The Evolutionary Basis of Strabismus and Nystagmus in Children 3030627209, 9783030627201

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The Evolutionary Basis of Strabismus and Nystagmus in Children

Michael C. Brodsky

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The Evolutionary Basis of Strabismus and Nystagmus in Children

Michael C. Brodsky

The Evolutionary Basis of Strabismus and Nystagmus in Children

Michael C. Brodsky Professor of Ophthalmology and Neurology Knights Templar Research Professor of Ophthalmology Mayo Clinic Rochester, MN USA

ISBN 978-3-030-62719-5    ISBN 978-3-030-62720-1 (eBook) https://doi.org/10.1007/978-3-030-62720-1 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To the winds of fate that charted my course on this unexpected scientific journey through our collective past.

Foreword

Let me congratulate you for picking up this book. Stay with it. You will be in for a fantastic journey. In ancient times, physicians, scientists, and philosophers were asking the same questions: What is the human experience; why are we here? Recall that Socrates is considered by some to be the father of Western medicine. As well as a great philosopher. Think also of Galileo Galilei, Sir Isaac Newton, or Charles Darwin. But somewhere along the path of the human experience, perhaps culminating in Descarte’s famous “I think, therefore I am,” physicians became increasingly focused on smaller and smaller parts of the whole. This is not all bad. Think of how a powerful telescope will allow study and observation of the smallest and most distant star. But when viewed through that lens, one loses perspective of the great surround. Literally, one cannot see the galaxy through all the stars. But if one looks through the “wrong end” of the telescope, although the view is minified, the surrounding celestial bodies can be seen and put in perspective. The greatest thinkers over time had the ability and desire to focus on both views, the detailed and the wide. It is exactly this type of original, broad-brush, and breakthrough thinking that characterizes Dr. Brodsky’s writings. They cross-correlate studies from a number of different disciplines. His ideas are bold and initially may seem iconoclastic, but they gradually weave a web that consolidates much of what we see in our strabismic patients. If one looks at strabismus through a telescope, we perhaps see crossed eyes, DVD, or an overacting inferior oblique muscle. But if we step back as Dr Brodsky has and look at the big picture through the other end of the telescope, through the wide angle lens of evolutionary biology, we see that many strabismic disorders are often the result of exaptations (a term describing a trait that has been co-opted for a use other than the one for which natural selection has built it), and atavisms (a reappearance of an ancestral trait that has been lost through evolutionary change over successive generations). Evolution is not the underpinning of perfect design. As Dr. Brodsky quotes R.W. Rodieck, “Evolution is not engineering-it is more like tinkering-­it is not design. The visual system never had an opportunity to be designed-or redesigned from scratch; instead, both form and function reflect its long, particular, and capricious history.” This is book truly sui generus—unlike any I have read. It is unique in format. The book consists of a collection of 20 articles (editorials, opinion pieces, and studies) that the author has previously published over the arc of his career. Each chapter is vii

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followed by a postscript written in 2020. These postscripts give insight into how the author’s views may have changed since the articles’ publication. They view each article through an ongoing evolution of understanding. As Brodsky states, “Anyone who tells you that they have the final answer is not a scientist. In science, models evolve with new and better data.” Although I had read each of these articles when initially published, I see the utility this book provides for reading them as parts of a piece. Each movement in a symphony may seem complete in and of itself. But when experienced in sequence, the full artistic message of the symphony can be more fully enjoyed. Similarly, each of these 20 chapters can stand alone shedding light on its given subject. But when read as parts of a whole thesis, we come to realize the author’s underlying message, “Our past is always with us.” Burton J. Kushner, MD Professor Emeritus, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Wisconsin, MD, USA

Preface

Pediatric ophthalmologists manage a unique collection of ocular motility disturbances that are rarely encountered in neurology and neuro-ophthalmology clinics. Conditions that abound include essential infantile esotropia, infantile nystagmus, latent nystagmus, dissociated vertical divergence, primary oblique muscle overaction, dissociated horizontal deviation, and intermittent exotropia. How do these developmental binocular disorders arise? Are they neurologic in origin? If so, what specific neurologic pathways are involved, and why are other signs of neurologic dysfunction conspicuous by their absence in so many affected patients? Science tends to ignore its own history. As it turns out, we can begin to understand this complex topic only by zooming out and trying to place these disorders in a broader physiological context. I have found that the fundamental explanations for the pediatric forms of early-onset strabismus and nystagmus lie buried away within the field of evolutionary biology. Although basic physiologic studies in animals identified primitive visual reflexes long ago, their significance to human visual development somehow eluded us. These ancestral visual reflexes can now be crosslinked with the many forms of pediatric strabismus and nystagmus, thus enabling us to understand the necessary origin of these ocular motor aberrations, and to elucidate the neurological pathways that mediate them. By examining the evolutionary underpinnings of these disorders, we can unlock the many hidden secrets that underlie and unify these perplexing disorders. Evolution (from the Latin evolutio), means an unfolding or an opening out of a curve, emergence or release from an envelop or enclosing structure, or a transformation. By understanding the evolutionary origins of the panoply of eye movement disturbances in infancy, we can grasp the deeper meaning of the complex pyrotechnic show of binocular eye movements that accompany infantile strabismus, and appreciate the necessity of each eye movement as a balancing act in one plane of visual space. In short, we can lift the veil to get a fleeting glimpse of why these complex movements occur. You simply cannot understand infantile strabismus unless you see it as a fingerprint of evolution. Much of the unique phenomenology we encounter in pediatric ophthalmology clinics can be explained by the fact that our two eyes once functioned together as balance organs. In infantile strabismus, the visual cortex is remodeled to the subcortical template, so that spontaneous cortical suppression of one eye can release these primitive subcortical reflexes in the same way that covering an eye does. ix

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Preface

The  intrusion of these subcortical eye movements reflects a primitive binocular tonus imbalance that disrupts binocular alignment and stable vision. Alas, many of these visually driven preternatural eye movements are simply the flip-side of vestibular eye movements in different planes. In neurology clinics, primitive reflexes or “release phenomena” are known to resurface when higher cortical functions become impaired, with different primitive reflexes emerging in early infancy than in adulthood. These disorders can be likened to “subconscious disorders” in Freudian psychiatry that intrude to wreak havoc on our psyches. This is true everywhere in life and in medicine, from neurology to psychiatry to culture to strabismus. Our past is always with us. This compilation of articles seeks to explain and to unify the common conditions that define pediatric ophthalmology as holdovers of primitive evolutionary reflexes that were not only useful but necessary in lateral-eyed animals. These reflexes linger within the substratum of the ocular motor system. They originally functioned to maintain vertical orientation during body rotations and to generate optokinetic responses to stabilize vision during body movements. These visuo-vestibular eye movements transmit motion input from the eyes to the vestibular nucleus, which provides the central integration to distinguish world movement from body movement. These primitive binocular reflexes lost their utility in frontal-eyed animals with binocular vision and stereopsis, but were not erased from our neurological scaffolding. They are suppressed by cortical vision in humans, but get reawakened when cortical binocular vision fails to develop in early infancy. They reside in the subcortical system, meaning the midbrain, brainstem, and cerebellum, which originally subserved luminance and motion detection in lateral-eyed afoveate animals. Without first seeing them in their proper evolutionary context, we are groping in the dark. So are these binocular visual disorders neurologic in origin? Well, yes and no. They are atavisms (from the Latin atavus, or “ancestor,” signifying a reappearance of an ancestral trait that has been lost through evolutionary change over successive generations). In humans, these atavistic binocular movements reflect persistent activation of subcortical visual pathways that are normally extinguished early in life. They arise from a finely orchestrated system of primitive visual pathways that are unfortunately disregarded in neuro-ophthalmology textbooks. As they are confined within the visual system and its connections to the vestibular system, they are not a “tip of the iceberg” of generalized neurological disease. But any preexisting neurologic disorder can destabilize early binocular alignment and secondarily precipitate these conditions. The following chapters will weave some context into what we are seeing and hopefully provide the reader with a conceptual synthesis to codify the stereotypical forms of early-onset strabismus and nystagmus that fill our pediatric ophthalmology clinics. Michael C. Brodsky Rochester, MN, USA

Acknowledgement

I am grateful to the Mayo Clinic for providing me with the research time to envision, assemble, and curate this unique collection. I am also indebted to the Knights Templar Eye Foundation, which generously provided research funding for the time and resources needed to prepare this book. Finally, I wish to thank Asja Rehse, my editor extraordinaire at Springer, who made it easy.

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Contents

1 Dissociated Vertical Divergence����������������������������������������������������������������   1 What Is DVD?��������������������������������������������������������������������������������������������    1 What Is a Dorsal Light Reflex?������������������������������������������������������������������    3 Is DVD a Dorsal Light Reflex?������������������������������������������������������������������    7 Is DVD a Skew Deviation?������������������������������������������������������������������������    9 Conclusions������������������������������������������������������������������������������������������������   11 Postscript����������������������������������������������������������������������������������������������������   14 2 DVD Remains a Moving Target!��������������������������������������������������������������  17 Variable Torsional Component������������������������������������������������������������������   18 Pseudoinferior Oblique Muscle Overaction����������������������������������������������   18 Additivity with Oblique Muscle Overaction����������������������������������������������   18 Association with Torticollis ����������������������������������������������������������������������   19 Relationship to latent nystagmus ��������������������������������������������������������������   20 Postscript����������������������������������������������������������������������������������������������������   22 3 Primary Oblique Muscle Overaction ������������������������������������������������������  25 Central Tonus Mechanisms for Primary Oblique Muscle Overaction ������������������������������������������������������������������������������������   26 Vestibular Interactions with the Ocular Motor System������������������������������   26 Superior Oblique Muscle Overaction and A-Pattern Strabismus in Neurologic Disorders����������������������������������������������������������������������������   31 Inferior Oblique Muscle Overaction and V-Pattern Strabismus in Congenital Esotropia������������������������������������������������������������������������������   34 Primary Oblique Muscle Overaction and Hering’s Law����������������������������   35 Oblique Muscle Overaction and Dissociated Vertical Divergence������������   37 Nonneurologic Causes of Oblique Muscle Overaction�����������������������������   37 Conclusions������������������������������������������������������������������������������������������������   38 Postscript����������������������������������������������������������������������������������������������������   42 4 Do You Really Need Your Oblique Muscles?������������������������������������������  45 Primary Adaptations in Oblique Muscle Function������������������������������������   45 Oblique Muscle Exaptations����������������������������������������������������������������������   47 From Visual Panorama to Frontal Binocular Vision������������������������������   47 Cyclovergence, Stereoscopic Perception, and the Pitch Plane��������������   47 xiii

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Cycloversion, Nonstereoscopic Perception, and the Roll Plane������������   54 Reversion From Exaptation to Adaptation��������������������������������������������   56 Conclusions������������������������������������������������������������������������������������������������   58 Postscript����������������������������������������������������������������������������������������������������   62 5 Latent Nystagmus��������������������������������������������������������������������������������������  65 What Is Latent Nystagmus? ����������������������������������������������������������������������   65 Nasotemporal Asymmetry and Latent Nystagmus������������������������������������   66 Is Latent Nystagmus a Vestibular Nystagmus?������������������������������������������   67 Neuroanatomy of Latent Nystagmus ����������������������������������������������������   68 Clinical Signs of Vestibular Origin��������������������������������������������������������   70 Evolutionary Underpinnings of Latent Nystagmus ������������������������������   73 Experimental Evidence That Latent Nystagmus Is Vestibular in Origin ������������������������������������������������������������������������������������������������   74 Conclusions������������������������������������������������������������������������������������������������   76 Postscript����������������������������������������������������������������������������������������������������   80 6 Dissociated Vertical Divergence����������������������������������������������������������������  83 Patients and Methods ��������������������������������������������������������������������������������   85 Results��������������������������������������������������������������������������������������������������������   85 Comment����������������������������������������������������������������������������������������������������   86 Postscript����������������������������������������������������������������������������������������������������   93 7 The Reversed Fixation Test ����������������������������������������������������������������������  95 Reversed Fixation Test ������������������������������������������������������������������������������   96 Scenario 1��������������������������������������������������������������������������������������������������   97 Scenario 2��������������������������������������������������������������������������������������������������   97 Scenario 3��������������������������������������������������������������������������������������������������  100 Scenario 4��������������������������������������������������������������������������������������������������  100 Comment����������������������������������������������������������������������������������������������������  100 Postscript����������������������������������������������������������������������������������������������������  104 8 Does Infantile Esotropia Arise From a Dissociated Deviation? ������������ 107 Postscript����������������������������������������������������������������������������������������������������  113 9 The Accessory Optic System �������������������������������������������������������������������� 115 What Is the AOS?��������������������������������������������������������������������������������������  115 Conclusions������������������������������������������������������������������������������������������������  120 Postscript����������������������������������������������������������������������������������������������������  123 10 Visuo-Vestibular Eye Movements ������������������������������������������������������������ 125 The Problem Is Gravity������������������������������������������������������������������������������  125 Bilaterally Symmetrical Organs Function as Balance Organs������������������  126 Lateral Eyes are Sensory Balance Organs ������������������������������������������������  126 Primitive Reflexes are Resurrected When Normal Neurodevelopment Fails to Occur ������������������������������������������������������������  126 Ocular Motor Incursions Operate as Visual Balancing Reflexes in Lateral-­Eyed Animals��������������������������������������������������������������  127

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Primitive Visual Reflexes are Evoked by a Physiologic Imbalance in Binocular Visual Input����������������������������������������������������������  129 Latent Nystagmus, Primary Oblique Overaction, and Dissociated Vertical Divergence are Visuo-Vestibular Eye Movements ����������������������  129 Visuo-Vestibular Eye Movements are Generated by Subcortical Central Vestibular Pathways����������������������������������������������������������������������  130 Visuo-Vestibular Eye Movements Arise from a Central Vestibular Imbalance that Dissociates Clinically into 3 Distinct Planes��������������������  130 Visual Reflexes are Stereoisomers of Vestibular Reflexes ������������������������  132 Conclusions������������������������������������������������������������������������������������������������  132 Postscript����������������������������������������������������������������������������������������������������  134 11 An Expanded View of Infantile Esotropia ���������������������������������������������� 137 Postscript����������������������������������������������������������������������������������������������������  144 12 The Lizard’s Tail: An Ocular Allegory���������������������������������������������������� 147 Postscript����������������������������������������������������������������������������������������������������  150 13 The Optokinetic Uncover Test������������������������������������������������������������������ 151 Methods������������������������������������������������������������������������������������������������������  152 Results��������������������������������������������������������������������������������������������������������  152 Comment����������������������������������������������������������������������������������������������������  154 Postscript����������������������������������������������������������������������������������������������������  163 14 A Unifying Neurologic Mechanism for Infantile Nystagmus���������������� 165 What Is the AOS?��������������������������������������������������������������������������������������  166 Role of the AOS in Infantile Nystagmus����������������������������������������������������  167 Pendularity ��������������������������������������������������������������������������������������������  167 Directionality ����������������������������������������������������������������������������������������  169 Foveation Periods����������������������������������������������������������������������������������  169 Absence of Oscillopsia��������������������������������������������������������������������������  169 Null Position������������������������������������������������������������������������������������������  170 Time of Onset����������������������������������������������������������������������������������������  170 Association with Seesaw Nystagmus����������������������������������������������������  171 Reversed Optokinetic Nystagmus����������������������������������������������������������  171 Augmentation by Fixation and Pursuit��������������������������������������������������  172 Association with Congenital Visual Loss����������������������������������������������  172 Superimposition of Latent Nystagmus��������������������������������������������������  172 Involvement of Cerebellar Pathways ����������������������������������������������������  173 Theories of Causation��������������������������������������������������������������������������������  175 Conclusions������������������������������������������������������������������������������������������������  176 Postscript����������������������������������������������������������������������������������������������������  182 15 Intermittent Exotropia and Accommodative Esotropia: Distinct Disorders or Two Ends of a Spectrum? ������������������������������������ 183 Postscript����������������������������������������������������������������������������������������������������  189

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Contents

16 An Optokinetic Clue to the Pathogenesis of Crossed Fixation in Infantile Esotropia������������������������������������������������������������������ 191 Postscript����������������������������������������������������������������������������������������������������  193 17 Is Infantile Esotropia Subcortical in Origin?������������������������������������������ 195 Introduction������������������������������������������������������������������������������������������������  195 Evolutionary Basis of Essential Infantile Esotropia (EIE)������������������������  196 Neuroanatomy of Monocular Nasotemporal Asymmetry (MNTA)����������  197 Evidence for a Subcortical Pathophysiology in Essential Infantile Esotropia (EIE)����������������������������������������������������������������������������  197 Potential Role of Prolonged Subcortical Neuroplasticity��������������������������  199 An Optokinetic Etiology for Essential Infantile Esotropia (EIE)?������������  200 Conclusion ������������������������������������������������������������������������������������������������  200 Postscript����������������������������������������������������������������������������������������������������  204 18 Phoria Adaptation: The Ghost in the Machine �������������������������������������� 207 Introduction������������������������������������������������������������������������������������������������  207 What Is Phoria Adaptation? ����������������������������������������������������������������������  208 Stimulus for Phoria Adaptation������������������������������������������������������������������  209 Measurement of Phoria Adaptation ����������������������������������������������������������  209 Resilience of Phoria Adaptation����������������������������������������������������������������  210 Time Course of Phoria Adaptation������������������������������������������������������������  210 Protean Clinical Manifestations����������������������������������������������������������������  211 Neural Substrate����������������������������������������������������������������������������������������  215 Future Questions����������������������������������������������������������������������������������������  217 Conclusions������������������������������������������������������������������������������������������������  217 Postscript����������������������������������������������������������������������������������������������������  222 19 Monocular Nasotemporal Optokinetic Asymmetry—Unraveling the Mystery ������������������������������������������������������������������������������������������������ 225 Postscript����������������������������������������������������������������������������������������������������  229 20 Infantile Nystagmus—Following the Trail of Evidence�������������������������� 231 Postscript����������������������������������������������������������������������������������������������������  234 Glossary of Terms���������������������������������������������������������������������������������������������� 235 Bibliography ������������������������������������������������������������������������������������������������������ 239 Index�������������������������������������������������������������������������������������������������������������������� 241

1

Dissociated Vertical Divergence A Human Dorsal Light Reflex

In the course of evolution, primitive responses to external stimuli are suppressed by newer neurologic reflexes. When newer systems fail to function properly, primitive reflexes that have been phylogenetically retained may reappear [1]. The emergence of dissociated vertical divergence (DVD) in children with early-onset strabismus may signal this type of atavistic response. It is my hypothesis that DVD is a human dorsal light reflex that produces a visually mediated modulation of central vestibular tone. This visuo-vestibular reflex, which is activated by fluctuations in binocular visual input, manifests in humans when binocular control mechanisms fail to develop in infancy.

What Is DVD? Dissociated vertical divergence is an enigmatic disorder characterized by a slow ascent of 1 eye that is followed, after a variable interval, by a slow descent of the higher eye back to the neutral position [2–4]. The deviating eye frequently extorts during its ascent, then intorts as it descends to resume fixation. Dissociated vertical divergence manifests when binocular visual input is mechanically, optically, or sensorially preempted (Fig. 1.1) [5, 6]. During the period of vertical misalignment, visual input from the hyperdeviated eye is usually suppressed by the brain so that affected individuals do not experience diplopia [2–4]. Since the intermittent hyperdeviation of 1 eye is unassociated with a corresponding hypotropia in the nondeviated eye on alternate cover testing, DVD is said to ignore Hering’s law and seems to defy explanation according to current concepts of neuroanatomy [4]. Dissociated vertical divergence is a postscript to any early disruption of normal binocular interactions [6]. It is seen most commonly in the setting of congenital

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_1

1

2

1  Dissociated Vertical Divergence

a

b

c

d

Fig. 1.1  Dissociated vertical divergence. (a) Absence of hyperdeviation with binocular fixation. (b) Right hyperdeviation and extorsion evoked by occlusion. (c) Left hyperdeviation and extorsion evoked by occlusion. (d) Absence of hyperdeviation during binocular occlusion (as viewed through translucent occluders)

esotropia but is also observed in association with congenital exotropia and after surgical realignment of the hypotropic eye in congenital “double elevator palsy” [6]. As succinctly stated by Helveston [3], “… DVD is a reflex type of event that is programmed to occur if the appropriate mechanisms for nullifying its expression are not functional.”

What Is a Dorsal Light Reflex?

3

A cogent neurophysiological explanation of DVD must account for the following observations: 1. Both eyes never drift up simultaneously (Fig. 1.1) [7]. 2. An inverse form of DVD, in which 1 eye drifts downward below horizontal position, has only rarely been observed [8]. Why should this intermittent vertical deviation manifest only as a hypertropia, and why should this hypertropia alternate between the 2 eyes? 3. DVD develops as a delayed phenomenon in children with infantile strabismus. It is usually first noted between 2 and 5 years of age [4]. 4. The amplitude of the hyperdeviation is often asymmetrical in the 2 eyes, and DVD may be unilateral in amblyopic eyes [2–4]. 5. The vertical amplitude of DVD is variable, making accurate measurement difficult [2, 3]. 6. The slow velocity of the upward and downward drift of the deviating eye does not resemble a saccade or pursuit movement but rather a slow divergence in which fixation is constantly maintained by the nondeviating eye [2, 3]. 7. Placement of a vertical prism before 1 eye will induce a corresponding vertical divergence [2]. 8. The amplitude of the vertical deviation is incrementally related to the asymmetry of visual input in the 2 eyes [2–4]. This effect is most clearly shown by the Bielschowsky phenomenon, in which filters of increasing density placed before the fixating eye cause the hypertropic eye to descend incrementally, sometimes into a hypotropic position [2]. 9. In some individuals, the horizontal component of DVD pre-dominates [9]. 10. DVD is accompanied by a manifest head tilt in approximately 35% of cases [10–12].

What Is a Dorsal Light Reflex? Dissociated vertical divergence recapitulates a primitive visuo-vestibular righting response in lateral-eyed animals (termed the dorsal light reflex or Lichtruckenreflex) [13]. To determine the role of DVD in humans, one must first understand the nature and function of the dorsal light reflex in lower animals. Animals need to know which way is up, since maintaining vertical orientation is important for balance, navigation, and survival. Primates rely predominantly on graviceptive input to the vestibular system (ie, gravity receptors within the 2 labyrinths) to maintain vertical orientation. However, many lower animals combine graviceptive input with weighted visual information from the 2 eyes to establish and maintain verticality. (The need to use visual input is evident when one considers that a fish swimming in turbulent waters is subjected to mechanical forces that produce constant fluctuations in vestibular input [14].)

4

1  Dissociated Vertical Divergence

In 1935, von Holst [15, 16] reported that a fish tends to orient its dorsal surface toward the direction of maximal light intensity (Fig. 1.2). A fish restrained in an upright position and illuminated from one side will move the eye that is ipsilateral to the light source downward and the contralateral eye upward (Fig. 1.2) [15–17]. These postural and ocular responses to asymmetrical illumination are righting reflexes that function to reorient the body and eyes with respect to the apparent visual vertical, as judged by the direction of maximal light. Either reflex is only partly compensatory, with its gain determined by the interplay of visual and vestibular drives [17]. von Holst [15, 16] discovered that visual and otolithic signals are yoked within the central vestibular system to establish postural orientation in the roll plane. In the restrained, labyrinthectomized fish, labyrinthine input can no longer curb this visually induced postural reflex, and the vertical divergence response to a lateral light stimulus is approximately doubled [17]. The enhancement of this visual righting reflex in the absence of vestibular input demonstrates that the dorsal light reflex is a visually mediated ocular tilt reaction that is counterbalanced by the otoliths [14]. If the dorsal light reflex in fish resulted from otolithic imbalance, ablation of the

a

13•

22•

27•

30•

60• Direction of Light 90•

b 30• 5•

60• 4•

6•

Direction of Light

3• 10•

12•

90•

Fig. 1.2  Dorsal light response in goldfish. (a) In the unrestrained goldfish, the degree of body tilt in the roll plane increases with increasing angles of illumination. (b) In the restrained goldfish, vertical divergence of the eyes increases with increasing angles of illumination. (Reprinted with permission from reference [18])

What Is a Dorsal Light Reflex?

5

otoliths would abolish it rather than increase it. When the right labyrinth is removed and the left eye is blinded, visual and utricular tone summate and the fish will commence permanent rolling to the right (Fig. 1.3) [14, 16]. When the left labyrinth and left eye are left intact, utricular and visual innervation oppose each other and normal postural responses are again observed [14, 16]. Thus, left utricular activation has an effect similar to that of unilateral illumination of the right eye, and it counteracts the effect of unilateral illumination of the left eye (Fig. 1.3). Visual information pertaining to light asymmetry converges with utricular input pertaining to gravitational asymmetry to modulate postural reflexes at the level of the vestibular nuclei [18]. The dorsal light reflex bears a profound resemblance to DVD (Table 1.1). (For purposes of comparison, dorsal can be conceptualized as the direction from which vertical sunlight illuminates the labyrinths in upright fish and humans.) In fish, the amplitude of the dorsal light response increases with the intensity of illumination. In DVD, the finding of variable vertical amplitudes in the 2 eyes must also be a Fig. 1.3  In fish, visual and utricular input is summated to establish postural orientation in the roll (frontal) plane. Curved arrows denote direction of body tilt induced by unilateral visual or utricular stimulation

Right Utricular Activation

Left Utricular Activation

Left eye illumination

Right eye illumination

Table 1.1  Similarities Between Dorsal Light Reflex in Goldfish and Dissociated Vertical Divergence in Humans Dorsal Light Reflex Dissociated Vertical Divergence Evoked by asymmetrical light input to the eyes Evoked by asymmetrical visual input to the eyes Visually deprived eye shifts dorsally

Visually deprived eye shifts dorsally

Tropotactic response*

Probably tropotactic

Magnitude of response dependent on strength of light stimulus

Magnitude of response dependent on degree of binocular visual disparity

Magnitude of response dependent on “mood” and external factors

Vertical amplitude variable

Long latency of vertical reequilibration after prolonged lateral illumination

Slow reversal of hyperdeviation after cessation of monocular occlusion

Decreasing exponential waveform

Decreasing exponential waveform

Body tilts in roll plane toward light (ie, toward the side of the preferred eye)

Presence and direction of head tilt variable

Right utricular output counteracts right eye illumination

Undetermined

*Functions to reestablish binocular equilibrium rather than to directionally orient the eyes toward incoming light

6

1  Dissociated Vertical Divergence

function of the degree of visual input asymmetry, as evidenced by the Bielschowsky phenomenon in which the amplitude of the DVD can be titrated by placing filters of varying density before the fixating eye [2]. von Holst devoted considerable discussion to the phenomenon of Umstimmung (change of bias), which is the variability of response from one trial to the next depending on internal and external factors (length of time in darkness, mood, hunger, immediate visibility of prey) [16, 19]. This variability is also a prominent feature of DVD. In DVD, the observed asymmetry in the hyperdeviation of the 2 eyes may reflect the momentary visual advantage of 1 eye, as determined by the degree of amblyopia or by fluctuations in the level of suppression [8]. In the dorsal light response and in DVD, the eyes diverge slowly and the divergence persists for a variable period after the inciting stimulus is removed [14]. The rate of each reaction shows a decreasing exponential waveform, suggesting that the driving force for both reactions is proportional to the deviation from an altered postural equilibrium [14, 20]. That DVD is a dorsal light reflex should not be taken to imply that it is also dependent on the direction of incoming light. von Holst observed that a fish that has had bilateral labyrinthectomy and 1 eye removed will commence permanent rolling rather than orient the remaining eye with reference to the light source [16]. This experiment demonstrates that the dorsal light response is a tropotactic response (ie, one that functions to reestablish binocular equilibrium rather than to directionally orient an eye toward incoming light) rather than a telotactic response (ie, a direct orientation toward or away from light without the necessity of maintaining bilateral balance) [13]. In humans with DVD, diffusion of light into 1 eye can produce a hyperdeviation similar to that which occurs during occlusion of that eye [3, 8, 21–23]. That DVD persists in the supine position [24] suggests that the dorsal light reflex in humans and lower animals functions as a binocular-disparity signal that produces a preprogrammed neural output to the extraocular muscles. This neural output retains its innervational characteristics regardless of light direction or body position. The role of the otoliths in inhibiting this visual postural reflex in humans is unknown. The reversal of vertical amplitude asymmetry induced by reclining in a head-hanging position supports the notion that otolithic input can modulate DVD to some degree [24]. Utricular counterbalancing might explain why the higher eye, in which vision is suppressed, eventually descends to its neutral position. Neuroanatomical studies have shown that direct retinofugal projections to the pretectal accessory optic nuclei and the lateral valvula cerebelli control the dorsal light reflex in goldfish [25–28]. Unilateral lesions of the ipsilateral pretectal nucleus or lateral valvuli cerebelli selectively abolish responses to light stimulation of the contralateral eye [27]. Bilateral lesions completely abolish this visually guided response, while lesions of the optic tectum have no such effect. In goldfish, only the caudal portion of the lateral valvuli cerebelli receives visual input from the contralateral retina via the ipsilateral pretectal nucleus. The rostral portion receives sensory vestibular (ie, utricular) input, which is integrated with visual input from the caudal portion to maintain optimal roll orientation. The valvula cerebelli has no analogous structure in the mammalian cerebellum, but it is likely

Is DVD a Dorsal Light Reflex?

7

that visuo-­vestibular information contributes to postural adjustment through the cerebellum [25].

Is DVD a Dorsal Light Reflex? How would a dorsal light reflex manifest in humans, who have frontally placed eyes, predominantly binocular visual fields, and stereopsis? Binocular vision must function to suppress this reflex, since a vertical divergence of the eyes would effectively abolish binocularity and stereopsis. When binocularity is poorly developed, however, this primitive reflex can reemerge if binocular visual input fluctuates. If reduced visual input to 1 eye is interpreted by the brain as visual tilt, then the dorsal light reflex should serve to equilibrate visual input between the 2 eyes. For this to be the case, the central vestibular system must interpret decreased visual input to 1 eye as being equivalent to a hypotropia, and respond with a vertical vergence signal. In humans, the oblique muscles have been found to play the predominant role in producing visual vertical divergence movements (Fig. 1.4), as elegantly demonstrated by Enright [29] and elaborated on by others [30, 31]. Clinical observation [2, 8] and scleral search coil recordings [30–32] in individuals with DVD have confirmed that extorsion and elevation of the deviating eye are accompanied by a reciprocal intorsion and depression of the fixating eye, which conforms to the visual vertical divergence response in humans [20]. The prominent role of the oblique muscles in restoring vertical fusion is evidenced by the dynamic extorsion of the rising eye that accompanies DVD, as well as the horizontal divergence of the non-fixating eye, which reflects the tertiary abducting function of these muscles [31]. In the case of DVD, reduced visual input in the left eye would activate the left inferior oblique and right superior oblique muscles to produce a cyclovertical divergence movement (Fig. 1.5) [31]. Contraction of these muscles produces a clockwise torsional movement of both eyes, together with infraduction of the right eye and supraduction of the left eye. Maintenance of fixation with the right eye would require simultaneous innervation to the elevators (superior rectus and inferior Fig. 1.4 Vertical divergence of the eyes in DVD. Vertical divergence produced by decreased visual input to the right eye (a) and left eye (b) show opposite vertical and torsional components. These divergence movements enable normal individuals to fuse small vertical image disparities

a

b

8

1  Dissociated Vertical Divergence

a

Visuo-vestibular Innervation

b

Visuo-vestibular + Fixational Innervation

Fig. 1.5  Visuo-vestibular and fixational innervation in dissociated vertical divergence with hyperdeviation of the left eye. In accord with the dorsal light reflex, decreased visual input in the left eye is equivalent to a hypotropia, which activates a vertical vergence mechanism to equilibrate the 2 eyes. (Arrow size denotes relative magnitudes of innervation.) (a) In humans, vertical vergence is mediated primarily by the oblique muscles, causing contraction of the inferior oblique muscle on the left and the superior oblique muscle on the right. Visuo-vestibular innervation, if unaffected by fixational innervation, would cause simultaneous elevation and extorsion of the left eye and depression and intorsion of the right eye. (b) Compensatory fixational innervation to the elevators is necessary to maintain a steady vertical position of the right eye. By Hering law, fixational innervation to the right eye will augment the effects of vestibular innervation to the inferior oblique and superior rectus muscles of the left eye, actively driving the hyperdeviation. Compensatory fixational innervation negates infraduction of the right eye but leaves it with a small intorsional predominance

oblique muscles) of the right eye to counteract the infraducting action of the superior oblique muscle. By Hering law, compensatory fixational innervation to the elevators of the fixating eye recruits the same muscles contralaterally, which would augment vestibular innervation to the superior rectus and inferior oblique muscles of the higher eye and actively drive the vertical component of the deviation (Fig. 1.5). Thus, the observed hyperdeviation in DVD is the composite of 2 visual righting reflexes: a visuo-vestibular reflex that activates a torsional divergence of the eyes and a compensatory fixational reflex that maintains fixation with the visually advantaged eye and produces an upward movement of the other eye. The pivotal role of the monocular fixation in DVD explains the nonexistence of simultaneous bilateral DVD and dictates that an upward movement of 1 eye never begins while the other eye is higher. It is only after the higher eye has completed its descent to the midposition that the other eye may start to ascend. The interplay between visuo-vestibular and fixational innervation explains the perplexing observation that, after removal of a cover from an eye of a patient with DVD, the higher eye will sometimes descend below the neutral position before resuming fixation [2–4]. A similar phenomenon is observed when occlusion of the

Is DVD a Skew Deviation?

9

fixating eye induces a downward refixation movement in the hyperdeviated eye, and the covered eye makes a simultaneous downward movement below midposition before ascending and extorting [2–4, 33, 34]. In both instances, a fixation shift provides a momentary glimpse into an underlying bias in central vestibular tone.

Is DVD a Skew Deviation? Skew deviation is a descriptive term used to denote an acquired, supranuclear, vertical misalignment of the eyes that fails to conform to known innervational patterns of the extraocular muscles [35]. It is seen primarily in patients with unilateral brainstem lesions, particularly those involving the brainstem tegmentum in the mesodiencephalon or the medulla [36–38], although injury to the peripheral vestibular system or the cerebellum can also cause it [39, 40]. It is now accepted that such lesions inhibit or activate unilateral graviceptive output in the roll plane, allowing utricular innervation from one side to predominate, which evokes an ocular tilt reaction [41, 42]. This utricular ocular tilt reaction produces a tonic or paroxysmal vertical divergence of the eyes (ie, skew deviation), which differs from DVD in that the higher eye intorts, the lower eye extorts, and the head tilts toward the lowermost eye [41–44] (Fig. 1.6). Brandt and Dieterich [40, 41] have determined that skew deviation is usually accompanied by binocular torsion, that both findings are components of the ocular tilt reaction, and that the only difference between skew deviation and an ocular tilt reaction is the presence of a head tilt. This utricular ocular tilt reaction is associated with a pathologic shift in the internal representation of the gravitational vector, and functions as a righting reflex to adjust the eyes, head, and body to a position that the a

b

c

Fig. 1.6  Utricular ocular tilt reaction in humans. When the eyes are frontally placed, a torsional component becomes necessary to neutralize a tilt in the roll plane. (a) Physiologic ocular tilt reaction. A rightward body tilt activates right utricular and inhibits left utricular pathways subserving graviceptive tone in the roll plane, resulting in vertical divergence with conjugate torsion of the eyes and head tilt toward the lowermost eye. (b) Normal eye position with head upright. (c) Pathologic ocular tilt reaction. A leftward ocular tilt reaction can be caused by an inhibitory lesion of the left utricular pathways or an excitatory lesion of the right utricular pathways

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1  Dissociated Vertical Divergence

central nervous system erroneously computes as being vertical [40–45]. The head tilt is not compensatory for the ocular misalignment or torsion. Rather, the vertical divergence, ocular torsion, and head tilt are all compensatory adjustments to the new subjective vertical [41]. Under physiological conditions, this ocular tilt reaction functions as a righting reflex that enables an organism to maintain gravitational orientation during tilt in the roll plane (as occurs when skiing or motorcycle riding). Tilting in the roll plane evokes a physiological skew deviation in lower animals and, to a lesser degree, in humans (Fig.  1.6) [42]. However, the purely vertical skew deviation in lower animals is supplanted by a torsional divergence movement in humans, since the eyes are frontally placed. No physiological position of body tilt evokes DVD, and no neurologic lesion has produced it [46]. The intermittent forms of acquired skew deviation that have been documented in patients with midbrain lesions have not been associated with extorsion of the ascending eye or intorsion of the descending eye, as occurs in DVD [36, 47–49]. Vertical divergence of the eyes with the “inverse” torsional characteristics of DVD is a signature of abnormal binocular vision. Evolutionary conservation of the dorsal light reflex as the visual counterpart of the utricular ocular tilt reaction (Fig.  1.3) would explain the acquisition of these inverse torsional movements in frontal-eyed animals. In humans, both ocular tilt reactions are conserved as complementary “mirror-­ image” righting reflexes, as evidenced by the observed extorsion of the rising eye in DVD and the intorsion of the rising eye in the utricular ocular tilt reaction (Table 1.2). In this context, DVD can be conceptualized as an inverse skew deviation. It is the visual counterpart of neurologic skew deviation; the former is a visuo-vestibular ocular tilt reaction, while the latter is a utricular ocular tilt reaction. An imbalance of visual input from the 2 eyes modulates the afferent limb of DVD, while an imbalance in graviceptive input from the utricles modulates the afferent limb of neurologic skew deviation. If the utricular ocular tilt reaction and the dorsal light reflex Table 1.2  Complementary Ocular Tilt Reactions in Humans

Pathophysiology

Dissociated Vertical Divergence 2–4 y Gradual Intermittent Extorsion of higher eye, intorsion of lower eye Binocular visual imbalance

Neurologic lesion

None

Subjective awareness of visual tilt Head tilt Perceived visual vertical

Undetermined Variable Undetermined

Diplopia Nystagmus

None Latent nystagmus

Age at onset Tempo of onset Variability Ocular torsion

Acquired Skew Deviation Any age Acute Usually constant Intorsion of higher eye, extorsion of lower eye Utricular imbalance (central or peripheral) Unilateral utricular, brainstem, or cerebellar lesion Variable Toward side of lower eye Rotated in direction of ocular torsion Vertical Seesaw or hemi-seesaw

Conclusions

11

function together as complementary righting responses in lower lateral-eyed animals (Fig. 1.3), it is difficult to imagine that one mechanism (the utricular ocular tilt reaction) would be retained to such a degree in frontal-eyed animals and the other (the dorsal light reflex) completely discarded. Indeed, small degrees of DVD can be evoked by monocular occlusion in some normal individuals [2, 50].

Conclusions Dissociated vertical divergence is a dorsal light reflex that utilizes binocular visual input to calibrate central vestibular tone. In lower animals, this human dorsal light reflex functions to equilibrate visual input by simultaneously increasing dorsal light input to one eye and decreasing it to the other. When binocular control mechanisms are poorly developed in humans, this dorsal light reflex evokes a phylogenetically newer vertical vergence movement of the eyes to produce an inappropriate vertical divergence with torsional characteristics opposite to those required to neutralize a body tilt (a righting reflex gone wrong). In the upright human, the observed ocular movement is upward because the eye with greater visual input is generally used for fixation and the movement of the visually disadvantaged eye is dorsally directed. The absence of a corresponding hypodeviation on alternate cover testing reflects the instantaneous shift in visual advantage to the uncovered eye that occurs with monocular occlusion. This hypothesis explains the reciprocal nature of the observed hyperdeviation, the dynamic torsion that distinguishes DVD from other forms of skew deviation, and the tight link between DVD and visual fixation. The existence of DVD provides testimony to the duality of the ocular tilt mechanism in humans, to the interplay between visual feedback and vestibular modulation of extraocular muscle tone, and to the evolutionary role of binocular vision in the suppression of this visuo-vestibular response. References 1. Nathan P. The nervous system. 2nd ed. Oxford, UK: Oxford University Press; 1982. p. 84–103. 2. Bielschowsky A. Disturbances of the vertical motor muscles of the eyes. Arch Ophthalmol. 1938;20:190–6. 3. Helveston EM. Dissociated vertical deviation: a clinical and laboratory study. Trans Am Ophthalmol Soc. 1980;78:734–79. 4. von Noorden GK. Binocular vision and ocular motility. In: Theory and management of strabismus. 4th ed. St Louis: CV Mosby; 1990. p. 341–5. 5. Flynn JT.  Strabismus: a neurodevelopmental approach. New  York: Springer-­ Verlag NY Inc; 1991. p. 71–4. 6. Olsen RJ, Scott WE. Dissociative phenomena in congenital monocular elevation deficiency. J AAPOS. 1998;2:72–8.

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7. Spielmann A. Les divergences verticales dissociées: excès desursum version lié à la fixation: ou les divergences verticales dissociées à travers un écran translucide. Ophtalmologie. 1987;1:457–60. 8. Guyton JS, Kirkman N. Ocular movement, I: mechanics, pathogenesis, and surgical treatment of alternating hypertropia (dissociated vertical divergence, double hypertropia) some related phenomena. Am J Ophthalmol. 1956;41:438–75. 9. Wilson ME, McClatchey SK.  Dissociated horizontal deviation. J Pediatr Ophthalmol Strabismus. 1991;28:90–5. 10. Anderson JR. Latent nystagmus and occlusion hyperphoria. Am J Ophthalmol. 1954;38:217–31. 11. Betchel RT, Kushner BJ, Morton GV. The relationship between dissociated vertical divergence (DVD) and head tilts. J Pediatr Ophthalmol Strabismus. 1996;33:303–6. 12. Santiago AP, Rosenbaum AL.  Dissociated vertical deviation and head tilts. J AAPOS. 1998;2:5–13. 13. Duke-Elder S. The effect of light on movement. In: Duke-Elder S, editor. System of ophthalmology: the eye in evolution. London, UK: Henry Kimpton; 1958. p. 27–81. 14. Pfeiffer W.  Equilibrium orientation in fish. Int Rev Gen Exp Zool. 1964;1:77–111. 15. von Holst E. Über den Lichtrückenreflex bei Fische. Pubbl Stn Zool Napoli II. 1935;15:143–8. 16. von Holst E.  Die Gleichgewichtssinne der Fische. Verh Dtsch Zool Ges. 1935;37:109–14. 17. Graf W, Meyer DL.  Central mechanisms counteract visually induced tonus asymmetries: a study of ocular responses to unilateral illumination in goldfish. J Comp Physiol. 1983;150:473–81. 18. Meyer DL, Bullock TH. The hypothesis of sense-organ-dependent tonus mechanisms: history of a concept. Ann N Y Acad Sci. 1977;290:3–17. 19. von Holst E.  Quantitative Untersuchungen über Umstimmungsvorgänge im Zentralnervensystem, I: der Einfluss des Appetits auf das Gleichge­ wichtsverhalten von Pterophyllum. Z Vergl Physiol. 1948;31:134–48. 20. van Rijn LJ, Simonsz HJ, ten Tusscher MPM.  Dissociated vertical deviation and eye torsion: relation to disparity-induced vertical vergence. Strabismus. 1997;5:13–20. 21. Verhoeff FH. Occlusion hypertropia. Arch Ophthalmol. 1941;25:780–95. 22. Crone RA. Alternating hyperphoria. Br J Ophthalmol. 1954;38:591–604. 23. Jampolsky A. Unequal visual inputs and strabismus management. In: Strabismus symposium: transactions of the New Orleans Academy of Ophthalmology. St Louis: CV Mosby Co; 1978. p. 358–492. 24. Goltz HC, Irving EL, Hill JA.  Dissociated vertical deviation: head and body orientation affect the amplitude and velocity of the vertical drift. J Pediatr Ophthalmol Strabismus. 1996;33:307–13. 25. Watanabe S, Takabayashi A, Takagi S, et al. Dorsal light response and changes of its responses under varying acceleration conditions. Adv Space Res. 1989;9:231–40.

Conclusions

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26. Yanagihara D, Watanabe S, Mitarai G. Neuroanatomical substrate for the dorsal light response, I: differential afferent connections of the lateral lobe of the valvula cerebelli in goldfish (Carassius auratus). Neurosci Res. 1993;16:25–32. 27. Yanagihara D, Watanabe S, Takagi S, Mitarai G. Neuroanatomical substrate for the dorsal light response, II: effects of kainic acid–induced lesions of the valvula cerebelli on the goldfish dorsal light response. Neurosci Res. 1993;16:33–6. 28. Mori S. Localization of extratectally evoked visual response in the corpus and valvula cerebelli in carp, and cerebellar contribution to “dorsal light reaction” behavior. Behav Brain Res. 1993;59:33–40. 29. Enright JT.  Unexpected role of the oblique muscles in the human vertical fusional reflex. J Physiol Lond. 1992;451:279–93. 30. van Rijn LJ, Collewijn H. Eye torsion associated with disparity-induced vertical vergence in humans. Vis Res. 1994;17:2307–16. 31. Guyton DL, Cheeseman EW, Ellis FJ, et al. Dissociated vertical deviation: an exaggerated normal eye movement used to damp cyclovertical latent nystagmus. Trans Am Ophthalmol Soc. 1998;96:389–429. 32. Inoue M, Kita Y.  Eye movements in dissociated vertical deviation. Nippon Ganka Gakkai Zasshi. 1993;97:1312–9. 33. Anderson JR. Latent nystagmus and occlusion hyperphoria. Br J Ophthalmol. 1954;38:217–31. 34. Caldwell E.  The significance of alternating sursumduction. Am Orthopt J. 1967;17:39–43. 35. Brodsky MC, Baker RS, Hamed LM.  Pediatric neuro-ophthalmology. New York: Springer Verlag NY Inc; 1996. p. 252–5. 36. Keane JR. Alternating skew deviation: 47 patients. Neurology. 1985;35:725–8. 37. Brandt T, Dieterich M. Different types of skew deviation. J Neurol Neurosurg Psychiatry. 1991;54:549–50. 38. Galetta SL, Liu GT, Raps EC, et al. Cyclodeviation in skew deviation. Am J Ophthalmol. 1994;118:509–14. 39. Mossman S, Halmagyi GM. Partial ocular tilt reaction due to unilateral cerebellar lesion. Neurology. 1997;49:491–3. 40. Brandt T, Dieterich M. Skew deviation with ocular torsion: a vestibular brainstem sign of topographic diagnostic value. Ann Neurol. 1993;33:528–34. 41. Brandt T, Dieterich M. Pathological eye-head coordination in roll: tonic ocular tilt reaction in mesencephalic and medullary lesions. Brain. 1987;110:649–66. 42. Jáuregui-Remaud K, Feldon M, Clarke A, et al. Skew deviation of the eyes in normal human subjects induced by semicircular canal stimulation. Neurosci Lett. 1996;205:135–7. 43. Halmagyi GM, Brandt T, Dieterich M, et al. Tonic contraversive ocular tilt reaction due to unilateral meso-diencephalic lesion. Neurology. 1990;40:1503–9. 44. Hedges TR, Hoyt WF.  Ocular tilt reaction due to an upper brainstem lesion: paroxysmal skew deviation, torsion, and oscillation of the eyes and head tilt. Ann Neurol. 1982;11:537–40. 45. Brandt T, Dieterich M.  Vestibular syndromes in the roll plane: topographic diagnosis from brainstem to cortex. Ann Neurol. 1994;36:337–447.

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1  Dissociated Vertical Divergence

46. Brandt T, Dieterich M.  Central vestibular syndromes in roll, pitch, and yaw planes. J Neuroophthalmol. 1995;15:291–303. 47. Mitchell JM, Smith JL, Quencer RM.  Periodic alternating skew deviation. J Clin Neuroophthalmol. 1981;1:5–8. 48. Greenberg HS, DeWitt LD.  Periodic nonalternating ocular skew deviation accompanied by head tilt and pathologic lid retraction. J Clin Neuroophthalmol. 1983;3:181–4. 49. Corbett JJ, Schatz NJ, Shults WT, et  al. Slowly alternating skew deviation: description of a pretectal syndrome in three patients. Ann Neurol. 1981;10:540–6. 50. van Rijn LJ, ten Tusscher MPM, de Jong I, Hendrikse F. Asymmetrical vertical phorias indicating dissociated vertical deviation in subjects with normal binocular vision. Vis Res. 1998;38:2973–8.

Postscript Although this article was dedicated to dissociated vertical divergence (DVD), which is considered to be a tertiary phenomenon in infantile strabismus, it was revelatory for me in that it “cracked the code” of infantile strabismus by showing DVD to be an atavistic visual reflex. Accordingly, it provided compelling evidence that titratable binocular deviations can arise from unbalanced binocular input through the subcortical visuo-vestibular pathways. Many who disagreed with this analysis fundamentally misunderstood it. Some pointed out that there is no vestibular imbalance in infantile strabismus. This is, of course, true, as it is the visual rather than the otolithic input that is fluctuating in DVD. More adamantly, they noted that the visual cortex is integral to DVD, as cortical suppression of one eye can activate it, suggesting to them that DVD must be a cortical phenomenon. However, our cortical visual motion pathways are reconfigured to the older subcortical pathways in infantile strabismus, so that cortical suppression can produce the same outcome as unequal luminance input in lateral eyed animals. This also explains how DVD can occur spontaneously when both eyes are open (and therefore receiving equal luminance input). As fixation has a stronger effect on DVD than luminance disparity, it is likely that conscious fixation evokes cortical suppression of one eye in patients with strabismus. So DVD can be activated both by an exteroceptive stimulus (covering one eye) or an interoceptive stimulus (cortical suppression). The unanswered question is whether covering one eye evokes DVD through subcortical pathways, whether it evokes cortical suppression and thereby evokes DVD, or whether both mechanisms can be operative to varying degrees. Some have questioned the existence of this subcortical mechanism by pointing out that there no subcortical photometer in humans. This is untrue. The melanopsin pathways that project from intrinsically sensitive retinal ganglion cells to the suprachiasmatic nucleus to entrain circadian rhythms. I once considered the melanopsin to be a good candidate system for DVD. This evolutionarily ancient opsin is selectively sensitive to blue light, which comes from the sky. However, preliminary luminance studies with my colleagues, Drs. Scott Larson and Randy Kardon at the

Postscript

15

University of Iowa, have not shown a selective effect of blue light binocular disparity in generating DVD.  In retrospect, this could have been predicted since the Bagolini bar, a red filter bar, is often placed over one eye to titrate DVD and thereby confirm the diagnosis. Whereas volitional body movements are controlled by the cerebral cortex, individual muscles are innervated by subcortical centers. Only within the vestibular system, where visual motion is encoded in canal referenced planes, can torsional eye movements be generated. To my mind, the fact that DVD is linked to cortical suppression (through fixation, occlusion, diffusion, or suffusion with light), is what distinguishes DVD as a human dorsal light reflex.

2

DVD Remains a Moving Target!

Dissociated vertical divergence (DVD) is an ocularmotor phenomenon that is observed in early-onset strabismus and that, until recently, has remained inexplicable. I have proposed that DVD is a dorsal light reflex that emerges in humans when early-onset strabismus precludes the development of normal binocular vision [1]. This hypothesis is based on physiologic studies that show that unequal light input to the 2 eyes of a vertically restrained fish produces a vertical divergence of the eyes, with depression of the eye that has greater visual input and elevation of the eye that has lesser visual input [2]. In unrestrained fish, unequal visual input induces a body tilt in the roll (frontal) plane toward the side with greater input (ie, a dorsal light reflex) [3]. Land-based animals cannot tilt in space without falling; therefore, a body tilt in aquatic animals is supplanted by a head tilt in humans. Because humans have frontally placed eyes, ocular rotation in the roll plane corresponds to a cyclovertical movement in which the eye with lesser visual input elevates and the eye with greater visual input is used for fixation [1]. Three-dimensional scleral search coil recordings have shown that DVD consists of a cyclovertical vergence movement of both eyes, followed by a vertical movement of both eyes that reestablishes fixation with the lowest eye [4, 5]. These prominent torsional movements implicate the oblique muscles as the primary activators of DVD [4, 5], as predicted long ago by Guyton and Kirkham [6]. For example, in DVD with hyperdeviation of the left eye, simultaneous innervation to the right superior oblique and the left inferior oblique muscles create a cyclovertical divergence of the eyes. When this occurs, vertical stabilization of the lower right eye necessitates upward fixational innervation to counteract the infraducting action of the superior oblique muscle. This conjugate fixational innervation to the superior rectus and inferior oblique muscles of both eyes stabilizes the right eye and actively drives the hyperdeviation in the left eye. Because both eyes are innervated simultaneously to produce this dissociated movement, one should not refer to the elevating eye as the “affected eye” or “the eye with DVD.”

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_2

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2  DVD Remains a Moving Target!

The superimposition of DVD on the static and dynamic innervational derangements associated with congenital esotropia expands its clinical expression to produce the following signs:

Variable Torsional Component The variable torsional component of DVD can be explained by considering the baseline torsional position of the eyes. von Noorden [7] has observed that when DVD is accompanied by “true” inferior oblique muscle overaction, the dynamic intorsion of the deviated eye is absent as it returns to primary position. Conversely, I have observed that patients with DVD and superior oblique muscle overaction often have a prominent torsional component that may exceed the vertical component of the deviation [8]. These observations suggest that the torsional amplitude of DVD is defined by the disparity between the extorsional position of the hyperdeviated eye during inferior oblique muscle activation, and the baseline torsional position of the globe. When the baseline position is one of extorsion (as occurs with inferior oblique muscle overaction) [9], this torsional disparity is minimal and the corresponding torsional movement is small as the extorted eye ascends and descends to an extorted position. When the baseline position of the globes is one of intorsion (as occurs with superior oblique muscle overaction), there is a large torsional disparity that is manifested as a prominent torsional movement as the eye ascends and descends.

Pseudoinferior Oblique Muscle Overaction DVD can manifest in adduction and thereby simulate inferior oblique muscle overaction. This finding is classically attributed to occlusion of the adducting eye by the nose [7, 10]. However, the notion that the child’s nose acts as an occluder is dubious, because young children have a poorly formed nasal bridge. Furthermore, alternate cover testing in lateral gaze (which can only be obtained when no occlusion is present) confirms that the adducting eye is elevated when the abducting eye is fixating in DVD. It has been my observation that spontaneous hyperdeviation of the adducting eye in DVD begins as the eye rotates into the vertical field of action of the inferior oblique muscle, suggesting that paroxysmal activation of the inferior oblique muscle can excessively elevate the adducted eye. As the eye moves into adduction, the increasing vertical action of the inferior oblique muscle explains how DVD can manifest primarily in adduction in the absence of true inferior oblique muscle overaction (ie, without hypotropia of the abducting eye, a V pattern, or fundus extorsion) [10, 11].

Additivity with Oblique Muscle Overaction In children with early-onset esotropia, DVD often coexists with oblique muscle overaction [7, 10–12]. Whereas DVD is caused by paroxysmal activation of the oblique muscles (with secondary fixational activation of the vertical rectus

Association with Torticollis

19

muscles), oblique muscle overaction is generally caused by sensory torsion of the globes that leads to tight oblique muscles [5, 9]. When both conditions are present, their additive effects determine the observed vertical deviation in lateral gaze [10, 11]. Although some believe that DVD is neither created nor abated by surgical weakening of the oblique muscles, the relative effects of oblique muscle surgery on the torsional and vertical components of DVD in different positions of gaze have not been measured.

Association with Torticollis DVD is often associated with an anomalous head tilt that may be directed toward or away from the side of the hyperdeviated eye [13–18]. In some patients, head tilting may be a compensatory means of controlling the hyperdeviation. Jampolsky [15, 16] has characterized the head tilt pattern in DVD in which a hyperdeviation of either eye increases or becomes manifest when the head is tilted to the opposite side. This observation is now understandable (and indeed predictable) on the basis of the torsional kinematics of DVD. For example, DVD with hyperdeviation of the left eye occurs when the right superior oblique and left inferior oblique muscles receive simultaneous innervation and a secondary fixational innervation is recruited to maintain monocular fixation with the lower (and visually preferred) right eye [5]. A head tilt to the right activates otolithic innervation to the right superior oblique and the left inferior oblique muscles and thereby increases the left hyperdeviation, whereas a head tilt to the left would recruit otolithic innervation to neutralize this cyclovertical divergence [19]. This reasoning suggests that a head tilt to the side of the hyperdeviating eye can serve as a compensatory means of recruiting otolithic innervation to control the hyperdeviation. Other patients with DVD have a head tilt pattern characterized by a hyperdeviation that becomes manifest or increases when the head is tilted to the same side [15–18]. According to Jampolsky [16], when fixation with 1 eye predominates in DVD, tonic fixational innervation to the contralateral superior rectus muscle can eventually lead to a contracture. If this contracture occurs, it can alter the head tilt response to one characteristic of superior rectus muscle contracture, with an increase in the vertical deviation on head tilt to the side of the hyperdeviating eye [16–18]. When superior rectus muscle contracture develops, a compensatory head tilt to the opposite side is presumably used to minimize otolithic innervation to the tight superior rectus muscle, and a head tilt to the side of the higher eye will make manifest or increase a hyperdeviation [16–18]. In this setting, surgical recession of a tight superior rectus muscle can reduce or eliminate the compensatory head tilt [18]. Some head tilts in children with DVD are accompanied by a manifest hyperdeviation [13, 14]. A dorsal light reflex in humans would produce a head tilt away from the side of the hyperdeviating eye. Such a tilt would reflect a central vision-­ dependent tonus asymmetry [19] and would potentiate the DVD. This head tilt does not exist to realign the eyes, and surgical treatment of the associated hyperdeviation should not eliminate it.

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2  DVD Remains a Moving Target!

Relationship to Latent Nystagmus Most children with congenital esotropia and DVD also have latent nystagmus [5, 7, 12, 14, 20]. Guyton et al5 have proposed that DVD is a compensatory movement that damps the cyclovertical component of latent nystagmus. von Noorden has argued that this variable damping of latent nystagmus could be an effect rather than the cause of DVD [5]. Pritchard [21] recently found DVD in 47% of patients with intermittent exotropia, most of whom had no latent nystagmus. Latent nystagmus, like DVD, is linked to unequal visual input to the extent that occlusion, suppression, or amblyopia makes it manifest and alternate occlusion reverses its direction. In describing DVD, Bielschowsky [22] noted that “. . . while this eye maintains constant fixation, the other eye, which is deviated upward behind the screen, will make at irregular intervals vertical movements of different extent. . . .” This observation correlates with eye movement recordings that show that DVD can be associated with a vertical latent nystagmus in the hyperdeviating eye [23, 24]. If latent nystagmus occurs because asymmetric visual input resets central vestibular tone in the yaw plane (ie, plane of rotation about an earth-vertical axis), then DVD might incorporate a similar oscillation. Alternatively, the cyclovertical divergence that occurs in DVD could translate a component of the latent nystagmus into the vertical plane, which could reduce the horizontal component and cause it to appear on eye movement recording as a vertical latent nystagmus. Ironically, these complex ocular kinematics ultimately raise basic diagnostic questions. Although the torsional component of DVD is not cosmetically problematic, what is its significance for the patient? When does it begin? Is it synonymous with the torsional nystagmus seen in uncorrected congenital esotropia? Is it associated with a shift in the subjective visual vertical? When DVD improves spontaneously, does it merely revert to a torsional component that is subclinical? Our fundamental treatment goals for DVD are also called into question. Is the goal of strabismus surgery simply to eliminate the vertical component of DVD? Does oblique muscle weakening selectively alter the torsional component? Can vertical rectus muscle surgery selectively reduce the vertical component of DVD at the expense of worsening the torsional component? Answers to these questions will inevitably redirect our approach to surgical treatment of DVD. In its essence, DVD is a balancing movement that uses binocular visual input to calibrate ocular motor and postural tone in the roll plane. As we undertake to recognize its subjective correlates and define its adaptational functions, we are reminded that DVD remains a moving target. References 1. Brodsky MC.  Dissociated vertical divergence: a righting reflex gone wrong. Arch Ophthalmol. 1999;117:1216–22. 2. von Holst E. Über den Lichtrückenreflex bei Fische. Pubbl Staz Zool (Napoli). 1935;15:143–8.

Relationship to latent nystagmus

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3. Graf W, Meyer DL.  Central mechanisms counteract visually induced tonus asymmetries: a study of ocular responses to unilateral illumination in goldfish. J Comp Physiol. 1983;150:473–81. 4. Van Rijn LJ, Collewijn H. Eye torsion associated with disparity-induced vertical vergence in humans. Vis Res. 1994;17:2307–16. 5. Guyton DL, Cheeseman EW, Ellis FJ, Straumann D, Zee DS. Dissociated vertical deviation: an exaggerated normal eye movement used to damp cyclovertical latent nystagmus. Trans Am Ophthalmol Soc. 1998;96:389–429. 6. Guyton JS, Kirkham N. Ocular movement, I: mechanics, pathogenesis, and surgical treatment of alternating hypertropia (dissociated vertical divergence, double hypertropia) and some related phenomena. Am J Ophthalmol. 1956;41:438–75. 7. von Noorden GK. Binocular vision and ocular motility: theory and management of strabismus. 4th ed. St Louis: Mosby–Year Book; 1990. p. 341–5. 8. Brodsky MC. Dissociated torsional deviation. Binoc Vis Q. 1999;14:6. 9. Guyton DL, Weingarten PE. Sensory torsion as the cause of primary oblique muscle overaction/underaction and A- and V-pattern strabismus. Binoc Vis Q. 1994;9:209–36. 10. Wilson ME, Parks MM. Primary inferior oblique overaction in congenital esotropia, accomodative esotropia, and intermittent exotropia. Ophthalmology. 1989;96:950–7. 11. McCall LC, Rosenbaum AL.  Incomitant dissociated vertical divergence and superior oblique overaction. Ophthalmology. 1991;98:911–8. 12. Helveston EM. Dissociated vertical deviation: a clinical and laboratory study. Trans Am Ophthalmol Soc. 1980;78:734–79. 13. Lang J.  Congenital convergent strabismus. Int Ophthalmol Clin. 1972;4: 88–92. 14. Crone RA. Alternating hyperphoria. Br J Ophthalmol. 1954;38:591–604. 15. Jampolsky A. Management of vertical strabismus. In: Pediatric ophthalmology and strabismus, transactions of the New Orleans Academy of Ophthalmology. New York: Raven Press; 1986. p. 157–64. 16. Jampolsky A. A new look at the head tilt test. In: Fuchs AF, Brandt TH, Büttner U, Zee DS, editors. Contemporary ocular motor and vestibular research: a tribute to David A. Robinson. Stuttgart: Springer Verlag; 1994. p. 432–9. 17. Betchel RT, Kushner BJ, Morton GV. The relationship between dissociated vertical divergence (DVD) and head tilts. J Pediatr Ophthalmol Strabismus. 1996;33:303–6. 18. Santiago AP, Rosenbaum AL.  Dissociated vertical deviation and head tilts. J AAPOS. 1998;2:5–11. 19. Brodsky MC. Vision-dependent tonus mechanisms of torticollis: an evolutionary perspective. Am Orthopt J. 1999;49:156–60. 20. Anderson JR. Latent nystagmus and occlusion hyperphoria. Am J Ophthalmol. 1954;38:217–31.

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21. Pritchard C. Incidence of dissociated vertical divergence in intermittent exotropia. Am Orthopt J. 1998;48:90–3. 22. Bielschowsky A. Disturbances of the vertical motor muscles of the eyes. Arch Ophthalmol. 1938;20:175–200. 23. Irving EL, Goltz HC, Steinbach MJ, Kraft SP. Objective video eye movement recording: a useful tool in diagnosis of dissociated vertical deviation. Binoc Vis Q. 1997;12:181–90. 24. Irving EL, Goltz HC, Steinbach MJ, Kraft SP. Vertical latent nystagmus component and vertical saccadic asymmetry in subjects with dissociated vertical deviation. J AAPOS. 1998;2:344–50.

Postscript In this extension of my original treatise, I address the clinical phenomenology of DVD. This analysis has stood the test of time. Occasionally, DVD can manifest as an enigmatic head tilt following strabismus surgery for infantile esotropia. The known mechanisms by which DVD can be accompanied by a head tilt are summarized in the following figure. Although the diagram depicts clear dichotomies, it often remains difficult if not impossible to categorically assign a distinct cause to the torticollis in any given patient (Fig. 2.1). The tug-of-war between the need for binocular fusion and the need for vertical orientation may explain the absence of torticollis in most patients with DVD. Congenital Esotropia Horizontal Realignment of the Eyes Binocutarity with Fixation Preference or Superimposed Hypertropia

Equal Vision

Symmetrical DVD

Asymmetrical DVD – Superior Rectus Contracture

No head tilt

Compensatory head tilt toward side of higher eye

Amblyopia

Unilateral DVD

+ Superior Rectus Contracture

Compensatory head tilt away from side of higher eye

Noncompensatory head tilt away from higher eye (dorsal light reflex)

Fig. 2.1  Clinical algorithm for the differential diagnosis of dissociated vertical divergence (DVD)-associated head tilts. (Used with permission from Brodsky MC, Jenkins R, Nucci P. Unexplained head tilt following surgical treatment of congenital esotropia: a postural manifestation of dissociated vertical divergence. Br J Ophthalmol. 2004;88:264-272, British Medical Association)

Postscript

23 Binocular

Occlusion OS

Occlusion OD

Light Fixation (Normal light)

Fig. 2.2  Video-oculography in a patient with bilateral DVD and latent nystagmus (upper panel) showing a brief true vertical divergence of the eyes, causing them to initially rotate in opposite directions when either eye is occluded (lower panel). Note that the latent nystagmus intensifies as the DVD develops. OD, right eye; OS, left eye. (With permission from Christoff A, Raab EL, Guyton DL, et al: DVD-A conceptual, clinical, and surgical overview. J AAPOS 2014;18:378-384. Elsevier Press)

For any number of reasons, I consider it implausible that DVD occurs to damp latent nystagmus. To accept this notion one would have to ignore all of the evolutionary evidence that both DVD and latent nystagmus are subcortical reflexes arising from unequal visual input from the two eyes. Many patients without latent nystagmus get DVD and, in most patients with both conditions, DVD does not appear to reduce the amplitude of latent nystagmus. In fact, most patients with DVD show an intensification of latent nystagmus when either eye is covered (Fig. 2.2). The presence of DVD in some patients with intermittent exotropia and no latent nystagmus dispels the notion that latent nystagmus must be the driving force for DVD to develop. No controlled studies have examined patients with latent nystagmus without DVD to see if these patients also show nystagmus damping. Importantly, latent nystagmus is of greater intensity when the poorer-­seeing eye is fixating. If DVD were occurring to damp latent nystagmus, one would necessarily expect to see a greater DVD amplitude when the patient was attempting to fixate with the poorer eye. However, the opposite is often the case. Latent nystagmus and DVD occur together but neither arises from the other. It is easy to confuse links and correlations with cause and effect.

