains controversial.
Unlike square-wave saccadic intrusions,
no animal models exist. Traditionally, clin-
icians have attributed saccadic oscillations,
including ocular flutter and opsoclonus,
to cerebellar dysfunction. 268 ' 418 However,
most reports of flutter and opsoclonus
lack reliable measurements of eye move-
ments. Without such records, it is often
difficult to determine whether saccadic os-
cillations are, or are not, separated by an
intersaccadic interval. Those that are not
probably have a different pathogenesis.
Thus, experimental inactivation of the
fastigial nucleus,1160 or cerebellectomy,1046
causes marked saccadic dysmetria but has
never been reported to cause flutter or
opsoclonus. On the other hand, coexis-
tence of opsoclonus and saccadic dysme-
tria has been documented in children, 1275
456 The Diagnosis of Disorders of Eye Movements
and imaging studies have demonstrated
changes of blood flow in the cerebellum in
patients with opsoclonus.1034
Another proposal to account for opso-
clonus and flutter is that these oscillations
are due to malfunction of the mechanism
by which omnipause neurons control the
onset of saccades.1536 However, experi-
mental lesions of the omnipause neurons
are reported to cause slowing of both hori-
zontal and vertical saccades,718 rather than
saccadic oscillations,1536 although it re-
mains possible that the neurotoxin in-
jected into the pons also affected adjacent
burst neurons. In two patients with sac-
cadic oscillations who came to autopsy, no
histopathologic changes were evident in
omnipause neurons.1142 A more recent im-
munopathological study of a patient with
saccadic oscillations in association with
cancer, however, demonstrated complete
absence of cells in the omnipause re-
gion.648 Finally, glycine has been identified
as the neurotransmitter of omnipause
neurons, 650 and poisoning with a glyciner-
gic antagonist, strychnine, is reported to
produce opsoclonus and myoclonus.141
Thus, glycinergic dysfunction (presum-
ably due to autoantibodies) might be re-
sponsible for the opsoclonus-myoclonus
syndrome.59 The possible pathogenesis of
saccadic intrusions and oscillations is dis-
cussed further in Chap. 3.
TREATMENTS FOR NYSTAGMUS
AND SACCADIC INTRUSIONS
Rational Basis for Therapy of
Abnormal Eye Movements
Before reviewing measures to treat abnor-
mal eye movements that disrupt clear vi-
sion, recall the visual requirements of eye
movements, which are discussed in Chap.
1 but restated here. Clear vision of an ob-
ject requires that its image be held fairly
steadily on the foveal region of the retina.
The image of the object of regard should
be within about 0.5° of the center of the
fovea, and, for objects with higher spatial
frequencies (such as Snellen optotypes),
retinal image motion should be held be-
low 5° per second. A "special case" seems
to be patients with congenital nystagmus,
who may intermittently have images mov-
ing across the retina with speeds exceed-
ing 100° per second but seldom complain
of oscillopsia.4>362 This appears to be par-
tially due to foveation periods—a brief
epoch during each cycle of the nystagmus
when the fovea is pointing at the object of
interest and the eye is temporarily still (see
Fig. 10-13).
A general point about treatment of ab-
normal eye movements is that measures
that suppress all eye movements (or their
effects on vision) may cause problems of
their own, since we need vestibular eye
movements to compensate for head move-
ments, especially when we are in motion.
In this regard, drug treatments that at-
tempt to quell just the oscillation, without
affecting normal eye movements, are to be
preferred. Other strategies include mea-
sures to place the eye in a versional or ver-
gence position in which nystagmus is min-
imized, optical devices that negate the
visual consequences of the oscillations,
procedures to weaken the extraocular
muscles, and application of somatosensory
or auditory stimuli to suppress nystagmus.
These approaches are summarized in
Table 10-8.
Pharmacological Treatments of
Abnormal Eye Movements
Knowledge of the pathogenesis of a form
of nystagmus should suggest the treat-
ment. This is the case for the acquired
form of periodic alternating nystagmus
(Display 10-5), for which an animal model
exists, pharmacological mechanisms have
been established, and a drug treatment
(baclofen) is usually effective.827 Such
knowledge is still lacking for most forms of
nystagmus and saccadic intrusions, how-
ever, although some effective therapies
have been established. Caution is required
in interpreting reports based on single
cases, especially when no reliable mea-
surements have been made of changes in
vision or of the ocular oscillations them-
selves. Most of our summary is derived
 Diagnosis of Central Disorders of Ocular Motility 457

Table 10-8. Treatments therapy measures are summarized in

for Nystagmus and Its the section on Acute Vertigo. Present
Visual Consequences approaches emphasize using "vestibular
sedatives" only for 24 to 48 hours if ver-
Drugs tigo and nausea are severe.69 After this
Gabapentin 62 time, exercises are encouraged to acceler-
ate the brain's ability to redress the imbal-
Baclofen62'394-579
ance.613 In the special case of benign
Clonazepam 311
paroxysmal positional vertigo (BPPV),
Valproate825 maneuvers to move otolithic debris out of
Trihexyphenidyl 104 - 615 - 828 the affected semicircular canal and exer-
Benztropine 104 cises to sustain recovery are usually effec-
Scopolamine104'555 tive. 174
Isoniazid 1391 Basic pharmacological studies have pro-
Carbamazepine434'1205 vided insights concerning the pharma-
Barbiturates 1000 cological substrate for the brain stem elab-
Alcohol479-5933 oration of the VOR and the neural
Acetazolamide 175 ' 560 - 1524
substrate for gaze holding (the neural
integrator). Gamma-aminobutyric acid
Memantine 1316
(GABA) has been shown to play roles in
Cannabis
both vestibular eye movements and eccen-
Optical Devices tric gaze holding. Unilateral microinjec-
Prisms (base-in or base-out)349-819'827 tion of muscimol, a GABA.f\ agonist,
o
into
Retinal image stabilization 1196 - 1505
the medial vestibular and prepositus hy-
poglossi nuclei (the NPH-MVN region) of
Special Procedures monkey and cat produces bilateral gaze-
Botulinum toxin839-1137-1190-1386 evoked nystagmus.943'1334 Furthermore,
Anderson-Kestenbaum procedure to shift prolongation of the peripheral vestibular
null point34-360-763'1549 signal by central pathways (the velocity-
Cuppers divergence procedure 315 - 1257 storage mechanism) in the nodulus and
Recession of horizontal rectus muscles609-1441 uvula is regulated by inhibitory pathways
Disinsertion of extraocular muscles1355 that use GABAB receptors.276 The velocity-
storage phenomenon in normal monkeys
Tenotomy and resuture 352
is suppressed by baclofen.276 Experimen-
Other Measures tal ablation of the nodulus and uvula pro-
Contact lenses367 duces excessive velocity storage that re-
Acupuncture 143 ' 679 sults in periodic alternating nystagmus,835
Biofeedback2-256 which is abolished by the GABAB agonist
baclofen.1447 A number of other neuro-
Cutaneous head and neck stimulation 1279
transmitters, including glycine, are in-
volved in central vestibular mechanisms.
Acetylcholine is known to be a primary
from controlled trials with, when possible,
neurotransmitter in the human vestibulo-
double-blind design.
cerebellum at several levels338 and in pro-
jections of nucleus prepositus hypoglossi
TREATMENT OF NYSTAGMUS DUE to the abducens nucleus (discussed in
TO PERIPHERAL OR CENTRAL Chap. 5).
VESTIBULAR IMBALANCE
Rationale for Treating Vestibular Treatment of Downbeat and
Forms of Nystagmus Upbeat Nystagmus
Most nystagmus due to peripheral vestib- The GABAA agonist clonazepam is re-
ular imbalance spontaneously resolves ported to reduce downbeat nystagmus
over the course of a few days. Current with a variety of etiologies;311 a single dose
458 The Diagnosis of Disorders of Eye Movements
of 1 to 2 mg of clonazepam may be used to
determine whether long-term therapy is
feasible. The GABAB agonist baclofen has
been reported to reduce upbeat or down-
beat nystagmus velocity and associated os-
cillopsia.394 However, in a double-blind
comparison of baclofen and gabapentin
neither drug produced consistent im-
provement. In some patients, the nystag-
mus was made worse.62 The cholinergic
drug physostigmine (an acetylcholine-
esterase inhibitor), given intravenously,
is reported to cause worsening of down-
beat nystagmus.394 Conversely, intravenous
scopolamine reduces downbeat nystag-
mus,104 but oral anticholinergic agents,
such as trihexyphenidyl, 828 produce only
modest improvement with substantial side
effects.
Treatment of Periodic
Alternating Nystagmus
This is the best example of a form of nys-
tagmus for which the drug treatment is
based on known pathophysiology and
pharmacology. Most patients reported
respond to the GABAB agonist ba-
clofen.492'579 Congenital periodic alternat-
ing nystagmus, which probably has a dif-
ferent pathogenesis, does not reliably
respond to baclofen.542
TREATMENT OF ACQUIRED
PENDULAR NYSTAGMUS
The neuropharmacology of this disorder
is unknown, and more than one mecha-
nism is likely to be involved. Early treat-
ment was with barbiturates,1000 but side ef-
fects from these and other sedative drugs
limit their usefulness. The hypertrophied
inferior olivary nucleus of patients with
oculopalatal myoclonus shows increased
acetylcholine esterase activity.777 This find-
ing suggesting cholinergic denervation
supersensitivity prompted trials of anti-
cholinergic agents. Initial studies sug-
gested that individual patients were
helped by trihexyphenidyl, 615 ' 687 but a
double-blind crossover trial of tri-
hexyphenidyl and tridihexethyl chloride
(a quaternary anticholinergic that does
not cross the blood-brain barrier) showed
only modest changes that were greater
with tridihexethyl chloride.828 Moreover,
no patient wished to continue with either
drug because of anticholinergic side ef-
fects. A double-blind comparison of in-
travenously administered scopolamine,
benztropine, and glycopyrrolate (a qua-
ternary agent devoid of central nervous
system activity) confirmed an earlier un-
controlled study: A single dose of scopo-
lamine effectively reduces nystagmus and
improves vision, whereas benztropine was
less effective, and glycopyrrolate had no
significant effect.104 The discrepancy be-
tween this study and that of oral tri-
hexyphenidyl might be due to the fact that
trihexyphenidyl selectively antagonizes
muscarinic receptors, while scopolamine
probably affects all five subtypes of mus-
carinic receptor.205 In any case, scopo-
lamine by intravenous injection is not a
practical treatment for acquired nystag-
mus, and there is need for a double-blind
evaluation of this drug and other anti-
cholinergic drugs administered by an oral
or transdermal route.
The best treatment responses of ac-
quired pendular nystagmus are to drugs
with GABAergic properties. Thus, clon-
azepam, valproate, and isoniazid help
some patients.825'1391 These clinical re-
ports, the experimental studies showing
that GABAergic mechanisms are impor-
tant for normal gaze holding,943'1334 and
the introduction of gabapentin (an anti-
convulsant with GABAergic action) led to
a multicenter double-blind study compar-
ing gabapentin to baclofen as therapy for
acquired nystagmus. 62 In a group of 15
patients with acquired pendular nystag-
mus, visual acuity improved significantly
with gabapentin, but not with baclofen
(see VIDEO: "Oculopalatal tremor") (Fig.
10-12). Gabapentin significantly reduced
acquired pendular nystagmus median eye
speed in all three planes, but baclofen did
so only in the vertical plane. In 10 of the
patients with acquired pendular nystag-
mus, the reduction of nystagmus with
gabapentin was substantial, and 8 of these
elected to continue taking the drug. These
findings suggest that gabapentin may be
an effective treatment for many patients
with acquired pendular nystagmus. Me-
 Diagnosis of Central Disorders of Ocular Motility
mantine, an agent with NMDA blocking,
AMPA receptor modulation, and dopamin-
ergic action, is also reported to be effective
in acquired pendular nystagmus.1316 It
is not currently available in the United
States.
TREATMENT OF OTHER FORMS
OF NYSTAGMUS
Seesaw nystagmus has been reported to
be improved by alcohol479'851 and clo-
nazepam.260 Familial episodic vertigo and
ataxia type 2 (EA-2) with nystagmus usu-
ally responds to treatment with aceta-
zolamide and calcium channel block-
ers.85'560'1524
TREATMENT OF SACCADIC
INTRUSIONS AND OSCILLATIONS
Treatments for Square-Wave Jerks
As reviewed in Chap. 3, both the frontal
eye field and the superior colliculus can be
pharmacologically inactivated using the
GABAA agonist muscimol, resulting in a
paucity of saccades.384-980 Inactivation of
the rostral pole of the superior colliculus
("fixation zone"), however, causes an excess
of inappropriate saccades.980 Diazepam,
clonazepam, and barbiturates were effec-
tive in abolishing high-amplitude square-
wave jerks and macrosaccadic oscillations
in one patient.1405 Amphetamines have also
been reported to suppress square-wave
jerks.310 Attempts to suppress the macrosac-
cadic oscillations of a patient with a dis-
crete pontine lesion (Fig. 10-16C) with
gabapentin produced only a modest re-
duction.57
Treatments for Ocular Flutter
and Opsoclonus
Propranolol, verapamil, clonazepam, and
thiamine have been reported to sup-
press saccadic oscillations in individual pa-
tients.49'1100-1102'1104 In opsoclonus associ-
ated with cancer, treatment of the tumor
itself often does not ameliorate the neuro-
logic syndrome. In children with neural
crest tumors, opsoclonus often responds
to corticosteroids780 and sometimes to in-
459
travenous immunoglobulin. 456 How-
ever, up to 50% of children are left with
long-term neurologic disabilities such as
ataxia, poor speech, and cognitive prob-
lems.1102'1104 Similar responses to steroids
occur in children with parainfectious or
idiopathic opsoclonus.1104 Whether ACTH
is superior to corticosteroid has not been
systematically studied. In adults with para-
neoplastic opsoclonus, the course of the
ocular oscillations is also largely indepen-
dent of the underlying tumor. It may not
improve following tumor therapy; it tends
to wax and wane and may spontaneously
resolve in some patients with untreated
tumor.489'1100 Treatment with ACTH or
corticosteroids has not been reliable.
Plasmapheresis and intravenous immuno-
globulins have occasionally proved effec-
tive.1097 Immunoadsorption therapy (plasma
exchange through a protein A column
that binds immune complexes and the Fc
portion of IgG molecules) may be effective
in abolition of both opsoclonus and myo-
clonus.248'421'1014
Optical Treatments of Abnormal
Eye Movements
Those patients whose nystagmus de-
creases during convergence may benefit
from wearing spectacle prisms that re-
quire convergence for single vision of far
targets. An effective arrangement is a pair
of 7.00 diopter base-out prisms, with
— 1.00 diopter spheres added to compen-
sate for the accommodation that accompa-
nies the induced convergence.349 The
spherical correction may not be needed in
presbyopic individuals. Especially in some
individuals with congenital nystagmus,
the improvement of vision due to nystag-
mus suppression when wearing base-out
prisms may be sufficient for them to qual-
ify for a driving license. Some patients
with acquired nystagmus may benefit
from such prisms.819 Occasional patients
whose nystagmus is worse during near
viewing are helped by base-in prisms.57
Theoretically, it should be possible to
use prisms to help patients whose nystag-
mus is quieter when the eyes are moved
 Continued on following page

460
 Diagnosis of Central Disorders of Ocular Motility 461

Figure 10-17. Effects of botulinum toxin injected into selected extraocular muscles (A-F) or into the retrobul-
bar space (G, H) on acquired nystagmus. The records in panels A-F are from a 27-year-old woman with multi-
ple sclerosis. Panels A (left eye) and B (right eye) display representative 1-sec records of her nystagmus as "scan
paths" prior to injection of with botulinum toxin. Panels C and D display characteristics of her nystagmus, 1
week after injection of the right medial rectus and 2 weeks after injection of the right lateral rectus muscle. The
horizontal component of nystagmus in the right eye was almost abolished, and visual acuity increased from
20/40+ 2 to 20/25~3 in this eye. The amplitude of the horizontal component of nystagmus in the left, noninjected
eye had increased, however, and visual acuity declined from 20/70 to 20/100. Panels E and F show saccades re-
corded at the same session as C and D. When the patient viewed with her right eye (F), saccades were generally
hypometric with pulse-step mismatches and postsaccadic drifts; some gaze-evoked nystagmus was also present.
When she viewed with her left eye (E), there was pronounced saccadic hypermetria, reflecting adaptive changes
made in response to viewing habitually with her paretic left eye (which had better vision) over the prior 2
weeks. The records in panels G and H are from a 28-year-old woman with predominantly torsional nystagmus
and oscillopsia that developed following hemorrhage from an arteriovenous malformation at the pon-
tomedullary junction. Panel G is a representative record of the nystagmus of her right eye. Panel H shows nys-
tagmus recorded 1 month after injection of 10 units of botulinum toxin into the right retrobulbar space. Al-
though her nystagmus was substantially reduced, visual acuity was little changed from 20/40, and vertical
diplopia detracted from reduction in her oscillopsia.

into a particular position in the orbit (the
null point or zone). For patients with con-
genital nystagmus, there is usually some
horizontal eye position in which nystag-
mus is minimized, and the eyes of patients
with downbeat nystagmus may be quieter
in up gaze. In practice, however, patients
use head turns to bring their eyes to the
quietest position, and only rarely are
prisms that produce a conjugate shift
helpful.
A different approach has been to use an
optical stabilization device that negates the
visual effects of eye movements.1196 This
system consists of a high-plus spectacle
lens worn in combination with a high-mi-
nus contact lens. The system is based on
the principle that stabilization of images
on the retina could be achieved if the
power of the spectacle lens focused the
primary image close to the center of rota-
tion of the eye. However, such images are
defocused, and a contact lens is required
to extend back the focus onto the retina.
Since the contact lens moves with the eye,
it does not negate the effect of retinal im-
age stabilization produced by the spectacle
lens. With such a system it is possible to
negate about 90% of the visual effects of
eye movements.836 The system has several
limitations, however. One is that it dis-
ables all eye movements (including the
vestibulo-ocular reflex and vergence), so it
is only useful while the patient is station-
ary and viewing monocularly. Another is
that with the highest-power components
(contact lens of —58.00 diopters and spec-
tacle lens of +32 diopters), the field of
view is limited. Some patients with ataxia
or tremor (such as those with multiple
462 The Diagnosis of Disorders of Eye Movements
sclerosis) have difficulty inserting the con-
tact lens. However, initial problems posed
by rigid polymethyl methacrylate contact
lenses have been overcome by develop-
ment of gas-permeable or even soft con-
tact lenses.1505 Most patients do not need
the highest-power components for oscil-
lopsia to be abolished and vision to be use-
ful. In selected patients, the device may
prove useful for limited periods of time,
such as the duration of a television pro-
gram. The effects of this optical system
should be differentiated from that of sim-
ply wearing contact lenses, which appear
to suppress congenital nystagmus, not ow-
ing to the mass of the lenses, but probably
through stimulation of trigeminal affer-
ents.367 The main therapy for latent nys-
tagmus consists of measures to improve vi-
sion, especially patching for amblyopia in
children.1439
Procedures to Weaken the
Extraocular Muscles
BOTULINUM TOXIN AS
TREATMENT OF NYSTAGMUS
Injection of botulinum toxin into either
the extraocular muscles or retrobulbar
space has been used to temporarily reduce
or abolish acquired nystagmus (Fig.
10-17).304'610 Several studies have re-
ported that some patients gain improved,
more stable vision.839'1137'1190'1386 Less of-
ten, botulinum toxin has been used to
treat congenital or latent nystagmus.237'872
Common side effects are ptosis and
diplopia, which may be more troublesome
than the visual consequences of the nys-
tagmus. Rarer complications include per-
sistent filamentary keratitis.1386
A major limitation of botulinum toxin
treatment for nystagmus is that it also im-
pairs normal eye movements, static eye
position being affected longer than the ef-
fect on saccades,14'674 which become hypo-
metric (Fig. 10-17). Impairment of the
vestibulo-ocular reflex causes patients to
complain of blurred vision, oscillopsia, or
vertigo when they walk. Another effect oc-
curs in patients who habitually view with
the injected, paretic eye. After several
days, adaptive changes take place (i.e., in-
creased innervation to compensate for ex-
traocular muscle weakness). Thus, for ex-
ample, saccadic adaptation is apparent in
the noninjected eye as hypermetric sac-
cades (Fig. 10-17). In addition, the nys-
tagmus itself may increase in the nonin-
jected eye.
In summary, botulinum toxin may abol-
ish nystagmus and improve vision in some
patients and may be acceptable to patients
who are prepared to view monocularly,
but its limited period of action and side ef-
fects often reduce its therapeutic value.
SURGICAL PROCEDURES
FOR NYSTAGMUS
Three surgical procedures on extraocular
muscles have been proposed as treatment
for selected patients with congenital nys-
tagmus; none have been properly eval-
uated for acquired nystagmus. One pro-
cedure is the Anderson-Kestenbaum
operation,^4'763 which aims to move the at-
tachments of the extraocular muscles so
that the null point corresponds to the
eyes' new central position. It is best
planned by measuring the nystagmus at
different gaze angles so that the surgeon
can calculate what is required to shift the
position of the null point.360'1549 In prac-
tice, the Anderson-Kestenbaum proce-
dure not only shifts and broadens the null
zone but also decreases nystagmus outside
of the null zone. However, it is of uncer-
tain value in the treatment of acquired
forms of nystagmus.
The Cuppers procedure aims to diverge
the eyes.315-1257 It may be helpful in pa-
tients with congenital nystagmus that is
suppressed during fixation of near targets,
and who have stereopsis. Studies compar-
ing these two methods indicate that either
the divergence procedure or combined
operations give better visual improvement
than the Anderson-Kestenbaum proce-
dure alone.734'1257'1549
A third surgical procedure for congeni-
tal nystagmus consists of large recession of
the horizontal rectus muscles.542'609'1441
Modest improvement of visual acuity is re-
ported, but further studies are required to
establish the role of this procedure and
 Diagnosis of Central Disorders of Ocular Motility
determine whether weakening the ex-
traocular muscles will induce adaptive
changes that will cause the nystagmus to
increase again.
Recently, the mechanisms by which these
operations may damp congenital nystag-
mus have been re-evaluated. L. F. Del-
FOsso has suggested that simply detaching
the muscles, dissecting the perimuscular
fascia and then re-attaching them at the
same site on the globe may suppress con-
genital nystagmus;352 experimental studies
support this hypothesis.620a Such a proce-
dure might have its effects by altering pro-
prioceptive input from the pallisade or-
gans that lie close to the attachment points
(see Extraocular Proprioception in Chap.
9).352 Further studies are required to estab-
lish the clinical value of the procedure.
There is a consensus that neurosurgery
does have a role in the therapy of the nys-
tagmus associated with the Arnold-Chiari
syndrome. Suboccipital decompression has
been reported to improve downbeat nys-
tagmus and prevent progression of other
neurologic deficits.1073'1313 Surgical treat-
ment of superior oblique myokymia is dis-
cussed in Chap. 9.
Application of Somatosensory
or Auditory Stimuli to
Suppress Nystagmus
Following up on the finding that wearing
contact lenses may suppress congenital
nystagmus, 367 it was documented that
electrical stimulation or vibration over the
forehead may suppress the oscillations in
some patients. 1279 These effects may be
exerted via the trigeminal system, which
receives extraocular proprioception (dis-
cussed in Chap. 9). Acupuncture adminis-
tered to the neck muscles may suppress
congenital nystagmus in some patients, by
a similar mechanism.143'679 Biofeedback
has also been reported to help some pa-
tients with this condition.2'256 However,
the role of any of these treatments outside
the laboratory has yet to be demonstrated,
and controlled trials are needed to evalu-
ate these and other measures reported to
improve congenital nystagmus. 425a
463
SKEW DEVIATION AND THE
OCULAR TILT REACTION (OTR)
Clinical Features of Skew
Deviation and OTR
Skew deviation is a vertical misalignment of
the visual axes caused by a disturbance of
prenuclear inputs (see VIDEOS: "Skew devi-
ation" and "Wallenberg's syndrome"). A
torsional and horizontal deviation may be
associated. The hypertropia may be nearly
the same in all positions of gaze (con-
comitant) or vary with eye position (non-
concomitant); sometimes it may even al-
ternate with eye position (e.g., right
hypertropia on right gaze, left hyper-
tropia on left gaze).744'972-1189'1527 When the
skew deviation is nonconcomitant, and es-
pecially if the pattern of misalignment re-
sembles that of an individual muscle palsy,
it may be difficult to differentiate from a
vertical extraocular muscle palsy; coexist-
ing signs of central neurologic dysfunction
usually clarify the localization. Skew devia-
tion has been reported in association with
a variety of abnormalities in the vestibular
periphery, the brain stem, or the cerebel-
lum.170'1723'738'973 It has also been reported
as a reversible finding associated with
raised intracranial pressure due to supra-
tentorial tumors or pseudotumor.482 In in-
fants, the presence of a skew deviation
may be the harbinger of a subsequent hor-
izontal strabismus.659
In some patients, skew deviation is asso-
ciated with ocular torsion (cyclodeviation)
and a head tilt, the ocular tilt reaction
(OTR)—see Figure 10-18. The OTR is
commonly tonic (sustained), 168 ' 172a but
may be paroxysmal. 602 ' 1118 Rarely, the
skew deviation may slowly alternate or
vary in magnitude over the course of a few
minutes.296'547'948 Usually, any pathologic
head tilt (ear to shoulder) is contralateral
to the hypertropic eye, and the ocular tor-
sion is such that the upper poles of the
eyes rotate toward the lower ear. This is in
contrast to physiologic counterrolling in
response to an induced head tilt, when the
ocular torsion is such that the upper poles
of the eyes rotate toward the higher ear.
The ocular torsion may be dissociated be-
464 The Diagnosis of Disorders of Eye Movements
Figure 10-18. The ocular tilt reaction represented as
a "motor compensation" of a lesion-induced appar-
ent eye-head tilt (dashed line), and which would be
opposite in direction to the apparent tilt. The eyes
and head are continuously adjusted to what the le-
sioned brain computes as being vertical. (Courtesy
Dr. Thomas Brandt, Munich, Germany.)
tween the two eyes.169'498 Torsional nystag-
mus (Display 10-4)is commonly associated
with acute skew deviation.60'498 Patients
with OTR also show a deviation of the sub-
jective visual vertical.168^170'172
The OTR is usually attributed to an im-
balance in otolith-ocular and otolith-collic
reflexes; these are part of a phylogeneti-
cally old righting response to a lateral tilt
of the head. In lateral-eyed animals, tilting
the head laterally around the longitudinal
(anterior-posterior) axis causes a disjunc-
tive, vertical (skew) deviation (one eye
goes up, the other down) that acts to hold
the visual axis of each eye close to the hori-
zon. In human subjects, who are frontal-
eyed, a static head tilt (ear to shoulder)
causes sustained conjugate counterrolling
of the eyes (ocular torsion) equal to about
10% of the head roll;60'285 thus the static
ocular response does not compensate for
the head tilt and is thought to be vestigial.
In normal subjects there may be skewing
during rotation of the head around its roll
(anterior-posterior) axis but the amount is
small, idiosyncratic, and dependent upon
the viewing distance.703 In contrast, pe-
ripheral or central lesions that disrupt
otolithic inputs often cause large amounts
of skew deviation (as much as 7°) and ocu-
lar torsion (as much as 25°). An imbalance
of posterior semicircular canal inputs may
also play a role;168 in this case, nystagmus
may also be present.60 In patients with
more rostral lesions in the midbrain, in-
terruption of descending pathways con-
trolling head posture may also contribute
to the head tilt of the OTR.169-172a Visual
factors (as in the change in head posture
to relieve vertical diplopia in fourth nerve
palsy) may also contribute to the head tilt
of the OTR. In this case it may be, in part,
a compensatory response to the perceived
tilt of the subjective visual vertical.168
Topologic Diagnosis of Skew
Deviation and the OTR
Acute peripheral vestibulopathy—lesions af-
fecting the vestibular organ or its nerve—
can cause skew deviation and the complete
OTR, based upon an imbalance in inputs
from the utricles.575'1149'1203'1493 The OTR
may also occur as a component of the Tul-
lio phenomenon, which is characterized by
sound-induced vestibular symptoms.392'947
It occurs in patients with a perilymph fis-
tula, or with abnormalities of the ossicular
chain and its connection with the mem-
branous labyrinth. In one well-studied pa-
tient, stimulation of the left ear with a spe-
cific auditory tone caused a head tilt to the
right, left hypertropia, intorsion of the left
eye, and extorsion of the right eye;392 this
effect was ascribed to mechanical stimula-
tion of the left utricle by a hypermobile
stapes. These results are consistent with
the effects of experimental stimulation of
the otoliths313 and the utricular nerve,1346
which causes ipsilateral hypertropia and
conjugate counterrolling.
The utricle projects predominantly to
the ipsilateral lateral vestibular nucleus,
and the saccule to the vestibular y-group.
Thus, disease of the vestibular nuclei (e.g.,
as part of Wallenberg's syndrome—lateral
medullary infarction) may also cause skew
deviation with hypotropia on the side of
the lesion.389 In addition, some patients
show an ipsilateral head tilt and disconju-
gate ocular torsion. The latter is an excy-
lotropia, with excyclodeviation of the ipsi-
lateral, lower eye, but small or absent

incyclodeviation of the contralateral,
higher eye.169'960
Patients with cerebellar lesions may also
show a skew deviation.971'973'1427'1527 Some
of these patients show an alternating skew
deviation that changes with the direction
of horizontal gaze; usually there is a hy-
perdeviation of the abducting eye. This
abnormality, too, is analogous to a phylo-
genetically old, otolith-mediated, righting
reflex present in lateral-eyed animals. In
this case, however, the reflex is related to
the ocular motor response that compen-
sates for fore and aft pitch of the head
when the eyes are directed laterally in the
orbit.1527 Although involvement of the
brain stem is also likely in some of these
patients, skew deviation has been reported
in patients who appear to have pure cere-
bellar disease.971 This suggests that, just as
the cerebellum governs the semicircular
canal-ocular reflex, it also influences the
otolith-ocular reflexes.89 Indeed, down-
beat nystagmus (Display 10-2), which is
sometimes attributable to disease of the
flocculus, commonly coexists with skew
deviation.
Utricular projections from the vestibu-
lar nuclei probably cross the midline and
ascend in the medial longitudinal fascicu-
lus. Therefore, unilateral internuclear
ophthalmoplegia is often associated with a
skew deviation, usually an ipsilateral hy-
pertropia.
In the midbrain, otolith projections con-
tact the third and fourth nerve nuclei, and
the interstitial nucleus of Cajal (INC) (see
Display 6-6). Mesencephalic lesions in
or around the INC may cause skew devia-
168 172a 573
t i on 738,744 and the oTR. ' ' When
the head tilt is sustained (tonic), it is con-
tralateral to the side of the lesion; usually
there is also a hypertropia that is ipsilat-
eral to the lesion and a conjugate cyclotor-
sion, with the ipsilateral eye intorting and
the contralateral eye extorting. Associated
defects of vertical eye movements and
oculomotor or trochlear nerve function,
including seesaw nystagmus, are com-
mon 33,578,1035 Combined fascicular or nu-
clear trochlear lesions and prenuclear le-
sions in the midbrain may cause extorsion
of the contralateral eye and contralateral
OTR.385'390 Some patients present with a
Diagnosis of Central Disorders of Ocular Motility 46
paroxysmal skew deviation (with or without a
head tilt). 602 ' 1118 In one patient with a
clearly defined lesion close to the right
INC, episodes of contralateral hyper-
tropia and ipsilateral head tilt occurred,
suggesting an irritative mechanism. 602
This interpretation of the findings in
paroxysmal skew deviation is supported
by the results of electrical stimulation near
the INC in monkeys, which produces an
ocular tilt reaction that consists of depres-
sion and extorsion of the ipsilateral eye
and elevation and intorsion of the con-
tralateral eye.1478 With the head free to
move, an ipsilateral head tilt also oc-
curs.1477 In humans, stimulation in the
region of the INC causes an ipsilateral
ocular tilt reaction.885 A microvascular
compression syndrome has also been sug-
gested as a cause of paroxysmal skew devi-
ation with torsional nystagmus. 1331
Midbrain lesions may also be associated
with a periodic alternating skew deviation that
alternates or varies in magnitude over the
course of a few minutes.296'547'948 The peri-
odicity of the phenomenon is reminiscent
of periodic alternating nystagmus (Display
10-5), and the two phenomena have been
reported to coexist.865 Skew deviation
may occasionally be seen as a feature of
epilepsy, presumably on the basis of exci-
tation from the cerebral hemispheres to
the portions of the vestibular nuclei that
mediate otolith-ocular reflexes.499
DISEASE OF THE
VESTIBULAR PERIPHERY
Disease of the vestibular organ or its nerve
may cause vertigo, oscillopsia, nystagmus,
and the ocular tilt reaction. Vestibular nys-
tagmus and the ocular tilt reaction are de-
scribed above; vertigo and oscillopsia are
discussed below.
Vertigo and Dizziness
Dizziness is a common symptom, but one
that is frequently not diagnosed satisfac-
torily, particularly in the elderly.67-328'797
46 The Diagnosis of Disorders of Eye Movements
Whether a patient is complaining of ver-
tigo or some other type of dizziness (such
as presyncopal faintness, loss of stable bal-
ance, or lightheadedness) can often be de-
termined by taking a careful history and
determining whether a series of provoca-
tive maneuvers at the bedside induces
the dizzy feeling (see Table 2-3, Chap.
2).401,1530 These procedures include test-
ing for orthostatic hypotension, the Val-
salva maneuver, tragal compression, pre-
sentation of loud tones with an
audiometer, mastoid vibration, hyperven-
tilation, positional testing, sudden head or
body turns, rotation in a swivel chair, and
any other stimulus that the patient has
identified as producing the dizziness.
Many patients who present with the com-
plaint of dizziness have a psychological
disorder such as agoraphobia, acrophobia,
phobic postural vertigo syndrome, or ves-
tibular symptoms that are a component of
panic attacks or depression.165'491'666 Some
of these patients have had vestibular dis-
orders in the past, or have a coexisting
vestibular disorder, and may show abnor-
malities on vestibular function tests.636'666'690
Vertigo is defined here as an illusory sen-
sation of motion of self or of the environ-
ment. Rotational vertigo usually indicates
disease of the semicircular canals or their
central connections. Linear vertiginous
sensations such as translation (e.g., lat-
eropulsion and levitation) or body tilt oc-
cur with disease of the otoliths or their
central connections. The sensation of ver-
tigo is often associated with vegetative
symptoms: nausea, weakness, and di-
aphoresis. Oscillopsia, on the other hand,
usually refers to illusory movements of the
seen environment that are often to and
fro; it is absent with the eyes closed.
Not all cases of vertigo are due to dis-
ease. Certain individuals are prone to de-
velop vertigo, unsteadiness, or malaise
with motion, at height, and when assum-
ing certain postures. Vertigo in these situ-
ations and in motion sickness probably
occurs because of a mismatch between ves-
tibular and other sensory inputs. 167 For di-
agnostic purposes, it is helpful to differ-
entiate between acute, recurrent, and
posturally induced vertigo.
Clinical Features of Acute
Peripheral Vestibulopathy
Sudden loss of tonic neural input from
one labyrinth or vestibular nerve causes
acute vertigo, nystagmus, and postural in-
stability (Display 10-15). The nystagmus
(Display 10-1) is typically mixed horizon-
tal-torsional, with slow phases directed to-
ward the side of the lesion. The nystagmus
is more marked on looking in the direc-
tion of the quick phases, following Alexan-
der's law. Quantitative three-dimensional
recordings of the response to head rota-
tions in different planes in patients with
acute vestibular neuritis suggest that the
brunt of the pathology is in the superior
division of the vestibular nerve.436'1500 The
direction of the spontaneous nystagmus
alone, however, cannot be used confi-
dently to predict which canals are in-
volved, perhaps because some adaptation
and rebalancing of tonic levels in the ves-
tibular nuclei may have taken place. Fol-
lowing vestibular neurectomy, the direc-
tion of nystagmus may be influenced by
whether some canal afferents run in the
spared cochlear division of the eighth cra-
nial nerve.161
Often the patient cannot decide the di-
rection of perceived rotation. This may be
because labyrinthine signals suggest rota-
tion in one direction but inappropriate ves-
tibular eye movements cause visual sensa-
tions that, when self-referred, imply
turning in the opposite direction. It is help-
ful, therefore, to inquire about the direc-
tion of rotation of the body when the eyes
are closed, which is away from the side of
the lesion. Usually, the acutely vertiginous
patient will lie on one side, with the affected
ear uppermost; it has been suggested that
this allows otolith influences, which cen-
trally converge with semicircular canal in-
puts, to reduce the nystagmus caused by
imbalance of the semicircular canals.469
Caloric testing is the most reliable
method of confirming that the vestibular
imbalance is peripheral in location. In pa-
tients with spontaneous nystagmus, irriga-
tion with a warm stimulus of the ear to
which slow phases of nystagmus are di-
rected is especially important; lack of any
 Diagnosis of Central Disorders of Ocular Motility 46

Display 10-15: Summary of Findings with Acute Unilateral

Loss of Labyrinthine Function
• Spontaneous nystagmus (see Display 10-1)

• Nystagmus induced by head shaking: after horizontal shaking, nystag-

mus beats away from affected ear; after vertical shaking, nystagmus
beats toward affected ear

• Ocular tilt reaction: skew deviation with ipsilateral hypotropia, head

tilt toward side of lesion, ipsilateral cyclodeviation (top poles of eyes
rolled ipsilaterally)

• Reduced vestibulo-ocular response to ipsilateral head thrusts, requir-

ing corrective saccades

• Absent caloric response on side of lesion; acutely, response from intact

side may be diminished

• Past-pointing and turning (Fukuda stepping test) toward the side of

the lesion

See also Pathophysiology of Disorders of the Vestibular System, in Chap. 2. For a schematic,
see Figure 10-18 in Chap. 10. For etiologies, see Table 10-9. (Related VIDEOS: "Head-shaking
nystagmus" and "Anterior inferior cerebellar artery [AICA] distribution infarction.")

effect upon the spontaneous nystagmus
implies disease affecting the stimulated
ear. The head thrust maneuver, with head ro-
tation toward the side of the paretic
labyrinth, is also a reliable sign of unilat-
eral loss of labyrinthine function. Rota-
tional testing in patients with acute pe-
ripheral lesions shows decreased and
asymmetric gain and decreased time con-
stant of the VOR. Quantitative aspects of
the changes in vestibular responses with
peripheral lesions are discussed further in
Laboratory Evaluation of Vestibular and
Optokinetic Function in Chap. 2.
Acute Vertigo
INFECTIONS CAUSING
ACUTE VERTIGO
When acute vertigo occurs without audi-
tory or neurologic disturbances (Table
10-9), particularly in children and young
adults, it is usually ascribed to a viral dis-
turbance of the vestibular nerve; it is often
referred to as vestibular neuronitis, vestibular
neuritis, or vestibular neurolabyrinthitis.^27'992
Although a definite etiology is not proven
in most cases, the histopathology is com-
patible with a viral affliction. 82 As dis-
cussed above, the brunt of the pathology
seems to be in the superior division of the
vestibular nerve. Sometimes such vertigo
occurs in epidemics, but the responsible
agent is usually not identified. Mumps,
measles, and infectious mononucleosis are
among the infections that may be sus-
pected if acute vertigo is accompanied by
deafness. Experimental studies of viral in-
fection of the inner ear have shown a se-
lective vulnerability to specific viruses of
the cochlea, labyrinth, or eighth nerve
ganglion.329 One well-recognized cause is
herpes zoster, which produces not just
vertigo but also a burning pain in the ear
followed by a vesicular eruption in the ex-
ternal auditory canal and concha. Deaf-
468 The Diagnosis of Disorders of Eye Movements
Table 10-9. Etiology of Vertigo
Acute Vertigo159'572
Physiologic vertigo:167 motion sickness, height
vertigo, postural vertigo (on head extension
or bending forward at the waist)
Infection of the labyrinth, the vestibular nerve,
or both: 229 - 992 by virus, 327 - 329 including
zoster;45'799-1112 acute and chronic bacterial
infections; syphilis; Lyme disease681-796'1177
Meniere's syndrome 37 - 1240
Trauma: by head injury,325'437'600-1045.1278.1385-1473
complication of ear surgery575
Perilymph fistula 458 ' 1114 . 1292 ' 1454
Otosclerosis1204-1369
Congenital anomalies of the inner ear89-982-1239
Vestibular atelectasis941-1018
Vestibular-masseter syndrome 646
Cogan's syndrome253'599-6083-902'1242-1436
Occlusive or hemorrhagic vascular disease of
the inner ear 38 - 451 - 541 - 1241
Brain stem hemorrhage, ischemia, and infarc-
tion (e.g., Wallenberg's syndrome)68-441-526'664
Cerebellar hemorrhage 766 or infarc-
tion 28 ' 246 ' 247 - 1019 - 1472
Arnold-Chiari malformation (Valsalva-induced
vertigo)23-1487
Multiple sclerosis480
Tumors of the brain stem,307 cerebellum,403-548
eighth cranial nerve,957 and petrous bone,
including glomus tumors 1309
Epilepsy92'496'721-779-1011'1233'1296-1328
Drugs and toxins 621 - 672 - 974 - 1249
Recurrent Vertigo
Meniere's syndrome 37 - 79 - 1064 - 1240
Syphilis1489
ness, ipsilateral facial pain, and facial
paralysis may also occur (Ramsay-Hunt
syndrome). 799 - 1112 Enhancement of the fa-
cial and vestibulocochlear nerves on MRI
has been reported.905 Bacterial infection
of the middle ear and serous otitis media
remain common causes of vertigo, espe-
cially in children.
TRAUMA CAUSING VERTIGO
Acute vertigo may be associated with head
trauma.325'457-600-1045 The injury is often
mild; frequently the patient also complains
Recurrent Vertigo—continued
Perilymph fistula 457 - 458 - 696 - 1114 - 1238 ' 1292 - 1454
Otosclerosis1060'1204'1369
Autoimmune conditions125'592'921'1398-1438
including Cogan's syndrome,253-599'6083'902'
1242,1436 Susac's syndrome, 66 - 1022 - 1344 and
giant cell arteritis926
Benign paroxysmal vertigo of child-
hood443'811'1062'1401
Epilepsy92'496'721'779-1011'1233-1296-1328
Migraine and its variants including basilar
artery migraine71-131'314'589'1221-1433
Familial vertigo, ataxia, and nystag-
mus 85,90,175,226,486,1411,1413
Hypothyroidism' 30
Brain stem ischemia68-441'451'526'541'1019-1028
Multiple sclerosis480
Posterior fossa tumors593
Microvascular compression 124 ' 171 ' 975
Vestibular atelectasis941'1018
Central angioma821
Recurrent idiopathic vestibulopathy 1198
Positionally Induced Vertigo
Benign paroxysmal positional vertigo ("cupulolithia-
sis" and "canalolithiasis")173
Alcohol436"'952
Central causes:
Cerebellar infarcts1210
Cerebellar tumors 548 - 1460
Multiple sclerosis480-729
Brain stem ischemia541
Arnold-Chiari malformation and other cran-
iocervical anomalies86
of headache and difficulty with concentra-
tion. Posttraumatic vertigo is commonly
caused by whiplash injuries incurred in
rear-end automobile accidents. About 50%
of such patients show abnormalities on
vestibular testing, such as reduced caloric
responses, positional nystagmus, and occa-
sionally increased, "hyperactive" vestibu-
lar responses.444-600-1045-1385 High-impact
aerobics has been implicated in patients
with otherwise unexplained vestibular
symptoms.1463 Temporal bone fractures
are often associated with vertigo and ves-
tibular damage.600-1473
 Diagnosis of Central Disorders of Ocular Motility
It has been suggested that disturbance
of cervical muscle afferents might be the
cause of vertigo in some patients (cervical
vertigo}. In support of this idea, injection
of local anesthetic into the neck of volun-
teer subjects produces a sensation of being
drawn toward the side of the cervical in-
jection, with ataxia but not nystagmus;
however, nystagmus does appear when
monkeys are injected with a local anes-
thetic in their neck muscles.333 Radical
neck surgery can lead to abnormal rota-
tional vestibular responses.705 Vibration of
neck muscles can lead to illusions of mo-
tion in normal subjects723 and to nystag-
mus in patients with unilateral loss of
function. 1501 Thus, there is a potential sub-
strate for cervical influences on vestibular
sensation, but further studies are required
to establish cervical vertigo as a clearly
identifiable clinical entity.
Trauma may also cause vertigo by creat-
ing a fistula between the perilymph and
middle ear. Perilymph fistula may follow
mastoid or stapes surgery, minor head
trauma (e.g., from diving into a swimming
pool), barotrauma (high altitude or under-
water),673'939'1114 strenuous exercise, sup-
pressed sneezing,1244 and air travel.696 A
useful clinical test consists of applying man-
ual pressure over the tragus or applying
pressure to the tympanic membrane with
the pneumatic otoscope; a positive result is
indicated by the production or exacerba-
tion of vertigo or the elicitation of nystag-
mus (Hennebert's sign). A positive Hen-
nebert's sign is not specific for an oval or
round window fistula, however. Other
causes include fistulas involving any of the
semicircular canals, or abnormal connec-
tions between the stapes footplate and the
otoliths, including vestibulofibrosis and a
hypermobile stapes. Pressure sensitivity
may also occur in Meniere's syndrome,
when the otolith organs become dilated and
abut the stapes footplate. A positive Hen-
nebert's sign has also been associated with
bilateral vestibular loss.15 Pressure-induced
signs can sometimes be documented by re-
cording eye movements or measuring body
sway as pressure on the tympanic mem-
brane is increased.1051'1278 Patients with fis-
tula may complain of imbalance, positional
vertigo, nystagmus, and hearing loss.
469
The Tullio phenomenon comprises ves-
tibular symptoms that include vertigo, os-
cillopsia, nystagmus (Fig. 10-3), the OTR,
and postural imbalance induced by audi-
tory stimuli (see VIDEO: "Tullio phenome-
non"). It is usually due to perilymph
fistula, but subluxation of the stapes foot-
plate and other ear pathology may be re-
sponsible.187'278'392'1051-1094'1188 The symp-
toms may be due to abnormal stimulation
of the semicircular canals or of the
otoliths. Patients may have an increased
click-evoked sacculocollic reflex, as re-
flected by increased surface EMG activity
over the sternocleidomastoid muscle.283 A
recently identified cause of the Tullio phe-
nomenon, with pressure sensitivity and
Valsalva-induced symptoms is dehiscence
of the roof of the superior semicircular ca-
nal.947 Such patients also have vertigo and
nystagmus induced by vibration of the
mastoid bone. The bony abnormality can
be identified on coronal and transverse
CT scans of the petrous bone; in particu-
larly bothersome cases, plugging of the
superior canal is an effective treatment.
Perilymph fistulas of the round or oval
window often resolve spontaneously, but
sometimes surgical repair is necessary.
Some patients with posttraumatic vertigo
develop benign paroxysmal positional ver-
tigo (BPPV).
A spontaneous oval or round window
fistula has also been invoked as a cause
of unexplained vertigo and dysequilib-
rium.458'1454 Unfortunately, there are no
reliable diagnostic tests for this syndrome.
Many patients in whom no other cause for
their vestibular symptoms is uncovered
have undergone an exploratory tympan-
otomy and patching of the oval and round
windows, even if no fistula is clearly identi-
fied. We suspect that only a small percent-
age of patients in this category are helped
surgically; the problem is how to identify
this subgroup.1238
TOXIC CAUSES OF VERTIGO
The most common toxic cause of acute
vertigo is ethyl alcohol. It is well known
that positional changes exacerbate the
vertigo of a hangover. The reason may be
that alcohol diffuses into the cupula and
470 The Diagnosis of Disorders of Eye Movements
endolymph at different rates and so cre-
ates a density gradient, making the cupula
gravity sensitive, the so-called buoyancy
hypothesis.163'436*
The aminoglycoside antibiotics are no-
torious for causing irreversible failure of
vestibular function without vertiginous
warning or hearing loss.574 A number of
other causes of acute vertigo are enumer-
ated in Table 10-9, and some are dis-
cussed in the following section.
Recurrent Vertigo
MENIERE'S SYNDROME
Meniere's syndrome (endolymphatic hydrops)
is a common cause of recurrent vertigo
that is usually accompanied by prominent
auditory symptoms. Attacks of vertigo,
fluctuating hearing loss and tinnitus, and
aural fullness are its hallmarks. A failure
of resorption of endolymph is presumed
to lead to an increase in endolymphatic
pressure. Symptoms are probably caused
both by direct compression of sensory
structures within the cochlea and vestibu-
lar labyrinth and by leakage of potassium-
rich endolymph onto the vestibular nerve
thrpugh breaks in the membrane separat-
ing the endolymph and perilymph spaces.
The vestibular nerve may first be excited
and then depressed in a depolarization
block.
A typical attack in Meniere's syndrome
is heralded by a sensation of fullness in the
ear, tinnitus, and impaired hearing. The
vertigo that ensues is often severe and
usually prostrates the patient. After sev-
eral hours, or sometimes longer, the attack
begins to abate. Sometimes the hearing
symptoms subside when the vertigo begins
(Lermoyez syndrome).
Examination during the attacks com-
monly shows nystagmus that changes its
direction during the attack. At the onset of
the attack, an irritative nystagmus with hori-
zontal slow phases directed away from the
affected ear (ipsilateral-beating nystag-
mus) may occur. Slow phases toward the
side of the lesion then appear soon after
the onset of the attack (the "paretic"
phase); finally another reversal of the di-
rection of the nystagmus, with slow phases
away from the affected ear, can occur a few
hours later (recovery nystagmus).919,1064 pos_
tural unsteadiness may persist for several
days. Vertigo may be the predominant
symptom in some patients with Meniere's
syndrome. Commonly, however, audio-
metric testing shows a characteristic fluc-
tuating low-frequency hearing loss with
recruitment. Electrocochleography (ECOG)
may show an increase in the ratio between
the summating and the action potential, a
pattern seen in Meniere's syndrome and
with perilymphatic fistula. An MRI scan
may show contrast enhancement of
labyrinthine structures during attacks,
but this finding must be distinguished
from changes due to acute viral infec-
tions, autoimmune diseases, and other
processes.481'905'1431
Some patients may suddenly fall without
warning; these events, which may even oc-
cur early in the course of the disease, are
referred to as Tumarkin's otolithic crisis'79 and
should be differentiated from other forms
of drop attack. Meniere's syndrome is a
disease of adults, often beginning in the
third or fourth decade; it rarely occurs
in children.596 The natural history of
Meniere's syndrome is one of progression
but often with extended periods of remis-
sion.546 Although the cause of Meniere's
syndrome is unknown, endolymphatic hy-
drops may follow other afflictions of the
ear including head trauma and viral infec-
tions.806'1240 An autoimmune basis has
been suggested for some patients with
Meniere's syndrome;592'1304 patients with
arteritis may present with a Meniere's-like
syndrome. 926 (See also the discussion of
Cogan's syndrome, below.) The incidence
of migraine is probably increased in pa-
tients with Meniere's syndrome.1130 The
distinction between the two conditions
may be difficult, since vestibular and audi-
tory symptoms and signs may occur with
classic migraine.204'2393'1043'1433
OTOSCLEROSIS
Otosclerosis, a common cause of domi-
nantly inherited deafness, may also cause
attacks of recurrent vertigo that may
mimic Meniere's syndrome.1060'1204'1369

