Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics: Strabismus - New Concepts in Pathophysiology, Diagnosis, and Treatment

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Essentials in Ophthalmology

Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics B. Lorenz Editors

M. C. Brodsky

Essentials in Ophthalmology

Glaucoma

G. K. Krieglstein Series Editors

Cataract and Refractive Surgery

R. N. Weinreb

Uveitis and Immunological Disorders Vitreo-retinal Surgery Medical Retina Oculoplastics and Orbit Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics Cornea and External Eye Disease

Editors Birgit Lorenz Michael C. Brodsky

Pediatric Ophthalmology, NeuroOphthalmology, Genetics Strabismus - New Concepts in Pathophysiology, Diagnosis, and Treatment

Series Editors

Volume Editors

Günter K. Krieglstein, MD Professor and Chairman Department of Ophthalmology University of Cologne Joseph-Stelzmann-Straße 9 50931 Köln Germany

Birgit Lorenz, MD Professor of Ophthalmology Klinik und Poliklinik für Augenheilkunde Justus-Liebig-University UKGM GmbH Giessen Campus Friedrichstraβe 18 35392 Giessen Germany

Robert N. Weinreb, MD Professor and Director Hamilton Glaucoma Center Department of Ophthalmology University of California at San Diego 9500 Gilman Drive La Jolla, CA 92093-0946 USA

ISBN: 978-3-540-85850-8

Michael C. Brodsky, MD Professor of Ophthalmology and Neurology Mayo Clinic Department of Ophthalmology 200 First Street SW Rochester, MN 55905 USA

e-ISBN: 978-3-540-85851-5

DOI: 10.1007/978-3-540-85851-5 Library of Congress Control Number: 2009938957 © Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, speciﬁcally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microﬁlm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, 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. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: wmx-Design, Heidelberg Printed on acid-free paper 9 8 7 6 5 4 3 2 1 (www.springer.com)

Foreword

The Essentials in Ophthalmology series represents an unique updating publication on the progress in all subspecialties of ophthalmology. In a quarterly rhythm, eight issues are published covering clinically relevant achievements in the whole ﬁeld of ophthalmology. This timely transfer of advancements for the best possible care of our eye patients has proven to be eﬀective. The initial working hypothesis of providing new knowledge immediately following publication in the peer-reviewed journal and not waiting for the textbook appears to be highly workable. We are now in the third cycle of the Essentials in Ophthalmology series, having been encouraged by read-

ership acceptance of the ﬁrst two series, each of eight volumes. This is a success that was made possible predominantly by the numerous opinion-leading authors and the outstanding section editors, as well as with the constructive support of the publisher. There are many good reasons to continue and still improve the dissemination of this didactic and clinically relevant information.

G.K. Krieglstein R.N. Weinreb

Series Editors

Preface

The ﬁeld of strabismology has long suﬀered from a discrepancy between its levels of sophistication in practice and theory. Although its diagnostic and therapeutic armamentarium has become quite advanced, the scientiﬁc understanding of disease pathogenesis has remained rudimentary. Consequently, educational training in strabismus diagnosis and treatment has become a didactic exercise in “learning the rules.” Recent advances in epidemiology, neuroimaging, genetics, and neurobiology have revolutionized our understanding of strabismus. Conceptualizing strabismus within an evolutionary framework has advanced our understanding of why it arises and provided new clues to its neurological underpinnings. As new information is consolidated, we are beginning to formulate a uniﬁed

philosophy of strabismus that integrates new concepts of pathogenesis into the clinic. This book provides a compendium of chapters that highlight new ideas in the ﬁeld of strabismus. We have assembled an international panel of contributors who have advanced our understanding of strabismus pathogenesis. Some chapters are new while others are derived from recent seminal articles that have challenged our understanding of strabismus diagnosis and treatment. Original sources for these chapters are appropriately acknowledged. We thank our innovative authors for their important contributions, and hope that the reader ﬁnds this edition both stimulating and enlightening. Birgit Lorenz Michael C. Brodsky

Contents

Chapter 1 Epidemiology of Pediatric Strabismus Amy E. Green-Simms and Brian G. Mohney

2.1.3 2.2 2.2.1

1.1 1.2 1.2.1 1.2.1.1 1.2.1.2 1.2.1.3 1.2.1.4 1.2.1.5 1.2.2 1.2.2.1 1.2.2.2 1.2.2.3 1.2.2.4 1.2.2.5 1.2.3 1.3 1.4 1.4.1 1.4.2 1.5 1.6

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Forms of Pediatric Strabismus . . . . . . . . . . Esodeviations . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Esotropia . . . . . . . . . . . . . . . . . . . Accommodative Esotropia. . . . . . . . . . . . . . Acquired Nonaccommodative Esotropia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abnormal Central Nervous System Esotropia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sensory Esotropia . . . . . . . . . . . . . . . . . . . . . . Exodeviations . . . . . . . . . . . . . . . . . . . . . . . . . . Intermittent Exotropia. . . . . . . . . . . . . . . . . . Congenital Exotropia . . . . . . . . . . . . . . . . . . . Convergence Insuﬃciency. . . . . . . . . . . . . . Abnormal Central Nervous System Exotropia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sensory Exotropia . . . . . . . . . . . . . . . . . . . . . . Hyperdeviations . . . . . . . . . . . . . . . . . . . . . . . Strabismus and Associated Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Changing Trends in Strabismus Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . Changes in Strabismus Prevalence . . . . . . Changes in Strabismus Surgery Rates . . . Worldwide Incidence and Prevalence of Childhood Strabismus . . . . . . . . . . . . . . . Incidence of Adult Strabismus . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 1 1 2 2

2.2.3 2 2 2 3 3 3 3 3 3 3

2.1.2

Binocular Alignment System. . . . . . . . . . . . Long-Term Maintenance of Binocular Alignment . . . . . . . . . . . . . . . . . Vergence Adaptation. . . . . . . . . . . . . . . . . . .

2.2.4 2.2.5 2.2.6 2.3 2.3.1 2.3.2 2.3.2.1 2.4

4 4 4 4 4 7 7

Chapter 2 Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation David L. Guyton 2.1 2.1.1

2.2.2

12 13 14

14 14 15 16 17 18 19 19 19

21 22

Chapter 3 A Dissociated Pathogenesis for Infantile Esotropia Michael C. Brodsky 3.1 3.2 3.3 3.4

11 3.5 11 12

Muscle Length Adaptation . . . . . . . . . . . . . Modeling the Binocular Alignment Control System. . . . . . . . . . . . . . Breakdown of the Binocular Alignment Control System. . . . . . . . . . . . . . Clariﬁcation of Unanswered Questions Regarding the Long-Term Binocular Alignment Control System. . . . . . . . . . . . . . . . . . . . . . . . . Changes in Strabismus as Bilateral Phenomena . . . . . . . . . . . . . . . . . . . Changes in Basic Muscle Length . . . . . . . . Version Stimulation and Vergence Stimulation . . . . . . . . . . . . . . . . . . Evidence Against the “Final Common Pathway”. . . . . . . . . . . . . . . . . . . . . Changes in Strabismus . . . . . . . . . . . . . . . . . Diagnostic Occlusion: And the Hazard of Prolonged Occlusion . . . . . . . . . Unilateral Changes in Strabismus . . . . . . . Supporting Evidence for Bilateral Feedback Control of Muscle Lengths. . . . Applications of Bilateral Feedback Control to Clinical Practice and to Future Research . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dissociated Eye Movements . . . . . . . . . . . . Tonus and its relationship to infantile esotropia . . . . . . . . . . . . . . . . . . . Esotropia and Exotropia as a Continuum . . . . . . . . . . . . . . . . . . . . . . . . . . . Distinguishing Esotonus from Convergence . . . . . . . . . . . . . . . . . . . . . Pathogenetic Role of Dissociated Eye Movements in Infantile Esotropia . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25 25 26 28 29 30

x

Contents

Chapter 4 The Monoﬁxation Syndrome: New Considerations on Pathophysiology Kyle Arnoldi 4.1 4.2 4.2.1 4.3 4.3.1 4.3.2 4.3.3 4.4 4.4.1 4.5 4.5.1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Normal and Anomalous Binocular Vision . . . . . . . . . . . . . . . . . . . . . . . . Binocular Correspondence: Anomalous, Normal, or Both?. . . . . . . . . . . MFS with Manifest Strabismus . . . . . . . . . . Esotropia is the Most Common form of MFS. . . . . . . . . . . . . . . . . . . . . . . . . . . . Esotropia Allows for Better Binocular Vision . . . . . . . . . . . . . . . . . . . . . . . . Esotropia is the Most Stable Form. . . . . . . Repairing and Producing MFS . . . . . . . . . . Animal Models for the Study of MFS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary MFS (Sensory Signs of Infantile-Onset Image Decorrelation) . . . Motor Signs of Infantile-Onset Image Decorrelation . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5.1.10

5.1.11 33 33 34 35 35

5.1.1 5.1.2 5.1.3 5.1.4 5.1.5

5.1.6 5.1.7

5.1.8

5.1.9

Esotropia as the Major Type of Developmental Strabismus . . . . . . . . . . Early-Onset (Infantile) Esotropia . . . . . . . . Early Cerebral Damage as the Major Risk Factor . . . . . . . . . . . . . . . . . . . Cytotoxic Insults to Cerebral Fibers. . . . . . Genetic Inﬂuences on Formation of Cerebral Connections . . . . . Development of Binocular Visuomotor Behavior in Normal Infants. . . . . . . . . . . . . . . . . . . . . . . Development of Sensorial Fusion and Stereopsis . . . . . . . . . . . . . . . . . . Development of Fusional Vergence and an Innate Convergence Bias . . . . . . . . . . . . . . . . . . . . . . Development of Motion Sensitivity and Conjugate Eye Tracking (Pursuit/OKN) . . . . . . . . . . . . . Development and Maldevelopment of Cortical Binocular Connections . . . . . . . . . . . . . . . . .

5.1.13

5.1.14 5.1.15

35 36 36

5.1.16

37

5.1.17

38

5.1.18

38 39

5.2

5.2.1

Chapter 5 Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment Lawrence Tychsen 5.1

5.1.12

5.2.2

41 41 41 42 42

42 43

6.1 6.2 6.2.1 6.2.2 6.2.3 6.2.4 6.2.5 6.3 6.4 6.5 6.5.1 6.5.2

44

44 46

46

46 47

47 50 50 50

51 52 52 54

Chapter 6 Neuroanatomical Strabismus Joseph L. Demer

44

44

Binocular Connections Join Monocular Compartments Within Area V1 (Striate Cortex) . . . . . . . . . . . . . . . . . Too Few Cortical Binocular Connections in Strabismic Primate. . . . . . Projections from Striate Cortex (Area V1) to Extrastriate Cortex (Areas MT/MST) . . . . . . . . . . . . . . . . . . . . . . . . Inter-Ocular Suppression Rather than Cooperation in Strabismic Cortex . . . . . . . . . . . . . . . . . . . . Naso-Temporal Inequalities of Cortical Suppression . . . . . . . . . . . . . . . . . Persistent Nasalward Visuomotor Biases in Strabismic Primate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Repair of Strabismic Human Infants: The Historical Controversy . . . . . . Repair of High-grade Fusion is Possible. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Timely Restoraion of Correclated Binocular Input: The Key to Repair . . . . . . Visual Cortex Mechanisms in Micro-Esotropia (Monoﬁxation Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuroanatomic Findings in Area V1 of Micro-Esotropic Primates . . . . Extrastriate Cortex in Micro-Esotropa. . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.5.3 6.6

General Etiologies of Strabismus. . . . . . . . Extraocular Myopathy . . . . . . . . . . . . . . . . . . Primary EOM Myopathy . . . . . . . . . . . . . . . . Immune Myopathy . . . . . . . . . . . . . . . . . . . . . Inﬂammatory Myositis. . . . . . . . . . . . . . . . . . Neoplastic Myositis. . . . . . . . . . . . . . . . . . . . . Traumatic Myopathy . . . . . . . . . . . . . . . . . . . Congenital Pulley Heterotopy . . . . . . . . . . Acquired Pulley Heterotopy . . . . . . . . . . . . “Divergence Paralysis” Esotropia . . . . . . . . Vertical Strabismus Due to Sagging Eye Syndrome . . . . . . . . . . . . . . . . . Postsurgical and Traumatic Pulley Heterotopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . Axial High Myopia. . . . . . . . . . . . . . . . . . . . . . Congenital Peripheral Neuropathy: The Congenital Cranial Dysinnervation Disorders (CCDDs) . . . . . .

59 59 59 60 61 61 61 62 63 64 65 65 65

66

Contents

6.6.1 6.6.2 6.6.3 6.6.4 6.6.5 6.7 6.7.1 6.7.2 6.7.3 6.7.4 6.8 6.8.1 6.8.2 6.8.3

Congenital Oculomotor (CN3) Palsy. . . . . Congenital Fibrosis of the Extraocular Muscles (CFEOM) . . . . . . . . . . . Congenital Trochlear (CN4) Palsy. . . . . . . . Duane’s Retraction Syndrome (DRS). . . . . . . . . . . . . . . . . . . . . . . . Moebius Syndrome . . . . . . . . . . . . . . . . . . . . Acquired Motor Neuropathy. . . . . . . . . . . . Oculomotor Palsy . . . . . . . . . . . . . . . . . . . . . . Trochlear Palsy . . . . . . . . . . . . . . . . . . . . . . . . . Abducens Palsy . . . . . . . . . . . . . . . . . . . . . . . . Inferior Oblique (IO) Palsy . . . . . . . . . . . . . . Central Abnormalities of Vergence and Gaze . . . . . . . . . . . . . . . . . . Developmental Esotropia and Exotropia . . . . . . . . . . . . . . . . . . . . . . . . . . Cerebellar Disease. . . . . . . . . . . . . . . . . . . . . . Horizontal Gaze Palsy and Progressive Scoliosis . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67 67 69 69 70 71 71 71 71 71 72 72 72

Chapter 8 The Value of Screening for Amblyopia Revisited Jill Carlton and Carolyn Czoski-Murray 8.1 8.2 8.2.1

8.2.1.1 8.2.1.2 8.2.1.3 8.2.1.4 8.2.2 8.2.3 8.2.4

72 72

8.3

8.3.1 8.3.2 8.3.3 8.3.4

Chapter 7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives to Understand Ocular Motility Disorders Antje Neugebauer and Julia Fricke

8.3.5 7.1

7.1.1

7.1.1.1 7.1.1.2 7.1.1.3 7.2

7.2.1

7.2.1.1 7.2.1.2

7.2.2

Congenital Cranial Dysinnervation Disorders: Facts About Ocular Motility Disorders . . . . . . . . . . . . . . . . . . . . . . The Concept of CCDDs: Ocular Motility Disorders as Neurodevelopmental Defects . . . . . . . . . . Brainstem and Cranial Nerve Development. . . . . . . . . . . . . . . . . . . . Single Disorders Representing CCDDs . . . . . . . . . . . . . . . . . . . Disorders Understood as CCDDs . . . . . . . . Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders . . . . . . . . . . . . . . . Congenital Ocular Elevation Deﬁciencies: A Neurodevelopmental View . . . . . . . . . . . . . Brown Syndrome. . . . . . . . . . . . . . . . . . . . . . . Congenital Monocular Elevation Deﬁciency and Vertical Retraction Syndrome . . . . . . . . . . . A Model of some Congenital Elevation Deﬁciencies as Neurodevelopmental Diseases . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77

77 78 78 81

8.3.6 8.4 8.4.1 8.4.2 8.4.3 8.4.4 8.4.5 8.4.6

83

8.4.7 8.4.8

83 83

8.4.9 8.5 8.5.1

87 8.5.2 89 91

8.5.3

Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What Is Screening? . . . . . . . . . . . . . . . . . . . . . Screening for Amblyopia, Strabismus, and/or Refractive Errors. . . . . . . . . . . . . . . . . . . . . . . . Screening for Amblyopia . . . . . . . . . . . . . . . Screening for Strabismus . . . . . . . . . . . . . . . Screening for Refractive Error . . . . . . . . . . . Screening for Other Ocular Conditions . . Diﬀerence Between a Screening and Diagnostic Test . . . . . . . . . . . . . . . . . . . . Justiﬁcation for Screening for Amblyopia and/or Strabismus . . . . . . . . . . Recent Reports Examining Pre-School Vision Screening . . . . . . . . . . . . Screening Tests for Amblyopia, Strabismus, and/or Refractive Error. . . . . . . . . . . . . . . . . . . . . . . . . Vision Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cover-Uncover Test. . . . . . . . . . . . . . . . . . . . . Stereoacuity . . . . . . . . . . . . . . . . . . . . . . . . . . . Photoscreening and/or Autorefraction . . . . . . . . . . . . . . . . . . . . . . . . . What to Do with Those Who Are Unable to Perform Screening Tests?. . . . . . . . . . . . . . . . . . . . . . . . Who Should Administer the Screening Program? . . . . . . . . . . . . . . . . Treatment of Amblyopia. . . . . . . . . . . . . . . . Type of Treatment . . . . . . . . . . . . . . . . . . . . . . Refractive Adaptation . . . . . . . . . . . . . . . . . . Conventional Occlusion . . . . . . . . . . . . . . . . Pharmacological Occlusion . . . . . . . . . . . . . Optical Penalization . . . . . . . . . . . . . . . . . . . . Eﬀective Treatment of Amblyopia in Older Children (Over the Age of 7 Years). . . . . . . . . . . . . . . . Treatment Compliance . . . . . . . . . . . . . . . . . Other Treatment Options for Amblyopia. . . . . . . . . . . . . . . . . . . . . . . . . . Recurrence of Amblyopia Following Therapy . . . . . . . . . . . . . . . . . . . . . Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . The Impact of Amblyopia Upon HRQoL. . . . . . . . . . . . . . . . . . . . . . . . . . . Stereoacuity and Motor Skills in Children with Amblyopia. . . . . . . . . . . . . Reading Speed and Reading Ability in Children with Amblyopia. . . . . .

95 96

96 97 97 97 97 97 98 98

100 100 100 101 101

102 102 103 103 103 104 104 104

104 105 105 105 106 106 106 106

xi

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Contents

8.5.4 8.5.5 8.5.6 8.5.7 8.5.8

Impact of Amblyopia Upon Education. . . . . . . . . . . . . . . . . . . . . . . . Emotional Well-Being and Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Impact of Strabismus Upon HRQoL. . . . . . . . . . . . . . . . . . . . . . . . . . . Critique of HRQoL Issues in Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . The Impact of the Condition or the Impact of Treatment? . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10.2.4 106 107 107 108 108 109

9.1.1 9.1.2 9.2 9.2.1 9.2.2 9.2.3 9.3 9.3.1 9.3.2 9.3.3 9.4 9.4.1 9.4.2 9.4.3 9.5

Amblyopia and Amblyogenic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Early Detection of Amblyopia. . . . . . . . . . . Brückner’s Original Description . . . . . . . . . Corneal Light Reﬂexes (First Purkinje Images) . . . . . . . . . . . . . . . . . . Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . Shortcomings and Pitfalls . . . . . . . . . . . . . . Fundus Red Reﬂex (Brückner Reﬂex) . . . . Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . Possibilities and Limitations . . . . . . . . . . . . Pupillary Light Reﬂexes. . . . . . . . . . . . . . . . . Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . Possibilities and Limitations . . . . . . . . . . . . Eye Movements with Alternating Illumination of the Pupils . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

113 113 114 114 114 115 115 115 116 119 120 120 121 121 121 122 122

Amblyopia Treatment 2009 . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features of Amblyopia. . . . . . . . . . Diagnosis of Amblyopia . . . . . . . . . . . . . . . . Natural History . . . . . . . . . . . . . . . . . . . . . . . . . Amblyopia Management . . . . . . . . . . . . . . . Refractive Correction . . . . . . . . . . . . . . . . . . . Occlusion by Patching. . . . . . . . . . . . . . . . . . Pharmacological Treatment with Atropine . . . . . . . . . . . . . . . . . . . . . . . . . .

11.1 11.1.1 11.1.2 11.1.3

11.1.4 11.1.5 11.2 11.2.1 11.2.2 11.2.3 11.2.4 11.2.5

11.3 125 125 125 126 126 127 127 127 128 129

130 131 131 131 131 132 132 132 133 133 133 134

Chapter 11 Best Age for Surgery for Infantile Esotropia: Lessons from the Early vs. Late Infantile Strabismus Surgery Study H. J. Simonsz and G. H. Kolling

11.2.6

Chapter 10 Amblyopia Treatment 2009 Michael X. Repka 10.1 10.1.1 10.1.2 10.1.3 10.1.4 10.1.5 10.2 10.2.1 10.2.2 10.2.3

10.4 10.4.1 10.4.2 10.5 10.5.1

Chapter 9 The Brückner Test Revisited Michael Gräf 9.1

10.3 10.3.1 10.3.2 10.3.3 10.3.4

Pharmacological Therapy Combined with a Plano Lens. . . . . . . . . . . . Other Treatment Issues . . . . . . . . . . . . . . . . . Bilateral Refractive Amblyopia . . . . . . . . . . Age Eﬀect. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maintenance Therapy . . . . . . . . . . . . . . . . . . Long-Term Persistence of an Amblyopia Treatment Beneﬁt. . . . . . . . Other Treatments . . . . . . . . . . . . . . . . . . . . . . Filters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Levodopa/Carbidopa Adjunctive Therapy . . . . . . . . . . . . . . . . . . . . Controversy. . . . . . . . . . . . . . . . . . . . . . . . . . . . Optic Neuropathy Rather than Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11.3.1 11.3.2 11.3.3 11.3.4

11.3.5

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Deﬁnition and Prevalence . . . . . . . . . . . . . . Sensory or Motor Etiology . . . . . . . . . . . . . . Pathogenesis: Lack of Binocular Horizontal Connections in the Visual Cortex. . . . . . . . . . . . . . . . . . . . . History. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Outcome Parameters . . . . . . . . . . . . . . . . . . . Outcome of Surgery in the ELISSS. . . . . . . Reasons for the ELISSS. . . . . . . . . . . . . . . . . . Summarized Methods of the ELISSS. . . . . Summarized Results of the ELISSS . . . . . . Binocular Vision at Age Six. . . . . . . . . . . . . . Horizontal Angle of Strabismus at Age Six . . . . . . . . . . . . . . . . . . Alignment is Associated with Binocular Vision . . . . . . . . . . . . . . . . . . . Number of Operations and Spontaneous Reduction into Microstrabismus Without Surgery. . . . . . . The Number of Operations Per Child and the Reoperation Rate in the ELISSS. . . . . . Reported Reoperation Rates . . . . . . . . . . . . Test-Retest Reliability Studies . . . . . . . . . . . Relation Between the Postoperative Angle of Strabismus and the Reoperation Rate. . . . . . . . . . . . . . . . . . . . . . . Scheduled for Surgery, but no Surgery Done at the End of the Study at the Age of Six Years . . . . . . . . . . . .

137 137 137

138 138 138 139 139 139 140 140 140 141

142 142 142 144

145

145

Contents

11.3.6 11.3.7 11.3.8

Spontaneous Reduction of the Angle. . . . . . . . . . . . . . . . . . . . . . . . . . . . Predictors of Spontaneous Reduction into Microstrabismus . . . . . . . . Random-Eﬀects Model Predicting the Angle and its Variation . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

146 146

146 149 149

Chapter 12 Management of Congenital Nystagmus with and without Strabismus Anil Kumar, Frank A. Proudlock, and Irene Gottlob

12.3.6.2 12.3.6.3 12.3.6.4 12.3.6.5

12.1.1.1 12.1.2 12.1.2.1 12.1.3 12.1.3.1

12.2 12.2.1 12.2.2 12.2.3 12.2.3.4 12.2.3.5

12.2.3.6 12.2.3.7 12.3 12.3.1 12.3.1.1 12.3.1.2 12.3.1.3 12.3.1.4 12.3.2 12.3.3 12.3.4 12.3.5 12.3.6 12.3.6.1

Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Nystagmus with and Without Sensory Deﬁcits . . . . . . . . . . . The Clinical Characteristics of Congenital Nystagmus. . . . . . . . . . . . . . . Manifest Latent Nystagmus (MLN) . . . . . . Clinical Characteristics of Manifest Latent Nystagmus (MLN). . . . Congenital Periodic Alternating Nystagmus (PAN). . . . . . . . . . . . . . . . . . . . . . . Clinical characteristics of congenital periodic alternating nystagmus . . . . . . . . . . . . . . . . . Compensatory Mechanisms . . . . . . . . . . . . Dampening by Versions . . . . . . . . . . . . . . . . Dampening by Vergence . . . . . . . . . . . . . . . Anomalous Head Posture (AHP) . . . . . . . . Measurement of AHP. . . . . . . . . . . . . . . . . . . Eﬀect of Monocular and Binocular Visual Acuity Testing on AHP. . . . . . . . . . . . . . . . . . . . . . . . . Testing AHP at Near . . . . . . . . . . . . . . . . . . . . The Eﬀect of Straightening the Head in Patients with AHP . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Optical Treatment . . . . . . . . . . . . . . . . . . . . . . Refractive Correction . . . . . . . . . . . . . . . . . . . Spectacles and Contact Lenses (CL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Low Visual Aids. . . . . . . . . . . . . . . . . . . . . . . . . Medication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acupuncture. . . . . . . . . . . . . . . . . . . . . . . . . . . Biofeedback . . . . . . . . . . . . . . . . . . . . . . . . . . . Botulinum Toxin-A (Botox). . . . . . . . . . . . . . Surgical Treatment of Congenital Nystagmus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of Horizontal AHP . . . . . . . .

13.1 13.2

154 154

13.2.2

156 157

13.2.3 13.2.4

157 13.2.5 158 13.2.6 159 160 160 160 160 160

161 162 162 162 162 162

13.3 13.4

13.5

164 165

168 169

Dissociated Deviations . . . . . . . . . . . . . . . . . Surgical Alternatives to Treat Patients with DVD . . . . . . . . . . . . . . . . . . . . . . Symmetric DVD with Good Bilateral Visual Acuity, with No Oblique Muscles Dysfunction . . . . . . . . . . . . . . . . . . . Bilateral DVD with Deep Unilateral Amblyopia . . . . . . . . . . . . . . . . . . . DVD with Inferior Oblique Overaction (IOOA) and V Pattern . . . . . . . . DVD with Superior Oblique Overaction (SOOA) and A Pattern . . . . . . . Symmetric vs. Asymmetric Surgeries for DVD . . . . . . . . . . . . . . . . . . . . . . DVD with Hypotropia of the Nonﬁxating Eye . . . . . . . . . . . . . . . . . . . . . . . . Dissociated Horizontal Deviation . . . . . . . Dissociated Torsional Deviation. Head tilts in patients with Dissociated Strabismus . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

174 175

175 175 176 177 178 178 179

180 182 182

Chapter 14 Surgical Implications of the Superior Oblique Frenulum Burton J. Kushner and Megumi Iizuka 14.1 14.2 14.2.1

162 163 163 163 164 164 164

166 167 167

Chapter 13 Surgical Management of Dissociated Deviations Susana Gamio

13.2.1 12.1 12.1.1

Management of Vertical AHP . . . . . . . . . . . Management of Head Tilt. . . . . . . . . . . . . . . Artiﬁcial Divergence Surgery . . . . . . . . . . . Surgery to Decrease the Intensity of Nystagmus . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14.2.2

14.2.3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical and Theoretical Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . The Eﬀect of Superior Rectus Muscle Recession on the Location of the Superior Oblique Tendon Before and After Cutting the Frenulum. . . . . . . . . The Eﬀect of the Frenulum on Superior Oblique Recession Using a Suspension Technique. . . . . . . . . . The Theoretical Eﬀect of the Superior Oblique Frenulum on the Posterior Partial Tenectomy of the Superior Oblique . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

185 186

186

188

189 192

xiii

xiv

Contents

Chapter 15 Pearls and Pitfalls in Surgical Management of Paralytic Strabismus Seyhan B. Özkan 15.1

15.1.1 15.1.2 15.1.3 15.1.4 15.2 15.2.1 15.2.2 15.3 15.4

General Principles of Surgical Treatment in Paralytic Strabismus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aims of Treatment. . . . . . . . . . . . . . . . . . . . . . Timing of Surgery . . . . . . . . . . . . . . . . . . . . . . Preoperative Assessment . . . . . . . . . . . . . . . Methods of Surgical Treatment . . . . . . . . . Third Nerve Palsy. . . . . . . . . . . . . . . . . . . . . . . Complete Third Nerve Palsy . . . . . . . . . . . . Incomplete Third Nerve Palsy . . . . . . . . . . . Fourth Nerve Palsy . . . . . . . . . . . . . . . . . . . . . Sixth Nerve Palsy . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16.2 16.3 16.3.1 16.3.1.1 16.3.1.2 16.3.1.3 195 195 195 196 197 198 198 199 200 204 205

Chapter 16 Modern Treatment Concepts in Graves Disease Anja Eckstein and Joachim Esser 16.1 16.1.1 16.1.2 16.1.2.1 16.1.3 16.1.3.1 16.1.3.2 16.1.3.3 16.1.4

Graves Orbitopathy (GO): Pathogenesis and Clinical Signs. . . . . . . . . Graves Orbitopathy is Part of a Systemic Disease: Graves Disease (GD) . . . . . . . . . . . Graves Orbitopathy−Clinical Signs . . . . . . Clinical Changes Result in Typical Symptoms. . . . . . . . . . . . . . . . . . . . . . Clinical Examination of GO . . . . . . . . . . . . . Signs of Activity . . . . . . . . . . . . . . . . . . . . . . . . Assessing Severity of GO . . . . . . . . . . . . . . . Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Classiﬁcation of GO. . . . . . . . . . . . . . . . . . . . .

16.3.1.4 16.3.1.5

16.3.1.6 16.3.2 16.3.2.1 16.3.2.2 16.3.2.3 16.4 16.4.1 16.4.2

207 16.5 207 208 208 208 208 209 211 211

16.5.1 16.5.2 16.6 16.6.1 16.6.2 16.6.3

Natural History . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of GO . . . . . . . . . . . . . . . . . . . . . . . Active Inﬂammatory Phase . . . . . . . . . . . . . Glucocorticoid Treatment . . . . . . . . . . . . . . Orbital Radiotherapy . . . . . . . . . . . . . . . . . . . Combined Therapy: Glucocorticoids and Orbital Radiotherapy. . . . . . . . . . . . . . . Other Immunosuppressive Treatments and New Developments . . . . . . . . . . . . . . . . Therapy of Dysthyroid Optic Neuropathy [DON] and Sight-Threatening Corneal Breakdown . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Simple Measures that may Alleviate Symptoms . . . . . . . . . . . . . . . Inactive Disease Stages. . . . . . . . . . . . . . . . . Orbital Decompression . . . . . . . . . . . . . . . . . Extraocular Muscle Surgery. . . . . . . . . . . . . Lid Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thyroid Dysfunction and GO. . . . . . . . . . . . Association Between Treatment of Hyperthyroidism and Course of GO . . . . . Relationship Between TSH-Receptor-Antibody (TRAb) Levels and Orbitopathy. . . . . . . . . . . . . . . . . Environmental and Genetic Inﬂuence on the Course of GO . . . . . . . . . . Relationship Between Cigarette Smoking and Graves Orbitopathy. . . . . . . Genetic Susceptibility . . . . . . . . . . . . . . . . . . Special Situations . . . . . . . . . . . . . . . . . . . . . . Euthyroid GO . . . . . . . . . . . . . . . . . . . . . . . . . . Childhood GO. . . . . . . . . . . . . . . . . . . . . . . . . . GO and Diabetes . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

212 213 213 213 213 213 213

214 214 215 215 216 217 220 220

220 221 221 221 222 222 222 222 223

Contributors

Kyle Arnoldi

Susana Gamio

Ross Eye Institute Department of Ophthalmology, University at Buﬀalo, Ross Eye Institute, 1176 Main Street, NY, 14209, USA

Gallo 1330, Ricardo Gutierrez Children’s Hospital, Matienzo 1731 First Floor E, Buenos Aires, Captial Fedral 1426, Argentina, South America

Michael C. Brodsky

Irene Gottlob

Departments of Ophthalmology and Neurology, Mayo Clinic 200 First Street, SW Rochester, MN 55905, USA

Jill Carlton

Department of Ophthalmology, Ricardo Gutiérrez Children’s Hospital, Buenos Aires, Argentina

Health Economics and Decision Science, CHARR, University of Sheﬃeld, Regent Court, 30 Regent Street, Sheﬃeld, S1 4DA, UK

Michael Gräf

Carolyn Czoski-Murray

Amy E. Greenberg

Leeds Institute of Health Sciences, University of Leeds, Room 1.26, 6 Charles Thackrah Building, 101 Clarendon Road, Leeds LS2 9LJ, UK

Department of Ophthalmology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA

Joseph L. Demer Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Box 957002, Los Angeles, CA 90095-7002, USA

Anja Eckstein University Eye Hospital, Hufelandstraβe 55, 45122 Essen, Germany

Marinus J.C. Eijkemans Department of Public Health, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands

Department of Ophthalmology, Justus-Liebig-University Giessen, Giessen Campus, Friedrichstraβe 18, 35385 Giessen, Germany

David L. Guyton The Krieger Children’s Eye Center at the Wilmer Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-9028, USA

Megumi Iizuka University of Toronto, St. Michael’s Hospital, 61 Queen Street East, 8th Floor, Care of the Eye Clinic, Toronto, ON, Canada M5C 2T2

Gerold H. Kolling Department of Ophthalmology, University Clinic Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany

A. S. Anil Kumar Julia Fricke Department of Ophthalmology, Kerpener Straβe 62, 50937 Köln, Germany

Department of Ophthalmology, University of Leicester, UK

xvi

Contributors

Burton J. Kushner

Frank A. Proudlock

Department of Ophthalmology and Visual Sciences, 2870 University Avenue, Suite 206, Madison, WI 53705, USA

Department of Ophthalmology, Ricardo Gutiérrez Children’s Hospital, Buenos Aires, Argentina

Birgit Lorenz

Michael X. Repka

Department of Ophthalmology, Justus-Liebig-University Giessen Giessen Campus Friedrichstraβe 18, 35392 Giessen Germany

Brian G. Mohney Department of Ophthalmology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA

Antje Neugebauer Department of Ophthalmology, Kerpener Straβe 62, 50937 Köln, Germany

Seyhan B. Özkan Guzelhisar Mah. 35. sok. No: 8/A, 09010 Aydin, Turkey

Johns Hopkins University School of Medicine, Wilmer 233, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287-9028, USA

Huibert J. Simonsz Department of Ophthalmology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands

Lawrence Tychsen St Louis Children’s Hospital at Washington University Medical Center, 1 Children’s Place, St Louis, MO 63110, USA

Chapter 1

Epidemiology of Pediatric Strabismus

1

Amy E. Green-Simms and Brian G. Mohney

Core Messages ■

■

■

■

■

Recognition and diagnosis of the individual forms of childhood strabismus are important for the best preservation of visual function. Esotropia is the most common form of pediatric ocular deviation in the West, whereas exotropia predominates in the East. Accommodative esotropia is the most prevalent form of strabismus in the West, comprising half of all esodeviations. Congenital, or infantile, esotropia accounts for less than 10% of all pediatric esotropia, a ﬁgure much smaller than once widely believed. Intermittent exotropia is the second most common form of childhood strabismus in the West

1.1

Introduction

Strabismus, or squint, is a disorder of ocular alignment. This overarching term may be further characterized by the direction of the misalignment: the preﬁx eso- describes an inward ocular deviation; exo-, an outward deviation; and hyper-, a vertical deviation. Descriptive suﬃxes include -tropia, a manifest deviation in which fusional control is not present, and -phoria, a latent deviation that is controlled by fusion. Strabismus detection, classiﬁcation, and treatment are especially important in pediatric populations as strabismus is a leading factor in the development of amblyopia, or a loss in visual function resulting from inadequate or abnormal visual system stimulation. This strong connection with amblyopia diﬀerentiates pediatric from adultonset strabismus, wherein vision and stereopsis are less likely to be irreversibly harmed. In children, strabismus should be corrected to decrease the occurrence of amblyopia, to maximize the potential for stereopsis, and to straighten the visual axes of the eyes. This chapter will review recent data on the epidemiology of pediatric strabismus. The information will focus

■

■

■

and the most commonly diagnosed form of exodeviation worldwide. Hyperdeviations are uncommon, with fourth cranial nerve palsy being the most prevalent etiology. Major independent risk factors associated with strabismus development include: prematurity, central nervous system (CNS) impairment, low birth weight, family history, and refractive error. Recent studies have reported a decline in the number of surgeries performed for strabismus; however, population-based data of congenital esotropia in the United States conﬁrms a more stable rate.

solely on tropic deviations rather than phorias and will encompass worldwide incidence and prevalence as well as clinical characteristics of the various strabismus subtypes.

1.2 Forms of Pediatric Strabismus 1.2.1

Esodeviations

Esodeviations are characterized by an intermittent or constant inward deviation of the eye or eyes (Fig. 1.1). Esotropia comprises approximately 60% of all strabismus in the West [1] whereas only about 30% in the East [2]. In the United States, children are diagnosed with esotropia at a mean age of 3.1 years [3], and 90% of esodeviations occur by 5 years of age [4]. Esotropia is more commonly associated with amblyopia than either exo- or hypertropia, occurring in one of three esotropic children vs. 1 of 12 exo- or hypertropic children [5]. There is no signiﬁcant gender predilection among any of the following subtypes of childhood esotropia.

2

1

Epidemiology of Pediatric Strabismus

1.2.1.3

Acquired Nonaccommodative Esotropia

Acquired nonaccommodative esotropia deﬁnes children whose deviation develops after 6 months of age and is not associated with accommodative eﬀort. This subtype has typically been thought of as uncommon and as portending underlying neurological disease. However, a recent population-based study showed that it is the second most common form of childhood esotropia [3], with an incidence of 1 in 257 children and is rarely the result of neurologic disease [8].

1

Fig. 1.1 A child with esotropia

1.2.1.4 1.2.1.1 Congenital Esotropia Congenital esotropia, also known as infantile or essential infantile esotropia, is generally deﬁned as a neurologically intact child with a constant nonaccommodative esotropia that develops by 6 months of age. This term is often confusing as children do not typically present at birth with their deviation. Moreover, esotropia measuring up to 40 prism diopters (PD) between weeks 4 and 20 of life has been reported to resolve in 27% of children [6]. Congenital esotropia has, for decades, been considered the most common form of strabismus. However, more recent reports have demonstrated that congenital esotropia is much less common than once believed. In a recent incidence study among children born over a 30-year time period in the US, 1 in 403 live births developed congenital esotropia [7]. Other recent reports from the same population reported similar results, with infantile esotropia making up only 8.1% of all forms of esotropia [3].

1.2.1.2

Abnormal Central Nervous System Esotropia

Esotropic children with a developmental or neurologic disorder may be classiﬁed under central nervous system (CNS) defects regardless of the age at onset or form of esotropia. The most commonly associated conditions include cerebral palsy, developmental delay, Down syndrome, and seizure disorder. CNS-associated esotropia makes up approximately 10% of all diagnosed esodeviations [3].

1.2.1.5 Sensory Esotropia Sensory esotropia includes patients with a unilateral or bilateral ocular condition that prevents normal fusion. This form of esodeviation is commonly associated with anisometropic amblyopia as well as with disorders of deprivation such as cataract, corneal scarring, and retinal or optic nerve disorders [3].

Accommodative Esotropia

Accommodative esotropia is characterized by an acquired constant or intermittent deviation that is corrected or reduced 10 PD or more after wearing hyperopic spectacles full time for at least 3 weeks. Patients can further be classiﬁed as having fully accommodative esotropia, in which the deviation is reduced to ≤8 PD, or partially accommodative esotropia, in which there is a residual deviation of 10 or more PD. Accommodative esotropia, including both the partially and fully accommodative forms, comprises approximately one half of all pediatric esotropia in the United States and is the most prevalent form of childhood strabismus in the West [3]. This form of esodeviation has been reported to occur in 1 in 92 children [3].

Summary for the Clinician ■ ■

■

■

Accommodative esotropia comprises approximately half of all pediatric esotropia. Acquired nonaccommodative esotropia is the second most common form of esodeviation in the West and is rarely associated with neurologic disease. Congenital esotropia, once thought to be the most common esodeviation, makes up less than 10% of all esotropia diagnosed in childhood. Amblyopia occurs in one of three children with esotropia, a rate signiﬁcantly higher than in children with either exotropia or hypertropia.

1.2

1.2.2

Exodeviations

Exotropia is a disorder of ocular alignment characterized by an outward deviation of the eye or eyes (Fig. 1.2). Exotropia is less common than esotropia among Western populations [1]; however, it is the predominant form of strabismus in the East [2]. Regardless of the relative prevalence, the age at presentation for children with exotropia tends to be older than for those with esotropia [4]. Amblyopia is less commonly associated with exotropia than esotropia [5].

1.2.2.1 Intermittent Exotropia Intermittent exotropia is an acquired, intermittent deviation of 10 or more PD unassociated with other ocular, paralytic, or neurologic disorders. It is the second most commonly diagnosed form of strabismus (at approximately 17%) in the United States [1] and the most commonly diagnosed subtype of exodeviation with an incidence of 1 in 155 children [9]. In a recent populationbased study, it was reported to occur nearly twice as often in girls compared with boys [10].

1.2.2.2 Congenital Exotropia Congenital exotropia includes children with a constant exodeviation that develops by 6 months of age. Although this condition is rare, many children will have associated neurologic or other disorders and should undergo CNS imaging [11]. This form of exotropia results in amblyopia much more often than other subtypes of divergent strabismus.

Forms of Pediatric Strabismus

3

exodeviation at near. It is the second most commonly diagnosed type of exodeviation and comprises approximately one in ﬁve children with exotropia [9] with an incidence of 1 in 411 children [9]. However, this disorder is likely to be under-diagnosed given the obscure symptoms and relatively imperceptible nature of the deviation to outside observers.

1.2.2.4

Abnormal Central Nervous System Exotropia

Exotropic children with a congenital or acquired developmental or neurological disorder may be grouped under CNS defects regardless of the age at onset. Approximately, 15% of children with exotropia may have neurologic abnormalities, most commonly cerebral palsy and developmental delay [9].

1.2.2.5 Sensory Exotropia Sensory exotropia includes children with a unilateral or bilateral ocular condition that prevents normal fusion, most commonly anisometropic amblyopia or cataract [9]. Children with sensory disturbances are more likely to develop exotropia (24 of 235 children, or 10.2%) than esotropia (15 of 221 children, or 6.8%) [12]. This diﬀerence may be in part due to the age at onset of visual impairment. Havertape and coauthors have shown that children with a unilateral or bilateral visual loss by 6 months of age are more likely to develop sensory esotropia, whereas those with an acquired visual loss are much more likely to develop sensory exotropia [13].

1.2.2.3 Convergence Insuﬃciency Convergence insuﬃciency describes children who are generally orthotropic at distance ﬁxation but whose eyes do not converge suﬃciently at near ﬁxation, leaving an

Summary for the Clinician ■

■ ■

Exotropia is the predominant form of strabismus among Asian populations; however, it is less common than esotropia in the West. Intermittent exotropia is the most commonly diagnosed form of exodeviation. Amblyopia is less commonly associated with exotropia than esotropia.

1.2.3

Fig. 1.2 A child with exotropia

Hyperdeviations

Hypertropia, or a vertical displacement of one eye relative to the other, is the least diagnosed form of strabismus [1]. Nearly one-third of all cases are associated with fourth cranial nerve palsy (Fig. 1.3), corresponding to an incidence of 1 in 1,264 children [14]. Other causes of

4

1

Epidemiology of Pediatric Strabismus

a

1

included children with CNS disorders or acquired nonaccommodative esotropia, distinct forms of early-onset esotropia that have been shown to occur more frequently than infantile esotropia. Acquired nonaccommodative esotropia, on the other hand, appears to be relatively prevalent and is a form of esotropia that is much more likely to develop fusion and normal stereopsis with treatment [8]. Intermittent exotropia, the most common form of exodeviation, is more prevalent than any other form of strabismus in Asia and, as a result, may be the most prevalent form of strabismus worldwide.

b 1.4.2 Changes in Strabismus Surgery Rates

Fig. 1.3 A child with left fourth nerve palsy showing, (a) right head tilt and (b) left hypertropia with left head tilt

hypertropia include primary inferior oblique overaction, Brown syndrome, and CNS-associated hypertropia [14].

There have been several reports from the United Kingdom describing a decrease in the incidence of strabismus or strabismus surgery in recent years [21–24]. Explanations for this decline have included the implementation of childhood vision screening programs and the more frequent correction of the full hyperopic refractive error. Contrasting data, however, has come from Louwagie et al.’s population-based cohort study reporting on the incidence of infantile esotropia as well as the incidence of surgery for infantile esotropia in Rochester, Minnesota, US [7]. From 1965 through 1994, there was no signiﬁcant change in the numbers of children diagnosed with infantile esotropia, and there was no signiﬁcant change in the number of surgeries performed on these children.

Summary for the Clinician 1.3 Strabismus and Associated Conditions A number of studies have demonstrated an association between prenatal and environmental factors and the development of strabismus. Signiﬁcant independent risk factors for strabismus include: family history, prematurity, low birth weight, low Apgar scores (at 1 and 5 min), maternal cigarette smoking, increasing maternal age, retinopathy of prematurity, refractive error, and anisometropia [15–20].

1.4 Changing Trends in Strabismus Epidemiology

■

■ ■

Congenital esotropia appears to be less prevalent than previously believed, whereas other forms such as acquired nonaccommodative esotropia are relatively common. Intermittent exotropia may be the most prevalent form of strabismus worldwide. The rate of pediatric strabismus surgery has recently been reported to be in decline; however, data from a population-based cohort of children with congenital esotropia in the United States found no change in strabismus incidence or surgical rate over a 30-year period (1965–1994).

1.4.1 Changes in Strabismus Prevalence Our understanding of the prevalence of childhood strabismus continues to change. As discussed earlier, congenital esotropia has recently been reported to occur less commonly than once widely believed, comprising only 8.1% of all diagnosed esodeviations [3]. The previously reported higher incidence of infantile esotropia may have

1.5 Worldwide Incidence and Prevalence of Childhood Strabismus Recent reports describe the prevalence of pediatric strabismus as ranging from 0.12% in 1.5-year-old Japanese children [25] to 20.1% in a cohort of low birth weight

1.5

5

Worldwide Incidence and Prevalence of Childhood Strabismus

Table 1.1. Pediatric strabismus prevalence rates by regions of the world Reference

Categorical

Number

Age of

Strabismus

Esotropia

Exotropia

Hypertropia

descriptions

of

subjects

prevalence

prevalence

prevalence

prevalence

within the

children

(years)

(%)

(%)

(%)

(%)

study

examined

North America Canada [31]

946

1.6–11.6

4.3

[32]

1,074

<3

3.2

2.0

1.0

0.09

2,619

6

4.5

2.7

1.7

0.08

306

6–7

1.6

3.2

1.2

[33] USA

[34]

[15]

[35]

[27]

([3]a, [9]a, [14]a) Mexico

Caucasian Hispanic

548

6–7

0.9

All races

39,227

0–7

4.5

Caucasian

17,931

0–7

5.4

4.1

1.3

African American

19,619

0–7

3.6

2.3

1.3

Caucasian

119

8–16

3.4

Asian

310

8–16

2.9

Hispanic

1,781

8–16

1.8

Black

9

8–16

1/9

Hispanic

3,003

0.5–6

2.4

0.9

1.5

African American

3,005

0.5–6

2.5

1.1

1.4

0–19

3.9

2.3

1.3

0.3

[36]

Population-based 1,035

12–13

2.3

1.2

0.8

0.4

[37]

343

3–6

1.2

0.6

0.6

[38]

4,784

5–6

4.4

3.6

0.8

[39]

6,634

2

1.5

1.1

0.4

[40]

7,538

7

2.3

1.7

0.5

[41]

1,582

8–9

4.0

3.4

0.6

Europe England

Ireland

0.1

Denmark

[42]

14,107

0–19

4.5

3.5

0.9

0.1

Sweden

[43]

6,004

0–7

3.9

3.4

0.4

0.05

[44]

1,046

12–13

2.7

1.4

0.7

0.6

[45]

3,126

≤10

2.7b

1.5

0.6

[46] Croatia

143

4–15

3.5

2.8

0.7

All children

20,045

Unspeciﬁed

4.0

2.1

1.8

Term

17,163

Unspeciﬁed

3.3

1.7

1.6

Preterm

2,882

Unspeciﬁed

8.0

4.7

3.3

[20]

1,739

6

2.8

1.6

1.2

[48]

2,353

12

2.7c

0.9

1.1

0.2

[47]

Australia

0

Asia Malaysia

[49] [50]

650

8

2.2

Near ﬁxation

4,634

7–15

0.7

0.5

1.8

Distance ﬁxation

4,634

7–15

0.7

0.6

0.2

(continued)

6

1

Epidemiology of Pediatric Strabismus

Table 1.1. (continued) Reference

1 China

[51]

Categorical

Number

Age of

Strabismus

Esotropia

Exotropia

Hypertropia

descriptions

of

subjects

prevalence

prevalence

prevalence

prevalence

within the

children

(years)

(%)

(%)

(%)

(%)

study

examined

Near ﬁxation

4,364

5–15

1.9

1.6

Distance ﬁxation

4,364

5–15

3.0

2.6

1,084

6–14

2.5

0.4

2.1

86,531

6–12

1.3d

0.3

0.7

e

[52] Japan

[53]

Study year 2003

[54]

Study year 2005

84,619

6–12

1.0

0.2

0.6

[25]

Five consecutive

33,929 total

1.5

0.01–0.1

0–0.03

0–0.07

33,193 total

3

0.2–0.3

0.02–0.1

0.2–0.3

[55]

862

6, 8, 11

1.6f

0.5

0.9

Thailand

[56]

3,898

1

0.6

India

[57]

6,447

5–15

0.5

0.3

0.2

[58]

10,605

≤15

0.4

Nepal

[59]

1,100

5–16

1.6

0.09

1.5

[60]

1,816

5–16

1.3

[61]

38,000

1–2.5

1.3

0.9

0.3

0.4

0.2

0.5

0.8

0.5

0.3

measurements between years 2000 and 2004 Five consecutive measurements between years 2000 and 2004 Taiwan

0.02

Middle East Israel Oman

[62]

6,292

6–7, 11–12

0.6

[63]

143,112

6–7

0.5

Cameroon

[64]

11,230

≤26

1.2

Nigeria

[65]

1,144

4–24

0.3

Ghana

[66]

957

6–22

0.2

Tanzania

[67]

1,386

7–19

0.5

Madagascar

[68]

1,081

8–14

0.7

0.06

Africa

a

Study of incidence rather than prevalence Strabismus prevalence includes 19 cases of microtropia c Strabismus prevalence includes 16 cases of microtropia d Strabismus prevalence includes 245 cases of “unknown” and 20 cases of “other” types of strabismus e Strabismus prevalence includes 110 cases of “unknown” and 23 cases of “other” types of strabismus f Strabismus prevalence includes two cases of “other” strabismus b

English children [26]. Prevalence studies, reporting on the number of people with a speciﬁc disease at a prescribed point in time, are found most commonly in the pediatric strabismus literature. However, this type of study may only capture a snapshot of childhood ocular deviations. Incidence reports, on the other hand, by including the number of new cases diagnosed during a

speciﬁc period of time, may survey any number of characteristics and their changes over time. Table 1.1 includes recent strabismus prevalence and incidence data organized by regions of the world. One overarching trend is that strabismus prevalence rates differ based on racial and ethnic background. Esodeviations are found with a relatively higher prevalence among

References

Caucasian populations, while exodeviations are more commonly reported among Asian and African children. As shown, North American, European, and Australian data contrast with epidemiologic information gathered from multiple studies in Asia and Africa. This trend is additionally evident among non-Caucasians in the US. In the Multi-Ethnic Pediatric Eye Disease Study group’s work describing strabismus prevalence among Hispanic and African-American children, for instance, exotropia was diagnosed more commonly than esotropia [27]. The basis of this diﬀerence may be in part linked with population-based diﬀerences in refractive error. Esotropia is commonly associated with hyperopia, whereas exotropia is more often diagnosed in children with myopia [28].

Summary for the Clinician ■

The prevalence of strabismus subtypes varies based on racial and ethnic background; Asians are primarily diagnosed with exotropia whereas Europeans, Australians, and Americans are predominantly diagnosed with esotropia.

1.6 Incidence of Adult Strabismus Although there is substantially less epidemiological information regarding adult strabismus, its prevalence has been reported as approximately 4% in the United States [29]. In a study of strabismus patients over 60 years of age, 29% developed their ocular deviation in childhood [30]. Beauchamp and colleagues similarly found that a minority, or 38%, of strabismus patients between 17 and 92 years of age developed their deviation before visual maturation [29]. Common causes of adult strabismus in descending order include neuroparalytic, restrictive, and sensory factors [30].