3

Primary Oblique Muscle Overaction The Brain Throws a Wild Pitch

Primary oblique muscle overaction is a common ocular motility disorder characterized by vertical incomitance of the eyes in lateral gaze [1]. In primary inferior oblique muscle overaction, an upshoot of the adducting eye occurs when gaze is directed into the field of action of the inferior oblique muscle, producing a greater upward excursion of the adducted eye than of the abducted eye [1]. The opposite occurs in primary superior oblique muscle overaction. Although ductions appear to be normal and there is no evidence of yoke muscle paresis, alternate cover testing discloses a vertical tropia of similar magnitude in the abducting eye. Primary inferior oblique muscle overaction is usually associated with ocular extorsion and V-pattern strabismus, whereas primary superior oblique muscle overaction is usually associated with ocular intorsion and A-pattern strabismus [2–5]. Superior oblique muscle overaction is often accompanied by other neurologic disease, whereas inferior oblique muscle overaction generally occurs in children who have congenital esotropia but no other overt neurologic abnormalities. Surgical weakening of the overacting oblique muscles improves versions, eliminates the associated A or V pattern, and reduces torsion. In 1916, Ohm [6–8] postulated that pattern strabismus and oblique muscle overaction may be due to abnormal vestibular innervation. Almost a century later, a unifying neurologic mechanism to explain primary oblique muscle overaction remains elusive. This ocular motor phenomenon seems to defy fundamental principles of physiology since nowhere else in the body do individual muscles bilaterally overact. The primary function of the oblique muscles in lower vertebrates such as fish is to counterrotate the eyes torsionally in response to pitch (fore-and-aft) movements of the body [9, 10]. As a fish pitches its body to swim upward or downward, a compensatory “wheel” rotation of the eyes is produced by the oblique muscles in response to vestibular stimulation [9]. The existence of this physiologic oblique muscle overaction in lower animals led us to question whether a central vestibular imbalance in the pitch plane might offer an explanation for the occurrence of

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_3

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primary oblique muscle overaction in humans. Clinical observations suggest that an imbalance in central vestibular premotor output to the extraocular muscle subnuclei can produce the primary oblique muscle overaction that accompanies congenital strabismus. This central vestibular imbalance develops when early loss of binocular vision or neurologic disease alters central vestibular output in the pitch plane to produce excessive tonus of the extraocular muscles that elevate the eyes (in the case of congenital esotropia and inferior oblique muscle overaction) or depress the eyes (in the case of neurologic disease and superior oblique muscle overaction).

 entral Tonus Mechanisms for Primary Oblique C Muscle Overaction The term tonus was originally coined by Ewald [11] to describe the state of excitation of a living muscle during rest. In 1977, Meyer and Bullock [12] advanced their tonus hypothesis, which states that neuronal tonus pools within the central nervous system receive multisensory input and that tonus asymmetries between antagonistic pools can produce tonic motor responses. According to this hypothesis, the eyes are not merely sensory organs but components of a multimodally driven tonus pool that calibrates baseline muscle tone (ie, tonus-inducing organs) [12, 13]. This hypothesis explains how sensory information collected by the eyes can help to govern extraocular muscle tonus. The bilateral positioning of the eyes and ears permits them to function as balance organs. Visual and graviceptive input are yoked together within the central vestibular system to determine optimal postural orientation. In his early pioneering studies of vision-dependent tonus responses in fish, von Holst [14] found that a posterior shift of a dorsal light source induces a pitch-up movement of the body, whereas an anterior shift induces a pitch-down movement, as if the animal is programmed to position the body so that the light source retains a dorsal orientation (Fig. 3.1). With the body stabilized in the upright position, an overhead light moving fore-and-aft evokes a wheel-turning movement of both eyes, which rotate to maintain torsional alignment with the light source (Fig. 3.1) [14–16]. Since light normally comes from overhead when a fish is upright, a posterior movement of the light is registered as a pitch forward movement of the body (ie, a movement of the body away from the light). This change in visual input evokes increased tonus to the inferior oblique muscles, which extort the eyes (Fig. 3.1). The observation that visual and vestibular input can alter postural and extraocular muscle tonus to produce a physiologic bilateral oblique muscle overaction in lower animals suggests that similar excitatory stimuli may be operative in strabismic humans with primary oblique muscle overaction.

Vestibular Interactions with the Ocular Motor System To understand why primary oblique muscle overaction so often accompanies early-­ onset strabismus, it is instructive to examine the components of central vestibular tone that influence eye position. The primary function of the vestibuloocular system

Vestibular Interactions with the Ocular Motor System

a

b

c

d

e

f

27

Fig. 3.1  Physiologic effects of gravistatic (postural) and visual input to the oblique muscle tonus in fish. These bilateral torsional eye movements function to align the eyes with the perceived visual vertical by modulating oblique muscle tonus. (a) A pitch-down body movement evokes increased inferior oblique muscle tonus and extorsion of the eyes. (b) A pitch-up movement evokes increased superior oblique muscle tonus and intorsion of the eyes. (c) In the unrestrained fish, an anterior light source evokes a pitch-down body movement. (d) In the unrestrained fish, a posterior light source evokes a pitch-up body movement. (e) In the restrained fish, anterior movement of overhead light evokes increased superior oblique muscle tonus and intorsion of both eyes. (f) In the restrained fish, posterior movement of overhead light evokes increased inferior oblique muscle tonus and extorsion of both eyes

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is to maintain eye position and stabilize fixation during head movements [16]. Vestibuloocular movements are the most primitive of all extraocular movements. As expounded by Walls, . . . the primitive function of the eye muscles was not to aim the eyes at all. Their original actions were all reflex and involuntary, and were designed to give the eyeball the attributes of a gyroscopically-stabilized ship, for the purpose of maintaining a constancy of the visual field despite chance buffetings and twistings of the animals body by water currents. [9] (p303)

In the rabbit, for example, a rightward body tilt along its long axis causes the right eye to be lower in space than the left eye. This tilt elicits a compensatory vertical divergence of the eyes to elevate the right eye and depress the left eye, thereby stabilizing the eyes in space [17–19]. A pitch forward of the body would produce a compensatory extorsional movement of both eyes [14, 15, 20]. Now consider the same pitch-down body movement in a rabbit that is fixating with the right eye maximally abducted and the left eye maximally adducted (Fig.  3.2). Since the eyes are laterally placed in the rabbit, this position of gaze

Fig. 3.2  Overhead view of a rabbit fixating an object in the right posterior visual field. Solid lines correspond to the visual axis of the abducted right eye and the adducted left eye. When the rabbit pitches forward (as when starting to run down a hill), the head rotates downward and the tail rotates upward. Although both eyes move downward in space, the left visual axis (which is directed toward the nose) rotates downward, while the right visual axis (which is directed toward the tail) rotates upward (curved arrows). This divergence of the visual axes corresponds to a right hypertropia that must be neutralized by vestibular innervation to elevate the lower left eye and depress the higher right eye. The compensatory vertical divergence for a pitch-forward position corresponds to primary inferior oblique muscle overaction

Vestibular Interactions with the Ocular Motor System

29

would direct the left visual axis anterior to its neutral position and the right visual axis posterior to its neutral position. A forward pitch in the body plane with the eyes in this position would tilt the left visual axis to a lower position in space than the right visual axis (Fig. 3.2). This tilt would necessitate compensatory vestibuloocular innervation to increase upward tonus in the left eye and increase downward tonus in the right eye, while extorting both eyes in response to the body pitch. Conversely, if the body were pitched back during dextroversion, the higher visual axis of the adducted left eye would necessitate increased downward tonus in the left eye and increased upward tonus in the right eye to stabilize the position of the eyes in space. The necessary vestibulo-ocular movements, which correspond to the vertical divergence in lateral gaze seen in humans with primary oblique muscle overaction, are programmed at an early evolutionary stage to assure stability of the visual field in all fields of gaze. In 1996, Zee [18] formulated this hypothesis to explain how the alternating skew deviation in lateral gaze that occurs in humans could be a reversion to a phylogenically old otolith-mediated righting reflex in lateral-eyed animals. Zee’s hypothesis also explains how superior oblique muscle overaction with alternating hypotropia of the adducting eye reflects a pitch-up otolithic bias and a downward tonus bias to the extraocular muscle plant, whereas inferior oblique muscle overaction with alternating hypertropia of the adducting eye would result from a pitch-down otolithic bias and an upward tonus bias to the extraocular muscle plant. In lateral-eyed animals and in humans, the semicircular canals are roughly aligned with the extraocular muscles (Fig. 3.3) [17]. When the head is rotated in a particular plane, a semicircular canal within the labyrinth detects acceleration and sends excitatory innervation to the extraocular muscle(s). Within the brainstem and Fig. 3.3  The close anatomical relationship of the semicircular canals and the extraocular muscles in humans is shown. (Figure modified with permission from Simpson and Graf [17])

Midline Optic Axis Superior Oblique 51°

Superior Rectus 23° Anterior

41° Semicircular Canals 56° Posterior

Top View

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cerebellum, peripheral vestibular input is summated to produce appropriate innervation to the extraocular muscle subnuclei and maintain the position of the eyes in space (Fig. 3.4) [18–22]. Each anterior semicircular canal provides excitatory innervation to the ipsilateral superior rectus and the contralateral inferior oblique muscles while inhibiting the yoked ipsilateral inferior rectus and contralateral superior oblique muscles (Fig. 3.4). Likewise, each posterior semicircular canal system provides excitatory innervation to the ipsilateral superior oblique and the contralateral inferior rectus muscles while inhibiting the ipsilateral inferior oblique and the contralateral superior rectus muscles. In humans, a pitch-up movement of the head (as occurs when raising the chin) activates both posterior semicircular canals, which send excitatory innervation to both depressors in both eyes. Like their target extraocular muscles, the semicircular canal pathways have a push-pull (yoke) relationship, so that activation of one canal inhibits the antagonist canal [19]. Thus, the

SR LR

MR IO

III

IV

MLF AC PC HC VI

LVN MVN

Fig. 3.4  Neuroanatomical projections from the labyrinths to the extraocular muscles. The orientation of the anterior semicircular canal corresponds to that of the ipsilateral superior rectus and contralateral inferior oblique muscles. The orientation of the posterior semicircular canals corresponds to that of the ipsilateral superior oblique and contralateral inferior rectus muscles. The orientation of each horizontal canal corresponds to that of the horizontal rectus muscles. Turning the head to the right stimulates the right horizontal canal to increase excitatory innervation to the right medial rectus muscle and left lateral rectus muscle so that the eyes rotate equally and opposite to the direction of head rotation. HC indicates horizontal canal; AC, anterior canal; PC, posterior canal; LVN, lateral vestibular nucleus; MVN, medial vestibular nucleus; VI, abducens nucleus; MLF, medial longitudinal fasciculus; IV, trochlear nucleus; III, oculomotor nucleus; SR, superior rectus muscle; MR, medial rectus muscle: LR, lateral rectus muscle; and IO, inferior oblique muscle. (Data modified with permission from Tusa [21])

Superior Oblique Muscle Overaction and A-Pattern Strabismus in Neurologic Disorders

31

pitch-up movement that excites both posterior canals also inhibits both anterior semicircular canals, which send inhibitory innervation to the ocular elevators. The result is an equal contraversive movement of both eyes to adjust for the pitch-up head movement. Injury to or inhibition of anterior canal pathways subserving upward eye movements causes a functional activation of the posterior canal downgaze pathways and produces downward eye movements [22]. In addition to the semicircular canals, each labyrinth contains otolithic sensors consisting of the utricle and the saccule [19]. While the semicircular canals respond to angular acceleration and produce dynamic vestibuloocular movements, the parallel otolithic system responds to linear acceleration and is sensitive to changes in static head position [19]. Damage to the semicircular canal pathways produces phasic ocular deviations and nystagmus, while damage to the otolithic projections corresponding to the semicircular canal pathways causes tonic ocular deviations (strabismus) [19, 23–25]. The otolithic pathways are not as well studied, but are believed to have similar projections to the corresponding canal pathways [19]. For the sake of simplicity, we refer to the otolithic pathways corresponding to a particular canal pathway simply as the anterior canal or posterior canal system, recognizing the similarity in projections between the otoliths and semicircular canals. Likewise, we also use the term anterior (or posterior) canal predominance to mean “predominance of the otolithic pathways corresponding to those of the anterior (or posterior) semicircular canals.” The otolithic pathways corresponding to the anterior and posterior semicircular canals are under different inhibitory control (Fig. 3.5) [19, 21, 22, 26, 27]. The anterior canals receive inhibitory connections from the cerebellar flocculi, while the posterior canals do not. Thus, a structural lesion or metabolic abnormality that inhibits output from the cerebellar flocculi can also disinhibit the anterior canals, resulting in an upward deviation of the eyes [21]. Conversely, bilateral lesions of the ventral tegmental tract or brachium conjunctivum can injure central pathways from the anterior semicircular canals and produce a posterior canal predominance, resulting in tonic downgaze. Maturation of cerebellar floccular inhibition to anterior canal pathways may be dependent on normal visual experience early in life. Ocular stabilization is normally modulated by visual and vestibular input. When binocular visual input is pre-empted, this multisensory mechanism may fall under greater weight of labyrinthine control, allowing excitatory anterior canal output to predominate [28].

 uperior Oblique Muscle Overaction and A-Pattern Strabismus S in Neurologic Disorders A bilateral lesion that injures both anterior canal pathways or disinhibits both posterior canal pathways will increase prenuclear innervation to the superior oblique and inferior rectus subnuclei, resulting in a posterior canal predominance and increased downward tonus to both eyes. This downward tonus must be overcome by fixational innervation (Fig.  3.6). Since the inferior rectus muscles retain their

32

3  Primary Oblique Muscle Overaction SR

IR

III N MLF BC

BC

I S O

BC

MLF

VTT SVN

SVN MVN VTT AC

AC

HC

HC Cerebellum

PC

FLO

NOD

PC

FLO

Fig. 3.5  Segregation of pathways controlling anterior and posterior canal tone. Only the anterior canal pathways receive inhibitory innervation by the cerebellar flocculus. A loss of modulation from the cerebellar flocculi could disinhibit the anterior canals and produce an upward tonus imbalance, leading to bilateral inferior oblique muscle overaction, bilateral extorsion, and V-pattern strabismus. FLO indicates flocculus; NOD, nodulus; AC, anterior canal; PC, posterior canal; HC, horizontal canal; SVN, superior vestibular nucleus; VTT, ventral tegmental tract; MVN, medial vestibular nucleus; MLF, medial longitudinal fasciculus; BC, brachium conjunctivum; III N, oculomotor nucleus (S, I, O, and M represent the oculomotor subnuclei); SR, superior rectus muscle; and IR, inferior rectus muscle. (Data modified with permission from Tusa [21])

vertical field of action in adduction while the superior oblique muscles have minimal vertical action in abduction, this downgaze predominance would produce a relative overdepression of the adducting eye in lateral gaze (Fig. 3.7). Activation of both superior oblique muscles produces bilateral intorsion in the primary position and an A pattern due to the tertiary abducting action of the superior oblique muscles in downgaze. In addition, binocular intorsion rotates the inferior rectus insertions laterally and reduces the adducting action of the inferior rectus muscles in downgaze. The vestibuloocular pathways pass through the posterior fossa and are susceptible to injury when structural abnormalities involve the brainstem or the cerebellum. In children with hydrocephalus and myelomeningocele, the constellation of

Superior Oblique Muscle Overaction and A-Pattern Strabismus in Neurologic Disorders Right Labyrlnth PC

Vestibular Innervation

33

Left Labyrlnth PC

a

HC

HC AC

PC

AC

Vestibular and Fixational Innervation

b

PC

HC

HC AC

AC

Fig. 3.6  Superior oblique muscle overaction. (a) Vestibular innervation. A central vestibular tonus imbalance corresponding to bilateral posterior canal predominance would produce tonic downgaze, divergence, and intorsion of the eyes if unopposed by fixational innervation. (b) Vestibular plus fixational innervation. Fixational innervation, which conforms to the Hering law, recruits bilateral innervation to the superior rectus and inferior oblique muscles to negate the vertical component of the downward tonus bias. Fixational innervation allows a disconjugate intorsional bias to persist. PC indicates posterior canal; HC, horizontal canal; and AC, anterior canal

Fig. 3.7  Superior oblique muscle overaction. The observed eye movements in different fields of gaze are a summation of fixational innervation that conforms to Hering’s law, and an underlying central vestibular imbalance that does not. All 4 depressors are receiving excessive vestibular innervation. Since the vertical action of the superior oblique muscles is maximal in adduction, the adducting eye exhibits a downshoot in adduction relative to the abducting eye. The tertiary abducting effects of the overacting superior oblique muscles are maximized by vestibular innervation in downgaze and minimized by fixational intervation in upgaze, producing an A pattern

A-pattern strabismus, bilateral superior oblique muscle overaction, and bilateral intorsion is often associated with tonic downgaze early in life [29–38]. Children with myelomeningocele not only have hydrocephalus but also frequently have an associated Chiari II malformation [35, 36]. Since prenuclear input to the vestibular system from the vestibulocerebellum is primarily inhibitory, bilateral compression

34

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of or injury to those vestibulocerebellar pathways activating the anterior canals would disinhibit the posterior canals and increase extraocular muscle tonus in their target muscles. Previous investigators [35–40] have speculated that bilateral superior oblique muscle overaction may be supranuclear or prenuclear in nature, citing the frequency with which it accompanies defective upgaze. Biglan [37, 38] attributed the overacting superior oblique muscles, A pattern, and chronic downward deviations of the eyes in children with myelomeningocele to defects in the vertical gaze pathways producing either a failure to inhibit the downgaze pathways or excessive stimulation of downward gaze. Acute comitant esotropia caused by neurologic disease such as hydrocephalus or Chiari malformation is often associated with bilateral superior oblique muscle overaction [39]. Although orbital anatomical factors have also been implicated as a cause of superior oblique muscle overaction in hydrocephalus [1, 29], the high frequency of structural abnormalities within the posterior fossa led Hamed [35, 36] and colleagues to propose that superior oblique muscle overaction and alternating skew deviation in lateral gaze may share a common neuroanatomical substrate. Recently, Hoyt [41] has observed that premature infants with periventricular leukomalacia or intraventricular hemorrhage may initially manifest a tonic downgaze that evolves into an A-pattern esotropia and bilateral superior oblique muscle overaction.

I nferior Oblique Muscle Overaction and V-Pattern Strabismus in Congenital Esotropia Clinical observations and eye movement recordings have documented abnormal ocular responses to vestibular stimulation in children with strabismus [42–45]. Gait and postural control have also been studied in children with different kinds of strabismus, and a defect of postural stability has been demonstrated in esotropic but not exotropic children [46, 47]. The high prevalence of incoordination and balance disorders in children with “isolated” congenital esotropia also supports the notion that early loss of single binocular vision associated with congenital esotropia may affect central vestibular tone [47]. Humans display an inherent upward tonus predominance of the eyes, which correlates with anatomical differences in the orientation of the anterior and posterior canals [28]. This inherent up-down asymmetry in central pathways may explain why vertical vestibular optokinetic responses normally favor upward rather than downward slow phases [48–51]. It may also explain why a slight downbeat nystagmus may be seen in individuals attempting to fixate an imaginary target in darkness [28, 52] and why a hyperphoria of the adducting eye can often be elicited in individuals fixating in lateral upgaze with a Maddox rod covering one eye [53]. The development of single binocular vision serves to increase downward tonus to the extraocular muscles and hold this inherent upward bias in check. Conversely, the disruption of single binocular vision associated with congenital esotropia reduces downward tonus to the extraocular muscles, perhaps by disrupting maturation of

Primary Oblique Muscle Overaction and Hering’s Law

35

inhibitory pathways from the cerebellar flocculi to the anterior canals. The resulting anterior canal predominance would increase upward tonus in the extraocular muscles and predispose to bilateral inferior oblique muscle overaction (Fig. 3.8). Prolonged occlusion of one eye can also induce inferior oblique muscle overaction in nonstrabismic humans with normal stereopsis [54, 55], suggesting that either prolonged interruption or early loss of single binocular vision may also be registered as forward pitch (ie, away from the light). The retention of this primitive vision-dependent tonus mechanism in humans would explain why poor sensory fusion leads to inferior oblique muscle overaction rather than superior oblique muscle overaction. The “neurologic lesion” that induces this central vestibular imbalance is loss of binocular visual input.

Primary Oblique Muscle Overaction and Hering’s Law Primary oblique muscle overaction appears to defy Hering’s law [56], which dictates that, in any volitional conjugate movement, both eyes receive equal innervation. As summarized by Bielschowsky, “all of the muscles of both eyes always participate in each movement; one half experiences an increase in tonus and the other half a decrease” [57] (p178). This control system optimizes binocular vision in all positions of gaze [56–58]. Although Hering’s law requires that the ocular

Vestibular Innervation

Right Labyrinth PC

Left Labyrinth PC

A

HC

HC AC

AC

Vestibular and Fixational Innervation PC

B

PC

HC

HC AC

AC

Fig. 3.8  Primary inferior oblique muscle overaction. (a) Visuovestibular innervation. Failure to develop normal binocular vision is associated with increased upward tonus to the eyes, perhaps through reduced anterior canal inhibition from the cerebellar flocculi. A central vestibular tonus imbalance corresponding to bilateral anterior canal predominance would produce tonic upgaze, horizontal divergence, and extorsion of the eyes if unopposed by fixational innervation. (b) Visuovestibular plus fixational innervation. Fixational innervation recruits equal innervation from the inferior rectus and superior oblique muscles to negate the vertical component of the upgaze bias, and allows the disconjugate extorsional bias to persist. PC indicates posterior canal; HC, horizontal canal; and AC, anterior canal

36

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motor system synthesize a conjugate signal to the motor neurons involved in the execution of any ocular movement, it should be evident from the previous discussion that equal innervation to any set of vertical yoke muscles would produce dissociated movements of the 2 eyes. To execute conjugate vertical eye movements, the extraocular muscles of both eyes must receive appropriate innervation to move the eyes equally rather than receiving equal innervation. Hering [56] made reference only to voluntary eye movements as conforming to his law of equal innervation. Since the semicircular canals and their corresponding otolithic pathways segregate innervation to each set of yoke muscles, it is not surprising that dissociated eye movements of central origin are generally associated with vestibular disease. Paradoxically, these dissociated movements may reflect the fact that the vertical yoked muscles receive roughly equal innervation rather than the necessary innervation to rotate the eyes equally in one plane. Our model of primary oblique muscle overaction as a pitch plane imbalance predicts that oblique muscles overact bilaterally in conjunction with rather than relative to their yoke vertical rectus muscles. In primary gaze, the torsional action of the overacting oblique muscles predominates in both eyes, producing the bilateral extorsion observed in primary inferior oblique muscle overaction and the bilateral intorsion observed in primary superior oblique muscle overaction. When both sets of elevators or depressors receive excessive central vestibular innervation, adduction of either eye produces excessive vertical excursion of the adducting eye as it moves into the vertical field of action of the overacting oblique muscle (Fig.  3.7). In this context, an upward tonus imbalance to both eyes manifests as bilateral overelevation of the adducting eye, and a downward tonus imbalance manifests as bilateral overdepression of the adducting eye. Volitional gaze out of the vertical field of action of the overacting yoke muscles recruits physiologic innervation to counterbalance the vertical tonus imbalance, while gaze into the vertical field of action of the overacting yoke muscles allows this underlying tonus imbalance to predominate, producing the A and V patterns observed clinically (Fig.  3.7). The ocular torsion produced by primary oblique muscle overaction also initiates a cascade of secondary mechanical events, including rotational displacement of the rectus muscle insertions, oblique muscle length adaptation, and mechanical tightening of the oblique muscles, as detailed elegantly by Guyton and Weingarten [5]. These peripheral responses augment the overelevation or overdepression of the adducting eye and the corresponding A and V pattern observed clinically. This neurologic model would also explain why primary oblique muscle overaction is usually associated with a negative Bielschowsky head-tilt test [1, 59]. A head tilt to either side recruits ipsilateral otolithic innervation to stimulate 1 of the 2 overacting vertical muscles in each eye while inhibiting the other. The net result for each eye is a minimal change in vertical tonus in the primary position. However, this model would predict that pitching the head forward and backward (ie, a vertical head-tilt test) would superimpose a physiologic tonus imbalance on the underlying central vestibular tonus imbalance in the pitch plane and thereby alter the amplitudes of an existing A or V pattern and the amplitudes of the associated hyperdeviations in lateral gaze. Accordingly, the clinical practice of pitching the patient’s head

Nonneurologic Causes of Oblique Muscle Overaction

37

forward and backward to obtain strabismus field measurements in upgaze and downgaze would augment an existing A or V pattern.

 blique Muscle Overaction and Dissociated O Vertical Divergence Dissociated vertical divergence may coexist with primary oblique muscle overaction [60]. Dissociated vertical divergence has been attributed to a central vestibular tonus imbalance in the roll plane induced by fluctuations of binocular visual input [60, 61]. This hypothesis is based on physiologic studies [60, 61] in fish that show that unequal visual input to the 2 eyes induces a reflex body tilt in the roll (frontal) plane toward the side with greater visual input. This dorsal light reflex is a balancing movement that uses light from the sky as a visual reference to maintain vertical orientation by equalizing luminance input to the 2 laterally placed eyes. In a vertically restrained fish, unequal visual input induces a vertical divergence of the eyes, with depression of the eye that has greater visual input and elevation of the eye that has lesser visual input. This vertical divergence of the eyes corresponds to the dissociated vertical divergence seen in humans who fail to develop single binocular vision secondary to early-onset strabismus. In humans with dissociated vertical divergence, suppression or mechanical occlusion of one eye increases upward tonus to the extraocular muscles of that eye and downward tonus to the extraocular muscles of the opposite eye [60, 61]. Simultaneous recruitment of central vestibular innervation to both elevators in the visually deprived eye has been invoked to explain the spontaneous overelevation in adduction that can be observed with dissociated vertical divergence, when no V pattern or baseline extorsion is present [60]. The observation that decreased visual input increases upward tonus to one eye (in the case of dissociated vertical divergence) and to both eyes (in the case of inferior oblique muscle overaction) attests to the retention of primitive vision-induced tonus mechanisms [62, 63] in humans, and to the atavistic resurgence of these primitive subcortical reflexes when strabismus precludes the development of binocular vision. Our neurologic model of primary oblique muscle overaction as a central vestibular tonus imbalance in the pitch plane complements the recently proposed theory of dissociated vertical divergence as a central vestibular tonus imbalance in the roll (frontal) plane, and begs the question of whether latent nystagmus might be similarly driven by a central vestibular tonus imbalance in the yaw (axial) plane.

Nonneurologic Causes of Oblique Muscle Overaction Most of the mechanisms invoked to explain the existence of A and V patterns with oblique muscle overaction have described orbital anatomical abnormalities that could account for the abnormal movements on a biomechanical basis [64–75]. It is beyond the scope of this article to review and critique all of them. In some patients,

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neurologic and anatomical causes of oblique muscle overaction may coexist. Children with hydrocephalus and tonic downgaze, for example, may also have frontal bossing with anterior displacement of the trochlea, which can increase tension on the superior oblique muscles and produce a mechanical superior oblique muscle overaction [1, 29]. Recently, Clark [76] and Demer [77] and their colleagues have used magnetic resonance imaging to demonstrate that heterotopia of extraocular muscle pulleys within the orbits can also produce overelevation or overdepression of the adducting eye and simulate oblique muscle overaction. Orbital pulley malposition may account for some children who have superior oblique muscle overaction and A-pattern strabismus in the absence of neurologic disease. Since orbital anatomical abnormalities can produce excessive vertical excursion of one or both eyes in the field of action of the oblique muscles, many authorities advocate use of the descriptive terms overelevation and overdepression of the adducting eye rather than the diagnostic term overaction of the oblique muscles to characterize these movements [1, 76].

Conclusions Lower lateral-eyed animals use light from the sky above and gravity from the earth below as major sources of sensory input to neuronal tonus pools within the central vestibular system. These neuronal tonus pools calibrate extraocular muscle and postural tonus to maintain vertical orientation. In lower animals, oblique muscle tonus is determined by luminance and gravitational input in the pitch plane. In humans, the brain leverages visual and gravistatic sensory input to calibrate extraocular muscle tonus in the pitch plane. Early loss of single binocular vision is treated by the central vestibular system as forward pitch, necessitating increased upward tonus to the extraocular muscles and manifesting as primary oblique muscle overaction. Neurologic lesions within the posterior fossa can produce the opposite central vestibular imbalance, in which a backward pitch evokes increased downward tonus to the extraocular muscles and produces primary superior oblique muscle overaction. This duality reflects an ancestral bimodal tuning of central vestibular output to the extraocular muscles that is subordinate to binocular vision in humans. References 1. von Noorden GK.  Binocular vision and ocular motility: theory and management of strabismus. 5th ed. St Louis: Mosby-Year Book Inc; 1996. p. 367–91. 2. Piper HF. Über die Bedeutung des V- and A-Phänomens beim Schielen. In: Sitzungsbericht 107 Versammlung Rheinland Westfalen Augenärzte. 1963:63. 3. Piper HF.  Verlagerte Muskelansätze als eine Urwsache des Schrägschielens (und ihre operative Korrektur). In: Sitzungsbericht 109 Versammlung Rheinland Westfalen Augenärzte. 1964:86. 4. Weiss JB. Ectopies et pseudoectopies maculaires par rotation. Bull Mem Soc Fr Ophtalmol. 1966;79:329–49.

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5. Guyton DL, Weingarten PE. Sensory torsion as the cause of primary oblique muscle overaction/underaction and A- and V-pattern strabismus. Binocul Vis Eye Muscle Surg Q. 1994;9(suppl):209–35. 6. Ohm J.  Das Ohrlabyrinth als Erzeuger des Schielens. Z Augenheilkd. 1916;36:253–73. 7. Ohm J.  Einige Abildungen von vestibulärem Schielen. Z Augenheilkd. 1918;39:204–7. 8. Ohm J. Schrägschielen. Arch Augenheilkd. 1928;39:619–43. 9. Walls GL.  The Vertebrate Eye and Its Adaptive Radiation. Bloomfield Hills: Cranbrook Institute of Science; 1942. p. 303. 10. Traill AB, Mark RF. Optic and static contributions to ocular counter-rotation in carp. Exp Biol. 1970;52:109–24. 11. Ewald JR.  Physiologische Untersuchungen über das Endorgan des Nervus Oktavus. Bergmann: Wiesbaden; 1892. 12. Meyer DL, Bullock TH. The hypothesis of sense-organ-dependent tonus mechanisms: history of a concept. Ann N Y Acad Sci. 1977;290:3–17. 13. Brodsky MC. Vision-dependent tonus mechanisms of torticollis: an evolutionary perspective. Am Orthopt J. 1999;49:158–62. 14. von Holst E. Über den Lichtrückenreflex bei der Fische. Pubbl Stn Zool Napoli II. 1935;15:143–58. 15. von Holst E.  Die Gleichgewichtssine der Fische. Verh Dtsch Zool Ges. 1935;37:109–14. 16. Walls GL. The evolutionary history of eye movements. Vis Res. 1962;2:69–80. 17. Simpson JI, Graf WG.  Eye-muscle geometry and compensatory eye movements in lateral-eyed and frontal-eyed animals. Ann N Y Acad Sci. 1981;374:20–30. 18. Zee DS.  Considerations on the mechanisms of alternating skew deviation in patients with cerebellar lesions. J Vestib Res. 1996;6:395–401. 19. Leigh RJ, Zee DS. The neurology of eye movements. 3rd ed. New York: Oxford University Press Inc; 1999. p. 19–89. 20. Graf W, Meyer DL. Eye position in fishes suggest different modes of interaction between commands and reflexes. J Comp Physiol. 1978;128:241–50. 21. Tusa RJ. Nystagmus: diagnostic and therapeutic strategies. Semin Ophthalmol. 1999;14:65–73. 22. Brandt T, Dieterich M.  Central vestibular syndromes in roll, pitch, and yaw planes. Neuro-Ophthalmology. 1995;15:291–303. 23. Brandt T, Dieterich M.  Vestibular syndromes in the roll plane: topographic diagnosis from brainstem to cortex. Ann Neurol. 1994;36:337–47. 24. Dieterich M, Brandt T. Wallenberg’s syndrome: lateropulsion, cyclorotation, and subjective visual vertical in thirty-six patients. Ann Neurol. 1992;31:399–408. 25. Glasauer S, Dieterich M, Brandt T. Simulation of pathological ocular counter-­ roll and skew torsion by a 3-D mathematical model. NeuroReport. 1999;10:1843–8. 26. Baloh RW, Spooner JW. Downbeat nystagmus: a type of central cerebellar nystagmus. Neurology. 1981;31:304–10.

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27. Straumann D, Zee DS, Solomon D.  Three-dimensional kinematics of ocular drift in humans with cerebellar atrophy. J Neurophysiol. 2000;83:1125–40. 28. Böhmer A, Straumann D.  Pathomechanism of mammalian downbeat nystagmus due to cerebellar lesion: a simple hypothesis. Neurosci Lett. 1998;250:127–30. 29. France TD. Strabismus in hydrocephalus. Am Orthopt J. 1975;25:101–5. 30. France TD. The association of “A” pattern strabismus with hydrocephalus. In: Moore S, Mein J, Stockbridge L, editors. Orthoptics: past, present, future: transactions of the Third International Orthoptic Congress, Boston, July 1–3, 1975. New York: Stratton; 1976. p. 287–92. 31. Rabinowicz IM, Walker JW.  Disorders of ocular motility in children with hydrocephalus. In: Moore S, Mein J, Stockbridge L, editors. Orthoptics: past, present, future: transactions of the Third International Orthoptic Congress, Boston, July 1–3, 1975. New York: Stratton; 1976. p. 279–86. 32. Maloley A, Weber S, Smith DR. A and V patterns of strabismus in meningomyelocele. Am Orthopt J. 1977;27:115–8. 33. Gaston H. Does the spina bifida clinic need an ophthalmologist? Z Kinderchir. 1985;40(suppl 1):46–50. 34. Lennerstrand G, Gallo JE. Neuro-ophthalmological evaluation of patients with myelomeninocele and Chiari malformations. Dev Med Child Neurol. 1990;32:415–22. 35. Hamed LM. Overaction of the superior oblique muscle: some nosologic considerations. Am Orthopt J. 1993;43:82–6. 36. Hamed LM, Maria BL, Quisling RG, Mickle JP. Alternating skew on lateral gaze: neuroanatomic pathway and relationship to superior oblique overaction. Ophthalmology. 1993;100:281–6. 37. Biglan AW. Ophthalmological complications of meningomyelocoele: a longitudinal study. Trans Am Ophthalmol Soc. 1990;88:389–462. 38. Biglan AW.  Strabismus associated with meningomyelocele. J Pediatr Ophthalmol Strabismus. 1995;32:309–14. 39. Hoyt CS, Fredrick DR. Serious neurologic disease presenting as comitant esotropia. In: Rosenbaum AL, Santiago AP, editors. Clinical strabismus management: principles and surgical techniques. Philadelphia: WB Saunders Co; 1999. p. 152–62. 40. Keane JR.  Alternating skew deviation: 47 patients. Neurology. 1985;35: 725–8. 41. Hoyt CS. Ocular motor consequences of cortical visual impairment. Paper presented at: Jampolsky Festschrift; April 10, 2000; San Francisco, CA. 42. Hoyt CS. Abnormalities of the vestibular response in congenital esotropia. Am J Ophthalmol. 1982;93:704–8. 43. Hoyt CS, Mousel DK, Weber AA. Transient supranuclear disturbances of gaze in healthy neonates. Am J Ophthalmol. 1980;89:708–13. 44. Doden W, Adams A. Elektronystagmographische Ergebnisse der Prüfung des optischvestibulären Systems bei Schielenden. Ber Dtsch Ophthalmol Ges. 1957;60:316–7.

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45. Salman SD, von Noorden GK.  Induced vestibular nystagmus in strabismic patients. Ann Otol Rhinol Laryngol. 1970;79:352–7. 46. Sandstedt P, Odenrick P, Lennerstrand G. Gait and postural control in children with divergent strabismus. Binocul Vis Eye Muscle Surg Q. 1986;1:141–6. 47. Lennerstrand G.  Central motor control in concomitant strabismus. Graefes Arch Clin Exp Ophthalmol. 1988;226:172–4. 48. Baloh RW, Demer JL.  Optokinetic-vestibular interaction in patients with increased gain in the vestibulo-ocular reflex. Exp Brain Res. 1991;83:427–33. 49. Baloh RW, Richman L, Yee RD, Honrubia V.  The dynamics of vertical eye movements in normal human subjects. Aviat Space Environ Med. 1983;54:32–8. 50. Böhmer A, Baloh RWL. Vertical optokinetic nystagmus and optokinetic after nnystagmus in humans. J Vestib Res. 1990;1:309–15. 51. Matsuo V, Cohen B. Vertical optokinetic nystagmus and vestibular nystagmus in the monkey: up-down asymmetry and effects of gravity. Exp Brain Res. 1984;53:197–216. 52. Goltz JC, Irving EL, Steinbach MJ, Eizenman M. Vertical eye position control in darkness: orbital position and body orientation interact to modulate drift velocity. Vis Res. 1997;37:789–98. 53. Slavin ML, Potash SD, Rubin SE. Asymptomatic physiologic hyperdeviation in peripheral gaze. Ophthalmology. 1988;95:778–81. 54. Liesch A, Simonsz HJ. Up- and downshoot in adduction after monocular patching in normal volunteers. Strabismus. 1993;1:25–36. 55. Neikter B. Effects of diagnostic occlusion on ocular alignment in normal subjects. Strabismus. 1994;2:67–77. 56. Hering E.  The theory of binocular vision (trans: Bridgeman B, Stark L). New York: Plenum Press; 1868. 57. Bielschowsky A. Disturbances of the vertical motor muscles of the eyes. Arch Ophthalmol. 1938;20:175–200. 58. Mays L. Has Hering been hooked? Nat Med. 1998;4:889–90. 59. Parks MM, Mitchell PR.  Oblique muscle dysfunction. In: Tasman W, Jaeger EA, editors. Duane’s clinical ophthalmology. Philadelphia: JB Lippincott; 1991. p. 1–9. 60. Brodsky MC. DVD remains a moving target! J AAPOS. 1999;3:325–7. 61. Brodsky MC.  Dissociated vertical divergence: a righting reflex gone wrong. Arch Ophthalmol. 1999;117:1216–22. 62. Graf W, Meyer DL.  Central mechanisms counteract visually induced tonus asymmetries: a study of ocular responses to unilateral illumination in goldfish. J Comp Physiol. 1983;150:473–81. 63. Pfeiffer W.  Equilibrium orientation in goldfish. Int Rev Gen Exp Zool. 1964;1:77–111. 64. Urist MJ.  The etiology of so-called A and V syndromes. Am J Ophthalmol. 1958;46:835–44. 65. Vallesca A. The A and V syndromes. Am J Ophthalmol. 1961;52:172–95. 66. Breinen GM. Vertically incomitant horizontal strabismus: the A-V syndromes. N Y State J Med. 1961;61:2243–9.

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67. Brown HW. Vertical deviations [In Symposium, Strabismus]. Trans Am Acad Ophthalmol Otolaryngol. 1953;57:157–62. 68. Urrets-Zavalia A, Solares-Zamora J, Olmos HR. Anthropological studies on the nature of cyclovertical squint. Br J Ophthalmol. 1961;45:578–96. 69. Fink W. The role of developmental anomalies in vertical muscle deficits. Am J Ophthalmol. 1955;40:529–53. 70. Gobin MH. Sagittalization of the oblique muscles as possible cause for the “A,” “V,” and “X” phenomena. Br J Ophthalmol. 1968;52:13–8. 71. Nakamura T, Awaya S, Miyake SL. Insertion anomalies of the horizontal muscles and dysfunctions of the oblique muscles in the A-V patterns [in Japanese]. Nippon Ganka Gakkai Zasshi. 1991;95:698–703. 72. Postic G. Etiopathogénie des syndromes A et V. Bull Mem Soc Fr Ophtalmol. 1965;78:240–52. 73. Limón de Brown E, Monasterio FO, de Saint Martine R, Feldman MS. Estrabismo en el sindrome de Treacher-Collins-Franceschetti. Cir Cir. 1993;60:210. 74. Locke JC. Heterotopia of the blind spot in ocular vertical muscle imbalance. Am J Ophthalmol. 1968;65:362–74. 75. Saunders RA, Holgate RC. Rectus muscle position in V-pattern strabismus: a study with coronal computed tomography scanning. Graefes Arch Clin Exp Ophthalmol. 1988;226:183–6. 76. Clark RA, Miller JM, Rosenbaum AL, Demer JL. Heterotopic muscle pulleys or oblique muscle dysfunction? J AAPOS. 1998;2:17–25. 77. Demer JL, Oh SY, Poukens V. Evidence for active control of rectus extraocular muscle pulleys. Invest Ophthalmol Vis Sci. 2000;41:1280–90.

Postscript The phenomenon of primary oblique muscle overaction is misunderstood by many. Some believe that it can be ascribed to anatomic derangements of the extraocular muscle positions and their connective tissue constraints within the orbit. These effects are indisputable in the small subset of children with craniosynostosis and other orbital anomalies. Others argue that “sensory” disconjugate torsion can gives rise to apparent oblique muscle overaction with the eventual development of secondary oblique muscle contracture. However, essential infantile esotropia and primary inferior oblique overaction each arise from increased bilateral tonus to the corresponding extraocular muscles. While secondary oblique muscle strengthening and contracture can intensify this torsion, there is no reason to attribute primary oblique muscle overaction to the torsion it produces. In pediatric ophthalmology, we routinely examine versions to look for extraocular muscle overaction whereas, in neuro-ophthalmology we often limitation our examination to ductions to look for rotational limitations. This neurodiagnostic dichotomy reflects the reality that prenuclear activations within subcortical centers produce innervational overaction of extraocular muscles, whereas nuclear or infranuclear lesions produce underaction. Isolated overaction of the medial and oblique

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muscles in infantile esotropia must therefore reflect prenuclear disinhibition of corresponding subcortical nuclei that control these specific extraocular muscles. These subcortical nuclei lie within the vestibular system, which receives afferent input not only from the two labyrinths but from the two eyes as well. In this article, Sean Donahue and I examined an early binocular visual disturbance (effecting visuo-vestibular system) or a posterior fossa injury (affecting the central vestibular system) can produce the necessary prenuclear disinhibition to explain primary oblique muscle overaction. A key concept is that bilateral oblique muscle overaction corresponds to a visual disturbance in the pitch (fore-aft) plane. This understanding was heavily influenced by the work of Brandt and Dieterich showing that the bilateral correlate of tilt is pitch (elaborated in Chap. 4), as well as by an evolutionary hypothesis by David Zee showing that pitch rotation during lateral gaze would produce vestibular findings corresponding to primary oblique muscle overaction (Zee DS: Considerations on the mechanisms of alternating skew deviations in patients with cerebellar lesions. J Vestib Res 1996;6:395–401). We used Brandt and Dieterich’s terminology anterior or posterior canal imbalance to signify bilateral neurologic injury to central otolithic pathways corresponding to these vertical semicircular canals. (Brandt T, Dieterich M: Central vestibular syndromes in roll, pitch, and yaw planes. J Neuro-Ophthalmol 1995;15:291–303). At the time, we did not understand that there existed a subcortical neurologic substrate for visual input to produce an extraocular muscle tonus imbalance in canal-based planes. Now, with the understanding of the accessory optic system as an optokinetic system encoded in canal based planes, this subcortical mechanism has come into focus. However, an optokinetic system would produce a dynamic imbalance, whereas primary oblique muscle overaction stands out as a tonic imbalance. It remains unclear whether altered luminance input is registered or modulated by the human accessory optic system.

4

Do You Really Need Your Oblique Muscles? Adaptations and Exaptations

The human extraocular muscles have evolved to meet the needs of a dynamic, 3-dimensional visual world. Under normal conditions, the extraocular muscles are choreographed to an ensemble of visual tracking, refixation movements, and vergence modulation that assures stable binocular fixation [1]. But a fundamental dichotomy defines the central programming of the human ocular motor plant. While the rectus muscles produce large ocular rotations into secondary and tertiary positions of gaze, the oblique muscles evoke very limited torsional excursions of the eyes [1]. With rare exceptions [2], large torsional eye movements cannot be generated by normal individuals in the absence of a head movement [3–7]. This disparity is also seen with vestibular eye movements in which a horizontal or vertical head rotation induces an ocular counterrotation that effectively stabilizes the position of the eyes in space, but a head tilt in the roll plane evokes a static ocular counterroll of only 10% [8]. This negligible static counterroll led Jampel [9] to conclude that the primary role of the oblique muscles in humans is to prevent torsion. So the question is whether the human oblique muscles retain only a vestigial function in which they are consigned to make a nominal contribution to vertical gaze, or whether the primary function of the human oblique muscles is to modulate torsional eye position and to maintain perceptual stability of the visual world.

Primary Adaptations in Oblique Muscle Function To address this basic question, one must first examine the role of the oblique muscles in lower animals. The extraocular muscles originally functioned to stabilize the eyes in space during body movements and corresponding rotations of the visual environment. In lateral-eyed vertebrates such as fish and rabbits, the oblique muscles produce torsional movements of the eyes in response to pitch movements of the body [10, 11]. When the animal pitches forward or backward, the oblique muscles

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_4

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produce a partial wheel-like counterrotation of both eyes that helps to stabilize the torsional position of the eyes in space [10, 11]. In fish, a directional shift in overhead luminance in the sagittal plane also produces an ipsidirectional pitch movement of the body (ie, a dorsal light reflex in the pitch plane) [11–13]. When the animal’s body is restrained during this stimulus, this dorsal light reflex causes both eyes to rotate torsionally so that their upper poles move in the same direction as the light source [12, 13]. Torsional optokinetic nystagmus has also been recorded in the rabbit, indicating that environmental rotation in the pitch plane can directly activate the oblique muscles [14]. The oblique muscles also contribute to ocular movements during roll (ie, rotations about the head-tail axis of the animal) [15]. A body tilt evokes utricular innervation to the ipsilateral superior rectus and superior oblique muscles (which are elevators in fish and rabbits) and the contralateral inferior rectus and inferior oblique muscles (which are depressors in fish and rabbits) [16]. The resulting supraduction of the lower eye and infraduction of the higher eye helps to stabilize the vertical position of the eyes during body roll. The magnitude of the ocular counterroll relative to a body roll is only approximately 50% in lateral-eyed animals such as rabbits [17]. A similar vertical divergence can also be induced by a rotating optokinetic cylinder rotating around the long axis of the fish [10] or by providing unequal visual input to the 2 eyes [11, 14]. For example, increasing visual input to the left eye of a fish by shining a light at an angle onto the top of a fish tank produces a body tilt toward the left in the freely swimming fish (a dorsal light reflex in the roll plane). When body roll is restrained, the same stimulus evokes a vertical divergence of the eyes (supraduction of the right eye and infraduction of the left) that tends to equalize visual input to the 2 eyes [18]. These primitive adaptations use visual and graviceptive input to set postural and extraocular muscle tonus during pitch and roll [19]. Human ocular torsion can be subdivided into cyclovergence (a disconjugate torsional rotation of the globes producing extorsion or intorsion of both eyes) and cycloversion [1, 7] (a conjugate torsional rotation of both globes producing intorsion of one eye and extorsion of the other eye). These 2 torsional eye movements in humans correspond to the torsional eye movements in lower animals induced by pitch and roll. Since pitch evokes a disconjugate torsional rotation (ie, either intorsion or extorsion of both eyes) in lateral-eyed animals, phylogenetic retention of this primitive adaptation in humans would mean that a pitch stimulus (a slant of the visual environment around the interaural axis) would evoke a cyclovergence response (a disconjugate torsional movement of both eyes) in humans, whereas a roll stimulus (a tilt of the head or the visual environment around the nasooccipital axis) would evoke a cycloversion response in humans. These primitive adaptations are indeed measurable in the laboratory as the small cyclovergence movements that are induced artificially by haploscopy or optically induced cyclodisparity [6, 20–24] and in the small cycloversion movements that are evoked by head tilt (ie, the human ocular counterroll to a graviceptive stimulus) [16], by torsional optokinetic stimuli [25–27], or by static-tilted visual stimuli [28, 29].

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Oblique Muscle Exaptations From Visual Panorama to Frontal Binocular Vision Although we retain our primitive adaptations, the function of the human oblique muscles has evolved to meet the needs of single binocular vision. In the course of evolution, primitive adaptations give way to exaptations. An adaptation is something fit (aptus) by construction for (ad) its usage [30]. Exaptation is a relatively new evolutionary concept advanced by Gould [30] to describe a feature, now useful to an organism, that did not arise as an adaptation for its present role, but that was subsequently co-opted for its current function. Such structures are fit (aptus) not by explicit molding for (ad) current use, but as a consequence of (ex) properties built for other reasons [30]. According to this definition, a mechanism must have a function and must enhance the fitness of its bearer to qualify as an exaptation [30, 31]. For example, the feathers of birds may have originally evolved for thermal insulation (an adaptation), only to be subsequently co-opted for flight (an exaptation) [31, 32].

Cyclovergence, Stereoscopic Perception, and the Pitch Plane According to Blakemore et  al [32], binocular animals have abandoned the enormous biologic advantage of panoramic vision in order to have their eyes pointing forward, the most obvious advantage of which is stereopsis. Frontal repositioning of the eyes seems to have exapted the oblique muscles to subserve stereopsis. Evolution has grafted a new torsional control system that is subordinate to binocular vision on top of the “primitive” dynamic torsional programming of the oblique muscles. Although the brain programs eye torsional position by regulating the tonus of all extraocular muscles, the oblique muscles have the predominant effect on ocular torsion. It is therefore instructive to examine torsional eye position as a function of oblique muscle innervation. How do the human oblique muscles subserve stereopsis? Under conditions of binocular fixation, an object closer in space than the fixation point will produce an image on the temporal retinas, while an object farther in space than the fixation point will produce an image on the nasal retinas [6]. This horizontal disparity forms the basis for stereoscopic perception. If one examines the circles that appear elevated on a Titmus stereoacuity test under binocular conditions, examination with each eye will show a nasal displacement of the circle in space, indicating that the image falls on the temporal retina in each eye when the circle is viewed binocularly. When the Titmus test is turned upside down so that the monocular image falls on the nasal retinas of each eye, the circles appear to lie behind the plane of the page. Now consider a binocular individual with normal stereopsis who is fixating on the center of a vertical object that is slanted so that its inferior aspect is closer than the superior aspect (Fig.  4.1). As the individual fixates the center of the slanted object, the visual image of the upper pole is postfixational, which means that it falls

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onto the nasal retina of each eye, whereas the visual image of the lower pole is pre-­ fixational, falling onto the temporal retina of each eye. The reader can appreciate this slant illusion by holding a pencil in the midsagittal plane with the upper pole slanted away from the body and the lower pole tilted toward the body. On occlusion of either eye, the upper pole of the pencil will appear to be tilted, with the upper pole leaning toward the side of the uncovered eye (Fig. 4.1) [33]. So under monocular conditions, the person perceives a disconjugate image torsion that is analogous to how the image would be seen if there were intorsion of each eye. If a vertical cyclodisparity in the 2 eyes is translated by the visual cortex into a binocular sensation of depth in the pitch plane (ie, slant), can retinal image torsion cause a vertical binocular image to be perceived as slanted in the pitch plane? The

a

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Fig. 4.1  Tilt is the monocular correlate of stereoscopic slant. (a) An individual binocularly viewing a vertical object that is slanted in the pitch plane. (b) The monocular images corresponding to the object are extorted when viewed with each eye

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answer is yes. The reader can appreciate this phenomenon by placing a white Maddox Rods over each of the 2 eyes in a trial frame, and looking toward a bright focal light source with the grids oriented horizontally to produce a vertical line (Fig. 4.2). Now counterrotate the lenses so that their upper pole of each line moves nasally and their lower pole moves temporally until the image of the binocular vertical line breaks into 2 tilted lines (Fig. 4.2). If the rotation is stopped at the break point, the torsional diplopia can be overcome and the 2 lines can be fused. When cyclofusion occurs, which is almost purely on a sensory (as opposed to a motor)

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Fig. 4.2  Binocular cyclodisparity of vertical lines is perceived stereoscopically as slant. (a) Rotation of horizontal double Maddox Rods to produce binocular image intorsion (as would be seen if both eyes were extorted). (b) Sensory cyclofusion causes the patient to stereoscopically perceive a vertical line (solid line) as slanted in the pitch (ie, sagittal) plane (dashed line)

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basis, the single line will suddenly appear to be stereoscopically slanted in the pitch plane, with the upper pole inclined toward the observer and the lower pole inclined away from the observer. The opposite inclination is seen when the upper poles of the Maddox Rods are rotated temporally. The original treatise by Wheatstone [34] describing his invention of the stereoscope in 1838 provided the first example of pitch stereopsis produced by dichoptic lines that are tilted in different directions. This stereoscopic effect shows us something remarkable about the normal binocular visual system. It tells us that when an isolated vertical image cyclodisparity falls within the physiologic range of sensory fusion, it is misregistered stereoscopically as a slant of the vertical object in the pitch plane [7, 21, 22, 32–38]. In a real world setting, however, perceived pitch is not solely a function of retinal cyclodisparity, but it depends both on the brain’s computation of registered eye rotation and on retinal cyclodisparity. So to create an accurate stereoscopic representation of vertical objects in the pitch plane, cyclovergence should not occur and the eyes must be locked into a well-defined static orientation relative to a given gaze position (ie, conforming to Donder’s law) [1, 7, 21, 22]. The innervational patterns of oblique muscle recruitment, which counteract the torsional actions of the rectus muscles in different positions of gaze, must also be subordinate to this goal. That binocular torsional control represents an active function of the human oblique muscles rather than an evolutionary loss of contractile function is seen in the kinematics of human convergence [39]. It has long been recognized that both eyes extort during convergence and that this extorsion increases in downgaze and decreases in upgaze [40, 41]. (Extorsion is even considered by some to be a component of the synkinetic near reflex [42].) While the existence of these cyclovergence movements were once thought to constitute a violation of Listing’s law, they can be reconciled with Listing’s law if it is assumed that convergence is associated with a temporal rotation of Listing’s plane in each eye (Fig. 4.3) [43]. Vertical rotation of the eyes around these temporally rotated axes produces incyclovergence of the eyes in upgaze and excyclovergence in downgaze [44–46]. Several lines of evidence suggest a neural and biomechanical basis for these cyclovergence movements. In monkeys, Mays et al [47] measured single cell recordings within the trochlear nucleus and found decreased unit activity during convergence. This decrease in firing rate was greater when the monkey converged in downgaze than in upgaze, a finding that corresponds to the observed convergence-associated torsional movements in humans. More recently, dynamic magnetic resonance imaging by Demer et al [48, 49] have found that downward rotation of the lateral rectus muscle pulley and medial rotation of the inferior rectus pulley during convergence, indicating that the inferior oblique muscle may also play a role in convergence-associated torsion, presumably via its collagenous attachments to the lateral rectus and inferior rectus muscles. From an evolutionary perspective, it is worth examining whether these torsional movements during convergence simply represent primitive adaptations that have been phylogenetically retained, like the small ocular counterroll which has no known function in humans [17]. In the lateral-eyed animal, upgaze corresponds to an intorsional movement of both eyes when the rotation is viewed from the frontal

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a

D

D LP

LP U

U

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D

D

U D LP

U D

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Fig. 4.3  View of both eyes from above demonstrating orientation of Listing’s plane (LP) during distance fixation (a) and convergence (b). Curved arrows denote cyclovergence movements of the eyes associated with vertical rotation about horizontal visual axes in Listing’s plane. A “saloon door” rotation of Listing’s plane, which is opposite in direction to the ocular rotation, can be used to reconcile the convergence-associated extorsion of the eyes in downgaze (D) and intorsion of the eyes in upgaze (U) with Listing’s law

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perspective, while downgaze corresponds to an extorsional rotation of both eyes. One could argue that convergence in humans may simply stress the system to a degree that prevents binocular suppression of these primitive rotations. However, recent studies suggest that the frontal binocular visual system has latched on to this primitive torsional bias and exapted it to subserve stereoscopic perception in the pitch plane [50, 51]. To subserve stereopsis, the oblique muscles have been exapted to torsionally align the eyes with their corresponding visual images in a way that preserves the binocular horizontal disparities that produce stereoscopic perception in different positions of vertical gaze [51]. This exaptation serves to minimize the brain’s computational load for stereoscopic perception [51]. Human cyclovergence is most robust at near fixation, where it plays an active role in stereoscopic vision. If convergence were not linked to cyclovergence, symmetrical convergence on a frontoparallel plane would induce incyclodisparity of the horizontal images in upgaze and excyclodisparity of the horizontal images in downgaze for each eye, solely on the basis of the geometric angle from which each eye views a planar surface. (The opposite cyclodisparity bias occurs for vertical visual landmarks due to projection geometry; however, it is reduced or reversed by the horizontal retinal shear that was described by Helmholtz [40].) In convergence, the increased intorsion of the eyes in upgaze and extorsion in downgaze helps to torsionally align the horizontal meridians of the eyes with their respective horizontal visual landmarks, thereby facilitating stereopsis. Since convergence is generally used for downgaze, where near objects are situated, the innervational link between convergence and extorsion presumably serves to set the operational position for stereopsis as slightly in downgaze, where near objects can be held by the arms and illuminated by overhead light [40, 41, 52]. Although the torsional movements associated with convergence are preprogrammed [17], they exhibit remarkable plasticity [53] and are enhanced by the depth perception of stereograms [54], demonstrating that they also rely on visual input to more accurately subserve the needs of binocular vision and depth perception. Without these torsional movements, convergence during vertical gaze would limit optimal stereoscopic perception to 1 gaze elevation, requiring repositioning of the head to optimize depth perception of targets at different earth elevations. Thus, this oblique muscle exaptation provides the luxury-­ optimizing stereopsis for targets at different eye elevations without the necessity of head movements in the pitch plane. Almost 30 years ago, Blakemore et al [32] recorded action potentials from binocular neurons in the cat’s visual cortex and measured orientation selectivity during simultaneous binocular stimulation. Certain binocular cells responded specifically to objects tilted in 3-dimensional space toward the cat or away from it [32]. Such binocular cells may form at least part of the substrate for sensory cyclofusion in humans. The survival value of stereoscopic spatial orientation explains why cyclofusional movements are so limited in primary gaze and why sensory cyclofusion is so well developed [3–7, 55, 56]. Sensory cyclofusion without motor cyclofusion is a prerequisite for pitch stereopsis (ie, slant perception). Motor cyclofusion of these torsionally disparate vertical landmarks would induce a misperception of stereoscopic slant for vertical lines. For any position of gaze, the oblique muscles must

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torsionally anchor the eyes to produce a stable motor substrate for slant perception of vertical objects. Psychophysical experiments have shown that horizontal visual landmarks are selectively used in humans to lock in torsional eye position, although the neural feedback loops for this process are unknown. As early as 1861, Nagel [35] observed that the rotation of horizontal fusion contours produced cyclovergence, while the rotation of vertical contours produced only a stereoscopic effect [28]. Ogle and Ellerbrock [37] noted that cyclofusion of torsionally disparate horizontal lines that were presented dichoptically with no visual background caused a previously fused vertical line to pitch in the sagittal plane. According to Bradshaw and Rogers [57], cyclovergence is not well driven by disparities along vertical meridians even when these are created by a real inclined surface. By inducing cyclodisparity of horizontal lines to the 2 eyes dichoptically, small cyclofusional eye movements can be elicited in humans under experimental conditions [7, 20, 23, 24, 37, 38, 56]. The small size of these cyclofusional movements suggests that the human cyclovergence system is equipped to provide a fine-motor modulation to a system that is designed primarily for stability rather than movement [7]. The greater stereoscopic value of vertically compared than horizontally tilted images explains why vertically oriented gratings evoke smaller cyclovergence movements than horizontally oriented gratings [23]. Humans inhabit a terrestrial environment composed of primarily vertical and horizontal landmarks that serve as reference points for vertical orientation [21, 22]. In a terrestrial setting, the most prominent horizontal contour is the horizon, which may be the main visual reference for stabilizing the eyes relative to the outside world [21]. While cyclodisparities of vertical contours may be caused by slant of the observed objects, cyclodisparities of horizontal contours indicate cyclovergence errors that need correction [20, 21]. As summarized by Howard and Rogers [33]: An orientation disparity between the images of lines in the horizontal plane of regard can be due only to eye misalignment, whereas an orientation disparity from a vertical line may be due to inclination of the line in depth. It would therefore be adaptive if cyclovergence were evoked only by disparities in horizontal elements, leaving residual disparities in vertical elements intact as clues for inclination.

If cyclodisparities in horizontal visual landmarks of the visual scene that occur at low stimulus frequencies and low amplitudes serve as the physiologic stimulus for cyclovergence as proposed by Howard and Zacher [58], then horizontal cyclofusion must serve to torsionally anchor the eyes, allowing the visual cortex to extract and construct a stable and reproducible representation for pitch stereopsis [7]. By using cyclodisparity of horizontally oriented lines as the feedback signal for torsional misalignment of the eyes and allowing cyclodisparity of vertically oriented lines to signal depth (ie, slant), the brain can recruit the oblique muscles to control cyclovergence and thereby assure accurate stereoscopic perception of vertical objects in the pitch plane. While a cyclodisparity of horizontal lines are the driving force for this cyclofusional reflex, stereopsis and vertical visual orientation are its emergent functions.

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If a binocular vertical cyclodisparity produces a stereoscopic sensation of pitch, then ocular torsion produced by cyclovertical muscle palsy should produce an abnormal sensation of pitch stereopsis. Not surprisingly, abnormal pitch stereopsis is a common symptom of acquired superior oblique palsy. Lindblom et al [59] found that adults with acquired unilateral or bilateral superior oblique palsy perceived the upper pole of a vertical rod as being tilted toward them in the sagittal plane under binocular conditions. This stereoscopic illusion corresponded to the associated extorsion of the paretic eye (Fig. 4.4). Subjects also perceived the unfused image corresponding to the eye with the superior oblique palsy as intorted (ie, tilted in the roll plane) relative to the other image. As seen in superior oblique palsy, the concept of Panum’s space can be extrapolated to torsional eye position. Ocular torsion within the realm of fusion induces an illusory pitch stereopsis of isolated vertical lines, while torsion outside the realm of fusion induces torsional diplopia in the roll plane [5, 60, 61]. Ocular torsion of 5°, as generally occurs with unilateral superior oblique palsy, is not an impediment to fusion, whereas ocular torsion of more than 10°, which accompanies bilateral superior oblique palsy, precludes fusion [6]. In unilateral superior oblique palsy, it is often stated that strabismus surgery or prismatic correction to vertically realign the eyes is sufficient to restore cyclofusion, even when the extorsion persists in the palsied eye. However, the persistence of extorsion in one eye is not without perceptual consequence, and it should be remembered that sensory fusion of torsional images can cause vertical objects to be perceived as slanted. Psychophysical experiments by Howard and Kaneko [62] have shown that an isolated shear disparity of vertical lines will induce a stereoscopic slant, whereas a cyclodisparity that twists both vertical and horizontal lines will not induce a perceived slant of the visual environment. These experiments would predict that patients with unilateral superior oblique palsy and extorsion of 1 eye would stereoscopically perceive isolated visual landmarks in the sagittal plane as slanted toward them.

Cycloversion, Nonstereoscopic Perception, and the Roll Plane Unlike cyclovergence, which is remarkably stable and seems to depend primarily on where the eyes are looking, human cycloversion shows both intrasubject and intersubject variation [39]. These findings implicate different neural control strategies for cycloversion and cyclovergence [39]. One explanation for this disparity is that cycloversion is probably not as important to stereoscopic vision as cyclovergence, which determines stereoscopic volume at any given pitch plane, alters slant perception of vertical objects, and is necessary for stereo constancy [39]. Nevertheless, large cycloversional movements of the eyes create a problem for stereoscopic perception. Misslisch et al [17] have argued that the superimposition of a primitive cycloversion movement of the eyes (such as an ocular counterroll evoked by a head tilt) on convergence would induce a cyclodisparity and disrupt stereoacuity. The brain strikes a balance between gyroscopic and stereoptic mechanisms by damping the ocular counterroll by approximately 70% in convergence [18]. In this

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a

Right Eye

Left Eye

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Fig. 4.4  Right superior oblique palsy. (a) Examiner’s view of patient’s retinas showing extorsion of the right eye. (b) Under binocular conditions, the patient perceives a vertical object (solid line) as stereoscopically slanted in the pitch plane (dashed line)

way, exaptations of the neural circuitry that steers our cyclovergence and cycloversion movements seem to override our primitive adaptations to promote stereopsis [39, 50]. While the human oblique muscles function under static conditions to constrain torsional rotation of the eyes, it is not the physiologic role of any muscle to simply constrain movement (check ligaments and muscle pulleys are better suited to this function). To the surprise of many, Tweed et al [63] have recently found that the human oblique muscles execute large cycloversional saccades immediately

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preceding head movements in the roll plane. The 3-dimensional scleral search coil recordings were performed as normal study participants observed a laser spot while their eyes were directed 20° downward. The subjects then made combined eye-head movements to refixate the laser spot as it jumped 20° (from right head tilt and right gaze to left head tilt and left gaze). Eye movement recordings showed that these subjects generated ipsiversive torsional saccades that ranged in size from 11° to 17° and averaged 14.5°. These cycloversional eye movements preceded the head movements by 20 to 60 milliseconds, indicating that these movements were not vestibular in origin. The eyes arrived at the target first and locked on, hanging in space as the head rotated around them (Fig. 4.5). When the head came to a halt, the ocular torsion relative to the head had stabilized near zero, and the eyes were poised for the swiftest possible response to further movement of the target. These torsional eye movements, which occur at the initiation of a head tilt and are not visible on gross inspection, may reveal another exaptation of our torsional control system. The human oblique muscles may have been exapted to generate saccadic torsional eye movements to reestablish roll plane orientation in anticipation of a postural rotation in the roll plane. These anticipatory saccades instantaneously recalibrate torsional eye position to provide a stable visual representation of tilt in the roll (frontal) plane. The evolution of frontally positioned eyes for stereopsis may have created a survival advantage for the grafting of this new torsional control system on top of the ancestral control system that produces the ocular counterroll (Table  4.1). Similar torsional saccades have not been observed in lateraleyed animals (although studies involving eye-head or eye-body coordination in animals are extremely difficult to perform).

Reversion From Exaptation to Adaptation Since ocular torsion within the realm of fusion can produce a stereoscopic tilt in the pitch plane, it seems reasonable to ask whether strabismus or other neurologic disease, which can be associated with a pathologic tilt in the internal

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Fig. 4.5  Depiction of torsional eye position during head tilt from side to side. (1) Initial torsional position during right head tilt. (2) During head tilt to the left, the eyes lead the head and quickly assume their final torsional position corresponding to the left head tilt. (3) The eyes “hang in space” until the head catches up. (4) Head tilt to the right produces the reverse sequence of torsional eye movements. (Reprinted with permission from The American Association for the Advancement of Science, copyright 1999 [63].)