Some patients also suffer from positional
vertigo. Diagnosis is relatively easy in pa-
tients with a conductive hearing loss, tin-
nitus, and a history of affected family
members. A CT scan of the petrous bone
may help.1431
INFLAMMATORY DISORDERS
CAUSING RECURRENT VERTIGO
Syphilis is a rare but important cause of
recurrent vertigo.1489 Inflammation of the
membranous labyrinth and osteitis of the
surrounding bone occur with both con-
genital and acquired forms. The clinical
picture is episodic vertigo with progres-
sive loss of vestibular and auditory func-
tion. Other features of syphilis may be
present, especially with the congenital
form. The results of the serum fluores-
cent treponemal antibody absorption
test (FTA) are positive, and cerebrospi-
nal fluid abnormalities may be present.
Lyme disease, another infectious process,
may cause a variety of vestibular syn-
dromes,681'796'1177 though the ocular motor
manifestations are more common.65
Cogan's syndrome is characterized by
interstitial keratitis, hearing loss, and re-
current attacks of vertigo that mimic
Meniere's syndrome.253'599'6083'902'1242'1436 It
is often associated with a systemic collagen
vascular disease, and some patients de-
velop aortic insufficiency; test results for
syphilis are negative. Corticosteroid ther-
apy usually produces improvement, and
should be instituted promptly for hearing
and vestibular loss. Susac's syndrome is
characterized by a triad of microangiopa-
thy of the brain and retina with eighth
nerve involvement.66'1022'1344 Young women
are most commonly affected. Patients have
an encephalopathy, branch retinal artery
occlusions, and a Meniere's-like syndrome
with spells of vertigo with lower-frequency
hearing loss. Other forms of immune in-
ner ear disease leading to progressive ves-
tibular and hearing loss, with or without
associated systemic involvement, have
been described.125'481'592'921'926'1398 Sarcoid
also has a predilection for the eighth cra-
nial nerve; it may even cause BPPV, pre-
sumably by selectively involving the supe-
rior division of the vestibular nerve.592-1438
Diagnosis of Central Disorders of Ocular Motility 471
MIGRAINE AND
RECURRENT VERTIGO
One distinctive clinical entity is benign
paroxysmal vertigo of childhood, which usu-
ally has its onset between the ages of 1 and
4 years.733'443'811'1062-1401 It is probably a
variant of migraine. The attacks are typi-
cally brief and consist of unsteadiness, pal-
lor, nausea, and vomiting. Older children
describe vertigo. Nystagmus or torticollis
may be noted; younger children may only
show torticollis. The attacks may come
every week or month, or in clusters, be-
tween which the children feel well. Tests of
labyrinthine function sometimes suggest a
peripheral abnormality. The attacks usu-
ally cease in the course of a few months or
years. Migraine and seizure disorders
should be considered first in the differen-
tial diagnosis of vertigo in childhood, al-
though there are other developmental
and metabolic causes, including vertigo as
a feature of acetazolamide-responsive, fa-
milial episodic vertigo and ataxia type 2
(EA-2).158'184'307'1062'1401
In adults, too, recurrent vertigo may be
a manifestation of migraine.2393,314,472,1221
As a component of migraine attacks, fre-
quently vertigo may overshadow the head-
ache and often occurs independent of
the headaches. Vertigo in migraine syn-
dromes tends to occur in two time frames:
lasting an hour or so, similar to a classic
migraine aura, and lasting for days or
sometimes weeks in a milder form, pro-
ducing motion sensitivity and imbal-
ance.314 Hearing loss may also be associ-
ated.1433 Headache and vertigo associated
with other symptoms, such as dysarthria
and ataxia, suggest a basilar-artery form of
migraine. Such attacks are particularly
common in adolescent girls131'589 but also
occur in older patients of both sexes.
VASCULAR DISORDERS AND
RECURRENT VERTIGO
In older individuals, transient attacks of
acute vertigo may be caused by vertebrobasi-
lar insufficiency.37'68'441'451'526'541'1019'1028 Usu-
ally associated neurologic symptoms or signs
point to a central disorder, but isolated at-
tacks due to ischemia, especially of the cau-
472 The Diagnosis of Disorders of Eye Movements
dal cerebellum, are not uncommon;526'1019
they may be the harbinger of brain stem or
cerebellar stroke. Isolated attacks of vertigo
may also be due to ischemia of the labyrinth,
commonly in the structures within the distri-
bution of the anterior vestibular artery (the
anterior and lateral semicircular canals and
the utricle). Since the anterior vestibular
artery is an end artery with poor collateral
supply, isolated attacks of vertigo may occur
without hearing loss or tinnitus in patients
with hypoperfusion of the labyrinth due to
vertebrobasilar insufficiency. Such attacks
may occasionally be associated with bilateral
hearing loss.664
Hemorrhage into the vestibular organ is
rare but can cause severe vertigo and
deafness.1241 Acute vertigo is often a
prominent symptom in brain stem and
cerebellar infarction, which are discussed
below.
EPILEPSY AND OTHER
MISCELLANEOUS CAUSES
OF VERTIGO
Other causes of recurrent vertigo are
listed in Table 10-9. Seizures—tornado
epilepsy—may cause vertiginous feelings,
but patients with epilepsy more commonly
experience vertigo as a side effect of anti-
convulsant and other medications. A pos-
terior fossa tumor rarely causes recurrent
vertigo. Tumors of the eighth cranial
nerve commonly are associated with pro-
gressive hearing loss rather than with ver-
tigo,126 although nearly half of such pa-
tients experience vertigo at some time
during the course.957 Vertigo is a promi-
nent feature of the rare familial episodic
vertigo and ataxia type 2 (EA-2), which
usually responds to acetazolamide and is
related to a calcium channel abnormality
on chromosome I9.90'175'486'1411'1413'1517a
UNDIAGNOSED RECURRENT
VERTIGO
Some patients report episodes of recur-
rent vertigo for which no cause can be
found. 1198 Long-term follow-up has shown
that about 30% develop into either
Meniere's syndrome or benign paroxys-
mal positional vertigo, while the other
70% remain undiagnosed. Some of these
patients almost certainly have vestibular
migraine. Less commonly, patients may
have attacks that affect first one and then
the other ear; the bilateral vestibular loss
causes oscillopsia with head movements
and during walking.76'77'1243 Examination
of the temporal bone of three patients who
had suffered recurrent episodes of vertigo
showed varying degrees of inflammation
and destruction within the vestibular sys-
tem, and mild involvement of the cochlear
system.680
Some patients with chronic unsteadi-
ness have the syndrome ofmal de debarque-
ment.198'984 This is an exaggerated form of
a normal response that many individuals
have when they return to land after sea
travel. Patients have a rocking and sway-
ing sensation, usually with no abnormali-
ties on examination or testing. The etiol-
ogy is unclear: psychiatric disorders,
migraine, fistulas, otolith disturbances,
and vascular loops have been invoked.
Fortunately, most patients will spontane-
ously recover or respond to antianxiety or
antidepressant medications and physical
therapy.
Recurrent attacks of disabling vertigo
have been attributed to vascular loops or
tortuous vessels that compress the eighth
cranial nerve, analogous to the syndromes
of hemifacial spasm and trigeminal neu-
ralgia. Microvascular decompression has
been reported to produce dramatic cures
in a large percentage of these patients.975
Clinical features that suggest the diagnosis
include short-lived episodes (seconds or
minutes) of vertigo or imbalance, often re-
lated to a change in head posture; hypera-
cusis or tinnitus; and a salutary response
to carbamazepine.171 Abnormalities of brain
stem auditory evoked potentials and an
exacerbation of symptoms or induction of
nystagmus with hyperventilation (altering
conduction on a compressed and demyeli-
nated nerve) also point to the diagnosis.
Unfortunately, reliable laboratory meth-
ods to identify such patients have not been
established,124'975 especially since many
asymptomatic normal individuals have
loops of the anterior inferior cerebellar
artery touching the eighth nerve complex
in or near the internal auditory meatus. In
 Diagnosis of Central Disorders of Ocular Motility
patients with unexplained vertigo or dyse-
quilibrium, the diagnosis of microvascular
compression of the vestibular nerve, or
of a spontaneous oval or round window
perilymphatic fistula, is often raised;
exploratory surgery is often considered.
There is no convincing evidence, however,
that patients will benefit from such proce-
dures unless they meet strict clinical
criteria.1238 Vestibular migraine, Meniere's
syndrome, epilepsy, multiple sclerosis,
and even benign paroxysmal positional
vertigo may have atypical presentations.
Unusual conditions such as familial
episodic vertigo and ataxia type 2 (EA-2)
should be considered and treated med-
ically before exploratory surgery for fis-
tula or microvascular compression.
Posturally-Induced Vertigo
BENIGN PAROXYSMAL
POSITIONAL VERTIGO (BPPV)
Clinical Features of BPPV
Barany first described BPPV. It was fur-
ther characterized by Dix and Hallpike.810
Classic BPPV usually arises from a poste-
rior semicircular canal that has become
gravity sensitive, but lateral-canal variants
are becoming increasingly recognized.
The syndrome is presumably caused by
floating debris—otoconia—either within
the long arm of the semicircular canal
(canalolithiasis, probably the most common
occurrence) or on the ampullary side of
the cupula, either floating free or adher-
ent to the cupula (cupulolithiasis). Typically,
patients complain of brief episodes of ver-
tigo precipitated by changes of head pos-
ture such as turning over in bed, looking
up to a high shelf, or backing a car out of a
garage. Patients can usually identify the
offending head position, which they often
carefully avoid. Many patients also com-
plain of mild postural instability between
attacks. Women are more commonly af-
fected than men. The condition affects all
age groups but is common in the elderly.
Spontaneous remissions are the rule, but
symptoms may trouble the patient in-
termittently for years. BPPV may fol-
low head injury, viral neurolabyrinthitis,
473
or labyrinthine ischemia and occasionally
occurs after assumption of unusual head
postures (e.g., prolonged reclining in a
dental chair or working underneath a
car), prolonged bedrest, or exposure to
continuous jarring, such as cycling over
rough terrain or high-impact aerobics.1463
In over half of affected patients, no cause
can be identified. 74
The clinical examination may help con-
firm the diagnosis (Fig. 10-19A,B). Hav-
ing reassured the patient (who is often
apprehensive of being moved) and em-
phasized the importance of keeping the
eyes open, the patient's head is turned 45°
to one shoulder and the head and neck
are quickly moved "en bloc" into a head-
hanging position (just over the edge of the
examining table, about 120° from the up-
right). This is the Dix-Hallpike maneuver.
Typically there is a latent period, usually
of about 2 to 5 seconds but sometimes as
long as 30 seconds, followed by a sensation
of discomfort and apprehension that will
sometimes cause the patient to cry out and
attempt to sit up. This is associated with
vertigo, nausea, and a burst of nystag-
mus (see VIDEO: "Nystagmus with benign
paroxysmal positional vertigo"). In the
typical variant due to involvement of the
posterior semicircular canal, the slow
phases are directed downward, with intor-
sion of the lower eye and extorsion of the
higher eye. Hence, the nystagmus is mixed
upbeat and torsional. The nystagmus usually
appears slightly disconjugate, more tor-
sional in the lower eye (on the side of the
dependent ear) and more vertical in the
upper eye. The nystagmus also appears to
change with the direction of gaze: On
looking to the dependent ear it seems
more torsional, and on looking to the
higher ear, more vertical. A small horizon-
tal component, greater in the lower eye,
with slow phases toward the dependent
ear, may also be evident if eye movements
are recorded. Three-dimensional search
coil recordings have shown that the slow
phases of BPPV rotate the eye in a plane
that is parallel to the posterior semicircu-
lar canal.438 This pattern of nystagmus
corresponds closely to the results of ex-
perimental stimulation of the posterior
semicircular canal of the dependent ear
474 The Diagnosis of Disorders of Eye Movements
(Fig. 2-2).277 The nystagmus increases for
up to 10 seconds but then begins to fa-
tigue and is usually gone by 40 seconds. In
other words, this testing induces position-
ing nystagmus rather than positional nystag-
mus. In a small proportion of patients with
BPPV, a low-amplitude, secondary nystag-
mus (in the opposite direction) may occur
after the primary nystagmus has resolved,
but this reversal is usually most prominent
when the patient sits up. Repeating this
procedure several times will decrease the
Figure 10-19. Diagnosis (Dix-Hallpike maneuver,
A-C) and treatment (Epley maneuver, D, E) of be-
nign paroxysmal positional vertigo due to otolithic
debris in the right posterior semicircular canal. For
each head position, the corresponding orientation of
the right labyrinth is shown, with the arrow pointing
to the presumed location of the otolithic debris in the
posterior semicircular canal. (A) The patient's head is
turned to the right shoulder. (B) The patient is
rapidly moved from sitting to head-hanging position,
with the head 45° below the horizontal and rotated to
the right, as shown in C. After a brief latency, vertigo
is induced and nystagmus commences; the direction
of the quick phases of nystagmus induced by this ma-
neuver are shown (more upbeat in leftgaze and more
torsional in rightgaze) (see VIDEO: "Nystagmus with
benign paroxysmal positional vertigo"). (D) The pa-
tient's head is held still for 15 sec after the nystagmus
and vertigo subside. Then the patient's head is ex-
tended slightly, and head and body are slowly rotated
to the patient's left, so that the head rotates through
180° from the orientation in C. The patient is held in
this position for 15-30 sec to allow time for the
otolithic debris to exit from the common crux of the
vertical canals (arrow). (E) Finally, the patient slowly
sits up, keeping the head turned to the left. The pa-
tient is encouraged to sustain a head-erect posture
for the next 24 hours (sleeping propped up), if possi-
ble. (Reproduced from Herdman SJ. Vestibular Re-
habilitation, second edition, Philadelphia: F.A. Davis;
1999, with permission).
Continued on following page
symptoms and make the signs more diffi-
cult to elicit; this lessening of the response
is of diagnostic value, because positional
nystagmus with central lesions usually
does not habituate with repeated testing.
If the classic pattern of nystagmus asso-
ciated with BPPV is not elicited with the
Dix-Hallpike maneuver to either side, the
patient should then be brought to the
supine position with the head centered on
the body. The patient's head (and body,
for comfort) should then be turned 90° to
 Diagnosis of Central Disorders of Ocular Motility
Figure 10-19.—continued
one side (right ear down), back to neutral
(head supine), and then 90° to the other
(left ear down). This is the best maneuver
with which to elicit a horizontal positional
nystagmus, as occurs, for example, with
the lateral canal variant of BPPV, which is
discussed later in this section.
Nystagmus associated with changes in
head posture is sometimes attributed to
extension, flexion, or lateral rotation of
the head on the body, but with rare ex-
ceptions, the nystagmus actually appears
because of a change in the position of
the head with respect to gravity. To make
this distinction, the trunk can be pitched
forward and the head hyperextended at
the neck, or the trunk pitched backward
and the head flexed on the neck, in order
to keep the attitude of the head with
respect to gravity the same as in the nor-
mal upright posture. If the vertigo is due
to flexion, extension, or rotation at the
neck, this maneuver should provoke nys-
tagmus.
475
The lateral-canal variant of BPPV, while
less common than the posterior canal
variant, has become increasingly recog-
nized.78'91'335'4393'1027'1320'1341 Lateral canal
BPPV may occur as a transient complica-
tion following positioning maneuvers used
in testing for, or treating, posterior canal
BPPV (and vice versa). 614 Patients may
have both lateral and posterior canal vari-
ants simultaneously or sequentially. Lat-
eral canal BPPV produces symptoms in
both the right-ear-down and left-ear-
down positions. There may be geotropic
nystagmus (beating toward the ground), in
which case the nystagmus is usually more
intense with the affected ear down, or
there may be apogeotropic nystagmus (beat-
ing away from the ground), in which case
the nystagmus may be more intense with
the intact ear down. This difference be-
tween the intensity of nystagmus in geot-
ropic and apogeotropic BBPV may repre-
sent Ewald's second law (ampulla movement
in the excitatory direction elicits a brisker
476 The Diagnosis of Disorders of Eye Movements
nystagmus than the opposing ampulla
movement in the inhibitory direction).
The nystagmus of lateral-canal BPPV
may reverse its direction if the offending
position of the head is maintained. When
the head is brought to the supine position
from a sustained lateral position, a nystag-
mus occurs as if the head were being
brought from supine to the opposite lat-
eral position (equivalent to the nystagmus
reversal that appears with posterior canal
BPPV when the patient sits upright). With
lateral-canal BPPV, the initial horizontal
nystagmus may last longer and be less sus-
ceptible to fatigue with repetitive testing
than the vertical-torsional nystagmus of
posterior-canal BPPV. The increased dura-
tion and the tendency for the nystagmus to
increase in intensity as the offending head
position is maintained may reflect the ac-
tion of both the central velocity-storage
mechanism (which perseverates periph-
eral labyrinthine signals, especially from
the lateral semicircular canal) and the con-
tinuous application of the equivalent of a
constant acceleration from gravity (espe-
cially when the offending particles are on
the ampulla side), causing the nystagmus
to grow. Canalolithiasis and cupulolithiasis
may both play a role in lateral-canal BPPV.
If the nystagmus is geotropic, the particles
probably are in the posterior portion of
the long arm of the lateral semicircular ca-
nal, relatively far from the cupula. If it is
apogeotropic, the particles could also be in
the long arm but in its anterior aspect rela-
tively close to the cupula, or on the oppo-
site, ampullary side of the cupula. Patients
may show geotropic nystagmus at some
times and apogeotropic at other times.
Presumably this is due to a difference in
the relative distance of the offending parti-
cles from the cupula within the long arm
of the lateral semicircular canal or due to
movement of the particles from the long
arm of the canal to the ampulla side with
certain provocative head maneuvers.
Anterior-canal BPPV is the most un-
usual variant. The nystagmus should be
downbeat with a torsional component but
is difficult to recognize with certainty.
Bilateral BPPV occasionally occurs, but
if the patient's head is not positioned
correctly during positional testing (not
moved exactly in the plane of the poste-
rior semicircular canal when testing the
unaffected side), debris on the affected
side can rest against the cupula and simu-
late an excitatory nystagmus from the un-
affected ear.1320 Rarely, the nystagmus of
BPPV may be purely vertical or purely
torsional due to debris floating in both
vertical canals at the same time (vertical
if the debris floats in the same direc-
tion, torsional if it floats in opposite direct-
ions). This circumstance is an exception
to the rule that pure vertical or pure tor-
sional nystagmus always indicates a cen-
tral problem.
In some patients, no nystagmus will be
elicited with postural testing; the diagnosis
must then be made based on the history. It
is helpful to reexamine the patient if
symptoms persist, especially at a time
when they exacerbate. Mastoid vibration
may help provoke the typical nystagmus.
If the nystagmus is not typical for BPPV,
an effort to identify disease of the brain
stem or cerebellum is appropriate, al-
though in most cases, no morbid disease
process will be found. Apart from the find-
ings during positional testing, other tests
of ocular motility may be normal. In a mi-
nority of patients, particularly those with a
prior history of viral or ischemic neuro-
labyrinthitis, the head-thrust maneuver
will show a unilateral deficit, or caloric re-
sponses are reduced in the affected ear.
Pathophysiology of BPPV
A combination of careful clinical observa-
tion, clinicopathologic correlation, and
physiologic experimentation has led to a
better understanding of the pathogenesis of
BPPV.129'173'422'810'849'1319'1320 Recent elec-
tron microscopic studies have confirmed
that the debris consists of otoconia.1471
Originally, it was thought that degener-
ated utricular otoliths became detached
and came to rest on the dependent cupula
of the posterior semicircular canal, a state
called cupulolithiasis.1^'1 More recent evi-
dence suggests that the more usual cause
may be free-floating debris on the other
side of the cupula in the long arm of the
 Diagnosis of Central Disorders of Ocular Motility
posterior semicircular canal, which is re-
ferred to as canalolithiasis.955'1065 The de-
bris may coalesce and act as a plug so that
under the pull of gravity, the moving de-
bris (either with a plunger-like action or
simply owing to hydrodynamic drag)
causes the cupula to move, inducing nys-
tagmus even when the head is still.173'422
In other words, the semicircular canal be-
comes a gravity detector. When the poste-
rior semicircular canal is moved into an
earth-vertical position, the net result is to
produce false excitatory signals from the
affected posterior semicircular canal.
These signals primarily cause the ipsilat-
eral superior oblique and contralateral in-
ferior rectus muscles to rotate the eyes in
a slow phase of nystagmus. The evidence
for involvement of the posterior semicir-
cular canal in BPPV is strengthened by
the report that surgical section of the pos-
terior ampullary nerve, which supplies the
posterior semicircular canal, or plugging
of the posterior semicircular canal, cures
the condition.497'1063 In a minority of pa-
tients, otolithic debris may preferentially
affect the lateral or rarely the anterior
semicircular canal. Exercises or maneu-
vers aimed at dispersing the otolithic de-
bris from the cupula may promote recov-
ery (see Treatment of Vertigo), although
many patients will eventually improve
spontaneously.
In patients in whom BPPV follows
acute, peripheral vestibulopathy (viral or
ischemic in origin), there may be selective
damage to the structures innervated by
the superior division of the vestibular
nerve and perfused by the anterior vestib-
ular artery: the anterior and lateral semi-
circular canals, and the utricle.436 Using
click-induced EMG potentials in the
sternocleidomastoid (a sacculocollic re-
flex), 281 ' 282 Murofushi and co-workers
found that this reflex was intact in all pa-
tients who developed BPPV after vestibu-
lar neurolabyrinthitis, implying sparing of
the inferior division of the vestibular
nerve.983 Taps on the head with a reflex
hammer can also be used to stimulate the
sacculocollic reflex and probe the function
of the saccule and the inferior division of
the vestibular nerve.581
477
OTHER CAUSES OF
POSITIONAL VERTIGO
Posturally induced vertigo due to central
disorders may be relatively mild, and the
nystagmus is usually more impressive than
the subjective disturbance (Table 10-9).
When the patient is placed in a head-
hanging position, usually the nystagmus
persists for as long as the head position is
maintained; rarely, the findings are simi-
lar to BPPV. Multiple sclerosis may cause
positionally induced nystagmus, some-
times with accompanying vertigo;480'729
such symptoms may be the first manifesta-
tion of the disease. Occasionally, a cerebel-
lar tumor,403 infarction, or hematoma 731
may produce postural vertigo or vomiting.
If nystagmus typical of BPPV is present
with the patient's head turned to the right
and to the left (bilateral BPPV), then head
injury or brain stem ischemia is more
likely to be implicated,875 but one must
watch for improper positioning of the
head during positional testing maneuvers
before diagnosing bilateral BPPV.1319 Iso-
lated vertigo due to neck movements that
lead to kinking of the vertebral artery
happens rarely; 1176 associated neurologic
symptoms are usually present.
Some normal subjects may show posi-
tional nystagmus—nystagmus that persists
following a horizontal change in head po-
sition (e.g., with the subject supine, head
turned to the right or left). 524 ' 917 It usually
beats in the same direction as the head is
turned. In some patients, the nystagmus
changes direction with lateral head turn,
either always beating toward the earth
(geotropic) or always beating away from
the earth (apogeotropic). Such nystagmus
most often reflects a lateral canal BPPV
syndrome, as discussed above. Alcohol in-
toxication can produce a horizontal posi-
tional nystagmus by making the cupula
relatively lighter (during intoxication) or
heavier (during sobering up) than the sur-
rounding endolymph, by virtue of differ-
ential absorption. During intoxication the
nystagmus is geotropic; as the subject
sobers up it is apogeotropic.4363'952
When due to central causes,93 positional
nystagmus is relatively unchanging in
slow-phase velocity and is almost always
Table 10-10. Some Commonly Used Vestibular Sedatives
Drug
Meclizine (Antivert)
Diphenhydramine (Benadryl)
Promethazine (Phenergan)
Prochlorperazine (Compazine)
Scopolamine ("Transderm Scop")
Droperidol ("Inapsine")
Ondansetron ("Zofran")
Class Dosage Comments Precautions
Antihistamine Oral: 25 mg or 50 mg, Peak effects 8 h after Asthma, glaucoma, prostate
Anticholinergic qd or bid ingestion; less sedative enlargement
Antihistamine Oral: 25-50 mg, q 4-6 h; Mildly sedative Asthma, glaucoma, prostate
Anticholinergic IM: 10-50mg enlargement
Antihistamine Oral: 25 mg, q 6 h; supp: More sedative, more Asthma, glaucoma, prostate
Anticholinergic 50 mg, q 12 h; IM: 25 mg antiemetic enlargement, epilepsy
Phenothiazine
Antihistamine Oral: 5-10 mg, q 6 h; supp: Sedative and antiemetic Liver disease; in combina-
Anticholinergic 25 mg, q!2h;IM:5-10 tion with CNS depressants
Phenothiazine mg, q 6 h or metoclopramide
Anticholinergic Transdermal patch, q 3 days; Less sedative, more Asthma, glaucoma, prostate
(nonselective peak effect 4-8 h after antiemetic, suitable enlargement
muscarinic) application only to prevent mo-
tion sickness; can cause
confusion, mydriasis,
"dependency"
Butyrophenone IM or slow IV, 2.5-5.0 mg, Powerful antiemetic; Can cause hypotension and
q!2h sedative extrapyramidal side
effects; precautions: in
liver and kidney disease
Serotonin 5-HT3 Oral: 4-8 mg, tid; 4 mg IV Antiemetic, developed for Headache; constipation
receptor patients receiving cancer
antagonist chemotherapy; may be
effective controlling vertigo
and nausea due to CNS
disease1141

associated with other neurologic symp-
toms or signs. The cause of horizontal po-
sitional nystagmus in central disorders
may relate to abnormalities of the linear
(translational) VOR (discussed in Chap.
2). Pure vertical positional nystagmus—
which is usually downbeating with respect
to the head—frequently signals a distur-
bance in the cerebellum or at the cranio-
cervical junction.
Characteristics of horizontal positional
nystagmus that suggest a central distur-
bance and usually demand imaging in-
clude (1) a sustained, large-amplitude
nystagmus that is present during visual
fixation; (2) nystagmus that occurs in
more than one head position; and (3) nys-
tagmus that has an associated vertical (and
especially downbeat) component. Even
with these caveats, most patients with posi-
tional vertigo and positional or position-
ing nystagmus who have no other neuro-
logic symptoms or signs will not have a
central disturbance as the cause of their
vestibular symptoms.
Treatment of Vertigo
General measures available for the treat-
ment of vertigo have been reviewed else-
where; 472 ' 1126 here we summarize some ba-
sic principles. In acute vertigo due to a
peripheral vestibular lesion such as a viral
or ischemic neurolabyrinthitis, functional
recovery is the rule in the ensuing weeks.
Drugs that have a sedative effect (Table
10-10) should be used sparingly for treat-
ment of vertigo, with the exception of
Meniere's syndrome; in this case, the
pathophysiology of the attack and the re-
covery relate to mechanical changes in the
labyrinth, not central compensation, so a
brief period of moderate sedation need
not have any deleterious effects related to
retarded central compensation. Patients
should be encouraged to get up and in-
crease their activities as soon as possible,
since there is evidence that failure to do so
will limit the recovery. Much current re-
search is aimed at finding medications
that promote vestibular compensation.1301
A course of specific vestibular exercises
may be indicated.613'1277 Those patients
Diagnosis of Central Disorders of Ocular Motility 479
who develop enduring vestibular symp-
toms may have an underlying central ner-
vous system disorder, typically involving
the cerebellum,487'1194 and imaging studies
are indicated.
Treatment of recurrent vertigo depends,
however, upon the nature of the underly-
ing disorder. For example, vertigo due
to migraine can usually be successfully
treated, whereas vertigo due to Meniere's
syndrome is often difficult to manage, al-
though a low-salt diet and diuretics help
some patients.196 Intratympanic gentam-
icin has been shown to be an effective
alternative to surgical ablation for in-
tractable vestibular symptoms in Meniere's
syndrome.25'120'1055
Benign paroxysmal positional vertigo is
effectively treated in most cases by par-
ticle repositioning maneuvers. Several
effective strategies have been de-
scribed.129'174'422'614'847'849'920'1025'1027'1256'1258'
HIS Tne Epley maneuver is summarized in
Figure 10-19. Drugs are not indicated in
this condition except to relieve symptoms
during the treatment maneuvers. Some
authors advocate use of a mastoid vibrator
during the repositioning maneuver to free
otolithic debris that is adherent to the wall
of the semicircular canal.422 A small per-
centage of patients do not improve with
exercises. As previously mentioned, surgi-
cal section of the nerve to the posterior
semicircular canal has been effective,497
but occlusion of the posterior semicircular
canal is currently the preferred interven-
tion.1063 We have never had to refer a pa-
tient with BPPV for surgical intervention.
OSCILLOPSIA
Oscillopsia is an illusion of movement of
the seen world. It is usually caused by ex-
cessive motion of images of stationary ob-
jects upon the retina (Table 10-11). Exces-
sive retinal slip not only causes oscillopsia
but also impairs vision. On the one hand,
the relationship between retinal image ve-
locity and visual acuity is a direct one: For
higher spatial frequencies, image motion
in excess of about 5°/sec impairs vi-
sion.235'375 On the other hand, the rela-
tionship between retinal image velocity
480 The Diagnosis of Disorders of Eye Movements
Table 10-11. Etiology of Oscillopsia
Oscillopsia With Head Movements: Abnormal
Vestibulo-Ocular Reflex
Peripheral vestibular hypofunction164>621'1141a
Aminoglycoside toxicity574-946'14593
Surgical section of eighth cranial nerve 471
Tumors914
Meningitis940
Congenital ear anomalies904'982
Hereditary vestibular areflexia 76 ' 1421 ' 1422
Cisplatin therapy772'991'998
Idiopathic77'81'440'1428
Dolichoectatic basilar artery 222 - 1026
Central vestibular dysfunction
Decreased VOR gain558-1122
Increased VOR gain1372'1532
Abnormal VOR phase558
Paresis of extraocular muscles (including ocular
motor nerve palsies)
Oscillopsia Due to Nystagmus
Acquired nystagmus (especially pendular nys-
tagmus, upbeat, downbeat, seesaw,
dissociated nystagmus)533'829-836'1505
Saccadic oscillations (psychogenic flutter/vol-
untary nystagmus, ocular flutter,
microsaccadic flutter and opsoclonus)
Superior oblique myokymia (monocular oscil-
lopsia—see Chap. 9)
Congenital nystagmus (uncommon under nat-
ural illumination) 829
Central Oscillopsia
With cerebral disorders: seizures, occipital
lobe infarction 113
With transcutaneous magnetic stimulation of
scalp726
and the development of Oscillopsia is less
consistent and varies among subjects. For
example, individuals with congenital nys-
tagmus, who often have images moving
across the retina with speeds exceeding
100°/sec,8 seldom complain of Oscillopsia
under normal viewing conditions. Ac-
quired disease affecting eye movements
produces Oscillopsia in three main ways:
an abnormal VOR, paresis of extraocular
muscles, and ocular oscillations—such as
nystagmus.
Oscillopsia Due to an
Abnormal VOR
An abnormal VOR may lead to Oscillopsia
during head movements via three mecha-
nisms: abnormal gain, abnormal phase
shift (timing) between eye and head rota-
tions, and a directional mismatch between
the vectors of the head rotation and eye
rotation (see Quantitative Aspects of the
Vestibular-Optokinetic System in Chap.
2). Peripheral or central dysfunction af-
fecting either the angular or the linear
VOR can lead to Oscillopsia.377'846 Espe-
cially in the acute phase of loss of vestibu-
lar sense due, for example, to bilateral
eighth nerve section471 or aminoglycoside
antibiotic intoxication,686 head rotations
will lead to Oscillopsia.
Patients with bilateral vestibular loss
may become excessively dependent upon
visual inputs for image stabilization and
consequently may develop visual discom-
fort and inappropriate body sway, while
standing still and attempting to watch
swaying trees on a windy day, for example.
This excessive visual dependence can be-
come a problem in any patient with an ac-
tive labyrinthine disorder, or even a past
history of one. It leads to the common
complaint of visual discomfort and un-
steadiness in such patients when they are
walking down shopping aisles in a super-
market, seeing action movies on a large
screen, looking out of the car through
windshield wipers, or walking or riding by
a picket fence.
Typically, Oscillopsia is worse during lo-
comotion (see (Fig. 7-1) but it may be no-
ticed during chewing food and, in the
most severe cases, it may occur due to
transmitted cardiac pulsation.686 In addi-
tion, dynamic visual acuity declines dur-
ing head movements; this decline can be
easily demonstrated at the bedside.208'876
Objectively, using the ophthalmoscope,
the optic disc will be seen to move with
every head rotation. Patients with essential
head tremor and vestibular failure may
show abnormal oscillations of the optic
disc during ophthalmoscopy.188 Because
any residual function of the VOR is pref-
erentially spared for higher-frequency
 Diagnosis of Central Disorders of Ocular Motility
stimuli, 75 the inadequacy of the vestibulo-
ocular reflex may sometimes be more evi-
dent during large-amplitude, back-and-
forth oscillations of the head at about 1
Hz; during these movements, saccades are
necessary to hold gaze steady during at-
tempted fixation. With time, however,
compensation takes place, owing to poten-
tiation of the cervico-ocular reflex, pre-
programing of compensatory eye move-
ments, perceptual changes,560a and other
factors (see Table 7-1, Chap. 7). Bilateral
vestibular loss may be the cause of gait im-
balance in the elderly,440 in whom the po-
tential for compensation is reduced.
Ototoxicity, especially associated with
administration of aminoglycoside antibi-
otics, is an important cause of loss of
the VOR.44'140'621'1249-1459a Intravenous gen-
tamicin is the most common culprit and its
toxicity may be insidious.946 It may occur
without hearing symptoms and even with
normal blood levels and relatively short
periods of administration. 574 Some pa-
tients who develop Ototoxicity may be ge-
netically predisposed to the drug's toxic
side effects.445'1110 Topical gentamicin may
occasionally lead to unwanted labyrinthine
loss when used to treat external ear infec-
tions.874 Intratympanic gentamicin is used
to purposefully ablate labyrinthine func-
tion as part of the treatment of intractable
Meniere's syndrome.37'120 Cisplatin is prob-
ably not as vestibulotoxic as originally
thought. 772 ' 991 ' 998
The differential diagnosis of bilat-
eral vestibular loss includes a number of
toxic, infectious, neoplastic, traumatic,
and inflammatory processes. 164,621,940,1 i4ia
Dolichoectasia of the vertebral or basilar
artery also may lead to bilateral loss, usu-
ally without involvement of hear-
ing.1026'1070 Bilaterally vestibular defi-
ciency may be associated with congenital
ear anomalies.982 Often no cause can be
identified for bilateral vestibular defi-
ciency.77'164'440-1421'1428 Idiopathic bilateral
vestibular loss is sometimes familial, inher-
ited as a dominant trait, and can be associ-
ated with migraine and recurrent attacks
of vertigo.76 These patients may have nor-
mal hearing. Acetazolamide may help the
attacks of vertigo and headaches, but it is
481
not yet clear if the bilateral loss can be
arrested or improved. Baloh and col-
leagues reported autopsy findings in a pa-
tient with isolated progressive loss of
labyrinthine function who also had ultra-
short vestibular time constants, but pre-
served amplitude of response.81 They
found loss of hair cells and altered mito-
chondria (and presumably abnormal en-
ergy metabolism) and suggested that these
factors could account for the pattern of
loss of vestibular function.
Oscillopsia may also occur with disor-
ders of the central nervous system that
change the gain or phase of the VOR.558
Thus, disease of the vestibulocerebellum
may cause vestibular hyper-responsive-
ness, particularly in the vertical plane.
This is common in patients with Arnold-
Chiari malformation. 1532 Occasionally, pa-
tients are reported with increased gain of
both the horizontal and vertical VOR. 1372
In some patients with vestibulocerebellar
dysfunction, the gain of the VOR is nor-
mal, but the phase relationship between
head and eye movements is abnormal and
causes retinal image slip.558 Lesions of the
medial longitudinal fasciculus producing
INO may cause a low gain of the vertical
VOR and produce oscillopsia with vertical
head movements. 533 ' 1122
Oscillopsia due to Paresis of
Extraocular Muscles
Weakness of extraocular muscles beside
causing diplopia may also lead to oscillop-
sia during head movements.1491 This is be-
cause the VOR is prevented from working
adequately in the paretic field of gaze. The
cause of the muscle weakness may be a
nerve palsy; neuromuscular disease, such
as myasthenia gravis; or restrictive dis-
eases of the orbit, such as thyroid ophthal-
mopathy. Disease of the extraocular mus-
cles themselves also limits ocular motility,
but the slow progression of these disor-
ders seems to allow patients time to make
perceptual adaptations to the slip of reti-
nal images during head movements.
These disorders of the extraocular mus-
482 The Diagnosis of Disorders of Eye Movements
cles are discussed in Chap. 9. Rarely, lens
subluxation following head trauma may
cause monocular oscillopsia that occurs
with each saccade.985
Oscillopsia Due to Nystagmus and
Other Abnormal Eye Movements
Oscillopsia may also be caused by ocular os-
cillations such as nystagmus (see The Na-
ture and Visual Consequences of Abnormal
Eye Movements That Prevent Steady Fixa-
tion). In such cases, oscillopsia occurs even
when the head is still.1491 Thus, acquired
pendular nystagmus, occurring in multiple
sclerosis or in association with palatal
tremor; downbeat and upbeat nystagmus;
and even gaze-evoked nystagmus may lead
to oscillopsia (see VIDEOS: "Acquired nys-
tagmus impairing vision"). In addition,
certain saccadic disorders such as ocular
flutter and opsoclonus (see VIDEOS: "Opso-
clonus") may cause oscillopsia. Superior
oblique myokymia may cause monocular
oscillopsia (see VIDEO: "Superior oblique
myokymia"). One method of bringing out
oscillopsia is to ask the patient to fixate on a
small light in a dark room and to indicate
the direction of the perceived movement of
the stationary light. The nystagmus caus-
ing oscillopsia is not always obvious on
gross examination.113 A sensitive and con-
venient way to detect instability of gaze is to
view the retina with an ophthalmoscope.
The magnitude of oscillopsia is usually
less than the magnitude of nystagmus. For
example, in patients with downbeat nys-
tagmus, oscillopsia is equivalent to about
one-third of what would be predicted
from the amplitude of the nystagmus.210'3923
This finding implies that the brain com-
pensates for the excessive retinal image
motion by using an extraretinal signal,
such as efference copy, to maintain visual
constancy.355-829 As previously mentioned,
oscillopsia is rarely a complaint in individ-
uals with congenital nystagmus, though
visual acuity may be impaired due to the
oscillation. Motion detection may be im-
paired in some individuals with congenital
nystagmus,388 but this cannot be the entire
explanation, since artificial stabilization of
images, paradoxically, may cause oscillop-
sia.355'829 Methods available for treatment
of nystagmus are listed in Table 10-8.
Finally, oscillopsia is rarely reported by
patients who do not have excessive retinal
image motion (i.e., have no nystagmus or
vestibular dysfunction) but, rather, seem
to have a disorder of those central mecha-
nisms that normally ensure a sense of vi-
sual constancy.113
OCULAR MOTOR SYNDROMES
CAUSED BY LESIONS IN
THE MEDULLA
Medullary Lesions Impairing
Gaze Holding
The medulla contains a number of struc-
tures that are important in the control of
eye movements: vestibular nuclei, perihy-
poglossal nuclei, medullary reticular for-
mation, inferior olivary nuclei, and resti-
form body. The perihypoglossal nuclei
consist of the nucleus prepositus hy-
poglossi (NPH), which lies in the floor of
the fourth ventricle; the nucleus intercala-
tus, and the nucleus of Roller. These nu-
clei have rich connections with other ocu-
lar motor structures. The NPH and the
adjacent medial vestibular nuclei (MVN)—
the NPH-MVN region—are critically im-
portant for holding horizontal positions
of gaze (the neural integrator).230 These
structures also participate in vertical gaze
holding, with contributions from more
rostral structures, especially the interstitial
nucleus of Cajal (see Display 6-6). With le-
sions in the paramedian structures of the
medulla, nystagmus (commonly upbeat
but sometimes horizontal with a gaze-
evoked component) is the most com-
mon finding (see VIDEO: "Upbeat nystag-
mus »).630,7ooa,98U388 Tumor or infarction
involving the paramedian medulla, in-
cluding the perihypoglossal nuclei, has
been described in patients with upbeat
nystagmus.514'754 Upbeat nystagmus has
also been described with a lesion involving
the nucleus intercalates.630 One medullary
component of the PMT cell groups (see
Display 6-4) is the medullary nucleus
 Diagnosis of Central Disorders of Ocular Motility
pararaphales, which receives vertical eye
position signals from the interstitial nu-
cleus of Cajal. Thus, medullary lesions
that affect this nucleus might cause upbeat
nystagmus. 221 Involvement of a ventral
tegmental pathway for the upward VOR
may lead to a downward vestibular bias
and a consequent upbeat nystagmus. 1121
A patient who died of lithium intoxica-
tion showed selective loss of neurons
and gliosis in the NPH-MVN region.295
Wernicke's encephalopathy commonly in-
volves the NPH-MVN region, which
may account for the gaze-evoked nystag-
mus and other ocular motor features
of this disease (see VIDEOS: "Wernicke's
encephalopathy").
Effects of Disease Involving the
Inferior Olivary Nucleus
Lesions of the inferior olivary nucleus or
its connections may produce the ocu-
lopalatal tremor (or myoclonus} syndrome
(see VIDEO: "Oculopalatal tremor"). This
condition, which usually develops weeks
to months after a brain stem or cerebellar
infarction, is discussed in the section on
Oculopalatal Tremor (Myoclonus). Ocu-
lopalatal tremor may also occur with de-
generative conditions;381'1311 a patient with
cyclovergent pendular eye oscillations and
synchronous palatal movements in associ-
ation with progressive ataxia has been de-
scribed.64
The main pathologic finding with pala-
tal tremor is hypertrophy of the inferior
olivary nucleus, which may be seen during
life using MRI. 381 > 1311 Histologically, the
olivary nucleus is enlarged, with hyper-
trophic neurons that contain increased
acetylcholinesterase reaction product. 777
Guillain and Mollaret postulated that dis-
ruption of connections between the den-
tate and the contralateral olivary nucleus
(which run via the red nucleus and central
tegmental tract) is responsible for the syn-
drome;561 however, the red nucleus has no
known role in eye movements. It has also
been proposed that the ocular oscillations
are due to an instability arising from the
projection from the inferior olive to the
483
flocculus, which is thought to be impor-
tant in the adaptive control of the VOR.993
Only rarely does Oculopalatal tremor re-
solve spontaneously. Gabapentin, cerule-
tide, and anticholinergic agents may help
some patients (see Table 10-8).62>685
Effects of Disease Restricted to
the Vestibular Nuclei
Occasionally, the acute manifestation of a
generalized disease process may be re-
stricted to the vestibular nuclei. For exam-
ple, vertigo may be the sole symptom of an
exacerbation of multiple sclerosis729 or of
brain stem ischemia.451'526'541 Nystagmus
caused by disease of the vestibular nuclei
may be purely horizontal, vertical, or
torsional, or mixed patterns may occur.
Moreover, nystagmus from a central ves-
tibular lesion can mimic that caused by pe-
ripheral vestibular disease.937 Paroxysmal
vertigo with nystagmus has been reported
with an arteriovenous malformation near
the vestibular nucleus, and close to the
middle cerebellar peduncle.821 The attacks
were successfully treated with carbamaze-
pine. Dolichoectasia of the basilar artery
may produce a variety of combinations of
central and peripheral vestibular syn-
dromes.221-1070 Microvascular compression
of the eighth nerve is reported to cause
paroxysmal vertigo.171
Wallenberg's Syndrome (Lateral
Medullary Infarction)
Most commonly, lesions of the vestibular
nuclei also affect neighboring structures,
in particular the cerebellar peduncles and
the perihypoglossal nuclei. The best-rec-
ognized syndrome involving the vestibular
nuclei is that due to lateral medullary in-
farction—Wallenberg's syndrome (Fig.
10-20) (Display 10-16). The typical find-
ings of Wallenberg's syndrome are ipsilat-
eral impairment of pain and temperature
sensation over the face, Horner's syndrome,
limb ataxia, and bulbar disturbance caus-
ing dysarthria and dysphagia.1199 Con-
tralaterally, pain and temperature sensa-
484 The Diagnosis of Disorders of Eye Movements

Figure 10-20. T2-weighted MRI scan of a patient with Wallenberg's syndrome, showing an area of infarction
(hyperintense signal indicated by arrowhead) that involved the left side of the medulla.

tion is impaired over the trunk and limbs.
The seventh cranial nerve may also be af-
fected if the infarct extends more rostrally.
The disorder is most commonly due to oc-
clusion of the ipsilateral vertebral artery;
occasionally the posterior inferior cerebel-
lar artery is selectively involved.454 Dissec-
tion of the vertebral artery (either sponta-
neous or traumatic, sometimes following
chiropractic manipulation) is occasionally
the cause.624 Rarely, demyelinating disease
may produce this syndrome.1297
The symptoms of Wallenberg's syn-
drome include vertigo and a variety of un-
usual sensations of body and environmen-
tal tilt, often so bizarre as to be thought to
be psychiatric in origin.1383 Patients may
report the whole room tilted on its side or
even upside down; such misperceptions
tend to be transient, whereas smaller tilts
of the subjective visual vertical tend to be
more persistent.166'1383 Similar symptoms
are occasionally reported in patients with-
out signs of lateral medullary infarction
and may be due to transient brain stem or
cerebellar ischemia.245'878 Such symptoms
may also occur with lesions in the cerebral
hemispheres.1305
Lateropulsion, a compelling sensation of
being pulled toward the side of the lesion,
 Diagnosis of Central Disorders of Ocular Motility 485

Display 10-16: Ocular Motor Findings in Wallenberg's

Syndrome of Lateral Medullary Infarction
• Lateropulsion (deviation) of the eyes toward the side of the lesion oc-
curs in darkness, behind closed lids, or with a blink

• Lateropulsion (ipsipulsion) of horizontal saccades: Ipsilateral (to the

lesion side) saccades are hypermetric; contralateral are hypometric

• Lateropulsion of vertical saccades causing an oblique trajectory, with

an inappropriate horizontal component toward the side of the lesion

• Torsipulsion—inappropriate torsional "blips"—may occur during

horizontal saccades

• Smooth pursuit is impaired for targets moving away from the side of
the lesion

• Spontaneous nystagmus (often mixed horizontal-torsional) occurs

with the eyes in central position; slow phases may be directed toward
or away from the side of the lesion

• Ocular tilt reaction (OTR): Skew deviation with ipsilateral hypotropia,

head tilt toward side of lesion, ipsilateral cyclodeviation (top poles of
eyes rolled ipsilaterally); ipsilateral deviation of subjective visual verti-
cal

For pathophysiology, see Disorders of Saccadic Accuracy in Chap. 3, and Skew Deviation and
the Ocular Tilt Reaction (OTR) and Figure 10-18 in Chap. 10. (Related VIDEOS: "Wallen-
berg's syndrome.")

is often a prominent complaint and is
also evident in the ocular motor find-
ings.88'651'786 If the patient is asked to fixate
straight ahead and then gently close the
lids, the eyes deviate conjugately toward
the side of the lesion (see VIDEO: "Wallen-
berg's syndrome"). This is reflected by the
corrective saccades that the patient must
make on eye opening to reacquire the tar-
get. Lateropulsion may appear with a
blink.
Saccadic eye movements are also affected
by the lateropulsion.88'178'223'1306'1445'1446'1449
Horizontally, saccades directed toward the
side of the lesion usually overshoot the tar-
get, and saccades directed away from the
side of the lesion undershoot the target
(see VIDEO: "Wallenberg's syndrome"); this
is referred to as ipsipulsion of saccades and
should be differentiated from contrapukion
of saccades that occurs with infarcts due to
occlusion of the superior cerebellar artery.
Quick phases of nystagmus are similarly af-
fected, so that in Wallenberg's syndrome
those directed away from the side of the le-
sion are smaller than those toward the le-
sion. On attempting a purely vertical refix-
ation, an oblique saccade directed toward
the side of the lesion is produced (see
VIDEO: "Wallenberg's syndrome"). Correc-
tive saccades then bring the eyes back to
the target.769 Saccades made in total dark-
ness also show lateropulsion, although in
one report the patient was still able to make
corrective saccades to the remembered lo-
cation of a previously seen target, implying
that the central nervous system had a
knowledge of actual eye position.1037 With
time, vertical saccades may become more
perverse; S-shaped saccadic trajectories
486 The Diagnosis of Disorders of Eye Movements

can appear a week or more after the onset
of the illness and may reflect an adaptive
strategy to correct the saccadic abnormal-
ity. Torsipulsion (inappropriate torsional sac-
cades during attempted horizontal or verti-
cal saccades) may also occur in association
with torsional nystagmus, which may be re-
garded as a violation of Listing's law (dis-
cussed in Chap. 9).607>960
When present, spontaneous nystagmus
in Wallenberg's syndrome is usually hori-
zontal or mixed horizontal-torsional with
a small vertical component.960 In central
position, the slow phase is usually directed
toward the side of the lesion, although it
may reverse direction in eccentric posi-
tions, suggesting coexistent involvement
of the gaze-holding mechanism. Lid nystag-
mus (synkinetic lid twitches with horizontal
quick phases) can also occur.321 The ocular
tilt reaction commonly occurs in Wallen-
berg's syndrome.389 The skew deviation
manifests as an ipsilateral hypotropia (see
VIDEO: "Wallenberg's syndrome").169 The
eyes are cyclodeviated toward the side of
the lesion, but unequally so that the lower
eye is more extorted. The head tilt is ipsi-
lateral.168 The skew deviation and head tilt
arise from imbalance in pathways mediat-
ing otolith responses. The subjective sen-
sations of tilt or inversion of the world
probably also reflect involvement of cen-

Figure 10-21. MRI scan showing infarction in the distribution of the anterior inferior cerebellar artery (AICA),
with the characteristic finding of bright signal on a T2-weighted image in the left middle cerebellar peduncle
(arrowhead). The patient also suffered loss of left vestibular function due to occlusion of the labyrinthine artery
(see VIDEO: "Anterior inferior cerebellar artery (AICA) distribution infarction").
 Diagnosis of Central Disorders of Ocular Motility
tral projections from the gravireceptors,
the utricle and the saccule.
Smooth pursuit is usually impaired, par-
ticularly for tracking targets moving away
from the side of the lesion.88'1449 Caloric
testing usually shows intact horizontal ca-
nal function. During both rotational and
caloric testing, there is a directional pre-
ponderance of slow phases, usually toward
the side of the lesion.88'423 Head nystag-
mus also occurs in some patients with Wal-
lenberg's syndrome.786
Many of the findings in Wallenberg's
syndrome, including the bizarre visual
disturbances and the skew deviation, may
reflect imbalance of otolith influences due
to direct involvement of the caudal aspects
of the vestibular nuclei. Involvement of
the restiform body, which carries olivo-
cerebellar projections, may also account
for some of the ocular motor findings, es-
pecially the steady-state deviation of the
eyes toward the side of the lesion and the
ipsipulsion of saccades.223'1306'1445'1446-1449
Ipsipulsion of saccades, with deviation of
the eyes to the side of the lesion, can be
produced experimentally by fastigial nu-
cleus lesions.1160 This finding supports the
hypothesis that in Wallenberg's syndrome
the interruption of climbing fiber input to
the dorsal cerebellar vermis releases Purk-
inje cell inhibition upon the underlying
fastigial nucleus, leading to the equivalent
of a lesion in the fastigial nucleus.1449 An
analogous increase in Purkinje cell inhibi-
tion from the flocculus to the vestibular
nucleus may also play a role in the nystag-
mus that these patients may develop (with
the slow phase toward the side of the le-
sion).
The vestibular nuclei and adjacent dor-
solateral brain stem are also supplied by
the anterior inferior cerebellar artery
(AICA). In addition, the AICA supplies
the inferior lateral cerebellum and is the
origin of the labyrinthine artery in most
individuals. Consequently, ischemia in the
distribution of the AICA (Fig. 10-21) may
cause vertigo, vomiting, hearing loss, fa-
cial palsy, and ipsilateral limb ataxia, along
with gaze holding and pursuit deficits,
and vestibular imbalance (see VIDEO: "An-
terior inferior cerebellar artery (AICA)
distribution infarction").541'1028 The AICA
487
syndrome is discussed further under
Cerebellar Infarction.
OCULAR MOTOR SYNDROMES
CAUSED BY DISEASE OF
THE CEREBELLUM
Clinicians have been cautious in attribut-
ing eye movement abnormalities specifi-
cally to cerebellar dysfunction because the
brain stem is so frequently involved in pa-
tients with lesions of the cerebellum.
Holmes638 and Cogan,263 however, recog-
nized specific cerebellar eye signs, and
modern clinical and experimental stud-
ies have clarified the functional deficits
that are caused by specific cerebellar le-
sions<867,1046,1131,1160,1161,1427,1447,1538
Three Principal
Cerebellar Syndromes
Based on discrete lesions and pharmacolog-
ical inactivation in monkeys, it is possible to
define three principal cerebellar syn-
dromes: the syndrome of the flocculus and
paraflocculus (see Display 6-10 and Display
10-17), the syndrome of the nodulus and
ventral uvula (see Display 6-11 and Display
10-18), and the syndrome of the dorsal ver-
mis (lobules VI and VII) and underlying
caudal fastigial nuclei (see Display 6-12,
Display 6-13, Display 10-19). In addition,
there is some evidence that the cerebellar
hemispheres contribute to the control of eye
movements. Thus, during voluntary sac-
cades made between two visual targets, or
remembered target locations in darkness,
fMRI demonstrates increased activation in
the hemispheres as well as in the midline
(vermis and fastigial nuclei), as is shown in
Figure 3-10 of Chap. 3. Furthermore, le-
sions restricted to one cerebellar hemi-
sphere impair ipsilateral smooth pursuit.1336
LESIONS OF THE FLOCCULUS
AND PARAFLOCCULUS
Lesions of the flocculus and parafloccu-
lus cause gaze-evoked nystagmus, re-
bound nystagmus, and downbeat nystag-
488 The Diagnosis of Disorders of Eye Movements

Display 10-17. Clinical Findings with Lesions Affecting the

Cerebellar Flocculus and Paraflocculus
• Impaired smooth pursuit and combined eye-head tracking ("VOR
suppression")

• Impaired ability to suppress caloric nystagmus by fixating a stationary

target

• Impaired gaze-holding function, leading to gaze-evoked nystagmus,

centripetal and rebound nystagmus

• Downbeat nystagmus, often greatest on looking laterally and down-

ward

• Impaired ability to adapt the VOR to changing visual needs

• Postsaccadic drift (pulse-step mismatch)

For related anatomy, see Display 6-10 and Figure 6-6 in Chap. 6. For related etiologies, see
Table 10-12 and Table 10-13. (Related VIDEOS: "Downbeat nystagmus" and "Gaze-evoked,
rebound, and downbeat nystagmus.")

mus (see VIDEOS: "Gaze-evoked, rebound,
and downbeat nystagmus"); impaired
smooth tracking either with eyes alone
(smooth pursuit) or with eyes and head;
postsaccadic drift; and loss of some adap-
tive capabilities, such as the ability to ad-
just the gain and direction of the VOR or
the pulse-step match for saccades. Unilat-
eral lesions produce ipsilateral deficits in
pursuit and gaze holding.1336'1444'1476 In
patients with cerebellar disease, pursuit
defects with the head still, defects in com-
bined eye-head tracking, and gaze-hold-
ing deficits frequently occur together, re-
flecting their common substrate in the
flocculus and vestibular nuclei.220 Quanti-
tatively, though, pursuit with the head
still is sometimes relatively more im-
paired.545'1458 Patients with cerebellar dis-
ease may show timing errors during track-

Display 10-18: Clinical Findings with Lesions Affecting the

Cerebellar Nodulus and Ventral Uvula
• Prolongation of vestibular responses (increased velocity storage)

• Loss of ability to suppress postrotational nystagmus by tilting the head

when the rotation stops

• Positional nystagmus; downbeat nystagmus

• Periodic alternating nystagmus in darkness (present in light if floccu-

lus and paraflocculus are also lesioned, which impairs visual fixation)

For related anatomy, see Display 6-11 and Figure 6-6 in Chap. 6. For some related etiolo-
gies, see Table 10-4. (Related VIDEO: "Periodic alternating nystagmus.")
 Diagnosis of Central Disorders of Ocular Motility 489

Display 10-19: Deficits Caused by Lesions of Dorsal Vermis,

Fastigial Nucleus and Uncinate Fasciculus
DORSAL VERMIS LESION*
• Ipsilateral hypometria and mild contralateral hypermetria of saccades

• Gaze is tonically deviated away from the side of the lesion

• Smooth pursuit is impaired for targets moving toward the side of the
lesion

UNILATERAL FASTIGIAL NUCLEUS LESIONt*

• Ipsilateral hypermetria and contralateral hypometria of saccades—
"ipsipulsion"

• Gaze is tonically deviated toward the side of the lesion

• Smooth pursuit is impaired for targets moving away from the side of
the lesion

• Similar defects are features of Wallenberg's syndrome

UNCINATE FASCICULUS (WHICH RUNS IN SUPERIOR CEREBELLAR

PEDUNCLE)
• Ipsilateral hypometria and contralateral hypermetria of saccades—
"contrapulsion"

*Based on experimental pharmacological inactivation

"("Corresponds to saccadic lateropulsion in Wallenberg's lateral medullary infarction (see
Display 10-16).
For related anatomy, see Display 6-12 and Display 6-13 in Chap. 6, and Figure 3-11 in
Chap. 3. For some related etiologies, see Table 10-13. (Related VIDEOS: "Saccadic hyperme-
tria" and "Wallenberg's syndrome.")

ing of a target moving in a periodic fash-
ion,1458 but there is some preservation of a
predictive capability.845 The ability to gen-
erate anticipatory smooth eye movements
of high speed at the onset of tracking is
also impaired in some cerebellar pa-
tients.964
LESIONS OF THE NODULUS
AND VENTRAL UVULA
Lesions of the nodulus and ventral uvula
lead to an increase in the duration of ves-
tibular responses that predisposes the in-
dividual to the development of periodic
alternating nystagmus (see VIDEO: "Peri-
odic alternating nystagmus"). Other ab-
normalities of the velocity-storage mecha-
nism are present, including a failure of
tilt-suppression of postrotatory nystag-
mus,569 and loss of habituation. Positional
nystagmus and downbeat nystagmus also
occur in patients with nodular lesions.
LESIONS OF THE DORSAL VERMIS
AND FASTIGIAL NUCLEI
Lesions of the dorsal vermis and fastigial
nuclei (fastigial oculomotor region—FOR)
cause saccadic dysmetria, typically hy-
490 The Diagnosis of Disorders of Eye Movements

pometria if the vermis alone is involved,
and hypermetria if the deep nuclei are in-
volved (see VIDEO: "Saccadic hypermetria")
(Fig. 10-22). Lesions of the fastigial nuclei
generally cause marked saccadic hyperme-
tria. The pattern of saccadic dysmetria that
occurs in cerebellar disease, as well as
whether or not corrective saccades occur,
may also vary with the type of visual stimu-
lus.195 Memory-guided saccades are dys-
metric, especially if the target moves dur-
ing the memory period.716'789 In some
patients with cerebellar disease, only cor-
rective saccades are dysmetric.162 Saccadic
dysmetria may be present for externally
triggered movements to a visual target but
not for internally triggered saccades dur-
ing scanning of a visual scene.223 Large tor-
sional "blips" that occur during voluntary
saccades constitute violations of Listing's
law (see Chap. 9) and have been reported
in patients with lesions involving the ver-
mis and fastigial nuclei.607 Dorsal vermal le-
sions may also produce mild deficits of pur-
suit,756-1079'1412 as well as defects in motion
perception.1002 Bilateral symmetric lesions
of the fastigial nuclei do not lead to pursuit
deficits,223 though unilateral lesions lead to
a contralateral deficit,1161 probably because
of an imbalance in eye acceleration signals.