References 1. Mohney BG (2007) Common forms of childhood strabismus in an incidence cohort. Am J Ophthalmol 144:465–467 2. Yu CB, Fan DS, Wong VW, et al (2002) Changing patterns of strabismus: a decade of experience in Hong Kong. Br J Ophthalmol 86:854–856 3. Greenberg, AE, Mohney BG, Diehl NN, et al (2007) Incidence and types of childhood esotropia: a populationbased study. Ophthalmology 114:170–174 4. Mohney BG, Greenberg AE, Diehl NN (2007) Age at strabismus diagnosis in an incidence cohort of children. Am J Ophthalmol 144:467–469

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5. Greenberg AE, Mohney BG, Diehl NN (2007) Prevalence of amblyopia in an incidence cohort of childhood strabismus. In: Transactions of the 31st meeting of the european strabismological association. Editor: Rosario Gomez de Liano. European Strabismological Association. DP- M-87972008. Madrid. Spain. Pg 51-54 6. Pediatric eye disease investigator group (2002) Spontaneous resolution of early-onset esotropia: experience of the Congenital Esotropia Observational Study.Am J Ophthalmol 133(1):109–118 7. Louwagie CR, Diehl NN, Greenberg AE, Mohney BG, et al (2009) Is the incidence of congenital esotropia declining? A population-based study from Olmsted County, Minnesota, 1965–1994. Arch Ophthalomol 127:200–203 8. Mohney BG (2001) Acquired nonaccommodative esotropia in childhood. JAAPOS 5(2):85–89 9. Govindan M, Mohney BG, Diehl NN, et al (2005) Incidence and types of childhood exotropia: a population-based study. Ophthalmology 112:1046–108 10. Nusz KJ, Mohney BG, Diehl NN (2005) Female predominance in intermittent exotropia. Am J Ophthalmol 140: 546–547 11. Hunter DG, Ellis FJ (1999) Prevalence of systemic and ocular disease in infantile exotropia: comparison with infantile esotropia. Ophthalmology 106:1951–1956 12. Mohney BG, Huﬀaker RK (2003) Common forms of childhood exotropia. Ophthalmology 110:2093–2096 13. Havertape SA, Cruz OA, Chu FC (2001) Sensory strabismus – eso or exo? J Pediatr Ophthalmol Strabismus 38: 327–330 14. Tollefson, MM, Mohney BG, Diehl NN, et al (2006) Incidence and types of childhood hypertropia: a population-based study. Ophthalmology 113:1142–1145 15. Chew E, Remaley NA, Tamboli A, et al (1994) Risk factors for esotropia and exotropia. Arch Ophthalmol 112: 1349–1354 16. Hakim RB, Tielsch JM (1992) Maternal cigarette smoking during pregnancy: a risk factor for childhood strabismus. Arch Ophthalmol 110:1459–1462 17. Holmstrom G, Rydberg A, Larsson E (2006) Prevalence and development of strabismus in 10-year-old premature children: a population-based study. J Pediatr Ophthalmol Strabismus 43:346–352 18. Mohney BG, Erie JC, Hodge DO, et al (1998) Congenital esotropia in Olmsted County, Minnesota. Ophthalmology 105:846–850 19. Pennefather PM, Clarke MP, Strong NP, et al (1999) Risk factors for strabismus in children born before 32 weeks’ gestation. Br J Ophthalmol 83:514–518 20. Robaei D, Rose KA, Kiﬂey A, et al (2006) Factors associated with childhood strabismus: ﬁndings from a populationbased study. Ophthalmology 113:1146–1153 21. Arora A, Williams B, Arora AK, et al (2005) Decreasing strabismus surgery. Br J Ophthalmol 89:409–412

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Epidemiology of Pediatric Strabismus

22. Carney CV, Lysons DA, Tapley JV (1995) Is the incidence of constant esotropia in childhood reducing? Eye 9(Suppl): 40–41 23. Ferguson JA, Goldacre MJ, Henderson J, et al (1991) Ophthalmology in the Oxford region: analysis of time trends from linked statistics. Eye 5(Pt 3):379–384 24. MacEwen CJ, Chakrabarti HS (2004) Why is squint surgery in children in decline? Br J Ophthalmol 88:509–511 25. Matuso T, Matsuo C, Matsuoka H, et al (2007) Detection of strabismus and amblyopia in 1.5- and 3-year-old children by a preschool vision-screening program in Japan. Acta Med Okayama 61(1):9–16 26. O’Connor AR, Stephenson TJ, Johnson A, et al (2002) Strabismus in children of birth weight less than 1701 g. Arch Ophthalmol 120:767–773 27. Multi-ethnic pediatric eye disease study group (2008) Prevalence of amblyopia and strabismus in African American and Hispanic children ages 6 to 72 months. Ophthalmology 115:1229–1236 28. Lambert SR (2002) Are there more exotropes than esotropes in Hong Kong? Br J Ophthalmol 86:835–836 29. Beauchamp GR, Black BC, Coats DK, et al (2003) The management of strabismus in adults – I. clinical characteristics and treatment. J AAPOS 7:233–240 30. Magramm I, Schlossman A (1991) Strabismus in patients over the age of 60 years. J Pediatr Ophthalmol Strabismus 28:28–31 31. Drover JR, Kean PG, Courage ML, et al (2008) Prevalence of amblyopia and other vision disorders in young Newfoundland and Labrador children. Can J Ophthalmol 43:89–94 32. Kornder LD, Nursey JN, Pratt-Johnson AJ, et al (1974) Detection of manifest strabismus in young children 1. A prospective study. Am J Ophthalmol 77:207–210 33. Kornder LD, Nursey JN, Pratt-Johnson AJ, et al (1974) Detection of manifest strabismus in young children 2. A retrospective study. Am J Ophthalmol 77:211–214 34. Fischbach LA, Lee DA, Englehardt RF, et al (1993) The prevalence of ocular disorders among Hispanic and Caucasian children screened by the UCLA mobile eye clinic. J Community Health 18(4): 201–211 35. Voo I, Lee DA, Oelrich FO (1998) Prevalences of ocular conditions among Hispanic, white, Asian, and black immigrant students examined by the UCLA mobile eye clinic. J Am Optom Assoc 69:255–261 36. Ohlsson, J, Villarreal G, Sjostrom A, et al (2003) Visual acuity, amblyopia, and ocular pathology in 12- to 13-yearold children in northern Mexico. J AAPOS 7:47–53 37. Juarez-Munoz, IE, Rodriguez-Godoy ME, GuadarramaSotelo ME, et al (1996) Frecuencia de trastornos oftalmologicos comunes en poblacion preescolar de una delegacion de la Ciudad de Mexico. Salud Publica Mex 38:212–216

38. Graham PA (1974) Epidemiology of strabismus. Br J Ophthalmol 58:224–231 39. Stayte M, Johnson A, Wortham C (1990) Ocular and visual defects in a geographically deﬁned population of 2-yearold children. Br J Ophthalmol 74:465–468 40. Williams C, Northstone K, Howard M, et al (2008) Prevalence and risk factors for common vision problems in children: data from the ALSPAC study. Br J Ophthalmol 92:959–964 41. Donnelly UM, Stewart NM, Hollinger M (2005) Prevalence and outcomes of childhood visual disorders. Ophthalmic Epidemiol 12:243–250 42. Frandsen AD (1960) Occurrence of squint: a clinicalstatistical study on the prevalence of squint and associated signs in diﬀerent groups and ages of the Danish population [dissertation] Acta Ophthalmol 62(Suppl):1 43. Nordlow W (1964) Squint – the frequency of onset at different ages, and the incidence of some associated defects in a Swedish population. Acta Ophthalmol (Copenh) 42: 1015–1037 44. Ohlsson J, Villarreal G, Sjostrom A, et al (2001) Visual acuity, residual amblyopia and ocular pathology in a screened population of 12–13-year-old children in Sweden. Acta Ophthalmol Scand 79:589–595 45. Kvarnstrom G, Jakobsson P, Lennerstrand G (2001) Visual screening of Swedish children: an opthalmological evaluation. Acta Ophthalmol Scand 79:240–244 46. Gronlund MA, Andersson S, Aring E, et al (2006) Ophthalmological ﬁndings in a sample of Swedish children aged 4–15 years. Acta Ophthalmol Scand 84:169–176 47. Karlica D, Galetovic D, Znaor L, et al (2008) Strabismus incidence in infants born in Split-Dalmatia county 2002– 2005. Acta Clin Croat 47:5–8 48. Robaei D, Kiﬂey A, Mitchell P (2006) Factors associated with a previous diagnosis of strabismus in a populationbased sample of 12-year-old Australian children. Am J Ophthalmol 142:1085–1087 49. Teoh GH, Yow CS (1982) Prevalence of squints and visual defects in Malaysian primary one school children. Med J Malaysia 37(4):336–337 50. Goh P-P, Abqariyah Y, Pokharel GP, et al (2005) Refractive error and visual impairment in school-age children in Gombak district, Malaysia. Ophthalmology 112: 678–685 51. He M, Zeng J, Liu Y, et al (2004) Refractive error and visual impairment in urban children in southern China. Invest Ophthalmol Vis Sci 45:793–799 52. Lu, P, Chen X, Zhang W, et al (2008) Prevalence of ocular disease in Tibetan primary school children. Can J Ophthalmol 43:95–99 53. Matsuo T, Matsuo C (2005) The prevalence of strabismus and amblyopia in Japanese elementary school children. Ophthalmic Epidemiology 12:31–36

References 54. Matsuo T, Matsuo C (2007) Comparison of prevalence rates of strabismus and amblyopia in Japanese elementary school children between the years 2003 and 2005. Acta Med Okayama 61(6):329–334 55. See L-C, Song H-S, Ku W-C, et al (1996) Neglect of childhood strabismus: Keelung Ann-Lo community ocular survey 1993–1995. Chang Gung Med J 19: 217–224 56. Tengtrisorn S, Singha P, Chuprapawan C (2005) Prevalence of abnormal vision in one-year-old Thai children, based on a prospective cohort study of Thai children. J Med Assoc Thai 88(Suppl 9):S114–S120 57. Murthy GVS, Gupta SK, Ellwein LB, et al (2002) Refractive error in children in an urban population in New Delhi. Invest Ophthalmol Vis Sci 43:623–631 58. Nirmalan PK, Vijayalakshmi P, Sheeladevi S, et al (2003) The Kariapatti pediatric eye evaluation project: baseline ophthalmic data of children aged 15 years or younger in southern India. Am J Ophthalmol 136: 703–709 59. Nepal BP, Koirala S, Adhikary S, et al (2003) Ocular morbidity in schoolchildren in Kathmandu. Br J Ophthalmol 87:531–534 60. Shrestha RK, Joshi MR, Ghising R, et al (2006) Ocular morbidity among children studying in private schools of Kathmandu valley: a prospective cross sectional study. Nepal Medical College Journal 8(1):43–46

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61. Friedman Z, Neumann E, Hyams SW, et al (1980) Ophthalmic screening of 38,000 children, age 1 to 2 ½ years, in child welfare clinics. J Pediatr Ophthalmol Strabismus 17:261–267 62. Lithander J (1998) Prevalence of amblyopia with anisometropia or strabismus among schoolchildren in the Sultanate of Oman. Acta Ophthalmol Scand 76:658–662 63. Khandekar RB, Abdu-Helmi S (2004) Magnitude and determinants of refractive error in Omani school children. Saudi Med J 25(10):1388–1393 64. Ebana Mvogo C, Bella-Hiag AI, Epesse E (1996) Le strabisme au Cameroun. J Fr Ophtalmol 19:705–709 65. Ajaiyeoba AI, Isawumi MA, Adeoye AO, et al (2007) Pattern of eye diseases and visual impairment among students in southwestern Nigeria. Int Ophthalmol 27:287–292 66. Ntim-Amponsah CT, Ofosu-Amaah S (2007) Prevalence of refractive error and other eye diseases in schoolchildren in the greater Accra region of Ghana. J Pediatr Ophthalmol Strabismus 44:294–297 67. Wedner SH, Ross DA, Balira R, et al (2000) Prevalence of eye diseases in primary school children in a rural area of Tanzania. Br J Ophthalmol 84:1291–1297 68. Auzemery A, Andriamanamihaja R, Boisier P (1995) Enquete sur la prevalence et les causes des aﬀections oculaires chez les enfants des ecoles primaries d’Antananarivo. Cahiers Sante 5:163–166

Chapter 2

Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation1

2

David L. Guyton

Core Messages ■

■

■

Patients with long-standing unilateral strabismus, such as “sensory” exotropia in the absence of fusion or esotropia with unilateral amblyopia, typically show bilateral deviations under anesthesia, often symmetric. Forced ductions usually show symmetric muscle tightness. Changes in extraocular muscle lengths thus appear to occur primarily bilaterally, whether or not fusion is present. With skeletal muscles responding to changes in stimulation by the gain or loss of sarcomeres, it is likely that abnormal or unguided vergence tonus,

2.1 Binocular Alignment System A vexing problem in the ﬁeld of strabismus is what causes strabismus to change over time. For example, why do patients with accommodative esotropia develop a basic component over time [2, 3]? Why do torsional deviations develop, with accompanying A and V patterns [4]? Why does superior oblique paresis change in its pattern of deviation over time? When vision is lost in one eye, or simply when fusion is lost, why does sensory exotropia develop? If we can get a handle on the underlying mechanism involved in these changes, we may be able to better guide our research and improve the care we give to our patients. This chapter is intended to provide some further insight to this predominant underlying mechanism that induces changes in strabismus, to a large extent, bilaterally. This does not refer to strabismus

1

Adapted from [1]. Reprinted with permission of the publisher.

■

which changes the lengths of the extraocular muscles bilaterally, is largely responsible for changes in the angle of strabismus over time. This mechanism helps explain the development of (1) increasing “basic” deviations in accommodative esotropia, (2) torsional deviations with apparent oblique muscle “overaction/underaction” and A and V patterns, (3) recurrent esotropia with early presbyopia, (4) occasional divergence insufﬁciency in presbyopes, and (5) basic cyclovertical deviations that mimic superior oblique muscle paresis.

in terms of the ﬁxation pattern, but rather in terms of the relative basic lengths of the extraocular muscles and the tonus of their vergence innervation. Before discussing the bilateral nature of strabismus changes, the two basic mechanisms are reviewed that regulate long-term binocular alignment.

2.1.1

Long-Term Maintenance of Binocular Alignment

In the normal situation, sensorimotor fusion maintains binocular alignment on a moment-by-moment basis, but there are two further mechanisms that maintain binocular alignment in the long term. The ﬁrst is a neurologic one, “vergence adaptation,” and the second is a muscular one, “muscle length adaptation.”

12

2

Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation

2.1.2 Vergence Adaptation

2

Neurologically, retinal image disparity invokes a fusional vergence response which moves the eyes in opposite directions to eliminate the retinal image disparity, accurate to within a few minutes of arc, both horizontally and vertically. This is sometimes called “fast” fusional vergence. It responds to retinal image disparity in less than a second, and if one eye is suddenly covered, it decays in 10–15 s or less [5]. It is feedback from fast fusional vergence that stimulates changes in tonic vergence, or vergence tonus, over time [6]. This process is sometimes called “slow” vergence, or vergence adaptation. Vergence adaptation occurs selectively for diﬀerent directions of gaze and for diﬀerent distances, as if the brain establishes a table of how much innervational tonus to provide to each extraocular muscle to keep the eyes aligned in each direction of gaze and at each distance – horizontally, vertically, and torsionally [7]. The eﬀects of vergence adaptation can persist for minutes to hours and perhaps much longer. Vergence adaptation wears oﬀ slowly when one eye is occluded or during sleep, but much faster in the presence of a competing vergence [6]. This mechanism was phenomenologically described as long ago as 1868 by Hering (cited in [8]), and in 1893 by Maddox (cited in [9]). Alfred Bielschowsky actually studied this early in his career, reporting with Hofmann in 1900 that vergence adaptation decays slowly, and with an exponential time course (cited in [10]). It has been studied extensively by Ellerbrock [8], Ogle and Prangen [11], Carter [6], Crone [12], Schor [10], and many others [9]. Clearly, by supplying learned tonus levels to keep the eyes roughly aligned in various direction of gaze, vergence adaptation signiﬁcantly eases the burden on sensorimotor fusion, leaving sensorimotor fusion free to ﬁne-tune the alignment of the eyes [6]. Vergence adaptation provides a tonic neural compensation for ocular deviations. It eliminates the anisophoria produced by new anisometropic spectacle lenses. It begins to decay slowly when one eye is covered, as evidenced by the “screening-up” of ocular deviations when measuring with the prism and alternate cover test. In the longer term, it is responsible for the “eating up” of prisms over minutes to days in the process called prism adaptation. Clinically, we often try to uncover the underlying deviation by occluding one eye. For example, Lancaster redgreen plots of incomitant strabismus with partial fusion often show best alignment in primary gaze, and in the reading position, those directions of gaze that are most used and, therefore, best adapted to. After a 30-min patch test, the plotted tropia often increases in these directions

of gaze, with increased comitance of the overall pattern of deviation [13]. However, maximum neuronal ﬁring rates impose limits on how much misalignment can be compensated for by vergence adaptation. In particular, orbital changes with skeletal growth require not only lengthening of the extraocular muscles, but also require relative changes in functional muscle length that are far beyond the capabilities of neurologic adaptation. It is the process of muscle length adaptation that comes to the rescue.

2.1.3

Muscle Length Adaptation

The topic of muscle length adaptation does not appear in most texts on strabismus. The historic assumptions have been that extraocular muscle lengths are determined genetically, and that the basic forms of strabismus are due to primary abnormalities in muscle anatomy, in innervation, or in neurologic tonus. However, there must be dynamic mechanisms involved in the regulation of basic muscle length which normally play a critical role in the long-term maintenance of binocular alignment. Tracer studies have shown that skeletal muscles throughout the body undergo continuous remodeling throughout life. In fact, the half-life of the contractile proteins in adult skeletal muscles is only 7–15 days [14]. Muscle physiologists in France and England [14– 16] discovered in the 1970s and 1980s that skeletal muscles intrinsically adapt their lengths, by serial addition or subtraction of sarcomeres at the ends of the myoﬁbrils, to maintain the proper overlap of the actin and myosin myoﬁlaments so as to obtain optimal force generation, velocity, and power output over the range of motion through which the muscle is most used [17]. The exact biologic mechanism that accomplishes this is still unknown. In 1994, Alan Scott [18] showed that the extraocular muscles can adapt their lengths in the same way as the other skeletal muscles throughout the body. He sutured one eye of a monkey to the lateral orbital wall in an exotropic position of approximately 30 prism diopters. After 2 months, when the basic lengths of the extraocular muscles were examined, the medial rectus muscle had gained sarcomeres, and the lateral rectus muscle had lost sarcomeres in the experimental animal, compared with control animals operated in the same manner and sacriﬁced immediately. Change in skeletal muscle length is not only responsive to the position in which the muscle is held, but also, and most importantly, in the case of the extraocular muscles, to the stimulation that it receives. If a muscle is not

2.2 Modeling the Binocular Alignment Control System

held in a stretched position, increased stimulation causes actual loss of sarcomeres with shortening of the basic muscle length [15, 16, 19]. This change in basic muscle length in response to the level of stimulation is precisely in the right direction to help maintain binocular alignment. In fact, it is probably the chronic average level of vergence tonus, as maintained by vergence adaptation and contributed to by the current level of fast fusional vergence, which provides the primary input to extraocular muscle length adaptation. This further feedback mechanism, that is, vergence tonus regulating muscle length adaptation, completes the dynamic feedback system for maintenance of long-term binocular alignment (Fig. 2.1). Retinal image disparity elicits fast fusional vergence, which leads in the short term to vergence adaptation, producing a change in vergence tonus, which stimulates muscle length adaptation over a longer term, all of which reduce the retinal image disparity. Each level of this marvelous three-level feedback process also works in the direction to ease the burden on the level that precedes it. Vergence adaptation frees up fast fusional vergence to be able to respond accurately to rapid changes in retinal image disparity. Muscle length adaptation relieves vergence adaptation of excessive demands, which would otherwise saturate neuronal ﬁring rates, and thereby eﬀectively resets vergence adaptation so that it can continue to function optimally in response to input from fast fusional vergence.

Basic muscle lengths (vergence tonus) Approx. functional muscle lengths (acute stimulation) Exact functional muscle lengths [perturbation] Retinal image disparity (diplopia) Fast fusional vergence Vergence adaptation Vergence tonus Muscle length adaptation

Fig. 2.1 Three-level dynamic feedback system for the maintenance of binocular alignment

13

2.2 Modeling the Binocular Alignment Control System The basic components are now in place to model the binocular alignment control system (Fig. 2.1), beginning with the existing basic muscle length of each muscle, determined by the number of sarcomeres. Each muscle is stimulated by the current level of vergence tonus to result in the approximate functional muscle length (the physical length) to yield aligned eyes. Acute vergence stimulation supplied by fast fusional vergence completes the binocular alignment process. However, a perturbation suddenly occurs, such as a hormonal growth spurt with a change in the divergence of the orbits, new glasses with a small change in prism eﬀect, or simply a switch of the object of regard from the computer screen to the bird out the window. Such a perturbation requires diﬀerent eye alignment and will thus result in misaligned eyes for the new task if no compensation is made. Nevertheless, misaligned eyes cause retinal image disparity, with a double image of the bird out the window, which the brain does not like. Hence, the brain responds with fast fusional vergence, changing the acute stimulation levels to the muscles. This yields new functional muscle lengths in the proper direction to compensate for the original perturbation, and realigns the eyes. Something else now happens. Sustained fast fusional vergence leads to vergence adaptation, which adjusts the basic level of vergence tonus to ease the burden on fast fusional vergence, freeing it to be able to respond to the next perturbation. However, there is a limit to the amount of vergence tonus that can be sustained, so something further happens. In response to the amount of overall vergence tonus, the muscle lengths slowly adapt to new basic lengths in the proper direction to reduce the original retinal image disparity. Once the basic muscle lengths have adapted, the neurologic feedback mechanisms that the original perturbation brought into play can subside, with the eyes aligned once again. Furthermore, the neurologic mechanisms can now be maximally responsive to the next perturbation. This is the normal functioning of the long-term (as well as short-term) binocular alignment control system. This is the feedback scheme that keeps the eyes aligned during the growth of the skull in early life, throughout the development of hand–eye coordination in oblique directions of gaze, and throughout the development of presbyopia, which would otherwise cause a signiﬁcant disruption of near vs. distance alignment.

14 2.2.1

2

2

Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation

Breakdown of the Binocular Alignment Control System

However, what happens when something goes wrong with this feedback system? Surely it is possible that abnormalities can be present, or can develop, at various levels within this system, any of which will lead to misalignment of the eyes. The most common abnormality is probably the absence of, or loss of, fast fusional vergence, which is simply referred to as fusion. Fusion is at a most critical position in this feedback pathway system. If fusion does not occur in response to retinal image disparity, stimulation levels do not change appropriately, and the entire system breaks down. With loss of input from the fast fusional vergence system, the longer-term mechanisms for binocular alignment, vergence adaptation [20], and muscle length adaptation [4] become freewheeling – in other words, without guidance. Neurologic feedback mechanisms do not necessarily shut oﬀ when their input disappears. They will often continue to function at a basal level, with a low level of output being generated. This basal output level can be biased in one direction or the other, and therefore, in this case, can continue to drive the muscle length adaptation mechanism slowly in one direction or the other, producing strabismus that was not there in the ﬁrst place, or causing progressive misalignment if strabismus was already present. A prime example of this mechanism is the phenomenon we call “sensory” exotropia. With loss of vision in one eye, fusion is lost, and as we have assumed in the past, the eye simply passively drifts outward over time. From this feedback mechanism, we can begin to understand that if one eye develops poor vision, and therefore, if the eyes have no need for convergence, the average vergence stimulation to the extraocular muscles (which had previously maintained alignment equilibrium) will shift slightly to less convergence and more divergence, actively driving the eyes into a position of exotropia. This sensory exotropia can thus be seen to be not a passive process after all, but an active driving of the eyes outward by the otherwise normal alignment mechanisms that have lost proper guidance.

2.2.2

Clariﬁcation of Unanswered Questions Regarding the Long-Term Binocular Alignment Control System

The description of the above-mentioned three-stage feedback model of the long-term binocular alignment control system is not new. Upon appreciating the evidence in the

literature that muscle length adaptation can be responsive to stimulation, the above-mentioned model was ﬁrst described by the author in a paper in Binocular Vision and Eye Muscle Surgery Quarterly in 1994 [4], with further elaboration in 2005 [21]. The model explained how defects in fusion, or the loss of fusion, which for this purpose were considered the same as loss of vision in one eye, could lead to “sensory”-type changes in strabismus. In particular, in the torsional dimension, lack of proper feedback to the torsional control mechanism would be expected to produce what we dubbed “sensory torsion,” leading to the development of what is probably erroneously called primary oblique muscle overaction, or underaction, with accompanying A- or V-pattern strabismus. It was not clear in 1994, however, whether extraocular muscle length adaptation responds to version stimulation. That is, will an extraocular muscle adapt its length for optimal function in the position in which it is held most of the time by version stimulation? If so, what are the relative roles of version and vergence stimulation in the regulation of extraocular muscle length? New observations have clariﬁed these questions. These observations, the resulting clariﬁcation, and the consequences to our understanding of strabismus are expected beneﬁts from this chapter.

2.2.3 Changes in Strabismus as a Bilateral Phenomenon The primary new observation of the author is that changes in strabismus occur, to a large extent, bilaterally. This is not speaking of strabismus in terms of the ﬁxation pattern, but rather in terms of the relative basic lengths of the extraocular muscles and the tonus of their innervation. In the case of sensory exotropia, one eye is always ﬁxing, and the other eye gradually turns outward over time. However, there is usually mild limitation of adduction of both eyes, and when that patient is put to sleep, very often both the eyes turn out. Figures 2.2–2.4 show examples of this bilateral phenomenon in patients with sensory exotropia. This observation was ﬁrst made by the author 25 years ago after a recess-resect procedure on a patient with sensory exotropia. The sensory exotropia recurred. When the patient was put back to sleep for a repeat recess-resect procedure on the same eye, the previously operated eye was straight. It was the sound eye that was turning out signiﬁcantly. The muscle changes that caused the original sensory exotropia had occurred bilaterally. Arthur Jampolsky [22] reported this phenomenon in 1986, but he oﬀered no explanation for it.

2.2 Modeling the Binocular Alignment Control System

Fig. 2.2 Eighty-year-old woman with dense amblyopia in her left eye since childhood, ﬁxing with her right eye only, all her life. Note the left sensory exotropia (top). Under general anesthesia (bottom), both eyes turn out, equally – and signiﬁcantly farther than the usual divergence seen under anesthesia

There is more evidence that changes in strabismus occur bilaterally over time. Infants with esotropia and amblyopia, where the amblyopic eye is practically constantly adducted during waking hours, usually show some limited abduction bilaterally and symmetric positions of the eyes under anesthesia. Furthermore, during surgery, both medial rectus muscles are usually equally and abnormally tight. They are both abnormally short. These children sometimes show a small head turn, ﬁxing with the sound eye in slight adduction [23], consistent with a short medial rectus muscle in the sound eye as well as in the amblyopic eye. Figure 2.5 shows the same phenomenon in an adult with esotropia and long-standing unilateral ﬁxation. There is still further evidence that changes in strabismus occur bilaterally. The torsional changes that are associated with primary A and V patterns are practically always bilateral, although sometimes asymmetric. If the eye with greater elevation in adduction is operated upon with an inferior oblique weakening procedure, the other eye soon shows as much or more elevation in adduction.

15

Fig. 2.3 Twenty-one-year-old man with left sensory exotropia (top), from a left macular scar since birth, with counting ﬁngers vision in his left eye. His eyes also turn out essentially equally under anesthesia (bottom)

2.2.4

Changes in Basic Muscle Length

These changes in strabismus occur because the muscles change their basic length, i.e., the number of sarcomeres. A basically short muscle has fewer sarcomeres than normal, and a basically long muscle has more sarcomeres than normal. As noted before, skeletal muscles are continually changing their basic lengths throughout life, by the serial addition or subtraction of sarcomeres, for optimal function in the position where they are usually held. However, if this were the only mechanism by which extraocular muscle basic lengths are regulated, we should expect the patient with sensory exotropia to show only the poor vision eye turning out under anesthesia, because the exodeviated eye would have adapted its muscle lengths for optimal function centered in far abduction. But this is not what we observe. Usually, both eyes in sensory exotropia turn out under general anesthesia, signiﬁcantly more than the usual divergence seen under anesthesia. There must be another mechanism that causes basic muscle

16

2

Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation

2

Fig. 2.4 Thirty-eight-year-old man after a right optic nerve injury 15 years before, with resulting blindness in his right eye. The ﬁxing left eye (top) turns out abnormally under anesthesia (bottom), but not as much as the blind right eye. Not every patient turns out equally

lengths to change bilaterally, and that mechanism is most surely related to stimulation, given the fact that chronic electrical stimulation has been shown to shorten muscles by causing the loss of sarcomeres [15].

2.2.5 Version Stimulation and Vergence Stimulation What type of stimulation do the extraocular muscles normally receive? If one thinks about it, the extraocular muscles between the two eyes are yoked as much as, or more than, any other muscles in the body. They are heavily bilaterally innervated. They are linked in versions, movements of the two eyes in the same directions, and in vergences, movements of the two eyes in opposite directions. Versions allow us to look in diﬀerent directions, while vergences allow us to change our gaze from distance to near. However, vergences also, and most importantly, ﬁne-tune both eyes to be aligned with the object of regard, in any direction of gaze and at any distance, as part of the process of sensorimotor fusion. Disparity between the two eyes’ images invokes a fusional vergence

Fig. 2.5 Thirty-four-year-old woman with esotropia since childhood with ﬁxation with her left eye only (top), for many years. Both eyes turn in signiﬁcantly under anesthesia (bottom)

response which moves the eyes in opposite directions to eliminate image disparity, accurate to within a few minutes of arc, both horizontally and vertically. Might one of these types of stimulation, version stimulation or vergence stimulation, be involved in the regulation of basic muscle lengths for long-term alignment of the two eyes? Clearly, version stimulation would not be expected to be useful in such regulation, because version stimulation moves both the eyes in the same direction. If the extraocular muscles do change their basic lengths in response to version stimulation, then in the normal state, the eﬀect would average to zero over time as the eyes look about in various directions. Vergence stimulation, on the other hand, is precisely the type of bilateral stimulation which could play a role in muscle length adaptation. If the basic muscle lengths of the extraocular muscles are altered for any reason from their current lengths, image disparity will be sensed by the brain, and fusional vergence will occur to restore binocular alignment. The same fusional vergence that realigns the eyes momentarily, leads via vergence adaptation to changes in vergence tonus. Changes in vergence tonus, representing chronic changes in the levels of stimulation,

2.2 Modeling the Binocular Alignment Control System

can indeed serve as the necessary and suﬃcient stimuli for chronic muscle length adaptation to adjust the basic muscle lengths. In the normal situation it is not necessary to postulate that basic extraocular muscle lengths respond only to vergence stimulation and not to version stimulation. As both vergence stimulation and version stimulation occur, both could be slowly stimulating muscle length adaptation. However, the eﬀect of the version stimulation would average out to zero over time. The vergence stimulation, on the other hand, would exert a net eﬀect, changing the basic muscle lengths in the directions necessary to reduce the need for the vergence stimulation in the ﬁrst place – a marvelous negative-feedback servomechanism, as pointed out previously. The mechanism just proposed would work in the normal situation, but there is strong evidence from what happens in strabismic states that extraocular muscle length adaptation responds to vergence stimulation primarily, and only minimally to version stimulation. And that is a fundamental diﬀerence between extraocular muscles and the other skeletal muscles. The evidence is the same as that noted earlier simply the observation that chronic monocular deviations of the eyes, as in sensory exotropia or in esotropia with unilateral amblyopia, practically always become binocular deviations under anesthesia, with bilaterally abnormal basic muscle lengths. The argument is this: In constant strabismic states where there is no fusion, there is no signiﬁcant fusional vergence stimulation, but version stimulation still exists. If the extraocular muscles should adapt their lengths according to version stimulation, then the muscle lengths in the deviating eye in the patient with sensory exotropia would totally adapt to the deviated position. The sound eye, spending its average time in straight ahead gaze, would have normal muscle lengths. However, this is clearly not the case, because in most cases of sensory exotropia, both eyes turn out under anesthesia, and in most cases of esotropia with unilateral amblyopia, the two eyes are essentially symmetric under anesthesia. By forced duction testing, especially in the cases of esotropia, the basic muscle lengths are clearly bilaterally abnormal. The position of the eyes when asleep probably has little or no eﬀect on muscle length adaptation, because Breinin has shown that electrical activity in the extraocular muscles essentially disappears in deep sleep [24], and decreased stimulation of skeletal muscles signiﬁcantly slows down muscle length adaptation, as shown by denervation experiments [19]. Figure 2.6 shows a patient illustrating the ineﬀectiveness of version stimulation. The muscle lengths clearly did not adapt to the positions in which the eyes were held by chronic everyday version stimulation.

17

Fig. 2.6 Thirty-three-year-old woman with esotropia since birth. Only her right eye was operated for the esotropia at the age of 2½ years. She has ﬁxed with her LE only (top), as long as she can remember, because of mild hyperopia and amblyopia in her right eye. Neither eye has adapted to these positions, because when she is placed under deep anesthesia (bottom), both the eyes deviate rightward. The muscle lengths clearly did not adapt in response to chronic everyday version stimulation

Therefore we must conclude that the stimulation from vergence tonus is the primary regulator of extraocular muscle length adaptation, and that its eﬀects are bilateral. In this regard, the regulation of the extraocular muscle lengths appears to be fundamentally diﬀerent from the regulation of the lengths of other skeletal muscles. Only the extraocular muscles experience this bilateral vergence stimulation. The other skeletal muscles receive primarily unilateral stimulation, or bilateral stimulation akin to version stimulation, and their lengths are responsive to these forms of stimulation as well as to stretching or slackening of the muscles depending on use.

2.2.6

Evidence Against the “Final Common Pathway”

There is a potential problem with the conclusion that vergence tonus is the primary regulator of extraocular

18

2

2

Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation

muscle length adaptation, and that its eﬀects are bilateral. Neurophysiologists, with few exceptions [25], have long believed that version and vergence stimulation, while arising in diﬀerent centers in the brainstem, are combined into a “ﬁnal common pathway” at the motoneurons whose axons constitute the motor nerves to the extraocular muscles [26, 27]. In other words, it has been believed that version and vergence stimulation are indistinguishable by the time the impulses reach the extraocular muscles. If that were the case, extraocular muscle length adaptation could not be preferentially responsive to vergence stimulation. Recent evidence suggests, however, that version and vergence signals may indeed remain segregated in the motor nerves and stimulate different ﬁber types in the extraocular muscles [28, 29]. It is tempting to speculate that those ﬁber types receiving vergence stimulation are those primarily responsible for muscle length adaptation, but such details have not yet been worked out. Recent experiments by Joel Miller support the notion of segregation of version and vergence signals by demonstrating that measured extraocular muscle tension shows discrepancies with electrical activity [30]. These observations argue against the ﬁnal common pathway concept and at least allow the thesis that vergence tonus is primarily responsible for muscle length adaptation.

2.3 Changes in Strabismus However, if the basic muscle lengths change primarily in response to vergence stimulation, how does constant strabismus change over time, when there is presumably no fusional vergence stimulation occurring? It is easy to answer this question in the case of sensory exotropia, because other forms of vergence are occurring. With poor vision in one eye, there is no advantage or incentive to actively align the eyes, or even to converge them when looking up close. With less convergence occurring than before vision was lost in one eye, and at least in older individuals, the normal balance between convergence and divergence is upset in favor of a slight divergence bias, and this divergence bias slowly but actively shortens both lateral rectus muscles and lengthens both medial rectus muscles over time, resulting in increasing exotropia. The deviation, of course, shows up only in the eye with poor vision, until the patient is put under anesthesia, when both the eyes turn out. Some patients with loss of vision or fusion develop esotropia, especially when vision is lost in early infancy. Vertical misalignment can also develop when vision is lost in one eye. It has been argued before that abnormal

ocular torsion, with associated A and V patterns, are forms of sensory deviations developing over time when fusion is faulty or absent [4]. Clearly, the simple decreased need to converge that occurs when vision is lost in one eye cannot explain the development of esotropia, vertical deviations, or torsional deviations. The many diﬀerent ways that strabismus can change over time, if linked to changes in vergence tonus, require a more general explanation. The explanation, as noted earlier, probably lies in the very nature of biologic control systems. When input to such control systems shuts down, the output rarely goes to zero, but rather goes to a baseline state that may be biased on either side of zero output. In the case of the ocular motor control systems, when the eyes become misaligned enough that fusional vergence cannot operate, retinal image disparities do not result in corrective vergences. In this case, the fusional vergence control mechanisms for horizontal, vertical, and torsional alignment probably do not shut down entirely, but rather decrease their outputs to small nonzero levels, with persistent weak vergence signals biased in one direction or the other, with the direction of this bias depending upon numerous factors. For example, young children often have a stronger convergence bias than divergence bias, as evidenced by the relative frequency of esotropia vs. exotropia in infancy. This may simply be a manifestation of more hyperopia in childhood, with the attendant increased convergence tonus from accommodative convergence. If vision is lost in one eye in early infancy, it is not surprising that a nonzero convergence bias in the horizontal alignment control system could shorten the medial rectus muscles over time, resulting in sensory esotropia. Likewise, when fusion is faulty or absent, either primarily or from horizontal misalignment early in life, a baseline output bias in the torsional alignment mechanism can drive the eyes into torsional misalignment with apparent oblique muscle dysfunction and accompanying A and V patterns. The torsion is often seen at ﬁrst only when awake, disappearing when under anesthesia [31]. Later, as the oblique muscle lengths change, the fundus torsion persists under anesthesia [32]. Still later, after soft tissue remodeling occurs in response to the chronic ocular torsion (the author’s interpretation), the eyes move more along the torted planes deﬁned by the muscle insertions, showing clinical oblique muscle “overaction” (elevation or depression in adduction), and on MRI studies, the connective tissue “pulleys” may be seen to have shifted [33] (the author’s interpretation). Furthermore, a baseline output bias in the cyclovertical alignment mechanism can drive the eyes into a basic

2.3

cyclovertical misalignment, a cyclovertical misalignment which we often call congenital superior oblique paresis, probably mistakenly, because we have no other term for it. Most cases of esotropia are not attributed to sixth nerve palsy, but we persist in attributing many cyclovertical deviations of unknown cause to fourth nerve palsy. Problems at other points in these control mechanisms can perhaps lead to strabismus in the ﬁrst place. An abnormality in vergence adaptation has been proposed to cause divergence insuﬃciency or convergence excess [34]. Poor or absent fusion from birth, in combination with a robust AC/A ratio, could lead to imbalance of muscle length adaptation on the eso side, with progressive esotropia, which we would call congenital esotropia. Alternatively, a higher than normal AC/A ratio [35] could strain fusion suﬃciently to cause intermittent esotropia, which would then progress to a constant esotropia [2, 3] by the feedback mechanisms just noted. In intermittent exotropia, only a minor defect in fusion could be the initial problem, but as fusion deteriorates, the feedbackdeprived muscle length adaptation mechanism will cause progressive worsening. Convergence brought into play to damp some forms of nystagmus clearly disrupts the normal alignment control mechanism, leading directly to shortened medial rectus muscles and esotropia. This is the “nystagmus blockage” or “nystagmus compensation” mechanism originally described by Adelstein and Cüppers (cited in [36]). And now that we know that manifest latent nystagmus as well as congenital nystagmus can be damped by convergence [37], this mechanism may be involved in Ciancia’s syndrome as well [38].

2.3.1 Diagnostic Occlusion: And the Hazard of Prolonged Occlusion Diagnostic occlusion of one eye has long been used as a valuable method to break down vergence adaptation to uncover the underlying deviation. Such occlusion will not reverse the eﬀects of muscle length adaptation in the short term, but will simply reduce the eﬀects of vergence adaptation over an exponential time course. Thirty to forty-ﬁve minutes of monocular occlusion are usually long enough to eliminate most vergence adaptation [13], although diagnostic monocular occlusion for up to 1–2 weeks has been reported. If diagnostic occlusion is continued for days, eliminating fusion, there is a very real possibility of creating new deviations by the stimulation of new extraocular muscle length adaptation. In the 1920 and 1930s, Marlow advocated occlusion for 7–10 days to fully uncover latent

Changes in Strabismus

19

deviations [39–41]. By careful study of Marlow’s published graphs [40], it is apparent that after 3–5 days of monocular occlusion, signiﬁcant changes in the monitored deviations often began to appear, and worsen. For example, hyperdeviations and torsional deviations began to appear when there had been none previously. Also, the occluded eye most often developed a hyperdeviation, regardless of which eye was covered, speaking against the uncovering of a latent hyperdeviation [42–44]. Rather than the uncovering of latent deviations, “Marlow occlusion” may indeed have promoted the onset of unguided vergence adaptation and even the onset of muscle length adaptation, with new deviations beginning to occur. The same may be the case in more recent studies by Viirre et al. [45] in monkeys, and by Liesch and Simonsz [46] in normal human subjects. In these studies, new vertical and torsional deviations were noted after 7 days of monocular occlusion of the monkeys and after 3 days of monocular occlusion of the human subjects.

2.3.2 Unilateral Changes in Strabismus Clearly, not all changes in strabismus are bilateral. Patients with loss of fusion from sixth nerve palsy develop an increasingly short and tight ipsilateral medial rectus muscle. The contralateral rectus muscle does not shorten concomitantly. This represents unilateral muscle length adaptation, but from a diﬀerent mechanism. When a skeletal muscle continues to be stimulated but is not stretched out from time to time, it progressively shortens via the active loss of sarcomeres [16]. This is the mechanism demonstrated by Alan Scott by suturing his monkey’s eye temporally [18], and is the mechanism determining changes in the medial and/or lateral rectus muscles in various types of Duane’s syndrome as documented by Collins, Jampolsky, and Howe [47] and by Castañera de Molina and Giñer Muñoz [48].

2.3.2.1

Supporting Evidence for Bilateral Feedback Control of Muscle Lengths

What further evidence is there for bilateral feedback control of muscle lengths? We have previously demonstrated that patients with consecutive esotropia following surgery for intermittent exotropia often develop intorsion or extorsion of the eyes, with accompanying oblique muscle overaction and A or V patterns, after having lost fusion for only 1 month [4, 49]. We attribute this to a type of “sensory torsional” deviation due to muscle length adaptation in the torsional dimension.

Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation

Weldon Wright, Katie Gotzler, and the author have recently collected a large series of patients with early presbyopia, mostly with deﬁcient or absent fusion, who have developed progressive esotropia probably from the increased convergence tonus accompanying the increasing eﬀort to accommodate. Seeking evidence that such patients are fairly common, we tabulated all the patients that the author had operated on for esotropia over a 17-year period where a reliable onset of the esotropia could be established. Compared with a similar number of patients operated on for exotropia, the esotropia population showed a signiﬁcantly increased onset of esotropia in their 30s and 40s, as expected [21]. This mechanism, involving muscle length adaptation, is probably responsible for other reports of esotropia developing in adulthood [50, 51] and is similar to the mechanism of hypoaccommodative esotropia occurring in children, as ﬁrst described by Costenbader [52]. Elizabeth Bell, Adam Bowen, and the author have also identiﬁed a series of presbyopic patients, aged 50 years and older, who either had a small amount of uncorrected hyperopia, or who often tried to function without needed correction for near, and developed divergence insuﬃciency in the later decades of life. They had intermittent or constant esotropia in the distance with diplopia, but could still fuse at near. They are best corrected by bilateral medial rectus muscle recessions [53, 54], with the ﬁnding that both medial rectus muscles tend to be tighter than normal by forced ductions at the beginning of surgery. In these patients, we suspect that chronic activation of the near triad [55], which can provide improved visual acuity via slight pupillary constriction, causes increased convergence tonus, leading to shortened medial rectus muscles and the characteristic pattern of divergence insuﬃciency. Of interest is that the presbyopic patients identiﬁed with uncorrected or undercorrected hyperopia showed a somewhat linear increase of distance esotropia with the amount of hyperopia (Bell, Bowen, and Guyton, unpublished). In the cyclovertical “plane,” which is not really a plane after all, we have long suspected that there should be a thing such as a basic cyclovertical deviation, an analog of straightforward esotropia in the horizontal plane. Recent evidence suggests that the oblique muscles play a much larger role in cyclovertical fusion than previously expected [56–58]. A chronic level of cyclovertical vergence might indeed drive the eyes into a basic cyclovertical deviation, one involving both the vertical rectus muscles and the oblique muscles. But what is this basic cyclovertical deviation? We do not have a name for it. The vast majority of idiopathic cyclovertical deviations are termed congenital superior oblique paresis, or congenital superior oblique palsy. Yet, recent

studies have shown that many patients with these deviations have superior oblique muscles with normal cross-sectional area and normal contractility [59, 60]. Demer et al. wrote in 1995 [59], “Of 19 SO muscles diagnosed to be palsied based on clinical criteria, MRI demonstrated that about half exhibited normal cross-sectional size and contractile characteristics.” Might there be no superior oblique paresis at all in these patients? After all, we do not speak of patients with congenital esotropia as having sixth nerve paresis! Howard Ying, Nicholas Ramey, and the author are currently investigating the patterns of cyclovertical strabismus that they can create in normal subjects. They have constructed a special haploscope that allows adaptation to increasing vertical, torsional, or horizontal disparities, with near ﬁxation, with ﬁelds of view of over 50°, utilizing video-oculography for recording. The entire apparatus can tilt, up to 45°, to the right or left. To conﬁrm the capability of this apparatus, Fig. 2.7 shows the expected counter roll with head tilt to the right and left before any adaptation. So far, we have adapted normal subjects to vertical disparities increasing to 6° for 30–45 min. With adaptation, we expect to ﬁnd that the hyperdeviations induced are accompanied by torsional changes, and that the patterns of misalignment induced, especially with forced head tilting, will help explain the patterns that heretofore have been associated with what is called congenital superior oblique paresis. The ﬁrst results appear promising. A normal subject with head straight was slowly adapted over 45 min, maintaining fusion, to an increasing left-over-right Ocular Counter Roll Clockwise[deg]

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Counterclockwise

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Right Eye Left Eye 5

–5

–10

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RHT 50

STR 100 time [s]

LHT 150

Fig. 2.7 Plot of torsional position for each eye shows ocular counter roll with 45° head tilt. A normal subject is continuously recorded with head straight (STR), right head tilt (RHT), and left head tilt (LHT) of 45°. Traces show counter rolling of both the eyes of 4–7°

2.4

Applications of Bilateral Feedback Control to Clinical Practice and to Future Research Vertical Difference R-L

2.4 Applications of Bilateral Feedback Control to Clinical Practice and to Future Research

Up[deg]

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15

Fig. 2.8 Vertical recordings, with head straight and tilted 45° to either side, after 45 min of adaptation, with head straight, to a left-over-right vertical disparity of 50+° ﬁelds of concentric circles. The relative positions of the two eyes are shown in the fusion-free, dissociated state. The negative values correspond to the induced right hypodeviation

vertical disparity. This arrangement simulated a relative right hyperdeviation, because the right eye had to move downward to fuse, and the left eye had to move upward. After adaptation, the relative positions of the eyes were measured in the fusion-free, dissociated state. The eyes had partially adapted to the simulated relative right hyperdeviation by developing a measured right hypodeviation. The relative shift of the right eye downward of 3° with head straight increased to 5° with right head tilt (RHT) and decreased to 0° with left head tilt (LHT) (see Fig. 2.8). These changes with forced head tilt are in the directions that are expected from increased tonus to the normal right superior oblique muscle and to the normal left inferior oblique muscle. This increased tonus was produced by vergence adaptation to the relative right hyperdeviation. The deviations recorded simply represent a basic cyclovertical deviation induced in a normal subject by vergence adaptation to a vertical disparity. The demonstration of such head-tilt changes accompanying the induced cyclovertical deviation is in favor of the belief that many deviations currently called congenital superior oblique paresis are nothing more than basic cyclovertical deviations of the eyes. To explore this thesis, these adaptation techniques will be used to study not only normal subjects but also patients with congenital and acquired forms of apparent superior oblique paresis.

Practically speaking, the consequences of muscle length adaptation are often best appreciated under deep general anesthesia, when the anatomic positions of the eyes can be seen and careful forced ductions can be performed. The decision about which eye or eyes to operate on, and which muscles, may best be postponed until obtaining these intraoperative ﬁndings. This has been advocated by many, including Roth in Switzerland [61], Jampolsky in the United States [22], and the author [62]. Because version stimulation is only minimally eﬀective in changing extraocular muscle length, surgery designed to eliminate or minimize extraocular muscle contracture by creating chronic version stimulation, for example, by recessing the contralateral medial rectus muscle, on the sound eye, in cases of sixth nerve palsy [63], may not work as well as expected. It has long been the teaching in the ﬁeld of strabismus to wait for stabilization of the angle of deviation before intervening surgically. However, the consequences of unguided vergence adaptation and muscle length adaptation suggest a revision of this teaching. If there is potential for fusion, it now appears that every eﬀort should be made to realign the eyes without delay, using glasses, prisms, and surgery when necessary, and not wait for stabilization. Waiting for stabilization may actually be harmful if there is fusion potential, for it is now known [64] that the chances for successful restoration of binocular vision decrease with each month that misalignment persists. On the other hand, if fusion potential is truly not present, early surgery may best be postponed. The biases that exist in the unguided vergence and muscle length adaptation mechanisms may themselves change over time, altering the angle of strabismus naturally. Waiting for stabilization of these biases, as reﬂected by stability of the deviation, may indeed be warranted in such cases. The challenge, therefore, lies in the accurate determination of fusion potential. Whenever strabismus is corrected, by whatever means, any fusion that develops will need to compete with any biases in the vergence and muscle length adaptation mechanisms in order for the eyes to remain straight. It is very possible that we shall learn in the future how to measure such destabilizing biases and learn how to minimize or counteract them by pharmacologic, surgical, or other interventional means, in order to help maintain good binocular alignment after we have achieved it. For example, selective activation of vergence should be able to change not only vergence adaptation, but also

22

2

2

Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation

muscle lengths over time. This of course is currently the goal of fusional vergence exercises as part of orthoptic training. However, eventually we may be able to supply vergence stimulation from external sources, such as is currently done with the transcutaneous electrical stimulation used in orthopedic applications to correct or prevent scoliosis as well as contractures in cases of hemiplegia or cerebral palsy [65]. To do this, we shall need to discover the diﬀerences between version and vergence stimulation of the extraocular muscles so as to be able to supply vergence stimulation selectively. To be sure, correction of strabismus in the future may possibly be by selective electrical stimulation rather than by surgery.

Summary for the Clinician ■

■

■

At least a three-level feedback control system exists for the maintenance of binocular alignment. Of particular interest is the unique regulation of extraocular muscle lengths by vergence stimulation as opposed to version stimulation. Even though we may treat these mechanisms in a black-box fashion in the beginning, we can use this understanding to explain currently observed phenomena such as the development of socalled oblique muscle dysfunction with the development of A and V patterns. We also can use this understanding to appreciate previously unrecognized patterns of misalignment such as the basic cyclovertical deviation that mimics superior oblique muscle paresis. Not all answers are yet known, and some of the mechanisms proposed in this chapter are still quite speculative. However, from such speculation, models such as those formulated here can help in the understanding of not only how strabismus changes over time, but also the causes of the many forms of strabismus, facilitating the development of preventive measures as well as better and longer-lasting treatment methods for the future.

References 1. Guyton DL (2006) The 10th Bielschowsky lecture: changes in strabismus over time: the roles of vergence tonus and muscle length adaptation. Binocular Vis Strabismus Quart 21:81–92 2. Parks MM (1975) Ocular motility and strabismus. Harper and Row, Hagerstown, Maryland, pp 101

3. Baker JD, Parks MM (1980) Early-onset accommodative esotropia. Am J Ophthalmol 90:11–18 4. Guyton DL, Weingarten PE (1994) Sensory torsion as the cause of primary oblique muscle overaction/underaction and A- and V-pattern strabismus. Binocul Vis Eye Muscle Surg Q 9:209–236 5. Ludvigh E, McKinnon P, Zaitzeﬀ L (1964) Temporal course of the relaxation of binocular duction (fusion) movements. Arch Ophthalmol 71:389–399 6. Carter DB (1965) Fixation disparity and heterophoria following prolonged wearing of prisms. Am J Optom Arch Am Acad Optom 42:141–152 7. Taylor MJ, Roberts DC, Zee DS (2000) Eﬀect of sustained cyclovergence on eye alignment: Rapid torsional phoria adaptation. Invest Ophthalmol Vis Sci 41:1076–1083 8. Ellerbrock VJ (1950) Tonicity induced by fusional movements. Am J Optom Arch Am Acad Optom 27:8–20 9. Cooper J (1992) Clinical implications of vergence adaptation. Optom Vis Sci 69:300–307 10. Schor CM (1979) The relationship between fusional vergence eye movements and ﬁxation disparity. Vis Res 19:1359–1367 11. Ogle KN, Prangen Ade H (1953) Observations on vertical divergences and hyperphorias. Arch Ophthalmol 49: 313–324 12. Crone RA, Hardjowijoto S (1979) What is normal binocular vision? Doc Ophthalmol 47(1):163–199 13. Hwang J-M, Guyton DL (1999) The Lancaster red-green test before and after occlusion in the evaluation of incomitant strabismus. J AAPOS 3:151–156 14. Goldspink G, Williams P (1992) Cellular mechanisms involved in the determination of muscle length and mass during growth; problems arising from imbalance between antagonists muscle groups. In: Proceedings of the mechanics of strabismus symposium. The Smith-Kettlewell Eye Research Institute, San Francisco, pp 195–206 15. Tabary J-C, Tardieu C, Tardieu G, Tabary C (1981) Experimental rapid sarcomere loss with concomitant hypoextensibility. Muscle Nerve 4:198–203 16. Williams PE, Catanese T, Lucey EG, Goldspink G (1988) The importance of stretch and contractile activity in the prevention of connective tissue accumulation in muscle. J Anat 158:109–114 17. Goldspink G, Williams P, Simpson H (2002) Gene expression in response to muscle stretch. In: Clinical orthopaedics and related research. Lippincott Williams and Wilkins, Philadelphia No. 403S, pp S146–S152 18. Scott AB (1994) Change of eye muscle sarcomeres according to eye position. J Pediatr Ophthalmol Strabismus 31:85–88 19. Hayat A, Tardieu C, Tabary J-C, Tabary C (1978) Eﬀfects of denervation on the reduction of sarcomere number in cat

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soleus muscle immobilized in shortened position during seven days. J Physiol (Paris) 74:563–567 Schor CM, Maxwell JS, Graf EW (2001) Plasticity of convergence-dependent variations of cyclovergence with vertical gaze. Vis Res 41:3353–3369 Wright WW, Gotzler KC, Guyton DL (2005) Esotropia associated with early presbyopia caused by inappropriate muscle length adaptation. J AAPOS 9:563–566 Jampolsky A (1986) Treatment of exodeviations. In: Pediatric ophthalmology and strabismus, trans new orleans acad ophthalmol. Raven, New York, pp 201–234 Gonzalez C, Jaros PA (1988) Strabismus surgery on the nonamblyopic eye. Graefe’s Arch Clin Exp Ophthalmol 226:304–308 Breinin GM (1957) The position of rest during anesthesia and sleep. AMA Arch Ophthalmol 57:323–326 Jampel RS (1967) Multiple motor systems in the extraocular muscles of man. Invest Ophthalmol 6:288–293 Keller EL, Robinson DA (1971) Absence of a stretch reﬂex in extraocular muscles of the monkey. J Neurophysiol 34:908–919 Scott AB, Collins CC (1973) Division of labor in human extraocular muscle. Arch Ophthalmol 90:319–322 Eberhorn AC, Büttner-Ennever JA, Horn AKE (2005) Identiﬁcation of motoneurons supplying multiply- or singly-innervated extraocular muscle ﬁbers in the rat. Neuroscience 137:891–903 Büttner-Ennever JA (2006) The extraocular motor nuclei: organization and functional neuroanatomy. Prog Brain Res 151:95–125 Miller JM (2003) No oculomotor plant, no ﬁnal common path. Strabismus 11:205–211 Guyton DL (1984) Discussion of Paez JH, Isenberg S, Apt L: torsion and elevation under general anesthesia and during voluntary eyelid closure (Bell phenomenon). J Pediatr Ophthalmol Strabismus 21:78 Eustis HS, Nussdorf JD (1966) Inferior oblique overaction in infantile esotropia: Fundus extorsion as a predictive sign. J Pediatr Ophthalmol Strabismus 33:85–88 Clark RA, Miller JM, Rosenbaum AL, Demer JL (1998) Heterotopic muscle pulleys or oblique muscle dysfunction? J AAPOS 2:17–25 Schor C, Horner D (1989) Adaptive disorders of accommodation and vergence in binocular dysfunction. Ophthal Physiol Opt 9:264–268 von Noorden GK (1988) Current concepts of infantile esotropia. Eye 2:343–357 von Noorden GK (1976) The nystagmus compensation (blockage) syndrome. Am J Ophthalmol 82:283–290 Guyton DL (2000) Dissociated vertical deviation: etiology, mechanism, and associated phenomena. J AAPOS 4:131–144

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38. Ciancia AO (1995) On infantile esotropia with nystagmus in abduction. J Pediatr Ophthalmol Strabismus 32: 280–288 39. Marlow FW (1921) Prolonged monocular occlusion as a test for the muscle balance. Am J Ophthalmol 4:238–250 40. Marlow FW (1927) Observations on the prolonged occlusion test. Am J Ophthalmol 10:567–574 41. Marlow FW (1938) A tentative interpretation of the ﬁndings of the prolonged occlusion test on an evolutionary basis. Arch Ophthalmol 19:194–204 42. Abraham SV (1931) Bell’s phenomenon and the fallacy of the occlusion test. Am J Ophthalmol 14:656–664 43. Beisbarth C (1932) Hyperphoria and the prolonged occlusion test. Am J Ophthalmol 15:1013–1015 44. Holmes JM, Kaz KM (1994) Recovery of phorias following monocular occlusion. J Pediatr Ophthalmol Strabismus 31:110–113 45. Viirre E, Cadera C, Vilis T (1987) The pattern of changes produced in the saccadic system and vestibuloocular reﬂex by visually patching one eye. J Neurophysiol 57: 92–103 46. Liesch A, Simonsz HJ (1993) Up-and downshoot in adduction after monocular patching in normal volunteers. Strabismus 1:25–36 47. Collins CC, Jampolsky A, Howe PS (1992) Mechanical limitations of rotation. In: Proceedings of the mechanics of strabismus symposium. The Smith-Kettlewell Eye Research Institute, San Francisco, pp 19–40 48. Castañera de Molina A, Giñer Muñoz ML (1997) Shortstiﬀ extraocular muscles: Mechanisms involved in EOM adaptations to squint. In: Prieto-Diaz J, Hauviller V (eds) XII Congreso del Consejo Latinoamericano de Estrabismo (CLADE). Graﬁca Lifra, La Plata, pp 503–508 49. Miller MM, Guyton DL (1994) Loss of fusion and the development of A or V patterns. J Pediatr Ophthalmol Strabismus 31:220–224 50. Olitsky SE, Juneja RA (1997) Adult onset esotropia with distance near disparity: a report of two cases. Binocul Vis Strabismus Q 12:265–267 51. Simon AL, Borchert M (1997) Etiology and prognosis of acute, late-onset esotropia. Ophthalmology 104: 1348–1352 52. Costenbader FD (1958) Clinical course and management of esotropia. In: Allen JH (ed) Strabismus ophthalmic symp II. Mosby, St Louis, pp 325–353 53. Thomas AH (2000) Divergence insuﬃciency. J AAPOS 4:359–361 54. Bothun ED, Archer SM (2005) Bilateral medial rectus muscle recession for divergence insuﬃciency pattern esotropia. J AAPOS 9:3–6 55. Sheedy JE, Saladin JJ (1975) Exophoria at near in presbyopia. Am J Optom Physiol Optics 53:474–481

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Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation

56. Enright JT (1992) Unexpected role of the oblique muscles in the human vertical fusion reﬂex. J Physiol 451: 279–293 57. van Rijn LJ, Collewijn H (1994) Eye torsion associated with disparity-induced vertical vergence in humans. Vis Res 34:2307–2316 58. Cheeseman EW Jr, Guyton DL (1999) Vertical fusional vergence: the key to dissociated vertical deviation. Arch Ophthalmol 117:1188–1191 59. Demer JL, Miller JM, Koo EY, Rosenbaum AL, Bateman JB (1995) True versus masquerading superior oblique palsies: muscle mechanisms revealed by magnetic resonance imaging. In: Lennerstrand G (ed) Update on strabismus and pediatric ophthalmology. CRC, Boca Raton, pp 303–306 60. Sato M, Amano E (2003) Clinical ﬁndings and surgical results of true and masquerading congenital superior oblique palsy. In: de Faber J-T (ed) Progress in strabismology. Swets and Zeitlinger, Lisse, The Netherlands, pp 211–214

61. Roth A (1983) Oculomotor asymmetry in concomitant strabismus and its consequences for the choice of surgical intervention. In: Castañera de Molina A (ed) Congenital disorders of ocular motility. Editorial JIMS, Barcelona, pp 89–97 62. Castelbuono AC, White JE, Guyton DL (1999) The use of (a)symmetry of the rest position of the eyes under general anesthesia or sedation-hypnosis in the design of strabismus surgery: a favorable pilot study in 51 exotropia cases. Binocul Vis Strabismus Q 14:285–290 63. Gonzalez C, Chen H.H, Ahmadi MA (2005) Sherrington innervational surgery in the treatment of chronic sixth nerve paresis. Binocul Vis Strabismus Q 209:159–166 64. Fawcett SL, Birch EE (2003) Risk factors for abnormal binocular vision after successful alignment of accommodative esotropia. J AAPOS 7:256–262 65. Farmer SE, James M (2001) Contractures in orthopaedic and neurological conditions: a review of causes and treatment. Disabil Rehabil 23:549–558

Chapter 3

A Dissociated Pathogenesis for Infantile Esotropia

3

Michael C. Brodsky

Core Messages ■

■

Binocular movements that result from unequal visual input to the two eyes are deﬁned as dissociated. Dissociated esotonus, an unrecognized form of binocular dissociation, underlies dissociated horizontal deviation.

3.1

Dissociated Eye Movements

Although the term dissociated has historically been restricted to the description of vergence eye movements [1–3], in a more general sense it describes any ocular movements that result from a change in the relative balance of visual input to the two eyes [4]. These movements arise almost exclusively in the setting of infantile strabismus [5], which has a strong predilection for esotropia over exotropia. Dissociated vertical divergence, latent nystagmus, and dissociated horizontal deviation represent the conditions in which dissociated visual input alter the position of the eyes [6–8]. It is held that infantile esotropia disrupts binocular control mechanisms and thereby engenders these dissociated eye movements [5]. This time-honored notion assumes a distinct and unrelated pathogenesis for infantile esotropia. It is equally possible, however, that infantile esotropia arises from an unrecognized form of dissociated deviation known as dissociated esotonus.

Summary for the Clinician ■

Dissociated eye movements include dissociated vertical divergence, latent nystagmus, and dissociated horizontal deviation.

■

■

Because dissociated eye movements arise in the setting of infantile strabismus, they have traditionally been considered to be the result of disrupted binocular vision. Dissociated eye movements may be the cause, rather than the eﬀect, of infantile esotropia.

3.2 Tonus and its relationship to infantile esotropia Tonus refers to the eﬀects of baseline innervation on musculature in the awake, alert state. Since the normal anatomic resting position of the eyes is an exodeviated position, extraocular muscle tonus plays a vital physiologic role in establishing ocular alignment [9]. Under normal conditions, binocular esotonus is superimposed upon the normal anatomic 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, dissociated esotonus gradually drives the two eyes in a “convergent” position, resulting in infantile esotropia. Thus, while convergence functions to actively alter horizontal eye position, tonus eﬀectively resets the baseline eye position. When superimposed upon a baseline orthoposition, dissociated esotonus manifests as an intermittent esotropia that is asymmetrical or unilateral (Fig. 3.1) [10]. More commonly, dissociated esotonus is superimposed upon 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 (Figs. 3.2 and 3.3) [11–17]. These variants of intermittent exotropia are known as dissociated horizontal deviation. The clinical features

26

3

A Dissociated Pathogenesis for Infantile Esotropia

3

Fig. 3.1 Dissociated horizontal deviation manifesting as a large unilateral intermittent esodeviation (from ref [6], with permission)

Fig. 3.2 Dissociated horizontal deviation with greater exodeviation in the left eye than the right eye (from ref [6], with permission)

distinguishing dissociated horizontal deviation from the nondissociated form of intermittent exotropia are summarized in Table 3.1.

Summary for the Clinician ■ ■

Tonus determines the contractile state of extraocular musculature under baseline conditions. Physiologic tonus maintains normal binocular alignment.