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Table 4.1  Oblique Muscle Adaptations and Exaptations Adaptations (Lateral-Eyed Animals) Pitch plane Dorsal light reflex Ocular counterroll (torsional)

Adaptations (Humans) Cyclovergence

Exaptations (Humans)

Primary oblique muscle overaction

Fusional cyclovergence (for pitch stereopsis)

Alternating skew deviation Cycloversion

Roll plane Dorsal light reflex

Ocular counterroll (vertical)

Dissociated vertical divergence (vertical component) Cycloversion to torsional optokinetic targets, static visual tilt, binocular vertical disparity Ocular counterroll (torsional), skew deviation

Dissociated vertical divergence (torsional component) ? Anticipatory torsional saccades

representation of the gravitational vertical, could recalibrate prenuclear innervation to the extraocular muscles and produce a torsional deviation of the eyes that conforms to this internal shift. Again, the answer is yes. One of the primitive functions of the human oblique muscles is to rotate the eyes toward the subjective visual vertical; when this internal representation is altered under pathologic conditions, ocular torsion is the inevitable result. In humans, as in lower animals, the central vestibular system uses weighted input from the 2 labyrinths and weighted visual input from the 2 eyes to establish subjective vertical orientation in pitch and roll [64, 65]. In humans, cycloversion is evoked by visual or graviceptive imbalance in the roll plane [64] whereas cyclovergence is evoked by a visual or graviceptive imbalance in the pitch plane [65]. In the roll plane, unilateral loss of otolithic tone secondary to brainstem, cerebellar, or utricular injury causes skew deviation, whereas asymmetrical visual input in humans with congenital strabismus evokes dissociated vertical divergence (Table) [65]. In skew deviation, unequal graviceptive tone from the otoliths produces a pathologic tilt in the internal representation of the visual vertical in the roll plane, which is associated with a corresponding torsional repositioning of both eyes and a vertical divergence of the eyes (Table 4.1) [66]. In dissociated vertical divergence, a dorsal light reflex in the roll plane is also associated with visually induced tilt in the subjective visual vertical, and the cycloversional component is ipsidirectional to the patient’s perceived visual tilt [67]. Since the cycloversional component of dissociated vertical divergence does not accompany the dorsal light reflex in lateral-eyed animals, and it cannot be accounted for by anatomical repositioning of the extraocular muscles, this component of the human dorsal light reflex seems to represent an exaptation to restore vertical orientation during monocular viewing [67]. The associated cycloversion movement that occurs when humans fuse vertically disparate images [68, 69] may indicate that binocular vertical disparity in humans is similarly misregistered by the brain as tilt [70].

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In the pitch plane, these same primitive adaptations are operative. Donahue and I [65] have proposed that primary oblique muscle overaction is associated with a slant of the internal representation of the visual vertical in the pitch plane. A subjective inclination of the superior portion of the visual environment toward the individual would produce a corresponding extorsion of both globes and lead to inferior oblique muscle overaction [65]. Conversely, structural neurologic disease within the brain stem or cerebellum would produce the intorsion and superior oblique muscle overaction so commonly seen in children with Chiari malformations, meningomyelocele, or hydrocephalus [65]. The alternating skew deviation on lateral gaze with bilateral abducting hypertropia that is associated with craniocervical disease may represent another central vestibular disturbance in the pitch plane [71, 72]. Under pathological conditions, the oblique muscles still function to keep the eyes in binocular torsional register with the perceived visual environment, and an altered torsional position of the eyes constitutes an ocular motor recalibration to the tilted or slanted internal representation of the visual world that characterizes central vestibular disease. By recognizing that a subjective tilt of the visual environment evokes a corrective torsional repositioning of both eyes, we can begin to place the horse before the cart in understanding congenital strabismus.

Conclusions To understand why you really need your oblique muscles, it is necessary to distinguish primitive adaptations, which originally evolved to stabilize laterally placed eyes during body pitch and roll, from exaptations, which subsequently evolved to meet the needs of frontal binocular vision. The human oblique muscles have been exapted to override primitive torsional adaptations with newer mechanisms that subserve stereopsis. These exaptations govern the relative torsional alignment of the eyes in different positions of gaze. Since perception of stereoscopic slant is a function of torsional eye position, the human oblique muscles modulate cyclovergence to establish a stable stereoscopic pitch representation of the visual world. In the roll plane, the human oblique muscles generate a cycloversion movement of the eyes just prior to volitional head movement to lock in a stable visual perception of tilt. These exaptations provide spatial accuracy and temporal continuity to our stereoscopic visual perception of slant and our nonstereoscopic visual perception of tilt. In a larger sense, they furnish us with a multifaceted torsional control system that provides 3-dimensional stability to the visual world and thereby improves fitness. Exaptations in human oblique muscle function do not completely erase more primitive adaptations. These primitive adaptations produce the small vestigial torsional eye movements that can be measured experimentally by inducing pitch or tilt of the external visual environment. They manifest clinically when congenital strabismus or other central vestibular disease alters our internal representation of the visual vertical. One may conclude that only our primitive adaptations are vestigial; our oblique muscles are not.

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References 1. Van Rijn LJ. Torsional eye movements in humans [master’s thesis]. Rotterdam: Universiteitsdrukkerij Erasmus Universiteit Rotterdam; 1994. p. 1–9. 2. Balliet R, Nakayama K. Training of voluntary torsion. Invest Ophthalmol Vis Sci. 1978;17:303–14. 3. von Noorden GK.  Clinical observations in cyclodeviations. Ophthalmology. 1979;86:1451–60. 4. Guyton DL, von Noorden GK.  Sensory adaptations to cyclodeviations. In: Proceedings of the third meeting of the International Strabismological Association, May 10–12. New York: Grune & Stratton; 1978. p. 1978. 5. Guyton DL.  Ocular torsion: sensorimotor principles. Graefes Arch Clin Exp Ophthalmol. 1988;226:241–5. 6. von Noorden GK.  Binocular vision and ocular motility: theory and management of strabismus. 5th ed. St Louis: CV Mosby; 1996. p. 8–84. 7. Van Rijn LJ, Van der Steen J, Collewijn H. Instability of ocular torsion during fixation: cyclovergence is more stable than cycloversion. Vis Res. 1994;34:1077–87. 8. Collewijn H, Van der Steen J, Ferman L, Jansen TC. Human ocular counterroll: assessment of static and dynamic properties from electromagnetic scleral coil recordings. Exp Brain Res. 1985;59:185–96. 9. Jampel RS. Ocular torsion and the primary retinal meridian. Am J Ophthalmol. 1981;91:14–24. 10. Walls GL.  The vertebrate eye and its adaptive radiation. Bloomfield Hills: Cranbrook Institute of Science; 1942. p. 301–4. 11. Graf W, Meyer DL. Eye positions in fishes suggest different modes of interaction between commands and reflexes. J Comp Physiol. 1978;128:241–50. 12. von Holst E. Über den Lichtrückenreflex bei der Fische. Pubbl Stn Zool Napoli II. 1935;15:143–58. 13. von Holst E.  Die Gleichgewichtssine der Fische. Verh Dtsch Zool Ges. 1935;37:109–14. 14. Collewijn H, Noorduin H. Vertical and torsional optokinetic eye movements in the rabbit. Pflügers Archiv. 1972;335:87–95. 15. Leigh RJ, Zee DS. The neurology of eye movements. 3rd ed. New York: Oxford University Press; 1999. p. 22. 16. Simpson JT, Graf W. Eye-muscle geometry and compensatory eye movements in lateral-eyed and frontal-eyed animals. Ann N Y Acad Sci. 1981;374:20–30. 17. Misslisch H, Tweed D, Hess BJM. Stereopsis outweighs gravity in the control of the eyes. J Neurosci. 2001;21:RC126, 1–5. 18. Graf W, Meyer DL.  Central mechanisms counteract visually-induced tonus asymmetries: a study of ocular responses to unilateral illumination in goldfish. J Comp Physiol. 1983;150:473–81. 19. Meyer DL, Bullock TH. The hypothesis of sense-organ-dependent tonus mechanisms: history of a concept. Ann N Y Acad Sci. 1977;290:3–17. 20. Crone RA, Everhard-Halm Y. Optically induced eye torsion, I: fusional cyclovergence. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1975;195:231–9.

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21. Van Rijn LJ, van der Steen J, Collewijn H. Eye torsion elicited by oscillating gratings: effects of orientation, wavelength, and stationary contours. Vis Res. 1994;34:533–40. 22. Collewijn H, Van der Steen J, Van Rijn LJ.  Binocular movements and depth perception. In: Gorea A, Fregnac Y, Kopoula Z, Findlay J, editors. Representations of vision. Trends and tacit assumptions in vision research. Cambridge, UK: Cambridge University Press; 1991. p. 165–83. 23. Howard IP, Sun L, Shen X. Cycloversion and cyclovergence: the effects of the area and position of the visual display. Exp Brain Res. 1994;100:509–14. 24. Guyton DL, Weingarten PE. Sensory torsion as the cause of primary oblique muscle overaction/underaction and A-and V-pattern strabismus. Binocul Vis Eye Muscle Surg Q. 1994;9:209–36. 25. Brecher GA.  Die optokinetische Auslösung von Augenrollung und rotatorischem Nystagmus. Pflügers Arch Gesamte Physiol Menschen Tiere. 1934;234:13–28. 26. Cheung BS, Howard IP. Optokinetic torsion: dynamics and relation to circularvection. Vis Res. 1991;31:1327–35. 27. Wade NJ, Swanston MT, Howard IP, Ono H, Shen X. Induced rotary motion and ocular torsion. Vis Res. 1991;31:1979–83. 28. Crone RA. Optically induced eye torsion, II: optostatic and optokinetic cycloversion. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1975;196:1–7. 29. Goodenough DR, Sigman E, Oltman PK, Rosso J, Mertz H.  Eye torsion in response to a tilted visual stimulus. Vis Res. 1979;19:1177–9. 30. Gould SJ. Exaptation: a crucial tool for evolutionary psychology. J Soc Issues. 1991;47:43–65. 31. Buss DM.  Adaptations, exaptations, and spandrels. Am Psychol. 1998;53:533–48. 32. Blakemore C, Fiorentini A, Maffei L. A second neural mechanism of binocular discrimination. J Physiol. 1972;226:725–49. 33. Howard IP, Rogers BJ.  Binocular vision and stereopsis. New  York: Oxford University Press; 1995. p. 381–426. 34. Wheatstone C. Contributions to the physiology of vision. Philos Trans R Soc Lond. 1838;128:371–94. 35. Nagel A. Das Sehen mit zwei Augen: Leipzig und Heidelberg 1861: Ref: Nagel A: Über das Vorkommen von wahren Rollungen des Auges um die Gesichtalinie. Albrecht Von Graefes Arch Ophthalmol. 1868;14:228–46. 36. Enright JT.  Stereopsis, cyclotorsional “noise” and the apparent vertical. Vis Res. 1990;30:1487–97. 37. Ogle KN, Ellerbrock VJ.  Cyclofusional movements. Arch Ophthalmol. 1946;36:700–35. 38. Sullivan MJ, Kertesz AE.  Peripheral stimulation and human cyclofusional response. Invest Ophthalmol Vis Sci. 1979;18:1287–90. 39. Porrill J, Ivins JP, Frisby JP. The variation of torsion with vergence and elevation. Vis Res. 1999;39:3934–50.

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40. von Helmholtz H.  Handbuch fur der Physiologischen Optik. Hamburg: Voss; 1867. 41. Hering E.  The theory of binocular vision (trans: Bridgeman B, Stark L). New York: Plenum Press; 1977. p. 129–45. 42. Allen MJ, Carter JH. The torsion component of the near reflex. Am J Optom. 1967;44:343–9. 43. Mok D, Ro A, Cadera W, Crawford JD, Vilis T. Rotation of Listing’s plane during vergence. Vis Res. 1992;32:2055–64. 44. Vilis T.  Physiology of three-dimensional eye movements: saccades and vergence. In: Fetter M, Misslisch H, Tweed D, editors. Three-dimensional kinematics of eye, head, and limb movements. Amsterdam: Harwood Academic Press; 1997. p. 56–72. 45. Mikhael S, Nicolle D, Vilis T. Rotation of Listing’s plane by horizontal, vertical, and oblique prism-induced vergence. Vis Res. 1995;35:3243–54. 46. Van den Berg AV, Van Rijn LJ, de Faber J-THN.  Excess cyclovergence in patients with intermittent exotropia. Vis Res. 1995;35:3265–78. 47. Mays LE, Zhang Y, Thorstad MH, Gamlin PDR. Trochlear unit activity during ocular convergence. J Neurophysiol. 1991;65:1484–91. 48. Demer JL, Oh SY, Poukens V. The orbital layers of human and monkey oblique extraocular muscles (EOMs) insert on the orbital connective tissue system [ARVO abstract]. Invest Ophthalmol Vis Sci. 2001;42:S517. 49. Demer JL.  Mechanical interactions of oblique extraocular muscles (EOMs) with actively controlled rectus pulleys maintain kinematics of linear oculomotor plant. Soc Neurosci. In press. 50. Tweed D.  Visual-motor optimization in binocular control. Vis Res. 1997;37:1939–51. 51. Schreiber K, Crawford JD, Fetter M, Tweed D. The motor side of depth vision. Nature. 2001;410:819–22. 52. Nakayama K.  Kinematics of normal and strabismic eyes. In: Schor CM, Ciuffreda KJ, editors. Vergence eye movements: basic and clinical aspects. Boston: Butterworths; 1983. p. 199–295. 53. Schor CM, Maxwell JS, Graf EW. Plasticity of convergence-dependent variations of cyclovergence with vertical gaze. Vis Res. 2001;41:3353–69. 54. Kapoula Z, Bernotas M, Haslwanter T.  Listing’s plane rotation with convergence: role of disparity, accommodation, and depth perception. Exp Brain Res. 1999;126:175–86. 55. Jampel RS, Stearns AB, Bugola J.  Cyclophoria or cyclovergence: illusion or reality? In: Moore S, Mein J, Stockbridge L, editors. Orthoptics: past, present, future. New York: Stratton Intercontinental Medical Book Corp; 1976. p. 403–8. 56. Crone RA. Human cyclofusional response. Vis Res. 1971;11:1357–8. 57. Bradshaw MF, Rogers BJ. Is cyclovergence state affected by the inclination of stereoscopic surfaces [ARVO abstract]? Invest Ophthalmol Vis Sci. 1994;35:1316. 58. Howard IP, Zacher JE.  Human cyclovergence as a function of stimulus frequency and amplitude. Exp Brain Res. 1991;85:445–50.

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59. Lindblom B, Westheimer G, Hoyt WF.  Torsional diplopia and its perceptual consequences. Neuroophthalmology. 1997;18:105–10. 60. Kertesz AE, Jones RW. Human cyclofusional response. Vis Res. 1970;10:891–6. 61. Angio G. A vertical horopter. Opt Acta (London). 1974;21:277–92. 62. Howard IP, Kaneko H. Relative shear disparities and the perception of surface inclination. Vis Res. 1994;34:2505–17. 63. Tweed D, Haslwanter T, Fetter M. Optimizing gaze control in three dimensions. Science. 1998;281:1363–6. 64. Brodsky MC.  Dissociated vertical divergence: a righting reflex gone wrong. Arch Ophthalmol. 1999;117:1216–22. 65. Brodsky MC, Donahue SP. Primary oblique muscle overaction: the brain throws a wild pitch. Arch Ophthalmol. 2001;119:1307–14. 66. Brandt T, Dieterich M. Skew deviation with ocular torsion: a vestibular brainstem sign of topographic diagnostic value. Ann Neurol. 1993;33:528–33. 67. Brodsky MC.  Subjective correlates of dissociated vertical divergence. Paper presented at: 27th Annual Meeting of the European Strabismologic Association; June 8, 2001; Florence, Italy. 68. Van Rijn LJ, Simonsz HJ, ten Tusscher MPM. Dissociated vertical deviation and eye torsion: relation to disparity-induced vertical divergence. Strabismus. 1997;5:13–20. 69. Cheeseman EW, Guyton DL. Vertical fusional vergence: the key to dissociated vertical deviation. Arch Ophthalmol. 1999;117:1188–91. 70. Brodsky MC. Vertical visual disparity and the human oblique muscles. Binocul Vis Strabismus Q. 2001;16:251–2. 71. Moster ML, Schatz NJ, Savino PJ, Benes S, Bosley TM, Sergott RC. Alternating skew on lateral gaze (bilateral abducting hypertropia). Ann Neurol. 1988;23:190–2. 72. Donahue SP, Brodsky MC.  Posterior canal predominance in bilateral skew deviation [letter]. Br J Ophthalmol. 2001;85:1395.

Postscript There continues to be tenacious resistance to the notion that human extraocular muscles can primarily overact due to excessive innervation. Yet we know that while cortical centers control body movements, subcortical centers control individual muscles. In infantile strabismus, this phenomenon results from persistent activation of visuo-vestibular pathways at the subcortical level. Its resurgence in humans with defective binocular vision represents a physiologic activation rather a neurological deficit. As disconjugate binocular torsion induces a relative retinal disparity that is perceived stereoscopically, these subcortical torsional pathways are necessarily extinguished early in infancy in the service of binocular vision and stereopsis. However, they continue to function in patients with infantile strabismus. The evolving human binocular visual system never knew that stereopsis was the goal. According to R.W.  Rodieck, “Evolution is not engineering-it is more like

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tinkering-­it is not design. The visual system never had an opportunity to be designed-­or redesigned from scratch; instead, both form and function reflect its long, particular, and capricious history.” (from The First Steps in Seeing. 1998, page 4, Sinauer Publications). What seems clear is that stereopsis necessitated exaptation of human oblique muscle function to constrain static torsion. Torsional control must be critical to binocular vision for evolution to have reconfigured this system. To this end, it is noteworthy that the superior rectus and superior oblique muscles uniquely receive crossed innervation from their brainstem nuclei. Why? To segregate the intorters on one side of the brainstem and the extorters on the other side. As discussed in Chap. 18, phoria adaptation also contributes to the stabilization of ocular torsion. Although ocular torsion is tightly constrained under normal binocular conditions, the human ocular counterroll of approximately 5% demonstrates that it is not absolute. A core concept here is that tilt is the monocular correlate of pitch. If both retinas are rotated in the same torsional direction, we perceive a stereoscopic tilt of the visual world, but if both are rotated in opposite directions (permitting fusion), we perceive a stereoscopic slant of the visual world, and our plane of optimal stereoscopic perception also becomes slanted away from us accordingly. Near is the ground, far is the sky. As we ambulate from an upright position, the terrestrial plane of the ground is pitched away from the visual axis as viewed from our upright position. Evolutionarily, this may explain a number of observations including our physiologic V pattern (to promote convergence in downgaze), and the binocular extorsion that is measurable during convergence (to actively rotate the vertical retinal meridians to maximize stereopsis. Everything fits together, although not by design. Interestingly, it was Darwin who first articulated the essential role of evolutionary reconfiguration. In his 1862 discussion of orchid evolution, he wrote that “When this or that part has been spoken of as contrived for some special purpose, it must not be supposed that it was originally always formed for that purpose. The regular course of events seems to be, that a part which originally served for one purpose, by slow changes became adapted for wholly different purposes.” Darwin C: On the Various Contrivances by which British Foreign Orchids are Fertilized by Insects, and on the Good Effects of Intercrossing. London, England: John Murray;1862, 346.

5

Latent Nystagmus Vestibular Nystagmus with a Twist

Vestibular disease holds little interest for the ophthalmologist. Although patients with vestibular disease can develop nystagmus, diplopia, and oscillopsia, these symptoms can be treated empirically. Peripheral vestibular disease is caused by injury to the labyrinth rather than to the eye, whereas central vestibular disease is caused by brainstem or cerebellar disorders involving the central vestibular pathways along their course to the ocular motor nuclei [1, 2]. But the ophthalmologist encounters a unique form of vestibular nystagmus that is caused by unbalanced input from the two eyes rather than from the two labyrinths. This visuo-­vestibular nystagmus is known as “latent nystagmus.” Congenital esotropia is associated with a clinical triad of latent nystagmus, inferior oblique muscle overaction, and dissociated vertical divergence [3]. These unique eye movements conform to primitive vision-dependent tonus mechanisms that are reactivated by congenital strabismus or early abnormal visual experience [4–7]. Evolutionary analogues of primary oblique muscle overaction and dissociated vertical divergence have been identified in lower vertebrates [5, 6]. In fish, these are physiologic extraocular movements that use weighted binocular visual input to modulate extraocular muscle tonus and to maintain visual orientation during body movements [5, 6]. The stimulus for bilateral inferior oblique muscle overaction corresponds to a visuo-vestibular imbalance in the sagittal (pitch) plane, while dissociated vertical divergence corresponds to a similar imbalance in the coronal (roll) plane [5–7]. We propose that latent nystagmus results from a similar visuo-vestibular tonus imbalance in the horizontal turning (yaw) plane.

What Is Latent Nystagmus? Latent nystagmus is a binocular horizontal oscillation that becomes apparent when 1 eye is covered. First described by Faucon in 1872 [8], latent nystagmus develops when congenital esotropia precludes frontal binocular vision early in infancy

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_5

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[9–13]. In this setting, a conjugate horizontal jerk nystagmus can be induced by covering 1 eye, blurring 1 eye, or reducing image brightness in 1 eye [1, 10, 14]. In latent nystagmus, the slow-phase rotation of the fixating eye is directed toward the nose and the fast-phase rotation of the fixating eye is directed toward the ear [1, 2, 14]. As such, fixation with the right eye generates a right-beating nystagmus, while fixation with the left eye produces a left-beating nystagmus [10]. In children with congenital esotropia and alternating fixation, the direction of nystagmus will spontaneously reverse when fixation is switched from one eye to the other [10–15]. Even after the eyes have been surgically realigned, occlusion of either eye will continue to induce latent nystagmus. The intensity of latent nystagmus is maximal in abduction and minimal in adduction, causing some patients to maintain a head turn to place the fixating eye in an adducted position. The intensity of latent nystagmus decreases when visual attention declines and increases during attempted fixation [13–22]. In fact, some patients can reverse the direction of their latent nystagmus by looking at an imagined target and mentally switching fixation from one eye to the other [16, 22]. In children with latent nystagmus, the development of amblyopia or the recurrence of ocular misalignment can disrupt binocular vision and make a latent nystagmus become manifest [23]. The magnitude of the resulting manifest latent nystagmus is proportional to the degree of the interocular visual disparity [1]. Most patients with clinical latent nystagmus actually have a small spontaneous jerk nystagmus that can be measured with both eyes open using eye movement recording [14]. However, successful treatment of amblyopia or strabismus can convert a manifest latent nystagmus to a clinical latent nystagmus [23]. Manifest latent nystagmus has also been reported in children with unilaterally reduced vision and sensory esotropia resulting from congenital disorders such as cataract or optic nerve hypoplasia [9–11]. In this setting, a child will often maintain a head turn to position the fixating eye in adduction [9–11]. Various theories have been advanced to explain latent nystagmus [24]. These include a primitive tonus imbalance [1], an egocentric disorder [14], a disorder of the subcortical optokinetic system [21], a subcortical maldevelopment of retinal slip control [22], abnormal cortical motion processing [25, 26], a disorder of proprioception [27], and an evolutionary preponderance of the nasal half of the retina [3, 28]. These disparate theories can be reconciled by considering the critical evolutionary function of the eyes as sensory balance organs.

Nasotemporal Asymmetry and Latent Nystagmus Latent nystagmus is associated with nasotemporal asymmetry of the horizontal optokinetic response during monocular viewing [25, 26]. However, not all patients with nasotemporal asymmetry have latent nystagmus [29]. In patients with nasotemporal asymmetry, the monocular optokinetic responses to nasally moving targets are brisk, while those to temporally moving targets are poor in each eye. This “nasalward” movement bias under monocular viewing conditions corresponds both

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in direction and in waveform to the nasalward slow-phase drift of the fixating eye in latent nystagmus [21, 29]. To our knowledge, Roelofs [30] first observed horizontal optokinetic asymmetry in patients with latent nystagmus in 1928. Fifty years later, experiments by van Hof–van Duin [31] and Wood et al [32] suggested that reduced binocularity in strabismus can lead to nasotemporal asymmetry. In 1977, Kommerell [33] suggested that latent nystagmus could be regarded as the consequence of horizontal optokinetic asymmetry. In 1982, Hoffman [34] developed a model to explain nasotemporal asymmetry based on combined cortical and subcortical input to the nucleus of the optic tract in the cat. In 1983, Schor [21] proposed that latent nystagmus and nasotemporal optokinetic asymmetry are mediated by the nucleus of the optic tract. Human nasotemporal asymmetry has received considerable attention because it persists throughout life in humans with congenital strabismus [15, 21, 25, 34–36]. Even after surgical realignment, nasotemporal asymmetry remains as a “footprint in the snow” of abnormal visual development [36]. Nasotemporal asymmetry is seen in rabbits, kittens, monkey infants, and human infants within the first 6 months of life [36]. The evolutionary retention of this primitive nasotemporal asymmetry in human infancy shows how ontogeny recapitulates phylogeny during human visual development [37, 38]. In ordinary life, large parts of the visual field move together during self-motion [39]. Optic flow occurs during translation (which is signaled by the otoliths and linear optic flow) and rotation (which is signaled by the semicircular canals and rotational optic flow) [39]. The low sensitivity to nasal to temporal optic flow in afoveate, lateraleyed animals is commonly assigned the function of preventing the locomoting animal from responding to the image motion of stationary contours during forward motion, while permitting full compensation for rotational input during turning movements [39–41]. The absence of nasotemporal optokinetic responses in lateral-eyed animals assures that during forward movements, ineffective temporalward eye movements do not destabilize images of objects that are directly ahead of the animal [39–41]. The optokinetic responses of both eyes are controlled by whichever eye is stimulated by temporal-to-nasal movement of the visual world [40]. Latent nystagmus recapitulates this monocularly driven horizontal optokinetic movement.

Is Latent Nystagmus a Vestibular Nystagmus? Vestibular eye movements are reflex contraversive rotations of the eyes that occur during involuntary head movements, acting to stabilize the position of the eyes in space and thereby maintain visual orientation [1, 2, 42, 43]. According to Walls, “ … vestibularly-controlled reflex eye movements are historically the oldest of all, with all other kinds of eye-muscle controls and operations accreted to them above the primitive fish level of evolution” [44] (p71). During head movements, input to the semicircular canals within the 2 labyrinths provides the afferent stimulus for the vestibulo-ocular reflex [1, 2, 43, 45]. The semicircular canals respond to angular

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acceleration and produce dynamic vestibulo-ocular eye movements. Damage to a horizontal semicircular canal pathway produces a nystagmus in the plane of the injured canal [43, 45]. In lateral- and frontaleyed animals, the geometry of the semicircular canals conforms closely with the orientation of the extraocular muscles [46]. When the head is rotated in a particular plane, a semicircular canal within the labyrinth detects acceleration and sends excitatory innervation to the corresponding extraocular muscles. Within the brainstem and cerebellum, peripheral vestibular input is summated to produce innervation to the appropriate extraocular muscle subnuclei and to maintain the position of the eyes in space. Each horizontal semicircular canal provides excitatory input to the ipsilateral medial rectus muscle and the contralateral lateral rectus muscle [1, 2, 43, 45]. Visual stabilization mechanisms act in concert with labyrinthine reflexes [43]. In normal life, optokinetic responses are elicited mainly by head movements, which also stimulate the vestibular system [39]. Because vestibular neurons receive such prominent visual and vestibular inputs, disrupting either input reduces the tonic activation of these neurons, with the effect of disturbing the responses to the other sensory modality [39]. Thus, labyrinthectomy eliminates optokinetic nystagmus in rabbits [47, 48], whereas blocking optic nerve activity with tetrodotoxin reduces the gain of the vestibulo-ocular reflex [39, 49]. According to Miles, each sensory modality “has played such a major role in the evolution of the other that it is impossible to understand the operation of either one in isolation” [41] (p393). A confluence of neuroanatomical, clinical, evolutionary, and experimental evidence has led us to conclude that latent nystagmus is a vestibular nystagmus that is brought about by unequal visual input from the 2 eyes rather than from the 2 ears (ie, a visuo-­vestibular nystagmus). The evidence that latent nystagmus arises when the 2 eyes revert to their primitive function as balance organs can be summarized as follows.

Neuroanatomy of Latent Nystagmus Studies in subhuman primates have shown that latent nystagmus arises as a result of incomplete development of visual input from occipitotemporal cortex to subcortical vestibular pathways [50, 51]. In monkeys with latent nystagmus, there is a loss of binocularity in the nucleus of the optic tract (NOT), the subcortical structure that feeds into the vestibular system, with most cells driven by the contralateral eye [50, 51]. The areas that normally provide binocular input to the NOT are the middle temporal (MT) visual area and the medial superior temporal (MST) visual area in occipitotemporal cortex. When strabismus is surgically induced in infant monkeys during the first 2 weeks of life, these monkeys also develop latent nystagmus and visual area MT/MST loses binocularity. If either eye is covered during infancy, visual area MT/ MST and NOT develop normal binocularity, but the striate cortex still shows loss of binocularity and these monkeys do not develop latent nystagmus [52]. This finding suggests that the initial cause of latent nystagmus is loss of binocularity in visual area MT/MST from the misaligned eye during the first few weeks of life [52].

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Neuroanatomical experiments have confirmed the Schor hypothesis [21] that the NOT is the generator of latent nystagmus [21, 34, 50–52]. A latent nystagmus occurs in monkeys following artificial induction of esotropia within the first 2 weeks of life [53]. Unilateral electrical stimulation of the NOT in binocularly deprived monkeys induces a conjugate nystagmus with the slow phases directed toward the side of stimulation [54, 55]. Latent nystagmus can be abolished by direct injection of muscimol, a potent γ-aminobutyric acid A agonist into the NOT in monkeys [50]. Simultaneous bilateral blockage of the NOT virtually abolishes latent nystagmus for the duration of the blockade [50]. Subcortical optokinetic responses are also mediated by the pretectal NOT [15, 21, 34–36]. The monocular pathways subserving nasotemporal asymmetry and its neutralization by binocularly driven pathways from the visual cortex were first elucidated by Hoffman in the cat [34, 35]. The cat NOT is a diffuse cell aggregation in the pretectum that is optimally located to integrate direct retinal and diffuse cortical projections [34]. These nuclei have high levels of spontaneous activity and operate in a push-pull fashion such that the sum of their opponent innervation determines the optokinetic response [21, 34]. The NOT contains neurons that are sensitive to visual motion [54]. Many units in the primate NOT have large receptive fields that are appropriate for encoding full-­ field visual motion to support optokinetic eye movements [54]. Stimulation of the right and left NOT results in optokinetic nystagmus with slow phases to the right and left, respectively [21]. Output from the NOT is maximal for horizontal movements but 0 for vertical movements [34]. This phylogenetically ancient subcortical system is depicted in Fig. 5.1. Crossed connections from each eye to the contralateral NOT transmit horizontal visual motion information to the vestibular nucleus before impinging on the ocular motor nuclei [40, 56]. Pretectal neurons in the left NOT receive only crossed input from the right eye and respond only to leftward motion, while those in the right NOT receive only crossed input from the left eye and respond only to rightward motion [15, 21, 36]. In the first 6 months of infancy, this subcortical system predominates in humans, so that temporally directed monocular optokinetic responses are poor in early infancy compared with nasally directed optokinetic responses [36]. By 6 months of age, cortical binocular pathways, which are responsive to temporally directed motion, provide a route whereby the NOT, with its specialized directional responses, can be accessed from either eye [37, 38]. In animals with well-developed foveae and frontal, stereoscopic vision, the visual inputs feeding directly to the pretectum are supplemented by inputs routed through the visual cortex that selectively respond to moving images with no positional disparity in the 2 eyes [57]. This coupling between optokinetic nystagmus and stereopsis allows frontal-eyed animals to selectively stabilize the moving images of those parts of the scene within a selected depth plane, while disregarding induced image motion of the visual world at other distances [40, 57]. In humans with congenital strabismus, binocularly driven corticopretectal pathways never become established, allowing the primitive monocular nasotemporal asymmetry to predominate.

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5  Latent Nystagmus LR

MR

MR

NOT

LR

NOT III

LGN

III LGN

MLF

AC PC HC Labyrinth R

L

R

L

VI

VI

VN

VN

CC

Cortex

AC PC HC Labyrinth R

L

R

L

Cortex

Fig. 5.1  Schematic diagram depicting cortical and optokinetic pathways. Cortical input to temporally directed movement, which is present only in frontal-eyed animals, requires the establishment of normal binocular cortical connections. This input is absent in humans with congenital strabismus. Direct crossed pathways from the eye to the nucleus of the optic tract provide nasalward subcortical optokinetic responses even when binocular cortical connections are absent (R and L represent monocular cortical cells corresponding to the right and left eyes, respectively). Note that the nucleus of the optic tract (NOT) relays horizontal visuo-vestibular information to the vestibular nucleus (VN), where it is integrated with horizontal vestibular input from the labyrinths to establish horizontal extraocular muscle tonus. LGN indicates lateral geniculate nucleus; CC, corpus callosum; V1, abducens nucleus; III, oculomotor nucleus; LR, lateral rectus muscle; MR, medial rectus muscle; AC, anterior canal; PC, posterior canal; and HC, horizontal canal

Clinical Signs of Vestibular Origin Bilateral positioning of the eyes and ears promotes survival by enabling the organism to crosslink input from different sense organs to impart balance. Each eye and its ipsilateral semicircular canals share the same directional bias to movement. For example, the right horizontal semicircular canal is activated by head rotation to the right (which induces a rotation of the visual world to the left) and inhibited by head rotation to the left (which induces a rotation of the visual world to the right) [2, 43,

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45, 58, 59]. The monaural and monocular directional biases summate, so that activation of the right horizontal semicircular canal during rightward head rotation is reinforced by the physiologic activation of the right eye by the induced nasal rotation of the visual world. The close geometrical relationship between the semicircular canals and the extraocular muscles presumably facilitates the integration of head motion and visual movement and their orderly summation to produce transformation to an appropriate ocular motor response [46, 60]. Latent nystagmus usually conforms to Alexander’s law, which states that the intensity of a peripheral vestibular nystagmus increases when the eyes are moved in the direction of the fast phase and decreases when the eyes are moved in the direction of the slow phase [2, 21, 60–63]. Latent nystagmus damps when the fixating eye is turned toward the nose (which is also the direction of the slow phase) and increases in intensity when the fixating eye is turned toward the ipsilateral ear (which is in the direction of the fast phase) [14, 15, 62, 63]. A similar damping of horizontal nystagmus is seen in peripheral horizontal vestibular nystagmus after disease or injury to 1 horizontal semicircular canal. By contrast, Alexander’s law does not apply to congenital nystagmus, which reverses direction in different positions of gaze. The contraversive head turn in latent nystagmus (ie, a head turn opposite in direction to the deviation of the fixating eye) also characterizes vestibular eye movements [2]. Additional evidence for the duality of optic and vestibular innervation can be elicited by occluding 1 eye in the patient with latent nystagmus, spinning the patient, suddenly stopping the spin, then immediately observing the effect of the postrotational nystagmus on the latent nystagmus when either eye is occluded. A horizontal nystagmus induced by body spinning nullifies or accentuates latent nystagmus depending on the direction of spin relative to the fixating eye (Fig. 5.2). For example, spinning the patient to the right excites the right horizontal canal and inhibits the left horizontal semicircular canal to induce a nystagmus with a slow-phase rotation to the left and a fast-phase rotation to the right. If the spin is suddenly stopped (after approximately 10 rotations), a shift in endolymph deflects the cupula in the opposite direction, causing transient excitation of the left horizontal semicircular canal and transient inhibition of the right horizontal semicircular canal and inducing a left-beating nystagmus (termed “postrotational nystagmus”). If the left eye is occluded to induce latent nystagmus prior to this maneuver, the latent nystagmus will diminish or disappear immediately following cessation of the spin. If the occluder is quickly moved to cover the right eye, the intensity of the latent nystagmus with the left eye viewing will be correspondingly increased relative to that observed with the left eye fixating before the spin. In this way, the clinician can observe how visual input is summated with vestibular input to establish central vestibular tone in the horizontal plane. The more visual input is dominated by 1 eye in latent nystagmus, the higher the velocity of the slow-phase rotations in the direction toward the opposite eye [22]. Simonsz and Kommerell [63] performed eye movement recordings before and after occlusion therapy for amblyopia in patients with latent nystagmus. After prolonged occlusion, the slow-phase velocity of the nystagmus in the amblyopic eye decreased to the same extent that the slow-phase velocity of the nystagmus in the preferred eye increased. The sum of the 2 slow-phase velocities remained the same in

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a

b O

V O

O

V O

++

c

d V O

––

––

V O

V O ++

––

V O ++

Fig. 5.2  Visual and vestibular interaction in latent nystagmus. Latent nystagmus decreases with spinning toward the fixating eye and increases with spinning toward the occluded eye. O represents direction of ocular (visuo-vestibular) tonus; V, direction of horizontal vestibular tonus. Both O and V correspond to the slow phase of the induced nystagmus. ++ Indicates stimulated horizontal semicircular canal; --, inhibited horizontal semicircular canal; (a) Occlusion of the left eye increases visuo-vestibular tonus to the left. (b) The patient with latent nystagmus is spun to the right to stimulate the right horizontal semicircular canal, which increases leftward horizontal vestibular tonus and causes a slow conjugate drift of both eyes to the left. At this point, the latent nystagmus would be enhanced by vestibular input (if the examiner could observe it). (c) When the spinning is suddenly stopped, the opposite vestibular stimulus is exerted, causing the left semicircular canal to drive the eyes to the right. This rightward vestibular tonus imbalance nullifies the leftward visual tonus imbalance induced by monocular fixation with the right eye, thereby reducing the intensity of the latent nystagmus. (d) When the occluder is quickly switched to the right eye, the visual tonus imbalance is augmented by an ipsidirectional visual tonus imbalance, increasing the intensity of the latent nystagmus

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straight-­ahead gaze, demonstrating that visual input to the 2 eyes (just like rotational input to the 2 horizontal canals) maintains a push-pull relationship [21, 63]. This observation lends further support to a vestibular underpinning for latent nystagmus. The clinical similarities between latent nystagmus and peripheral vestibular nystagmus are summarized in Table 5.1.

Evolutionary Underpinnings of Latent Nystagmus The notion of latent nystagmus as a horizontal visuo-vestibular tonus imbalance provides conceptual unification with its associated inferior oblique overaction and dissociated vertical divergence in patients with congenital esotropia. The evolutionary progenitors of all of these visuo-vestibular movements use binocular input to establish physical orientation in space. These primitive reflexes rely on a dissociated form of binocular vision between the 2 laterally placed eyes, which has been superseded by normal cortical binocular vision in humans [5]. In congenital esotropia, however, these primitive subcortical reflexes are not erased by binocular cortical input. Eye movement recordings have demonstrated that dissociated vertical divergence incorporates a vertical latent nystagmus, suggesting a shared common origin for these movements [64]. Given that visual and labyrinthine input are pooled together within the central vestibular system of lower animals [65–67], a visual counterpart to peripheral vestibular nystagmus would seem necessary on evolutionary grounds. Many authors have attributed latent nystagmus as a tonus imbalance of the horizontal extraocular muscles [1, 4, 7, 14, 19, 68]. Latent nystagmus corresponds to a tropotactic vision-­ induced tonus imbalance (ie, one that functions to reestablish binocular equilibrium rather than to directionally orient an eye toward incoming light) [69]. Ohm recognized the physiologic coaptation of visual and vestibular innervation and its role in the generation of latent nystagmus long before others did (as was also the case with dissociated vertical divergence and primary oblique muscle overaction) [70–73]. In a monograph written near the end of his life, he stated, “The impulses that originate from both eyes keep both vestibular nuclei in equilibrium. The equilibrium becomes unbalanced when one eye is being occluded. Then, a nystagmus beating towards the Table 5.1  Peripheral Vestibular Nystagmus vs Latent Nystagmus Peripheral Vestibular Nystagmus Induced by unequal bilateral labyrinthine input Stimulation of right horizontal semicircular canal evokes a conjugate right-beating nystagmus Nystagmus intensity proportional to the degree of horizontal canal imbalance Damps during gaze away from the side of the normal canal Conforms to Alexander’s law Modulated by subcortical neural pathways

Latent Nystagmus Induced by unequal binocularvisual input Stimulation of right eye evokes a conjugate right-beating nystagmus Nystagmus intensity proportional to the degree of binocularvisual imbalance Damps during gaze away from the side of the fixating eye Conforms to Alexander’s law Modulated by cortical and subcortical neural pathways

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side of the open eye appears” [72]. Kestenbaum [10] emphasized that latent nystagmus could not be attributed to luminance per se, since shining a bright light in the right eye worked like occlusion of the right eye and caused a left-beating nystagmus. He noted that the presence of a sharper visual image on the retina of one eye than the other appeared to be the decisive stimulus for inducing latent nystagmus. Predominance of a primitive visuo-vestibular imbalance provides an evolutionary basis for the shift in egocenter that has been invoked to explain latent nystagmus [14]. According to this hypothesis, the egocenter is localized to the median body plane under normal binocular conditions, but shifts to the side of the fixating eye under monocular conditions. Dell’Osso et al [14] hypothesized that humans with latent nystagmus retain an abnormal egocenter in the median plane even under monocular conditions, causing the fixating eye to drift toward midline. In the lateral-­ eyed animal, fixation with the right eye would instantaneously shift the egocenter to the left of the object of regard, necessitating a body turn to frontalize the object and a contraversive eye rotation to maintain fixation [14]. As neatly summarized by Dichgans and Brandt: … the results of visual and vestibular stimulation on egocentric localization indicate the close similarity in the perceptual consequences of stimulation of the two organs. The assumption of a unitary central representation of egocentric space, based on visual and vestibular (as well as acoustic and somatosensory) afferents is perceptually obvious [42] (pp763–764). It remains to be determined whether a higher order egocentric shift could cause the visuo-vestibular imbalance which generates the linear slow phase of latent nystagmus.

 xperimental Evidence That Latent Nystagmus Is Vestibular E in Origin Optokinetic responses are fundamentally intertwined with vestibular responses, and a major site of this commingling is the vestibular complex [39]. Waespe and Henn [58] and Henn et al [59] performed single-cell recordings from the medial vestibular nucleus in monkeys and found that single neurons can be activated either by body rotation or optokinetic stimulation. Units that were excited by head acceleration to the left were also exited by motion of optokinetic stripes to the right. Most cells responded to both the whole-field visual motion, as well as to the vestibular indications of head rotation, and the responses of vestibular neurons followed approximately the same time course as the delayed component of optokinetic nystagmus [58, 59]. As summarized by Dichgans and Brandt: All of the recent studies performed in awake animals show a tonic modulation of resting discharge of vestibular units in response to exclusive constant velocity motion of the visual surround. The modulation, although to a variable degree, seems to occur in the great majority of horizontal semicircular canal-dependent units of all vertebrate species tested. A unit which is excited by a head acceleration, say, to the left is also excited by motion of the surround to the right, which represents the optokinetic stimulus that in man would cause the sensation of turning to the left [42] (pp781,783).

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This underlying vestibular response to both visual motion and body rotational stimuli may explain the overlapping nystagmus response that characterizes latent, optokinetic, and peripheral vestibular nystagmus [2, 19, 21, 62, 71]. This overlap may reflect the fact that all 3 movements subserve a similar physiologic function (ie, detection of rotation of the body and visual environment). Latent nystagmus, optokinetic nystagmus, and the vestibuloocular reflex also show velocity storage, a phenomenon in which constant vestibular input or visual flow in the same direction is stored for up to 20 seconds in the brainstem, even when the stimulus is terminated (Table  5.2) [50, 51]. The presence of velocity storage serves to enhance the slow-tracking eye movements to vestibular stimulation and optic flow response at low frequencies of rotation [2, 74]. Although latent nystagmus has variously been attributed to anomalous cortical motion processing [25, 26], or a cortical pursuit asymmetry [53, 75], the absence of velocity storage mechanism within the pursuit system implicates the vestibular system as the generator of latent nystagmus.

Table 5.2  Experimental Evidence That Latent Nystagmus Is Vestibular in Origin Latent Nystagmus in Monkeys Covering one eye causes conjugate nystagmus in both eyes with slow phases directed to the same side as the activated NOT (contralateral to the viewing eye) [50, 51]. The velocity of the slow phases of When one eye is covered, the velocity of nystagmus from electrical the slow phases of stimulation of NOT slowly nystagmus slowly increases. When stimulation is increases. When the eye stopped, the slow-phase is uncovered, the functioning eye velocity slowly slow-phase eye velocity decays. This slow increase and slow decay in eye velocity is due slowly decays [51]. to the charging and discharge of the vestibular velocity storage system [54, 55]. Chemical suppression NOT projects to the vestibular velocity storage system and NOT of NOT blocks OKAN and suppresses latent is responsible for eliciting nystagmus [50]. optokinetic after nystagmus (OKAN), which is the portion of optokinetic nystagmus that is mediated by the velocity storage system [54, 55].

Nucleus of the Optic Tract (NOT) in Monkeys Electrical stimulation of NOT on one side causes conjugate nystagmus in both eyes with slow phases directed to the same side as the stimulated NOT [54, 55].

Latent Nystagmus in Humans Same

Slow rise and slow decay is usually not seen because the eye velocity in humans is much slower (1–5 dynes [d/s]) than that found in monkeys (20–90 d/s). In some humans, latent nystagmus eye velocity can be 20 d/s and in those cases a slow rise and slow decay is found (R.J.T., unpublished data). Unknown

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Conclusions Latent nystagmus is a unique form of vestibular nystagmus that is evoked by unbalanced visual input from the 2 eyes rather than unequal rotational input from the 2 labyrinths. The neurophysiological substrate for latent nystagmus is operative in lateral-eyed animals and in human infants with undeveloped binocular corticopretectal pathways. When congenital esotropia disrupts the establishment of these binocular visual connections, visual input from the fixating eye to the contralateral NOT evokes a visuo-vestibular counterrotation of the eyes that corresponds to a turning or twisting movement of the body toward the object of regard (“vestibular nystagmus with a twist”). In this setting, unbalanced binocular visual input can induce a motion bias in the vestibular nucleus to generate the visual counterpart of horizontal labyrinthine nystagmus, namely, latent nystagmus. As the eyes rotate frontally during evolution, this visuo-vestibular function is sacrificed, but the central nervous system retains these latent subcortical visual pathways. Latent nystagmus is nature’s proclamation that our 2 eyes, when dissociated from birth, can revert to their ancestral function as sensory balance organs. References 1. Cogan DG.  Nystagumus. In: Neurology of the ocular muscles. 2nd ed. Springfield: Charles C Thomas Publishers; 1956. p. 226–7. 2. Leigh RJ, Zee DS.  Diagnosis of central disorders of ocular motility. In: The neurology of eye movements. 3rd ed. New  York: Oxford University Press; 1999. p. 445–7. 3. Lang J. The congenital strabismus syndrome. Strabismus. 2000;8:195–9. 4. Brodsky MC. Vision-dependent tonus mechanisms of torticollis: an evolutionary perspective. Am Orthopt J. 1999;50:158–62. 5. Brodsky MC.  Dissociated vertical divergence: a righting reflex gone wrong. Arch Ophthalmol. 1999;117:1216–22. 6. Brodsky MC, Donahue SP. Primary oblique muscle overaction: the brain throws a wild pitch. Arch Ophthalmol. 2001;119:1307–14. 7. Brodsky MC. DVD remains a moving target! J AAPOS. 1999;3:325–7. 8. Faucon A.  Nystagmus par insuffisance des Droits externes. J Ophtal Paris. 1872;1:233–41. 9. Harcourt B. Manifest latent nystagmus affecting patients with uniocular congenital blindness. In: Gregersen E, editor. Transactions of the European Strabismological Associations. Copenhagen: European Strabisomological Associations; 1984. p. 259–64. 10. Kestenbaum A.  Nystagmus. In: Clinical methods of neuro-ophthalmologic examination. New York: Grune & Stratton Inc; 1947. p. 234–5. 11. Kushner BJ.  Infantile uniocular blindness with bilateral nystagmus: a syndrome. Arch Ophthalmol. 1995;113:1298–300. 12. Shawkat FS, Harris CM, Taylor DS. Spontaneous reversal of nystagmus in the dark. Br J Ophthalmol. 2001;85:428–31.

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13. Dell’Osso LF, Traccis S, Abel LA.  Strabismus—a necessary condition for latent and manifest latent nystagmus. Neuro-ophthalmology. 1983;3:247–57. 14. Dell’Osso LF, Schmidt D, Daroff RB. Latent, manifest latent, and congenital nystagmus. Arch Ophthalmol. 1979;97:1877–85. 15. Kommerell G. The relationship between infantile strabismus and latent nystagmus. Eye. 1996;10:274–81. 16. Dell’Osso LF, Abel LA, Daroff RB. Latent/manifest latent nystagmus reversal using an ocular prosthesis: implications for vision and ocular dominance. Invest Ophthalmol Vis Sci. 1987;28:1873–6. 17. Ciancia AO.  On infantile esotropia with nystagmus in abduction. J Pediatr Ophthalmol Strabismus. 1995;32:280–8. 18. Melek N. El nistagmus en la esotopia con limitacion bilateral de la abduccion. Paper presented at: Anales del V o Congreso del CLADE; Guaruja, Brazil; 1978: 27–31. 19. Gresty MA, Metcalfe T, Timms C, et al. Neurology of latent nystagmus. Brain. 1992;115:1303–21. 20. Abadi RV, Scallan C. Manifest latent and congenital nystagmus waveforms in the same subject: a need to reconsider the underlying mechanism of nystagmus. Neuro-ophthalmology. 1999;21:211–21. 21. Schor CM. Subcortical binocular suppression affects the development of latent and optokinetic nystagmus. Am J Optom Physiol Optic. 1983;60:481–502. 22. Kommerell G, Zee DS.  Latent nystagmus: release and suppression at will. Invest Ophthalmol Vis Sci. 1993;34:1785–92. 23. Zubcov AA, Reinecke RD, Gottlob I, et al. Treatment of manifest latent nystagmus. Am J Ophthalmol. 1990;110:160–7. 24. Sekiya H, Hasegawa S, Mukuno K, Ishikawa S. Sensitivity of nasal and temporal hemiretinas in latent nystagmus and strabismus evaluated using the light reflex. Br J Ophthalmol. 1994;78:327–31. 25. Tychsen L, Lisberger SG.  Maldevelopment of visual motion processing in humans who had strabismus with onset in infancy. J Neurosci. 1986;6:2495–508. 26. Norcia AM, Garcia H, Humphry R, et al. Anomalous motion VEPs in infants and in infantile esotropia. Invest Ophthalmol Vis Sci. 1991;32:436–9. 27. Ishikawa S.  Latent nystagmus and its etiology. In: Reinecke RD, edi tor. Strabismus: proceedings of the International Strabismological Association, Kyoto, Japan. New York: Grune & Stratton Inc; 1978. p. 203–14. 28. Lange J. A new hypothesis on latent nystagmus and on the congenital squint syndrome. In: van Dalen AT, Houtman WA, editors. Strabismus symposium, Amsterdam 1981, Documenta ophthalmologic proceedings series, vol. 32. Norwell: Kluwer Academic Publishers; 1982. p. 83–8. 29. Shallo-Hoffman J, Faldon M, Hague S, et al. Motion detection deficits in infantile esotropia without nystagmus. Invest Ophthalmol Vis Sci. 1997;38:219–26. 30. Roelofs CO. Nystagmus latens. Arch Augenheilkd. 1928;98:401–47. 31. van Hof-van Duin J. Early and permanent effects of monocular deprivation on pattern discrimination and visuomotor behaviour in cats. Brain Res. 1976;111:261–76.

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32. Wood CC, Spear PD, Braun JJ. Direction specific deficits in horizontal optokinetic nystagmus following removal of the visual cortex in the cat. Brain Res. 1977;60:231–7. 33. Kommerell G. Beziehungen zwischen Strabismus un Nystagmus. In: Kommerell G, editor. Augenbewegungsstörungen, Neurophysiologie und Klinik: Symposion der Deutschen Ophthalmologischen Gesellschaft, Freiburg, 1977. Munich: Bergmann; 1978. p. 367–73. 34. Hoffman K-P. Cortical versus subcortical contributions to the optokinetic reflex in the cat. In: Lennerstrand G, Keller EL, editors. Basis of ocular motility: proceedings of a Wenner-Gren Center and Smith-Kettlewell Eye Research Foundation I International Symposium. New  York: Pergamon Press; 1982. p. 303–11. 35. Hoffman KP. Neural basis for optokinetic defects in experimental animals with strabismus. In: Kaufman H, editor. Transactions of the 16th Meeting of the European Strabismological Association. Giessen: European Strabismological Association; 1987. p. 35–46. 36. Braddick O. Where is the nasotemporal asymmetry? Curr Biol. 1996;6:250–3. 37. Atkinson J.  Development of optokinetic nystagmus in the human infant and monkey infant: an analogue to development in kittens. In: Freeman RD, editor. Developmental neurobiology of vision. New  York: Plenum Publishing Corp; 1979. p. 277–87. 38. Naegele JR, Held R. The postnatal development of monocular optokinetic nystagmus. Vis Res. 1982;22:341–6. 39. Wallman J. Subcortical optokinetic mechanisms. In: Miles FA, Wallman J, editors. Visual motion and its role in the stabilization of gaze. Amsterdam: Elsevier Science; 1993. p. 321–42. 40. Ohmi M, Howard IP, Eveleigh B. Directional preponderance in human optokinetic nystagmus. Exp Brain Res. 1986;63:387–94. 41. Miles FA. The sensing of rotational and translational optic flow by the primate optokinetic system. In: Miles FA, Wallman J, editors. Visual motion and its role in the stabilization of gaze. Amsterdam: Elsevier Science; 1993. p. 393–403. 42. Dichgans J, Brandt TH.  Visual-vestibular interaction: effects on self-motion perception postural control. In: Held R, Leibowitz HW, Teuber HL, editors. Handbook of sensory physiology, vol. 8. Berlin: Springer; 1978. p. 755–804. 43. Markham CH. How does the brain generate horizontal vestibular nystagmus? In: Baloh RW, Halmagyi GM, editors. Basic vestibular mechanisms: part 1. New York: Oxford University Press; 1996. p. 48–61. 44. Walls GL. The evolutionary history of eye movements. Vis Res. 1962;2:69–80. 45. Cohen BL. Eye movements from semicircular canal nerve stimulation in the cat. Ann Otol Rhinol Laryngol. 1964;73:153–70. 46. Simpson JI, Graf WG.  Eye-muscle geometry and compensatory eye movements in lateral-eyed animals and frontal-eyed animals. Ann N Y Acad Sci. 1981;374:20–30. 47. Baarsma EA, Collewijn H. Changes in compensatory eye movements after unilateral labyrinthectomy in the rabbit. Arch Otorhinolaryngol. 1975;211:219–30.

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48. Barmack NH, Pettorossi VE, Erickson RG. The influence of bilateral labyrinthectomy on horizontal and vertical optokinetic reflexes in the rabbit. Brain Res. 1980;196:520–4. 49. Collewijn H, Van der Steen J. Visual control of the vestibuloocular reflex in the rabbit: a multi-level interaction. In: Glickstein M, Yeo C, Stein J, editors. Cerebellum and neuronal plasticity. New York: Plenum Publishing Corp; 1987. p. 277–91. 50. Mustari MJ, Tusa RJ, Burrows AF, Fuchs AF, Livingston CA. Gaze-stabilizing deficits and latent nystagmus in monkeys with early-onset visual deprivation: role of the pretectal NOT. J Neurophysiol. 2001;86:662–75. 51. Tusa RJ, Mustari MJ, Burrows AF, Fuchs AF.  Gaze-stabilizing deficits and latent nystagmus in monkeys with brief, early-onset visual deprivation: eye movement recordings. J Neurophysiol. 2001;86:651–61. 52. Tusa RJ, Mustari MJ, Das VE, Boothe RG.  Animal models for visual deprivation-­ induced strabismus and nystagmus. Ann N Y Acad Sci. 2002;956:346–60. 53. Kiorpes L, Walton PJ, O’Keefe LP, Movshon JA, Lisberger SG. Effect of early-­ onset artificial strabismus on pursuit eye movements and on neuronal responses in area MT of macaque monkeys. J Neurosci. 1996;16:6537–53. 54. Mustari MJ, Fuchs AF. Discharge patterns of neurons in the pretectal nucleus of the optic tract in the monkey. J Neurophysiol. 1990;64:77–90. 55. Schiff D, Cohen B, Raphan T. Nystagmus induced by stimulation of the nucleus of the optic tract in the monkey. Exp Brain Res. 1988;70:1–40. 56. Cazin L, Precht W, Lannou K. Optokinetic responses of vestibular nucleus neurons in the rat. Pflugers Arch. 1980;38:31–8. 57. Howard IP, Simpson WA. Human optokinetic nystagmus is linked to the stereoscopic system. Exp Brain Res. 1989;78:309–14. 58. Waespe W, Henn V. Neuronal activity in the vestibular nuclei of the alert monkey during vestibular and optokinetic stimulation. Exp Brain Res. 1977;27:523–38. 59. Henn V, Cohen B, Young LR. Visual-vestibular interaction in motion perception and the generation of nystagmus. Neurosci Res Program Bull. 1980;18:457–651. 60. Ezure K, Graf W. A quantitative analysis of the spatial organization of the vestibuloocular reflexes in lateral-and frontal-eyed animals, I: orientation of semicircular canals and extraocular muscles. Neuroscience. 1984;12:85–93. 61. Robinson DA, Zee DS, Hain TC, Holmes A, Rosenberg LF. Alexander’s law: its behavior and origin in the human vestibulo-ocular reflex. Ann Neurol. 1984;16:714–22. 62. Dell’Osso LF, Jacobs JB. A normal ocular motor system model that simulates the dual mode fast-phases of latent/manifest nystagmus. Biol Cybern. 2001;85:459–71. 63. Simonsz HJ, Kommerell G. Effect of prolonged monocular occlusion on latent nystagmus. Neuro-ophthalmology. 1992;12:185–92.

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64. Irving EL, Goltz HC, Steinbach MJ, Kraft SP. Vertical latent nystagmus component and vertical saccadic asymmetry in subjects with dissociated vertical deviation. J AAPOS. 1998;2:344–50. 65. Pfeiffer W.  Equilibrium orientation in fish. Int Rev Gen Exp Zool. 1964;1: 77–111. 66. Meyer DL, Bullock TH. The hypothesis of sense-organ-dependent tonus mechanisms: history of a concept. Ann N Y Acad Sci. 1977;290:3–17. 67. Graf W, Meyer DL.  Central mechanisms counteract visually induced tonus asymmetries: a study of ocular responses to unilateral illumination in goldfish. J Comp Physiol. 1983;150:473–81. 68. Keiner GB. Physiology and pathology of optomotor reflexes. Am J Ophthalmol. 1956;42:233–49. 69. Duke-Elder S. The effect of light on movement. In: System of ophthalmology: the eye in evolution. London: Henry Klimpton; 1958. p. 27–81. 70. Ohm J. Der latente Nystagmus bei angeborener einseitiger Blindheit. Graefes Archiv Ophthalmol Archiv Augenheilkd. 1948;148:318. 71. Ohm J.  Der latent Nystagmus im Stockdunkeln. Arch Augenheilkd. 1928;99:417–38. 72. Ohm J.  Nystagmus und Schielen bei Sehschwachen und Blinden. Stuttgart: Ferdinand Enke; 1958. p. 81. 73. Fetter M, Zee DS. Recovery from unilateral labyrinthectomy in rhesus monkey. J Neurophysiol. 1998;59:370–93. 74. Cohen B, Henn V, Raphan T, Dennett D.  Velocity storage, nystagmus, and visual-vestibular interactions in humans. Ann N Y Acad Sci. 1981;374:421–33. 75. Tychsen L, Hurtig RR, Scott WE. Pursuit is impaired but the vestibulo-ocular reflex is normal in infantile strabismus. Arch Ophthalmol. 1985;103:536–59.

Postscript This treatise proposes that latent nystagmus is driven subcortically by binocular imbalance from the two eyes. The diagram in Fig. 5.1 shows a simplified depiction of this concept. As summarized in Chap. 17, the subcortical visuo-vestibular circuitry is more complex, with motion pathways from the NOT-DTN projecting to the dorsal cap of the inferior olive, then down to the cerebellar flocculus, before connecting with the vestibular nucleus. Some investigators believe that latent nystagmus is cortical in origin. As with DVD, cortical suppression can generate latent nystagmus. However, cortical suppression activates the subcortical circuitry that generates latent nystagmus. So designating latent nystagmus as cortical or subcortical misses the point. Chris Harris nicely summarized the evidence for and against a strictly cortical and subcortical position (Harris C: Latent nystagmus. Continuing Education Training, Course code C-31801, www.optometry.co.uk/clinical). Both templates are integral to latent nystagmus, but this oscillation clearly arises from a primitive subcortical visual motion bias that was present evolutionarily before the cortex ever developed. The

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prominent torsional ocular rotations that accompany latent nystagmus further attest to their visuo-­vestibular origin. Again, the unanswered question is whether covering one eye evokes DVD directly via the subcortical circuitry, indirectly via the cortex, or both. What accounts for the jump from optokinesis as the stimulus for monocular nasotemporal asymmetry (MNTA) to fixation as the stimulus for latent nystagmus? Evolutionarily, motion gives way to fixation. Things have to move for fixation to occur. The modulation of latent nystagmus by fixation occurs because cortical reflexes are retrofitted to subcortical ones. One concern with the subcortical hypothesis for MNTA and latent nystagmus has been that directionally-selective horizontal retinal ganglion cells have been found in rats, rabbits, and cats, but not in primates. Some believe that the sweep of nasalward motion across consecutive ganglion cells could encode the equivalent directional signal. Alternatively, it could be that these directional ganglion cells have not yet been found in primates, as they are probably relatively rare so it would not be an easy task to find them in tissue as densely packed as the primate retina. This analysis calls into question the misguided classification of latent nystagmus as “fusion maldevelopment nystagmus.” This designation, proposed by a self-­ appointed NIH-sponsored committee, implies that the primary cause of essential infantile esotropia and latent nystagmus is a primary defect in cortical fusional development. There is no evidence that this is the case. It is more plausible that fusion maldevelopment and latent nystagmus are both inevitable outcomes of an early binocular misalignment that eventuates in infantile esotropia. Chap. 17 demonstrates how prolonged subcortical neuroplasticity could allow subcortical MNTA to generate both essential infantile esotropia and latent nystagmus, with the observed reconfiguration of cortical motion pathways occurring as a secondary phenomenon.

6

Dissociated Vertical Divergence Perceptual Correlates of the Human Dorsal Light Reflex

In living organisms, light from the sky above and gravity from the earth below have led to the evolution of sensory organs for vision and balance. The bright sky serves as a hemispheric light source that provides a stable visual reference for which way is up. In lower animals, the central vestibular system integrates visual input from the 2 eyes and graviceptive output from the 2 labyrinths to modulate postural and extraocular muscle tonus and maintain vertical orientation [1–3]. Although visual input is usually subordinate to vestibular input in establishing postural orientation, some lateral-eyed animals also maintain vertical orientation by equalizing visual input to the 2 eyes [4]. Many fish and insects exhibit a dorsal light reflex in which illumination from one side evokes a reflex body tilt toward the light [4–7]. When a light is shined down from the right side, for example, the right eye receives greater visual input than the left eye (Fig. 6.1). This binocular disparity would only exist in nature if the animal were tilted with its right side toward the sky. This visual imbalance causes the central vestibular system to register a leftward body tilt relative to the body position that would be necessary for the 2 eyes to receive equal binocular visual input, and to reflexively alter postural tonus to correct the tilt [1–4] (Fig. 6.1). In a vertically stabilized fish, the same stimulus evokes a vertical divergence of the eyes to reorient the interpupillary axis relative to the new light source, causing the eye with lesser visual input to shift dorsally, and the eye with greater visual input to shift ventrally [3] (Fig. 6.1). The term dorsal pertains to the back or upper aspect of an animal. The dorsal aspect of the head in fish, quadrupeds, and bipeds corresponds to the top of the head. In bipeds such as humans, the back retains its phylogenetic dorsal orientation, although it is no longer the upper aspect in the upright position. Humans with congenital strabismus who never develop single binocular vision exhibit an atavistic resurgence of the dorsal light reflex in the form of dissociated vertical divergence (DVD) [8]. When these strabismic humans fixate monocularly, the nonfixating eye exhibits a slow dorsal rotation termed dissociated vertical deviation. This dorsal

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_6

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a

b

Fig. 6.1  In the fish, increasing luminance to the right eye by shining a light from the 1-o’clock position (as seen by the animal) shifts subjective vertical clockwise toward the 1-o’clock position (as seen by the animal). Visual objects aligned with the gravitational vertical are therefore misregistered as being tilted counterclockwise toward the 11-o’clock position relative to the animal’s subjective vertical. (a) Vertical objects and the animal’s body are subjectively misregistered as being tilted counterclockwise, necessitating a clockwise body tilt toward the body position that is necessary for equal binocularvisual input. (b) When a corrective body tilt is prevented, the ocular component of this righting reflex evokes a vertical divergence of the eyes to rotate the interpupillary axis toward a position that is perpendicular to the altered subjective vertical

rotation can be elicited by optically or mechanically reducing visual input to either eye. It can also occur spontaneously when there is a fluctuating degree of sensory suppression in one or both eyes [8]. Eye movement recordings have confirmed that DVD comprises a cyclovertical divergence in which the fixating eye depresses and intorts while the nonfixating eye elevates and extorts [9–11]. Thus, the alternative term, dissociated vertical divergence, provides a more accurate mechanistic description of this movement [8]. In fish, abrupt fluctuations in binocular visual input cause the central vestibular system to register a tilt, and the ensuing dorsal light reflex serves to annul this tilt by realigning the eyes and body to new a orientation that the brain interprets as vertical. If DVD is a human dorsal light reflex, then humans with DVD might be expected to experience a perceived visual tilt (ie, a sensation that the visual environment is tilted) when the gradient of visual input to the 2 eyes is abruptly altered. In this case, the cyclovertical divergence associated with DVD should serve to reduce or eliminate the perception of tilt. Alternatively, if DVD is not a human dorsal light reflex, then the torsional component of DVD might be expected to induce a perception of visual tilt. In this case, patients should perceive no visual tilt prior to the onset of

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DVD, but a perceived visual tilt should be present after the DVD has occurred. To elucidate the perceptual correlates of DVD, I examined visual tilt perception in 9 patients with DVD and 9 normal control subjects.