Figure 10-22. Cerebellar disease causing saccadic dysmetria. A CT showed a large cystic astrocytoma, primarily
involving the dorsal vermis of the cerebellum. The patient's only clinical deficit was saccadic dysmetria (see
VIDEO: "Saccadic hypermetria"). Other ocular motor and general neurologic findings were normal.
 Diagnosis of Central Disorders of Ocular Motility
Other Disorders of Eye
Movements Attributed to
Cerebellar Disease
Disorders of ocular alignment encountered
in association with cerebellar disease in-
clude esotropia, especially for distance
viewing (divergence paralysis); alternat-
ing skew deviations1427'1527; disconjugate
(poorly yoked) saccades; and disconjugate
gaze-evoked nystagmus.1427
Fixation is commonly disrupted in pa-
tients with cerebellar disease, either by
nystagmus or saccadic intrusions. In ad-
dition to the forms of nystagmus that
are part of the three principal cerebel-
lar syndromes, divergent nystagmus (Fig.
10-6),1509 centripetal nystagmus (Display
10-7),824 central position upbeating nys-
tagmus (see VIDEO: "Upbeat nystagmus"),322
seesaw nystagmus (Fig. 10-8),1547 and ac-
quired pendular nystagmus (see VIDEOS:
"Acquired nystagmus impairing vision")62
have all been reported in patients with
cerebellar disease. Hyperventilation-in-
duced downbeat nystagmus may occur in
some patients with cerebellar disease, per-
haps reflecting abnormalities of calcium
channels that are known to occur in some
forms of cerebellar degeneration.1452 A va-
riety of saccadic intrusions occur com-
monly in association with cerebellar dis-
ease but may not be specific for it.
One example is square-wave jerks (Fig
10-16A), which are a common finding in
patients with Friedreich's ataxia. 1117 ' 1312
A singular disturbance of smooth pursuit
is the presence of torsional nystagmus
during vertical tracking.461 This has been
described in patients with cavernous an-
giomas in the middle cerebellar peduncle.
The direction of such torsional nystagmus
changes with the direction of the pursuit,
with the eye velocity of the slow phase of
the torsional nystagmus being directly
proportional to the eye velocity of the slow
phase of pursuit. This sign may occur be-
cause smooth pursuit is programmed in,
or superimposed upon, a phylogenetically
old, vertical "labyrinthine-optokinetic"
coordinate system so that for a pure verti-
cal pursuit movement to occur opposite
torsional components must cancel (as is
the case for a pure vertical vestibular nys-
491
tagmus). The middle cerebellar peduncle
carries information to the cerebellum
from the pontine nuclei, including the nu-
cleus reticularis tegmenti pontis (NRTP),
which may contain vertical pursuit signals
encoded with a torsional component.
Other vestibular abnormalities are re-
ported in patients with cerebellar disease,
including vestibular hyperresponsiveness
(increased VOR gain),1372 increased re-
sponsiveness of the cervico-ocular re-
flex,189 abnormalities of off-vertical axis
rotation (OVAR) with an increase in the
modulation component and a decrease in
the bias component,313 and impaired re-
sponses to linear translation (L-VOR).89
The cerebellum is also important in
long-term adaptive functions that keep eye
movements appropriate to the visual stim-
ulus. For example, adaptive properties of
the VOR are impaired in patients with
cerebellar lesions.1502 This adaptive or "re-
pair shop" function of the cerebellum
probably accounts for both the enduring
nature of the ocular motor deficits that ac-
company diffuse cerebellar lesions and,
perhaps, the somewhat variable effects of
cerebellar lesions. Thus, inherent, idio-
syncratic abnormalities in brain stem or
peripheral ocular motor mechanisms that
are normally "repaired" by the cerebellum
may reappear after cerebellar lesions. For
example, some patients with cerebellar
disease may not be able to adapt to a pho-
ria induced by wearing prisms.568'944 Chil-
dren with cerebellar lesions often make
better recoveries than do adults.832'1456 If
cerebellar ablation is performed in neona-
tal monkeys, almost complete recovery oc-
curs, provided that the deep cerebellar
nuclei are left intact; if they are not, gaze
holding and smooth pursuit never fully
recover.413
Developmental Anomalies of the
Hindbrain and Cerebellum
Arnold-Chiari malformation is an anom-
aly of the hindbrain involving the caudal
cerebellum (including the vestibulocere-
bellum, flocculus, paraflocculus [tonsils],
uvula, and nodulus) and the caudal me-
492 The Diagnosis of Disorders of Eye Movements
dulla. In Chiari type I malformation, the
cerebellar tonsils are displaced caudally
into the foramen magnum, the medulla
is elongated, and a meningomyelocele is
only rarely present. Such patients often
present with symptoms in adult life. In
Chiari type II malformation, both the
fourth ventricle and inferior vermis ex-
tend below the foramen magnum, the
brain stem and spinal cord are thin, and a
lumbar meningomyelocele is usually pres-
ent. Patients with type II malformation
usually present in childhood, but, in
milder cases, onset of symptoms is delayed
until adulthood. Presenting symptoms in-
clude oscillopsia (brought on or exacer-
bated by head movements) and Valsalva-
induced dizziness, vertigo, cervical pain,
and headaches.1487 A variety of ocular mo-
tor abnormalities, especially downbeat
nystagmus (both spontaneous and posi-
tional), has been reported in patients
with Arnold-Chiari malformation (Table
10-12). Many of these signs are repro-
duced by vestibulocerebellar lesions in
monkeys.1538 The positional nystagmus of
posterior fossa lesions548'731-1460 must be
differentiated from the more common be-
nign paroxysmal positional nystagmus of
the labyrinth. Diagnosis is by MRI, with
sagittal views of the craniocervical junc-
tion (Fig. 10-23).157-1113 Patients often im-
prove after suboccipital decompression,
although it may take months for the
eye movement abnormalities to dimin-
ish.1073'1313
The Dandy-Walker syndrome consists of
malformation of the cerebellar vermis, a
membranous cyst of the fourth ventricle,
and malformations of the cerebellar cor-
tex and deep cerebellar nuclei. Patients
may show a mild saccadic dysmetria,
though eye movements may be normal.832
Ocular motor abnormalities, including
nystagmus and strabismus, have also been
reported in patients with agenesis of the
vermis227 or hypoplasia of the entire
cerebellum.1218 Other rare syndromes as-
sociated with anomalous cerebellar devel-
opment include Coffin-Siris syndrome (de-
velopmental delay, hypotonia, cutaneous
changes, and abnormalities of the roof of
the fourth ventricle)341 and Joubert's syn-
drome (a variable combination of episodic
Table 10-12. Disturbances in Eye
Movements Encountered in
Arnold-Chiari Syndrome
Downbeat nystagmus (occasionally with a tor-
sional component), worse on lateral
gaze267,580,731,1313,1509,1532
Divergence nystagmus 1509
Convergence nystagmus 972
Horizontal nystagmus (unidirectional, present
with eyes in central position—see Fig. 10-7)
Periodic alternating nystagmus492
Gaze-evoked nystagmus23
Rebound nystagmus including torsional re-
bound1337
Seesaw nystagmus1547
Impaired pursuit (and VOR cancellation)1532
Impaired OKN with slow buildup of eye
velocity in response to a constant-velocity
stimulus1509
Strabismus20'247*-864
Divergence paralysis864
Skew deviation accentuated or alternating on
lateral gaze1527
Saccadic dysmetria47
Internuclear ophthalmoplegia47
Increased VOR gain1532
Shortened VOR time constant and impaired
tilt suppression569
Positional nystagmus86
tachypnea, psychomotor retardation, reti-
nal dystrophy, torsional nystagmus, skew
deviation, ocular motor apraxia, agenesis
of the cerebellar vermis, and fibrosis of the
extraocular muscles).508'764'807'903'1216
Ocular Motor Findings in the
Hereditary Ataxias
With the identification of several genes re-
sponsible for the hereditary ataxias has
come an attempt to link phenotype with
genotype. Substantial efforts have been
made to achieve this goal by identifying
distinctive syndromes of abnormal eye
movements. Some results of these studies
are summarized in Table 10-13. While it
appears that certain findings are quite dis-
tinctive for one gene mutation, there is
enough overlap to advise caution in trying
 Diagnosis of Central Disorders of Ocular Motility 493

Figure 10-23. MRI scan showing caudal displacement of the cerebellar tonsils below the foramen magnum,
with flattening of the brain stem, typical of Arnold-Chiari malformation.

to assign an individual to one group on family with SCA3 (Machado-Joseph dis-

the basis of eye movements findings alone.
So, for example, the presence of very slow
saccades is suggestive of spinocerebellar
ataxia type 2 (SCA2) (see VIDEO: "Slow hori-
zontal saccades") formerly called olivopon-
tocerebellar degeneration of Wadia and Swami,
in which pontine saccadic burst cells are
also involved.649'1443 Similarly, the pres-
ence of prominent downbeat, gaze-evoked,
and rebound nystagmus, with normal ve-
locity saccades, is typical of SCA6,525'1539
which may also correspond to late-onset,
Holmes-type cerebellar degeneration and
to the autosomal dominant "pure" cere-
bellar ataxia (autosomal dominant cere-
bellar ataxia—ADCA3—of Harding) (see
VIDEOS: "Gaze-evoked, rebound and down-
beat nystagmus").586 However, saccades
may also be slow in patients with SCA1,211
and we have recorded slow saccades and
downbeat nystagmus in members of a
ease).789 The clinical picture changes as
the disease develops.774 Another factor
may be that the severity of the disturbance
in any one individual may correlate with
the number of trinucleotide repeats, al-
though only a small number of repeats
(fewer than 30) may be associated with
certain diseases, such as SCA6.1548 Fur-
thermore, there is some suggestion of
overlap between certain syndromes, such
as SCA6 and familial episodic vertigo and
ataxia type 2 (EA-2), both of which
affect the calcium channel (CACNL1A4)
gene.90'175'509 Features of the episodic atax-
ias are summarized in Table 10-13. Fi-
nally, some patients with genetically con-
firmed SCA1 have been reported to show
clinical and neuropathologic findings in-
distinguishable from multiple system atro-
phy.515 Thus, the clinician must keep in
mind a broad spectrum of differential di-
Table 10-13. Ocular Motor Findings in Hereditary Ataxias*

Current Name Other Distinguishing

(Possible Former Name) Chromosome Ocular Motor Findings^ Features

SCA1 6p Saccades mildly slow and hypermetric; Pyramidal tract signs; dysphagia; optic
GEN; RBN; VOR gain decreased nerve pallor

SCA2 (olivopontocerebellar atrophy) 12q Very slow saccades, especially horizon- Cerebellar dysarthria; hypoactive ten-
tally don reflexes

SCA3 (Machado-Joseph disease) 14q Saccadic hypometria and hypermetria; Faciolingual myokymia; dystonia;
GEN; RBN; SWJ; VOR gain de- parkinsonism
creased; strabismus

SCA4 16q Not systematically studied Sensory axonal neuropathy

SCA5 1 1 -centromere Not systematically studied Mild ataxia

SCA6 (Holmes type; ADCA3 of Harding) 19p Normal velocity, dysmetric saccades; Late onset; "Pure" cerebellar atrophy
DBN; GEN; RBN; SWJ; VOR gain with loss of Purkinje cells
increased or decreased

SCA7 (ADCA2 of Harding) 3p Slow saccades; supranuclear ophthal- Pigmentary maculopathy and visual
moplegia loss; hearing loss; extrapyramidal
signs

Dentatorubral pallidoluysian atrophy 12p Slow saccades Epilepsy, myoclonus, choreoathetosis,

(Haw River syndrome) dementia

Episodic Ataxia (EA)-l 12pl3 (potassium No vertigo Brief attacks of ataxia; interictal
channel) myokymia
Episodic Ataxia (EA)-2 19p (calcium channel) Vertigo; interictal nystagmus Prolonged attacks; may show progres-
sive ataxia; possible overlap with
SCA6
Friedreich's ataxia (classic and atypical 9q SWJ; VOR gain decreased Recessive; onset usually before 20
forms) years; sensory loss; areflexia;
Babinski responses; cardiomyopa-
thy; diabetes

Hereditary Vitamin E deficiency (alpha- 8q Progressive gaze restriction; slow sac- Recessive; Friedreich-like picture;
tocopherol transfer protein gene); also cades; dissociated nystagmus, in retinitis pigmentosa may be
abetalipoproteinemia which adduction is faster than associated
abduction
Ataxia telangiectasia (Louis-Bar syndrome) 1 Iq Ocular motor apraxia: hypometria, in- Recessive; oculocutaneous telangiecta-
creased latency, normal velocity of sia; radiosensitivity; immunological
saccades; head thrusts; GEN; PAN; disorders; cancer; elevated alpha-
SWJ fetoprotein
* References 211,212,3243,525,773,774,866,963,1117,1151,1218a,i233a, 1312,1327,1474,1514,1517a
tlmpaired smooth pursuit eye movements are a common finding in most forms of cerebellar degeneration ADCA: autosomal dominant cerebellar ataxia (Harding's clas-
sification)586: (ADCA1: "ataxia plus"; ADCA2: ataxia with macular retinopathy; ACDA3: pure cerebellar ataxia); DBN: downbeat nystagmus; EA: episodic ataxia; GEN:
gaze-evoked nystagmus; PAN: periodic alternating nystagmus; RBN: rebound nystagmus; SCA: spinocerebellar ataxia; SWJ: square-wave jerks; VOR: vestibulo-ocular
reflex.
496 The Diagnosis of Disorders of Eye Movements
agnoses when confronted by a patient with
progressive ataxia and abnormal eye
movements. Progress in understanding
the underlying molecular genetics of these
disorders may clarify the pathogenesis of
the phenotypes.
Paraneoplastic Cerebcllar
Degeneration
This is a rare "remote effect" of can-
cer, usually occurring in association with
small-cell lung cancer and breast and
ovarian carcinoma.36'910'1100 The onset of
symptoms is usually acute or subacute,
with the development of severe midline
and appendicular ataxia, dysarthria, and
downbeat nystagmus (see VIDEO: "Down-
beat nystagmus"). Many patients will show
Yo or Hu antineuronal antibodies. Since
pathologic studies indicate total loss of
Purkinje cells, such patients have effec-
tively lost all output from the cerebellar
cortex. The common finding of primary-
position downbeat nystagmus, therefore,
is of interest because it tends to confirm
that asymmetric, inhibitory projections of
the cerebellum to the central connections
of the semicircular canals can cause this
nystagmus (see Pathogenesis of Cen-
tral Vestibular Nystagmus). Treatment is
presently unsatisfactory.1102'1437 A cerebel-
lar syndrome may also complicate treat-
ment of cancer or leukemia with cytosine
arabinoside.144
Cerebellar Infarction
Three branches of the posterior circula-
tion supply the cerebellum: the poste-
rior-inferior cerebellar artery, the ante-
rior-inferior cerebellar artery, and the
superior cerebellar artery.1358 Occlusion in
these vessels often produces concurrent
brain stem infarction, making precise clin-
icopathologic correlation difficult.
The posterior-inferior cerebellar artery
(PICA) arises from the vertebral artery
and supplies the lateral medulla, the infe-
rior cerebellar peduncle, and the nodulus
and uvula. Thus, occlusion of the PICA
may cause Wallenberg's syndrome. Infarc-
tion in the distribution of the distal PICA
may cause acute vertigo and nystagmus
that often simulates an acute peripheral
vestibular lesion.410'897'1192 These symp-
toms are probably due to a central vestibu-
lar imbalance created by asymmetric in-
farction in the vestibulocerebellum, which
normally has a tonic inhibitory effect upon
the vestibular nuclei. Such patients may
have prominent gaze-evoked nystagmus,
which helps differentiate this cerebellar
lesion from an acute peripheral vestibu-
lopathy.
The anterior-inferior cerebellar artery
(AICA) is usually the most caudal large ves-
sel arising from the basilar artery. It sup-
plies portions of the vestibular nuclei, ad-
jacent dorsolateral brain stem, and inferior
lateral cerebellum (often including the
flocculus). In addition, the AICA is the ori-
gin of the labyrinthine artery in most indi-
viduals and also sends a twig to the cere-
bellar flocculus in the cerebellopontine
angle. Consequently, ischemia in the AICA
distribution (Fig. 10-21) may cause ver-
tigo, vomiting, hearing loss, facial palsy,
and ipsilateral limb ataxia. Unilateral loss
of vestibular function may cause asymmet-
ric responses with rapid head turns [see
VIDEO: "Anterior inferior cerebellar artery
(AICA) distribution infarction"]. In addi-
tion, there may be gaze-evoked nystagmus,
impaired smooth pursuit, and sponta-
neous vestibular nystagmus.27-541'1028
The superior cerebellar artery (SCA)
arises from the rostral basilar artery and
supplies the superior surface of the cere-
bellar hemisphere and vermis and the su-
perior cerebellar peduncle. Infarction in
the territory of the superior cerebellar
artery causes ataxia of gait and limbs, and
vertigo.115'1120'1409 A characteristic abnor-
mality is saccadic contrapulsion. This con-
sists of an overshooting of contralateral
saccades and an undershooting of ipsilat-
eral saccades; attempted vertical saccades
are oblique, with a horizontal component
away from the side of the lesion. Thus, the
disorder is the opposite of the saccadic ip-
sipulsion seen in Wallenberg's syndrome
and probably reflects interruption of out-
puts from the fastigial nucleus running in
the uncinate fasciculus next to the supe-
rior cerebellar peduncle.1332'1448 Infarction
restricted to the posterior-inferior vermis
 Diagnosis of Central Disorders of Ocular Motility 497

has been reported to selectively impair the inability to suppress postrotational

pursuit and optokinetic eye movements.1079
Cerebellar Mass Lesions
Cerebellar hemorrhage, tumors, infarction,
abscesses, cysts, and extraaxial hematomas
may all cause cerebellar eye signs by direct
involvement of cerebellar parenchyma.
However, acutely expanding or large cere-
bellar mass lesions, such as hemorrhage, of-
ten also compress the brain stem and pro-
duce additional signs (see VIDEO: "Ocular
bobbing"). Either vertical or horizontal
gaze disorders can occur depending upon
whether the direction of compression is ros-
tral or forward, respectively. Acute cerebel-
lar hemorrhage frequently causes nystag-
mus, horizontal gaze palsy (usually toward
the side of the lesion), and skew deviation.
These signs are, in part, due to brain stem
compression. The third, fourth, and sixth
cranial nerves may also be affected. Ocular
motor dysfunction may also be caused by
secondary obstructive hydrocephalus and
increased intracranial pressure.
Medulloblastoma arising in the poste-
rior medullary velum frequently causes
positional nystagmus, presumably due to
involvement of the nodulus and uvula.543
Such involvement may also account for
nystagmus by tilting the head.569 Tumors
within the fourth ventricle may affect
the cerebellar nuclei, vestibulocerebellum,
and dorsal medulla, sometimes producing
upbeat or downbeat nystagmus.
Acoustic schwannoma may compress
the cerebellar flocculus and paraflocculus,
which lie in the cerebellopontine angle,
and so cause the flocculo-nodular syn-
drome (Display 10-17). In addition, pa-
tients may show Bruns' nystagmus, in
which there is a "coarse" gaze-evoked nys-
tagmus beating toward the side of the
lesion and a "fine" vestibular nystagmus
beating away from the side of the le-
sion.80'200'1004 Asymmetry of the caloric re-
sponses and of rotational testing may be
observed,119'954 but the most sensitive and
specific method used to detect small tu-
mors is MRI with gadolinium.1109
OCULAR MOTOR SYNDROMES
CAUSED BY DISEASE OF
THE PONS
Lesions of the Abducens Nucleus
Lesions of the abducens nucleus (see Dis-
play 6-1) cause an ipsilateral palsy of hor-
izontal conjugate gaze (Display 10-20).

Display 10-20: Clinical Findings with Lesions of the

Abducens Nucleus
• Loss of all conjugate movements toward the side of the lesion—"ipsi-
lateral, horizontal gaze palsy"

• Contralateral gaze deviation, in acute phase

• Vergence and vertical movements are spared

• In the intact hemifield of gaze, horizontal movements may be pre-

served, but ipsilaterally directed saccades are slow

• Horizontal gaze-evoked nystagmus on looking contralaterally

• Ipsilateral facial palsy often associated

For related anatomy, see Display 6-1 and Figure 6-1 in Chap. 6
498 The Diagnosis of Disorders of Eye Movements
Movements of both eyes are affected be-
cause the abducens nucleus contains two
main groups of neurons: abducens mo-
toneurons, which innervate the ipsilateral
lateral rectus muscle, and abducens inter-
nuclear neurons, which cross the midline
and ascend in the medial longitudinal fas-
ciculus to innervate the contralateral me-
dial rectus motoneurons (see Fig. 6-1,
Chap. 6). Vergence movements of the eyes
are spared, so some adduction of the con-
tralateral eye may be possible with a near
stimulus. These movements are spared be-
cause vergence depends mainly on inputs
passing directly to medial rectus motoneu-
rons in the oculomotor nucleus. Saccadic,
pursuit, optokinetic, and vestibular move-
ments are still present in the contralateral
hemifield but are impaired when directed
toward the side of the lesion. Thus, in the
case of a left abducens nucleus lesion, sac-
cades from center to right gaze are pre-
served because they depend on projec-
tions to the intact abducens nucleus from
the excitatory burst neurons of the right
paramedian pontine reticular formation
(PPRF). Saccades from right gaze to center
are slow because they depend solely on
projections to the intact, right abducens
nucleus from the inhibitory burst neurons
of the left medullary reticular formation;
thus eye velocity is a function of antagonist
muscle relaxation rather than agonist con-
traction. Another factor in asymmetry of
residual movements may be horizontal
gaze-evoked nystagmus on looking con-
tralaterally (to the right, in the above ex-
ample). Such nystagmus is probably due
to interruption of fibers of passage from
the medial vestibular nucleus, which pro-
vide an eye position signal to the con-
tralateral abducens nucleus,30 or due to
interruption of fibers from cell groups of
the paramedian tracts (PMT), which lie at
the rostral end of the abducens nucleus
(see Display 6-4).988 Clinical lesions re-
stricted to the abducens nucleus are
rare. 116,629,933,988,1083 More commonly, the
abducens nucleus is affected in association
with adjacent tegmental structures, espe-
cially the medial longitudinal fasciculus
and the paramedian reticular formation.
An ipsilateral facial palsy usually occurs
with abducens nucleus lesions, owing to
involvement of the adjacent genu of the
seventh cranial nerve. Mobius syndrome, a
congenital brain stem anomaly with hori-
zontal gaze disturbances often with an as-
sociated facial palsy,29 may represent con-
genital hypoplasia of the abducens and
facial nuclei. Failure of development of
the abducens motoneurons, but not the
internuclear neurons, accounts for some
of the findings in Duane's syndrome. Both
Mobius and Duane's syndromes are dis-
cussed in Chap. 9.
Lesions of the Paramedian Pontine
Reticular Formation (PPRF)
Although the predominant effect of de-
structive lesions of the paramedian pon-
tine reticular formation (PPRF) falls on
ipsilateral horizontal saccades (Display
10-21), other horizontal and vertical eye
movements may be affected because the
PPRF contains several different popula-
tions of neurons that are important for
generating saccades (see Display 6-3), as
well as fibers of passage. Excitatory burst
neurons, which are important in the gen-
eration of horizontal saccades, lie in dor-
somedial portions of the nucleus pontis
centralis caudalis (see Fig. 6-2, 649
Chap. 6),
rostral to the abducens nucleus. Excita-
tory burst neurons project to the ipsilat-
eral abducens nucleus. At the level of the
abducens nucleus lies the nucleus raphe
interpositus, which contains omnipause
neurons that inhibit all burst neurons
(horizontal and vertical) except during
saccades. Caudal to the abducens nucleus,
in the dorsomedial tegmentum, lie the in-
hibitory burst neurons, which receive in-
puts from the ipsilateral excitatory burst
neurons but project to the contralateral
abducens nucleus. Additional cell groups
involved in the control of eye movements
lie within the PPRF, such as the nucleus
pararaphales, a member of the cell groups
of the paramedian tracts (PMT) (see Dis-
play 6-4) that project to the cerebellar
flocculus.217 Finally, the PPRF and adja-
cent pons contain fibers of passage that
carry vestibular, pursuit, and gaze-holding
signals to the abducens nucleus.
 Diagnosis of Central Disorders of Ocular Motility 499

Display 10-21: Clinical Findings with Lesions of the Parame-

dian Pontine Reticular Formation (PPRF)
• Loss of horizontal saccades directed toward the side of the lesion, in
all fields of gaze

• Contralateral gaze deviation, in acute phase

• Gaze-evoked nystagmus on looking contralateral to the lesion

• Ipsilateral smooth pursuit and vestibular eye movements may be pre-

served or impaired

• Bilateral lesions cause total horizontal gaze palsy and slowing of verti-
cal saccades

For related anatomy, see Display 6-3 and Figure 6-2 in Chap. 6. (Related VIDEOS: "Pontine
gaze palsy.")

Unilateral lesions of the PPRF, such as
infarction, cause an ipsilateral, conjugate,
horizontal gaze palsy that may involve all
classes of eye movements, but vestibular
and even pursuit eye movements are
sometimes spared.707'785'1084 Acutely, the
eyes may be deviated contralaterally. Nys-
tagmus occurs when gaze is directed into
the intact contralateral field of movement,
with quick phases directed away from the
lesioned side; this is usually accentuated in
darkness. Ipsilaterally directed saccades
and quick phases are small and slow and
do not carry the eye past the midline.
The degree of slowing of saccades di-
rected toward the lesioned side, when
made in the intact field of gaze, may de-
pend upon whether or not inhibitory
burst neurons, which project to the con-
tralateral abducens nucleus, are involved.
Recall that excitatory saccadic inputs
reach the abducens nucleus from the ipsi-
lateral population of excitatory burst cells
in the PPRF, whereas inhibitory saccadic
inputs originate from contralateral in-
hibitory burst cells in the medulla (Fig.
6-1, Chap. 6). Thus, if the lesion is re-
stricted to the ipsilateral abducens nu-
cleus, saccades from the opposite field of
gaze to the midline may be present but
slow, since inhibition of the antagonists
(i.e., the ipsilateral medial rectus and con-
tralateral lateral rectus) is intact. However,
if the PPRF is extensively involved, partic-
ularly in its more caudal part, inhibition is
also affected, so saccades directed toward
the lesioned side are absent.988 Rapid eye
movements directed to the side opposite
the lesion appear normal. Vertical sac-
cades may be slightly slow and misdirected
obliquely away from the side of the lesion,
owing to an inappropriate horizontal com-
ponent. 710
Smooth-pursuit movements and slow
phases of optokinetic nystagmus may be
preserved, in both directions, within the
intact field of movement, but usually they
cannot bring the eyes across the midline.
Sometimes, horizontal pursuit or optoki-
netic responses are asymmetrically im-
paired. It has been suggested that more
rostral brain stem lesions tend to cause ip-
silateral smooth-pursuit deficits, whereas
caudal brain stem lesions lead to contralat-
eral deficits.708 More basal lesions in the
pons, however, tend to impair ipsilateral
or bilateral pursuit.505'1368'1444 Because of
the confluence of pursuit pathways in the
brain stem and its cerebellar connections,
the direction of a pursuit deficit with a
brain stem lesion is not reliable for deter-
mining the side of the lesion.490 In some
patients vestibular stimuli drive the eyes
past the midline.319 Presumably, either the
00
5 The Diagnosis of Disorders of Eye Movements

Figure 10-24. Horizontal gaze palsy (see Case History: Horizontal gaze palsy due to pontine metastasis for clin-
ical details) (see VIDEOS: "Pontine gaze palsy"). (A) A CT demonstrates a right-sided brain stem mass with a ring
of contrast enhancement. (B, C, and D) Movements of the left eye, recorded by electro-oculography. The time
scale, at top, is in seconds. (B) The patient is able to make normal saccades to the left but saccades to the right
are slow. Gaze-evoked nystagmus is present on gaze to the left. The patient is unable to make saccades into the
right field of gaze. (C) The patient is rotated clockwise in a vestibular chair, in darkness, at 60;dg/sec, starting at
the arrow time mark. The vestibulo-ocular reflex drives her eyes to the left, but quick phases of nystagmus are
small, infrequent, and slow. (D) She is rotated counterclockwise, in darkness, at 60;dg/sec, starting at the arrow
time mark. The vestibulo-ocular reflex drives her eyes over into the right field of gaze, which saccades and pur-
suit could not do. Normal slow and quick phases of nystagmus occur.
Continued on following page

PPRF lesion is more rostral in such indi-
viduals or the ipsilateral abducens nucleus
and its direct vestibular input are in-
tact.348'707 In an occasional patient, vestibu-
lar stimuli can only drive the contralateral
adducting eye into the ipsilateral field.
This finding implies a lesion of one PPRF
and the ipsilateral abducens nerve but
sparing the abducens nucleus. The follow-
ing case illustrates the range of abnormali-
ties that can occur with pontine lesions.
CASE HISTORY: Horizontal gaze palsy
due to pontine metastasis (see VIDEOS:
"Pontine gaze palsy").
A 52-year-old woman presented with a history
of left-sided paresthesia and unsteadiness for 6
weeks and the recent onset of horizontal
diplopia. She was alert and her cranial nerves
were normal apart from a right Horner's syn-
drome and her eye movements. She had a mild
left hemiparesis with a left extensor plantar re-
 Diagnosis of Central Disorders of Ocular Motility 501

Figure 10-24.—continued

sponse. Joint position and vibration senses
were impaired on the left side of the body. Her
gait was markedly ataxic. A CT (Fig. 10-24A)
and vertebral arteriography demonstrated a
right brain stem mass, suggestive of tumor.
She was unable to move her eyes to the right
past the midline using either saccadic or pur-
suit eye movements. Head rotation to the left,
however, drove the eyes past the midline, but
the left eye abducted incompletely. Vergence
movements also induced the left eye to cross
the midline. Vertical eye movements appeared
normal. Figure 10-24B shows that her sac-
cades to the right were slow, whereas saccades
to the left were of normal velocity. Gaze-evoked
nystagmus was present on looking to the left,
with slow phases toward the midline. When
she was rotated to the right in darkness
(Fig.lO-24C), there was a good vestibular re-
sponse with the eyes moving to the left. How-
ever, quick phases directed to the right were
small, slow, and infrequent. When she was ro-
tated to the left (Fig.lO-24D), slow phases to
the right occurred, with good quick phases di-
rected to the left.
The patient was treated with radiation and
steroids but her disease progressed. She subse-
quently lost all abduction of the right eye (sixth
502 The Diagnosis of Disorders of Eye Movements
nerve palsy) but she could still adduct the left
eye during head rotation. The patient died a
few months later; no autopsy was performed.
Comment: This patient initially showed a
right horizontal gaze palsy that selectively im-
paired saccades and smooth pursuit. In addi-
tion, she had partial involvement of the fasci-
cles of the right abducens nerve. Thus,
preservation of rightward movements of her
left eye for the vestibulo-ocular reflex indicated
that her right abducens nucleus was intact, but
its saccadic and smooth pursuit inputs were se-
lectively interrupted. (She also lacked a facial
palsy, which is almost invariable with abducens
nucleus lesions.) In the intact hemifield of
gaze, saccades and quick phases to the right
were very slow. This finding probably reflects
loss of not only the excitatory connections from
the right PPRF to the right abducens nucleus
but also the projections from the right PPRF,
via the inhibitory burst neurons, to the con-
tralateral abducens nucleus. Impaired gaze-
holding function to the left may have reflected
involvement of fibers of passage providing an
eye position signal to the contralateral ab-
ducens nucleus, 30 or interruption of projec-
tions from cell groups of the paramedian tracts
to the flocculus.217'988 As the disease pro-
gressed, she lost all abduction of her right eye,
consistent with the right fascicular sixth nerve
palsy. She could still adduct the left eye with a
vestibular stimulus, however, suggesting that
the right abducens nucleus and its internuclear
pathway to the left oculomotor nucleus (via the
medial longitudinal fasciculus) were intact.
Convergence was preserved because these in-
puts mainly reach the medial rectus motoneu-
rons directly in the midbrain (see Fig. 6-1, in
Chap. 6).
Bilateral lesions restricted to the PPRF are
uncommon. Discrete infarction585 or tu-
mor1012 can cause a selective loss of sac-
cades, leaving smooth pursuit and the
vestibulo-ocular reflex relatively pre-
served. Such a selective deficit implies loss
or dysfunction of saccadic burst neurons
but sparing of fibers of passage conveying
smooth pursuit and the vestibulo-ocular
reflex. Experimental lesions of the PPRF
in monkeys, using neurotoxins that spare
fibers of passage, may cause a similar
deficit.611 During the recovery phase from
horizontal gaze palsies, patients may sub-
stitute convergence for impaired conju-
gate adduction and then cross-fixate to ex-
tend their range of view.110 Furthermore,
during recovery from bilateral gaze palsies
due to vascular lesions, involuntary synki-
netic divergence and convergence move-
ments may appear with horizontal or ver-
tical gaze.149-203 Although bilateral pontine
lesions may abolish all horizontal eye
movements, with chronic lesions such as
tumors, reflex eye movements may be
spared.73-1084
Bilateral pontine lesions may also im-
pair vertical eye movements, especially
saccades.397'585'1387 Thus, slow vertical sac-
cades are reported in patients with dis-
crete, bilateral pontine lesions585'612'1293
and in monkeys following bilateral lesions
of the PPRF using neurotoxins.611'718 Since
omnipause cells project to horizontal burst
neurons in the pons and to vertical burst
neurons located in the midbrain, pontine
lesions could lead to desynchronization of
the discharge of both sets of burst neurons
and, consequently, to slow vertical as well
as horizontal saccades. When vertical ves-
tibular and smooth pursuit eye move-
ments are also affected, involvement of the
medial longitudinal fasciculus (MLF) and
other pathways ascending through the
pons may be the explanation.
Lesions of the Medial Longitudinal
Fasciculus: Internuclear
Ophthalmoplegia UNO)
Lesions affecting the medial longitudinal
fasciculus (MLF) (see Display 6-2) cause
INO. Both horizontal and vertical eye
movements are affected (Display 10-22).
This is because some of the axons in the
MLF carry a command for conjugate hori-
zontal movements from abducens internu-
clear neurons to the medial rectus subdivi-
sion of the contralateral oculomotor
nucleus (Fig. 6-1, in Chap. 6), while other
axons carry vestibular and smooth pursuit
signals from neurons in the vestibular nu-
clei to midbrain nuclei concerned with
vertical gaze (Fig. 6-5, in Chap. 6).
 Diagnosis of Central Disorders of Ocular Motility 503

Display 10-22: Clinical Features of Internuclear

Ophthalmoplegia (INO)
• Weakness of the ipsilateral medial rectus muscle for conjugate eye
movements—especially saccades, leading to "adduction lag"

• Adduction may be preserved during convergence

• Nystagmus or postsaccadic drift on abduction of the eye contralateral

to the lesion—"dissociated nystagmus"

• Skew deviation—hypertropia on the side of the lesion

• Dissociated vertical nystagmus—downbeat in the ipsilateral eye and

torsional in the contralateral eye

• Bilateral INO also causes gaze-evoked vertical nystagmus, impaired

vertical pursuit, and decreased vertical vestibular responses

• Small-amplitude saccadic intrusions may interrupt fixation

For related anatomy, see Display 6-2, Figure 6-1, and Figure 6-5 in Chap. 6. For records of
eye movements, see Figure 10-26 and Figure 10-27 of Chap. 10. For related etiologies, see
Table 10-14. (Related VIDEOS: "Bilateral internuclear ophthalmoplegia," "Skew deviation,"
and "Unilateral internuclear ophthalmoplegia.")

CLINICAL MANIFESTATIONS present, suggesting increased vergence

OF INO
The cardinal sign of INO is paresis of ad-
duction by the eye on the side of the MLF
lesion during conjugate movements (see
VIDEOS: "Unilateral internuclear ophthal-
moplegia"). The same eye may be able to
adduct during convergence movements
(see VIDEO: "Bilateral internuclear oph-
thalmoplegia"). Different degrees of INO
cause paralysis of adduction or paresis
that is only apparent as slowing of adduct-
ing saccades. Making the clinical diagnosis
of INO often rests on judging the conju-
gacy of large horizontal saccades, looking
for relative slowing of the adducting
movement, called adduction lag. A com-
monly associated feature is nystagmus on
abduction of the eye contralateral to the
lesion. Disconjugacy of the quick phases of
this nystagmus with slowing of the adduct-
ing eye (a form of dissociated nystagmus)
is very suggestive of INO. Convergence
eye movements may be preserved, im-
paired, or, acutely, an esophoria may be
tone.60 Skew deviation also often accompa-
nies INO, with hypertropia on the side of
the lesion (see VIDEO: "Skew deviation").
Dissociated vertical nystagmus—downbeat
in the ipsilateral eye and torsional in the
contralateral eye—may be present. Bilat-
eral INO often causes additional findings:
gaze-evoked vertical nystagmus, impaired
vertical pursuit, and decreased vertical
vestibular responses. Small-amplitude sac-
cadic intrusions may interrupt fixation.
INO may cause diplopia or oscillopsia.
ETIOLOGY OF INO
Many disorders have been reported to
cause INO, and these are summarized in
Table 10-14. As a generalization, unilat-
eral INO is most commonly related to
ischemia, although even in these cases the
other side is often subtly involved. Bilat-
eral INO is commonly due to demyelina-
tion associated with multiple sclerosis, but
even in multiple sclerosis the INO may be
quite asymmetric.480 In some patients, it
504 The Diagnosis of Disorders of Eye Movements
Table 10-14. Etiology of
Internuclear Ophthalmoplegia
Multiple sclerosis (commonly bilateral);989'1339
postirradiation demyelination853
Brain stem infarction (commonly unilat-
eral), 783,951,1392 including complication of ar-
teriography800'1135 and hemorrhage231
Brain stem and fourth ventricular tu-
804
mors46,275,i236,i396 and mesencephalic clefts
Arnold-Chiari malformation and associated
hydrocephalus and syringobul-
Dia47,269,336,1013,1209,1494
Infection: bacterial, viral, and other forms of
meningoencephalitis;269'675'908 in association
with AIDS582-1076
Hydrocephalus,1013 subdural hematoma,383
supratentorial arteriovenous malforma-
tion292
Nutritional disorders: Wernicke's en-
cephalopathy,273 pernicious anemia717
Metabolic disorders: hepatic encephalopa-
thy,232 maple syrup urine disease,1531 abeta-
lipoproteinemia,1510 Fabry's disease632
Drug intoxications: phenothiazines,291 tricyclic
antidepressants,398'655 narcotics,416'1155 pro-
pranolol,306 lithium,347 barbiturates 97
Cancer: carcinomatous infiltration 470 or re-
mote effect1093
Head trauma,749'977'1338 and cervical hyperex-
tension,698 or manipulation 1525
Degenerative conditions: progressive supranu-
clear palsy911
Syphilis269
Pseudo-internuclear ophthalmoplegia of myas-
thenia gravis,517 and Miller Fisher
syndrome1352
may be possible to demonstrate a lesion in
the MLF with MRI (Fig. 10-25);987 thin
cuts and sagittal, T2-weighted images may
be required.
PATHOGENESIS OF FINDINGS
ININO
Paresis of Adduction in INO
Adduction weakness for conjugate move-
ments is due to involvement of axons of
abducens internuclear neurons; thus, con-
jugate commands coming into the ab-
ducens nucleus are not properly relayed
to the medial rectus motoneurons in the
contralateral oculomotor nucleus. Al-
though the weakness of the medial rectus
affects all types of conjugate eye move-
ments, it is most evident during saccades,
the speed of which depends on a strong
agonist contraction. When INO is due to
demyelinating diseases, there may be a
discrepancy between the involvement of
saccades and other movements because
demyelinated fibers cannot carry the
high-frequency discharges required dur-
ing the saccadic pulse but can sustain
lower-frequency discharges that occur with
other movements. This dissociation is re-
flected in a pulse-step mismatch (see Fig.
3-13, Chap. 3) since saccade speed (deter-
mined by the high-frequency "pulse" of
innervation) is diminished out of propor-
tion to the limitation in range of adduc-
tion (determined by the low-frequency
"step" of innervation). These findings are
evident in the records shown in Figure
10-26 (top right panel) (see VIDEOS:
"Unilateral internuclear ophthalmoplegia"),
which are taken from a patient with a
right-sided INO. When she attempted to
look to the left, the adducting saccades of
the right eye were slow and hypometric;
each consisted of a hypometric pulse fol-
lowed by a glissadic drift of the eye toward
the target. In the left eye, abducting sac-
cades were hypermetric—overshooting
the target—and were followed by a glis-
sadic backward drift of the eye. A series of
such small saccades and drifts would give
the appearance of dissociated nystagmus.
As noted above, adduction lag is brought
out clinically by asking the patient to make
large horizontal saccades back and forth
across the midline or by using a hand-held
optokinetic drum or tape to produce nys-
tagmus that allows easy comparison of the
movements of the two eyes.364 Measure-
ment of saccades to compare the peak ve-
locity of abduction and adduction allows
identification of subtle degrees of INO
(Fig. 10-27), but these results should be
interpreted with caution because normal
subjects show greater peak velocities in
the abducting eye. A solution to this prob-
lem is to compare the ratio of measure-
ments from the two eyes. Thus, normal
subjects show little variation in the ratio ei-
ther of peak eye velocity,1419 or of peak ac-
celeration,468 of the adducting saccades to
Figure 10-25. T2-weighted MRI scan showing an infarct involving the left medial longitudinal fasciculus (hy-
perintense signal indicated by arrowhead), in a patient with internuclear ophthalmoplegia, skew deviation (left
hyperdeviation), and ocular tilt reaction (see VIDEO: "Skew deviation").

Figure 10-26. Effects of habitual monocular viewing on the eye movements of a patient with unilateral, right
internuclear ophthalmoplegia. "Prepatch" data were obtained after habitual binocular viewing, but the patient
preferred to fixate with the right eye. "Postpatch" data were obtained after 5 days of patching of the right eye to
ensure habitual left-eye viewing. Left eye viewing and right eye viewing refer to the viewing conditions at the time
the eye movements were recorded. Note the postpatch decrease in the abduction nystagmus of the left eye (de-
crease in the size of the abduction saccadic pulse and of the backward postsaccadic drift), with a commensurate
decrease in the size of the saccadic pulse and increase of the onward postsaccadic drift for the adduction sac-
cades made by the right eye. These changes were independent of which eye was viewing during the recording
session. Patching led to little change in the adducting saccades made by the left eye or abducting saccades made
by the right eye (vertical bar indicates ± 20°; horizontal bar, 500 msec). (From Zee DS, Hain TC, Carl JR. Ab-
duction nystagmus in internuclear ophthalmoplegia. Ann Neurol 1987;21:383-8, with permission of Lippincott
Williams and Wilkins.) rnr
505
506 The Diagnosis of Disorders of Eye Movements

Figure 10-27. Subtle adduction lag due to bilateral internuclear ophthalmoplegia (infrared reflection tech-
nique). The patient makes saccades to targets located at 0 degrees, and at 15 degrees right and left. The velocity
of adducting saccades of either eye is lower than that of corresponding abducting saccades. For rightward
movements, the initial saccade of the right eye is hypometric and the right eye drifts back toward central posi-
tion, causing abduction or dissociated nystagmus. LEP, left eye position; LEV, left eye velocity; REP, right eye
position; REV, right eye velocity.

abducting saccades. Patients with INO
show adduction/abduction ratios of peak
velocity or peak acceleration that consis-
tently fall outside the ranges for normal
subjects. Mild abnormalities of saccadic
abduction in the affected eye may also
characterize INO: hypometria with cen-
tripetal drifts501 and slowing.1370 These
changes in abducting saccades may be due
to impaired ability to inhibit the affected
medial rectus, although Kommerell was
unable to find any evidence of impaired
medial rectus inhibition in one patient
with a unilateral INO in whom he per-
formed ocular electromyography.783
Dissociated Nystagmus in INO
Several explanations have been offered to
account for the dissociated nystagmus of
INO, which are not necessarily mutually
exclusive. The hypothesis that has re-
ceived the most experimental support is
that the nystagmus reflects the brain's at-
tempts to compensate for the adduction
weakness. Such compensation entails an
adaptive increase in innervation to the ad-
ducting eye, which, because of Hering's
law of equal innervation, must be accom-
panied by a commensurate change in the
innervation to the strong, abducting eye.
Although this adaptive change may help
get the paretic eye on target, it leads to
overshooting saccades and postsaccadic
drift of the abducting eye—a pulse-step
mismatch that has the appearance of an
abducting nystagmus. If this is the case,
the oscillation is initiated by a saccade and,
thus, is not truly nystagmus.
One line of support for this proposal
comes from the observation that abduc-
tion nystagmus is not observed in acute
experimental INO induced by injecting li-
docaine into the MLF.501 This result im-
plies that the cause of abduction nystag-
mus must be due to processes outside the
MLF or to an adaptive response to the ini-
tial adduction weakness. Second, in pa-
 Diagnosis of Central Disorders of Ocular Motility
tients with unilateral INO, patching the
eye with the adduction weakness for sev-
eral days almost abolished the overshoot
and pulse-step mismatch of the abducting
eye (Fig 10-26).1533 A third line of support
for the proposition that the abduction nys-
tagmus is a compensatory response to a
"peripheral" weakness comes from the ob-
servation that surgically caused medial
rectus weakness leads to a similar nystag-
mus, and this nystagmus resolves if the
eye with the weak medial rectus is patched
for several days.1442
Another probable mechanism for an ab-
duction nystagmus is a dissociated gaze-
evoked nystagmus that appears more
prominent in the abducting eye because of
the adduction weakness. In contrast to the
abducting nystagmus produced by adap-
tation, such gaze-evoked abduction nys-
tagmus is usually relatively sustained, and
the postsaccadic drift would bring the eye
to the central position if it were not inter-
rupted by corrective eccentric saccades.
Interruption of paramedian tracts that
run near the MLF and carry fibers to and
from the flocculus might be responsible
for the finding. 217
Centripetal drift of the eye in abduction
nystagmus does not seem to be due to loss
of inhibition of the medial rectus of the
eye contralateral to the lesion, since both
electrophysiological studies in animals626
and an ocular electromyographic study in
a patient783 showed no evidence for such
loss of inhibition. Furthermore, as noted
above, experimental INO produced by lo-
cal anesthetic blockade of the MLF does
not acutely produce abducting nystagmus
in the contralateral eye.501 The possibility
of increased convergence tone has some
experimental support, 501 ' 1340 and is dis-
cussed further in the following section.
However, of these hypotheses, the only
one that accounts for the observed hyper-
metria of the abducting eye is the one that
proposes that the abduction nystagmus is
a compensatory response.
Abnormalities of Vergence in INO
Changes in vergence in patients with INO
are variable and preclude a single expla-
nation. When patients are able to con-
507
verge despite absence of voluntary adduc-
tion, a caudal lesion with preservation of
the medial rectus motoneurons has been
assumed. 800 However, some caution is re-
quired in applying this "rule," since me-
dial rectus motoneurons lie in three sub-
groups (Fig. 9-9B, Chap. 9), and recent
evidence suggests that the smaller mo-
toneurons that are located on the perime-
ter of the oculomotor nucleus receive a
larger vergence input than do the larger
motoneurons that lie ventrally.216 Further-
more, even when experimental INO is in-
duced by injecting lidocaine into the MLF
between the levels of the trochlear and ab-
ducens nuclei, vergence is affected; the re-
ported increase in accommodative ver-
gence led to the suggestion that the MLF
normally carries an inappropriate ver-
gence signal.501 We have encountered oc-
casional patients with acute INO and
esophoria.60 A more common finding,
however, especially with bilateral INO, is
exotropia ("wall-eyed bilateral INO"—
WEBINO). 782 Such exotropia does not
necessarily imply loss of vergence (see
VIDEO: "Bilateral internuclear ophthalmo-
plegia"). In one patient with bilateral
INO, clinicopathologic correlation failed
to find a cause for the loss of con-
vergence.1339 Although the presence of in-
tact convergence is important, its absence
does not necessarily imply a rostral lesion
involving the medial rectus nuclear subdi-
vision. This may be because some patients
simply cannot produce a strong conver-
gence effort, and the vertical disparity that
occurs when a unilateral INO is associated
with a skew deviation (see following sec-
tion) may interfere with convergence ef-
fort. Thus, caution is required in trying to
localize INO on the basis of whether con-
vergence is "preserved" or "absent" (cor-
responding to the posterior INO and an-
terior INO of Cogan,263 respectively).
More systematic studies are required to
better understand the changes in vergence
that occur with INO.
Skew Deviation in INO
Skew deviation commonly occurs with uni-
lateral INO; the higher eye is usually on the
side of the lesion (see VIDEO: "Skew devia-
508 The Diagnosis of Disorders of Eye Movements
tion"). The associated adduction defect, as
well as incyclorotation of the hypertropic
eye, makes this vertical deviation easy to dif-
ferentiate from trochlear nerve palsy. Skew
deviation is probably due to interruption of
central projections from otolithic inputs
that ascend in the MLF (see Skew Deviation
and the Ocular Tilt Reaction [OTR]).
Vertical Nystagmus in INO
Nystagmus that is downbeat in the ipsilat-
eral eye and torsional in the contralateral
eye, in association with unilateral INO,1024
can be related to interruption of the path-
ways mediating the vertical VOR (Fig.
2-3, Chap. 2). Thus, posterior semicircu-
lar canal pathways mediating excitation
pass through the MLF, but some anterior
semicircular canal pathways do not. Ex-
perimental INO, produced by lidocaine
blockade, causes ipsilateral hypertropia
and unilateral downbeating nystagmus. 501
Patients with a unilateral INO may also
have an ipsiversive torsional nystagmus
(top poles of the eyes cyclorotate so as to
beat toward the side of the lesion).343 The
torsional nystagmus is sometimes dissoci-
ated and is usually but not always associ-
ated with a skew deviation. It may relate to
interruption of pathways between the ves-
tibular nuclei and the interstitial nucleus
of Cajal (INC) (see Display 6-6, Chap. 6).
Bilateral INO
Bilateral lesions of the MLF cause bilateral
adduction weakness, bilateral abduction
nystagmus, and impaired vertical vestibu-
lar and pursuit eye movements (see Fig.
6-5). Studies of the effects of experimen-
tal426 and clinical bilateral lesions of the
MLF 1122 have clarified the deficits in verti-
cal gaze that occur with INO. These
deficits follow both unilateral and bilateral
lesions, though they are more enduring
with bilateral ones.1122 Both the upward
and downward vestibulo-ocular reflexes
have reduced gain, and eye velocity may
lag head velocity; the consequence is ap-
preciable drift of images upon the retina
and oscillopsia during vertical head rota-
tions. Vertical optokinetic nystagmus is
impaired and vertical optokinetic after-
nystagmus is abolished. Vertical smooth
pursuit is moderately impaired. The
vestibulo-ocular reflex is not apprecia-
bly canceled during combined eye-head
tracking. Vertical gaze holding is also im-
paired. However, the partial preservation
of vertical gaze holding in INO—or after
lesions of the prepositus and medial ves-
tibular nuclei—confirms that the intersti-
tial nucleus of Cajal plays the major role as
the vertical neural integrator.298
Some patients with bilateral INO have
been noted to have impaired fixation. In
such patients, sporadic bursts of monocu-
lar abducting saccades may occur in each
eye. The presence of saccadic intrusions in
patients with bilateral INO suggests in-
volvement of the brain stem in addition to
the MLF.618
Visual Symptoms Due to INO
Patients with INO may have no visual
symptoms, particularly when there is no
limitation of adduction. In other cases, the
presence of either limitation of adduction
or skew deviation may cause diplopia that
is horizontal, vertical, or oblique. Some
patients with INO complain of oscillop-
sia.533 In the horizontal plane, this usually
occurs from either the adduction lag or
the abduction nystagmus. In the vertical
plane, however, it occurs during head
movements and is caused by a deficient
vertical vestibulo-ocular reflex.558 In many
patients, visual symptoms become less
bothersome or resolve completely, either
because of recovery of function of MLF
axons400 or because of more central adap-
tive mechanisms.
Variants of INO
Lesions that damage the MLF may also
damage adjacent structures such as the ab-
ducens nucleus; these syndromes are dis-
cussed in the following section on the "one-
and-a-half syndrome." The so-called
posterior INO of Lutz,889 in which abduction
(but not adduction) is impaired during sac-
cades and pursuit but apparently not dur-
ing vestibular stimuli, is rare. Three possi-
ble explanations may account for these
findings. First, patients with an abducens
 Diagnosis of Central Disorders of Ocular Motility 509

palsy may show nystagmus in the contralat-
eral adducting eye if the weak abducting
eye is used preferentially for fixation.1042
This nystagmus could reflect the same type
of mechanism (an adaptive response or a
dissociated nystagmus) that accounts for
the abducting nystagmus that develops in
patients with typical INO. Second, it has
been shown that experimental inactivation
of the oculomotor internuclear neurons,
which project to the contralateral abducens
nucleus, causes hypometria and slowing of
abducting saccades.259 Thus, midbrain le-
sions might lead to contralateral abduction
weakness. Third, it has been suggested that
interruption of an extra-MLF pathway
from the PPRF, which inhibits medial rectus
motoneurons, causes the abduction pare-
sis;1370 however, this pathway is more likely
to be the projection of pontine omnipause
neurons to the riMLF (see Fig. 6-5).215
Combined Unilateral Conjugate
Gaze Palsy and INO:
"One-and-a-half Syndrome"
and Other Variants
Combined lesions of the abducens nucleus
or PPRF and adjacent MLF on one side of
the brain stem cause an ipsilateral hori-
zontal gaze palsy and INO so that the only
preserved horizontal eye movement is ab-
duction of the contralateral eye (Display
10-23)—hence the name ''one-and-a-half
^drow."146'194'348'450'1271'1455 Such patients
may show an exotropia when attempting
to look straight ahead: The eye opposite
the side of the lesion is deviated outward.
This strabismus has been attributed to the
unopposed drives of the intact pontine
gaze center (paralyticpontine exotropia).782'1271
The spared abduction saccades of the con-
tralateral eye are followed by centripetal
drift so that a nystagmus similar to that of
the abducting eye in INO is present. Occa-
sionally, the ipsilateral horizontal vestibu-
lar responses may be preserved when vol-
untary gaze is abolished,146-348 suggesting
that the pontine lesion is more rostral in
the PPRF, or more discrete in the caudal
PPRF,707 sparing the vestibular projections
to the abducens nucleus. Although at-
tempts at conjugate (versional) move-
ments elicit no adduction, vergence move-
ments may be preserved. Ocular bobbing
(see Eye Movements in Stupor and Coma)
may accompany the one-and-a-half syn-
drome.725 The presence of a peripheral fa-
cial weakness on the same side as the gaze
palsy in one-and-a-half syndrome suggests
involvement of the abducens nucleus,
genu of CN VII, and the adjacent MLF.414a
The one-and-a-half syndrome may be
due to brain stem ischemia,146'1271'1513
multiple sclerosis,1455 tumor,689'1007 hemor-
rhage,1044 or trauma.1299 Occasionally, focal
vascular lesions producing the one-and-a-
half syndrome can be treated surgically.1124

Display 10-23: Clinical Features of "One-and-a-half'

Syndrome
• Ipsilateral horizontal gaze palsy and internuclear ophthalmoplegia

• Only surviving horizontal conjugate movement is abduction of the

contralateral eye

• Paralytic pontine exotropia on looking straight ahead (one eye is devi-

ated laterally)