3.3 Esotropia and Exotropia as a Continuum 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 that includes a variety of diﬀerent conditions with speciﬁc 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 two conditions often coexist, and perhaps acknowledging some diagnostic ambiguity [13, 15–17, 18, 19]. So what are the innervational substrates for these distinct but overlapping categories of intermittent exotropia? Although Burian believed intermittent exotropia to be caused by an active divergence mechanism [20], independent studies have found that these patients are approximately 30 PD more exotropic when deeply anesthetized than in the awake state [21, 22], suggesting that intermittent exotropia

3.3

Esotropia and Exotropia as a Continuum

27

Fig. 3.3 Dissociated horizontal deviation manifesting as a large left exodeviation when the patient ﬁxates with the preferred right eye (top and left) and converting to a right esodeviation with dissociated vertical divergence when the patient ﬁxates with the nonpreferred left eye (bottom). (All photographs courtesy of Michael Gräf, M.D and from ref [6], with permission)

actually results from intermittent fusional control of a large baseline exodeviation [23, 24]. 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 (Figs. 3.2 and 3.3) [6–8]. The distinction between intermittent exotropia and dissociated horizontal deviation lies 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

Table 3.1. Clinical signs distinguishing dissociated horizontal deviation from other forms of intermittent exotropia [6, 7] Dissociated horizontal deviation

Nondissociated intermittent exotropia

Amplitude of exodeviation is dependent on the ﬁxating eye (i.e., asymmetrical)

Amplitude of exodeviation is independent of the ﬁxating eye (i.e., symmetrical)

Slow velocity of spontaneous exodeviation

Rapid velocity of spontaneous exodeviation

Variable amplitude of spontaneous exodeviation

Constant amplitude of spontaneous exodeviation

Positive Bielschowsky phenomenon

Negative Bielschowsky phenomenon

Associated latent nystagmus and torsional ocular rotations, prominent dissociated vertical divergence

No associated latent nystagmus or torsional ocular rotations, little if any dissociated vertical divergence

Positive reversed ﬁxation test

Negative reversed ﬁxation test

28

3

3

A Dissociated Pathogenesis for Infantile Esotropia

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 [6–8], 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) [25]. 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 upon 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 [26, 27]. Some infants exhibit an intermittent form of exotropia with other dissociated eye movements [28], suggesting a component of dissociated horizontal deviation. Patients with primary dissociated horizontal deviation also display an intermittent exodeviation of one or both eyes with dissociated ocular signs [13]. All of these conditions share a common pathophysiology wherein dissociated esotonus is superimposed upon a baseline exodeviation to produce an intermittent exodeviation, which varies in size depending upon 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 two eyes, or an exodeviation of the nonpreferred eye with a paradoxical esodeviation of the preferred eye. In classifying these disorders pathogenetically, it becomes critically important to distinguish sensory motor 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.

Summary for the Clinician ■

Dissociated esotonus can be superimposed upon the baseline position of the eyes to produce intermittent esotropia or intermittent exotropia.

3.4

Distinguishing Esotonus from Convergence

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 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 two eyes [21, 29]. The importance of this distinction lies in the 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 convergent eye movements during the ﬁrst 2 months of life, and that these convergent 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. Our ﬁnding of dissociated esotonus shows how we retain a primitive tonus system, independent of convergence output, which can operate under conditions of unequal visual input to reset eye position to a new baseline “convergent” position.

3.5

Pathogenetic Role of Dissociated Eye Movements in Infantile Esotropia

Summary for the Clinician ■

Since large convergent movements in early infancy are predictive of normal binocular alignment, infantile esotropia does not result from excessive convergence.

3.5

Pathogenetic Role of Dissociated Eye Movements in Infantile Esotropia

Contrary to the stereotype of “congenital” esotropia as a large-angle deviation that is present at birth, most cases of “congenital” esotropia are acquired (i.e., “infantile” in origin) [25, 32]. 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 [32, 33]. Ing 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 [34]. 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 [35] suggests that it is actively driven primarily by an imbalance in peripheral visual input. In a recent hypothesis, Guyton 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 [36]. 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 [36]. 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. Dissociated esotonus may 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 [15, 17] shows that peripheral luminance reﬂexes are retained, as in dissociated vertical divergence [37]. In this setting, both peripheral (luminance and optokinetic)

29

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 re-establish 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 considerably under general anesthesia [18, 22, 29, 38, 39], however, suggests that esotonus is the driving force for infantile esotropia, and that mechanical eﬀects play a secondary role in its pathogenesis. It is possible that 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 [18]. 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 [18]. By contrast, early infantile esotropia is often characterized by similar visual acuity in the two eyes, and 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 horizontal tonus imbalance that is actually responsible for its inception.

Summary for the Clinician ■ ■ ■

Dissociated esotonus may provide the physiologic substrate for vergence adaption in infancy. If so, then dissociated esotonus is the cause, rather than the eﬀect, of infantile esotropia. The prevailing concept of infantile esotropia as the proximate cause of dissociated deviations may need to be revised.

Acknowledgment Portions of this chapter have previously been published in a thesis for the American Ophthalmological Society [6] and in its two derivative papers published in the Archives of Ophthalmology [7, 8]. All figures in this chapter are used with permission from the American Medical Association and the American Ophthalmological Society. This chapter is abstracted from an American Ophthalmological Society thesis [6].

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A Dissociated Pathogenesis for Infantile Esotropia

References

3

1. Bielschowsky A (1904) Über die Genese einseitiger Vertikalbewegungen der Augen. Z Augenheilkd 12: 545–557 2. Bielschowsky A (1930) Die einseitigen und gegensinnigen (“dissoziierten”) Vertikalbewegungen der Augen. Albrecht Von Graefes Arch Ophthalmol 125:493–553 3. Bielschowsky A (1938) Disturbances of the vertical motor muscles of the eye. Arch Ophthalmol 20:175–200 4. Lyle TK (1950) Worth and Chavasse’s Squint. The binocular reﬂexes and treatment of strabismus. Blakiston, Philadelphia, pp 40–41 5. Brodsky MC (2005) Visuo-vestibular eye movements. Infantile Strabismus in Three Dimensions. Arch Ophthalmol 123:837–842 6. Brodsky MC (2007) Dissociated horizontal deviation: clinical spectrum, pathogenesis, evolutionary underpinnings, diagnosis, treatment, and potential role in the development of infantile esotropia. Transact Am Acad Ophthalmol 105: 272–293 7. Brodsky MC, Fray KJ (2007) Dissociated horizontal deviation after surgery for infantile esotropia – clinical characteristics and proposed pathophysiologic mechanisms. Arch Ophthalmol 125:1683–1692 8. Brodsky MC, Fray KJ (2007) Does infantile esotropia arise from a dissociated deviation? Arch Ophthalmol 125: 1683–1692. 9. Proceedings of the Smith-Kettlewell Ocular Motor Tonus Symposium. Tiberon, California, (June 2–4, 2006) pp 2–4 10. Spielmann A (1990) Déséquilibres verticaux et torsionnels dans le strabisme précoce. Bull Soc Ophtalmol Fr 4: 373–384 11. Quintana-Pali L (1990) Desviacion horizontal disociada. Bol Oftalmol Hosp de la Luz 42:91–94 12. Romero-Apis D, Castellanos-Bracamontes A (1990) Desviacion horizontal disociada (DHD). Rev Mex Oftalmol 64:169–173 13. Romero-Apis D, Castellanos-Bracamontes A (1992) Dissociated Horizontal deviation: clinical ﬁndings and surgical results in 20 patients. Binoc Vis Q 7:173–178 14. Spielmann AC, Spielmann A (2004) Antinomic deviations: esodeviation associated with exodeviation. In: Faber TJ (ed) Transactions 28th meeting European strabismological association, Bergen, Norway, June 2003. Taylor and Francis, London, pp 173–176 15. Wilson ME, McClatchey SK (1991) Dissociated horizontal deviation. J Pediatr Ophthalmol Strabismus 28:90–95 16. Wilson ME (1993) The dissociated strabismus complex. Binocul Vis Strabismus Q 8:45–46 17. Zabalo S, Girett C, Domínguez D, Ciancia A (1993) Exotropia intermitente con desviación vertical discodiada. Arch Oftalmol B Aires 68:11–20

18. Thouvenin D, Nogue S, Fontes L, Norbert O (2004) Strabismus after treatment of unilateral congenital cataracts. A clinical model for strabismus physiopathogenesis? In: de Faber (ed) Transactions 28th European strabismological association meeting, Bergen, Norway, 2003. London, Taylor and Francis, pp 147–152 19. Wilson ME, Hutchinson AK, Saunders RA (2000) Outcomes from surgical treatment for dissociated horizontal deviation. J AAPOS 4:94–101 20. Burian HM (1971) Pathophysiology of exodeviations. In: Manley DR (ed) Symposium on horizontal ocular deviations. CV Mosby, St Louis, pp 119–127 21. Jampolsky A (1970) Ocular divergence mechanisms. Trans Am Acad Ophthalmol 68:808 22. Romano P, Gabriel L, Bennett W, et al (1988) Stage I intraoperative adjustment of eye muscle surgery under general anesthesia: consideration of graduated adjustment. Graefes Arch Clin Exp Ophthalmol 226:235–240 23. Kushner BK (1992) Exotropic deviations: a functional classiﬁcation and approach to treatment. Am Orthop J 38: 81–93 24. Kushner BJ, Morton GV (1998) Distance/near diﬀerences in intermittent exotropia. Arch Ophthalmol 116:478–486 25. Pritchard C (1998) Incidence of dissociated vertical deviation in intermittent exotropia. Am Orthop J 48: 90–93 26. Moore S, Cohen RL (1985) Congenital exotropia. Am Orthop J 35:68–70 27. Rubin SE, Nelson LB, Wagner RS, et al (1988) Infantile exotropia in healthy infants. Ophthalmic Surg 19: 792–794 28. Hunter DG, Kelly JB, Ellis FJ (2001) Long-term outcome of uncomplicated infantile exotropia. J AAPOS 5: 352–356 29. Jampolsky A (2005) Strabismus and its management? In: Taylor DS, Hoyt CS (eds) Pediatric ophthalmology and strabismus, 3rd edn. Elsevier Saunders, London, New York, pp 1001–1010 30. Horwood A (2003) Too much or too little: neonatal ocular misalignment frequency can predict lateral abnormality. Br J Ophthalmol 87:1142–1145 31. Horwood AM, Riddell PM (2004) Can misalignments in typical infants be used as a model for infantile esotropia? Invest Ophthalmol Vis Sci 45:714–720 32. Pediatric eye disease investigator group. (2002) Spontaneous resolution of early-onset esotropia: Experience of the congenital esotropia observational study. Am J Ophthalmol 133:109–118 33. Pediatric eye disease investigator group. (2002) The clinical spectrum of early-onset esotropia: Experience of the congenital esotropia observational study. Am J Ophthalmol 133:102–108

References 34. Ing MR (1994) Progressive increase in the quantity of deviation in congenital esotropia. Trans Am Ophthalmol Soc 92:117–131 35. Fawcett SL, Wang YZ, Birch EE (2005) The critical period for susceptibility of human stereopsis. Invest Ophthalmol Vis Sci 46:521–525 36. Guyton DL (2006) Changes in strabismus over time: the roles of vergence tonus and muscle length adaptation. Binocul Vis Strabismus Q 21:81–92

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37. Brodsky MC (1999) Dissociated vertical divergence. A righting reﬂex gone wrong. Arch Ophthalmol 117: 1215–1222 38. Apt L, Isenberg S (1977) Eye position of strabismic patients under general anesthesia. Am J Ophthalmol 84: 574–579 39. Roth A, Speeg-Schatz C (1995) Eye muscle surgery. Basic data, operative techniques, surgical strategy. Swets and Zeitlinger, Masson, Paris, pp 283–324

Chapter 4

The Monoﬁxation Syndrome: New Considerations on Pathophysiology

4

Kyle Arnoldi

Core Messages ■

■

Parks’ monoﬁxation syndrome (MFS) is an abnormality of binocular vision consisting of a foveal suppression scotoma, peripheral sensory fusion, fusional vergence, and stereopsis. A majority of cases also demonstrate small angle strabismus or amblyopia, but these are secondary to the monoﬁxation and not characteristics of the syndrome. Animal studies have begun to clarify the pathways for normal binocular vision, and anatomic and metabolic adaptations which may result in monoﬁxation.

4.1

Introduction

In 1969, in his American Ophthalmological Society thesis, Marshall Parks described 100 patients with a speciﬁc set of sensory ﬁndings: a foveal suppression scotoma; peripheral sensory fusion; motor fusion amplitudes (fusional vergence); and gross stereopsis. He termed this constellation of ﬁndings the monoﬁxation syndrome (MFS) to distinguish it from biﬁxation (or bi-foveal ﬁxation) [1]. Parks outlined four principle causes of MFS: (1) anisometropia (found in 6% of his cases); (2) corrected strabismus (66%); (3) an organic macular lesion (1%); and (4) primary MFS (19%). Another 8% had both anisometropia and a history of strabismus. Although 66% of his cases had a small angle, manifest, horizontal ocular deviation, strabismus is not included as a characteristic of MFS, emphasizing that this is a sensory disorder. Similarly, Parks considered amblyopia a variable feature rather than a characteristic of the syndrome, occurring as a result of MFS in 77%. Like the small angle manifest strabismus, he felt the presence or absence of amblyopia was dependent on associated factors such as a history of infantile strabismus or anisometropia. Since its original description, there has been much study and debate regarding questions that Parks himself

■

■

■

MFS associated with small angle esotropia is the most common form, the most stable, and the form that allows for the best binocular vision. This may be due to the natural superiority of the nasal retina and its input to the visual cortex. Monoﬁxation is a desirable state when biﬁxation is not possible. Nothing is gained, and much can be lost, if a cure is attempted. Very early repair of strabismus or anisometropia may prevent the development of monoﬁxation in favor of biﬁxation.

raised in his original manuscript. Why would an orthotropic patient with no history of strabismus or anisometropia have primary MFS? Is the foveal suppression the cause or the result of MFS? Why do some cases manifest a small tropia in the presence of motor fusion amplitudes that are more than suﬃcient to overcome the deviation? What is the state of binocular correspondence in the strabismic and nonstrabismic cases of MFS? Can monoﬁxation be prevented? Can it be cured? And if so, should a cure be attempted? Recent clinical and laboratory studies have shed some light on the features and pathophysiology of MFS which may help us begin to answer some of these questions.

4.2 Normal and Anomalous Binocular Vision The MFS is an abnormality of binocular vision. In normal binocular vision, bilateral retinal input from overlapping visual ﬁelds is projected to the same general location in the visual cortex, stimulating adjacent ocular dominance columns of opposite ocularity [2]. This close proximity of input from the two eyes corresponding to the same point in space facilitates the communication necessary for binocular single vision. This communication appears to take

34

4

4

The Monoﬁxation Syndrome: New Considerations on Pathophysiology

place within a population of binocular cells, neurons that receive input from both eyes and are sensitive to image disparity. These cells are prevalent throughout the superﬁcial and deep layers of area V1, as well as several areas outside the striate cortex such as areas V2, MT (middle temporal visual area or area V5), and MST (medial superior temporal visual area), and play a major role in the appreciation of stereopsis and in generating disparity vergence (motor fusion). In the presence of strabismus, inputs from the same point in space will stimulate nonadjacent ocular dominance columns, cells that would ordinarily not communicate with each other horizontally, or synapse with the same binocular cell further downstream in visual processing. Unrepaired, large angle infantile-onset strabismus has been shown to have devastating eﬀects on the population of binocular cells. The supply of binocular cells throughout area V1 is decimated [3]. Yet objective evidence of binocular cortical processing has been found in human subjects with small angle strabismus and MFS [4, 5]. The question then arises, how is it that these patients can achieve fusion and stereopsis? One theory is that the cortical adaptation that occurs in response to a small angle ocular deviation is limited to suppression of the foveal ocular dominance columns in area V1. This would preserve the parafoveal columns and allow for normal, though limited binocular communication with gross stereopsis [3]. This theory also implies that the anomalous motor fusion present in MFS is also driven by the disparity-sensitive neurons that are located at this earliest stage of binocular processing [6]. In this paradigm, retinal correspondence would be considered normal, as no cortical rewiring would be needed to maintain fusion in the presence of a small deviation. Other researchers have found evidence of an adaptation that results in binocular vision in MFS; one that occurs further downstream from area V1, in areas V2, V3, and beyond. This adaptation does involve a rewiring that could be considered the anatomic basis of anomalous retinal correspondence (ARC) [7, 8]. For example, it has been demonstrated in esotropic cats that if the angle of strabismus is small (<10°), the binocular neurons in the lateral suprasylvian cortex (area LS) may be spared, though their receptive ﬁelds are shifted so that normally noncorresponding retinal elements may communicate [9, 10]. Area LS of the cat is functionally analogous to area MT in the primate. Regardless of where the adaptation takes place, it appears that the visual cortex may be most successful in achieving fusion in the presence of a tropia when it can combine information from cell populations that are no more than two cortical neurons distant [11]. At approximately 7 mm in length, the typical cortical neuron is

theoretically capable of joining visual receptive ﬁelds up to 2.5° (4.4D) distant [6]. In Parks’ original description, manifest deviations no larger than 8D were consistent with MFS. A two-neuron chain could allow the fovea to eﬀectively communicate with a peripheral retinal element that is up to 8.7D away, providing support to Parks’ clinical observations.

4.2.1

Binocular Correspondence: Anomalous, Normal, or Both?

Interestingly, one of the questions raised by Parks and debated for decades is whether the binocular vision that is the prominent feature of MFS should be called ARC, normal correspondence (NRC) with an expansion of Panum’s fusional space in the peripheral ﬁeld (Parks’ conclusion), or even a combination of the two. Some authors have found NRC in the central visual ﬁeld, with ARC in the periphery [8, 12]; others have found ARC centrally, and NRC peripherally [13]. Certainly, the angle of strabismus is small enough and the peripheral receptive ﬁelds large enough that it is conceivable peripheral fusion might be achieved without requiring a rewiring of the visual cortex (see Sect. 4.2). On the other hand, it seems unlikely that stereoacuity as ﬁne as 70 seconds of arc, which has been found in MFS, could be consistent with a foveal suppression scotoma of up to 5° with NRC. Perhaps stereoacuity at this level is the result of an expansion of Panum’s area surrounding the ﬁxation point. However, such an adaptation, should it be found, would surely be termed anomalous. What do we mean when we say a patient has ARC? The state of retinal correspondence has historically been deﬁned as characteristic responses to speciﬁc clinical sensory tests; responses which can be manipulated by many diﬀerent external factors [14]. Test results are also inﬂuenced by both the patient’s ability to communicate and the examiner’s interpretation of the response. It is not uncommon for the same subject to demonstrate characteristic ARC responses on some tests and NRC responses on others. It has been assumed that ARC is the result of a shift in the perceptual mapping of the deviated eye under binocular conditions, and these tests are designed to determine the subjective visual direction of at least one retinal element. However, in human subjects with ARC, no cortical shift in topography was found with pattern VEP, though this does not rule out a shift occurring in cortical areas further downstream [7]. It is important to remember that the concepts of the horopter, Panum’s fusional space, and binocular correspondence are simply geometric and psychophysical constructs used to describe binocular vision. Until we know how this binocular vision is achieved in the visual cortex,

4.3

perhaps it is more important to recognize that patients with MFS indeed have binocular correspondence, rather than how we label that correspondence. Either way, as discussed earlier, animal studies are beginning to reveal a possible anatomical basis for the clinical observations described in MFS. Until these anomalous neural connections can be shown in a human subject with the clinical features of MFS, the debate remains unresolved.

4.3

MFS with Manifest Strabismus

The majority of patients with MFS have a manifest strabismus, and esotropia is the most prevalent form by a wide margin. The prevalence of micro-esotropia in several large series of primary and secondary MFS has been reported from 61 to 90% [1, 15]. MFS with small angle exotropia is less common, occurring in 8–21% [1, 15, 16]. The prevalence of MFS associated with small angle vertical strabismus is extremely low at 0–3% in large series [1, 15, 16]. Choi and Isenberg described 40 cases of MFS with a vertical tropia; however, the prevalence of this variety of MFS cannot be determined from their report [17].

4.3.1

Esotropia is the Most Common Form of MFS

Apparently, monoﬁxation can be achieved and maintained with any type of strabismus. However, the esotropic variety of MFS is so prevalent it is unlikely that this occurs by chance. New evidence suggests that a convergent deviation may be the default position if orthotropia with biﬁxation is not possible [6]. As discussed in Sect. 4.2, studies comparing normal and strabismic monkeys have found that an early onset unrepaired strabismus will deplete the supply of binocular connections in area V1, as well as cause low metabolic activity (suppression) in ocular dominance columns corresponding to the deviating eye [3, 6, 18]. Binocular processing begins in the layers above and below input layer 4 of area V1 in the striate cortex, but continues in several diﬀerent populations of binocular cells within and beyond area V1 that are sensitive to either relative or absolute retinal image disparity. These cell groups give rise to stereopsis or fusional vergence, respectively [19]. Vergence neurons sensitive to crossed disparity (convergence) appear to be naturally more numerous than those coding for uncrossed disparity (divergence) in normal monkeys [6]. It is possible that more convergence neurons survive the early insult simply because there is a preponderance of them to begin with. The timing of the insult is probably also contributory to the prevalence of small angle esotropia in MFS. Eye

MFS with Manifest Strabismus

35

alignment and fusional vergence is immature in neonates, but more often results in transient over-convergence as opposed to over-divergence [20]. Pathways for nasally directed pursuit are more developed at birth compared with those for temporally directed pursuit. Interruption of maturation due to an insult such as early-onset, unrepaired strabismus, leads to permanent monocular naso-temporal pursuit asymmetry [21]. It may also lead to latent nystagmus, which typically features a pathologic nasally directed pursuit movement of the ﬁxating eye, followed by a physiologic temporal-ward reﬁxation saccade [18]. These motor ﬁndings associated with infantile esotropia seem to suggest that the infant visual system is biased to convergent alignment when normal development is interrupted.

4.3.2

Esotropia Allows for Better Binocular Vision

Fusion and stereopsis may be more likely to develop if the ocular deviation is less than 9D though presumably, the greater the number of cortical neurons necessary to link nonadjacent ocular dominance columns, the poorer the quality of the resulting binocular vision. Deviations up to 20D have been shown to support peripheral sensory fusion [14], if not stereopsis, so it is no surprise that peripheral fusion is a feature of MFS. However, in a recent study, the maximum angle of horizontal strabismus consistent with true stereopsis was found to be only 4D [16], which happens to correspond with the approximate length of one cortical neuron. The maximum angle of strabismus that still allows for fusional vergence is not yet known, though the most robust convergence response to binocular image disparity in monkeys with MFS occurs at 4.0–4.5D of crossed disparity [22], once again corresponding with the length of the average cortical neuron. The motor fusion amplitudes of human subjects with MFS have been found to be within the normal range by some [1, 13, 23], and present but subnormal by others [24]. Though patients with MFS often have fusional vergence suﬃcient to overcome small angles of strabismus, most patients with MFS maintain a manifest strabismus. The logical conclusion is that, in patients with MFS, there is a greater functional beneﬁt to keeping the eyes slightly misaligned, particularly on the esotropic side. MFS with esotropia diﬀers slightly from MFS with exo- or hypertropia. Not only is it more common, but it is the form that allows for the best binocular vision. In a large series, the micro-ET group out-performed the other two alignment categories by a wide margin in each of the three sensory categories: sensory fusion, motor fusion, and stereopsis [15]. The most striking diﬀerence in the sensory exam was found in the motor fusion category.

36

4

4 The Monoﬁxation Syndrome: New Considerations on Pathophysiology

Both primary and secondary micro-esotropes were signiﬁcantly more likely to have disparity vergence than the exotropes or hypertropes. Why might binocular vision be better in MFS with esotropia? In esotropia, the fovea of the ﬁxating eye must communicate with a nonfoveal point on the nasal retina of the deviating eye to achieve fusion. In exotropia, the ﬁxating fovea must link with a point on the temporal retina of the deviating eye. However, not all areas of the retina are created equal. Temporal retina is at a competitive disadvantage, even in the normal, nonstrabismic visual system. Cones and ganglion cells are 1.5-fold less numerous in the temporal retina [25–28]. LGN layers receiving input from the ipsilateral temporal retina have fewer cells and less volume [29]. And in the visual cortex, temporal ocular dominance columns occupy less territory than nasal columns, with the diﬀerence increasing dramatically with retinal eccentricity [30]. Temporal retina matures slower than nasal retina in normal human infants [31]. Spatial resolution and vernier acuity are poorer in the temporal retina of normal eyes [32–34]. The critical period for the development of the temporal retina and its connections in the visual cortex begins later and takes longer to complete than that for nasal retina [31]. And ﬁnally, the neural mechanisms underlying disparity detection from uncrossed disparity (as would occur in exotropia) are naturally more sensitive to image decorrelation than those from crossed disparity [35]. If the critical period is interrupted by strabismus, the temporal retina should be selectively penalized, potentially magnifying the anatomic and physiological asymmetry. This presents a particular problem for exotropia. If inputs from the temporal retina are less numerous, delayed in development, relatively suppressed, and more vulnerable to the deleterious eﬀects of image decorrelation, the foveal cortical neurons of the dominant eye would have comparatively few neurons from the deviated eye with which to work. The larger the angle of exotropia, the fewer are the temporal cortical neurons available to link with the columns of the dominant eye because of the increase in the ratio of dominance with retinal eccentricity. The relative suppression of these temporal neurons may result in poor quality communication, even if a link could be established.

4.3.3

Esotropia is the Most Stable Form

Good binocular vision is associated with stability, but does not guarantee lasting alignment. Studies have found that stability of alignment in microtropia is not permanent,

even in the presence of high-quality binocular vision [15, 36, 37]. Twenty-four to 26% of MFS cases deteriorate over a period of 5.5–17.5 years [15, 36, 37]. In these studies, deterioration was not the result of loss of sensory status. Following treatment, 48–80% of subjects were able to regain monoﬁxation status. Stability of MFS with exo- or hypertropia appears to be more vulnerable to insults to the visual system such as dense amblyopia or a signiﬁcant change in the refractive error over time [15]. Dense amblyopia appears to be disruptive to an already fragile binocular connection in exotropia, and may contribute to instability in the majority of exotropic patients. Drastic changes in refractive error in MFS with exotropia appear to have a similar destabilizing eﬀect. Neither of these factors appears to have an eﬀect on long-term stability in micro-esotropia, however. Instability of alignment in MFS is also associated with the presence of vertically incomitant horizontal strabismus, oblique dysfunction, and a history of large-angle infantile esotropia. Micro-esotropes were statistically less likely to have a history of any of these associated motility disorders in one study [15].

4.4

Repairing and Producing MFS

Any mechanic will tell you that one of the best ways to understand something is to take it apart and reassemble it. Can MFS be “taken apart” or cured? Curing MFS means elimination of the foveal suppression scotoma, which is relatively simple to accomplish, and restoring biﬁxation with fusion and high grade stereopsis, which is considerably more diﬃcult. Most researchers (including Parks) believe that a patient with MFS cannot be restored to biﬁxation [1, 13, 38, 39]. There is also very little in the current literature to suggest that this is possible. A single study claims to have cured MFS in nine patients [40], and another reports a spontaneous resolution of MFS and amblyopia in a small group of older children and teenagers [41]. In the former study, of 30 patients with amblyopia and eccentric ﬁxation, nine improved stereoacuity below the threshold for MFS (60 s of arc or better) that coincided with improvement in visual acuity. However, since stereoacuity is dependent on spatial resolution as well as alignment, and at least seven of these patients had no manifest strabismus prior to occlusion therapy, it may be that the treatment simply cured amblyopia, rather than MFS. To the contrary, there seems to be opinion backed by evidence to suggest that MFS cannot be cured, but more importantly, a cure should not be attempted [42].

4.4

Antisuppression and treatment of ARC typically lead to insuperable diplopia (see Case 4.1) [39, 43]. For those with an associated small tropia, nothing is gained by attempted correction of the deviation with surgery or prism, because the monoﬁxation persists and the deviation recurs. Normal or near-normal fusional vergence in these patients assures that alignment will be maintained at the visual system’s preferred angle, regardless of attempts at intervention. In addition, patients with MFS are typically asymptomatic and already enjoy high quality binocular vision. If biﬁxation could be restored, it may not result in a signiﬁcant improvement in quality of life. Can MFS be restored once deconstructed? If it is possible to lose the suppression ability due to trauma, occlusion or loss of vision in the preferred eye, or therapeutic intervention, might it be possible to restore it? Very little has been published in this area. The cases in the literature suggest that suppression cannot be relearned once unlearned [43]. However, the prognosis may depend on what caused the loss of suppression, as Case 4.2 shows. Because MFS cannot or perhaps should not be cured once established, a better question might be “Can MFS be prevented in favor of biﬁxation?” Parks hypothesized that, for those cases of secondary MFS, correction of the underlying pathology, whether strabismus or anisometropia, before 6 months of age may be the answer. This is a challenging hypothesis to study in human subjects; such early intervention is often logistically diﬃcult. An animal model is better suited to answer this question.

4.4.1 Animal Models for the Study of MFS There are several valid methods for creating the clinical conditions associated with the development of MFS. Large angle esotropia has been surgically induced in infant monkeys [23], or simulated with the use of prism glasses [18, 21]. One can create large angle sensory strabismus through monocular or binocular occlusion early in life [44–46]. One can also create an animal model for anisometropia by using optical defocus with minus lenses [47, 48]. With each of these methods, the timing of the repair of the induced strabismus or anisometropia determines the sensory outcome. If the image decorrelation is repaired in the infant monkey by 3 weeks of age (correlates to 3 months in human infants), biﬁxation can result in some animals [3, 6]. If delayed for up to 24 weeks, biﬁxation is not possible, but MFS can result. If delayed longer than 24 months, not only do the monkeys show a lack of sensory fusion, motor fusion and stereopsis, but they tend to develop latent nystagmus, asymmetry of pursuit and OKN, A- and V- pattern incomitance, and

Repairing and Producing MFS

37

Case 4.1 A 5-year old female was diagnosed with monoﬁxation syndrome following a failed pre-school vision screening. The patient completed a course of optometric vision training designed to eliminate the foveal suppression scotoma in the left eye. Once constant, intractable diplopia was present, and the patient was referred to an orthoptist and pediatric ophthalmologist for the management of diplopia. The patient was 6-years old when presented to the ophthalmologist. Vsc: 20/20 20/25 Motility: Dsc LET 5Δ with simultaneous prism and cover test Builds to E 20Δ with prism and alternate cover Nsc LET 5Δ with simultaneous prism and cover Builds to E(T) 20Δ with prism and alternate cover Sensory: Constant, uncrossed diplopia at distance and near, unrelieved with any combination of prism. Amblyoscope examination: Objective angle (Grade I target) = +20 Subjective angle (Grade I target) = +5 Grade II: constant, variable diplopia, no sensory fusion, no suppression; as image approaches +5 on amblyoscope, diplopia converts from uncrossed to crossed. Management: Bilateral medial rectus recessions were done for the decompensating near deviation. At the 1-day postoperative visit, the diplopia was unchanged. Examination results at that visit are as follows. Post-op Motility: Dsc: LET 5Δ with simultaneous prism and cover test Builds to E 20Δ with prism and alternate cover test Nsc: LET 5Δ with simultaneous prism and cover test Builds to E 20Δ with prism and alternate cover test Post-op Exam 2: At 1 month following surgery, the motility and sensory examinations were unchanged from presentation. The patient was oﬀered an occlusion foil to alleviate the diplopia. The mother declined as she viewed this as “a step backwards” after all the vision therapy that was done.

38

4 The Monoﬁxation Syndrome: New Considerations on Pathophysiology

Case 4.2

4

A 16-year old female with a history of monoﬁxation syndrome presents with a 3-month history of constant horizontal diplopia. The onset of the diplopia was abrupt, following closed head trauma without loss of consciousness, secondary to a motor vehicle accident. The patient reports that the diplopic image is always present, but is not always in the same location relative to ﬁxation and appears to be constantly moving. Previous records document a stable RET 6Δ, with a superimposed phoria of up to 18Δ in addition to the sensory features of monoﬁxation syndrome. Vcc: 20/20 OD Rx: +0.50 +1.00 ´ 090 20/20 OS Plano Motility: Dcc: RET variable from 8Δ to 25Δ Ncc: RET variable from 10Δ to 25Δ Sensory: Constant uncrossed horizontal diplopia of variable magnitude, unrelieved with prism. The addition of base-out prism in free space appears to cause an increase in the esodeviation, with diplopia. Amblyoscope examination: Objective angle (Grade I targets) = +25 There was no subjective angle at which the patient could appreciate sensory fusion with either Grade I or II targets. Management: The patient was prescribed a dense occlusion foil (Bangerter Light Perception foil) for the right lens of the glasses. At her 2-week follow-up, the ﬁlter strength was reduced to Bangerter 0.2. Two weeks later, the strength was reduced again to Bangerter 0.4. The ﬁlter was discontinued 1 month later, with complete resolution of the diplopia. Her sensory and motor examination returned to baseline level, and has been stable for over 2 years.

dissociated vertical deviation [18, 21, 45, 46]. Research shows that in the animal model, shorter durations of image decorrelation result in better sensory outcomes. These results imply that excellent outcomes may be possible in the human if alignment is restored within 90 days of the onset of strabismus. This suggests that, if monoﬁxation is to be prevented in favor of biﬁxation, very early detection and intervention is necessary.

4.5 Primary MFS (Sensory Signs of Infantile-Onset Image Decorrelation) The problem of primary MFS is one that has perplexed Parks and others. Primary MFS accounts for 16–19% of all cases of monoﬁxation [1, 15]. This subpopulation is interesting, as it may represent the visual cortex’s active choice when bifoveal ﬁxation is not possible for some reason. But what is that reason? One theory that has been debated for decades is the possibility that some individuals have an inherent inability to bi-ﬁxate. However, no evidence of a genetic absence of disparity detectors has been uncovered thus far. In a recent study, there was no data found to support the hypothesis that MFS is a motor adaptation to an inherent ARC [13]. To the contrary, since animal studies have demonstrated that even a brief interval of image decorrelation early in the critical period of development can lead to MFS, one answer may be that the patient had strabismus or anisometropia that spontaneously resolved in early infancy. In a recent study, the presence of image decorrelation for only 3 days, if occurring at the height of the critical period, was found to cause dramatic changes in cortical processing of binocular input in monkeys [49]. The ﬁrst change caused by early image decorrelation is suppression in area V1, beyond the input level in layer four. Apparently, once begun, this process of low metabolic activity spreads quickly. The longer the period of image decorrelation, the more prevalent the suppression becomes in all layers of V1. Once suppression is established, the developing cortex may have no choice but to work around it to achieve the best binocular vision possible under the circumstances.

4.5.1 Motor Signs of Infantile-Onset Image Decorrelation Secondary abnormalities of ocular motility associated with early-onset image decorrelation are well documented. Patients with uncorrected infantile-onset strabismus often develop latent nystagmus, dissociated vertical deviation, and A- or V-pattern incomitance, as well as demonstrate persistent naso-temporal pursuit and OKN asymmetry (see Sect. 4.5). The age of onset of binocular decorrelation appears to determine whether these signs will be present, and the duration of binocular decorrelation determines the severity [18, 21, 44–46]. Occasionally these motor signs may be observed in cases of secondary MFS (see Sect. 4.3.3) following strabismus repair, but they are particularly rare in primary MFS. The only secondary abnormality that has been found consistently thus far is

References

asymmetry of the motion VEP response, which appears to be associated with foveal suppression [4]. One possible explanation for this lack of motor evidence of the long-term image decorrelation in MFS is that the motor signs such as pursuit asymmetry are present, but subclinical. Another possibility is that the angle of strabismus is so small in primary MFS that the cortex does not recognize the decorrelation and the motor pathways develop normally. A third possibility is that it is the high quality of the binocular vision that is present in MFS that somehow prevents the development of these motor sequelae. This is yet another query to be added to Parks’ long list of questions about The Monoﬁxation Syndrome.

Summary for the Clinician ■

■

■

■

The MFS has much to teach us about both normal and abnormal binocular vision. Even as some answers begin to reveal themselves, more questions arise. Monoﬁxation may be preventable if the cause of the image decorrelation is detected and repaired promptly, probably within 60–90 days of onset. Once monoﬁxation is present, attempting a cure is unwise. MFS, particularly with small angle esotropia, is relatively stable and allows for good binocular vision so there is little to be gained. Antisuppression and anti-ARC therapies designed to restore bifoveal ﬁxation typically result in intractable diplopia. Attempted repair of the associated strabismus with surgery or prism will not create biﬁxation once monoﬁxation is established. MFS can decompensate with time, even in the presence of good binocular vision. Patients with this condition should be followed periodically, and any changes in acuity or refractive error addressed promptly to minimize the risk of deterioration with loss of binocular vision.

References 1. Parks MM (1969) The monoﬁxation syndrome. Tr Am Ophthalm Soc 67:609–657 2. Hubel DH, Wiesel TN (1977) Functional architecture of macaque monkey visual cortex. Philos Trans Roy Soc Lond. 198:1–59 3. Tychsen L (2005) Can ophthalmologists repair the brain in infantile esotropia? Early surgery, stereopsis, monoﬁxation syndrome, and the legacy of Marshall Parks. J AAPOS 9:510–521

39

4. Fawcett SL, Birch EE (2000) Motion VEPs, stereopsis, and bifoveal fusion in children with strabismus. Invest Ophthalmol Vis Sci 41:411–416 5. Struck MC, VerHoeve JN, France TD (1996) Binocular cortical interactions in the monoﬁxation syndrome. J Pediatr Ophthalmol Strabismus 33:291–297 6. Tychsen L (2007) Causing and curing infantile esotropia in primates: the role of decorelated binocular input. Trans Am Ophthalmol Soc 105:564–593 7. McCormack G (1990) Normal retinotopic mapping in human strabismus with anomalous retinal correspondence. Invest Ophthalmol Vis Sci 31:559–568 8. Sireteanu R, Fronius M (1989) Diﬀerent patterns of retinal correspondence in the central and peripheral visual ﬁeld of strabismics. Invest Ophthalmol Vis Sci 30:2023–2033 9. Grant S, Berman NE (1991) Mechanism of anomalous retinal correspondence: maintenance of binocularity with alteration of receptive-ﬁeld position in the lateral suprasylvian (LS) visual area of strabismic cats. Vis Neurosci 7:259–281 10. Sireteanu R, Best J (1992) Squint-induced modiﬁcation of visual receptive ﬁelds in the lateral syprasylvian cortex of the cat: binocular interaction, vertical eﬀect, and anomalous correspondence. Eur J Neurophysiol 4:235–242 11. Wong AMF, Lueder GT, Burkhalter A, Tychsen L (2000) Anomalous retinal correspondence: neuro-anatomic mechanism in strabismic monkeys and clinical ﬁndings in strabismic children. J AAPOS 4:168–174 12. Fronius M, Sireteanu R (1989) Monocular geometry is selectively distorted in the central visual ﬁeld of strabismic amblyopes. Invest Ophthalmol Vis Sci 30:2034–2044 13. Harwerth RS, Fredenburg PM (2003) Binocular vision with primary microstrabismus. Invest Ophthalmol Vis Sci 44:4293–4306 14. Arnoldi K (2004) The VII Burian memorial lecture: factors contributing to the outcome of sensory testing in patients with anomalous binocular correspondence. In: Verlohr D, Georgievski Z, Rydberg A (eds) Global perspectives converge downunder, the transactions of the Xth international orthoptic congress. International Orthoptic Association, Melbourne, Australia, pp 73–80 15. Arnoldi K (2001) Monoﬁxation with eso-, exo-, or hypertropia: is there a diﬀerence? Am Orthopt J 51:55–66 16. Leske DA, Holmes JM (2004) Maximum angle of horizontal strabismus consistent with true stereopsis. J AAPOS 8:28–34 17. Choi DG, Isenberg SJ (2001) Vertical strabismus in monoﬁxation syndrome. J AAPOS 5:5–8 18. Richards M, Wong A, Foeller P, Bradley D, Tychsen L (2008) Duration of binocular decorrelation predicts the severity of latent (fusion maldevelopment) nystagmus in strabismus macaque monkeys. Invest Ophthalmol Vis Sci 49:1872–1878

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The Monoﬁxation Syndrome: New Considerations on Pathophysiology

19. Neri P, Bridge H, Heeger DJ (2004) Stereoscopic processing of absolute and relative disparity in human visual cortex. J Neurophysiol 92:1880–1991 20. Horwood A (2003) Neonatal ocular misalignments reﬂect vergence development but rarely become esotropia. Br J Ophthalol 87:1146–1150 21. Hasany A, Wong A, Foeller P, Bradley D, Tychsen L (2008) Duration of binocular decorrelation in infancy predicts the severity of nasotemporal pursuit asymmetries in strabismic macaque monkeys. Neuroscience 156:403–411 22. Tychsen L, Scott C (2003) Maldevelopment of convergence eye movements in macaque monkeys with small- and large-angle infantile esotropia. Invest Ophthalmol Vis Sci 44:3358–3368 23. Harwerth RS, Smith EL, Crawford ML, von Noorden GK (1997) Stereopsis and disparity vergence in monkeys with subnormal binocular vision. Vis Res 37:483–493 24. Borman DK, Kertesz AE (1985) Fusional responses of strabismics to foveal and extrafoveal stimulation. Invest Ophthalmol Vis Sci 26:1731–1739 25. Curcio CA, Allen KA (1990) Topography of ganglion cells in human retina. J Comp Neurol 300:5–25 26. Curcio CA, Sloan KR, Kalina RE, Hendrickson AE (1990) Human photoreceptor topography. J Comp Neurol 292:497–523 27. Perry VH, Silveira LC, Cowey A (1990) Pathways mediating resolution in the primate retina. Cib Found Symp 155:5–14 28. Wässle H, Grünert U, Röhrenbeck J, Boycott BB (1990) Retinal ganglion cell density and cortical magniﬁcation factor in the primate. Vis Research 30:1897–1911 29. Tychsen L, Kim D, Burkhalter A (1994) Naso-temporal asymmetries in geniculo-striate pathway of normal adult macaque. Invest Ophthalmol Vis Sci Suppl 35:1773 30. Tychsen L, Burkhalter A (1997) Nasotemporal asymmetries in V1: ocular dominance columns of infants, adult, and strabismic macaque monkeys. J Comp Neurol 388:32–46 31. Lewis TL, Maurer D (1992) The development of the temporal and nasal visual ﬁelds during infancy. Vis Research 32:903–911 32. Beirne RO, Zlatkova MB, Anderson RS (2005) Changes in human short-wavelenth-sensitive and achromatic resolution acuity with retinal eccentricity and meridian. Vis Neurosci 22:79–86 33. Bowering ER, Maurer D, Lewis TL, Brent HP (1993) Sensitivity in the nasal and temporal hemiﬁelds in children

34. 35.

36.

37.

38.

39. 40.

41. 42. 43. 44. 45.

46.

47.

48.

49.

treated for cataract. Invest Ophthalmol Vis Sci 34: 3501–3509 Merigan WH, Katz LM (1990) Spatial resolution across the macaque retina. Vis Research 30:985–991 Cisarik PM, Harwerth RS (2008) The eﬀects of interocular correlation and contrast on stereoscopic depth magnitude estimation. Optom Vis Sci 85:164–173 Arthur BW, Smith JT, Scott WE (1989) Long-term stability of alignment in the monoﬁxation syndrome. J Pediatr Ophthalmol Strabismus 26:224–231 Hunt MG, Keech RV (2005) Characteristics and course of patients with deteriorated monoﬁxation syndrome. J AAPOS 9:533–536 Pratt-Johnson JA, Tillson G (2001) Management of strabismus and amblyopia, 2nd edn. Thieme, New York, Stuttgart, pp 113 vonNoorden GK, Campos EC (2002) Binocular vision and ocular motility, 6th edn. Mosby, St. Louis, pp 544 Houston CA, Cleary M, Dutton GN, McFadsean RM (1998) Clinical characteristics of microtropia – is microtropia a ﬁxed phenomenon? Br J Ophthalmol 82:219–224 Keiner EC (1978) Spontaneous recovery in microstrabismus. Ophthalmologica 177:280–283 vonNoorden GK, Campos EC (2002) Binocular vision and ocular motility, 6th edn. Mosby, St. Louis, pp 344–345 Quéré MA, Lavenant G, Péchereau A (1993) Les diplopies incoercibles post-thérapeutiques. J Fr Orthopt 25:191 Das VE, Fu LN, Mustari MJ, Tusa RJ (2005) Incomitance in monkeys with strabismus. Strabismus 13:33–41 Fu LN, Tusa RJ, Mustari MJ, Das VE (2007) Horizontal saccade disconjugacy in strabismic monkeys. Invest Ophthalmol Vis Sci 48:3107–3114 Tusa RJ, Mustari MJ, Das VE, Boothe RG (2002) Animal models for visual deprivation-induced strabismus and nystagmus. Ann NY Acad Sci 956:346–360 Wensveen JM, Harwerth RS, Smith EL (2003) Binocular deﬁcits associated with early alternating monocular defocus. I. Behavioral observations. J Neurophysiol 90: 3001–3011 Zhang B, Matsura K, Mori T, Wensveen JM, Harwerth RS, Smith EL Chino Y (2003) Binocular deﬁcits associated with early alternating monocular defocus, neurophysiological observations. J Neurophysiol 90:3012–3023 Zhang B, Bi H, Sakai E, Maruko I, Zheng J, Smith EL, Chino YM (2005) Rapid plasticity of binocular connections in developing monkey visual cortex (V1). Pro Natl Acad Sci USA 102:9026–9031

Chapter 5

Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment

5

Lawrence Tychsen

Core Messages ■

■

■

■

Proper alignment of the eyes requires information sharing (fusion) between monocular visual input channels in the CNS; the ﬁrst locus for fusion in the CNS of primates is the striate cerebral cortex (area V1). Fusion behaviors and V1 binocular connections are immature at birth, maturing during a critical period in the ﬁrst months of life; maturation of fusion and V1 binocular connections requires correlated (synchronized) input from each eye. Nasalward biases are present innately in the neural pathways of normal primates before maturation of binocularity. Esotropia and the associated nasalward gaze biases of infantile strabismus can be produced

5.1

Esotropia as the Major Type of Developmental Strabismus

Esotropia is the leading form of developmental strabismus. Therefore, unraveling the causal mechanism and response to treatment is an important public health issue. The purpose of this chapter is to review knowledge gained over the last two decades that: (a) implicates cerebral cortex maldevelopment as the cause, and (b) explains how repair of cortical circuits may be the key to functional cures.

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■

■

■

reliably in normal primates by impeding the maturation of fusional/binocular connections in V1. Infantile esotropia occurs predominantly in human infants who have perinatal insults that would impair correlated visual input to V1. Surgical realignment of the eyes during the critical period of normal binocular maturation may achieve functional sensory and motor cures. If surgery fails to restore bifoveal fusion, subnormal fusion (micro-esotropia/monoﬁxation) may be achieved within boundaries set by the properties of neurons in V1 and extrastriate cortex. Late-onset (e.g., accommodative) esotropia is easier to treat because the fusional connections in V1 matured substantially before the emergence of eye misalignment.

early-onset esotropia are predominantly emmetropic [1], whereas late-onset esotropia is associated commonly with a substantial hypermetropic refractive error (accommodative esotropia). The most prevalent form of developmental strabismus in humans is concomitant, constant, nonaccommodative, early-onset esotropia. Most of these cases have onset in the ﬁrst 12 months of life, i.e., infantile-onset. Infantile esotropia may be considered the paradigmatic form of strabismus in all primates, as it is also the most frequent type of natural strabismus observed in monkeys [2].

5.1.1 Early-Onset (Infantile) Esotropia Esotropia has a bimodal, age-of-onset distribution. The largest peak (comprising ~40% of all strabismus) occurs at or before age 12–18 months, with a second, smaller “late onset” esotropia peak at age 3–4 years. Children with

5.1.2

Early Cerebral Damage as the Major Risk Factor

If infantile esotropia is a paradigmatic form of strabismus, investigations designed to reveal pathophysiologic

42

5

5

Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment

mechanisms should begin by asking what factors contribute to its causation. At highest risk are infants who suﬀer cerebral maldevelopment from a variety of causes (Table 5.1), especially insults to the parieto-occipital cortex and underlying white matter (geniculostriate projections or optic radiations) [3, 5–7]. Periventricular and intraventricular hemorrhage in the neonatal period increases the prevalence of infantile strabismus 50–100fold. Less speciﬁc cerebral insults, e.g., from very low birth weight (with or without retinopathy of prematurity) or Down syndrome, increase the risk above that of otherwise healthy infants by factors of 20–30-fold [4, 7–10].

5.1.3

5.1.4

Genetic Inﬂuences on Formation of Cerebral Connections

Genetic factors also play a causal role. Large-scale studies have documented that ~30% of children born to a strabismic parent will themselves develop strabismus [18]. Twin studies reveal a concordance rate for monozygous twins of 73% [19]. Less than 100% concordance implies that intrauterine or perinatal (“environmental”) factors alter the expression of the strabismic genotype. Maumenee and associates analyzed the pedigrees of 173 families containing probands with infantile esotropia [20]. The results suggested a multifactorial or Mendelian codominant inheritance pattern. Codominant means that both alleles of a single gene contribute to the phenotype but with diﬀerent thresholds for expression of each allele. These genes could conceivably encode cortical neurotrophins, or axon guidance and maturation. Any of these genetically modulated factors could increase the susceptibility to disruption of visual cortical connections in otherwise healthy infants.

Cytotoxic Insults to Cerebral Fibers

The occipital lobes in newborns are vulnerable to damage [6, 12–14]. Premature infants frequently suﬀer injury to the optic radiations near the occipital trigone. Balanced binocular input requires equally strong projections from each eye through this periventricular zone. The ﬁbers connect the lateral geniculate laminae to the ocular dominance columns (ODCs) of the striate cortex. The projections are immature at birth and the quality of signal ﬂow would be critically dependent upon the function of oligodendrocytes, which insulate the visual ﬁbers. Neonatal oligodendrocytes are especially vulnerable to cytotoxic insult [15]. The striate cortex is also susceptible to hypoxic injury because it has the highest neuron-to-glia ratio in the entire cerebrum [16] and the highest regional cerebral glucose consumption [17].

5.1.5 Development of Binocular Visuomotor Behavior in Normal Infants Esotropia is rarely present at birth. For this reason alone, “infantile esotropia” is a more appropriate descriptor than “congenital esotropia.” Constant misalignment of the visual axes appears typically after a latency of several months, becoming conspicuous on average between the ages of 2 and 5 months [11, 21, 22]. To understand visuomotor maldevelopment in strabismic infants during this period, it is helpful to understand the development of binocular fusion and vergence in normal infants (Table 5.2) during the same 2–5-month postnatal interval.

Table 5.1. Cerebral damage risk factors for infantile-onset strabismus

a

Type

Prevalence strabismus (%)

Author(s)

Intraventricular hemorrhage with hydrocephalus

100

[3]

Cerebral visual pathway white matter injury

76

[4]

Occipitoparietal hemorrhage or leukomalacia

54–57

[5, 6]

Very low birth weight infants (<1,500 g)

33a

[7]

Very low birth weight (<1,251 g) and prethreshold retinopathy of prematurity

30

[8]

Very low birth weight (<1,251 g) and normal neuroimaging

17

[4]

Down syndrome

21–41

[9, 10]

Healthy full-term infants

0.5–1.0

[11]

Additional 17% of infants had persistent asymmetric OKN

5.1 Esotropia as the Major Type of Developmental Strabismus

43

Table 5.2. Binocular development and visuomotor behaviors in infant primate Immature behavior

Chief ﬁndings before onset of mature behavior

Investigator(s)

Binocular disparity sensitivity absent before ~3–5 mos

Stereo-blindness Convergent disparity sensitivity emerges earlier than divergent

[23] [24, 25] [26]

Binocular sensorial fusion absent before ~3–5 mos

Equal attraction to rivalrous vs. fusible stimuli

[27, 25] [28]

Fusional (binocular) vergence unstable before ~3–5 mos

Binocular alignment errors common despite accommodative capacity

[29, 30] [27] [31] [32, 33]

Nasalward bias of vergence pronounced before ~3–5 mos

Nasalward bias of cortically mediated motion sensitivity before ~6 mos

Transient convergence errors 4X divergence errors Convergent disparity sensitivity present earlier than divergent

[34]

Convergence fusion range exceeds divergence by 2:1

[32, 33]

Motion VEP nasotemporal asymmetry Stronger preferential sensitivity to nasalward motion

[35, 36] [37] [38] [39]

Nasalward bias of pursuit/OKN before ~6 mos

Nasalward motion evokes stronger OKN/pursuit

[40] [41]

Nasotemporal asymmetry resolves after onset binocularity

[42] [43] [44] [45]

Nasalward bias of gaze-holding before ~6 mos

Nasalward slow phase drift of eye position Persists as latent ﬁxation nystagmus with binocular maldevelopment

5.1.6 Development of Sensorial Fusion and Stereopsis Binocular disparity sensitivity and binocular fusion are absent in infants less than several months of age, as demonstrated by several methods, most notably studies that have used forced preferential looking (FPL) techniques [23–25, 27, 28]. The FPL studies show that stereopsis emerges abruptly in humans during the ﬁrst 3–5 months of postnatal

[42] [46] [47]

life, achieving adult-like levels of sensitivity. Sensitivity to crossed (near) disparity appears on average several weeks before that to uncrossed (far) disparity [24]. During this same interval infants begin to display an aversion to stimuli that cause binocular rivalry (i.e., nonfusable stimuli). Visually evoked potentials in normal infants, recorded using dichoptic viewing and dichoptic stimuli, show comparable results [43, 48, 49]. Onset of binocular signal summation occurs after, but not before, ~3 months of age.

44

5

Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment

5.1.7 Development of Fusional Vergence and an Innate Convergence Bias

5

Fusional vergence eye movements mature during an equivalent period in early infancy. In the ﬁrst 2 months of life, alignment is unstable and the responses to step or ramp changes in disparity are often markedly inaccurate [32, 33]. The inaccuracy cannot be ascribed to errors of accommodation. Accommodative precision during this period consistently exceeds that of fusional (disparity) vergence [29, 30, 33]. Studies of fusional vergence development in normal infants reveal an innate bias for convergence [32, 33]. Transient convergence errors of large degree exceed divergence errors by a ratio of 4:1. The fusional vergence response to crossed (convergent) disparity is also intact earlier and substantially more robust than that to divergent disparity. The innate bias favoring fusional convergence in primates persists after full maturation of normal binocular disparity sensitivity. Fusional convergence capacity exceeds the range of divergence capacity by a mean ratio of 2:1 [50, 51].

5.1.8

Development of Motion Sensitivity and Conjugate Eye Tracking (Pursuit/OKN)

The innate nasalward bias of the vergence pathway has analogs in the visual processing of horizontal motion, both for perception and conjugate eye tracking. In the ﬁrst months of life, VEPs elicited by oscillating grating stimuli (motion VEPs) show a pronounced nasotemporal asymmetry under conditions of monocular viewing [35–38]. The direction of the asymmetry is inverted when viewing with the right vs. left eye. Monocular FPL testing reveals greater sensitivity to nasalward motion [39]. Monocular pursuit and optokinetic tracking show strong biases favoring nasalward target motion when viewing with either eye [40, 41, 43–45]. Optokinetic after-nystagmus (slow phase eye movement in the dark after extinction of stimulus motion) is characterized by a consistent nasalward drift of eye position [42]. These nasalward motion biases are most pronounced before the onset of sensorial fusion and stereopsis, but systematically diminish thereafter.

5.1.9 Development and Maldevelopment of Cortical Binocular Connections Knowledge of visual cortex development (Table 5.3) is important for understanding the neural mechanisms that could cause strabismus, for several reasons. First, the visual cortex is the initial locus in the CNS at which visual signals from the two eyes are combined and a combination of visual signals is necessary to generate the vergence error commands that guide eye alignment. Second, the most common form of strabismus (esotropia) appears coincident with maturation of cortically mediated, binocular, sensorimotor behaviors in normal infants. Third, perinatal insults to the immature visual cortex are linked strongly to subsequent onset of strabismus. And ﬁnally, the constellation of sensory and motor deﬁcits in infantile strabismus can be explained by known cortical pathway mechanisms.

5.1.10

Binocular Connections Join Monocular Compartments Within Area V1 (Striate Cortex)

Aﬀerents from each eye are segregated in monocular lamina of the lateral geniculate nucleus (LGN) and at the input layer (4C) of ODCs of the striate cortex, or visual area V1 (Fig. 5.1) [52, 53]. The ﬁrst stage of binocular processing in the primate CNS is made possible by horizontal connections between ODCs of opposite ocularity, above and below layer 4C [52, 68, 70]. Physiological recordings in normal neonatal and adult monkeys show monocular responses in layer 4C and binocular responses from the majority of neurons in V1 layers 4B and 2–6 [52, 54, 63]. The binocular responses in the neonate are cruder and weaker than those recorded in normal adult [58, 59, 77]. Binocular disparity sensitive neurons are present in the neonatal cortex, but the spatial tuning is poor and they are characterized by a high binocular suppression (inhibition) index. The immature neuronal response properties are attributed to unreﬁned, weak excitatory horizontal binocular connections between ODCs. These axonal connections help deﬁne the segregation of ODCs [62, 77]. ODC borders are immature (fuzzy) at birth but adult-like (sharply deﬁned) by 3–6 weeks postnatally [60, 78] (the equivalent of 3–6 months in humans, 1 week of monkey visual development is comparable with 1 month in humans [79]).

5.1 Esotropia as the Major Type of Developmental Strabismus

45

Table 5.3. Development of neural pathways in normal and strabismic primate Neurobiological principle

Physiology/anatomy

Investigator(s)

Striate cortex (area V1) is the ﬁrst CNS locus for binocular processing

Right and left eye inputs remain segregated in LGN and input layer (4C) in V1

[52, 53]

Binocular responses recorded from neurons in V1 lamina beyond layer 4C

[54]

Neurons in V1 layers 2–6 are sensitive to binocular disparity

[55]

Segregation of RE/LE ODCs immature at birth Binocular (disparity sensitive) neurons present at birth but tuning poor

[56] [57]

Immature binocular neurons have weak excitatory horizontal connections between ODCs and high suppression index

[58, 59] [60, 61] [62]

Maturation of binocular connectivity in V1 requires correlated RE/LE input

Absence of correlation causes lack of disparity sensitivity and loss of horizontal connections in V1

[63, 64, 65] [66] [67, 68, 69, 70]

V1 feeds forward to extrastriate visual areas MT/MST which control ipsiversive eye tracking and gaze holding

Extrastriate areas MT/MST mediate pursuit/OKN and recieve feedforward (binocular)projections from V1 lamina 4B Lesions of MST impair ipsiversive pursuit/OKN and gaze holding

[71, 72] [73, 74] [75]

V1 feed forward connections to MT/MST at birth are monocular from ODCs driven by the contralateral eye

Before maturation of binocularity, a nasalward movement bias is apparent when viewing with either eye (RE viewing evokes leftward pursuit/OKN/gaze drift; LE viewing evokes rightward pursuit/OKN/gaze drift)

[76]

Nasalward + temporalward neurons are present in = numbers within V1/MT but nasalward have innate connectivity advantage

[77] [13]

MST inputs from the ipsilateral eye require maturation of binocular V1/MT connections

If binocularity matures, monocular viewing evokes equal nasalward/temporalward eye movement + stable gaze

[76] [13, 47]

MST neurons encode both vergence and pursuit/OKN

Disparity sensitive neurons in MST also mediate vergence If binocularity fails to mature, monocular viewing evokes nasalward pursuit/OKN and inappropriate convergence

[81] [80] [105] [82, 47]

Convergence motoneurons are more numerous

Convergence neurons outnumber divergence neurons 3:2 in the midbrain of normal primates

[122, 123]

Binocular structure + function in V1is immature at birth

46

5

Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment

a

2/3 4B

Fusion/stereopsis Alignment and Balanced Gaze

5 Ocular Dominance Columns of V1 (Striate Cortex)

4C

R

4B

R

L

Correlated Activity

LGN

2/3

L

b

4C

Stereo-blindness R

L

R

L Periventricular White Matter Projections

Fig. 5.1 Neuroanatomic basis for binocular vision. Monocular retinogeniculate projections from left eye (temporal retina-nasal visual hemiﬁled) and right eye (nasal retina-temporal hemiﬁeld) remain segregated up to and within the input layer of ocular dominance columns (ODCs) in V1, layer 4C (striate visual cortex). Binocular vision is made possible by horizontal connections between ODCs of opposite ocularity in upper layers 4B and 2/3 (as well as lower layers 5/6, not shown). RE inputs red; LE inputs blue

5.1.11 Too Few Cortical Binocular Connections in Strabismic Primate Maturation of binocular connections in V1 requires correlated (synchronous) activity between right and left eye inputs (Fig. 5.2a) [66]. Decorrelation of inputs, by natural strabismus [68, 70], or as a consequence of experimental manipulations that produce retinal image noncorrespondence [66, 67], causes loss of binocular horizontal connections (Fig. 5.2b). Monocular connections between ODCs of the same ocularity are maintained. The loss is due to excessive pruning of connections, beyond the normal process of axon retraction and reﬁnement that takes place within and between ODCs in the ﬁrst weeks of life. (Captured in the neuroscience dictum: “Cells that ﬁre together, wire together. Cells that ﬁre apart, depart.”) The paucity of binocular connections is accompanied by loss of binocular responsiveness and disparity sensitivity, measured electrophysiologically, in V1 neurons [55, 63, 64]. The companion behavioral deﬁcits are stereoblindness and absence of fusional vergence [47, 65].