Patients and Methods Nine patients with bilateral DVD were examined prospectively and consecutively. Children who had been treated with previous cyclovertical muscle surgery were excluded from the study since the resulting fundus torsion could influence the perception of tilt. Dissociated vertical divergence was diagnosed when occlusion of either eye evoked a dorsal rotation of the occluded eye. The amplitude of the DVD was measured in both eyes using the vertical prism under cover test. Visual acuity was measured in each eye, versions were examined, field measurements were obtained, and a dilated retinal examination was performed to look for static torsion. To determine whether patients experienced a perceived visual tilt (ie, a perceived tilt of the visual environment without any sensation of body tilt) or subjective tilt (ie, a perceived tilt of the body) under monocular conditions, each patient was instructed to view a pencil held vertically in the sagittal plane midway between the 2 eyes during occlusion of each eye and during alternate occlusion of the eyes. The patient’s head was maintained in the upright position before and during testing. Care was taken to assure that the pencil was not slanted forward or backward in the sagittal plane, as a slant would optically induce a monocular image tilt. Each patient was instructed to hold up his or her index finger and to move this finger to demonstrate any perceived movement of the pencil as each eye was occluded. The cover test and alternate cover test were repeated 3 to 4 times in each patient to assure that perceptual responses were consistent from one trial to the next. When a perceived motion was noted, the patient was specifically asked whether the pencil appeared to move sideways or to tilt. The patient was then asked, “does it look like the pencil is moving, or does it feel like you are moving?” A labyrinthine imbalance such as that brought on by spinning or by disease of the semicircular canals, is generally perceived as a sensation of body movement in space. Thus, a perceived sensation of body movement in space would suggest that unequal visual input is inducing a labyrinthine imbalance, while perceived visual tilt with no sensation of body movement would suggest that the neural pathways activated by unequal visual input do not directly alter the relative output of the 2 labyrinths. This test was also performed in 9 control subjects who had normal stereopsis and no history of strabismus.

Results Patient ages ranged from 4½ to 51 years. All but 1 patient was younger than 15 years. Seven patients had a history of congenital strabismus that had been treated with only horizontal muscle surgery. One child with prominent DVD had a history of perinatal bruising of both eyelids, but had never developed congenital esotropia,

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latent nystagmus, or nasotemporal asymmetry. (The term nasotemporal asymmetry refers to a disparity in monocular nasally directed and temporally directed optokinetic responses, with normal nasal optokinetic responses, and impaired temporal optokinetic responses. This asymmetry is normal within the first 6 months of life and is retained throughout life in patients with congenital esotropia.) One adult with no history of horizontal strabismus also had bilateral DVD with no latent nystagmus or nasotemporal asymmetry. All patients were neurologically normal except for one prematurely born child with congenital esotropia and delayed walking who probably had periventricular leukomalacia. The amplitude of the DVD in the 2 eyes was symmetrical in 5 patients and asymmetrical in 4 patients. Six patients had grossly visible latent nystagmus. Three patients had bilateral inferior oblique muscle overaction with a “V” pattern and bilateral static extorsion of the globes. The one patient with a history of prematurity had bilateral superior oblique muscle overaction with an “A” pattern and intorsion of the globes. On monocular occlusion, 8 patients reported an instantaneous tilt of the pencil with its top tipped toward the side of the covered eye (Fig. 6.2). This immediate perception of a tilt seemed to precede any motor movement of the uncovered eye and was probably caused by a change in perception only. This visual tilt was followed quickly by a perceived rotation of the pencil back to vertical, which coincided with a dorsally directed drift of the covered eye. (Note that if the fixating eye is making a torsional movement, the subject will perceive the pencil as moving in the opposite direction that the eye is rotating. Thus, if the subject sees the rotation of the pencil such that the top goes from being nasally tipped to straight up, this means that the 12-o’clock meridian of the cornea is rotating nasally. So an apparent extorsional movement of the pencil would correspond to an intorsional movement of the globe. This intorsional movement in the fixating eye begins the phenomenon known as DVD [9–11].) The one patient who did not report a perceived tilt was the adult who had idiopathic DVD and no other history of strabismus. In patients who had markedly asymmetrical DVD, the visual tilt was usually observed only when the dominant eye was covered. All 8 patients who reported a sensation of visual tilt denied any sensation of head or body tilt. No spontaneous head tilting was observed during alternate cover testing. Three patients also perceived a sideways movement of the pencil during alternate occlusion. One adult with DVD perceived no visual tilt or sideways movement on occlusion of either eye. All 9 control subjects reported a horizontal movement of the pencil without tilt on alternate occlusion.

Comment In DVD, monocular occlusion evokes a subjective tilt of the visual environment, which is followed by a cyclovertical divergence of the eyes and a perceived rotation of the tilted visual environment back to the vertical. This sequence of perceptual changes suggests that the cycloversional component of the DVD functions to

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Fig. 6.2  Visual tilt evoked by monocular occlusion in the strabismic human with dissociated vertical divergence. Gray image of the pencil denotes perceived visual tilt immediately following occlusion of one eye. Curved arrows denote the perceived rotation of the tilted visual image back to vertical, coinciding with the appearance of dissociated vertical divergence. On occlusion of either eye, the vertical pencil positioned in the sagittal plane is perceived as instantaneously tilted, with its upper pole tipped toward the side of the covered eye. This subjective visual tilt is quickly followed by a perceived rotation back to vertical that coincides with the cyclovertical divergence of the eyes

correct a perceived tilt and to thereby reestablish vertical orientation under conditions of monocular fixation. In this discussion, I adhere to the convention in vestibular research of describing subjective visual tilt from the point of view of the subject rather than the examiner, although figures are shown from the perspective of the examiner to facilitate clinical application. According to this convention, when a patient looks “to the right,” it is to the patient’s right rather than the examiner’s right, and so a clockwise rotation of visual environment or a torsional rotation of the patient’s eyes must also be defined as clockwise from the patient’s perspective. True vertical corresponds to the gravitational vertical. Our perception of true vertical is influenced by graviceptive input to the 2 labyrinths and visual input to the 2 eyes. Subjective vertical applies to an individual’s internal vertical orientation relative to true earth coordinates. When the subjective vertical is altered by neurologic disease or abnormal binocular vision input, the patient will experience a subjective visual tilt, which is a percieved tilt of the visual environment relative to the subjective vertical [8]. As shown in Fig. 6.1, increased luminance input to the right eye of a fish tilts the

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subjective vertical clockwise (as viewed by the animal), so that a vertical visual stimulus would then appear to be tilted counterclockwise relative to the subjective vertical. The direction of perceived visual tilt in DVD corresponds to the postural responses of lateral-eyed animals that exhibit a dorsal light reflex. The same perceptual shift is reported by strabismic humans with DVD when a binocular visual imbalance is induced by occlusion of one eye (Fig. 6.2). Thus, with occlusion of the left eye, a right eye predominance would shift the subjective vertical clockwise (as seen by the patient), so that true vertical then appears to be rotated counterclockwise relative to the patient’s altered subjective vertical (Fig.  6.3). This counterclockwise tilt of the

SV

SV

Fig. 6.3  Depiction of perceived visual tilt following monocular occlusion in patients with dissociated vertical divergence. SV indicates the subjective vertical (the patient’s internal representation of vertical). A perceived tilt of the visual environment (a tilt of the subjective visual vertical) is determined by the position of vertical objects in the visual world relative to the internal representation of vertical (ie, relative to the subjective vertical). Left, Occlusion of the left eye evokes a monocular tilt in the subjective vertical. Since the visual environment is perceived in relation to the tilted subjective vertical, which the patient perceives as vertical, the monocular visual environment, as viewed with the right eye, is now perceived as tilted counterclockwise relative to the patient’s subjective vertical. Right, The human dorsal light reflex is a twofold movement consisting of a primitive vertical divergence, which realigns the interpupillary axis with the tilted subjective vertical (as in fish), and a newer cycloversional movement that rotates both eyes torsionally in the direction of the tilted visual environment. This counterclockwise cycloversional movement (ie, intorsion of the right eye and extorsion of the left eye) produces a clockwise rotation in the subject’s tilted visual environment to realign it with the tilted subjective vertical (which the subject perceives as vertical), thereby annulling the subjective visual tilt

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visual world, which is seen monocularly with the uncovered right eye, evokes a cyclovertical divergence movement of the eyes to erase the perceived tilt (Fig. 6.3). I have proposed that DVD is an atavistic resurgence of the dorsal light reflex that is evoked by a binocular visual disparity in humans with early-onset strabismus [8]. Since the eyes retain some of their primitive function as balance organs in humans, unequal visual input induces a central vestibular imbalance in which the internal sense of vertical no longer corresponds to the gravitational vertical (Fig. 6.3) [8]. Some patients with DVD also have a head tilt away from the side of the hyperdeviated eye [12, 13], which corresponds to the postural component of the dorsal light reflex in fish [14]. This head tilt, which is not compensatory for binocular vision [12, 13], may serve to align the head to the tilted internal vertical representation (ie, the subjective vertical) [14]. Under monocular viewing conditions, patients with DVD may experience a “schizophrenic” perceptual situation in which the eyes tell the brain that the external world and the body are tilted relative to the altered internal representation of vertical, while the otoliths tell the brain that the head is upright [8]. A similar sensory conflict is induced when humans view a tilted visual world under experimental conditions [15]. Under the latter circumstances, the brain strikes a compromise, and the subjective visual vertical is tilted to an intermediate position between what the eyes and labyrinths are telling the brain [15]. In DVD, the dorsal rotation of the visually deprived eye corresponds to the vertical divergence induced by the primitive dorsal light reflex. Although the deviating eye is said to drift “upward” in humans with DVD, the direction of rotation is not necessarily upward in space but always dorsal relative to the head, regardless of whether the patient is positioned in the upright, supine, or head-hanging position [16]. Humans with DVD also display a phylogenetically newer cycloversional movement that corrects the perceived tilt of the visual environment [17]. This ipsidirectional cycloversional movement can also be evoked by viewing torsional optokinetic stimuli or by inducing a static visual tilt of the visual environment [18–22]. All of these visual stimuli evoke a reflex cycloversional movement, which serves to align the tilted visual environment with the tilted internal representation of vertical [22]. Thus, the human dorsal light reflex comprises a twofold movement—a vertical divergence to realign the interpupillary axis of the eyes relative to the altered internal representation of the vertical, and a cycloversional movement that torsionally rotates the eyes in the direction of the tilted visual world to correct the perceived visual tilt (Fig. 6.3). The vertical component of the human dorsal light reflex is a primitive adaptation that corresponds to the purely vertical divergence in fish. The phylogenetically newer cycloversional component conforms to Stephen Jay Gould’s definition of an exaptation, which is a feature that did not arise as a primary adaptation, but one that was subsequently co-opted or grafted on to meet the newer demands of evolution (in this case, frontally placed eyes) [23]. According to Gould, exaptations are features that were not originally built by natural selection for their current role, but that now enhance fitness (in this case, by restoring vertical orientation under monocular viewing conditions in the frontal-eyed human) [23].

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The human dorsal light reflex demonstrates how the central vestibular system can uncouple the vertical and torsional components of a cycloversional movement to allow each component to subserve its corrective function relative to specific conditions of a perceived tilt. During head or body tilt in humans, altered otolithic tone (ie, unbalanced input from the 2 labyrinths rather than from the 2 eyes) stimulates elevation and intorsion of the lower eye in space, and depression and extorsion of the higher eye in space [24]. This stimulus forms the basis of the Bielschowsky Head Tilt Test [25]. In DVD, however, the elevating eye extorts, and the depressing eye intorts, producing a cyclovertical divergence in which the torsional eye movements are opposite to those evoked by head tilt [8]. This dissociation could occur only if the central vestibular system separately processes visual disparity input and graviceptive input from the trunk and otoliths, then integrates them to establish subjective vertical orientation as it does in fish [1, 8]. The central ocular motor command centers must be at liberty to implement separate commands for vertical divergence and cycloversion in humans, although the 2 signals produce a single integrated extraocular movement. This study needs to be viewed in light of its inherent limitations. First, it is a qualitative and subjective study that was performed in a clinic setting. The advantage of this simple method is that it enables the practicing ophthalmologist to confirm or refute these results without the need for special instrumentation. This disadvantage is that, because eye movement recordings were not obtained, a precise and quantitative temporal relationship between the appearance of DVD and the resolution of the subjective visual tilt could not be confirmed. Second, it is well recognized that both eyes normally extort in convergence [26]. One could therefore question whether the perceived image intorsion when the dominant eye is uncovered might result from each eye being in an extorted convergent position relative to the vertical object. If this were the case, however, one would expect the control group to have experienced the same perceptual changes since their eyes would also extort during convergence. However, this did not occur. Third, von Helmholtz [27] determined that the subjective vertical retinal meridian is tilted approximately 1° in each eye, with its top tipped temporally [27]. This subjective tilt could cause the top of a vertical line to appear to be tipped nasally (ie, tilted toward the side of the covered eye, as shown in Fig. 6.2) [28]. As such, it could be argued that this small degree of extorsional tilt in the subjective vertical retinal meridians of each eye could potentially contribute to the perception that the monocular image appears instanteously intorted when either eye is uncovered. If this were the case; however, one would again expect the control group to have perceived a similar visual tilt. Yet, only patients with DVD perceived a visual tilt under monocular conditions, suggesting that this effect did not influence the results of this study. Furthermore, the original von Helmholtz measurements of the subjective retinal vertical, like standard horopter measurements, were obtained using isolated visual stimuli in the absence of any surrounding contextual cues. In this study, normal background contextual cues were present, so one would not expect patients in either group to detect this small vertical bias.

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Fourth, it is not clear why the group of patients with DVD were less likely than the control group to report a perceived lateral movement of the pencil when the cover was switched from one eye to the other. It could be that the perception of tilt overrides the perception of lateral movement in these patients; that surgically corrected congenital esotropia is associated with an altered perception of visual space under monocular conditions; or that I was more attuned to elucidating the direction and sequential changes of the perceived tilt in patients with DVD, and that verbal or nonverbal cues could have influenced patient responses. Last, one could argue that if DVD is not a human dorsal light reflex, this cyclovertical divergence could be the cause rather than the result of the observed perceptual changes. In other words, extorsion of the covered eye in DVD could cause the vertical pencil to appear momentarily intorted when the either eye is uncovered. As the eye intorts to fixate, the image would extort, producing a similar sequence of perceptions as observed. If this were the case, one would expect patients with DVD to report that the image of the pencil shifted from an initial position of intorsion to a final position of extorsion. However, all patients with DVD stated that the tilted image of the pencil appeared vertical following its rotation, which would only occur if this reflex cycloversional movement served to correct the monocular visual tilt. This perceptual response suggests that this complex cyclovertical movement must function to reestablish vertical visual orientation when binocular vision is preempted. In conclusion, DVD is associated with a subjective tilt of the visual environment and a reflex cyclovertical divergence of the eyes. This subjective visual tilt appears to drive both components of the resulting cyclovertical divergence. These perceptual correlates add to the accumulating body of evidence that DVD is a human dorsal light reflex, which serves to restore vertical visual orientation under monocular conditions. In DVD, a subjective sensation of visual tilt under monocular viewing conditions evokes 2 compensatory eye movements—a phylogenetically older vertical divergence movement (ie, a primitive adaptation) to realign the eyes relative to the altered internal representation of vertical, and an exaptive cycloversion movement that torsionally rotates the eyes in the direction of the tilted visual environment to restore vertical visual orientation by neutralizing the perceived visual tilt. The vertical component of this movement corresponds to the ancestral dorsal light reflex in fish, while the cycloversional component of the human dorsal light reflex appears to be an exaptation that functions to annul the subjective visual tilt under monocular conditions when the eyes are frontally placed. This twofold reflex movement corresponds both in theory and in actuality to the ocular motor response that would result from a tilted internal representation of the visual vertical. In the human dorsal light reflex, the direction of the cycloversion movement relative to the vertical divergence is opposite to that observed during a head tilt in space, demonstrating that the vertical divergence and the cycloversional component of visual tilt are independently programmed, and that these 2 extraocular movements can be dissociated by unequal visual input to the 2 eyes in humans with congenital strabismus.

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References 1. Pfeiffer W.  Equilibrium orientation in fish. Int Rev Gen Exp Zool. 1964;1:77–111. 2. Meyer DL, Bullock TH. The hypothesis of sense-organ-dependent tonus mechanisms: history of a concept. Ann N Y Acad Sci. 1977;290:3–17. 3. Graf W, Meyer DL.  Central mechanisms counteract visually induced tonus asymmetries: a study of ocular responses to unilateral illumination in goldfish. J Comp Physiol. 1983;150:473–81. 4. Duke-Elder S.  The effect of light on movement. In: Duke-Elder S, editor. System of ophthalmology: the eye in evolution. London: Henry Klimpton; 1958. p. 27–81. 5. von Holst E. Über den Lichtrückenreflex bei Fische. Pubbl Staz Zool Napoli. 1935;II(15):143–8. 6. von Holst E.  Die Gleichgewichtssine der Fische. Verh Dtsch Zool Ges. 1935;37:109–14. 7. Mittelstaedt H. Interaction of eye-, head-, and trunk-bound information in spatial perception and control. J Vestib Res. 1997;7:283–302. 8. Brodsky MC.  Dissociated vertical divergence: a righting reflex gone wrong. Arch Ophthalmol. 1999;117:1216–22. 9. Van Rijn LJ, Collewijn H. Eye torsion associated with disparity-induced vertical vergence in humans. Vis Res. 1994;17:2307–16. 10. Inoue M, Kita Y.  Eye movements in dissociated vertical deviation. Nippon Ganka Gakkai Zasshi. 1993;97:1312–9. 11. Guyton DL, Cheeseman EW, Ellis FJ, et al. Dissociated vertical deviation: an exaggerated normal eye movement used to to damp cyclovertical latent nystagmus. Trans Am Ophthalmol Soc. 1998;96:389–429. 12. Crone RA. Alternating hyperphoria. Br J Ophthalmol. 1954;38:591–604. 13. Lang J.  Squint dating from birth or with early onset. In: Transactions of the First International Congress of Orthoptists. London: Henry Klimpton; 1968. p. 231–7. 14. Brodsky MC. DVD remains a moving target! J AAPOS. 1999;3:325–7. 15. Mittelstaedt H. The subjective visual vertical as a function of visual and extraretinal cues. Acta Psychol. 1986;63:63–85. 16. Goltz HC, Irving EL, Hill JA.  Dissociated vertical deviation: head and body orientation affect the amplitude and velocity of the vertical drift. J Pediatr Ophthalmol Strabismus. 1996;33:307–13. 17. van Rijn LJ, Simonsz HJ, ten Tusscher MPM.  Dissociated vertical deviation and eye torsion: relation to disparity-induced vertical vergence. Strabismus. 1997;5:13–20. 18. Brecher GA.  Die optokinetische Auslösung von Augenrollung und rotatorischem Nystagmus. Pfugers Arch Gesamte Physiol Menschen Tiere. 1934;234:13–28. 19. Crone RA. Optically-induced eye torsion, II: optostatic and optokinetic cycloversion. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1975;196:1–7.

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20. Crone RA, Everhard-Halm Y. Optically-induced eye torsion, I: fusional cyclovergence. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1975;195:231–9. 21. Goodenough DR, Sigman E, Oltman PK, et  al. Eye torsion in response to a tilted visual stimulus. Vis Res. 1979;19:1177–9. 22. Brodsky MC. Do you really need your oblique muscles? adaptations and exaptations. Arch Ophthalmol. 2002;120:820–8. 23. Gould SJ. Exaptation: a crucial tool for evolutionary psychology. J Soc Issues. 1991;47:43–65. 24. Kori AA, Schmid-Priscoveanu A, Straumann D. Vertical divergence and counterroll movements evoked by whole-body position steps about the roll axis of the head in humans. J Neurophysiol. 2001;85:671–8. 25. Hofmann FB, Bielschowsky A. Die Verwertung der Kopfneigung zur Diagnose der Augenmuskellähmungen aus der Heber und Senkergruppe. Graefes Arch Ophthalmol. 1900;51:174. 26. Allen MJ, Carter JH. The torsion component of the near reflex. Am J Optom. 1967;44:343–9. 27. von Helmholtz H.  Handbuch der Physiologischen Optik. Vol 3. Treatise on physiological optics (trans: Southall JPC). Rochester: Optical Society of America; 1925. 28. von Tschermak-Seysenegg A.  Introduction to physiological optics (trans: Boeder P). Springfield: Charles C Thomas; 1952. p. 140–2.

Postscript This article deals with the complex issue of why the torsional eye movements in DVD are opposite in direction to those produced by the vestibular pathways. In my original analysis of DVD, I had explained this phenomenon teleologically by stating that the torsional directions between vestibular and visual pathways had to be opposite in direction to summate to zero under conditions of normal functioning. In this analysis, I demonstrate that monocular occlusion is associated with a subjective sensation of tilt, which is rapidly corrected by the DVD. The absence of any subjective tilt after a DVD torsional movement occurs suggests that these movements are corrective in nature (i.e. that DVD is indeed a righting reflex). From there, I use the direction of the perceived visual tilt to deconstruct the vertical component of DVD, which rotates the eyes back to the altered internal orientation for true vertical (i.e. toward the subjective vertical) from torsional component (which is directed toward and thereby corrects the perceived tilt of the visual world (termed the subjective visual vertical). Whereas the perceived true vertical and the position of the world rotate in the same direction during body tilt, in visual tilts they scissor apart, necessitating torsional movements that are opposite in direction to those produced by body tilt. The neurologic pathways by which these visual torsional movements are separately mediated in humans remain unknown.

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In its essence, DVD is a tilt rather than a hyperdeviation. If the reader tilts his or her head to the left and looks in the mirror, they will find that the right eye is higher than the left in space. Do they suddenly have a large right hypertropia? No, they have a tilt with no true hypertropia. The true hypertropia is actually the magnitude of the total vertical deviation in space minus the tilt. That is why you can have a true hypertropia superimposed upon a DVD. The vertical component of DVD is therefore a tilt in physical space to realign the eyes with internal orientation of the individual. On top of this, the gyroscopic torsional component of DVD creates a roll movement to restore restore vertical orientation of the outside world. Despite its atavistic origin, DVD reflects complex computational processing at many levels within the visual system.

7

The Reversed Fixation Test A Diagnostic Test for Dissociated Horizontal Deviation

The adjective “Dissociated” was first used to describe binocular eye movements by Bielschowsky; he applied the term “dissociated vertical divergence” to the alternating hyperdeviation that accompanies congenital strabismus [1–3]. In 1976, Raab [4] described the slow unilateral abduction of the deviating eye as a horizontal variant of dissociated vertical divergence. In 1990, Spielmann [5] assigned the name “dissociated horizontal deviation” to patients with infantile strabismus with intermittent esodeviation of either eye. Spielmann noted that some esodeviations are smaller when the child is visually inattentive than when the child is fixating or during cover testing. This finding suggested that monocular fixation can increase esotonus in some patients with infantile strabismus [5]. Beginning also in 1990, several clinical reports applied the term “dissociated horizontal deviation” to intermittent exodeviations that were larger in 1 eye or confined to 1 eye on alternate cover testing, ie, dissociated [6–11]. Affected patients manifested an exodeviation of variable amplitude [6–11]. Associated findings such as dissociated vertical divergence, latent nystagmus, and sensorial suppression of 1 eye (even when the eyes were aligned) also distinguished this form of dissociated horizontal deviation from intermittent exotropia [6–8]. The exodeviation was noted to be larger during periods of visual inattention [9]. The authors of these reports advocated limiting surgery to a single lateral rectus muscle in the exodeviating eye (recession with or without a posterior fixation suture) for unilateral cases of dissociated horizontal deviation, while reserving bilateral lateral rectus muscle recession for cases of so-called bilateral dissociated horizontal deviation or unilateral dissociated horizontal deviation combined with exotropia [6–11].

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_7

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Dissociated horizontal deviation has to be defined as the horizontal vergence that is brought about by a change in the balance of visual inputs derived from the right and left eyes. The etiology of dissociated horizontal deviation is open to conjecture. Zubcov et al12 proposed that greater degrees of convergence might be used to damp larger degrees of latent nystagmus that develop when the eye with poorer vision is fixating. However, it is equally possible that the latent nystagmus is not causal and that the change in vergence results from the fixation shift from one eye to the other, with the unequal damping of latent nystagmus occurring as a side effect [13]. Depending on the baseline horizontal deviation of the eyes under binocular conditions, the same fixation-induced vergence mechanism could manifest as a dissociated esotropia or dissociated exotropia. Many cases of asymmetrical esodeviation and exodeviation are attributable to conditions that simulate dissociated horizontal deviation [13, 14]. For example, many patients with asymmetrical exodeviations have a history of strabismus surgery for infantile esotropia [11, 15]. In such cases, a slipped, overrecessed, or weak medial rectus muscle or a tight lateral rectus muscle can produce an incomitance with an increase of the squint angle when the eye with impaired motility is forced to fixate. Dissociated horizontal deviation must also be considered in the postoperative patient with congenital strabismus who develops an intermittent exodeviation that spontaneously changes to esotropia [16, 17]. Before considering this diagnosis, the examiner must also exclude a convergence substitution movement in patients with impaired volitional gaze [13, 14]. The examiner must also place the patient in the full cycloplegic refraction to exclude unequal accommodative convergence caused by uncorrected anisometropia. For example, a patient with anisohyperopia (plano OD; + 5.00 OS) may show 15 prism diopters of exotropia when fixating with the right eye, and 10 prism diopters of esotropia when fixating with the left eye. Thus, to confirm the diagnosis of dissociated horizontal deviation, the head posture, the direction of gaze, the fixation distance, and the degree of accommodation must remain unchanged as fixation switches from one eye to the other [13, 14]. The reversed fixation test, as described by Mattheus and Kommerell [15–17], was developed to measure dissociated deviations. This test makes it possible to rule out simulating conditions. The performance of this test with prisms and its outcomes in different situations of horizontal deviation are described below.

Reversed Fixation Test Consider a patient who has had surgery for infantile esotropia and subsequently developed an intermittent exodeviation of the left eye. Alternate cover testing shows that only the left eye drifts out under the cover. The reversed fixation test is now necessary to confirm or rule out the presence of a dissociated deviation.

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Scenario 1 Step 1: A base-in prism is placed before the left eye to neutralize the exodeviation. The left eye is covered for about 5 seconds. The cover is then switched briefly to the right eye then immediately back to the left eye to confirm that the exodeviation is neutralized. If not, the prism is changed and the procedure repeated until the exodeviation of the left eye is neutralized, eg, by 25 prism diopters. With the prism held before the left eye, the occluder is moved to cover the right eye. No movement of the left eye is seen (Fig. 7.1, top). Step 2: (Reversed fixation test): After about 5 seconds, the occluder again is briefly switched from the right eye to the left eye (with the prism still held in place in front of the left eye). No movement of the right eye is observed (Fig. 7.1, bottom). This means that the 25 prism diopters are also corrective for left eye fixation. Interpretation: The absence of right eye movement in the reversed fixation test demonstrates that the exotropia is not dissociated. Rather, this patient may have an adduction deficit of the right eye due to postoperative slippage of the right medial rectus muscle.

Scenario 2 Step 1: A 25 prism diopter base-in prism placed before the left eye is found to neutralize the exodeviation. With the 25 prism diopter base-in prism still in front of the left eye, the right eye is covered for several seconds (Fig. 7.2, top). No movement of the left eye is seen. Step 2: (Reversed fixation test): With the prism still in front of the left eye, after several seconds the occluder is switched from the right eye to the left eye. An abduction saccade of the right eye is observed, corresponding to an adducted position of the right eye under the cover (Fig. 7.2, bottom). This adducted position can be measured by having a second observer (or the patient) place a base-out prism in front of the right eye while keeping the right eye occluded. Then the cover is for a short moment switched to the left eye and immediately back to the right eye to observe whether the adducted position of the right eye is neutralized. If not, the prism is changed and the procedure repeated until the adducted position is neutralized, eg, by a 25 prism diopter base-out prism. Interpretation: In this situation, there is less esotonus when the right eye is fixating than when the left eye is fixating. Thus, when the left eye is made to fixate in its unchanged, abducted position (through the prism), the right eye assumes an adducted position of the same size behind the cover, ie, there is no squint angle. This patient has a dissociated component of 25 prism diopters which equals the entire exodeviation of the left eye (provided that unequal accommodative convergence is excluded by dynamic retinoscopy or by maximum visual acuity at distance with the patient in his or her corrected cycloplegic refraction). If there is no horizontal incomitance, the patient will also be orthotropic in straight gaze as long as the left eye is fixating.

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25∆

25∆

Fig. 7.1  Intermittent exotropia. Top: Following neutralization with a 25 prism diopter base-in prism, no change in esotonus occurs when the occluder is shifted to the right eye. Bottom: Therefore, no movement of the right eye is seen when the occluder is again shifted to the left eye, demonstrating that the exotropia is not dissociated

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25∆

25∆

25∆

Fig. 7.2  Dissociated horizontal deviation. Top: Following neutralization with a 25 prism diopter base-in prism, the esotonus increases when the occluder is shifted to the right eye. Bottom: Reversed fixation test. When the occluder is again shifted to the left eye, a 25 prism diopter abduction saccade of the right eye is seen, demonstrating the dissociated nature of the exodeviation

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Scenario 3 Step 1: A 25 prism diopter base-in prism is placed before the left eye to neutralize the exodeviation. With the prism held before the left eye, the occluder is moved to cover the right eye. No movement of the left eye is seen (Fig. 7.3, top). Step 2: (Reversed fixation test): With the prism still in front of the left eye, the occluder is briefly switched from the right eye to the left eye, then immediately back to the right eye. An abduction saccade of the right eye is observed, corresponding to an adducted position of the right eye under the cover (Fig. 7.3, bottom). When measured with a second observer (or the patient) placing a base-out prism in front of the right eye, the size of the abduction saccade is 10 prism diopters. Interpretation: Assuming that unequal accommodative convergence has been ruled out, this patient has 10 prism diopters of dissociated horizontal component superimposed on 25 prism diopters of underlying exotropia. The patient who spontaneously alternates fixation, will alternately manifest an exodeviation of 15 prism diopters in the right eye and an exodeviation of 25 prism diopters in the left eye.

Scenario 4 Consider the patient with the same history who manifests a large exodeviation during periods of visual inattention. Alternate cover testing shows a large exodeviation of the left eye and a small esodeviation of the right eye. Step 1: A 25 prism diopter base-in prism is placed before the left eye to neutralize the exodeviation. With the prism held before the left eye, the occluder is moved to cover the right eye. No movement of the left eye is seen (Fig. 7.4, top). Step 2: (Reversed fixation test): With the prism still in front of the left eye, the occluder is switched from the right eye to the left eye. An abduction saccade of the right eye is observed, corresponding to an adducted position of the right eye under the cover. When measured with a second observer (or the patient) placing a base-out prism in front of the right eye, the size of the abduction saccade is 30 prism diopters (Fig. 7.4, bottom). Interpretation: Assuming that unequal accommodative convergence has been ruled out, this patient alternately manifests an exotropia of 25 prism diopters in the left eye and an esotropia of 5 prism diopters in the right eye, attributable to a dissociated component of 30 prism diopters.

Comment The dissociated component of congenital strabismus may be inapparent on initial examination and variable under binocular conditions. The reversed fixation test was devised by Mattheus and Kommerell [15–17] as a technique to visualize the dissociated component in patients with dissociated vertical divergence. The reversed fixation test is particularly useful for distinguishing dissociated vertical divergence

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25∆

25∆

10∆

Fig. 7.3  Dissociated horizontal deviation. Top: Following neutralization with a 25 prism diopter base-in prism, the esotonus increases when the occluder is shifted to the right eye. Bottom: Reversed fixation test. When the occluder is again shifted to the left eye, a 10 prism diopter abduction saccade of the right eye is seen, demonstrating the partially dissociated nature of the exodeviation

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25∆

25∆

30∆

Fig. 7.4  Dissociated horizontal deviation with coexistent exodeviation and esodeviation. Top: Following neutralization with a 25 prism diopter base-in prism, the esotonus significantly increases when the occluder is shifted to the right eye. Bottom: Reversed fixation test. When the occluder is again shifted to the left eye, a 30 prism diopter abduction saccade of the right eye is seen, demonstrating that this patient has 25 prism diopters of exotropia (causing the exodeviation of the left eye) with an additional dissociated component of 30 prism diopters (causing the 5 prism diopter esodeviation of the right eye during left eye fixation as shown in the top figure)

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from the nondissociated vertical divergence caused, for example, by primary oblique muscle overaction [17]. In the horizontal plane, a major advantage of the reversed fixation test is that an incomitant horizontal deviation will not be misdiagnosed as “dissociated.” This test allows the examiner to measure a dissociated component as the difference between the squint angle when the right eye is fixating and the angle when the left eye is fixating, without any change of the horizontal gaze direction. If the reversed fixation test shows that the angle is the same on right and left eye fixation, a dissociated component of the deviation has been ruled out. Since fixation per se (with either eye) can evoke differing degrees of esotonus, the degree of exodeviation that is apparent with visual inattention (eg, when the patient is asked to remember an event 24 hours ago or to solve a mathematical task) can be larger than that measured when either eye is used to fixate [11, 14]. The reversed fixation test shows that dissociated horizontal deviation exists in a minority of patients with unilateral exodeviation [13, 14]. While this disorder is referred to as dissociated horizontal deviation in the left or the right eye, it is well to remember that the dissociated component results from a change in vergence tonus on a supranuclear level when the fixating eye is switched, and that it actually involves both eyes. In conclusion, dissociated horizontal deviation is a unique clinical disorder that can be diagnosed only after a variety of other simulating conditions have been excluded. The reversed fixation test is a decisive test for the diagnosis of dissociated horizontal deviation. With the reversed fixation test, keeping the neutralizing prism in its position in front of the same eye, a change in the fixation from one eye to the other normally does not alter the strabismus angle. With corrected cycloplegic refraction, when prism alternate cover testing discloses a movement of the eye not viewing through the prism, a dissociated component of the strabismus is established. References 1. Bielschowsky A. Über die Genese einseitiger Vertikalbewegungen der Augen. Z Augenheilkd. 1904;12:545–57. 2. Bielschowsky A.  Die einseitigen und gegensinnigen (“dissoziierten”) Vertikalbewegungen der Augen. Albrecht Von Graefes Arch Ophthalmol. 1930;125:493–553. 3. Bielschowsky A. Disturbances of the vertical motor muscles of the eye. Arch Ophthalmol. 1938;20:175–200. 4. Raab EL. Dissociated vertical deviation in combined motor anomalies. In: Fells P, editor. Proceedings of the Second Congress of the International Strabismological Association. Marseilles: Diffusion Générale de Libraire; 1976. p. 189–93. 5. Spielmann A. Déséquilibres verticaux et torsionnels dans le strabisme précoce. Bull Soc Ophtalmol Fr. 1990;4:373–84. 6. Romero-Apis D, Castellanos-Bracamontes A. Desviacion horizontal disociada (DHD). Rev Mex Oftalmol. 1990;64:169–73.

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7. Quintana-Pali L.  Desviacion horizontal disociada. Bol Hosp Oftalmol. 1990;42:91–4. 8. Wilson ME, McClatchey SK.  Dissociated horizontal deviation. J Pediatr Ophthalmol Strabismus. 1991;28:90–5. 9. Romero-Apis D, Castellanos-Bracamontes A. Dissociated horizontal deviation: clinical findings & surgical results in 20 patients. Binocul Vis Strabismus Q. 1992;7:173–8. 10. Wilson ME.  The dissociated strabismus complex. Binocul Vis Strabismus Q. 1993;8:45–6. 11. Wilson ME, Hutchinson AK, Saunders RA. Outcomes from surgical treatment for dissociated horizontal deviation. J AAPOS. 2000;4:94–101. 12. Zubcov AA, Reinecke RD, Calhoun JH. Asymmetric horizontal tropias, DVD, and manifest latent nystagmus: an explanation of dissociated horizontal deviation. J Pediatr Ophthalmol Strabismus. 1990;27:59–64. 13. Gräf M. Dissociated horizontal deviations (DHD): terminology, diagnosis and etiology. In: Faber TJ, editor. Transactions of the 26th Meeting of the European Strabismological Association, Florence, June 2001. Tokyo: Swets & Zeitlinger; 2001. p. 105–8. 14. Gräf M. Dissociated horizontal deviations (DHD): nomenclature and etiology: an orientating attempt in terminological confusion. Klin Monatsbl Augenheilkd. 2001;218:401–5. 15. Mattheus S, Deberitz I, Kommerell G. Differentialdiagnose zwischen inkomitierendem und dissoziiertem Schielen. Arbeitskreis Schielbehandlung Berufsverband Augenärzte Deutschlands. 1978;10:135–7. 16. Kommerell G, Mattheus S.  Reversed fixation test (RFT), a new tool for the diagnosis of dissociated vertical deviation. In: Reinecke RD, editor. Strabismus. Orlando: Grune & Stratton; 1984. p. 721–8. 17. Mattheus S, Kommerell G. Reversed fixation test as a means to differentiate between dissociated and nondissociated strabismus. Strabismus. 1996;4:3–9.

Postscript This paper documented the reversed fixation test (RFT) as a determinative test for dissociated horizontal deviation (DHD), as first articulated by Michael Gräf in 2001. Note that an equal amount of esotonus exerted by fixation with each of the two eyes would yield a negative reversed fixation test in the presence with DHD. Such cases would have equal exodeviations with each eye fixing. Thus, some cases of DHD will inevitably fly under our radar. After further study, it became clear to me that the diagrams in this article incorrectly depict large shifts in eye position corresponding to the reversed fixation test (RFT). In point of fact, they are tiny, on the order of 2–8 PD. This tiny shift occurs because the reversed fixation test measures only the difference in dissociated esotonus that is exerted when each of the two eyes are fixating. Since fixation with one eye is already exerting considerable esotonus, and the deviation has been corrected

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by a base in prism, the switch to fixation with the eye that exerts greater or lesser esotonus would show a movement that reflects the difference. Thus, even a small shift is still significant for DHD. By inference, when intermittent exotropia is accompanied by a positive reversed fixation test, one can probably conclude that its onset was within the first six months of life. However, other cases of intermittent exotropia are accompanied by DVD (either manifest or measurable on prism and alternate cover testing). This association may reflect that fact that DVD is a primitive visual reflex that is present all of us, so if intermittent exotropia begins early in life, DVD can be coexpressed as well.

8

Does Infantile Esotropia Arise From a Dissociated Deviation?

Tonus refers to the effects of baseline innervation on musculature in the awake, alert state [1]. Since the normal anatomical resting position of the eyes is one of exodeviation, extraocular muscle tonus plays a vital physiologic role in establishing ocular alignment. Under normal conditions, binocular esotonus is superimposed on the baseline anatomical position of rest to maintain approximate ocular alignment, save for a minimal exophoria that is easily overcome by active convergence. When binocular visual input is preempted early in life, monocular fixation may give rise to a larger dissociated esotonus that gradually drives the 2 eyes into a “convergent” position, resulting in infantile esotropia [2]. In our companion article [2], we examine clinical and evolutionary evidence for the proposition that dissociated horizontal deviation is a clinical expression of dissociated esotonus. When superimposed on a baseline orthoposition, dissociated esotonus manifests as an intermittent esotropia that is asymmetrical or unilateral [3]. More commonly, dissociated esotonus is superimposed on a baseline exodeviation, producing an intermittent exodeviation that is asymmetrical, unilateral, or associated with a paradoxical esodeviation when the nonpreferred eye is used for fixation [4–11]. Although the term dissociated has historically been restricted to the description of vergence eye movements [12–14], in a more general sense it describes any ocular movements that result from a change in the relative balance of visual input from the 2 eyes [15]. These movements arise almost exclusively in the setting of infantile strabismus [16], which has a strong predilection for esotropia over exotropia. It is held that infantile esotropia disrupts binocular control mechanisms and thereby engenders these dissociated eye movements [16]. This time-honored notion assumes a distinct and unrelated pathogenesis for infantile esotropia. The purpose of this analysis is to raise an unexamined question regarding the pathogenesis of infantile esotropia. Since dissociated deviations almost uniquely accompany infantile strabismus, could infantile esotropia arise from a dissociated deviation? Our findings raise the possibility that dissociated esotonus could be the proximate cause of infantile esotropia.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_8

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Contrary to the stereotype of “congenital” esotropia as a large-angle deviation that is present at birth, most cases are acquired (ie, “infantile” in origin) [17, 18]. Furthermore, the eyes do not simply snap in to their final esotropic position. Before 12 weeks of age, nascent infantile esotropia is an intermittent, variable esodeviation that gradually becomes constant after building in intensity to a large fixed angle of horizontal misalignment [17, 18]. Ing [19] has noted that 50% of patients with infantile esotropia show an increase in the measured angle between the time of first examination and the date of surgery. Clearly, unequal visual input in infancy must produce a gradual and progressive increase in the angle of esotropia. That this esodeviation appears during the early period when stereopsis is developing, but before macular anatomy has matured sufficiently to provide high-resolution acuity [20], suggests that it is actively driven primarily by an imbalance in peripheral visual input. In a recent hypothesis, Guyton [21] has invoked vergence adaptation and muscle length adaptation to explain how a small innervational bias (such as the convergence produced by increased accommodative effort in the presbyope) can build slowly over time into a large constant deviation. Vergence adaptation refers to the tonus levels that normally operate to maintain a baseline ocular alignment and thereby minimize retinal image disparity. According to Guyton, vergence adaptation can allow primitive ocular motor biases to gradually amplify and create strabismic deviations under pathological conditions [21]. Muscle length adaptation refers to the change in extraocular muscle length due to gain or loss of sarcomeres. Muscle length adaption is driven in part by the physiologic effects of vergence adaptation. Our results suggest that dissociated esotonus could provide the sensorimotor substrate for vergence adaptation when binocular cortical control mechanisms fail to take hold. The finding of a positive Bielschowsky phenomenon in dissociated horizontal deviation [5, 8] shows that peripheral luminance reflexes are retained, as in dissociated vertical divergence [22]. In this setting, both peripheral (luminance and optokinetic) and central (fixational) reflexes augment dissociated esotonus and lead over time to infantile esotropia. Subcortical visual reflexes would provide the default system through which dissociated esotonus operates to reestablish the baseline horizontal eye position. This process can ultimately lead to loss of sarcomeres and secondary shortening of the medial rectus muscles. The fact that the eyes straighten to an almost normal baseline position under general anesthesia [23–27], however, suggests that esotonus is the driving force for infantile esotropia and that mechanical effects play a secondary role in its pathogenesis. It is therefore possible that the stable large-angle esodeviation that we recognize as infantile esotropia simply represents the final stage of dissociated esotonus. As with many other forms of ocular misalignment, the constant esodeviation that develops over time may eventually obscure the pathogenesis. Early monocular visual loss is known to generate esotonus and reproduce the same constellation of dissociated eye movements that accompany infantile esotropia [25]. Patients with unilateral congenital cataract often develop large-angle esotropia, latent nystagmus, dissociated vertical divergence, and a head turn to fixate in adduction with the preferred eye [25]. By contrast, early infantile esotropia is often

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characterized by similar visual acuity in the 2 eyes, with alternating suppression of the nonfixating eye. So perhaps dissociated horizontal deviation is not an epiphenomenon of infantile esotropia but a “footprint in the snow” of the dissociated esotonus that is responsible for its inception. There remains the unfortunate tendency in the strabismus literature to conflate esotonus of the eyes as a baseline innervation with convergence of the eyes as an active function. Jampolsky [28, 29] has emphasized the mechanistic importance of distinguishing between convergence as an active binocular function and esotonus as a baseline innervational state that is centrally driven by unequal visual input to the 2 eyes. The importance of this distinction lies in understanding that convergence implies a deviation from baseline under normal conditions of sensory input, whereas tonus implies a return to baseline under altered conditions of sensory input. The distinction between convergence (the effect) and monocular esotonus (the cause) lies at the heart of understanding infantile esotropia. Horwood and colleagues have recently shown that normal infants display fleeting large-angle convergence eye movements during the first 2 months of life and that these spontaneous convergence movements are ultimately predictive of normal binocular alignment [30]. By contrast, infantile esotropia tends to increase over the period when this excessive convergence is disappearing in normal infants [31]. This time course challenges the dubious assumption that infantile esotropia arises from excessive convergence output. The evidence for dissociated esotonus suggests that we retain a primitive tonus system, independent of convergence output, that can operate under conditions of unequal visual input to reset eye position to a new baseline “convergent” position. This mechanism would explain why infantile esotropia is so much more common than infantile exotropia. If the dissociated esotonus that manifests as dissociated horizontal deviation gives rise to infantile esotropia, why does dissociated horizontal deviation manifest as an intermittent exotropia? Although we use the term intermittent exotropia diagnostically, it is ultimately a descriptive term comprising a variety of conditions with different diagnostic implications. The intermittent exodeviation caused by dissociated horizontal deviation simply constitutes one distinct form of intermittent exotropia with its own unique pathophysiology. Many clinicians apply the hybrid term intermittent exotropia/dissociated horizontal deviation, implying that the 2 conditions often coexist, and perhaps acknowledging some diagnostic ambiguity [5–10]. So what are the innervational substrates for these distinct but overlapping categories of intermittent exotropia? Although Burian [32] believed intermittent exotropia to be caused by an active divergence mechanism, independent studies have found that these patients are approximately 30 prism diopters more exotropic when deeply anesthetized than in the awake state [26, 27], suggesting that intermittent exotropia actually results from intermittent fusional control of a large baseline exodeviation [33, 34]. When intermittent exotropia is associated with dissociated horizontal deviation, fixation with either eye superimposes dissociated esotonus on the baseline exodeviation to produce a variable intermittent exodeviation [2]. The distinction between nondissociated intermittent exotropia and dissociated horizontal deviation lies

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primarily in the relative activation of binocular fusion (which behaves as an all-or-­ nothing phenomenon in most forms of intermittent exotropia) vs dissociated esotonus (which functions as an open-loop process without reference to ultimate binocular alignment in dissociated horizontal deviation). Because fixation with the nonpreferred eye exerts greater esotonus [2], the baseline exodeviation can be unilateral, asymmetrical, or associated with a paradoxical esotropia when the nonpreferred eye is used for fixation. Infantile esotropia and intermittent exotropia are universally regarded as distinct forms of strabismus that occupy opposite points on a clinical spectrum. In contrast to infantile esotropia, intermittent exotropia usually has a later onset and is rarely associated with prominent dissociated eye movements (although small degrees of dissociated vertical divergence can be detected) [35]. At first glance, it is difficult to imagine how these diametrical forms of horizontal misalignment are not mutually exclusive. The beauty of dissociated horizontal deviation is that it allows us to recast horizontal strabismus as the relative balance of mechanical and innervational forces, without regard to final eye position. Dissociated esotonus can still be expressed from an exodeviated position, because it is generated by unbalanced binocular input that exerts its influence on any baseline deviation. Consequently, intermittent exotropia is a common clinical manifestation of dissociated esotonus. Mechanistically, there is nothing sacred about orthotropia as a clinical demarcation and nothing signatory about the direction of horizontal misalignment. In this light, dissociated horizontal deviation is transformed from a clinical curiosity to a fundamental piece of the puzzle for understanding horizontal strabismus. The exotropic form of dissociated horizontal deviation uniquely embodies the coexistence of the mechanical exodeviating forces that give rise to intermittent exotropia and the dissociated esotonus that may give rise to infantile esotropia. For example, infantile exotropia is often accompanied by dissociated eye movements such as latent nystagmus and dissociated vertical divergence [36, 37]. Some infants exhibit an intermittent form of exotropia with other dissociated eye movements [38], suggesting a component of dissociated horizontal deviation. Patients with primary dissociated horizontal deviation also display an intermittent exodeviation of one or both eyes with other signs of dissociation [6]. All of these conditions share a common pathophysiology wherein dissociated esotonus is superimposed on a baseline exodeviation to produce an intermittent exodeviation that varies in size depending on which eye is used for fixation. In patients without binocular fusion, dissociated esotonus can cause a constant exodeviation to appear intermittent. In patients who retain binocular fusion, it can produce a combined clinical picture of intermittent exotropia (with intermittent fusion), an asymmetrical exodeviation of the 2 eyes, or an exodeviation of the nonpreferred eye with a paradoxical esodeviation of the preferred eye. In classifying these disorders pathogenetically, it is critically important to distinguish sensorimotor factors from the different forms of ocular misalignment that they ultimately produce. Dissociated horizontal deviation shows us how it is only the resultant horizontal deviations, and not the underlying conditions, that are diametrically opposed.

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In conclusion, our findings raise the intriguing possibility that dissociated esotonus, an unrecognized dissociated eye movement, may be the cause, rather than the effect, of infantile esotropia. If this proves to be the case, then the prevailing concept of infantile esotropia as the proximate cause of dissociated deviations may need to be revised. References 1. To cross or not to cross: the proceedings of the Ocular Motor Tonus Symposium sponsored by the Smith-Kettlewell Eye Research Institute, Tiberon, CA, June 2–4, 2006. p. 2–4. http://www.ski.org/Tonus/index.html. 2. Brodsky MC, Fray KJ. Dissociated horizontal deviation after surgery for infantile esotropia: clinical characteristics and proposed pathophysiologic mechanisms. Arch Ophthalmol. 2007;125(12):1683–92. 3. Spielmann A. Déséquilibres verticauxet torsionnels dans le strabisme précoce. Bull Soc Ophtalmol Fr. 1990;4:373–84. 4. Romero-Apis D, Castellanos-Bracamontes A. Desviacion horizontal disociada (DHD). Rev Mex Oftalmol. 1990;64:169–73. 5. Wilson ME, McClatchey SK.  Dissociated horizontal deviation. J Pediatr Ophthalmol Strabismus. 1991;28(2):90–5. 6. Romero-Apis D, Castellanos-Bracamontes A. Dissociated horizontal deviation: clinical findings and surgical results in 20 patients. Binocul Vis Strabismus Q. 1992;7:173–8. 7. Quintana-Pali L.  Desviacion horizontal disociada. Bol Hosp Oftalmol. 1990;42:91–4. 8. Zabalo S, Girett C, Domínguez D, Ciancia A. Exotropia intermitente con desviación vertical discodiada. Arch Oftalmol B Aires. 1993;68:11–20. 9. Wilson ME.  The dissociated strabismus complex. Binocul Vis Strabismus Q. 1993;8:45–6. 10. Wilson ME, Hutchinson AK, Saunders RA. Outcomes from surgical treatment for dissociated horizontal deviation. J AAPOS. 2000;4(2):94–101. 11. Spielmann AC, Spielmann A.  Antinomic deviations: esodeviation associated with exodeviation. In: Faber TJ, editor. Transactions 28th Meeting European Strabismological Association, Bergen, Norway, June, vol. 2003. London: Taylor & Francis; 2004. p. 173–6. 12. Bielschowsky A. Über die Genese einseitiger Vertikalbewegungen der Augen. Z Augenheilkd. 1904;12:545–57. 13. Bielschowsky A.  Die einseitigen und gegensinnigen (“dissoziierten”) Vertikalbewegungen der Augen. Albrecht Von Graefes Arch Ophthalmol. 1930;125:493–553. 14. Bielschowsky A. Disturbances of the vertical motor muscles of the eye. Arch Ophthalmol. 1938;20:175–200. 15. Lyle TK. Worth and Chavasse’s Squint. The binocular reflexes and treatment of strabismus. Philadelphia: Blakiston; 1950. p. 40–1. 16. Brodsky MC.  Visuo-vestibular eye movements: infantile strabismus in three dimensions. Arch Ophthalmol. 2005;123(6):837–42.

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17. Pediatric Eye Disease Investigator Group. The clinical spectrum of early-onset esotropia: experience of the congenital esotropia observational study. Am J Ophthalmol. 2002;133(1):102–8. 18. Pediatric Eye Disease Investigator Group. Spontaneous resolution of early-­ onset esotropia: experience of the congenital esotropia observational study. Am J Ophthalmol. 2002;133(1):109–18. 19. Ing MR. Progressive increase in the quantity of deviation in congenital esotropia. Trans Am Ophthalmol Soc. 1994;92:117–31. 20. Fawcett SL, Wang YZ, Birch EE. The critical period for susceptibility of human stereopsis. Invest Ophthalmol Vis Sci. 2005;46(2):521–5. 21. Guyton DL. Changes in strabismus over time: the roles of vergence tonus and muscle length adaptation. Binocul Vis Strabismus Q. 2006;21(2):81–92. 22. Brodsky MC.  Dissociated vertical divergence: a righting reflex gone wrong. Arch Ophthalmol. 1999;117(9):1216–22. 23. Roth A, Speeg-Schatz C. Eye muscle surgery. Basic data, operative techniques, surgical strategy. Paris: Swets & Zeitlinger; 1995. p. 283–324. 24. Jampolsky A. Strabismus and its management? In: Taylor DS, Hoyt CS, editors. Pediatric ophthalmology and strabismus. 3rd ed. London: Elsevier Saunders; 2005. p. 1001–10. 25. Thouvenin D, Nogue S, Fontes L, Norbert O.  Strabismus after treatment of unilateral congenital cataracts: a clinical model for strabismus physiopathogenesis? In: Faber d, editor. Transactions 28th European Strabismological Association Meeting, Bergen, Norway, vol. 2003. London: Taylor & Francis; 2004. p. 147–52. 26. Apt L, Isenberg S. Eye position of strabismic patients under general anesthesia. Am J Ophthalmol. 1977;84(4):574–9. 27. Romano PE, Gabriel L, Bennett W, et al. Stage I intraoperative adjustment of eye muscle surgery under general anesthesia: consideration of graduated adjustment. Graefes Arch Clin Exp Ophthalmol. 1988;226(3):235–40. 28. Jampolsky A.  Ocular divergence mechanisms. Trans Am Ophthalmol Soc. 1970;68:730–808. 29. Jampolsky A. Unequal visual inputs in strabismus management: a comparison of human and animal strabismus. In: Symposium on strabismus: transactions of the New Orleans Academy of Ophthalmology. St Louis: CV Mosby; 1978. p. 422–5. 30. Horwood A. Too much or too little: neonatal ocular misalignment frequency can predict lateral abnormality. Br J Ophthalmol. 2003;87(9):1142–5. 31. Horwood AM, Riddell PM. Can misalignments in typical infants be used as a model for infantile esotropia? Invest Ophthalmol Vis Sci. 2004;45(2):714–20. 32. Burian HM.  Pathophysiology of exodeviations. In: Manley DR, editor. Symposium on horizontal ocular deviations. St Louis: CV Mosby; 1971. p. 119–27. 33. Kushner BK. Exotropic deviations: a functional classification and approach to treatment. Am Orthopt J. 1988;38:81–93.

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34. Kushner BJ, Morton GV.  Distance/near differences in intermittent exotropia. Arch Ophthalmol. 1998;116(4):478–86. 35. Pritchard C. Incidence of dissociated vertical deviation in intermittent exotropia. Am Orthopt J. 1998;48:90–3. 36. Moore S, Cohen RL. Congenital exotropia. Am Orthopt J. 1985;35:68–70. 37. Rubin SE, Nelson LB, Wagner RS, et al. Infantile exotropia in healthy infants. Ophthalmic Surg. 1988;19(11):792–4. 38. Hunter DG, Kelly JB, Ellis FJ. Long-term outcome of uncomplicated infantile exotropia. J AAPOS. 2001;5(6):352–6.

Postscript This editorial elaborates on the previous chapter and further expands on from my AOS thesis on dissociated horizontal deviation (DHD), which proposed that we have been thinking about DHD the wrong way. Rather than being a dissociated exodeviation, DHD actually arises when monocular fixation causes dissociated esotonus to be superimposed on baseline exodeviation (usually following strabismus surgery for infantile esotropia). In this setting, fixation with the poorer eye generates a greater degree of dissociated esotonus, sometimes causing the baseline esotropia to convert to an esotropia. Therefore, when patients become inattentive, a much larger exodeviation becomes evident. It was Michael Gräf at the University of Giessen who first recognized that monocular fixation evokes convergence in DHD. He has since devised the “17 x 13” test to elicit this phenomenon. Just ask the patient to multiply 17 x 13 and you will see the large baseline exodeviation appear. I referred to this particular quality of DHD as the “Heisenberg Uncertainty Principle” of clinical strabismus measurement, wherein the act of measuring a horizontal deviation by occluding either eye inevitably changes the measurement you obtain (in this case by evoking monocular fixation with its commensurate esotonus). Strabismus surgery based on the measured deviation (using prism and alternate cover testing), will correct the measurements but leave a large residual exodeviation during periods of inattention. My early interest in DHD was directed at the establishing utility of the reversed fixation test in identifying dissociated esotonus (Chap 7). This quick clinical test works well except when the dissociated esotonus happens to be equal in the two eyes. In this essay, I propose that the dissociated esotonus that characterizes DHD could be the underlying cause of essential infantile esotropia. Accordingly, what we recognize as essential infantile esotropia may be the end-stage phenotype of dissociated esotonus. In patients with infantile or consecutive exotropia, the innervational effects of dissociated esotonus are easily visualized. In infantile esotropia, however, the dissociated esotonus is fully expressed, rendering it impossible to visualize DHD during monocular fixation. This mechanism also explains why we occasionally see DHD manifesting as an intermittent esotropia of varying amplitude depending on which eye is fixating. (Fig. 8.1).

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Fig. 8.1  Preoperative photos of DHD showing eye position during (a) period of inattention, (b) left eye fixation at near, (c) right eye fixation at near. (Reprinted with permission from Brodsky MC: Intermittent esotropia in an adult. JAMA Ophthalmol 2021, with permission from the American Medical Association)

The Accessory Optic System The Fugitive Visual Control System in Infantile Strabismus

Infantile strabismus is characterized by dissociated binocular vision, which is the normal condition in lateral-eyed animals [1, 2]. Early binocular misalignment gives rise to dissociated eye movements (changes in eye position evoked by unequal visual input to the 2 eyes) [3]. These include latent nystagmus, dissociated vertical divergence, and dissociated horizontal deviation [1–3], all of which have a prominent torsional component. Primary oblique muscle overaction, which accompanies infantile strabismus but is not dissociated in nature, is also characterized by a torsional misalignment of the eyes [4]. These binocular deviations all correspond to normal visuovestibular reflexes that are operative in lateral-eyed animals [1–4]. Evolutionarily, these visual reflexes antedate development of the visual cortex, which does not generate torsional eye movements in humans [5]. Therefore, any attempt to anatomize infantile strabismus must explain the reemergence of these atavistic reflexes, as well as their prominent torsional components. I propose that the accessory optic system (AOS), an atavistic subcortical visual motion detection system, could generate the dissociated and non-­ dissociated torsional eye movements that accompany human infantile strabismus.

What Is the AOS? The AOS consists of 3 nuclei at the mesodiencephalic border that receive direct retinal input from the accessory optic tract (AOT) [6–9] (Fig. 9.1). The AOT comprises an inferior and a superior fasciculus, with its superior fasciculus divided into a posterior branch, a middle branch, and an anterior branch that is identical to the original transpeduncular tract (tractus peduncularis transversus) discovered in 1870 by Gudden [10, 11]. The number of accessory optic fibers is small [7]. In almost all mammalian species, most optic fibers reach the accessory optic nuclei via the transpeduncular tract, which is visible as it courses over the brachium of the superior colliculus [12].

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_9

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Fig. 9.1  Neuroanatomical connections of the accessory optic system. The brainstem is depicted from the front (with the left-hand side of the animal on the right-hand side of the drawing). Accessory terminal nuclei include the dorsoterminal nucleus (DTN), which lies adjacent to the nucleus of the optic tract (NOT); medial terminal nucleus (MTN); lateral terminal nucleus (LTN); and principal part of the inferior olive (IOp). Optokinetic input from the right retina crosses to the left accessory optic nuclei (depicted), which send ipsilateral projections to the left dorsal cap (DC) of the inferior olive and then back to the right flocculus (not shown), resulting in a double decussation of motion pathways from each eye. (Adapted with permission from Simpson et al. [12]) CP indicates posterior commissure; D, nucleus of Darkschewitsch; DMNm, deep mesencephalic nucleus, pars medialis; EW, nucleus of Edinger-Westphal; INC, interstitial nucleus of Cajal; inSFp, intersitial nucleus of the superior fasciculus, posterior fibers; MAO, medial accessory nucleus, inferior olivary complex; ML, medial lemniscus; MLF, medial longitudinal fasciculus; PAGm, periaqueductal gray, medial part; pdl, dorsolateral division, basal pontine complex; pm, medial division, basal pontine complex; pv, ventral division, basal pontine complex; PVG, periventricular gray; RN, red nucleus; rpc, pontine reticular nucleus, pars caudalis; rpo, pontine reticular nucleus, pars oralis; vl, lateral vestibular nucleus; VLO, ventrolateral outgrowth, inferior olivary complex; vm, medial vestibular nucleus; vs, superior vestibular nucleus; vsp, spinal vestibular nucleus; VTRZ, visual tegmental relay zone; β, nucleus β of the inferior olive; 3n, oculomotor nerve; 4n, trochlear nerve; and 6n, abducens nerve

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In most mammalian species, the AOS is composed of 3 paired terminal nuclei, namely, the dorsoterminal nucleus (DTN), the lateroterminal nucleus (LTN), and the medioterminal nucleus (MTN), which receive innervation from primary optic fibers [7–9]. Input to these 3 accessory optic terminal nuclei is predominantly from the contralateral eye [7–9, 11, 12]. Along with the nucleus of the optic tract (NOT), these 3 terminal nuclei project differentially to the dorsal cap of the inferior olive [13–16], which provides the only source of climbing fibers to the flocculonodular lobe of the cerebellum [7–9, 13–17]. In this way, cells of the AOS converge with those of the vestibular system in the vestibulocerebellum [7–9]. Despite its name, the AOS is a primary visual system receiving direct visual information from the retina via 1 or more AOTs [13] that are responsible for visuovestibular interaction in afoveate animals [7, 16, 17]. Its retinal input is derived from ON–type direction-sensitive ganglion cells. The AOS neurons have large receptive fields (averaging about 40° vertically and 60° horizontally), are direction selective, and have a preference for slow-moving stimuli [7–9, 12, 13]. The AOS processes information about the speed and direction of movement of large textured parts of the visual world [7–9]. The AOS signals self-motion as a function of slip of the visual world over the retinal surface and generates corrective eye movements to stabilize the retinal image [7–9]. As an analyzer of self-motion, the AOS subserves visual proprioception in the afoveate animal [7–9]. The AOS is a visual system that is organized in vestibular coordinates [7–9]. According to results of experimental studies by Simpson and colleagues, visual and vestibular signals that produce compensatory eye movements are organized about a common set of axes derived from the orientation of the semicircular canals (Fig. 9.2) [7, 9, 12, 16, 17]. Because the AOS is directionally sensitive to low-velocity movements while the vestibular system typically responds to movements of higher velocity, the AOS and vestibular labyrinths form 2 complementary systems to detect self-motion and promote image stabilization so that objects in the visual world can be quickly and accurately analyzed [7, 8, 12, 13]. The AOS exists in all vertebrate classes [6, 7, 18, 19], including humans [20], but it has been studied most extensively in the rabbit. The 3 preferred directions for cells in the accessory optic terminal nuclei define 3 directions in visual space, namely, horizontally from posterior to anterior for the DTN, vertically up and down for the MTN, and vertically down for the LTN [7–9, 11–14, 21]. Its 3 pretectal accessory optic nuclei are closely related to the NOT and receive input predominantly from the contralateral eye [7–9, 12, 13]. Direction-sensitive ON-type retinal ganglion cells encode retinal image slip [22, 23] and transmit this information to the AOS, inferior olive [24] floccular climbing fibers [25], and floccular Purkinje cells [26]. These 3 pairs of channels remain anatomically distinguishable within the AOS, inferior olive, and floccular zones, which (when stimulated) elicit eye movements organized in a canal-like coordinate system [18, 27–29]. Each pair conveys signals about flow of the visual surround about 1 of 3 rotation axes, which are approximately collinear with the best-response axes of the semicircular canals and the rotation axes of the extraocular muscles [28].

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Rotation Axes Visual Climbing Fibers (Left Flocculus of Dominant Eye) VA

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Fig. 9.2  Spatial orientation of preferred axes of 3-dimensional rotation for dorsal cap neurons in the right inferior olive recorded during optokinetic stimulation in a spherical enclosure. (Adapted with permission from Van der Steen et al. [27] VA indicates vertical axis)

The rabbit flocculus ipsilateral to the seeing eye is optimally sensitive to optokinetic stimulation about a 135° axis, while the flocculus contralateral to the seeing eye is optimally sensitive to optokinetic stimulation around a horizontal 45° axis (Fig. 9.3) [26–29]. For horizontal stimulation, the DTN and its adjacent NOT are selectively sensitive to nasally directed optokinetic stimulation presented to the contralateral eye [7, 8, 12, 13]. Conversely, electrical microstimulation in the alert rabbit’s flocculus produces abduction of the ipsilateral eye [27, 29, 30] or dissociated torsional and vertical rotations of the 2 eyes, corresponding to the plane of 1 semicircular canal [26–30]. Because floccular motion detection for each eye is not fully represented on its own side of the body, monocular optokinetic responses must be derived from the synthesis of bilateral floccular representations [28]. Therefore, the flocculus provides a subcortical binocular visual system that generates asymmetrical torsional eye movements under dissociated conditions of optokinetic stimulation [28]. Studies using decortication have revealed contributions from the visual cortex to the AOS. Disruption of contributions from the visual cortex to the AOS by strabismus may alter the inherent biases of the accessory optic nuclei [31–33]. The

What Is the AOS?