• Vergence and vertical movements may be spared

For related anatomy, see Display 6-2, Display 6-3, and Figure 6-1 in Chap. 6.
510 The Diagnosis of Disorders of Eye Movements
Bilateral INO and an associated sixth
nerve palsy may mimic the one-and-a half-
syndrome. A case of one-and-a-half syn-
drome has been described in which only
adduction in one eye was spared.238 The
patient had mucormycosis that caused a
sixth nerve palsy due to cavernous sinus
involvement on one side and on the other
side had a horizontal gaze palsy due to ca-
rotid artery occlusion. Lesions that dam-
age the MLF and ipsilateral abducens fas-
cicle produce horizontal ophthalmoplegia
in the ipsilateral eye from the combination
of an INO and a sixth nerve palsy. Lesions
that damage the MLF on one side and the
PPRF or abducens nucleus on the oppo-
site side produce a horizontal gaze palsy
toward the same side as the involved
PPRF or abducens nucleus. In such cases,
the INO cannot be diagnosed because of
the overriding horizontal gaze palsy. Dam-
age to the MLF on one side and to the
contralateral abducens nerve fascicle will
produce abduction weakness of the con-
tralateral eye combined with adduction
weakness of the ipsilateral eye. In this set-
ting, there will be a pseudo-horizontal gaze
palsy on attempted horizontal gaze away
from the side of the MLF lesion. This di-
agnosis may be suspected in a patient who
appears to have a horizontal gaze palsy
that is asymmetric, with one eye (usually
the adducting eye) being more limited
than the other.
Selective Cell Vulnerability in
the Pons
Certain metabolic, toxic, and degenerative
conditions may cause selective deficits of
ocular motility that suggest a predominant
loss of one population of brain stem neu-
rons concerned with eye movements. Such
a process has been proposed to explain
slow saccades and saccadic oscillations.
SLOW SACCADES WITH
PONTINE DISEASE
Disorders that are reported to cause slow
saccades are listed in Table 10-15. Pre-
dominant slowing of horizontal saccades
Table 10-15. Etiology of
Slow Saccades
Spinocerebellar ataxias (SCA), especially
SCA2 (olivopontocerebellar
atrophy)211'643'1039'1151'1220'1443'1485
Huntington's disease286'815'833
Progressive supranuclear palsy1186'1429
Parkinson's (advanced cases)1480 and related
diseases;332'1496 Lytico-Bodig854
Whipple's disease776
Lipid storage diseases1187'1247
Wilson's disease770
Drug intoxications: anticonvulsants, 1361 ' 1371
benzodiazepines118°
Tetanus932
In dementia: Alzheimer's disease (stimulus-
dependent), 465 and in association with
AIDS1009
Lesions of the paramedian pontine reticular
formation585
Internuclear ophthalmoplegia1533
Paraneoplastic syndromes 70 ' 303
Amyotrophic lateral sclerosis (some cases)54
Peripheral nerve palsy, diseases affecting the
neuromuscular junction and extraocular
muscle, restrictive ophthalmopathy
generally occurs in hereditary degenera-
tive disorders that involve the pons, espe-
cially spinocerebellar ataxia type 2 (olivo-
pontocerebellar atrophy of Wadia and
Swami) (see VIDEO: "Slow horizontal sac-
cades").211'1443'1535 As discussed above, al-
though attempts have been made to
define the phenotypic disorder of eye
movements for each genetically deter-
mined disorder, exceptions occur. In dis-
eases that principally affect the midbrain,
such as progressive supranuclear palsy
(PSP), vertical saccades become slow be-
fore horizontal ones do. Selective slowing
of horizontal saccades in association with
facial spasms has been described as a prob-
able paraneoplastic phenomenon in asso-
ciation with prostatic cancer.70
In some patients with slow horizontal
saccades, blinks of the eyelids may actually
speed up these movements; 1528 the expla-
nation for this phenomenon is uncertain
but is more likely to involve the effects of
blinks upon pause and burst neurons than

momentary deprivation of vision (see Sac-
cades and Movements of the Eyelids, in
Chap. 3). Some patients with slow saccades
are able to generate smooth-pursuit move-
ments of up to about 20° per second. It is
difficult to distinguish a considerably
slowed saccade from pursuit, however, so
whether or not pursuit function is truly in-
tact in such patients is not established.
Conversely, if the saccades are so slow that
they cannot bring the eye to the moving
target, then even if pursuit is intact it may
not appear so, as the eye appears to lag
the target. Vestibular stimulation elicits
normal compensatory slow phases, but
quick phases of nystagmus are either ab-
sent or are slow and show approximately
the same abnormal relationship between
amplitude and peak velocity as do volun-
tary saccades. Patients with olivoponto-
cerebellar degeneration usually make nor-
mal-amplitude saccades despite their low
velocity. Patients with slow saccades may
use a variety of strategies of eye-head co-
ordination to move their eyes more
quickly to the target (see Eye-Head Move-
ments in Patients With Slow or Inaccurate
Saccades, Chap. 7).
The simplest explanation for slow hori-
zontal saccades is that excitatory burst
neurons in the PPRF are involved.649
However, experimental lesions of the om-
nipause neurons using excitoxins are also
reported to cause slow horizontal and ver-
tical saccades.718 In some patients with se-
lective slowing of horizontal saccades, both
burst and omnipause cell populations may
be affected, 585 but selective involvement of
the excitatory burst neurons has been
demonstrated in olivopontocerebellar at-
rophy of the type described by Wadia and
Swami.649 An alternative explanation for
saccadic slowing is that it represents ab-
normal inputs to the paramedian reticular
formation. Thus, experimental lesions or
pharmacological inactivation of the frontal
eye field or superior colliculus causes
slowing of saccades (discussed in Chap. 3).
SACCADIC OSCILLATIONS WITH
PONTINE LESIONS
Saccadic oscillations that lack any intersac-
cadic interval (ocular flutter and opso-
Diagnosis of Central Disorders of Ocular Motility 511
clonus—Fig. 10-15E) (see VIDEOS: "Opso-
clonus") have been attributed to disease
that selectively affects the omnipause neu-
rons,1536 which are located in the nucleus
raphe interpositus in the midline of the
pons at the level of the abducens nucleus
(Fig. 6-2, Chap. 6). However, experimen-
tal lesions of the omnipause region with
excitotoxin caused slow saccades rather
than oscillations.718 Furthermore, neu-
ropathologic examination of the brain of
two patients who had manifest opsoclonus
as the remote effect of lung cancer did not
disclose changes in the omnipause popu-
lation.1142 A more recent immunopatho-
logic study of a patient with saccadic oscil-
lations in association with cancer did
demonstrate complete absence of cells in
the omnipause region, however.648 Thus,
it remains possible that lesions restricted
to omnipause cells may cause saccadic os-
cillations, but alternative mechanisms are
possible, as discussed in the section on sac-
cadic oscillations. Macrosaccadic oscilla-
tions (see VIDEO: "Macrosaccadic oscilla-
tions") (Fig.lO-16C)—an extreme form of
saccadic dysmetria—have been reported
with a paramedian lesion involving the
tegmentum and basis pontis,55 although it
is more usually a feature of cerebellar dis-
ease.
OCULAR MOTOR SYNDROMES
CAUSED BY LESIONS OF
THE MESENCEPHALON
Modern Concepts of Vertical
Gaze Palsies
The midbrain is important in the control
of vertical eye movements, especially sac-
cades and gaze holding. Patients with
acute palsies of vertical gaze usually have
lesions localized to structures lying in the
high mesencephalon (Display 10-24). In
evaluating the patient with a disturbance
of vertical gaze, first it is crucial to test not
just range of movement but also to deter-
mine whether there are selective defects of
saccades or of smooth pursuit, vestibular,
or vergence eye movements. Although
certain lesions may cause paralysis of
512 The Diagnosis of Disorders of Eye Movements

Display 10-24: Commonly Reported Localization of Acute

Vertical Gaze Palsies*
PARALYSIS OF DOWN GAZE
• Selective saccadic loss: bilateral riMLF lesions

• Involvement of all types of eye movement: INC or PC affected

PARALYSIS OF UP GAZE
• All types of eye movements are involved: PC and INC

COMBINED UP GAZE AND DOWN GAZE

• Selective saccadic loss: bilateral riMLF lesion

• Involvement of all eye movements: INC or PC also affected

*riMLF: rostral interstitial nucleus of MLF; INC: interstitial nucleus of Cajal; PC: posterior
commissure.
For related anatomy, see Brain Stem Connections for Vertical and Torsional Movements, Fig-
ure 6-4, and Figure 6-5 in Chap. 6. For related etiologies, see Table 10-17. (Related VIDEOS:
"Niemann-Pick type C disease" and "Vertical saccadic palsy.")

all upward or downward movements, or
both, selective defects of ocular motility
are more common. Second, it is also im-
portant to test the torsional vestibulo-
ocular reflex, noting whether quick
phases of nystagmus occur in both direc-
tions as the patient's head rolls from side
to side. Third, examine ocular alignment,
looking for signs of oculomotor or
trochlear palsy, and for evidence for skew
deviation and the ocular tilt reaction.
Fourth, look for abnormalities of eyelid
movements and the pupils, which are
common features of vertical gaze disor-
ders.
Although human studies have made im-
portant contributions to understanding
the control of vertical gaze, the value of
many older reports is limited either by
lack of information concerning the effects
of lesions on each class of eye movements
or by uncertainty as to the degree of in-
volvement of the important structures for
vertical gaze. Over the past 20 years, the
pathways critical for vertical gaze have
been defined using modern anatomical
and physiological techniques, and the be-
havioral deficits that have resulted when
such pathways are selectively lesioned
have been measured. These experimental
studies, which are summarized in Chap. 6,
have defined the roles of three key struc-
tures in the control of vertical gaze: the
rostral interstitial nucleus of the medial
longitudinal fasciculus (riMLF), the inter-
stitial nucleus of Cajal (INC), and the pos-
terior commissure.
Lesions of the riMLF and Vertical
Saccadic Palsy
In interpreting vertical saccadic palsies, it
is helpful to bear in mind several key facts.
The first is the anatomic location of the
riMLF (see Display 6-5), which contains
the burst neurons that generate vertical
and torsional saccades. The riMLF lies
dorsomedial to the rostral pole of the red
nucleus, medial to the fields of Forel, lat-
eral to the periaqueductal gray and the nu-
cleus of Darkschewitsch, and immediately
rostral to the interstitial nucleus of Cajal
 Diagnosis of Central Disorders of Ocular Motility 513

(see Fig. 6-3 and Fig. 6-4, Chap. 6). Sec-
ond, the riMLF receives its blood supply
from a small perforating vessel (the poste-
rior thalamosubthalamic paramedian artery)
that arises between the bifurcation of the
basilar artery and the origin of the poste-
rior communicating artery, with a single
vessel often supplying both riMLFs.240'1074
Certain details concerning the projections
of the riMLF are clinically relevant. Each
riMLF projects bilaterally to motoneurons
for the elevator muscles (superior rectus
and inferior oblique) but ipsilaterally to
motoneurons for the depressor muscles
(inferior rectus and superior oblique).966'967
Note that these bilateral projections proba-
bly are not achieved via the posterior com-
missure but occur at the level of the oculo-
motor and trochlear nuclei. What this
means is that unilateral riMLF lesions are
more likely to affect downward than up-
ward saccades. Furthermore, each burst
neuron in the riMLF sends axon collaterals
to motoneurons supplying yoke muscle
pairs; this appears to be part of the neural
substrate for Hering's law in the vertical
plane.965 Thus, riMLF lesions (unilateral
or bilateral) would be expected to cause
vertical saccadic defects that are mainly
conjugate. A final anatomic point is that al-
though each riMLF contains burst neurons
to drive upward or downward saccades,
the right riMLF is responsible for torsional
quick phases that are clockwise from the
point of view of the patient (extorsion of
the right eye and intorsion of the left eye),
and the left riMLF is responsible for coun-
terclockwise quick phases. Thus, although
the effects of a unilateral riMLF lesion on
vertical saccades may be minor, it will abol-
ish ipsitorsional quick phases and produce
a cyclorotation of both eyes (shift of List-
ing's plane).
Lesions of the riMLF are usually in-
farcts in the distribution of the posterior
thalamosubthalamic paramedian artery,
which may be paired or single, and which
may also supply the rostromedial red nu-
cleus, adjacent subthalamus, the poste-
rior-inferior portion of the dorsomedial

Display 10-25: Clinical Findings with Lesions of the Rostral

Interstitial Nucleus of the MLF (riMLF)
UNILATERAL LESION
• A mild and variable defect of downward saccades
• Loss of ipsitorsional quick phases (e.g., clockwise* quick phases are
lost with right riMLF lesions)

• Static, contralesional torsional deviation with torsional nystagmus

beating contralesionally

BILATERAL LESION
• More profound defect of vertical saccades that may be more pro-
nounced for downward than upward eye movements

• Vertical gaze holding, VOR and pursuit, and horizontal saccades are
preserved

*Torsional rotations are defined from the viewpoint of the patient, not the observer, so
clockwise means that the upper pole of the right eye would rotate temporally (extorsion) and
the upper pole of the left eye, nasally (intorsion).
For related anatomy, see Display 6-5, Figure 6-4, and Figure 6-5 in Chap. 6. For related
etiologies, see Table 10-17. (Related VIDEO: "Vertical saccadic palsy.")
514 The Diagnosis of Disorders of Eye Movements

Figure 10-28. T2-weighted MRI scans showing small, hyperintense bilateral lesions (arrowheads) within the
rostral midbrain (A) and caudal thalamus (B), which presumably involved the rostral interstitial nucleus of the
MLF. This stroke was in the distribution of the thalamic and subthalamic perforating vessels coming off of the
proximal portion of the posterior cerebral artery (see VIDEO: "Vertical saccadic palsy").

nucleus and the parafascicular nucleus of
the thalamus. Older reports of vertical
gaze disorders have been reviewed in a
modern context,214'1080 and here we focus
on recent reports.
Based on experimental studies,1347 a
unilateral lesion of the riMLF would be
expected to cause a minimal defect in ver-
tical saccades (mainly downward) but a
distinct defect in generating ipsitorsional
quick phases (Display 10-25). Patients
have been reported with such find-
ings.837-1148 They also have a static, con-
tralesional torsional deviation with tor-
sional nystagmus beating contralesionally.608
Other patients with a unilateral riMLF

Figure 10-28.—continued
lesion have been described as having
greater defects of vertical saccades or
other eye movements. In the case of
Ranalli and colleagues,1123 the infarct had
spread partly into the adjacent interstitial
nucleus of Cajal; saccades were absent
above the central position, and slow and
limited below. Smooth pursuit and the
vestibulo-ocular reflex were also affected
in the vertical plane, being restricted in
range and of reduced gain. These addi-
tional defects might be attributed to in-
Diagnosis of Central Disorders of Ocular Motility 515
volvement of the interstitial nucleus of Ca-
jal. In another patient who had a discrete,
unilateral riMLF lesion associated with bi-
lateral infarction in the base of the pons,
there was a vertical saccadic palsy, but
other eye movements were spared.148
Bilateral lesions of the riMLF are more
common and have been reported to cause
loss either of downward saccades (Fig.
10-28) (see VIDEO: "Vertical saccadic
palsy") or of all vertical saccades. The ex-
planation for selective paralysis of down-
516 The Diagnosis of Disorders of Eye Movements

ward saccades has centered on which part
of the riMLF is affected and how this par-
tial lesion might affect emerging axons
from burst neurons for upward or down-
ward saccades.1080 Impairment of vertical
smooth pursuit and the vestibulo-ocular
reflex probably reflects involvement of ad-
jacent structures such as the MLF and in-
terstitial nucleus of Cajal. Somnolence or
memory impairment may imply coexistent
involvement of medial thalamic nuclei. A
vertical one-and-a-half syndrome has been
reported, with either loss of all downward
movements and selective loss of upward
movements in one eye346 or impairment of
all upward eye movements and a selective
deficit of downward saccades in the eye on
the side of the lesion.150 Since each burst
neuron in the riMLF sends axon collater-
als to yoke muscle pairs, such deficits im-
ply that a lesion close to the motoneurons
of the muscle must be responsible for the
disconjugate deficit.
Lesions of the Interstitial Nucleus
of Cajal (INC)
Recent experimental work has demon-
strated that the INC (see Display 6-6)
plays a key role in holding eccentric verti-
cal gaze (Display 10-26).298>608b Further-
more, the INC appears to project exclu-
sively to the ocular motoneurons via the
posterior commissure (see next section).
However, it seems that the defect of verti-
cal gaze associated with INC lesions is not
just one of vertical gaze-evoked nystag-
mus.1066 Bilateral pharmacological inacti-
vation of INC in monkeys greatly restricts
the vertical range of all classes of conju-
gate eye movements, although saccades do

Display 10-26: Findings with Lesions of the Interstitial

Nucleus of Cajal (INC)*
UNILATERAL LESIONS OR INACTIVATION
• Impaired gaze-holding function in the vertical and torsional planes
following saccades to tertiary positions; VOR less affected

• Ocular tilt reaction: skew deviation (ipsilateral hypertropia), extorsion

of the contralateral eye and intorsion of the ipsilateral eye, and con-
tralateral head tilt

• Torsional nystagmus that has ipsilesional quick phases—top pole

rotates to the side of the lesion; downbeat component may also be
present

BILATERAL LESIONS OR INACTIVATION

• Reduced range of all vertical eye movements but saccades not slowed

• Impaired gaze-holding after all vertical and torsional movements; up-

beat nystagmus

• Neck retroflexion

*Based mainly on experimental pharmacological inactivation.

For related anatomy, see Display 6-6, Figure 6-4, and Figure 6-5 in Chap. 6. For schematic
of OTR, see Figure 10-18 of Chap. 10. For related etiologies, see Table 10-17. (Related
VIDEO: "Skew deviation.")
 Diagnosis of Central Disorders of Ocular Motility
not become slow.608b With these new
pieces of information, it is instructive to
reexamine how frequently the INC has
been reported as being involved in cases
of vertical gaze disturbance.214-1080'1123
While bilateral lesions of INC mainly af-
fect vertical gaze, unilateral lesions pro-
duce the ocular tilt reaction and torsional
nystagmus with compensatory ipsilesional
quick phases (which helps differentiate it
from torsional nystagmus due to riMLF le-
sions).172a'608
Effects of Lesions of the Posterior
Commissure and Nucleus of the
Posterior Commissure (nPC)
Lesions of the posterior commissure
are traditionally equated with a syndrome
of loss of upward gaze and associated
findings (Table 10-16) generally known
by a variety of names: dorsal midbrain
syndrome, Parinaud's syndrome, Koeber-
Salus-Elschnig syndrome, pretectal syn-
drome, and Sylvian aqueduct syn-
drome.319'1067'1069 In the past, paralysis of
upward gaze was ascribed to destruction of
the superior colliculi, but this is not the
case.21'1068 Unilateral midbrain lesions that
create the same ocular motor syndrome
may do so by interrupting the afferent
and efferent connections of the posterior
commissure.51'214-1123'1300 Experimental in-
activation of the posterior commissure
with lidocaine causes vertical gaze-evoked
nystagmus,1066 but electrolytic lesions cause
greater deficits (Display 10-27).1067'1069
Thus, it seems that the clinical syndrome
associated with posterior commissure le-
sions is due to more than axon projections
of the INC (see Display 6-7) and also rep-
resents lesioning the nucleus of the poste-
rior commissure (nPC), which may be im-
portant for the control of vertical gaze and
eyelid movements. Cells in the nPC project
through the posterior commissure to con-
tact the riMLF, INC, and the M-group of
neurons; the M-group relays to the central
caudal subdivision of the oculomotor nu-
cleus (Fig. 9-9) and may coordinate vertical
eye and lid movements.1231
The vertical gaze defect observed with
clinical lesions affecting the posterior corn-
517
Table 10-16. Features of The Dorsal
Midbrain Syndrome2i4,3i9,745,75i)io8o,i379
Limitation of Upward Eye Movements
Saccades
Smooth pursuit
Vestibulo-ocular reflex
Bell's phenomenon
Dissociation of Lid and Eye Movements
Lid Retraction (Collier's Sign)
Ptosis
Disturbances of Downward Eye Movements
Downward gaze preference ("setting sun"
sign)
Downbeating nystagmus
Downward saccades and smooth pursuit may
be impaired, but vestibular movements are
relatively preserved
Disturbances of Vergence Eye Movements
Convergence-retraction nystagmus
Paralysis of convergence
Spasm of convergence
Paralysis of divergence
A- or V-pattern exotropia
Pseudo-abducens palsy
Pretectal pseudobobbing
Fixation Instability (Square-Wave Jerks)
Skew Deviation
Pupillary Abnormalities (Light-Near Dissociation)
missure usually affects all types of eye
movements, though the VOR and Bell's
phenomenon may sometimes be spared.
Eyelid abnormalities occur: Collier's
"tucked lid" sign (or lid retraction),287 or
less commonly, ptosis. Below the horizon-
tal meridian, vertical saccades can be
made but are usually slow. Acutely, the
eyes may be tonically deviated downward
('setting sun sign"); this finding is prom-
inent in premature infants who have
suffered intraventricular hemorrhage.1356
Transient downward deviation of the eyes
occasionally occurs in normal infants, but,
in such cases, the eyes can be easily driven
above the horizontal meridian by the ver-
tical doll's-head maneuver.663 Tonic up-
ward gaze deviation of the eyes has been
reported in some patients with midbrain
518 The Diagnosis of Disorders of Eye Movements

Display 10-27: Findings with Lesions of the

Posterior Commissure
• Impairment of all classes of vertical eye movements, especially up-
ward, with loss of vertical gaze-holding (neural integrator) function

• Attempted upward or horizontal saccades evoke convergence-retrac-

tion nystagmus—asynchronous convergent saccades

• Pathologic lid retraction while looking straight ahead (Collier's sign)

• Pupils are large and show a smaller reaction to light than to a near
stimulus

For related anatomy, see Display 6-7, Figure 6-4, and Figure 6-5 in Chap. 6. For related eti-
ologies, see Table 10-17. (Related VIDEO: "Convergence-retraction nystagmus.")

lesions,96 and following hypoxic-ischemic
insults.743 Oculogyric crises are discussed
under the section on Parkinson's disease.
Episodic tonic up gaze may also occur in
otherwise normal infants,18 although some
may later show horizontal strabismus and
intellectual or language disability.598
The dorsal midbrain syndrome also
includes disturbance of horizontal eye
movements, especially vergence. In some
patients, convergence is paralyzed, while
in others it is excessive and causes conver-
gence spasm. During horizontal saccades,
the abducting eye may move more slowly
than its adducting fellow. This finding has
been called pseudo-abducens palsy319 and
may reflect excess of convergence tone. It
may lead to an early symptom of poste-
rior commissure lesions: reading difficulty
caused by a transient inability to find, and
to focus both eyes on, the beginning of the
next line when a horizontal saccade is
made. Convergence-retraction nystagmus
may also occur following experimental le-
sions of the posterior commissure1067'1069
and in patients with disease of the mid-
brain.1029 Convergence-retraction nystag-
mus is properly regarded as a saccadic dis-
order since it consists of asynchronous,
opposed saccades whenever upward quick
phases are stimulated (see VIDEO: "Con-
vergence-retraction nystagmus"). Conver-
gence is often evident during attempted
large upward movements and contrasts
with the transient divergence that occurs
in normal subjects.1529 Pupillary reac-
tions are also commonly affected. Usually,
the pupils are large and react better to an
accommodative stimulus than to light—
light-near dissociation.
A variety of disease processes may affect
the region of the posterior commissure and
disrupt vertical gaze (Table 10-17 ). Pineal
tumors produce the dorsal midbrain syn-
drome either by direct pressure on the pos-
terior commissure or by causing obstruc-
tive hydrocephalus.72 Hydrocephalus may
produce this syndrome by enlarging the
aqueduct and third ventricle or the suprap-
ineal recess and so stretching or compress-
ing the posterior commissure.294 The fol-
lowing case history illustrates certain
features of the dorsal midbrain syndrome.
CASE HISTORY: Vertical gaze palsy with
midbrain hemorrhage
A 38-year-old woman presented with a 10-day
history of fever, sores in her mouth, bruises, and
profound tiredness. Hematological findings
were consistent with monocytic leukemia in bias-
tic crisis. One day after admission she became
stuporous and developed a right hemiparesis.
On examination the left pupil was oval, ap-
proximately 5 mm in diameter, and fixed. The
right pupil was 3 mm and fully reactive. There
was a full range of horizontal eye movements,
 Diagnosis of Central Disorders of Ocular Motility 519

Table 10-17. Etiology of Disorders of Vertical Gaze

Tumor
Classically, pineal germinoma or teratoma in an adolescent male; also pineo-
cytoma, pineoblastoma, glioma, metastasis51'72'213'1099

Hydrocephalus
Usually aqueductal stenosis leading to dilatation of the third ventricle and
aqueduct or enlargement of the suprapineal recess with pressure on the
posterior commissure482'1050

Vascular
Midbrain or thalamic hemorrhage,447'448'1211'1367 infarc-
tion,133'147'151'214'795'930'1080 or subdural hematoma1150

Metabolic
Niemann-Pick variants,270'442'1187 Gaucher's disease,270-1435 Tay-Sachs
disease,700 Maple syrup urine disease,894'1531 Wilson's disease,770 ker-
nicterus661

Drug-induced
Barbiturates,414 carbamazepine,117 neuroleptic agents830

Degenerative
Progressive supranuclear palsy,1186'1321'1429 Huntington's disease,286'815'833
cortical basal degeneration,511'1145'1147 diffuse Lewy body disease,863
others1220'1496

Miscellaneous
Multiple sclerosis,1295 Whipple's disease,16-776'1248 hypoxia,755 encephalitis,72
syphilis,1059'1315 aneurysm,293 trauma,735 neurosurgical procedure,1250 mes-
encephalic clefts,804 tuberculoma, trauma, benign transient form of child-
hood18'663-1053

but with continuous square-wave jerks during
attempted fixation. She had complete paralysis
of vertical eye movements above the midline.
Below the horizontal meridian, downward
pursuit was abnormal and saccades, both up
and down, appeared slow. There was a down-
ward beating nystagmus on attempting to look
down. Horizontal saccades appeared to be of
normal velocity but horizontal pursuit was bi-
laterally impaired. There was some horizontal
gaze-evoked nystagmus. Vergence could not be
elicited.
Computed tomography (Fig. 10-29A) dem-
onstrated a hemorrhage in the left mesen-
cephalon. The patient died a few days later. Ex-
amination of the brain confirmed the presence
of the midbrain hemorrhage with compression
and displacement of the aqueduct and the pos-
terior commissure (Fig. 10-29B).
Comment: This patient showed evidence of
left oculomotor nerve dysfunction and dorsal
midbrain syndrome. Although CT indicated
a unilateral mesencephalic lesion, autopsy
showed that the posterior commissure was
compressed. Moreover, the hemorrhage was
located so as to affect fibers coursing into and
out of the posterior commissure. Involvement
of the left cerebral peduncle accounted for the
right hemiparesis.
Clinical Manifestations of Other
Mesencephalic Lesions
The effects of lesions affecting other mes-
encephalic structures are less certain. The
periaqueductal gray matter of the mesen-
cephalon is known to contain both burst-
tonic cells and neurons that cease dis-
charge during saccades. Selective loss of
down gaze with tonic upward deviation of
520 The Diagnosis of Disorders of Eye Movements

the eyes has been reported with lesions af-

fecting the periaqueductal gray matter of
the midbrain.692>1367
Rarely, both elevator muscles of one eye
may be selectively impaired with midbrain
lesions. This double elevator palsy may
be a supranuclear paresis of monocular el-
evation, because in the central position,
the eyes are nearly straight and only on
looking upward does a vertical disconju-
gacy become evident.642'699 This disorder
has been described with midbrain infarc-
tion and tumor, and the lesion may be
located ipsilaterally or contralaterally to
the palsy.642 Rarely, it is congenital.111'1543
Monocular elevator palsy may be asso-
ciated with a contralateral downgaze
palsy.1484
Because the superior rectus is a
stronger elevator than the inferior oblique,
certainty of weakness of the inferior
oblique is sometimes lacking. If both
these muscles are weak, then a nuclear le-
sion is unlikely, because the inferior
oblique is supplied by the ipsilateral ocu- Figure 10-29. Upgaze paralysis due to midbrain
hemorrhage (see Case History: Vertical gaze palsy
lomotor nucleus and the superior rectus with midbrain hemorrhage text for details). (A) This
is supplied by the contralateral oculomo- CT scan shows the appearance of a left midbrain
tor nucleus. It is possible, therefore, that hemorrhage (right side of scan shows left side of
the site of the lesion for monocular eleva- brain). (B) At autopsy, the hemorrhage was shown to
compress the aqueduct and posterior commissure
tor palsy is prenuclear. However, if this is (basal view).
the case, the lesion must lie close to the Continued on following page
ocular motoneurons because the saccadic
signals from each riMLF project bilater-
ally to the elevator subnuclei (see Fig.
6-5, Chap. 6). A more plausible explana- Bielschowsky phenomenon}?19 Paramedian
tion for monocular elevator palsy is that it midbrain lesions often involve the oculo-
is due to a lesion selectively involving the motor nerve nucleus, producing a com-
oculomotor fascicles supplying the infe- bination of nuclear and prenuclear
rior oblique and superior rectus muscles deficits. Nuclear oculomotor nerve palsies
as the third nerve exits the brain stem.503 are often characterized by bilateral eleva-
In most instances, however, patients with tor and lid weakness, and pupillary ab-
restricted elevation of one eye will have normalities are common (discussed in
more common processes such as thyroid Chap. 9). Occasionally, large midbrain le-
ophthalmopathy, blowout fracture of sions may lead to complete ophthalmo-
the orbit, myasthenia gravis, and restric- plegia.1166'1495
tive ophthalmopathies (see Table 9-4 in As discussed in Chap. 3, the central
Chap. 9). mesencephalic reticular formation (cMRF)
Unilateral, paramedian midbrain lesions has extensive connections with structures
may sometimes cause midbrain paresis of concerned with saccadic eye movements
horizontal gaze; the descending smooth- such as the superior colliculus, supple-
pursuit pathway is affected, causing im- mentary eye fields, and PPRF (see Display
pairment of ipsilateral, horizontal smooth 6-9). The effects of lesions in this area are
pursuit. 1519 Contralateral saccades may summarized in Display 10-28 and dis-
also be affected,154'909'1519 but the hori- cussed in the following section on progres-
zontal VOR tends to be spared (Roth- sive supranuclear palsy.
 Diagnosis of Central Disorders of Ocular Motility 521

Figure 10-29.—continued

Selective Cell Vulnerability in ized by abnormal eye movements (Display

the Mesencephalon 10-29); disturbance of tone and posture,
leading to falls; difficulties with swallowing
PROGRESSIVE SUPRANUCLEAR and speech; and mental slowing.317'871'1321
PALSY (PSP) The disturbance of eye movements is usu-
ally present early in the course, but oc-
Clinical Features of PSP casionally it is noted late or not at
Progressive supranuclear palsy is a degen- all.sso.ii44,i 186 The condition is typically fa-
erative disease of later life. It is character- tal within 5 to 10 years of its onset,520'899
 Display 10-28: Findings with Unilateral Lesions of the
Central Mesencephalic Reticular
Formation (cMRF)*
• Ipsilateral gaze shift
• Hypermetria of contralateral and upward saccades; hypometria of ip-
silateral and downward saccades
• Fixation disrupted by saccadic intrusions directed away from the side
of inactivation
*Based on experimental pharmacological inactivation.
For related anatomy and pathophysiology, see Display 6-9 and Figure 6-3 in Chap. 6. For re-
lated clinical etiologies, see Table 10-17.

Display 10-29: Clinical Features of Progressive Supranuclear

Palsy (PSP)
• Slow vertical saccades, especially down, with a preserved range of
movement, may be the first sign of the disorder; later, loss of vertical
saccades and quick phases
• Horizontal saccades become slow and hypometric
• Disruption of steady gaze by horizontal saccadic intrusions (square-
wave jerks)
• Impaired smooth pursuit, vertically (reduced range) and horizontally
(with catch-up saccades)
• Smooth eye-head tracking may be relatively preserved, especially ver-
tically
• Preservation of vestibulo-ocular reflex
• Horizontal disconjugacy suggesting INO
• Loss of convergence
• Ultimately, all eye movements may be lost, but vestibular movements
are the last to go
• Eyelid disorders: apraxia of lid opening, lid lag, blepharospasm, in-
ability to suppress a blink to a bright light
For related anatomy, see Brainstem Connections for Vertical and Torsional Movements, Fig-
ure 6-4, and Figure 6-5 in Chap. 6. For recorded examples, see Figure 7-5B in Chap. 7 and
Figure 10-30 in Chap. 10. (Related VIDEOS: "Lid-opening apraxia" and "Square-wave jerks.")

522
 Diagnosis of Central Disorders of Ocular Motility
death commonly being due to aspiration
pneumonia. Several recent reports have
documented familial cases that are proba-
bly inherited in a dominant fashion but
the disease is usually sporadic.340'1362
The initial ocular motor deficit consists
of slowing of vertical saccades and quick
phases, either down or up (Fig. 10-30).
Vertical smooth pursuit is relatively pre-
served, and a large-field visual stimulus of-
ten elicits much better visual tracking than
a small target, probably due to an inability
to make catchup saccades when tracking
the small target. Combined eye-head
tracking may also be relatively spared (see
Fig. 7-5B, Chap. 7). As the disease pro-
gresses, the range of movements possible
with vertical saccades and pursuit declines
and eventually no voluntary vertical eye
movements are possible. However, the
VOR is preserved until late in the disease
(although a characteristic nuchal rigidity
may make the vertical doll's head maneu-
ver difficult).
Horizontal eye movements also show char-
acteristic changes: impaired fixation with
square-wave jerks (see VIDEO: "Square-
wave jerks"), impaired pursuit, impaired
smooth eye-head tracking, and saccades
and quick phases that are small and even-
tually slow.1127'1394 In some patients, the in-
volvement of voluntary horizontal eye
movements resembles internuclear oph-
thalmoplegia, although vestibular stimula-
tion may overcome the limitation of ad-
duction.911 Convergence eye movements
are also commonly impaired. Late in the
disease, the ocular motor deficit may prog-
ress to a complete ophthalmoplegia. Pa-
tients with absent quick phases but intact
vestibular slow phases may also show sus-
tained head turns during body rotation.135
There are a variety of eyelid abnormali-
ties in PSP: blepharospasm, lid-opening
apraxia (see VIDEO: "Lid-opening apraxia"),
eye-closing apraxia, lid retraction, and lid
lag.342'477 These patients also show an in-
ability to inhibit a blink when a light is
shone in their eyes, a visual "glabellar" or
Myerson's sign. More than one of these
abnormalities may coexist in a single pa-
tient. Bell's phenomenon is usually absent.
Studies of eye movements in PSP have
provided some insights into the disturbance
523
of attention that occurs in this disorder. The
latency (reaction time) of horizontal sac-
cades in PSP is prolonged in some pa-
tients, but in others, saccadic latency (us-
ing a gap paradigm, in which the fixation
target goes out before the new peripheral
target appears) is reduced so that patients
show short-latency or express saccades.1088
Patients with PSP also make errors when
they are required to look in the opposite
direction to that in which a target sud-
denly appears—the antisaccade task. Both
the presence of express saccades and er-
rors on the antisaccade task suggest de-
fects in frontal lobe function, and al-
though neuropathologic changes there
are mild, positron emission scanning indi-
cates profound frontal hypometabo-
lism.519
Neuropathologic Findings in PSP
Pathologically, there are widespread neu-
rofibrillary tangles, with neuronal loss and
gliosis in many subcortical and brain stem
areas, partially sparing the neocortex and
hippocampus.288'713-1321'1426 Affected struc-
tures include the globus pallidus, substan-
tia nigra (pars compacta and reticulata),
periaqueductal gray, brain stem reticular
formation, and superior colliculi.288'588 Ab-
normality of the microtubule-binding pro-
tein tau occurs in PSP.290 Both CT and
MRI show atrophy of the midbrain and
dilatation of the quadrigeminal cisterns,
aqueduct, and third and fourth ven-
tricles.1234 In addition, there may be atro-
phy and hypometabolism of the anterior
corpus callosum, reflecting involvement of
frontal cortex.1503 Some brains show fea-
tures which overlap with the appearances
in other parkinsonian conditions.431
Pathogenesis of Ocular Motor
Findings in PSP
The clinical feature that is most distinctive
early in the course of PSP is the selective
slowing of vertical saccades. This finding
probably reflects involvement of the riMLF
along with much of the brain stem reticular
formation.1321 In addition, there is docu-
mented involvement of the nucleus raphe
interpositus in the pons, in which are lo-
524
 Diagnosis of Central Disorders of Ocular Motility 525

cated omnipause neurons (see Fig.
6-2).1140 Another common finding is sac-
cadic intrusions (square-wave jerks), which
might be related to involvement of the su-
perior colliculus and the adjacent central
mesencephalic reticular formation (cMRF)
(see Display 6-9), which have reciprocal
connections. Experimental lesions or inac-
tivation of either the cMRF or the rostral
pole of the superior colliculus causes fixa-
tion to become disrupted by saccadic intru-
sions (see Display 10-28).980-1451 Further-
more, involvement of the substantia nigra,
pars reticulata (SNpr) in PSP might inter-
fere with the normal initiation and sup-
pression of saccades via its projections to
the superior colliculus (discussed in Chap.
3). Thus, antisaccade responses are abnor-
mal in some PSP patients.1088 Abnormali-
ties of smooth pursuit in PSP can be related
to extensive involvement of the dorsolat-
eral pontine nuclei,900 which are known to
constitute an important relay in the pursuit
pathway between visual cortical areas and
the cerebellum (see Fig. 6-7, in Chap. 6).
Differential Diagnosis of PSP
A number of other conditions can mimic
PSP, although patients who show slow ver-
tical saccades, horizontal square-wave
jerks, and normal vestibular eye move-
ments and report dysphagia and frequent
falls usually have this disorder. Similar
syndromes may be caused by multiple in-
farcts affecting the basal ganglia, internal
capsule, and midbrain.408'970 Whipple's
disease, discussed in the following section,
can also mimic PSP, and oculomasticatory
myorhythmia may be absent. Of the
parkinsonian degenerative disorders, few
produce slow vertical saccades early in the
course, although the vertical range of
movement may be limited.1186'1429 Thus,
cortical-basal ganglionic degeneration
usually does not cause slow saccades but is
associated with increased saccadic la-
tency.1186 Other features of this degenera-
tion are focal dystonia, ideomotor apraxia,
alien hand syndrome, myoclonus, and
an asymmetric akinetic-rigid syndrome
with late onset of gait or balance distur-
bances.122'511'871'1145 Parkinson's disease
seldom produces slow saccades until late
in the course,1186'1429-1480 and the response
to levodopa is absent in PSP. Diffuse Lewy
body disease is reported to mimic both
PSp332,432,863 anc j Parkinson's disease,880
but descriptions or measurements of verti-
cal saccade dynamics are not yet available.
Other basal ganglia disorders that have
been reported to show features similar to
PSP include idiopathic striopallidodentate
calcification,1220 autosomal dominant
parkinsonism and dementia with pallido-
pontonigral degeneration,1496 and multi-
ple system atrophy (MSA).1127 However,
measurements of vertical saccade velocity
in MSA have been normal.1186 In addition,
disorders causing the dorsal midbrain syn-
drome (Table 10-17), such as hydro-
cephalus,308 can produce a clinical picture
that has some similarities to PSP.
Presently, there are no effective treat-
ments for PSP, although individual pa-
tients may benefit from tricyclic antide-
pressants, serotonergic or adrenergic
agents, or dopamine agonists such as
bromocriptine.510'788a'1006
WHIPPLE'S DISEASE
This is a rare systemic disorder character-
ized by weight loss, diarrhea, arthralgia,

Figure 10-30. Ocular motor findings in progressive supranuclear palsy. Horizontal and vertical eye movements
were recorded by the magnetic search coil technique; the time scale at the top of each record is in seconds. (A)
Vertical saccades, particularly downward, are slow but generally orthometric. (B) Vertical smooth pursuit is rel-
atively preserved, with occasional small catch-up saccades best seen on the velocity trace. In both A and B, the
horizontal fixation abnormality, square-wave jerks, is evident. (C) Horizontal saccades are hypometric; a "stair-
case" of small saccades is necessary to acquire the target. (D) Horizontal smooth pursuit shows decreased gain
(eye velocity/target velocity) and the superimposed, corrective saccades. (E and F) Peak-velocity/amplitude rela-
tionships for this patient's vertical (E) and horizontal (F) saccades. Confidence limits from a group of normal
subjects are shown by the broken lines. Vertical saccades are slow, whereas most horizontal saccades are of nor-
mal velocity.
526 The Diagnosis of Disorders of Eye Movements
lymphadenopathy, and fever. It may in-
volve, and even be confined to, the ner-
vous system.776'881 It causes a defect of ocu-
lar motility that may mimic PSP. Initially,
vertical saccades and quick phases are in-
volved, but eventually, all eye movements
may be lost. A highly characteristic finding
is pendular, usually vergence, oscillations
(see VIDEO: "Whipple's disease") and con-
current contractions of the masticatory
muscles, oculomasticatory myorhythmia.l248>1290
The pendular vergence oscillations are
associated with a vertical saccadic palsy.1119
Ophthalmoplegia with myorhythmia of
the leg, but not of the eyes or jaw, is
reported.1119 Whipple's disease can now
be diagnosed using polymerase chain
reaction (PCR) analysis of involved tis-
sue,882 and can be treated with antibi-
otics.463
AMYOTROPHIC LATERAL
SCLEROSIS AND EYE MOVEMENTS
Clinically, amyotrophic lateral sclerosis
(ALS) spares eye movements until very
late in the course of the disease, despite se-
vere weakness of the skeletal and bulbar
muscles. Neuropathologic studies have in-
dicated that the ocular motoneurons
themselves are spared except in very ad-
vanced cases.950-1038 The sparing of ocular
motoneurons has been related to lower
concentrations of glycinergic and mus-
carinic receptors and to differences in glu-
tamate transporter molecules compared
with motoneurons in other nuclei affected
by ALS.928'1482
Studies using reliable methods for mea-
suring eye movements and modern test
paradigms have defined the spectrum of
disturbances of eye movements that may
be encountered in ALS. In most patients,
the velocities and latencies of visually
guided saccades are normal. However,
memory-guided saccades are inaccurate,
and there are increased errors on the anti-
saccade task. 1272 These findings are consis-
tent with frontal lobe involvement in ALS.
Square-wave jerks are more frequent than
in control subjects.1272 Impaired or asym-
metric smooth pursuit has also been re-
ported.9'13
Standing apart from this general pic-
ture is a subset of patients in whom disor-
dered eye movements are more promi-
nent early in the course. Such patients
usually show slowing of vertical saccades,
impairment of smooth pursuit, and gaze-
evoked nystagmus.516'803'906 In two well-
studied patients, slow vertical saccades
correlated with loss of neurons from the
riMLF at autopsy.54 Whether such patients
constitute a separate disease entity has yet
to be determined.
OCULAR MOTOR SYNDROMES
CAUSED BY LESIONS IN THE
SUPERIOR COLLICULUS
Lesions confined to the superior colliculi
are rare in humans. One patient who had
undergone removal of an angioma from
the right superior colliculus showed per-
sistent limitation of upward gaze, imply-
ing pretectal damage, but a full range of
horizontal eye movements.623 Systematic
testing of horizontal saccades demon-
strated a paucity of spontaneous refuta-
tions contralateral to the side of the lesion.
Saccades to the left occurred after a nor-
mal latency but were hypometric. These
findings are similar to those after experi-
mental ablation or pharmacological inacti-
vation of the superior colliculi in mon-
keys.21 A second patient who had a
hematoma largely restricted to the right
superior colliculus showed defects in la-
tency and accuracy for contralateral sac-
cades and increased numbers of inappro-
priate saccades in the antisaccade task.1092
OCULAR MOTOR SYNDROMES
CAUSED BY LESIONS IN
THE DIENCEPHALON
Effects of Thalamic Lesions on
Eye Movements
Lesions affecting the thalamus (see Dis-
play 6-22) are characterized by distur-
bances of both horizontal and vertical gaze
(Display 10-30).447 Conjugate deviation of
 Diagnosis of Central Disorders of Ocular Motility 527

Display 10-30. Clinical Effects of Diencephalic Lesions

THALAMIC LESIONS (CENTRAL NUCLEI)
• Conjugate gaze deviation away from the side of the lesion (wrong-way
deviation)

• Sustained downward deviation of the eyes, (due to compression of the

dorsal midbrain), sometimes with convergence—thalamic esotropia

LESIONS OF THE PULVINAR

• Pulvinar lesions in humans may cause difficulties in shifting gaze into
the contralateral hemifield, decrease in spontaneous scanning, and
loss of stereoacuity
For related anatomy, see Display 6-18 and Display 6-22 in Chap. 6. For pathophysiology of
saccadic defects see The Role of the Internal Medullary Lamina (IML) in Saccade Genera-
tion and The Role of the Pulvinar in Saccade Generation in Chap. 3.

the eyes contralateral to the side of the le-
sion—wrong-way deviation—may occur with
hemorrhage affecting the medial thala-
mus.450'737 The reason for this contraver-
sive deviation is unclear. The descending
pathways from the frontal eye fields to the
pons have not yet crossed at this level, al-
though the notion of an ocular motor de-
cussation is less certain now than in the
past. Involvement of the descending path-
way for smooth pursuit might lead to a
paretic, contraversive deviation of the
eyes,1264 but a patient with a defect of
smooth pursuit directed toward the side of
a small hemorrhage in the posterior thala-
mus and adjacent internal capsule still
showed an ipsiversive gaze preference.180a
Another possibility is that wrong-way devi-
ation may be an irritative phenomenon;
electrical stimulation in the region of the
thalamic intramedullary lamina (IML)
elicits contralaterally directed saccades
(discussed in Chap. 3).
Tonic downward gaze deviation of the
eyes, with convergence and miosis, is an-
other common feature of thalamic hemor-
rhage; affected patients appear to peer at
their noses.448 In autopsied cases, the
hemorrhage usually has extended into or
compressed the midbrain. Hence, forced
downward deviation of the eyes probably
represents a compressive effect of the
hemorrhage on structures responsible for
up gaze. Resolution of the downward de-
viation has followed treatment of raised
intracranial pressure,1450 suggesting that
traction on mesencephalic structures or
hydrocephalus may be responsible in
some patients.
Thalamic esotropia occurring with cau-
dal thalamic lesions may be marked and
sometimes is unassociated with downward
deviation;527'620 it may reflect a distur-
bance of vergence inputs to the oculomo-
tor nuclei (organic convergence spasm, see
Chap. 8). Combined lesions of the thala-
mus and midbrain may unilaterally impair
convergence.868
Patients with posterolateral thalamic in-
farctions may have disturbances of the
subjective visual vertical (either ipsilateral
or contralateral).391 However, the ocular
tilt reaction is not present unless the ros-
tral midbrain is also involved.
Infarction of the caudal thalamus,
caused by occlusion of the proximal por-
tion of the posterior cerebral artery or its
perforator branch, the posterior thala-
mosubthalamic paramedian artery, is re-
ported to produce paralysis of down gaze.
528 The Diagnosis of Disorders of Eye Movements
In fact, this deficit is probably due to in-
volvement of the adjacent riMLF or its im-
mediate premotor inputs (see Display
10-24).257'1284 Some patients also show im-
pairment of horizontal gaze, perhaps
due to interruption of descending path-
ways133'852 or of the mesencephalic reticu-
lar formation. 1451 Associated disturbances
of arousal and short-term memory have
been ascribed to involvement of adja-
cent thalamic nuclei.128'1464 Experimen-
tally, combined lesions of the superior
colliculus and caudal thalamus in mon-
keys lead to an enduring saccadic hy-
pometria without corrective saccades;22
similar results in humans would confirm
the importance of the caudal thalamus
and superior colliculus in the generation
of saccades.
Patients with lesions affecting the central
thalamic nuclei (of the internal medullary
lamina) show a specific defect: Memory-
guided saccades become inaccurate only if
the eyes move to a new position during the
memory period (e.g., a smooth-pursuit
movement).507 This finding suggests that
the central thalamus normally relays an
efference copy (in this case, of the gaze
shift during the memory period) to cor-
tical areas that program memory-guided
saccades. Lesions in the posterior pari-
etal cortex and the supplementary eye
fields of the frontal lobes create similar
deficits.409'603'1086
Effects of Pulvinar Lesions on
Eye Movements
Studies of patients with lesions of the pulv-
inar (see Display 6-18) have documented
difficulties in shifting attention and gaze
into the contralateral hemifield, mani-
fested by a paucity and prolonged latency
for visually guided saccades (Display
10-30).1033>1546 These results are consistent
with some reported effects of pharmaco-
logical and destructive lesions of the pulv-
inar in the monkey and point to the im-
portance of this thalamic nucleus in
directing visual attention.112'1434 Pulvinar
lesions are also reported to cause loss of
stereoacuity.1354
OCULAR MOTOR
ABNORMALITIES AND DISEASE
OF THE BASAL GANGLIA
Parkinson's Disease and
Conditions Causing Parkinsonism
PARKINSON'S DISEASE (PD)
Clinical Findings in PD
Most patients with PD show only minor
abnormalities at the bedside that often
cannot be differentiated from findings in
healthy elderly subjects. Thus, steady fixa-
tion may be disrupted by saccadic intru-
sions (square-wave jerks), 1128 - 1480 but these
are also seen in some normal elderly sub-
jects.617 Similarly, moderate restriction of
the range of upward gaze is frequently ob-
served in normal elderly individuals as
well as in patients with PD.244 Smooth pur-
suit may be impaired, but not appreciably
more so than in some age-matched nor-
mals.1186 Convergence insufficiency is a
common and often symptomatic distur-
bance.1136 The application of modern test
paradigms in a laboratory setting, how-
ever, can identify a number of distur-
bances in PD, especially affecting saccades
and smooth pursuit (Display 10-31).
Saccadic Abnormalities in PD
Saccades in PD are typically hypometric,
especially vertically.979'1125'1186'1480 A char-
acteristic finding is that hypometria be-
comes more marked when patients are
asked to perform self-paced refixations be-
tween two continuously visible targets.
This effect is not, however, due simply to
the persistence of the target light. Saccades
made in anticipation of the appearance of
a target light or to a remembered target lo-
cation are also hypometric.299'884'887 In fact,
patients with PD have difficulty in generat-
ing sequences of memory-guided saccades
to all types of stimuli.997'1424 In contrast,
saccades made reflexively to novel visual
stimuli are of normal amplitude and usu-
ally are promptly initiated.1186'1429 Thus,
it appears that parkinsonian patients are
unable to generate internally saccades
that are appropriate to accurately shift
 Diagnosis of Central Disorders of Ocular Motility 529

Display 10-31: Clinical Findings in Parkinson's Disease

• Fixation may be disrupted by square-wave jerks

• Hypometria of horizontal and vertical saccades, especially when pa-

tients are asked to perform rapid, self-paced refixations between two
continuously visible targets

• Normal saccadic velocity except in some advanced cases

• Impaired smooth pursuit, horizontally and vertically, due partly to in-

adequate catch-up saccades

• Vestibular eye movements normal for natural head movements

• Impaired convergence

• Oculogyric crises

• Lid lag

For pathophysiology, see The Role of the Basal Ganglia in Saccade Generation, in Chap. 3.

gaze.192-1420-1459 Despite this pattern of hy-
pometria, patients can still shift their
gaze, using a series of saccades, to the lo-
cation of a target that is briefly flashed;
this indicates a retained ability to encode
the location of objects in extrapersonal
space.299'1480 The saccadic initiation defect
to command or to continuously visible tar-
gets appears to be more marked in the
vertical plane; upward saccades especially
may be hypometric. In contrast, vertical
saccades to randomly appearing visual tar-
gets are normal.1357 If downward saccades
are abnormal or the velocity of vertical sac-
cades in either direction is decreased, a di-
agnosis of progressive supranuclear palsy
(PSP) is more likely.
Saccadic latencies during nonpredictive
tracking may be normal or mildly in-
creased.192'1480 During self-paced refixa-
tions between two visible targets, inter-
saccadic intervals increase above values
during nonpredictable tracking. 299 - 1420 Ap-
plication of the "gap" paradigm has dem-
onstrated that PD patients are able to
make express saccades.1429 Saccadic veloc-
ity is usually normal, except in some ad-
vanced cases.1186'1429'1480
Patients with advanced PD may show
greater defects on certain tests than pa-
tients with mild or moderate disease.
Thus, patients with mild PD perform nor-
mally on the antisaccade task,771'886 but
with advanced disease, errors increase,302
especially when patients are also taking
anticholinergic drugs.771 Patients with ad-
vanced PD may also make large errors
when they make saccades to remembered
target locations.302
Rapid eye-head movements (gaze saccades)
may also be abnormal in PD; affected pa-
tients tend not to move their heads unless
instructed to do.1481 During rapid eye-
head gaze shifts, in response to either
predictable or nonpredictable step dis-
placements of the target, patients show in-
creased latency and slowing of head move-
ments.
Smooth Pursuit in PD
Smooth-pursuit movements are usually
impaired in PD, though mildly affected
patients differ little from age-matched
control subjects.1186'1459 During tracking of
a target moving in a predictable, sinu-
530 The Diagnosis of Disorders of Eye Movements
soidal pattern, pursuit gain (eye velocity/
target velocity) is decreased, leading to
catchup saccades.1125'1480 It appears that at
least part of the defect during tracking of
a smoothly moving target is that the
catchup saccades are hypometric; thus,
the cumulative tracking eye movement is
less than that of the target.1459 Despite the
impairment of smooth-pursuit gain, the
phase relationship between eye and target
movement during tracking of a periodic
target is normal;192 this implies a normal
predictive smooth tracking strategy.
Visuovestibular interactions in PD
Both caloric and low-frequency rotational
vestibular responses, in darkness, may be hy-
poactive in patients with PD.1132'1479 How-
ever, at higher frequencies of head rota-
tion, and particularly during visual
fixation, the gain of the VOR is close to
1.0, which accounts for the lack of com-
plaint of oscillopsia in patients with PD.1479
Combined eye-head tracking (VOR can-
cellation or suppression) is abnormal to a
similar degree as smooth pursuit with the
head stationary in most patients with PD
(see Disorders of Smooth Eye-Head Track-
ing in Chap. 7).545'1459'1479 PD patients
show a variety of disorders of eyelid move-
ments, including lid retraction on looking
straight ahead and lid lag on down gaze.52
Effects of Treatment on Eye
Movements in PD
In general, levodopa treatment of PD does
not seem to improve the ocular mo-
tor deficits except for improvement of
saccadic accuracy (i.e., saccades become
larger).513'1125 Some newly diagnosed pa-
tients with idiopathic PD may show im-
proved smooth pursuit after the institu-
tion of dopaminergic therapy.513 In one
patient with advanced PD, electrical stim-
ulation of the pallidum was reported to
improve performance on memory-guided
and antisaccade tasks.1333 Conversely, pal-
lidotomy is reported to induce square-
wave jerks in parkinsonian patients.603
In patients with parkinsonism due
to methyl-4-phenyl-1,2,3,6-tetrahydropy-
ridine (MPTP) toxicity, saccadic latency
was shortened and saccadic accuracy was
improved by dopaminergic agents; in ad-
dition, reflex blepharospasm in these pa-
tients was improved.653 In monkeys who
received MPTP, saccadic abnormalities—
including increased latency, increased du-
ration, decreased rate of spontaneous sac-
cades, and inappropriate saccades—were
all reversed by dopaminergic ther-
apy.197'1245 In those patients with idio-
pathic PD who show pronounced drug-
related fluctuations, there is disagreement
as to whether smooth pursuit shows an
increase in gain during "on" peri-
ods.512'1125'1265 The dopaminergic pars
compacta of the substantia nigra does not
appear to contain neurons related to eye
movement, whereas the pars reticulata
does.627 (The influence of the substantia
nigra pars reticulata [SNpr] and the ni-
grocollicular pathway in the control of sac-
cades is discussed in Chaps. 3 and 6.) In
monkeys with MPTP-induced parkinson-
ism, cerebral metabolic rate was reduced
in the frontal eye fields and paralamellar
mediodorsal thalamus;633 it is possible that
these metabolic changes are secondary to
loss of projections from the dopamine-de-
pleted substantia nigra.
OTHER CONDITIONS
CAUSING PARKINSONISM
Patients with the syndrome of amy-
otrophic lateral sclerosis, parkinsonism,
and dementia (Lytico-Bodig), which is en-
countered in the inhabitants of the islands
of the South Pacific Ocean, including
Guam, may show more severe deficits than
those with idiopathic PD, including limita-
tion of vertical gaze.854 A common diag-
nostic challenge is to differentiate patients
with other parkinsonian states from those
with PD; although general neurologic
findings and response to levodopa are im-
portant factors, a careful observation or
measurement of eye movements can often
help. Thus, as discussed above, slow verti-
cal saccades usually indicate progressive
supranuclear palsy. Slow saccades are also
characteristic of Creutzfeldt-Jakob disease,
but in both horizontal and vertical
planes.544 Cortical-basal ganglionic degen-
eration does not cause slow saccades, but
the latency of visually guided saccades is
increased beyond that typical of PD.1186'1429
 Diagnosis of Central Disorders of Ocular Motility 531

Eye movements in multiple system atro- by a pharmacological imbalance common

phy are similar to those in PD; vertical sac-
cades are not slow but are hypometric.1186
At present there are no published quanti-
tative data on vertical saccades in diffuse
Lewy-body disease, which is reported to
cause a vertical gaze palsy.332'863
OCULOGYRIC CRISIS
This unusual state was once commonly en-
countered as a feature of postencephalitic
parkinsonism but is now usually a side
effect of drugs, especially neuroleptic
agents.830 A typical attack is ushered in by
feelings of fear or depression, which give
rise to an obsessive fixation on a thought.
The eyes typically deviate upward, and
sometimes laterally; they rarely deviate
downward. During the period of upward
deviation, the movements of the eyes in
the upper field of gaze appear nearly nor-
mal. Affected patients have great difficulty
in looking down, except when they com-
bine a blink and downward saccade. Thus,
the ocular disorder may reflect an imbal-
ance of the vertical gaze-holding mecha-
nism (neural integrator). Anticholinergic
drugs promptly terminate the thought dis-
order and ocular deviation, a finding that
has led to the suggestion that the disorders
of thought and eye movements are linked
to both.830 Delayed oculogyric crises have
been described after striatocapsular infarc-
tion,873 and with bilateral putaminal hem-
orrhage.1282 Oculogyric crises are distinct
from the brief upward ocular deviations
that occur in Tourette's syndrome,474 Rett's
syndrome,460 Lesch-Nyhan disease,7033 in
children with benign paroxysmal tonic
upgaze,663 in many patients with tardive
dyskinesia,459 and rarely as a dopa-induced
dyskinesia in Parkinson's disease.8673 In
some patients with tardive dyskinesias,
however, the upward eye deviations are
more sustained and also have the charac-
teristic neuropsychologic syndrome of ocu-
logyric crises.1200 Episodic brief spells of
tonic up gaze have also been reported after
bilateral lentiform lesions.765
Huntington's Disease (HD)
CLINICAL FINDINGS IN HD
Huntington's disease produces distur-
bances of voluntary gaze, especially sac-
cades (Display 10-32).286-815'816'833'1375 The
disease is due to a defect of the IT 15 gene
on chromosome 4, causing increased GAG
triplet repeat length and the protein
"huntingtin". Initiation of saccades may be
difficult with prolonged latencies, espe-