Esotropia and Gaze Asymmetries R

L

R

L

De-Correlated Activity

Fig. 5.2 Horizontal connections for binocular vision in V1 of normal (correlated activity) vs. strabismic (decorrelated) primate, layer 2–4B. (a) V1 of normal primates is characterized by equal numbers of monocular and binocular connections. (b) In strabismic primates, the connections are predominantly monocular (i.e., a paucity of binocular connections). RE inputs red; LE blue; binocular violet

5.1.12 Projections from Striate Cortex (Area V1) to Extrastriate Cortex (Areas MT/MST) Projections from V1 layer 4B feed forward to regions of extrastriate visual cortex, in particular the middle temporal and middle superior temporal area (MT/MST) [75]. MT and MST mediate pursuit/OKN and a closely related type of tracking movement, ocular following [73, 74]. MT/MST neurons are directionally selective and sensitive to binocular disparity, guiding both conjugate and disconjugate (near-far) tracking [80–82]. In normal primates, greater than 90% of MT/MST neurons exhibit balanced, binocular responses. In strabismic primates, the responses are predominantly monocular, indicating that the loss of binocularity found in V1 is passed on in the projections to MT/MST.

5.1.13

Inter-Ocular Suppression Rather than Cooperation in Strabismic Cortex

When the eyes are misaligned, suppression is necessary to avoid diplopia or visual confusion. Suppression is a major sensorial abnormality in humans and monkeys

5.1 Esotropia as the Major Type of Developmental Strabismus

with infantile strabismus. Visual inputs may be suppressed from one eye continuously (causing unilateral amblyopia), or commonly in infantile strabismus, from each eye alternately ~50% of the time (alternate ﬁxation) [83, 84]. In normal animals, horizontal connections between ODCs can mediate suppression when conﬂicting stimuli activate neurons in neighboring ODCs [85, 86]. The mitochondrial enzyme cytochrome oxidase (CO) is used to reveal neuronal activity within ODCs [87–89]. In normal primates, the input layer of area V1, layer 4C, shows a uniform pattern of CO activity in right eye and left eye columns (Fig. 5.3a), reﬂecting equal activity (absence of inter-ocular suppression). Unequal CO activity is a general ﬁnding in area V1 of primates who have strabismus [78, 90], amblyopia [91], or both [92]. The unequal activity is seen as reduced CO activity (metabolic suppression) in the ODCs driven by one eye in each cerebral hemisphere (Fig. 5.3b). When strabismus is combined with amblyopia, metabolic suppression is more pronounced. The CO abnormality in monkey cortex correlates with clinical observations in strabismic humans. Binocularity is impaired to a greater degree, and suppression tends to be more pronounced, in patients who have combined

a

2/3 4B

Equal Neuronal Metabolic Activity

4C

R

L

R

L

Normal

b Inter-ocular Metabolic Suppression R

L

R

L

Strabismic

Fig. 5.3 Metabolic activity in neighboring ODCs within V1 of normal vs. strabismic primate. (a) In normal, Layer 4C stains uniformly for the metabolic enzyme cytochrome oxidase (CO) (shown as brown), indicating equal activity in right-eye vs. left-eye columns. (b) In strabismic, a narrow monocular zone within the dominant ODCs (shown here as left-eye) shows normal metabolic activity (brown), but ODCs belonging to the suppressed eye (shown as right-eye) and binocular border zones between ODCs are pale, connoting abnormally low – i.e., suppressed – activity

47

strabismus and amblyopia, as compared with strabismus alone (that is, alternating ﬁxation). The metabolic abnormalities are found throughout V1 when suppression is widespread; alternatively, suppression is conﬁned to zones of V1 that match retinotopically the location of a suppression scotoma. The metabolic suppression is not found in the LGN, which is composed of neurons driven monocularly from each eye without binocular interaction. These ﬁndings imply that abnormal binocular interaction in V1 leads to heightened competition between ODCs of opposite ocularity, with suppression of metabolic activity in opposite-eye ODCs. The abnormalitis add to our knowledge of the brain damage caused by unrepaired strabismus. As noted in the preceding sections, the eﬀects include an ~50% reduction in longrange, excitatory binocular horizontal connections joining ODCs of opposite ocularity [70, 93]. In the presence of strabismus, the remaining 50% of binocular connections (long-range, short-range or a combination) may be predominantly inhibitory.

5.1.14

Naso-Temporal Inequalities of Cortical Suppression

Psychophysical studies of the development of the visual hemiﬁelds in normal human infants indicate that temporal retina sensitivity matures slower than nasal retina sensitivity [94, 95]. The nasotemporal asymmetry in sensitivity diminishes if the infant develops normal vision, but lower temporal sensitivity remains permanently if early binocular development is disrupted by strabismus or amblyopia [96–98] (for review, see [78]). In strabismic animals, metabolic suppression tends to be most apparent in ODCs driven by the ipsilateral eye in V1 of both the right and left hemispheres. Ipsilateral inputs originate from the temporal hemi-retinae of each eye, implying that inputs to V1 from the temporal hemiretinae are at a developmental disadvantage [78, 92, 99]. The human psychophysical ﬁndings, together with the monkey anatomic ﬁndings, reinforce the conclusion that abnormal binocular experience in early infancy unfairly punishes visual neurons that are slow to develop and fewer in number, that is, those driven by the temporal hemiretina [78].

5.1.15 Persistent Nasalward Visuomotor Biases in Strabismic Primate If normal maturation of binocularity is impeded by eye misalignment, the innate nasalward biases of eye tracking

48

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Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment

do not resolve – they persist and become pronounced [46, 100–102]. Normally, area MST in each cerebral hemisphere encodes ipsiversive eye tracking and gaze holding (Fig. 5.4). Ablations within MST impair ipsiversive pursuit/OKN, and excitation of MST evokes ipsiversive (slow

phase) gaze drift. In newborns, the outputs from V1 to each area MST appear to favor innately the contralateral eye (i.e., inputs from the right eye make stronger connection – through area V1 of both hemispheres – to area MST of the left hemisphere) [13, 76]. The contralateral-

Strabismic

Normal

chi RE

LE

RE

LE

RE

LE

RE

LE

call

nasalward gaze instability

stable gaze

Fig. 5.4 Neural network diagrams showing visual signal ﬂow for pursuit and gaze holding in strabismic vs. normal primates. Paucity of mature binocular connections explains behavioral asymmetries evident as asymmetric pursuit/OKN and latent ﬁxation nystagmus. Note that in all primates, pursuit area neurons in each hemisphere encode ipsilaterally directed pursuit. Signal ﬂow is initiated by a moving stimulus in the monocular visual ﬁeld, which evokes a response in visual area neurons (i.e., V1/MT). Each eye at birth has access – through innate, monocular connections – to the pursuit area neurons (e.g., MSTd) of the contralateral hemisphere. Access to pursuit neurons of the ipsilateral hemisphere requires mature, binocular connections. Strabismic/nasalward gaze instability: moving from top to bottom, starting with target motion in monocular visual ﬁeld of right eye. Retinal ganglion cell ﬁbers from the nasal and temporal hemiretinae (eye) decussate at the optic chiasm (chi), synapse at the LGN, and project to alternating rows of ODCs in V1 (visual area rectangles). In each V1, ODCs representing the nasal hemiretinae (temporal visual hemi-ﬁeld) occupy slightly more cortical territory than those representing the temporal hemiretinae (nasal hemiﬁeld), but each ODC contains neurons sensitive to nasally directed vs. temporally directed motion (half circles shaped like the matching hemiﬁeld, arrows indicate directional preference). Visual area neurons (including those beyond V1 in area MT) are sensitive to both nasally directed and temporally directed motion, but only those encoding nasally directed motion are wired innately – through monocular connections – to the pursuit area. Normal/stable gaze: binocular connections are present, linking neurons with similar orientation/directional preferences within ODCs of opposite ocularity (diagonal lines between columns). Viewing with the right eye, visual neurons preferring nasally directed motion project to the left hemisphere pursuit area; visual neurons preferring temporally directed motion project to the right hemisphere pursuit area. Temporally directed visual area neurons gain access to pursuit area neurons only through binocular connections. Call corpus callosum, through which visual area neurons in each hemisphere project to opposite pursuit area. Bold lines active neurons and neuronal projections

5.1 Esotropia as the Major Type of Developmental Strabismus

eye-to-MST connectivity advantage is consistent with an innate, contralateral-eye-to-V1 connectivity advantage. (Captured in twin dictums: “ﬁrst come, ﬁrst served ”and “majority rules.”) V1 neurons in each hemisphere, driven by the nasal hemiretinae (contralateral eye), develop earlier and outnumber (by a ratio of ~53:47 in primate) neurons from the temporal hemiretinae (ipsilateral eye). Area MST on the side ipsilateral to the viewing eye can only be accessed through binocular V1/MT connections. The contralateral eye-to-MST connectivity bias provides a mechanism for the nasalward tracking bias, evident before onset of binocularity (Fig. 5.4). Right eye viewing activates right eye ODCs in each area V1. Right eye ODCs connect preferentially to the left area MST. The left area MST mediates ipsiversive/leftward tracking, which is nasalward tracking with respect to the viewing (right) eye. When binocular connections mature, right

eye ODCs gain equal access to neurons within areas MST of the right and left hemisphere, and the nasalward bias disappears. (Captured in the dictum: “Tracking from ear to nose will balance as binocularity grows.”) If binocular connections are lost, the nasalward bias persists and is exaggerated. The bias is evident clinically (Fig. 5.5) as a pathologic naso-temporal asymmetry of pursuit/OKN and a nasalward (slow phase) drift of gaze-holding (latent nystagmus) [103, 104]. Area MST neurons are sensitive to binocular disparity and also drive fusional vergence eye movements [80, 82]. Eye movement recordings in a primate with infantile esotropia showed inappropriate activation of convergence whenever nasalward monocular OKN was evoked [105]. Neuroanatomic analysis of V1 in this monkey showed a paucity of binocular connections and metabolic evidence of heightened interocular suppression. The

Fusional Vergence (esotropia)

Fig. 5.5 Nasalward vergence and gaze asymmetries in strabismic humans and monkeys. Fusional vergence: esodeviation of the nonﬁxating eye, evident as alternating esotropia. Tracking pursuit/OKN: horizontal smooth pursuit is asymmetric during monocular viewing. Pursuit is smooth (normal) when target motion is nasalward in the visual ﬁeld. Pursuit is cogwheel (low gain-abnormal) when the target moves temporalward. The movements of the two eyes are conjugate, and the direction of the asymmetry reverses instantaneously with a change of ﬁxating eye, so that the direction of robust pursuit is always for nasalward motion in the visual ﬁeld. Gaze holdinglatent nystagmus: viewing with the right-eye, both eyes have a nasalward slow-phase drift, followed by temporalward refoveating fast-phase microsaccades. The direction of the nystagmus reverses instantaneously when the left eye is ﬁxating, so that the slow phase is nasalward with respect to the ﬁxating eye

49

Tracking (pursuit/OKN)

Gaze Holding (latent nystagmus)

50

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Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment

conclusion drawn from these observations was that MST neurons promote esotropia (i.e., a bias for nasalward vergence) when binocularity fails to develop in V1. The mechanism is attractive, because it ties together the nasalward biases of vergence, pursuit/OKN and gaze holding (latent nystagmus) in cortical regions vulnerable to perinatal damage. Outputs from the cortical areas noted earlier (V1, MT/ MST) and related cortical areas descend to brainstem visual relay and premotor neuron pools immediately adjacent to the motor nuclei (Fig. 5.5) [106]. Even in the absence of cortical maldevelopments, the vergence system is unbalanced, favoring convergence. Midbrain premotor neurons driving convergence outnumber those driving divergence, by a ratio of 3:2.

5.1.16 Repair of Strabismic Human Infants: The Historical Controversy Is repair of binocular V1 connections possible, restoring normal fusion and stereopsis, while preventing or reversing the constellation of ocular motor maldevelopments? The answer to this question is rooted in a debate between two competing twentieth century schools of treatment philosophy, derived from the eminent British strabismologists, Claude Worth and Bernard Chavasse. Worth postulated in 1903 that esotropic infants suﬀered “an irreparable defect of the fusion faculty” [107]. Their brain was congenitally incapable of achieving substantial binocular vision. Early surgical treatment was therefore unfounded because it was futile. Chavasse on the other hand – attracted by the Pavlovian physiology of the 1920 and 1930s – believed that the brain machinery for fusion was present in esotropic infants, but the development of “conditioned reﬂexes” for binocular fusion were impeded by factors such as weakness of the motor limb [108]. He postulated (in his text published in 1939) that if the eyes could be realigned during what he believed to be a period of reﬂex learning, binocular fusion could be restored.

5.1.17 Repair of High-grade Fusion is Possible New knowledge of stereopsis development in the 1980s bolstered the rationale in favor of early surgery, as articulated by disciples of Chavasse in the U.S., most notably August Costenbader, Marshall Parks, and a series of Parks’ trainees [109, 110]. The new knowledge prompted a gradual reexamination of old data and inspired important case studies – in the 1980 and 1990s – on the eﬃcacy of early strabismus surgery [111–114]. These reports

showed that if stable, binocular alignment was not achieved until age 24 months, the chances of repairing stereopsis were nil. If stable alignment was achieved by age 6 months, the chances of repairing stereopsis were good, and a substantial percentage of the infants regained robust stereopsis, i.e., random dot stereopsis with thresholds on the order of 60–400 arcsec. Scrutiny of early alignment data in infantile esotropia has produced more reﬁned and forceful conclusions. Figure 5.6a is replotted data on stereopsis outcomes in over 100 consecutive infantile esotropes [112]. The Y-axis is prevalence of stereopsis after surgical alignment, and the X-axis is age of onset or duration of misalignment before surgery. The dashed line at 40% represents the average prevalence of stereopsis when all infants operated upon by 2 years of age are grouped together, without regard to age at correction or duration before correction. The noise in the data – relating age at alignment to stereopsis outcome – is related to the fact that onset of strabismus is idiosyncratic, varying considerably from infant to infant, and distributed randomly in the interval 2–6 months of age. There is no systematic relationship between age of onset of esotropia and subsequent attainment of stereopsis. However, when the data is reanalyzed with strict attention to duration of misalignment, a strong correlation is evident between shorter durations of misalignment and restoration of stereopsis (Fig. 5.6b). Excellent outcomes are achievable in infants operated upon within 60 days of onset of strabismus (“early surgery”) [112]. The clinical dictum that follows is that age at surgery should be tailored to age of onset and not chronological age. Esotropic infants who regain high grade stereopsis also regain robust fusional vergence [112–114]. Clinical observation also suggests that they have a lower prevalence of recurrent esotropia (or exotropia), pursuit/OKN asymmetry, motion VEP asymmetry, latent nystagmus, and dissociated vertical deviation (DVD). However, ocular motor recording is diﬃcult to perform in children and detailed, quantitative information is lacking.

5.1.18 Timely Restoraion of Correlated Binocular Input: The Key to Repair Eye movement studies of strabismic infant monkeys have helped ﬁll gaps in clinical knowledge. The studies have shown that normal motor and sensory pathway development can be restored when the timeliness of therapy conforms to that of early surgery in humans [47, 115]. If binocular image correlation is restored in strabismic monkeys within 3 weeks of onset of strabismus (the equivalent of 3 months in humans), fusional vergence,

5.2 Visual Cortex Mechanisms in Micro-Esotropia (Monoﬁxation Syndrome)

a

pursuit/OKN and gaze holding return to normal (Fig. 5.6c). The repair of ocular motor behavior occurs with repair of stereopsis and restoration of normal motion responses (motion VEPs). If decorrelation persists in strabismic monkeys until the equivalent of 12 months’ duration in humans, esotropia and stereoblindness persist. Prolonged-decorrelation animals exhibit latent nystagmus, pursuit/OKN asymmetry, motion VEP asymmetry, and DVD. The quality of behavioral repair correlates with the quality of neuroanatomic repair in V1 (Fig. 5.6c). “Early repair” monkeys (i.e., those who have shorter durations of decorrelation) have a normal complement of binocular horizontal excitatory connections between ODCs of opposite ocularity, and “delayed repair” (longer durations of decorrelation) monkeys a paucity. The restoration of binocular connections in V1 of “early repair” monkeys appears to have equally beneﬁcal eﬀects on downstream areas of extrastriate cortex (MT/MST) driving the ocular motor neurons of the brainstem. The beneﬁt is evident as symmetric nasotemporal eye tracking, stable gaze holding, and more normal fusional vergence.

% Children with Stereopsis

100 80 60 40 20 0 1

2

3

4

5

6

Age on Onset (months)

b % Children with Stereopsis

100 80 60 40 20 0 0-2

3-5

6-8

51

9-11 12-18 19-24

Duration of Misalignment (months)

c

5.2 Visual Cortex Mechanisms in MicroEsotropia (Monoﬁxation Syndrome)

40

Magnitude of Deficit (SD multiples)

Pur Asym

30

Nyst

20

Stereo

10

Eso DVD V1 binoc

0 0

24 3 6 9 12 Duration of Decorrelation (weeks)

Fig. 5.6 Repair of random-dot stereopsis after surgical realignment of the eyes in children with infantile esotropia, and analogous ﬁndings in strabismic monkeys. (a) Prevalence of stereopsis as a function of age-of-onset of strabismus. No systematic relationship is evident. (b) High prevalence (~80%) of stereopsis in infants who were aligned within 2 months of onset of strabismus. Probability of stereopsis was negligible in infants who had durations of strabismus exceeding ~12 months. Redrawn from data of Birch et al. [112]. (c) Magnitude of behavioral deﬁcits increases systematically as a function of decorrelation-duration in monkeys. One week of monkey visual development is equivalent of 1 month in humans. Pur Asymm horizontal pursuit asymmetry; Nyst velocity of latent nystagmus; Stereo random dot stereopsis deﬁcit; Eso angle of esotropia; DVD magnitude of dissociated vertical deviation; V1 binoc reduction in binocular connections between RE and LE ODCs in V1 (striate cortex)

As outlined earlier, recent data on early correction of infantile strabismus suggests that it is a curable disorder. But early surgery is the exception rather than the rule of current clinical practice in the U.S. and Europe. The majority of infants who have esotropia are corrected 6 or more months after onset of misalignment. The chances of rescuing bifoveal fusion after this interval are slim. Most infants are aligned to within 8 PD of orthotropia (microesotropia) and regain a degree of subnormal stereopsis and motor fusion, i.e., monoﬁxation syndrome. Monoﬁxation syndrome occurs as a primary disorder (prevalence 1%) or, more commonly, as a secondary phenomenon, after delayed treatment of large magnitude strabismus [116, 117]. The syndrome also occurs in monkeys [118]. The major sensory and motor features of monoﬁxation syndrome are listed in Table 5.4. Neural mechanisms for the ﬁrst two features listed in Table 5.4 are not diﬃcult to explain. Receptive ﬁelds in V1 – representing the fovea – are tiny and have narrow tolerances. Any defocusing or other decorrelation of one eye’s inputs would produce a conﬂict in neighboring V1 columns and promote suppression of ODCs corresponding to the weaker eye. The fovea subtends ~5° of the retinotopic map of V1, thus a suppression scotoma of ≤5° makes sense. Feature two, subnormal stereopsis,

52

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Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment

Table 5.4. Monoﬁxation (Microstrabismus) Syndrome

5

Clinical Feature

Possible Neural Mechanism

1. Foveal suppression scotoma of 3-5 deg in the non-preferred eyea when viewing binocularly

Inhibitory-connection-mediated metabolic suppression of decorrelated activity in V1 foveal ODCs of non-preferred eye

2. Subnormal stereopsis (threshold 60-3000 arc sec)

Broader disparity tuning of parafoveal neurons in V1/MT (foveal neurons suppressed)

3. Stable microesotropiab less than ~ 4-8 PD (~2.5-5 deg)

Small angle ≈ average horizontal neuron length in V1, eso by default to convergent disparity coding of major MST population

4. Fusional vergence amplitudes intact for disparities >2.5-5 deg (>4-8 PD)

V1 excitatory horizontal binocular connections (and V1/MT/ MST disparity neurons) intact beyond region of foveal suppression

a

subnormal acuity (amblyopia) in the non-preferred eye in 34% of corrected infantile esotropes and 100% of anisometropes. microexotropia in ≤10%

b

could be explained along similar lines. Stereoscopic thresholds increase exponentially from the fovea to more eccentric positions along the retinotopic map of the visual ﬁeld. If foveal ODCs are suppressed and parafoveal ODCs are left to mediate stereopsis; stereopsis is degraded but not obliterated. But it is features three and four of the monoﬁxation syndrome, the visuomotor signs, that are most intriguing. If binocular development is perturbed so that right and left eye foveal ODCs (receptive ﬁelds) do not enjoy perfectly correlated activity, why should the fall back position of visual cortex be set so predictably ~2–4° (~4–8 prism diopters or PD) of micro-esotropia (Fig. 5.7)? And if the heterotropia exceeds that range, why is fusional vergence typically absent?

5.2.1 Neuroanatomic Findings in Area V1 of Micro-Esotropic Primates Studies of ODCs and neuronal axons in area V1 have revealed a possible mechanism. The overall pattern and width of ODCs in V1 (~400 mm [0.40 mm]) is the same in normal and strabismic monkeys [70, 78]. Horizontal axon length was measured for neurons within the V1 region corresponding to visual ﬁeld eccentricities of 0–10° (i.e., the representation of the fovea, parafovea and macula). The length is similar in both normal and strabismic monkeys, on average ~7 mm [70, 119]. In a primate with normal eye alignment, the ODC representing the foveola (or 0° eccentricity) of the left eye is immediately adjacent to the column representing the foveola of the right eye. The side-by-side arrangement of the “foveolar” columns in normal V1 is well within the range of horizontal axonal connections needed to allow those ODCs to communicate for high-grade binocular fusion.

In a primate with microesotropia and a right eye ﬁxation preference (Fig. 5.7), a neuron within a foveolar (0°) column of the ﬁxating, right eye must link up with a nonadjacent column representing the pseudo-foveola of the deviated, left eye. Based on retinotopic maps of V1 in macaque monkey, a horizontal axon ~7 mm in length could join ODCs (and receptive ﬁelds) that were up to but not further than 2.5° apart, or converting deg to PD, not more than 4.4 PD. Shown here is a 2-dimensional map representing V1 from the right cerebral hemisphere (left visual hemi-ﬁeld) of a microesotropic macaque. The sulci and gyri have been unfolded and the visual ﬁeld representation superimposed using standard retinotopic landmarks. One horizontal axon, originating within the foveal representation at 0–1° eccentricity, could link to a receptive ﬁeld shifted 2.5° or 4.4 PD distant (Fig. 5.7). Two neurons strung together could join receptive ﬁelds 5° or 8.7 PD apart. The conclusion that emerges is that the 4–8 PD “rule” of the monoﬁxation syndrome is explicable as a combination of innate V1 neuron size and V1 topography. The visuomotor system of the strabismic primate appears to achieve subnormal, but stable binocular fusion so long as the angle of deviation is conﬁned to a distance corresponding to not more than one to two V1 neurons [119].

5.2.2

Extrastriate Cortex in Micro-Esotropa

Neuronal response properties of the vergence-related region of extrastriate visual cortex, MST, may also explain the 2.5°-microesotropia rule in monoﬁxation syndrome. MST receives downstream projections from disparity-sensitive cells, both in V1 and in MT. The majority of binocular neurons in V1, MT and MST encode absolute disparity [82, 120]. Absolute disparity

5.2 Visual Cortex Mechanisms in Micro-Esotropia (Monoﬁxation Syndrome) Fig. 5.7 (a) Monoﬁxator/ microesotrope exhibits a deviation of the visiual axes on cover testing of approximately 4 PD (~2.5°), which in this case is shown as a left eye microesotropia (dark arrowhead pseudofovea position in deviated eye). When fusional vergence or prism adaptation is tested in such a patient, the angle of deviation tends to persistently return to that 2.3° angle. (b) Two-dimensional map representing V1 from the right cerebral hemisphere (left visual hemi-ﬁeld) of a microesotropic primate. The sulci and gyri have been unfolded and the visual ﬁeld representation superimposed using standard retinotopic landmarks. One horizontal axon (average length ~7 mm), originating within the foveal representation at 0–1° eccentricity, could link to a receptive ﬁeld shifted 2.5° or 4.4 PD distant. Two neurons strung together could join receptive ﬁelds 5° or 8.7 PD apart. The conclusion that emerges is that the 4–8 PD “rule” of monoﬁxation/ microesotropia syndrome is explicable as a combination of innate V1 neuron size (one to two axon lengths) and V1 topography

53

a 2.5°° (4.4 PD) Left Esotropia

0°°

b

2.5°°

0°°

Right V-1

Left Visual Field

D Monocular Region

10°° 40°°

20°°

80°°

5°°

2.5°° 0°°

135°°

20°°

FOVEA H.M.

180°° 40°°

4.5°°

M

10°°

H.M. L

135°° V

180°°

7 mm 14 mm

sensitivity (the location of an image on each retina with respect to the foveola, or 0° eccentricity) guides vergence, as opposed to relative disparity sensitivity (the location of an image in depth with respect to other images), which is necessary for stereopsis. The largest population of vergence-related neurons in MST of normal monkeys drives the eyes to ~2.5° of convergent (crossed) disparity [82]. (The next largest population encodes ~2.5° of divergence.) Normal primates have the strongest short-latency vergence responses to convergent disparities of ~2.5° [121]. Insults that impair the development of binocular connections in immature V1 would be expected to impair the (downstream) development of the entire population of

80°°

45°°

0°°

4.4 PD ≈ 1axon 8.7 PD ≈ 2axon

binocular MST neurons. The probability of surviving an insult would be the greatest for the most populous neurons: those encoding ~2.5° (~4.4 PD) of convergence. In the presence of a generally weakened pool of disparitysensitive neurons, the vergence system may default to the vergence commanded by the surviving population. A 2.5° convergence angle could be kept stable (preventing deterioration to large angle strabismus) by the next most populous remaining neurons, those encoding 2.5° of divergence. These mechanism are attractive because they can account for the direction, approximate magnitude, and stability of microesotropia, with retention of a capacity for fusional (e.g., prism) vergence responses evoked by disparities >2.5°.

54

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84. Pratt-Johnson JA, Tillson G (1984) Suppression in strabismus – an update. Br J Ophthalmol 68:174–178 85. Hirsch JA, Gilbert CD (1991) Synaptic physiology of horizontal connections in primary visual cortex. J Neurosci 11:1800–1809 86. Weliky M, Kandler K, Fitzpatrick D, et al (1995) Patterns of excitation and inhibition evoked by horizontal connections in visual cortex share a common relationship to orientation columns. Neuron 15:541–552 87. Deyoe EA, Trusk TC, Wong-Riley MT (1995) Activity correlates of cytochrome oxidase-deﬁned compartments in granular and supragranular layers of primary visual cortex of the macaque monkey. Vis Neurosci 12:629–639 88. Horton JC (1984) Cytochrome oxidase patches: a new cytoarchitectonic feature of monkey visual cortex. Philos Trans R Soc Lond B Biol Sci 304:199–253 89. Wong-Riley MTT (1994) Primate visual cortex: dynamic metabolic organization and plasticity revealed by cytochrome oxidase. In: Peters A, Rockland KS (eds) Cerebral cortex. Plenum, New York 90. Fenstemaker SB, Kiorpes L, Movshon JA (2001) Eﬀects of experimental strabismus on the architecture of macaque monkey striate cortex. J Comp Neurol 438:300–317 91. Horton JC, Hocking DR, Kiorpes L (1997) Pattern of ocular dominance columns and cytochrome oxidase activity in a macaque monkey with naturally occurring anisometropic amblyopia. Vis Neurosci 14:681–689 92. Wong AMF, Burkhalter A, Tychsen L (2005) Suppression of metabolic activity caused by infantile strabismus and strabismic amblyopia in striate visual cortex of macaque monkeys. J AAPOS 9:37–47 93. Tychsen L (2007) Causing and curing infantile eostropia in primates: the role of de-correlated binocular input (an American ophthalmological society thesis). Trans Am Ophthalmol Soc 105:564–593 94. Lewis TL, Maurer D (1992) The development of the temporal and nasal visual ﬁelds during infancy. Vision Res 32:903–911 95. Lewis TL, Maurer D, Blackburn K (1985) The development of young infants’ ability to detect stimuli in the nasal visual ﬁeld. Vision Res. 25:943–950 96. Bowering ER, Maurer D, Lewis TL, et al (1993) Sensitivity in the nasal and temporal hemiﬁelds in children treated for cataract. Invest Ophthalmol Vis Sci 34:3501–3509 97. Sireteanu R, Fronius M (1982) Naso-temporal asymmetries in human amblyopia: consequence of long-term interocular suppression. Vision Res 21:1055–1063 98. Sireteanu R, Fronius M (1989) Visual ﬁeld losses in strabismic amblyopes. Klin Monatsbl Augenheilkd 194:261–269 99. Horton JC, Hocking DR, Adams DL (1999) Metabolic mapping of suppression scotomas in striate cortex of macaques with experimental strabismus. J Neurosci 19:7111–7129

References 100. Schor CM, Levi DM (1980) Disturbances of small-ﬁeld horizontal and vertical optokinetic nystagmus in amblyopia. Invest Ophthalmol Vis Sci 19:668–683 101. Tychsen L, Lisberger SG (1986) Maldevelopment of visual motion processing in humans who had strabismus with onset in infancy. J Neurosci 6:2495–2508 102. Tychsen L, Rastelli A, Steinman S, et al (1996) Biases of motion perception revealed by reversing gratings in humans who had infantile-onset strabismus. Dev Med Child Neurol 38:408–422 103. Hasany A, Wong A, Foeller P, et al (2008) Duration of binocular decorrelation in infancy predicts the severity of nasotemporal pursuit asymmetries in strabismic macaque monkeys. Neuroscience 156:403–411 104. Richards M, Wong A, Foeller P, et al (2008) Duration of binocular decorrelation predicts the severity of latent (fusion maldevelopment) nystagmus in strabismic macaque monkeys. Invest Ophthalmol Vis Sci 49: 1872–1878 105. Yildirim C, Tychsen L (2000) Disjunctive optokinetic nystagmus in a naturally esotropic macaque monkey: interactions between nasotemporal asymmetries of versional eye movement and convergence. Ophthalmic Res 32:172–180 106. Leigh RJ, Zee DS (1999) The neurology of eye movements. Oxford University, New York 107. Worth C (1903) Squint. Its causes, pathology, and treatment. Blakiston, Philadelphia 108. Chavasse F (1939) Worth’s squint or the binocular reﬂexes and the treatment of strabismus. 7th Bailliere Tindall and Cox, London 109. Costenbader FD (1961) Infantile esotropia. Trans Am Ophthalmol Soc 59:397–429 110. Ing M, Costenbader FD, Parks MM, et al (1966) Early surgery for congenital esotropia. Am J Ophthalmol 61:1419–1427 111. Birch EE, Stager DR, Everett ME (1995) Random dot stereoacuity following surgical correction of infantile esotropia. J Pediatr Ophthalmol Strabismus 32:231–235

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112. Birch EE, Fawcett S, Stager DR (2000) Why does early surgical alignment improve stereopsis outcomes in infantile esotropia? J AAPOS 4:10–14 113. Ing MR (1995) Surgical alignment prior to six months of age for congenital esotropia. Trans Am Ophthalmol Soc 93:135–146 114. Wright KW, Edelman PM, McVey JH, et al (1994) Highgrade stereo acuity after early surgery for congenital esotropia. Arch Ophthalmol 112:913–919 115. Tychsen L, Wong AMF, Foeller P, et al (2004) Early versus delayed repair of infantile strabismus in macaque monkeys: II. Eﬀects on motion visually evoked responses. Invest Ophthalmol Vis Sci 45:821–827 116. Lang J (1968) Evaluation in small angle strabismus or microtopia, Strabismus symposium Gieben. Karger, Basel 117. Parks MM (1969) The monoﬁxation syndrome. Tr Am Ophthalmol Soc 67:609–657 118. Tychsen L, Scott C (2003) Maldevelopment of convergence eye movements in macaque monkeys with small and largeangle infantile esotropia. Invest Ophthalmol Vis Sci 44:3358–3368 119. Wong AMF, Lueder GT, Burkhalter A, et al (2000) Anomalous retinal correspondence: neuroanatomic mechanism in strabismic monkeys and clinical ﬁndings in strabismic children. J AAPOS 4:168–174 120. Cumming BG, Parker AJ (1999) Binocular neurons in V1 of awake monkeys are selective for absolute, not relative, disparity. J Neurosci 19:5602–6218 121. Masson GS, Busettini C, Miles FA (1997) Vergence eye movements in response to binocular disparity without depth perception. Nature 389:283–286 122. Mays LE (1983) Neurophysiological correlates of vergence eye movements. In: Schor CM, Ciuﬀreda KJ (eds) Vergence eye movements: basic and clinical aspects. Butterworths, Boston 123. Mays LE (1984) Neural control of vergence eye movements: convergence and divergence neurons in midbrain. J Neurophysiol 51:1091–1108

Chapter 6

Neuroanatomical Strabismus

6

Joseph L. Demer

Core Messages ■

Strabismus may arise from identiﬁable structural abnormalities of the extraocular muscles (EOMs) or their innervation. Congenital or acquired myopathies aﬀect EOM function or structure to impair normal relaxation and force generation. Abnormalities of EOM paths may produce strabismus by altering EOM pulling directions. Path abnormalities arise from abnormalities of the location and stability of the connective tissue pulleys that inﬂuence EOM paths. Pulley disorders may be congenital or acquired, and produce pattern strabismus, divergence paralysis esotropia, and horizontal or vertical incomitant strabismus. Structural abnormalities of EOMs or their associated connective tissues may be demonstrated by clinical orbital imaging.

6.1 General Etiologies of Strabismus Strabismus, deﬁned as misalignment of the visual directions of the two eyes, may arise from several general causes. These include primary myopathies of extraocular muscles (EOMs), disorders of the connective tissues that comprise the globe’s gimbal system, peripheral disorders of nerves controlling the EOMs, and central disorders of fusional vergence commands (Table 6.1). This chapter emphasizes causes of strabismus that can be characterized as mechanistically speciﬁc pathologies of the subcortical nervous system, EOMs, and associated connective tissues. Such pathologies are termed neuroanatomical because their causes can, at least in principle, be demonstrated anatomically using appropriate clinical methods, and are distinct from developmental forms of strabismus that arise from complex abnormalities in cerebral cortex.

■

Strabismus may also arise from abnormalities of peripheral innervation of the EOMs. Congenital cranial dysinnervation disorders (CCDDs) typically produce hypoplasia and loss of function of insuﬃciently innervated EOMs, with contracture of their more normally innervated antagonists. High resolution imaging can directly demonstrate hypoplastic and misdirected motor nerves to the EOMs in the CCDDs, sometimes with additional abnormalities of the optic or other cranial nerves. Some forms of strabismus may be associated with abnormalities of the brainstem or cerebellum that are demonstrable by clinical imaging. However, typical forms of developmental strabismus such as concomitant esotropia and exotropia are not associated with EOM abnormalities.

6.2 6.2.1

Extraocular Myopathy Primary EOM Myopathy

Primary EOM myopathy may be due to congenital metabolic disorder, acquired inﬂammation, or mechanical trauma. Chronic progressive external ophthalmoplegia (CPEO) features insidious onset of slowly progressive, typically symmetric, external ophthalmoplegia [1]. Manifestations of CPEO range from involvement limited to the eyelids and EOMs to systemic and encephalopathic features. Tissues with high oxidative metabolism such as muscle, brain, and heart are most aﬀected [2]. The association between CPEO and heart block is called Kearns– Sayre syndrome [3]. Ragged red ﬁbers, as demonstrated on modiﬁed trichrome stain, can be seen in limb and EOMs in nearly all cases of Kearns–Sayre syndrome and occasionally in isolated CPEO [3]. Molecular diagnosis of

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Table 6.1. Etiologies of strabismus Category

Examples

Primary myopathies

Mitochondrial myopathy, endocrine myopathy, traumatic myopathy

Orbital connective tissue disorders

Pulley heterotopy, pulley instability, pulley hindrance

Peripheral motor neuropathies

Congenital cranial dysinnervation disorders (CCDDs), acquired peripheral ocular motor neuropathy

Subcortical vergence disorders

Horizontal gaze palsy and progressive scoliosis, cerebellar disease

Cortical disorders of vergence

Infantile strabismus, intermittent exotropia, accommodative esotropia

6

CPEO is problematic, since most cases are caused by sporadic mitochondrial DNA deletions. More clinically useful may be T1-weighted magnetic resonance imaging (MRI), which in CPEO demonstrates abnormal bright signal within clinically weak EOMs having generally normal size [1] (Fig. 6.1). Other cases of chronic, ﬁxed EOM weakness are associated with obvious EOM atrophy (Table 6.2).

6.2.2

Fig. 6.1 Coronal T1-weighted magnetic resonance imaging (MRI) of a right orbit of a patient with chronic progressive external ophthalmoplegia (CPEO) demonstrating abnormal bright signal within extraocular muscles that are of generally normal size. IR inferior rectus muscle; LR lateral rectus muscle; ON optic nerve; SO superior oblique muscle; SR superior rectus muscle

Immune Myopathy

Immune EOM myopathy, also known as endocrine myopathy or thyroid eye disease (TED), is typically associated with immune dysthyroidism but may follow an independent temporal course [4]. TED begins with inﬂammation and inﬁltration of EOMs, orbital connective tissues, or both. A classical presentation of TED involves inﬂammatory enlargement of EOMs producing upper eyelid retraction, proptosis, and restrictive ophthalmoplegia. Chronic EOM enlargement and ﬁbrosis persists following resolution of inﬂammation. Orbital imaging by MRI or computed X-ray tomography (CT) typically demonstrates enlargement of EOM bellies, sparing the terminal tendons. MRI demonstrates abnormal internal signal in involved EOMs (Fig. 6.2). Rectus EOMs, particularly the inferior and medial rectus (MR) muscles, demonstrate the most common clinical involvement, although all EOMs, including the obliques (Fig. 6.2), may be involved. Restrictive strabismus is typical in TED, most commonly involving limitation of supraduction.

Fig. 6.2 Coronal T1-weighted MRI of both orbits of a patient with thyroid eye disease (TED) demonstrating enlargement and in all rectus and the SO muscles. IR inferior rectus muscle; LR lateral rectus muscle; MR medial rectus muscle; ON optic nerve; SO superior oblique muscle; SR superior rectus muscle

6.2

Extraocular Myopathy

61

Table 6.2. Types of extraocular myopathy Cause

Main clinical features

Imaging ﬁndings

Laboratory diagnostic tests

Metabolic

Progressive weakness

Normal EOM size, bright T1 MRI signal

Muscle biopsy for ragged red ﬁbers, electrocardiogram

Immune myopathy

Restriction, inﬂammatory signs

EOM belly enlargement and/or orbital fat enlargement

Thyroid function tests

Inﬂammatory myositis

Restriction and/or weakness, inﬂammatory signs

EOM belly and tendon enlargement

Tests for vasculitis, inﬂammation, sarcoidosis

Neoplastic myopathy

Restriction and/or weakness, and/or inﬂammatory signs

Nodular EOM enlargement, or orbital mass

Metastatic evaluation, EOM biopsy

Mechanical

Weakness or restriction

EOM discontinuity or displacement, possible orbital fracture

Another presentation in TED is inﬂammatory enlargement of the nonmuscular orbital connective tissues, particularly orbital fat. Proptosis is the main feature, but strabismus may arise due to forward displacement of the globe relative to ﬁxed structures such as the ﬁxed anchors of the trochlea and the soft pulley system of the other EOMs.

6.2.3

Inﬂammatory Myositis

Myositis of EOMs not due to thyroid ophthalmopathy typically involves both the EOM belly and tendon. Immunologic mechanisms with a host of triggers are believed to be the cause [5].

6.2.4

Neoplastic Myositis

Primary or metastatic neoplasms may cause strabismus by inducing EOM weakness or restriction. In such cases, orbital imaging may demonstrate nodular EOM enlargement or a contiguous orbital mass [6]. Biopsy of the involved EOM may be helpful for diagnosis if likely metastatic source is not already known.

Summary for the Clinician ■ ■

Old orbital fractures may complicate the presentation of strabismus of recent origin. Patients may not recall old orbital fractures.

6.2.5 Traumatic Myopathy Direct trauma to EOMs may compromise their function and produce strabismus. Sharp objects penetrating the orbit may disinsert EOM tendons from the globe,

transect or avulse EOM bellies, or avulse motor nerves to EOMs. Clinically unrecognized penetration of the orbit by thin, sharp objections may occur in the setting of more widespread facial trauma, since entry wounds through the eyelid crease or conjunctival fornix are concealed by edema and heal very quickly. High-resolution orbital imaging by CT or MRI may be valuable in the evaluation of strabismus associated with facial trauma, to detect direct EOM trauma and distinguish this from weakness of structurally intact EOMs due to traumatic cranial neuropathy [7]. Blunt orbital trauma may produce blow-out fractures of the orbital walls, most commonly the thinner medial and inferior walls [8, 9]. In larger orbital fractures, EOMs and orbital connective tissues herniate into the adjacent sinuses via relatively large bony defects. Large blow-out fractures are associated with enophthalmos, but not often with strabismus unless there is direct EOM trauma. Smaller orbital fractures may exhibit a trap-door mechanism, with a displaced bone fragment trapping an EOM or part of the connective tissue pulley system. Especially in children in whom inﬂammatory signs may not be clinically evident, an EOM may become entrapped and strangulated in a trap-door orbital fracture. Entrapment and strangulation of an EOM constitutes a situation demanding emergent surgical release, while immediate repair is not typically critical for most blow-out fractures. An entrapped EOM is very likely to exhibit clinical weakness on force generation testing, as well as producing a mechanical restriction to forced duction testing. Old, forgotten blow-out fractures may complicate the presentation of acquired strabismus due to other causes [10]. Even in the absence of EOM entrapment in an orbital fracture, connective tissues of the orbital pulley system may become entrapped in the fracture. Such a situation

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may be associated with the clinical ﬁndings of limitation of active duction in the EOM’s ﬁeld of action due to pulley hindrance (discussed below), as well as mechanical restriction to the opposite direction of passive rotation using forceps. In the usual clinical setting of generalized orbital and eyelid edema, these clinical ﬁndings can be indistinguishable from those of EOM entrapment in an orbital fracture. It is therefore desirable to promptly obtain an adequate imaging study, such as a CT or MRI scan, that can identify any possible tissue entrapped in an orbital fracture. Expeditious, if not emergent, release of entrapped EOMs or pulley tissue should be performed within several days before scarring makes repositioning impossible [11].

Summary for the Clinician ■ ■

Orbital pulley disorders can cause strabismus. Strabismus due to pulley disorders can clinically mimic restrictive or paralytic strabismus.

6.3

Congenital Pulley Heterotopy

The direction of ocular rotation imparted by any EOM is deﬁned by the relative locations of its scleral insertion and pulley; EOM path direction posterior to the pulley is not directionally important [12–14]. Every EOM can produce horizontal, vertical, and torsional actions, in relative proportions depending on pulley and insertion locations. Thus, alterations in positions of the horizontal rectus pulleys can impart substantial vertical and torsional actions to the medial and lateral rectus (LR) EOMs, while alterations in positions of the vertical rectus pulleys can impart substantial horizontal actions to the vertical rectus EOMs (Table 6.3). The MR and LR pulleys are directly suspended by ﬁbroelastic connective tissues from anteriorly located entheses, or anchors, on the orbital bones [15]. The medial enthesis is at the posterior lacrimal crest, while the lateral enthesis is at Whitnall’s tubercle. The inferior (IR) and superior rectus (SR) pulleys are somewhat indirectly supported by, in both cases, the medial and lateral enthe-

ses. Malpositioning of the entheses, or malpositioning of the orbital bones to which the entheses join, can therefore cause signiﬁcant alterations in rectus EOM pulling directions. More signiﬁcant still, the pulling directions of the four horizontal rectus EOMs can be purely horizontal only if their respective pulleys all lie on a horizontal line exactly transverse to the mid-sagittal plane of the skull. Any other orientation of the horizontal rectus pulleys in the two orbits will impart vertically imbalanced actions to the binocularly yoked agonist pairs: the MR in one orbit and the LR in the opposite orbit. This eﬀect is not related to the activity of the oblique EOMs, and probably cannot be counteracted by them. Symmetric heterotopy of the rectus pulley arrays in the orbits produces two clinical ﬁndings: imbalanced versions in oblique gaze directions (formerly but incorrectly attributed to oblique EOM dysfunction) and vertically incomitant horizontal strabismus [16, 17]. MRI has demonstrated the coronal plane locations of rectus EOM pulleys to be stereotypic in normal [17, 18] and most strabismic subjects [18]. The 95% conﬁdence intervals of coronal plane pulley coordinates are less than ±1 mm [18]. A computer model of binocular alignment incorporates passive elastic pulleys [19] and is now available as the application Orbit. The expected eﬀect of coronal plane heterotopy (malpositioning) of pulleys can be computed using Orbit [20]. Many cases of incomitant cyclovertical strabismus are associated with heterotopy of one or more rectus EOM pulleys exceeding two standard deviations from normal. Patterns of incomitance in individual patients consistently match those predicted by Orbit simulation based on measured pulley locations, suggesting that pulley heterotopy caused the strabismus [21, 22]. When the LR pulley is located superiorly to the MR pulley in both orbits (Fig. 6.3a), the MR exerts an infraducting action in adduction relative to that of the LR, causing excessive infraduction in extreme adduction, since only the abducting eye can ﬁxate a target in this position. This heterotopic pulley conﬁguration is typically associated with a nasal placement of the SR pulley relative to the IR pulley, such that the array of the four rectus pulleys has been incyclo rotated about the orbital

Table 6.3. Pattern strabismus associated with pulley heterotopy and eyelid conﬁguration Incomitance

Horizontal pulleys LR

Vertical pulleys

MR

IR

Lateral canthal inclination SR

A pattern

Superior

Inferior

Temporal

Nasal

Superior

V pattern

Inferior

Superior

Nasal

Temporal

Inferior

6.4 Acquired Pulley Heterotopy

63

Fig. 6.3 Coronal T2 fast spin echo MRI showing typical pulley conﬁgurations of both orbits for (a) A and V (b) pattern strabismus

center. In supraversion, the SR exerts an adducting action, while in infraversion, the IR exerts an abducting action. Binocular alignment is consequently more divergent in infraversion than in supraversion, constituting an A pattern strabismus. When the LR pulley is located inferiorly to the MR pulley in both orbits (Fig. 6.3b), the MR exerts a supraducting action in adduction relative to that of the LR, causing excessive supraduction in extreme adduction, since only the abducting eye can ﬁxate a target in this position. This heterotopic pulley conﬁguration is typically associated with a temporal placement of the SR pulley relative to the IR pulley, such that the array of the four rectus pulleys has been excyclo rotated about the orbital center [16]. In supraversion, the SR exerts an abducting action, while in infraversion, the IR exerts an adducting action. Binocular alignment is consequently more convergent in infraversion than in supraversion, constituting a V pattern strabismus. Bony deformity of the orbits, such as that associated with craniosynostosis, is a common cause of congenital pulley heterotopy. Such a deformity and pulley heterotopy

need not be bilaterally symmetrical; when asymmetrical, the resulting strabismus may be horizontally as well as vertically incomitant, resembling dysfunction of a single oblique EOM. Osseous deformity with pulley heterotopy may be suspected when external facial features are asymmetrical, or when there is a signiﬁcant inclination to one or both the palpebral apertures [12, 23]. The medial and lateral canthal tendons normally insert on the orbital bones near the medial and lateral entheses of the pulley system, respectively. A superior (“mongoloid”) inclination of the lateral palpebral canthus is associated with A pattern incomitance, while an inferior inclination of the lateral palpebral canthus is associated with V pattern incomitance.

6.4

Acquired Pulley Heterotopy

The inferior oblique’s (IO’s) orbital layer inserts partly on the conjoined IO–IR pulleys, partly on the IO sheath temporally and partly on the LR pulley’s inferior aspect

64

6

6 Neuroanatomical Strabismus

[15, 24]. Consequently, the IO exerts a tonic nasalward force on the IR pulley, and a tonic inferior force on the LR pulley [24]. In youth, these active muscular forces are balanced by the elastic stiﬀness of the pulley connective tissue suspensions, particularly by the elasticity of a ligament connecting the LR with the SR pulleys that is termed the LR–SR band [15, 25]. The suspensory tissues of the orbital pulleys become gradually attenuated during normal aging [15, 25], causing predictable inferior shifts in horizontal rectus pulley positions [26], and making the pulleys of order people more susceptible to the eﬀects of trauma and surgery.

Summary for the Clinician ■

■

Pulley connective tissue degeneration in older people can cause horizontal or vertical strabismus. Involutional eyelid changes and blepharoptosis suggest that pulley tissues may also be degenerating.

6.5 “Divergence Paralysis” Esotropia While the locations of the vertical rectus pulleys remain constant during the lifespan of a normal person, the horizontal rectus pulleys gradually “sag” inferiorly by 2–3 mm by the seventh decade of life [26]. This converts some of the horizontal force of the horizontal rectus EOMs to infraducting force, without any abducens neuropathy or deﬁciency of the magnitude of LR force generation. Abducting saccades maintain normal peak velocities [27].

When horizontal pulley sag occurs symmetrically, there is no eﬀect on horizontal binocular alignment, since the MR and LR muscles experience balanced force reductions [25]. The additional infraducting force contributed by the horizontal rectus EOMs is most likely to be the cause of the predictably reduced supraducting ability of older people [28]. More severe LR–SR band degeneration may permit the LR to shift farther inferiorly than does the MR pulley (Fig. 6.4). In this case, more of LR abducting force is converted to infraducting force than is the corresponding situation for MR adducting force. The imbalance leads to a convergent shift in alignment most evident during distance viewing when the visual axes of the eyes should be parallel, while there may be little or no esodeviation during near viewing where physiologic convergence is required. This situation has been described as “divergence paralysis esotropia,” a clinical entity in which there is esotropia predominantly or exclusively present during distance but not near viewing, and in which there is no evidence of LR paresis, e.g., abducting saccadic velocities and abduction range are normal [27]. When bilaterally symmetrical, the vertical eﬀect in the two eyes is matched, avoiding vertical strabismus. “Divergence paralysis esotropia” due to LR pulley sag typically occurs in older people with retracted upper eyelid creases and blepharoptosis due to dehiscence of the levator tendon from the tarsal plate [25]. Both the blepharoptosis and strabismus presumably result from orbital connective tissue degeneration in the absence of EOM neuropathy or myopathy. Patients typically retain excellent fusional convergence and binocular fusional potential. While divergence paralysis esotropia can be

Fig. 6.4 Coronal histological sections of human left orbits of ages ranging from childhood to the ninth decade of life, showing attenuation and ultimate rupture of the LR–SR band with inferior sag of the LR pulley relative to the center of the medial rectus pulley (denoted by the yellow horizontal line). Masson’s trichrome stains collagen blue and muscle dark red. (Copyright nonexclusively assigned to American Academy of Ophthalmology, 2008.)

6.5 “Divergence Paralysis” Esotropia Table 6.4. Alignment eﬀect of LR–SR band degeneration Symmetry

Resulting strabismus

Bilaterally symmetric

Divergence paralysis esotropia

Asymmetric

Hypotropia ± Esotropia

very successfully treated by multiple conventional strabismus surgical approaches that counteract esodeviation (e.g., MR recession or LR resection), it is the author’s experience that the required surgical dosage must be about double that required for other forms of esotropia. Surgical repair of LR pulley sag is not typically required in divergence paralysis esotropia (Table 6.4).

6.5.1 Vertical Strabismus Due to Sagging Eye Syndrome Asymmetric stretching or catastrophic rupture of the LR–SR band may suddenly impart a marked infraducting action to the involved LR muscle, even creating restriction to passive supraduction [25] (Fig. 6.5). The clinical presentation may be acute onset of hypotropia with deﬁciency of supraduction that might be mistaken for SR paralysis or IR restriction in the absence of adequate orbital imaging. Orbital imaging secures the

Fig. 6.5 Coronal MRI of left orbit of older patient demonstrating marked inferior displacement of LR pulley in sagging eye syndrome associated with acute onset hypotropia. LR lateral rectus muscle; MR medial rectus muscle

65

diagnosis of sagging eye syndrome (Fig. 6.5). While it may sometimes be possible to surgically repair the ruptured or stretched LR–SR band to normalize LR pulley position, severe degeneration may render this ligament irreparable. In that event, posterior surgical ligature between the lateral margin of the SR muscle and the superior margin of the LR muscle may be required to normalize LR path [25].

6.5.2 Postsurgical and Traumatic Pulley Heterotopy Rectus pulley suspensions may be damaged by surgical dissections. Again, the LR pulley is most susceptible to this eﬀect of aggressive anterior dissection at strabismus, retinal, or orbital surgery. For instance, damage to the LR–SR band during endoscopic orbital decompression surgery may present as restrictive hypotropia in adduction.

6.5.3

Axial High Myopia

Inferior displacement of the LR muscle is also a well-recognized cause of strabismus in high myopes [29]. Known as “heavy eye” syndrome or myopic strabismus ﬁxus, this syndrome is characterized by esotropia and hypotropia due to conversion of LR muscle action from abduction to infraduction [29, 30]. Patients with “heavy eye” syndrome have impaired abduction and supraduction due to degeneration of the LR–SR band, allowing inferior LR pulley displacement causing inferior shift in LR muscle path that may become so extreme as to approach that of the LR. Abducting LR force is converted into infraducting force, resulting in large-angle esotropia and hypotropia. Since axial length in this condition is typically 30 mm or more, strabismus associated with axial high myopia was formerly (but misleadingly) termed the “heavy eye syndrome” under the assumption that an enlarged globe would sink inferiorly in the orbit [31]. Clinical orbital imaging is of great value in diagnosis of this condition, since it conﬁrms the diagnosis of LR displacement, and excludes alternative or coexisting conditions that may require diﬀerent surgical treatment, or preclude treatment altogether. For example, with or without inferior displacement of the LR pulley, a severely staphyomatous globe may ﬁll the bony orbit so completely that duction is limited [32], or the LR muscle may have suﬀered neuropathic paralysis and have become atrophic. If the cause of the esotropia is simply inferior displacement of the LR pulley due to LR–SR band degeneration, an eﬀective treatment may be identical to that used in the sagging eye

66

6 Neuroanatomical Strabismus

Summary for the Clinician ■

6 ■ ■

6.6

Numerous structural abnormalities of extraocular muscles and associated connective tissues may cause strabismus. Structural causes of strabismus may mimic neurological causes of strabismus. High-quality orbital imaging is generally necessary to diagnose structural abnormalities of extraocular muscles and associated connective tissues that cause strabismus.

syndrome in the absence of high myopia: posterior surgical ligature between the lateral margin of the SR muscle and the superior margin of the LR muscle.

Congenital Peripheral Neuropathy: The Congenital Cranial Dysinnervation Disorders (CCDDs)

Certain congenital forms of strabismus occur despite normal orbital connective tissues and pulleys, as the result of deﬁciency or misdirection of motor nerves to the EOMs. Genetic causes of many of the CCDDs are described in chapter 7 in this volume by Antje Neugebauer and Julia Fricke, and will not be discussed here in this chapter that emphasizes the pathophysiology of strabismus. It is useful to understand two general principles in the functional anatomy of these CCDDs. First, EOMs with insuﬃcient motor innervation are hypoplastic and hypofunctional. Second, eﬀectively innervated antagonists of congenitally noninnervated EOMs exhibit contracture and increased stiﬀness (Table 6.5).

Table 6.5. Main imaging ﬁndings in CCDDs Disorder

Orbital ﬁndings

Skull base ﬁndings

Congenital oculomotor palsy

Variable hypoplasia of inferior oblique (IO), IR, medial rectus (MR), SR, and LPS;

Profound hypoplasia of oculomotor nerves

hypoplasia of intraorbital oculomotor nerve branches Congenital ﬁbrosis of extraocular muscles

Profound hypoplasia of SR and LPS;

Profound hypoplasia of oculomotor nerves

± moderate MR, IO, SO hypoplasia; ± LR dysplasia; hypoplasia of intraorbital motor nerves; mild ON hypoplasia Congenital trochlear palsy

Aﬀected SO hypoplasia

None (normal trochlear nerve usually too small to image)

Duane syndrome

Hypoplasia or aplasia of superior LR;

± Ipsilateral abducens nerve hypoplasia

dysplasia of inferior LR; ± longitudinal LR splitting; ± abducens nerve aplasia; oculomotor nerve innervates inferior LR Moebius syndrome

Hypoplasia of deep portions of all myopathies of extraocular muscles (EOMs);

Normal subarachnoid cranial nerves innervating orbit

curvature of anterior rectus EOMs; narrowing of deep bony orbits; ON straightening; Intraorbital motor nerve hypoplasia Horizontal gaze palsy with progressive scoliosis

Normal

Hypoplastic and ﬁssured medulla and pons

6.6 Congenital Peripheral Neuropathy: The Congenital Cranial Dysinnervation Disorders (CCDDs)

6.6.1

Congenital Oculomotor (CN3) Palsy

Congenital oculomotor (CN3) palsy is typically partial. It may appear clinically bilateral or unilateral, although on careful evaluation apparently unilateral cases may be discovered to be bilateral albeit highly asymmetrical [33]. Patients may present with variable deﬁciencies of adduction, supraduction, and infraduction, along with variable mydriasis and blepharoptosis. Aﬀected EOMs are hypoplastic, corresponding to their functional deﬁciencies. Intraorbital motor nerves to EOMs innervated by CN3 are hypoplastic, as is the subarachnoid CN3 (Fig. 6.6).