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Fig. 9.3  Sensitivity to monocular optokinetic stimulation in a spherical enclosure. (a) Responses of posterior axis climbing fiber Purkinje cells to stimulation presented to the ipsilateral left eye. (b) Responses of anterior axis climbing fiber Purkinje cells to stimulation presented to the contralateral eye. CCW indicates counterclockwise optokinetic rotation; CW, clockwise optokinetic rotation. (Adapted with permission from Van der Steen et al. [27])

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ipsilateral visual cortex is necessary for several response properties that distinguish DTN and LTN neurons in the cat from those in the rabbit. Following decortication, cat DTN and LTN neurons lose their binocularity and become almost totally dominated by the contralateral eye [33]. For example, LTN neurons excited by upward movement, which in the cat are equal in number to those excited by downward movement, become less numerous so that the cat LTN becomes like that of the rabbit, consisting of neurons excited by slow downward movements to the contralateral eye [33]. Unlike the LTN and DTN, neurons in the cat MTN are largely monocular and similar to those in the rabbit [12]. The monocular nasotemporal optokinetic asymmetry that characterizes infantile strabismus is known to result from monocular cortical input to the NOT and DTN [34], unmasking a subcortical visuovestibular bias that generates latent nystagmus [35]. The AOS provides a neuroanatomical substrate whereby vertical monocular subcortical motion biases could generate the canal-based torsional eye movements that characterize primary oblique muscle overaction and dissociated vertical divergence [2, 4]. Although we observe and analyze these eye movements in yaw, pitch, and roll [2], they are encoded in a canal-­ oriented push-pull bilateral coordinate system that detects optokinetic flow in every direction [36]. Photic stimulation can activate the AOT in the rabbit [4, 37]. The AOS neurons show the same responses to retinal illumination as ON-type direction-sensitive retinal ganglion cells, being excited only at the onset of retinal stimulation [23], and generate a firing response that is related to light intensity [32]. In this way, the AOS may implement the visuovestibular reflexes that characterize infantile strabismus [1, 2]. However, because the AOS is primarily a motion detector, central modulation of the primitive luminance reflexes that characterize infantile strabismus may require input from additional subcortical visual pathways. It is possible that other primitive luminance pathways may provide parallel subcortical luminance input to the visuovestibular system [38]. Like the AOS, luminance input that modulates the dorsal light reflex in fish (which corresponds to dissociated vertical divergence and primary oblique muscle overaction in humans with infantile strabismus) [1, 2] is transmitted to the central pretectal nucleus in the contralateral midbrain and then down to the vestibulocerebellum, which integrates visual and vestibular input [39]. These luminance and motion pathways may constitute the subcortical equivalents of the “what” and “where” visual streams within the association visual cortex. How these subcortical visual streams intercommunicate to consolidate spatial and temporal summation of visual information at the subcortical levels remains a mystery. But the likelihood that they provide the innervational substrate for the atavistic eye movements that characterize infantile strabismus should not be ignored.

Conclusions The AOS provides a critical piece of the puzzle for infantile strabismus by serving as a neuroanatomic substrate for visuovestibular eye movements. The AOS is atavistic, present in humans, subcortical, crossed, and sensitive to optokinetic motion. It

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operates in a canal-based coordinate system and generates dissociated torsional eye movements. For these reasons, the AOS is uniquely suited to generate the dissociated eye movements that characterize infantile strabismus. The fact that its retinal fibers terminate in the 3 nuclei of the AOT along with the adjacent NOT (a part of the pretectal nuclear complex that generates latent nystagmus) lends further credence to this hypothesis. Dissociated binocular vision in infancy may unlock this atavistic visual system, generating canal-based ocular rotations that we anthropomorphize to diagnose “torsion” in the frontal plane. This analysis implies that mutations involving the AOS or its target zones within the cerebellar flocculus could provide a potential template for infantile strabismus. If so, then the age-old dichotomy postulated by Worth (congenital defect in cortical fusion) and Chavesse (early binocular misalignment) [40] could be explained by binocular subcortical dysfunction intrinsic to the visuovestibular system. References 1. Brodsky MC.  Dissociated vertical divergence: a righting reflex gone wrong. Arch Ophthalmol. 1999;117(9):1216–22. 2. Brodsky MC. Visuo-vestibular eye movements: infantile strabismus in 3 dimensions. Arch Ophthalmol. 2005;123(6):837–42. 3. Brodsky MC. Dissociated horizontal deviation: clinical spectrum, pathogenesis, evolutionary underpinnings, diagnosis, treatment, and potential role in the development of infantile esotropia (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2007;105:272–93. 4. Brodsky MC, Donahue SP. Primary oblique muscle overaction: the brain throws a wild pitch. Arch Ophthalmol. 2001;119(9):1307–14. 5. Brodsky MC. Dissociated vertical divergence: cortical or subcortical in origin? Strabismus. 2011;19(2):67–70. 6. Marg E. The accessory optic system. Ann N Y Acad Sci. 1964;117:35–52. 7. Simpson JI, Soodak RE, Hess R. The accessory optic system and its relation to the vestibulocerebellum. Prog Brain Res. 1979;50:715–24. 8. Simpson JI, Leonard CS, Soodak RE. The accessory optic system: analyzer of self-motion. Ann N Y Acad Sci. 1988;545:170–9. 9. Simpson JI. The accessory optic system. Annu Rev Neurosci. 1984;7:13–41. 10. Gudden B.  Ueber einen bisher nicht eschriebenen Nervenfasernstrang im Gehirne der Säugethiere und des Menschen. Arch Psychiatry. 1870;2:364–6. 11. Gudden B.  Ueber den Tractus peduncularis transversus. Arch Psychiatry. 1881;11:415–23. 12. Simpson JI, Giolli RA, Blanks RH.  The pretectal nuclear complex and the accessory optic system. Rev Oculomot Res. 1988;2:335–64. 13. Giolli RA, Blanks RHI, Lui F. The accessory optic system: basic organization with an update on connectivity, neurochemistry, and function. Prog Brain Res. 2006;151:407–40. 14. Takeda T, Maekawa K. The origin of the pretectoolivary tract: a study using the horseradish peroxidase method. Brain Res. 1976;117(2):319–25.

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15. Maekawa K, Takeda T. Afferent pathways from the visual system to the cerebellar flocculus of the rabbit. In: Baker R, Berthoz A, editors. Control of gaze by brain stem neurons: developments in neuroscience. Amsterdam: Elsevier/ North-Holland Biomed; 1977. p. 187–95. 16. Maekawa K, Simpson JI. Climbing fiber activation of Purkinje cells in the flocculus by impulses transferred through the visual pathway. Brain Res. 1972;39(1):245–51. 17. Maekawa K, Simpson JI. Climbing fiber responses evoked in vestibulocerebellum of rabbit from visual system. J Neurophysiol. 1973;36(4):649–66. 18. Ebbesson SO.  On the organization of central visual pathways in vertebrates. Brain Behav Evol. 1970;3(1):178–94. 19. Cooper HM, Magnin M. A common mammalian plan of accessory optic system organization revealed in all primates. Nature. 1986;324(6096):457–9. 20. Fredericks CA, Giolli RA, Blanks RH, Sadun AA. The human accessory optic system. Brain Res. 1988;454(1–2):116–22. 21. Simpson JI, Leonard CS, Soodak RE.  The accessory optic system of rabbit. II.  Spatial organization of direction selectivity. J Neurophysiol. 1988;60(6):2055–72. 22. Oyster CW.  The analysis of image motion by the rabbit retina. J Physiol. 1968;199(3):613–35. 23. Soodak RE, Simpson JI. The accessory optic system of rabbit. I. Basic visual response properties. J Neurophysiol. 1988;60(6):2037–54. 24. Leonard CS, Simpson JI, Graf W. Spatial organization of visual messages of the rabbit’s cerebellar flocculus. I. Typology of inferior olive neurons of the dorsal cap of Kooy. J Neurophysiol. 1988;60(6):2073–90. 25. Simpson JI, Graf W, Leonard CS. Three-dimensional representation of retinal image movement by climbing fiber activity. In: Strata P, editor. The olivocerebellar system in motor control. Berlin: Springer Verlag; 1989. p.  323–37. Experimental Brain Research Series 17. 26. Graf W, Simpson JI, Leonard CS. Spatial organization of visual messages of the rabbit’s cerebellar flocculus. II. Complex and simple spike responses of Purkinje cells. J Neurophysiol. 1988;60(6):2091–121. 27. Van der Steen J, Simpson JI, Tan J. Representation of three-dimensional eye movements in the cerebellar flocculus of the rabbit. In: Schmid R, Zambarbieri D, editors. Oculomotor control and cognitive processes. Amsterdam: Elsevier; 1991. p. 63–77. 28. Tan HS, van der Steen J, Simpson JI, Collewijn H. Three-dimensional organization of optokinetic responses in the rabbit. J Neurophysiol. 1993;69(2):303–17. 29. Simpson JI, Van der Steen J, Tan J, Graf W, Leonard CS. Representations of ocular rotations in the cerebellar flocculus of the rabbit. Prog Brain Res. 1989;80:213–23. 30. Ito M, Nisimaru N, Yamamoto M.  Specific patterns of neuronal connexions involved in the control of the rabbit’s vestibulo-ocular reflexes by the cerebellar flocculus. J Physiol. 1977;265(3):833–54.

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31. Grasse KL, Cynader MS. Response properties of single units in the accessory optic system of the dark-reared cat. Brain Res. 1986;392(1–2):199–210. 32. Grasse KL, Cynader MS.  The accessory optic system of the monocularly deprived cat. Brain Res. 1987;428(2):229–41. 33. Grasse KL, Cynader MS, Douglas RM. Alterations in response properties in the lateral and dorsal terminal nuclei of the cat accessory optic system following visual cortex lesions. Exp Brain Res. 1984;55(1):69–80. 34. Hoffmann KP. Cortical vs subcortical contributions to the optokinetic reflex in the cat. In: Lennerstrand G, Zee DS, Keller EL, editors. Functional basis of ocular motility disorders. Oxford, UK: Pergamon; 1982. p. 303–10. 35. Brodsky MC, Tusa RJ. Latent nystagmus: vestibular nystagmus with a twist. Arch Ophthalmol. 2004;122(2):202–9. 36. Simpson JI, Graf W. The selection of reference frames by nature and its investigators. Rev Oculomot Res. 1985;1:3–16. 37. Hamasaki D, Marg E. Microelectrode study of accessory optic tract in the rabbit. Am J Phys. 1962;202:480–6. 38. Schiller PH. Parallel information processing channels created in the retina. Proc Natl Acad Sci U S A. 2010;107(40):17087–94. 39. Yanagihara D, Watanabe S, Takagi S, Mitarai G. Neuroanatomical substrate for the dorsal light response. II. Effects of kainic acid-induced lesions of the valvula cerebelli on the goldfish dorsal light response. Neurosci Res. 1993;16(1):33–7. 40. Chavesse FB, Worth CA, Lyle TK.  The binocular reflexes and treatment of strabismus. Philadelphia: Blakeston; 1950.

Postscript The accessory optic system (AOS) provides a critical piece of the puzzle in infantile strabismus by explaining how visual motion can be processed in a vestibular coordinate system. The existence of this subcortical system explains how torsional eye movements can be generated in response to unequal binocular visual input, and how individual extraocular muscles can be driven to overact when binocular visual development is comprised. The clear implication is that this atavistic system somehow remains functional in infantile strabismus and infantile nystagmus. This proposition is not so bold when one considers that our extraocular muscles are oriented in a semicircular canal-based planar coordinate system. The AOS subserves optokinesis, however, so it remains unclear whether primitive luminance pathways are encoded in a similar coordinate system, or whether luminance disparity generates correlative input the AOS. The reader would be remiss in not asking why humans retain primitive neurologic systems such as the AOS after newer cortical systems develop. A satisfying answer can be found in John Allman’s 1999 book Evolving Brains. In one section, during a visit to a power generation plant in the 1970s, he noted that several

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different control systems, some ancient, others new, were situated adjacent to each other. Some contained pneumatic controls and a system of controls based on vacuum tube technology, while the newer control systems relied upon computer-driven control systems. Yet, these systems were all used together to control the generation of electricity at the plant. When he asked why the archaic systems had not been superseded by the new ones, he was told that the demand for power had always been too great for the plant to ever be shut down. He concluded that “The brain has evolved in the same manner as the control systems in this power plant. The brain, like the power plant, can never be shut down and fundamentally reconfigured, even between generations. All the old control systems must remain in place, and new ones with additional capacities are added and integrated in such a way as to enhance survival.” The subcortical visual pathways are old school. They are concerned with side vision, while the visual cortex is more concerned with central vision (as evidenced by its generous macular representation). Yet the human AOS remains functional within the first 2–3 months of life of infancy. The implication of this article is that direct retinotectal input to the AOS may perpetuate its function and thereby generate the unique eye movements that characterize (and possibly generate) infantile strabismus. Accordingly, infantile strabismus may be generated primarily by the AOS, or be perpetuated secondarily by the AOS only when cortical binocular vision fails to develop. It may even be that the secondary reconfiguration of the motion visual cortex, as first proposed by Hoffman, stimulates the AOS to retain the necessary neuroplasticity to subserve this function. Long ago, Clifton Schor proposed that cortical suppression of one eye could momentarily disinhibit the subcortical pathways to allow their retinotectal input to predominate. Any combination of these mechanisms could be operative. Anyone who tells you that they have the final answer is not a scientist. In science, models evolve with new and better data. Science is a series of leaps, with new hypotheses leading to ongoing falsifications. So keep an open mind.

Visuo-Vestibular Eye Movements Infantile Strabismus in 3 Dimensions

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Infantile strabismus inaugurates a triad of stereotypical eye movements comprising latent nystagmus, primary inferior oblique muscle overaction, and dissociated vertical divergence [1]. These unique ocular movements have long been a medical curiosity because they are not encountered in other forms of neurological disease. Their coexistence in patients with infantile strabismus implicates a common pathophysiology. Until we understand how these eye movements cohere into a larger whole, “they remain intellectual orphans” [2]. The purpose of this article is to examine the physical laws that govern these ocular movements, to integrate these movements into “an organized whole in a way that snaps existing and heretofore patternless data into a highly symmetrical pattern” [3], and to examine the evolutionary forces that underlie their clinical expression in infantile strabismus. An evolutionary undergird for these ocular movements can be constructed from the following physiologic principles.

The Problem Is Gravity Why is symmetry ubiquitous in the animal kingdom? More specifically, what is the evolutionary origin of the bilateral symmetry that dictates that we have 2 eyes, ears, arms, and legs situated equidistant from the midline? The problem of symmetry in biological systems is a complex subject of ongoing study [4–6]. One of the evolutionary functions of biological symmetry is balance. Because of the earth’s gravitational field, survival requires that animals maintain vertical orientation. An animal that falls tends to get eaten. For living organisms, gravity necessitates balance. Because physical symmetry promotes balance, biological symmetry is an important part of nature’s solution to the problem of gravity.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_10

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Bilaterally Symmetrical Organs Function as Balance Organs The evolution of bilaterally symmetrical organs situated equidistant from the sagittal plane promotes balance by virtue of physical weight alone. Our 2 lungs, when inflated with air, become ballast in water. But many bilateral structures also function as physiologic balance organs. While it is axiomatic that our 2 labyrinths superintend balance, other bilateral organs modulate balance in different ways. Our 2 cerebral hemispheres each control motor tone in the contralateral limbs. Our 2 cerebellar hemispheres clearly control balance. Even the 2 kidneys have been shown to function in part as balance organs [7].

Lateral Eyes are Sensory Balance Organs Our ancestral environment is characterized by 2 physical constants: light from the sky above and gravity from the earth below [8]. Although the sun is the source of light, it adds little to the overall brightness of the sky. Throughout evolution, the bright sky has served as a space-stable luminance hemisphere [8]. Because light comes from above, when the eyes are laterally positioned, vertical alignment is signaled by equal luminance to the 2 eyes. Evolution has programmed this visual cue into our balance system to optimize survival. While it is axiomatic that our 2 labyrinths keep us informed of our relation to our gravitational position (a static otolithic system) and movement (a dynamic semicircular canal system), our 2 eyes subserve the same function because an animal cannot rely solely on vestibular input during momentary physical perturbations by wind and waves [9]. The striking correspondence of eye-muscle position to semicircular canal and extraocular muscle orientation permits the eyes and ears to subserve balance in lockstep. As summarized by Duke-Elder [10], … the control of the movements of living animals, both plants and animals, by light is a fundamental function of great phylogenetic age, preceding the acquirement of vision and, indeed, leading directly to its development. The association of the functions of equilibration and orientation with the visual system of higher animals is in every sense basic.

 rimitive Reflexes are Resurrected When Normal P Neurodevelopment Fails to Occur Many primitive reflexes that promoted survival in the ancestral setting lose their beneficial function as evolution proceeds [11, 12]. With progressive encephalization, newer cortical reflexes are grafted onto older subcortical reflexes, which persist in latent form even when they no longer serve a useful function [13, 14]. Abnormal neurodevelopment in infancy is associated with a persistence of numerous subcortical reflexes (Table 10.1) [15]. In pediatric neurology, these primitive reflexes are among the clinical signposts of abnormal neurodevelopment [15]. In pediatric

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Table 10.1  Normal Developmental Reflexes (Modified From Swaiman) [15] Reflex Adductor spread of knee jerk Moro Palmar grasp Planter grasp Routing Tonic neck response

Appearance Age Birth Birth Birth Birth Birth Birth

Disappearance Age, mo 7–8 5–6 6 9–10 3 5–6

ophthalmology, these echoes from our visual ancestry signal maldevelopment of cortical binocular vision. In the developing visual system, monocular nasotemporal asymmetry is perhaps the quintessential example of a visual reflex in which ontogeny recapitulates phylogeny. Nasotemporal asymmetry refers to a monocular horizontal optokinetic response that is brisk in the nasal direction and poor or absent in the temporal direction [16]. This directional optokinetic bias is normal in lateral-eyed animals and in human infants within the first 6 months of life. Humans with infantile strabismus retain a nasotemporal asymmetry that provides the monocularly driven horizontal movement bias for latent nystagmus [16].

 cular Motor Incursions Operate as Visual Balancing Reflexes O in Lateral-Eyed Animals Primitive visual reflexes rely on a dissociated form of binocular vision between the 2 laterally placed eyes, which has been superseded by cortical binocular vision in humans [9]. Humans experience frontal binocular vision with forfeiture of peripheral vision in exchange for cortical fusion and stereopsis. Infantile strabismus recreates the dissociated binocular condition that allows lateraleyed animals to process dissociated luminance and visual input from each eye with little or no binocular overlap. Infantile strabismus effectively disables the newer cortical binocular system and unveils the primitive visual reflexes that have been inscribed into our primitive ocular motor control system [14, 16]. The resurrection of these primitive visual reflexes generates a triad of ocular movements that have come to define infantile strabismus. This symphony of eye movements reveals each of the primitive visual reflexes that use dissociated binocular visual input to maintain physical orientation in 3-dimensional space. Latent nystagmus corresponds to the optokinetic component of ocular rotation that is driven monocularly by nasal optic flow during a turning movement of the body in lateral-eyed animals [16]. When infantile esotropia disrupts the establishment of binocular visual connections, visual input from the fixating eye to the contralateral nucleus of the optic tract evokes a counterrotation of the eyes that corresponds to a turning movement of the body toward the object of regard. The clinical expression of this visual reflex is also evident in the monocular

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nasotemporal asymmetry to horizontal optokinetic stimulation that characterizes infantile strabismus [16]. Dissociated vertical divergence corresponds to the dorsal light reflex that has been observed in fish and other lateral-eyed animals when unequal luminance to the 2 eyes evokes a body tilt or vertical divergence of the eyes toward the side with greater luminance [8, 9]. In humans, dissociated vertical divergence is a visual balancing reflex that uses weighted binocular visual input to orient eye position to the perceived vertical (Fig. 10.1) [8, 9]. The exaptation of a cycloversional movement into the human dorsal light reflex permits active modulation of perceived visual tilt when the eyes are frontally positioned [8]. Primary inferior oblique muscle overaction corresponds to a similar dorsal light reflex that is induced in fish when a forward or backward shift in overhead luminance evokes an ipsidirectional body pitch or torsional rotation of the eyes backward to reorient the body with respect to the light [19]. These binocular torsional rotations of the eyes constitute a physiologic form of primary oblique muscle

Fixation + Light

Fixation

Fixation + Light

Fig. 10.1  Ohm’s visual balancing metaphor for dissociated vertical divergence [17] as depicted by Mattheus and Kommerell [18]. Position of the scales corresponds to the relative vertical positions of the eyes in dissociated vertical divergence as determined by binocular visual input. White retina indicates light input, dark retina indicates no light input, and x corresponds to the presence of fixation in light or in darkness. (Reprinted with permission from Aeolus Press, Buren, the Netherlands)

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overaction that can be induced by altering binocular visual input. In humans, a forward or backward rotation relative to overhead light sends excitatory innervation to each of the elevators or each of the depressors. Because the vestibular system segregates innervation to its target extraocular muscles, the vertical actions of the human oblique muscles summate in adduction with those of the rectus muscles to produce the innervational overelevation of the adducting eye that defines primary inferior oblique muscle overaction. The fundamental association of primary oblique muscle overaction with early loss of binocular vision in humans suggests that the brain registers abnormal binocular visual input as forward rotation [19].

 rimitive Visual Reflexes are Evoked by a Physiologic P Imbalance in Binocular Visual Input Most patients with infantile esotropia have no neurologic disease. From where do these involuntary ocular rotations arise? Stereotypical eye movements that do not fit any paradigm must come from somewhere. As stated by Keiner, “Nothing comes from nothing”[14] (p151). The source of these dynamic intrusions has eluded us for the simple reason that they arise from a physiologic imbalance rather than from a neurologic lesion. They are harmonics of our earlier orchestration that bubble to the surface when they are not superseded by cortical binocular reflexes. Just as physiologic vestibular movements reflect the degree of unbalanced labyrinthine input, the size of these eye movements are proportional to the degree of binocular visual imbalance, which can fluctuate depending on momentary cortical suppression of either eye. Because the eye movements of infantile strabismus are calibrated by weighted binocular visual input, they increase in proportion to the disparity of visual input from the 2 eyes [9].

 atent Nystagmus, Primary Oblique Overaction, L and Dissociated Vertical Divergence are Visuo-Vestibular Eye Movements In lateral-eyed animals, visual and labyrinthine input are pooled together within the central vestibular system to establish central vestibular tone [17–19]. Based on momentary fluctuations in bilateral input, the central vestibular system constantly modulates eye position and body position to maintain physical orientation in 3-dimensional space [8]. Vestibular input predominates over visual input, but both systems are integrated at the level of the vestibular nucleus to maintain balance [20–22]. In infantile strabismus, binocular visual imbalance alone can alter central vestibular tone [9]. Because input to the vestibular nucleus can be directly driven by the balance of visual input from the 2 eyes, this unique form of central vestibular imbalance does not require that the central nervous system receive an imbalance of labyrinthine input [9]. It is as if infantile strabismus transforms the 2 eyes into physiologic vestibules. These unique eye movements are visuo-vestibular in origin.

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 isuo-Vestibular Eye Movements are Generated by Subcortical V Central Vestibular Pathways In the absence of binocular cortical development, the system defaults to a subcortical control system in which the central vestibular system is the gyroscope that sets postural tonus to the extraocular muscles. These subcortical motor pathways receive both afferent input from the optic nerves and efferent input from the visual cortex. As with the pupillary light reflex, however, cortical input can modulate these subcortical reflexes [23]. Thus, voluntary or involuntary suppression of 1 eye can activate latent nystagmus and dissociated vertical divergence [24, 25]. The clinical expression of these subcortical reflexes in the setting of infantile strabismus reflects the evolution of a hierarchical visual system in which cortical binocular vision can hold our subcortical reflexes in check [26]. In infantile strabismus, subcortical visual reflexes are reactivated because the system reverts to a dissociated binocular system [27].

 isuo-Vestibular Eye Movements Arise from a Central V Vestibular Imbalance that Dissociates Clinically into 3 Distinct Planes Vestibular eye movements are governed by the anatomical orientation of the labyrinths and occur in 3 major head-referenced planes [28]. Yaw rotation occurs around the z or vertical axis, pitch rotation occurs around the y or interaural axis, and roll rotation occurs around the x or nasal-occipital axis (Fig. 10.2). While vestibular eye movements are driven by sensory input from the 2 labyrinths, visuo-vestibular eye movements are driven by visual input from the 2 eyes. In infantile strabismus, the 2 Fig. 10.2 Cartesian coordinate system for yaw, pitch, and roll movements of the head. (Axes differ from those of the Fick coordinate system for eye rotation.)

Z

Yaw

Roll

X

Pitch

Y

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eyes function as physiologic vestibules that can directly modulate central vestibular tone in a complementary way to a labyrinthine imbalance. These visuo-vestibular eye movements generate latent nystagmus in the yaw plane, primary oblique muscle overaction in the pitch plane, and dissociated vertical divergence in the roll plane (Table 10.2) [16]. Ultimately, all 3 visuo-vestibular eye movements are clinical expressions of a visually induced imbalance in central vestibular tone, as evidenced by the fact that they manifest as rotations in the same head-referenced planes as vestibular eye movements, which are governed by the orientation of the anatomical components of the 2 labyrinths [9, 16, 19]. One could geometrically display any variable combination of these 3 movements as a single vector in 3-dimensional space based on the size and direction of each movement in its corresponding plane. Because these visuo-vestibular movements correspond to vector components of a single central vestibular imbalance in 3-dimensional space, it is not surprising that their clinical features can overlap. Thus, dissociated vertical divergence incorporates a vertical latent nystagmus, revealing the shared common origin of these movements [29]. Clinically, primary oblique muscle overaction and dissociated vertical divergence often summate to produce an admixture of overelevation in adduction [30]. Similarly, latent nystagmus incorporates vertical and torsional movements that overlap those of dissociated vertical divergence [31]. Each plane of rotation imparts unique clinical features to its visuo-vestibular response. The fact that latent nystagmus is a dynamic imbalance while primary oblique muscle overaction and dissociated vertical divergence are tonic imbalances probably reflects the natural head and body movements that occur in the 3 orthogonal planes of physical space. During navigation, an animal may turn its head and body back and forth rapidly, but pitch or tilt movements tend to be slow and sustained. Our evolutionary programming has devised its compensations accordingly. Thus, the nucleus of the optic tract responds to optokinetic motion in the yaw plane while subcortical neural pathways that modulate the dorsal light reflex produce a tonic postural readjustment to a perceived vertical orientation [16]. Accordingly, horizontal optokinetic input is yoked to horizontal canal input in the yaw plane, but pitch and roll visual stimuli are yoked to otolithic input. The cerebellar flocculus may modulate spatially oriented sensorimotor transformations for visuo-vestibular eye movements [32].

Table 10.2  Planar Components of Central Vestibular Disease Vestibular Counterpart (Peripheral Plane Visuo-Vestibular Imbalance vs Central) Yaw Latent nystagmus Horizontal vestibular nystagmus (peripheral) Pitch Primary inferior oblique Bilateral alternating of skew overaction deviation (central) Roll Dissociated vertical Skew deviation (central) divergence

Vestibular Ocular Reflex Dynamic Tonic Tonic

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Visual Reflexes are Stereoisomers of Vestibular Reflexes For each plane of head rotation, visuo-vestibular eye movements generate a 3-dimensional rotation of the eyes that is a mirror image of its corresponding vestibulo-­ocular imbalance. Thus, latent nystagmus is the visual counterpart to horizontal vestibular nystagmus, primary oblique muscle overaction is the mirror-image visual counterpart to bilateral alternating skew deviation, and dissociated vertical divergence is the visual counterpart to the ocular tilt reaction of which skew deviation is a component. For unity to exist under physiologic conditions, visuo-­vestibular eye movements must complement vestibulo-ocular movements so that their additive functions summate to 0 in each plane. This central yoking of binocular and bilabyrinthine sensory input within the central vestibular system underscores the role of symmetry in our evolutionary design and explains the close geometric correspondence between the semicircular canals and the extraocular muscles [33]. The system fits together nicely.

Conclusions The eye movements of infantile strabismus are harmonics of our earlier orchestration; echoes of our visual ancestry. Visual analogues of latent nystagmus, dissociated vertical divergence, and primary oblique muscle overaction are found in the normal visuo-vestibular eye movements of lateral-eyed animals. These visual reflexes subserve balance by enabling the animal to leverage fluctuations in binocular visual input to maintain postural orientation. By disrupting the development of frontal binocular vision, infantile strabismus permits our primitive visual reflexes to “bubble to the surface.” The resulting ocular intrusion movements reflect an imbalance of binocular visual input in 3 planes of physical space. These overlapping visuo-vestibular eye movements can be deconstructed clinically into their 3 dimensions, corresponding to yaw, pitch, and roll. The symphony of binocular movements that accompanies infantile strabismus is a necessary expression of our primitive heritage that impelled them into being. At a higher level, these movements reveal the wisdom of antiquity by reminding us how survival in a gravitational world once necessitated the evolution of a physical symmetry and its co-orchestration at both anatomical and physiologic levels. Infantile strabismus provides a natural experiment to uncover the primitive visual reflexes that lie buried within us. These visual reflexes are humanity’s umbilical cord reaching back to a time when the 2 eyes functioned together as sensory balance organs. In infantile strabismus, dissociated binocular vision remains the fulcrum on which the visuo-vestibular system teeters. The beauty of infantile strabismus is that each piece of our visual ancestry is laid out in bold relief. We see unraveled before us a blazing display of the primitive visual reflexes that were once necessary to maintain physical orientation in 3- dimensional space.

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More importantly, these preternatural eye movements provide a unique glimpse into a larger universal system of physical order. As eloquently stated by the 19th-­ century English author Thomas de Quincey: Even the articulate or brutal sounds of the globe must be all so many languages and ciphers that somewhere have their corresponding keys—have their own grammar and syntax; and thus the least things in the universe must be secret mirrors to the greatest [34]. References 1. Lang J. The infantile strabismus syndrome. Strabismus. 2000;8:195–9. 2. Pylyshyn ZW. Computation and cognition. Cambridge, MA: MIT Press; 1986. 3. Miller AI. Insights of genius, vol. 333. Cambridge, MA: MIT Press; 1996. 4. Gardner M.  Fearful symmetry. In: The night is large: collected essays, 1938-1995. New York: St Martin’s Griffen; 1996. p. 3–12. 5. Gardner M.  The Ambidextrous Universe. WH Freeman & Company: New York; 1990. 6. McManus C. Right hand, left hand: the origins of asymmetry in brains, bodies, atoms, and cultures. Cambridge, MA: Harvard University Press; 2002. p. 1–412. 7. Mittelstaedt H. Interaction of eye-, head-, and trunk-bound information in spatial perception and control. J Vestib Res. 1997;7:283–302. 8. Brodsky MC.  Dissociated vertical divergence: perceptual correlates of the human dorsal light reflex. Arch Ophthalmol. 2002;120:1174–8. 9. Brodsky MC.  Dissociated vertical divergence: a righting reflex gone wrong. Arch Ophthalmol. 1999;117:1216–22. 10. Duke-Elder S. The effect of light on movement. In: System of ophthalmology: the eye in evolution. London, UK: Henry Klimpton; 1958. p. 27–81. 11. Wolpert L. Principles of development. Oxford, UK: Oxford University Press; 1998. p. 443. 12. Schott JM, Rosser MN.  The grasp and other primitive reflexes. J Neurol Neurosurg Psychiatry. 2003;74:558–60. 13. Zeeman WPC.  Biologisches zum horopterproblem. Ophthalmologica. 1949;117:254–75. 14. Keiner GBJ. New viewpoints on the origin of squint. Martinus Nijhoff: Hague; 1951. p. 1–221. 15. Swaiman KF.  Pediatric neurology: principles and practice. CV Mosby: St Louis; 1999. 16. Brodsky MC, Tusa RJ. Latent nystagmus: vestibular nystagmus with a twist. Arch Ophthalmol. 2004;122:202–9. 17. Ohm J.  Nystagmus und Schielen bei Sehschwachen und Blinden. Stuttgart: Enke; 1958. p. 22. 18. Mattheus S, Kommerell G. Reversed fixation test as a means to differentiate between dissociated and nondissociated strabismus. Strabismus. 1996;4:3–9. 19. Brodsky MC, Donahue SP. Primary oblique muscle overaction: the brain throws a wild pitch. Arch Ophthalmol. 2001;119:1307–14. 20. Pfeiffer W.  Equilibrium orientation in fish. Int Rev Gen Exp Zool. 1964;1:77–111.

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21. Meyer DL, Bullock TH. The hypothesis of sense-organ-dependent tonus mechanisms: history of a concept. Ann N Y Acad Sci. 1977;290:3–17. 22. Graf W, Meyer DL.  Central mechanisms counteract visually induced tonus asymmetries: a study of ocular responses to unilateral illumination in goldfish. J Comp Physiol. 1983;150:473–81. 23. Kardon R. The pupil. In: Adler’s physiology of the eye: clinical application. St Louis: CV Mosby; 2002. p. 714–33. 24. Dell’Osso LF, Abel LA, Daroff RB. Latent/ manifest latent nystagmus reversal using an ocular prosthesis: implications for vision and ocular dominance. Invest Ophthalmol Vis Sci. 1987;28:1873–6. 25. Kommerell G, Zee DS.  Latent nystagmus: release and suppression at will. Invest Ophthalmol Vis Sci. 1993;34:1785–92. 26. Lyle TK. Worth and Chavesse’s Squint: the binocular reflexes and the treatment of strabismus. 8th ed. Philadelphia: Blakiston Co; 1950. p. 15–20. 27. Schor CM. Neural control of eye movements. In: Adler’s physiology of the eye: clinical application. St Louis: CV Mosby; 2002. p. 834–9. 28. Leigh RJ, Zee DS.  The neurology of eye movements. 3rd ed. Oxford, UK: Oxford University Press; 1999. p. 263. 29. Irving EL, Goltz HC, Steinbach MJ, Kraft SP. Vertical latent nystagmus component and vertical saccadic asymmetry in subjects with dissociated vertical deviation. J AAPOS. 1998;2:344–50. 30. von Noorden GK.  Binocular vision and ocular motility: theory and management of strabismus. 4th ed. St Louis: Mosby-Year Book; 1990. p. 341–5. 31. Guyton DL. Dissociated vertical deviation: etiology, mechanisms, and associated phenomena. J AAPOS. 2000;4:131–44. 32. Simpson JI, Van der Steen J, Tan J, et al. Representations of ocular rotations in the cerebellar flocculus of the rabbit. In: JHJ A, Hulliger M, editors. Progress in brain research, vol. 80; 1989. p. 213–23. 33. Simpson JI, Graf WG.  Eye-muscle geometry and compensatory eye movements in lateral-eyed animals and frontal-eyed animals. Ann N Y Acad Sci. 1981;374:20–30. 34. De Quincey T. The Collected Writings of Thomas De Quincey, vol. 1. London: A & C Black; 1896-1897. p. 129.

Postscript This teleological analysis attempts to reconstruct infantile strabismus based on fundamental physical principles involving the basic orientation of the vestibular canalbased system and the corollary orientation of the extraocular muscles. The goal is to try to not only show how dissociated movements occur, but to provide a raison d’etre for these movements. In this article, I propose that the two eyes revert to their secondary function as balance organs in the setting of infantile strabismus, and that the unique dissociated eye movements of infantile strabismus are visuo-vestibular in origin. This conclusion is based on the substantial experimental evidence that the

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subcortical visuo-vestibular pathways mediate similar movements in lower animals, where binocular from the two eyes gets transmitted via the cerebellum to the vestibular nucleus, where it is yoked together with binaural input from the two labyrinths. The article then explains how each of the three recognized dissociated eye movements can be understood as arising from a binocular visual imbalance in one of three orthogonal planes of visual space. Accordingly, a new classification of visuo-­vestibular eye movements becomes necessary to define and describe these dissociated eye movements. At the time this article was published, I did not realize that the accessory optic system (AOS) provided the requisite subcortical neurologic substrate to naturally encode visual motion in a semicircular canal coordinate system. As discussed later in Chap. 9, this atavistic system inevitably generates torsional eye movements as viewed from the frontal-plane. Torsional eye movements can only be generated at the level of the vestibular system (from either labyrinthine or early binocular visual imbalance). It is not known whether the AOS is reconfigured to produce the inverse torsional ocular rotations to those arising from vestibular stimulation in frontal-eyed animals. While these subterranean visual pathways are strictly subcortical in lateral-­ eyed animals, the visual cortex becomes secondarily reconfigured (or retrofitted) to match the subcortical template, enabling these visuo-vestibular movements to be secondarily driven through the visual cortex in primates. This is why differing evolutionary perspectives can easily give rise to opposing scientific positions in the field of strabismus. This analysis codifies the different dissociated eye movements in infantile strabismus into a single unified construct. Despite the usefulness of this Cartesian coordinate system (yaw, pitch, and roll) in classifying dissociated eye movements, however, Simpson and Graf have emphasized that this semicircular canal-based coordinate system does not naturally encode the extrinsic rectangular Cartesian reference frame of orthogonal movements specific to yaw, pitch, and roll that we interpret in this context. Indeed, this canal-based geometric template requires a sensorimotor transformation to generate the variable ocular kinematics that characterize different vertebrate species. (for detailed analysis see Simpson JI, Graf W: The selection of reference frames by nature and its investigators. In Berthoz & Melvll Jones (eds): Adaptive mechanisms in gaze control: Facts and Theories, 1995, Elsevier Science, pp 3–16). It is surprising to many that the human cerebellum is also organized in a canal-­ based coordinate system that bilaterally summates to generate pursuit movements in two dimensions. (Fitzgibbon EG et al: Torsional nystagmus during vertical pursuit. J Neuro-Ophthalmol 1996;16:79–90). The normal cerebellum functions as a sensorimotor integrator to minimize torsion and effectively compress this three-­ dimensional visuo-vestibular template into a two-dimensional plane conducive to foveal pursuit and stereopsis. The ultimate irony is that our ocular motor system must be compressed into two dimensions for our visual cortex to process the visual world in three dimensions.

An Expanded View of Infantile Esotropia Bottoms Up!

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In the August issue of the Archives, Dr Lawrence Tychsen wrote an accompanying editorial [1] to my article on the accessory optic system (AOS) and its potential role in infantile strabismus [2]. I thank him for sharing his thoughts and taking an interest in this work and am pleased to have the opportunity to comment further on this subject. Some believe that infantile esotropia is caused solely by abnormal binocular connections within the visual cortex. These connections include the primary visual cortex as well as higher cortical centers within the middle temporal area/medial superior temporal area that are involved in visual motion processing [2–4]. According to this view, latent nystagmus is attributed to a cortical pursuit imbalance in the middle temporal area/medial superior temporal area with disinhibition of convergence leading to infantile esotropia [5]. The finding of a normal vestibular ocular response is thought to rule out involvement of the vestibular system in infantile esotropia [6]. The other dissociated movements that accompany infantile esotropia are then attributed to active vergence damping at the cortical level [2]. This model requires that visually driven torsional eye movements be generated by the visual cortex and appears to be supported by the failure of decortication to reproduce dissociated eye movements [7]. Accordingly, periventricular leukomalacia is considered a neurologic model for infantile esotropia [2]. Because the visual cortex is readily accessible for study in monkeys, most of the investigational study of infantile esotropia has been focused on that area. Therefore, it is understandable that this general perspective is held by some investigators. What are the shortcomings of this perspective? First, it attributes infantile esotropia to binocular alterations within the cerebral cortex that are secondary to binocular misalignment rather than causal. Hubel and Wiesel [8] first showed that cutting extraocular muscles in kittens induces alternating strabismus and corollary changes within ocular dominance columns in the primary visual cortex. These changes were clearly the effect, rather than the cause, of infantile strabismus. In humans, no better evidence for this phenomenon can be found than in the work of Tychsen and coworkers [3, 9], who have induced infantile © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_11

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esotropia in monkeys using base-out prisms and concluded that abnormal cortical binocular vision is the cause of infantile esotropia. Such experiments confirm that cortical binocular alterations following abnormal binocular visual experience can lead to infantile esotropia. Second, the conclusion that latent nystagmus arises from a cortical smooth pursuit defect [5, 6] ignores the evolutionary record. Latent nystagmus is driven by a normal monocular nasotemporal optokinetic asymmetry that fails to resolve in children with infantile esotropia [5, 10]. This nasal optokinetic preponderance manifests as latent nystagmus when fixation with either eye induces a tonic deviation of both eyes with nasalward drift of the fixating eye [11–15]. The question is whether this optokinetic asymmetry is generated at the cortical or the subcortical level, and there is experimental evidence that can be taken to support either conclusion [13–15]. What is clear is that the same monocular nasotemporal optokinetic asymmetry is present in lower vertebrates that do not possess a visual cortex [16, 17]. Hoffmann [18] has shown in cats that development of binocular corticotectal pathways to the nucleus of the optic tract (NOT) and the dorsal terminal nucleus is necessary to cancel this asymmetry within the first year of life. So phylogenetically and ontogenetically, the monocular nasotemporal optokinetic asymmetry that drives latent nystagmus antedates development of the binocular visual cortex. The neuroanatomical substrate of this optokinetic asymmetry has been mapped to normal subcortical visual pathways that travel first from the retina to the contralateral NOT and dorsal terminal nucleus (a part of the AOS) in the pretectum and then via the cerebellar flocculus to the vestibular nuclei [19–22]. These subcortical, visuovestibular pathways modulate optokinetic responses to whole-field movement (optic flow) in afoveate animals as opposed to cortical pursuit (a foveal function) [21]. Given that the monocular nasotemporal optokinetic asymmetry that generates latent nystagmus derives from a subcortical, afoveate, optokinetic pathway, a binocular defect in cortical (foveal) smooth pursuit cannot be the primary cause of latent nystagmus. The proximate cause of latent nystagmus is that these subcortical optokinetic pathways remain operational. Since cortical pursuit pathways do not generate torsional eye movements, one simply cannot explain the large torsional movements that accompany latent nystagmus without invoking activation of these subcortical visual pathways that project to the vestibular nuclei. In this context, latent nystagmus conforms to a visuovestibular nystagmus that is ultimately driven by subcortical binocular visual input to the vestibular nuclei [10, 23]. Latent nystagmus also shows the phenomenon of velocity storage [24, 25], which is unique to vestibular eye movements [26]. As expected, the vestibular ocular reflex remains normal [6] because labyrinthine input to the vestibular system is unaffected. Optokinetic eye movements provide the pursuit system for lateral-eyed afoveate animals [17]. In primates, the subcortical NOT has commissioned the cortex to provide integrated visual motion information from the 2 hemifields through the middle temporal area and medial superior temporal area [27]. Efferent signals from the NOT and dorsal terminal nucleus may transmit velocity error information to the pursuit system [28]. Pursuit and visuovestibular pathways remain functionally intermingled within the medial superior temporal area of the primate motion visual cortex [29,

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30]. Therefore, it is not surprising that this visual motion asymmetry is represented at the cortical level, causing smooth pursuit to be coordinately impaired [31]. So if one looks for cortical visual motion asymmetry in primates with latent nystagmus, one will find it and conclude that latent nystagmus must be cortical in origin. Third, the notion that binocular cortical alterations unmask an innate convergence bias to produce infantile esotropia is problematic at several levels [32]. Horwood [33, 34] has shown that normal infants display large, fleeting, convergence movements of the eyes during the first 4 months of life, which are indicative of an emerging vergence system. A greater frequency of these convergence movements between ages 2 and 4 months is predictive of normal binocular development and a lower likelihood of developing infantile esotropia [33]. If infantile esotropia represents excessive convergence, why would normal infants display more excessive convergence movements than infants who are destined to develop infantile esotropia? It is also noteworthy that the prevalence of infantile esotropia increases during a period in which these convergence movements are disappearing in normal infants [34]. Jampolsky [35, 36] has emphasized the importance of distinguishing between convergence as an active binocular function and esotonus as a passive innervational output that is centrally driven by unequal visual input to the two eyes. Patients with accommodative esotropia show excessive convergence, while those with infantile esotropia do not. Misinterpreting infantile esotropia as a motor outcome of excessive convergence also supports the misconception that dissociated vertical divergence and dissociated horizontal deviation can be dismissed as excessive vergence damping of latent nystagmus [37], despite the fact that latent nystagmus is not present in some patients who have these other dissociated eye movements [32]. Fourth, the claim that early neurologic perturbation of cortical visual input is a high risk factor for the motor components of infantile strabismus is certainly correct, but the motor effects are due to a secondary involvement of lower motor circuits. Children with neurologic disease constitute the minority in those with findings that define infantile esotropia. There is no substantial evidence that injury to the developing cerebral cortex is necessary for infantile esotropia to develop [38]. Indeed, the absence of neurologic disease is definitional for infantile esotropia. So while neurologic injury is a risk factor for the development of esotropia in infancy, it should not be inferred from this association that infantile esotropia is a “soft sign” of neurologic disease. This leads to a concern about the use of periventricular leukomalacia as a neurologic model for infantile esotropia. It is true that this condition produces preterm injury to binocular visual input as evidenced by the bilateral focal white matter injury to the optic radiations that are visible on magnetic resonance imaging [39]. It is also the case that periventricular leukomalacia is a neurologic disease that can cause elements of the infantile esotropia syndrome to be expressed. However, children with periventricular leukomalacia have a different constellation of clinical findings (including tonic downgaze, primary superior oblique overaction, optic nerve hypoplasia, spontaneous conversion of esotropia to exotropia) from those seen in infantile esotropia [39]. Furthermore, periventricular leukomalacia is now recognized as a global injury to both cortical and subcortical structures (including the thalamus, basal ganglia, and cerebellum) [40], making it a poor model for infantile esotropia caused by isolated injury to binocular cortical visual inputs.

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Although dissociated eye movements are an expression of subcortical visual reflexes in lower animals, there is no question that the human visual cortex is altered by infantile esotropia [3–5, 8, 41] and that cortical suppression of one eye (brought about by fixation, blurring, occlusion, or volition) is a necessary physiological condition to generate dissociated eye movements in humans [38, 42, 43]. After normal corticopretectal connections become established in primates, subcortical retinopretectal projections may lose their influence and be replaced by cortical afferents [44], which would explain the absence of dissociated eye movements in some [7, 13, 45] but not all [46] patients following “decortication.” There is ample evidence that once cortical binocular vision is disrupted early in infancy, infantile esotropia and its dissociated eye movements are generated and operationalized down-stream at the subcortical level [23]. Because studies of infantile esotropia have been largely limited to the cortex, it is on the subcortical limb of the operation that analysis should now be focused. What is the line of evidence showing that strabismus is generated in the basement of the brain? The evidence can be summarized as follows [23]: 1. Lateral-eyed animals have dissociated binocular vision. 2. Lateral-eyed animals display a constellation of subcortical visual reflexes that are driven by unbalanced visual input to the two eyes. 3. These subcortical reflexes are visuovestibular in origin (meaning that dissociated binocular visual input is conveyed to the vestibular nucleus and to the vestibulocerebellum, where luminance and optokinetic input are modulated). 4. Developmental disorders that impair cortical development can allow primitive subcortical reflexes to be expressed in humans [23]. 5. Humans have evolved from lower animals and retain a vestibulocerebellum and an atavistic AOS. 6. Humans who have dissociated binocular vision early in development (most commonly, but not exclusively, infantile esotropia) display a unique constellation of dissociated eye movements. 7. Each of these dissociated eye movements in humans conforms to subcortical visual reflexes that are operative in lateral-eyed animals, are evoked by fluctuating binocular visual input, operate in one plane of visual space, and are driven by optokinetic input or luminance disparity. 8. These dissociated eye movements (latent nystagmus, primary oblique muscle overaction, dissociated vertical divergence, dissociated horizontal deviation) therefore seem to arise from subcortical visual reflexes in lateral-eyed animals and are triggered in humans by cortical suppression of one eye. 9. All of these dissociated eye movements have a prominent torsional component. 10. Human torsional eye movements and other cyclovertical deviations such as skew deviation are a signature of vestibular disease and are conspicuously absent with lesions at the level of the cerebral cortex [47].

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This evidence supports the view that dissociated eye movements are generated in the basement of the brain by primitive visual pathways that are modulated by the binocular visual cortex. As the AOS modulates full-field optokinetic movements similar to the NOT and operates in the canal-based coordinate system, it emerges as an attractive candidate for generating these atavistic torsional movements [1]. In the evolutionary sense, these are not abnormal eye movements but are normal eye movements that are resurgent. A comprehensive neuroanatomical model for infantile esotropia must therefore incorporate the cortico-mesencephalic-cerebellar pathways (not brainstem) [1], which are known to provide a sensorimotor circuit for the control and modulation of eye movements in human and nonhuman primates [22]. For these reasons, we should consider that the “cause” of infantile esotropia lies not only upstairs in the cerebral cortex but also downstairs in the cerebellar cortex. In humans, neurologic lesions such as midline cerebellar tumors [48] and Chiari malformations [49] can also cause acquired comitant esotropia. In the rabbit, stimulation of the dorsal cap of the inferior olive (which provides visual climbing fibers to the cerebellar flocculus) inhibits reflex contractions to the contralateral medial rectus muscle and the ipsilateral inferior oblique muscle [50–52]. In this context, bilateral floccular inhibition would provide one mechanism whereby infantile esotropia and bilateral inferior oblique overaction could be generated without “convergence.” This body of evidence leads to the conclusion that infantile esotropia may also incorporate subcortical optokinetic pathways such as the AOS. As genetic studies provide molecular localization, we could find that lesions anywhere along this expanded roadmap may provide the ocular motor derangements to derail development of cortical binocularity and give rise to infantile strabismus. Depending on their localization (visual cortex, AOS, cerebellar flocculus), targeted neuropharmacologic treatments may become available. References 1. Tychsen L. The cause of infantile strabismus lies upstairs in the cerebral cortex, not downstairs in the brainstem. Arch Ophthalmol. 2012;130(8):1060–1. 2. Brodsky MC. The accessory optic system: the fugitive visual control system in infantile strabismus. Arch Ophthalmol. 2012;130(8):1055–9. 3. Tychsen L. Causing and curing infantile esotropia in primates: the role of decorrelated binocular input (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2007;105:564–93. 4. Tychsen L, Richards M, Wong A, et al. Spectrum of infantile esotropia in primates: behavior, brains, and orbits. J AAPOS. 2008;12(4):375–80. 5. Tychsen L, Richards M, Wong A, Foeller P, Bradley D, Burkhalter A. The neural mechanism for latent (fusion maldevelopment) nystagmus. J Neuroophthalmol. 2010;30(3):276–83. 6. Tychsen L, Hurtig RR, Scott WE. Pursuit is impaired but the vestibule-ocular reflex is normal in infantile strabismus. Arch Ophthalmol. 1985;103(4):536–9. 7. Tychsen L. Absence of subcortical pathway optokinetic eye movements in an infant with cortical blindness. Strabismus. 1996;4(1):11–4.

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8. Hubel DH, Wiesel TN. Binocular interaction in striate cortex of kittens reared with artificial squint. J Neurophysiol. 1965;28(6):1041–59. 9. Tychsen L, Richards M, Wong AM, et al. Decorrelation of cerebral visual inputs as the sufficient cause of infantile esotropia. Am Orthopt J. 2008;58:60–9. 10. Brodsky MC, Tusa RJ. Latent nystagmus: vestibular nystagmus with a twist. Arch Ophthalmol. 2004;122(2):202–9. 11. Kommerell G. Beziehungen zwischen Strabismus un Nystagmus. In: Kommerell G, editor. Augenbewegungsstörungen, Neurophysiologie und Klinik: Symposium der Deutschen Ophthalmologischen Gesellschaft, Freiburg, 1977. Munich: Bergmann; 1978. p. 367–73. 12. Schor CM. Subcortical binocular suppression affects the development of latent and optokinetic nystagmus. Am J Optom Physiol Optic. 1983;60(6):481–502. 13. Kommerell G. Ocular motor phenomena in infantile strabismus: asymmetry in optokinetic nystagmus and pursuit, latent nystagmus, and dissociated vertical divergence. In: Lennerstrand G, von Noorden GK, Campos EC, editors. Strabismus and amblyopia: experimental basis for advances in clinical management. London, UK: Macmillan; 1988. p. 99–109. 14. Kommerell G. The relationship between infantile strabismus and latent nystagmus. Eye. 1996;10(pt 2):274–81. 15. Braddick O. Where is the naso-temporal asymmetry? motion processing. Curr Biol. 1996;6(3):250–3. 16. Tauber ES, Atkin A. Optomotor responses to monocular stimulation: relation to visual system organization. Science. 1968;160(3834):1365–7. 17. Easter SS Jr. Pursuit eye movements in goldfish (Carassius auratus). Vis Res. 1972;12(4):673–88. 18. Hoffmann KP. Cortical vs subcortical contribution to the optokinetic reflex in the cat. In: Lennerstrand G, Zee DS, Keller EL, editors. Basis of ocular motility: proceedings of a Wenner-Gren Center and Smith-Kettlewell Eye Research Foundation International Symposium. New York: Pergamon; 1982. p. 303–11. 19. Langer T, Fuchs AF, Chubb MC, Scudder CA, Lisberger SG. Floccular efferents in the rhesus macaque as revealed by autoradiography and horseradish peroxidase. J Comp Neurol. 1985;235(1):26–37. 20. Büttner U, Boyle R, Markert G, et al. Cerebellar control of eye movements. In: Freund HJ, Büttner U, Cohen B, Noth J, editors. Progress in brain research. Amsterdam: Elsevier; 1996. p. 225–33. 21. Simpson JI, Giolli RA, Blanks RHI. The pretectal nuclear complex and accessory optic system. In: Buettner-Ennever JA, editor. Neuroanatomy of the oculomotor system. Amsterdam: Elsevier; 1988. p. 335–64. 22. Voogd J, Schraa-Tam CKL, van der Geest JN, De Zeeuw CI. Visuomotor cerebellum in human and nonhuman primates. Cerebellum. 2012;11(2):392–410. 23. Brodsky MC. Visuo-vestibular eye movements: infantile strabismus in 3 dimensions. Arch Ophthalmol. 2005;123(6):837–42. 24. Tusa RJ, Mustari MJ, Burrows AF, Fuchs AF.  Gaze-stabilizing deficits and latent nystagmus in monkeys with brief, early-onset visual deprivation: eye movement recordings. J Neurophysiol. 2001;86(2):651–61.

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25. Mustari MJ, Tusa RJ, Burrows AF, Fuchs AF, Livingston CA. Gaze-stabilizing deficits and latent nystagmus in monkeys with early-onset visual deprivation: role of the pretectal NOT. J Neurophysiol. 2001;86(2):662–75. 26. Laurens J, Angelaki DE. The functional significance of velocity storage and its dependence on gravity. Exp Brain Res. 2011;210(3–4):407–22. 27. Ilg UJ, Hoffmann KP. Functional grouping of the cortico-pretectal projection. J Neurophysiol. 1993;70(2):867–9. 28. Hoffmann KP, Ilg U. Role of the pretectum and accessory optic system in pursuit eye movements of the monkey. In: Berthoz A, editor. Multisensory control of movement. Oxford, UK: Oxford University Press; 1993. p. 93–111. 29. Fetsch CR, Rajguru SM, Karunaratne A, Gu Y, Angelaki DE, Deangelis GC.  Spatiotemporal properties of vestibular responses in area MSTd. J Neurophysiol. 2010;104(3):1506–22. 30. Chen A, DeAngelis GC, Angelaki DE.  Convergence of vestibular and visual self-motion signals in an area of the posterior sylvian fissure. J Neurosci. 2011;31(32):11617–27. 31. Distler C, Hoffmann KP. Private lines of cortical visual information to the nucleus of the optic tract and dorsolateral pontine nucleus. Prog Brain Res. 2008;171:363–8. 32. Brodsky MC. Dissociated horizontal deviation: clinical spectrum, pathogenesis, evolutionary underpinnings, diagnosis, treatment, and potential role in the development of infantile esotropia (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2007;105:272–93. 33. Horwood A. Neonatal ocular misalignments reflect vergence development but rarely become esotropia. Br J Ophthalmol. 2003;87(9):1146–50. 34. Horwood A. Too much or too little: neonatal ocular misalignment frequency can predict later abnormality. Br J Ophthalmol. 2003;87(9):1142–5. 35. Jampolsky A.  Ocular divergence mechanisms. Trans Am Ophthalmol Soc. 1970;68:730–822. 36. Jampolsky A. Unequal visual inputs in strabismus management: a comparison of human and animal strabismus. In: Burian HM, editor. Symposium on strabismus: transactions of the New Orleans Academy of Ophthalmology. St Louis: Mosby; 1978. p. 422–5. 37. Guyton DL, Cheeseman EWJ Jr, Ellis FJ, Straumann D, Zee DS. Dissociated vertical deviation: an exaggerated normal eye movement used to damp cyclovertical latent nystagmus. Trans Am Ophthalmol Soc. 1998;96:389–429. 38. Brodsky MC. The role of cortical alterations in infantile strabismus. Strabismus. 2012;20(1):35–6. https://doi.org/10.3109/09273972.2011.650817. 39. Brodsky MC, Fray KJ, Glasier CM.  Perinatal cortical and subcortical visual loss: mechanisms of injury and associated ophthalmologic signs. Ophthalmology. 2002;109(1):85–94. 40. Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 2009;8(1):110–24. 41. Kiorpes L, Walton PJ, O’Keefe LP, Movshon JA, Lisberger SG.  Effects of early-onset artificial strabismus on pursuit eye movements and on neuronal responses in area MT of macaque monkeys. J Neurosci. 1996;16(20):6537–53.

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Postscript This article challenges the dogmatic position that essential infantile esotropia is caused by a primary abnormality within the visual cortex. This Worthian concept of essential infantile esotropia (EIE) arises a priori from the fact that the primary visual cortex provides a necessary substrate for single binocular vision and stereopsis, and empirically from the finding that cortical motion pathways and correlative pursuit functions are measurably abnormal. The intuitive reasoning has long been that if the visual cortex subserves binocular vision and stereopsis, and these vital

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functions are disrupted in humans with EIE, then a primary aberration within the visual cortex must causes the eyes to cross. There is no evidence that this is the case. This commentary argues that the observed cortical aberrations could be the effect rather than the cause of EIE.  According to this Chavessian hypothesis, the early binocular misalignment that disrupts cortical visual development can be generated in the basement of the brain (i.e. within the cerebellar cortex). As elaborated on in Chap. 17, there is a considerable body of evidence that this is likely to be the case. Based on the studies of Anna Horwood, the long-held belief that primary visual cortical aberrations disinhibit convergence is untenable, given that normal neonates demonstrate large convergence movements, which are predictive of normal binocular alignment. Increased medial rectus and inferior oblique muscle tonus (the cause) is different from convergence (the effect). So what is the source of this altered extraocular muscle tonus? The subcortical accessory optic system, which remains operational in the first 2–3 months of human infancy, is the only neurologic system that is equipped to cause individual extraocular muscles to overact and generate the dissociated torsional eye movements that accompany EIE. As detailed in Chap. 17, extended subcortical neuroplasticity could generate EIE in the absence of neurologic disease. Alternatively, early binocular misalignment could perpetuate the function of these subcortical visual motion pathways and cause cortical motion pathways to secondarily remodel. Whether the subcortical/cortical debate represents a dichotomy or a continuum will soon be solved at the level of genetics. Does a genetic mutation or epigenetic signal within the subcortical visual pathways turn off a promotor region for normal inactivation of the AOS, leading to a cascade of secondary cortical changes, or does failure to produce a functional protein within the binocular visual cortex generate reversion to an older evolutionary program that secondarily reactivates that atavistic subcortical system? Or are the subcortical and cortical visual systems both reprogrammed by a combination of genetic and epigenetic factors? Time will tell. Ironically, those who advocate for early strabismus surgery in EIE are often those who attribute it to a primary fusion maldevelopment within the visual cortex (in which case timing of surgery shouldn’t matter). The occasional finding that very early strabismus surgery (at 3–4 months of age) can occasionally restore full stereopsis further militates against a primary cortical defect in binocular vision as the underlying cause. Similarly, the association of monofixation syndrome (the inevitable outcome of infantile esotropia) with a stable sensory motor situation makes it difficult to invoke the visual cortex as the underlying cause. You can’t have it both ways. For how could same visual cortical aberration cause EIE preoperatively only to fortify binocular vision postoperatively?

The Lizard’s Tail: An Ocular Allegory

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Charles Darwin first articulated the essential role of evolutionary reconfiguration. In his 1862 discussion of orchid evolution, he wrote that “When this or that part has been spoken of as contrived for some special purpose, it must not be supposed that it was originally always formed for this sole purpose. The regular course of events seems to be, that a part which originally served for one purpose by slow changes becomes adapted for different purposes” [1]. In 1982, Gould and Vrba applied the term exaptation to define “features that now enhance fitness but were not designed by natural selection for their current role” [2]. For example, birds’ feathers originally designed for thermal regulation are co-opted for flying [2, 3]. The universal role of “redesign” in the evolution of complex biological and behavioral systems is now recognized at genetic and cellular levels. As pointed out by Zetterberg and Zetterberg [4], the resourcefulness of evolution is also conspicuous in the evolutionary history of the eye. In the zebrafish embryo, for example, the not really finished (nrf) gene is essential for development of photoreceptors. However, its primary role in chickens is to promote erythropoiesis and in humans to facilitate nuclear–mitochondrial interactions in a variety of cell types [5]. Which brings us to the question of why lizards have tails. The remarkable ability of Agama lizards to land safely after jumping was the theme of a recent study in Nature [6]. The investigators filmed Agama lizards as they jumped from a horizontal platform onto a vertical wall. They found that these lizards utilize flexion and extension movements of their tails to position their trunks at the optimal pitch angle for landing. As discussed in an accompanying editorial by Alexander [7], this midair balancing act relies on the principle of conservation of angular momentum, which dictates that the angular momentum of a system remains constant unless an external torque acts upon it: When the lizard’s trunk starts to rotate forward, it bends its tail upward to pitch its trunk backward and maintain aerial stability (Fig. 12.1a) [8]. A body swinging a flexible tail experiences less rotation in the pitch plane (the sagittal plane of forward or backward rotation around a horizontal axis) than a body with no tail or a rigid tail [6]. So the lizard’s tail serves as a balance organ to maintain midair inertial control of the pitch position (and the tilt position by swinging © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_12

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b

Fig. 12.1  Conservation of angular momentum. (Modified from Alexander [7], with permission)

from side to side) [7], locking the body into its necessary spatial coordinates. A similar effect is used by tightrope walkers who carry a long balancing pole (really a counterbalancing pole). When the tightrope walker starts to tip to the left, he or she raises the right side of the pole to restore vertical orientation (Fig. 12.1b) [7]. So what does this observation have to do with ophthalmology? The human oblique muscles have evolved to become the “lizard’s tail” of the oculomotor system. The ancestral function of these ocular appendages in lateral-eyed animals was to gyroscopically stabilize the eyes during pitch rotation of the body [9–11], which requires generating a movement of sufficient speed and magnitude to minimize full-­ field retinal slip and maintain stability of the visual percept. These torsional eye movements are sensorially driven by a coordinated input to the central vestibular system from the eyes (luminance and optokinesis) and the labyrinths [12]. In infantile strabismus, the absence of binocular vision recalls this mechanism and unleashes a primitive torsional bias, leading to primary oblique muscle overaction and correlative torsion [13]. What we call primary oblique muscle overaction may be driven by a central vestibular imbalance involving the normal gyroscopic orientation of the pitch plane that results from dissociated binocular visual input [13, 14]. Atavism is the appearance in an individual of characteristics presumed to have been present in some remote ancestor, or a reversion to an earlier biological type [15]. One clinical hallmark of an atavism is that it tends to reappear when higher developmental functions become disabled. In this setting, the primary oblique muscle overaction of infantile esotropia may be a declaration of atavistic reversion from the cortical binocular system to its subcortical progenitor that uses the perceived vertical to establish the torsional coordinates of the eyes [13]. With rare exceptions [16], binocular humans do not have tails and some consider the function of the human ocular oblique muscles to be largely vestigial. Ask a patient to twist his or her eyes in one direction or the other, and you will be met with

The Lizard’s Tail: An Ocular Allegory

149

a blank stare. So what good are muscles that do not produce movements and are inaccessible to volitional drive (except in trained subjects) [17]. Jampel [18, 19] postulated that the human ocular oblique muscles function to prevent torsion by counteracting the torsional actions of the vertical rectus muscles when the head or body inclines. Because conjugate torsion of the eyes creates the perception of tilt and disconjugate torsion is interpreted as stereoscopic pitch of the visual world [8], torsional stability simplifies a variety of central computations, equipping the visual cortex to construct a stable internal representation of visual space as it navigates the 3-dimensional world. The human oblique muscles are the only extraocular muscles to have contrived functional origins within anterior orbits, directionalizing their posterior insertions to anchor the primary retinal meridians as the rectus muscles contract to rotate the eyes. Like the lizard’s swinging tail, the human oblique muscles have been evolutionarily positioned and acrobatically reprogrammed to impose rotational stability during combined head and eye movements as they coordinately orchestrate binocular alignment in all fields of gaze. This is a wondrous balancing act! References 1. Darwin C. On the various contrivances by which British and foreign orchids are fertilized by insects, and on the good effects of intercrosssing. London, UK: John Murray; 1862. p. 346. 2. Gould SJ, Vrba ES. Exaptation: a missing term in the science of form. J Soc Issues. 1991;47:43–65. 3. Buss DM, Haselton MG, Bleske AL, Wakefield JC. Adaptations, exaptations, and spandrels. Am Psychol. 1998;53:533–48. 4. Zetterberg H, Zetterberg M.  Evolution, exaptation, and stereopsis. Arch Ophthalmol. 2005;123:1281. 5. Becker TS, Burgess SM, Amsterdam AH, et al. not really finished is crucial for development of the zebrafish outer retina and encodes a transcription factor highly homologous to human nuclear respiratory factor-1 and avian initiation binding repressor. Development. 1998;125:4369–78. 6. Libby T, Moore TY, Chang-Sui E, et al. Tail-assisted pitch control in lizards, robots, and dinosaurs. Nature. 2012;481:181–4. 7. Alexander RM. Leaping lizards and dinosaurs. Nature. 2012;481:148–9. 8. Jusufi A, Kawano DT, Libby T, Full RJ. Righting and turning in mid-air using appendage inertia: reptile tails, analytical models and bio-inspired robots. Bioinsp Biomim. 2010;5(045001):1–12. 9. Von Holst E. Über den Lichtrückenreflex bei der Fische. Pubbl Stn Zool Napoli II. 1935;15:143–58. 10. Walls GL.  The vertebrate eye and its adaptive radiation. Bloomfield Hills: Cranbrook Institute of Science; 1942. p. 303. 11. Collewijn H, Noorduin H. Vertical and torsional optokinetic eye movements in the rabbit. Pflügers Arch. 1972;335:87–95. 12. Graf W, Meyer DL. Eye positions in fishes suggest different modes of interaction between commands and reflexes. J Comp Physiol. 1978;128:241–50.

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13. Brodsky MC, Donahue SP. Primary oblique muscle overaction: the brain throws a wild pitch. Arch Ophthalmol. 2001;119:1307–14. 14. Brodsky MC. Do you really need your oblique muscles? Adaptations and exaptations. Arch Ophthalmol. 2002;120:820–8. 15. Stedman’s medical dictionary. 26th ed. Baltimore: Williams & Wilkins; 1995. p. 161. 16. Ledely FO.  Evolution and the human tail: a case report. N Engl J Med. 1982;306:1212–5. 17. Balliet R, Nakayama K. Training of voluntary torsion. Invest Ophthalmol Vis Sci. 1978;17:303–14. 18. Jampel RS. Ocular torsion and the function of the vertical extraocular muscles. Am J Ophthalmol. 1975;79:292–304. 19. Jampel RS. Ocular torsion and the primary retinal meridian. Am J Ophthalmol. 1981;91:14–24.