Display 10-32: Ocular Motor Findings in

Huntington's Disease
• Difficulties initiating saccades—facilitated by an associated head thrust
or blink

• Difficulties suppressing reflexive saccades to novel visual stimuli (es-

pecially during the antisaccade task)

• Slow saccades, especially vertically, and in patients with early age of

onset

• Impairment of smooth pursuit

• Preservation of VOR and gaze holding

For pathophysiology, see The Role of the Basal Ganglia in Saccade Generation, in Chap. 3.
For a recorded example, see Figure 10-31 of Chap. 10.
532 The Diagnosis of Disorders of Eye Movements

cially when the saccade is made to com-
mand or in anticipation of a target that is
moving in a predictable fashion. An obliga-
tory blink or head turn may be used to
start the eye moving.1522 Saccades may be
slow in the horizontal or vertical plane; this
deficit can often be detected early in the
disease if eye movements are measured,286
but it may not be evident clinically until
late in the course.833 Saccades may be
slower in patients who become sympto-
matic at an earlier age, and it has been sug-
gested that such individuals are more
likely to have inherited the disease from
their father.817 Slowing of vertical saccades
probably does not occur in patients with
chorea due to nondegenerative conditions
or tardive dyskinesia.654 Smooth pursuit
may also be impaired with decreased gain,
but it often is relatively spared compared
with saccades. By contrast, gaze holding
and the VOR are well preserved. Late in
the disease, rotational stimulation causes
the eyes to tonically deviate with few or no
quick phases. Longitudinal studies of sac-
cades have documented progressive slow-
ing and prolongation of reaction time.1191
Fixation is abnormal in some patients with
Huntington's disease because of saccadic
intrusions.833 This defect of steady fixation
is particularly evident when patients view a
textured background. 286
PATHOGENESIS OF OCULAR
MOTOR FINDINGS IN HD
The paradoxical findings of difficulty in
initiating voluntary saccades, but with an
excess of extraneous saccades during at-
tempted fixation, has been further eluci-
dated using novel test stimuli. These have
revealed an excessive distractibility in, for
example, tasks in which patients are re-
quired to look in the direction opposite
that in which a target suddenly appears
(antisaccade task, Fig. 10-31).816 A second

Figure 10-31. The antisaccade task. A patient, who had Huntington's disease, was instructed to look in the op-
posite "mirror" location of the target light as soon as it was turned on. She was unable to do this and, instead,
first made a saccade toward the target light and then corrected her mistake and looked in the opposite (correct)
direction. The target reappeared in the mirror location, at which time the patient held fixation and then, when
the target returned to central position, made a saccade to it to await the onset of the next trial. H, horizontal; V,
vertical; time marks indicate 1-sec intervals. (From Lasker AG, Zee DS, Hain TC, Folstein SE, Singer HS. Sac-
cades in Huntington's disease: initiation defects and distractability. Neurology 1987;37:364-70, with permission
of Lippincott, Williams and Wilkins.)
 Diagnosis of Central Disorders of Ocular Motility
finding is that saccades to visual stimuli
are made at normal latency, while those
made to command are delayed. These
findings can be related to the parallel
pathways that control the various types of
saccadic responses. On the one hand, dis-
ease affecting either the frontal lobes or
the caudate nucleus, which inhibits the
substantia nigra pars reticulata (SNpr),
may lead to difficulties in initiating volun-
tary saccades in tasks that require learned
or predictive behavior.627 On the other
hand, Huntington's disease also affects
the SNpr.1054 Since this structure inhibits
the superior colliculus (nigrocollicular
projection), and so suppresses reflexive
saccades to visual stimuli, one might ex-
pect excessive distractibility during at-
tempted fixation. The slowing of saccades
might reflect involvement of saccadic
burst neurons, 778 but at least some patho-
logic evidence suggests that disturbance
of prenuclear inputs, such as the superior
colliculus or frontal eye fields, is responsi-
ble.834 The ability of blinks to initiate or
speed-up saccades is reviewed in Sac-
cades and Movements of the Eyelids, in
Chap. 3).
EYE MOVEMENTS AND THE
DIAGNOSIS OF HD
Despite the near-ubiquitous finding of ab-
normal eye movements in Huntington's
disease, some individuals who have been
studied at a presymptomatic point in their
disease have shown normal eye move-
ments.286'1184 Thus, routine testing of eye
movements cannot be regarded as a reli-
able method for determining which off-
spring of affected patients will go on to de-
velop the disease. Some improvement of
the eye movement abnormalities in HD
has been reported with sulpiride.1139
Disorders to be considered in the differ-
ential diagnosis of HD include neuroacan-
thocytosis, although abnormal eye move-
ments have not been described as an
important feature of this disorder.1146 Den-
tatorubropallidoluysian atrophy,1010 also
called the Haw River syndrome,209 is an-
other GAG triplet repeat disease (B37, chro-
mosome 12) and is characterized by slow
saccades but also by more myoclonus and
ataxia than in HD.
533
Other Diseases of Basal Ganglia
A number of other conditions that involve
the basal ganglia may cause abnormal eye
movements. Wilson's disease and Nie-
mann-Pick variants are discussed under
Ocular Motor Manifestations of Metabolic
and Deficiency Diseases. Caudate hemor-
rhage has been associated with ipsilateral
gaze preference,1322 consistent with exper-
imental dopamine depletion of this struc-
ture. 727 Patients with bilateral lentiform
nucleus lesions show abnormalities of
predictive and memory-guided saccades
(both internally generated), but visually
guided saccades and antisaccades (both
triggered by a visual target) are nor-
mal.1425 It has been suggested that defects
in the control of predictive smooth-pur-
suit eye movements are a feature of striatal
damage.844
Patients with Gilles de la Tourette's syn-
drome may show abnormalities such as
blepharospasm and eye tics that include
involuntary gaze deviations.420'474 Routine
testing of saccades, fixation, and pursuit is
normal, 153 but patients show increased la-
tency and decreased peak velocity of anti-
saccades, as well as impaired sequencing
of memory-guided saccades.999'1335 The lid
abnormalities of Tourette's syndrome
must be distinguished from benign eye
movement tics, which children often out-
grow.134'1273
Patients with essential blepharospasm
generally show normal eye movements, 376
although saccadic latencies may be in-
creased in certain visually guided and
memory-guided saccade tasks.43'152 Pa-
tients with spasmodic torticollis may show
abnormalities of vestibular function in-
cluding the torsional VOR.60'1326 Whether
vestibular abnormalities are the cause or
a secondary effect of spasmodic torticol-
lis has not been settled, but affected pa-
tients do show changes in their percep-
tions of the visual vertical and straight
ahead.31'32
Patients with tardive dyskinesia may dis-
play increased saccade distractibility.1364
Patients with active Sydenham's chorea
are reported to show saccadic hy-
pometria.233 In Lesch-Nyhan disease, a
hereditary disorder characterized by hy-
peruricemia, recurrent self-injurious be-
534 The Diagnosis of Disorders of Eye Movements
havior and extrapyramidal features, pa-
tients show impaired ability to make vol-
untary saccades, errors on the antisaccade
task, blepharospasm, and intermittent
gaze deviations similar to Tourette's syn-
drome.703a
OCULAR MOTOR SYNDROMES
CAUSED BY LESIONS IN THE
CEREBRAL HEMISPHERES
In reviewing the effects of cerebral hemi-
sphere lesions on eye movements, first we
describe the effects of acute lesions; second,
we identify the enduring effects of large,
unilateral lesions; and then we discuss the
effects of lesions limited to specific lobes,
referring to the scheme laid out in Chap. 6.
Ocular motor apraxia, the manifestations
of epileptic seizures, and the effects of dif-
fuse processes, such as those causing de-
mentia, are dealt with subsequently.
Disturbances of Gaze With Acute
Hemispheric Lesions
Following an acute lesion of one cerebral
hemisphere, the eyes often deviate conju-
gately toward the side of the lesion—
Prevost's or Vulpian's sign (Display
10-33).531-1382 The head is also often
turned in the same direction (see Chap.
7). Sustained horizontal gaze deviation is
more common after large, right-sided
strokes that predominantly involve post-
Rolandic cortex or the subcortical fron-
toparietal region and the internal
capsule.339'1377'1382 Left hemispheric le-
sions that produce gaze deviations are
usually large, covering the entire fronto-
temporo-parietal area. With right-sided
lesions, visual hemineglect is also often
present and may contribute to the "gaze
preference."794 In general, the larger the
lesion, the more persistent the conjugate
deviation. However, most horizontal gaze
deviations that occur following a hemi-
spheric stroke resolve within a week.
When the gaze deviations are more persis-
tent, there is often a prior lesion in the
contralateral hemisphere.1323
Most patients show a conjugate gaze de-
viation that is ipsilateral to the side of the
hemispheric lesion; they appear to "look
away from their hemiparesis." Rarely,
hemispheric lesions (usually hemorrhages)
may cause a contralateral gaze deviation
so that the patient appears to "look toward
the hemiparesis";1075'1264 such wrong-way
deviations are more common with thala-
mic lesions450 or with pontine lesions that
lie below the level of the presumed ocular
motor decussation. Another cause of a
wrong-way deviation is epilepsy; when the
patient is first examined, it should be con-
firmed that the gaze deviation is sustained
and not a transient phenomenon that
would suggest seizures.
Although the gaze deviation due to a
hemispheric lesion may be quite marked
during the acute phase, it is usually possi-
ble to drive the eyes across the middle of
the orbits with a head rotation or caloric
stimulation. This preservation of the
range of reflexive eye movements is help-
ful in distinguishing the gaze deviation
from a pontine lesion, in which vestibular
stimuli often fail to drive the eyes across
the midline.319 When quick phases of
caloric nystagmus are absent, conscious-
ness is usually, but not always, impaired
owing to shift of intracranial con-
tents.265'1098
The defect of eye movements after a
large hemispheric lesion often corre-
sponds to craniotopic coordinates: There
is difficulty moving the eyes in the con-
tralateral orbital hemifield. Even within
the remaining field of movement, how-
ever, other abnormalities are evident. For
example, some patients show a small-
amplitude nystagmus with ipsilateral
quick phases; a similar finding is reported
acutely after hemidecortication in the
monkey.1403 The slow phases of this nys-
tagmus may reflect unopposed pursuit
drives directed away from the side of the
lesion; recall that unilateral hemispheric
lesions produce predominant deficits for
contralateral saccades but ipsilateral
smooth-pursuit and optokinetic responses
(see Fig. 4-11). Support for this interpre-
tation comes from measurement of opto-
kinetic visual tracking in patients with
ipsiversive gaze deviation; responses to
 Diagnosis of Central Disorders of Ocular Motility 535

Display 10-33: Topological Diagnosis of Acute Conjugate

Deviations of the Eyes
SUSTAINED HORIZONTAL CONJUGATE GAZE DEVIATION
• Ipsilateral ("looks away from the hemiparesis"): destructive hemi-
spheric lesions (e.g., infarcts), especially with large, posterior, and
right-sided location

• Contralateral ("looks toward the hemiparesis"): pontine lesions; thala-

mic lesions, and rarely with other supratentorial disease (wrong-way
deviation)

INTERMITTENT HORIZONTAL CONJUGATE GAZE DEVIATION

• Usually a manifestation of epileptic seizures

SUSTAINED UPWARD GAZE DEVIATION

• Following hypoxic-ischemic insult

• Drug effects and oculogyric crisis

SUSTAINED DOWNWARD GAZE

• Thalamic hemorrhage

• Lesions compressing the dorsal midbrain, such as hemorrhage, tu-

mor, hydrocephalus

For related anatomy, see Descending Parallel Pathways That Control Voluntary Gaze, Brain
Stem Connections for Vertical and Torsional Movements, Figure 6-4, and Figure 6-5 in
Chap. 6.

stimulus motion toward the intact hemi-
sphere are much greater.959 Within the
preserved field of movement, contralateral
saccades are hypometric.959'1381 Vertical
saccades may also show abnormalities;
they are dysmetric with an inappropriate
horizontal component toward the side of
the lesion.464 Because normally both hemi-
spheres must be activated to elicit a purely
vertical saccade, the loss of one hemi-
sphere may cause the abnormal trajectory.
In general, for comparably sized lesions,
ocular motor defects—both pursuit and
saccades—are more profound when the le-
sion is in the nondominant hemisphere.843
Some further insights into the effects of
acute inactivation of one hemisphere
come from observations of gaze control
following intracarotid injection of barbitu-
rate (the Wada test to determine cerebral
dominance).856'927 At the onset of hemi-
paresis, a transient horizontal gaze devia-
tion may occur, which is more common
with right-sided injections, providing fur-
ther evidence for the dominance of the
right hemisphere in directing attention.
During the period of hemiparesis of the
Wada test, contralateral and ipsilateral
saccades are still possible, with relatively
minor slowing of the contralateral ones.
This persistence of voluntary saccades is
probably due to the influence of posterior
cerebral areas, which receive blood supply
from the vertebrobasilar system and which
536 The Diagnosis of Disorders of Eye Movements

project, independently of the frontal eye
fields, to the superior colliculus.856
Enduring Disturbances of Gaze
Caused by Unilateral
Hemispheric Lesions
Persisting ocular motor deficits caused by
large lesions (such as hemidecortication for
intractable seizures) are summarized in
Table 10-18. Though there may be no rest-
ing deviation of the eyes, Cogan pointed
out that forced eyelid closure may cause a
contralateral "spastic" conjugate eye move-
ment, the mechanism of which is not un-
derstood.261'1343 This sign occurs most fre-
quently with parietotemporal lesions. Con-
jugate deviation during attempted lid
closure in patients with hemispheric lesions
differs from the deviation (lateropulsion)
that occurs in Wallenberg's syndrome (lat-
eral medullary infarction (see VIDEO: "Wal-
lenberg's syndrome"). With hemispheric
lesions, the eyes deviate only with active lid
closure or attempted lid closure, but in
Wallenberg's syndrome, the deviation oc-
curs even with the eyes open in darkness.
In central position, a small-amplitude
nystagmus may be present (best seen dur-
ing ophthalmoscopy, with slow phases di-

Table 10-18. Enduring Effects of Large Unilateral Lesions of

the Cerebral Hemispheres Upon Ocular Motor Function

Fixation
In darkness, eyes usually drift away from the side of the lesion. This
may also be evident during fixation (on ophthalmoscopic exami-
nation*) as nystagmus with quick phases toward the side of the
lesion.1270 Square-wave jerks1267

Saccades
Slower horizontal saccades to both sides, especially contralaterally; latency
longer for small saccades directed contralateral to the side of the le-
sion;1397 inaccurate (hypometric and hypermetric) saccades into the
"blind" hemifield.1270'1397 Vertical saccades may have inappropriate hori-
zontal component464

Smooth Pursuit
Reduced pursuit gain toward the side of the lesion; smooth-pursuit gain
away from the side of the lesion may be increased for low-velocity tar-
gets1270'1395

Optokinetic
Reduced gain for stimuli directed toward the side of the lesion; impaired
optokinetic after-nystagmus; may be relatively preserved compared with
pursuit, with prolonged buildup of slow-phase velocity87-604

Vestibular
During sinusoidal head rotation, VOR gain in darkness may be slightly
asymmetric (greater for eye movements away from the side of the lesion);
with attempted fixation of an imagined or real stationary target, the asym-
metry is increased.424'665'1269 No asymmetry of response with rapid head
turns 665

Forced Eyelid Closure

Eyes usually deviate conjugately away from the side of the lesion (Cogan's
"spasticity of conjugate gaze")1343
*Remember that the direction of eye movements appears inverted during ophthal-
moscopy.

rected toward the side of the intact hemi-
sphere; it may represent an imbalance in
smooth-pursuit tone.1270 Horizontal pur-
suit gain (eye velocity/target velocity) is
low for tracking of targets moving toward
the side of the lesion for all stimulus veloc-
ities. For targets moving slowly toward the
intact hemisphere, the eye movements
may be too fast (pursuit gain greater than
1.0), requiring back-up saccades (see Fig
4-1 IB); for higher target velocities, pur-
suit gain toward the intact side is nor-
mal.1270'1395 This disturbance of smooth
pursuit probably reflects loss of both pos-
terior (occipital-parietal-temporal) and
frontal influences; possible pathogenetic
mechanisms are discussed in the following
sections, where the effects of lobar lesions
are separately considered.
A convenient way to demonstrate this
asymmetry of smooth pursuit is with a
hand-held optokinetic drum or tape.272
The response is decreased when the
stripes are moved toward the side of the
lesion. At the bedside, this "optokinetic"
response is usually judged according to
the frequency and amplitude of quick
phases. Since these quick-phase variables
also depend on slow-phase velocity, a
decreased response (reduced gain) may
reflect impaired slow-phase generation,
impaired quick-phase generation, or a
combination of the two.
Hemidecortication causes abnormalities
of both contralateral and ipsilateral hori-
zontal saccades.1270'1397 Saccades are usu-
ally slower than normal for refixations
into the hemianopic field, and sometimes
into the intact hemifield. Saccadic latency
is also prolonged in both directions.1270
For small refixations, contralaterally di-
rected saccades have greater latencies
than ipsilateral saccades. Prolonged sac-
cadic reaction time may reflect (1) defects
in visual detection due to the hemianopia,
(2} defects in directing visual attention,
and (3) abnormal motor programing. Sac-
cadic accuracy is impaired asymmetrically:
Most contralaterally directed saccades do
not put the eye on target.1397
The horizontal VOR may be mildly
asymmetric in hemidecorticate patients at
lower test frequencies; the gain (eye veloc-
ity/head velocity) is greater for compensa-
Diagnosis of Central Disorders of Ocular Motility 537
tory eye movements directed away from
the side of the lesion.424 More asymmetry
appears when visual fixation and vestibu-
lar stimulation are combined (during rota-
tion while fixating a stationary object),
probably reflecting the ipsilateral smooth
pursuit deficit. The asymmetry is still
present during head rotation if the patient
imagines a stationary object.1269 However,
if the head is suddenly and rapidly rotated
during fixation of a stationary target, gaze
is perturbed no more than in normal sub-
jects,665 consistent with the absence of os-
cillopsia in patients with hemispheric le-
sions as they make head movements
during natural activities.
Effects of Focal Hemispheric
Lesions on Gaze
EFFECTS OF LESIONS OF
POSTERIOR OCCIPITOTEMPORAL
CORTICAL AREAS ON GAZE
Unilateral lesions of the occipital lobes
cause a contralateral visual field defect
and an ocular motor deficit (saccadic dys-
metria) that reflects the patient's homony-
mous hemianopia (Display 10-34). Sac-
cades into the hemianopic visual field are
dysmetric (usually hypometric), and simi-
lar patterns of saccades are reported with
acoustic targets, implying some degree of
common motor programing, perhaps in-
fluenced by associated defects in directing
spatial attention.1389 Characteristic pat-
terns are also shown in patients who have
hemianopic dyslexia.1544
Patients with hemianopia may show
compensatory strategies to increase sac-
cadic accuracy,938 unless hemineglect is
also present.1003 These strategies include a
staircase of search saccades with back-
ward, glissadic drifts; a deliberate over-
shooting saccade to bring the target into
the intact hemifield of vision; and, with
predictable targets, saccades using mem-
ory of previous attempts. Such findings
have been used to develop simple clinical
tests for distinguishing hemianopia with
and without neglect.931 Rapid gaze shifts
achieved by combined movements of eye
and head also show increased latency of
538 The Diagnosis of Disorders of Eye Movements

Display 10-34: Effects of Lesions of Posterior Cortical Areas

PRIMARY VISUAL CORTEX
• Acutely: Unable to make saccades or generate smooth pursuit in re-
sponse to visual stimuli presented into the blind field

• Chronically: Strategies develop to scan the environment and place the

image of an object of interest in the intact visual field

MIDDLE TEMPORAL VISUAL AREA (MT, V5)

• Retinotopic defect of motion vision causing saccades and smooth pur-
suit to be impaired when visual stimuli fall in the affected visual field

MEDIAL SUPERIOR TEMPORAL VISUAL AREA (MST)

• Directional defect of smooth pursuit, with decreased gain for ipsilat-
eral target motion

• Superimposed retinotopic defect, similar to MT lesions

POSTERIOR INSULA ("VESTIBULAR CORTEX")

• Contralateral tilts of subjective visual vertical
• Circularvection abolished during optokinetic stimulation

For related anatomy, see Display 6-14, Display 6-15, Figure 6-7, and Figure 6-8, in Chap. 6.
For review of vestibular cortex, see Chap. 2. For recorded examples of the effects of clinical
lesions, see Figure 4-8 and Figure 4-11 in Chap. 4.

head movements and development of
compensatory strategies when looking to
the hemianopic side.1521 Smooth pursuit
remains intact with unilateral lesions of
the striate cortex, provided the moving
stimulus is presented to the intact hemi-
field,1252 and optokinetic nystagmus
elicited at the bedside is usually symmet-
ric. Within the affected visual field, mo-
tion detection is usually abolished.105
However, functional imaging suggests that
secondary visual areas at the occipitopari-
etal region, lying anterior to an occipital
lesion, may still respond to moving stimuli
either due to extrastriate or interhemi-
spheric callosal inputs.1663
Bilateral occipital lesions cause cortical
blindness. A patient with bilateral, con-
genital occipital lesions and little residual
vision was reported to be able to make vol-
untary saccades but not smooth pur-
suit.1156 Optokinetic responses are present
in monkeys following bilateral occipital
lobectomy,1537 but this is probably not
the case in humans.183-1423 Focal occipital
seizures have been reported to cause ei-
ther contralateral or ipsilateral deviation
of the eyes and nystagmus.
Patients with more anterior lesions that
involve cortex at the junction of areas 19,
37, and 39 (see Display 6-14), close to the
intersection of the ascending limb of the
inferior temporal sulcus and the lateral
occipital sulcus (see Fig.6-8, Chap. 6), are
reported to show defects of motion per-
ception (akinetopsia),1283 and impairment
 Diagnosis of Central Disorders of Ocular Motility
of smooth pursuit, 826 ' 1373 similar to those
described in monkeys with middle tempo-
ral visual area (MT) lesions (see Fig. 4-8).
Similarly, lesions may also involve the ho-
mologue of the medial superior temporal
visual area (MST) and produce a track-
ing deficit similar to that in monkeys,
with impairment of ipsilateral pursuit
and a defect of motion processing affect-
ing the contralateral visual hemifield (Fig.
4_H). 103,106,605,826,961,1373 Tnese tracking
defects with lesions affecting posterior cor-
tical lesions are most evident when the re-
sponses to step-ramp stimuli are mea-
sured (see Abnormalities of Pursuit
Initiation in Chap. 4). Patients with bilat-
eral MST lesions may experience illusory
motion of the stationary world during
smooth pursuit. 566
Lesions affecting vestibular cortex, a
component of which lies in the posterior
aspect of the superior temporal gyrus
[parieto-insular-vestibular cortex (PIVC)]
(see Display 6-15 and Fig. 6-8) cause con-
tralateral tilts of the subjective visual verti-
cal.172 In addition, such lesions may abol-
ish the sense of self-rotation (circularvection)
that normally occurs with optokinetic
stimulation,1330 and may impair memory-
guided saccades if patients are rotated to a
new position during the memory pe-
riod.682 Patients with lesions involving the
medial temporal lobe and hippocampus
show impairment in the ability to generate
sequences of saccades, even though spatial
memory is intact.990 Seizures emanating in
the temporal lobes may cause a variety of
vestibular sensations. Though a mild feel-
ing of dizziness is common with a variety
of seizure types, a true sensation of rota-
tion, vestibular or tornado epilepsy, is a
rare but well-described epileptic phenom-
enon _92,496,779,1011,1233,1296
EFFECTS OF PARIETAL LOBE
LESIONS ON GAZE
Acute unilateral lesions involving the pari-
etal lobe (see Display 6-16, Display 6-17,
and Fig. 6-8) often cause an ipsilateral
horizontal gaze deviation or preference.
Especially when the lesion is right-sided,
there is also contralateral inattention. Bi-
539
lateral ptosis may also occur with acute
right parietal lesions,61 although it more
commonly occurs with disease located in
midbrain (especially involving the oculo-
motor nucleus), with Miller Fisher syn-
drome, or with disorders of the neu-
romuscular junction or the extraocular
muscles (see Chap. 9). The defect of ocu-
lar motility often corresponds to cran-
iotopic coordinates, reflecting the normal
role of parietal areas in directing visual at-
tention in head-centered or spatial coordi-
nates; this is discussed further under
Disturbances of Gaze With Acute Hemi-
spheric Lesions. Although ocular motor
defects associated with parietal lesions
may be partly due to difficulties in shifting
attention from one position to another
in extrapersonal space,1103 there are also
distinct and specific effects on saccadic
and pursuit eye movements (Display
10-35). 1°78,1453
The latency of visually guided saccades
to targets presented in either visual hemi-
field is increased with right-sided lesions;
with left-sided lesions, only saccades to
contralateral targets are delayed.1089 These
increases in saccadic latency are more
marked when the fixation light remains
on during testing (overlap paradigm) than
when it is turned off just before the target
light appears (gap paradigm);1090 this may
reflect difficulties in disengaging attention
prior to initiating the saccade. The accu-
racy of saccades to contralateral targets
may also be impaired, but the most im-
pressive dysmetria occurs when patients
are required to respond to a double-step
stimulus, in which the target jumps twice
before a response can be initiated.409'603 If
the target jumps first into the contralateral
hemifield and then into the ipsilateral
field, patients cannot make accurate sac-
cades to the final target position, even
though it lies in the "intact" hemifield.
This finding has been taken as evidence
that the parietal lobe plays a pivotal role in
computing target position from both vi-
sual stimuli and an efference copy of eye
movements (in this case, the change in eye
position due to the first saccade).409-603
Asymmetry of smooth pursuit and opto-
kinetic tracking has traditionally been
540 The Diagnosis of Disorders of Eye Movements

Display 10-35: Effects of Parietal Lobe Lesions

UNILATERAL LESIONS (ESPECIALLY RIGHT-SIDED)
• Contralateral inattention

• Ipsilateral gaze deviation or preference

• Increased latency for visually guided saccades
• Errors on responses to double-step stimulus

• Impaired smooth pursuit if target moves across textured background

BILATERAL PARIETAL LESIONS

• Balint's syndrome: peripheral visual inattention (simultanagnosia), in-
accurate arm pointing (optic ataxia), difficulty in making visually
guided saccades. (If all voluntary eye movements are affected, involve-
ment of frontal lobes is likely, and the term "ocular motor apraxia" has
been used)

For related anatomy, see Display 6-16, Display 6-17, and Figure 6-8 in Chap. 6. (Related
VIDEOS: "Acquired ocular motor apraxia.")

ascribed to parietal lobe lesions. Thus, de-
creased nystagmus elicited when a hand-
held optokinetic drum or tape moves to-
ward the side of the lesion has been taken
as indicating involvement of the inferior
parietal lobule and underlying deep white
matter.272'605 Functional imaging studies
suggest that secondary visual areas at
the temporooccipitoparietal junction are
probably responsible for these defects in
smooth tracking (see Fig. 6-7). More spe-
cific to parietal lobe lesions is loss of the
ability to attend to the image of a moving
target and to "ignore" the smeared images
of the stationary background consequent
to the eye movement. Thus, patients with
lesions affecting Brodmann area 40 show
impaired smooth pursuit when the target
moves across a structured background
compared with pursuit across a dark back-
ground.820 Impairment of the same mech-
anism may explain why patients with pari-
etal lesions show relative preservation of
responses to full-field optokinetic stimuli,
which demand less selective visual atten-
tion.87 Bilateral posterior parietal lesions
cause Balint's syndrome,1085 which is dis-
cussed below, under Ocular Motor Apraxia.
EFFECTS OF FRONTAL LOBE
LESIONS ON GAZE
Experimental and clinical studies, re-
viewed in Chap. 6, have made it possible
to identify three distinct regions in the
frontal lobes that contribute to the control
of eye movements (see Fig. 6-8): the
frontal eye field (FEF) (see Display 6-19),
the supplementary eye field (SEF) (see
Display 6-20) in the supplementary motor
area, and the dorsolateral prefrontal cor-
tex (DLPC) (see Display 6-21). Although
there is some overlap of function, lesions
affecting each of these three areas pro-
duce certain behavioral deficits that are
distinctive (Display 10-36).1082
Effects of FEF Lesions on Gaze
Acute lesions of the FEF may produce an
ipsilateral horizontal gaze deviation that
resolves with time.319'1226 Acute pharma-
 Display 10-36: Effects of Frontal Lobe Lesions
EFFECTS OF LESIONS OF THE FRONTAL EYE FIELD (FEF)
IN MONKEYS, ACUTE UNILATERAL PHARMACOLOGICAL
INACTIVATION OF FEF WITH MUSCIMOL PRODUCES
• An ocular motor scotoma, so that all voluntary contralateral saccades
with sizes and directions corresponding to the injection site are abolished
• Gaze preference toward the side of the lesion
• Impaired smooth pursuit, especially toward side of the lesion

IN HUMANS, CHRONIC UNILATERAL LESIONS AFFECTING THE

FEF CAUSE
• Bilateral increase in reaction time of saccades made to visual targets in
"overlap" task, to remembered target locations, and to imagined tar-
gets during the "antisaccade" task
• Hypometria of saccades made to visual or remembered targets located
contralateral to the side of the lesion
• Reduced ability to make saccades in anticipation of predictable step-
ping movement of a target, when the target moves away from the side
of the lesion
• Impaired ability to inhibit inappropriate saccades to a novel visual
stimulus
• Impairment of smooth pursuit and optokinetic following of targets
moving toward the side of the lesion

EFFECTS OF LESIONS OF THE SUPPLEMENTARY EYE FIELD (SEF)

• Lesions involving the SEF in humans do not affect visually guided
saccades
• Memory-guided saccades become inaccurate if gaze shifts during the
memory period
• Impaired ability to make a remembered sequence of saccades to an ar-
ray of visible targets (especially with left-sided lesions)

EFFECTS OF LESIONS OF DORSOLATERAL PREFRONTAL

CORTEX(DLPC)
• Pharmacological blockade of Dl dopamine receptors causes inaccu-
racy of saccades made to remembered target locations lying contralat-
eral to the side of injection
• Patients with lesions affecting this area show defects of predictive sac-
cades, memory-guided saccades, and antisaccades

For related anatomy, see Display 6-19, Display 6-20, Display 6-21, and Figure 6-8, in Chap.
6. For pathophysiology of saccadic disorders, see The Role of the Frontal Lobe in Saccade
Generation in Chap. 3.
542 The Diagnosis of Disorders of Eye Movements
cological inactivation of the FEF also
abolishes all contralateral, voluntary sac-
cades.384'1307 Rarely, contralateral deviation
has been observed with acute, hemor-
rhagic frontal lesions1264 or frontoparietal
lesions.1075
The enduring deficits of saccades and
smooth pursuit with FEF lesions are often
not obvious at the bedside and require
laboratory testing to identify. Thus, an in-
creased reaction time to initiate a saccade
is more evident when the fixation light
remains on during testing (overlap par-
adigm), when saccades are made to re-
membered target locations, and espe-
cially during the antisaccade task (Fig.
10-31). 1086,1152 These increases in latencies
occur whether the target is located ipsilat-
eral or contralateral to the lesion. There is
mild hypometria of saccades made to vi-
sual or remembered targets located con-
tralateral to the side of the lesion.177'896'1152
Another deficit concerns the ability to
make saccades in anticipation of target
jumps that occur predictably, when the
target moves away from the side of the le-
S i on .38o,io9o,i263 Mild slowing of contralat-
eral saccades occurs in some patients.1263
Deep, unilateral frontal lobe lesions cause
increased latency for contralateral sac-
cades.1091 This deficit is probably due to
damage of efferent and afferent connec-
tions of the frontal eye fields. Paradoxi-
cally, patients with FEF lesions may show
difficulty in suppressing saccades to novel
visual targets—for example, during the
antisaccade task.1152
FEF lesions also impair smooth
pursuit.176'605'843'844'962-1152 With unilateral
FEF lesions, horizontal pursuit is im-
paired bilaterally, but more so for tracking
of targets moving toward the side of the le-
sion. Both the initiation and maintenance
of pursuit are affected, more so at higher
target speeds and frequencies.
Effects of SEF Lesions on Gaze
Visually guided saccades are not notice-
ably affected by SEF lesions, and memory-
guided saccades only become inaccurate if
there is a gaze shift during the memory
period.1086 The defect that is characteristic
of SEF lesions is a loss of the ability to
make a sequence of saccades to an array of
visible targets in the order that they were
turned on.504'506 This is especially true
with left-sided SEF lesions. Thus, the SEF
seems essential for programing a series of
saccades as part of a learned behavior.
Note, however, that impaired ability to re-
member a sequence of saccades also oc-
curs with lesions affecting the hippocam-
pus.990 SEF lesions may also impair the
predictive smooth-pursuit response.605-843
Effects of DLPC Lesions on Gaze
Pharmacological inactivation of the DLPC
with Dj dopamine antagonists specifically
impairs the ability of monkeys to make ac-
curate memory-guided saccades toward
contralateral targets.1222 Similarly, patients
with lesions affecting the DLPC show de-
fects of memory-guided saccades, antisac-
cades, and predictive saccades.564'1086'1087
Pursuit defects with unilateral DLPC le-
sions may be bilateral.843
Memory-guided saccades are also affected
by lesions involving the posterior portion of
the right cingulate cortex. Such patients also
make increased errors on the antisaccade
test and when they attempt to make, from
memory, a sequence of saccades.5053
Ocular Motor Apraxia
ACQUIRED OCULAR
MOTOR APRAXIA
Acute bilateral frontal or frontoparietal le-
sions may produce a striking disturbance
of ocular motility that has been called ac-
quired ocular motor apraxia.M4'1081 It is usu-
ally due to bihemispheric infarcts and may
be a complication of cardiopulmonary by-
pass.382 It is characterized by loss of volun-
tary control of saccades and pursuit, with
preservation of certain reflex movements.
Patients have difficulties making horizon-
tal and vertical saccades to command and
following a pointer moved by the exam-
iner (see VIDEO: "Acquired ocular motor
apraxia"). Gaze shifts are achieved more
easily with combined eye-head move-
ments, often in association with a blink.
Vestibular eye movements (both slow and
 Diagnosis of Central Disorders of Ocular Motility
quick phases) are preserved. In addition,
some patients are able to initiate saccades
reflexively to novel visual targets. The de-
fect of voluntary eye movements probably
reflects disruption of descending path-
ways both from the frontal eye fields and
the parietal cortex (see Fig. 6-8 and Fig.
3-8), so the superior colliculus and brain
stem reticular formation are bereft of their
cortical inputs. The behavioral deficit is
similar to that produced by bilateral, com-
bined, experimental lesions of the frontal
eye fields and superior colliculus,1226 or
frontal and parietal eye fields.890
When a similar disorder of ocular motil-
ity, called psychic paralysis of gaze, is associ-
ated with inaccurate arm pointing (optic
ataxia) and disturbance of visual attention
(simultagnosia), the eponym Balint's syn-
drome has been used.265'637'639-667'1081'1154'1410
The lesions are more parietal or occipital,
and voluntary saccades may be made
more easily than in response to visual
stimuli.1085 Thus, the main abnormal-
ity appears to be a defect in the visual
guidance of saccades, manifested by in-
creased latency and decreased accuracy
and impaired ability to conduct visual
search.109'888-1545 Smooth pursuit is also im-
paired.840 Spontaneous blinking may be
absent.1461 In one patient, the visual scene
was reported to fade during fixation and
to be restored by intentional blinks.535
(The effects of blinks on eye movements
are reviewed in Saccades and Movements
of the Eyelids, in Chap. 3).
Some patients with ocular motor
apraxia may show spasm of fixation, the
inability to generate a voluntary eye move-
ment to shift gaze when a fixation target is
continuously present; only when the fixa-
tion target is removed can a gaze shift
be made.639 Holmes,639 assisted by Denny-
Brown, noted that if affected patients
viewed a homogenous white screen, then
voluntary eye movements became possi-
ble. The anatomic basis for this distur-
bance is uncertain, although defects in the
inhibitory control of the superior collicu-
lus by the substantia nigra pars reticulata
(SNpr) have been proposed.709
The following case history illustrates
some features of the syndrome of acquired
ocular motor apraxia.
543
CASE HISTORY: Acquired Ocular Motor
Apraxia in Multiple Sclerosis (see video:
"Acquired ocular motor apraxia")
A 28-year-old woman was in good health until
8 months prior to admission, when she suf-
fered a "whiplash" neck injury in an automo-
bile accident. Subsequently, she developed
transient mild weakness of the left side of the
body, which resolved in a few weeks. She suf-
fered several further transient neurologic
deficits, including loss of vision in first the right
and then the left eye. Just prior to admission,
she developed right-sided weakness, difficulty
with speech, and emotional behavior that her
husband characterized as "child-like."
On examination, she had striking immobility
of gaze. She was emotionally labile and had dif-
ficulties with calculations and short-term mem-
ory, but was cooperative and could follow in-
structions. Both optic discs were pale. Her
visual acuity was 20/200 OS and 20/100 OD.
She had no difficulty in recognizing or naming
objects. There were bilateral pyramidal tract
signs.
With the head still, she had great difficulty
initiating saccades to command or to visual tar-
gets. When saccades did occur, they were often
associated with a blink. With her head free to
move, she could change gaze more easily. Her
saccades were of small amplitude but appeared
to be of normal velocity. On occasion, she
would change gaze by moving first the trunk,
then her head, and finally making a small sac-
cade. With an optokinetic tape, quick phases of
nystagmus were easily elicited, though they
seemed to be reduced in frequency. Smooth
tracking was also impaired. Rotational testing
elicited normal quick and slow phases of vestib-
ular nystagmus.
Computed tomography (Fig. 10-32) showed
bilateral lucencies in the centrum semiovale
and deep portions of the posterior frontal and
parietal lobes. Spinal fluid findings supported
a diagnosis of multiple sclerosis. She improved
while in the hospital and 1 year later was re-
ported to have no ocular motor deficit.
Comment: This patient's ocular motor
deficit involved voluntary eye movements: sac-
cades and pursuit. Her "reflex" eye move-
ments—vestibular nystagmus—and eye-head
gaze shifts were relatively spared. Thus, the
term ocular motor apraxia might be correctly ap-
544 The Diagnosis of Disorders of Eye Movements

Figure 10-32. Two CT scans of the cerebral hemispheres of a patient with multiple sclerosis, who presented
with "apraxia of gaze" (see Case history: Acquired ocular motor apraxia in multiple sclerosis for details). The
scans show bilateral lucencies located in the centrum semiovale (A) and in the deep portions of the posterior
frontal and adjacent parietal lobes (B).
Continued on following page

plied to this deficit, which reflects disease in-
volving both cerebral hemispheres.
CONGENITAL OCULAR
MOTOR APRAXIA
Congenital ocular motor apraxia was first
described by Cogan.262'266'271 An abnor-
mality may be recognized at several
months of age when the child does not ap-
pear to fixate upon objects normally and
may be thought to be blind. Some chil-
dren with congenital ocular motor apraxia
have also been reported to have had a
transient head and limb tremor in the first
few days of life. Between the ages of 4 and
6 months, characteristic, thrusting hori-
zontal head movements develop (see
VIDEO: "Congenital ocular motor apraxia"),
sometimes with prominent blinking or
even rubbing of the eyelids when the child
attempts to change fixation. In children
with poor head control, development of
head thrusting may be delayed or absent.
Almost all patients also show a defect in
generating quick phases of nystagmus,591
which can usually be appreciated at the
bedside by manual spinning of the pa-
tient, either when holding the child out at
arm's length or by rotating the child on a
swivel chair—if necessary, sitting in an
adult's lap (see VIDEO: "Congenital ocular
motor apraxia"). Despite difficulties in
 Diagnosis of Central Disorders of Ocular Motility
Figure 10-32.—continued
shifting horizontal gaze, vertical voluntary
eye movements are normal.
Measurements of eye and head move-
ments have documented the characteris-
tics of this disorder.439'591'1540 With the
head immobilized, patients show both im-
paired initiation (increased latency) and
decreased amplitude (hypometria) of vol-
untary saccades in response to either a
simple verbal command to look left or
right or, less so, to track a step displace-
ment of a target (Fig. 10-33). Saccades are
also delayed during attempted refixations
between auditory targets in complete
darkness, so the saccadic initiation abnor-
mality cannot be ascribed to a defect of the
visual responses. Saccadic velocities are
normal and saccades or quick phases of
nystagmus of large amplitude can occa-
sionally be generated. These findings indi-
cate that, in these patients, the premotor
455
brain stem burst neurons that generate
saccadic eye movements are intact. Espe-
cially in younger patients, however, the
timing and amplitude (but not velocity) of
quick phases of vestibular and optokinetic
nystagmus may be impaired; the eyes in-
termittently deviate tonically in the direc-
tion of the slow phase because of a defect
in the initiation of the quick phase of nys-
tagmus. Sometimes the saccade defect
(and head thrusts) is asymmetric. 241 Pur-
suit eye movements may also be of low
gain, but the corrective saccades are usu-
ally promptly generated. The defects in
congenital ocular motor apraxia are usu-
ally restricted to the horizontal plane, an
important differential diagnostic point,
because most acquired cases also have de-
fects in the vertical plane.
The head thrusts made by affected pa-
tients probably reflect one of several adap-
546 The Diagnosis of Disorders of Eye Movements

Figure 10-33. Eye-head coordination in congenital ocular motor apraxia. Responses to nonpredictable 40°
changes in target position (arrows indicate target steps). Eye, eye position in the head; Head, head position in
space; Gaze, eye position in space (sum of head in space and eye in head). Note that the head positions axis is
inverted. Left panel: Initial saccade and head movement begin nearly synchronously; Head movement over-
shoots its final position. Center panel: Head moves first and causes a brief, backward eye movement before the
initial saccade; Right panel: Net change of head movement is negligible, but it facilitates an accurate gaze shift
(see VIDEO: "Congenital ocular motor apraxia"). (From Zee DS, Yee RD, Singer HS. Congenital ocular motor
apraxia. Brain 1977;100:581-99, copyright Oxford University Press.)

tive strategies to facilitate changes in The cause of congenital ocular motor

gaze.425'1540 Younger patients appear to
use their intact VOR, which drives their
eyes into an extreme contraversive posi-
tion in the orbit. As the head continues to
move past the target, the eyes are dragged
along in space until they become aligned
with the target. Then the head rotates
backward and the eyes maintain fixation
as they are brought back to the central po-
sition in the orbit by the VOR. In contrast,
older patients appear to use the head
movement per se to trigger the generation
of a saccadic eye movement that cannot
normally be made with the head still (Fig
10-33, right panel). This strategy may re-
flect the use of a phylogenetically old link-
age between head and saccadic eye move-
ments that occurs reflexively in afoveate
animals, when they desire to redirect their
center of visual attention (see Rapid Gaze
Shifts Achieved by Combined Eye-Head
Movements, in Chap. 7).
apraxia is unknown. Cogan suggested that
it may reflect a delay in the normal devel-
opment of the mechanisms by which we
assume voluntary control over eye move-
ments. 271 Affected patients usually im-
prove with age: The head movements be-
come less prominent as the patients are
better able to direct their eyes voluntarily.
The presence of normal-velocity saccades
suggests an intact brain stem mechanism
for generating eye movements. The
propensity of these children to blink in or-
der to initiate a saccade suggests a prob-
lem with gating of brain stem burst neu-
rons.1528 (The effects of blinks on eye
movements are reviewed in Saccades and
Movements of the Eyelids, in Chap. 3).
Delayed psychomotor development (es-
pecially in learning to read and in speech),
infantile hypotonia, strabismus, incoordi-
nation, torsional nystagmus, and clumsi-
ness occur in some patients.1197 Associated
 Diagnosis of Central Disorders of Ocular Motility
anomalies include agenesis of the corpus
callosum, collicular abnormalities, and
cerebellar vermian dysplasia or hypoplasia
(for example, as part of Joubert's syn-
drome).1217'1276'1483 It seems more likely
that such anomalies are markers of abnor-
mal development rather than being di-
rectly responsible for the eye movement
disorder. Congenital ocular motor apraxia
is occasionally familial and has been re-
ported in monozygotic twins.565'1107
Apart from the idiopathic type of con-
genital ocular motor apraxia, a variety of
hereditary disorders that directly involve
the brain stem mechanisms for generating
saccades are characterized by the develop-
ment of a strategy of head thrusting or
blinking to shift gaze, and hence superfi-
cially appear as congenital ocular motor
apraxia. Some of these conditions are dis-
cussed in the section on Ocular Motor
Manifestations Of Metabolic And Defi-
ciency Disorders. Other disorders reported
in association with horizontal saccadic fail-
ure include GM1 gangliosidosis, Krabbe's
leukodystrophy, peroxisomal assembly dis-
orders, Lesch-Nyhan disease,7033 propri-
onic acidemia, Bardet-Biedl syndrome,
Cornelia de Lange syndrome, and a variety
of developmental abnormalities of the mid-
line cerebellum.591 These disorders can be
distinguished from Cogan's form of con-
genital ocular motor apraxia when vertical
saccades are affected and when saccades
are slow. In early stages of these diseases,
however, distinguishing the ocular motor
apraxia from Cogan's type may be
difficult.270 Purely vertical ocular motor
apraxia is rare and usually reflects direct in-
volvement of saccade-generating pathways
in the midbrain or pons (Display 10-24).412
Eye Movements During
Epileptic Seizures
Eye and head movements are common
manifestations of epileptic seizures, if
carefully looked for. A variety of abnormal
eye movements has been reported, includ-
ing horizontal or vertical conjugate gaze
deviation, and skew deviation.499 Horizon-
tal gaze deviations are usually contralat-
547
eral, but occasionally ipsilateral, to the
side of the seizure focus.1329'1378 The dis-
tinction between a paretic and epileptic
gaze deviation (Display 10-33) is made
by observing the patient's eye for a few
minutes; epileptic deviations are seldom
sustained. Epileptic seizures also cause
a variety of forms of nystagmus: conju-
gate, retraction, convergence, or mono-
cular.590'695'721'1169'1289'1374'1399 Convergence
nystagmus has been reported with ei-
ther periodic lateralizing epileptiform
discharges1516 or burst-suppression pat-
terns.180-1005 Epileptic nystagmus has also
been reported with typical absence
seizures1457 and with infantile spasms.647
Eyelid flutter may be the only clinical
manifestation of seizures.945 Some patients
may show both intermittent gaze devia-
tions and nystagmus.1374 How can these
diverse manifestations be related to the
known mechanisms that control gaze,
which we summarized in Chap. 6?
Although eye movements may be a
manifestation of a seizure focus in any
lobe,958 the most commonly reported site
in patients with epileptic nystagmus is the
temporo-occipital-parietal region.721'722 In
most such cases, the eyes initially deviate
contralateral to the seizure focus. This ini-
tial deviation may be due to activation of
the parietal eye fields, which, in the mon-
key homologue (the lateral intraparietal
area, LIP), have a low electrical threshold
for eliciting saccades. In one such patient,
who had a right temporo-occipital focus,
the seizure began with a contraversive (left-
ward) gaze deviation due to a staircase of
small saccades.1374 After a few seconds,
left-beating nystagmus commenced, with
slow phases that showed a decreasing-ve-
locity waveform. The nystagmus was ac-
companied by high-voltage 11-14 Hz
spike activity that did not spread to frontal
cortex. At the end of the seizure, the eyes
returned to central position. It seems pos-
sible that the centripetal slow phases of
such nystagmus are similar to those of
gaze-evoked nystagmus (Fig. 10-1B). The
reason for the unsustained gaze deviation,
centripetal drifts, and nystagmus may be
either effects of anticonvulsants1374 or im-
paired consciousness831 or a deficient eye
position signal due to seizure activity ema-
548 The Diagnosis of Disorders of Eye Movements
nating from cortical areas.958 Rarely, pa-
tients show an initial gaze deviation that is
ipsiversive and is followed by quick phases
which generate nystagmus.721'1399 In such
cases, activation of pursuit mechanisms at
the occipitotemporoparietal junction (Fig.
6-8) may be responsible. Experimental
studies in awake monkeys indicate that the
threshold for stimulating pursuit eye
movements is lower than that for stimulat-
ing saccades.781 Support for this hypothe-
sis comes from documentation that the
slow phases of subsequent nystagmus are
linear (see Fig 10-1 A) and move the eyes
across the midline. A further point is that
such patients are usually awake, and the
quick phases are then generated in re-
sponse to the pursuit-mediated eye devia-
tion. Finally, a patient with a temporopari-
etal seizure focus has been described who
showed no gaze deviation prior to onset of
nystagmus.496 Her attacks were accompa-
nied by vertigo, and slow phases were lin-
ear, suggesting involvement of the cortical
areas involved in vestibular and optoki-
netic or pursuit mechanisms (Fig. 6-7).
Thus, contraversive quick phases in
epileptic patients may be due to two dif-
ferent mechanisms: (1) primary, contra-
versive saccades due to epileptic activity in
the saccadic regions, followed by cen-
tripetal drift due to impaired gaze hold-
ing; and (2) secondary, reflexive contra-
versive saccades, which correct for slow
ipsiversive deviation across the midline
due to epileptic activation of either the
smooth-pursuit or optokinetic regions. In
patients with coexistent brain stem lesions,
the only manifestation of epileptic activity
may be rapid, small-amplitude, vertical
eye movements.1289 The absence of hori-
zontal movements suggests dysfunction of
the paramedian pontine reticular forma-
tion (PPRF—see Display 10-21).
Frontal lobe foci may cause contraver-
sive deviations but, if bilateral, will lead to
vertical deviations of gaze.720 These results
are consistent with stimulation studies in
monkeys: Unilateral stimulation of the
frontal eye field typically causes oblique
saccades with a contralateral horizontal
component; the direction of the vertical
saccade depends upon a cortical map.199
Purely vertical movements require bilat-
eral stimulation of the frontal eye fields.
Because there are also neurons in the
frontal eye fields that contribute to smooth
pursuit, it is theoretically possible that
frontal lobe foci could lead to an ipsiver-
sive deviation.
Head turning is a common accompani-
ment of epileptic gaze deviation (see Head
Turning as a Feature of Epilepsy, in Chap.
7). In patients who are conscious during
the seizure, a frontal focus is likely and the
initial direction of head turning is usually,
but not invariably, contralateral to the
seizure focus.1497'1498 A contralateral focus
is also likely in a patient who shows
marked and sustained lateral positioning
of head and eyes. In patients who are un-
conscious during the seizure, the focus
may arise from any lobe and head turning
may be toward or away from the side of
the lesion.518'1030
As discussed above, seizures emanating
from the superior temporal lobes may
cause a variety of vestibular sensations,
and occipital lobe seizures may produce
oscillopsia.113 Rarely, seizures may be pre-
cipitated by movements of the eyes such as
convergence1430 or sustained lateral devia-
tion.1262 We have observed a patient in
whom left horizontal gaze deviation con-
sistently precipitated adversive seizures,
with head turning to the left and tonic
flexion of the left elbow. He had recently
undergone partial resection of a right
frontotemporal glioblastoma.
Finally, disturbances of gaze during dis-
turbance of consciousness need not imply
epilepsy. Experimentally induced syncope
is reported to cause tonic upward gaze de-
viation and downbeat nystagmus.848 An in-
crease in the gain of the vestibulo-ocular re-
flex was also noted. Consideration of all the
clinical and laboratory findings is required
before a diagnosis of epilepsy can be made.
ABNORMALITIES OF EYE
MOVEMENTS IN PATIENTS
WITH DEMENTIA
A variety of disease processes that cause
global impairment of cognitive function
may also impair the control of eye move-
 Diagnosis of Central Disorders of Ocular Motility
ments. Often the changes are subtle at the
bedside, and they may require special test-
ing procedures. However, application of
experimental paradigms that are known
to test specific cortical and subcortical ar-
eas has proved useful in better defining
the extent of involvement in these dis-
eases. Moreover, although no test is diag-
nostically specific, serial testing provides
one index of progression of the disease
and so may be useful in evaluating new
therapies.
Alzheimer's Disease
Most disorders of eye movements in Alz-
heimer's disease reflect an underlying loss
of the ability to focus or shift visual atten-
tion. Thus, the ability to sustain steady fix-
ation of a visual target may be disrupted
by large saccadic intrusions, which are dis-
tinct from the small, to-and-fro square-
wave jerks (Fig. 10-16A) that are also com-
mon in this age group.617'711'969'1267 These
larger, inappropriate saccades are often
due to a distracting stimulus or occur be-
cause patients cannot suppress eye move-
ments made in anticipation of the ex-
pected appearance of a stimulus. 656 They
have been studied using the antisaccade test
stimulus, in which the subject is required
to suppress a reflexive saccade toward a
visual stimulus and, instead, look in the
opposite direction (Fig. 10-31).312'465 Pa-
tients affected by Alzheimer's disease are
quite unable to suppress such reflexive
saccades; this has been called a visual grasp
reflex.465
When patients with Alzheimer's disease
make visually guided saccades, the reac-
tion time is prolonged if the appearance of
the target is unpredictable.465-619'1096 Sac-
cades are hypometric465 and may be slow if
the target stimulus is unpredictable,465
more so vertically.656 When patients with
Alzheimer's disease are asked to study a
complex visual scene, their ability to scan
it with saccades is diminished.316'969 This
impaired ability to direct visual attention
may mimic Balint's syndrome.635
Smooth pursuit in patients with Alzhei-
mer's disease often shows reduced gain,
with catch-up saccades, for all frequencies
549
and velocities of target motion, with a fur-
ther decline for higher target accelera-
tions.466'1518 Similar to what occurs during
fixation, smooth pursuit may be disrupted
by large saccadic intrusions as the patient
looks toward the anticipated target posi-
tion. Predictive aspects of smooth pursuit
are relatively preserved in this disorder, as
is the vestibulo-ocular reflex.805
In summary, in Alzheimer's disease, the
impaired ability to suppress saccades to
novel visual stimuli on the antisaccade task
suggests frontal lobe involvement, whereas
patients who show impaired ability to shift
visual attention probably have parietal
lobe involvement. Impairment of smooth
pursuit may reflect involvement of sec-
ondary visual areas in parietal cortex, and
it is of interest that one patient with Pick's
disease, which predominantly affects the
frontal and temporal lobes, had relative
preservation of smooth pursuit.668
Creutzfeldt-Jakob Disease
Patients with Creutzfeldt-Jakob disease
may show limitation of vertical gaze and
slow vertical saccades, and two rare forms
of nystagmus, periodic alternating nystag-
mus (see Display 10-5) and centripetal
nystagmus (see Display 10-7).544'606 Even-
tually, patients may lose saccades and
quick phases, but continue to show peri-
odic alternating gaze deviation.544 Other
affected patients show sustained gaze or
skew deviations with head turns. 1515 This
spectrum of disturbance of eye move-
ments attests to prominent involvement of
the cerebellum and brain stem in some
patients with Creutzfeldt-Jakob disease.
Overdoses of lithium or bismuth may lead
to syndromes that mimic Creutzfeldt-
Jakob disease.532'1302 Cerebellar eye signs
are typically found in another prion disor-
der, Gerstmann-Straussler-Scheinker dis-
ease.429'1511
AIDS and Dementia
Human immunodeficiency virus (HIV)
encephalopathy may cause several distur-
bances of ocular motility reflecting frontal
550 The Diagnosis of Disorders of Eye Movements
lobe involvement, including increased er-
rors on the antisaccade task (Fig. 10-31),
increased fixation instability, and increased
latencies of saccades, especially verti-
cally.706'942 Some patients may develop ac-
quired ocular motor apraxia.179 Others
show signs suggesting cerebellar and brain
stem involvement, including gaze-evoked
and dissociated nystagmus,1076 slow sac-
cades,1009 and ocular flutter.715 Decreased
or asymmetric pursuit gain is a common
finding.706'1349 In addition, patients with
AIDS may show a number of ocular motor
abnormalities, reflecting the effects of op-
portunistic infection or coexistent neopla-
sia.309'582'601'752
EYE MOVEMENT DISORDERS
IN PSYCHIATRIC ILLNESSES
Although abnormalities of voluntary gaze
have long been associated with insanity, it
was Diefendorf and Dodge who, in 1908,
first suggested that eye tracking is abnor-
mal in dementia praecox (schizophre-
nia).387 A substantial research effort has
gone into trying to delineate the eye
movement abnormalities encountered in
psychosis.861 Initial studies were thwarted
by poor recording techniques and meth-
ods of analysis that bear no relevance to
the physiologic properties of eye move-
ments.669 More recent reports agree
that smooth pursuit is abnormal in most
schizophrenics: Eye acceleration at onset
of pursuit is decreased, the gain of
sustained pursuit is reduced, and the
number of catch-up saccades is in-
creased.428'478'858'968'1350'1366 Another ab-
normality that interferes with smooth
pursuit in schizophrenics is saccadic intru-
sions.857'869 These consist of small to-and-
fro square-wave jerks (Fig 10-16A) and
larger anticipatory saccades that are also
followed, after about 0.5 to 1.5 seconds, by
a corrective saccade that brings the eyes
back to the target.
How specific for schizophrenia are the
abnormalities of eye movements that oc-
cur during tests of smooth pursuit? Low-
gain pursuit eye movements may occur in
some patients with affective disorders, but
it is suggested that the disruption of pur-
suit by saccades is more specific.428'478
However, square-wave jerks occur in a
variety of conditions, and anticipatory
saccades are not peculiar to schizophren-
ics; they also occur in Alzheimer's dis-
ease,466 and in normal subjects as they
track a target moving across a textured
background.733 Furthermore, cigarette
smoking—a habit common among schizo-
phrenics—is known to induce square-
wave jerks1287 and may influence smooth-
pursuit gain (see Effects of Drugs on Eye
Movements).1040 Finally, the possible con-
tribution of neuroleptic medications to the
saccadic intrusions is not completely set-
tled, although unmedicated schizophren-
ics do show lower smooth-pursuit gain
than controls.478'669'6693'1351 Whether psy-
chiatrically well relatives of schizophrenics
show a similar tracking disorder is in dis-
pute.641-870 There is some evidence that
impaired smooth pursuit may be due to a
deficit in motion perception.1342 However,
the disorder of smooth pursuit in schizo-
phrenia resembles the disturbance oc-
curring in monkeys after frontal lobe le-
sions.892 Functional imaging has supported
this hypothesis, linking impaired smooth
tracking with hypometabolism in the
frontal eye fields.1179
Consonant with this line of reasoning,
the most consistent abnormalities in schiz-
ophrenia have concerned the voluntary
control of saccades, and especially those
functions that depend on the frontal lobes.
Although simple tests of saccades demon-
strate increased saccadic latencies and hy-
pometria compared with control subjects
or patients with affective disorders,895-968'1227
the most impressive findings are with tests
requiring imagination, memory, or pre-
diction. Thus, schizophrenics show sac-
cade abnormalities similar to those in
patients with frontal lobe or basal gan-
glia disease, including excessive dis-
tractibility in the antisaccade task (Fig.
10-31).300'669a'1365 Such distractibility is
present in schizophrenics who have re-
ceived no neuroleptic drugs for 6 months
and is not a feature of bipolar affective dis-
order or obsessive-compulsive states.924
Schizophrenics also show defects in mem-
ory-guided saccades, suggesting dysfunc-
 Diagnosis of Central Disorders of Ocular Motility
tion of dorsolateral prefrontal cortex.1061
However, schizophrenics are able to gen-
erate express saccades, depending on the
length of the gap between the disappear-
ance of the fixation light and the appear-
ance of the target.258 Taken together with
results from patients with cortical lesions,
these findings suggest that in schizophre-
nia there is impaired frontal lobe influ-
ence on the programming of saccades.484
Evidence has also been presented from
tests of saccadic eye movements that sug-
gests disturbed frontal lobe function in pa-
tients with obsessive-compulsive disor-
de^ 1170,1376
EYE MOVEMENTS IN STUPOR
AND COMA
The ocular motor examination is espe-
cially useful for evaluating the uncon-
scious patient because both arousal and
eye movement are controlled by neurons
in the brain stem reticular formation. Co-
matose patients do not make eye move-
ments that depend upon cortical visual
processing; voluntary saccades and smooth
pursuit are in abeyance. Quick phases of
nystagmus, too, may be absent. The ocular
motor examination of the unconscious pa-
tient, therefore, consists of observing the
resting position of the eyes, looking for
any spontaneous movements, and reflex-
ively inducing eye movements.206'452'831'1098
Resting Position of the Eyes in
Unconscious Patients
Conjugate, horizontal deviation of the
eyes is common in coma (Display 10-33).
If this is due to lesions above the brain
stem ocular motor decussation (between
the midbrain and pons), then the eyes are
usually directed toward the side of the le-
sion and away from the hemiparesis. A
vestibular stimulus, though, can usually
drive the eyes across the midline. If the
conjugate deviation is due to a lesion be-
low the ocular motor decussation, then the
eyes will be directed away from the side of
the lesion and toward the hemiparesis.
551
This situation is typically seen with pon-
tine lesions but also in some patients with
thalamic lesions,450 and rarely with hemi-
spheric disease above the thalamus (so-
called wrong-way deviation).1075'1264
Intermittent deviation of the eyes and
head turning are usually due to seizure ac-
tivity. At the onset of each attack, gaze is
usually deviated contralateral to the side
of the seizure focus; it may be followed by
nystagmus with contralaterally directed
quick phases. Toward the end of the
seizure, gaze drifts to an ipsilateral
(paretic) position (see Eye Movements
During Epileptic Seizures).
Tonic downward gaze deviation of the
eyes, often accompanied by convergence,
occurs in thalamic hemorrhage447'448 and
with lesions affecting the dorsal midbrain.
It may be induced by unilateral caloric
stimulation, after the initial horizontal de-
viation subsides, in patients with coma due
to sedative drugs.1288 Forced downward
deviation of the eyes has also been re-
ported in patients feigning coma or
seizures.1172
Tonic upward gaze deviation of the eyes
occurs following a hypoxic-ischemic in-
sult, even when no pathologic lesions are
found in the midbrain.743 In those patients
that survive, downbeating nystagmus de-
velops. It has been suggested that upward
drift is due to loss of inhibition on the up-
ward vertical VOR.995 Upward deviation
also occurs as a component of oculogyric
crises, which usually occur as a side effect
of certain drugs, especially neuroleptic
agents.830 Tonic uninhibited elevation of
the lids (eyes-open coma) may also occur in
unconscious patients and may be related
to pontomesencephalic dysfunction. 739
Deviations of the visual axes in coma may
be due to palsied oculomotor, trochlear, or
abducens nerve (see Clinical Features of
Ocular Nerve Palsies, in Chap. 9), skew
deviation, or a phoria that is normally
compensated for by fusional mechanisms.
Restrictive ophthalmopathy, particularly
blow-out fracture of the orbit, may be a
mechanism in patients who have suffered
head trauma. Diagnosis of the cause of the
deviation depends upon determining
whether the range of movement of the
eyes, induced by head rotation or caloric
552 The Diagnosis of Disorders of Eye Movements

stimulation (see Reflex Eye Movements in metabolic encephalopathy,232'455 or with

Unconscious Patients, below), is reduced
in a pattern corresponding to specific
muscle weakness. In addition, involve-
ment of the pupils and other brain stem
reflexes may help with the diagnosis.
Complete oculomotor nerve palsy causes
pupillary dilatation, ptosis, and deviation
of the eye "down and out." Pupillary in-
volvement is an early sign of uncal hernia-
tion,1098 and disturbance of eye move-
ments usually follows.748 Vertical tropias
are usually due to skew deviation or to
trochlear nerve palsy, which is common
following head trauma. Bilateral abducens
palsy occurs when increased intracranial
pressure compromises the nerves as they
bend over the petroclinoid ligament. Oc-
casionally, skew deviation and internu-
clear ophthalmoplegia are encountered in
drug intoxication.29U98,4i6,655,i 155
Spontaneous Eye Movements in
Unconscious Patients
Always consider epileptic seizures in the
unconscious patient who shows sponta-
neous eye movements (see discussion in
preceding section). Slow conjugate or dis-
conjugate roving eye movements are simi-
lar to the eye movements of light sleep
(but slower than the rapid movements of
paradoxical or REM sleep). They imply
that brain stem gaze mechanisms are in-
tact.452 A spectrum of abnormal eye move-
ments is encountered almost exclusively in
unconscious patients and is summarized
in Table 10-19.