6.6.2

Congenital Fibrosis of the Extraocular Muscles (CFEOM)

In many fundamental respects similar to congenital CN3 palsy, CFEOM is a heritable congenital CN3 hypoplasia with frequent misdirection of remaining ﬁbers, more profoundly aﬀecting the superior than inferior division of CN3. Three distinct phenotypes, CFEOM1–3, are recognized. The classic form, CFEOM1 (MIM 135700), is

Fig. 6.6 FIESTA MRI demonstrating hypoplasia of the subarachnoid oculomotor nerve (CN3). (a) Normal subject. (b) Dominant Duane retraction syndrome (DRS) linked to chromosome 2 (DURS2). (c) Congenital oculomotor palsy. (d) Congenital ﬁbrosis of the extraocular muscles type 1 (CFEOM1)

67

typiﬁed by bilateral congenital blepharoptosis and ophthalmoplegia, with the eyes restricted to infraduction below the horizontal midline [34]. Horizontal strabismus may coexist (Tables 6.5, 6.6). Forced duction testing in CFEOM1 demonstrates restriction to passive supraduction, consistent with surgical observations of increased extraocular muscle (EOM) stiffness. Older pathologic reports of specimens of resected EOMs in CFEOM suggested replacement by fibrous tissue [35–37]. The classic concept of CFEOM as a primary myopathy, however, was challenged by autopsy findings in a subject from a pedigree with the KIF21A mutation [34]. Engle et al. alternatively suggested that CFEOM1 is a primary disorder of EOM motor neuron development, leading to hypoplasia or atrophy of the EOMs they innervate, and secondary contracture of their antagonists [34]. Older reports of “fibrosis” in EOM tendons are likely to have been artifacts of inadvertent biopsy of distal EOM tendons [34]. Orbital MRI in CFEOM1 demonstrates hypoplasia of the motor nerves normally innervated by CN3, most profound for the SR and levator palpebrae superioris corresponding to the clinically prominent hypotropia

68

6 Neuroanatomical Strabismus

Table 6.6. Imaging features in acquired neuropathic extraocular muscle palsy Muscle

6

Size

Contractility

Path

Inferior oblique

Reduced 40%

Reduced

Normal

IR

Small posteriorly

Reduced

Centrifugal inﬂection

Lateral rectus

Reduced 50–90% posteriorly

Reduced

Centrifugal inﬂection

Levator palpebrae superioris

Small

Cannot evaluate

Normal

Medial rectus

Small posteriorly

Reduced

Normal

SO

Reduced 40–50%

Reduced

Normal

SR

Small posteriorly

Reduced

Normal

and blepharoptosis (Fig. 6.7a, b) [38]. Intraorbital motor branches of CN3 are also hypoplastic (Fig. 6.7c). MRI in CFEOM1 demonstrates marked hypoplasia of the subarachnoid CN3. Signiﬁcant but usually subclinical optic nerve (ON) hypoplasia occurs in CFEOM1, as may superior oblique (SO) muscle hypoplasia presumably due to trochlear nerve (CN4) hypoplasia. The posterior parts of multiple EOMs may be dysplastic in CFEOM, although their anterior portions generally appear normal both by MRI and at EOM surgery. The frequent occurrence of synergistic eye movements and the Marcus Gunn jaw winking phenomenon in CFEOM1 [39, 40] suggests motor axonal misrouting.

Fig. 6.7 Typical orbital MRI ﬁndings in CFEOM1. (a) Sagittal view showing profound hypoplasia of the SR and levator palpebrae superioris. (b) Coronal view in mid-orbit showing profound hypoplasia of the SR. (c) Deep orbital view demonstrating proximity and presumed innervation of the inferior zone of the LR by an aberrant of the inferior division of the oculomotor nerve (CN3)

More direct evidence of this misrouting is provided by high-resolution MRI showing innervation of the inferior zone of the LR by a branch of CN3 that would normally be fated to innervate the IR. In most cases, when a patient with CFEOM1 attempts deorsumversion, the eyes abduct dye to LR contraction, increasing the exotropia present in central gaze. In CFEOM1, CN6 innervates the superior zone of the LR muscle. Patients with CFEOM2 (OMIM 602078) have congenitally bilateral exotropic ophthalmoplegia and blepharoptosis. This rare recessive disorder occurs in consan guineous pedigrees. The orbital and cranial nerve phenotype of CFEOM2 have not been studied in detail.

6.6 Congenital Peripheral Neuropathy: The Congenital Cranial Dysinnervation Disorders (CCDDs)

The third CFEOM variant, CFEOM3, encompasses patients with CFEOM not classiﬁable as either CFEOM1 or CFEOM2. This “atypical” group includes unilateral cases who have orthotropic central gaze, or whose central gaze is hypotropic but who can supraduct above the central position. Subjects with CFEOM3 have asymmetrical blepharoptosis, limited supraduction, variable ophthalmoplegia, and are usually exotropic. MRI demonstrates asymmetrical levator palpebrae superioris and SR atrophy correlating with blepharoptosis and deﬁcient supraduction, and small orbital motor nerves [41]. While at least one subarachnoid CN is hypoplastic, ophthalmoplegia occurs only when subarachoid CN3 width is less than the 2.5th percentile of normal. Multiple EOMs exhibit variable hypoplasia, correlating with duction in individual orbits. A-pattern exotropia is frequent in CFEOM3, correlating with LR misinnervation by CN3. ON crosssections are slightly subnormal, but rectus pulley locations are normal [42]. Some cases of CFEOM3 are associated with brain abnormalities including corpus callosum hypoplasia.

Summary for the Clinician ■

CFEOM is not a primary muscle disorder, but rather a cranial nerve disorder.

6.6.3

Congenital Trochlear (CN4) Palsy

While SO hypoplasia may coexist with other CCDDs such as CFEOM, SO dysfunction may not be clinically evident in the setting of diﬀuse external ophthalmoplegia or anomalous innervation of other EOMs. Isolated congenital CN4 palsy is often suspected in the presence of clinical evidence of ipsilateral hypertropia increasing on contralateral gaze, and with head tilt toward the ipsilateral shoulder. While the congenital nature of the disorder appears clear when there is a history of lifelong spontaneous head tilt to the contralateral shoulder, in many cases present after many years of compensation for what the history suggests has been a progressive condition without identiﬁable cause. Whether lifelong or insidious, orbital imaging in presumably congenital SO palsy demonstrates reduction in SO muscle size, and reduction in the normal contractile increase in SO cross-section due to infraduction (Fig. 6.8). Since even the normal subarachnoid CN4 cannot be reliably imaged by MRI, correlations with CN4 size have not been made in congenital CN4 palsy.

6.6.4

69

Duane’s Retraction Syndrome (DRS)

Pure congenital abducens (CN6) palsy is exceptionally rare except as secondary to an obvious intrauterine or neonatal pathology such as tumor or hydrocephalus. Rather, in congenital developmental CN6 palsy, the LR is innervated or coinnervated by a branch of CN3, usually a motor branch ordinarily fated to innervate the MR. In this respect, the situation is similar to CFEOM. DRS is characterized by congenital abduction deﬁcit, narrowing of the palpebral ﬁssure on adduction, and globe retraction with occasional upshoot or downshoot in adduction [43]. Early electrophysiological studies suggested absence of normal abducens (CN6) innervation to the LR muscle as the cause of DRS, with paradoxical LR innervation in adduction [44, 45]. Absence of the CN6 nerve and motor neurons has been conﬁrmed in one sporadic unilateral [46] and another bilateral autopsy case of DRS [47]. Parsa et al. ﬁrst used MRI to demonstrate absence of the subarachnoid portion of CN6 in DRS [48], a ﬁnding that has been conﬁrmed in 6 of 11 additional cases [49], and later correlated with the presence of residual abduction in multiple cases [50, 51]. Innervation of the LR by CN6 is deﬁcient in both DRS and CN6 palsy, although unlike CN6 palsy, the eyes in central gaze are frequently aligned in DRS [52]. While most DRS cases are sporadic, a dominant form DURS2 is linked to chromosome 2. MRI demonstrated that DRS linked to the DURS2 locus is associated with bilateral abnormalities of many orbital motor nerves, and structural abnormalities of all EOMs except those innervated by the inferior division of CN3 [53]. Orbital motor nerves are typically small, with CN6 often nondetectable. Lateral rectus (LR) muscles are often structurally abnormal, often with MRI and motility evidence of oculomotor nerve (CN3) innervation from vertical rectus EOMs leading to A or V patterns of strabismus. Cases may include SO, SR, and LPS hypoplasia, sparing only the MR, IR, and IO EOMs. The subarachnoid CN3 may be small. Therefore, DURS2-linked DRS is a diﬀuse CCDD involving but not limited to CN6.

Summary for the Clinician ■

■

CCDDs are nonprogressive developmental disorders featuring reduced and aberrant innervation. Subnormal innervation of some EOMs in CCDDs leads to secondary EOM hypoplasia, dysplasia, and weakness.

70 ■ ■

6 ■

6

Neuroanatomical Strabismus

Antagonists of hypoplastic EOMs become secondarily stiﬀ. Neuromuscular features may vary between orbits of the same patient, and among patients with identical genetic CCDDs. High-resolution imaging of EOMs and their peripheral innervation can be clinically valuable for strabismus management in CCDDs.

6.6.5

Moebius Syndrome

Moebius syndrome typically presents as a sporadic trait with congenital facial (CN7) palsy and abduction

Fig. 6.8 Coronal T2-weighted MRI of both orbits in left SO palsy demonstrating marked reduction in SO cross-section, as well as reduction in normal contractile increase in cross-section from up to down gaze

impairment. Moebius syndrome is a heterogeneous clinical disorder whose clinical deﬁnition has evolved in the recent literature. Minimum criteria include congenital facial palsy with impairment of ocular abduction [54–56]. The wide clinical spectrum and multiple areas of brainstem involvement in patients with Moebius syndrome have led to its early conceptualization as a developmental disorder of the brainstem, rather than an isolated cranial nerve developmental disorder [56]. However, Moebius syndrome may present with total facial paralysis and complete external ophthalmoplegia, where MRI demonstrates a normal brainstem and subarachnoid portions of motor cranial nerves innervating the orbit, but marked hypoplasia of the deep portions of the EOMs.

6.7

6.7

Acquired Motor Neuropathy

On orbital imaging, the hallmarks of EOM denervation are atrophy of the EOM belly, and loss of normal contractile increase in EOM cross-section in the EOM’s ﬁeld of action.

6.7.1

Oculomotor Palsy

Chronic oculomotor palsy is associated with neurogenic atrophy of the associated EOMs, but the degree of atrophy appears to be related to the presence of any residual innervation or reinnervation, either normal or aberrant [7]. Little or no EOM atrophy may be present when there is aberrant innervation, even if this innervation would normally have been directed to another EOM. High-resolution imaging in chronic oculomotor palsy also demonstrates atrophy of the intraorbital branches of the oculomotor nerve [7], similar to that observed in CFEOM.

6.7.2 Trochlear Palsy Theoretical, experimental, and much clinical evidence support the idea that acute, unilateral SO palsy produces a small ipsilateral hypertropia that increases with contralateral gaze, and with head tilt to the ipsilateral shoulder [57, 58]. The basis of this “three-step test” is traditionally believed to be related to Ocular Counter Rolling (OCR), so that the eye ipsilateral to head tilt is normally intorted by the SO and SR muscles whose vertical actions cancel [59]. However, ipsilateral to a palsied SO, unopposed SR elevating action is supposed to create hypertropia. The three-step test has been the cornerstone of diagnosis and classiﬁcation cyclovertical strabismus for generations of clinicians [60]. When the three-step test is positive, clinicians infer SO weakness and attribute the large amount of interindividual alignment variability to secondary changes [61] such as “IO overaction” and “SR contracture.” Much evidence, however, indicate that the three-step test’s mechanism is misunderstood. Kushner has pointed out that if traditional teaching were true, then IO weakening, the most common surgery for SO palsy, should increase the head-tilt-dependent change in hypertropia; however, the opposite is observed [62]. Among numerous inconsistencies with common clinical observations [62], bilateral should cause greater head-tilt-dependent change in hypertropia than unilateral SO palsy; however, the opposite is found [63]. Simulation of putative eﬀects head tilt in SO palsy suggests that SO weakness alone cannot account for typical three-step test ﬁndings [64].

Acquired Motor Neuropathy

71

Summary for the Clinician ■ ■

The three-step test is not speciﬁc for trochlear palsy. Orbital imaging conﬁrms neurogenic atrophy of the SO muscle.

High-resolution MRI has quantiﬁed normal changes in SO cross-section with vertical gaze, and SO atrophy and loss of gaze-related contractility typical of SO palsy [23, 65–67]. Following experimental intracranial trochlear neurectomy in monkey, the SO atrophies within 5 weeks to a stable overall size 60% of normal; this atrophy occurs entirely within the global layer, where ﬁber size is reduced by 80%, sparing the orbital layer [68]. A striking and consistent MRI ﬁnding has been nonspeciﬁcity of the three-step test for structural abnormalities of the SO belly, tendon, and trochlea, found in only in ~50% of patients [69]. Even in patients selected because MRI demonstrated profound SO atrophy, there was no correlation between clinical motility and IO size or contractility [67]. Multiple conditions can simulate the “SO palsy” pattern of incomitant hypertropia [70]. Vestibular lesions produce head-tilt-dependent hypertropia, also known as skew deviation [71] that can mimic SO palsy by the threestep test [72]. Pulley heterotopy can simulate SO palsy [16, 73], and is probably not its result, since SO atrophy is not associated with signiﬁcant alterations in pulley position in central gaze [21].

6.7.3 Abducens Palsy Denervation of the LR is associated with muscle belly atrophy [74, 75], loss of contractile thickening during attempted abduction, and a centrifugal bowing of the LR path away from the orbital center with accentuation of the transverse inﬂection in LR path near the posterior mouth of the LR pulley sleeve (Fig. 6.9) [76]. Such changes in atrophic LR path elongate its length, a factor that tends to increase passive elastic tension of the paralyzed LR [77].

6.7.4

Inferior Oblique (IO) Palsy

Since the inferior division of CN3 innervates the IO, IO palsy commonly accompanies weakness of multiple EOMs produced by a proximal lesion to this large motor nerve. However, the IO’s motor nerve follows a relatively lengthy isolated course along the lateral margin of the IR

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6 Neuroanatomical Strabismus

Fig. 6.9 Orbital T2-weighted MRI in chronic left abducens palsy. Axial view above shows thinning and lateral inﬂection of palsied LR muscle, which in coronal view below is seen to have reduced cross-section

muscle, entering the IO in the EOM’s posterior surface relatively superﬁcially in the orbit when compared with innervation to the other EOMs. Isolated acquired neuropathic IO palsy is thus anatomically possible. When it occurs, IO palsy is associated with denervation atrophy of the IO belly [78].

6.8 Central Abnormalities of Vergence and Gaze Several common causes of strabismus are not associated with abnormalities of the EOMs, motor nerves, or orbital connective tissues. The forms of strabismus arise from abnormalities in the central nervous system, some of which are structural lesions that may be imaged.

Summary for the Clinician ■

Developmental esotropia and exotropia are not associated with structural abnormalities in the orbit.

6.8.1 Developmental Esotropia and Exotropia Human infantile and accommodative esotropia are not known to be associated with anatomic abnormalities in the orbit. Naturally and artiﬁcially esotropic and exotropic monkeys also exhibit latent nystagmus and other features typical of human childhood strabismus, but these monkeys have normal horizontal EOM structure, normal EOM locations, and normal intraorbital EOM innervation [79]. However, strabismic monkeys have microscopic evidence of abnormalities in visual cortical area V1 [80], and most likely also other visual cortical areas.

6.8.2

Cerebellar Disease

The cerebellum contributed toward binocular alignment [81]. Hereditary cerebellar degeneration is often associated with convergence insuﬃciency, and in advanced cases often produces cerebellar atrophy [82]. Cerebellar or brainstem tumors may be associated with acute onset of concomitant esotropia in children [83]. Acquired cerebellar damage, such as by infarction, may produce skew deviation other strabismus.

6.8.3 Horizontal Gaze Palsy and Progressive Scoliosis Horizontal gaze palsy and progressive scoliosis is a recessive disorder of axon path ﬁnding in the central nervous system. Patients have essentially complete horizontal ophthalmoplegia despite intact EOMs and peripheral motor innervation to them, but MRI demonstrates dysplasia of the hindbrain suggestive of a sagittal ﬁssure interrupting decussating white matter tracts [84].

References 1. Ortube MC, Bhola R, Demer JL (2006) Orbital magnetic resonance imaging of extraocular muscles in chronic progressive external ophthalmoplegia: Speciﬁc diagnostic ﬁndings. J AAPOS 10:414–418 2. Biousse V, Newman NJ (2001) Neuro-ophthalmology of mitochondrial diseases. Semin Neurol 3:275–291 3. Vilarinho L, Santorelli FM, Cardoso ML, et al (1998) Mitochondrial DNA analysis in ocular myopathy.Observations in 29 portuguese patients. Euro Neurol 39: 148–153 4. Kuriyan AE, Phipps RP, Feldon SE (2008) The eye and thyroid disease. Cur Opin Ophthalmol 19:499–506

References 5. Wolf AB, Yang MB, Archer SM (2007) Postoperative myositis in reoperated extraocular muscles. J AAPOS 11: 373–376 6. Capone AJ, Slamovits TL (1990) Discrete metastasis of solid tumors to extraocular muscles. Arch Ophthalmol 108:237–243 7. Demer JL (2003) A 12 year, prospective study of extraocular muscle imaging in complex strabismus. J AAPOS 6:337–347 8. Koornneef L (1982) Current concepts on the management of orbital blow-out fractures. Ann Plast Surg 9:185–200 9. Wojno TH (1987) The incidence of extraoular muscle and cranial nerve palsy in orbital ﬂoor blow-out fractures. Ophthalmol 94:682–687 10. Ortube MC, Rosenbaum AL, Goldberg RA, et al (2004) Orbital imaging demonstrates occult blow out fracture in complex strabismus. J AAPOS 8:264–273 11. Tse R, Allen L, Matic D (2007) The white-eyed medial blowout fracture. Plast Reconstr Surg 119:277–286 12. Demer JL (2004) Pivotal role of orbital connective tissues in binocular alignment and strabismus. The Friedenwald lecture. Invest Ophthalmol Vis Sci 45:729–738 13. Demer JL (2006) Current concepts of mechanical and neural factors in ocular motility. Cur Opin Neurol 19:4–13 14. Demer JL (2006) Ocular motility in a time of revolutionary paradigm shift. Invest Ophthalmol Vis Sci 15. Kono R, Poukens V, Demer JL (2002) Quantitative analysis of the structure of the human extraocular muscle pulley system. Invest Ophthalmol Vis Sci 43:2923–2932 16. Clark RA, Miller JM, Rosenbaum AL, et al (1998) Heterotopic muscle pulleys or oblique muscle dysfunction? J AAPOS 2:17–25 17. Miller JM, Demer JL Biomechanical modeling in strabismus surgery. In: Rosenbaum AL, Santiago P (eds) (1999) Clinical strabismus management: principles and techniques. Mosby, St. Louis 18. Clark RA, Miller JM, Demer JL (1997) Location and stability of rectus muscle pulleys inferred from muscle paths. Invest Ophthalmol Vis Sci 38:227–240 19. Miller JM (2007) Understanding and misunderstanding extraocular muscle pulleys. J Vision 7:1–15 20. Miller JM, Pavlovski DS, Shaemeva I (1999). Orbit 1.8 gaze mechanics simulation. Eidactics, San Francisco 21. Clark RA, Miller JM, Demer JL (1998) Displacement of the medial rectus pulley in superior oblique palsy. Invest Ophthalmol Vis Sci 39:207–212 22. Demer JL, Clark RA, Miller JM (1999) Heterotopy of extraocular muscle pulleys causes incomitant strabismus. In: Lennerstrand G (ed) Advances in strabismology. Aeolus, Buren, The Netherlands 23. Velez FG, Clark RA, Demer JL (2000) Facial asymmetry in superior oblique palsy and pulley heterotopy. J AAPOS 4:233–239

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24. Demer JL, Oh SY, Clark RA, et al (2003) Evidence for a pulley of the inferior oblique muscle. Invest Ophthalmol Vis Sci 44:3856–3865 25. Rutar T, Demer JL (2009) “Heavy eye syndrome” in the absence of high myopia: A connective tissue degeneration in elderly strabismic patients. J AAPOS 13(1):36–44 26. Clark RA, Demer JL (2002) Eﬀect of aging on human rectus extraocular muscle paths demonstrated by magnetic resonance imaging. Am J Ophthalmol 134:872–878 27. Lim L, Rosenbaum AL, Demer JL (1995) Saccadic velocity analysis in patients with digergence paralysis. J Pediatr Ophthalmol Strabismus 32:76–81 28. Clark RA, Isenberg SJ (2001) The range of ocular movements decreases with aging. J AAPOS 5:26–30 29. Krzizok TH, Schroeder BU (1999) Measurement of recti eye muscle paths by magnetic resonance imaging in highly myopic and normal subjects. Invest Ophthalmol Vis Sci 40:2554–2560 30. Kowal L, Troski M, Gilford E (1994) MRI in the heavy eye phenomenon. Aust N Zeal J Ophthalmol 22:125–126 31. Ward DM (1956) The heavy eye phenomenon. Trans Ophthalmol Soc U K 87:717–726 32. Demer JL, von Noorden GK (1989) High myopia as an unusual cause of restrictive motility disturbance. Surv Ophthalmol 33:281–284 33. Wu J, Isenberg S, DJ L (2006) Magnetic resonance imaging demonstrates neuropathology in congenital inferior division oculomotor palsy. J AAPOS 10:473–475 34. Engle EC, Goumnerov BC, McKeown CA, et al (1997) Oculomotor nerve and muscle abnormalities in congenital ﬁbrosis of the extraocular muscles. Ann Neurol 41:314–325 35. Apt L, Axelrod N (1978) Generalized ﬁbrosis of the extraocular muscles. Am J Ophthalmol 85:822–829 36. Brodsky MC, Pollock SC, Buckley EG (1989) Neural misdirection in congenital ocular ﬁbrosis syndrome: Implications and pathogenesis. J Pediatr Ophthalmol Strabismus 26:159–161 37. Harley RD, Rodrigues MM, Crawford JS (1978) Congenital ﬁbrosis of the extraocular muscles. Trans Am Ophtlalmol Soc 76:197–226 38. Demer JL, Clark RA, Engle EC (2005) Magnetic resonance imaging evidence for widespread orbital dysinnervation in congenital ﬁbrosis of extraocular muscles due to mutations in KIF21A. Invest Ophthalmol Vis Sci 46:530–539 39. Brodsky MC (1998) Hereditary external ophthalmoplegia, synergistic divergence, jaw winking, and oculocutaneous hypopigmentation. Ophthalmology 105:717–725 40. Yamada K, Andrews C, Chan W-M, et al (2003) Heterozygous mutations of the kinesin KIF21A in congenital ﬁbrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet 35:318–321

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41. Demer JL, Clark RA, Engle EC (2009) Magnetic resonance imaging evidence of an asymmetrical endophenotype in congenital ﬁbrosis of extraocular muscles type 3. Invest Ophthalmol Vis Sci (in preparation) 42. Clark RA, Engle EC, Demer JL (2009) Magnetic resonance imaging (MRI) of the endophenotype of congenital ﬁbrosis of the extraocular muscles type 3 (CFEOM3). Abstracts of 35th Annual Meeting of the American Association for Pediatric Ophthalmology and Strabismus. J Am Assoc Pediatr Ophthmol Strabismus 13(1):e13 43. Duane A (1905) Congenital deﬁciency of abduction associated with impairment of adduction, retraction movements, contraction of the palpebral ﬁssure and oblique movements of the eye. Arch Ophthalmol 34:133–159 44. Huber A (1974) Electrophysiology of the retraction syndromes. Br J Ophthalmol 58:293–300 45. Strachan IM, Brown BH (1972) Electromyography of extraocular muscles in Duane’s syndrome. Br J Ophthalmol 56:594–599 46. Miller NR, Kiel SM, Green WR, et al (1982) Unilateral Duane’s retraction syndrome (type 1). Arch Ophthalmol 100:1468–1472 47. Hotchkiss MG, Miller NR, Clark AW, et al (1980) Bilateral Duane’s retraction syndrome. A clinical-pathologic case report. Archives of Ophthalmology 98:870–874 48. Parsa CF, Grant E, Dillon WP, et al (1998) Absence of the abducens nerve in Duane syndrome veriﬁed by magnetic resonance imaging. Am J Ophthalmol 125:399–401 49. Ozkurt H, Basak M, Oral Y, et al (2003) Magnetic resonance imaging in Duane’s retraction syndrome. J Pediatr Ophthalmol Strabismus 40:19–22 50. Kim JH, Hwang J-M (2005) Hypoplastic oculomotor nerve and absent abducens nerve in congenital ﬁbrosis syndrome and synergistic divergence with magnetic resonance imaging. Ophthalmology 112:728–732 51. Kim JH, Hwang JM (2005) Presence of abducens nerve according to the type of Duane’s retraction syndrome. Ophthalmology 112:109–113 52. DeRespinis PA, Caputo AR, Wagner RS, et al (1993) Duane’s Retraction Syndrome. Surv Ophthalmol 38:257–288 53. Demer JL, Clark RA, Lim KH, et al (2007) Magnetic resonance imaging evidence for widespread orbital dysinnervation in dominant Duane’s retraction syndrome linked to the DURS2 locus. Invest Ophthalmol Vis Sci 48:194–202 54. Kumar D (1990) Moebius syndrome. J Med Genet 27: 122–126 55. MacDermot KD, Winter RM, Taylor D, et al (1991) Oculofacialbulbar palsy in mother and son: review of 26 reports of familial transmission within the ‘Mobius spectrum of defects’. J Med Genet 28:18–26

56. Verzijl HT, van der Zwaag B, Cruysberg JR, et al (2003) Mobius syndrome redeﬁned: a syndrome of rhombencephalic maldevelopment. Neurology 61:327–333 57. Bielschowsky A (1939) Lectures on motor anomalies. XI. Etiology, prognosis, and treatment of ocular paralyses. Am J Ophthalmol 22:723–734 58. von Noorden GK, Murray E, Wong SY (1986) Superior oblique paralysis. A review of 270 cases. Arch Ophthalmol 104:1771–1776 59. Adler FE (1946) Physiologic factors in diﬀerential diagnosis of paralysis of superior rectus and superior oblique muscles. Arch Ophthalmol 36:661–673 60. Scott WE, Kraft SP (1986) Classiﬁcation and treatment of superior oblique palsies: II. Bilateral superior oblique palsies. In: Caldwell D (ed) Pediaric ophthalmology and strabismus: transactions of the New Orleans academy of ophthalmology. Raven, New York 61. Straumann D, Steﬀen H, Landau K, et al (2003) Primary position and Listing’s law in acquired and congenital trochlear nerve palsy. Invest Ophthalmol Vis Sci 44:4282–4292 62. Kushner BJ (2004) Ocular torsion: Rotations around the “WHY” axis. J AAPOS 8:1–12 63. Kushner BJ (1988) The diagnosis and treatment of bilateral masked superior oblique palsy. Am J Ophthalmol 105:186–194 64. Robinson DA (1985) Bielschowsky head-tilt test–II. Quantitative mechanics of the Bielschowsky head-tilt test. Vision Res 25:1983–1988 65. Chan TK, Demer JL (1999) Clinical features of congenital absence of the superior oblique muscle as demonstrated by orbital imaging. J AAPOS 3:143–150 66. Demer JL, Miller JM (1995) Magnetic resonance imaging of the functional anatomy of the superior oblique muscle. Invest Ophthalmol Vis Sci 36:906–913 67. Kono R, Demer JL (2003) Magnetic resonance imaging of the functional anatomy of the inferior oblique muscle in superior oblique palsy. Ophthalmology 110:1219–1229 68. Demer JL, Poukens V, Ying H, et al (2008) Eﬀects of acute trochlear denervation on primate superior oblique (SO) muscle: diﬀerential sparing of orbital layer. ARVO Abstracts: #4495 69. Demer JL, Miller MJ, Koo EY, et al (1995) True versus masquerading superior oblique palsies: muscle mechanisms revealed by magnetic resonance imaging. In: Lennerstrand G (ed) Update on strabismus and pediatric ophthalmology. CRC, Boca Raton (FL) 70. Kushner BJ (1987) Errors in the three-step test in the diagnosis of vertical strabismus. Ophthalmology 96:127–132 71. Brodsky ME (2003) Three dimensions of skew deviation. Br J Ophthalmol 87:1440–1441

References 72. Donahue SP, Lavin PJ, Hamed LM (1999) Tonic ocular tilt reaction simulating a superior oblique palsy: diagnostic confusion with the 3-step test. Arch Ophthalmol 117:347–352 73. Kono R, Okanobu H, Ohtsuki H, et al (2008) Displacement of the rectus muscle pulleys simulating superior oblique palsy. Jpn J Ophthalmol 52:36–43 74. Clark RA, Rosenbaum AL, Demer JL (1999) Magnetic resonance imaging after surgical transposition deﬁnes the anteroposterior location of the rectus muscle pulleys. J AAPOS 3:9–14 75. Clark RA, Demer JL (2002) Rectus extraocular muscle pulley displacement after surgical transposition and posterior ﬁxation for treatment of paralytic strabismus. Am J Ophthalmol 133:119–128 76. Demer JL (2008) Inﬂection in inactive lateral rectus muscle: Evidence suggesting focal mechanical eﬀects of connective tissues. Invest Ophthalmol Vis Sci 49:4858–4864 77. Clark RA, Demer JL (2008) Posterior inﬂection of weakened lateral rectus path: Connective tissue factors reduce response to lateral rectus recession. Am J Ophthalmol 147(1):127–133.e2 78. Ela-Dalman N, Velez FG, Demer JL, et al (2008) High resolution MRI demonstrates reduced inferior oblique muscle

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size in isolated inferior oblique palsy. J AAPOS 12(6): 602–607 Narasimhan A, Tychsen LT, Poukens V, et al (2007) Horizontal rectus muscle anatomy in naturally and artiﬁcially strabismic monkeys. Invest Ophthalmol Vis Sci 48:2576–2588 Tychsen L, Wong AM, Burkhalter A (2004) Paucity of horizontal connections for binocular vision in V1 of naturally strabismic macaques: Cytochrome oxidase compartment speciﬁcity. J Comp Neurol 474:261–275 Takagi M, Tamargo R, Zee DS (2003) Effects of lesions of the cerebellar oculomotor vermis on eye movements in primate: binocular control. Prog Brain Res 142: 19–33 Durig JS, Jen JC, Demer JL (2002) Ocular motility in genetically deﬁned autosomal dominant cerebellar ataxia. Am J Ophthalmol 133:718–721 Williams AS, Hoyt CS (1989) Acute comitant esotropia in children with brain tumors. Arch Ophthalmol 107: 376–378 Jen JC, Chan WM, Bosley TM, et al (2004) Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 304:1509–1513

Chapter 7

Congenital Cranial Dysinnervation Disorders: Facts and Perspectives to Understand Ocular Motility Disorders

7

Antje Neugebauer and Julia Fricke

Core Messages ■

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Congenital cranial dysinnervation disorders (CCDDs) are a group of neurodevelopmental diseases of the brainstem and the cranial nerves. Endogenic or exogenic disturbances lead to a primary dysinnervation of structures supplied by cranial nerves. Motility disturbances and potentially structural changes occur. Secondary dysinnervation occurs if ﬁbers of other cranial nerves innervate the primarily misinnervated structures. Synkinetic movements or cocontractions of antagonists result and may lead to structural changes in the muscles involved. Neurogenetic studies proved congenital ﬁbrosis of the extraocular muscles (CFEOM), isolated and

7.1

Congenital Cranial Dysinnervation Disorders: Facts About Ocular Motility Disorders

Electromyographic, clinicopathologic, neuroradiologic and genetic studies changed the view upon some congenital ocular motor disorders dramatically during the last decades [1–8]. Many of them that were formerly understood as congenital structural anomalies of the extraocular muscles [9] can now be explained as consequent to disorders in brainstem or cranial nerve development. Neurogenetic studies and amongst them particularly those of the workgroup of E. Engle improved our understanding of classic representatives of congenital eye motility disorders such as congenital ﬁbrosis of the extraocular muscles (CFEOM) and Duane retraction syndrome [2, 3, 6, 10–15, 21, 22]. In familial cases, mutations were found in genes that play crucial roles in

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syndromic forms of Duane syndrome and horizontal gaze palsy with progressive scoliosis (HGPPS) to be related to mutations in genes that play a role in brainstem and cranial nerve development. By clinical features and theoretic considerations some forms of congenital ptosis, congenital fourth nerve palsy, Möbius syndrome and Marcus Gunn jaw winking phenomenon are understood as CCDDs. Other congenital disturbances of ocular motility with ﬁbrotic features such as congenital Brown syndrome, congenital monocular elevation palsy and vertical retraction syndrome may be discussed as CCDDs.

cranial nerve development. The typical motility patterns in these diseases and the muscular anomalies can now be explained as changes secondary to incomplete, absent or paradoxical innervation of the eye muscles.

7.1.1 The Concept of CCDDs: Ocular Motility Disorders as Neurodevelopmental Defects With the term congenital cranial dysinnervation disorders (CCDDs) coined in 2002 [16] a new entity was established that convincingly encompasses diﬀerent congenital, nonprogressive diseases sharing etiopathologic features. The underlying concept postulates a defect in the prenatal development of the neuronal structures supplying innervation of the cranial region. As to the nature of this defect, primary genetic disorders in the neurodevelopmental plan or exogenic inﬂuences are a possibility.

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So it has to be stressed that although by genetic investigations in familial cases of congenital cranial dysinnervation single gene defects could be found to be responsible for hereditary forms of CCDDs the mechanism by which congenital cranial dysinnervations may occur is not necessarily genetic. Nevertheless, the proof that mutations in genes playing a role in brainstem development are causative for the phenotypes of CCDDs was important to elicit the neurodevelopmental nature of the disorders. Whether the cause of a single disorder in cranial nerve development is genetic or exogenic, the consequences of lack of innervation of the target muscles are common features: the underaction of the non- or underdeveloped cranial nerve is referred to as primary dysinnervation, which may lead to secondary ﬁbrotic changes in the target muscles. Substitutional innervation of the target muscles by cranial nerve ﬁbers originally destined for other muscles is referred to as secondary dysinnervation, in these cases paradoxical and sometimes synkinetic and cocontractive motility patterns result. As CCDDs of ocular motility namely the development of the third, fourth and sixth cranial nerves and the formation of brainstem structures involved in ocular motor control are of interest. A brief summary of the steps involved in proper development of the brainstem structures supplying ocular motility may indicate diﬀerent stages at which hazardous inﬂuences can induce speciﬁc lesions.

7.1.1.1

Brainstem and Cranial Nerve Development

From the ﬁrst induction of neural tissue in the developing organism to the proper innervation of an extraocular eye muscle by a cranial nerve a lot of consecutive steps have to be taken that depend on the inborn genetic plan for development and on the conditions in the surroundings of the organism. Major steps are anterior–posterior patterning of the neural system as well as dorsal–ventral patterning, segmentation with formation of brainstem nuclei, axon sprouting and axon guidance requiring neuronal interaction with chemoattractants and chemorepellents that interact with axonal receptors and guide the axonal growth cone away from or toward the midline and toward the target muscle. Some genes involved in these developmental processes are highly conserved during the development of species. That is why insight into the developmental plans of invertebrates helps us to understand the developmental steps in mammals. The role of so called homeobox genes that form a genomic sequence that is encoding developmental steps in anterior–posterior patterning and segmentation is a

prominent example for this. The hox homeobox cluster encoding sequential processes of diﬀerentiation both in time and space has been studied in the genome of Drosophila melanogaster. In mammals related sequences that encode diﬀerent steps in hindbrain diﬀerentiation are identiﬁed on four chromosomes thus multiplying the information for single developmental steps [17–19]. Genes for axonal guidance are preserved through the species as well and that is why basic research in this ﬁeld is helpful to understand disease mechanisms in CCDDs. A good example is the interaction between slits and netrin as proteins expressed in the midline of the nervous system and growing neurons that express receptors that interact with them. Generally proteins of the slit group act as repellents from the midline and netrin acts as an attractant. In the hindbrain an intricate interplay between slits and the receptors of the robo-group and dcc that is a netrin receptor guides growing axons either away from or across the midline. Further guidance molecules are the semaphorins and ephrins, which interact with various receptor complexes [17–20]. By now we have only narrow insight into some of the genetically determined interactions in normal cranial development. Future investigations with linkage analysis in familial disorders and investigations targeting on candidate genes are likely to elucidate the role of further genes in these processes. Hitherto mutations in six genes are identiﬁed as causative in CCDDs, more gene loci are mapped. Two genes are involved in the pathologic process in CFEOM [21, 22], most probably interacting in axon function and nuclear formation, three genes up to now are found mutated in different subgroups of Duane retraction syndrome [6, 10, 23, 24]. The example of the diﬀerent mutated genes causing Duane retraction syndrome shows that the interference with diﬀerent steps of development may lead to similar phenotypes: one gene is a homeobox gene controlling the development of one hindbrain segment: one gene is a presumed transcription factor and one gene seems to regulate axonal outgrowth in cranial nerves. One gene is found mutated in a complex disorder of horizontal gaze, termed horizontal gaze palsy with progressive scoliosis (HGPPS), this gene encodes for one of the transmembrane receptors in the slit-robo interaction [15].

7.1.1.2

Single Disorders Representing CCDDs

Congenital Fibrosis of the Extraocular Muscles (CFEOM) CFEOM was described already in 1879 by Heuck [25]. This disorder drew the attention of Elizabeth Engle to the

7.1

Congenital Cranial Dysinnervation Disorders: Facts About Ocular Motility Disorders

entity of ocular motility disorders [2] and in 2001 it was the ﬁrst congenital eye motility disorder in which a gene relevant in cranial nerve development was identiﬁed to be mutated in familial cases [21]. Clinically, CFEOM is characterized by gross motility disorders and sometimes paradoxical motility [26–28] in eye muscles and in the lid muscle that are supplied by the third cranial nerve and in some forms by the third and fourth cranial nerves (Fig. 7.1). According to clinical traits, three subgroups have been described, and a recent review [29] covers these disorders. CFEOM1 is an autosomal dominant anomaly characterized by bilateral ptosis and bilateral elevation deﬁciency of the eyes, both leading to a compensatory chin-up head posture. Intraoperatively passive motility is found to be restricted, and especially the elevation of the globe is hindered. Clinicopathologic studies showed ﬁbrous changes in the eye muscles that formerly led to the assumption that the disorder was primarily myogenic. More recent neuropathologic studies revealed abnormalities in the inferior part of the oculomotor nucleus and absence of the superior part of the nerve and hypoplasia of the target muscles of this nerve, which are the superior rectus and the levator palpebrae [14]. With mutations found in the gene KIF21A [22] in families with this disorder, it could be shown that alterations in a kinesin promoting axonal transport processes in neurons play an etiopathologic role in CFEOM1. Thus clinic, pathologic and genetic ﬁndings are consistent in this disorder with the notion of a primary defective innervation in the muscles usually supplied by the superior part of the third nerve, stemming from neurons located in the inferior part of the third nerve nucleus. The ﬁbrous changes in the noninnervated muscles can be understood as secondary changes due to noninnervation of the muscle ﬁbers.

Fig. 7.1 Patient with bilateral congenital ﬁbrosis of the extraocular muscles (CFEOM). After bilateral inferior rectus recession, the patient still adopts a 10° chin-up head posture to ﬁxate due to ptosis and residual elevation deﬁciency

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CFEOM2 is inherited in an autosomal recessive mode; features are bilateral ptosis and an exotropia with adduction deﬁciency and varying disorders in vertical alignment and motility. In this entity a lack of innervation both of the third and the fourth cranial nerves is presumed [2, 29]. Mutations in the gene ARIX/PHOX2A have been found in several pedigrees. From animal experiments it can be derived that ARIX is necessary for proper third and fourth nerve development [21, 29, 30]. CFEOM3 is an autosomal dominant disorder with varying penetrance and varying symptoms including unilateral or bilateral ptosis and motility deﬁciencies of the muscles usually supplied by the third nerve. KIF21A has been found mutated in this phenotype but there seems to be a heterogeneous genetic background because linkage analyses in diﬀerent families also indicate other genetic loci. Clinical overlap with congenital motility disorders classiﬁed as vertical retraction syndrome is possible [31, 32].

Duane Retraction Syndrome Duane retraction syndrome represents the most frequent and the most prominent congenital cranial dysinnervation disorder (CCDD). In 1905 Alexander Duane published a paper titled “Congenital deﬁciency of abduction, associated with impairment of adduction, retraction movements, contraction of the palpebral ﬁssure and oblique movements of the eye” [33]. This title still gives the full description of the main features of the syndrome known today as Duane or retraction syndrome (Fig. 7.2). In primary gaze, esotropia is the most common ﬁnding but a considerable number of patients are orthotropic and about 20% are exotropic [34]. Many patients adopt a head posture to maintain binocular single vision. Although this constellation of ocular motility disorders had been described earlier by others, it was the merit of Alexander Duane to set up a large series of own and published cases, thus accumulating the data of 54 patients. The early etiopathologic theories put forward mainly focused on mechanical changes in the horizontal rectus muscles. In 1959, Breinin performed electromyographic examinations in Duane retraction syndrome and found no potential in the lateral rectus muscle on abduction but a response in the lateral rectus on intended adduction [1]. Thus a paradoxical innervation of the lateral rectus was realized. A further milestone were clinicopathologic studies by Hotchkiss and Miller who found absent sixth nerves in Duane retraction syndrome and conﬁrmed pathologic ﬁndings by Mantucci dating from 1946 where a hypoplastic sixth nerve nucleus and absence of the sixth nerve were described. Miller showed that lateral rectus innervation was taken over by ﬁbers of the third nerve [4, 7, 8].

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Congenital Cranial Dysinnervation Disorders: Facts and Perspectives

Fig. 7.2 Patient with Duane syndrome in the left eye. Near alignment in primary gaze (b), adduction deﬁciency and downward movement on right gaze (a), abduction deﬁciency on left gaze (c). Lateral view of the globe on left gaze (d), retraction of the globe on right gaze (e)

a

d

b e c

Neuroradiologic studies later on also diagnosed hypoplasia of the sixth nerve in Duane syndrome [35–37]. In a thorough review De Respinis [34] gives data on demographic and epidemiologic features of the disease. Duane syndrome is estimated to account for 1–4% of strabismus cases. Pooled data of major studies showed a predilection of left eyes with 59%; 23% occurred in the right eye and 18% were bilateral cases. Sixty percent of the patients were female. The spectrum of associated nonocular ﬁndings encompasses miswiring syndromes as Marcus Gunn phenomenon and crocodile tears, vertebral anomalies as the Klippel-Feil anomaly and hearing problems. Syndromes encompassing Duane syndrome are Wildervanck or cervico-oculo-acoustic syndrome with Duane syndrome, sensorineural deafness and the Klippel-Feil anomaly as traits and Okihiro syndrome that combines Duane syndrome with radial ray anomalies. An induction of Duane syndrome by teratogens is possible; some patients with thalidomide embryopathy suﬀer from uni- or bilateral Duane syndrome [34, 86]. The ﬁrst mutation to be identiﬁed as causative for Duane retraction syndrome was found in patients with familial Okihiro syndrome or Duane radial ray syndrome (DRRS) [6, 10] in SALL4, a gene that encodes a transcription factor. The molecular mechanisms by which Duane syndrome and radial anomalies are induced are not yet clear. In sporadic cases of Duane syndrome up to now no mutations in SALL4 were found [39]. In the recently described Bosley-Salih-Alorainy syndrome (BSAS), bilateral Duane syndrome combines variably with sensorineural deafness, carotid artery malformations, delayed motor development and sometimes autistic disorders. The syndrome is inherited in an autosomal recessive mode. In diﬀerent pedigrees, mutations

in HOXA1 were found to be causative [2, 38, 40, 41]. HOXA1 encodes one homeobox gene that is important for hindbrain segmentation. Individuals suﬀering from the Athabascan brainstem dysgenesis syndrome (ABDS), a sporadic disorder that beyond the traits of BSAS causes central hypoventilation, mental retardation and varying accompanying signs including cardiac anomalies and facial weakness were found to have homozygous HOXA1 mutations. In patients with isolated Duane anomaly, no abnormalities in the HOXA1 gene were found [38, 42]. The third gene involved in the genesis of Duane syndrome is CHN1. It has been found mutated in several pedigrees with familial Duane syndrome inherited as a dominant trait [23]. Clinically these patients displayed not only reduced abduction and the pattern of often bilateral Duane syndrome but also some abnormalities in the vertically acting eye muscles innervated by the third nerve. The gene CHN1 encodes a2-Chimaerin, a protein that plays a role in the information ﬂow induced by ephrin and ephrin-receptor interaction that leads to growth cone changes inﬂuencing the guidance of a growing axon [44]. In a chick in ovo model, it could be shown that changes comparable with those induced by the gain of function mutations found in CHN1 lead to incomplete outgrowth of ocular motoneurons [23]. The current pathophysiologic concept for Duane syndrome putting together clinical, electrophysiologic, clinicopathologic, neuroradiologic and genetic ﬁndings looks upon the disorder as a CCDD in which innervation of the lateral rectus by sixth nerve ﬁbers is not full or absent and third nerve ﬁbers, mainly those primarily intended for the medial rectus take over some innervation of the lateral rectus. Thus, in primary position the underlying paresis is partly or fully compensated for the lateral rectus

7.1

Congenital Cranial Dysinnervation Disorders: Facts About Ocular Motility Disorders

receives nerve impulses of the third nerve, thus keeping the angle of squint in primary gaze relatively small with regard to the motility deﬁciency in abduction. Sometimes even overcompensation with a divergent angle in primary position or synergistic divergence on adduction occurs. The most common pattern of motility in Duane syndrome is an abduction deﬁciency, accompanied by a slighter adduction deﬁciency that results from the lateral rectus cocontracting on intended adduction. This cocontraction results in retraction of the globe and narrowing of the palpebral ﬁssure on adduction.

Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) A disturbance in the SLIT/ROBO signaling pathway has been found out to be the cause of a complex CCDD that leads to a horizontal gaze palsy with unaﬀected vertical eye movements. In the entity of so-called HGPPS hindbrain anomalies and ocular motor anomalies can be explained by disorders of the pathﬁnding of ﬁbers that normally cross the midline in the hindbrain. Mutations in the ROBO3 gene that encodes a transmembrane receptor molecule that normally seems to promote midline crossing of some hindbrain axons were identiﬁed in patients with HGPPS [15, 45]. The neuroanatomic correlates for the typical eye motility pattern (Fig. 7.3) are not fully understood, special neuroradiologic techniques could show that the typical hypoplastic appearance of the hindbrain on conventional NMR goes along with noncrossing ﬁbers of ascending and descending tracts [46–48]. Neurologic examinations conﬁrm that atypical lack of crossing ﬁbers exists [49]. The nature of the progressive scoliosis which means a signiﬁcant impairment to the patients may be to be neurogenic.

7.1.1.3

Disorders Understood as CCDDs

The pathophysiological concept of CCDDs also helps to understand other congenital, nonprogressive disorders and syndromes in which the proper motor innervation of cranial muscles is lacking, deﬁcient or substituted. Such syndromes in which the causative mechanism is not yet fully understood encompass disturbances in the third, fourth, sixth and seventh cranial nerves. Congenital ptosis is a part of the features of CFEOM and in this context proven to be a CCDD. As an isolated trait it is in some forms also presumed to represent a minor variant of dysinnervation in the target area of the third nerve. Familial cases hint to genetic causes and gene loci already have been identiﬁed.

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a

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d

e

Fig. 7.3 Patient with familial horizontal gaze palsy and progressive scoliosis (HGPPS). Patient after bilateral medial rectus recession for esotropia. Fixation in primary gaze with binocular functions (c). Only slight adduction movements on intended right (b) and left (d) gaze. Unimpaired elevation (a) and depression (e)

Congenital synkinetic movements of the lid on jaw movements often with congenital ptosis are referred to as Marcus Gunn phenomenon and hint to a paradoxical innervation in the levator palpebrae by ﬁbers of the motor portion of the ﬁfth nerve (Fig. 7.4). Misrouting of sixth and seventh nerve ﬁbers into the levator palpebrae also has been described [28, 47, 50, 51]. One of our patients

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7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives

a

b

7

Fig. 7.4 Patient with Marcus Gunn lid synkinesis (a, b). Opening of the right lid on sucking on the paciﬁer (b)

CCDDs by Traboulsi [52, 53]. Familial cases are described [54, 55] but an associated gene locus is not yet identiﬁed. In a study targeting on ARIX as a candidate gene in congenital trochlear palsy, no mutation was identiﬁed yet the authors hint to a high rate of polymorphisms [55]. Synkinetic movements of the superior oblique on mouth opening and swallowing have been described [47].

displays lid opening on intended downgaze on adduction, hinting to a possible miswiring of fourth nerve neurons in this case (Fig. 7.5). Congenital fourth nerve palsy may represent a CCDD with only primary dysinnervation resulting in elevation of the eye on adduction and reduced depression on adduction (Fig. 7.6). The disorder was put into the context with

a

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f

g

h

i

Fig. 7.5 Patient presumed to have aberrant innervation of the right lid by fourth nerve ﬁbers. Lid opening on left downgaze (i), slightly widened right palpebral ﬁssure in primary gaze position (e), slightly ptotic lid on abduction of the right eye (d, g)

a

b

Fig. 7.6 Patient with congenital fourth nerve palsy in the right eye. Normal right gaze (a), elevation on adduction on left gaze (b)

7.2

Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders

Some more descriptions of single synkinetic disorders concerning the sixth nerve and its target muscle such as abduction of the globe on mouth opening, upgaze and drinking exist [47]. A typical combination of mostly bilateral sixth nerve and seventh nerve underaction can be observed in Möbius syndrome. Recent publications hint to the total spectrum of Möbius syndrome that is broader and encompasses also combinations of horizontal gaze palsies or bilateral Duane syndrome and facial weakness and presumably lower brainstem disorders such as pharyngeal and tongue anomalies. But also third nerve anomalies reminding of CFEOM are described. Furthermore limb anomalies and problems of motor coordination occur. Thus Möbius syndrome covers features of a more generalized developmental brainstem syndrome [56, 57]. Isolated uni- or bilateral facial palsy is described as a familial disorder; gene loci are mapped [16, 53].

In 1949, H.W. Brown (1898–1978) at the First Strabismus Symposium in Iowa City gave a lecture on congenital structural muscle anomalies. In this talk and in the subsequent publication, he discussed congenital motility disorders with ﬁbrotic features such as retraction syndrome, strabismus ﬁxus, vertical retraction syndrome and general ﬁbrosis syndrome. Furthermore, under the name of superior oblique tendon sheath syndrome, he introduced a special form of congenital elevation deﬁciency in this context that since then is known as congenital Brown syndrome [9, 58]. We investigate whether there is evidence that more congenital eye motility disorders than currently listed, namely Brown syndrome, Double elevator palsy and vertical retraction syndrome represent congenitial cranial dysinnervation disorders.

7.2.1

Summary for the Clinician ■

■

Congenital Ocular Elevation Deﬁciencies: A Neurodevelopmental View

7.2.1.1 Brown Syndrome

A group of congenital ocular motility disorders are caused by developmental disturbances. These are nonprogressive, incomitant forms of strabismus with certain typical motility patterns and clinical features such as synkinetic movements that help to establish the diagnosis. Because of the developmental origin some of these motility disorders occur in syndromatic constellations. A thorough general examination is necessary.

7.2

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Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders

While some of the congenital ocular motility disorders with restrictive features are explained, others are not yet understood.

Motility Findings Brown syndrome is an oculomotor disturbance characterized by an elevation deﬁciency on adduction, normal or near normal elevation on abduction, mild elevation deﬁciency in straight upgaze, positive forced duction test and no or only slight superior oblique hyper function as cardinal features. Sometimes a head posture is adopted, hypotropia of the aﬀected eye in primary position may occur, a relative divergence of the eyes in upgaze may exist and sometimes widening of the lid ﬁssure on adduction can be observed [59, 60] (Fig. 7.7). In acquired cases, Brown syndrome results from damage that hinders the passage of the superior oblique tendon through the trochlea. The pathogenesis in congenital cases is not completely understood [60–63]. Brown’s initial assumption that a congenital palsy of the inferior oblique leads to secondary changes in the superior oblique tendon sheath was disproven by

a

b

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d

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f

Fig. 7.7 Patient with right-sided Brown syndrome. Minimal hypotropia in primary gaze (e). Slight elevation deﬁciency in right upgaze (a), marked elevation deﬁciency in left upgaze (c). Slight depression on adduction in left gaze (f)

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Congenital Cranial Dysinnervation Disorders: Facts and Perspectives

electromyography, which showed normal innervation in the inferior oblique. Brown subsequently regarded the disorder to be caused by a structural anomaly in a superior oblique tendon sheath [59, 64]. Many studies report structural anomalies in the tendon and its surrounding tissue. Current textbooks explain Brown syndrome as a form of restrictive strabismus and suggest varying anomalies in the superior oblique muscle or its tendon and the trochlea complex including the surrounding tissues [60–63]. The notion of Brown syndrome as a misinnervation syndrome was put forward already in 1969 by Papst and Stein who in an electromyographic study demonstrated paradoxical innervation of the superior oblique muscle on intended elevation in adduction of the globe. The authors interpreted this ﬁnding in analogy to the paradoxical coinnervation found in Duane retraction syndrome and postulated a neurodevelopmental origin of the syndrome. Other authors conﬁrmed the results by electromyography, so that a total of ﬁve cases with electromyographic recording of paradoxical innervation to the superior oblique are reported by three diﬀerent investigators [43, 65, 66, De Decker, personal communication, 2004]. Nevertheless, this explanation currently is not widely accepted. One argument put forward against the hypothesis of a paradoxical innervation refers to an electromyographic study by Catford and Hart [67] who could not ﬁnd paradoxical innervation in patients with Brown syndrome. But the patients examined by Catford and Hart mostly displayed late onset of Brown syndrome and may represent acquired cases. A second counter-argument points to the common ﬁnding of a positive forced duction test under anesthesia in congenital Brown syndrome that hints to a mechanical component rather than to a mere innervational one [62]. Discussing the question whether a passive restriction of the globe under anesthesia on forced duction to elevation in adduction contradicts the hypothesis of a primary misinnervation, one has to consider that a misinnervation could lead to secondary changes in the muscle, tendon, trochlea and surrounding connective tissues. In the publication by Gutowski that deﬁnes CCDDs it is summarized that “dysinnervation may be associated with secondary muscle pathology and/or other orbital and bony structural abnormalities” [16]. In the light of the understanding of CCDDs, we think it worthwhile to reconsider the question whether Brown syndrome represents a misinnervation disorder. The hypothesis is that a primary developmental dysinnervation of the superior oblique muscle as it occurs in congenital fourth nerve palsy is accompanied by a secondary dysinnervation of the superior oblique by ﬁbers of the third nerve.

Up to now CCDDs with secondary dysinnervation of ocular target muscles by nerve ﬁbers intended for other eye muscles are described for defects in the sixth nerve, for the third nerve and for combined defects of the third and fourth nerve but not for isolated defects in the fourth nerve. Misinnervation by ﬁbers normally intended for the antagonists of the primary dysinnervated muscles occurs in Duane syndrome and often keeps the deviation of the eyes in primary position remarkably small. A misinnervation of a non- or underinnervated superior oblique muscle by ﬁbers intended for the inferior oblique or the medial rectus would eliminate the elevation on adduction found in congenital fourth nerve palsy. Furthermore, the vertical and torsional angles of deviation in primary position would be kept small by a coinnervation by ﬁbers normally running to the inferior oblique muscle. First, because the antagonist of the primarily paretic superior oblique muscle might receive less nerve ﬁbers and second, because its tone now simultaneously is antagonized by a tone in the superior oblique. An aberrant innervation in the superior oblique by ﬁbers intended for the inferior oblique would result in blockage of elevation in adduction by cocontraction of the two muscles. This could be the explanation for the elevation deﬁciency on adduction. Primary dysinnervation in some muscular regions and cocontraction of the muscle against the action of the inferior oblique could lead to structural changes in the superior oblique and thus explain restriction against elevation in adduction in the forced duction test. A cocontraction of the superior and inferior oblique that both have their functional origin anterior to their insertion could also be claimed to explain widening of the lid ﬁssure on adduction. This would be an eﬀect reverse to the narrowing of the lid ﬁssure on adduction by retraction of the globe in Duane syndrome. A paradoxical coinnervation in the lid due to compensation of a hypoplasia in the subnucleus of the levator palpebrae could also be possible. As well passive forces by a secondarily tight superior oblique as active forces by a potential coinnervation of the superior oblique by ﬁbers originally destined for the medial rectus would explain depression of the globe on adduction. Moreover, an overcompensation of the primary defect by misrouting of axons intended for the antagonist of the underinnervated muscle could occur as it is the case in the subset of Duane syndrome with exotropia. Clarke described three cases with a depression on adduction of the globe that was primarily diagnosed as Brown syndrome but was in this publication presented as an own entity. In these cases, an innervation of the

7.2

Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders

superior oblique by ﬁbers primarily destined to the medial rectus would be possible [68]. At last even a miswiring of ﬁbers prone to the superior rectus could be discussed. This would explain why many patients show also a minor elevation deﬁciency in abduction. Thus, the motility ﬁndings of Brown syndrome could be explained by an aberrant innervation of a primarily dysinnervated superior oblique muscle. We analyzed the literature and our own data of 87 patients examined for congenital Brown syndrome in our clinic in the years 1995–2007 for information supporting or contradicting the hypothesis that the typical features of congenital Brown syndrome result from primary and secondary misinnervation.

Saccadic Eye Movements Barton [69] in a study on vertical saccades described the eye tracking of vertical saccades in a patient with Brown syndrome. Reproducibly, there occurred a marked and punctuated lateral shift, described as a “horizontal ﬂip,” of the globe in the upward saccades and a medial shift in the downward saccades. Under the proposed hypothesis, this would be explained by an additional abductor acting by cocontraction of the superior oblique when the eye comes into the ﬁeld of action of the inferior oblique. The authors compare the ﬂip movement of the eye to that in horizontal saccades in Duane syndrome. With the onset of cocontraction, a ﬂip could occur by the sudden action of the antagonist. Comorbidity In the majority of cases Brown syndrome represents an isolated disease. Among the diseases reported to accompany Brown syndrome interestingly CCDDs such as Duane syndrome, congenital Ptosis, crocodile tears and Marcus Gunn phenomenon [70] are prevailing. Contralateral congenital fourth nerve palsy is frequent as well [71–73]. Moreover, colobomata and cardiac malformations are named. In our 87 patients, three demonstrated additional Duane syndrome, two ptosis, one incomplete lid closure and one Marcus Gunn yaw winking phenomenon. In 13/87 patients, (14.9%) contralateral fourth nerve palsy with superior oblique underaction in downgaze was documented. Figure 7.8 shows a patient with right-sided Duane syndrome and left-sided Brown syndrome. The coincidence with CCDDs could be caused by common pathogenetic mechanisms interfering with brainstem and cranial nerve development. The high incidence of contralateral fourth nerve palsies also is of interest with regard to a potential

85

a

b

c

d

Fig. 7.8 Patient with right-sided Duane and left-sided Brown syndrome. Right upgaze (a) shows abduction deﬁciency in the right eye and elevation deﬁciency on adduction on the left side. Right gaze (b) shows abduction deﬁciency in the right eye and widening of the palpebral ﬁssure in the left eye. Eyes shown in primary gaze (c). Left gaze (d) shows narrowing of the right lid ﬁssure

misinnervation disorder in Brown syndrome. In these cases a bilateral disturbance of trochlear nerve development could be postulated that in the side with Brown syndrome is answered by a misinnervation or restrictive alteration in the superior oblique and in the other side leads to the symptoms of fourth nerve palsy.