Postscript This metaphorical article examines the inherent complexities of compensatory balancing movements that are critical in our daily functioning, and demonstrates how our ocular oblique muscles have been reassigned to execute this function. The principle of conservation of angular momentum is operationalized at an unconscious level. When initiating a leftward turn on a bicycle, for example, I notice that my handle bars move instantaneously to the right just before the turn. Obviously, I am actively turning the handle bars, but this movement is completely unconscious. This paradoxical movement also involves conservation of angular momentum. In order to turn left, I have to first get my body leaning to the left. But how can I do this? By quickly rotating the handlebars to the right, my body is shifted to the left to conserve angular momentum. Just like the tightrope walker.

The Optokinetic Uncover Test Subcortical Optokinesis in Infantile Esotropia

13

Infantile esotropia is characterized by the idiopathic onset of crossed eyes within the first 6 months of life [1]. It is often accompanied by crossed fixation, primary oblique muscle overaction, latent nystagmus, and dissociated vertical divergence [2]. This constellation of findings is also seen in the setting of prematurity and other neurological disorders [3]. Patients with infantile esotropia retain a monocular nasotemporal optokinetic asymmetry (MNTA) characterized by brisk monocular optokinetic responses to nasally moving optokinetic targets and poor monocular optokinetic responses to temporally moving optokinetic targets [4–8]. The phenomenon of MNTA is believed to underlie latent nystagmus [4, 7–10]. In primates and humans, MNTA is normally seen during the first several months of life [10–22]. Its spontaneous resolution coincides with maturation of binocular cortical pursuit pathways that provide the temporal component for the optokinetic reflex from each eye [10–21]. Accordingly, the persistence of MNTA in infantile strabismus has been attributed to a cortical pursuit deficit caused by early failure of cortical binocular vision to develop [22–24]. Neonates show poor pursuit responses to focal moving stimuli but demonstrate strong optokinetic responses to large full-field rotating stimuli [19–21]. These full-­ field responses are attributed to the activation of subcortical optokinetic pathways that modulate full-field rotational optokinetic responses and remain active until maturation of binocular cortical pursuit pathways within the first 6 months of life [19–21]. This MNTA is seen in lateraleyed afoveate animals during turning movements, in which the full-field velocity of the nasalward optokinetic stimulus to one eye determines optokinetic rotation of both eyes. Because MNTA antedates development of the visual cortex both phylogenetically and ontogenetically, debate has

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_13

151

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been waged as to whether the persistent MNTA in humans with strabismus is caused by a cortical pursuit defect, a persistent activation of subcortical optokinetic pathways, or a combination of both [3, 8, 10, 19, 25]. Cortical pursuit movements in foveate animals require foveal (or perifoveal) stimulation, while subcortical optokinetic movements in afoveate animals are generated by full-field optic flow detected by peripheral retina [26]. If the persistence of MNTA in humans with infantile strabismus is caused solely by defective cortical pursuit, its activation should necessitate foveal (or parafoveal) fixation. We devised the optokinetic uncover test to examine the role of peripheral retinal motion input in generating horizontal optokinetic responses in patients with infantile strabismus.

Methods Ten patients had a history of infantile esotropia confirmed by MNTA on optokinetic testing using a handheld rotating drum (Fig. 13.1). Patients ranged in age from 1 to 38 years, and all underwent full ophthalmological examinations with special attention to signs of crossed fixation, latent nystagmus, primary oblique muscle overaction, and amblyopia assessed by the inability to maintain fixation with one eye (Table 13.1). Seven of 10 patients had no history of neurological disease, developmental delay, or prematurity. Two of these patients had undergone previous strabismus surgery and had residual esotropia. Three of 10 patients had mild neurological disease. Two patients with mild prematurity and speech and fine-motor delays, as well as 1 patient with Down syndrome, were included because their clinical findings otherwise conformed to those of infantile esotropia.

Results On optokinetic testing, all patients showed brisk responses to nasally directed monocular optokinetic targets and poor responses to temporally directed optokinetic targets with each eye. During attempted pursuit of temporally directed optokinetic targets, removal of the occluder from the contralateral eye produced an immediate improvement in optokinetic responses. In 3 patients with alternating fixation, this improved optokinetic response produced a fixation shift to the contralateral eye, allowing the optokinetic response to be foveally driven by the eye receiving the nasally directed stimulus. In 7 patients with a fixation preference for one eye, this improved optokinetic response was accompanied by an immediate or delayed fixation shift when the preferred eye was uncovered and by maintenance of fixation when the nonpreferred eye was uncovered. In 3 patients, 3-dimensional video-oculography (Sensorimotoric Instruments) was performed using a full-field optokinetic stimulus projected on a flat surface (stripe width of 2.2° and velocity of 15° per second with the patient viewing at 3 m). These recordings confirmed that uncovering the contralateral eye produced improvement in the optokinetic waveform regardless of whether a change in fixation occurred (Fig.  13.1). In 3 patients with mild

Results

153 Rightward CKN Stimulus

Cover left eye

Right eye Left eye

Uncover right eye

Cover Right eye

Cover left eye

25 20 15 10 5 0 –5 –10 –15 –20 –25 –30

Left

Right

Uncover left eye

Leftward CKN Stimulus Reverse OKN direction

Right eye fixing

Left eye fixing

Left eye fixing

Right eye fixing

Fig. 13.1  Video-oculography tracing of horizontal optokinetic responses to full-field stripes (patient 4 in the video; http://www.jamaophth.com). Red line corresponds to the right eye horizontal position. Blue line corresponds to the left eye horizontal position. The first 3 beats show a poor optokinetic response when the right (amblyopic) eye is fixing a rightward (temporalward) optokinetic target. When the left eye is uncovered, the tracing improves, and fixation shifts to the left (nonamblyopic) eye. The right eye is then covered, while maintaining a rightward (nasalward) monocular stimulus to the left eye, resulting in a strong optokinetic response. The drum direction is then reversed to leftward, creating a monocular temporalward stimulus to the left eye, which produces a poor optokinetic response. When the right eye is uncovered, allowing it to receive a nasalward stimulus, the optokinetic response improves even though the left eye maintains fixation. Covering the left eye to induce a rightward (nasalward) monocular optokinetic stimulus leads to further improvement in the optokinetic waveform. OKN indicates optokinetic nystagmus Table 13.1  Profiles of 10 Patients Manifesting Monocular Nasotemporal Optokinetic Asymmetry

a

Patient No./Sex/ Age, y 1/M/4 2/M/4

Latent Nystagmus No Yes

Dissociated Vertical Divergence No Yes

Fixation Preference Right eye Left eye

Angle at Amblyopia Neara Yes 30 Yes 20

3/M/2 4/F/27 5/F/5

No Yes No

No Yes No

Left eye Left eye None

Yes Yes No

25 10 40

6/F/38 7/M/6 8/M/2 9/F/1 10/M/4

Yes Yes No No No

Yes Yes No No No

Left eye Left eye None None None

No Yes No No No

18 20 50 45 45

Systemic or Neurological Disease No Speech and fine-motor delay No No Mild speech and motor delay No No No No Trisomy 21

Prism diopter esotropia unless otherwise indicated

neurological disease or prematurity, the optokinetic uncover test produced results identical to those in 7 patients with idiopathic infantile esotropia. Six of the untreated patients subsequently underwent strabismus surgery to correct their infantile esotropia. Other clinical findings are summarized in the Table.

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Comment In all patients with infantile esotropia, defective temporalward monocular optokinetic responses in the fixating eye improved when the esotropic nonfixating eye was uncovered, allowing it to receive nasalward optokinetic input under binocular conditions. From a practical viewpoint, this observation shows that the examiner should not test for MNTA when the patient has both eyes open in the patient and assume that the suppressed eye will not contribute to the optokinetic response in a patient with infantile esotropia. At a mechanistic level, this observation challenges the long-standing assumption that MNTA in humans with infantile esotropia can be attributed solely to defective cortical pursuit. In our patients, the modulation of horizontal optokinetic responses by the nonfoveal retina of the esotropic eye suggests that subcortical optokinetic pathways must continue to modulate peripheral optic flow in humans with infantile strabismus. This improvement of optokinetic waveform is consistent with the clinical observation that patients with manifest latent nystagmus show a visible worsening of their nystagmus when the deviated eye is covered [27]. In a 1936 publication, Ter Braak [28] showed that afoveate animals, such as the rabbit, generate optokinetic nystagmus in response to movement of large objects, despite the fact that they did not track small objects. In the monkey, these full-field optokinetic responses persisted after decortication, suggesting that they were mediated by a subcortical optokinetic system [29, 30]. In the rabbit, each eye is driven by mainly forward (nasalward) optokinetic motion, which provides the stimulus for the optokinetic responses of both eyes [31]. These asymmetrical subcortical optokinetic responses are now known to be modulated by the contralateral nucleus of the optic tract (NOT) and dorsal terminal nucleus (DTN) of the accessory optic system within the mesencephalon, which respond only to ipsilateral optokinetic stimulation (nasalward for the viewing eye) [32]. In rabbits and in monkeys, these pathways project down to the inferior olive and contralateral flocculus and then on to the vestibular nuclei to modulate visuovestibular responses to full-field optokinetic rotation during turning movements (Fig. 13.2) [33–35]. In primates, development of binocular corticopretectal pathways to the NOT and the DTN of the accessory optic system, which provide ipsilateral pursuit responses (temporalward for the viewing eye), are necessary to cancel this optokinetic asymmetry within the first year of life (Fig. 13.3) [11–18, 36]. These corticopretectal projections to the NOT-DTN come predominantly from the middle temporal area and the medial superior temporal area, as well as from V1 and V2 [16], while those to accessory optic nuclei (lateral terminal nucleus and medial terminal nucleus) come exclusively from the middle temporal area and the medial superior temporal area [37]. Within the superior temporal sulcus, the middle temporal area is involved in motion detection and is responsible for pursuit movements, while the medial superior temporal area modulates pursuit and visuovestibular detection of optic flow [38, 39]. As normal binocular cortical pursuit pathways become established within the first 6 months of human life, visuovestibular responses to full-field optokinetic stimulation become

Comment

155

“encephalized” as they are incorporated into the cortical pursuit system (Fig. 13.3) [18, 19]. In humans, these same subcortical optokinetic pathways retain their nasalward directional predominance and are believed to mediate the full-field horizontal optokinetic responses that are observed in early infancy until they are rendered inactive by the establishment of binocular cortical pursuit pathways (Fig.  13.3) [20, 21]. However, the general notion that they can retain function in the absence of cortical input has been controversial [25, 40]. For example, it has been suggested that the relative preservation of responses to nasally directed stimuli in patients with incomplete bilateral occipital lobe destruction could be owing to remnants of the subcortical projection to the NOT-DTN that may have been released from cortical control [25, 40, 41]. Ter Braak and Schenk [42] described a patient with acquired cortical blindness who retained some preservation of full-field optokinetic responses, but subsequent studies [43, 44] have found no evidence of this effect. These findings suggest that subcortical optokinetic pathways, once “shut off” after the first few months of life, are incapable of reactivating [21, 22]. However, they do not address the question of whether specific derangements in binocular cortical development can act to preserve their function. Our finding that peripheral retinal optokinetic input can override defective foveal pursuit suggests that infantile strabismus allows these subcortical optokinetic pathways (which rely on peripheral retinal input) to remain operational. Unlike “decortication,” infantile strabismus may maintain the function of the subcortical visual pathways in a way that prevents them from being shut off. In 1983, Schor [8] proposed that selective maldevelopment of cortical binocular vision could provide a competitive advantage to reinforce the activation of direct subcortical projections from the nasal retina of each eye to the contralateral NOT-DTN and thereby potentiate their function. According to Hoffmann and colleagues [11, 17], the Hebbian mechanism of synaptic formation predicts that only neurons firing in a correlated manner (in this case, sharing the same direction sensitivity) become consolidated during development. Through this activity-dependent mechanism, the ipsilateral direction sensitivity of the NOT-DTN would preferentially allow crossed nasal retinogeniculate pathways that connect monocularly through the visual cortex to establish corticofugal connections to the ipsilateral NOT-DTN, enabling these latent subcortical pathways to remain functional in infantile esotropia (Fig. 13.4) [11, 17]. In this way, infantile esotropia could remodel the cortical motion pathways to selectively maintain the nasally biased subcortical gateway through which unbalanced binocular visual input can turn the gears on these evolutionarily ancient eye movement control systems (Fig. 13.4) [45]. The fact that cortical suppression can elicit latent nystagmus [46], and that peripheral retinal input can also drive this response, suggests that selective preservation of crossed corticopretectal connections may allow these latent subcortical mechanisms to be expressed in infantile esotropia. This explanation has several implications for the MNTA that characterizes infantile esotropia. First, a selective preservation of crossed monocular nasal retinal projections from the contralateral eye would eliminate the temporal retinal projections subserving cortical pursuit from the ipsilateral eye, explaining why the cortical

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EOM

NOT-DTN

NPH O M N

P P R F

V1

NRTP

d.c. 10

LGN

STS (MT/MST)

Cer

VN

Fig. 13.2  Neuroanatomical pathways involved in the optokinetic reflex and optokinetic nystagmus system of the right half of the brain in the squirrel monkey. The connections of the nasal retina of the left eye and the temporal retina of the right eye are shown. Cer indicates cerebellum; d.c. IO, dorsal cap of inferior olive; EOM, extraocular muscles; GS, Scarpa ganglion of the vestibular nerve; LGN, lateral geniculate nucleus; NOT-DTN, nucleus of the optic tract–dorsal terminal nucleus; NPH, nucleus prepositus hypoglossus; NRTP, nucleus reticularis tegmenti pontis; OMN, ocular motor nuclei; PPRF, paramedian pontine reticular formation; STS, movement sensitive areas of the middle temporal area (MT) and the medial superior temporal area (MST) in the cortex around the superotemporal sulcus; V1, primary visual cortex; and VN, complex of the brainstem vestibular nuclei. (Modified from the chapter by Behrens et al [35] with permission)

Comment

157 Early Infancy

a

Late Infancy

b

Binocular stimulus

R R+L

NOT-DTN

L

Binocular stimulus

In V1-only monocular cells Binocular cells

NOT-DTN

LGN

SCC

SCC MST

MST MT

L

R+L R

V1

LGN

R+L V1

R

MT

L

MST

MST

MT

L

R+L R

V1

R+L V1

L

MT

R

Fig. 13.3  Normal cortical and subcortical projections during early human development. (Based on a model proposed by Hoffmann [36]). The brain is viewed from the top of the head, so the left eye is on the left. (a) In early infancy, a leftward optokinetic stimulus is transmitted contralaterally via a subcortical pathway from the nasal retina of the right eye to the left nucleus of the optic tract–dorsal terminal nucleus (NOT-DTN) (solid red arrow), which is sensitive to leftward motion. Ipsilateral corticofugal input from binocular cells in the left hemisphere to the NOT-DTN (interrupted green arrow) has not yet developed. (b) Later in infancy, horizontal optokinetic responses become encephalized by late infancy as binocular cortical pursuit pathways become fully operational (solid green arrow) and subcortical optokinetic pathways regress (interrupted red arrow). At this stage, a leftward optokinetic stimulus to both eyes stimulates corticofugal pathways projecting from binocular cells in V1 to the middle temporal area (MT) and the medial superior temporal area (MST) and on to the ipsilateral NOT-DTN.  L indicates left eye monocular cells; LGN, lateral geniculate nucleus; R, right eye monocular cells; R + L, cortical binocular cells (that are absent in early infancy); and SCC, semicircular canals

component of the optokinetic asymmetry can be monocularly driven in infantile esotropia and binocularly driven with a hemispheric lesion involving the cortical pursuit pathways. Second, this neurodevelopmental derangement would help to explain how the cortical motion asymmetry in infantile esotropia is dictated the directionality of tne NOT-DTN [47–49]. Third, it suggests that infantile esotropia can arrest development of the nascent optokinetic system at a stage wherein MNTA

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can be generated from the visual cortex (top down) or from subcortical pathways (bottom up). Fourth, as divined by Schor [8] 30 years ago, the associated monocular corticofugal projections from the motion centers in the middle temporal area and the medial superior temporal area to the other ipsilateral accessory optic nuclei that control cyclovertical rotations of the eyes would (by a similar Hebbian mechanism) explain the torsional optokinetic biases [6] and complex cyclovertical movements that accompany latent nystagmus but remain conspicuously absent in a hemispheric (binocular) pursuit defect. Fifth, the ability of subcortical visual pathways (Fig. 13.2) to be activated bidirectionally via subcortical and cortical visual pathways would render obsolete the debate about neuroanatomical localization in infantile esotropia [3]. This study has several inherent limitations. First, we did not use a circular full-­ field optokinetic apparatus, which produces the sensation of circularvection (the false sensation of physical rotation) and is believed to be necessary to directly stimulate the visuovestibular system [50]. Although this testing paradigm would have fortified our conclusions, we were only able to confirm our observation using a flat full-field optokinetic stimulus, which (like the optokinetic drum) probably elicits pursuit responses in healthy individuals [50]. However, the enhancement of temporalward foveal optokinetic responses when peripheral retina of the nonfixating eye was exposed to nasalward optokinetic motion demonstrates that cortical pursuit cannot be the only system involved in the generation of MNTA (and latent nystagmus, by inference). A selective preservation of crossed cortical projections to the NOTDTN from the nasal retina of the contralateral eye (Fig. 13.4) would allow nasalward cortical pursuit pathways to generate subcortical visuovestibular eye movements (with their associated torsional components), rendering these 2 classes of eye movement indistinguishable in the setting of infantile esotropia. Second, some of the patients with infantile esotropia had undergone previous strabismus surgery. Consequently, the angle of the esotropic deviation was smaller than that seen in infantile esotropia. Therefore, it cannot be assumed that the optokinetic uncover test would have necessarily shown a positive response in these patients with infantile esotropia prior to surgery. Nevertheless, all of our patients with unoperated infantile esotropia showed this effect, and all of our patients had an angle of deviation large enough to preclude perifoveal fixation, confirming that this binocular optokinetic mechanism arises from the synthesis of foveal and peripheral retinal input. Third, the inclusion of some patients with mild neurological disease could potentially challenge the results of our study. However, given that all patients showed the same pattern of responses on the optokinetic uncover test, our results suggest that these patients share a common pathogenesis for their infantile esotropia. Fourth, because optokinetic motion is known to displace the eyes in the direction of the fast phase [51], it might be argued that this displacement could have led to the false conclusion that the uncovered esodeviated eye was not fixating when the eye receiving temporal optokinetic stimulation was uncovered. As shown in the video, however, the fixating eye was clearly evident in all patients, and videooculography confirmed that the nasal retina of the esotropic eye could drive the optokinetic response. In conclusion, the results of this study provide evidence that human subcortical optokinetic pathways may remain active in the presence of infantile

Comment

159 Infantile Esotropia Optokinetic Uncover Test

a

b Occluder removed

Occluder

R R+L

NOT-DTN

L

In V1-only monocular cells Binocular cells

NOT-DTN

LGN

Transmission only from Not from

L

L R

V1

R

L SCC

SCC MST MT

LGN

V1

R

MST MT

MST MT

L

L R

V1

V1

MST MT

R

Fig. 13.4  Optokinetic uncover test in infantile esotropia. (a) When the right eye is covered and the left eye receives a leftward (temporal) optokinetic stimulus, the temporal retina is ineffective in generating a response. The absence of binocular cells within the visual cortex means that temporally directed stimuli cannot be transmitted to the ipsilateral nucleus of the optic tract–dorsal terminal nucleus (NOT-DTN) because maturation of this function requires an early directional match between action potentials originating from binocular cortical cells in the middle temporal area (MT) and the medial superior temporal area (MST) with those projecting from the right eye via the ipsidirectional subcortical pathway to the NOT-DTN. (b) When the right eye is uncovered, the nasalward optokinetic stimulus to the right retina generates a leftward optokinetic response that could be mediated by crossed subcortical connections to the NOT-DTN (small red arrow) or through the retinogeniculate pathway to the monocular right eye cells within V1 of the left hemisphere to MT-MST, where corticofugal projections can establish connections with cells in the left NOT-DTN that share the same leftward direction preference (large red arrow). The fact that this nasalward response can be driven by peripheral retina suggests that subcortical (bottom up) optokinetic pathways rather than cortical foveal pursuit (top down) pathways have a predominant role in this response. L indicates left eye monocular cells; LGN, lateral geniculate nucleus; R, right eye monocular cells; R + L, cortical binocular cells (that are absent in infantile esotropia); and SCC, semicircular canals

esotropia. Selective preservation of corticotectal projections from the nasal retina of the contralateral eye would enable these subcortical visual pathways to retain their original function in the setting of infantile esotropia. The optokinetic uncover test provides a unique insight into the role of peripheral motion detection under binocular conditions, allowing us to deconstruct the optokinetic system into its cortical and subcortical components. The intrinsic monocular optokinetic biases that define these subcortical pathways may be the proximate cause of MNTA, while failure of the binocular cortical pursuit pathways to develop may provide the permissive cause that allows these subcortical pathways to remain functional.

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References 1. Campos EC. Why do the eyes cross? a review and discussion of the nature and origin of essential infantile esotropia, microstrabismus, accommodative esotropia, and acute comitant esotropia. J AAPOS. 2008;12(4):326–31. 2. Brodsky MC. Visuo-vestibular eye movements: infantile strabismus in 3 dimensions. Arch Ophthalmol. 2005;123(6):837–42. 3. Brodsky MC.  An expanded view of infantile esotropia: bottoms up! Arch Ophthalmol. 2012;130(9):1199–202. 4. Kommerell G. Ocular motor phenomena in infantile strabismus: asymmetry in optokinetic nystagmus and pursuit, latent nystagmus, and dissociated vertical divergence. In: Lennerstrand G, von Noorden GK, Campos EC, editors. Strabismus and amblyopia: experimental basis for advances in clinical management. New York: Macmillan Press; 1988. p. 99–109. 5. Wright KW. Clinical optokinetic nystagmus asymmetry in treated esotropes. J Pediatr Ophthalmol Strabismus. 1996;33(3):153–5. 6. Valmaggia C, Proudlock F, Gottlob I. Optokinetic nystagmus in strabismus: are asymmetries related to binocularity? Invest Ophthalmol Vis Sci. 2003;44(12):5142–50. 7. Kommerell G. Beziehungen zwischen Strabismus un Nystagmus. In: Kommerell G, editor. Augenbewegungsstörungen, Neurophysiologie und Klinik: Symposium der Deutschen Ophthalmologischen Gesellschaft, Freiburg, 1977. Munich: Bergmann; 1978. p. 367–73. 8. Schor CM. Subcortical binocular suppression affects the development of latent and optokinetic nystagmus. Am J Optom Physiol Optic. 1983;60(6):481–502. 9. Kiorpes L, Walton PJ, O’Keefe LP, Movshon JA, Lisberger SG.  Effects of early-onset artificial strabismus on pursuit eye movements and on neuronal responses in area MT of macaque monkeys. J Neurosci. 1996;16(20):6537–53. 10. Brodsky MC, Tusa RJ. Latent nystagmus: vestibular nystagmus with a twist. Arch Ophthalmol. 2004;122(2):202–9. 11. Hoffmann KP. Neural basis for optokinetic defects in animals with strabismus. In: Kaufmann H, editor. Transactions of the European Strabismological Association: 16th Meeting. 1987. p. 35–46. 12. Dürsteler MR, Wurtz RH. Pursuit and optokinetic deficits following chemical lesions of cortical areas MT and MST. J Neurophysiol. 1988;60(3):940–65. 13. Hoffmann KP, Ilg U. Role of the pretectum and accessory optic system in pursuit eye movements of the monkey. In: Berthoz A, editor. Multisensory control of movement. Oxford, UK: Oxford University Press; 1993. p. 93–111. 14. Movshon JA, Lisberger SG, Kiorpes L, et al. Effects of artificial strabismus on pursuit eye movements and MT neurons in macaque monkeys. Perception. 1995;24:6–7. 15. Distler C, Hoffmann KP.  Cortical input to the nucleus of the optic tract and dorsal terminal nucleus (NOT-DTN) in macaques: a retrograde tracing study. Cereb Cortex. 2001;11(6):572–80. 16. Distler C, Mustari MJ, Hoffmann KP. Cortical projections to the nucleus of the optic tract and dorsal terminal nucleus and to the dorsolateral pontine nucleus in macaques: a dual retrograde tracing study. J Comp Neurol. 2002;444(2):144–58.

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17. Hoffmann KP, Bremmer F, Thiele A, Distler C. Directional asymmetry of neurons in cortical areas MT and MST projecting to the NOT-DTN in macaques. J Neurophysiol. 2002;87(4):2113–23. 18. Distler C, Hoffmann KP.  Visual pathway for the optokinetic reflex in infant macaque monkeys. J Neurosci. 2011;31(48):17659–68. 19. Braddick O. Where is the naso-temporal asymmetry? motion processing. Curr Biol. 1996;6(3):250–3. 20. Braddick O, Atkinson J, Wattam-Bell J. Normal and anomalous development of visual motion processing: motion coherence and “dorsal-stream vulnerability”. Neuropsychologia. 2003;41(13):1769–84. 21. Braddick O, Atkinson J.  Development of human visual function. Vis Res. 2011;51(13):1588–609. 22. Tychsen L. Causing and curing infantile esotropia in primates: the role of decorrelated binocular input (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2007;105:564–93. 23. Tychsen L, Richards M, Wong A, Foeller P, Bradley D, Burkhalter A. The neural mechanism for latent (fusion maldevelopment) nystagmus. J Neuroophthalmol. 2010;30(3):276–83. 24. Tychsen L, Hurtig RR, Scott WE. Pursuit is impaired but the vestibulo-ocular reflex is normal in infantile strabismus. Arch Ophthalmol. 1985;103(4):536–9. 25. Kommerell G. The relationship between infantile strabismus and latent nystagmus. Eye (Lond). 1996;10(pt 2):274–81. 26. Winterson BJ, Steinman RM. The effect of luminance on human smooth pursuit of perifoveal and foveal targets. Vis Res. 1978;18(9):1165–72. 27. Dell’Osso LF, Schmidt D, Daroff RB. Latent, manifest latent, and congenital nystagmus. Arch Ophthalmol. 1979;97(10):1877–85. 28. Ter Braak JWG.  Untersuchen uber optokinetischen nystagmus. Arch Neerlandaises Physiol. 1936;21:309–76. 29. Yee RD, Baloh RW, Honrubia V. Study of congenital nystagmus: optokinetic nystagmus. Br J Ophthalmol. 1980;64(12):926–32. 30. Ter Braak JWG, Van Vliet AGM.  Subcortical optokinetic nystagmus in the monkey. Psychiatr Neurol Neurochir. 1963;66:277–83. 31. Collewijn H, Noorduin H.  Conjugate and disjunctive optokinetic eye movements in the rabbit, evoked by rotatory and translatory motion. Pflugers Arch. 1972;335(3):173–85. 32. Simpson JI, Soodak RE, Hess R. The accessory optic system and its relation to the vestibulocerebellum. In: Granit R, Pampeiano O, editors. Reflex control of posture and movement. Amsterdam: Elsevier; 1979. p. 715–24. 33. Langer T, Fuchs AF, Chubb MC, et al. Floccular efferents in the rhesus macaque as revealed by autoradiography and horseradish peroxidase. J Comp Neurol. 1985;235(1):26–37. 34. Buttner U, Boyle R, Markert G, et al. Cerebellar control of eye movements. In: Freund HJ, Buttner U, Cohen B, Noth J, editors. Progress in brain research. Amsterdam: Elsevier; 1986. p. 225–33. 35. Behrens F, Grusser OJ, Roggenkämper P. Open-loop and closed-loop optokinetic nystagmus in squirrel monkeys (Saimiri sciureus) and in man. In: Allum

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JHJ, Hulliger M, editors. Progress in brain research. Amsterdam: Elsevier; 1989. p. 183–96. 36. Hoffmann KP. Cortical versus subcortical contribution to the optokinetic reflex in the cat. In: Lennerstrand G, Zee DS, Keller EL, editors. Basis of ocular motility: proceedings of a Wenner-Gren Center and Smith-Kettlewell Eye Research Foundation I International Symposium. New  York: Pergamon Press; 1982. p. 303–11. 37. Lui F, Gregory KM, Blanks RHI, Giolli RA. Projections from visual areas of the cerebral cortex to pretectal nuclear complex, terminal accessory optic nuclei, and superior colliculus in macaque monkey. J Comp Neurol. 1995;363(3):439–60. 38. Fetsch CR, Rajguru SM, Karunaratne A, Gu Y, Angelaki DE, Deangelis GC.  Spatiotemporal properties of vestibular responses in area MSTd. J Neurophysiol. 2010;104(3):1506–22. 39. Chen A, DeAngelis GC, Angelaki DE.  Convergence of vestibular and visual selfmotion signals in an area of the posterior sylvian fissure. J Neurosci. 2011;31(32):11617–27. 40. Mehdorn E. Nasal-temporal OKN-asymmetries after bilateral occipital infarction in man. In: Lennerstrand G, Zee DS, Keller EL, editors. Functional basis of ocular motility disorders. Oxford, UK: Pergamon Press; 1982. p. 321–4. 41. Zee DS, Tusa RJ, Herdman SJ, Butler PH, Gücer G. Effects of occipital lobectomy upon eye movements in primate. J Neurophysiol. 1987;58(4):883–907. 42. Ter Braak JWG, Schenk VWD. Visual reactions in a case of long-standing cortical blindness. J Neurol Neurosurg Psychiatry. 1971;34:140–7. 43. Jung R, Kornhuber HH. Results of electronystagmography in man: the value of optokinetic, vestibular, and spontaneous nystagmus for neurologic diagnosis and research. In: Bender MB, editor. The ocular motor system. New  York: Harper & Row; 1964. p. 428–88. 44. Tychsen L. Absence of subcortical pathway optokinetic eye movements in an infant with cortical blindness. Strabismus. 1996;4(1):11–4. 45. Brodsky MC. The accessory optic system: the fugitive visual control system in infantile strabismus. Arch Ophthalmol. 2012;130(8):1055–8. 46. Kommerell G, Zee DS.  Latent nystagmus: release and suppression at will. Invest Ophthalmol Vis Sci. 1993;34(5):1785–92. 47. Norcia AM, Garcia H, Humphry R, Holmes A, Hamer RD, Orel-Bixler D.  Anomalous motion VEPs in infants and in infantile esotropia. Invest Ophthalmol Vis Sci. 1991;32(2):436–9. 48. Tychsen L, Lisberger SG.  Maldevelopment of visual motion processing in humans who had strabismus with onset in infancy. J Neurosci. 1986;6(9):2495–508. 49. Shallo-Hoffmann J, Faldon M, Hague S, Riordan-Eva P, Fells P, Gresty M. Motion detection deficits in infantile esotropia without nystagmus. Invest Ophthalmol Vis Sci. 1997;38(1):219–26.

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50. Tian J, Zee DS, Walker MF. Rotational and translational optokinetic nystagmus have different kinematics. Vis Res. 2007;47(7):1003–10. 51. Garbutt S, Harwood MR, Harris CM. Anticompensatory eye position (“contraversion”) in optokinetic nystagmus. Ann N Y Acad Sci. 2002;956:445–8.

Postscript Our consistent observation that the nasalward optokinetic input to the cortically-­ suppressed, esodeviated eye can override foveal input to the fixating eye demonstrates that subcortical optokinesis remains operative in patients with EIE.  This clinical observation has potential implications for children with other visual disorders as well. For example, it has been noted that children with cortical blindness do not have optokinetic responses, and therefore inferred that the subcortical accessory optic system (AOS) cannot remain operative. This conclusion should be taken with a grain of salt for several reasons. First, this reasoning is tautological, as the ones who do show optokinetic responses are deemed to have incomplete cortical blindness. Second, although the normal accessory optic system remains functional in the first 2–3 months of life, optokinetic responses have never been tested during this early time period to see if they are initially present in children with cortical blindness. Finally, we have reported that many infants with seemingly isolated cortical visual injury have absent vestibulo-ocular reflexes, suggesting that coexistent subcortical injury may not always be evident on neuroimaging studies. To my knowledge, the potential role of the accessory optic system in motion detection in humans with “blindsight” has not been investigated.

A Unifying Neurologic Mechanism for Infantile Nystagmus

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Infantile nystagmus is conjugate oscillation of the eyes that may appear in isolation but more often appears in conjunction with afferent visual deficits, such as aniridia, albinism, optic nerve hypoplasia, congenital retinal dystrophies, isolated foveal hypoplasia, congenital cataracts, and achiasma. Infantile nystagmus is defined by the following general features [1–3]:

1. A predominantly horizontal pendular or jerk nystagmus 2. Onset occasionally at birth but usually at age 2 to 3 months 3. Unlike vestibular nystagmus, infantile nystagmus stays horizontal in upgaze 4. Nystagmus often damps during near fixation 5. Absence of oscillopsia, vertigo, or imbalance 6. Central or eccentric null position 7. Apparent inversion or “reversal” of optokinetic nystagmus in approximately two-thirds of cases 8. Increase in the oscillation during attempted fixation or pursuit 9. Presence of foveation periods on eye movement recordings and 10. Absence of neurologic abnormalities outside of the visual system

At least 50% of patients with infantile nystagmus have associated maldevelopment of the retinas or optic nerves [4–6]. Patients without detectable visual system deficits often show X-linked or autosomal dominant inheritance of infantile nystagmus [7, 8]. A gene (FRMD7; OMIM: 300628) with strong expression in the developing neural retina has been identified as a cause of X-linked infantile nystagmus [9–11]. Eye movement recordings show a number of waveforms that have in common short foveation periods that follow each refixation movement [1]. Although neuronal misdirection of the anterior pathways through the chiasm can facilitate the © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_14

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development of infantile nystagmus in patients with albinism and achiasma, most patients with infantile nystagmus have normal hemispheric visual-evoked potentials, indicatingthat chiasmal misdirection is not necessary to generate this oscillation [12, 13]. We have come to see infantile and latent nystagmus as existing on a clinical and neuroanatomic continuum. In humans, infantile strabismus creates a dissociated form of binocular vision in which the 2 eyes are subjected to unequal visual input. When cortical binocular vision fails to develop in infancy, we hypothesize that the ocular motor disturbances of infantile strabismus correspond to subcortical binocular visual reflexes that are operative in lateral-eyed animals [14]. Dissociated eye movements, such as latent nystagmus, manifest when the nascent binocular cortical pursuit pathways fail to suppress monocularly driven subcortical optokinetic pathways that are modulated by the nucleus of the optic tract and the dorsal terminal nucleus (NOT-DTN) of the accessory optic system (AOS) [15, 16]. It therefore seems reasonable to question whether infantile nystagmus, a binocular oscillation often associated with reduced central vision in both eyes, could similarly arise from an atavistic resurgence of this subcortical visual system. We propose that abnormal development of binocular foveal vision allows the AOS, a primitive subcortical “pursuit” system, to remain expressed in humans and that the inherent antagonism between the cortical and subcortical pursuit systems is manifested in the form of infantile nystagmus. We use the term isolated instead of idiopathic (ie, unknown cause) infantile nystagmus because the latter is incorrect as well as misleading (ie, nystagmus in patients with associated sensory deficits is not caused by those deficits; correlation—even time-locked correlation—does not equal causality). The direct cause of infantile nystagmus has been attributed [17, 18] to the normally oscillating part of the smooth pursuit system. Ocular motility studies [1–3] have shown the nystagmus exhibited by patients with and without associated visual sensory deficits to be identical. Because infantile nystagmus is a single entity with a known cause, there is no foundation for arbitrarily describing the nystagmus of one subset of patients as idiopathic.

What Is the AOS? As detailed in a recent publication [16], the AOS is a primary visual system receiving direct visual information from the retina via one or more accessory optic tracts [19]. The AOS is responsible for visuovestibular interaction in afoveate animals [20–22]. Its retinal input is derived from ON-type direction-sensitive ganglion cells. The AOS neurons have large receptive fields (averaging approximately 40° vertically and 60° horizontally), are direction selective, and have a preference for slow-­moving stimuli [19, 22–25]. The AOS processes information about the speed and direction of movement of large textured parts of the visual world [20, 23, 24]. After accounting for an eye movement-generated slip (efference copy), the AOS signals motion as a function of slip of the visual world over the retinal surface and generates corrective eye movements to stabilize the retinal image [20, 23, 24]. As

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an analyzer of world motion, the AOS subserves visual proprioception in the afoveate animal [20, 23, 24]. Ontogenetically, the function of this subcortical optokinetic system antedates full maturation of the vestibuloocular reflex in lower vertebrates [26, 27]. The AOS is involved in determining self-motion and is uniquely organized in a vestibular coordinate system [20, 23, 24]. Experimental studies by Simpson and colleagues [20, 23, 25] indicate that visual and vestibular signals that produce compensatory eye movements are organized about a common set of axes derived from the orientation of the semicircular canals. Because the AOS is directionally sensitive to low-velocity movements, whereas the vestibular system typically responds to movements of higher velocity, the AOS and vestibular labyrinths form 2 complementary systems to detect self-motion and promote image stabilization so that objects in the visual world can be quickly and accurately analyzed [19, 20, 24, 25]. The AOS exists in all vertebrate classes [20, 28–30], including humans [31]. In human infancy, the AOS is believed to generate full-field subcortical optokinetic responses within the first 2 months of life before normal binocular cortical pursuit pathways supersede this phylogenetically ancient subcortical system (Fig.  14.1) [32–36].

Role of the AOS in Infantile Nystagmus Full-field optokinetic nystagmus and foveal pursuit are diametrically opposed ocular motor functions—you have to turn one off to have the other [36]. Failure to do so produces a discordance wherein activation of one system provides visual feedback that reactivates the other system in a positive feedback manner. The following clinical and experimental evidence support this mechanism as the substrate for the horizontal oscillations of infantile nystagmus.

Pendularity The pendular nature of infantile nystagmus may reflect the balanced antagonism of these hierarchical optokinetic systems. Pendular pursuit oscillations result from negative feedback and excessive time delay in the internal pursuit feedback loop. Most of the control systems in nature (as well as those constructed by man) use negative feedback (part of the output is fed back to subtract from the input). This system produces a stable, time-invariant control structure. However, when there is an increased delay in that feedback pathway, the resulting phase shift in the feedback signal causes an effective reversal in its sign. For example, a 180° phase delay in a sine wave results in the positive portion coinciding with the original negative portion. Because the feedback is negative by design (ie, the feedback signal is multiplied by −1), that delayed positive portion becomes negative and it sums with the undelayed negative portion of the original signal. This signal continues to grow with each cycle. The result is an oscillation similar to that produced in auditorium

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Fig. 14.1  Depiction of the Brain, as Viewed From Above, Showing Normal Cortical and Subcortical Projections During Early Human Development. (a) Early in infancy, horizontal optokinetic stimuli (shown as leftward or rightward motion) from each nasal retina are transmitted via a subcortical pathway to the contralateral nucleus of the optic tract-dorsal terminal nucleus (NOT-­ DTN) of the accessory optic system (solid red arrow), which is directionally sensitive to ipsiversive motion (ie, nasalward for the contralateral eye). During this early stage of development, the cortical pursuit pathways (shown as corticofugal projection from the middle temporal area-medial superior temporal area [MT-MST] to the ipsilateral NOT-DTN) have not yet become functional (interrupted green arrows). (b) Later in infancy, horizontal optokinetic responses become encephalized, binocular cortical pursuit pathways become fully operational (solid green arrows), and subcortical optokinetic pathways regress (interrupted red arrows). L indicates left eye monocular cells; LGN, lateral geniculate nucleus; R, right eye monocular cells; R+L, cortical binocular cells; SCC, splenium of the corpus callosum; and VI, primary visual cortex. Based on the model proposed by Hoffmann [32]

microphone and speaker systems when the volume (gain) is too high for the short, built-in time delay from microphone to speaker In infantile nystagmus, the antagonistic pursuit signals produced by coexpression of the cortical pursuit system and the subcortical AOS (which functions as an afoveate full-field pursuit system) may provide the substrate for the underlying pendular oscillation. Saccadic refixation movements get secondarily superimposed to provide the variable waveforms that have been identified within the oscillation [1].

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Directionality Infantile nystagmus manifests clinically as a predominantly horizontal conjugate nystagmus. This trajectory may reflect the antagonism between the subcortical NOT-DTN (which generates monocularly driven optokinetic responses) and the middle temporal area and medial superior temporal area (MT-MST) within the visual cortex, which generates binocular horizontal pursuit movements. In monkeys, MST generates optokinetic responses that are largely visuovestibular in origin [37, 38] and maximally responsive to side-to-side full-field optic flow [39, 40]. This intrinsic directional sensitivity could explain why infantile nystagmus is usually maximal in the horizontal plane, reflecting delayed (in isolated cases) or deranged (in the cases with structural abnormalities with in the eye or neuronal misdirection) maturation of the horizontal pursuit pathways involving MT-MST in the visual cortex. This predominant mismatch between horizontal cortical and subcortical motion pathways could also explain how the oscillation of infantile nystagmus maintains its horizontal trajectory in upgaze, unlike in vestibular nystagmus. The rare patients with vertical or oblique nystagmus [41, 42] need further study to better understand how our hypothesis may apply to them.

Foveation Periods Unique to infantile nystagmus is its association with brief foveation periods following saccadic refixation [43–45]. These foveation periods utilize the preserved ability of the fixation and cortical pursuit systems to stabilize the eyes on target until an incursion of the subcortical optokinetic signal modulated by the AOS succeeds in derailing these functions. During foveation periods, ocular motor functions, such as fixation, pursuit, and the optokinetic and vestibuloocular reflexes, continue to function robustly in infantile nystagmus despite the superimposition of a pendular oscillation [43–45].

Absence of Oscillopsia The absence of oscillopsia during normal eye movements arises from an efference copy that reconstructs target and world motion so that the perception of either is not influenced by the sweeping of the visual world across the retinas [46–48]. The absence of oscillopsia in infantile nystagmus requires an online efference copy to correct for a constantly changing (in amplitude and waveform) oscillation [46–48]. There is some evidence [24] that efference copy may be embedded within the functioning AOS.  This would explain why rare patients who first express infantile nystagmus in their adolescence do not invariably experience oscillopsia [49].

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Null Position Infantile nystagmus is often associated with an eccentric horizontal null position leading to a gaze preference. In infantile nystagmus, this null position is the binocular equivalent of the monocular optokinetic bias that defines latent nystagmus. In the presence of infantile esotropia, the visuovestibular-optokinetic imbalance that drives latent nystagmus is modulated by the differential activity of each NOT-DTN, which is sensitive to nasally directed input from the contralateral eye [50]. In the setting of infantile nystagmus, this model would predict that any superimposed binocular visual imbalance could generate a horizontal null position without strabismus via asymmetrical activation of the NOT-DTN.

Time of Onset Infantile nystagmus is usually noted between the second and third months of life [4]. The developmental time course of infantile nystagmus overlaps that of infantile esotropia in that both conditions first appear during early infancy when binocular cortical pursuit pathways normally mature sufficiently to overtake the subcortical optokinetic system. During the first 2 months of human life, cortical pursuit pathways have not fully matured, and full-field optokinetic eye movements are attributed to subcortical visual systems, such as the NOT and the AOS [34, 35]. Ontogeny recapitulates phylogeny as the emergence of infantile nystagmus coincides with the developmental maturation of the cortical pursuit pathways, which fail to exert their predominance over the subcortical optokinetic pathways in the first 2 months of life. When maturation of these cortical pathways is delayed or deranged, the subcortical pathways continue to function, with the persistent antagonism between these 2 systems expressed in the form of infantile nystagmus. The fact that antagonism cannot be established in children with cortical visual loss demonstrates how an intact visual cortex is necessary for infantile nystagmus to develop [51–53]. Once the visual cortex has developed, the subcortical optokinetic pathways normally cease to function, which explains why infantile nystagmus does not arise when central binocular visual loss develops after early infancy [53]. This explanation does not account for cases of infantile nystagmus that have been noted to appear at birth because the cortical pursuit system is not yet operational [33–35]. Animal models [54–57] suggest that genetic mutations can invert the directional sensitivity of the subcortical AOS to allow this oscillation to be expressed. Inversion of the retinal slip, the error signal of the subcortical optokinetic feedback loop, has been demonstrated in an albino rabbit [54] and in achiasmatic zebrafish belladonna mutant [55–57], which shows nystagmus in light with waveform characteristics superficially resembling infantile nystagmus. Inversion of the subcortical error signal within the AOS could produce an unstable feedback mechanism that would tend to increase retinal slip [57]. That result would allow

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infantile nystagmus to manifest as the cortical pursuit system matures and would preclude accurate calibration of pursuit damping. When mutational effects are localized to the subcortical optokinetic system, electrophysiologic symmetry may be preserved within the visual cortex. Conversely, some infants with normal vision exhibit a transient nystagmus that disappears as the visual system matures in the postnatal period [58], perhaps reflecting an atavistic expression of the normal AOS before it is inactivated as normal connections from cortical pursuit pathways become established. There is always the alternative that, in cases of isolated infantile nystagmus appearing at birth, pursuit-system damping calibration is precluded by some other factor (eg, genetic) independent of sensory loss or AOS directional inversion.

Association with Seesaw Nystagmus Eye movement recordings have shown that infantile nystagmus is accompanied by a subclinical seesaw nystagmus [59]. Seesaw nystagmus is a cyclovertical oscillation of the eyes that has been attributed to reactivation of the lateral and medial terminal nuclei within the AOS [60]. Because torsional eye movements are not generated within the visual cortex [50], reactivation of the AOS seems necessary to explain the coexistent cyclovertical component of this oscillation. In rare infantile nystagmus cases with achiasma or hypochiasma, a clinically visible seesaw nystagmus is also present [61].

Reversed Optokinetic Nystagmus Despite their apparent reversal, the optokinetic responses in infantile nystagmus are not reversed; affected patients still generate the correct optokinetic responses during each foveation period. These responses are driven by the (still intact) cortical pursuit system [44]. So-called reversed horizontal optokinetic responses in infantile nystagmus are attributable to a shift in the null zone brought about by viewing horizontal optokinetic targets [62, 63]. Underlying this dynamic null shift may be the breakthrough responses of the AOS to full-field optokinetic stimuli that are reactivated by the fully functioning pursuit system. Optokinetic motion is known to displace the resting position of eyes in the direction of the fast phase [64]. For example, rightward-moving optokinetic targets would displace the eyes to the right, simulating right gaze and generatinga right-­ beating nystagmus. This binocular displacement would produce the appearance of a reversed optokinetic nystagmus because the shift in gaze position to the right is equivalent to a displacement of the null position to the left [53]. In this scenario, the optokinetic shift in gaze position to the right tells the (still active) AOS that the world has rotated to the left, reinforcing a right-beating nystagmus.

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Augmentation by Fixation and Pursuit In contradistinction to peripheral vestibular nystagmus, the intensity of infantile nystagmus increases during visual activity involving fixation or pursuit [65–67]. Thus, daydreaming in the light will diminish infantile nystagmus, whereas any active gaze effort in the dark will evoke it [68]. The fixation system works synergistically with the pursuit system and helps it to function smoothly by correcting for small position errors. When fixation and pursuit are activated by attention to the external visual world, infantile nystagmus intensifies because of increased antagonism between the cortical and subcortical optokinetic inputs.

Association with Congenital Visual Loss Approximately half of the cases of infantile nystagmus are accompanied by structural or electrophysiologic derangements involving central foveal vision in both eyes [4–6]. The common denominator in these disorders is binocular maldevelopment of central foveal vision subserving high-frequency contrast sensitivity. When present from birth, these derangements preclude the normal development of cortical foveal pursuit and promote persistent expression of the subcortical optokinetic pathways driven by the NOT-DTN. Animal models [54–57] demonstrate that albinism and achiasma can also alter the trajectories of the subcortical optokinetic pathways. Hereditary forms of infantile nystagmus are commonly associated with no other detectable visual system abnormalities. However, a study by Weiss and Kelly [69] found that patients with isolated infantile nystagmus showed delayed development of normal grating acuity responses. This finding suggests that patients with apparently isolated infantile nystagmus may have a genetically determined maturational delay in binocular development of cortical vision. Developmental retardation in the maturation of cortical pursuit during the necessary time window could lead to persistent activation of the subcortical optokinetic system and promote the expression of infantile nystagmus. If a perturbation in developmental timing alone is sufficient to permit the AOS to generate subcortical optokinetic responses, this temporal delay could explain the occurrence of infantile nystagmus in patients who ultimately develop otherwise normal visual systems. In these infants, genetic mutations or developmental perturbations that delay the normal bilateral maturation of cortical (foveal) pursuit pathways could be sufficient to allow the subcortical optokinetic system to remain functional.

Superimposition of Latent Nystagmus Infantile nystagmus syndrome and latent nystagmus (also termed fusion maldevelopment nystagmus syndrome) [70] exist on a continuum wherein early loss of vision in both eyes (eg, from bilateral congenital cataracts or bilateral optic nerve hypoplasia) precipitates infantile nystagmus, whereas early visual loss in one eye (eg, from

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a unilateral congenital cataract or unilateral optic nerve hypoplasia) gives rise to a manifest latent nystagmus [71]. Furthermore, infantile nystagmus is often accompanied by a superimposed latent nystagmus [72] causing visual acuity to be further degraded under conditions of monocular testing [73]. Like infantile nystagmus, latent nystagmus has a torsional component and requires persistent activation of subcortical optokinetic pathways for its expression [50]. Latent nystagmus is generated by nasalward motion input to the NOT-DTN of the AOS from the contralateral eye [50]. Latent nystagmus reflects a monocular optokinetic predominance in the nasal direction that is mediated subcortically by the NOT-DTN (a part of the AOS) within the mesencephalon [15, 50, 74]. This monocular, subcortical, nasotemporal optokinetic asymmetry is normal in lateral-eyed animals but suppressed in humans with cortical binocular vision [75]. Whereas latent nystagmus represents a unilateral activation of nasally directed subcortical optokinetic pathways, infantile nystagmus signals a bilateral activation of subcortical optokinetic pathways. This interrelationship explains how binocular central visual loss from birth gives rise to infantile nystagmus, whereas monocular visual loss from birth gives rise to esotropia with latent nystagmus. It also predicts that latent nystagmus should be superimposed on infantile nystagmus when strabismus coexists. This framework allows us to cross-correlate these 2 oscillations and conceptualize them as involving the same neurologic pathways along a continuum of top-down (cortical-subcortical) optokinetic imbalance in infantile nystagmus and side-to-side (binocular) optokinetic imbalance in latent nystagmus. Infantile nystagmus could be considered the binocular form of latent nystagmus. The waveform differences arise from the functional sites affected by these imbalances (a tonic imbalance in the visuovestibular system resulting in latent nystagmus and an interference with the calibration of the pursuit-system damping causing infantile nystagmus).

Involvement of Cerebellar Pathways The responses of the AOS are modulated by the flocculus within the vestibulocerebellum. Experimental findings from numerous studies [76] implicated an integral role for the cerebellum in the modulation of infantile nystagmus. High-resolution magnetic resonance imaging using voxel-based morphometry has found that gray matter volume increases within cortical area V5/MT, the fusiform gyrus, and the vestibulocerebellum. These changes may relate to the antagonism between cortical pursuit and the subcortical AOS, the effort involved in maintaining fixation, or both. In situ hybridization studies [9, 77, 78] on the embryonic human brain have shown that the FRMD7 mutation that characterizes X-linked infantile nystagmus is expressed in the developing forebrain, midbrain, cerebellum, primordium, spinal cord, and neural retina. Barreiro et al [79] modeled the ocular motor system and concluded that infantile nystagmus could result from adaptive cerebellar mechanisms. Yoshida et al [80] found that mutant mice deficient in the glutamate receptor δ2 subunit, which have limited plasticity of synapses onto Purkinje cells, also have

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Fig. 14.2  Diagram of Cortical and Subcortical Optokinetic Pathways Mediating Infantile Nystagmus. We propose that cortico-mesencephalic-cerebellar pathways involving the middle temporal area–medial superior temporal area (MT-MST), the accessory optic system (AOS), the nucleus of the optic tract, and the flocculus of the cerebellum generate this horizontal oscillation. Pathways for horizontal eye movements are shaded blue, pathways for movements around an oblique horizontal axis are shaded in red, and mossy fiber pathways (unrelated to the climbing fiber pathways mediating the AOS) are shaded in green. Ant C indicates anterior canal; C2, FI, F2, F3, and F4, layers within the cerebellar flocculus; DC, dorsal cap; Front, frontal plane; Hor, horizontal plane; Hor C, horizontal canal; Inf O, inferior oblique muscle; Lat R, lateral rectus muscle; Med R, medial rectus muscle; MT, middle temporal area; MST, middle superior temporal area; NPT, nuclei of the paramedian tracts; NRTP, nucleus reticularis tegmenti pontis; Prep Hyp, nucleus prepositus hypoglossi; Sag, sagittal plane; Sup R, superior rectus muscle; VI, V2, cortical areas; and VLO, ventrolateral outgrowth. Question marks indicate disputed projection of the nucleus of the optic tract to the vestibular nuclei and the NRTP. (Modified from Voogd et al. [83])

oscillations of approximately 10 Hz in Purkinje cell responses and eye movements that resemble pendular infantile nystagmus. Finally, periodic alternating nystagmus is modulated by the nodulus of the vestibulocerebellum and requires the coexistence of a visual deficit and a vestibular malfunction [81, 82]. Thomas et al [10] showed that periodic alternating nystagmus occurs predominantly with missense mutations in FRMD7 and concluded that this is most likely related to instability of the optokinetic-vestibular systems. Perhaps efferent activity from the cerebellar flocculus modulates the slow eye movements of

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infantile nystagmus while the cerebellar nodulus and uvula give rise to periodic alternating nystagmus. These findings do not imply that infantile nystagmus is anatomically localized within the cerebellum but that the vestibulocerebellum actively participates in generating this oscillation (Fig. 14.2) [83].

Theories of Causation Other causational theories for infantile nystagmus have invoked atavistic evolutionary mechanisms to explain the oscillation. Yee et al [84] examined the role of the subcortical AOS in humans and concluded from their optokinetic measurements that infantile nystagmus must be due to an inherent defect in the subcortical optokinetic system. Dell’Osso [85] rebutted this conclusion and pointed out that the apparent full-field optokinetic defects could be attributed to the nystagmus itself rather than to an inherent defect in the subcortical optokinetic system. Kommerell and Mehdorn [86] ascribed infantile nystagmus to a primary defect in the optokinetic system, which can no longer maintain retinal slip control. Kommerell [87] and Kommerell et  al [88] inferred that, because patients with infantile nystagmus can differentiate velocities of optokinetic stimuli, the defect cannot be in the retinocortical pathway and must be between the cortex and the ocular motor centers in the brainstem. Optican and Zee [89] reproduced some of the waveforms of infantile nystagmus by using a computer model to create a reversal in the sign of the velocity pathway to make the neural integrator unstable. However, the demonstration of simultaneous decelerating (due to a leaky neural integrator) and accelerating (due to infantile nystagmus) slow eye movements in a family who had both deficits disproved the hypothetical explanation [90]. Jacobs and Dell’Osso [17] modeled infantile nystagmus as attributable to an intrinsic instability in the foveal pursuit system. According to this model, evolution has necessarily designed the cortical pursuit system to operate on the threshold of oscillation to provide minimal response time without instability [18]. Given that the normal horizontal pursuit system is intrinsically underdamped, it is almost guaranteed that some individuals will fail to achieve the delicate balance between quasiinstability (underdamped) and total instability (undamped), manifesting as infantile nystagmus. Harris and Berry [91, 92] have proposed that contrast sensitivity to low spatial frequencies is enhanced by motion of an image across the retina and that the best compromise between moving the image and maintaining the image on the fovea (or its remnant) is to oscillate the eyes with jerk nystagmus with increasing velocity waveforms, as is seen empirically in infantile nystagmus. During infancy, “evolution would need to tread a fine line by programming the development of ocular motor control in tandem with foveal maturation to maximize visual contrast without causing nystagmus” [92] (p68). Accordingly, loss of high spatial-frequency information (whether caused by foveal, optic nerve, or optical aberrations) could lead to an atavistic resurgence of low-frequency peripheral retinal visual mechanisms that enhance their function during oscillation of the eyes [92].

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Our hypothesis reconciles these aforementioned theories by proposing that the absence of timely maturation of high-frequency (foveal) motion sensitivity, by whatever cause, must secondarily delay development of high-frequency cortical pursuit pathways, lifting the developmental brakes on the peripheral retinal motion input to the AOS to precipitate infantile nystagmus. In this setting, persistent activation of a normal AOS could be responsible for the abnormal retinal slip control postulated by Kommerell and Mehdorn [86]. Although an abnormal AOS may contribute to infantile nystagmus in patients with albinism or achiasma (as well as in those infants that have nystagmus at birth), the preponderance of evidence points to a persistent activation of a normal AOS that disrupts retinal slip control during attempted fixation and foveal pursuit. This hypothesis explains how the saccadic, pursuit, and optokinetic systems can continue to function normally in infantile nystagmus despite the superimposed aberrations that this oscillation generates. It also assigns a specific neuroanatomic correlate to the ocular motor control systems that have long been suspected to generate infantile nystagmus. By virtue of this analysis, it becomes clear that infantile nystagmus arises from a neuroanatomically dispersed system of cortico-mesencephalic-cerebellar feedback loops (Fig. 14.2) [83].

Conclusions We hypothesize that infantile nystagmus signals a breakdown in the armistice between subcortical and cortical optokinetic pathways during early development. Neuroanatomically, infantile nystagmus arises from a discordance between the foveate smooth pursuit modulated by the visual cortex and the afoveate full-field optokinetic system modulated by the AOS.  Under conditions of normal visual development, cortical smooth pursuit overrides and suppresses the contradirectional optokinetic input that is generated by the AOS after the first few months of life. However, delayed or diminished development of central foveal vision may unleash the fundamental antagonism between subcortical optokinetic pathways and cortical pursuit, causing infantile nystagmus to be expressed. Because the AOS functions as a subcortical pursuit system in afoveate animals, its reactivation in humans explains the paradox that infantile nystagmus is inherent to the pursuit system, yet pursuit gain remains normal. Through the prism of evolution, infantile nystagmus can be seen as a clinical expression of the fundamental antagonism between the subcortical optokinetic system and the cortical foveal pursuit system. Because these visual motion detection systems need to be coordinately expressed for infantile nystagmus to arise, this palindromic oscillation does not develop in afoveate lateral-eyed animals or in humans with cortical visual loss. In isolated cases, infantile nystagmus may reflect slow development of central foveal vision, which impedes maturation of cortical pursuit and allows the AOS to establish a foothold and exert its influence. Based on this model, it seems plausible that isolated infantile nystagmus could also arise from a genetic failure to inactivate the AOS even in the absence of abnormal foveal visual development.

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Finally, we have proposed a hypothetical framework wherein 2 distinctly different types of oscillations (infantile nystagmus and latent nystagmus) may be linked. Although each has its own direct motor cause (uncalibrated pursuit damping or tonic visuovestibular imbalance, respectively), they share a common root. That possibility is supported by the following observations: infantile nystagmus may exhibit a latent component; infantile nystagmus may coexist with latent nystagmus; the “null” that is characteristic of infantile nystagmus is hypothesized to arise from the same Alexander law variation of slow-phase velocity that governs latent nystagmus; and the low-amplitude, high-frequency pendular oscillation of NOT-DTN nystagmus is often found superimposed on both infantile and latent nystagmus waveforms. As with all hypotheses, novel experiments in animals and humans will be required to either disprove or support our proposed framework. References 1. Dell’Osso LF, Daroff RB.  Congenital nystagmus waveforms and foveation strategy. Doc Ophthalmol. 1975;39(1):155–82. 2. Brodsky MC.  Pediatric neuro-ophthalmology. 2nd ed. New  York: Springer; 2010. p. 383–94. 3. Hertle RW, Dell’Osso LF. Nystagmus in infancy and childhood: current concepts in mechanisms, diagnoses, and management. New  York: Oxford University Press; 2013. p. 1–323. 4. Gelbart SS, Hoyt CS. Congenital nystagmus: a clinical perspective in infancy. Graefes Arch Clin Exp Ophthalmol. 1988;226(2):178–80. 5. Sarvananthan N, Surendran M, Roberts EO, et al. The prevalence of nystagmus: the Leicestershire nystagmus surgery. Invest Ophthalmol Vis Sci. 2009;50(11):5201–6. 6. Hertle RW. Examination and refractive management of patients with nystagmus. Surv Ophthalmol. 2000;45(3):215–22. 7. Self JE, Ennis S, Collins A, et al. Fine mapping of the X-linked recessive congenital idiopathic nystagmus locus at Xq24-q26.3. Mol Vis. 2006;12:1211–6. 8. Self J, Lotery A. The molecular genetics of congenital idiopathic nystagmus. Semin Ophthalmol. 2006;21(2):87–90. 9. Tarpey P, Thomas S, Sarvananthan N, et  al. Mutations in FRMD7,  a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus. Nat Genet. 2006;38(11):1242–4. 10. Thomas S, Proudlock FA, Sarvananthan N, et al. Phenotypical characteristics of idiopathic infantile nystagmus with and without mutations in FRMD7. Brain. 2008;131(pt 5):1259–67. 11. Watkins RJ, Patil R, Goult BT, Thomas MG, Gottlob I, Shackleton S. A novel interaction between FRMD7 and CASK: evidence for a causal role in idiopathic infantile nystagmus. Hum Mol Genet. 2013;22(10):2105–18. 12. Guo SQ, Reinecke RD, Fendick M, Calhoun JH. Visual pathway abnormalities in albinism and infantile nystagmus: VECPs and stereoacuity measurements. J Pediatr Ophthalmol Strabismus. 1989;26(2):97–104.

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Postscript The strength of this analysis is that it explains virtually all components of infantile nystagmus and affirms that this neurologic oscillation is confined within the visual system. The recent finding that babies of “methadone moms” have delayed cortical visual maturation leading to persistent infantile nystagmus also supports this hypothesis. As summarized in Chap. 20, lines of evidence from several different studies support an central role for the accessory optic system in that pathogenesis of infantile nystagmus. How often the genetic mutations leading to idiopathic infantile nystagmus exert their cellular effects via retinal electrochemical aberrations, extended subcortical neuroplasticity, delayed visual cortical maturation, or by enhancing an intrinsic ocular motor instability remains to be determined.

Intermittent Exotropia and Accommodative Esotropia: Distinct Disorders or Two Ends of a Spectrum?