Table 10-19. Spontaneous Eye Movements Occurring in

Unconscious Patients

Term Description Significance

Ocular bobbing Rapid, conjugate, downward Pontine strokes; 114,324,449,732,

Ocular dipping or inverse oc-
ular bobbing
movement; slow return to
primary position
Slow downward movement;
rapid return to primary
position
814,1168,1345,1380,1541 other
structural,156'1049'1195 meta-
bolic,404 or toxic disor-
ders594
Unreliable for localization;
follows hypoxic-ischemic
insult or metabolic disor-
(Jgj-775,883,1164,1165,1201,1317,1417

Reverse ocular bobbing Rapid upward movement; Unreliable for localization;

Reverse ocular dipping or
converse bobbing
Ping-pong gaze
Periodic alternating gaze de-
viation
Vertical "myoclonus"
Monocular movements
slow return to primary po-
sition
Slow upward movement;
rapid return to primary
position
Horizontal conjugate devia-
tion of the eyes, alternating
every few seconds
Horizontal conjugate devia-
tion of the eyes, alternating
every 2 minutes
Vertical pendular oscillations
(2-3 Hz)
Small, intermittent, rapid
monocular horizontal, ver-
tical, or torsional move-
ments
may occur with metabolic
disorders323'1384
Unreliable for localization;
pontine infarction and with
AIDS522-929
Bilateral cerebral hemi-
spheric dysfunction 676
Hepatic encephalopathy;58
disorders causing periodic
alternating nystagmus and
unconsciousness or vegeta-
tive state544
Pontine strokes747
Pontine or midbrain destruc-
tive lesions, perhaps with
coexistent seizures1289
 Diagnosis of Central Disorders of Ocular Motility 553

Ocular bobbing consists of intermittent,
usually conjugate, rapid downward move-
ment of the eyes followed by a slower re-
turn to the central position (see VIDEO:
"Ocular bobbing").114-449'929 Reflex hori-
zontal eye movements are usually absent.
Ocular bobbing is a classic sign of intrinsic
pontine lesions, usually hemorrhage, but it
has also been reported with cerebellar le-
sions that secondarily compress the pons
(Fig. 10-34), as well as in metabolic or toxic
encephalopathy. A variant, inverse bobbing,
has an initial downward movement that is
slow and the return to midposition is
rapid; this has also been called ocular dip-
ping. Reverse ocular bobbing consists of rapid
deviation of the eyes upward and a slow re-
turn to the horizontal. Finally, the term re-
verse ocular dipping or converse bobbing has
been used to describe a slow upward drift
of the eyes followed by a rapid return to
central position. Rarely, the bobbing is
variably disconjugate.503a These variants of
ocular bobbing are less reliable for localiza-
tion. Nevertheless, the report that some
patients have shown several types of bob-
bing suggests a common underlying
pathophysiology.201'522'1173'1384 Since the
pathways that mediate upward and down-
ward eye movements differ anatomically,
and probably pharmacologically, it seems
likely that these movements represent a
varying imbalance of mechanisms for verti-
cal gaze. Rarely, large-amplitude vertical

Figure 10-34. A CT of a patient who developed ocular bobbing (see VIDEO: "Ocular bobbing"), showing acute
hemorrhagic infarction of the cerebellum with swelling that compressed the pons.
554 The Diagnosis of Disorders of Eye Movements
pendular oscillations (myoclonus), in associ-
ation with horizontal gaze palsy, occur in
the acute phase of a brain stem stroke;747
some patients survive to develop ocu-
lopalatal tremor. Repetitive vertical eye
movements, including variants of ocular
bobbing, that contain convergent-diver-
gent components usually indicate disease
affecting the dorsal midbrain.745'1015'1175
Monocular bobbing movements may occur
as a synkinesis with jaw movement and are
a variant of the Marcus Gunn jaw winking
phenomenon, involving the inferior rectus
in otherwise normal individuals.1031 Ping-
pong gaze consists of slow, horizontal, con-
jugate deviations of the eyes alternating
every few seconds.676 Ping-pong gaze usu-
ally occurs with bilateral infarction of the
cerebral hemispheres or of the cerebral pe-
duncles.812 Sometimes a rapid horizontal
head rotation will induce transient oscilla-
tions with a similar periodicity to ping-
pong gaze in patients with bilateral hemi-
spheric disease.831 A saccadic form of
ping-pong gaze has been reported as a
transient finding in patients who survive in
a persistent vegetative state.704 Periodic al-
ternating gaze deviation, in which conju-
gate gaze deviations change direction
every 2 minutes, has been reported in he-
patic encephalopathy.58 This phenomenon
is related to periodic alternating nystag-
mus (see Display 10-5).
Rapid, small-amplitude, vertical eye
movements may be the only manifestation
of epileptic seizures in patients with coex-
istent brain stem injury.1289 Rapid, monoc-
ular eye movements with horizontal, verti-
cal, or torsional components, which occur
in coma, may also indicate brain stem dys-
function.
Identification of patients who are con-
scious but quadriplegic, the locked-in or
de-efferented state, depends upon identi-
fying preserved voluntary vertical eye
movements.813'1098 The syndrome is typi-
cally caused by pontine infarction with a
variable loss of voluntary and reflex hori-
zontal movements, so that eyelid or verti-
cal eye movements may be the only means
of communication in the acute illness. The
locked-in syndrome also occurs with mid-
brain lesions, in which case ptosis and
ophthalmoplegia may be associated.935
Reflex Eye Movements in
Unconscious Patients
The examination of the unconscious pa-
tient is incomplete without attempting to
elicit reflex eye movements, either by
head rotation (the doll's-head or oculo-
cephalic maneuver) or by caloric stimula-
tion.206'1001'1098 Always check that there has
been no neck injury or abnormality before
rotating the head, and inspect the tym-
panic membranes before carrying out
caloric testing.
What do these time-honored clinical
methods test? Head rotation, with the
patient supine, potentially stimulates
the labyrinthine semicircular canals, the
otoliths, and neck muscle proprioceptors.
Unless there has been prior loss of vestib-
ular function (e.g., from aminoglycoside
antibiotic toxicity), the contribution made
by neck muscle proprioceptors in generat-
ing reflex eye movements (the COR) is in-
significant.831 Furthermore, the otolithic
contribution is probably small compared
with that of the labyrinthine semicircular
canals. Finally, although visually mediated
eye movements, such as fixation and
smooth pursuit, can influence the eye
movements produced by head rotation in
normal, awake subjects, this is unlikely
to be the case in unconscious patients.
Therefore, eye rotations induced by head
rotation in unconscious individuals are
principally due to the effects of the semi-
circular canals and their central connec-
tions—the VOR. Conventionally, high-
frequency (1 to 2 Hz) quasi-sinusoidal
rotations are applied, or position-step
stimuli, which consist of a sudden head
turn to a new steady position. Both hori-
zontal and vertical rotations should be
performed. If small-amplitude head rota-
tions—are performed, the adequacy of the
VOR can be estimated by observing the
optic disc of one eye with an ophthalmo-
scope.1526 If reflex eye movements are in-
tact in an unconscious patient, then when
the head is rapidly rotated horizontally to
a new position (position-step stimulus),
the eyes are carried into a corner of the
orbit (Fig. 10-35). If the head is held sta-
tionary in its new position, the eyes may
drift back to the midline. This implies that
 Diagnosis of Central Disorders of Ocular Motility 555

Figure 10-35. The vestibule-ocular reflex in coma. (A) The response of a normal subject, in darkness, to a sud-
den, rapid or "step" head turn. An initial vestibular slow phase is interrupted by a quick phase. The new eye po-
sition is held steadily. (B) Eye movements of an unconscious patient. The patient had suffered bilateral infarc-
tion of the cerebral hemispheres and also had hepatic dysfunction. Pupils were 3 mm, equal, and reactive to
light. Noxious stimuli produced no eye opening or verbal response but caused extensor posturing in the right
upper extremity and abnormal flexor posturing in the left upper extremity. A step rotation of the head to the
left produced a vestibular eye movement to the right, without any quick phase. Subsequently, the eyes drifted
back to the midline with a negative exponential waveform. This reflects the "leaky" nature of the neural inte-
grator, which depends upon brain stem and cerebellum. Eye movements were recorded by electro-oculogra-
phy. Calibration is approximate for the unconscious patient. Time scale, at top, is in sec.

the gaze-holding mechanism (neural inte-
grator) is not functioning normally. Pa-
tients with more rapid centripetal drift
may have more severe brain injury.831
Caloric irrigation of the external audi-
tory meatus causes convection currents of
the vestibular endolymph that displace the
cupula of a semicircular canal; thus, this
procedure also tests the VOR. The canal
stimulated depends upon the orientation
of the head; with the head elevated 30°
from supine position, the horizontal
canals are principally stimulated. Large
quantities (100 ml or more) of ice water
may be necessary. Caloric stimulation with
ice water may be a more effective stimulus
than head rotation, perhaps owing to the
sustained nature of the stimulus as well as
556 The Diagnosis of Disorders of Eye Movements
the arousing effect of the cold water. Com-
bined cold caloric stimulation and head
rotation may be the most effective stimu-
lus in the unconscious patient,452 produc-
ing tonic deviation of the eyes toward the
irrigated ear.
In testing reflex eye movements in un-
responsive patients, it is important to note
the magnitude of the response and
whether or not the ocular deviation is con-
jugate; the dynamic response to position-
step head rotations; and the occurrence of
any quick phases of nystagmus, particu-
larly during caloric stimulation. When re-
flex eye movements are present in an un-
responsive patient, the brain stem is likely
to be structurally intact. When reflex eye
movements are abnormal or absent, the
cause may be structural disease (especially
brain stem strokes), metabolic and defi-
ciency states (including Wernicke's en-
cephalopathy), or drug intoxication (see
Table 10-21).583'1171 Complete ophthalmo-
plegia in an unresponsive patient should
also prompt consideration of acute neu-
ropathy (such as Guillain-Barre syn-
drome) and neuromuscular block due to
drugs or botulism. 746 Vertical reflex eye
movements may be impaired with disease
of the midbrain1406 or bilateral lesions of
the MLR Pontine lesions may abolish the
reflex eye movements in the horizontal
plane but spare the vertical responses. Im-
paired abduction suggests sixth nerve
palsy; impaired adduction implies either
internuclear ophthalmoplegia or third
nerve palsy. Occasionally, impaired adduc-
tion to vestibular stimulation may be ob-
served in patients with metabolic coma232
or drug intoxication.291'398'416'655'1155 Pa-
tients in barbiturate coma may show
downward deviation of their eyes with
caloric stimuli,1288 or no response. When
used in combination with other clinical
signs, reflex eye movements have been
useful in predicting the outcome of
coma.859'976
Quick phases of nystagmus are usually
absent in acutely unconscious patients, so
their presence, without a tonic deviation
of the eyes, should raise the possibility of
feigned coma. In patients who are stu-
porous but uncooperative, caloric nystag-
mus may be a useful way of inducing eye
movements that cannot be initiated volun-
tarily. For example, in a patient with a
pineal tumor, retraction nystagmus was in-
duced with caloric stimulation.1291 Patients
who survive coma but who are left in a
persistent vegetative state, with severe
damage of the cerebral hemispheres but
preservation of the brain stem,1098 regain
nystagmus with caloric or rotational stim-
ulation.831 Recovery of eye tracking of the
examiner or family members is an indica-
tion of those patients who may show some
recovery from this state.39 Caloric nystag-
mus has been reported in patients with
neocortical death and an isoelectric elec-
troencephalogram.1003
OCULAR MOTOR DYSFUNCTION
AND MULTIPLE SCLEROSIS
Multiple sclerosis causes a variety of ocular
motor deficits (Display 10-37), of which
bilateral internuclear ophthalmoplegia
(INO) (see VIDEO: "Bilateral internuclear
ophthalmoplegia"), cerebellar eye signs
(including gaze-evoked nystagmus), and
acquired pendular nystagmus (Fig. 10-11)
are most commonly recognized.480-1324
The pendular nystagmus is frequently vi-
sually disabling (see VIDEOS: "Acquired
nystagmus impairing vision").48'879 Acute
vertigo may occur during an exacerba-
tion, and sometimes is recurrent and trou-
blesome.
Measurement of eye movements may
help make the diagnosis during early
stages of the disease by demonstrating
saccadic abnormalities, especially INO
(Fig. 10-27). Detection of a saccadic abnor-
mality may be better when targets are pre-
sented randomly, so that neither their
time of onset nor their location can be pre-
dicted. Large saccades (20° or greater) are
more likely to show changes in velocity
than are small saccades.936 Comparison of
the peak velocity of abducting and adduct-
ing saccades to identify subtle degrees of
INO requires caution because normal sub-
jects show greater peak velocities in the
abducting eye. A solution to this problem
is to compare the ratio of movements of
the two eyes (i.e., measures of conjugacy
 Diagnosis of Central Disorders of Ocular Motility 557

Display 10-37: Common Ocular Motor Manifestations of

Multiple Sclerosis
• Internuclear ophthalmoplegia (INO), usually bilateral

• Gaze-evoked nystagmus

• Acquired pendular nystagmus

• Upbeat, downbeat, or torsional nystagmus

• Positionally induced nystagmus

• Saccadic dysmetria

• Saccadic oscillations, such as flutter

• Impaired smooth pursuit and combined eye-head tracking (VOR sup-

pression)

• Impaired optokinetic responses

For recorded examples, see Figure 10-6, Figure 10-11, Figure 10-17, Figure 10-26, and
Figure 10-27 of Chap. 10. (Related VIDEOS: "Acquired nystagmus impairing vision," "Bilat-
eral internuclear ophthalmoplegia," "Unilateral internuclear ophthalmoplegia," and "Up-
beat nystagmus.")

during saccades). Normal subjects show
little variation in the ratio of either peak
eye velocity1419 or peak acceleration467-468
of the adducting saccades to abducting
saccades. Patients with INO have greater
disconjugacy of saccades, manifested as
adduction/abduction ratios of peak veloc-
ity or peak acceleration that fall outside
corresponding ranges for normal subjects.
Other saccadic abnormalities in multiple
sclerosis include prolonged latency, inac-
curacy, and decreased velocity.181'936'1138
Some patients with multiple sclerosis show
saccadic oscillations and intrusions (see
Display 10-14).49'618
Smooth-pursuit gain may be de-
creased.1138'1266 Impaired cancellation of
the horizontal VOR has been reported.1266
Abnormalities of vertical gaze holding,
smooth pursuit, and eyehead tracking oc-
cur in patients with bilateral INO, 1122 be-
cause the medial longitudinal fasciculus
(MLF) (Display 6-2) carries signals im-
portant for nonsaccadic vertical move-
ments. Other abnormalities include hori-
zontal and vertical gaze palsies,907-1455
gaze-evoked blepharoclonus,740 upbeat
and downbeat nystagmus,86'446'912 various
vestibular and optokinetic abnormali-
ties,670'729 superior oblique myokymia
(Chap. 9), and convergence spasm (Chap.
8). Patients may also develop oculomotor,
trochlear or abducens palsies (see Chap.
9). An MRI is often successful in identify-
ing brain stem or cerebellar lesions re-
sponsible for such abnormalities.145
Diagnosis of early multiple sclerosis de-
pends on demonstration of lesions dissem-
inated throughout the nervous system.
Early diagnosis has become more impor-
tant because beta-interferon may reduce
the rate of relapses. Sometimes, subtle
deficits of ocular motility provide a sensi-
tive method for identifying subclinical le-
sions, but there is need for caution: These
tests are not specific for multiple sclerosis.
The clinician must weigh the results of oc-
ular motor studies with other clinical or
558 The Diagnosis of Disorders of Eye Movements
laboratory findings before making a diag-
nosis. Recent studies have demonstrated
that gabapentin62 and memantine 1316 may
ameliorate the visually disabling acquired
pendular nystagmus that often occurs in
multiple sclerosis (see Treatment of Ac-
quired Pendular Nystagmus).
OCULAR MOTOR
MANIFESTATIONS OF
METABOLIC AND DEFICIENCY
DISORDERS
The current genetic revolution has illumi-
nated the biochemical basis for many dis-
orders, and so the spectrum of diseases
considered "metabolic" now incorporates
some disorders previously described as
"degenerative." With this caveat in mind,
Table 10-20. Ocular Motor Manifestations of Certain Neurogenetic,
Metabolic, and Deficiency Disorders
Disorder
Tay-Sachs disease
Adult-onset hexosaminidase A deficiency
Gaucher's disease (noninfantile, neu-
ronopathic form)
Niemann-Pick type C
Branch-chain amino acid disorders (e.g.,
Maple syrup urine disease)
Wernicke's encephalopathy
Leigh's syndrome
Vitamin E deficiency: hereditary (e.g.,
abetalipoproteinemia) or acquired
Pelizaeus-Merzbacher disease
Wilson's disease
Kernicterus
Joubert's syndrome
Ataxia telangiectasia (Louis-Bar syn-
drome, 1 lq22-23) and variants
we review selected metabolic and defi-
ciency disorders. Some of the main ocular
motor findings of selected hereditary dis-
orders are listed in Table 10-20.
It is important to note that some normal
infants who ultimately develop normally
may show transient ocular motor "abnor-
malities." These include upward or down-
ward deviation of the eyes (but with a full
range of reflex vertical movement), inter-
mittent opsoclonus, and skew devia-
tion. 18,598,659,663,1053 However, skew devia-
tion and transient tonic up gaze may be
associated with later appearance of hori-
zontal strabismus and intellectual or lan-
guage disability.598 Premature babies may
show reduced excursion of the adducting
eye with caloric stimulation, suggesting in-
ternuclear ophthalmoparesis, but a full
deviation of both eyes usually occurs with
rotational stimuli, although quick phases
Disturbance of Eye Movement
Impairment of vertical and horizontal gaze700
Impairment of vertical gaze587
Initially, horizontal saccadic palsy; later, loss of volun-
tary gaze1071>1435>1490
Initially, selective vertical saccadic palsy;1187 later, loss
of voluntary gaze270>442.625
Adduction and upgaze impairment894'1531
Spectrum ranging from gaze-evoked and upbeat nys-
tagmus to complete ophthalmoplegia (see
text)273'337-495
Similar to that in Wernicke's encephalopa-
thy399,578,956,1251
Progressive restriction of horizontal and vertical gaze;
dissociated nystagmus, in which adduction is faster
than abduction 301 ' 1510
Pendular nystagmus; upbeat nystagmus; ocular motor
apraxia; saccade dysmetria and other cerebellar
signs including truncal titubation1008'1393
Slow vertical saccades;770 gaze distractibility850
Vertical gaze palsy661
Alternating skew deviation; seesaw and pendular nys-
tagmus; pigmentary degeneration of the retina903
Saccade initiation defects with head thrusts; gaze-
evoked and periodic alternating nystag-
mus!9,502,866,1327
 Diagnosis of Central Disorders of Ocular Motility
of nystagmus may be absent.1469 The time
constant (as a reflection of duration) of the
VOR in newborns is low (typically 6 sec-
onds) and does not reach adult values un-
til the infant is about 2 months old.1469
The lipid storage diseases are often
characterized by gaze palsies. Tay-Sachs
disease impairs vertical and, subsequently,
horizontal eye movements. Adult-onset
hexosaminidase A deficiency also prefer-
entially affects vertical gaze.587 Variants of
Niemann-Pick disease that begin after the
first year of life (previously called the sea-
blue histiocyte syndrome or juvenile dys-
tonic lipidosis) are characterized by
deficits of voluntary vertical eye move-
ments.270 Early in the course of Niemann-
Pick type C (2S) disease, which presents
during adolescence with intellectual im-
pairment, ataxia, and dysarthria, there
may be selective slowing of vertical
saccades; other eye movements (includ-
ing horizontal saccades) are normal
(see VIDEO: "Niemann-Pick type C dis-
ease").270-1187 Diagonal saccades may show
a curved trajectory (Fig.3-3B), evident
during the clinical examination. Gaucher's
disease is associated with a more promi-
nent deficit of horizontal gaze; in adult pa-
tients, slow saccades may be a prominent
finding.1071'1435
Wernicke's encephalopathy is characterized
by the triad of ophthalmoplegia, mental
confusion, and gait ataxia.225 It is caused
by thiamine deficiency and is most com-
monly encountered in alcoholics. The oc-
ular motor findings include weakness of
abduction, gaze-evoked nystagmus, inter-
nuclear ophthalmoplegia, central posi-
tional vertical nystagmus (usually upbeat),
impaired vestibular responses to caloric
and rotational stimulation, and horizontal
and vertical gaze palsies that may progress
to total ophthalmoplegia (see VIDEO: "Wer-
nicke's encephalopathy'').273'297'337.495.945*
The ophthalmoplegia is bilateral but may
be asymmetric. Experimental thiamine
deficiency in monkeys causes an orderly
progression of ophthalmoplegia associ-
ated with well-circumscribed histopatho-
logic changes.274 These changes consist of
neuronal loss and gliosis in the oculomo-
tor, trochlear, abducens, and vestibular
nuclei. In humans, demyelination, vascu-
559
lar changes, and hemorrhage may occur;
in addition to the sites listed above, the le-
sions are found in the periventricular re-
gions of the thalamus, the hypothalamus,
the periaqueductal gray matter, the supe-
rior vermis of the cerebellum, and the
dorsal motor nucleus of the vagus (Fig.
10-36).945a Thus, gaze-evoked nystagmus
and the impaired caloric responses can be
attributed to vestibular nucleus involve-
ment (NPH-MVN region). The abduction
weakness may reflect involvement of the
abducens nerve, and the internuclear
ophthalmoplegia (INO) may reflect in-
volvement of the medial longitudinal fas-
ciculus. Paralysis of horizontal gaze may
be due to involvement of the abducens nu-
cleus, and total ophthalmoplegia may in-
dicate involvement of all the ocular motor
nerve nuclei. Affected areas of the brain
most likely contain neurons that use high
amounts of glucose and are therefore par-
ticularly dependent upon thiamine, an
important coenzyme in glucose metabo-
lism.1492 Administration of thiamine usu-
ally causes rapid improvement of the
ocular motor signs, although complete re-
covery may take several weeks. Coexistent
magnesium deficiency should also be
treated. In those patients with Wernicke's
disease who go on to develop Korsakoff's
syndrome, which is primarily characterized
by a severe and enduring memory loss,
ocular motor abnormalities may per-
sist.759'760 The ocular motor abnormalities
include slow and inaccurate saccades, im-
paired smooth pursuit, and gaze-evoked
nystagmus.
Leigh's syndrome is a subacute necrotizing
encephalopathy of infancy or childhood
characterized by psychomotor retardation,
seizures, and brain stem abnormalities that
involve eye movements.1542 It may either
be caused by abnormalities of mitochon-
drial DNA or be an autosomal recessive
disorder. Deficiency of respiratory chain
complexes I and IV has been identified.956
Early onset cases show disturbances of ocu-
lar motility similar to that caused by exper-
imental thiamine deficiency or Wernicke's
encephalopathy. In addition, seesaw nys-
tagmus (Display 10-6) and the ocular tilt
reaction (OTR) are reported in Leigh's
syndrome.578 Later-onset cases share clini-
560 The Diagnosis of Disorders of Eye Movements

Figure 10-36. An MRI scan of a patient with Wernicke's encephalopathy,945a showing signal changes under the
floor of the fourth ventricle (arrowheads) that indicate involvement of the medial vestibular nucleus-nucleus
prepositus hypoglossi complex at the pontomedullary junction (see VIDEO: "Wernicke's encephalopathy").

cal features with other disorders of mito-
chondrial DNA (discussed in Chap. 9).
Pelizaeus-Merzbacher disease is an X-
linked recessive dysmyelinating disease.540
Affected children may have ocular motor
apraxia and cerebellar signs including sac-
cadic dysmetria and pendular nystagmus
(see VIDEO: "Pelizaeus-Merzbacher dis-
ease").1008'1393 The peroxisomal assembly
disorders, such as the neonatal form of
adrenoleukodystrophy, also may be associ-
ated with pendular nystagmus, 790 as is
another congenital disorder affecting
myelin, Cockayne's syndrome. 280
Vitamin E deficiency may cause a pro-
gressive neurologic condition character-
ized by areflexia, cerebellar ataxia, and
loss of joint position sense.242 Ocular mo-
tor involvement includes progressive gaze
restriction, sometimes with strabismus. Vi-
tamin E deficiency occurs in childhood,
when it may be due to abetalipoproteine-
mia (Bassen-Kornzweig disease).1510 It is
also reported in adults with bowel disease
that interferes with fat absorption182 or as
an inherited ataxia on chromosome 8ql3,
the site of the alpha-tocopherol transfer
protein gene.1052-1514 Vitamin E deficiency
 Diagnosis of Central Disorders of Ocular Motility
is characterized by a dissociated ophthal-
moplegia, and by nystagmus in which ad-
duction is fast but with a limited range and
abduction is slow but with a full range.1510
These findings presumably reflect a mix-
ture of central and peripheral pathology.
Wilson's disease, hepatolenticular degen-
eration, is an autosomal recessive, inher-
ited disorder of copper metabolism. The
defect is in a copper-transporting ATPase
with the gene at q 14.3 on chromosome 13.
A CT typically shows hypodense areas,
and PET scanning indicates a decreased
rate of glucose metabolism in the globus
pallidum and putamen.597 The classic clin-
ical picture is a movement disorder with
dysarthria, psychiatric symptoms and as-
sociated liver disease. Ocular motor disor-
ders in Wilson's disease include a dis-
tractibility of gaze, with inability to
voluntarily fix upon an object unless other,
competing, visual stimuli are removed
(e.g., fixation of a solitary light in an other-
wise dark room).850 Slow vertical saccades
have also been reported in one patient
with Wilson's disease.770 A lid-opening
apraxia has been noted.750 Using the mag-
netic search coil technique, we have mea-
sured the eye movements of a 19-year-old
man who showed marked distractibility of
gaze but whose saccades were of normal
velocity. The eye movements of Wilson's
disease, therefore, show some similarities
to those described in Huntington's disease
and Alzheimer's disease. The distractibility
in both conditions may be due to involve-
ment of the inhibitory pathways from the
basal ganglia to the superior colliculus, as
discussed in Chap. 3.
EFFECTS OF DRUGS ON
EYE MOVEMENTS
Many drugs affect eye movements; Table
10-21 summarizes reports of effects of
certain individual agents. Drugs taken in
combination (e.g., anticonvulsants) can
cause defects in ocular motility with rela-
tively nontoxic blood levels.1371 For exam-
ple, patients taking a combination of
phenytoin and carbamazepine may com-
plain of oscillopsia, which is due to sponta-
561
neous nystagmus, an inappropriate VOR,
or diplopia.1134 Many drugs affect central
vestibular and cerebellar connections and
cause ataxia and gaze-evoked nystag-
mus.1126
Although all classes of eye movements
may be affected by therapeutic doses of vari-
ous drugs, smooth pursuit, eccentric gaze
holding, and convergence are particularly
susceptible. So, for example, diazepam,
methadone, phenytoin, barbiturates, chlo-
ral hydrate, and alcohol all impair
smooth-pursuit tracking. However, some
drugs have specific effects on ocular motil-
ity and thus have provided insights into
both the function of the ocular motor sys-
tem and the mode of drug action. For ex-
ample, diazepam (a benzodiazepine) re-
duces saccadic peak velocity but does
not impair accuracy, whereas methadone
shows the converse effect. Diazepam re-
duces the gain of the VOR; in experimen-
tal animals the time constant is prolonged,
but in humans it is reduced.1058
In toxic doses, all eye movements may be
impaired by neuroactive drugs, particu-
larly when consciousness is impaired.
Phenytoin may cause a complete ophthal-
moplegia in an awake patient, and thera-
peutic levels may cause ophthalmoplegia
in patients in stupor.1171 Phenytoin and di-
azepam can lead to opsoclonus.345 The tri-
cyclic antidepressants may cause com-
plete, or internuclear, ophthalmoplegia in
stuporous -patients. Lithium intoxication
causes a variety of abnormalities, includ-
ing fixation instability and downbeat nys-
tagmus.462 In one patient, who prior to
death showed marked impairment of all
types of horizontal eye movements and
downbeat nystagmus, neuronal loss was
mainly confined to the nucleus prepositus
hypoglossi and adjacent medial vestibular
nuclei.295 Thus, the pathophysiology was
similar to that produced by experimental
lesions of these nuclei in monkeys: 230 The
neural integrator (gaze-holding network)
was disrupted. The propensity of lithium
to damage this area of the medulla has
been attributed to the proximity to the
choroid plexus of the fourth ventricle
(and hence high local levels of lithium). 295
Cerebellar damage may also occur after
lithium intoxication.1232
 Table 10-21. Effects of Drugs on Eye Movements
Drug Reported Effect

Benzodiazepines Reduced velocity and increased duration of

saccacjes 137,427,714,1058,1180,1414,1416

Impaired smooth pursuit138'1181-1224

Decreased gain and change of time constant of
VOR142'1057
Divergence paralysis 42
Tricyclic antidepressants Internuclear ophthalmoplegia398'655
Partial or total gaze palsy1116'1310
Opsoclonus50
Phenytoin Impaired smooth pursuit and VOR suppres-
sion136
Gaze-evoked nystagmus616-1143
Downbeat nystagmus121
Periodic alternating nystagmus228
Partial or total gaze palsy475
Convergence spasm563
Carbamazepine Decreased velocity of saccades10143'1361
Impaired smooth pursuit 334
Gaze-evoked nystagmus 1134 ' 1308 ' 1408
Oculogyric crisis117
Downbeat nystagmus250
Partial or total gaze palsy978'1016
Phenobarbital and other Reduced peak saccadic velocity1224'1361
barbiturates Gaze-evoked nystagmus1129
Impaired smooth pursuit 1224
Impaired vergence1475
Decreased VOR gain331
Internuclear ophthalmoplegia97
Perverted caloric responses1288
Vertical nystagmus 855
Partial or total gaze palsy97'414
Phenothiazines Oculogyric crisis830
Internuclear ophthalmoplegia291
Lithium carbonate Saccadic dysmetria41
Impaired smooth pursuit 860
Gaze-evoked nystagmus 41
Downbeat nystagmus295'462'577'1488
Opsoclonus279
Oculogyric crisis1214
Internuclear ophthalmoplegia347
Partial or total gaze palsy295
Continued on following page

562
 Diagnosis of Central Disorders of Ocular Motility 536

Table 10-21.—continued
Drug Reported Effect
Amphetamines Reduced saccadic latency1360
Increased accommodative convergence/accom-
modation ratio1475
Alcohol (ethanol) Reduced peak velocity, increased latency, and
hypometria of saccades83'728'967a
Impaired smooth pursuit 83 ' 9673 and VOR sup-
pression95
Gaze-evoked nystagmus 83
Positionally induced nystagmus 163 ' 436a
Reversal of compensation of vestibular lesions127
Tobacco and nicotine Decreased saccadic latency1162
Upbeat nystagmus in darkness 1285 - 1286
Square-wave jerks 1285 - 1287 ' 1363
Impaired horizontal and vertical smooth
pursuit 1286 - 1287
Methadone and other Saccadic hypometria 1182
narcotics Impaired smooth pursuit 1183
Internuclear ophthalmoplegia416
Baclofen Reduced VOR time constant 276
Partial or total gaze palsy 1072
For therapeutic effects see Table 10-8
Beta blockers Diplopia1462
Internuclear ophthalmoplegia306
Choral hydrate Impaired smooth pursuit 862

Nitrous oxide Reduced saccadic peak velocity898

Impaired smooth pursuit898
Risperidone Reduced peak velocity and increased latency of
saccades1348
Cocaine Opsoclonus 417 ' 1225
Phencyclidine (PGP) Nystagmus 98

In addition to drugs, certain toxins are
reported to affect eye movements. Some,
such as chlordecone1359 and thallium, 893
cause saccadic oscillations. Intoxication
with hydrocarbons is reported to cause
vestibulopathy,634'1056 and exposure to
trichloroethylene and other solvents may
affect pursuit, visual suppression of the
VOR, and saccades.974 Prolonged toluene
abuse, especially in glue-sniffing addic-
tion, may lead to a variety of ocular motor
disturbances, including pendular and
downbeat nystagmus 891 ' 901 and saccadic
oscillations.953
Tobacco and nicotine have a number of
ocular motor effects. They cause upbeat
nystagmus,1285'1286 impaired pursuit,1287
decrease in saccade latency,1162 and in-
creased square-wave jerks during pur-
suit,1363 but with normal performance on
564 The Diagnosis of Disorders of Eye Movements
the antisaccade test.1163 Cocaine also can
affect eye movements. The most dramatic
abnormality is opsoclonus.378'417'1225 A va-
riety of drugs are ototoxic, notably the
aminoglycoside antibiotics. These are dis-
cussed under the section on Oscillopsia.
Finally, systematic study of the effects of
new drugs on eye movements is likely to
provide insights into the pharmacological
substrate of the ocular motor system and
lead to the development of novel treat-
ments for abnormal eye movements that
prevent clear vision.
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APPENDIX A: A SUMMARY SCHEME
FOR THE BEDSIDE OCULAR MOTOR
EXAMINATION (With video examples
of abnormal responses)
Although the order and specific details of
testing may be modified according to the
nature of the clinical problem, systematic
examination of each ocular motor subsys-
tem is worthwhile, particularly in evaluat-
ing signs such as nystagmus. Here we
outline a scheme for examining eye move-
ments, providing video examples of ab-
normal findings for certain tests. The
technical details of each step in the ocular
motor examination are described in the
respective chapters. The reader should
note that ocular motor signs are rarely di-
agnostic touchstones; they require inter-
pretation in the context of the history and
full examination.
1. General Features:
a. Look for abnormal head postures,
such as turns or tilts (see VIDEO:
"Skew deviation"), abnormal patterns
of eye-head coordination—such as
the head thrusts of ocular motor
apraxia (see VIDEOS: "Acquired ocular
motor apraxia," "Congenital ocular
motor apraxia"), and head tremors
(see VIDEO: "Spasmus Nutans").
b. Look for abnormalities of the lids in-
cluding ptosis, lid-opening apraxia
(see VIDEO: "Lid-opening apraxia"),
retraction, and aberrant regenera-
tion.
2. Visual Examination:
a. Measure corrected visual acuity and
perform confrontation visual fields
with each eye viewing.
b. Check color vision (Ishihara or
Hardy-Rand-Rittler plates), to screen
for optic neuropathy e.g., in patients
with monocular pendular nystagmus.
c. Test stereopsis (e.g., Titmus Optical
or Randot stimuli), especially when
ocular misalignment is thought to be
of early onset.
d. Test pupillary reflexes.
3. Range of Movement and Alignment of
the Visual Axes:
a. Establish range of motion with duc-
tions (one eye viewing) and versions
(both eyes viewing) (see VIDEO: "Ab-
ducens nerve palsy").
b. Test ocular misalignment (in patients
with diplopia or strabismus).
• Confirm that diplopia is only pres-
ent during binocular viewing
• Subjective tests, such as the red
glass, and Maddox rod (Fig. 9-11)
• The cover test (Fig. 9-12) (see
VIDEO: "Oculomotor nerve palsy")
for tropias
• The alternate cover test (Fig. 9-13)
(see VIDEOS: "Oculomotor nerve
palsy") for phorias. Measure devia-
tion at both near and far, and in
the cardinal positions of gaze
• Quantify with prisms by nullifying
the deviation as measured with al-
ternate cover test (Fig. 9-13) or
Maddox rod (Fig. 9-11)
• For vertical deviations, use the
Bielschowsky head-tilt test (Fig.
9-14) (see VIDEOS: "Trochlear nerve
palsy"), to diagnose superior oblique
muscle paresis
4. Fixation (using simple visual inspec-
tion, the ophthalmoscope, and Frenzel
goggles:
a. In primary position: Look for extra-
611
612 Appendix A
neous saccades (see VIDEOS: "Macro-
saccadic oscillations," "Square-wave
jerks") and nystagmus (see VIDEO: "Ac-
quired nystagmus impairing vision").
b. In eccentric gaze: Look for gaze-
evoked and then rebound nystag-
mus (see VIDEOS: "Gaze-evoked, re-
bound, and downbeat nystagmus").
c. Determine the position of the eyes
under closed lids by noting correc-
tive movements when the patients
open their eyes (e.g. steady-state de-
viation of the eyes toward the side of
the lesion in Wallenberg's syndrome)
(see VIDEOS: "Wallenberg's syndrome").
d. In patients with nystagmus, the time
in the cycle when the image of the
target is brought to the fovea can be
determined during ophthalmoscopy
by having the patient fix upon the
center of the ophthalmoscope cross
hairs.
5. Vestibular:
a. Measure visual acuity (Snellen chart)
before and during head shaking
(horizontal and vertical) at a fre-
quency of greater than 1 cycle/sec.
b. Look for corrective saccades during
sinusoidal head oscillations at about
1 Hz and following brief but high ac-
celeration head thrusts, while the pa-
tient is required to fix upon a target
straight ahead (see VIDEO: "Anterior
inferior cerebellar artery (AICA) dis-
tribution infarction").
c. Using Frenzel goggles,* after 10 to
15 seconds of brisk head shaking,
first in the horizontal, then in the
vertical plane, look for nystagmus
(see VIDEO: "Head-shaking nystag-
mus"). In cases of suspected bilateral
vestibular loss, look for nystagmus
following circular head-shaking.
* Frenzel goggles consist of 10- to 20-diopter
spherical convex lenses that defocus the pa-
tient's vision (so preventing fixation of objects)
and also provide the examiner with a magni-
fied, illuminated view of the patient's eyes. An
alternative is +20 diopter lenses mounted in a
spectacle frame and fitted with side-blinkers.
The room lights should be turned off and ei-
ther the lights of the goggles or a pen light
used to illuminate the eyes.
d. Using the ophthalmoscope, watch for
abnormal movement of the retinal
vessels or optic nerve head with the
head still. Recall that the direction of
horizontal or vertical motion of the
retina is opposite to that of the front
of the eye. Alternately cover and un-
cover the other eye to see if any drift
of the retina is brought out or exac-
erbated by the removal of fixation.
Watch for oscillation of the optic disc
during small-amplitude head shak-
ing at a frequency of greater than 1
cycle/sec to see if the gain of the VOR
is correct. If the gain is too high, the
disc appears to move with the head,
if too low, opposite the head.
e. Use positional maneuvers to elicit
nystagmus. First use the Dix-
Hallpike maneuver: The head is
turned 45°to the right or left. Then
the patient is brought to a supine po-
sition with the head just below the
horizontal (Fig. 10-19); observe any
nystagmus, preferably behind Fren-
zel goggles (see VIDEO: "Nystagmus
with benign paroxysmal positional
vertigo"). The patient is then
brought back to the upright posi-
tion; look again for nystagmus. The
same maneuver is then repeated
with the head turned 45° in the op-
posite direction. Second, with the
patient lying supine, rotate the head
to the right ear down, then straight
back, then left ear down positions.
f. With Frenzel goggles or using the
ophthalmoscope to observe for nys-
tagmus, use small amounts of ice wa-
ter (less than 1 ml) to elicit the mini-
mal ice water caloric test.
g. Rotate the patient in a swivel chair to
elicit perrotational nystagmus; when
the chair stops, look for postrota-
tional nystagmus. Test responses in
each plane of head rotation: hori-
zontal (head upright), vertical (head
tilted over 90°, ear-to-shoulder), or
torsional (head looking to the ceil-
ing).
h. Use the Valsalva maneuver (against a
closed glottis and pinched nostrils),
tragal compression, and mastoid vi-
bration to elicit nystagmus.

6. Saccades:
a. Observe spontaneous saccades, sac-
cades to visual or auditory targets,
and saccades to command. Note
latency, velocity (see VIDEO: "Slow
horizontal saccades"), trajectory
(see VIDEO: "Niemann-Pick type C
disease"), accuracy (see VIDEO:
"Saccadic hypermetria"), and con-
jugacy (see VIDEO: "Unilateral in-
ternuclear ophthalmoplegia").
b. Assess quick phases induced by
vestibular rotation or caloric stim-
uli, and a hand-held optokinetic
drum or tape. During vertical
stimulation, with stripes moving
down, check for retraction nystag-
mus (see VIDEO: "Convergence-re-
traction nystagmus").
7. Smooth Pursuit:
a. Instruct the patient to track a
small moving target smoothly, hor-
izontally and vertically. Look for
corrective saccades that indicate
an inappropriate smooth-pursuit
gain. If the gain is low, saccades
will be catch-up; if the gain is too
high, saccades will be back-up.
b. Use a small optokinetic drum,
tape, or mirror to bring out pur-
suit asymmetries, or "inverted"
Appendix A 613
optokinetic nystagmus, as occurs
with congenital nystagmus.
8. Eye-Head Coordination:
a. Assess head and eye movements
(latency, accuracy, velocity) dur-
ing combined eye-head rapid (sac-
cadic) refixations (see VIDEOS: "Ac-
quired ocular motor apraxia").
b. Test cancellation of the vestibulo-
ocular reflex by asking the patient
to fixate a target moving with the
head. Look for corrective sac-
cades.
9. Vergence:
a. Test vergence to disparity stimuli
(place a prism in front of one eye).
b. Test vergence to accommodative
stimuli: With one eye covered, the
other eye alternately fixes upon
the near and distant targets (Fig.
8-1).
c. Test vergence to combined dispar-
ity and accommodative stimuli by
asking the patient to fixate a target
brought in along the midsagittal
plane toward the nose (see VIDEO:
"Bilateral internuclear ophthal-
moplegia").
d. Note pupillary changes during
vergence movements.
APPENDIX B
Methods Available for Measuring Eye Movements
Method
Clinical observation, oph-
thalmoscopy
D.C. electro-oculography
(EOG)
Infrared differential limbus
reflection technique
Purkinje image tracker
(lens and cornea)
Video-based systems (track-
ing pupil or reflected
corneal images)
Magnetic search coil tech-
nique using scleral annu-
lus
Ocular electromyography
(EMG)
614
Advantages
Simple, no discomfort, resolu-
tion of 10 minutes of arc, ef-
fective way to assess fixation14
Noninvasive, minimal discom-
fort; can accurately record a
large range of horizontal
movement (±40°); resolution
of about 1°; applicable to chil-
dren and poorly cooperative
patients. The most widely
used clinical method to re-
cord eye movements
Noninvasive, minimal discom-
fort; resolution of 0.5°or bet-
ter; little noise
Noninvasive; resolution of
0.5°or better; little noise
Noninvasive, minimal discom-
fort; resolution of 0.5°or bet-
ter; noise depends on camera
resolution and digitization
rate
Sensitive to < 1 minute of arc;
precise; potential linear range
of ± 180°; capable of measur-
ing horizontal, vertical, and
torsional rotations of eyes and
head
Provides information about ex-
traocular muscle activity; es-
pecially useful in problems of
anomalous innervation or
contraction10
Disadvantages
No "record" to analyze. May be
difficult to distinguish differ-
ent types of oscillations or to
judge eye velocity
Electrical and electromyo-
graphic noise, lid artifact; un-
stable baseline, requiring re-
peat calibration and
adaptation to level of ambient
lighting. Unreliable for verti-
cal eye movements. Cost de-
pends mainly on amplifiers
selected, but usually not very
expensive
Limited range (±20°horizon-
tally and ±10°vertically). In-
termediate cost
Lens motion artifact. Subject's
head must be immobilized on
bite bar. Expensive to buy and
maintain
Subject required to wear head-
gear, which may be bulky; ve-
locity noise of system may
limit analysis of slow eye
movements. May be expen-
sive
Subject required to wear scleral
annulus on eye; topical anes-
thetic drops required. Large
(2 m) field coils are expen-
sive; scleral annulus for mea-
suring 3-D rotations is expen-
sive
Uncomfortable; technically dif-
ficult. With a few exceptions
(prior to strabismus surgery)
probably only justifiable for
research