Epidemiologic Features Under the hypothesis of a similar etiology, we compared epidemiologic data for Brown and Duane syndrome because both the fourth and sixth cranial nerves have developmentally an origin of rhombomeres which is different from the third nerve [52]. Laterality De Respinis [34] reviewed publications on Duane syndrome and ﬁgured out side distribution from pooled data of diﬀerent studies. We pooled the data of ten studies on Brown syndrome [60, 65, 74–81] and of our own series. In a total of 11 studies, including 246 patients with congenital Brown syndrome the right side was aﬀected in 53%, the left side in 38% and both sides in 9%.

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7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives

In the series on Duane syndrome [34], a total of 835 cases were analyzed. In 59% the left eye was aﬀected, in 23% the right eye and in 18% bilaterality was found. Assuming that in Duane syndrome the pathophysiologic mechanism has a tendency to aﬀect rather the left eye, these data seem contradictory to a common pathogenesis. This contradiction resolves because the ﬁbers of the fourth nerve are crossing and the nucleus of the fourth nerve lies contralaterally. The hypothesis stating a primary brainstem related pathophysiologic mechanism of Brown syndrome, the data concerning laterality show an interesting parallel between Duane and Brown syndrome. Nevertheless a higher bilateral incidence in Brown syndrome has to be noticed. But if according to the hypothesis congenital Brown syndrome would represent a subgroup of congenital fourth nerve palsy in which paradoxical coinnervation occurs, cases with a contralateral fourth nerve palsy should be understood as bilateral with regard to the underlying pathology, thus the percentage of bilateral cases would increase signiﬁcantly.

Sex Distribution Pooled data of ten and our own studies [60, 65, 74–81] encompassing 246 patients showed the aﬀection of 55% females and 45% males. For Duane syndrome de Respinis [34] found in pooled data of 835 patients, 58% were women and 42% were men. Again, an analogy between the entities of Brown and Duane syndrome under the hypothesis of a similar pathophysiologic mechanism could be drawn. Incidence Incidence of Brown syndrome is estimated to be 1 per 430–450 strabismus cases, i.e., 0.22% [60]. Duane syndrome occurs in at least 1% of strabismus cases [34]. Both syndromes are rare but a 4 times greater incidence of Duane syndrome remains to be explained. Stating a failed innervation of the superior oblique muscle by ﬁbers of the fourth nerve and paradoxical innervation of the superior oblique in Brown syndrome one would have to add the cases of uni- or bilateral congenital fourth nerve palsy to ﬁgure out the incidence of the underlying pathophysiologic entity of a developmental fourth nerve disorder. Heredity In Brown syndrome, most cases seem to occur spontaneously. Of the 126 cases in the 1973 report of Brown [59] 2 are familial, although it cannot be conﬁrmed whether all 126 cases were congenital ones, but at least 100 can be estimated

to have been congenital in this series. Wright summarizes the incidence of inheritance by 2% in Brown syndrome and found 1 of 38 cases, thus 3%, with inheritance in his own series. Wright hints to eight reports of inheritance in the literature with a total of 23 involved patients, he himself adding another one [60]. Lobefalo [82] reported a family with autosomal distal arthrogryposis multiplex congenita and Brown syndrome; thus, we overlook a total of ten descriptions of familial Brown syndrome. Three of the reports of familial Brown syndrome involve monocygotic twins with mirror images. In Duane syndrome, mirror images in twins are also described. But, although there are as in Brown syndrome far more sporadic than familial cases, the amount of hereditary cases in Duane syndrome with about 10% is greater than in Brown syndrome. As well in Brown syndrome as in Duane syndrome, the familial cases are presumed to be mostly inherited by an autosomal dominant transmission [34, 83, 84]. A genetic study performed under the assumption that Brown syndrome might be looked upon in the context of the other congenital strabismus syndromes already has been done in a family with familial aﬀection [85]. ARIX was not found to be mutated. But the case reports of the patients should be read carefully for the late onset of symptoms in the teenage years should also let an acquired pathology maybe on the basis of a familial rheumatic disposition being taken into consideration. Thus, this paper in our opinion does not contradict the hypothesis in question. Of our 87 patients, 21 patients had a positive family history in regard to strabismus or amblyopia (24.1%). Three patients (3.4%) had relatives with Brown syndrome: two pairs of brothers, amongst them one pair of twins with “mirror images” and one parent child constellation. One patient’s grandfather was reported to us to be “unable to move the eyes to the right or left.” We had no opportunity to examine the patient but a video of him showed a condition that might represent bilateral Duane syndrome or horizontal gaze palsy.

Potential Induction of the Syndrome Among the developmental defects caused by thalidomide there are also cranial miswiring syndromes. We investigated whether in thalidomide embryopathy also Brown syndrome is described. In 21 patients with thalidomide embryopathy and ocular motility disorders, Miller [86] describes nine patients with Duane syndrome and two patients with decreased function of the right-sided inferior oblique; furthermore, patients suﬀered from gaze paresis, isolated abduction weakness, aberrant lacrimation and facial nerve palsy.

7.2

Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders

It could be discussed whether the patients described with inferior oblique underaction were patients with a paradoxical coinnervation in fourth nerve hypo- or aplasia. Saito in a neurological work-up of the data of 137 patients with thalidomide embryopathy described three patients with disturbances of the fourth nerve [87].

Radiologic Findings Imaging studies in Brown syndrome displayed diﬀerent pathologies. Enlargement and irregularities in the trochlear complex were shown by Sener et al. Bhola et al. examined three patients with Brown syndrome, two of whom showed hypoplasia on NMR tomography in the muscular portion of the superior oblique – a remarkable ﬁnding with regard to the hypothesis of a primary developmental disorder in the fourth nerve underlying Brown syndrome. To test the hypothesis of a fourth nerve dysinnervation in Brown syndrome, Kolling and coworkers examined the trochlear nerve with nuclear magnetic resonance imaging and presented their results at the 12th meeting of the Bielschowsky society in 2007 [unpublished data]. In two of four patients, the trochlear nerve was found absent on the side of the motility deﬁciency a ﬁnding in favor of the hypothesis. Muscular anomalies were not found in these patients [80, 88]. Natural Course in Brown Syndrome As to the natural course of the disease, reports are inconsistent. Whereas Wright states that congenital Brown syndrome yields rather stable ﬁndings, many authors report spontaneous improvement or even resolution [89–91]. In most of our patients ﬁndings were quite stable but in single cases – for example, at the age of 2 years in one of the twins with mirror image – we saw signiﬁcant spontaneous improvement. The ﬁnding of spontaneous resolutions challenges the hypothesis of a dysinnervation. But one has to consider that the hypothesis states secondary ﬁbrotic changes. Also under the assumption of a mere mechanical cause of Brown syndrome, spontaneous improvements remain to be explained. Any explanation such as growth changes of the orbital anatomy or changes in ﬁbrotic tissues would serve under both assumptions. In the setting of cocontraction, changes in ﬁbrous strands even may be more probable. Furthermore, the postnatal plasticity of the neuromuscular connections with potential processes of initial polyneuronal innervation and gradual synapse elimination in the eye muscles is not well examined especially under the condition of coinnervation [18].

87

Intra-and Postoperative Findings Structural changes in the superior oblique tendon in Brown syndrome have been described by many surgeons [79, 92, 103]. In our series, 28 patients underwent operation, in 20 cases the surgical protocol mentions tightness of the tendon, in one case in which a tucking procedure was performed on the inferior oblique also ﬁbrotic changes in this muscle were reported. Surgical results are often disappointing as indicated by the multitude of approaches suggested. Surgeons often recognize a disappointing discrepancy between intraoperative ﬁndings after interventions on the superior oblique in that passive motility is improved after the procedure but active motility in the postoperative course is still not improved signiﬁcantly. Papst and Stein in their thorough early discussion of a potential misinnervation already hinted to this ﬁnding as an argument for an innervational abnormality in Brown syndrome [43, 66, 93]. We summarize from our studies that the hypothesis of Brown syndrome as a neurodevelopmental disorder should still be pursued to be veriﬁed or falsiﬁed.

7.2.1.2

Congenital Monocular Elevation Deﬁciency and Vertical Retraction Syndrome

While in congenital Brown syndrome an elevation deﬁciency of the eye exists if the globe is adducted, in congenital monocular elevation deﬁciency or in “double elevator palsy,” elevation of the globe is hindered in adduction as well as in abduction. An early description of the disorder is given by White in 1942 [94]. Acquired and congenital cases are reported. Congenital cases are characterized by orthotropia or hypotropia in primary position, true ptosis or pseudoptosis in the majority of cases. In a considerable number of cases restriction of the globe to forced duction into elevation is found. Often the lid shows paradoxical movements on yaw movements, i.e., the Marcus Gunn phenomenon. Furthermore dissociated vertical deviation (DVD) is present, sometimes it occurs after operation. Often Bell’s phenomenon is preserved although elevation on following movements, saccades and in compensatory eye movements cannot be elicited [62] (Fig. 7.9). Olson and Scott report a series of 31 patients with congenital monocular elevation deﬁciency in which they registered pseudptosis in 90%, true ptosis in 64%, chin-up head position in 77%, hypotropia in primary gaze in 97%

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Congenital Cranial Dysinnervation Disorders: Facts and Perspectives

a

7 b

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Fig. 7.9 Patient with congenital monocular elevation deﬁciency in the right eye. Elevation of the right eye hindered in right upgaze (a), straight upgaze (b) and left upgaze (c). Higher elevation of the right eye on lid closure, Bell’s phenomenon, (d) than on elevation (b)

with a mean of 20 PD, Marcus Gunn jaw winking in 28%, reduced or absent Bell’s phenomenon in 75% and restriction to elevation on forced duction in 42% of those tested [95]. In our own series of 23 patients with double elevator palsy in eight cases Bell’s phenomenon was positive. The fact that in some cases elevation of the globe is preserved under the conditions of Bell’s phenomenon, DVD or under anesthesia [96] led several authors to conclude that double elevator palsy represents a supranuclear disorder and seemed to exclude an infranuclear disorder. Some authors discuss a fascicular lesion [62, 94, 97].

Further, the ﬁnding that elevation is hindered in abduction, which means in the ﬁeld of action of the superior rectus, and in adduction, which means in the ﬁeld of action of the inferior oblique, led many observers to exclude a nuclear disorder: for the third nerve, the subnucleus for the innervation of the superior rectus lies contralaterally, and for the inferior oblique, it lies ipsilaterally in the mesencephalon. Remarkably, as in Brown syndrome, which was initially understood as a paresis of the inferior oblique in a case of so-called double elevator palsy, innervation of the inferior oblique was found normal in an electromyographic examination [98]. It was speculated that a longstanding palsy of the superior rectus alone also would impede elevation on adduction and that an inferior oblique palsy not necessarily is required to produce the typical motility pattern, [62, 94] thus a nuclear origin conﬁned to the subnucleus of the superior rectus was not out of discussion. In cases with resistance to forced duction, impairment of Bell’s phenomenon also exists, where sometimes a primarily ﬁbrotic origin is presumed. Thus supranuclear, nuclear, fascicular and muscular etiologies are discussed for the rare disorder of congenital monocular elevation deﬁciency. With the Marcus Gunn phenomenon, ptosis and restriction as accompanying signs some features exist that could be compatible with a neurodevelopmental origin of double elevator palsy. A case with the combination of Duane syndrome and double elevator palsy has been reported [99]. In our series of 23 patients, two showed contralateral fourth nerve palsy. Three of our patients showed retraction of the globe on vertical eye movements. This leads to similarities with vertical retraction syndrome that also had been included by Brown into the structural anomalies [9]. Descriptions of vertical retraction syndrome are inconsistent in that some authors describe only anomalies in vertical eye movements with retraction of the globe with narrowing of the lid ﬁssure; others describe vertical motility disorders with retraction combined with horizontal abnormalities that resemble Duane syndrome. Vertical retraction syndrome seems to be even rarer than congenital monocular elevation deﬁciency. A secondary misinnervation as cause for the retraction of the globe on vertical movements would be a possible explanation. The view upon congenital double elevator palsy and vertical retraction syndrome as neurodevelopmental disorders would require a model that solves the question why Bell’s phenomenon remains intact in some cases.

7.2

Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders

7.2.2

A Model of some Congenital Elevation Deﬁciencies as Neurodevelopmental Diseases

Our inquiries into the ﬁeld of congenital elevation deﬁciencies lead us to hypothesize that these disorders might represent rather a continuum of developmental disorders than distinct diseases. Clinically, it is sometimes hard to diﬀerentiate between a Brown syndrome and a congenital monocular elevation deﬁciency. Wright in his review hinted to 70% of patients that had been operated and that demonstrated signiﬁcant elevation deﬁciency in abduction [60]. In 76 own examinations of patients with congenital Brown syndrome, we found 66% to have remarkable hindrance of elevation in abduction. We remarked that some patients with typical Brown syndrome display a slight ptosis on the aﬀected side. Patients with congenital monocular elevation deﬁciency may display retraction on up- or downgaze so that clear diﬀerentiation from vertical retraction syndrome may be diﬃcult. At last even diﬀerentiation between a unilateral congenital ﬁbrosis syndrome and these disturbances may be diﬃcult. Thus one might ask for an explanation taking into account that borders are not clear cut. In prenatal development segmentation, anterior– posterior and dorso–ventral patterning is achieved by

89

sequential activation of genes and the building up of gradients of mediators for developmental steps. The crossing of ﬁbers in certain segments of the brainstem depends on the integrity of the cascade of interactions between substances mediating attraction to and repulsion from the midline and their receptors. The mutations in the ROBO3 gene leading to HGPPS are an example of a locally deﬁned failure of midline crossing of certain neurons. If such a failure occurred in the lower mesencephalic region, an isolated uni- or bilateral fourth nerve palsy could result. If ﬁbers of the third nerve e.g., ﬁbers intended for the superior rectus or the inferior oblique would enter the superior oblique paradoxical innervation could result in the motility pattern of Brown syndrome (Fig. 7.10). If the defect extended higher to the region of the crossing ﬁbers of the third nerve, the subnucleus sending ﬁbers across the midline that lies next to the fourth nerve and innervates the levator palpebrae muscle would be aﬀected and fourth nerve palsy or Brown syndrome accompanied by ptosis would result. A substitutional innervation, e.g., by ﬁbers of the motor portion of the ﬁfth nerve or of the third nerve would compensate the primary dysinnervation partially but lead to synkinetic movements of the lid on jaw movements as Marcus Gunn phenomenon or on downgaze producing a lid lag or on adduction producing widening of the lid ﬁssure.

superior rectus, MIF

Fig. 7.10 Model of congenital Brown syndrome as a neurodevelopmental disorder. A schematic drawing shows the third and fourth nerve nuclei in the brainstem. A unilateral gradual disturbance exists that mostly aﬀects the fourth nerve nucleus or its crossing neurons. An x indicates disruption of normal fourth nerve innervation. Dashed lines indicate secondary misinnervation of the superior oblique by third nerve ﬁbers. Note that this misinnervation does not run topographically in the way shown. The lines just indicate which muscles might share innervation

superior rectus, SIF

N. IIInucleus

levator palpebrae, SIF N. IV-nucleus

superior oblique, SIF

x N.IV

N.IIIfibers

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Congenital Cranial Dysinnervation Disorders: Facts and Perspectives

Further extension would encompass the subnucleus for the superior rectus. Brown syndrome and ptosis would be accompanied by an elevation deﬁciency in abduction, thus completing the image of congenital monocular elevation deﬁciency. If the superior rectus is innervated by ﬁbers of its main antagonist, retraction movements as well as depression deﬁciency result. Interestingly, recent studies on the functional neuroanatomy of the third nerve nucleus state a dual innervation of the eye muscles. So called single innervated muscle ﬁbers (SIF) and multiple innervated muscle ﬁbers (MIF) receive input each from a special subset of motoneurons that diﬀer in their histologic appearance from neurons innervating SIF ﬁbers. These are located in distinct regions of the third nerve nucleus [100, 101]. Such a dual innervation would make it necessary to reconsider the presumption of a ﬁnal common path in eye muscle innervation. The principle itself as introduced by Sherrington referred to the motoneuron as the ﬁnal path [102] and is not in question but it has been adopted in a way that looked upon the eye muscle as a structure with

homogeneous innervation. In consequence of the idea of a dual innervation of the eye muscles, concepts of supranuclear disorders in general have to be reconsidered. The motoneuron group innervating the MIF of the superior rectus is found in the so-called S-group, which in man lies in the cranial part of the nucleus. The functional role of the MIF ﬁbers is not yet elucidated but they are presumed to play a role in tonic muscle activity [100, 101]. One could speculate that MIF neurons play a role in the mediation of Bell’s phenomenon and further that these neurons either by their special cytologic features or just by their cranial position are not reached by the pathologic process hindering midline crossing. This would explain why Bell’s phenomenon remains intact in some cases of monocular elevation deﬁciency. Thus the concept of a supranuclear disorder would not be necessary. This model would explain Brown syndrome, congenital monocular elevation deﬁciency and vertical retraction syndrome as disorders of mesencephalic disturbance of midline crossing of fourth and third nerve ﬁbers with dysinnervation (Fig. 7.11). superior rectus, MIF

N.III superior rectus, SIF

N. IIInucleus

N. IVnucleus

N.Vfibers

x

7

7

x

levator palpebrae, SIF

superior oblique, SIF

x N.IV

N.IIIfibers

Fig. 7.11 Model of congenital monocular elevation deﬁciency as a neurodevelopmental disorder. A schematic drawing shows the third and fourth nerve nuclei in the brainstem. A unilateral gradual disturbance exists that mostly aﬀects the fourth and third nerve nuclei or their crossing neurons. An x indicates disruption of normal fourth nerve innervation and disruption of the crossing ﬁbers of the third nerve, resulting in primary misinnervation of the superior oblique, superior rectus and levator palpebrae. Dashed lines indicate secondary misinnervation of these muscles by third nerve ﬁbers originally intended and leading impulses for the medial rectus, inferior oblique and inferior rectus. Note that this misinnervation does not run topographically in the way shown. The lines just indicate which muscles might share innervation. Green line indicates multiple innervated muscle ﬁbers (MIF) for tonic innervation of the superior rectus not aﬀected by the lesion

References

The clinical ﬁndings seem consistent, future studies namely genetic studies in familial cases or on candidate genes will help to test this model.

Summary for the Clinician ■

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Congenital Brown syndrome, congenital monocular elevation deﬁciency and vertical retraction syndrome as nonprogressive forms of strabismus with ﬁbrotic changes share features with CCDDs and are found to be accompanied intraindividually or familial by other CCDDs. Electromyographic, neuroradiologic and surgical ﬁndings support the hypothesis that Brown syndrome represents a CCDD. Genetic linkage analysis or examination of candidate genes might prove or disprove a model that hypothesizes a continuous spectrum of congenital neurodevelopmental elevation disorders.

Acknowledgment The data of our own Brown syndrome [103] series and the literature on this topic as discussed in chapter 7.2.1.1 were evaluated in cooperation with Gregor Schaaf.

References 1. Breinin GM (1957) Electromyography: a tool in ocular and neurologic diagnosis. II. Muscle palsy. Arch Ophthalmol 57:165–175 2. Engle EC (2007) Oculomotility disorders arising from disruptions in brainstem motor neuron development. Arch Neurol 64(5):633–637 3. Engle EC, Leigh RJ (2002) Genes, brainstem development, and eye movements. Neurology 59(3):304–305 4. Hotchkiss MG, Miller NR, Clark AW, et al (1980) Bilateral Duane’s retraction syndrome. A clinical-pathologic case report. Arch Ophtalmol 98:870–874 5. Huber A, Esslen E (1969) Duane’s syndrome; observations on the pathogenesis and etiology of diﬀerent formes of the Stilling-Duane-Turk-retraction syndrome. Doc Ophthalmol 26:619–628 6. Kohlhase J, Heinrich M, Schubert L, Liebers M, et al (2002) Okihiro syndrome is caused by SALL4 mutations. Hum Mol Genet 11(23):2979–2987 7. Miller NR (2005) Strabismus syndromes: the congenital cranial dysinnervation disorders (CCDDs). In: Taylor D, Hoyt CS (eds) Pediatric ophthalmology and strabismus. Elsevier, Saunders, Edinburgh, London

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8. Miller NR, Kiel SM, Green WR, et al (1982) Unilateral Duane’s retraction syndrome (TypI). Arch Ophthalmol 100(9):1468–1472 9. Brown HW (1950) Congenital structural muscle anomalies. In: Allen JH (ed) Strabismus ophthalmic symposium I. VC Mosby, St. Louis 10. Al-Baradie R, Yamada K, St Hilaire C, et al (2002) Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SALL family. Am J Hum Genet 71(5):1195–1199 Epub 2002 Oct 22 11. Engle EC (2002) Applications of molecular genetics to the understanding of congenital ocular motility disorders. Ann N Y Acad Sci 956:55–63 12. Engle EC (2006) The genetic basis of complex strabismus. Pediatr Res 59(3):343–348 13. Engle EC (2007) Genetic basis of congenital strabismus. Arch Ophthalmol 125(2):189–195 14. Engle EC, Goumnerov BC, McKeown CA, et al (1997) Oculomotor nerve and muscle abnormalities in congenital ﬁbrosis of the extraocular muscles. Ann Neurol 41(3): 314–325 15. Jen JC, Chan WM, Bosley TM, et al (2004) Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 304(5676):1509–1513. Epub 2004 Apr 22 16. Gutowski NJ, Bosley TM, Engle EC (2003) The congenital cranial dysinnervation disorders. Neuromuscul Disord 13:573–578 17. Hans ten Donkelaar J, Lammens M, Hori A (2006) Clinical neuroembryology. Springer, Berlin 18. Purves D (ed) (2008) Neuroscience, 4th edn. Sinauer Associates, Massachusetts 19. Sanes DH (ed) (2006) Development of the nervous system, 2nd edn. Elsevier, Amsterdam 20. Woods CG (2004) Crossing the Midline. Science 304: 1455–1456 21. Nakano M, Yamada K, Fain J, et al (2001) Homozygous mutations in ARIX(PHOX2A) result in congenital ﬁbrosis of the extraocular muscles type 2. Nat Genet 29(3): 315–320 22. Yamada K, Andrews C, Chan WM, et al (2003) Heterozygous mutations of the kinesin KIF21A in congenital ﬁbrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet 35(4):318–321. Epub 2003 Nov 2 23. Miyake N, Chilton J, Psatha M, et al (2008) Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane’s retraction syndrome. Science 321(5890):839–843. Epub 2008 Jul 24 24. Tischﬁeld MA, Bosley TM, Salih MA (2005) Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet 37 (10):1035–1037. Epub 2005 Sep 11

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25. Heuck G (1879) Über angeborenen vererbten Beweglichkeitsdefect der Augen. Klin Monatsbl Augenheilkd 17: 253–278 26. Brodsky MC, Pollock SC, Buckley EG (1989) Neural misdirection in congenital ocular ﬁbrosis syndrome: implications and pathogenesis. Pediatr Ophthalmol Strabismus 26(4):159–161 27. Cibis GW (1984) Congenital familial external ophthalmoplegia with co-contraction. Ophthalmic Paediatr Genet 4:163–167 28. Yamada K, Hunter DG, Andrews C, et al (2005) A novel KIF21A mutation in a patient with congenital ﬁbrosis of the extraocular muscles and Marcus Gunn jaw-winking phenomenon. Arch Ophthalmol 123(9):1254–1259 29. Heidary G, Engle EC, Hunter DG (2008) Congenital ﬁbrosis of the extraocular muscles. Semin Ophthalmol 23(1):3–8 30. Yazdani A, Chung DC, Abbaszadegan, et al (2005) A novel PHOX2A/ARIX mutation in an Iranian family with congenital ﬁbrosis of extraocular muscles type 2 (CFEOM2). Am J Ophthalmol 136(5):861–865 31. Hanisch F, Bau V, Zierz S (2005) Congenital ﬁbrosis of extraocular muscles (CFEOM) and other phenotypes of congenital cranial dysinnervation syndromes (CCDD). Nervenarzt 76(4):395–402 32. Yamada K, Chan WM, Andrews C, et al (2004) Identiﬁcation of KIF21A mutations as a rare cause of congenital ﬁbrosis of the extraocular muscles type 3 (CFEOM3). Invest Ophthalmol Vis Sci 45(7):2218–2223 33. Duane A (1905) Congenital deﬁciency of abduction, associated with impairment of adduction, retraction movements, contraction of the palpebral ﬁssure and oblique movements of the eye. Arch Ophthalmol 34:139–159 34. De Respinis PA, Caputo AR, Wagner RS, et al (1993) Duane’s retraction syndrome. Surv Ophthalmol 38: 257–288 35. Kim HJ, Hwang JM (2005) Presence of the abducens nerve according to the type of Duane’s retraction syndrome. Ophthalmology 112(1):109–113 36. Ozkurt H, Basak M, Oral Y, et al (2003) Magnetic resonance imaging in Duane’s retraction syndrome. J Pediatr Ophthalmol Strabismus 40(1):19–22 37. Parsa CF, Grant E, Dillon WP Jr (1998) Absence of the abducens nerve in Duane syndrome veriﬁed by magnetic resonance imaging. Am J Ophthalmol 125(3):399–401 38. Tischﬁeld MA, Chan WM, Grunert JF, et al (2006) HOXA1 mutations are not a common cause of Duane anomaly. Am J Med Genet A 140(8):900–902 39. Wabbels BK, Lorenz B, Kohlhase J (2004) No evidence of SALL4-mutations in isolated sporadic duane retraction “syndrome” (DURS). Am J Med Genet A 131(2):216–218 40. Bosley TM, Salih MA, Alorainy IA, et al (2007) Clinical characterization of the HOXA1 syndrome BSAS variant. Neurology 69(12):1245–1253

41. Bosley TM, Alorainy IA, Salih MA, et al (2008) The clinical spectrum of homozygous HOXA1 mutations. Am J Med Genet A 146A(10):1235–1240 42. Holve S, Friedman B, Hoyme HE, et al (2003) Athabascan brainstem dysgenesis syndrome. Am J Med Genet A 120A(2):169–173 43. Stein HJ, Papst W (1969) Elektromyographische Untersuchungen zur Pathogenese und Therapie des Musculus obliquus superior-Sehnenscheidensyndroms (BrownSyndrom). Ber Zusammenkunft Dtsch Ophthalmol Ges 69:618–624 44. Wegmeyer H, Egea J, Rabe N, et al (2007) EphA4-dependent axon guidance is mediated by the RacGAP a2-Chimaerin. Neuron 55:756–767 45. Chan WM, Traboulsi EI, Arthur B, et al (2006) Horizontal gaze palsy with progressive scoliosis can result from compound heterozygous mutations in ROBO3. J Med Genet 43(3):e11 46. Haller S, Wetzel SG, Lütschg J (2008) Functional MRI, DTI and neurophysiology in horizontal gaze palsy with progressive scoliosis. Neuroradiology 50:453–459 47. Pieh C, Lagrèze WA (2007) Angeborene Fehlinnervationssyndrome. Ophthalmologe 104:1083–1096 48. Sicotte NL, Salamon G, Shattuck DW, et al (2006) Diﬀusion tensor MRI shows abnormal brainstem crossing ﬁbers associated with ROBO3 mutations. Neurology 67(3): 519–521 49. Amoiridis G, Tzagournissakis M, Christodoulou P, et al (2006) Patients with horizontal gaze palsy and progressive scoliosis due to ROBO3 E319K mutation have both uncrossed and crossed central nervous system pathways and perform normally on neuropsychological testing. Neurol Neurosurg Psychiatry 77:1047–1053; originally published online 13 Jun 2006 50. Brodsky MC (1991) Platysma-levator synkinesis in congenital third nerve palsy. Arch Ophthalmol 109:620 51. Brodsky MC (1998) Hereditary external ophthalmoplegia, synergistic divergence, jaw winking and oculocutaneous hypopigmentation. Ophthalmology 105:717–725 52. Traboulsi EI (2004) Congenital abnormalities of cranial nerve development: overview, molecular mechanisms, and further evidence of heterogeneity and complexity of syndromes with congenital limitation of eye movements. Trans Am Ophthalmol Soc 102:373–389 53. Traboulsi EI (2007) Congenital cranial dysinnervation disorders and more. J AAPOS 11(3):215–217 54. Astle WF, Rosenbaum AL (1985) Familial congenital fourth cranial nerve palsy. Arch Ophthalmol 103:532–535 55. Jiang Y, Matsuo T, Fuliwara H, et al (2005) ARIX and PHOX2B Polymorphisms in patients with congenital superior oblique muscle palsy. Acta Med Okayama 59(2): 55–62

References 56. De Souza-Dias CR, Goldchmitt M (2007) Further considerations about the ophthalmic features of the Möbius sequence, with data of 28 cases. Arq Bras Oftalmol 70(3): 451–457 57. Verzijl HT, van der Zwaag B, Cruysberg JR, et al (2003) Möbius syndrome redeﬁned: a syndrome of rhombencephalic maldevelopment. Neurology 61(3):327–333 58. Von Noorden GK (2002) The history of strabismology. Wayenborgh, Ostende 59. Brown HW (1973) True and simulated superior oblique tendon sheath syndromes. Doc Ophthalmol 34:123–136 60. Wright KW (1999) Brown’s syndrome: diagnosis and management. Trans Am Ophthalmol Soc 47:1023–1107 61. Esser J, Mühlendyck H (2004) Jaensch-Brown-Syndrom. In: Kaufmann H (ed) Strabismus. Georg Thieme, Stuttgart, New York 62. Von Noorden GK, Campos EC (2002) Binocular vision and ocular motility, 6th edn. Mosby, St. Louis 63. Wright KW (ed) (2003) Pediatric ophthalmology and strabismus, 2nd edn. Springer, New York 64. D’Esposito M, Cotticelli L, Caccia-Perugini G, et al (1974) La Pseudoparalisis dell’oblique inferiore. Acta Neurol (Napoli) 29(6):625–658 65. Feric-Seiwerth F, Celic M (1972) Contribution to the knowledge of the superior oblique tendon sheath syndrome. In: Mein J et al (ed) Orthoptics – proceedings of the second international orthoptic congress, Amsterdam 1971. Excerpta Medica, Amsterdam, pp 354–359 66. Papst W, Stein HJ (1969) Zur Ätiologie des Musculusobliquus-superior-Sehnenscheidensyndroms. Klin Monatsbl Augenheilkd 154:506–518 67. Catford GV, Hart JCD (1971) Superior oblique tendon sheath syndrome. An electromyographical study. Brit J Ophthalmol 55:155–160 68. Clarke WN, Noël LP (1985) Depression in adduction syndrome. Can J Ophthalmol 20:23–28 69. Barton JJ, Intriligator JM (2001) Vertical saccades in superior oblique palsy and Brown’s syndrome.J Neuroophthalmol 21:250–255 70. Wilson ME, Eustis HS, Parks MM (1989) Brown’s syndrome. Surv Ophthalmol 34:153–172 71. Bhola R, Sharma P, Saxena R, et al (2004) Magnetic resonance imaging of an unusual case of Brown’s Syndrome with contralteral superior oblique palsy. J AAPO 8(2): 196–197 72. Castanera de Molina A, Munoz GL (1991) Brown syndrome associated with contralateral superior oblique palsy: a case report. J Pediatr Ophthalmol Strabismus 28: 310–313 73. Clarke WN, Noël LP (1993) Brown’s syndrome with contralateral inferior oblique overaction: a possible mechanism. Can J Ophthalmol 28(5):213–216 74. Berk AT, Erkan D, Sener C, et al (1994) Congenital Brown’s syndrome: clinical and surgical approach. Eur J Ophthalmol 4:138–143

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75. Crawford JS, Orton RB, Labow-Daily L (1980) Late results of superior oblique muscle tenotomy in true Brown’s syndrome. Am J Ophthalmol 89:824–829 76. Eustis HS, O’Reilly C, Crawford JS (1987) Management of superior oblique palsy after surgery for true Brown’s syndrome. J Pediatr Ophthalmol Strabismus 24:10–16 77. Hadjadj E, Conrath J, Ridings B, et al (1998) Syndrome de Brown: actualités. J Fr Optalmol 21:276–282 78. Maggi R, Maggi C (2002) Tendon surgery in Brown’s syndrome. J Pediatr Opthalmol Strabismus 39:33–38 79. Parks MM, Eustis HS (1987) Simultaneous superior oblique tenotomy and inferior oblique recession in Brown’s syndrome. Ophthalmology 94:1043–1048 80. Sener EC, Özkan SB, Aribal ME, et al (1996) Evaluation of congenital Brown’s syndrome with magnetic resonance imaging. Eye 10:492–496 81. Von Noorden GK, Olivier P (1982) Superior oblique tenectomy in Brown’s syndrome. Ophthalmology 89:303–309 82. Lobefalo L, Mancini AT, Petitti MT, et al. (1999) A family with autosomal dominant distal arthrogryposis multiplex congenita and Brown syndrome. Ophthalmic Genet 20(4): 233–241 83. Mc Kusick VA (1990). Mendelian inheritance in Man, 9th edn. John Hopkins Univ, Baltimore 84. Paul OT, Hardage LK (1994) The heritability of strabismus. Ophthalmic Genet 15(1):1–18 85. Iannaccone A, McIntosh N, Ciccarelli ML (2002) Familial unilateral Brown syndrome. Ophthalmic Genet 23(3): 175–184 86. Miller MT (1991) Thalidomide embryopathy: a model for the study of congenital incomitant horizontal strabismus. Trans Am Ophthalmol Soc 89:623–674 87. Kida M (ed) (1987) Thalidomide embryopathy in Japan. Kodansha, Tokyo 88. Bhola R, Rosenbaum AL, Ortube MC, et al (2005) Highresolution magnetic imaging demonstrates varied anatomic abnormalities in Brown syndrome. J AAPOS 9(5): 438–448 89. Capasso L, Torre A, Gagliardi V (2001) Spontaneous resolution of congenital bilateral Brown’s Syndrome. Ophthalmologica 215:372–375 90. Gregersen E, Rindziunski E (1993) Brown’s syndrome. Acta Ophthalmol 71:371–376 91. Kaban TJ, Smith K, Orton RB, et al (1993) Natural history of presumed congenital Brown syndrome. Arch Ophthalmol 111:943–946 92. Mühlendyck H (1996) Jaensch-Brown-Syndrom – Ursache und operatives Vorgehen. Klin Monatsbl Augenheilkd 208:37–47 93. Crawford JS (1976) Surgical treatment of true Brown’s syndrome. Am J Ophthalmol 81:289–296 94. White JW (1942) Paralysis of the superior rectus and inferior oblique muscles in the same eye. Arch Ophthalmol 27:366–371

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95. Olson RJ, Scott WE (1998) Dissociative phenomena in congenital monocular elevation deﬁciency. J AAPOS 2:72–8 96. Mims JL 3rd (2005) “Double elevator palsy” eye supraducts during stage II general anesthesia supporting hypothesis of (supra)nuclear etiology. Binocul Vis Strabismus Q 20(4): 199–204 97. Leigh RJ, Zee DS (2006) The neurology of eye movements, 4th edn. Oxford University, Oxford, New York 98. Bell J A, Fielder A, Viney S (1990) Congenital double elevator palsy in identical twins. J Clin Neuro-ophthalmol 10(1):32–34 99. Verma MJ, Faridi MM (1992) Ocular motility disturbances (Duane retraction syndrome and double elevator palsy) with congenital heart disease, a rare association with Goldenhar syndrome–a case report. Indian J Ophthalmol 40(2):61–62

100. Büttner-Ennever JA (2006) The extraocular motor nuclei: organization and functional neuroanatomy. In: BüttnerEnnever JA (ed) Neuroanatomy of the oculomotor system. Elsevier, Amsterdam 101. Horn AK, Eberhorn A, Härtig W, et al (2008) Perioculomotor cell groups in monkey and man deﬁned by their histochemical and functional properties: reappraisal of the Edinger-Westphal nucleus. J Comp Neurol 507(3): 1317–1335 102. Sherrington CS (1979) Selected writings of Sir Charles Sherrington. In: Denny-Brown D (ed) Oxford University, Oxford 103. Parks MM, Brown M (1975) Superior oblique tendon sheath syndrome of Brown. Am J Ophthalmol 79(1): 82–86

Chapter 8

The Value of Screening for Amblyopia Revisited

8

Jill Carlton and Carolyn Czoski-Murray

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Vision screening for children may be considered in terms of detection of amblyopia, strabismus, and/or refractive error. Variations exist within and between countries regarding vision screening for children in terms of program content, referral criteria, and personnel. Recommendations state pre-school vision screening programs be conducted by orthoptists or by professionals trained and supported by orthoptists. The justiﬁcations of vision screening for children include an increased risk of blindness to the healthy eye as a result of injury or disease in adults with amblyopia. An increased risk of blindness is present as the non-amblyopic eye of an amblyope may become diseased or injured. A recent report found that screening for amblyopia could not be considered as cost-eﬀective, but acknowledged that much uncertainty exists surrounding the short- and long-term implications of the condition(s). Further research is needed to provide such evidence. Treatment of amblyopia associated with refractive error should incorporate a period of observation with glasses-wear alone to allow for “refractive adaptation” (also known as “optical treatment of amblyopia”). Improvements in visual acuity (VA) can occur up to and beyond 20 weeks after glasses are prescribed. Most improvement

8.1 Amblyopia Amblyopia is a sensory anomaly deﬁned as defective unilateral or bilateral visual acuity (VA). There are a number of classiﬁcations of amblyopia based on the etiological cause(s). The reported prevalence of amblyopia varies widely, from 1–5%. Diﬀerences in prevalence can be attributed to the population studied (e.g. ethnicity), and

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occurs in weeks 4–12. In some cases, further amblyopia therapy may not be required. Children who undergo amblyopia therapy at an early age have been found to respond more quickly to occlusion than older children, and require less occlusion in total. There is evidence to suggest that successful treatment of children aged over 7 years can be achieved in cases of anisometropic, strabismic, and mixed etiology amblyopia. Atropine has been found to be as eﬀective as patching in the treatment of both moderate and severe amblyopia. Recurrence of amblyopia may occur following treatment, with reported rates of 7–27%. Factors inﬂuencing recurrence include age of the child at cessation of treatment, VA at the time of cessation of treatment, and the type of amblyopia that is present. Reported health-related quality of life (HRQoL) implications of amblyopia include the impact of the condition upon stereoacuity; ﬁne motor skills; reading speed; and interpersonal relationships. The reported HRQoL implications of strabismus are related to physical appearance, particularly upon self-image and interpersonal relationships. Surgical correction of strabismus has been reported to improve HRQoL.

whether the study sample was taken from a clinical cohort (where a greater prevalence would be expected), or a population-based study. However, the most important factor that can account for the diﬀerences in the reported prevalence rates is that of amblyopia deﬁnition. Over the recent years, a deﬁnition of amblyopia based upon a diﬀerence in VA of two or more Snellen or logMAR lines between eyes has been adopted. However, there is no universally

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accepted deﬁnition of amblyopia in terms of VA deﬁcit. Studies that report on amblyopia prevalence, diagnosis, and/or treatment must be interpreted carefully, and often cannot be directly compared. Nonetheless, amblyopia is considered to be a common condition which occurs in childhood, and if left untreated, will remain present throughout adult life. This chapter will explore what is meant by screening; detection of amblyopia and strabismus through screening programs; amblyopia treatment; and consequences of amblyopia and its treatment (both in the long and short term).

8.2 What Is Screening? The purpose of screening is to identify persons as being at greater or lesser risk of developing, or having, a particular condition. The United Kingdom (UK) National Screening Committee (NSC) deﬁned screening as “a public health service in which members of a deﬁned population, who do not necessarily perceive that they are at risk of, or are already aﬀected by, a disease or its complications, are asked a question or oﬀered a test to identify those individuals who are more likely to be helped than harmed by further tests or treatment to reduce the risk of a disease or its complications” [1]. There are recognized criteria for screening relating to the condition itself, diagnosis, treatment, and cost. These are summarized in Table 8.1.

8.2.1 Screening for Amblyopia, Strabismus, and/or Refractive Errors Screening for amblyopia, strabismus, and/or refractive errors has long been an emotive and contentious issue. Diﬀerences in health care provision from one country to another can make it diﬃcult to draw inferences on the possible beneﬁts and risks associated with the implementation or withdrawal of such programs. For example, differences exist between the UK and the United States of America (USA). Within the UK, vision screening of children was developed as part of the child health surveillance programs established during the 1960s and 1970s. The appropriateness of such programs was called into question following a systematic review of their eﬀectiveness [2]. In 2003, the Health For All Children Report (also known as Hall 4) recommended changes in the way children are monitored and referred for suspected amblyopia and strabismus [3], and the Child Health Promotion Program (CHPP) recommended all children to be screened for visual impairment between 4 and 5 years of age by an orthoptist-led service [4]. This recommendation has been adopted regionally in the UK, although not universally. Within the USA, there are also widespread diﬀerences regarding pre-school vision screening guidelines, policies, and procedures. Recommendations from the American Academy of Ophthalmology (AAO), American Association for Pediatric Ophthalmology and Strabismus

Table 8.1. Summary of criteria for screening [72] Category

Criteria

Condition

The condition should be an important health problem, whose epidemiology and natural history are understood. There should be a recognizable risk factor or early symptomatic stage

Diagnosis

There should be a simple, safe, precise, and validated screening test which is acceptable to the population. There should be an agreed policy on further investigation of individuals with a positive test result

Treatment

There should be an eﬀective treatment or intervention for those identiﬁed as having the disease or condition, with evidence of early treatment leading to better outcome than late treatment. There should be agreed evidence-based policies regarding which individuals should be oﬀered treatment

Program

There should be evidence from high-quality randomized controlled trials (RCTs) that the screening program is eﬀective in reducing mortality or morbidity. There should be evidence that the complete screening program (including the test, diagnostic procedures, and treatment) is clinically, socially, and ethically acceptable. The beneﬁt of the program should outweigh the physical and psychological harm. The cost of the program should be economically balanced in relation to expenditure on medical care as a whole (i.e. value for money)

8.2

(AAPOS), and the American Academy of Pediatrics (AAP) are that vision screening should be performed on children between the ages of 3 and 3 ½ years [5]. Despite the existence of such recommendations, current practice within the USA is totally non-standardized, with much variability by state and locality. This was highlighted by Ciner et al. [6], who recommended that speciﬁc components of a pre-school vision screening program ought to be considered, including the tests to be conducted, parental education on the condition, and recording and referral criteria. Over recent years, there has been a call to make any recommendations for vision screening for children more evidenced-based, and advances in the literature regarding screening test accuracy and treatment of amblyopia will only serve to facilitate this. However, the implementation of any recommendations is often driven by political rather than clinical factors.

What Is Screening?

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of the strabismus would be suggestive that amblyopia is likely to develop within the critical period of vision development.

8.2.1.3 Screening for Refractive Error Screening for refractive error alone is not commonplace. The justiﬁcation would be that the presence of signiﬁcant refractive error may impact upon educational progress and daily living. The existence of unequal refractive error (anisometropia) could be deemed an amblyogenic risk factor. Indeed, the correction of any clinically signiﬁcant refractive error during the critical period of vision development supports the notion of pre-school vision screening.

8.2.1.4 Screening for Other Ocular Conditions 8.2.1.1 Screening for Amblyopia The purpose of pre-school vision screening for amblyopia is to detect children with unilateral or bilateral amblyopia. Accurate detection of amblyopia is primarily achieved through VA testing. The value of conducting other tests for the purpose of screening for amblyopia alone is minimal; some would argue additional tests could be included in the screening program to detect amblyogenic factors (e.g. strabismus or refractive error).

Any form of pre-school vision screening is likely to result in detection of other ocular conditions. These may include ocular pathologies such as cataract or retinoblastoma; or may be related to motility, such as Duane’s or Brown’s syndrome. Whilst such conditions are of great clinical importance, not least because of their association with systemic health problems, the justiﬁcation of screening for detection of these conditions alone cannot be justiﬁed. To screen for such conditions in isolation is neither practical nor appropriate. The economic beneﬁt of adding such conditions to a screening program for amblyopia and/or strabismus is negligible.

8.2.1.2 Screening for Strabismus The purpose or value for pre-school vision screening for strabismus alone could be questioned. It may be argued that large, cosmetically apparent strabismus would be observed by parents or guardians and/or health care practitioners. Once noted, appropriate referral to an ophthalmologist would be initiated. Therefore, the justiﬁcation of pre-school vision screening for large-angled strabismus may not be valid. The detection of smallangle strabismus, however, is not as easy and requires expert testing from orthoptists and ophthalmologists. The value of such detection remains under debate. If the strabismus is so small that it is not cosmetically obvious, then it is unlikely that surgical treatment for the condition would be undertaken. To that end, the value of screening may be questioned. An argument for screening could be that the presence of a small-angle strabismus is an amblyogenic factor: amblyopia may not be present at the time of screening; however, the existence

8.2.2

Diﬀerence Between a Screening and Diagnostic Test

There is diﬀerence between a screening test and a diagnostic test. As the name implies, a screening test is used to identify and eliminate those with a given problem(s); there is no requirement for it to quantify the extent of any deﬁcit or problem, or indeed for it to provide any information for diagnosis. A diagnostic test provides information that can be used to help make a clinical diagnosis, and/or inﬂuence the management plan of the condition. A diagnostic test often quantiﬁes the extent or severity of the condition. For example, photoscreening is used to detect refractive error (screening test); however, the results would not be used to diagnose the extent of the refractive error present or indeed for the prescription of glasses. This would be achieved through refraction (diagnostic test).

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8 The Value of Screening for Amblyopia Revisited

Justiﬁcation for Screening for Amblyopia and/or Strabismus

The justiﬁcation of pre-school vision screening for amblyopia and/or strabismus remains a controversial issue. Referring to the NSC criteria of screening, the condition to be screened should be an important clinical condition. The evidence relating to the condition’s importance and impact relate primarily to the consequence of amblyopia and/or strabismus in the short or long term. It has been recognized that there is a detrimental eﬀect of having reduced vision in one eye (as is the case with unilateral amblyopia). Brown et al. [7] stated that in the presence of ocular disease, yet good VA in both eyes, subjects reported to have a higher HRQoL than those with good VA in only one eye. One of the arguments regarding the consequence of amblyopia refers to the risk of blindness to the healthy eye as a result of injury or disease. Rahi et al. [8] reported on the ﬁndings of the British Ophthalmological Surveillance Unit (BOSU), a national surveillance scheme for the study of rare ophthalmological disorders or events. Over a 2-year period, the number of individuals with unilateral amblyopia with a newly acquired loss of vision in the non-amblyopic eye was recorded. The authors were able to report on the total population lifetime risk and annual rate of permanent visual impairment or blindness attributable to loss of vision in the non-amblyopic eye. In addition, the projected lifetime risk and annual rate of permanent visual impairment or blindness attributable to loss of vision in the non-amblyopic eye in individuals with amblyopia were reported. It was found that the lifetime risk of visual impairment increased substantially from the age of 15 to 64 years and by 95 years of age (incidence per 100,000 total UK population, 5.67 [4.33–7.01 CI] compared with 32.98, [29.06–36.89 CI]). This can be attributed to the increased prevalence of other ocular disorders that occur with increasing age (such as cataract and agerelated macular degeneration). The authors stated that every year as a result of disease aﬀecting the nonamblyopic eye, at least 185 people in the UK with unilateral amblyopia have vision loss to a level that is associated with detriment to quality of life. It is possible that the incidence rates are greater than this, with only the minimum estimates of the risk of visual impairment after disease in the non-amblyopic eye being reported. The authors stated that the lifetime risk of serious vision loss for an individual with amblyopia was substantial and in the region of 1.2–3.3%. This was supported by Chua and Mitchell [9], who found that people with

amblyopia had almost three times the risk of visual impairment in their better-seeing eye compared with people without amblyopia. More recently, Van Leeuwen et al. [10] examined the excess risk of bilateral visual impairment among individuals with amblyopia as part of the Rotterdam study (a population-based prospective cohort study of the frequency and determinants of common cardiovascular, locomotor, neurological, and ophthalmological diseases). They found that the estimated lifetime risk of bilateral visual impairment is almost doubled in those who also have a diagnosis of amblyopia. The authors reported that the number of individuals needed to treat to prevent one case of binocular visual impairment is 12.5. When vision loss in the non-amblyopic eye in the presence of amblyopia does occur (through injury or disease), the eﬀect on the individual is often devastating. There have been reported cases of plasticity in the visual system, even in adulthood, whereby improvements in VA in the amblyopic eye have been observed [11]. Another argument for the notion of pre-school vision screening for amblyopia and/or strabismus is the impact of having either condition on quality of life. This will be examined in more detail towards the end of the chapter.

8.2.4 Recent Reports Examining Pre-School Vision Screening The scarcity of evidence that would allow decision makers in the UK NHS to fund screening programs with conﬁdence that it is an eﬃcient use of limited health care resources has made screening for amblyopia problematic. To be cost-eﬀective, a program has to demonstrate that it is ﬁrst clinically eﬀective. Issues of how disinvestment in existing technologies or health care programs is carried out is becoming increasingly important in the UK health care setting, as new evidence-based technologies are mandated by the National Institute for Health and Clinical Excellence (NICE). Decisions concerning which programs can continue to be funded from the health care budgets that are under increasing pressure due to the mandated programs from NICE are being made in local areas. The problems associated with older established programs relate mainly to the reality that often these were implemented many years ago when evidence was limited, or they were never subject to the level of scrutiny that is currently expected for any new technology or program. The recent review of screening for amblyopia is one such area.

8.2

In 2008, the Health Technology Assessment report on pre-school vision screening was updated, examining both the clinical and cost eﬀectiveness of screening programs for amblyopia and strabismus in children up to the ages of 4–5 years [12]. A systematic review of the literature examining the clinical and cost eﬀectiveness of screening children for amblyopia and strabismus before the age of 5 years was undertaken. Cost eﬀectiveness and expected value of perfect information (EVPI) modeling was reported. EVPI modeling is used in cost-eﬀectiveness analysis to attempt to establish the beneﬁts of undertaking research that would reduce the costs of uncertainty. The cost of uncertainty in this case is that the wrong disinvestment decision could be made. Following a review of the literature, a natural history model was constructed which described the incidence and progression of amblyopia up to the age of 7 years. As is customary, a separate model which extrapolated the costs and eﬀects of amblyopia over an individual’s remaining lifetime was also constructed. These models were incorporated into a separate screening model that represented the potential impact of treatment. The expected health outcome for the individual was deﬁned as the expected number of cases remaining in a population of 7-year-olds, that is, those children for whom treatment was either unsuccessful or who had failed to be detected. A post-screening model was constructed to estimate the long-term eﬀects of childhood amblyopia on a cohort of individuals who would have bilateral or unilateral vision loss over a 93-year time horizon. The costs associated with the screening program and the beneﬁts (expressed as utility weights) were applied to both vision loss across the model’s time horizon, which allowed us to give the estimated costs, and to the consequences of amblyopia. The model population was informed by the literature reviews. It was identiﬁed during the data extraction process that there was a signiﬁcant lack of quantitative data available which could be used in the model. This problem was addressed by having a pragmatic approach to estimate the transitions in the model for which amblyogenic factors translated into a number of VA states. A number of experts, who were able to conﬁrm or reject the plausibility of the assumptions that were made, were consulted. It was not possible to use any empirical data which could have informed the eﬀectiveness of treatment for amblyogenic factors. It was assumed that by removing the risk factor for refractive error, the outcome would be 100% eﬀective. Strabismus treatment is acknowledged to be less successful; therefore, the

What Is Screening?

99

outcomes for removing the amblyogenic risk were considered to be between 0 and 30%. Carlton et al. [12] reported that the available evidence did not support the screening program for amblyopia and amblyogenic factors. Economic evaluation showed that screening for amblyopia and strabismus in children could not be considered as a cost-eﬀective use of resources. Analysis of cost eﬀectiveness using the available research data found that screening was not cost-eﬀective at currently accepted quality adjusted life years (QALY) values. (QALYs are used in cost-utility studies, and consider both the duration of health states and their impact on HRQoL [13]). However, the lack of evidence highlighted a need for further research on the impact of amblyopia and amblyogenic factors in the long-term. The lack of evidence surrounding the long-term impact of amblyopia increased the level of uncertainty in the model. By making a number of assumptions on utility loss (i.e. the impact on quality of life), the model demonstrated that screening could become highly cost-eﬀective. EVPI modeling showed that the value of eliminating uncertainty ranges between £17,000 to over £100,000 per QALY. In other words, the impact of amblyopia upon a person’s quality of life (in the short or long term) is still unknown, and guesstimates of such impact lead only to more uncertainty. These ﬁndings may not provide the ideal result for decision makers, as the answers are not clear cut. Cost eﬀectiveness alone should not be the deciding factor in the provision of pre-school vision screening. For example, the issue of equity may also need to be considered. This is particularly relevant in communities where there may be a greater prevalence of amblyopia or strabismus which could not be detected or acted upon by parental observation alone. The ﬁgures reported earlier, linking the cost per QALY, are those which are applied to new technologies. The QALY threshold for disinvestment is undeﬁned at present. The German Institute for Quality and Eﬃciency in Healthcare (IQWIG) is an independent scientiﬁc institute that investigates the beneﬁts and harms of medical interventions. In producing reports on the assessment of an intervention (such as screening), IQWIG adheres to strict inclusion and exclusion criteria in the reviewing of existing literature surrounding the given subject. In 2008, IQWIG assessed the beneﬁts of screening for visual impairment in children up to the age of 6 years [14]. They concluded that “no robust conclusions” could be directly inferred from the studies identiﬁed in their review. To that end, the notion of pre-school vision screening could neither be supported nor rejected.

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Summary for the Clinician ■

8 ■

■

■

■

The purpose of screening is to identify persons as being at greater or lesser risk of developing, or having a particular condition. Screening should be considered in terms of the condition, diagnosis, treatment, and the screening program itself. Vision screening for children may be considered in terms of detection of amblyopia, strabismus, and/or refractive error. Variations exist within and between countries regarding vision screening for children in terms of program content, referral criteria, and personnel. The justiﬁcations of vision screening for children include an increased risk of blindness to the healthy eye as a result of injury or disease in adults with amblyopia. An increased risk of blindness is present, as the non-amblyopic eye of an amblyope may become diseased or injured. Recent reports indicate that further evidence is required to support the notion of pre-school vision screening despite seminal research examining diagnosis, treatment, and consequence of amblyopia, strabismus, and/or refractive error.

8.3 Screening Tests for Amblyopia, Strabismus, and/or Refractive Error The accurate detection of amblyopia, strabismus, and/or refractive error undoubtedly forms a critical factor in the reported success of any pre-school vision screening program. However, much variation exists both within and between countries as to the content of vision screening programs. This includes the age at which the child is screened, referral criteria of the screening program, and indeed, the personnel administering the tests that form the screening program. Owing to such diﬀerences, it is often diﬃcult to make direct comparisons between studies that report on vision screening success. Much has been contributed to the literature over recent years, largely through the work of the Vision in Preschoolers Study (VIP). VIP is a multi-centre study, conducted in the USA, whose purpose is to evaluate whether there are tests, or combinations of tests, that can be used eﬀectively in preschool vision testing. The eﬀectiveness of a screening test in detecting a condition is considered in terms of sensitivity, speciﬁcity, and positive and negative predictive values. Sensitivity is deﬁned as the proportion of individuals with the target

condition in a population who are correctly identiﬁed by a screening test. Speciﬁcity is the proportion of individuals free of the target condition in a population who are correctly identiﬁed by a screening test. Positive predictive values describe the proportion of individuals with a positive result who have a target condition; and negative predictive value is the proportion of individuals who test negative and who do not have a target condition.

8.3.1 Vision Tests The use of crowded logMAR acuity is the gold-standard VA measure in adults both within clinical and research settings. This is also becoming the case with VA measurement in children. Steps have been made to identify normative values of pediatric VA using diﬀerent vision tests, protocols of testing, and repeatability of testing [15–19]. The preference as to which vision test that is to be included in a screening program is not always clear. Often a number of vision tests may be included within the one screening program to incorporate factors such as a child’s comprehension and ability to perform a test. It is outside the scope of this chapter to report upon the relative sensitivity and speciﬁcity of each vision test. However, it should be noted that the cut-oﬀ points used for referral within a screening program should be directly related to the speciﬁc vision tests used within that screening program. In other words, it should not be generic, with an arbitrary referral point (such as 0.2 logMAR or worse). A VA level that is achieved using one vision test may be diﬀerent from that achieved using an alternative vision test. The referral criteria should be stipulated for each vision test that could be used within the screening program.

8.3.2

Cover-Uncover Test

The cover-uncover test is used to detect the presence of strabismus, and is deemed to be the gold standard for detecting strabismus. However, there are few studies that report on the sensitivity and speciﬁcity of the test itself. Williams et al. [20] were able to report on the sensitivity and speciﬁcity of the cover-uncover test on children who had been screened at the ages of 8, 12, 18, 25, 31 and 37 months. At 37 months, the sensitivity of the test was calculated to be 75% (95% CI, 0.577–0.899%), with a speciﬁcity of 100%. The VIP study also assessed the eﬀectiveness of the cover-uncover test in detecting strabismus, amblyopia, reduced VA, and refractive error [21]. The results are

8.3

101

Screening Tests for Amblyopia, Strabismus, and/or Refractive Error

Table 8.2. Sensitivity of cover-uncover test when speciﬁcity was set to 0.94 [21] Test

Amblyopia n = 75 (95% CI)

Strabismus n = 48 (95% CI)

Refractive error n = 240 (95% CI)

Reduced VA n = 132 (95% CI)

Cover-uncover

0.27 (0.17–0.37)

0.60 (0.46–0.74)

0.16 (0.11–0.21)

0.06 (0.02–0.10)

n = number of children

summarized in Table 8.2. The results of this study indicated that the cover-uncover test is more sensitive at detecting the presence of strabismus compared with detecting the presence of amblyopia, refractive error, or reduced VA.

8.3.3 Stereoacuity The inclusion of stereoacuity tests within pre-school vision screening programs could be considered as a contentious issue. VIP [22] stated that most guidelines recommend a test of stereopsis. However, if a child was found to have normal VA, no strabismus, and no clinically signiﬁcant refractive error, yet failed to demonstrate adequate evidence of stereoacuity, should they be referred for further investigation? A number of stereotests are available for use as part of a pre-school vision screening program; however, normative pediatric values of stereopsis have not been identiﬁed for some of these tests. In the absence of such data, the appropriateness of inclusion of such tests could be questioned. Stereotests that involve a pass/fail response could be deemed as more appropriate for the purpose of screening for vision problems.

The VIP has reported on the testability of two diﬀerent stereotests used to screen for vision disorders, the Random Dot E and the Stereo Smile test [21, 23]. The results reported by condition type are summarized in Table 8.3. The results indicated that both the stereotests are more accurate at detecting the presence of amblyopia and strabismus compared with that for reduced VA or refractive error. In a further study, VIP examined the sensitivity of the same stereotests when the speciﬁcity was set at 0.94. The results are summarized in Table 8.4, and show that the Stereo Smile test was more accurate than the Random Dot E in detecting most target conditions of screening.