15

In clinical diagnosis, we often imbue medical disorders with distinct personalities based on a constellation of findings with little understanding of their underlying causes. Our purpose here is to juxtapose intermittent exotropia and accommodative esotropia and to consider the possibility that they represent a continuum of horizontal deviation, rather than distinct mechanisms of disease. Over years of observation, we have come to view intermittent exotropia and accommodative esotropia as diametrical disorders of horizontal eye position that use common binocular control mechanisms. Intermittent exotropia is characterized by a gradual, progressive exodeviation of either eye that is present mainly during distance fixation or when the patient is inattentive [1–3]. The measured deviation usually is greater at distance and, except in a small, definable group of patients with a high accommodative convergence-to-­ accommodation ratio [4], strabismus surgery targeted for the distance deviation produces surprisingly little risk for surgical overcorrection at near [5]. This phenomenon is attributed to the observation that the resting position of the eyes (as determined under nondepolarizing paralyzing anesthesia) is abnormally divergent in patients with intermittent exotropia [2, 6–9], so that extra fusional convergence effort is necessary to view near objects binocularly [10, 11]. In this condition, the measured near deviation is reduced artificially by a phenomenon that Kushner termed tenacious proximal fusion, meaning that fusional convergence initially masks the true exophoria at near until prolonged patching causes it to become manifest [10, 11]. We believe tenacious proximal fusion is a manifestation of phoria adaptation, a compensatory mechanism that resets binocular alignment toward orthophoria, thereby compensating for developmental, environmental, or pathologic alterations in the binocular mechanism to restore the dynamic range (or fusion reserve) in which fast fusional vergence can function [12]. Phoria adaptation operates independently of the immediate vergence system and thereby minimizes the need for vergence control. Although phoria adaptation is elicited classically by introducing prisms before the eyes to induce a vergence error, this compensatory mechanism also can function to reduce or eliminate the measured phoria. Patients with © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_15

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intermittent forms of strabismus, such as intermittent exotropia and accommodative esotropia, retain the ability to respond to vergence perturbations using this fusional mechanism. Phoria adaptation has been considered by some to be a cerebellar-­ dependent response [13–15], but midbrain vergence-related neurons also may play a role [16]. Conversely, accommodative esotropia is characterized by a gradually progressive esodeviation that is often greater with near fixation [17, 18]. Accommodative esotropia has long been attributed to uncorrected hyperopia that increases accommodative effort with corollary accommodative convergence. Compared with other forms of strabismus, accommodative esotropia more often is associated with a high accommodative convergence to accommodation (AC/A) ratio, which generates a larger esodeviation during near fixation. In the absence of accommodative effort, patients with accommodative esotropia are conceptualized as having an esodeviation that is produced solely by their increased accommodative demand in the alert state, which is necessarily greater for near. In patients with a greater near esodeviation, however, surgical correction targeted for the near deviation generally does not produce overcorrection of the distance deviation, suggesting that the true distance esodeviation must be greater than the measured distance esodeviation [19–23]. Accordingly, patients with larger near deviations may have a large distance esophoria, but be exhibiting a “tenacious” distance fusion, which again may be a healthy sign of phoria adaptation. That patients with accommodative esotropia can “eat up prisms,” allowing the examiner to build the measured esodeviation slowly with prism adaptation [ 24–26], suggests that this is the case. The need to augment standard surgical doses for accommodative esotropia also suggests that these patients may be concealing a larger esodeviation than can be measured with prism and alternate cover testing (as opposed to controlling one, which would necessitate a corresponding phoria). Thus, the effects of phoria adaptation become admixed with those of disparity-driven nonaccommodative convergence (in intermittent exotropia) or blur-driven accommodative convergence (in accommodative esotropia) to produce some of the defining clinical signs of each condition. Recent discoveries by Horwood et al [27] and Horwood and Riddell [28–30] at the University of Reading have cast new light on the pathogenesis of intermittent exotropia and its juxtaposition to accommodative esotropia. These examiners used a specially designed remote haploscopic video-refractor to manipulate blur, disparity, and proximal looming cues separately while simultaneously monitoring accommodation and vergence angles [27–30]. To the surprise of many, these investigators found that disparity cues provide the primary drive for both convergence and accommodation in normal subjects [27, 30]. This observation may explain why monocular accommodation responses (which eliminate disparity cues) so often are worse than binocular ones [27]. These investigators have found that patients with intermittent exotropia underaccommodate in the exodeviated state during distance fixation and overaccommodate in the orthotropic state during near fixation [28]. This unexpected finding of underaccommodation at distance does not arise from an inherent defect in accommodation, but presumably reflects the fact that the

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control of intermittent exotropia is driven primarily by retinal disparity (which is less at distance than at near) [28]. Patients with intermittent exotropia seem to use disparity-induced vergence cues to restore binocular alignment, with greater convergence stress demand during near fixation triggering overaccommodation, and possibly contributing to the development of myopia over time [31]. Other investigators have used different methodologies to draw similar conclusions regarding the primary role of disparity-induced vergence in controlling intermittent exodeviations [32–34]. That binocular disparity seems to provide a stronger cue than blur for both vergence and accommodation suggests that assessment of the convergence accommodation to convergence (CA/C) ratio may be more mechanistically accurate in normal subjects as well as in those with intermittent exotropia [28, 35]. Horwood and Riddell [29, 30] found patients with accommodative esotropia to be more responsive to blur than to disparity, causing their excessive accommodative demand to miscalibrate vergence position to produce an open-loop esodeviation that often is greater for near fixation. To the extent that they are driven by blur, assessment of the accommodative convergence-to-accommodation ratio provides a more accurate mechanistic assessment of the resulting esotropia at any given distance [29]. The confluence of these findings raises the question of whether intermittent exotropia and accommodative esotropia exist on a spectrum from disparity-driven convergence accommodation to blur-driven accommodation convergence (Fig. 15.1). If so, there is no evidence that this duality results from inherent innervational differences. Rather, they seem to reflect only the physiologic demands placed on the

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Fig. 15.1  Systemic model representations of synkinetic interaction between accommodation and vergence highlights that those two motor systems are cross-linked and produce blur-driven accommodation or convergence and disparity-driven convergence or accommodation [40]. Phoria adaptation then changes the motor output of the vergence system to adjust binocular alignment at fixation distances that readily permit binocular fusion. Black lines signify major operational pathways, whereas dashed lines signify functional crosslinkages between these pathways. AC/A = accommodative convergence-to-accommodation ratio; CA/C = convergence accommodation-to-­ convergence ratio; + − positive feedback loop; − = negative feedback loop

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binocular visual system by the nature of the deviation and refractive error. Long ago, Jampolsky [36] first presented evidence and maintained that there is no active centrally mediated divergence and that apparent horizontal divergence movements of the eyes are effectuated by deconvergence. In this way, both the central convergence and accommodation centers function conjointly as an on-off system rather than a pushpull system. It may reflect the existence of a central convergence center alone that is, at its core, the neurologic substrate for intermittent exotropia and accommodative esotropia, which both involve the modulation of central convergence effort. But why should intermittent exotropia be more sensitive to disparity and accommodative esotropia be more sensitive to blur? Evolutionarily, the crossed nasal retina is more attuned to blur because there is minimal disparity when each eye sees a different side, as is the case in fish and rabbits. However, the uncrossed temporal retina is attuned to binocular disparity in the midline, which may explain in part the expression of these compensatory responses under pathologic conditions in humans. These mechanisms fit well with the original evolutionary functions of each hemiretina, which must be retained in humans even after the evolution of crossed chiasm segregates them into 2 hemispheres. The observation that both conditions are anchored to the accommodative system (indirectly or directly) may help to explain their gradual onset, their progressive nature, their occasional clinical overlap [37–39], and their clinical manifestations. Does the presence of tenacious proximal fusion in intermittent exotropia and tenacious distance fusion in some cases of accommodative esotropia reflect an independent compensating role of phoria adaptation in resetting horizontal vergence tone? Although phoria adaptation usually is elicited by introducing prisms before the eyes to induce a vergence error, this neural adaptation also can function to reset the measured phoria and thereby negate strabismus. Strabismic patients may retain the ability to respond to perturbations using this mechanism, perhaps even in enhanced form. Furthermore, it makes physiologic sense that phoria adaptation must be confined to the specific range of fixation distance that constrains the deviation to fall within the limits of its compensatory fusional range. For this to be the case, both intermittent exotropia and accommodative esotropia must invoke a binocular stabilization mechanism (i.e., phoria adaptation) that conceals the basic phoria measurements that we extract after prolonged occlusion. Perhaps at a sensorimotor level, near convergence is more robust (because of proximal or other factors), so that the demands on phoria adaptation are actually less at near than at distance in intermittent exotropia. Phoria adaptation would explain how a distance-near disparity in accommodative esotropia can be managed effectively with medial rectus recessions to target the near esodeviation without overcorrecting a much smaller distance esodeviation [23]. This hidden mechanism would signify that some children with distance-near disparity have a distance esodeviation that “flies under the radar” of our routine clinical examination by prism and alternate cover testing. One test for this hypothesis would be to repeat prism and alternate cover testing after prolonged occlusion of one eye in patients with accommodative esotropia who have greater esodeviations at near than distance. If phoria adaptation is operative, one would expect

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prolonged occlusion of one eye to increase the distance esodeviation to approximate the near deviation, as suggested by results of a recent study [41]. If phoria adaptation is not operative, one would expect prolonged occlusion of one eye to induce a large postoperative exophoria at distance when the near esodeviation is eliminated. We have not found this to be the case. As new physiologic discoveries emerge, we soon may come to see intermittent exotropia and accommodative esotropia as two sides of the same coin. References 1. Jampolsky A.  Differential diagnostic characteristics of intermittent exotropia and true exophoria. Am Orthopt J. 1954;4:48–55. 2. Knapp P.  Divergent deviations. In: Allen JH, editor. Strabismus ophthalmic symposium II. St. Louis: Mosby; 1958. p. 354–63. 3. Parks MM.  Concomitant exodeviations. In: Tasma W, Jaeger EA, editors. Duane’s clinical ophthalmology. Philadelphia: Lippincott; 1991. p. 1–14. 4. Kushner BJ. Diagnosis and treatment of exotropia with a high accommodation convergence-accommodation ratio. Arch Ophthalmol. 1999;117:221–4. 5. Kushner BJ. The distance angle to target in surgery for intermittent exotropia. Arch Ophthalmol. 1998;116:189–94. 6. Jampolsky A.  Treatment of exodeviations. In: Pediatric ophthalmology and strabismus: transactions of the New Orleans Academy of Ophthalmology. New York: Raven Press; 1986. p. 201–34. 7. Guyton DL. The 10th Bielschowsky Lecture. Changes in strabismus over time: the roles of vergence tonus and muscle length adaptation. Binocul Vis Strabismus Q. 2006;21:81–92. 8. Breinin GM.  The position of rest during anesthesia and sleep; electromyographic observations. AMA Arch Ophthalmol. 1957;57:323–6. 9. Lancaster WB.  Terminology with extended comments of the position of rest and on fixation. In: Allen JH, editor. Strabismus ophthalmic symposium II. St. Louis: Mosby; 1958. p. 503–22. 10. Kushner BJ. Exotropic deviations: a functional classification and approach to treatment. Am Orthopt J. 1988;38:81–93. 11. Kushner BJ, Morton GV.  Distance/near differences in intermittent exotropia. Arch Ophthalmol. 1998;116:478–86. 12. Leigh J, Zee DS. The neurology of eye movements. 4th ed. New York: Oxford University Press; 2006. p. 361–4. 13. Milder DG, Reinecke RD. Phoria adaptation to prisms. A cerebellar-dependent response. Arch Neurol. 1983;40:339–42. 14. Kono R, Hasebe S, Ohtsuki H, et  al. Impaired vertical phoria adaptation in patients with cerebellar dysfunction. Invest Ophthalmol Vis Sci. 2002;43:673–8. 15. Takagi M, Tamargo R, Zee DS. Effects of lesions of the cerebellar oculomotor vermis on eye movements in primate: binocular control. Prog Brain Res. 2003;142:19–33. 16. Morley JW, Judge SJ, Lindsey JW.  Role of monkey midbrain near-response neurons in phoria adaptation. J Neurophysiol. 1992;67:1475–92.

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17. Costenbader F. Clinical course and management of esotropia. In: Allen JH, editor. Strabismus ophthalmic symposium II. St. Louis: Mosby; 1958. p. 325–53. 18. Parks MM.  Concomitant esodeviations. In: Ocular motility and strabismus. Hagerstown: Harper & Row; 1975. p. 99–111. 19. Parks MM.  Accommodative esotropia: cause and treatment. Am Orthopt J. 1955;5:74–9. 20. Wright KW, Bruce-Lyle L. Augmented surgery for esotropia associated with high hypermetropia. J Pediatr Ophthalmol Strabismus. 1993;30:167–70. 21. West CE, Repka MX. A comparison of surgical techniques for the treatment of acquired esotropia with increased accommodative convergence/accommodation ratio. J Pediatr Ophthalmol Strabismus. 1994;31:232–7. 22. Arnoldi KA, Tychsen L. Surgery for esotropia with a high accommodative convergence/accommodation ratio: effects on accommodative vergence and binocularity. Ophthalmic Surg Lasers. 1996;27:342–8. 23. Kushner BJ. Surgical treatment of teenagers with high AC/A ratios. Am Orthopt J. 2014;64:37–42. 24. Cipolli C, Bolzani R, Corazza R, et al. Vergence movements in comitant strabismus. Percept Mot Skills. 1990;71:1259–64. 25. Kutschke PJ, Scott WE, Stewart SA.  Prism adaptation for esotropia with a distance-­near disparity. J Pediatr Ophthalmol Strabismus. 1979;29:12–5. 26. Repka MX, Connett JE, Baker JD, Rosenbaum AL. Surgery in the prism adaptation study: accuracy and dose response. Prism Adaptation Study Research Group. J Pediatr Ophthalmol Strabismus. 1992;29:150–6. 27. Horwood AM, Riddell PM, Toor SS.  Convergence-accommodation beats accommodative convergence. In: Haugen OH, editor. 35th Meeting of the European Strabismological Association. Romania September: Bucharest; 2012. p. 2–5. 28. Horwood AM, Riddell PM. Evidence that convergence rather than accommodation controls intermittent distance exotropia. Acta Ophthalmol. 2012;90:e109–17. 29. Horwood AM, Riddell PM.  Accommodation and vergence response gains to different near cues characterize specific esotropias. Strabismus. 2013;21:155–64. 30. Horwood AM, Riddell PM. Disparity-driven vs blur-driven models of accommodation and convergence in binocular vision and intermittent strabismus. J AAPOS. 2014;18:576–83. 31. Ekdawi NS, Nusz KJ, Diehl NN, Mohney BG.  The development of myopia among children with intermittent exotropia. Am J Ophthalmol. 2010;149:503–7. 32. Ahn SJ, Yang HK, Hwang J-M. Binocular visual acuity in intermittent exotropia: role of accommodative convergence. Am J Ophthalmol. 2012;154:981–6. 33. Laird PW, Hatt SR, Leske DA, Holmes JM.  Distance stereoacuity in prism-­ induced convergence stress. J AAPOS. 2008;12:370–4. 34. Laird PW, Hatt SR, Leske DA, Holmes JM. Stereoacuity and binocular visual acuity in prism-induced exodeviation. J AAPOS. 2007;11:362–6. 35. McLin L, Schor C. Voluntary effort as a stimulus to accommodation and vergence. Invest Ophthalmol Vis Sci. 1988;29:1739–46.

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36. Jampolsky A.  Ocular divergence mechanisms. Trans Am Ophthalmol Soc. 1970;68:730–822. 37. Beneish R, Williams F, Polomeno RC, Little JM. Consecutive exotropia after correction of hyperopia. Can J Ophthalmol. 1981;16:16–8. 38. Raab EL.  Consecutive accommodative esotropia. J Pediatr Ophthalmol Strabismus. 1985;22:58–9. 39. Weir CR, Cleary M, Dutton GN. Spontaneous consecutive extropia in children with motor fusion. Br J Ophthalmol. 2001;85:242–3. 40. Schor C.  Influence of accommodative and vergence adaptation on binocular motor disorders. Am J Optom Physiol Optic. 1988;65:464–75. 41. Garretty T.  Convergence excess esotropia: a proposed new classification and the effect of monocular occlusion on the Ac/A ratio. J Pediatr Ophthalmol Strabismus. 2010;47:308–12.

Postscript In this piece, we invoke phoria adaptation to explain why strabismus surgery targeted for the greater distance exodeviation does not overcorrect the smaller near exodeviation in intermittent exotropia, and why strabismus surgery targeted for the greater near esodeviation does not overcorrect the smaller distance esodeviation in accommodative esotropia with high AC/A ratio. The selective effects of phoria adaptation as a function of distance may reflect that fact that near fixation (where convergence is superimposed upon a baseline exodeviation) brings the eyes closest to orthotropia in intermittent exotropia whereas distance fixation (i.e. nonaccommodation) may bring the eyes close to orthotropia in accommodative esotropia. Phoria adaptation will selectively compensate where it can. This analysis led to my subsequent publication invoking phoria adaptation as the major source of normal binocular tonus and an integral component of these intermittent forms of horizontal strabismus. Thus, while visuo-vestibular tonus predominates under the dissociated binocular conditions that characterize infantile strabismus, phoria adaptation provides the major extraocular muscle tonus pool under most other binocular conditions. The myriad effects of phoria adaptation are addressed more comprehensively in Chap. 18.

An Optokinetic Clue to the Pathogenesis of Crossed Fixation in Infantile Esotropia

16

Infantile esotropia is characterized by crossed fixation, wherein each eye fixates objects within the contralateral side of visual space [1]. Crossed fixation is attributed classically to foveal proximity to the position of the object of regard on the nonsuppressed retina [2]. However, we report a clinical observation that calls this classic interpretation into question. We describe 3 children with infantile esotropia who exhibited a spontaneous fixation switch when the horizontal direction of a rotating optokinetic drum was reversed. Case Description  All 3 children had isolated infantile esotropia. When viewing a horizontally rotating optokinetic drum under monocular viewing conditions, all displayed brisk optokinetic responses to nasalward optokinetic targets and poor optokinetic responses to temporalward optokinetic targets. When viewing a horizontally rotating optokinetic drum under binocular viewing conditions, all spontaneously fixated with the eye exposed to nasalward optokinetic motion. When the horizontal direction of optokinetic rotation was reversed so that the contralateral eye was receiving nasalward optokinetic input, a spontaneous fixation shift occurred after 5 to 10 seconds. Discussion  In infantile esotropia, we found that a fixation switch can be induced solely by a reversal of viewed horizontal motion direction in the frontal plane. Because the eyes remain esotropic under conditions of nonfixation, it is generally assumed that having crossed eyes naturally predisposes to crossed fixation because the visual axis of the opposite eye most closely approximates an object of regard. Dickey et al [3] have noted that, as the object of regard is moved from one side to the other, a midline fixation switch to the other eye spontaneously occurs in the absence of amblyopia. The image of the fixation target falls on the cortically suppressed nasal retina area of the esodeviating eye, making this fixation switch hard to reconcile with the mechanism of foveal proximity to a nonsuppressed area of peripheral retina. Given that the fixation target is moving nasally with respect to the eye destined to take up fixation, this fixation switch could also be triggered by the © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_16

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nasal direction of the movement (relative to the nonfixating eye) rather than the midline position of the fixated object. During optokinetic stimulation, the spontaneous fixation shift in our 3 patients was always from the eye with temporally directed optokinetic input to the eye with nasally directed optokinetic input. Because infantile esotropia necessitates a large refixation saccade to shift fixation in primary position, this observation challenges the notion that foveal proximity to a stimulated area of nonsuppressed retina leads to the phenomenon of crossed fixation. Our findings suggest that this peripheral monocular nasotemporal asymmetry provides a stronger fixation stimulus than foveal proximity. Monocular nasotemporal optokinetic asymmetry arises from a subcortical optokinetic system that is present in lateral-eyed afoveate animals [4], and is detectable in normal binocular humans within the first several months of life [5]. It is mediated by crossed (nasal) retinal pathways to the accessory optic system and nucleus of the optic tract within the midbrain [4, 5]. In infantile esotropia, it persists throughout life and is attributed to a failure of early cortical binocular vision to develop [5]. The persistence of monocular nasotemporal optokinetic asymmetry in humans creates the equivalent of a temporalward motion hemianopia during fixation with either eye. In infantile esotropia, however, both nasal retinas become frontally directed, raising the intriguing possibility that infantile esotropia provides a positional reconfiguration to restore bidirectional motion detection under binocular conditions in humans with early binocular misalignment. This mechanism could explain why the eyes remain crossed even during nonfixation, and why directional optokinetic reversal can elicit a fixation switch in humans with infantile esotropia. This subcortical optokinetic response would remain operative despite cortical suppression of the esodeviating eye. References 1. Costenbader F. Clinical course and management of esotropia. In: Allen JH, editor. Strabismus ophthalmic symposium II. Trans New Orleans Acad Ophthalmol. St. Louis: Mosby; 1958. p. 325–53. 2. Agaoglu MN, LeSage SK, Joshi AC, et  al. Spatial patterns of fixationswitch behavior in strabismic monkeys. Invest Ophthalmol Vis Sci. 2014;55:1259–68. 3. Dickey CF, Metz HS, Stewart SA, et al. The diagnosis of amblyopia in crossed fixation. J Pediatr Ophthalmol Strabismus. 1991;28:171–5. 4. Wallman J. Subcortical optokinetic mechanisms. In: Miles FA, Wallman J, editors. Visual motion and its role in stabilization of gaze. Amsterdam: Elsevier Science; 1993. p. 321–42. 5. Braddick O. Where is the naso-temporal asymmetry? Motion processing. Curr Biol. 1996;6:250–3.

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Postscript This report demonstrates that patients with essential infantile esotropia (EIE) and crossed fixation tend to switch fixation to the eye receiving nasalward optokinetic input, suggesting that monocular nasotemporal optokinetic asymmetry (MNTA) could underlie the phenomenon of crossed fixation. As MNTA derives from the nasal retina, EIE can be conceptualized as a condition wherein the nasal retinas are repositioned to lie within the frontal plane, thereby permitting bidirectional horizontal motion detection (nasalward for each fixing eye). This explanation should not imply that EIE is generated for the purpose of restoring horizontal motion bidirectionality, but that the preexisting nasalward deviation of both eyes can be exapted under binocular conditions to promote this critical function. This mechanism dovetails with the subcortical hypothesis in the following chapter to suggest that a dynamic (optokinetic) imbalance could underlie a static deviation (essential infantile esotropia).

Is Infantile Esotropia Subcortical in Origin?

17

Introduction Essential infantile esotropia (EIE) is characterized by a progressive nasalward deviation of the eyes that develops within the first 6 months of life [10, 14, 32]. It presents in the absence of additional neurological disease and is therefore isolated to the sensorimotor visual system within the brain [9]. It is accompanied by a unique constellation of dissociated eye movements (such as dissociated vertical divergence, latent nystagmus, and dissociated horizontal deviation), which are driven by unbalanced binocular visual input and incorporate prominent torsional movements of the eyes [9]. Most cases are nonhereditary and have no defined genetic etiology [26]. In EIE, both eyes are maintained in an adducted position necessitating a head turn to fixate with either eye (termed crossed fixation) (Fig. 17.1). However, the child can volitionally abduct either eye fully, demonstrating that this condition is prenuclear in origin. When the child is sedated using nondepolarizing paralyzing general anesthesia, the eyes assume a fairly normal position [37]. Thus, EIE has to be caused by increased prenuclear innervation (or tonus) to the medial rectus and inferior oblique muscles in the awake state [9, 10]. The fact that normal neonates exhibit large convergence movements, and that these excessive convergence movements predict development of normal binocular alignment [20], suggests that EIE does not arise from a cortical disinhibition of convergence centers within the midbrain [9]. At the outset, several indicators of a subcortical origin for EIE are evident [10]. Neuroanatomy dictates that volitional body movements are innervated by the cerebral cortex, while individual muscles are innervated by subcortical centers [10]. The fact that individual extraocular muscles become hyperinnervated in EIE therefore suggests a subcortical origin for this prenuclear innervation. A defining feature of EIE is the persistence of subcortical visual reflexes with torsional rotations of the eyes [10]. Dynamic torsional movements of the eyes are generated by vestibular control centers, suggesting that EIE may also arise subcortically within prenuclear visual pathways that directly modulate by visual motion input [10].

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Fig. 17.1  Essential infantile esotropia. Note tonic nasalward deviation of both eyes

The dissociated binocular rotations that accompany EIE are directionally driven by unequal binocular visual input to the two eyes [7]. Each of these movements have precise analogs in lower lateral-eyed animals, and the subcortical neuroanatomical pathways for all of these movements are well-established [7]. For example, MNTA underlies the clinical phenomenon of latent nystagmus in humans [6, 22, 35] while dissociated vertical divergence conforms to a human dorsal light reflex [7]. The expression of these atavisms suggests that this subcortical visual motion circuitry is integral to the pathogenesis of EIE [9, 10].

Evolutionary Basis of Essential Infantile Esotropia (EIE) The fundamental evolutionary clue to the pathogenesis of EIE lies in the ubiquitous finding of monocular nasotemporal asymmetry (MNTA) to horizontal optokinetic stimuli. Patients with infantile esotropia show brisk nasalward, and absent temporalward optokinetic responses [6, 22, 35, 40, 42]. This MNTA persists throughout life after surgical realignment of the eyes. Although it can be measured electrophysiologically within the visual cortex this horizontal optokinetic asymmetry is found in most lateral-eyed afoveate animals and used for the detection of fullfield optokinetic flow [27, 28, 36, 41]. It is modulated by the nucleus of the optic tract and the dorsal terminal nucleus of the accessory optic system (NOT-DTN) within the midbrain [28, 41]. In lateral-eyed animals, these centers generate visuo-­ vestibular eye movements by sending visual motion signals through the vestibulocerebellum to the vestibular nucleus, which rotates the eyes at the appropriate speed and direction to minimize retinal slip [1, 2, 13, 24]. These visuo-vestibular pathways may continue to remain operational in humans with EIE. Phylogenetically and ontogenetically, MNTA antedates development of the visual cortex [9, 27, 36]. In lateral-eyed animals, MNTA may help to prevent temporalward optokinetic stimuli from pinning the eyes back as the animal is moving forward [28, 31, 41]. Another evolutionary advantage conferred by this reflex may derive from the fact that the nose and mouth are positioned “nasally” to the eyes, necessitating accurate nasalward optokinetic tracking as the animal turns toward

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potential food substances seen by either eye. During this turning movement, the opposite eye is subjected to a temporalward full-field optokinetic stimulus that may be of different velocity (when objects in its field of vision are situated at a different distance). Having the eye with nasalward optokinetic input dictate the response for both eyes allows the animal to accurately track the world it is turning toward and disregard the world from which it is turning away. In normal human infants, this subcortical full-field optokinetic imbalance is evolutionarily retained and expressed within the first few months of life. Phylogenetically, this persistence of MNTA in EIE represents another atavism. Ontogenetically, EIE often develops during the time period when the subcortical motion pathways are normally turned off (i.e., 3–6 months of age). This time course is often taken as evidence that EIE must be cortical in origin, but it could also signify that EIE represents a state of extended subcortical neuroplasticity [7].

 euroanatomy of Monocular Nasotemporal N Asymmetry (MNTA) The diagram (Fig. 17.2) shows the neuroanatomy of MNTA in lateral-eyed animals [1, 2]. The subcortical motion pathways are normally operative in the early months of human infancy [4, 5]. In EIE, investigators have studied and characterized the secondary aberrations within the motion pathways of the visual cortex. However, the innervational changes that generate esotonus in early infancy probably arise from within subcortical motion pathways that remain functional in humans that develop EIE [10]. In Fig. 17.2, the left eye is receiving nasalward optokinetic input, which crosses through the chiasm to the right NOT and DTN of the AOS. These structures respond to rightward optokinetic input (nasalward for the left eye), and project their output signal to the dorsal cap of the inferior olive, which acts as a comparator of motor commands from the cerebral cortex and brainstem nuclei and feedback from receptors via the spinal cord, visual system, and vestibular organs. The inferior olive relays gated information to the cerebellar flocculus, which processes visuo-vestibular input [1, 2, 13, 24]. The cerebellar flocculus sends its output signal to the vestibular nucleus, which integrates visual motion input from the eyes with head motion input from the labyrinths. The vestibular nucleus provides a prenuclear signal to the ocular motor nuclei, which innervate the appropriate extraocular muscles to minimize retinal slip.

 vidence for a Subcortical Pathophysiology in Essential E Infantile Esotropia (EIE) How could persistence of subcortical MNTA lead to the development of EIE? Beginning at 2–3 months of age, binocular cells from the visual cortex, which are bidirectionally sensitive to horizontal optokinetic motion, begin to establish connections to the NOT-DTN, allowing foveal pursuit to override the monocular

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EOM

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Fig. 17.2  Schematic diagram depicting the optokinetic system in the right half of the brain during leftward rotation of the visual world (i.e., nasalward for the left eye). Bold lines depict nasalward subcortical optokinetic pathways mediated by the nasal retina of each eye. Dashed lines depict temporalward optokinetic pathways mediated by temporal retina of each eye. Cer, cerebellum; dclO, dorsal cap of the inferior olive; GS, ganglion Scarpae; LGN, lateral geniculate nucleus, NOT, nucleus of the optic tract; NPH; nucleus prepositus hypoglossus; NRTP, nucleus reticularis tegmenti pontis; OMN, ocular motor nuclei; PPRF, paramedian pontine reticular formation; STS, cortical pursuit areas MT and MST; around the superotemporal sulcus; V1, primary visual cortex; VN, comlex of the brainstem vestibular nuclei. (Reproduced with permission from Behrens et al. [2], Springer-Verlag, 1989)

subcortical optokinetic bias. By 6 months of age, monocular horizontal responses to optokinetic stimuli become symmetrical. According to the Hoffmann hypothesis [17–19], when the development of cortical binocular vision is preempted, no binocular corticotectal connections are established because there are no binocular cells in V1. And because “neurons that fire together wire together” [16], only the crossed nasal fibers from the left eye can stream through the right visual motion cortex (MT/ MST) to hook up to the right NOT-DTN, because these are the pathways that have the same directional sensitivity. So the visual motion cortex becomes an extension of the subcortical optokinetic system. Thus, while the visuo-vestibular pathways are normally subsumed by the cortical pursuit system in humans, EIE effectively causes

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the opposite to occur, resulting in a motion visual cortex that is reconfigured to match the directional template of the subcortical visual pathways. The electrophysiologic and perceptual detection of cortical motion asymmetries within the visual cortex of patients with EIE [23, 30, 39], has unfortunately led to the dogmatic conclusion that EIE must be caused by a primary problem within the visual cortex [38]. However, these findings are exactly what you would see if the cortical foveal pursuit pathways secondarily reconfigured themselves to match the preexisting subcortical template for full-field OKNs. This ontogenetic retrofitting of cortical horizontal motion pathways establishes a modified circuit wherein the human subcortical motion pathways can be driven “top-down” by nasalward foveal pursuit pathways within the visual cortex (mainly MT but also MST) [19]. When this occurs, MNTA can be secondarily driven through the visual cortex. Consequently, the cortical suppression of one eye that accompanies EIE can trigger subcortical visual reflexes such as latent nystagmus and dissociated vertical divergence [7, 21]. So although you can detect evidence of MNTA within the motion pathways of the visual cortex, this is likely the effect, rather than the cause, of the problem. The primary cause lies within the subcortical visual motion circuitry. This transposition of cause and effect is the major conceptual oversight in the cortical model of EIE.  Infantile esotropia does not require a primary defect in binocular vision. Indeed, there is no evidence that one exists.

Potential Role of Prolonged Subcortical Neuroplasticity The human subcortical full-field optokinetic system remains operational within the first few months of human life [4, 5], (when MNTA is normally detectable in infancy). As cortical binocular vision matures, symmetrical horizontal optokinetic responses develop [3, 22]. Since subcortical motion pathways normally shut down as cortical motion pathways develop, one could question whether the persistence of subcortical reflexes could be a secondary consequence of a primary dysgenesis within the visual cortex. The fact that the retinotectal pathways normally shut down at approximately the same time as the binocular cortical pursuit pathways become established certainly makes it plausible that their corticotectal connections with NOT-DTN provide a contributory signal to inactivate them. However, there is evidence that the subcortical pathways do not remain active in the absence of cortical binocular vision [29]. Infants with homonymous hemianopia due to early unilateral hemispherectomy, for example, do not continue to express MNTA to full-field optokinetic input beyond first few months of life [29]. This observation suggests that subcortical pathways may have a predefined period of plasticity that causes them to shut down after several months of infant life, regardless of whether functioning binocular cortical pursuit pathways can establish corticotectal connections with the NOT-DTN.  There is something unique in children with EIE that permits subcortical motion pathways within the human accessory optic system to remain operational [8]. A mutation or metabolic perturbation within

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the subcortical pathways could also enhance their neuroplasticity and preserve their function throughout life, increasing baseline esotonus and derailing binocular alignment to necessitate a secondary remodeling of the visual cortex, which could then serve to further perpetuate their function. Although corticofugal output can influence subcortical plasticity in the mature mammalian visual motor system [25], any direct role of normal corticotectal connections in extinguishing the subcortical visual motion pathways in human infancy remains to be established.

An Optokinetic Etiology for Essential Infantile Esotropia (EIE)? If persistent MNTA represents a state of enhanced subcortical neuroplasticity, can simultaneous subcortical optokinetic input from both nasal retinas drive the eyes into an esotropic position? In lateral-eyed animals, the answer is yes. Under real world conditions, a lateral-eyed animal only rarely receives simultaneous nasalward optokinetic flow when it moves backward in space. But in the laboratory, disconjugate full-field optokinetic input to both eyes can generate esotropia (nasalward optokinesis) or exotropia (temporalward optokinesis). This phenomenon has been demonstrated in rabbits [15], and more recently in zebrafish (Video 1 in the online version at https://doi.org/10.1016/bs.pbr.2019.04.001) [33]. So binocular nasalward optokinetic input has the potential to drive the eyes into an esotropic position. Although binocular MNTA has been speculated to cause EIE at the level of the visual cortex [38], the nasal retina of the esodeviated eye is cortically suppressed, so the two eyes cannot generate simultaneous cortical responses. But at the subcortical level, there is no interocular suppression [12]. So both eyes can be pulled in simultaneously, just like in fish and in rabbits. Although monocular fixation with either eye may be integral to the pathogenesis of EIE [11], a stable esotropia soon persists during nonfixation, demonstrating how this subcortical binocular nasalward drive can be maintained by simultaneous full-field viewing with both eyes. This mechanism would require that the subcortical optokinetic system remain operational despite cortical suppression of the esodeviating eye. Figure 17.3 juxtaposes the proposed subcortical and cortical mechanisms of pathogenesis for EIE.

Conclusion EIE conforms to a state of extended subcortical neuroplasticity in which subcortical visual pathways fail to shut down within the third month of life, allowing an early subcortical nasalward optokinetic bias to simultaneously drive the eyes into an esodeviated position. When this occurs, the cortical motion pathways may secondarily reconfigure themselves to this monocular subcortical template. Some forms of EIE (those secondary to a motor impedance of binocular fusion) may actually correspond to a genetic mutation or perturbation that extends subcortical neuroplasticity. If so, then EIE would simply represent a default to an older ocular motor

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control system that retains its neuroplasticity and continues to be expressed. Accordingly, as the visual cortex becomes monocular, the subcortical visual motion system may become binocular [7, 10, 34], meaning that both nasal retinas are simultaneously activated at the subcortical level to drive the eyes inward to generate EIE. Neural integration or set-point adaptation [43] may then reestablish a stable esodeviation of the eyes. Based upon this analysis, we should consider the possibility that EIE is subcortical in origin, and that its associated cortical motion asymmetries may be the inevitable effect, rather than the underlying cause, of early binocular misalignment. Accordingly, EIE can be conceptualized as a kind of evolutionary footprint, wherein the two nasal retinas are repositioned into the frontal plane, but they continue to do the same thing as in lateral-eyed animals. In humans, this positional reconfiguration solves a practical problem by restoring horizontal optokinetic bidirectionality. Whichever direction a target an object is moving, the child can effectively follow it with the eye that is receiving nasalward optokinetic input. This explains why a spontaneous fixation switch can be elicited by directional reversal of horizontal optokinetic motion in children with EIE [12]. As we learn more about mechanisms of subcortical neuroplasticity, we may come to understand EIE as another inevitable expression of our ancestral visual pathways within basement of the brain. Pathogenesis of Infantile Esotropia SUBCORTICAL Visuovestibular System (Full-Field, Afoveate)

CORTICAL Nascent Pursuit System (Cortical, Foveate)

NOT-DTN AOS

MT/MST MNTA

MNTA MT/MST

EIE/LN

Maturation of Horizontal Cortical Pursuit

Cortical Disinhibition of Convergence

Maturation of Cortical Pursuit

Horizontal Alignment Single Binocular Vision Fusion Stereopsis

Cortical Inhibition of Convergence

Fig. 17.3  Flow chart juxtaposing primary subcortical and cortical mechanisms for development of EIE. MNTA, monocular nasotemporal asymmetry; AOS, accessory optic system; DTN, dorsal terminal nucleus of the accessory optic system; EIE, essential infantile esotropia; LN, latent nystagmus; MST, medial superior temporal area; MT, middle temporal area; NOT, nucleus of the optic tract

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References 1. Behrens F, Grusser O-J. The effect of monocular pattern deprivation and open-­ loop stimulation on optokinetic nystagmus in squirrel monkeys (Saimiri sciureus). In: Flohr H, editor. Post-Lesion Plasticity. Berlin: Springer; 1988. p. 453–72. 2. Behrens F, Grusser O-J, Roggenkämper P. Open and closed-loop optokinetic nystagmus in squirrel monkeys (Saimiri sciureus) and in man. In: Allum JHJ, Hulliger M, editors. Progress in Brain Research, vol. 89. Amsterdam: Elsevier; 1989. p. 183–6. 3. Braddick O. Where is the naso-temporal asymmetry? Curr Biol. 1996;6:274–81. 4. Braddick O, Atkinson J.  Development of human visual function. Vis Res. 2011;51:1588–609. 5. Braddick O, Atkinson J, Wattam-Bell J. Normal and anomalous development of visual motion processing motion coherence and ‘dorsal-stream’ vulnerability. Neurophsychologia. 2003;41:1769–84. 6. Brodsky MC.  Latent nystagmus: vestibular nystagmus with a twist. Arch Ophthalmol. 2004;122:202–9. 7. Brodsky MC. Visuo-vestibular eye movements: infantile strabismus in 3 dimensions. Arch Ophthalmol. 2005;123:837–42. 8. Brodsky MC. The accessory optic system: the fugitive visual control system in infantile strabismus. Arch Ophthalmol. 2012a;130:1055–9. 9. Brodsky MC.  An expanded view of infantile esotropia: bottoms up! Arch Ophthalmol. 2012b;130:1199–202. 10. Brodsky MC.  Essential infantile esotropia: potential pathogenetic role of extended subcortical neuroplasticity. Invest Ophthalmol Vis Sci. 2018;59:1964–8. 11. Brodsky MC, Fray KF. Does infantile esotropia arise from a dissociated deviation? Arch Ophthalmol. 2007;125:1703–6. 12. Brodsky MC, Klaehn LD. An optokinetic clue to the pathogenesis of crossed fixation in infantile esotropia. Ophthalmology. 2017;124:272–3. 13. Buttner U, Boyle R, Markert G, et al. Cerebellar control of eye movements. In: Freund HJ, Buttner U, Cohen B, Noth J, editors. Progress in Brain Research. Amsterdam: Elsevier; 1986. p. 225–33. 14. Campos EC. Why do the eyes cross? A review and discussion of the nature and origin of essential infantile esotropia, microstrabismus, accommodative esotropia, and acute comitant esotropia. J AAPOS. 2008;12:326–31. 15. Collewijn H.  The oculomotor system of the Rabbit and its plasticity. Berlin/ Heidelberg/New York: Springer-Verlag; 1981. p. 67–8. 16. Hebb DO. The organization of behavior. New York: Wiley and Sons; 1949. 17. Hoffman KP. Neural basis for optokinetic defects in experimental models with strabismus. In: Kaufmann H, editor. Transactions of the 16th Meeting of the European Strabismological Association. Giessen: Gahmig Druck Giessen; 1987. p. 35–6. 18. Hoffmann KP. Cortical vs subcortical contribution to the optokinetic reflex in the cat. In: Lennerstrand G, Zee DS, Keller EL, editors. Basis of ocular

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motility: proceedings of a Wenner-Gren Center and Smith-Kettlewell Eye Research Foundation International Symposium. New  York: Pergamon; 1982. p. 303–11. 19. Hoffmann KP, Bremmer F, Thiele A, Distler C. Directional asymmetry of neurons in cortical areas MT and MST projecting to the NOT-DTN in macaques. J Neurophysiol. 2002;87:113–2123. 20. Horwood A. Neonatal ocular misalignments reflect vergence development but rarely become esotropia. Br J Ophthalmol. 2003;87:1146–50. 21. Kommerell G. The relationship between infantile strabismus and latent nystagmus. Eye. 1996;10:274–81. 22. Kommerell G, von Noorden GK. Ocular motor phenomena in infantile strabismus: asymmetry in optokinetic nystagmus and pursuit, latent nystagmus, and dissociated vertical divergence. In: Lennerstrand G, Campos EC, editors. Strabismus and Amblyopia: Experimental Basis for Advances in Clinical Management. London: Macmillan; 1988. p. 99–109. 23. Kommerell G, Ullrich D, Gilles U, Bach M. Asymmetry of motion VEP in infantile strabismus and central vestibular nystagmus. Doc Ophthalmol. 1995;89:373–81. 24. Langer T, Fuchs AF, Chubb MC, et al. Floccular afferents in the rhesus macaque as revealed by autoradiography and horseradish peroxidase. J Comp Neurol. 1985;235:26–37. 25. Liu B, Hubermann AD, Scanziani M. Corticofugal output from visual cortex promotes plasticity of innate motor behavior. Nature. 2016;538:383–7. 26. Maconachie GD, Gottlob I, McLean RJ. Risk factors and genetics in common comitant strabismus: a systematic review of the literature. JAMA Ophthalmol. 2013;131:1179–86. 27. Masseck OA, Hoffmann KP.  Comparative neurobiology of the optokinetic reflex. Ann N Y Acad Sci. 2009;1164:430–9. 28. Miles FA. The sensing of rotational and translational optic flow by the primate optokinetic system. In: Miles FA, Wallman J, editors. Visual Motion and its Role in the Stabilization of Gaze. Amsterdam: Elsevier Science; 1993. p. 393–403. 29. Morrone MC, Atkinson J, Cioni G, et al. Developmental changes in optokinetic mechanisms in the absence of unilateral cortical control. NeuroReport. 1999;10:1–7. 30. Norcia AM. Abnormal motion processing and binocularity: infantile esotropia as a model system for effects of early interruptions of binocularity. Eye. 1996;10:259–65. 31. Ohmi M, Howard IP, Everleigh B. Directional preponderance in human optokinetic nystagmus. Exp Brain Res. 1986;63:387–94. 32. Pediatric Eye Disease Investigator Group. The clinical spectrum of early-onset esotropia. Experience of the Congenital Esotropia Observational Study. Am J Ophthalmol. 2002;33:102–8. 33. Portugues R, Feierstein CE, Engert F, Orger MB. Whole brain activity maps reveal stereotyped, distributed networks for visuomotor behavior. Neuron. 2014;81:1328–43.

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34. Ramdya P, Engert F. Emergence of binocular functional properties in a monocular neural circuit. Nat Neurosci. 2008;11:1083–90. 35. Schor CM. Subcortical binocular suppression affects the development of latent and optokinetic nystagmus. Am J Optom Physiol Optic. 1983;60:481–502. 36. Tauber ES, Atkin A. Optomotor responses to monocular stimulation. Relation to visual system organization. Science. 1968;160:1365–7. 37. Thouvenin D, Sotiropoulos MC, Arné J, Fournié PR.  Esotropias that totally resolve under general anesthesia treated exclusively with bilateral fadenoperation. Strabismus. 2008;16:131–8. 38. Tychsen L. The cause of infantile strabismus lies upstairs in the cerebral cortex, not downstairs in the brainstem. Arch Ophthalmol. 2012;130:1060–1. 39. Tychsen L, Lisberger SG.  Maldevelopment of visual motion processing in humans who had strabismus with onset in infancy. J Neurosci. 1986;6:2495–508. 40. Valmaggia C, Proudlock F, Gottlob I. Optokinetic nystagmus in strabismus: are asymmetries related to binocularity? Invest Ophthalmol Vis Sci. 2003;44:5142–50. 41. Wallmann J.  Subcortical optokinetic mechanisms. In: Miles FA, Wallman J, editors. Visual motion and its role in the stabilization of gaze. Amsterdam: Elsevier Science; 1993. p. 321–42. 42. Wright K.  Clinical optokinetic nystagmus asymmetry in treated esotropes. J Pediatr Ophthalmol Strabismus. 1996;33:99–109. 43. Zee DS, Leigh RJ. Ocular stability and set-point adaptation. Philos Trans R Soc Lond Ser B Biol Sci. 2017;372(1718):20160199.  https://doi.org/10.1098/ rstb.2016.0199.

Postscript Single binocular vision and stereopsis are known to reside within the visual cortex. By extension, essential infantile esotropia (EIE) has long been considered to be cortical in origin. This a priori assumption is seemingly corroborated by the finding of optokinetic asymmetry within cortical motion pathways. This analysis examines the alternative possibility that extended subcortical neuroplasticity can lead to EIE. It invokes the argument that persistent binocular optokinetic input at the subcortical level (i.e. monocular nasotemporal asymmetry) can drive the eyes inexorably into an esotropic position despite the presence of alternating cortical suppression. Accordingly, EIE can be genetic or epigenetic (i.e. arising experientially from early binocular misalignment) in origin. This model further invokes the mechanism proposed by Hoffmann hypothesis wherein the cortical visual motion pathways become secondarily reconfigured to match the subcortical template. Once this occurs, then cortical suppression of either eye can actively drive the dissociated eye movements that characterize EIE. Whether cortical suppression allows the subcortical motion pathways to generate these movements (Schor C: Subcortical binocular suppression affects the development of latent and optokinetic nystagmus. Am J Optom Physiol Opt 1983;60:481–502), or

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whether the remodeled cortical pursuit pathways drive the movements through the NOT-DTN has yet to be determined. Either way, the system eventually reverts to a subcortical blueprint that can now be funneled in through the visual cortex. And since the dissociated eye movements conform to the original function of the subcortical pathways, we can begin to understand how and why this cortical reconfiguration must have happened. This mechanism is likely age dependent, with subcortical pathways known to predominate within the first few months of human life, and the altered cortical motion pathways predominating later. The dichotomy between central and peripheral retina, as described by Marshall Parks (see Binocular Vision in Duane’s Clinical Ophthalmology, Lippincott, 1991) may have had its evolutionary origin in the subcortical (extrafoveal) versus cortical (foveal) visual systems. The primate visual cortex recapitulates this dichotomy in its dorsal (visual motion) and ventral (visual detail) pathways. It is critical to distinguish cause and effect in disease pathogenesis. This analysis raises the possibility that EIE may be subcortical in origin, with the cortical motion pathways becoming secondarily reconfigured to match their subcortical template. Accordingly, decreased binocularity and stereopsis that accompany EIE may be secondary rather than primary. Nevertheless, they may give rise to cortical suppression which can perpetuate EIE and its dissociated deviations. At the very least, it seems that aberrations within the subcortical and cortical visual motion pathways are both integral to the pathogenesis of EIE. Accordingly, the misguided term fusion maldevelopment syndrome should be discarded, as it connotes a chain of causation that necessarily originates within the visual cortex, and thereby converts a terminological confusion into a conceptual one.

Phoria Adaptation: The Ghost in the Machine

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Introduction I esteem it a great honor to be invited to give the 50th Scobee Lecture here in my hometown of San Francisco. Dr. Richard Scobee was revered as a consummate teacher, clinician, and diagnostician. His teachings permeate our field to such a degree that we don’t always recognize them in the fabric of what we do. Dr. Scobee served as a founding member of the American Orthoptic Council and founded the American Orthoptic Journal, which was first published in 1951, just a year before his untimely death. His definitive textbook, The Oculorotary Muscles [2], provided the foundation for the field of orthoptics, and created a cogent framework for what was to become an emerging field of study. So it was nice that, while preparing this lecture, so many of Dr. Scobee’s seminal observations seemed to resurface within a new context. I hope that my choice of topics helps to carry the torch and honor his memory. A phoria refers to any deviation of the eyes from one of alignment (orthophoria) when binocular visual input is preempted [3]. Strabismus occurs when a phoria persists under binocular conditions, resulting in a manifest deviation (a tropia). Strabismus surgery is predicated on the notion that alternate occlusion unmasks the underlying phoria. By targeting surgical dosing to the measured phoria, the resting position of binocular alignment can be reset to near zero, allowing fusion to actively maintain binocular alignment. As pointed out by Lancaster, it is tacitly assumed that the resting deviation when the fusion reflex is preempted (i.e. under conditions of monocular fixation) is identical to the resting deviation when the fixation reflex is prevented in both eyes. A recent study has shown this to be the case for humans with normal binocular vision (Brodsky) [4]. Despite the fact that our eyes stay straight, binocular vision is not a static function [5]. Maintaining binocular vision is a dynamic force, controlled by both momentary peripheral fusion (termed motor fusion), tonic vergence, and vergence adaptation (termed phoria adaptation) that provides the necessary neural integration to minimize the baseline phoria and thereby stabilize binocular vision. Changes © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_18

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in vergence consist of a fast phasic response followed by a slow tonic response. Alternate occlusion represents the elimination of fast fusional vergences, which must then be followed by a longer decay of the slow fusional vergence response [6]. A prism bar measures step-like changes which is more reflective of the rapid phasic response while synoptophore testing measures the slow tonic response.

What Is Phoria Adaptation? Phoria adaptation is the slow buildup of tonic vergence innervation to establish and sustain a new vergence set point following placement of a prism over one or both eyes [7–10]. Phoria adaptation recalibrates extraocular muscle tonus to realign the visual axes and thereby meet the demands of binocular alignment [11], and restore the dynamic range (or fusional reserve) in which fast fusional vergence can function [12]. Phoria adaptation resets binocular alignment toward orthophoria; thereby compensating for developmental, environmental, or pathologic alterations in the binocular mechanism [12]. Because phoria adaptation is stimulated by the effort put forth by the fast fusional vergence system, repeated tests of fusional amplitude will increase the limits of fusional movement [13, 14]. After removal of a prism, the rate of disappearance of this change in tonus is inversely proportional to the length of time this tonicity is maintained [6, 8, 13, 14]. Clinical investigation into phoria adaptation as a malleable but invisible force encompasses the history of pediatric ophthalmology, capturing the interest of many progenitors of our field such as Hering [15], Maddox [16], Hofmann and Bielschowsky [1, 17], Ogle [18, 19], Reinecke [10], and Guyton [20]. Its slow time decay was characterized by Hofmann and Bielschowsky over a century ago [1, 6, 9, 20]. Phoria adaptation provides an innervational repository to modulate vergence tonus to stabilize horizontal, vertical, and torsional binocular alignment [21]. Phoria adaptation serves to establish a new equilibrium as the starting position for further vergence eye movements and thus decreases the effort for either convergence or divergence eye movements [22]. This resiliency and tenacity means that a measured phoria can change transiently following active vergence effort [5, 13, 14]. Because of its lingering effects, however, phoria adaptation can alter measurements of both vergence ranges (which reflect activity of both the fast and the slow vergence system) and also of vergence facility (which examine the patient’s ability to shift rapidly between divergence and convergence as a function of the fast fusional vergence system) [7, 23]. For this reason, phorias are routinely measured before vergence amplitudes are measured [6]. Although phoria adaptation is classically elicited by introducing prisms before one eye to induce a vergence error, this compensatory mechanism can insinuate itself into many forms of intermittent strabismus. Because phoria adaptation has a memory, its slow dissipation serves to mask or conceal a large phoria on clinical examination [17]. Phoria adaptation operates independently of the fast vergence system and thereby minimizes the fixation disparity that results in the need for vergence control [9, 18]. Ogle and Prangen found that an increase in slow fusional vergence was

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accompanied by a reciprocal reduction in fast fusional vergence [19]. However, these two complementary systems may exist on a spectrum wherein some individuals who use disparity as a primary driver of fusional vergence show larger phorias and less inherent capacity for phoria adaptation, while others show strong phoria adaptation and minimal disparity-driven vergence (written communication, Anna Horwood, July 20, 2017).

Stimulus for Phoria Adaptation Binocular disparity does not generate phoria adaptation. There is always binocular disparity in a complex world (in different planes even when the eyes are aligned), and this binocular disparity is a necessary stimulus for stereopsis. While binocular retinal image disparity provides the stimulus for the fast fusional vergence system, it is the motor signal from the fast fusional vergence system that serves as the error signal for phoria adaptation [5]. The input to the slow neural integrator for phoria adaptation is generated by the output or effort of fast fusional vergence. Because there has to be an effort to fuse for phoria adaptation to be recruited, fixation disparity induced by a conflict in vergence and accommodation may provide a driving stimulus for prism-induced phoria adaptation [9] (Fig. 18.1). The fast vergence system has a neural integrator with a short halflife of 10–15 s [7, 14]. By contrast, phoria adaptation consists of a more stable neural integrator that leaks with a much longer time constant (varying from minutes to several days) [5, 9]. The output of the slow neural integrator allows for a reciprocal reduction of the output of fast fusional vergence by means of the negative feedback loop in which the system is trying to adapt until the phoria is controlling the entire response [9]. As the slow fusional vergence system charges up, the fast fusional vergence system decays to maintain a constant total output [6, 7]. This feedback loop presumably reduces the fatigue and eyestrain that would result from the prolonged use of the fast vergence system [7–9].

Measurement of Phoria Adaptation Phoria adaptation can be estimated but not precisely quantified, due in part to the fact that it is slower to dissipate after an extended period of fusional demands [6, 9, 13, 17]. Measurement of fusional vergence amplitudes using a prism bar placed before one eye under binocular conditions and prolonged monocular occlusion are two examination techniques that help to uncover the degree to which phoria adaptation is operative [9]. Depending on the preexisting level of phoria adaptation, prism bar testing can serve to induce or dissipate phoria adaptation (a critical distinction not determinable by the examiner), whereas prolonged occlusion removes the input of disparity vergence and presumably dissipates any preexisting phoria adaptation. Although monocular occlusion may dissipate phoria adaptation, it remains unclear whether prism bars and monocular occlusion operate by equivalent mechanisms and produce similar endpoints, since monocular occlusion seems to exert other

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Ac Target binocular paraliax

+

FD

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+

Fast fusional vergence

Tc

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+ Pc

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+ +

Vergence response

Phoria adaptation

Fig. 18.1  Diagram depicting feedback interaction between slow and fast fusional vergence. The fast fusional vergence system uses binocular retinal image disparity as its input signal. Phoria adaptation uses the motor output of the fast fusional vergence system as its error signal to reset tonic vergence and reduce fixation disparity. The output of this slow neural integrator then allows for reciprocal reduction of fast fusional vergence by means of a negative feedback loop to keep the final innervational output constant

effects that go beyond disrupting fusional vergence and dissipating phoria adaptation (similar to those of Marlow occlusion) [6, 24]. Monocular occlusion may also disrupt other adaptive processes that have different time constants.

Resilience of Phoria Adaptation In patients with intermittent strabismus, phoria adaptation seems to operate most effectively at fixation distances that place binocular alignment within its range [25]. It can also correct different degrees of deviation in different fields of gaze [20, 21, 25, 26]. This phenomenon explains patients ready adjustment to the prismatic effects of anisometropic spectacles in different fields of gaze [6, 27–30]. The finding that noncomitant vertical phoria adaptation dissipates much more quickly than comitant phoria adaptation (31 min versus 83 min) [31], demonstrates the coexistence of both global and local mechanisms that subserve phoria adaptation, each having different capabilities and time courses of action [5, 26].

Time Course of Phoria Adaptation Phoria adaptation begins to initiate quickly but builds and dissipates more slowly [1, 6, 9]. Even brief presentations of small disparities may be enough to alter phoria adaptation [14]. Estimates for initiation have ranged from as little as 100 ms to 30  min of binocular visual experience [9, 32, 33]. These wide ranges probably reflect some degree of immediate initiation followed by a slower buildup period [7]. According to Henson and North, phoria adaptation is substantially complete after 2–3  min of binocular visual experience [33]. An earlier study by Ogle et  al. had found that vertical prism adaptation was complete within 3–7  min and that

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adaptation followed a logarithmic curve [18]. A larger prism takes longer to adapt to but does not increase adaptation time in a linear manner [7]. However, the rate at which phoria adaptation dissipates varies considerably, ranging from 30 s in some individuals to several days in others [7]. This measured variability may in part reflect the inherently different time constants for phoria adaptation between individuals, as well as the inverse correlation between the degree of phoria adaptation and the duration of the previous vergence effort [7, 13, 34]. Rosenfield et al. found that 20 min of monocular occlusion was sufficient to estimate the latent deviation [35]. However, a longstanding phoria adaptation may require hours to fully dissipate [5, 31, 36–38].

Protean Clinical Manifestations Phoria adaptation infuses our binocular alignment with a kind of inertia [13], which can corrupt or override our clinical measurements. Conversely, when phoria adaptation is fully operational, the phoria that we measure with prism and alternate cover testing can be spuriously low. Prolonged patching often increases the measured deviation by breaking down phoria adaptation to reset binocular misalignment toward its uncompensated value. Phoria adaptation comes in many guises, with clinical effects that are much more protean than generally appreciated. What follows are some examples of conditions in which alternate cover testing of the phoria measurement fails us when the superimposed effects of phoria adaptation are not recognized. 1. Stillness: Over a century ago, Sherrington remarked that “The role of muscle as an executant of movements is so striking that its office in preventing movement and displacement is somewhat overlooked” [39]. An overlooked but essential quality of phoria adaptation is the stillness that it confers upon our binocular alignment. While friction accounts for the stillness of many inanimate objects, stillness is a formidable task for biological systems. As articulated by Carpenter: “Why do we take stillness so much for granted? … That while a muscle is maintaining a constant length and thus doing no work, the actin-myosin bonds between the sliding filaments are ceaselessly breaking and reforming, consuming ATP and so wastefully turning precious energy into heat rather than work. To maintain a stationary gaze demands that the brain sends continual commands to the contractile fibers in the ocular muscles and poses as many problems as moving the eyes fast. Thus, stillness is not an easy task” [40]. In fact, biological systems are never truly still, as evidenced by the tiny fixational intrusions which promote stability of visual perception via the Troxler phenomenon [41]. Phoria adaptation also explains the recent observation that the brain does not require visual input to maintain binocular alignment in the dark on a short-­ term basis [4]. 2. Orthophorization: Despite the baseline divergent anatomical position of the eyes within the orbits, normal humans have little or no measurable horizontal phoria on alternate cover testing [10]. Phoria adaptation provides the interstitial

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force to maintain approximate orthophoria, which explains why “distance phorias are not normally distributed but instead showed abnormally high clustering near orthophoria prior to an extended period of monocular occlusion” [6]. An extended period of reading prior to a phoria measurement may generate a more convergent phoria [14]. 3. “Latent” phoria: When measuring a binocular deviation with progressive prisms, neutralization frequently occurs long before the deviation can be reversed with a stronger prism. This finding of a “latent phoria” probably reflects the hidden presence of phoria adaptation [1, 6, 14]. It is therefore customary to assign the value of the full deviation to the maximum measured angle that produces no reversal of the initial deviation. When we say “This patient has a small intermittent exotropia that slowly builds to 35 prism diopters,” we are tacitly acknowledging the effects of phoria adaptation. 4. Accommodative esotropia: Phoria adaptation may mask the true esodeviation in children with accommodative esotropia, who are known to “eat up prisms,” meaning that when temporary prisms are placed on top of the full cycloplegic refraction to neutralize the esodeviation, a portion of the esodeviation will slowly recur through the prismatic correction. Accordingly, surgery based on the initial measurements may lead to undercorrection [42]. In this setting, it is unknown whether phoria adaptation unmasks the full esodeviation or whether it actively generates a larger esodeviation [43]. There is further controversy as to whether the robust prism adaptation response in accommodative esotropia reflects or requires the presence of anomalous retinal correspondence [44]. Some children with accommodative esotropia have a greater esodeviation at near, associated with a high AC/A ratio or convergence excess. Nevertheless, strabismus surgery targeted to the larger near esodeviation does not produce surgical overcorrection of the distance esodeviation. This finding suggests that the measured distance deviation is artificially low, a finding which implicates phoria adaptation [6, 12]. The recent finding that both prism adaptation and prolonged monocular occlusion can increase the distance deviation further supports this notion [45, 46]. So phoria adaptation may explain why you can target surgery for the near deviation and not overcorrect for distance. Although phoria adaptation is a disparity-driven response, vergence aftereffects can also adapt to accommodative vergence (and vice versa), demonstrating a versatile complementary crosslinking and plasticity between the tonic vergence and accommodative systems to match changing demands [47–49] (Fig. 18.2). Thus, in some people (like those with accommodative esotropia), accommodation drives vergence to produce an AC/A ratio while in others (like those with intermittent exotropia), convergence drives accommodation to produce a CA/C ratio [12]. Phoria adaptation can sometimes result from sustaining a vergence effort for as little as 30 s [5]. “Cellphone vision,” which follows prolonged reading of small font at close range, causes distant objects to appear distorted (not quite blurred but not quite double) for several minutes. This symptom may be driven by the

Protean Clinical Manifestations

Phoria adaptation

Accommodative esotropia – + Diopters

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Blur

Accommodation

++

++ CA/C

Target distance Angle +

– Intermittent exotropia

Distance realignment

AC/A Disparity

Convergence

+

+ ++

Near realignment

Phoria adaptation

Fig. 18.2  Diagram depicting the general mechanism of phoria adaptation as it influences vergence-­accommodation interaction. Blur-driven accommodation implements a similar neural integrator as does disparity-driven vergence to program tonicity. Note the cross-linking that generates accommodation-linked convergence (AC/A) and convergence-linked accommodation (CA/C). For both convergence and for the accommodative system, the fast system provides the immediate phasic response to a change in disparity or blur. The tonic adaptation uses the motor output of the fast system to provide a slower adjustment in the tonic level of accommodation or vergence. In both systems, phoria adaptation is driven by the motor signal and not by sensory input to the motor signal. And in some people (like those with accommodative esotropia), accommodation drives vergence to produce an AC/A ratio while in others like those with intermittent exotropia, convergence drives accommodation to produce a CA/C ratio. Phoria adaptation explains why strabismus surgery targeted for the distance deviation does not overcorrect the near deviation in intermittent exotropia, and why strabismus surgery targeted to the near deviation does not overcorrect the distance deviation in accommodative esotropia. (Reprinted from Ref. [12], with permission)

transitory effects of phoria adaptation, which throws the vergence system into disarray by causing an esophoria, perhaps contributed to by the secondary effects of tonic accommodation [49]. 5. Intermittent exotropia: Patients with intermittent exotropia display a greater distance than near exodeviation on initial alternate cover testing. It was Scobee who noted that the near exodeviation usually increases to approximate the distance exodeviation after 45  min of monocular occlusion [2]. This “tenacious proximal fusion” [50] reflects the role of phoria adaptation, which impedes expression of the full near exodeviation [12]. Although it is generally believed the presence of large convergence amplitudes are necessary to control intermittent exotropia, it may be that phoria adaptation serves this function [12], which would explain why correlative fusional convergence amplitudes (i.e. equal to the amplitude of the exodeviation plus superimposed convergence amplitudes) are no longer detectable immediately following surgical correction of the exodeviation (Fig.  18.2). So phoria adaptation also explains why we can target surgery for the distance deviation and not overcorrect the near deviation (except in the rare patients who have a true high AC/A ratio).

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Prism adaptation or prolonged monocular occlusion can also increase the measured angle in patients with intermittent exotropia and more accurately direct surgical dosing [51–53]. However, its use as a stand-alone treatment to reduce hemiretinal suppression and restore binocular control in intermittent exotropia has never met with success, perhaps owing to the correlative dissipation of phoria adaptation that ensues. While some patients with intermittent exotropia immediately break down to their full deviation (indicating control by fast vergence), others break down slowly with prism and alternate cover testing, suggesting that phoria adaptation is being used to control the deviation. The prognosis for relative postoperative control in these two overlapping groups is unknown. 6. Congenital superior oblique palsy: Patients with congenital superior oblique palsy are said to have “increased fusional vergence amplitudes,” meaning that these patients will “eat up prisms” and show a large induced vertical deviation when a base down prism bar is increased progressively before the paretic eye. This stepwise dissipation of fusional control to yield a measured deviation far beyond the normal range of vertical divergence probably reflects the slow dissipation of phoria adaptation [6, 54]. As with intermittent exotropia, these “increased vertical fusional amplitudes” disappear immediately following successful strabismus surgery, signifying that phoria adaptation rather than peripheral fusion was masking the true hyperdeviation. 7. Postoperative prism adaptation: When performing strabismus surgery in adults who have worn prisms to treat diplopia, we admonish them to discontinue their prism glasses postoperatively [6, 8]. We do this not only to prevent postoperative diplopia, but to prevent a prism-induced recurrence of the deviation. Instructing patients not to wear their prisms after strabismus surgery betrays an unconscious awareness of phoria adaptation. 8. Physiologic skew deviation: Despite the predicted effects of otolithic input to the extraocular muscles, normal binocular individuals have no measurable hyperphoria during head tilt to either side [55]. Phoria adaptation may provide the “antivestibular” force that maintains orthophoria during head tilt. Despite its slow decay, it retains a fluidity which allows it to kick in to different degrees in different fields of gaze. This is not surprising since the vestibular system and the binocular system each rely upon a central neural integrator with a slow decay (velocity storage for the vestibular system and phoria adaptation for the eyes) to produce a perseverative signal that stabilizes balance and perception. This interconnection may explain why phoria adaptation can modify vestibulo-ocular adaptation [56] and vice versa [5, 57]. As pointed out to me by Cameron Parsa, MD, and Stephen Archer, MD, many patients have tiny amounts of skew deviation (on the order of 1–2 PD) yet they are unable to fuse it, and they do not prism adapt when a vertical prism is used to eliminate the diplopia. So the central vestibular pathways that generate skew deviation may also be integral to the pathogenesis of phoria adaptation. 9. Fusional vergence amplitudes: As divined long ago by Ogle et  al., phoria adaptation is not a measure of fusional reserves, since the same fusional reserves

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are measurable before and after adaptation [18]. Strong evidence for this mechanism for phoria adaptation is evident in patients with intermittent exotropia as well as those with congenital superior oblique palsy. Phoria adaptation can create the false appearance of large fusional vergence amplitudes when it masks a latent phoria [14]. Phoria adaptation explains why the measured divergence break and recovery points are lower when tested after convergence [7, 23, 58–60]. It also explains Scobee’s observation that fusional vergence amplitudes, as measured at near, seem to correlate with the horizontal phoria measurement as measured at distance [61]. Scobee found that patients with greater amounts of exophoria at distance tend to have greater amounts of measured fusional divergence at near, while patients with esophoria at distance tend to have smaller amounts of prism divergence at near. Thus, the slow dissipation of phoria adaptation is indistinguishable from the measurement of fusional divergence amplitudes. 10. Spread of comitance: Although we generally attribute spread of comitance to extraocular muscle contracture, phoria adaptation can initiate and perpetuate spread of comitance long before extraocular muscle contracture develops [22, 25, 26, 31]. For example, Kolling et al. found that prolonged occlusion restored incomitance in patients with superior oblique palsy and spread of comitance [62]. Similarly, the esodeviation in sixth nerve palsy may become more comitant over time, a phenomenon sometimes attributed to ipsilateral medial rectus contracture. However, medial rectus contracture should produce a spread of incomitance. So this paradoxical spread of comitance is more likely attributable to phoria adaptation, which can vary in different fields of gaze. As emphasized by Guyton [20], phoria adaptation can eventuate in muscle length adaptation and secondary anatomical extraocular muscle contracture.

Neural Substrate Phoria adaptation has been considered by some [10, 63], but not others [64], to be a cerebellar response, but midbrain vergence-related neurons may also play a role [65]. Visual adaptations to reversing prisms in the cat are preempted by lesions in the vestibulocerebellum [66]. In monkeys, removal of the cerebellar vermis (but not the flocculus) has been shown to disrupt phoria adaptation [67, 68]. When prisms are placed before one eye of an orthotropic patient, the visual image discordance is interpreted as an error signal. Adaptation and learning to correct motor error signals is modulated at the level of the vestibulocerebellum [10, 69]. It, therefore, seems likely that phoria adaptation is similarly mediated by both climbing and mossy fibers within the cerebellum, which implement modifiable, adaptive, and “plastic” responses [10] (Fig.  18.3) [70]. The cerebellum receives continuous information via the mossy fiber system. The climbing fiber system originates from the inferior olivary nucleus and provides a powerful timing and error signal to Purkinje cells. The inferior olivary nucleus acts as a comparator of motor commands from the cerebral cortex, brainstem nuclei and receives feedback from

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Inhibitory interneuron Parallel fiber

Purkinje cell

Granule cell Deep cerebellar nucleus

Climbing fiber

Mossy fiber Inferior olive Phoria adaptation Tonic vergence innervation

Binocular alignment

Fast vergence motor error signal

Fig. 18.3  Diagram depicting cerebellar candidate pathways for the modulation of phoria adaptation. Complex spikes from mossy fibers transmit ongoing vergence information from the two eyes while slow simple spikes from climbing fibers input through inferior olive provide the error signal to modulate Purkinje cell output to the deep cerebellar nuclei and generate phoria adaptation. (Modified from Ref. [70], with permission)

receptors via the spinal cord, visual system, or vestibular organs. The inferior olive senses the error and recalibrates the tonic firing of the Purkinje cells. The increased frequency of inferior olivary nucleus discharge and complex spikes in the Purkinje cells triggers long-term depression of the synapse between the parallel fibers and the Purkinje cells, thereby resetting the single spike discharge rate to produce the necessary motor learning and adaptation. The Purkinje cell provides profound inhibition via GABA to the cerebellar nuclei, which provide the output of the cerebellum. It is therefore likely that the neural circuitry subserving phoria adaptation is not localized to a specific area but modulated by cortical, midbrain, and cerebellar circuitry [10, 65, 66].

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Future Questions Is there a critical time period for the development of phoria adaptation? Could deficient phoria adaptation (due to a leaky neural integrator) engender some common forms of strabismus? [6, 8, 71, 72] Can hemiretinal suppression impede phoria adaptation to allow intermittent deviations to perpetuate with time? [25] Since horizontal phoria adaptation is stronger in the convergent direction [6, 9, 73], could phoria adaptation function as an on-off system rather than a push-pull system? Accordingly, could accommodative esotropia reflect a state of augmented phoria adaptation (driven by the accommodative cross-linkage instead of by vergence input), and intermittent exotropia reflect a state of deficient phoria adaptation? Do measured horizontal fusional divergence amplitudes simply represent the dissipation of horizontal phoria adaptation rather than the effects of an active divergence mechanism? Is deficient phoria adaptation associated with specific symptomatology? [8] Conversely, could some patients grow sensorially accustomed to a high level of phoria adaptation and feel subjectively uncomfortable when strabismus surgery removes the need for it? Do prism adaptation and prolonged monocular occlusion ultimately uncover the effects of phoria adaptation to the same extent? Should strabismus surgery be calibrated according to the measured phoria or to the deviation produced by the induced phoria adaptation? Does phoria adaptation supersede dissociated esotonus following surgical realignment of the eyes? Are the horizontal, vertical, and torsional components of phoria adaptation [25] anatomically segregated but mediated by the same final common pathways? Can a focal neurological lesion selectively disable a single component of phoria adaptation?