The table summarizes techniques cur-
rently available to measure rotations of
the eyes, each methodology having its
strengths and limitations.3'6'13 At present,
the magnetic search coil technique (Fig.
1-1) is generally regarded as the most reli-
able and versatile method,12 and it is used
widely to measure eye movements in hu-
mans and many animal species. It allows
measurement of eye rotations around all
three axes,2'7 with a sensitivity of greater
than 5 minutes of arc (the standard devia-
tion of system noise is typically less than
0.02°), a potential linear range of 360°, a
bandwidth of 0 to 500 Hz, minimal drift,
insensitivity to translation of the eye, and
an unlimited field of view. One disadvan-
tage is that the subject must wear a "con-
tact lens" (a Silastic annulus in which are
imbedded coils of fine wire); this annulus
is placed after applying topical anesthetic
eyedrops. Our experience, based on
studying over 500 patients, is that the scle-
ral search coil is well tolerated for periods
of up to 60 minutes, even by those with
advanced neurological disease. A disad-
vantage is the potential for corneal abra-
sion, but the incidence in our laboratories
is less than 1 in 500. It is especially valu-
able for measuring eye movements in pa-
tients who cannot reliably point their eyes
at calibration targets (e.g., due to nystag-
mus), since the scleral annulus that the pa-
tient wears can be precalibrated on a pro-
tractor device.
Electro-oculography (EOG) is widely
used for clinical testing because it allows
measurement of a large range of move-
ment and is relatively inexpensive. How-
ever, it suffers from a number of lim-
itations including inability to reliably
measure vertical eye movements, 1 low sen-
sitivity (due to muscle artifact and other
noise sources), baseline drift, and limited
bandwidth due to the filtering required to
remove noise from the signal.
Photoelectric methods that track the
limbus (scleral-iris edge) of the eye by
measuring the amount of scattered light
from infrared sources are generally more
sensitive and reliable than EOG9 but pro-
vide a limited linear range, especially ver-
tically. In addition, most photoelectric sys-
tems use photodetectors that must be
Appendix B 615
mounted close to the eyes, so they may re-
strict the field of view. Photoelectric meth-
ods also suffer from potentially large er-
rors if there is lateral motion of the
sensors relative to the eye.
Another approach has been to measure
movement of images reflected by the eye
as it rotates; a stationary source of infrared
light can be used. Because the center of
curvature of the corneal bulge differs
from the center of rotation of the globe,
eye movements cause displacement of the
corneal, or first Purkinje, image. Alterna-
tively, the video image of the pupil can be
tracked. However, measurement of move-
ment of one such image suffers from the
disadvantage that movement of the trans-
ducer relative to the subject's head will be
interpreted as eye rotation. In systems
that measure eye rotation by tracking only
corneal reflections, 1 mm of lateral motion
of the sensor relative to the eyes intro-
duces errors of approximately 10°.13 For
systems that measure eye rotations by
tracking only the center of the pupil, the
errors are approximately 5° per 1 mm of
lateral motion. Since it is very difficult to
eliminate this lateral motion completely,
an alternative approach is to measure
movement of reflected light from one sur-
face of the eye (e.g., the cornea) in con-
junction with another reflected image
(e.g., the pupil, or the fourth Purkinje im-
age from the posterior surface of the lens).
Such an approach allows measurement of
horizontal and vertical eye movements
that is insensitive to translation of the eye
with respect to the transducer. The latter
is the case because the circumferences of
rotation of the two images differ, and
hence the two images move relative to one
another during rotation but not during
translation.
One such method that has been used
mainly as a research tool is the double
Purkinje image tracker, which uses the
first and fourth Purkinje images.4 This
tracker suffers from disadvantages that
limit its usefulness, especially in evaluating
patients; failure to detect the rather dim
fourth image of certain subjects; the pres-
ence of an artifact due to lens movement
during saccades; the requirement that the
subject's head be fixed on a bite-bar, and
616 Appendix B
substantial expense to purchase and main-
tain. An alternative has been to measure
the first Purkinje image and the pupil,
and this approach, which is technically
easier, has been incorporated in a number
of recently developed video-based ocu-
lography systems.5'6'8'11 The conventional
video camera has a bandwidth of 0 to 30
Hz (imposed by its frame rate 60 Hz),
which suffices for smooth-pursuit eye
movements but is inadequate to accurately
measure saccades. However, the current
development of faster, smaller, and more
sensitive cameras may make video-based
systems the method of choice in the next
few years.
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INDEX
Page numbers followed by d, f and t indicate displays, figures and tables,
respectively.
Abducens fascicles, disorders affecting, 352t, 355
Abducens internuclear neurons, 216, 216f
vergence eye movements and, 297-298
Abducens nerve, anatomy of, 331, 332f
Abducens nerve disorders
affecting cavernous portion, 352t, 355-356
affecting orbital portion, 352t
affecting petrous portion, 352t, 355
affecting subarachnoid portion, 352t, 355
affecting superior orbital fissure, 352t
Abducens nerve palsy, 348f-349f
bilateral, 356
in children, 356
clinical features of, 351
divergence paralysis and, 309
etiology of, 351, 352t
laboratory evaluation of, 35It
management of, 356
partial, saccadic adaptation after, 124-125
pseudo-, 518
Abducens nucleus, 217d
anatomy of, 216f, 331,333f
disorders affecting, 352-355, 352t
horizontal conjugate eye movements and,
216-220, 216f, 218f
lesions of, 220-221, 352-353, 497-498, 497d
combined, 509-510
vergence eye movements and, 296
Abetalipoproteinemia, 558t, 560
AC/A ratio, 292
abnormalities of, 307-310
defined,288t
environmental modification of, 303
in internuclear ophthalmoplegia, 298
measurement of, 306
Accessory optic system, smooth pursuit and, 172,
173
Accommodation
adaptive mechanism for, 302-303, 303f
convergence-linked, 288t, 292
defined, 288t
measurement of, 291
near triad and, 290-291
vergence and, interactions between, 291-292,
302-303, 303f
Accommodative vergence, 12, 290, 291f, 306
Accommodative-linked convergence, 288t
Acetazolamide, 459
Acetylcholine
gaze-holding and, 203
myasthenia gravis and, 375-377
vestibular eye movements and, 457
Acoustic schwannoma (acoustic neuroma)
Bruns' nystagmus and, 431
flocculo-nodular syndrome and, 497
hyperventilation-induced nystagmus and, 414
Acquired immune deficiency syndrome. See
HIV/AIDS
Acquired pendular nystagmus
See Pendular nystagmus, acquired
Acquired ocular motor apraxia, 542-544, 544f-545f
ACTH (adrenocorticotropic hormone), for opso-
clonus, 459
Acupuncture, for nystagmus, 463
Adaptation
central, in myasthenia gravis, 377-378
disconjugate, 304-306, 305f
prism. See Phoria
saccadic, 124-126
smooth pursuit, 160
vestibulo-ocular reflex 48-53
Adduction, upshoot in, 350
Adduction lag, in internuclear ophthalmoplegia,
503, 504, 506, 506f
Adrenocorticotropic hormone, for opsoclonus, 459
Adult-onset hexosaminidase A deficiency, 558t,
559
Aerobics, vertigo and, 468
Afferents
otolith, 29
vestibular, 28-31,32-33
After-nystagmus, optokinetic. See Optokinetic after-
nystagmus
Age. See also Children; Infant(s)
smooth pursuit and, 160, 163-164, 178
square-wave jerks and, 180
vergence eye movements and, 290
vestibulo-ocular reflex and, 42
AICA. See Anterior inferior cerebellar artery
AIDS. See HIV/AIDS
Albinism, congenital nystagmus and, 445
Alcohol
gaze-evoked nystagmus and, 430, 563t
positional nystagmus and, 477, 479
treatment for seesaw nystagmus, 459
vertigo and, 469-470
Alexander's law, 209, 412
ALS (amyotrophic lateral sclerosis), 526
ophthalmoplegia and, 369
Alternate cover test, 341, 34If, 342
Alternating sursumduction, 350
Alzheimer's disease
eye movement abnormalities in, 549
saccadic abnormalities in, 133
617
618 Index
Amblyopia
nystagmus and, 435, 445
strabismus and, 350
Amino acid disorders, branch-chain, 558t
Aminoglycosides
ototoxicity of, 481
vertigo and, 470
Amphetamines, 459, 563t
Amyloid, restrictive ophthalmopathy in, 383
Amyotrophic lateral sclerosis, 526
ophthalmoplegia and, 369
Anderson-Kestenbaum operation, for congenital
nystagmus, 462
Aneurysm(s)
basilar artery, oculomotor nerve and, 362t, 364
carotid artery
abducens nerve palsy and, 355
oculomotor nerve palsy and, 365
trochlear nerve palsy and, 359
intracavernous, oculomotor nerve palsy and, 365
posterior communicating, oculomotor nerve palsy
and,365
Angular vestibulo-ocular reflex, see Rotational
vestibulo-ocular reflex
Anisometropia, adaptation to, 304-306, 305f
Annulus of Zinn, 323, 325f
Anterior semicircular canal BPPV, 476
Anterior inferior cerebellar artery, 24
infarction in the distribution of, 486f, 487, 496
Anterior vestibular artery, 25
Anti-acetycholine receptor antibodies, in myasthenia
gravis, 376-377
Anticholinergic agents, treatment of nystagmus and,
458
Anticipatory eye movements, smooth pursuit and,
158-159
Anticonvulsants, gaze-evoked nystagmus and, 430
Anti-GQlb antibody, 372
Antidepressants, 561, 562t
Anti-Hu antibody, 454, 496
Anti-Ri antibody, 454
Anti-Yo antibody, 496
Antisaccade task, 532f
Alzheimer's disease and, 549
in clinical examination, 96-97
frontal lobe lesions and, 542
Huntington's disease and, 532-533, 532f
Apogeotropic nystagmus, 475, 476
Apoplexy, pituitary, 365, 366f-367f
Apraxia, ocular motor. See Ocular motor apraxia
Area 7a, gaze control and, 236f, 238-239
Arnold-Chiari malformation, 421, 423f, 491-492,
493f
convergence nystagmus and, 441-442
diagnosis of, 62
divergence nystagmus and, 441
eye movement disturbances in, 492t
oscillopsia and, 481
treatment of, 463
Arterial aneurysms. See Aneurysm(s)
Arteritis, giant-cell, restrictive ophthalmopathy in,
383
Ascending tract of Deiters, 31
Ataxia(s)
familial episodic vertigo and, 430, 459, 472, 493,
495t
hereditary, ocular motor findings in, 492-496,
494t-495t
spinocerebellar, 493, 494t-495t, 510
Ataxia telangiectasia, 495t, 558t
Auditory stimuli, treatment for nystagmus, 463
Baclofen, 563t
for nystagmus, 458
for periodic alternating nystagmus, 458
vestibular eye movements and, 457
Balint's syndrome, 117-118, 240, 540, 543
Barbecue-spit rotation, 67
Barbiturates, 459, 562t
Bardet-Biedl syndrome, horizontal saccade failure
and, 547
Basal ganglia
caudate nucleus of, 120, 248, 533
disease of, ocular motor abnormalities and,
528-534
saccade generation and, 119-121, 248
substantia nigra pars reticulata, 120-121, 533
in voluntary control of eye movements, 14
Basilar artery
aneurysm of, oculomotor nerve palsy and, 362t,
364
dolichoectasia of, 483
Bassen-Kornzweig disease, 560
Bechterew's phenomenon, 69
Becker's dystrophy, 379-380
Benedikt's syndrome, 364
Benign paroxysmal positional vertigo (BPPV)
anterior-canal variant, 476
bilateral, 476
canalolithiasis, 473, 476, 477
clinical features of, 473-476
diagnosis of, 61, 473-476, 474f-475f
lateral-canal, 475-476
nystagmus with, 68, 412, 473-474
pathophysiology of, 476-477
treatment of, 457, 474f-475f, 479
Benign paroxysmal vertigo of childhood, 471
Benzodiazepines, 561, 562t
Benztropine, treatment for acquired pendular nys-
tagmus, 458
Beta blockers, 563t
Bickerstaff's brain stem encephalitis, 372
Bielschowsky head-tilt test, 342-344, 343f
Binocular vision, latent nystagmus and, 446-
447
Biofeedback, for treatment of nystagmus, 463
Bismuth intoxication, 549
Blepharospasm, 533
Blindness. See Vision, loss of
Blinks
frequency of, 127
saccadesand, 127-128, 127f
Blowout fracture of orbit, 371
Bobbing, ocular, 552t, 553, 553f
Bode plot, of vestibulo-ocular reflex, 39, 39f
Botulinum toxin, 373
for nystagmus, 460f-461f, 462
Bow-tie nystagmus, 417, 419f
BPPV. See Benign paroxysmal positional
vertigo

Brain stem
conjugate eye movements and horizontal,
215-221, 216f,218f
vertical and torsional, 220f, 221-228, 224f-225f
lesions of, ophthalmoplegia and, 369, 369t
saccadic intrusions and, 455
saccadic pulse generator in, 103-104, 110, 11 If
in vertical smooth pursuit, 226-228
VOR elaboration by, 29-35, 30t, 32f
Brain stem encephalitis, 372, 453
Brain stem ischemia
horizontal gaze palsy and, 502
positional vertigo and, 477
vertical gaze palsy and, 519t
Branch-chain amino acid disorders, 558t
Brodman area 40, lesions of, smooth pursuit and, 169
Brown's syndrome, 359
Bruns' nystagmus, 431
Builup neurons, collicular, 114
Burst neurons, 103
collicular, 113
excitatory, 104-105
inhibitory, 104
for horizontal saccades, 103-104
long-lead, 105-106, 121
midbrain, 104-105
pontomedullary, 104
premotor, 104-105
saccadic oscillations and, 133-134
vergence, 297, 297f, 301
for vertical and torsional saccades, 104-105
Burst-position neurons, 31
Burst-tonic cells, vergence, 297, 301
CA/C ratio, 292
defined,288t
modification of, 303
Cajal, interstitial nucleus of. See Interstitial nucleus
of Cajal
Calcium channel blockers, treatment for familial
episodic vertigo and ataxia type 2, 459
Caloric testing
acute peripheral vestibulopathy and, 466-467
bedside, 63
nystagmus and, 64-65
quantitative, 64-65
in unconscious patients, 555-556
Campylobacter jejuni infection, Guillain-Barre syn-
drome and,371
Canalolithiasis, 473, 476, 477. See also BPPV
Carbamazepine, 457t, 562t
Carotid artery aneurysm
abducens nerve palsy and, 355
oculomotor nerve palsy and, 365
trochlear nerve palsy and, 359
Carotid cavernous fistula
multiple ocular motor nerve palsies and, 370
restrictive ophthalmopathy in, 383
Caudate nucleus
hemorrhage of, 533
Huntington's disease and, 533
saccade generation and, 120, 248
Cavernous sinus syndromes, multiple ocular motor
nerve palsies and, 369-370, 369t
Index 619
Central adaptation, in myasthenia gravis, 377-378
Central eye position, defined, 322t
Central mesencephalic reticular formation, 227,
228d
eye-head saccades and, 270
lesions of, 106, 227, 522d. See also Progressive
supranuclear palsy
long-lead burst neurons in, 105-106
Central nucleus
anatomy of, 333
nuclear oculomotor palsy and, 361
Central otolith connections, lesions of, 71
Central vestibular nystagmus, 415-424
clinical features of, 415-421, 4l7f-419f, 423f
etiology of, 415t, 420t, 422t
horizontal, 421, 423f
pathogenesis of, 421-422, 424
perverted, 421
Centripetal drift
clinical evaluation of, 208-209
correction of, 202-203
myasthenia gravis and, 375
Centripetal nystagmus, 210, 429, 429d, 431
Centronuclear myopathy, 380
Cerebellar arteries, infarction in the territories of,
487, 487f, 496-497
Cerebellar eye signs, 487-497
Cerebellar syndromes, 487-490
Cerebellar tonsils, displacement of, in Arnold-Chiari
malformation, 492, 493f
Cerebellar vermis, 23Id
vergence eye movements and, 299
Cerebellectomy, total, 124, 126, 171
Cerebellum 23Id, 232d. See also Vestibulocerebellum
adaptive control of eye movements and, 13, 491
anatomy of, 229f
conjugate eye movements and, 228-233, 229f
degeneration of, paraneoplastic, 496
developmental anomalies of. See Arnold-Chiari
malformation
dorsal vermis of, see Dorsal vermis
downbeat nystagmus and, 422, 424, 496
fastigial nucleus of. See Fastigial nucleus
fixation and, 181, 491
flocculus of. See Flocculus(i)
gaze holding and, 206-207, 206f
gaze-evoked nystagmus and, 430, 496
hemorrhage of, 497
lesions of
mass, 497
ocular bobbing and, 553, 553f
ocular motor syndromes caused by, 487-497,
490f, 492t, 493f, 494t-495t
neural integration and, deficient, 206-207, 206f
nodulus of. See Nodulus
opsoclonus and, 455-456
paraflocculus of. See Paraflocculus(i)
periodic alternating nystagmus and, 425
positional nystagmus and, 479
positional vertigo and, 477
recurrent vertigo and, 471-472
saccade generation and, 121-124, 121f, 123f
saccadic adaptation and, 126
skew deviation and, 465
smooth pursuit and, 171-172
tumors of, 497
620 Index

Cerebellum (continued) history-taking, 58-59

vergence eye movements and, 298-299, 303
vestibular lesions and, recovery from, 53
VOR adaptation and, 54-56, 55f
Cerebral cortex, in voluntary control of eye move-
ments, 14,233-245
Cerebral hemispheres
lesions of
acute, 534-536
focal, 537-542
head turning paresis and, 276-277
ocular motor syndromes caused by, 534-548
unilateral
horizontal nystagmus and, 435-436
large, 536-537, 536t
smooth pursuit and, 181-182, 182f-183f, 184,
436
VOR abnormalities and, 71, 537
saccadic intrusions and, 455
vergence eye movements and, 299
voluntary control of eye movements and, 233-250
descending parallel pathways in, 246-250
frontal lobe in, 242-246
parietal lobe in, 236f, 238-241
posterior cortical areas in, 234-237, 235f, 236f
pulvinar in, 241-242
study of, approaches to, 233-234
temporal lobe in, 236f, 237-238
Cervical muscles, viscoelasticity of, head stability
and, 265
Cervical vertigo, 469
Cervicocollic reflex, head stability and, 265
Cervico-ocular reflex, 47-48
nystagmus and, 415
purpose of, 267-268
Chiari malformation, 491-492
Children
abducens nerve palsy in, 356
dyslexia in, saccadic eye movements and, 96,
100-101
ocular motor abnormalities in infants, 558-559,
560
vertigo in, 471
Chloral hydrate, 563t
Chlordecone, 563
Chordoma, abducens nerve palsy and, 355
Chronic progressive external ophthalmoplegia,
379-381, 379t
Chronic relapsing neuropathies causing ophthalmo-
plegia, 372
Cigarette smoking, 563-564, 563t
Cingulate cortex
gaze control and, 245-246
lesions of, 542
Circularvection, 46
defined,20t
posterior cortical lesions and, 539
Claude's syndrome, 364
Clinical examination, 611-613
of fixation, 177-178
of saccades, 128-129
of smooth pursuit, 178-179
in vestibular disorders, 57-63, 59t
bedside caloric testing, 63
dynamic vestibular imbalance tests, 60-61
general principles, 57-58
positional testing, 60-61
static vestibular imbalance tests, 59-60
vestibular gain testing, 62-63
Clivus tumor, abducens nerve palsy and, 355
Clonazepam
for acquired pendular nystagmus, 458
for downbeat nystagmus, 457-458
for saccadic intrusions and oscillations, 459
Clostridium botulinum, 373
Cocaine, 454t, 563t, 564
Cockayne's syndrome, 559
Coffin-Siris syndrome, 492
Cogan's eyelid twitch sign, 374
Cogan's congenital ocular motor apraxia, 544-546
Cogan's syndrome, recurrent vertigo and, 471
Collier's "tucked lid" sign, 517
Coma, eye movements in, 551-556, 552t, 553f,
555f
Compensation, versus adaptation, 48
Concomitance, spread of, 342
Concomitant deviation
defined,322t
strabismus and, clinical features and diagnosis of,
348-350
Congenital amaurosis, Leber's, 433, 434f-435f
Congenital anomalous innervation of extraocular
muscles, 353-355, 354f
Congenital epidermoid tumor, hyperventilation-in-
duced nystagmus and, 413, 413f
Congenital extraocular fibrosis, 383
Congenital myopathies, 380
Congenital nystagmus, 276, 345, 442-449, 443d
clinical features of, 442-444, 444f
latent nystagmus and, 445-446, 446d
pathogenesis of, 444-445
smooth pursuit and, 186
strabismus and, 444
treatment of, 461, 462, 463
Congenital ocular motor apraxia, 98-99, 544-547,
546f
Congenital oculomotor nerve palsy, 363
Conjugate eye movements
cerebellar influences on, 228-233, 229f
horizontal. See Horizontal eye movements, conju-
gate
midbrain influences on, 221-228
neural integrator for, 7
physiologic basis for, 336-337
pontine influences on, 215-221
vertical and torsional, brain stem connections for,
220f, 221-228, 224f-225f
voluntary control of, 233-250. See also Cerebral
hemispheres, voluntary control of eye
movements and
Conjugate gaze deviations, 535d
with acute hemispheric lesions, 534-536
in epileptic seizures, 547, 548
in unconscious patients, 551, 552t, 554
Conjugate gaze palsy, unilateral, internuclear oph-
thalmoplegia and. See One-and-a-half syn-
drome
Contact lens-spectacle lens combinations for treat-
ment of nystagmus, 461-462
Contextual cues, in VOR adaptation, 51, 52f
Contrapulsion, saccadic, 132, 496

Control systems analysis
of smooth pursuit, 174-177
in study of eye movements, 15
Convergence
accommodative-linked, 288t
lid nystagmus and, 308, 449, 486
ocular motorneurons during, 296, 296f
saccades and, 293, 294f
Convergence-induced nystagmus, 308
Convergence insufficiency, 307
Convergence-linked accommodation, 288t, 292
Convergence-retraction nystagmus, 307
dorsal midbrain syndrome and, 518
Convergence spasm, 308-309
Convergent-divergent nystagmus, 308, 439, 441-442
Convergent-divergent pendular oscillations, 441
Converse bobbing, 552t, 553
COR. See Cervico-ocular reflex
Corneal reflection techniques, for measurement of
saccadic eye movements, 129, 614t
Cornelia de Lange syndrome, horizontal saccade
failure and, 547
Corollary discharge, 14
Corrective saccades, 10, 98
Corresponding retinal elements, defined, 288t
Corticopontine projections, 249
Corticosteroids
for Cogan's syndrome, 471
for opsoclonus, 459
Counterrolling, ocular, 20t, 21, 22
Cover tests, 340-342, 340f-341f
Cover-uncover test, 340
CPEO. See Chronic progressive external ophthalmo-
plegia
Creutzfeldt-Jakob disease, 530, 549
Cristae, anatomy of, 24, 26f
Cross-coupling, of nystagmus, 60-61
Crossed diplopia, defined, 322t
Cupula, 24, 25
Cuppers procedure, for nystagmus, 462
Cupulolithiasis, 473, 476. See also BPPV
Cyclic oculomotor nerve palsy, 363
Cyclodeviation
defined,322t
of superior oblique palsy, 290
Cyclovergence, 290
Cyclovergence nystagmus, 441
Dandy-Walker syndrome, 492
Deiters, ascending tract of, 31
Dementia
AIDS and,549-550
eye movement abnormalities in, 548-550
head nystagmus in, 276
Demyelinative disease. See also Multiple sclerosis
acquired pendular nystagmus with, 437, 438
internuclear ophthalmoplegia and, 504
Dentatorubropallidoluysian atrophy, 533
Descending parallel pathways
for saccades, 11 If, 118, 249-250
voluntary gaze control by, 246-250, 247f
Descending pursuit pathway, smooth pursuit and,
170,235f
Descending vestibular nucleus, 30, 31
Index 621
Diabetes
abducens nerve infarction and, 356
oculomotor nerve infarction and, 366-367
trochlear nerve infarction and, 359
Diazepam, 459, 561
Diencephalon, lesions of, ocular motor syndromes
caused by, 526-528
Diplopia, 287, 321. See also Strabismus
clinical testing in, 337-344
convergence insufficiency and, 307
crossed, 322t, 339
examination in, 338-344
Bielschowsky head-tilt test, 342-344, 343f
cover tests, 340-342, 340f-341f
range of eye movements, 338
subjective testing, 337f, 338-340, 339f
history and, 337-338
in internuclear ophthalmoplegia, 508
monocular, 337
uncrossed, 323t, 339
Dipping, ocular, 552t, 553
Disconjugate adaptation, 304-306, 305f
Disconjugate nystagmus, 408
Disjunctive eye movements. See Vergence eye move-
ments
Disparity
fixation, 289, 302
relative versus absolute, 289
Disparity-induced vergence, 12, 287-290, 299-300,
306
Dissociated nystagmus, 408, 506-507
Dissociated vertical deviation (DVD), 350, 427
Divergence
repetitive, 308
saccades and, 293, 294f
synergistic, 363
upbeat nystagmus and, 417, 419f
Divergence insufficiency, 309
Divergence paralysis, 309-310
Divergence (Cuppers) procedure, for nystagmus,
462
Divergent nystagmus, 308
Arnold-Chiari malformation and, 441
convergent-, 308, 439, 441-442
Divergent pendular oscillations, convergent-, 441
Dix-Hallpike maneuver, 61
for benign paroxysmal positional vertigo,
473-474, 474f-475f
Dizziness. See also Vertigo
diagnosis of, 465-466
DNA, mitochondrial, disorders of, 380-381
Dolichoectasia, of basilar artery, 483
Doll's head maneuver, 554
Donders'law, 13,326
Dorsal midbrain syndrome, 517-519, 517t
Dorsal terminal nucleus, optokinetic response and,
173
Dorsal vermis, 23Id
in adaptive control of eye movements, 13
gaze control and, 231-232
lesions of, 122, 232, 489-490, 489d, 490f
saccade generation and, 122, 123f
saccadic adaptation and, 126
smooth pursuit and, 171
Dorsolateral pontine nuclei, smooth pursuit and,
170
622 Index
Dorsolateral prefrontal cortex, 117, 245d
gaze control and, 236f, 244-246
lesions of, 245, 541d, 542
projections of, 248
saccade generation and, 117
Dorsomedial pulvinar, gaze control and, 242
Double elevator palsy, 520
Double vision. See Diplopia
Double-step stimulus motion, saccadic eye move-
ment response to, 99, 99f
Downbeat nystagmus, 70, 416d
cerebellum and, 422, 424, 496
clinical features of, 415-416
convergence and, 308
etiology of, 415t
with increasing velocity waveforms, 41 Of, 416,
4l7f
oscillopsia and, 482
pathogenesis of, 421-422, 424
skew deviation and, 465
treatment of, 457-458, 463
Downward eye movements, scheme for, 225f
Drug(s). See Medication(s); specific drug
Duane's syndrome, 353-355
Duchenne's dystrophy, 379-380
Duction, defined, 322t
Duction test, forced, 338
Duncker illusion, 157
Dynamic overshoots, postsaccade, 94
Dynamic vestibular imbalance, 60-61
Dyslexia
fixation abnormalities and, 101
saccadic eye movements and, 96, 100-101
Dysmetria
cerebellar disease causing, 489-490, 490f
clinical examination of, 128
pathophysiology of, 132
pulse, 97, 130
pulse-step mismatch, 97, 130, 13If
Dystrophies, muscular, extraocular muscles in,
379-380
Dystrophin, genetic abnormalities of, 379-380
EA-2. See Episodic vertigo and ataxia type 2
EBN (excitatory burst neurons), 104-105
Eccentric rotation
defined,20t
in otolith-ocular testing, 66
VOR gain and, 44-45
Edrophonium test
in Lambert-Eaton myasthenic syndrome, 374
in myasthenia gravis, 375, 376f, 377-378
Efference copy, 14
memory-guided saccades and, 98
smooth pursuit and, 176
spatial localization and, 102
thalamic lesions and, 528
Efferents, vestibular, 29-30
Elderly persons
smooth pursuit responses in, 160, 163-164, 178
square-wave jerks in, 180
vergence eye movements in, 290
vestibulo-ocular reflex in, 42
Electromyography (EMG), 614
myasthenia gravis and, 378
otolith-ocular testing and, 67
Electro-oculography, 129, 614, 615
Encephalitis
brain stem, Bickerstaff's, 372
parainfectious, opsoclonus and, 453
End-point nystagmus, 209, 407, 430-431, 430d
EOG (electro-oculography), 129, 614, 615
Epidermoid tumor, congenital, hyperventilation-
induced nystagmus and, 413, 413f
Epileptic seizures
eyelid flutter, 547
eye movements during, 547-548, 551, 552,
554
head turning during, 277, 548
recurrent vertigo and, 472
skew deviation and, 465
Episodic ataxias, ocular motor findings in, 493, 494t-
495t
Episodic vertigo and ataxia type 2
nystagmus and, 430, 459
ocular motor findings in, 493, 495t
vertigo and, 472
Epley maneuver, for benign paroxysmal positional
vertigo, 474f-475f, 479
Esotropia
defined, 322t
induction of, congenital nystagmus and, 444
A or V pattern, 350
thalamic, 308, 527
Ewald's second law, 28, 29, 61, 475-476
Excitatory burst neurons, 104-105
Excyclodeviation, defined, 322t
Excyclotropia, 464-465
Exocentric cues, spatial constancy and, 101-102
Exotropia
defined, 322t
intermittent, 290
in internuclear ophthalmoplegia, 507
pontine, paralytic, 509
Express saccades, 9It, 96
Extraocular muscle(s). See also specific muscle
actions of, 324t
anatomy of, 323-327, 325f-326f
congenital anomalous innervation of, 353-355,
354f
congenital fibrosis of, restrictive ophthalmopathy
and,383
discharge rate of, eye movements and, 329, 330f-
331f
fibers of, types of, 327-329, 328f
muscular dystrophies and, 379-380
myasthenia gravis and, 374-375, 376f
nontwitch fibers of, 327
paresis of, oscillopsia and, 481-482
pulling directions of, 325-327, 326f
structure and function of, 327-331, 328f
twitch fibers of, 327
weakening of, for treatment of nystagmus,
462-463
Extraocular proprioception, 329, 332
Eye movements, 3-16. See also specific type, e.g., Ver-
gence eye movements
adaptive control of, 13

analysis of, quantitative approaches to, 37-40,
64-66
dynamic properties of, in paralytic strabismus,
346-348, 348f-349f
fixation-preventing. See Nystagmus; Saccadic in-
trusions
functional classes of, 4, 4t, 5-6
head movements and. See Eye-head movements
measurement of, 3-4, 4f, 614t
in nystagmus, 409
monocular, in unconscious patients, 552t, 554
range of, assessment of, 338
recordings of, for detection of saccadic abnormali-
ties, 129-130.6141
and spatial localization, 14-15
spontaneous, in unconscious patients, 552-554,
552t
study of
scientific method applied to, 15
value of, 3-5
three-dimensional aspects of, 12-13, 325-327
visual requirements of, 5, 5f
voluntary control of, 13-14, 233-250. See also
Cerebral hemispheres, voluntary control of
eye movements and
Eye position
axis of rotation and, 408-409
central, 13, 322t
in head, 265
neural encoding of, 35
primary, 13, 322t
resting
return to, 198, 199f
in unconscious patients, 551-552
in space. See Gaze
Eye-head movements, 11-12
disorders of, 274-278, 275t
examination of, 273
laboratory evaluation of, 273-274, 279f
in ocular motor apraxia, 545-546, 546f
stabilization of head and, 263-265, 264f
disorders of, 275-276, 275t
tracking and. See Eye-head tracking
voluntary control of, 265-274
disorders of, 275t, 276-278
rapid gaze shifts and, 265-271, 267f, 268f
smooth tracking and, 271-274, 27If
Eye-head saccades, 265-271
adaptive changes of, 268-269
dysmetric, 278
functions of, 265-266
neural substrate for, 269-271
caudal superior colliculus, 270
frontal eye field, 270-271
gigantocellular head-movement region, 269
mesencephalic reticular formation, 270
paramedian pontine reticular formation,
269-270
rostral interstitial nucleus of medial longitudinal
fasciculus, 270
in Parkinson's disease, 528-529
saccadic command/VOR interaction in, 267-269,
268f
to unexpected and expected targets, 266,
267f
Index 623
Eye-head tracking, 271-274, 27If
disorders of, 278, 279f
examination of, 273
laboratory evaluation of, 273-274, 279f
neural substrate for, 272-273
smooth pursuit versus, 279f
vestibulo-ocular reflex negation during, 227,
271-272, 27If, 273-274, 279f
Eyelid abnormalities
dorsal midbrain syndrome and, 517, 517t
myasthenia gravis and, 374
progressive supranuclear palsy and, 523
Eyelid flutter, in epileptic seizures, 547
Eyelid movements, saccades and, 126-128, 127f
Eyelid nystagmus, 308, 449, 486
Eye-neck reticulospinal neurons, 270
Facial palsy, abducens nucleus lesions and, 498
Familial episodic vertigo and ataxia type 2
nystagmus and, 430, 459
ocular motor findings in, 493, 495t
vertigo and, 472
Familial myasthenic syndrome, 374
Fascia, orbital, anatomy of, 323-325, 324f
Fastigial nucleus, 232d
in adaptive control of eye movements, 13
gaze control and, 232-233
lesions of, 122, 123-124, 232-233, 489-490, 489d,
490f
posterior. See Fastigial oculomotor region
saccadic adaptation and, 126
smooth pursuit and, 171-172
Fastigial oculomotor region, 122, 232d
gaze control and, 232
lesions of, 489-490, 489d, 490f
saccade generation and, 122-124, 123f
smooth pursuit and, 171-172
vergence eye movements and, 298
Fatigue nystagmus, 375, 377, 431
FEF. See Frontal eye field
First-degree nystagmus (see Alexander's law), 412
Fistula(s)
carotid cavernous
multiple ocular motor nerve palsies and, 370
restrictive ophthalmopathy in, 383
perilymph
ocular tilt reaction and, 464
vertigo and, 469
Fixation
abnormalities of, 180-181
developmental dyslexia and, 101
cerebellum and, 181, 491
clinical examination of, 177-178
defined,11
eye movements during, 5, 5f
gaze stability and, 152-153, 152f-153f
laboratory evaluation of, 179-180
latent nystagmus and, 185-186
nystagmus and, 59-60, 180-181
ocular motor neurons during, 200, 200f
smooth pursuit versus, 153-156, 154f-155f
spasm of, 96, 543
Fixation disparity, 289, 302
624 Index
Floccular target neuron, 31, 53-54, 55-56
Flocculus(i), 230d
compression of, 497
downbeat nystagmus and, 422, 424
gaze control and, 228-231
gaze holding and, 206
lesions of, 55, 71, 171, 230, 487-489, 488d
saccadic adaptation and, 126
smooth pursuit and, 171
vergence eye movements and, 298
VOR adaptation and, 53-56, 55f
Flocculo-nodular syndrome, 497, 488d
Flutter
eyelid, in epileptic seizures, 547
ocular. See Ocular flutter
psychogenic, 455
Forced duction test, 338
Fourth nerve palsy. See Trochlear nerve palsy
Foveation periods
in congenital nystagmus, 443, 444f
in latent nystagmus, 445
Foville's syndrome, 353
Fracture(s)
orbital blowout, 371
temporal bone, vertigo and, 468
Frenzel goggles, 59-60, 612
Friedreich's ataxia, ocular motor findings in, 495t
Frontal eye field, 243d. See also Frontal lobe(s)
eye-head saccades and, 270-271
gaze control and, 242-244
lesions of, 116, 244, 249, 540, 541d, 542
localization of, 242
pharmacologic inactivation of, 243-244, 249
projections of, 247-248, 247f
saccade generation and, 115-116
smooth pursuit and, 169-170
Frontal lobe(s). See also Dorsolateral prefrontal cor-
tex; Frontal eye field
gaze control and, 242-246
Huntington's disease and, 533
lesions of, 96, 528, 540-542, 541d
saccade generation and, 115-117
supplemental eye field of. See Supplemental eye field
vergence eye movements and, 299
Frontoparietal lesions, ocular motor apraxia and,
542
Functional imaging, cerebral control of eye move-
ments and, 233
Fusion, defined, 288t
Fusional adaptive mechanism, 302-303, 303f
Fusional vergence, 12, 287-290, 299-300, 306
GABA. See Gamma-aminobutyric acid
Gabapentin
for acquired pendular nystagmus, 458
for macrosaccadic oscillations, 459
Gain. See also Pursuit gain; Vestibular gain
defined,20t
saccadic, 129-130
Gamma-aminobutyric acid
gaze holding and, 203
vestibular eye movements and, 34, 457
Gap stimulus, saccades made to, 95-96
Gaucher's disease, 558t, 559
Gaze
angle of, 6
cardinal positions of, 322t
defined, 265
horizontal. See Horizontal gaze
rapid changes in, eye-head movements and,
265-271, 267f, 268f. See also Eye-head sac-
cades
stability of
disorders of, 275t, 276-278
testing of, 59-60
vestibular loss and, 275-276, 275t
visual fixation and, 152-153, 152f-153f
vertical. See Vertical gaze
Gaze control, 14
cerebral hemispheres and, 233-250, 237d, 238d,
239d, 24Id, 243d, 245d, 246d See also Cere-
bral hemispheres, voluntary control of eye
movements and
dorsal vermis and, 231-232, 23Id
fastigial nucleus and, 232-233, 232d
midbrain and, 221-227
ponsand,215-221
vestibulocerebellum and, 228-231
Gaze deviations, 535d
with acute hemispheric lesions, 534-536
in epileptic seizures, 547, 548
periodic alternating, 552t, 554
in unconscious patients, 551, 552t, 554
Gaze holding
abnormal. See Gaze-evoked nystagmus; Rebound
nystagmus
clinical evaluation of, 208-209
horizontal, 203-204
medullary lesions impairing, 482-483
neural substrate for, 203-208
cerebellum, 206-207, 206f
interstitial nucleus of Cajal, 205-206
NPH-MVN region, 203-205, 205f-206f
vertical, 204, 205-206, 223, 225-226
Gaze palsy,
horizontal, 499
vertical, 512d
complete, 369
Gaze saccades. See Eye-head saccades
Gaze-evoked nystagmus, 7, 13If, 410, 41 Of, 429d
cerebellum and, 430, 496
clinical evaluation of, 208-209
clinical features of, 427-430, 429f
end-point nystagmus versus, 430-431, 430d
oscillopsia and, 482
pathogenesis of, 209-210
vertical, 210, 227
vestibular imbalance and, 209-210
Gaze-paretic nystagmus, 208, 428-429
Gaze-velocity Purkinje cells, in adaptive control of
eye movements, 54
Gegenrucke (square wave jerks), 449
Gentamicin, ototoxicity of, 481
Geotropic nystagmus, 475, 476
Gerstmann-Straussler-Scheinker disease, 549
Giant-cell arteritis, restrictive ophthalmopathy in,
383
Gigantocellular head-movement region, eye-head
saccades and, 269
Gilles de la Tourette's syndrome, 533
 Index 625

Glissade, 93-94, 97, 130, 131f sustained, vestibulo-ocular response to, 23

Global effect, saccadic accuracy and, 97 versus tilts, 43, 43f
Global fibers, 329 Head trauma
Glycine, 34, 456, 457 oculomotor nerve palsy due to, 367
GM1 gangliosidosis, horizontal saccade failure and, ophthalmoplegia and, 371
547 positional vertigo and, 477
Goggles, Frenzel, 59-60, 612 trochlear nerve palsy due to, 357-359
Gradenigo's syndrome, 355, 356 vertigo and, 468
Graves' ophthalmopathy, 381-383, 382f Head tremor, 276
Gray matter, periaqueductal, 227, 519-520 Head turn(s)
Guillain-Barre syndrome, 371, 372 congenital nystagmus and, 444
in epileptic seizures, 277, 548
paresis of, 276-277
strabismus and, 345-346
Habituation, of vestibulo-ocular reflex, 48-49 Headache, migraine
Hair cells (vestibular), 24, 26f ophthalmoplegic, 363
Harada-Ito procedure, 361 recurrent vertigo and, 470, 471
Haw River syndrome, 533 Head-tilt test
Head Bielschowsky, 342-344, 343f
injury of. See Head trauma physiologic basis of, 343-344
stability of, 263-265, 264f, 274 Hearing loss, Meniere's syndrome and, 470
disorders of, 275t, 276-278 Heimann-Bielschowsky phenomenon, 433, 435
vestibular loss and, 275-276, 275t Hemianopia, occipital lobe lesions and, 537-538
Head movements. See also Eye-head movements; Hemidecortication, 537
Eye-head tracking Hemi-seesaw nystagmus, 426, 428, 428d, 428t, 435
examination of, 273 Hemorrhage
oscillopsia and, 275 caudate, 533
rotational. See Head rotation(s) cerebellar, 497
translational. See Head translation(s) midbrain, vertical gaze palsy with, 518-519, 520f-
vestibulo-ocular response to, 8-9, 8f-9f 521f
visual acuity and, 480-481 thalamic, 527
voluntary control of, disorders of, 276-278 vestibular organ, recurrent vertigo and, 472
Head nodding, in spasmus nutans, 448 Hennebert's sign, 469
Head nystagmus. See Vestibulocollic reflex Hepatic encephalopathy, periodic alternating gaze
Head oscillations, congenital nystagmus and, 444 deviation and, 554
Head position Hereditary ataxias, ocular motor findings in,
nystagmus and, 475 492-496, 494t-495t
in spasmus nutans, 447 Hering's law, 336
vestibular perception of, 56 Herpes zoster, acute vertigo caused by, 467-468
Head pursuit. See Eye-head tracking Hess screen test, 339
Head rotation(s), 21-22, 263, 263f Heterophoria
active, 66 accommodative vergence testing and, 306
eccentric cover test for, 340f, 341
in otolith-ocular testing, 66 defined,322t
VOR gain and, 44-45 Heterotropia
in pitch, 263, 263f, 264, 265 cover test for, 340, 340f
in roll, 22, 263, 263f defined,322t
sustained, vestibulo-ocular response to, 9-10, 9f, Hexosaminidase A deficiency, adult-onset, 558t, 559
23 Hindbrain, developmental anomalies of, 491-492
in unconscious patients, 554-555 Hippocampus, lesions of, 539
in yaw, 263, 263f, 264 History taking
Head saccades. See Eye-head saccades diplopia and, 337-338
Head shaking nystagmus, 60-61, 412 nystagmus and, 407
Head thrusts in vestibular disorders, 58-59
acute peripheral vestibulopathy and, 467 HIV/AIDS
dynamic vestibular imbalance and, 61 dementia and, 549-550
in ocular motor apraxia, 545-546, 546f ophthalmoplegia and, 369
Head tilt(s), 22, 275 Homonymous hemianopia, eye movements and,
ocular tilt reaction, in, 275-276 101,537
complaints of, history-taking in, 58-59 Horizontal eye movements
skew deviation and, 71 conjugate
strabismus and, 346 brain stem connections for, 215-221, 216f, 218f
versus translation, 43, 43f internuclear ophthalmoplegia and, 221
in Wallenberg's syndrome, 486-487 NPH-MVN lesions and, 203, 205f
Head translation(s), 21-22 pontine lesions and, 497-502
axes of, 263 dorsal midbrain syndrome and, 518
626 Index
Horizontal eye movements (continued).
fusional, 287-289
progressive supranuclear palsy and, 523, 524f-
525f
Horizontal gaze
midbrain paresis of, 520
paralysis of
acquired, 352-353, 352t
pontine disease and, 497-502, 500f-501f
pseudo-horizontal gaze palsy, 510
unilateral, internuclear ophthalrnoplegia and.
See One-and-a-half syndrome
Horizontal gaze holding, 203-204
Horizontal saccades
back-to-back, pathophysiology of, 133
burst neurons for, 103-104
failure of, disorders associated with, 547
models for, 106-107, 108f
slow, pathophysiology of, 131, 132
Horizontal semicircular canals, 33-34
Horizontal smooth pursuit
anatomical scheme for, 235f
asymmetric impairment of, 181-182, 182f-183f, 184
Horizontal strabismus, 349-350
Human immunodeficiency virus. See HIV/AIDS
Huntington's disease, 53Id
antisaccades in, 532f
clinical findings in, 531-532
diagnosis of, 533
pathogenesis of, 532-533
saccade initiation in, 132-133
Hydrocarbons, exposure to, 563
Hydrocephalus
dorsal midbrain syndrome and, 518
obstructive, pretectal pseudobobbing and, 442
trochlear palsy and, 359
Hypermetric saccades, 97, 132
in myasthenia gravis, 376f, 377, 378
Hyperosmolar coma, opsoclonus and, 454-455
Hypertension, oculomotor nerve infarction and, 365
Hypertropia
defined, 322t
skew deviation and, 463
Hyperventilation, nystagmus caused by, 62,
412-414, 413f
Hypometric saccades, 97, 13If, 132
Hypotropia, skew deviation and, 464. See also Ocular
tilt reaction
IBN (inhibitory burst neurons), 104
Immunoadsorption therapy, for opsoclonus, 459
Immunoglobulin therapy, for opsoclonus, 459
INC. See Interstitial nucleus of Cajal
Incyclodeviation, defined, 322t
Infant(s). See also Children
ocular motor abnormalities in, 558-559, 560
Infections, acute vertigo caused by, 467-468
Inferior cerebellar artery, infarction in the distribu-
tion of, 487, 48 7f, 496
Inferior oblique muscle, 323-324, 324t
overactivity of, 323-324, 324t
paralysis of, 363
Inferior olivary nucleus, 228
oculopalatal tremor and, 439, 483
Inferior parietal lobule, gaze control and, 238, 239
Inferior pulvinar, gaze control and, 241-242
Inferior rectus muscle, 323, 324t, 326
paralysis of, 363
Inferior vestibular nerve, 25
Inferior vestibular nucleus, 31, 32
Inflammatory disorders, recurrent vertigo and,
468t, 471
Infrared differential limbus reflection technique,
614,615
Inhibitory burst neurons, 104
Inner ear disease, recurrent vertigo and, 471
Intermittent deviation, in unconscious patients, 551
Intermittent exotropia, 290
Internal auditory artery, 24-25
Internal medullary lamina, saccade generation and,
119
Internuclear ophthalrnoplegia, 7, 503d, 502-509
bilateral, 508
clinical features of, 503
etiology of, 503-504, 504t, 505f
horizontal conjugate eye movements and, 221
multiple sclerosis and, 556-557
pathogenesis of, 504, 505f, 506-509, 506f
pseudo-, myasthenia gravis and, 375
saccadic abnormalities in, 13If
saccadic adaptation after, 125
skew deviation and, 465, 507-508
unilateral conjugate gaze palsy and. See One-and-
a-half syndrome
variants of, 508-509
vergence eye movements and, 298, 507
Interstitial nucleus of Cajal, 32f, 226d
gaze holding and, 205-206, 223, 225-226
gaze-evoked nystagmus and, 428, 429
jerk seesaw nystagmus and, 426
lesions of, 225-226, 516d, 516-517
ocular tilt reaction and, 223, 225
skew deviation and, 465
vertical and torsional saccades and, 105
Intracavernous aneurysm, oculomotor nerve and,
365
Intralaminar thalamic nuclei
gaze control and, 246d
lesions of 527d
Inverse ocular bobbing, 552t, 553
Inverse optokinetic responses, 186
"Inversion" of smooth pursuit, 186
Irritative nystagmus, in Meniere's syndrome, 470
Ischemia, brain stem
horizontal gaze palsy and, 502
positional vertigo and, 477
vertical gaze palsy and, 519t
Isoniazid, for acquired pendular nystagmus, 458
Jerk nystagmus, 407, 426, 428, 428t
Joubert's syndrome, 492, 558t
Kearns-Sayre syndrome, 380-381, 38It
Kernicterus, 558t
Kinocilium, 24
Koeber-Salus-Elschnig syndrome, 517

Korsakoff 's syndrome, 559
Krabbe's leukodystrophy, horizontal saccade failure
and,547
Laboratory evaluation
of eye-head movements, 273-274, 279f
of smooth pursuit, 179-180
of vestibular and optokinetic function, 63-67, 64t
Labyrinth, vestibular
function of, acute unilateral loss of, 466-467, 467d
lesions of
bilateral, 70
mechanisms of recovery from, 51-53
unilateral, 67-70
membranous
blood supply of, 24-25
innervation of, 25
structure of, 24, 26f
Labyrinthine artery, 24
Lambert-Eaton myasthenic syndrome, 373-374
Lancaster red-green test, 339-340
Latent nystagmus, 446d
clinical features of, 445-446
pathogenesis of, 446-447
smooth pursuit and, 182, 185-186
treatment of, 462
Lateral canal variant of BPPV, 475-476
Lateral semicircular canals, 33-34
Lateral intraparietal area
gaze control and, 240
vergence eye movements and, 299
Lateral medullary infarction. See Wallenberg's syn-
drome
Lateral pulvinar, gaze control and, 241-242
Lateral rectus muscle, 323, 324t, 326, 328f
Lateral suprasylvian area, vergence eye movements
and,299
Lateral thalamic nucleus, ventroposterior, vestibular
sensation and, 57
Lateral vestibular nucleus, 31
lesions of, nystagmus and, 71
Lateropulsion, in Wallenberg's syndrome, 124,
484-485, 536
Leaky neural integrator, 201, 202f, 429d
cerebellum and, 206-207, 206f
Leber's congenital amaurosis, 433, 434f-435f
Leigh's syndrome, 558t, 559-560
Lentiform nucleus, lesions of, 533
Lermoyez syndrome, recurrent vertigo in, 470
Lesch-Nyhan disease, 533-534
horizontal saccade failure and, 547
Levator palpebrae superioris, 126-127, 328
Lewy-body disease, 531
Lid nystagmus, 308, 449, 486. See also Eyelid entries
Light-near dissociation, 518
LIP neurons, saccade generation and, 118
Listing's law, 13, 109, 290, 326-327
Listing's plane, 325f, 326
Lithium carbonate, 561, 562t
Lithium intoxication, 430, 549
Local-feedback model, for saccades, 107, 108f
Locked-in syndrome, eye movements during, 554
Long-lead burst neurons, 105-106
Look nystagmus, 98
Index 627
Louis-Bar syndrome (ataxia telangiectasia), 558t
Lutz, posterior internuclear ophthalmoplegia of,
508-509
Lyme disease, recurrent vertigo and, 471
Lytico-Bodig syndrome, 530
Machado-Joseph disease, 494t
Macrosaccadic oscillations, 133, 450d, 451, 451f,
452f-453f
myasthenia gravis and, 375, 376f, 378
treatment of, 459
Macrosquare-wave jerks, 450d, 451, 45If
Maculae, 24, 26f, 28
otolith, physical properties of, 28, 27f
Maddox rod test, 339, 339f
Magnetic resonance imaging, internuclear ophthal-
moplegia and,504, 505f
Magnetic search coil technique, 129, 409, 614, 615
Main sequence relationship, for saccades, 91
Mai de debarquement, 472
Maple syrup urine disease, 558t
Marcus Gunn jaw winking, 554
Mastoid vibration, 62, 412, 466
Measles, acute vertigo caused by, 467
Medial longitudinal fasciculus, 217d
horizontal conjugate eye movements and, 216,
216f, 217, 218f
lesions of, 221, 227, 502-509, 503d, 504t, 505f-
506f
bilateral, 508
combined, 509-510
oscillopsia and, 481
rostral interstitial nucleus of. See Rostral interstitial
nucleus of medial longitudinal fasciculus
vergence eye movements and, 297-298
Medial rectus muscle, 323, 324t
Medial superior temporal visual area, 237d
gaze control and, 234, 235f, 236-237, 236f
lesions of, 234, 236, 538d, 539
smooth pursuit and, 167-169
vergence eye movements and, 299—300
Medial vestibular nucleus, 3It, 32f, 33
disease of, 482-483
gaze holding and, 203-205, 205f-206f
gaze-evoked nystagmus and, 428, 429
lesions of, 71,221
Wernicke's encephalopathy and, 559, 560f
Medication(s)
downbeat nystagmus and, 415, 415t
effects on eye movements of, 561-562, 562t-563t
gaze-evoked nystagmus and, 430
for nystagmus, 456-459, 457t
opsoclonus and, 454-455
Medullary lesions
nystagmus and, 420, 482-483
ocular motor syndromes caused by, 482-487
Medulloblastoma, 497
MELAS, 381
Memantine, for acquired pendular nystagmus,
458-459
Membranous labyrinth
blood supply of, 24-25
innervation of, 25
structure of, 24, 26f
628 Index

Memory-guided saccades Motion in depth, stimuli for, 289

accuracy of, 97-98 Motor correspondence, law of, 336
efference copy and, 98 MPTP (methyl-r-phenyl-1,2,3,6-tetrahydropyri-
frontal lobe lesions and, 54Id, 542 dine), parkinsonism caused by, 530
thalamic lesions and, 528 MRI (magnetic resonance imaging), internuclear
Meniere's syndrome, vertigo and, 469, 470 ophthalmoplegia and, 504, 505f
Meningeal processes, oculomotor nerve and, 364 MST (medial superior temporal visual area), 237d
Meningioma, abducens nerve and, 355 MT (middle temporal visual area), 237d
MERRF, 381 Multiple ocular motor nerve palsies, 368-373, 369t
Mesencephalic reticular formation. See also Central Multiple sclerosis
mesencephalic reticular formation acquired pendular nystagmus with, 437
eye-head saccades and, 270 ocular motor apraxia in, 543-544, 544f-545f
saccadic intrusions and, 455 ocular motor dysfunction and, 556-558
vergence eye movements and, 296-298, 297f internuclear ophthalmoplegia and, 504
Mesencephalon. See Midbrain positional vertigo and, 477
Metabolic disorders, ocular motor manifestations of, Mumps, acute vertigo caused by, 467
558-561,558t Muscimol
Metabolic encephalopathy, ocular bobbing and, 553 gaze holding and, 203
Metastatic tumor deposits, restrictive ophthal- saccadic eye movements and, 114
mopathy in, 383 vestibular eye movements and, 457
Methadone, 562, 563t Muscle(s). See Extraocular muscle(s); specific muscle
Methyl-r-phenyl-l,2,3,6-tetrahydropyridine Muscle-paretic nystagmus, 377
(MPTP), parkinsonism caused by, 530 Muscular dystrophies, extraocular muscles in,
M-group of neurons 379-380
in eyelid movements, 127 MVN. See Medial vestibular nucleus
vertical eye movements and, 227-228 Myasthenia gravis
Microflutter, 452-453, 452f-453f adaptation and, 377-378
Microsaccades, suppression of, 153 clinical features of, 374-375, 375t, 376f
Microvascular decompression, for recurrent vertigo, diagnosis of, eye movements and, 378-379
472-473 ocular motor findings in, 374-375, 375t
Midbrain. See also specific structures, e.g., Interstitial pathophysiology of, 375-378
nucleus of Cajal saccades and, 130, 375, 377, 378
burst neurons in, for saccades, 104-105 sleep test, 374
dorsal midbrain syndrome, 517t treatment of, 379
hemorrhage of, vertical gaze palsy with, 518-519, Myasthenic (Lambert-Eaton) syndrome, 373
520f-521f Myoclonus
lesions of oculopalatal, acquired pendular nystagmus and,
convergence nystagmus and, 441 438, 439, 440f, 483
ocular motor syndromes caused by, 511-526 opsoclonus-, 453
skew deviation and, 465 vertical, 552t, 553-554
paramedian, 520 Myopathies, congenital, 380
periaqueductal gray matter of, 227, 519-520 Myotonic dystrophy, 380
selective cell vulnerability in, 521-526, 524f-525f Myotubular myopathy, 380
Midbrain paresis of horizontal gaze, 520
Middle cerebellar peduncle, torsional nystagmus
and,491
Middle ear infection, acute vertigo and, 468 Narcotics, 562, 563t
Middle temporal visual area, 237d Nasal-temporal asymmetry
gaze control and, 234, 235f, 236-237, 236f of optokinetic response, 173
lesions of, 234, 236, 538d, 539 smooth pursuit and, 182
smooth pursuit and, 164, 166f-167f, 167 Near cells, 299
vergence eye movements and, 299-300 Near triad, 290-291
Migraine defined, 288t
ophthalmoplegic, 363 spasm of, 308-309
recurrent vertigo and, 470, 471 Negative feedback control systems, for smooth pur-
Millard-Gubler syndrome, 355 suit, 174-177, I75f
Miller Fisher syndrome, 371-372 Neostigmine test, in myasthenia gravis, 378
Mitochondrial DNA disorders, progressive external Neural crest tumors, opsoclonus and, 453-454
ophthalmoplegia and, 380-381 Neural integrator, 7
MLF. See Medial longitudinal fasciculus abnormalities of, 209-211
Mobius syndrome, 353 centripetal nystagmus and, 210, 429d
Monocular diplopia, 337 gaze-evoked nystagmus and, 208-209, 429d
Monocular eye movements, in unconscious patients, instability, 210
552t, 554 pathogenesis of, 209-210
Monocular nystagmus, 433 rebound nystagmus and, 210-211
Mononucleosis, acute vertigo caused by, 467 gaze holding and, 203-208, 205f-206f
 Index 629

leaky, 201, 202f, 429d Nucleus reticularis tegmenti pontis, 220f

cerebellum and, 206-207, 206f long-lead burst neurons in, 106
neural coding of ocular motor signal and, saccade generation and, 121-122, 123f, 231
199-20 l,200f smooth pursuit and, 170
neural network as, 207-208 vergence eye movements and, 298-299
quantitative aspects of, 201-203, 202f Nystagmus
time constant of, 201-202, 202f abduction, 506-507
vergence eye movements and, 300-301 Alexander's classification of, 209, 412
Neural network, as neural integrator, 207-208 apogeotropic, 475, 476
Neuroacanthocytosis, 533 bow-tie, 417, 419f
Neuroblastoma, opsoclonus and, 454 Bruns',431
Neurogenetic disorders, ocular motor manifesta- caloric-induced, 64-65
tions of, 558t centripetal, 210, 429, 429d, 431
Neuromuscular junction disorders, 373-379 cerebellum and, 491
botulism, 373, 374f congenital. See Congenital nystagmus
Lambert-Eaton myasthenic syndrome, 373-374 convergence and, 307-308
myasthenia gravis, 374-379, 375t, 376f convergent-divergent forms of, 439, 441-442
Neuromuscular transmission, failure of, in myasthe- cross-coupling of, 60-61
nia gravis, 375-377 cyclovergence, 441
Neurons. See specific type of neuron, e.g., Ocular defined, 407
motoneurons dementia and, 549
Neuropathy(ies) diagnosis of, pathophysiological approach to,
chronic relapsing, 372 409-411
ischemic, trochlear nerve palsy and, 359 direction-changing, 62
ophthalmoplegia caused by, 371-372 direction-fixed, 62
Neurotransmitters/neuropeptides, in vestibular disconjugate, 408
adaptation, 56 dissociated, 408, 506-507
Newborns, ocular motor abnormalities in, 558-559 divergence, 308, 42If
Nicotine, 563-564, 563t downbeat. See Downbeat nystagmus
Niemann-Pick disease, 558t, 559 end-point, 209, 407, 430-431, 430d
Nodulus, 231d in epileptic seizures, 547
lesions of, 55, 70, 230-231, 488, 488d, 489 examination of, 408-409
tilt-suppression testing of, 67 fatigue, 375, 377,431
velocity storage and, 230 first-degree, 412
Nonconcomitant deviation, defined, 322t fixation and, 59-60, 180-181
Nonconcomitant strabismus, 339 gaze-paretic, 208, 428-429
dynamic properties of, 346-348, 348f-349f geotropic, 475, 476
nonparalytic versus, 344 head. See Vestibulocollic reflex
Nontwitch muscle fibers, 327 head-shaking, 60-61,412
Nothnagel's syndrome, 364 hemi-seesaw, 426, 428, 428t, 435
NPH. See Nucleus prepositus hypoglossi hemispheric lesions and, 432d, 536-537
Nucleus. See named nucleus(i) history-taking in, 407
Nucleus incertus, gaze control and, 229 horizontal
Nucleus intercalatus, upbeat nystagmus and, 482 central vestibular, 421, 423f
Nucleus of fields of Forel. See Rostral interstitial nu- hemispheric lesions and, 432d, 435-436
cleus of medial longitudinal fasciculus hyperventilation-induced, 62, 412-414, 413f
Nucleus of optic tract irritative, 470
latent nystagmus and, 185, 446 jerk, 407, 426, 428,428t
optokinetic response and, 173 latent. See Latent nystagmus
smooth pursuit and, 172-173 lid, 308, 449, 486
Nucleus of prerubral fields. See Rostral interstitial look, 98
nucleus of medial longitudinal fasciculus measurement of, 409, 41 Of
Nucleus pararaphales, gaze control and, 228-229 medullary lesions and, 420, 482-483
Nucleus prepositus hypoglossi, 33 monocular, 433
disease of, 482-483 muscle-paretic, 377
gaze holding and, 203-205, 205f-206f nature of, 407
gaze-evoked nystagmus and, 428, 429 occlusion. See Latent nystagmus
lesions of, 221 optokinetic. See Optokinetic nystagmus
downbeat nystagmus and, 424 oscillopsia and, 482
nystagmus and, 71 pathological, 407
principal connections of, 203, 204t pendular. See Pendular nystagmus
Wernicke's encephalopathy and, 559, 560f periodic alternating, 70, 345, 424-426, 425d,
Nucleus raphe interpositus, omnipause neurons in, 425t, 458
forsaccades, 104, 218f per-rotational, 25
Nucleus reticularis gigantocellularis, eye-head sac- physiologic, 209, 407, 430-431
cades and, 218f, 269 positional, 61-62, 477, 479
630 Index
Nystagmus (continued).
positional vertigo and, 68, 412, 473-474
positioning, 61, 474, 474f, 475
postrotational, 25
tilt-suppression of, 67
quick phases of. See Quick phases
rebound, 210-211, 429, 429d, 429f, 431
recovery, 61,69,470
reversal phases of, VOR adaptation and, 49
saccadic intrusions versus, 407
saw-tooth pattern of, 41 Of, 411
second-degree, 412
seesaw. See Seesaw nystagmus
slow phase of, 409, 41 Of
sound-induced, 62, 414f
spontaneous. See Spontaneous nystagmus
stare, 98
third-degree, 412
torsional. See Torsional nystagmus
treatment of, 456, 457t
auditory or somatosensory stimuli in, 463
botulinum toxin in, 460f-461f, 462
optical, 459, 461-462
pharmacologic, 456-459, 457t
surgical, 462-463
unidirectional, 412
upbeat. See Upbeat nystagmus
vertical, 422, 441,508
vestibular. See Vestibular nystagmus
vestibular nuclei lesions and, 70-71
visual consequences of, 407
visual system disorders and, 432-439, 432d, 434f-
435f
voluntary, 455
Wallenberg's syndrome and, 71, 420
windmill, 426
Nystagmus blockage syndrome, 444, 445
Oblique muscles. See also Extraocular muscle(s)
actions of, 323-324, 324t
inferior
overactivity of, 323-324, 324t
paralysis of, 363
paralysis of, diagnosis of, 343
superior. See Superior oblique muscle
Oblique myokymia, superior, 359-361, 360f
Oblique saccades, 94, 95f, 107, 109
Occipital lobe, lesions of, 173, 234, 537-538
Occipitotemporoparietal junction, smooth pursuit
and, 168
Occlusion, diagnostic, 342
Occlusion nystagmus. See Latent nystagmus
Ocular alignment
disorders of, cerebellar disease causing, 491
maintenance of, adaptive mechanisms for,
302-306, 303f, 305f
Ocular bobbing, 552t, 553, 553f
Ocular counterrolling, 20t, 21, 22
Ocular dipping, 552t, 553
Ocular flutter, 450d, 45If, 452, 452f-453f
etiology of, 454t
oscillopsia and, 482
pathogenesis of, 455-456
pathophysiology of, 133
with pontine lesions, 511
treatment of, 459
Ocular motor apraxia
acquired, 542-544, 544f-545f
congenital, 544-547, 546f
quick phases and, 98-99
eye-head coordination in, 277-278
saccadic abnormalities in, 132
vertical, 547
Ocular motor examination, 611-613. See also Clinical
examination
Ocular motor nerve palsies. See also specific type, e.g.,
Abducens nerve palsy
differential diagnosis of, 35It
laboratory evaluation of, 35It
multiple, 368-373
brain stem lesions and, 369, 369t
carotid cavernous fistula and, 370
cavernous sinus and superior orbital fissure syn-
dromes and,369-370, 369t
etiology of, 369t
head trauma and, 371
Tolosa-Hunt syndrome and, 370-371
neuropathies causing, 371-372
saccadic adaptation after, 124-125
Ocular motoneurons
discharge properties of
during convergence, 296, 296f
during fixation and smooth pursuit, 200, 200f
during saccades, 296, 296f
during saccades, pulse-step innervation of, 6-7, 7f,
102-103
Ocular motor range, 266
restricted, eye-head movements in, 278
Ocular motor signal, neural coding of, 199-201,
200f
Ocular neuromyotonia, 372-373
Ocular oscillations, congenital, nature of, 442
Ocular tilt reaction, 69, 275-276. See also Skew devi-
ation
clinical features of, 463-464, 464f
defined,463
interstitial nucleus of Cajal and, 223, 225
jerk seesaw nystagmus and, 426
pathogenesis of, 464
topologic diagnosis of, 464-465
Tullio phenomenon and, 464
Wallenberg's syndrome and, 486
Ocular-following response, 24
Oculocephalic maneuver, 554
Oculogyric crisis, 531
Oculomasticatory myorhythmia (Whipple's disease),
308, 526
convergent-divergent pendular oscillations and,
441
Oculomotor fascicles
anatomy of, 334-335
disorders affecting, 362t, 363-364
Oculomotor internuclear neurons
pharmacologic inactivation of, 362-363
vergence eye movements and, 297-298
Oculomotor nerve
aberrant regeneration of, 367-368
anatomy of, 333-336, 333f, 334f-335f
cavernous portion of, disorders affecting, 362t,
365, 366f-367f
 Index 631