8.3.4

Photoscreening and/or Autorefraction

The use of photoscreeners and/or autorefractors in pre-school vision screening is extremely varied. Within the USA, they are commonplace, and the variety of different makes and models make summarizing literature extremely diﬃcult. The use of such instruments within

Table 8.3. Sensitivity of Random Dot E and stereo smile by condition typea [23] Stereotest

Amblyopia

Reduced VA

Strabismus

Refractive error

Year 1 n = 796

n = 75

n = 132

n = 48

n = 240

Random Dot E

0.63

0.38

0.60

0.47

Year 2 n = 1037

n = 88

n = 114

n = 62

n = 299

0.77

0.30

0.68

0.51

Stereo smile

Speciﬁcity

0.90 0.91

a

n = number of children; may have more than one condition

Table 8.4. Sensitivity of Random Dot E and stereo smile when speciﬁcity was set to 0.94a [21]

a

Test

Amblyopia (95% CI)

Strabismus (95% CI)

Refractive error (95% CI)

Reduced VA (95% CI)

Random Dot E

0.28 (0.18–0.38)

0.29 (0.16–0.42)

0.23 (0.18–0.23)

0.24 (0.17–0.31)

Stereo smile

0.61 (0.51–0.71)

0.58 (0.46–0.70)

0.37 (0.32–0.42)

0.20 (0.13–0.27)

May have more than one condition

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UK pre-school vision screening programs is much less frequent. When considering the appropriateness of photoscreeners and/or autorefractors in pre-school vision screening, it is important to recognize their accuracy when compared with a gold standard (usually a refraction performed under full cycloplegia). There are notable advantages and disadvantages of photoscreening when compared with autorefraction. One of the main diﬀerences is that of cost. After the initial expense of purchase, there is minimal additional cost to autorefraction. Photoscreening, however, requires printing of the image, and depending upon who is administering the test, interpretation of the results. The implications of both these factors lead to a higher overall expense when incorporated into a vision screening program. It should also be noted that the primary aim of the use of a photoscreener or autorefractor is the detection of refractive error. That is, it may detect an amblyogenic factor, but not amblyopia itself. Similarly, the presence of strabismus may also be detected, although understandably, the sensitivity and speciﬁcity rates of these are considerably lower than those of detecting refractive error. It is beyond the scope of this chapter to review and appraise literature describing speciﬁc photorefractors and/or autorefractors. Important points to note when considering such articles include the study population (including age, ethnicity, and whether general or clinical); test setting (e.g. environment); sensitivity and speciﬁcity of the test; the personnel conducting the test; and whether any comparison is made to the gold standard (in this case, full refraction under cycloplegia).

8.3.5 What to Do with Those Who Are Unable to Perform Screening Tests? Successful testing of children is largely dependent on the child’s cooperation and compliance. The decision about whether to refer those children who are unable to perform screening tests is diﬃcult. Some would argue that such children ought to be referred for further investigation, for the reason that they are unable to perform the screening tests due to the presence of an ocular condition. Others would say that this may not be the case, and that cooperation may be the true issue. The prevalence of ocular conditions amongst children who were unable to perform pre-school screening tests has been investigated and it was found that pre-school children who were unable to perform the screening test were at a higher risk of higher amblyopia, strabismus, signiﬁcant refractive error, or unexplained low VA compared with those who had passed the screening test [24]. This led the authors to

recommend that these children ought to be referred or retested at a later date possibly with a diﬀerent test. The impact of recall and re-testing, or automatic referral will undoubtedly aﬀect the overall clinical and cost eﬀectiveness of any pre-school vision program.

8.3.6 Who Should Administer the Screening Program? Within the UK, it is recommended that pre-school vision screening programs be conducted by orthoptists or by professionals trained and supported by orthoptists [3, 4]. In the USA, pre-school vision screening is usually conducted by nurses and lay people. The use of lay people to administer screening tests does have advantages, particularly when considering the economic burden of a screening program. Lay screeners are a cheaper alternative to eye care professionals, such as orthoptists, optometrists, or ophthalmologists. Concerns regarding training and assessment of lay screeners have been raised; are lay screeners as accurate as eye care professionals in detecting amblyopia, strabismus, and/or refractive error? This question was addressed by VIP, who assessed the performance of lay screeners in administering pre-school vision screening tests compared to nurse screeners [25]. In this study, the screening tests conducted included assessment of refractive error, VA, and stereoacuity. Two hand-held autorefractors were used to detect the presence of refractive error. VA was assessed at two diﬀerent testing distances; a linear test was performed at 10 feet, and a single, crowded test administered at 5 feet. The results of the study demonstrated that although nurse screeners appeared to have slightly higher sensitivities in the assessment of refractive error and presence of stereoacuity compared with lay screeners, the differences were not statistically signiﬁcant. However, when examining the results of VA testing, the authors reported that nurse screeners achieved signiﬁcantly higher sensitivity than lay screeners with the linear VA test. Whilst the authors made no recommendations for future screening protocol strategies, their results could be interpreted in two ways. The lack of statistically signiﬁcant diﬀerences in detection of refractive error or stereoacuity with tests administered by lay screeners could support the use of such personnel in vision screening programs. However, the diﬀerences observed in VA testing between lay screeners and nurse screeners could suggest that nurse screeners would be more eﬀective in detecting vision anomalies. Diﬀerences in screening programs between countries will undoubtedly continue to exist; however, recommendations as to

8.4

who should conduct screening based upon personnel costs alone may not be appropriate.

Summary for the Clinician ■

■

■ ■

Content of vision screening programs vary widely. Most involve assessment of VA for which a large number of tests are available. The gold standard is a crowded logMAR-based test. Referral criteria should be speciﬁc for the test used. The use of photoscreeners and/or autorefractors in vision screening programs is not universal. The use of photoscreeners and/or autorefractors will have an impact upon the cost eﬀectiveness of screening. The inclusion of stereotests in pre-school vision screening programs could be questioned. Recommendations state that pre-school vision screening programs be conducted by orthoptists or by professionals trained and supported by orthoptists.

8.4 Treatment of Amblyopia The clinical management of amblyopia is determined following careful consideration on a case-per-case basis, taking into account a number of factors including the type of amblyopia present, the patient’s age, and the level of VA in the amblyopic eye. Nonetheless, advances in evidence-based medicine have led to a number of recognized studies that have reinforced or altered clinical practice in the management of this condition. The Pediatric Eye Disease Investigator Group (PEDIG), based in the USA, is a multi-centre group dedicated to clinical research in strabismus, amblyopia and other eye disorders aﬀecting children. Funded by the National Eye Institute (NEI), this group has investigated many aspects of the clinical course of amblyopia and its treatment. The Monitored Occlusion Treatment of Amblyopia Study Cooperative (MOTAS Cooperative) is a multidisciplinary group of ophthalmologists, orthoptists, basic scientists, and statisticians dedicated to investigating amblyopia treatment. Based in London (UK), it is funded by the charities Guide Dogs for the Blind Association, and Fight for Sight. They have conducted two clinical trials to identify the response of amblyopia to occlusion therapy. Data from both the studies conducted by PEDIG and the MOTAS Cooperative have contributed to our understanding of the management of amblyopia.

Treatment of Amblyopia

103

8.4.1 Type of Treatment Amblyopia is treated by obscuring the image from the good eye to promote the use of the amblyopic eye. This can be achieved through occlusion treatment (patching or pharmacological occlusion, in the form of atropine), or through optical penalization. There are notable advantages and disadvantages to diﬀerent treatment modalities in terms of compliance, ease of administration, and VA outcome. Comparison of studies investigating the eﬀectiveness of treatment of amblyopia is hindered, due to differing deﬁnitions of both “amblyopia” and “treatment success”. In addition, clinicians have long recognized that the amount of treatment prescribed and the amount of treatment actually undertaken may diﬀer. Objective measurement of the amount of occlusion worn has been made possible with the introduction of occlusion dose monitors (ODM). ODMs were developed and validated by the Monitored Occlusion Treatment for Amblyopia Study (MOTAS) Cooperative (UK), and since then, have been used to examine whether there is a dose response to occlusion therapy.

8.4.2

Refractive Adaptation

One of the main concepts that have arisen over the recent years in amblyopia treatment is that of refractive adaptation (or “optical treatment of amblyopia” as it is sometimes known [26]. There has been increasing evidence to suggest that the treatment of amblyopia in the presence of refractive error should incorporate observation of VA following the prescription of glasses alone [26–29]. These studies report increases in VA in subjects such that some did not require any additional treatment for their amblyopia. Prior to such studies, it was uncertain whether observed improvements in VA achieved were the result of amblyopia therapy (i.e. occlusion) or due to glasses-wear alone. It is becoming increasingly clear that refractive adaptation is a recognized period in amblyopia therapy. The time taken to reach this period, however, remains under debate. The MOTAS studies utilized a period of 18-week observation [27–29]; however, the PEDIG reported that 83% of their study group demonstrated stability of improvement in VA before 15 weeks, but one patient improved in 30 weeks [26]. Improvements in VA have been described to occur after 20 weeks, but not considerably, with the majority of improvement having occurred in weeks 4–12 [30]. One of the arguments supporting the notion of vision screening is the detection of bilateral refractive error.

104

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8 The Value of Screening for Amblyopia Revisited

Wallace et al. [31], as part of the PEDIG study, examined the improvements in VA in children with bilateral refractive amblyopia aged between 3 and 10 years. They reported that correction of refractive error improved VA, with only 12% of the cohort requiring additional amblyopia therapy in the form of occlusion or atropine.

8.4.3 Conventional Occlusion Patching treatment is often initiated as the ﬁrst-line approach in amblyopia therapy. One advantage of patching treatment is that the eﬀects are reversible; that is, once the patch is removed, the non-amblyopic eye is favored, which is not the case with pharmacological occlusion. Since the acknowledgement of refractive adaptation, it has been necessary to conﬁrm that occlusion therapy is also eﬀective in the management of amblyopia. PEDIG compared the eﬀect of daily patching vs. a control group of amblyopes in children aged 3–7 years, following a period of refractive adaptation. An improvement in VA was observed in both the groups after 5 weeks, and as expected, a greater improvement was reported in the patched group [32]. The MOTAS Cooperative investigated the amount of occlusion required to improve VA and explored the doseresponse relationship in amblyopia therapy [28]. They found that most children required between 150 and 250 h of occlusion, irrespective of the type of amblyopia present. Speciﬁc characteristics were observed to aﬀect the response, such as the age of the patient; where older children required a greater amount of occlusion to achieve similar gains in VA compared with their younger counterparts. Younger children have been observed to respond more quickly and with less occlusion than older children; however, the ﬁnal level of VA achieved has been similar for all ages [29]. Traditionally, clinicians have recommended near-visual activities whilst occlusion therapy is undertaken; however, there has been little research to justify such advice. The PEDIG investigated whether performing such activities inﬂuenced the improvement in VA outcome when treating amblyopia in conjunction with occlusion therapy [33]. No statistical evidence to support the notion that near visual activities improved VA outcome in their study group was found. It should be noted that the study group were prescribed only 2 h of patching per day, and that the authors made no inference as to whether the results would be similar in subjects patched for a greater or lesser time.

8.4.4 Pharmacological Occlusion Pharmacological occlusion (i.e. atropine) has notable beneﬁts; it could be argued that it carries with it less of a social stigma compared with the wearing of an eye patch.

One disadvantage of pharmacological occlusion is that the eﬀects are not readily reversible; it can take several weeks for the eﬀects of atropine to wear oﬀ. Concerns also exist regarding its eﬃcacy as a treatment modality, with some clinicians believing it to be a less eﬀective treatment when compared with conventional occlusion. Studies conducted by PEDIG examined the eﬀectiveness of conventional occlusion vs. pharmacological occlusion in the treatment of moderate amblyopia (20/40–20/80) [34] and severe amblyopia (20/100–20/400) [35]. Either treatment modality was found to be appropriate with similar improvements in VA in either group. The decision towards which therapy should be adopted may now be based on other factors. One such factor may be the instillation of the atropine itself. The eﬀect of diﬀerent atropine regimens in the treatment of moderate amblyopia (20/40– 20/80) was investigated. Comparisons were made between the observed eﬀects of daily atropine instillation and those of weekend-only atropine instillation [36]. Both groups were observed to show improvements in VA of similar magnitudes. It could be argued that the need for daily atropine instillation is redundant, thereby improving the therapeutic experience for the child. This in itself may encourage parents and/or clinicians to adopt this treatment modality.

8.4.5

Optical Penalization

Another treatment option in the management of amblyopia is that of optical penalization. This is where lenses are used to induce a defocused image of the non-amblyopic eye. Tejedor and Ogallar [37] directly compared the eﬀects of atropine vs. optical penalization in the treatment of mild to moderate amblyopia (VA of at least 20/60). This small study found greater improvements in VA in the atropine group after 6 months of therapy, which may be attributed to the child peeking over or around the glasses and thereby not achieving the desired eﬀect of optical penalization. Although optical penalization remains a useful treatment option in speciﬁc clinical situations, it is often not considered as an appropriate ﬁrstline choice of therapy in the management of amblyopia.

8.4.6

Eﬀective Treatment of Amblyopia in Older Children (Over the Age of 7 Years)

There has been strong evidence that treatment for amblyopia is more eﬀective prior to the age of 7 years. Despite this, amblyopia therapy has been reported to be successful in older children with either anisometropic [38–42] and/or strabismic amblyopia [40–42]. Treatment

8.4

of strabismic amblyopia in the older child should be pursued with caution, as there is a notable risk of reducing the density of suppression, and thereby inducing intractable diplopia in these patients. A number of studies that reported on improvements in VA in older children with strabismic or mixed etiology amblyopia following treatment have not reported on whether the density of suppression had been measured, or if any other side-eﬀects had been observed [40–42]. Despite some evidence to suggest that successful treatment of amblyopia in the older child is possible, earlier intervention is more advantageous, and to that end supports the notion of pre-school vision screening.

8.4.7 Treatment Compliance The successful management of amblyopia is intrinsically linked to treatment compliance and adherence to therapy. This in itself is multi-factorial in nature. The development and application of ODMs has meant that reasons for non-compliance can be more thoroughly investigated. In particular, ODMs have highlighted the discrepancy between the amount of occlusion prescribed and the amount administered. Clinicians have long recognized that the amount of occlusion carried out often falls short of their recommended treatment plan. Stewart et al. [29] reported on the eﬀect of 6 h a day occlusion compared with 12 h a day occlusion in the treatment of strabismic and/or anisometropia amblyopia. They found that the amount of occlusion received was 66 and 50% of their prescribed 6 and 12 h a day, respectively. Such information ought to be taken into account when prescribing occlusion therapy. Loudon et al. [43] examined some of the limiting factors of occlusion therapy for amblyopia and reported that parental ﬂuency in the national language and level of education were both predictors of low compliance. Parental understanding of the condition and treatment has also been reported as being an important factor in the successful management of amblyopia. Adherence to treatment must be considered not only in terms of the child complying with therapy, but in the parent/guardian administering the treatment as advocated by the ophthalmologist and/or orthoptist. Searle et al. [44] found two variables that were signiﬁcant predictors of compliance with occlusion therapy. They reported that self-eﬃcacy (the belief in the ability to patch their child) was positively associated with treatment compliance. The parental belief that occlusion therapy inhibits the child’s activities was negatively associated with treatment compliance.

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8.4.8 Other Treatment Options for Amblyopia The use of photorefractive keratectomy (PRK) for the treatment of anisometropia in children has not been fully investigated and concerns exist surrounding the longterm response to refractive surgery in terms of VA and corneal status. However, it could be postulated that if the amblyopic risk factor of high anisometropia is removed early, then the possibility of development of dense amblyopia would be reduced. Paysse et al. [45] reported the results of a small study of children with high anisometropia, and found improvements in both VA and stereopsis following treatment. However, compliance with amblyopia therapy remained unaﬀected in this study group following treatment. The use of refractive surgery in children is not commonplace and there remains a need for a large randomized clinical trial to fully investigate the possible beneﬁts of this form of treatment.

8.4.9 Recurrence of Amblyopia Following Therapy Recurrence of amblyopia has been observed in patients following the cessation of treatment, with rates varying widely. Some recent studies have sought to identify factors that may inﬂuence whether recurrence is likely to occur [46–49]. These include age of termination of treatment, VA at the time of cessation of treatment, and the type of amblyopia present. Recurrence in amblyopia was noted in 7–27%, with a low reported recurrence in children who underwent treatment after the age of 7 years [49]. Age of the child at the cessation of treatment does appear to be a factor, with recurrence inversely correlated with patient age [46].

Summary for the Clinician ■

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Treatment of amblyopia associated with refractive error should incorporate a period of observation with glasses-wear alone to allow for “refractive adaptation” or “optical treatment of amblyopia”. Improvements in VA can occur up to and beyond 20 weeks after glasses are prescribed, but most improvement occurs in weeks 4–12. In some cases, further amblyopia therapy may not be required. There is evidence to suggest that children who undergo amblyopia therapy at an early age respond more quickly to occlusion than older children, and require less occlusion in total.

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Pharmacological occlusion, in the form of atropine, has been found to be as eﬀective as conventional occlusion (patching) in the treatment of both moderate and severe amblyopia. Weekendonly atropine instillation has been shown to produce similar improvements in VA as daily atropine instillation in the treatment of moderate amblyopia. There is evidence to suggest that successful treatment of children aged over 7 years can be achieved in cases of anisometropic, strabismic, and mixed etiology amblyopia. The development of ODM has informed not only the occlusion-dose response of amblyopia treatment, but also reasons for poor treatment compliance. Parental understanding of the condition and belief in therapy may inﬂuence treatment outcome. Recurrence of amblyopia may occur following treatment, with reported rates of 7–27%. Factors inﬂuencing recurrence include age of the child at cessation of treatment, VA at the time of cessation of treatment, and the type of amblyopia present.

8.5.2 Stereoacuity and Motor Skills in Children with Amblyopia Stereoacuity and motor skills have been reported to be impaired in children with amblyopia. Webber et al. [50] investigated the functional impact of amblyopia in children by assessing the ﬁne motor skills of those with amblyopia compared with age-matched control subjects. It was noted that the subjects with amblyopia performed signiﬁcantly worse in most of the ﬁne motor skills tests conducted as part of the study, particularly in the tasks related to time. The results were even more noticeable in those children with a diagnosis of amblyopia and strabismus. Hrisos et al. [51] investigated the inﬂuence of VA and stereoacuity on the performance of pre-school children undertaking tasks that required visuomotor skills and visuospatial ability. The authors reported that reduced monocular VA itself did not relate to any ability of task performance, but stereoacuity was found to aﬀect task performance, with subjects with reduced steroacuity noted to have poorer responses to neurodevelopment tasks. Such studies support the notion that amblyopia is associated with negative implications to HRQoL.

8.5.3 Reading Speed and Reading Ability in Children with Amblyopia

8.5

Quality of Life

When considering the application of any screening program, thought should be made regarding the impact of testing for the target condition, the impact that the target condition has upon a person, and the impact that subsequent treatment of that target condition may have upon a person. One of the ways in which the health impact of a disease or condition can be assessed is through measures of quality of life, or HRQoL. Over recent years, there has been a growing body of evidence which has examined the impact of amblyopia and/or strabismus upon a person’s physical and emotional well-being.

Reading speed and reading ability has been assessed in children with amblyopia. Stifter et al. [52] reported that maximum reading speed was signiﬁcantly reduced in those with the condition. Therefore, they could be deemed to have a functional reading impairment when compared with normal-sighted controls. It is recognized that reading ability is multi-factorial in nature, and is inﬂuenced by comprehension. The study does not imply that children with unilateral amblyopia are poor readers under binocular conditions, for the binocular VA and reading acuity of the two groups were comparable.

8.5.4 Impact of Amblyopia Upon Education 8.5.1 The Impact of Amblyopia Upon HRQoL There have been a number of studies that have investigated the impact of amblyopia upon HRQoL. These have examined the eﬀect of amblyopia upon stereoacuity and motor skills [50, 51], reading speed ability [52], educational attainment [9], and emotional well-being [44, 53–58].

Chua and Mitchell [9], as part of the Blue Mountains Eye Study in Australia (a population-based survey of people aged 49 years or older), examined the consequences of amblyopia on education, occupation, and long-term vision loss. In their study population, the presence of amblyopia was not found to be signiﬁcantly associated with lifetime occupational class. However, fewer people with amblyopia were found to have completed higher university degrees. This ﬁnding was supported by Rahi

8.5

et al. [59], who reported on ﬁndings of the 1958 British birth cohort with respect to any association of amblyopia with diverse educational, health, and social outcomes. The authors could ﬁnd no statistical evidence between the presence of amblyopia and educational attainment or paid employment.

8.5.5

Emotional Well-Being and Amblyopia

The psychosocial impact of amblyopia and its treatment has been explored from both the parental and child perspective [56]. Children have reported feelings of shame and negativity associated with amblyopia, particularly following the start of treatment. The initiation of therapy can draw adverse attention from others, and children have reported that they felt interrogated by others about their treatment (particularly if their treatment involved the wearing of glasses and a patch). It is important to recognize that the impact of amblyopia therapy may be experienced not only by the child, but also by family members [54]. This could result in impaired relationships between the child and parent/ guardian, but also between siblings. Parents often state that their child may be more clingy or demanding when occlusion is worn; that the child’s compliance with occlusion can lead to negative behavioral changes or that their child appears to be less conﬁdent when wearing their patch or glasses [56]. The issue of peer victimization and bullying associated with amblyopia has been recognized [55, 56, 58]. This may be in response to the wearing of glasses and/or occlusion therapy. Horwood et al. [58], as part of the Avon Longitudinal Study of Parents and Children (ALSPAC) conducted in the UK, investigated whether wearing glasses, having manifest strabismus, or having a history of wearing an eye patch pre-disposed pre-adolescent children to being victimized more frequently at school. In this study, the outcome measure used to assess whether bullying had occurred was through a structured face-toface interview, conducted with the child at the age of 8.5 years. Children were asked if they had experienced or used any forms of overt or relational bullying. The authors reported that those children who wore glasses or had a history of wearing an eye patch were 35–37% more likely to be victims of physical or verbal bullying (after adjustment for social class and maternal education). Williams et al. [55] argued the case for pre-school vision screening in that those who had undertaken screening were likely to have concluded amblyopia therapy early (i.e. before school starts), and thus would avoid

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adverse reactions from their peers. They compared two groups that had been oﬀered pre-school vision screening at the age of 3 years with those who had not; and asked the children at age 8 years whether they had been bullied through a standard structured interview. The authors reported an almost 50% reduction in children who reported having been bullied in the group that had been oﬀered pre-school screening, compared with the group who had not. Not all children undertaking amblyopia therapy ﬁnd the treatment a negative experience. Indeed, in a study by Choong et al. [53], the authors found no signiﬁcant changes in parental (carer’s) stress or the child’s psychosocial well-being between an occluded and non-occluded group. One factor that did result in changes in parental attitude towards the child was the issuing of glasses. A statistically signiﬁcant diﬀerence was found, where carers felt more negative towards their child once glasses were prescribed. As glasses form an integral part of amblyopia therapy, it could be deemed that the results do in fact demonstrate psychosocial implications of amblyopia treatment, particularly from the carer’s perspective. Conﬂicting evidence exists in the adult population. Rahi et al. [59] reported that adults with amblyopia were no more likely to be bullied (either at the age of 7 or 11 years), and could ﬁnd no evidence for an association between the presence of amblyopia and participation in social activities in either childhood or adult life. The authors also stated that those with amblyopia were no more likely to report depression or psychological distress in adult life. This ﬁnding was not supported by Packwood et al. [57], who explored the psychosocial implications of growing up and living with amblyopia in a group of adult subjects. The authors reported that those with amblyopia experienced more distress in several areas of psychological well-being, including somatization, obsession-compulsion, interpersonal sensitivity, anxiety, and depression. Taken in isolation, the impact of any one of the aforementioned problems may be minimally associated with detriment to HRQoL. However, the cumulative eﬀect of impaired reading, motor skills, and psychosocial impact of amblyopia, for example, might inﬂuence HRQoL to a greater degree.

8.5.6 The Impact of Strabismus Upon HRQoL The psychosocial implications of strabismus are more accepted and recognized, particularly in cases of cosmetically obvious strabismus. Detrimental implications of strabismus include a negative self-image, reduced

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self-conﬁdence, low self-esteem, and poor interpersonal relationships [60]. The presence of a cosmetically noticeable strabismus has also been reported to impact upon a person’s ability to gain employment [61, 62], and in a person’s ability to attract a partner [63]. Furthermore, the presence of strabismus does not only aﬀect those in adulthood. Uretman et al. [64] determined that children with strabismus were perceived in a negative light by adults. The age at which the emergence of negative attitudes towards those with strabismus develops has been studied. Paysse et al. [65] reported that at approximately 6 years of age, children begin to express a negative attitude towards strabismus. In adults, it has been documented that those with strabismus experience more social anxiety and use social avoidance strategies compared with the general population [66, 67]. It could be argued, therefore, that surgical correction of strabismus serves to provide psychosocial beneﬁts, and thus improves HRQoL. Improvements in quality of life following strabismus surgery are well documented in adults [66–69]; however, its eﬀect on children is not as extensively researched. Archer et al. [70] reported on a group of 98 children who underwent strabismus surgery (although it is unclear whether the purpose of surgery was purely cosmetic or functional in nature). The authors stated that following surgery, there were signiﬁcant improvements in a number of quality of life dimensions, including those of anxiety, social relations, and developmental satisfaction (parental response). The results concur with those found in an adult population, and it can therefore be deemed that the psychosocial beneﬁts reported in adults following strabismus surgery are also applicable to children.

8.5.7

Critique of HRQoL Issues in Amblyopia

Methods of determining the impact of amblyopia and/or strabismus upon HRQoL diﬀer greatly from one study to another. Some report changes in psychosocial behavior and well-being using a purpose-designed questionnaire [60, 62, 63, 67, 71]. Whilst their ﬁndings are of great clinical importance, it can be diﬃcult to compare one study with another due to diﬀerences in methodologies. One key component that must be considered when addressing the issue of HRQoL and amblyopia and/or strabismus is that of the perspective from which the results are taken. That is, are the results taken from responses from the parent, the child, or from an adult with a history of amblyopia and/or strabismus? The

ﬁndings of each study are equally valid; however, it must be recognized that there may be levels of bias exerted depending upon which methodology is applied. For example, studies that report from the parental perspective [53, 54, 56, 70] may in fact be capturing parental opinion regarding the condition and/or its treatment, rather than a true measure of HRQoL changes. Studies that involve adults with a history of amblyopia and/or strabismus [57] are asking subjects to recall childhood experiences. It is possible that adult experiences have since “tainted” the recall of such events, either exaggerating or diminishing the true changes in HRQoL experienced as a child. Perhaps, studies that report from the child perspective [55, 56, 58] could be considered the most valid. They deliver insight into what is experienced at the time. However, they are not without their weaknesses. What they fail to do is inform as to whether the impact of amblyopia and/or strabismus (as a condition, or its treatment) is appreciated in the longer term, that is, into adulthood.

8.5.8 The Impact of the Condition or the Impact of Treatment? It can be diﬃcult to fully distinguish whether any reported detriment to HRQoL in amblyopia is due to the condition itself or its treatment. This is not a factor when considering strabismus. Strabismus (particularly that of large angle strabismus) is cosmetically noticeable and it is the impact that that has upon the person which can aﬀect HRQoL. Therefore, it can be said that any study that reports on HRQoL and strabismus is reporting on the eﬀect that the condition has upon a person’s well-being. With amblyopia, this is not the case. The condition itself cannot be identiﬁed by peers. What is noted is the eﬀect of treatment upon HRQoL, with the instigation of glasses or occlusion therapy. Studies that report on changes in HRQoL in amblyopia, frequently report on the impact of the treatment upon quality of life rather than the condition itself [44, 53–55, 55–57]. Alternative studies do report on the impact of amblyopia; however, the measures of these studies are of adult-related issues (such as employment, educational attainment, and risk of losing vision in the nonamblyopic eye) [9, 59]. It is not possible to determine whether the same HRQoL changes that occur in childhood are appreciated in adulthood, because the measures used in the identiﬁed studies are so diﬀerent. Nonetheless, it can be concluded that there is evidence to suggest that there are HRQoL issues related to amblyopia and/or strabismus and its treatment.

References

Summary for the Clinician ■

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There have been a number of studies investigating HRQoL implications of amblyopia and/or strabismus over recent years. These have involved studies with children who have the condition, or adults who had previously undergone treatment. Studies have reported amblyopia to impact upon stereoacuity, ﬁne motor skills, and reading speed. The presence of amblyopia does not appear to have any impact on educational attainment or paid employment in adult life. Amblyopia (more speciﬁcally amblyopia treatment) has been shown to impact negatively upon a child’s emotional well-being; and may also aﬀect relationships between the child and parent/guardian. The issue of bullying and amblyopia treatment requires further investigation. Some studies reported that children who had glasses or had a history of occlusion therapy were more likely to be victims of bullying. However, other studies refuted this. Taken in isolation, the impact of any one of the aforementioned problems may be minimally associated with detriment to HRQoL. However, the cumulative eﬀect of impaired reading, motor skills, and psychosocial impact of amblyopia, for example, might inﬂuence HRQoL to a greater degree. The reported HRQoL implications of strabismus are related to physical appearance and the impact of strabismus upon self-image and interpersonal relationships. Surgical correction of strabismus has been reported to improve HRQoL.

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6. Ciner E, Dobson V, Schmidt P, Allen D, Cyert L, Maguire M, et al (1999) A survey of vision screening policy of preschool children in the United States. Surv Ophthalmol 43(5):445–457 7. Brown MM, Grown GC, Sharma S, Busbee B, Brown H (2001) Quality of life associated with unilateral and bilateral good vision. Ophthalmology 108:643–648 8. Rahi JS, Logan S, Timms C, Russell-Eggitt I, Taylor D (2002) Risk, causes, and outcomes of visual impairment after loss of vision in the non-amblyopic eye: a populationbased study. Lancet 360:597–602 9. Chua B, Mitchell P (2004) Consequences of amblyopia on education, occupation, and long term vision loss. Br J Ophthalmol 88:1119–1121 10. Van Leeuwen RE (2007) Risk of bilateral visual impairment in individuals with amblyopia: the rotterdam study. Br J Ophthalmol 91(11):1450–1451 11. Rahi JS, Logan S, Borja MC, Timms C, Russell-Eggitt I, Taylor D (2002) Prediction of improved vision in the amblyopic eye after visual loss in the non-amblyopic eye. Lancet 360:621–622 12. Carlton J, Karnon J, Czoski-Murray C, Smith KJ, Marr J (2008) The clinical eﬀectiveness and cost-eﬀectiveness of screening programmes for amblyopia and strabismus in children up to the age of 4–5 years: a systematic review and economic evaluation. Health Technol Assess 12(25):iii-194 13. Gold M, Siegel J, Russell L, Weinstein M (1996) Costeﬀectiveness in health and medicine. Oxford University, New York 14. IQWiG (2008) Screening for visual impairment in children: executive summary (translation of the executive summary of the ﬁnal report). IQWiG Reports – Commission No S05–02 15. Drover JR, Felius J, Cheng CS, Morale SE, Wyatt L, Birch EE (2008) Normative pediatric visual acuity using single surrounded HOTV optotypes on the electronic visual acuity tester following the amblyopia treatment study protocol. J AAPOS 12(2):145–149 16. Sonksen PMW (2008) The Sonksen logMAR test of visual acuity: II. Age norms from 2 years 9 months to 8 years. J AAPOS 12(1):18–22 17. Shea SJ, Gaccon L (2006) In the absence of strabismus what constitutes a visual deﬁcit in children? Br J Ophthalmol 90(1):40–43 18. Birch EE, Strauber SF, Beck RW, Holmes JM, Pediatric eye disease investigator group (2008) Comparison of the amblyopia treatment study HOTV and the electronic-early treatment of diabetic retinopathy study visual acuity protocols in amblyopic children aged 5 to 11 years. J AAPOS 13(1):75–78 19. Chen SI, Chandna A, Norcia AM, Pettet M, Stone D (2006) The repeatability of best corrected acuity in normal and

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Chapter 9

The Brückner Test Revisited

9

Michael Gräf

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The Brückner test is useful to detect various amblyogenic disorders. After a short training, every physician can perform the test. The test as originally described consists of four elements to observe: (1) the position of the ﬁrst Purkinje images (corneal light reﬂexes), (2) the fundus red reﬂex in the pupil, (3) pupillary light reﬂexes, and (4) any movement of the eyes when illumination alters from one eye to the other. Asymmetry in corneal light reﬂexes on both eyes may indicate strabismus. However, small deviations are not reliably detected, and asymmetry can also be caused by diﬀerent angle kappa in both eyes. Performance of the red reﬂex test requires a direct ophthalmoscope. Substitution by an otoscope, indirect ophthalmoscope, or any other light source causes loss of test validity. The red reﬂex test allows for detection of refractive error, strabismus and organic disorders such as opacities of the optic media and distinct pathologies of the fundus. Media opacity is easily detected at a test distance of 0.3 m and less, examining each eye separately.

9.1 Amblyopia and Amblyogenic Disorders Amblyopia is estimated to aﬀect approximately 2–5% of the population in Western countries and is a signiﬁcant preventable cause of vision loss in children and adults [1–8]. Amblyogenic risk factors include ptosis, media opacity, fundus pathologies, strabismus and refractive error [9–11]. When these risk factors are detected at an early age, amblyopia can be prevented or minimized more eﬀectively [3, 12–14]. One signiﬁcant limiting factor of most amblyopia screening programs is the reliance on the subjective responses of the child being tested.

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■ ■

■

Any optically relevant opacity will be apparent by a shadow in the red reﬂex. Detection of refractive error can be improved by extending the test distance up to 4 m and observing the brightness of the red reﬂex in both eyes simultaneously. While usually at a distance of 1 m, the red reﬂex is brighter in the more ametropic eye, the reﬂex in this eye becomes increasingly darker with increasing test distance. With increasing test distance, myopia and hypermetropia, which are not compensated by accommodation, cause signiﬁcant dimming, and anisometropia causes increasing asymmetry. The test sensitivity to detect microstrabismus by asymmetric fundus red reﬂex is low. Testing pupillary light reﬂexes is recommendable to assess visual aﬀerence, pupillomotor eﬀerence and pupil responsiveness. It is hardly suitable to diagnose or exclude amblyopia and amblyogenic disorders. Testing for ﬁxation movements caused by switching illumination from one eye to the other is similar to the cover test. Data on diagnostic validity of this procedure are lacking.

9.1.1 Early Detection of Amblyopia Early detection of amblyopia and amblyogenic factors requires objective methods that are independent of any verbal response of the child. Refractive error and strabismus are the most frequent causes of amblyopia. So, methods are necessary that indicate ametropia and strabismus with a high sensitivity and speciﬁcity. Refractometry or retinoscopy in cycloplegia is the most reliable way to detect and measure ametropia in childhood. However, this requires experience of the examiner and the possibility to perform both cycloplegia and measurement. These

114

9

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The Brückner Test Revisited

conditions as well as parental readiness are often lacking. Non-cycloplegic photorefractive screening is not a tantamount substitute of refractometry in cycloplegia [15, 16]. Besides, the technical equipment is relatively expensive, and therefore hardly any paediatrician or general practitioner performs photorefractometry. Even the Brückner test is not routinely used by paediatricians, although preconditions for performance are ideal and the test is recommended for paediatric screening examinations in Germany [17]. The Brückner test is a readily available screening tool that can be used with newborns, infants and preverbal children by non-ophthalmologists [18, 19]. The test requires not more than a direct ophthalmoscope and only few seconds for performance.

9.1.2 Brückner’s Original Description In 1962, Roland Brückner (1912–1996), an ophthalmologist in Basel, Switzerland, reported on ‘Exact strabismus diagnostic in ½- to 3-year-old children by a simple procedure, the “transillumination test”’ [18]. Brückner illuminated both pupils from a distance of 1 m and assessed the following criteria: ■ ■ ■ ■

Position of ﬁrst Purkinje images relative to the pupil Colour of the fundus red reﬂex in the pupil Size and constriction of the pupils Eye movements with and illumination of the pupils

Assessment of the ﬁrst two criteria requires simultaneous illumination of both eyes, whereas assessment of the following two criteria requires alternate illumination. Three years later, Brückner added an article on ‘Practical exercises with the transillumination test for early diagnosis of strabismus’, emphasizing the essential component of the test, which is the assessment of the red reﬂex of the fundus when the pupil is lighted and viewed with a direct ophthalmoscope [19]. This particular component was new concerning strabismus diagnostic and in the aftermath called Brückner test in the closer sense. It has also been called the Brückner reﬂex [3, 20].

9.2 Corneal Light Reﬂexes (First Purkinje Images) Assessment of the ﬁrst Purkinje images in the two eyes allows for more exact strabismus diagnostic than mere assessment of the position of the cornea within the palpebral ﬁssure. The latter depends on the conﬁguration of

the lids and the root of the nose. In infants and toddlers, as well as in Asians, epicanthus which is nasally covering the lid ﬁssure can be suggestive of esotropia.

9.2.1

Physiology

Purkinje described that when the eye is being illuminated by an examination light, reﬂexes appear from the corneal surface, the corneal endothelium, and both the anterior and posterior surface of the lens. The ﬁrst Purkinje image coming from the corneal tear ﬁlm is brightest. Usually it appears slightly nasally of the centre of the cornea and the pupil, when the eye is ﬁxating a light source which is held directly below the pupil of the observer. Slight eccentricity of the corneal light reﬂex is caused by the diﬀerence between the visual line and the pupillary axis, the angle k, which is similar to the angle g [21]. When the eye turns in a distinct direction, the position of the corneal light reﬂex relative to the pupil will shift to the opposite direction. Conjugate gaze movements induce parallel shift of the images in both eyes. This causes asymmetry in the two images, if their positions were symmetric at ﬁrst. For instance, right gaze induces nasal shift of the image in the right eye and temporal shift of the image in the left eye. The same will happen, when the light source is moved to the righthand side from the observer’s point of view or when the observer assesses the image position from left-hand side beside the light source. Non-conjugate eye movements or manifest strabismus cause a non-parallel shift or position, respectively, of the images on both eyes. For instance, when the left eye ﬁxates the light and the right eye is esotropic, then the ﬁrst Purkinje image on the right eye will be temporally dislocated. So, this method in principle allows for detection of strabismus. The idea to measure squint angles by using corneal light reﬂexes arose at the end of the nineteenth century [22, 23]. Hirschberg assumed that 1-mm shift of the corneal light reﬂex corresponded to an angle of 7° by which the eye is turned [22]. At the end of the twentieth century, empiric studies proved that within the range of small and moderate deviation the correct ratio is 12°/mm [10, 24, 25]. Nevertheless, up to the twenty-ﬁrst century, the wrong ratio of 7°/mm is still wide spread. Recognition of asymmetry in the Purkinje images can be improved by evaluating photographs [26]. In laboratory trials, photographic Hirschberg testing was eﬀective in approximately 80% of cases in detecting a deviating eye in strabismus of about 5 prism dioptres [27]. Regarding more accurate diagnostic, the alteration of relative position of the ﬁrst and the fourth Purkinje images due to deviation of the visual axis have

9.3 Fundus Red Reﬂex (Brückner Reﬂex)

115

been studied [11, 28–32]. However, the fourth Purkinje image is not visible clearly enough by performing the Brückner test.

9.2.2

Performance

Assessment of the corneal light reﬂex for symmetry on both eyes requires a small light source, which must be ﬁxated by the patient. To avoid glaring the patient, the light should not be too bright. The observer compares the position of the corneal reﬂex images in the two eyes in relation to the pupils. Physiologically, the images appear approximately 0.5 mm nasal to the centre of the pupil. The eccentricity depends on the individual angle k. The images may be better visible when the observer looks above the ophthalmoscope. Then the pupils appear black and there is more luminance contrast of the images. If the iris is dark brown with low contrast to the black pupil, looking through the ophthalmoscope is advantageous. Favourite test distances are around 0.5 m. Closer test distance may cause defence in children and also adequate convergence might not be warranted. Larger distance makes it diﬃcult to detect small asymmetry.

9.2.3

Shortcomings and Pitfalls

False-negative ﬁndings are likely in case of small squint angle. Since misalignment of 6° corresponds to not more than 0.5 mm asymmetry in the position of the corneal light reﬂexes, it is evident that small angle strabismus can hardly be identiﬁed by this method. Asymmetry in the angle k between both eyes can veil strabismus. Ectopia and anomalies of the pupil have to be considered. False-positive ﬁnding of strabismus can be caused by parallel shift of the reﬂex images in the two eyes when the light is horizontally displaced. The light source must be exactly beneath (not beside!) the visual axis of the observer’s ﬁxating eye. Severe bias occurs when the light is hold under one eye while the other eye is ﬁxating: Taken the angle k were equal in both eyes, the interpupillary distance were 60 mm, and the examination distance were 0.5 m, then the resulting asymmetry would correspond to 12°. A similar mistake occurs by evaluating ﬂashlight photographs, which were recorded with the ﬂashlight beside the objective (Fig. 9.1). With the ﬂashlight coaxially or above the objective, this bias can be avoided, but it cannot be assured that the child was really ﬁxating the camera [33].

Fig. 9.1 Corneal light reﬂexes in a 12-month-old girl. In this case, asymmetry of the corneal light reﬂex between both eyes is caused by ﬂashlight position beside the objective of the camera. So, the image of the ﬂashlight on the right eye is more and the image on the left eye is less nasally decentred. At 9 o’clock in front of both pupils, images of a window

Summary for the Clinician ■

Evaluating the corneal light reﬂexes in both eyes for symmetry allows to detect manifest strabismus and to estimate its size. Exclusion of strabismus is impossible because slight asymmetry corresponding to small squint angle can hardly be recognized and asymmetry in the angles k in both eyes can both, simulate or mask strabismus. Bias occurs when the patient ﬁxates a point beside the examination light or when the light is not on the examiner’s visual line.

9.3

Fundus Red Reﬂex (Brückner Reﬂex)

Performing the ‘transillumination’ test requires a direct ophthalmoscope. Looking through the ophthalmoscope, the examiner can see the patient’s pupil shining red, caused by the light reﬂected by the choroid and the retinal surface of the eye. The fundus reﬂex was also called Brückner reﬂex [3, 20]. Colour and brightness of the fundus reﬂex depend on brightness of the examination light, consistence and refractive quality of the optical media, pigmentation of the fundus and refractive state of the eye. Any opacity of the optic media causes an abnormally dark or lacking red reﬂex in the region of the opacity. Slight nuclear cataract may be visible by a darker ring, which is caused by the equator of the nucleus (Fig. 9.2). Posterior pole cataract causes a black shadow in the centre of the pupil. Frequently, a very small shadow is visible nasally below the centre of the pupil as the correlate of Mittendorf ’s spot. With eye movement these shadows move to the opposite direction within the pupil while shadow caused by corneal opacity or anterior cataract will move to the same direction. An examiner who is familiar with the Brückner test will probably detect every optically relevant cataract, albeit we are not aware of any scientiﬁc study on

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9

Fig. 9.2 Visualization of organic pathologies in the fundus reﬂex test. Top (better left), nuclear cataract OS>OD. OD, beginning cataract visible by a dark ring corresponding to the equator of the lens. OS, advanced cataract causing signiﬁcant central shadow. Bottom (better right), large peripheral retinoblastoma OS already visible by partial leukocoria when looking above the ophthalmoscope. Both examples show that organic ﬁndings are better visible with magniﬁcation by shorter distance compared to “armlength” distance

the sensitivity of the Brückner test to detect media opacity. Visualizing media opacity and pathologies of the fundus the Brückner reﬂex is extremely important for paediatricians, general practitioners and others who are not equipped to perform slitlamp biomicroscopy and indirect ophthalmoscopy. Abnormally, bright, white or dark fundus reﬂex can also be caused by the optic nerve head and by pathologies of the fundus, such as coloboma, retinoblastoma, toxoplasmosis scars and medullated nerve ﬁbres. When the patient takes up central ﬁxation of the ophthalmoscope light, there is normally a constriction of the pupils and dimming of both fundus reﬂexes [18]. By interfering with this dimming phenomenon, manifest strabismus and anisometropia can produce asymmetry in the brightness and colour of the fundus reﬂexes in both eyes. Brückner stressed the point that strabismus could be reliably detected by this asymmetry. Traditionally, the deviated or more ametropic eye was described to have the brighter reﬂex [9, 18]. Regarding ametropia, however, examination distance is a decisive factor. At larger distance, the more ametropic eye yields the darker fundus reﬂex [34].

9.3.1

Physiology

Examination of the fundus red reﬂex can roughly be compared with direct ophthalmoscopy performed at a large distance so that only very small part of the fundus is visible. Provided central ﬁxation of the patient, the fundus red reﬂex represents the patient’s fovea. To explain the dimming of the red reﬂex when the patient takes up ﬁxation, Brückner discussed various factors [18]. Pupillary constriction, diﬀerent reﬂectivity of the central and peripheral retinal surface and accuracy of accommodation were assumed to be the major causes of dimming and change in colour [18, 35–37]. Backscattering of the light by the retinal nerve ﬁbre layer proportional to the thickness of the layer and changes arising from variation in retinal pigment epithelium density, with the retina displaying the characteristics of a diﬀuse reﬂector, were further discussed but not as primary factors of dimming [35]. Mere pupillary constriction does not explain asymmetric dimming due to strabismus, but it may amplify eﬀects of defocus and retinal reﬂectivity. Brückner’s idea that diﬀerence in reﬂectivity between the central and para-central or peripheral retinal surface contribute to

9.3 Fundus Red Reﬂex (Brückner Reﬂex)

the dimming phenomenon was refreshed by Roe and Guyton who described specular reﬂection of the retina from the internal limiting membrane that changes slope with ocular rotation [35, 36]. The fundus reﬂex is not solely caused by reﬂection from the choroid and the retinal pigment epithelium but, to a minor part, also by reﬂection from the retinal surface. If signiﬁcant light were reﬂected from the internal limiting membrane of the retina, the slope of the foveal pit would reﬂect enough light away from the pupil. Because this part of light would not be reﬂected back to the observer, the red reﬂex would appear darkened [35, 36]. Misalignment of one eye with light being reﬂected from the para-foveal retinal surface, which is rather perpendicular to the direction of the incoming light, increases coaxial reﬂection and thus the brightness of the fundus reﬂex (Fig. 9.3). This might also explain the lack of dimming in newborns and young infants as a consequence of development of the foveal pit. While most infants 8 months of age and older show dimming of the fundus reﬂexes in both eyes occurring with central ﬁxation, neonates and most infants younger than 2 months of age do not show dimming of the fundus reﬂex with ﬁxation and between 2 and 8 months of age up to 28% of infants have asymmetric dimming of the fundus reﬂexes in the two eyes [9]. So, in newborns and young infants, asymmetry may represent a normal stage of development and symmetry does not exclude strabismus. Another mechanism might be oﬀ-axis aberration resulting in poor image formation on the retina. Roe and Guyton believed the fundus reﬂex would appear darker in an eye that is ﬁxating and focusing on the ophthalmoscope light because the light source in the ophthalmoscope and its retinal image are conjugate to one another.

117

If an eye is deviated, oﬀ-axis optical aberrations will decrease the conjugacy of the ophthalmoscope light and the retina. If the fovea is not exactly conjugate to the light source, the light from the retina spills passed the light source into the examiner’s eye, increasing the brightness of the red reﬂex [35, 36]. This hypothesis might ﬁt with the observation that – at the traditional examination distance of 1 m – the fundus red reﬂex in the (more) ametropic eye is usually brighter compared to an emmetropic eye. The hypothesis corresponds to the assumption that accuracy of accommodation is one reason of dimming. Foveal dimming of the red reﬂex allows for sensitive discrimination between subsequent central and eccentric illumination of the same eye. Dimming occurred in 97.2% of trials with ﬁxation of the light compared with ﬁxation of a target between 2.5 and 10° beside the light, regardless of the angle of eccentricity. This rate did not decrease when the pupil was dilated by mydriatic eye drops (Gräf et al., MS in preparation). However, the static inter-ocular difference in the reﬂexes due to strabismus was less apparent. In young adults, simulated esotropia with squint angles up to 5° was detected in not more than 62%. The deviated eye was identiﬁed by the brighter red reﬂex in 48%. Esotropia of 7.5 and 10° was detected in 85 and 97% with identiﬁcation of the deviated eye in 75 and 86% (Table 9.1). To achieve these rates, very discreet red reﬂex asymmetry was considered. The rate of false-positive ﬁndings was 36% (Gräf et al., MS in preparation). These results conﬁrm prior ﬁndings [38]. When esotropia of, for example, 8 prism dioptres was simulated by ﬁxating a near target, not more than two thirds of strabismus conditions were detected [27]. One might argue that these were only laboratory studies, but an increase in sensitivity and speciﬁcity in young children compared with highly cooperative

200 µm

Fig. 9.3 Optic coherence tomography (spectralis OCT) of the normal central fundus. Part of the light is already reﬂected from the surface of the retina. Due to the slope of the foveal pit part of the light is reﬂected away from the pupil. This might in part explain that the red reﬂex darkens when the patient takes up central ﬁxation of the ophthalmoscope light

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Table 9.1. Results of red reﬂex test in simulated esotropia and orthotropia (control condition)

9

Simulated esotropia

Number of trials

Test negative (%)

Test positive (%)

Correct localization (%)

Esotropia 2–5°

100

38

62

48

Esotropia 7.5°

100

15

85

76

Esotropia 10°

100

3

97

86

Orthotropia

300

64

36

–

Test negative symmetric red reﬂex; test positive inter-ocular asymmetry in red reﬂex; correct localization brighter red reﬂex in the deviated eye Gräf et al., (in preparation)

adults is rather unlikely. Strabismus detection will hardly improve by extending the test distance, except indirectly, by detection of anisometropia which frequently accompanies esotropia [35]. There might be a chance to improve test sensitivity and speciﬁcity by using a short-pass ﬁlter that blocks the reﬂexes coming from the retinal pigment epithelium and the choroid and thus augments asymmetry caused by asymmetric light reﬂection from the internal limiting membrane. Considering optical basics, examination distance must be an essential factor inﬂuencing the red reﬂex in case of refractive error. Uncorrected ametropia causes defocus of the retinal image of the light source. On the way back to the observer, this image is projected through the pupil. A myopic eye focuses the light beams at the far point of the eye. Beyond the far point, the light bundle is divergent. In case of hypermetropia, which is not compensated by accommodation, the light beams depart the eye as a primarily divergent bundle. With increasing

distance between the observer and the patient, the portion of the reﬂected light bundle reaching the observer’s pupil decreases. So, when the observer moves backwards, the brighter reﬂex, which at a distance of 1 m, usually corresponds to the (more) ametropic eye, becomes darker (Fig. 9.4) [34]. The test sensitivity to detect unilateral refractive error by the weak reﬂex in the ametropic eye at a test distance of 4 m is better compared with the traditional test at a distance of 1 m or less [30]. Using a direct ophthalmoscope, unilateral myopia of 1–4 diopters was detected in 60–82% of trials at 1 m but in 100% of trials at 4 m (Table 9.2). Unilateral hypermetropia of 1–4 diopters was detected in 34–80% of trials at 1 m but in 52–98% of trials at 4 m. Compared with experts, results of students were weaker at 1 m but equivalent at 4 m [34]. The low rate of false-positive ﬁndings shows that rather discreet asymmetry was not considered pathologic in that study, in contrast to the study on simulated strabismus, (Fig. 9.5).

Fig. 9.4 Anisometropia of 5 dioptres (emmetropia OD, hypermetropia OS). Fundus red reﬂex recorded at distances of 1 m (top) and 4 m (bottom). This amount of anisometropia causes red reﬂex asymmetry already at the traditional distance with the reﬂex from the more ametropic eye being somewhat brighter. At the extended distance the red reﬂex of the (more) ametropic eye is much darker

9.3 Fundus Red Reﬂex (Brückner Reﬂex)

119

Table 9.2. Sensitivity (50 trials for each condition) and false-positive ﬁndings (in 225 trials) of the Brückner reﬂex to detect unilateral spherical ametropia [34] Simulated unilateral ametropia

Experts 1 m (%)

Experts 4 m (%)

Students 1 m (%)

Students 4 m (%)

Hypermetropia 1 diopters

34

52

8

60

Hypermetropia 2 diopters

58

94

40

100

Hypermetropia 3 diopters

76

96

56

100

Hypermetropia 4 diopters

80

98

64

100

Myopia 1 diopters

60

100

32

68

Myopia 2 diopters

80

100

28

100

Myopia 3 diopters

74

98

40

100

Myopia 4 diopters

82

100

36

100

False-positive tests

3.1

4.0

1.5

3.0

Results for unilateral astigmatism showed also the higher detection rates at 4 m distance (Table 9.3). On the basis of these results, it is recommendable to perform the test also at a distance of 4 m to detect refractive error more sensitively [34]. Paysse et al. compared the ability of paediatric residents to diﬀerentiate asymmetric from symmetric red reﬂex in ten patients and six control subjects. Four patients were anisometropic by 2.25–5.5 dioptres without strabismus. In the entire group, paediatric residents achieved a test sensitivity of 61% and a speciﬁcity of 71% [3]. Gole and Douglas reported a test sensitivity of 86% and a speciﬁcity of not more than 65%. The Brückner test was performed by a medical student [20]. In these two studies, the test distance was 1 m. In a group of anisometropic patients, we achieved a sensitivity of 32.5% at that distance, and a speciﬁcity of 93.3%. At a distance of 4 m, sensitivity increased to 77.5% and speciﬁcity was 80%

[34]. These rates that depend on patient selection and observer experience are not representative for a real screening situation in early infancy.

9.3.2

Performance

It is commonly recommended to perform the test at a distance of about 1 m or less (‘arm’s length distance’) by simultaneously illuminating both eyes of a patient, and to compare colour and brightness of the pupillary red reﬂexes for symmetry [3, 18, 19, 35, 37, 38, 40, 41]. The room light should be dimmed but the room should not be completely dark [18]. Using a direct ophthalmoscope is mandatory. Otoscope or ﬂashlight illumination will not yield the same optical phenomena because the characteristic of the emitted light is diﬀerent. The light beam must be directed simultaneous

Table 9.3. Sensitivity (50 trials for each condition) and false-positive ﬁndings (in 400 trials) of the Brückner reﬂex to detect unilateral astigmatismus simplex [30] Simulated astigmatism

With the rule 1 m (%)

Against rule 1 m (%)

With the rule 4 m (%)

Against rule 4 m (%)

Hypermetropic 1 diopters

44

44

62

46

Hypermetropic 2 diopters

58

60

88

72

Hypermetropic 3 diopters

76

66

100

82

Hypermetropic 4 diopters

88

72

100

100

Myopic 1 diopters

50

22

44

74

Myopic 2 diopters

60

48

74

98

Myopic 3 diopters

60

70

86

100

Myopic 4 diopters

70

80

92

100

False-positive tests

5.5

5.25

120

9

9

The Brückner Test Revisited

into both eyes to enable accurate comparison of the red reﬂexes. Light intensity can be varied during the examination. It should not be too high to avoid glare. Detection of small media opacity is easier at 0.5–0.1 m, examining each eye separately and using a convex lens in the ophthalmoscope, if necessary. To improve detection of refractive error, the examiner should then go 4 m backwards continuously observing the pupils simultaneously for luminance of the red reﬂexes. By the same way, it is possible to check for correct spectacle correction.

a

b 9.3.3

Possibilities and Limitations

Severe media opacity is visible by lacking or dark fundus red reﬂex, regardless of distance. Small media opacity and pathologies of the fundus are best visible at a short distance. Any asymmetry in brightness and colour of the reﬂexes is predictive of amblyogenic risk factors [18, 19, 37, 38]. While the test is very sensitive to detect media opacity, detection of small-angle strabismus is limited. Detection of ametropia (particularly myopia) and anisometropia can be improved by extending the test distance, but nevertheless, isometropic hypermetropia cannot be detected reliably. Inter-ocular asymmetry in the red reﬂex can be caused by anisocoria and is also frequent in the age range below 8 months.

Summary for the Clinician ■

The fundus red reﬂex test is an excellent complement and a possibility for ophthalmologists, orthoptists, paediatricians, and general practitioners to recognize various eye disorders very early. It is also a valuable tool for use in developmental countries. At a short distance relevant media opacity can be reliably detected by darkening of the red reﬂex. Testing for refractive error is better performed at an extended distance. Uni- or bilateral partially or completely weak or lacking red reﬂex is always pathological.

c

d

e

f

Fig. 9.5 Brückner reﬂex at 4 m distance in case of emmetropia OU (a) and simulated hypermetropia OS (anisometropia) of 1 diopter (b), 2 diopters (c), 3 diopters (d), and 4 diopters (e). For comparison, simulated myopia OS of 1 diopter (f) [34]

9.4 Pupillary Light Reﬂexes Pupillary light reﬂexes are being tested to detect pathologies in the iris, in the eﬀerent branch of the pupillary light reﬂex loop, in the midbrain, or in the aﬀerent branch of the reﬂex loop. Regarding strabismus diagnostic, Brückner described two criteria:

1. Dimming of the red reﬂex when the child is centrally ﬁxating the ophthalmoscope light. 2. Reduced direct pupillary light reﬂex in the amblyopic eye compared with the direct light reﬂex in the nonamblyopic eye.

9.4 Pupillary Light Reﬂexes

This step requires monocular illumination of the pupils. Brückner reported pupillary constriction in the deviated eye when the light beam was changed from the ﬁxating eye onto the strabismic eye, as soon as this eye took up ﬁxation. Permanent ﬁxation with the previously illuminated dominant eye yields an eccentric retinal image of the ophthalmoscope light in the deviated eye. Despite dark adaptation of the deviated eye, the pupillomotor eﬀect of the eccentric illumination can be weaker than that of the central illumination in the fellow eye. So, the response to alternating illumination may either look like relative aﬀerent pupillomotor deﬁcit or dimming of the red reﬂex in the amblyopic eye occurs after some latency when the amblyopic eye takes up ﬁxation.

9.4.1

Physiology

Illumination of one eye causes symmetric constriction of both pupils [42–46]. In unilateral amaurosis, pupillary constriction is lacking in both eyes when only the blind eye is being illuminated. Illumination of the other eye causes normal constriction of the pupils in both eyes. Less severe aﬀerent disorders show a similar pattern except residual reaction to illumination of the (more severely) concerned eye. Discreet aﬀerent disorders can be found by the swinging ﬂash light test [42–44]. Aiming at strabismus diagnostic, the observer has to watch any eye movement occurring after the change of the illumination to the other eye. If the previously deviated eye which is now being illuminated takes up ﬁxation, the movement of this eye may be visible, and the pupils will constrict because foveal illumination

121

has a stronger pupillomotor eﬀect compared with paracentral illumination. Pupillary constriction is also induced by the increased light sensitivity of the ‘dark-adapted’ eye. In the clinical situation, it is hardly possible to discriminate between these two mechanisms. If the strabismic eye fails to take up central ﬁxation, an aﬀerent pupillomotor defect component may be simulated when this eye is being illuminated or there is in fact a relative aﬀerent pupillary defect (RAPD) due to amblyopia [47–50]. Figure 9.6 shows that already minimal eccentricity of illumination reduces pupillary constriction compared with a central illumination.

9.4.2

Performance

The examiner directs the light cone on the patient’s right eye and observes constriction of each pupil. The procedure is repeated illuminating the patient’s left eye. If both pupils are normally reactive, which is mostly the case, comparison of the direct light reﬂexes of both eyes will be suﬃcient [51–52]. If only one pupil is reactive, this pupil can be used to compare the constriction with subsequent illumination of the right and the left eye. The pupillary constriction has to be equal in latency, speed and amplitude, regardless of the eye illuminated.