Conclusions Phoria adaptation provides the central tonus mechanism that recalibrates binocular alignment to minimize the demands on fusional vergence, and thereby promote sensorimotor fusion. It is generated by a central neural integrator, probably within the cerebellum, that provides inertia, stability, and plasticity to human binocular vision. Although this shadow control system is often considered synonymous with “tonic vergence,” phoria adaptation generates a deeper level of perseverative tonicity to maintain baseline extraocular muscle tonus so that sensorimotor fusion can be quickly and accurately superimposed. Clinically, its activation cannot readily be distinguished from its dissipation. Phoria adaptation is deeply entrenched before most of our prism measurements take place, making its effects virtually invisible to the clinician. As it so often adulterates our clinical strabismus measurements, it is truly the ghost in the machine. As the effects of phoria adaptation may linger even after the largest possible phoria is measured [74], this analysis begs the question of whether a “true phoria” can even exist [17], or whether all measured phorias inevitably incorporate some degree of phoria adaptation. The ubiquity and robustness of this cerebellar learning

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mechanism in frontal binocular animals, and its augmentation in acquired forms of intermittent strabismus, would explain why our measured deviations so often underestimate the larger deviations that are obtained after prolonged occlusion or prism adaptation. When the effects of phoria adaptation fly under our radar, the resulting clinical measurements are often artificially low, and surgical undercorrections can be predicted. Thus, phoria adaptation may help to explain the trend toward progressively higher surgical dosing over the last century in intermittent exotropia and accommodative esotropia. Conversely, the malleability and plasticity of this shadow control system due to its inherent ability to “learn” may also explain why strabismus surgery is so often successful [75]. References 1. Hofmann FB, Bielschowsky A.  Uber due der Willkue entzogenen Fusions-­ Bewegungen der Augen. Arch Gesamte Physiol Menschen Tiere. 1900;80:1–40. https://doi.org/10.1007/BF01661926. 2. Scobee RG. The oculorotary muscles. St Louis: C.V. Mosby; 1952. p. 1–359. 3. Lancaster WB. Terminology with extended comments on the position of rest and on fixation. In: Allen JH, editor. Strabismus ophthalmic symposium II. St. Louis: Mosby; 1958. p. 503–22. 4. Jung J, Klaehn L, Brodsky MC. Stability of human binocular alignment in the dark and under conditions of nonfixation. J AAPOS. 2016;20:357–63. https:// doi.org/10.1016/j.jaapos.2016.05.011. 5. Leigh J, Zee DS. The neurology of eye movements. 4th ed. New York: Oxford University Press; 2015. p. 545–6. 6. Cooper J.  Clinical implications of vergence adaptation. Optom Vis Sci. 1992;69:300–7. https://doi.org/10.1097/00006324-­199204000-­00008. 7. McDaniel C.  Phoria adaptation in clinical vergence testing. Optometry. 2010;81:469–75. https://doi.org/10.1016/j.optm.2010.01.012. 8. Carter DB. Fixation disparity and heterophoria following prolonged wearing of prisms. Am J Optom. 1965;42:141–51.  https://doi.org/10.1097/00006324-­ 196503000-­00001. 9. Schor CM. The influence of rapid prism adaptation upon fixation disparity. Vis Res. 1979;19:757–65. https://doi.org/10.1016/0042-­6989(79)90151-­2. 10. Milder DG, Reinecke RD. Phoria adaptation to prisms. A cerebellar dependent response. Arch Neurol. 1983;40:339–42.  https://doi.org/10.1001/ archneur.1983.04050060039005. 11. Spencer S, Firth AY.  Stereoacuity is affected by induced phoria but returns toward baseline during vergence adaptation. J AAPOS. 2007;11:465–8. https:// doi.org/10.1016/j.jaapos.2007.03.014. 12. Brodsky MC, Jung J. Intermittent exotropia and accommodative esotropia: distinct disorders or two ends of a spectrum. Ophthalmology. 2015;122:1543–6. https://doi.org/10.1016/j.ophtha.2015.03.004. 13. Ellerbrock VJ.  Tonicity induced by fusional movements. Am J Optom Arch Am Acad Optom. 1950;27:8–20.  https://doi.org/10.1097/00006324-­ 195001000-­00003.

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14. Toole AJ, Fogt N.  The forced vergence cover test and phoria adaptation. Ophthalmic Physiol Opt. 2007;27:461–72. https://doi.org/10.1111/j.1475-­1313 .2007.00498.x. 15. Hering E. Die Lehre von binocularen Sehen. Leipzig: Englemann; 1868. 16. Maddox EE. The clinical use of prisms: and the decenring of lenses (Enlarged 5th Edition). London: John Wright & Co; 1907. 17. Bielschowsky A. Lectures on motor anomalies. Hanover: Dartmouth College Publications; 1940. p. 15–7. 18. Ogle KN, Martens TG, Dyer JA. Oculomotor imbalance in binocular vision and fixation disparity. London: Henry Kimpton; 1967. 19. Ogle KN, Prangen AD. Observations on vertical divergences and hyperphorias. Arch Ophthalmol. 1953;49:313–34.  https://doi.org/10.1001/archo pht.1953.00920020322009. 20. Guyton DL. The 10th Bielschowsky lecture. Changes in strabismus over time. The roles of vergence tonus and muscle length adaptation. Binocul Vis Strabismus Q. 2002;21:81–92. 21. Taylor MJ, Roberts DC, Zee DS.  Effect of sustained cyclovergence on eye alignment: rapid torsional phoria adaptation. Invest Ophthalmol Vis Sci. 2000;41:1076–83. 22. Dysli M, Abegg M.  Gaze-dependent phoria and vergence adaptation. J Vis. 2016;16(2):1–12. https://doi.org/10.1167/16.3.2. 23. Fray KJ.  Fusional amplitudes: exploring where fusion falters. Am Orthopt J. 2013;63:41–54. https://doi.org/10.3368/aoj.63.1.41. 24. Graf EW, Maxwell JS, Schor CM. Changes in cyclotorsion and vertical alignment during prolonged monocular occlusion. Vis Res. 2002;42:1185–94. https:// doi.org/10.1016/S0042-­6989(02)00047-­0. 25. Schor CM, Maxwell JS, McCandless J, Graf E. Adaptive control of vergence in humans. Ann N Y Acad Sci. 2002;956:297–305.  https://doi.org/10.1111/ nyas.2002.956.issue-­1. 26. Maxwell JS, Schor CM. Mechanisms of vertical phoria adaptation revealed by time-course and two dimensional spatiotopic maps. Vis Res. 1994;34:241–51. https://doi.org/10.1016/0042-­6989(94)90336-­0. 27. Cooper H, Dharamsh Sethi B, Henson DB.  Vergence adaptive change with a prism induced noncomitant disparity. Am J Optom Physiol Optic. 1985;62:247–63. 28. Henson DB, Dharamshi BG. Oculomotor adaptation to induced heterophoria and anisometropia. Invest Ophthalmol Vis Sci. 1982;22:234–40. 29. Cooper Ellerbrock VJ, Fry GA. Effects induced by anisometropic corrections. Am J Optom Arch Am Acad Optom. 1942;19:444–59.  https://doi. org/10.1097/00006324-­194211000-­00002. 30. Ellerbrock VJ, Fry GA.  Effects induced by anisometropic corrections. Am J Optom Arch Am Acad Optom. 1942;19:444–59.  https://doi. org/10.1097/00006324-­194211000-­00002. 31. Graf WE, Maxwell JS, Schor CM. Comparison of the time courses of concomitant and nonconcomitant vertical phoria adaptation. Vis Res. 2003;43:567–76. https://doi.org/10.1016/S0042-­6989(02)00597-­7.

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32. Henson DB, North R. Adaptation to prism-induced heterophoria. Am J Optom PhysiolOptic.1980;57:129. https://doi.org/10.1097/00006324-­198003000-­00001. 33. Larson W.  An investigation of prism adaptation latency. Optom Vis Sci. 1994;71:38–42. https://doi.org/10.1097/00006324-­199401000-­00008. 34. Fogt N, Toole A. The effect of saccades and brief fusional stimuli on phoria adaptation. Optom Vis Sci. 2001;78:815–24.  https://doi. org/10.1097/00006324-­200111000-­00011. 35. Rosenfeld M, Chun TW, Fischer SE. Effect of prolonged dissociation on the subjective measurement of near heterophoria. Ophthalmic Physiol Opt. 1997;17:478–82. https://doi.org/10.1111/j.1475-­1313.1997.tb00086.x. 36. Howard IP, Allison RS, Zacher JE.  The dynamics of vertical vergence. Exp Brain Res. 1997;116:153–9. https://doi.org/10.1007/PL00005735. 37. Hwang JM, Guyton DL. The Lancaster red-green test before and after occlusion in the evaluation of incomitant strabismus. J AAPOS. 1999;3:151–6. https:// doi.org/10.1016/S1091-­8531(99)70060-­1. 38. Niekter B.  Horizontal and vertical deviations after prism neutralization and diagnostic occlusiogn in intermittent exotropia. Strabismus. 1994;2:13–22.  https://doi.org/10.3109/09273979409105049. 39. Sherrington CS.  Postural activity of muscle and nerve. Brain. 1915;38:191–234. https://doi.org/10.1093/brain/38.3.191. 40. Carpenter RHS. What Sherrington missed: the ubiquity of the neural integrator. Ann N Y Acad Sci. 2011;1233:208–13.  https://doi.org/10.1111/j.1749-­6632 .2011.06110.x. 41. Moses RA, editor. Adler’s physiology of the eye. 7th ed. St. Louis: CV Mosby; 1981. p. 678–9. 42. Repka MX, Connett JE, Scott WE. One year surgical outcome after prism adaptation for the management of acquired esotropia. Ophthalmology. 1996;103:922–8. https://doi.org/10.1016/S0161-­6420(96)30586-­1. 43. Kushner BJ. Strabismus: practical pearls you won’t find in textbooks, vol. 68. New York: Springer; 2017. 44. von Noorden GK.  Binocular vision and ocular motility: theory and management of strabismus. St. Louis: CV Mosby; 1996. p. 507. 45. Garretty T. The effect of prism adaptation on the angle of deviation in convergence excess esotropia and possible consequences for surgical planning. Strabismus. 2018;26:111–7. https://doi.org/10.1080/09273972.2018.1481435. 46. Garretty TL. Convergence excess esotropia: a proposed new classification and the effects of monocular occlusion on the AC/A ratio. J Pediatr Ophthalmol Strabismus. 2010;47:308–12. https://doi.org/10.3928/01913913-­20100118-­03. 47. Schor CM, Kotular JC.  Dynamic interactions between accommodation and convergence are velocity sensitive. Vis Res. 1986;26:927–42.  https://doi. org/10.1016/0042-­6989(86)90151-­3. 48. Schor C.  Influence of accommodative and vergence adaptation on binocular motor disorders. Am J Optom Physiol Opt. 1988;65:464–7.  https://doi. org/10.1097/00006324-­198806000-­00006.

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49. Gowrisankaran S, Satgunam P, Fogt N. Phoria adaptation can be induced by accommodative convergence. Invest Ophthalmol Vis Sci. 2007;48:907. 50. Kushner BJ. Tenacious proximal fusion: the Scobee phenomenon. Am Orthopt J. 2015;65:73–80. https://doi.org/10.3368/aoj.65.1.73. 51. Othsuki H, Hasebe S, Kono R, et al. Prism adaptation response is useful for predicting surgical outcome in selected types of intermittent exotropia. Am J Ophthalmol. 2001;131:117–22. https://doi.org/10.1016/S0002-­9394(00)00704-­2. 52. Dadeya S, Kamlesh NS. Usefulness of the prism adaptation test in patients with intermittent exotropia. J Pediatr Ophthalmol Strabismus. 2003;40:85–9. https:// doi.org/10.3928/0191-­3913-­20030301-­07. 53. Zahavi A, Friling R, Ron Y, et  al. Evaluation of ocular motility deviation changes in exotropic patients after cycloplegic eye drops versus prism adaptation test. Eur J Ophthalmol. 2019;29(5):482–5.  https://doi. org/10.1177/1120672118803518. 54. Ohtsuka H, Hasabe S, Furuse T, et al. Contribution of vergence adaptation to difference in vertical deviation between distance and near viewing in patients with superior oblique palsy. Am J Ophthalmol. 2002;134:252–60. https://doi. org/10.1016/S0002-­9394(02)01519-­2. 55. Brodsky MC, Haslwanter T, Kori AA, Straumann D.  The role of voluntary effort in the Bielschowsky head tilt test: a clinical and oculographic assessment. Binocul Vis Strabismus Q. 2000;15:325–30. 56. Lewis RF, Clendaniel RA, Zee DS.  Vergence-dependent adaptation of the vestibulo-­ ocular reflex. Exp Brain Res. 2003;152:335–40.  https://doi. org/10.1007/s00221-­003-­1563-­9. 57. Sato F, Akao T, Kurkin S, et al. Adaptive changes in vergence eye movements induced by vergence-vestibular interaction training in monkeys. Exp Brain Res. 2004;156:164–73. https://doi.org/10.1007/s00221-­003-­1777-­x. 58. Alpern M. The zone of clear vision at the upper levels of accommodation and convergence. Am J Optom Arch Am Acad Optom. 1950;27:491–513. https:// doi.org/10.1097/00006324-­195010000-­00003. 59. Rowe FJ. Fusional vergence measures and their significance in clinical assessment. Strabismus. 2010;18:9–17. https://doi.org/10.3109/09273971003758412. 60. Lanca CC, Rowe FJ. Variability of fusion vergence measurements in heterophoria. Strabismus. 2016;24:63–9. https://doi.org/10.3109/09273972.2016.1159234. 61. Scobee RG, Green EL. Relationships between lateral heterophoria, prism vergence, and the near point of convergence. Am J Ophthalmol. 1948;31:427–55. https://doi.org/10.1016/0002-­9394(48)92164-­3. 62. Kolling GH, Steffen H, Baader A, et al. Diagnostic occlusion test in cases of unilateral strabismus sursoadductorus. Strabismus. 2004;12:41–50. https://doi. org/10.1076/stra.12.1.41.29016. 63. Kono R, Hasebe S, Ohtsuki H, et  al. Impaired vertical phoria adaptation in patients with cerebellar dysfunction. Invest Ophthalmol Vis Sci. 2002;43:673–8. 64. Hain TC, Luebke AE. Phoria adaptation in patients with cerebellar dysfunction. Invest Ophthalmol Vis Sci. 1990;31:1394–7.

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65. Morley JW, Judge SJ, Lindsey JW.  Role of monkey midbrain near-response neurons in phoria adaptation. J Neurophysiol. 1992;67:1475–92.  https://doi. org/10.1152/jn.1992.67.6.1475. 66. Robinson DA. Adaptive gain control of the vestibulo-ocular reflex by the cerebellum. J Neurophysiol. 1976;39:954–69. https://doi.org/10.1152/jn.1976.39.5.954. 67. Takagi M, Tamargo R, Zee DS. Effects of lesions of the cerebellar oculomotor vermis on eye movements in primate: binocular control. Prog Brain Res. 2003;142:19–33. 68. Judge SJ. Optically-induced changes in tonic vergence and AC/A ratio in normal monkeys and monkeys with lesions of the flocculus and the ventral paraflocculus. Exp Brain Res. 1987;66:1–9. https://doi.org/10.1007/BF00236195. 69. Ito M, Shiida T, Yagi N, et al. There cerebellar modification of the rabbit’s horizontal vestibulo-ocular reflex induced by sustained head rotation combined with visual stimulation. Proc Jpn Acad. 1974;50:85–9. https://doi.org/10.2183/ pjab1945.50.85. 70. Kandel R, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ. Principles of neural science. 5th ed. New York: McGraw Hill; 2013. p. 967–8. 71. Prezekoracka-Krawczyk A, Michalak KP, Pyzalska P. Deficient vergence prism adaptation in subjects with decompensated heterophoria. PLoS ONE. 2019;14(1):e0211039. https://doi.org/10.1371/journal.pone.0211039. 72. Przekoracka-Krawczyk A, Michalak KP, Pyzalska P, Lappe M. Deficient vergence prism adaptation in subjects with decompensated heterophoria. PLoS One. 2019;14(1):e0211039. https://doi.org/10.1371/journal.pone.0211039. 73. Alpern M. The zone of clear single vision at the upper levels of accommodation and convergence. Am J Optom Arch Am Acad Optom. 1950;27:8–20. https:// doi.org/10.1097/00006324-­195010000-­00003. 74. North RV, Begumpara S, Henson DB.  Effects of prolonged forced vergence upon the adaptation system. Ophthalmic Physiol Opt. 1986;6:391–6.  https:// doi.org/10.1111/j.1475-­1313.1986.tb01158.x. 75. Archer S.  Why strabismus surgery works: the legend of the dose-response curve. J AAPOS. 2018;22(1):1.e1–1.e6.  https://doi.org/10.1016/j. jaapos.2017.12.001.

Postscript In this Richard G. Scobee lecture, I argue that phoria adaptation is the major source of binocular tonus. I extrapolate this notion to explain the tenacity of normal binocular vision. I grapple with the notion that much of what we designate as fusional vergence amplitudes represents phoria adaptation. Finally, I propose that phoria adaptation is a normal cerebellar learning process that is driven by a neural integrator that provides plasticity to real world binocular function. Phoria adaptation provides a unifying explanation for myriad clinical effects that exert themselves in normal binocular vision and in different disease states.

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As the binocular tonus mechanism for phoria adaptation differs from that which superintends dissociated eye movements in infantile strabismus, one can conclude that human binocular vision can be superintended by two distinct tonus pools, each having a strong contribution from the neural integrators within the cerebellum, with the operative coordinate system dictated by genetic, neurologic, epigenetic, and environmental factors as yet undetermined. It is clear, however, that newer this binocular tonus system can still kick in to maintain binocular alignment after surgical realignment of the eyes in children with essential infantile esotropia. Perhaps, a secondary maldevelopment of phoria adaptation could explain the delayed onset of consecutive exotropia in some surgically-treated patients.

Monocular Nasotemporal Optokinetic Asymmetry—Unraveling the Mystery

19

Pediatric ophthalmologists encounter a unique visuomotor phenomenon known as monocular nasotemporal optokinetic asymmetry (MNTA) [1, 2]. This condition is characterized by brisk nasalward and poor temporalward optokinetic responses under monocular conditions of viewing (Fig. 19.1A–B). Babies with normal vision display this subcortical optokinetic bias within the first few months of life, until cortical binocular vision is firmly established [1–3]. When infantile strabismus precludes normal binocular development, however, this optokinetic asymmetry persists throughout life [4–7]. In this way, MNTA provides a diagnostic “footprint in the snow” of infantile strabismus. It also gives rise to latent nystagmus and underlies its unique association with infantile strabismus [8–11]. What is the origin of MNTA, and how can we explain its unique association with infantile strabismus? MNTA is an ancestral visual reflex that is present in most lateral-­eyed afoveate animals [12, 13]. The afoveate retina in lateral-eyed animals, such as fish and rabbits, corresponds to the human nasal retina, because it views the ipsilateral (temporal) visual field. Its retinotectal pathways project contralaterally to the nucleus of the optic tract and the dorsal terminal nucleus of the accessory optic tract (NOT-DTN) of the midbrain [14–17], which are sensitive to full-field motion and facilitate optokinetic stabilization of retinal slip during body movements. The subcortical circuitry for optokinetic asymmetry is shared by all vertebrates [16]. During navigation, survival depends on distinguishing real-world motion from body motion [15–17]. To this end, the optokinetic system encodes full-field visual motion separately from labyrinthine signaling of head motion. MNTA enables the animal to see where it is going during both translational and rotational body movements [15–17]. Consider a fish with two eyes that each see the ipsilateral side of visual space. When it swims forward, it would be visually disruptive to have both eyes driven backward by optokinetic responses to radial optic flow as it passes stationary contours that move posteriorly relative to the body (Fig. 19.1C). Because fish are buoyant, they may also need to use posterior optic flow to detect self-motion

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a

b

c

d

Fig. 19.1  Monocular nasotemporal optokinetic asymmetry. (A–B) In the human with infantile strabismus, monocular viewing results in strong nasalward optokinetic responses (solid lines) and poor temporalward optokinetic responses (dashed lines) relative the viewing eye. (C) In a fish that is swimming forward, temporalward optokinetic responses (dashed lines) in response optic flow would rotate the eyes posteriorly and impede visualization of the oncoming visual scene. (D) In a fish that is turning to the right, nasalward rotation of nearby contours in the right hemifield of visual space necessitates a strong and accurate optokinetic response in the right eye (solid curved line). As the fish turns away from the left hemifield of visual space, more distant visual contours seen by the left eye (dashed curved line) are moving at slower velocities; therefore, the nasalward visual input to the right eye dictates the optokinetic responses of both eyes

[18]. It is therefore evolutionarily advantages to minimize temporalward optokinetic responses to a receding visual world [15–18]. As aquatic visibility can be low, fish swim closer to features that provide optokinetic input, enabling them to use temporal optic flow to judge self-motion [18].

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But this is only half the story. When the animal turns to one side, it needs to track the visual world that is moving nasally, because that is the area it is turning toward (Fig.  19.1D). Because the nose and mouth are median (ie, nasal) to the eyes, accurate tracking of nasalward circumferential optic flow may help to stabilize the rapid visual motion of the approaching hemifield, as the animal rotates toward a salient nearby nutrient [17] to inspect it with the nose and ingest it with the mouth. At the same time, the opposite eye is seeing an area from which the animal is turning away, with objects likely at a further distance and therefore producing less retinal slip, so that the eye receiving nasalward visual input must dictate the optokinetic response for both eyes. So MNTA provides an ingenious evolutionary solution to enable the lateral-eyed animal to use optokinetic rotation to visually navigate both translation and rotation. In the zebrafish pretectum, monocularly and binocularly driven clusters of directionally selective horizontal motion detection cells are hierarchically organized to distinguish between translational and rotational optic flow [19]. Ontegeny recapitulates phylogeny for primitive reflexes within the developing human visual system. In humans with infantile strabismus, the cortical optokinetic pathways reconfigure to the monocular subcortical template, so that MNTA can be modulated through the cortical pursuit centers as they establish ipsilateral connections to each NOT-DTN [20–23]. The resulting cortical pursuit asymmetry can now generate MNTA to foveated optokinetic targets [24–26]. In this setting, infantile esotropia confers the binocular advantage of restoring horizontal optokinetic bidirectionality in the presence of MNTA [24]. Horizontal visual motion can be followed in either direction simply by switching fixation to the eye receiving nasalward input [27]. In infantile esotropia, the human nasal retinas realign in the frontal plane but continue to function as they originally did in lateral-eyed afoveate animals. What an evolutionary wonder! References 1. Atkinson J.  Development of optokinetic nystagmus in the human infant and monkey infant: an analogue to development in kittens. In: Freeman R, editor. Developmental neurobiology of vision. New  York: Plenum Press Nato Advanced Study Institute Series; 1979. p. 277–87. 2. Naegele J, Held R. The post-natal development of monocular optokinetic nystagmus in infants. Vis Res. 1982;22:341–6. 3. Flynn JT.  Vestibulo-optokinetic interactions in strabismus. Am Orthopt J. 1982;32:36–47. 4. Mein J. The asymmetric optokinetic response. Br Orthopt. 1983;40:1–3. 5. Wright KW. Clinical optokinetic nystagmus asymmetry in treated esotropes. J Pediatr Ophthalmol Strabismus. 1996;33:99–109. 6. Valmaggia C, Proudlock F, Gottlob I. Optokinetic nystagmus in strabismus: are asymmetries related to binocularity? Invest Ophthalmol Vis Sci. 2003;44:5142–50. 7. Schor C, Fusaro R, Wilson N, McKee SP. Prediction of early-onset esotropia from components of the infantile squint syndrome. Invest Ophthalmol Vis Sci. 1997;38:719–40.

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8. Kommerell G. Ocular motor phenomena in infantile strabismus: asymmetry in optokinetic nystagmus and pursuit, latent nystagmus, and dissociated vertical divergence. In: Lennerstrand G, von Noorden GK, Campos EC, editors. Strabismus and amblyopia: experimental basis for advances in clinical management. London, UK: Macmillan; 1988. p. 99–109. 9. Kommerell G, Mehdorn E. Is an optokinetic defect the cause of congenital and latent nystagmus? In: Lennerstrand G, Zee DS, Keller EL, editors. Functional basis of ocular motility disorders. New York: Pergamon Press; 1982. p. 159–67. 10. Schor CM. Subcortical binocular suppression affects the development of latent and optokinetic nystagmus. Am J Optom Physiol Optic. 1983;60:481–502. 11. Brodsky MC.  Latent nystagmus: Vestibular nystagmus with a twist. Arch Ophthalmol. 2004;122:202–9. 12. Tauber ES, Atkin A. Optomotor responses to monocular stimulation. Relation to visual system organization. Science. 1968;160:1365–7. 13. Masseck OA, Hoffmann KP.  Comparative neurobiology of the optokinetic reflex. Ann N Y Acad Sci. 2009;1164:430–9. 14. Collewijn H, Noorduin H. Conjugate and disjunctive optokinetic movements in the rabbit, evoked by rotatory and translator motion. Pflugers Arch. 1972;335:173–85. 15. Ohmi M, Howard IP, Everleigh B. Directional predominance in human optokinetic nystagmus. Exp Brain Res. 1986;63:387–94. 16. Wallmann J.  Subcortical optokinetic mechanisms. In: Miles FA, Wallman J, editors. Visual motion and its role in the stabilization of gaze. Amsterdam: Elsevier Science; 1993. p. 321–42. 17. Miles FA. The sensing of rotational and translational optic flow by the primate optokinetic system. In: Miles FA, Wallman J, editors. Visual motion and its role in the stabilization of gaze. Amsterdam: Elsevier Science; 1993. p. 393–403. 18. Scholtyssek C, Dacke M, Kröger R, Baird E. Control of self-motion in dynamic fluids: fish do it differently from bees. Biol Lett. 2014;10:20140279. 19. Kubo F, Hablitzel B, Dal Maschio M, et al. Functional architecture of an optic flow responsive area that drives horizontal eye movements and zebrafish. Neuron. 2014;81:1344–59. 20. Hoffman KP. Control of the optokinetic reflex by the nucleus of the optic tract in primates. Prog Brain Res. 1989;80:173–82. 21. Hoffmann K-P.  Neural basis for optokinetic defects in experimental animals with strabismus. In: Kaufmann H, editor. Transactions of the 16th Meeting of the European Strabismological Association. Giessen, September 1987. Giessen: Gahmig Druck Giessen; 1987. p. 35–6. 22. Distler C, Hoffmann K-P. Development of the optokinetic response in macaques: A comparison with cat and man. Ann N Y Acad Sci. 2003;1004:10–8. 23. Braddick O. Where is the naso-temporal asymmetry? Curr Biol. 1996;6:250–3. 24. Brodsky MC.  Is infantile esotropia subcortical in origin? Prog Brain Res. 2019;248:183–93. 25. Tychsen L, Hurtig RR, Scott WE. Pursuit is impaired but the vestibulo-ocular reflex is normal in infantile strabismus. Arch Ophthalmol. 1985;103:536–9.

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26. Joshi AC, Aqaoglu MN, Das V. Comparison of naso-temporal asymmetry during monocular smooth pursuit, optokinetic nystagmus, and ocular following response in strabismic monkeys. Strabismus. 2017;25:47–55. 27. Brodsky MC, Klaehn LD. An optokinetic clue to the pathogenesis of crossed fixation in infantile esotropia. Ophthalmology. 2017;124:272–3.

Postscript This article examines the reason why monocular nasotemporal asymmetry (MNTA) is integral in lateral-eyed afoveate animals, and shows how subcortical visual reflexes cause the visual cortex to secondarily reconfigure when the substrate for binocular vision fails to develop within a critical time window. Many pediatric ophthalmologists do not routinely check for MNTA, which is surprising, as I have found it to be a critical determinant of timing of strabismus that often dictates surgical dosing. MNTA readily distinguishes essential infantile esotropia from accommodative esotropia, which requires higher surgical dosing to restore binocular alignment. As clinical overlap can exist (e.g. essential infantile esotropia with an accommodative component), and a parent’s estimate of onset can be misleading, the absence of MNTA suggests that you may need to augment the standard recession. However, it is important to use an optokinetic drum with colored animals rather than stripes to engage a young child’s attention. Although the argument that ontology recapitulates phylogeny, first popularized by Haeckel in 1866, has been refuted as a general neurodevelopmental principle, it is indisputable that this concept applies to the development of human visual motor reflexes. The persistence of MNTA in humans with infantile strabismus demonstrates this principle. The fact that this optokinetic reflex is phylogenetically ancient (present long before the development of the visual cortex), further shows that its cortical representation is secondary to a reconfiguration of the visual motion cortex to the subcortical visual template in binocular humans with early onset strabismus (actually, fish are also “binocular,” as both eyes see at the same time). Once embedded in patients with strabismus, MNTA persists indefinitely throughout life, making it a valuable neurodiagnostic sign. MNTA is easy to detect clinically, and it anchors the examiner to the evolutionary nature of infantile strabismus. So give it a go.

Infantile Nystagmus—Following the Trail of Evidence

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As a fastidious ophthalmology resident 35 years ago, I remember thinking that there would someday be an easy way to understand and explain the constant horizontal oscillations of the eyes that characterize infantile nystagmus. Although its terminology has since evolved from congenital nystagmus [1] to infantile nystagmus (as the oscillation is usually not present at birth) [2], this terminology is itself somewhat shaky, because the genetic or anatomical conditions that lead to the oscillation are clearly present at birth. At that time, it was becoming increasingly apparent that a surprising number of cases had underlying anatomical abnormalities affecting retinal or optic nerve function to reduce central visual acuity from birth [3]. Estimates of the prevalence of patients with underlying sensory visual anomalies approximated 80%-90%, as close clinical examination [3] and hemispheric visual evoked potentials [4, 5] disclosed cases with subtle albinism, and electroretinography demonstrated other cases arising from congenital retinal dystrophies such as achromatopsia and congenital stationary night blindness [6, 7]. The recent advent of optical coherence tomography (OCT) [8] and targeted next-generation genetic sequencing [9, 10] as core constituents of the infantile nystagmus evaluation may uncover sensory visual abnormalities in a higher proportion of cases. Nevertheless, many hereditary forms of infantile nystagmus have no detectable sensory visual defect [6]. The x-linked forms have been isolated to the FRMD7 gene [11], whereas the autosomal dominant forms have been isolated to a handful of other genes [12]. Fast forward 30 years, when I became interested in the role of subcortical optokinesis in human vision. Lateraleyed animals use a subcortical optokinetic system mediated by the nucleus of the optic tract and the dorsal terminal nucleus of the accessory optic system (AOS) in the midbrain to track full-field visual motion by generating horizontal optokinetic responses to minimize retinal slip [13]. Ontogeny recapitulates phylogeny in the developing visual system, as this phylogenetically older subcortical visual system remains active within the first 2–3 months of human life [14, 15]. Foveal pursuit pathways from the binocular visual cortex then mature and establish connections with

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1_20

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the nucleus of the optic tract and the dorsal terminal nucleus of the AOS as the subcortical visual system permanently ceases to function [15]. In 2014, Lou Dell’Osso and I proposed that this critical period for subcortical neuroplasticity may be necessary to prevent conflicting optokinetic signals from arising, since following a foveated object to the right (cortical pursuit) causes the entire visual world to sweep across the retina to the left, creating a full-field optokinetic stimulus that would drive the eyes away from the foveated target [16]. Delayed cortical visual development, as has been documented in infantile nystagmus [17], could allow the subcortical optokinetic system to remain operational. If the subcortical AOS failed to become extinguished, both optokinetic systems would trigger each other in a positive feedback loop. This reverberating circuit would generate an “optokinetic tug-of-war,” causing the eyes to oscillate horizontally, producing what we have come to recognize as infantile nystagmus. This mechanism seemed to explain a number of clinical findings, most notably: (1) infantile nystagmus is isolated to the visual system; (2) infantile nystagmus begins at 2–3 months of age, when the AOS normally turns off; (3) humans with infantile nystagmus usually have “reversed” optokinetic responses, consistent with the notion that the still-functional subcortical optokinetic system overrides foveal pursuit to generate the optokinetic response; and (4) humans with cortical visual loss don’t have infantile nystagmus, again showing that the cortical and subcortical visual motion systems both have to remain operational to produce this palindromic effect on eye position [16]. More recently, Yonehara and colleagues [18] studied the mouse model idiopathic infantile nystagmus caused by the FRMD7 gene and found that the gene affected a starburst amacrine cell within the retina, providing asymmetric inhibition to direction-­selective retinal ganglion cells that project to the nucleus of the optic tract and the dorsal terminal nucleus of the AOS and subserve horizontal optokinesis. This experimental study was confounded by the finding that FRMD7 mice do not display infantile nystagmus despite the fact that they have complete loss of horizontal optokinetic responses. Nevertheless, it dovetailed nicely with our proposed mechanism that a primary retinal abnormality involving the optokinetic system could lead to infantile nystagmus. More importantly, it suggested, that, if you drill down deep enough to hone in on the starburst amacrine cell, what we call “idiopathic” infantile nystagmus could actually arise from defective electrochemical transmission at the cellular level, qualifying it nosologically as a sensory disorder associated with infantile nystagmus. In a landmark study published last year, Winkelman et al [19] studied 3 patients with infantile nystagmus associated with an X-linked form of congenital stationary night blindness due to NYX or CACNA1F mutations, along with a mouse model that had the same NYX gene mutation and also lacked the functional nyctalopin protein on bipolar cells at their synapse with the photoreceptors. Both the patients and the mice showed horizontally oscillating eye movements at a frequency of 4–7 Hz. Impressive was the fact that, in the mouse model, the ON direction-selective ganglion cells, which detect global motion and project to the AOS, showed electrical oscillations at the same frequency as the ocular oscillations. The individual retinal ganglion cells oscillated asynchronously in the dark, but the oscillations became synchronous when the retina was stimulated with light and contrast,

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together sending a strong oscillating global motion signal to the AOS. Intravitreal injection of pharmacologic agents to modify the frequency of ganglion cell oscillations produced correlative changes in the nystagmus frequency. This study showed that, at least in congenital stationary night blindness, the ocular oscillations can be driven directly by electrical oscillations at the level of the retinal ganglion cells. Given that ON and OFF retinal ganglion cells were firing out of phase by 180 degrees, they considered the likely presynaptic source to be the AII amacrine cells, which drive both cells with an opposite sign to produce an oscillatory firing in antiphase. These amacrine cells contain an intrinsic, membranepotential oscillator, consisting of a fast sodium channel and both a fast and slow potassium channel. Altered input from the ON-bipolar cells places the amacrine membrane potential outside of its normal working range, which causes the AII amacrine cells to oscillate and drives the ON and OFF retinal ganglion cells in antiphase to produce pendular ocular oscillations. These exciting new findings raise the possibility that electrochemical retinal dysfunction at the cellular level can directly modulate motion input to the subcortical optokinetic system to eventuate in infantile nystagmus. It therefore seems likely that similar electrochemical cellular aberrations will be found in other genetic forms of isolated infantile nystagmus to explain the similar timing of onset and nystagmus waveforms in all patient groups. The Austrian psychotherapist Alfred Adler (originally an ophthalmologist) famously stated that “the only normal people are the ones you don’t know very well.” [20] As we zoom down on the cellular and electrochemical aberrations within the retina, we may come to find that the same holds true for individuals with infantile nystagmus. If so, then any meaningful distinction between isolated and sensory infantile nystagmus may soon disappear. References 1. Cogan DG. Congenital nystagmus. Can J Ophthalmol. 1967;2:4–10. 2. Hertle RW, Maldanado VK, Maybodi M, Yang D.  Clinical and ocular motor analysis of infantile nystagmus syndrome in the first 6 months of life. Br J Ophthalmol. 2002;86:670–5. 3. Simon JW. Albinotic characteristics in congenital nystagmus. Am J Ophthalmol. 1984;97:320–37. 4. Creel D, Witkop CJ, King RA. Asymmetrical visual evoked potentials in human albinos: Evidence for visual system anomalies. Invest Ophthalmol Vis Sci. 1974;13:430. 5. Apkarian P, Shallo-Hoffmann J.  VEP projections in congenital nystagmus; VEP asymmetry in albinism: a comparison study. Invest Ophthalmol Vis Sci. 1991;32:2653–61. 6. Gelbart SS, Hoyt CS. Congenital nystagmus: a clinical perspective in infancy. Graefes Arch Clin Exp Ophthalmol. 1988;226:178–80. 7. Weiss AH, Biersdorf WR. Visual sensory disorders in congenital nystagmus. Ophthalmology. 1989;96:517–23. 8. Lee H, Sheth V, Bibi M, et al. Potential of handheld optical coherence tomography to determine cause of infantile nystagmus by using foveal morphology. Ophthalmology. 2017;120:2714–24.

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9. Thomas MG, Maconachie G, Sheth V, McLean RJ, Gottlob I. Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-­ generation sequencing. Eur J Hum Genet. 2017;25:725–34. 10. O’Gorman L, Normal CS, Michels L, et  al. A small gene sequencing panel realises a high diagnostic rate in patients with congenital nystagmus following basic phenotyping. Sci Rep. 2019;9:13229. 11. Thomas S, Proudlock FA, Sarvananthan N, et al. Phenotypical characteristics of idiopathic infantile nystagmus with and without mutaitons in FRMD7. Brain. 2008;131:1259–67. 12. Gottlob I, Proudlock F. Aetiology of infantile nystagmus. Curr Opin Neurol. 2014;27:83–91. 13. Wallmann J.  Subcortical optokinetic mechanisms. In: Miles FA, Wallman J, editors. Visual motion and its role in the stabilization of gaze. Amsterdam: Elsevier Science; 1993. p. 321–2. 14. Braddick O, Atkinson J.  Development of human visual function. Vis Res. 2011;51:1588–609. 15. Hoffmann KP. Development of the optokinetic response in macaques: a comparison with cat and man. Ann N Y Acad Sci. 2003;1004:10–8. 16. Brodsky MC, Dell’Osso LF. Neurologic mechanisms of infantile nystagmus. JAMA Ophthalmol. 2014;132:761–8. 17. Weiss AH, Kelly JP.  Acuity development in infantile nystagmus. Invest Ophthalmol Vis Sci. 2007;48:4093–9. 18. Yonehara K, Fiscella M, Drinnenberg A, et  al. Congenital nystagmus gene  FRMD7  is necessary for establishing a neuronal circuit asymmetry for direction selectivity. Neuron. 2016;89:177–93. 19. Winkelman BJH, Howlett MHC, Hölzel MB, et al. Nystagmus in patients with congenital stationary night blindness (CSNB) originates from synchronously firing retinal ganglion cells. PLoS Biol. 2019;e3000174:17. 20. Patel A.  Person of the month: Alfred Adler (1870-1937). Int J Indian Psych. 2016;3:1.

Postscript Many subclinical retinal disorders still fly beneath the radar of our clinical detection and are therefore diagnosed as “idiopathic” infantile nystagmus. It is not my intention to state categorically that underlying retinal dysfunction is strictly necessary for infantile nystagmus to develop. It is certainly possible that some cases of infantile nystagmus arise spontaneously from an inherent instability of the ocular motor system. Most cases of so-called “idiopathic” infantile nystagmus have underlying genetic mutations. As the downstream effects of these mutations are further elucidated, it will be interesting to see whether the cellular aberrations they produce can be confined to the ocular motor system, or whether they inevitably perturb the sensory visual system to some degree.

Glossary of Terms

Accessory optic system (AOS)  the three terminal midbrain nuclei that receive and process crossed retinal input related to full-field motion of the visual world Anterior canal predominance  excessive central innervation from the portions of the otoliths corresponding to the anterior semicircular canals, leading to tonic upgaze with bilateral inferior oblique muscle overaction. Atavism  a modification of a biological structure whereby an ancestral trait reappears after having been lost through evolutionary change in successive generations. Central vestibular imbalance  A disruption in input to the vestibular system due to stimulation or injury to the brainstem or cerebellar neurologic pathways that transmit information from the labyrinths and eyes. Cerebellar flocculus  a portion of the ancient vestibulocerebellum concerned with integrating visual and vestibular information to provide ocular stabilization, and with coordination of the eyes and head during gaze pursuit. Cortical suppression  Inhibition of visual input from one eye within the visual cortex, usually seen in individuals with strabismus. Dissociated deviations  the tonic deviations and variable binocular movements that arise from unequal binocular visual input in the setting of infantile strabismus Dissociated esotonus  a differing degree of tonic medial rectus innervation (unrelated to convergence) generated by monocular fixation with each of the two eyes in infantile strabismus. Dissociated vertical divergence  A dorsal drift of either eye evoked by monocular occlusion or spontaneous cortical suppression of the hyperdeviating eye in individuals with infantile strabismus. Dorsal  referring to either the back of the organism or the top of the skull Dorsal light reflex (DLR)  a body tilt (or a vertical divergence of the eyes) induced by unequal luminance input to the two eyes in lateral-eyed animals. Dorsal terminal nucleus of the accessory optic system (DTN-AOS)  the component of the midbrain accessory optic system that, together with the nucleus

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of the optic tract (NOT), generates optokinetic responses to full-field nasalward visual motion. Luminance  the intensity of light per unit area emitted from a surface. Monocular nasotemporal optokinetic asymmetry (MNTA)  a nasalward optokinetic predominance under conditions of monocular fixation in lateral-eyed animals and in primates with infantile strabismus. Nucleus of the optic tract (NOT)  a pretectal nucleus that generates horizontal optokinesis in response to full-field motion of the visual world. Ocular tilt reaction (OTR)  the triad of vertical divergence of the eyes, binocular torsion, and head tilt evoked by unequal static graviceptive input from the two otoliths. Otolithic  pertaining to static vestibular input from the two otoliths. Optokinesis  the ocular motor response to visual motion consisting of repetitive series of alternating slow and fast ocular rotations. Phoria adaptation (PA)  a slow central adaptation of tonic vergence to reset the baseline phoria that is induced by prisms or by the attempt to fuse in individuals with strabismus. Pitch  a fore-or-aft rotation around a side-to-side axis. Pitch plane  corresponding to the sagittal plane (for head and eye rotations). Posterior canal predominance  excessive central innervation from the portions of the otoliths corresponding to the posterior semicircular canals, leading to tonic downgaze with bilateral superior oblique muscle overaction. Roll  rotation about the front-to-back axis (or nasooccipital axis of the head) resulting in tilt. Roll plane  corresponding to the coronal plane (for head and eye rotations). Skew deviation  One component of the ocular tilt reaction consisting of a vertical misalignment of the eyes induced by unequal input from the two otoliths, usually due to a neurologic lesion involving their central connections within the vestibular system. Subjective vertical  the internal sense of vertical, or the perceived orientation of “true vertical” based on labyrinthine and visual binocular input. Subjective visual tilt  a tilt of the perceived visual world (real or imagined) relative to the subjective vertical. Subjective visual vertical (SVV) the perceived vertical position of the visual world relative to the subjective vertical. Teleotactic  a physical response that occurs without the necessity of maintaining bilateral (or binocular) balance. Tonus  the excitatory effects of baseline innervation on skeletal or extraocular musculature in the awake alert state. Tropotactic a physical response that reestablishes bilateral (or binocular) equilibrium Ventral  referring to the front or the lower side of an organism. Vestibular nucleus (VN)  an embryologically displaced cerebellar nucleus within the midbrain that modulates input from the labyrinths and the two eyes to stabilize balance

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Visuo-vestibular  Referring to the subcortical visual pathways that transmit binocular visual input to the vestibular nuclei to generate infantile strabismus and its accompaniments. Yaw  rotation about the vertical or longitudinal axis resulting in a turn. Yaw plane  referring to the horizontal plane (for head and eye rotations).

Bibliography

Chapter 1, Brodsky MC.  Dissociated vertical divergence: a righting reflex gone wrong. Arch Ophthalmol. 1999;117:1216–22. Chapter 2, Brodsky MC. DVD remains a moving target. J AAPOS. 1999;3:325–7. Chapter 3, Brodsky MC, Donahue SP. Primary oblique muscle overaction: the brain throws a wild pitch. Arch Ophthalmol. 2001;119:1307–14. Chapter 4, Brodsky MC. Do you really need your oblique muscles: adaptations and exaptations. Arch Ophthalmol. 2001;120:820–8. Chapter 5, Brodsky MC, Tusa RJ.  Latent nystagmus: vestibular nystagmus with a twist. Arch Ophthalmol. 2004;122:202–9. Chapter 6, Brodsky MC. Dissociated vertical divergence: perceptual correlates of the human dorsal light reflex. Arch Ophthalmol. 2002;120:1174–8. Chapter 7, Brodsky MC, Gräf MH, Kommerell G. The reversed fixation test: a diagnostic test for dissociated horizontal deviation. Arch Ophthalmol. 2005;123:1085–7. Chapter 8, Brodsky MC, Fray KJ. Does infantile esotropia arise from a dissociated deviation? Arch Ophthalmol. 2007;125:1703–5. Chapter 9, Brodsky MC. The accessory optic system: the fugitive visual control system in infantile strabismus. Arch Ophthalmol. 2012;130:1055–9. Chapter 10, Brodsky MC. Visuo-vestibular eye movements. Arch Ophthalmol. 2005;123:837–42. Chapter 11, Brodsky MC. An expanded view of infantile esotropia: bottoms up! Arch Ophthalmol. 2012;130:1199–202. Chapter 12, Brodsky MC. The lizard’s tail: an ocular allegory. Ophthalmology. 2013;120:225–6. Chapter 13, Brodsky MC, Klaehn L.  The optokinetic uncover test: a new insight into infantile esotropia. Arch Ophthalmol. 2014;131:761–5. Chapter 14, Brodsky MC, Dell’Osso LF. A unifying neurological mechanism for infantile nystagmus. JAMA Ophthalmol. 2014;132:761–8. Chapter 15, Brodsky MC, Jung J. Infantile exotropia and accommodative esotropia: distinct disorders or two ends of a spectrum? Ophthalmology. 2015;122:1544–6. Chapter 16, Brodsky MC, Klaehn L. An optokinetic clue to the pathogenesis of infantile esotropia. Ophthalmology. 2017;124:272–3. Chapter 17, Brodsky MC.  Is infantile esotropia subcortical in origin? Prog Brain Res. 2019;248:183–93. Chapter 18, Brodsky MC. Phoria adaptation: the ghost in the machine. J Binoc Vis Ocular Motility. 2020;70:1–10. Chapter 19, Brodsky MC. Monocular nasotemporal optokinetic asymmetry: unravelling the mystery. J AAPOS. 2019;23:219–21. Chapter 20, Brodsky MC.  Infantile nystagmus: following the trail of evidence. J AAPOS. 2020;24:70–1.

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Index

A Accessory optic system (AOS), 115, 117, 123, 135, 137, 163, 166, 167, 231 canal-based coordinate system, 121 decortication, 118 DTN and LTN neurons, 120 neuroanatomical connections, 116 photic stimulation, 120 primary visual system, 117 signals self-motion, 117 spherical enclosure, monocular optokinetic stimulation, sensitivity, 119 visual system, 117 Accessory optic tract (AOT), 115, 166 Accommodation-linked convergence (AC/A), 184, 185, 189, 213 Accommodative esotropia, 183–187, 212–213 Adaptation, 36, 45–46, 50, 56–58, 89, 108, 183–187, 189 reversion from exaptation to, 56–58 Adler, Alfred, 233 Alexander’s law, 71, 73 Amacrine, 232, 233 Angular momentum, 147, 148 Anterior canal or posterior canal system, 30, 31 A-pattern strabismus, 25, 31–34, 38, 86 Asymmetrical esodeviation, 96 Asymmetry, 5, 6, 19, 66, 86 monocular nasotemporal optokinetic, 81, 127, 151, 152, 154, 155, 157–159, 192, 193, 196, 197, 199, 200, 225, 226, 229 nasotemporal, 66, 67, 86 Nasotemporal optokinetic, 67 Atavism, 148, 196, 197 Atavistic torsional movements, 141

B Bagolini bar, 15 Balance organs, 26, 66, 68, 76, 89, 126, 132, 147 bilaterally symmetrical organs function as, 126 Balancing movement, 20 Base-in prism, 97, 99–102 Bidirectional horizontal motion detection, 193 Bielschowsky Head Tilt Test, 90 Binocular control mechanisms, 1, 11, 107, 183 Binocular deviations, 14, 115, 212 Binocular disparity, 6, 15, 83, 185, 186, 209 Binocular eye movements, 95 Binocular misalignment, 81, 115, 137, 145, 192, 201, 204, 211 Binocular tonus mechanism, 223 Binocular torsional control, 50 Binocular vertical cyclodisparity, 54 Binocular vision, 7, 10, 11, 26, 34, 35, 37, 38, 47, 58, 62, 65, 66, 83, 89, 115, 121, 124, 127, 129, 130, 132, 138, 144, 145, 148, 151, 155, 166, 173, 198, 199 Binocular visual disturbance, 43 Binocular visual imbalance, 88, 129, 135, 170 Binocular visual input abrupt fluctuations, 85 physiologic imbalance in, 129 Binocular visual system, 62 Bipolar cells, 232 Blur-driven accommodation convergence, 175, 176, 213 Body tilt, 4, 5, 9, 10, 17, 37, 46, 83, 84, 86, 90, 93, 128

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 M. C. Brodsky, The Evolutionary Basis of Strabismus and Nystagmus in Children, https://doi.org/10.1007/978-3-030-62720-1

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242 C Canal-based coordinate system, 68, 135, 141 Canal-based planes, 43 Cartesian coordinate system, 130, 135 Causation, theories of, 175–176 Cellphone vision, 213 Central tonus mechanisms, primary oblique muscle overaction, 26 Central vestibular disease, 58, 65, 131 Central vestibular innervation, 36, 37 Central vestibular imbalance, visuo-vestibular eye movements from, 130, 131 Cerebellar pathways, 141, 173–175 Chavessian hypothesis, 145 Chiari malformation, 34, 58, 141 Coexistent exodeviation, 102 Compensatory balancing movements, 150 Congenital esotropia, 65, 91, 108 inferior oblique muscle overaction and V-pattern strabismus in, 34, 35 Congenital strabismus, dissociated component of, 100 Congenital superior oblique palsy, 214 Congenital visual loss, 172 Convergence accommodation to convergence (CA/C), 185, 212, 213 Cortical motion asymmetries, 157, 199, 201 Cortical pursuit movements, 152 Cortical visual motion, 14, 53, 139, 204, 205 Cortico-mesencephalic-cerebellar pathways, 141, 174, 176 Craniosynostosis, 42 Crossed fixation, 151, 152, 191–192, 196 Cyclodisparities, 53 binocular vertical, 54 vertical, 48 Cyclovergence, 46–48, 50, 52–54, 57 Cycloversion, 46, 54–56, 58 Cyclovertical divergence movement, 7, 8, 89 D Darwin, Charles, 147 Decortication, 118, 120, 140, 154, 155 Diopter base-in prism, 97–102 Directionality, 157, 169, 201, 227 Direction-sensitive ON-type retinal ganglion cells, 117 Dissociated deviation, infantile esotropia, 107–111 Dissociated esotonus, 104, 107–111, 113, 217 Dissociated horizontal deviation (DHD), 95, 96, 99, 102, 104, 109, 110, 113

Index Dissociated vertical divergence (DVD), 1, 3, 14, 17, 128 additivity with oblique muscle overaction, 18, 19 association with torticollis, 19 balancing movement, 20 clinical algorithm, differential diagnosis, 22 clinical phenomenology of, 22 dorsal light reflex, 7–9 fundamental treatment goals for, 20 latent nystagmus, 20, 23 neurophysiological explanation, 3 primary oblique muscle overaction and, 37 pseudoinferior oblique muscle overaction, 18 skew deviation, 9–11 superimposition of, 18 variable torsional component, 18 visuo-vestibular eye movements, 129 Dorsal cap (DC) of the inferior olive, 116 Dorsal light reflex, 3–6, 37, 46, 57, 83, 84, 88, 89, 91, 120, 128, 131, 196 dissociated vertical divergence, 7–9 Dorsal rotation, 83–84, 89 Dorsal terminal nucleus (DTN), 116, 117, 138, 154, 159, 166, 196, 201, 225, 231, 232 Double elevator palsy, 2 Dynamic imbalance, 43, 131 Dynamic torsional movements, 195 E Electrical microstimulation, 118 Esodeviation, 95, 100, 102, 107, 108, 184–187, 201, 212, 215 Esotonus, 139 Essential infantile esotropia (EIE), 144, 145, 163, 193, 196, 204 crossed fixation, 195 evolutionary basis of, 196–197 optokinetic etiology for, 200 prenuclear, 195 progressive nasalward deviation, 195 subcortical origin, 195 subcortical pathophysiology in, 197–199 Exaptation, 47, 54, 56–58, 89, 147 Exodeviation, 95–97, 99–103, 107, 110, 113, 183, 189, 213 Extraocular muscle overaction, 42 Extraocular muscles, 6, 9, 11, 26, 29, 30, 43, 45, 62, 65, 68, 71, 108, 123, 126, 129, 132, 134, 145, 156, 189, 197

Index F Fine-motor modulation, 53 Fixational innervation, 8, 17, 19, 31, 33, 35 Foveation periods, 165, 169, 171 FRMD7 gene, 232 Frontal binocular vision, 47, 58, 65, 127, 132 Fundamental dichotomy, 45 Fusional vergence amplitudes, 209, 214–215, 223 Fusion maldevelopment nystagmus, 81 Fusion maldevelopment syndrome, 205 G Gait, 34 Goldfish, dorsal light response in, 4, 5 H Handheld rotating drum, 152 Hering law, 8, 33 Hoffmann hypothesis, 198, 204 Horizontal nystagmus, 71 Horizontal optokinetic responses, video-­ oculography tracing of, 153–155 Human cyclovergence, 52, 53 Human dorsal light reflex amplitude of DVD, 86 binocular visual input, abrupt fluctuations, 84 central vestibular system, 90 dorsal rotation, 84 monocular occlusion, 86 patients and methods, 85 subjective tilt, 91 subjective vertical, 87, 89 subjective vertical retinal meridian, 90 true vertical, 87 twofold movement, 89 vision and balance, sensory organs for, 83 Human ocular torsion, 46 Hydrocephalus, 32–34, 38, 58 Hyperdeviation, 1–3, 6, 8, 11, 17–19, 94, 95, 214 I Idiopathic infantile nystagmus, 182, 232, 234 Infantile esotropia, 22, 42, 109, 110, 113, 137–141, 145, 191, 192, 227 Infantile Nystagmus, 165–182, 231–233 absence of oscillopsia, 169 cerebellar pathways, 173, 174 congenital visual loss, 172

243 conjugate oscillation, 165 directionality, 169 fixation, 172 foveation periods, 169 infantile nystagmus, 173 null position, 170 pendularity, 167 pursuit, 172 reversed optokinetic nystagmus, 171 seesaw nystagmus, 171 time of onset, 170 Infantile strabismus, 3, 14, 62, 95, 107, 120, 124, 125, 129, 132, 137, 139, 141, 151, 152, 154, 155, 166, 225, 227 Inferior oblique muscle overaction, 18, 25, 26, 28, 29, 32, 34, 35, 65, 86, 128, 129 Intermittent exotropia, 98, 105, 109, 110, 183–187, 189 Interoceptive stimulus, 14 Intrinsic ocular motor instability, 182 Inverse skew deviation, 10 Invoked vergence adaptation, 108 L Labyrinthectomy, 6, 68 Labyrinthine imbalance, 85, 131 Labyrinthine input, 4, 73, 129, 138 Labyrinths, 5, 43, 57, 65, 70, 76, 83, 85, 87, 89, 90, 117, 126, 130, 131, 135, 148, 167, 197 Latent nystagmus, 65, 66, 80, 127, 225 dissociated vertical divergence, 20 evolutionary underpinnings of, 73, 74 experimental evidence, 74, 75 nasotemporal asymmetry and, 66, 67 neuroanatomy of, 68, 69 superimposition of, 172–173 vestibular nystagmus, 67, 68 vestibular origin, clinical signs of, 70–73 visuo-vestibular eye movements, 129 Lateral eyes, 126 Lateral-eyed animals, 3, 11, 29, 38, 46, 50, 57, 67, 74, 76, 83, 88, 115, 127–129, 132, 135, 140, 166, 173, 176, 196, 200, 201, 225, 227 Lateral valvuli cerebelli, 6 Listing’s law, 50 Lichtruckenreflex, see Dorsal light reflex Lower lateral-eyed animals, 11, 38, 196 Luminance, 14, 15, 37, 38, 46, 74, 84, 108, 120, 123, 126–128 Luminance pathways, 120, 123

244 M Maddox Rods, 34, 49, 50 Medial superior temporal (MST), 68, 137, 138, 154, 157–159, 169, 174, 201 Medioterminal nucleus (MTN), 117 Melanopsin pathways, 14 Methadone moms, 182 Middle temporal (MT) visual area, 68 Monocular fixation, 8, 19, 72, 87, 95, 107, 113, 200, 207 Monocular nasotemporal optokinetic asymmetry (MNTA), 81, 127, 151, 152, 154, 155, 157–159, 192, 193, 196, 197, 199, 200, 225, 226, 229 neuroanatomy of, 197 Monocular occlusion, 11, 85–88, 209, 211–214, 217 Monocular optokinetic stimulation, sensitivity to, 119 Monocular visual loss, 108, 173 Monofixation syndrome, 145 Motion pathways, 80, 120 Muscle length adaptation, 36, 108, 215 N Nasalward movement, 66 Nasotemporal asymmetry, 86, 105, 127, 128, 192, 196, 204 Nasotemporal optokinetic asymmetry, 67, 120, 138, 151, 173, 192, 193 Neuroanatomy, latent nystagmus, 68, 69 Neurologic disorders, superior oblique muscle overaction and A-pattern strabismus in, 31, 34 Neurologic lesion, 10, 35, 38, 129, 141 Nonstereoscopic perception, 54–66 Nucleus of the optic tract (NOT), 67, 68, 75, 117, 127, 138, 154, 157, 159, 166, 168, 174, 192, 198, 225, 231, 232 Nucleus of the optic tract–dorsal terminal nucleus (NOT-DTN), 157, 159, 166, 225 Null position, 170, 171 O Oblique muscle function cyclovergence, stereoscopic perception, and Pitch Plane, 47, 48, 50, 52–54 cycloversion, nonstereoscopic perception and the Roll Plane, 54–56 frontal binocular vision, from visual panorama, 47

Index primary adaptations in, 45, 46 reversion, exaptation to adaptation, 56–58 Oblique muscle overaction, dissociated vertical divergence, 18 Oblique muscles, 46, 148, 149 inferior overaction, 18, 25, 26, 28, 29, 32, 34, 35, 65, 86, 128, 129 ocular, 150 primary overaction, 25, 26 pseudoinferior overaction, dissociated vertical divergence, 18 superior overaction, 25, 31, 33, 34 Oscillopsia, absence of, 169 Ocular motor incursions, visuo-vestibular eye movements, 127–129 Ocular motor system, vestibular interactions with, 26, 28–32, 173 Ocular oblique muscles, 150 Ocular stabilization, 31, 186 Ocular tilt reactions, 4, 10, 132 Ohm’s visual balancing metaphor, for dissociated vertical divergence, 128 Optical coherence tomography (OCT), 231 Optic flow, 67, 75, 138, 152, 154, 225–227 Optokinesis, 81, 123, 148, 163, 200, 231, 232 Optokinetic, 138, 141, 151–159, 191, 192, 231–233 Optokinetic eye movements, 69, 138, 170 Optokinetic input, 116, 131, 154, 155, 163, 172, 176, 191–193, 201, 204, 226 Optokinetic pathways, 70, 138, 151, 152, 154, 155, 158, 166, 170, 172–174, 176, 198, 227 Optokinetic responses, 68, 74 horizontal, video-oculography tracing of, 153 subcortical, 69 Orchid evolution, 63, 147 Otolithic pathways, 31, 36 Otoliths, 4, 6, 19, 29, 31, 57, 90, 131, 214 P Panum’s space, 54 Paradoxical movement, 150 Pendularity, 167–168 Perceived visual tilt, depiction of, 88 Perceptual correlates, human dorsal light reflex amplitude of DVD, 86 binocular visual input, abrupt fluctuations, 84 central vestibular system, 90 dorsal rotation, 84

Index monocular occlusion, 86 patients and methods, 85 subjective tilt, 91 subjective vertical, 87, 89 subjective vertical retinal meridian, 90 true vertical, 87 twofold movement, 89 vision and balance, sensory organs for, 83 Peripheral vestibular disease, 65 Periventricular leukomalacia, 34, 86, 137, 139 Phoria adaptation, 183–187, 189, 208, 223 accommodative esotropia, 212–213 binocular tonus mechanism, 223 congenital superior oblique palsy, 214 fusional vergence amplitudes, 215 intermittent exotropia, 213, 214 latent phoria, 212 measurement, 209 neural substrate, 215–216 orthophorization, 212 physiologic skew deviation, 214 postoperative prism adaptation, 214 protean clinical manifestations, 211–215 resilience, 210 spread of comitance, 215 stillness, 211 stimulus, 209 time course, 210 Photic stimulation, 120 Physiologic skew deviation, 215 Physiologic V pattern, 63 Pitch plane, 47, 49, 50, 52–54 Pitch-down body movement, 27, 28 Postoperative prism adaptation, 215 Postrotational nystagmus, 71 Postural control, 34 Predominant mechanism, 205 Primary adaptations, oblique muscle function, 45, 46 Primary inferior oblique muscle overaction, 25, 28, 35, 128, 129 Primary oblique muscle overaction, 25, 26 and dissociated vertical divergence, 37 and Hering’s law, 35, 36 central tonus mechanisms for, 26 congenital esotropia, inferior oblique muscle overaction and V-pattern strabismus in, 34, 35 gravistatic and visual input, physiologic effects of, 27 neurologic disorders, superior oblique muscle overaction and A-pattern strabismus in, 31, 34 nonneurologic causes of, 37, 38

245 ocular motor system, vestibular interactions with, 26, 28–32 phenomenon of, 42 Primary oblique overaction, visuo-vestibular eye movements, 129 Primitive reflexes, 1, 73, 126, 227 Primitive visual reflexes, 127, 129, 132 Prolonged occlusion, 35, 71, 186, 187, 215, 218 Prolonged subcortical neuroplasticity, potential role of, 199–200 Pseudoinferior oblique muscle overaction, 18 R Retinal disparity, 62, 185 Retinotectal input, 124 Reversed fixation test (RFT), 96, 97, 100, 104 advantage of, 103 horizontal deviation, 103 Reversed optokinetic nystagmus, 171 Roll plane, 54–56 S Seesaw nystagmus, 171 Semicircular canals, 29–31, 67, 68, 70, 71, 85, 117, 132, 157, 159, 167, 174 Sensory balance organs, 66, 76, 126, 132 Sensory disconjugate torsion, 42 Single binocular vision, 34, 35, 37, 38, 47, 83, 204 Skew deviation, dissociated vertical divergence, 9–11 Stereoisomers, vestibular reflexes, 132 Stereopsis, 7, 47, 50, 52, 54, 62, 63, 85, 127, 144, 145, 204, 205, 209 Stereoscopic effect, 50, 53 Stereoscopic perception, 47, 49, 50, 52–54 Structural neurologic disease, 58 Subcortical, 138, 140, 151, 152, 154, 155, 159, 196–201, 225, 227 Subcortical accessory optic system, 145, 163 Subcortical central vestibular pathways, 130 Subcortical mechanism, 14, 43, 155 Subcortical optokinesis, 163, 231 Subcortical optokinetic responses, 69, 154, 167, 172, 192 Subcortical visual pathways, 76, 120, 124, 138, 145, 155, 158, 159, 200 Subjective visual tilt, 87, 88, 90, 91 Subjective visual vertical, 20, 57, 88, 89, 93 Superior oblique muscle overaction, 18, 25, 31–34, 58, 86

246 Superior oblique palsy, 54 congenital superior oblique palsy, 214–215 T Telotactic, 6 Tenacious proximal fusion, 183, 213 Titmus stereoacuity test, 47 Tonic imbalances, 43, 131, 173 Tonic vergence, 207, 208, 210, 212, 217 Tonus, 19, 26, 27, 29, 32, 34–38, 43, 47, 66, 72, 80, 107, 130, 189, 208, 217 Torsional eye movements, 15, 45, 46, 56, 58, 90, 93, 115, 118, 120, 121, 123, 135, 137, 138, 145, 148, 171 Torticollis, 19, 22 Tropotactic, 5, 6 True hypertropia, 94 True vertical, 23, 87, 88, 93 U Umstimmung, 6 Unequal accommodative convergence, 96, 97, 100 Utricular ocular tilt reaction, 9 V Variable torsional component, 18 Ventral tegmental tract, 31, 32 Vergence adaptation, 108 Vertical cyclodisparity, 48, 54 Vertical head-tilt test, 36 Vestibular eye movements, 45, 67, 71, 120, 130 Vestibular interactions, with ocular motor system, 26, 29–31 Vestibular nystagmus, 65, 67–76 evolutionary underpinnings, latent nystagmus, 73–74

Index experimental evidence, 74–75 latent nystagmus, 68–70 vestibular origin, 70–73 Vestibular origin, clinical signs of, 70–73 Vestibular reflexes, 115, 120, 132 Vestibulocerebellum, 33, 117, 120, 173–175, 196, 215 Vestibulo-ocular movements, 29, 132 Vestibuloocular pathways, 32 Vestigial function, 148 Video-oculography, 23, 152, 153 Visual acuity, 85, 97, 109, 173, 231 Visual field, 7, 28, 67 Visual righting reflex, 4 Visual tilt perceived, depiction of, 88 subjective, 87 Visual stabilization mechanisms, 68 Visuo-vestibular, 8, 138, 140, 154, 158 Visuo-vestibular eye movements, 135, 196 balance organs, bilaterally symmetrical organs function as, 126 central vestibular disease, 131 from central vestibular imbalance, 130, 131 latent nystagmus, primary oblique overaction, and dissociated vertical divergence, 129 ocular motor incursions, 127–129 primitive reflexes, 126, 127 primitive visual reflexes, 129 sensory balance organs, lateral eyes, 126 subcortical central vestibular pathways, generated by, 130 visual reflexes, 132 Visuo-vestibular imbalance, 35, 65, 74, 131 Visuo-vestibular tonus predominates, 189 Volitional body movements, 15, 195 von Holst, Erich, 6 V-pattern strabismus, 32, 34–35, 86