compression of, at tentorial edge, 362t, 364-365 Opsoclonus-myoclonus, 453

infarction of, 365-367 Optic chiasm lesions, seesaw nystagmus and, 427,
inferior division of, 335-336, 368 432d,435
subarachnoid portion of, disorders affecting, 362t, Optic nerve disease, nystagmus and, 432d, 433,
364 434f-435f, 435
superior division of, 335, 368 Optic system, accessory, smooth pursuit and, 172,
superior orbital fissure of, disorders affecting, 173
352t, 362t, 369-370, 369t Optic tract, nucleus of
Oculomotor nerve palsy latent nystagmus and, 185, 446
clinical features of, 361 optokinetic response and, 173
congenital, 363 smooth pursuit and, 172-173
with cyclic spasms, 363 Optical devices, for nystagmus, 459, 461-462
etiology of, 362t Optokinetic, defined, 11
laboratory evaluation of, 35It Optokinetic after-nystagmus, 20t, 46-47
management of, 368 labyrinthine lesions and, 72
nuclear, 361-363, 362t loss of, 69
orbital, 362t measurement of, 47, 66
partial, 368 neurophysiological correlate for, 36
pupil-sparing, 364 reversal phase of, 49
trauma-induced, 367 velocity storage and, 35
Oculomotor nucleus Optokinetic function
anatomy of, 333-335, 334f-335f clinical examination of, 57-63, 59t, 613
paralysis of, 361-363, 362t laboratory evaluation of, 64, 64t
Oculopalatal tremor (myoclonus), acquired pendu- Optokinetic nystagmus, 20t, 46, 407
lar nystagmus and, 438, 439, 440f, 483 direct component of, 24
Oculopharyngeal dystrophy, 380 gain of, 46
Off-vertical axis rotation (OVAR) peripheral vestibular disease and, 58
defined, 20t visual system lesions and, 58
dynamic otolith imbalance and, 69 Optokinetic responses
irregular otolith afferents and, 29 with cortical lesions, 536t
velocity storage and, 35 inversion of, 186
OKAN. See Optokinetic after-nystagmus nasal-temporal asymmetry of, 173
OKN. See Optokinetic nystagmus neural substrate for, 36-37, 37f
Olivary nucleus, inferior, 228 Optokinetic system, 9-10, 9f. See also Vestibular-op-
oculopalatal tremor and, 439, 483 tokinetic system
Olivopontocerebellar degeneration, slow saccades disorders of, 72
and,511 as supplement to vestibulo-ocular reflex, 23
Omnipause neurons Orbicularis oculi muscle, in blinks, 127, 127f
for saccades, 104, 105, 106f, 219d Orbital blowout fracture, 371
saccadic oscillations and, 134, 511 Orbital fascia, anatomy of, 323-325, 324f
vergence and, 294, 294f Orbital fibers, 329
One-and-a-half syndrome, 221, 509d, 509-510 Orbital fissure, superior, disorders affecting, 352t,
Ophthalmopathy(ies) 362t, 369-370, 369t
restrictive, 381-383 Orbital mechanics, 6-7, 7f, 199, 200f
thyroid, 381-383, 382f Orbital myositis, 371,383
Ophthalmoplegia Orbital location of ocular motor nerve palsies, 352t,
brain stem lesions causing, 369, 369t 362t, 369t
chronic progressive external, 379-381, 379t Orbital oculomotor nerve palsy, 362t
head trauma and, 371 Orbital pseudotumor, 383
neuropathies causing, 371-372 Orthophoria, defined, 322t
painful, Tolosa-Hunt syndrome and, 370-371 Orthotropia, defined, 322t
thiamine deficiency and, 559 Oscillations
Ophthalmoplegia plus, 379 head, congenital nystagmus and, 444
Ophthalmoplegic migraine, 363, 371 macrosaccadic. See Macrosaccadic oscillations
Ophthalmoscopy, 614 ocular, congenital, 442
static vestibular imbalance and, 59-60 pendular, convergent-divergent, 441
vestibular gain abnormalities and, 63 saccadic. See Saccadic oscillations
Opsoclonus, 450d, 452, 452f-453f square-wave, 451. See also Square-wave jerks
cancer and,453,454 vergence, 308
etiology of, 453, 454t Oscillopsia, 479-482
oscillopsia and, 482 abnormal eye movements and, 482
pathogenesis of, 455-456 abnormal VOR and, 480-481
pathophysiology of, 133-134 defined,20t
with pontine lesions, 511 etiology of, 479-480, 480t
sustained, 453 extraocular muscle paresis and, 481-482
treatment of, 459 head movements and, 275
632 Index
Oscillopsia (continued).
history-taking, 59
internuclear ophthalmoplegia and, 508
labyrinthine functional loss and, 70, 480-481
Ossicular chain abnormalities, ocular tilt reaction
and,464
Otoconia, 24, 473, 476-477
Otolith afferents, 29
Otolith connections, central, lesions of, 71
Otolith imbalance, skew deviation and, 71, 464. See
also Ocular tilt reaction
Otolith maculae, physical properties of, 28-30, 27f
Otolith organs. See also Saccule; Utricle
hemorrhage of, recurrent vertigo and, 472
mechanism of action of, 28
translational VOR and, 9
Otolithic debris, 473, 476-477
Otolithic imbalance
dynamic, 69
unilateral vestibular disease and, 69
Otolithic input, central imbalance of, vertical nystag-
mus and,422
Otolith-ocular reflex(es)
adaptive properties of, 51
static, 22
testing of, 66-67
vestibular commissure in, 35-36
Otosclerosis, recurrent vertigo and, 470-471
Ototoxicity, 481
OTR. See Ocular tilt reaction
Oval window fistula, vertigo and, 469
OVAR. See Off-vertical axis rotation
Overlap stimulus, saccades made to, 95-96
Palatal myoclonus, essential rhythmic, 439
Palisade tendon organs, extraocular proprioception
and,329
Panum's area, 287, 289
Parafloccullus(i), 230d
compression of, 497
gaze control and, 228-231
gaze holding and, 206
lesions of, 55, 71, 171, 230, 487-489, 488d
smooth pursuit and, 171
VOR adaptation and, 53-56, 55f
Paralytic pontine exotropia, 509
Paralytic strabismus, defined, 322t
Paramedian artery, thalamosubthalamic, posterior,
infarction of, 513-514
Paramedian midbrain lesions, 520
Paramedian pontine reticular formation, 219d
burst neurons in, for horizontal saccades, 103-104
eye-head saccades and, 269-270
horizontal conjugate eye movements and, 217,
218f, 219
lesions of, 221, 498-502, 499d, 500f-501f
Paramedian tracts cell groups of, 31, 219d
gaze control and, 228-229
horizontal conjugate eye movements and, 217,
218-219
upbeat nystagmus and, 424, 482-483
Paraneoplastic cerebellar degeneration, 496
Parasellar tumors, seesaw nystagmus and, 427, 435
Parasites, restrictive ophthalmopathy with, 383
Parietal eye field, 24Id
gaze control and, 240-241
lesions of, 118, 240-241, 540d
projections of, 248
saccade generation and, 118
Parietal lobe, 239d, 24Id
gaze control and, 236f, 238-241
lesions of, 539-540, 540d
saccade generation and, 117-118
Parieto-insular-vestibular cortex, 238d
lesions of, 538d, 539
vestibular sensation and, 57
Parinaud's syndrome, 517
Parkinsonism, conditions causing, 530-531
Parkinson's disease, 276, 525
clinical features in, 528, 529d
saccadic abnormalities in, 528-529
smooth pursuit in, 529-530
treatment of, ocular effects of, 530
visuovestibular interactions in, 530
Paroxysmal vertigo, benign
of childhood, 471
positional. See Benign paroxysmal positional ver-
tigo
Past-pointing, strabismus and, 345
Pediatric patients. See Children; Infant(s)
Pedunculopontine pathway, 247-248
Pelizaeus-Merzbacher disease, 437, 558t, 560
Pendular nystagmus, 181, 407, 410, 41 Of
acquired, 436-439, 438d
clinical features of, 436-437, 436f, 438
with demyelinative disease, 437, 438
oculopalatal tremor and, 438, 439, 440f
oscillopsia and, 482
treatment of, 458-459
Whipple's disease and, 438
etiology of, 437t
Pendular oscillations, convergent-divergent, 441
Periaqueductal gray matter, 227, 519-520
Perilymph fistula
ocular tilt reaction and, 464
vertigo and, 469
Periodic alternating gaze deviations, 552t, 554
Periodic alternating nystagmus, 70, 345, 424-426,
425d, 425t, 458
Peripheral vestibular nystagmus, 411-415, 413f,
414f, 466
Peripheral vestibular system
anatomy and physiology of, 24-29, 26f-28f
disorders of
acute, clinical features of, 466-467
ocular tilt reaction in, 464
optokinetic system and, 58, 72
oscillopsia in, 479-482
pathophysiology of, 67-70, 68t
vertigo and dizziness in, 465-466. See also Ver-
tigo
Peristriate cortex, gaze control and, 234, 235f,
236-237, 236f
Peroxisomal assembly disorders, horizontal saccade
failure and, 547
Per-rotational nystagmus, 25
Perverted vestibular nystagmus, 421
Phase, defined, 20t
Phasic innervation, 6-7
Phencyclidine, 563t

Phenobarbital, 562t
Phenothiazines, 562t
Phenytoin, 561,562t
Phoria
cover test for, 340f, 341
defined, 288t, 322t
vertical, 350
Phoria adaptation, 302-303, 303f
anisometropia and, 304-306, 305f
Photoelectric eye tracking methods, 614, 615
Physiologic nystagmus, 209, 407
Physostigmine, nystagmus and, 458
Pick's sign, 449
Pineal tumors, dorsal midbrain syndrome and,
518
Ping-pong gaze, 552t, 554
periodic alternating nystagmus versus, 424
Pitch, head rotations in, 263, 263f, 264, 265
Pituitary apoplexy, 365, 366f-367f
Pituitary tumors, seesaw nystagmus and, 435
Plus-minus lid syndrome, nuclear oculomotor palsy
and, 361
PMT. See Paramedian tracts
Pons. See also Paramedian pontine reticular forma-
tion
descending pursuit pathway to, smooth pursuit
and,170, 235f
disease of
ocular motor syndromes caused by, 497-511
slow saccades with, 510-511, 510t
horizontal saccades and, 103
lesions of
bilateral, 502
ocular bobbing and, 553
saccadic oscillations with, 511
selective cell vulnerability in, 510-511, 510t
Pontine exotropia, paralytic, 509
Pontomedullary burst neurons, for saccades, 104
Position. See also Eye position; Head position
primary, 322t
secondary, 322t
Positional nystagmus, 61-62, 477, 479
Positional testing, 61-62
Positional vertigo
etiology of, 468t, 473-477, 479
nystagmus and, 68, 412, 473-474
paroxysmal, benign. See Benign paroxysmal posi-
tional vertigo
Positioning nystagmus, 61, 474, 475
Position-vestibular-pause cells, 33, 226
eye-head pursuit and, 272
Posterior canals, 33, 34
Posterior cerebellar vermis, lesions of, 232
Posterior commissure, 226d
lesions of, 223, 518d
vertical gaze palsies and, 517-519, 5l7t
nucleus of
lesions of, 517
vertical gaze holding and, 227
vertical gaze holding and, 223, 226, 227
Posterior communicating aneurysm, oculomotor
nerve and, 365
Posterior cortical areas, 237d
lesions affecting, 538d
circularvection and, 539
nystagmus and, 432d
Index 633
voluntary control of eye movements and, 234-237,
235f, 236f
Posterior fastigial nucleus. See Fastigial oculomotor
region
Posterior fossa tumor, recurrent vertigo and,
472
Posterior inferior cerebellar artery, infarction in the
territory of, 496. See also Wallenberg's Syn-
drome
Posterior internuclear ophthalmoplegia of Lutz,
508-509
Posterior interposed nucleus, vergence eye move-
ments and,298
Posterior occipitotemporal cortical areas, lesions of,
537-539
Posterior parietal cortex, 239d
gaze control and, 236f, 238-240
lesions of, 117-118,239-240,528
saccade generation and, 117-118
smooth pursuit and, 169
Posterior temporal lobe, 57, 238d
gaze control and, 236f, 237-238
lesions of, 538d, 539
Posterior thalamosubthalamic paramedian artery, in-
farction of, 513-514
Posterior vestibular artery, 25
Postrotational nystagmus, 25
tilt-suppression of, 67
Postsaccadic drift, 93-94, 97, 130, 131f
Postsaccadic suppression, acquired pendular nystag-
mus and,437
Postural instability
acute peripheral vestibulopathy and, 466
Meniere syndrome and, 470
PPRF. See Paramedian pontine reticular formation
Predictable target motion, smooth pursuit responses
during, 158-159, 162f-163f, 163
Prefrontal cortex, lesions of, memory-guided sac-
cades and, 98
Premotor burst neurons, for saccades, 104-105
Premotor commands, for vergence eye movements,
296-298, 297f
Presbyopia, visual complaints associated with,
306
Pretectal pseudobobbing, 307, 442
Pretectal syndrome, 517
Prevost's sign, 534
Primary deviation, 341
defined,322t
pathophysiology of, 344-345
Primary position, defined, 322t
Primary visual cortex, 237d
gaze control and, 234, 235f, 236f
lesions of, 537-539, 538d
smooth pursuit and, 164
Prism adaptation. See Phoria
Prism diopter, defined, 288t
Prisms
alternate cover test with, 342
for nystagmus, 459, 461
reversing, VOR adaptation to, 49-50
Progressive external ophthalmoplegia, 379-381,
379t
Progressive supranuclear palsy, 522d
clinical features of, 521-523, 524f-525f
differential diagnosis of, 525
634 Index

Progressive supranuclear palsy (continued). progressive supranuclear palsy and, 512, 524f-
head nystagmus in, 276 525f
neuropathologic findings in, 523 Wallenberg's syndrome and, 485
ocular motor findings in, 523, 524f-525f, 525 Quiver movement, in myasthenia gravis, 375, 377
saccadic abnormalities in, 133
slow saccades in, 510
treatment of, 525
Propranolol, for saccadic oscillations, 459 Raeder's paratrigeminal syndrome, 371
Proprioception, extraocular, spatial localization and, Rapid gaze shifts. See Gaze, rapid changes in
14,329-331 Rapid head turns. See Head thrusts
Proprionic acidemia, horizontal saccade failure and, Rashbass stimulus, smooth pursuit and, 154f-155f,
547 158,159-160, 179, 181
Prosaccades, 96-97 Raymond's syndrome, 355
Proximity of targets, vergence eye movements and, Reading, saccades during, 100-101
287 Rebound nystagmus, 210-211, 429, 429d, 429f, 431
Pseudo-abducens nerve palsy, 307, 442, 518 Reciprocal innervation, law of, 336
Pseudobobbing, pretectal, 307, 442 Recovery nystagmus, 61, 69, 470
Pseudo-horizontal gaze palsy, 510 Rectus muscles
Pseudo-internuclear ophthalmoplegia, myasthenia actions of, 323, 324t
gravis and, 375 inferior, 323, 324t, 326
Pseudorandom chair rotations, 65 paralysis of, 363
Pseudotumor, orbital, 383 lateral, 323, 324t, 326, 328f, 345, 353
Psychiatric illness, eye movement disorders in, medial, 323, 324t
550-551 pulleys of, 324-325, 324f
Psychogenic flutter, 455 superior, 323, 324t, 326
Ptosis Red glass test, 339
myasthenia gravis and, 374 Red-green test, 339-340
nuclear oculomotor palsy and, 361, 362 Reflex(es)
Pulleys, 324-325 cervicocollic, 265
Pulse dysmetria, 97, 130 cervico-ocular, 47-48, 267-268, 415
Pulse-step mismatch, in internuclear ophthalmople- field-holding, 153
gia, 504, 505f otolith-ocular. See Otolith-ocular reflex(es)
Pulse-step mismatch dysmetria, 97, 130, 131f sacculocollic, 67
Pulse-step of innervation, 6-7, 7f, 200 vestibulocollic. See Vestibulocollic reflex
Pulse-step-slide of innervation, 102-103, 103f vestibulo-ocular. See Vestibulo-ocular reflex
Pulvinar, 24Id vestibulosaccadic, 268
gaze control and, 241-242 visual grasp, 549
lesions of, 119, 242, 527d, 528 Reflex eye movements, in unconscious patients,
saccade generation and, 119 554-556, 555f
Pupillary constriction, near triad and, 291 Reflexive saccades, 911
Pupil-sparing oculomotor nerve palsy, 364 Relapsing neuropathies, chronic, 372
Purkinje cells. See also Cerebellum Repetitive divergence, 308
of dorsal vermis, 122 Restiform body, Wallenberg's syndrome and, 487
of flocculus, 230 Restrictive ophthalmopathies, 381-383
Purkinje image tracker, 614t, 615-616 congenital fibrosis of extraocular muscles and,
Pursuit gain 383
closed-loop, 174, 175f Retina
high,178 disorders of, nystagmus and, 433, 434f-435f
low, 178, 182 image motion on, visual acuity and, 5
measurement of, 179-180 stimulus location on, smooth pursuit and,
open-loop, 174, I75f, 176 156-157
steady-state, 163 Retinal blur, vergence eye movements and, 287
Pursuit pathway, descending, 170, 235f Retinal elements, corresponding, defined, 288t
Pursuit system. See Smooth pursuit Retinal error velocity, 174, I75f
Pursuit vergence, commands for, 301 Retinal image velocity, oscillopsia and, 479-480
Putamen, saccade generation and, 120, 248 Retinitis pigmentosa, pendular seesaw nystagmus
and, 427, 433
Reverse ocular bobbing, 552t, 553
Reverse ocular dipping, 552t, 553
Quick phases, 9f, 10. See also Saccades Reversing prisms, VOR adaptation to, 49-50
congenital ocular motor apraxia and, 98-99 riMLF. See Rostral interstitial nucleus of medial lon-
defined, 91t gitudinal fasciculus
in epileptic seizures, 548 Ringing (oscillations), during smooth pursuit, 160
functions of, 266 Risperidone, 563t
myasthenia gravis and, 375 Roll, head rotations in, 22, 263, 263f
 Index 635

Rostral interstitial nucleus of medial longitudinal eyelid movements and, 126-128, 127f
fasciculus, 222d frontal lobe lesions and, 542
burst neurons in, for saccades, 103-104 gaze. See Eye-head saccades
eye-head saccades and, 270 hemidecortication and, 537
jerk seesaw nystagmus and, 426 horizontal. See Horizontal saccades
lesions of, 223, 513d inappropriate. See Saccadic intrusions
bilateral, 514f-515f, 515-516 initiation of, 94-97
unilateral, 514-515 clinical examination of, 128, 613
vertical saccadic palsy and, 512-516, 514f-515f disorders of, 132-133
projections of, 223, 225f ipsipulsion of, 485
vertical and torsional saccades and, 220f, 221-223, latency of. See Saccade(s), initiation of
224f-225f main sequence for, 91
Rostral mesencephalon, vertical saccades and, 103 measurement of, 129-130
Rotation(s) memory-guided. See Memory-guided saccades
axis of, 409 models for, 106-110
barbecue-spit, 67 multiple sclerosis and, 556-557
head. See Head rotation(s) myasthenia gravis and, 375, 377, 378
off-vertical axis (OVAR), 20t, 29, 36, 69 neural signal for, 6, 7f
planes of, 325-326, 325f neurophysiology of, 102-126
torsional, 4f, 13 adaptive control of accuracy and, 124-126
velocity step, 39-40, 40f basal ganglia and, 119-121
Rotational magnification, 50, 304 brain stem pathways, 102-106
Rotational testing brain stem pulse generator, 103-104
quantitative, 65-66 higher-level control of, 110, 11 If
swivel chair, 62 cerebellum and, 121-124, 121f, 123f
Rotational vertigo, 58 frontal lobe and, 115-117
Rotational (angular) vestibulo-ocular reflex, 8, 20t, long-lead burst neurons, 105-106
21,22, 28, 40-42, 41f ocular motoneuron commands, 102-103,
Roth-Bielschowsky phenomenon, 520 103f
Round window fistula, vertigo and, 469 omnipause neurons, 105, 106f
r-VOR. See Rotational vestibulo-ocular reflex parietal lobe and, 117-118
premotor burst neurons, 104-105
pulse generation models, 106-110, 108f
superior colliculus and, 110-115
Saccade(s) thalamus and, 118-119
abnormalities of oblique, 94, 95f, 107, 109
accuracy disorders, 132 ocular motor neurons during, 296, 296f
clinical examination of, 128-129 paralytic strabismus and, 346, 348f
eye-head strategies in, 277-278 Parkinson's disease and, 528-529
inappropriate saccades, 133-134 pulse-step of innervation during, 6-7, 7f
initiation disorders, 132-133 purpose of, 90-91
measurement of, 129-130 quick phases. See Quick phases
pathophysiology of, 130-134, 131f reflexive, 911
velocity disorders, 130-132 restrictive ophthalmopathies and, 381
in Wallenberg's syndrome, 132, 485-486 slow. See Slow saccades
accuracy of, 97-98 small, pathophysiology of, 130
adaptive control of, 124-126 spatial constancy and, 101-102
disorders of, 132 spontaneous, defined, 911
adaptive control of, 124-126 superfast, in myasthenia gravis, 377
experimentally induced, 125-126 three-dimensional, models for, 109-110
neural substrate for, 126 torsipulsion of, 486
amplitude of, 91-92, 92f, 129 trajectories of, 94, 95f
averaging, 97 curved, 132
ballistic nature of, 99-100, 99f measurement of, 130
chronic progressive external ophthalmoplegia velocity of, 91-92, 92f
and,379 disorders of, 130-132
classification of, 91, 91t vergence and, interactions between, 293-295,
corrective, 10, 98 294f
dementia and, 549 during visual search and reading, 100-101
descending parallel pathways for, 11 If, 118 visual stability during, 101
relative importance of, 249-250 visually guided, accuracy of, 97
drift after, 93-94, 97, 130, 131f voluntary, 10, 90-91, 9It, 110
duration of, 92, 92f waveforms of, 92-94, 93f
express, 91t, 96 Saccadic command, VOR and, interaction between,
eye-head. See Eye-head saccades 267-269, 268f
636 Index

Saccadic contrapulsion, superior cerebellar artery Secondary deviation, 341

infarction and, 496 defined,322t
Saccadic dysmetria. See Dysmetria pathophysiology of, 344-345
Saccadic gain, measurement of, 129-130 Secondary position, defined, 322t
Saccadic hypermetria. See Hypermetric saccades Second-degree nystagmus, 412. See also Alexander's
Saccadic hypometria. See Hypometric saccades Law
Saccadic intrusions, 133-134, 449-456, 450d Sedatives
clinical features of, 450 gaze-evoked nystagmus and, 430
defined, 407 for vertigo, 478t, 479
examination of, 408-409 Seesaw nystagmus, 426-428, 427f, 428t, 428d
history-taking and, 407 optic chiasm and, 427, 432, 435
measurement of, 409 treatment of, 459
nature and visual consequences of, 407 SEP. See Supplemental eye field
nystagmus versus, 407 Seizures. See Epileptic seizures
pathogenesis of, 455-456 Self-rotation, illusion of. See Circularvection
schematic of, 45If Semicircular canal(s)
schizophrenia and, 550 angular VOR and, 8
spectrum of, 449, 452f-453f anterior, 33, 34
treatment of, 456-457, 459 endolymph flow within, 26-27
Saccadic oscillations, 133-134, 450d. See also Sac- floating debris in, 473, 476-477
cadic intrusions lateral, 34
with intersaccadic interval mechanical properties of, 25-27
clinical features of, 450 posterior, 34
pathogenesis of, 455 stimulation of, 27f, 28
recordings of, 452f-453f vertical, 33
schematic of, 45If VOR and, 28-29
voluntary, 455 Sensation, vestibular, 56-57
without intersaccadic interval. See Ocular flutter; Sensory fusion, 287
Opsoclonus Serous otitis media, acute vertigo and, 468
Saccadic pulse intrusions, 450d, 451-452 "Setting sun sign," 517
Saccadic pulse generator, saccadic oscillations and, Sixth nerve palsy. See Abducens nerve palsy
134 Sixth sense, 56
Saccadic suppression, 101 Skew deviation, 350. See also Ocular tilt reaction
Saccadic system, 9f, 10 clinical features of, 463
behavior of, 91-102 defined, 463
accuracy, 97-98 in internuclear ophthalmoplegia, 465, 507-508
ballistic nature, 99-100, 99f otolith lesions and, 71, 464
efference copy, 98 paroxysmal, 465
initiation time, 94-97 pathogenesis of, 464
quick phases of nystagmus, 98-99 periodic alternating, 465
trajectories, 94, 95f topologic diagnosis of, 464-465
velocity and duration, 91-92, 92f in Wallenberg's syndrome, 71, 486
visual consequences, 101-102 Skewness ratio, for saccades, 93
during visual search and reading, 100-101 Skull base, tumors arising from, abducens nerve
waveforms, 92-94, 93f and,355-356
Saccadic vergence, commands for, 301 Sleep test, for ocular myasthenia, 374
Saccadomania. See Opsoclonus Slide of innervation, 102-103, 103f
Saccular macula, 28 Slow saccades
Saccule, 28, 29 ataxias and, 493
Sacculocollic reflex, 67 botulism and, 373, 374f
Sacculus, 28 clinical examination of, 128
Sampled data model, of saccadic eye movements, etiology 510t
99-100 eye-head movements in, 278
Sarcoid myasthenia gravis and, 375, 376f
recurrent vertigo and, 471 pathophysiology of, 130-132, 131f
restrictive ophthalmopathy in, 383 pontine disease and, 510-511, 51 Ot
Scan path, 100 progressive supranuclear palsy and, 512, 524f-
Schizophrenia 525f
eye movement disorders in, 550-551 Slow-control response, 153
saccadic abnormalities in, 133 Small saccades, pathophysiology of, 130
Schwannoma, acoustic Smoking, 563-564, 563t
flocculo-nodular syndrome and, 497 Smooth pursuit, 10-11
hyperventilation-induced nystagmus and, 414 abnormalities of, 181-186
Scopolamine, nystagmus and, 458 acceleration saturation, 160, 163, 182
Search coil technique, for measurement of eye adaptive control of, 160
movements, 129, 409, 614, 615 age and,160, 163-164, 178

anatomic scheme for, 165f, 173-174, 235f
clinical examination of, 178-179
congenital nystagmus and, 186
defined, 11
dementia and, 549
disorders of, cerebellar disease causing, 491
eye-head tracking versus, 279f
fixation versus, 153-156, 154f-155f
frontal lobe lesions and, 542
with head and eyes. See Eye-head tracking
hemispheric lesions and, 537
horizontal
anatomical scheme for, 235f
asymmetric impairment of, 181-182, 182f-183f,
184
initiation of, 154f-155f, 159-160, 161f
abnormalities of, 181-182, 182f-183f
measurement of, 179
inversion of, 186
laboratory evaluation of, 179-180
latent nystagmus and, 182, 185-186
models of, 174-177, I75f
neural substrate for, 164-174, 165f, 235f,
236-237
accessory optic system, 172, 173
cerebellum, 171-172
descending pathways, 170, 235f
frontal and supplemental eye fields, 169-170
medial superior temporal visual area, 167-169
middle temporal visual area, 164, 166f-167f,
167
nucleus of optic tract, 172-173
posterior parietal cortex, 169
primary visual cortex, 164
offset of, 154f, 155f, 160
optic flow and, 152
optokinetic nystagmus and, 46
paralytic strabismus and, 347, 348f-349f
parietal lobe lesions and, 539-540
Parkinson's disease and, 529-530
posterior cortical lesions and, 539
purpose of, 151-152
quantitative aspects of, 154f-155f, 159-164, 161f-
163f
schizophrenia and, 550
stimulus for, 156-159
background of, 157
complex, 157-158
dynamic properties of, 154f, 158
nonvisual, 158
predictable target motion, 158-159
retinal location of, 156-157
size of, 157
during sustained tracking, 160-164, 162f-163f,
182,184-185
translational VOR (t-VOR) and, 43
vertical
brain stem connections for, 226-228
downbeat nystagmus and, 416, 424
impairment of, 184-185
VOR cancellation by, 271-272, 27 If
Wallenberg's syndrome and, 487
SNpr. See Substantia nigra pars reticulata
Solvents, exposure to, 563
Somatosensory stimuli, for nystagmus, 463
Sound-induced nystagmus, 62, 414f
Index 637
Spasm
convergence, 308—309
cyclic, in oculomotor nerve palsy, 363
Spasm of fixation, 96, 543
Spasmodic torticollis, vestibular imbalance in, 276,
533
Spasmus nutans, 447d
clinical features of, 447-448, 448f
nystagmus and, 435
pathogenesis of, 448-449
Spatial constancy, saccades and, 101-102
Spatial localization, eye movements and, 14-15
Spectacle correction
anisometropic, 304-306, 305f
VOR adaptation and, 50
Spectacle lens-contact lens combinations for treat-
ment of nystagmus, 461-462
Sphere diopter, defined, 288t
Spinocerebellar ataxias, 493, 494t-495t, 510
Splenius capitis muscle, head turning and, 277
Spontaneous eye movements, in unconscious pa-
tients, 552-554,552t
Spontaneous nystagmus, 67-68, 70
smooth tracking and, 178-179
vestibular imbalance and, 68
Wallenberg's syndrome and, 486
Spontaneous saccades, defined, 91t
Spread of concomitance, 342
Square-wave jerks, 133, 449, 450d, 45 If, 452f-453f
fixation and, 180
treatment of, 459
Square-wave oscillations, 451
Square-wave pulses, 451, 45If
Stare nystagmus, 98
Static otolith-ocular reflex, 22
Static vestibular imbalance, 59-60, 64
Step-ramp stimulus, smooth pursuit and, 154f-155f,
158,159-160, 179, 181
Stereocilia, 24
Stereomotion, 289
Stereopsis, defined, 288t
Sternocleidomastoid muscle, head turning and,
277
Strabismus, 321. See also Diplopia
botulinum toxin for, 373
concomitant, clinical features and diagnosis of,
348-350
congenital nystagmus and, 444
defined,322t
examination in, 338-344
Bielschowsky head-tilt test, 342-344, 343f
cover tests, 340-342, 340f-341f
range of eye movements, 338
subjective diplopia testing, 337f, 338-340, 339f
head tilts and turns in, 345-346
horizontal, 349-350
latent nystagmus and, 185, 445
paralytic (nonconcomitant), 339
dynamic properties of, 346-348, 348f-349f
nonparalytic versus, 344
past-pointing and egocentric localization distur-
bance in, 345
primary and secondary deviation in, 344-345
symptomatology of, 337-338
Striatal-nigral-collicular pathway, gaze control and,
248
638 Index

Striate cortex, 237d Susac's syndrome, recurrent vertigo and, 471

gaze control and, 234, 235f, 236f
lesions of, 234
smooth pursuit and, 164
Striola, 24
Stupor, eye movements in, 551-556, 552t, 553f, 555f
Subarachnoid abducens nerve disorders, 352t, 355
Subarachnoid disease
abducens nerve palsy, 352t
multiple ocular motor nerve palsies, 369t
oculomotor nerve palsy, 362t, 364
trochlear nerve palsy, 358t
Substantia nigra pars reticulata, 248
Huntington's disease and, 533
saccade generation and, 120-121
Superfast saccades, in myasthenia gravis, 377
Superior cerebellar artery, distribution infarction in,
496-497
Superior cerebellar peduncle, lesions of, 489d
Superior colliculus
descending pathways to, for gaze control, 14,
248-249
eye-head saccades and, 270
fixation neurons, 113-114
functional anatomy of, 112f, 113
lesions of, 114-115, 249-250, 526
express saccades and, 96
ocular motor syndromes caused by, 526
pharmacologic inactivation of, 114
projections to, 110, 11 If
during saccade generation, 113-114
saccadic intrusions and, 455
stimulation of, 112f, 113
visual and motor layers of, 110-111, 112f
Superior oblique muscle, 323-324, 324t
paralysis of
cyclodeviation of, 290
diagnosis of, 342-344, 343f
head tilts in, 346
pulling directions of, 326, 326f
Superior oblique myokymia
clinical features of, 359-361, 360f
oscillopsia and, 482
treatment of, 361
Superior orbital fissure, disorders affecting, 352t,
362t, 369-370, 369t
Superior rectus muscle
in eyelid movements, 127
paralysis of, nuclear oculomotor palsy and, 361
Superior temporal gyrus, vestibular sensation and, 57
Superior temporal visual area, medial. See Medial
superior temporal visual area
Superior vestibular nerve, 25
Superior vestibular nucleus, 30
lesions of, nystagmus and, 71
Supplementary eye field, 245d
gaze control and, 244, 245
lesions of, 244, 528, 541d, 542
projections of, 248
saccade generation and, 116-117
smooth pursuit and, 170
Supranuclear palsy, progressive. See Progressive
supranuclear palsy
Sursumduction
alternating, 350
unilateral, 350
Sustained head rotations, vestibulo-ocular response
to, 9-10, 9f, 23
Sustained target motion, smooth pursuit responses
to, 160-164, 162f-163f, 182, 184-185
Sydenham's chorea, 533
Sylvian aqueduct syndrome, 517
Synergistic divergence, 363
Syphilis, recurrent vertigo and, 471
Syringobulbia, torsional nystagmus and, 420
Tardive dyskinesia, 533
Target motion
predictable, smooth pursuit responses to,
158-159, 162f-163f, 163
sustained, smooth pursuit responses to, 160-164,
162f-163f, 182, 184-185
Tay-Sachs disease, 558t, 559
Temporal bone fractures, vertigo and, 468
Temporal lobe, 238d
gaze control and, 236f, 237-238
lesions of, 539
vestibular sensation and, 57
Temporal visual area. See Medial superior temporal
visual area; Middle temporal visual area
Temporo-occipital junction, visual tracking and,
166f-167f, 181
Temporo-parieto-occipital junction, gaze control
and,234
Tenon's capsule, 323, 324f
Tensilon test
in Lambert-Eaton myasthenic syndrome, 374
in myasthenia gravis, 375, 376f, 377-378
Tertiary deviation, defined, 322t
Thalamic esotropia, 308, 527
Thalamic nucleus, lateral, ventroposterior, vestibular
sensation and, 57
Thalamosubthalamic paramedian artery, posterior,
infarction in the distribution of, 513-514
Thalamus
intralaminar nuclei of, gaze control and, 246d
lesions of, 526-528, 527d
saccade generation and, 118-119
Thallium, exposure to, 563
Thiamine, for saccadic oscillations, 459
Thiamine deficiency, ophthalmoplegia and, 559
Third nerve palsy. See Oculomotor nerve palsy
Third-degree nystagmus, 412
Three-dimensional aspects
of eye movements, 12-13
of nystagmus, 408-409
of vestibulo-ocular reflex, 45-46
Thyroid ophthalmopathy, 381-383, 382f
Thyrotropin releasing hormone stimulation test,
Graves' ophthalmopathy and, 382
Time constant
defined,20t
neural integrator, 201-202, 202f
vestibulo-ocular reflex, 37-40, 40f
abnormalities of, central lesions and, 71
determinants of, 45
reduced, 68-69
in rotational testing, 65
Tobacco, 563-564, 563t
 Index 639

Tolosa-Hunt syndrome, painful ophthalmoplegia management of, 359

and,370-371 superior oblique myokymia and, 359-361, 360f
Toluene, exposure to, 563 Trochlear nucleus
Toluene abuse, acquired pendular nystagmus with, anatomy of, 331, 333, 333f
437 disorders affecting, 357, 358t
Tonic cells, vergence, 297, 301 Tropia, 302
Tonic innervation, 6-7 cover test for, 340, 340f
Tonic vergence, 287 defined, 288t, 322t
Torsional conjugate eye movements, brain stem con- Tullio phenomenon, 62, 414, 414f
nections for, 220f, 221-228, 224f-225f ocular tilt reaction and, 464
Torsional eye rotations, measurement of, 4f, 13 vertigo and, 469
Torsional nystagmus, 60, 422d, 491 Tumarkin's otolithic crisis, 470
cerebellum and, 491 Tumor(s)
clinical features of, 420-421, 422 cerebellar, 497
etiology of, 422t clivus, abducens nerve and, 355
Torsional saccades congenital epidermoid, hyperventilation-induced
burst neurons for, 104-105 nystagmus and, 413, 413f
rostral interstitial nucleus of medial longitudinal multiple ocular motor nerve palsies and, 370
fasciculus and, 220f, 221-223, 224f-225f neural crest, opsoclonus and, 453-454
Torsional vergence, 290 oculomotor nerve palsy and, 365, 366f-367f
Torticollis optic nerve, nystagmus and, 435
in benign, paroxysmal vertigo of childhood, parasellar, 427, 435
471 pineal, 518
spasmodic, vestibular imbalance in, 276, 533 pituitary, 435
Tourette's syndrome, 533 posterior fossa, recurrent vertigo and, 472
Toxic causes of acute vertigo, 469-470 skull base, abducens nerve and, 355-356
Toxic chemicals, opsoclonus and, 454-455 trochlear palsy and, 359
Toxic encephalopathy, ocular bobbing and, 553 T-VOR. See Translational vestibulo-ocular reflex
Toxicity Twitch muscle fibers, 327
from drugs, 481, 561-564, 562t-563t
Toxins, effects on eye movements of, 562t-563t,
563-564
Tracking. See also Smooth pursuit Uncinate fasciculus, lesions of, 489d
diagonal, smooth pursuit and, 160, 161f Unconscious patient, eye movements in,
eye-head. See Eye-head tracking 551-556, 552t,553f,555f
sustained, smooth pursuit responses to, 160-164, Uncrossed diplopia, defined, 323t
162f-163f, 182, 184-185 Unidirectional nystagmus, 412
Tragal compression, 62, 466 Unilateral sursumduction, 350
Trajectories, of saccades, 94, 95f, 130, 132 Upbeat nystagmus, 420d
Transcranial magnetic stimulation, cerebral control clinical features of, 417-420, 418f-419f
of eye movements and, 233 divergence and, 308, 417, 419f
Translational movements. See Head translation(s) etiology of, 420t
Translational vestibulo-ocular reflex, 9, 9f, 21, medullary lesions and, 482-483
42-43,43f oscillopsia and, 482
Transthalamic pathway, 247 pathogenesis of, 421, 424
Trauma treatment of, 458
oculomotor nerve palsy due to, 367 Upshoot in adduction, 350
ophthalmoplegia and, 371 Upward eye movements, scheme for, 225f
positional vertigo and, 477 Utricle, 28
trochlear nerve palsy due to, 357-359 disorders of, skew deviation and, 464
vertigo and, 468-469 Utricular macula, 28
Treatment for nystagmus and saccadic intrusions, Utricular nerve, stimulation of, 27f, 28
456-463,457t Uvula, 23Id
Treatment of vertigo 478t, 479 lesions of, 70, 488d
Trichloroethylene, exposure to, 563 smooth pursuit and, 171
Tricyclic antidepressants, 561, 562t ventral, lesions of, 55, 230-231, 488, 489
Trihexyphenidyl, as treatment for nystagmus, 458
Trochlea, 324
Trochlear fascicles, disorders affecting, 357, 358t
Trochlear nerve, anatomy of 331-333, 332f V pattern esotropia, 350
Trochlear nerve palsy V5 (middle temporal visual area), 237d
clinical features of, 357 Valproate, for acquired pendular nystagmus,
differential diagnosis of, 357 458
etiology of, 358t, 359 Valsalva maneuver, 62
head trauma causing, 357-359 Vascular disorders, recurrent vertigo and,
laboratory evaluation of, 35It 471-472
640 Index

Velocity step rotations, vestibular-optokinetic re- Vergence insufficiency, 307

sponse to, 37-39, 40f Vergence integrator, 7, 300-301
Velocity step stimulus Vergence oscillations, 308
defined,20t Vergence tone, resting level of, 287
vestibular gain and, 37-39, 40f Vergence tonic cells, 297, 301
Velocity storage, 35-36, 201, 230 Vermis, 23Id
asymmetry of, 60-61 cerebellar, 299
defined,20t dorsal. See Dorsal vermis
loss of, 68-69 oculomotor, 299
optokinetic after-nystagmus and, 47 posterior, lesions of, 232
optokinetic testing and, 66 Version. See also Conjugate eye movements
VOR time constant and, 45 defined, 288t, 323t
Ventral intraparietal area, gaze control and, 236f, Vertebrobasilar insufficiency, recurrent vertigo and,
239 471-472
Ventral uvula, 23Id Vertical canals, 33-34
lesions of, 55, 230-231, 488, 488d, 489 Vertical conjugate eye movements, brain stem con-
velocity storage and, 230 nections for, 220f, 221-228, 224f-225f
Ventroposterior lateral thalamic nucleus, vestibular Vertical fusional eye movements, 289-290
sensation and, 57 Vertical gaze
Verapamil, for saccadic oscillations, 459 disorders of, etiology of, 512d, 519t
Vergence interstitial nucleus of Cajal and, 223, 225-226,
defined,323t 516-517
tonic, 287 paralysis of
torsional, 290 convergent-divergent pendular oscillations and,
vertical, 289-290 441
Vergence burst cells, 297, 297f, 301 with midbrain hemorrhage, 518-519, 520f-521f
Vergence burst-tonic cells, 297, 301 modern concepts of, 511-512
Vergence excess, 307 rostral interstitial nucleus of medial longitudinal
Vergence eye movements, 4t, 6, 12 fasciculus and, 512-516, 514f-515f
abnormalities of, 307-310 posterior commissure and, 223, 226, 517-519, 5l7t
in internuclear ophthalmoplegia, 507 Vertical gaze holding, 204, 205-206, 223, 225-226
accommodation and, interactions between, Vertical gaze-evoked nystagmus, 210, 227
291-292, 302-303, 303f Vertical myoclonus, 552t, 553-554
accommodative (blur), 12, 290, 291f, 306 Vertical nystagmus. See also Downbeat nystagmus;
adaptive mechanisms for, ocular alignment main- Upbeat nystagmus; Pendularnystagmus
tenance and, 302-306, 303f, 305f with convergent-divergent horizontal component,
age and,290 441
anatomic substrate for, 295—296 internuclear ophthalmoplegia and, 508
cerebellar control of, 298-299, 303 Vertical ocular motor apraxia, 547
cerebral control of, 299 Vertical ocular motor deviation, diagnosis of,
defined,288t 342-344, 343f
dorsal midbrain syndrome and, 517t, 518 Vertical phoria, 350
dynamic properties of, 292-295 Vertical saccades
assessment of, 306-307 burst neurons for, 104-105
examination of, 306-307 rostral interstitial nucleus of medial longitudinal
fusional (disparity), 12 fasciculus and, 220f, 221-223, 224f-225f
assessment of, 306 slow
horizontal, 287-289 pathophysiology of, 131-132
torsional, 290 progressive supranuclear palsy and, 512, 524f-
vertical, 289-290 525f
visual physiology of, 299-300 Vertical saccadic palsy, 512d, 513d
motor commands for, 296, 296f rostral interstitial nucleus of medial longitudinal fas-
near triad and, 290-291 ciculus lesions and, 512-516, 513d, 514f-515f
neural substrates of, 295-300 Whipple's disease and, 526
premotor commands for, 296-298, 297f Vertical smooth pursuit
pure, 292-293 brain stem connections for, 226-228
pursuit, commands for, 301 downbeat nystagmus and, 416, 424
saccades and, interactions between, 293-295, 294f impairment of, 184-185
saccadic, 301 Vertical strabismus, 350
stimuli to, 287 Vertical vergence, 289-290
supranuclear control of, conceptual models of, Vertical vestibulo-ocular reflex, 227, 416
300-301 Vertigo
symmetric, 295 acute, 466
terms related to, 288t etiology of, 467-470, 468t
types of, 12 treatment of, 478t, 479
 Index 641

bacterial infections, 468 lesions of

cervical, 469 nystagmus and, 71
in childhood, 471 unilateral, 67-70
defined, 20t, 466 Vestibular (neuronitis, neurolabyrinthitis)
diagnosis of, 466 acute vertigo and, 467, 468t
disabling, 472 hyperventilation-induced nystagmus and, 414
etiology of, 468t Vestibular nucleus(i)
familial episodic. See Familial episodic vertigo and anatomy of, 29-30, 30t, 32f
ataxia type 2 descending, 30-31
history taking in, 58 disorders of, 464, 483
positional lesions of, 221,483
etiology of, 468t, 473-477, 479 nystagmus and, 70-71, 415
nystagmus and, 68, 412, 473-474, 475f medial. See Medial vestibular nucleus
paroxysmal, benign. See Benign paroxysmal po- optokinetic stimulation of, 37, 37f
sitional vertigo Vestibular nystagmus
positional testing, 61-62 central. See Central vestibular nystagmus
recurrent gaze position and, 64
etiology of, 468t, 470-473 peripheral, 41 Id, 411-415, 413f, 414f, 466
treatment of, 479 perverted, 421
rotational, 58 test for, 62
treatment of, 475f, 478t, 479 treatment of, 457-458
Wallenberg's syndrome and, 484 Vestibular sensation, 56-57
Vestibular artery, 25 Vestibular system, peripheral. See Peripheral vestibu-
Vestibular commissure, 35 lar system
velocity storage and, 35-36 Vestibular tone, imbalance of. See Vestibular imbal-
vestibular lesions and, recovery from, 53 ance
Vestibular cortex, 57, 238d Vestibular-optokinetic system, 19-73
gaze control and, 236f, 237-238 disorders of, 67-72, 68t
lesions of, 538, 539 bilateral loss of vestibular function, 70
Vestibular eye movements, vertical, brain stem con- central vestibular lesions, 70-72
nections for, 3It, 32f, 226-228 optokinetic disorders, 72
Vestibular function unilateral disease of labyrinth or vestibular
clinical examination of, 57-63, 59t, 612 nerve, 67-70
laboratory evaluation of, 63-66, 64t function of, 21-24
loss of clinical examination of, 57-63, 59t, 612-613
acute, 466-467 laboratory evaluation of, 63-67, 64t
bilateral, 70,480-481 historical study of, 20-21
head and gaze stabilization and, 275-276, quantitative aspects of, 37-48, 38f-41f, 43f
275t terms and abbreviations relating to, 20t
unilateral, 67-70 vestibular sensation and, 56-57
Vestibular gain vestibulocerebellar influences on, 53-56, 55f
abnormalities of Vestibular-visual interactions, 23-24. See also
central lesions and, 71 Vestibulo-ocular reflex, cancellation of
detection of, 62-63 in Parkinson's disease, 530
oscillopsia and, 481 Vestibulocerebellum, 230d, 23Id
determinants of, 40-45, 4If, 43f in adaptive control of eye movements, 13
general characteristics of, 37-39 anatomic connections of, 53-54
for impulsive stimuli (velocity steps), 39-40, 40f downbeat nystagmus and, 424
for sine-wave stimuli, 38f-39f, 39 electrophysiologic properties of, 54
Vestibular hair cells, 24, 26f gaze control and, 228-231
Vestibular imbalance, 467d. See also Vestibular nys- gaze-evoked nystagmus and, 430
tagmus infarction in, 496
acute, 466-467 lesions of, 54
dynamic, 60-61,68-69 oscillopsia and, 481
gaze-evoked nystagmus and, 209-210 smooth pursuit and, 171
static, 59-60, 64, 67-68 VOR adaptation and, 53-56, 55f, 230
Vestibular lesions, central, 70-72 Vestibulo-cochlear artery, 25
Vestibular loss. See Vestibular function, loss of Vestibulocollic reflex
Vestibular nerve(s), 25 examination of, 273
afferent head stability and, 265, 276
anatomy of, 31-33 in Wallenberg's syndrome, 487
irregular, 29 Vestibulocortical projections, 56-57
neural activity in, 28-29 Vestibulo-ocular projections, direct, 30t
regular, 28-29 Vestibulo-ocular reflex
efferent, 28 abnormal, oscillopsia and, 480-481
642 Index
Vestibulo-ocular reflex (continued).
adaptation of, 48-53
after labyrinthine lesion, 51-53
context-driven, 51, 52f
cross-axis, 50-51
habituation as, 48-49
short-term, 49
vestibulocerebellar influences on, 53-56, 55f,
230
visually induced, 49-51
age and, 42
anatomic organization of, 29-34, 30t, 32f
angular. See rotational
brain stem elaboration of, 29-35, 30t, 32f
cancellation of, 24, 271-272, 27If, 416
downbeat nystagmus and, 416
during eye-head tracking, 227, 271-272, 27If,
273-274, 279f
measurement of, 273-274, 279f
smooth pursuit and, 271-272, 27lf
in coma, 554-555, 555f
defined, 20t
elementary, 22
gain. See Vestibular gain
head rotations and translations and, 21-22
hemidecortication and, 537
laboratory evaluation of, 63-66, 64t
measurement of, 67
neurophysiology of, 35
in newborns, 559
in paralytic strabismus, 347-348, 348f-349f
in Parkinson's disease, 530
phase
abnormalities of, 71, 481
changes in, 51
determinants of, 45
general characteristics, 39
rotational, 8-9, 8f, 20t, 21, 22, 28, 40-42, 41f
saccadic command and, interaction between,
267-269, 268f
time constant, 39-40, 40f
abnormalities of, central lesions and, 71
determinants of, 45
reduced, 68-69
in rotational testing, 65
translational, 9, 9f, 21, 42-43, 43f
velocity-storage mechanism and, 35-36
vertical, downbeat nystagmus and, 416
vestibular afferents and, 29
Vestibulopathy, acute, peripheral, 466-467
Vestibulosaccadic reflex, 268
Video-based oculography systems, 614, 616
Viral infections, acute vertigo caused by, 467-468
Vision
binocular, latent nystagmus and, 446-447
double. See Diplopia
loss of
internuclear ophthalmoplegia and, 508
labyrinthine function and, 70
nystagmus and, 433, 434f-435f
occipital lobe lesions and, 538
pendular seesaw nystagmus and, 427-428
strabismus and, 350
Vision-mediated eye movements, latency to action
of, 22
Visual acuity
distance from fovea and, 5
head movement and, 480-481
retinal image motion and, 5
Visual axis(es)
concomitant, 336
defined, 323t, 325f
deviations of, 336-337
in unconscious patients, 551-552
misalignment of. See Strabismus; specific type, e.g.,
Skew deviation
nonconcomitant, 336-337
Visual confusion, 287, 337
Visual cortex, 237d
primary
gaze control and, 234, 235f, 236f
lesions of, 537-539
smooth pursuit and, 164
vergence eye movements and, 299
Visual fixation. See Fixation
Visual grasp reflex, Alzheimer's disease and, 549
Visual inputs
disturbance of
vestibulo-ocular reflex and, 72
in Wallenberg's syndrome, 484
saccadic suppression of, 101
Visual physiology, of fusional eye movements,
299-300
Visual search, saccades during, 100-101
Visual system disorders, nystagmus and, 432-439,
432d, 434f-435f
Visuovestibular interactions, 23-24
in Parkinson's disease, 530
Vitamin E deficiency, 558t, 560-561
Voluntary nystagmus, 450d, 455
Voluntary saccades, 10, 90-91, 911, 110
Voluntary saccadic oscillations, 455
VOR. See Vestibulo-ocular reflex
Vulpian's sign, 534
Wada test, 535-536
Wallenberg's syndrome, 221, 483-487, 484f,
485d
complaints of tilts in, 58-59
eye-hand coordination in, 276
lateropulsion in, 124, 484-485, 536
nystagmus and, 71, 420
saccadic abnormalities in, 132, 485-486
skew deviation and, 71, 486
Waveforms
increasing velocity, 41 Of, 416, 4l7f
of saccades, 92-94, 93f
Weber's syndrome, 364
Wernicke's encephalopathy, ocular motor manifesta-
tions of, 558t, 559, 560f
Wegener's granulomatusis, 383
Whiplash injuries, vertigo and, 468
Whipple's disease, 525-526
acquired pendular nystagmus and, 438
oculomasticatory myorhythmia and, 308,
526
Wilson's disease, 558t, 561
Windmill nystagmus, 426
 Index 643

Wrong-way deviation Zinn, annulus of, 323, 325f

hemispheric lesions and, 534 Zoster, acute vertigo caused by, 467-468
thalamic lesions and, 527

Yaw, head rotations in, 263, 263f, 264

Y-group, 31,227d
vertical VOR and, 227
Yoke muscle pairs, 336-337
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 CD-ROM DOCUMENTATION

Neurology of Eye Movements 3E CD-ROM

R. John Leigh and David S. Zee

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