9.4.3

Possibilities and Limitations

RAPD is typical of severe asymmetric retinal lesion or asymmetric lesion of the optic nerve including the optic chiasm. Amblyogenic disorders, such as refractive error,

gaze direction 10º 5º 0º –5º

Fig. 9.6 Video-oculographic registration of the change in pupil diameter with alternating ﬁxation of the ophthalmoscope light and low illuminated visual targets 2.5, 5, 7.5, and 10° right (positive values) and left (negative values) of the ophthalmoscope light. Fixation of the ophthalmoscope light induced more pupillary constriction than ﬁxation of a target as few as 2.5° beside

–10º pupil diameter 6 mm 4 mm 2 mm 0 mm 0

5

10

15

20

25 30 35 time / seconds

40

45

50

55

60

122

9

9

The Brückner Test Revisited

media opacity or any other pre-retinal disorder, generally do not cause an apparent RAPD. Thompson reported that a careful look revealed small RAPD in less than half of amblyopic eyes. This defect was generally less than 0.5 log units [46], and the size of possible RAPD did not correlate well with the visual acuity of the amblyopic eye [47–50]. Regarding strabismus diagnostic it may be an advantage that children usually look directly to the light. Manifest strabismus may be detected by the eye movement when illumination changes from one eye to the other and the child changes ﬁxation. However, it is hardly possible to detect strabismus by RAPD.

Summary for the Clinician ■

Severe unilateral amblyopia might be detected by RAPD in the amblyopic eye, but usually, the pupillary light reﬂexes are hardly suitable to detect strabismus or amblyopia.

9.5

Eye Movements with Alternating Illumination of the Pupils

Provided central ﬁxation and absence of strabismus, alternation of illumination to the other eye should not elicit any gaze movement. In case of manifest strabismus, there may be a movement of the illuminated eye from its previous strabismic position towards the light, together with a conjugate movement of the other eye. However, in case of severe amblyopia or uniocular dominance, this movement may be lacking. If the angle of eccentric ﬁxation is identical with the angle of abnormal retinal correspondence, there will also be no ﬁxation movement [53, 54]. These patterns are well known from cover testing. Since it is possible that the child keeps ﬁxation of the ophthalmoscope with the dominant eye because this eye is not occluded, cover testing is safer and certainly more sensitive to detect strabismus.

Summary for the Clinician ■

Brückner’s transillumination test allows for very sensitive detection of media opacity. Therefore, every ophthalmologic examination in early childhood should include the Brückner test. The test is suitable to detect strabismus but it does not allow for suﬃcient detection of small angle strabismus. Reliable strabismus diagnostic in childhood requires additional cover testing and testing of random dot stereopsis. The transillu-

mination test allows for detection of refractive error, particularly at an extended test distance. Nevertheless, reliable detection of amblyogenic ametropia requires refractometry or retinoscopy in cycloplegia.

References 1. Ehrlich MI, Reinecke RD, Simons K (1983) Preschool vision screening for amblyopia and strabismus. Programs, methods, guidelines. Surv Ophthalmol 28:145–163 2. Flynn JT (1991) Amblyopia revisited. J Pediatr Ophthalmol Strabismus 28:183–201 3. Paysse EA, Williams GC, Coats DK, Williams EA (2001) Detection of red reﬂex asymmetry by pediatric residents using the Brückner reﬂex versus the MTI photoscreener. Pediatrics 108:E74 4. Tychsen L (1992) Binocular vision. In: Hart WM Jr (ed) Adler’s physiology of the eye: clinical application. Mosby, St Louis, pp 837–838 5. Rahi J, Logan S, Timms C (2002) Risk, causes and outcomes of visual impairment after loss of vision in the nonamblyopic eye. Lancet 360:597–602 6. Rahi J S, Logan S, Borja MC, Timms C, Russell-Eggitt, Taylor D (2002) Prediction of improved vision in the amblyopic eye after visual loss in the non-amblyopic eye. Lancet 360:621–622 7. Van Leeuwen R, Eijkemans MJ, Vingerling JR, Hofman A, de Jong PT, Simonsz HJ (2007) Risk of bilateral visual impairment in individuals with amblyopia: the Rotterdam study. Br J Ophthalmol 91:1450–1451 8. Webber AL, Wood JM, Gole GA, Brown B (2008) The eﬀect of amblyopia on ﬁne motor skills in children. Invest Ophthalmol Vis Sci 49:594–603 9. Archer SM (1988) Developmental aspects of the Brückner test. Ophthalmology 95:1096–1101 10. Barry JC (1999) Hier irrte Hirschberg: Der richtige Winkelfaktor beträgt 12°/mm Hornhautreﬂexdezentrierung. Geometrisch-optische Analyse verschiedener Methoden der Strabismometrie. Klin Monatsbl Augenheilkd 215: 104–113 11. Barry JC, Eﬀert R, Hoﬀmann N (1996) Detection and diagnosis of small ocular misalignment with the Purkinje reﬂex pattern method. Klin Monatsbl Augenheilkd 208:167–180 12. Coats D, Jenkins R (1997) Vision assessment of the pediatric patient. Reﬁnements. Am Acad Ophthalmol 1:1 13. Donahue SP (2006) Relationship between anisometropia, patient age, and the development of amblyopia. Am J Ophthalmol 142:132–140 14. Sjöstrand J, Abrahamsson M (1990) Risk factors in amblyopia. Eye 4:787–793

References 15. Ehrt O, Weber A, Boergen KP (2007) Screening for refractive errors in preschool children with the vision screener. Strabismus 15:13–19 16. Schaeﬀel F, Mathis U, Brüggemann G (2007) Noncycloplegic refractive screening in pre-school children with the “power-refractor” in a pediatric practice. Optom Vis Sci 84:630–639 17. Zentralinstitut für kassenärztliche Versorgung (1991) Hinweise zur Durchführung der Früherkennungsuntersuchungen im Kindesalter. Deutscher Ärzte Verlag, Köln 18. Brückner R (1962) Exakte Strabismusdiagnostik bei 1/2bis 3jährigen Kindern mit einem einfachen Verfahren, dem “Durchleuchtungstest”. Ophthalmologica 144: 184–198 19. Brückner R (1965) Praktische Übungen mit dem Durchleuchtungstest zur Frühdiagnose des Strabismus. Ophthalmologica 149:497–503 20. Gole GM, Douglas LM (1995) Validity of the Brückner reﬂex in the detection of amblyopia. Aust N Z J Ophthalmol 23:281–285 21. Kaufmann H (1995) Störungen des Binokularsehens. Terminologie. In Kaufmann H (ed) Strabismus. Enke, Stuttgart, pp 162–165 22. Hirschberg J (1886) Beiträge zur Lehre vom Schielen und von der Schieloperation. Zbl prakt Augenheilkd 10:5–9 23. Smith P (1892) On the corneal reﬂex of the ophthalmoscope as a test of ﬁxation and deviation. Ophthalmic Rev 11:37–42 24. Brodie SE (1987) Photographic calibration of the Hirschberg test. Invest Ophthalmol Vis Sci 28:736–742 25. DeRespinis PA, Naidu E, Brodie SE (1989) Calibration of Hirschberg test photographs under clinical conditions. Ophthalmology 96:944–949 26. Kaakinen K, Tommila V (1979) A clinical study on the detection of strabismus, anisometropia or ametropia of children by simultaneous photography of the corneal and the fundus reﬂexes. Acta Ophthalmol 57:600–611 27. Griﬃn JR, McLin LN, Schor CM (1989) Photographic method for Brückner and Hirschberg testing. Optom Vis Sci 66:474–479 28. Barry JC, Eﬀert R, Kaupp A (1992) Objective measurement of small angles of strabismus in infants and children with photographic refection pattern evaluation. Ophthalmology 99:320–328 29. Barry JC, Eﬀert R, Kaupp A, Burhoﬀ A (1994) Measurement of ocular alignment with photographic Purkinje I and IV reﬂection pattern evaluation. Invest Ophthalmol Vis Sci 35:4219–4235 30. Barry JC, Eﬀert R, Reim M, Meyer-Ebrecht D (1994) Computational principles in Purkinje I and IV reﬂection pattern evaluation for the assessment of ocular alignment. Invest Ophthalmol Vis Sci 35:4205–4218

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31. Eﬀert R, Barry JC, Colberg R, Kaupp A, Scherer G (1995) Self-assessment of angles of strabismus with photographic Purkinje I and IV reﬂection pattern evaluation. Graefes Arch Clin Exp Ophthalmol 233:494–506 32. Eﬀert R, Barry JC, Dahm M, Kaupp A (1991) A new photographic method for measuring squint angles in infants and small children. Klin Monatsbl Augenheilkd. 198: 284–289 33. Becker R, Gräf M (2006) Systematische Fehler bei der fotograﬁschen Beurteilung der Hornhautspiegelbilder. Klin Monatsbl Augenheilkd 223:294–296 34. Gräf M, Jung A (2008) The Brückner test: extended distance improves sensitivity for ametropia. Graefes Arch Clin Exp Ophthalmol 246:135–141 35. Roe LD, Guyton DL (1984) Perspectives in refraction. Surv Ophthalmol 28:405–408 36. Roe LD, Guyton DL (1984) The light that leaks: Brückner and the red reﬂex. Surv Ophthalmol 28:655–670 37. Tongue AC, Cibis GW (1981) Brückner test. Ophthalmology 88:1041–1044 38. Griﬃn JR, Cotter SA (1986) The Brückner test: evaluation of clinical usefulness. Am J Optom Physiol Opt 63: 957–961 39. Leﬀertstra LJ (1977) Vergleichende Untersuchungen auf unterschiedliche Refraktionsänderungen beider Augen bei Patienten mit Strabismus convergens. Klin Monatsbl Augenheilkd 170:74–79 40. Carrera A, Saornil MA, Zamora MI, Maderuelo A, Canamares S, Pastor JC (1993) Detecting amblyogenic diseases with the photographic Brückner test. Strabismus 1:3–9 41. Noorden GKv, Campos EC (2002) Binocular vision and ocular motility. Mosby, St Louis 42. Levatin P (1959) Pupillary escape in disease of the retina or optic nerve. Arch Ophthalmol 62:768–779 43. Loewenfeld IE (1993) The pupil. Wayne State University, Detroit 44. Miller, NR (1995) Walsh and Hoyth’s clinical neuroophthalmology, Vol. I-V. Williams and Wilkins, Baltimore 45. Miller JM, Leising Hall H, Greivenkamp JE, Guyton DL (1994) Quantiﬁcation of the Brückner test for strabismus. Invest Ophthalmol Vis Sci 36:897–905 46. Thompson HS (1992) The pupil. In Hart WM Jr (ed) Adler’s physiology of the eye. Mosby, St. Louis, pp 412–441 47. Firth AY (1990) Pupillary responses in amblyopia. Br J Ophthalmol 74:676–680 48. Greenwald MJ, Folk ER (1983) Aﬀerent pupillary defects in amblyopia. J Pediatr Ophthalmol Strabismus 20: 63–67 49. Kase M, Nagata R, Yoshida A, Hanada I (1984) Pupillary light reﬂex in amblyopia. Invest Ophthalmol Vis Sci 25: 467–471

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50. Portnoy JZ, Thompson HS, Lennarson L, Corbett JJ (1983) Pupillary defects in amblyopia. Am J Ophthalmol 96: 609–614 51. Gruber H, Lessel MR (1982) Modiﬁkation des swinging ﬂashlight tests. Klin Monatsbl Augenheilkd 181: 402–403 52. Jiang MQ, Thompson HS, Lam BL (1989) Kestenbaum’s number as an indicator of pupillomotor input asymmetry. Am J Ophthalmol 107:528–530

53. Rüssmann W, Fricke J, Neugebauer A (2004) Nachweis der Fehlstellung mit dem Ab- und Aufdecktest. In: Kaufmann H (ed) Strabismus. Thieme, Stuttgart, pp 341–344 54. Rüssmann W, Kaufmann H (2008) Augenbewegungsstörungen. In: Straub W, Kroll P, Küchle J (eds) Augenärztliche Untersuchungsmethoden. Enke, Stuttgart, pp 637–643

Chapter 10

Amblyopia Treatment 2009

10

Michael X. Repka

Core Messages ■

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Wearing optimum refractive correction before initiation of patching or other amblyopia therapy is associated with improvement in amblyopia in about three quarters of children and a cure in about one fourth. This improvement may facilitate subsequent treatment. For initial therapy of moderate anisometropic and strabismic amblyopia among children 3–7 years of age, patching and atropine are equivalent. Atropine is slightly more acceptable than patching on the basis of parental questioning. For initial therapy of moderate amblyopia, 2 h of daily patching or twice weekly topical atropine

10.1 Amblyopia Treatment 2009 10.1.1

Introduction

Amblyopia management, long based on consensus or clinical wisdom [1, 2], has been developing an evidencebased foundation over the last decade. We have seen the completion of a series of randomized treatment trials and prospective observational studies over the last 10 years. These studies have dealt solely with the most common forms of amblyopia, those due to anisometropia, strabismus or a combination. Spectacle correction is the base on which all treatment for amblyopia must be built. Both patching and atropine penalization are eﬀective as initial management of moderate amblyopia. Initial dosages of 2 h daily of patching or twice weekly atropine have been shown to be eﬀective and can be considered suitable for initial therapy. Severe amblyopia may be initially managed with 6 h of patching. Intensiﬁed treatment for patients who are incompletely treated is logical to prescribe, yet not proven in clinical trials.

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administered to the sound eye are equally eﬀective. For initial therapy of severe amblyopia for children 3 to less than 7 years of age, 6 h of daily patching and full-time patching appear to be equally eﬀective. Amblyopia therapy can be beneﬁcial for older children up to 17 years of age, especially if they have not been previously treated. There have not been any studies to date which demonstrate the best therapy for patients with residual amblyopia following initial therapy. There are also no studies that have identiﬁed the best treatments for deprivation amblyopia.

The strict age cut-oﬀ of 7 or 8 years for therapy has been shown to be incorrect. Children through at least 13 years of age should be considered suitable for a trial of amblyopia therapy, as a large proportion will experience improvement [3]. Management of deprivation amblyopia, such as seen with unilateral aphakia or trauma, remains diﬃcult, frustrating to the families, and often unsuccessful. There is little new information on management of these patients.

10.1.2

Epidemiology

Amblyopia is considered the most common cause of monocular visual impairment in both children and young and middle-aged adults, in up to 4% of individuals [4].Simons, 1996 #181; [5]. It has been suggested that the prevalence is higher in underserved communities [6]. A study conducted by the National Eye Institute found amblyopia to be the leading cause of monocular vision loss in the 20–70-year-old age group [4]. These

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estimates have been based on school- or clinic-based studies. Two very recent population-based studies from the United States have reported prevalence estimates for amblyopia among preschool-aged children in urban areas. One study from Baltimore, Maryland, found the prevalence of amblyopia to be 1.8% in Whites and 0.8% in AfricanAmericans [7]. The authors extrapolated their ﬁnding to suggest that there are approximately 271,000 cases of amblyopia among children 30–71 months of age in the United States. The second study, completed in Los Angeles, California, detected amblyopia in 2.6% of Hispanic/Latino children and 1.5% of African-American children, with 78% of cases of amblyopia attributable to refractive error [8]. A study of a birth cohort at age 7 years in the United Kingdom found 3.6% of children to have amblyopia [9]. There was a suggestion in this latter study that amblyopia prevalence correlated mildly with lower socioeconomic status. Whatever the actual percentage of amblyopia in a population, this disease remains a common ocular problem among children. The causes of amblyopia depend on the population studied. In one treatment trial, amblyopia was associated with strabismus (37%), Anisometropia (38%) or both combined (24%) [10]. In another retrospective series, amblyopia was associated with strabismus (57%), anisometropia (17%) or both (27%) [11].

10.1.3 Clinical Features of Amblyopia Visual loss in amblyopia as measured with high-contrast opotoypes varies from mild to severe. The literature suggests that about 25% of cases have visual acuity in the amblyopic eye worse than 20/100 and about 75%, 20/100 or better [12, 13]. The more common causes of amblyopia are strabismus and moderate anisometropia, each accounting for about 35%, with 25% having both anisometropia and strabismus [10, 11]. Much less common is amblyopia related to high anisomyopia, bilateral high ametropia and disease of the anterior visual pathways (e.g., optic nerve hypoplasia). Although good results have been occasionally reported with conventional treatment, these cases are typically more diﬃcult to treat successfully. Other features of amblyopia include a reduction in contrast sensitivity and possibly reading ability. Most studies have found a reduction in contrast sensitivity in eyes with amblyopia using sinusoidal gratings [14–16], whereas minimal loss has been reported with Pelli-Robson charts, which test intermediate spatial frequencies [16, 17]. Detection of a deﬁcit of contrast sensitivity after treatment

of strabismic and anisometropic amblyopia is slight in the intermediate spatial frequencies tested with the low-contrast letters of the Pelli-Robson charts [16, 17]. We have recently conﬁrmed this ﬁnding of only a minimal deﬁcit with Pelli-Robson charts 3–7 years after enrollment in an amblyopia treatment trial [18]. Most studies of reading ability of amblyopic patients have tested the subjects binocularly, rather than monocularly, generally over a wide range of ages. Some of these studies have indicated that binocular reading ability in children with amblyopia is impaired [19, 20], whereas others have reported that reading ability is not aﬀected [21]. PEDIG recently reported the monocular oral reading speed, accuracy, ﬂuency and comprehension of 79 children with previously treated amblyopia at a mean age of 10.3 years [22]. We found the amblyopic eyes to be slightly slower and less accurate compared with fellow eyes, while comprehension was similar. Because of our study design we could not compare these children to a non-amblyopic population, so the impact of the monocular loss of vision on the patient’s binocular reading ability remains to be thoroughly explored.

10.1.4 Diagnosis of Amblyopia The diagnosis of amblyopia requires detection of a diﬀerence in visual acuity between the two eyes while wearing a necessary spectacle correction. For children who can have optotype acuity accurately measured, this remains the method of choice, in fact arguably, the only method. The test should employ either crowded or line optotypes. The clinician should exercise caution when interpreting the results of optotype testing. The variability of the instrument needs to be considered. Speciﬁcally, what is the expected variability of a second measurement when there has been no actual change in the visual acuity? For the Amblyopia Treatment Study Visual acuity testing protocol of single surrounded HOTV, we found high testability after age 3 years, with 93% of retests within 0.1 logMAR. More importantly, the visual acuity needs to diﬀer by more than 0.18 logMAR for the diﬀerence to likely be true [23]. In my experience a one-line change from a prior visit nearly always led to a change in therapy prescribed, usually an escalation. In children the test– retest variability is very high. For children 7–<13 years, a change in visual acuity must be at least 0.2 logMAR (ten letters) from a previous acuity measure to be unlikely resulting from measurement variability [24]. These two studies of rigorously administered visual acuity testing protocols remind clinicians that substantial variability of visual acuity results is present in children and careful

10.2

consideration of testing results before adjusting therapy is warranted. A recent article has also conﬁrmed that the visual acuity may vary from test strategy to test strategy. The ATSHOTV protocol overestimated the visual acuity relative to the E-ETDRS protocol (0.68 lines for amblyopic eyes; 0.25 lines for fellow eyes) [25]. Fixation preference testing has long been the clinical method of choice (in fact the only method in widespread clinical use) for determining amblyopia in children unable to perform a quantitative acuity on an eye chart. The examiner determines the preference for ﬁxation in a strabismic patient simply by determining the eye being used. For the orthotropic patient, a strabismus is created with a 10- or 12-prism diopters vertical prism and the assessment of ﬁxation preference is again made. If the patient alternated or at least could hold with the lesspreferred eye through a blink or a pursuit movement, no amblyopia was felt present. Two recent reports using the same testing protocol have found that the test is much less reliable than we have thought. These research groups tested children 30 to less than 72 months with ﬁxation preference testing and optotype acuity. Fixation preference testing identiﬁed only 15% of preschool children who had an IOD of two lines or more on visual acuity testing and 25% of those with an IOD of three lines or more [26]. There were an insuﬃcient number of children with strabismus to comment on that subgroup. In the Multiethnic Pediatric Eye Disease Study (MEPEDS), the authors reported sensitivity of ﬁxation preference testing for amblyopia among children with anisometropia was 20% (9/44), although speciﬁcity was 94% (102/109). Among strabismic children, sensitivity was 69% (9/13; worse in children 30–47 than 48–72 months old), and speciﬁcity was 79% (70/89) [27]. Hakim found that 75% of strabismic children had positive test results by ﬁxation preference testing, but only 13% had an IOD of two lines or more [28]. The obvious, albeit controversial confusion, is that ﬁxation preference testing misses most cases of amblyopia when used in a screening setting. In addition, the use of ﬁxation preference testing in a clinical setting for managing a patient with strabismus would likely lead to substantial overtreatment.

10.1.5

Natural History

Limited natural history data are available for amblyopia as nearly all patients diagnosed are prescribed some therapy. Although compliance is quite variable, most children receive some intervention. Some authors have

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suggested a tendency to spontaneous improvement of the visual acuity deﬁcit associated with amblyopia [29, 30]. Alternatively, another research group found that patients who did not comply with treatment deteriorated over time [31]. It is safe to comment that we do not know enough about the natural history of this common condition.

Summary for the Clinician ■

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Current estimates of the prevalence of amblyopia among preschool aged children in the Unites States range from 0.8 to 2.8%, with the highest rate found among Hispanic Americans. Most cases are associated at least in part with refractive error. Fixation preference testing for amblyopia is unreliable for the detection of amblyopia. It also appears to not be suﬃciently reliable to guide amblyopia therapy in many children. Care is needed when interpreting sequential measurements of visual acuity when made with diﬀerent instruments or testing paradigms.

10.2 Amblyopia Management Best practice for management of amblyopia had been based on clinician consensus [1]. However, no randomized trial had ever been done comparing no treatment to any amblyopia treatment. During the last 5 years, a large number of clinical trials assessing methods of amblyopia treatment have allowed the incorporation of evidencebased information into the practice of amblyopia care based on the earlier guidelines.

10.2.1

Refractive Correction

The value of an accurate refraction can not be underestimated in the management of amblyopia. These data are essential for both the diagnosis of amblyopia and the subsequent optimum treatment of the amblyopia. For security of the amblyopia diagnosis, the presence of an anisometropia helps substantiate the presence of amblyopia. The refractive error requires a measurement obtained under adequate cycloplegia, usually 1% cyclopentolate or similar cycloplegic. Many clinicians instill a topical anesthetic before the cycloplegic agent to prolong the retention of the cycloplegic drug in the tear ﬁlm.

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Prescribed glasses for ametropia are not controversial. The prescription for an esotropia patient should be full plus power [32]. Even if this power slightly blurs distance vision, it will not have a deleterious eﬀect at the child’s usual working distance. For the microstrabismic or orthotropic child, under correcting the hypermetropia symmetrically by up to 1.50 diopters avoids the problem of distance blur and does not seem to detract from the treatment outcome. For the exotropic patient, the anisometropia and any myopia need to be corrected. High hypermetropia should be partially corrected. What has been controversial among clinicians is what to do (and when) once the eyeglasses prescription is written and spectacles obtained. Some clinicians have routinely started patching at the same time, while others have waited a variable amount of time. Recent research has provided some guidance on this clinical decision, speciﬁcally the value of glasses alone in the management of amblyopia. In the United Kingdom, Stewart et al found a mean improvement of 2.4 lines in 65 children 3–8 years of age were treated with spectacles, taking an average of 14 weeks to reach best visual acuity [33]. Surprisingly, improvement was noted among both anisometropic and strabismic patients. These authors have termed this eﬀect refractive adaptation, although that term is potentially confusing since the refraction does not actually adapt. Rather the improvement represents the remediation of the amblyopia by optical correction alone. In a larger recent prospective study investigators in North America enrolled 84 children 3 to <7 years old with untreated anisometropic amblyopia ranging from 20/40 to 20/250 [34]. Optimal refractive correction was provided in accordance with consensus guidelines similar to those above. VA was measured with the new spectacle correction at baseline and at 5-week intervals until VA stabilized or amblyopia resolved. VA improved with optical correction alone by ≥2 lines in 77% of the patients and remarkably resolved in 27% [34]. Although the study was designed and powered for children with anisometropia, strabismic and combined strabismic–anisometropic patients were enrolled in a parallel pilot study following the same protocol to determine if such patients could respond to spectacle correction alone [35]. Twelve patients with previously untreated strabismic amblyopia were prescribed spectacles and examined at 5-week intervals until visual acuity was not improved from the prior visit. Amblyopic eye acuity improved by ≥2 lines from spectacle-corrected baseline acuity in 9 (75%), resolving in three. Mean change from baseline to maximum improvement was 2.2 ± 1.8 lines. Improvement continued for up to 25 weeks. Data on the ocular alignment after instituting the glasses were not available. Improvement in the visual acuity of

amblyopic strabismic patients was not expected to occur so often so PEDIG has launched an adequately powered prospective study of the impact of spectacle correction alone to explore this result.

10.2.2

Occlusion by Patching

The beneﬁcial eﬀect of occlusion with an adhesive patch in the management of amblyopia has long been considered obvious. Some randomized-controlled treatment trials have compared treatments, without an untreated control, led to criticism that the improvements experienced were due to age or learning eﬀects or possibly the beneﬁts of spectacles alone as noted earlier [36]. To address that issue, PEDIG conducted a RCT comparing occlusion to spectacles only. Before enrollment, the patients wore glasses until their vision stabilized between two consecutive visits. They were then randomized to continue spectacles alone compared with 2 h of daily patching. Improvement in VA of the amblyopic eye from baseline to 5 weeks averaged 1.1 lines in the patching group and 0.5 lines in the control group (P = 0.006), and improvement from baseline to best measured VA at any visit averaged 2.2 lines in the patching group and 1.3 lines in the control group (P < 0.001) [37]. Thus, occlusion was better but surprisingly there was continuing beneﬁt of the spectacles alone, reinforcing how important this aspect of therapy must be. The dosage of occlusion therapy prescribed has historically ranged widely, from a few minutes to all waking hours per day. Some clinicians have prescribed fewer hours for fear of damaging the binocular visual system. In the initial PEDIG trial, comparing atropine to patching, both treatments were found to be equally eﬀective [38]. Subgroup analysis of diﬀering dosages from 6 h daily to full time (all waking hours less one daily) found no advantage of prescribing more hours [39]. This led us to design two studies directed at exploring occlusion dosage. In the ﬁrst trial, we compared 2 with 6 h daily for the initial treatment of moderate amblyopia, 20/40–20/80, for a period of 4 months [40]. Visual acuity in the amblyopic eye improved a similar amount in both groups. The improvement in the amblyopic eye from baseline to 4 months averaged 2.40 lines in each group (P = 0.98). The 4-month visual acuity was ≥20/30 and/or improved from baseline by ≥3 lines in 62% in each group (P = 1.00). We did not follow and treat these patients after 4 months so we do not know if a diﬀerence might develop. In the second trial of patching dosage, we compared 6 with full time or all waking hours less 1 h for severe amblyopia, 20/100–20/400 [41]. VA in the amblyopic eye improved to a similar extent in both groups. The improvement in

10.2

the amblyopic eye acuity from the baseline to 17 weeks averaged 4.8 lines in the 6-h group and 4.7 lines in the full-time group (P = 0.45). However, 75% of patients in both groups were 20/40 or worse after therapy. There is a natural concern about amblyopia therapy, particularly with higher dosages, causing loss of vision in the sound eye. The sound eye lost two or more lines in 4% of the 6-h group and in 11% of the full-time group. Nearly all patients returned to their baseline level with follow-up, typically by just stopping all patching. These patching dosage data show that for initial treatment of amblyopia due to strabismus, anisometropia or both combined, beginning with the lower dosage of occlusion does not lessen the chance of success and may make the treatment more feasible. However, only about one in four patients with moderate amblyopia was 20/25 or better and one in four children with severe amblyopia was 20/32 or better. These studies have taught much about initial patching therapy, but they have left substantial uncertainty about what to do for those children who are not completely corrected. Some clinicians have misinterpreted the results and have recommended stopping therapy when the visual acuity ceases to improve with these prescribed doses. What needs to be explored is whether an increased dose or a change in treatment approach will allow more complete correction. At present, clinicians and parents will have to make that judgment without the results of a RCT to guide the choice. Logically, some period of more intense therapy should be administered before discontinuing treatment.

10.2.3 Pharmacological Treatment with Atropine To ﬁnd an eﬀective, yet easy to administer, treatment of amblyopia has been a goal pursued by clinicians treating amblyopia in response to the complaints and diﬃculties associated with occlusion therapy. This pursuit has led to many failed treatments that were launched with great fanfare, but ultimate abandonment. For more than a century, clinicians have used pharmacological penalization of the sound eye to make the child use the amblyopic eye and thereby improve the visual acuity of that eye. Most clinicians typically used this treatment for patching failures or noncompliance. Case series reported eﬀectiveness, but the common belief was that this was an inferior treatment. The largest prospective study was completed in 2002, comparing once daily atropine to patching 6 or more hours per day for moderate amblyopia 20/30–20/100 [38]. Visual acuity improved in

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both groups: 2.84 lines in the atropine group and 3.16 lines in the patching group. The patching group did get better faster, but by 6 months, the diﬀerence of 0.034 was clinically inconsequential. Both treatments were well tolerated, although the atropine was easier to administer based on parental questionnaires. These children were followed in the study for an additional 18 months to describe prescribed treatment and stability of the improvement. Treatment was determined by the investigator [42]. Remarkably, and at odds with clinical wisdom, nearly 90% received some treatment during this period. Eighty percent received the same treatment and 25% received the alternate treatment (some patients received both). At 2 years, visual acuity in the amblyopic eye improved a mean of 3.6 lines in the atropine group and 3.7 lines in the patching group. This difference in visual acuity between treatment groups was small: 0.01 logMAR (95% conﬁdence interval, −0.02 to 0.04). Thus, the relative equivalence of the techniques and the persistence of the treatment beneﬁt were reaﬃrmed. Stereoacuity outcomes were similar suggesting no untoward relative eﬀect of either of the two treatments. One concern regarding amblyopia therapy is the potential for inducing or worsening a strabismus. In addition, most authors have suggested treating amblyopia before undertaking strabismus surgery. This study evaluated the chance of inducing a strabismus, but also the chance of improving a strabismus with amblyopia treatment. Of the 161 patients with no strabismus, similar proportions initially assigned to the patching and atropine groups developed new strabismus by 2 years (18 vs. 16%, P < 0.84) [43]. Of the new cases of strabismus, only two patients in the patching group and three patients in the atropine group developed a deviation that was greater than 8D. Perhaps surprisingly, of the 105 patients with strabismus greater than 8D at enrollment, 13% of those in the patching group and 16% of those in the atropine group improved to orthotropia without strabismus surgery. These data show that strabismus may develop or resolve with amblyopia therapy in about equal proportions. The dosage of atropine in the original PEDIG trial was once daily. This design was consistent with the desire to maximize the likelihood of ﬁnding beneﬁt if there was one. While that study was underway, the beneﬁt of less frequent administration was suggested by Simons and coworkers [44]. They reported reasonable improvement from less frequent administration. This was plausible since the duration of cycloplegia was often more than 1 day. This ﬁnding led PEDIG to develop a clinical trial, which compared daily atropine to weekend atropine.

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The atropine dosage treatment trial included 168 children younger than 7 years with amblyopia in the range of 20/40–20/80 associated with strabismus, anisometropia or both. They were randomized to either daily or weekend atropine [45]. The improvement of the amblyopic eye from baseline to 4 months averaged 2.3 lines in each group. The visual acuity of the amblyopic eye at study completion was either (1) at least 20/25 or (2) better than or equal to the sound eye in 39 children (47%) in the daily group and 45 children (53%) in the weekend group. The visual acuity of the sound eye at the end of follow-up was reduced by two lines in one patient in each group. Stereoacuity outcomes were similar in the two groups. Patients who were not cured continued on the randomized treatment beyond the 4-month outcome exam. They improved an average of 0.8 additional lines (0.7 lines among the 22 daily group patients and 0.8 lines among the 31 weekend group patients). At the time of study completion, 39 (47%) of the patients in the daily group and 45 (53%) in the weekend group had an amblyopic eye acuity that was either (1) 20/25 or better or (2) the same or better than the sound eye acuity, provided that the sound eye acuity had not decreased from enrollment. The mean amblyopic eye acuity at study completion was 0.23 logMAR in the daily group and 0.21 logMAR in the weekend group (approximately 20/32). The mean sound eye visual acuity at enrollment was 0.05 logMAR (approximately 20/25), with 81% of the sound eyes having acuity of 20/25 or better. Among patients who improved two or more lines from baseline during the study, 30% of patients achieved their best acuity at 5 weeks, 50% at 4 months, 7% at 6 months, 10% at 8 months and 3% at 10 months. These results were similar in the two atropine treatment groups. Thus, a 4-month treatment period with atropine will treat most patients but is not suﬃcient to complete treatment for all. Thus, treatment should be continued until there is good evidence that a plateau in improvement has been achieved. There is a chance of visual impairment of the sound eye so care needs to be taken. In this study 1% of sound eyes lost two or more lines of acuity at last follow up. As expected, light sensitivity was common, reported by 16% of children. Facial ﬂushing and fever, a more worrisome side eﬀect, was reported by 1% of the children. Summarizing, weekend atropine for moderate amblyopia is eﬀective in improving visual acuity. The amount of improvement was comparable with that seen with 4 months of 2 or 6 h of daily patching [40]. Parents need to realize that most children will need at least 4 months of treatment irrespective of which therapy and dosage. Twice weekly atropine is fairly unobtrusive for preschool

children, should easily be incorporated into a child’s daily activities, and is likely to be attractive to a large proportion of parents. However, as with patching if the visual acuity improvement is not complete increasing the dosage or changing to an alternative therapy should be considered. The eﬀectiveness of such a treatment remains to be proven.

10.2.4 Pharmacological Therapy Combined with a Plano Lens Investigators have long looked for ways to intensify their treatments, implicitly recognizing that the prescribed therapy did not always have the desired eﬀect. For atropine penalization of the sound eye, it has been long noted that adding optical penalization, by removing all hypermetropic correction from the sound eye, would add optical blur at distance to complement the cycloplegic blur provided at near. A retrospective report included 42 children (mean age, 4.7 years) treated with daily atropine and a plano lens for the sound eye [46]. Important caveats were that eligible patients had failed patching treatment and had at least 1.75 D of sound eye hypermetropia. Surprisingly, they found a mean improvement in amblyopic eye visual acuity from 20/113 to 20/37 after 10 weeks of treatment with atropine and a plano lens to the sound eye. This was a remarkable achievement. However, Morrison and colleagues cautioned that this treatment resulted in a case of severe treatment-related amblyopia in the sound eye when parental noncompliance occurs [47]. To explore the value of this “augmented atropine approach,” PEDIG randomized 180 children with moderate amblyopia (visual acuities of 20/40–20/100) to weekend atropine use augmented by a plano lens or weekend atropine use alone [48]. At 18 weeks, amblyopic eye improvement averaged 2.8 lines in the group that received atropine plus a plano lens and 2.4 lines in the group that received atropine alone (mean diﬀerence between groups adjusted for baseline acuity, 0.3 line; 95% conﬁdence interval, −0.2–0.8 line). Amblyopic eye visual acuity was 20/25 or better in 24 patients (29%) in the group that received atropine only and 35 patients (40%) in the group that received atropine plus a plano lens (P = 0.03). However, more patients in the group that received atropine plus a plano lens had reduced sound eye visual acuity at 18 weeks; fortunately, there were no cases of persistent reverse amblyopia. The important conclusion is that in spite of intuition, augmentation of weekend atropine use with a plano lens does not substantially improve amblyopic eye visual acuity when compared with weekend atropine use alone.

10.3 Other Treatment Issues

Summary for the Clinician ■

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■

■

■

A series of trials has shown that for amblyopia from anisometropia, strabismus or both combined, initial therapy should be refractive correction with the expectation of substantial improvement. Occlusion is signiﬁcantly more eﬀective than spectacles alone. Atropine and patching are equally eﬀective for initial treatment of mild amblyopia among children 3 to less than 7 years of age. Initial dosages of 2 h of patching and weekend atropine are similar in eﬀectiveness to more intensive therapy as initial treatment. Expect that about 80% of the children will be 20/30 (6/9, 0.66) or better in the sound eye after treatment completion. Augmented pharmacological treatment with a plano lens for the sound eye is not associated with substantial beneﬁt as initial therapy, but is associated with a risk of visual loss in the sound eye.

10.3 Other Treatment Issues 10.3.1 Bilateral Refractive Amblyopia The management of bilateral amblyopia from hypermetropia and/or astigmatism has been the subject of several reports. The incidence was 4 of 830 (0.5%) children at entry into school in an older report [49]. Small case series have found substantial beneﬁt to treatment with spectacle correction. In one study, 10 of 12 children (83%) improved to 20/40 or better in both eyes with a mean follow-up of 22 months [50]. A recent report study found that 21 of 36 children (58%) achieved a visual acuity of 20/25 or better in at least one eye with a mean follow-up of 3.3 years [51]. Neither study was suﬃcient large to develop reasonable estimates for the chance of success for these children. PEDIG undertook a prospective observational study of bilateral refractive amblyopia [52]. Inclusion criteria included 20/40–20/400 best-corrected visual acuity in the presence of 4.00 diopters or more of hypermetropia by spherical equivalent, 2.00 diopters or more of astigmatism, or both in each eye. Mean binocular visual acuity improved from 0.50 logMAR (20/63) at baseline to 0.11 logMAR (20/25) at 1 year (mean improvement, 3.9 lines; 95% conﬁdence interval, 3.5–4.2). Mean improvement was 3.4 lines (95% CI, 3.2–3.7) for children with

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moderate amblyopia (20/40–20/80) and 6.3 lines (95% CI, 5.1–7.5) for children with severe amblyopia (20/100– 20/320). Maximum improvement was achieved after 13 weeks for some, yet only after a year for others. The obvious conclusion is that glasses should be prescribed to children at an early age and worn as much of the time as possible.

10.3.2

Age Eﬀect

Most clinicians have held that amblyopia treatment is best accomplished when children are young and certainly before age 8 years. Among preschool children treated with either patching or atropine there was no age eﬀect identiﬁed [53]. This ﬁnding along with case reports of eﬃcacy in older children, teens and even adults led PEDIG to undertake a treatment trial of subjects 7–17 years of age [3]. In the 7 to 12-year-olds (n = 404), treatment was 2–6 h of patching daily plus daily atropine. Fifty-three percent of the treatment group improved at least ten letters compared with 25% of the optical correction group (P < 0.001). In the 13 to 17-year-olds (n = 103) treatment was 2–6 h of patching per day, improvement rates of ten letters or more were 25 and 23%, respectively (adjusted P = 0.22). More striking was the improvement among patients not previously treated; 47 and 20% of the two age groups, respectively. Most patients were left with a residual visual acuity deﬁcit. This means that older children who had never been treated should have a trial of treatment.

10.3.3

Maintenance Therapy

Clinical wisdom has suggested that amblyopia therapy should not be abruptly stopped, but rather needs to be continued for a period of time to reduce the chance of recurrence [1]. This approach was indirectly studied by taking some patients from some of the early PEDIG trials and whose therapy was being stopped or maintained on a low dose of occlusion [54]. The recurrence rate was 24% (35 of 145) (95% conﬁdence interval 17–32%). There was no diﬀerence between patching and atropine. In patients treated with patching of 6–8 h per day, recurrence was more common (42%) when treatment was abruptly stopped compared with tapering to 2 h per day before cessation (14%, odds ratio 4.4, 95% conﬁdence interval 1.0–18.7). Absent additional data seems prudent to monitor all patients and to taper occlusion therapy (6 or more hours) and daily atropine therapy.

132 10.3.4

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Long-Term Persistence of an Amblyopia Treatment Beneﬁt

The longevity of the improvement in VA achieved with amblyopia treatment has been questioned. Short-term recurrence and the need to repeat therapy is well known. The best estimates are about 25% will recur during the ﬁrst year after cessation of therapy [55–57]. Most of these cases will occur in the ﬁrst 6 months after cessation of therapy. Based on clinical experience most of the recurrences can be successfully treated, but prospective data are needed. The long-term beneﬁt of amblyopia therapy would only be proven if the improvement in acuity experienced by the amblyopic eye is maintained. There are substantial data published in this area, which is quite troublesome. The extent of deterioration reported in retrospective outcome studies of children treated for amblyopia to be as high as 58% in spite of interim treatment, thereby reducing the actual beneﬁt of therapy [58–63]. To address this question, prospectively, children 3–<8 years enrolled in our trial comparing patching to atropine were followed at 2 years after randomization, and a subgroup reexamined at age 10 years, 3–7 years after randomization [64]. Two years after randomization visual acuity in the amblyopic eye improved a mean of 3.7 lines in the patching group and 3.6 lines in the atropine group. In both treatment groups, the mean amblyopic eye acuity was approximately 20/32, 1.8 lines worse than the mean sound eye. At age 10 years, 169 patients had an amblyopic eye VA of 0.17 logMAR (approximately 20/32), and 46% of amblyopic eyes had an acuity of 20/25 or better [65]. Age younger than 5 years at entry into the randomized trial was associated with a better visual acuity outcome (P < 001). Mean amblyopic and sound eye visual acuities at age 10 years were similar in the original treatment groups (P = 0.56 and P = 0.80, respectively). The good news here is that the visual acuity improvement was maintained. However, 88% of all of these patients were treated at least once between the primary 6-month outcome and the age 10 years evaluation. In addition, these children were part of a clinical trial, which may improve compliance with therapy and follow up compared with the general population. Amblyopia treatment is considered cost-eﬀective among the spectrum of eye and health care interventions [66, 67]. However, there is substantial uncertainty concerning the eﬀect of treatment on quality of life in the future. Economic modeling cannot account for the impact of adaptation to the visual impairment from a young age compared with that of later onset. A large cohort study of adults in the United Kingdom was

unable to ﬁnd signiﬁcant diﬀerences in educational, social, or employment attainment between amblyopic and control subjects [68]. Conversely, a questionnairebased study of adults with amblyopia and strabismus on their quality of life found lifelong beneﬁts as perceived by those patients [69].

Summary for the Clinician ■

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Amblyopia therapy appears to lead to a persistent improvement in visual acuity of the amblyopic eye. Amblyopia therapy for children from 7 to 17 years should be considered if there is no history of an adequate trial of treatment. More research is needed to understand the eﬀect of amblyopia on patient outcomes.

10.4 Other Treatments Clinicians have long known that the standard treatment of patching and even atropine were not always successful. They have therefore sought alternatives to occlusion therapy as primary and secondary treatment of amblyopia.

10.4.1

Filters

Bangerter foils were introduced nearly 50 years ago to provide a graded reduction of image quality to the sound eye [70]. The eight ﬁlter densities were designed to reduce visual acuity of the sound eye to a range of 20/25–20/300. Selecting the proper blur level would force the patient to use the amblyopic eye. The ﬁlters are worn on the back surface of the spectacle lens are for the most part are not readily apparent. Proponents have suggested that the improved appearance compared with a patch would increase patient compliance. In addition, ﬁlters do not cause skin irritation. Finally, one could postulate that Bangerter foils are less disruptive to binocular function during treatment compared with patching. The key disadvantage of Bangerter foils is that glasses must be worn and the child must not look around the device. One small uncontrolled case series on primary use of this treatment comes from Iacobucci and associates [71]. They treated 15 children, 3–8 years old, with amblyopia of 20/30–20/60 for a mean duration of 9 months. Two thirds of patients (10 of 15) obtained amblyopic eye acuity of 20/20 or better or equal to that of the sound eye. Of the remaining ﬁve patients, four attained amblyopic eye acuity of 20/25 or

10.5

20/30 or within a half line of the sound eye. Bangerter ﬁlters, as in this study, are prescribed for longer periods than either patching or atropine because they are well tolerated. Bangerter ﬁlters have not been compared with patching or atropine. PEDIG has completed a clinical trial comparing Bangerter ﬁlters (0.2 and 0.3 densities) to 2 h of daily occlusion. The results are currently being analyzed.

10.4.2

Levodopa/Carbidopa Adjunctive Therapy

Levodopa is used to treat adults with Parkinson disease and children with dopamine responsive dystonia. Dopamine is a neurotransmitter that does not cross the blood–brain barrier. However, levodopa administered orally crosses the blood–brain barrier, where it is converted to dopamine. Levodopa is typically used in combination with carbidopa, a peripheral decarboxylase inhibitor that prevents the peripheral breakdown of levodopa. This reduces the dose of levodopa and thereby reduces the primary side eﬀects of nausea and emesis. A randomized longitudinal double masked placebo control trial of ten amblyopic children aged 6–14 years [72]. The dosing averaged 0.5 mg/kg/tid and lasted for 3 weeks. Visual acuity of the amblyopic eyes improved by 2.7 lines in the levodopa treated group, and by 1.6 lines in the subjects treated with placebo. One month after the termination of treatment, the levodopa-carbidopa group maintained a 1.2-line improvement in visual acuity. A 1-week, randomized, placebo-controlled study was performed with 62 children with amblyopia who were between 7 and 17 years of age. Subjects were instructed to occlude the dominant eye for 3 h per day. Visual acuity improved from 0.59 to 0.45 in the levodopa–carbidopa group (average dose 0.51 mg/kg/tid) and from 0.69 to 0.63 in the control group (P = 0.023) [73]. In a prospective randomized trial, 72 subjects with amblyopia were distributed into three groups [74]. Group A subjects received levodopa alone, group B received levodopa (0.50 mg/kg/t.i.d.) and part-time occlusion (3 h/ day), and group C received levodopa and all waking horus occlusion of the sound eye. Although 53/72 subjects (74%) had an improvement in visual acuity (maximum = 4.6 Snellen lines; mean 1.6 Snellen lines, ≤10 years; mean 1.1 Snellen lines, >10 years) after treatment, 52% of those who improved had regression in visual acuity when measured after 1 year. A follow-up report of three longitudinal studies (9–27 months) using levodopa (0.55 mg/kg/t.i.d.) plus occlusion for treatment of amblyopia included 30/33 (91%) of

Controversy

133

participating subjects. Subjects who received levodopa plus occlusion demonstrated signiﬁcant regression of visual acuity after stopping the medication. On average, the amount of regression over 6 months of follow-up averaged 1.4 lines, similar to that experienced by those receiving occlusion only [75]. Forty children 6–<18 years were randomized to 4 weeks of levodopa (1.86 mg/kg/day (1.33–2.36 mg/kg/ day) plus full-time occlusion or full-time occlusion only [76]. No diﬀerence in visual acuity outcome was found.

Summary for the Clinician ■

■

Bangerter ﬁlters appear to be a useful option but data compared with those of other treatments are not yet available. Many pilot studies have shown some improvement when patching is combined with levodopa/ carbidopa for about 8 weeks. Durability of the treatment eﬀect and a comparison with patching alone needs to be completed.

10.5 Controversy 10.5.1

Optic Neuropathy Rather than Amblyopia

Every clinician managing a child with amblyopia must be aware of the masquerade of an optic neuropathy as an amblyopia. Careful attention to pupillary signs, appearance of the optic nerve and response to therapy are needed. An amblyopic patient who does not improve (or deteriorates) with conventional therapies should be continually reassessed for the presence of an optic neuropathy. Such a situation might be an optic neuropathy related to compression or other progressive damage of the aﬀerent visual pathway, such as from an optic glioma or a craniopharyngioma. More controversially is the role of static optic nerve abnormalities in the genesis of visual loss diagnosed as amblyopia. It has been suggested by Lempert that these ﬁndings are very common. He has reported termed “dysversion” or hypoplasia in optic nerve photographs in 45% of 205 amblyopic eyes [77, 78]. More recently, Lempert has reported reduced optic disc rim areas for both amblyopic and fellow eyes with the reduction most prominent in the amblyopic eyes [79]. If there was an abnormality of the optic nerve, we would expect that the retinal nerve ﬁber layer thickness would be reduced. Such investigations based on optical coherence tomography have not

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found any substantive diﬀerence among amblyopic, fellow, and normal eyes [80–82]. In addition, it has never been clear why patients with an optic neuropathy would show the substantial improvement in visual acuity seen during management of most cases of amblyopia.

Summary for the Clinician ■ ■

The presence of an optic nerve abnormality in “typical” amblyopia remains controversial. The value of optic nerve head analysis in the management of most cases of amblyopia is not clariﬁed.

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58. Fletcher MC, Silverman SJ, Boyd J, et al (1969) Biostatistical studies: comparison of the management of suppression amblyopia by conventional patching, intensive hospital pleoptics, and intermittent oﬃce pleoptics. Am Orthopt J 19:404–407 59. Gregersen E, Rindziunski E (1965) “Conventional” occlusion in the treatment of squint amblyopia. a 10-year followup. Acta Ophthalmol (Copenh) 43:462–474 60. Leiba H, Shimshoni M, Oliver M, et al (2001) Long-term follow-up of occlusion therapy in amblyopia. Ophthalmology 108:1552–1555 61. Levartovsky S, Oliver M, Gottesman N, et al (1995) Factors aﬀecting long term results of successfully treated amblyopia: initial visual acuity and type of amblyopia. Br J Ophthalmol 79:225–228 62. Rutstein RP, Fuhr PS (1992) Eﬃcacy and stability of amblyopia therapy. Optom Vis Sci 69:747–754 63. Sparrow JC, Flynn JT (1977) Amblyopia: a long-term followup. J Pediatr Ophthalmol 14:333–336 64. Pediatric eye disease investigator group (2005) Two-year follow-up of a 6-month randomized trial of atropine vs patching for treatment of moderate amblyopia in children. Arch Ophthalmol 123:149–157 65. Pediatric eye disease investigator group (2008) A randomized trial of atropine versus patching for treatment of moderate amblyopia: follow-up at 10 years of age. Arch Ophthalmol 126:1039–1044 66. Konig HH, Barry JC (2004) Cost eﬀectiveness of treatment for amblyopia: an analysis based on a probabilistic Markov model. Br J Ophthalmol 88:606–612 67. Membreno JH, Brown MM, et al (2002) A cost-utility analysis of therapy for amblyopia. Ophthalmology 109: 2265–2271 68. Rahi JS, Cumberland PM, Peckham CS (2006) Does amblyopia aﬀect educational, health, and social outcomes? Findings from 1958 British birth cohort. BMJ 332: 820–825 69. van de Graaf ES, van der Sterre GW, van Kempen-du Saar H, et al (2007) Amblyopia and strabismus questionnaire (A&SQ): clinical validation in a historic cohort. Graefes Arch Clin Exp Ophthalmol 245:1589–1595

70. Bangerter (1958) Orthoptische Behandlung des Begleit schielens. pleoptik (monokulare orthoptik). Acta XVIII concilium ophthalmologica, Excerpta Medica Foundation 1:105–128 71. Iacobucci IL, Archer SM, Furr BA, et al (2001) Bangerter foils in the treatment of moderate amblyopia. Am Orthopt J 54:84–91 72. Leguire LE, Rogers GL, Bremer DL, et al (1993) Levodopa/ carbidopa for childhood amblyopia. Invest Ophthalmol Vis Sci 34:3090–3095 73. Procianoy E, Fuchs FD, Procianoy L, et al (1999) The eﬀect of increasing doses of levodopa on children with strabismic amblyopia. J AAPOS 3:337–340 74. Mohan K, Dhankar V, Sharma A (2001) Visual acuities after levodopa adminstration in amblyopia. J Pediatr Ophthalmol Strabismus 38:62–67 75. Leguire LE, Komaromy KL, Nairus TM, et al (2002) Longterm follow-up of l-dopa treatment in children with amblyopia. J Pediatr Ophthalmol Strabismus 39: 326–330 76. Bhartiya P, Sharma P, Biswas NR, et al (2002) Levodopacarbidopa with occlusion in older children with amblyopia. J AAPOS 6:368–372 77. Lempert P (2000) Optic nerve hypoplasia and small eyes in presumed amblyopia. J AAPOS 4:258–266 78. Lempert P, Porter L (1998) Dysversion of the optic disc and axial length measurements in a presumed amblyopic population. J AAPOS 2:207–213 79. Lempert P (2008) Retinal area and optic disc rim area in amblyopic, fellow, and normal hyperopic eyes: a hypothesis for decreased acuity in amblyopia. Ophthalmology 115:2259–2261 80. Altintas O, Yuksel N, Ozkan B, et al (2005) Thickness of the retinal nerve ﬁber layer, macular thickness, and macular volume in patients with strabismic amblyopia. J Pediatr Ophthalmol Strabismus 42:216–221 81. Repka MX, Goldenberg-Cohen N, Edwards AR (2006) Retinal nerve ﬁber layer thickness in amblyopic eyes. Am J Ophthalmol 142:247–251 82. Yen M, Cheng C, Wang A (2004) Retinal nerve ﬁber layer thickness in unilateral amblyopia. Invest Ophthalmol Vis Sci 45:2224–2230

Chapter 11

Best Age for Surgery for Infantile Esotropia: Lessons from the Early vs. Late Infantile Strabismus Surgery Study

11

H.J. Simonsz, G. H. Kolling, and the Early vs. Late Infantile Strabismus Surgery Study Group

Core Messages ■

■

The result of surgery for infantile esotropia (IE) can be described by the following outcome parameters: (1) the binocular vision conserved or regained by early surgery, (2) the postoperative angle of strabismus and the long-term stability of alignment, and (3) the number of operations needed to reach these goals or the chance of spontaneous reduction of the strabismus into a microstrabismus without surgery. To judge the best age for surgery in a speciﬁc child with IE, the expected outcome of surgery should be estimated according to these parameters. There have been no studies with prospectively assigned early- and late-surgery groups and an evaluation according to intention-to-treat, other than the Early vs. Late Infantile Strabismus Surgery Study (ELISSS). The primary outcome of that study was that 13.5% of those operated at approximately 20 months of age against 3.9% (P =

11.1 11.1.1

Introduction Deﬁnition and Prevalence

Infantile esotropia (IE) is deﬁned as an esotropia with an onset before the age of 6 months, with a large angle of strabismus, no or mild amblyopia, small to moderate hypermetropia, latent nystagmus, dissociated vertical deviation, limitation of abduction, and absent or reduced binocular vision, in the absence of nervous system disorders [1, 2]. IE aﬀects approximately 0.25% of the population [3–5]. A higher prevalence has been found previously in studies where little distinction was made between

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0.001) of those operated at approximately 49 months recognized the Titmus Houseﬂy at the age of 6 years; there was no diﬀerence in stereopsis beyond Titmus Houseﬂy. Reoperation rates were 28.7% in the early and 24.6% in the late group. 8.2% of the children scheduled for early surgery and 20.1% of the children scheduled for late surgery had not been operated at the age of 6 years; most developed a microstrabismus. Esotropia less than 14° at baseline at approximately 11 months of age had not been operated at the age of 6 years in 35% of the cases. Hypermetropia around spher. + 4 increased the likelihood of regression without surgery, underscoring the need of full refractive correction. Findings of substantially ﬁner stereopsis after very early surgery await conﬁrmation in a randomized controlled trial.

esotropia with and without nervous system impairment. In a recent study among 627 consecutive strabismus patients younger than 19 years [6], 4.8% had congenital esotropia without and 7.0% congenital esotropia with nervous system impairment, including any nervous system impairment except speech delay.

11.1.2

Sensory or Motor Etiology

IE may have diﬀerent causes, ranging from sensory to motor defects. Prematurity, low birth weight, and low Apgar scores are signiﬁcant risk factors for IE [5]. Motor fusion, i.e., translating image disparity information into a

138

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Best Age for Surgery for Infantile Esotropia

vergence command to facilitate stereopsis, is a complex cerebral function that may well falter in nervous system damage, explaining the bad outcome of early surgery in such cases [7, 8]. On the other hand, if esotropia results from some motor disorder, like a congenital palsy or an anatomical anomaly of an eye muscle or the bony orbit, early surgery may well contribute to regain or conserve binocular vision with ﬁne stereopsis. As the cause of IE, whether sensory or motor, is the predominant determinant of the degree of binocular vision that may be conserved or regained by surgery, there is a strong need for ﬁner distinction among the subtypes of IE. IE should be considered, similar to the working deﬁnition formulated for congenital cerebral palsy [9], as a group of permanent, but not unchanging, disorders with strabismus and disability of fusional vergence and binocular vision, due to a nonprogressive interference, lesion, or maldevelopment of the immature brain, the orbit, the eyes, or its muscles, that can be diﬀerentiated according to location, extent, and timing of the period of development. Such an open matrix ﬁts both congenital esotropia without nervous system impairment and congenital esotropia with nervous system impairment, and also includes very early cases of accommodative esotropia that overlap with IE.

11.1.3

Pathogenesis: Lack of Binocular Horizontal Connections in the Visual Cortex

In IE, the horizontal binocular connections above and below the input layer in the visual cortex, which link ocular dominance columns of the right and left eyes [10], do not develop (sensory cause) or cannot develop (motor cause). They develop if the inputs from the right and left eye are obtained from corresponding images, facilitating fusional vergence and stereopsis [11–13]. At birth, each eye projects via both visual cortices to the contralateral middle temporal and medial superior temporal area, sensitive to motion and disparity, and responsible for ipsiversive OKR, ipsiversive pursuit, vergence, and gaze holding. Accordingly, infants can follow objects moving towards the nose more easily, the so called nasotemporal OKR and pursuit bias. The ipsilateral middle temporal and medial superior temporal areas are accessed via the binocular horizontal connections in V1 that only develop if binocular vision is possible. When these fail to develop, the nasotemporal bias persists and latent nystagmus develops [14–17]. The duration of the lack of binocular vision determines the

severity of the nasotemporal pursuit asymmetry [18] and of the latent nystagmus [19]. In cats and macaque monkeys made to squint shortly after birth by cutting the medial rectus muscles [10], cutting the lateral rectus muscles [20], or ﬁtting with prism goggles [21, 22], there is a lack of binocular horizontal connections in the visual cortex, correlated with the duration of the lack of binocular vision [22]. The restoration of binocular vision by removal of the prism goggles, simulating early surgery, demonstrated in these animals [18, 22], stresses the feasibility of early surgery in IE cases when its cause is motor. In another animal model, esotropia was found to occur naturally in macaque monkeys [23]. This seems more like IE in children than surgically induced esotropia [24], but many of the macaques had high hypermetropia [23, 24], their accessory lateral rectus muscle was absent [25], or their horizontal recti were twice as large as those of, albeit younger, controls [24].

11.1.4

History

Whatever its cause, whether sensory or motor, the end state of IE is characterized by lack of binocular vision, first described by Claud Alley Worth in 1903 [26] when he wrote: “In the human infant the motor coordinations of the eyes are already partially developed at birth. During the first few months of life these serve (in the absence of any disturbing influence) to maintain approximately the normal relative directions of the eyes. … When the fusion faculty has begun to develop, the instinctive tendency to blend the images formed in the two eyes … will keep the eyes straight. When the fusion faculty is fairly well developed, neither hypermetropia, nor anisometropia, nor heterophoria can cause squint. … Sometimes, however, owing to a congenital defect, the fusion faculty develops later than it should, or it develops very imperfectly, or it may never develop at all. Then, in this case, there is nothing but the motor coordinations to preserve the normal relative directions of the eyes, and anything which disturbs the balance of these coordinations will cause a permanent squint.”

11.1.5

Outcome Parameters

Several case-series studies opposing this view reported stereopsis in 35–80% after surgery at the age of 0–6 months [27–35]. Current US standard age of ﬁrst surgery

11.2

is approximately 12–18 months of age, and in many European countries, surgery for IE is performed at the age of 2 or 3 years. There has been a call recently for surgery within 2 months of the onset of esotropia [36]. However, there have been no randomized studies with prospectively assigned early-surgery and late-surgery groups and an evaluation according to intention-totreat. Elliot and Shaﬁq [37] concluded in their Cochrane review: “As there are no randomised controlled trials in the area at present, it has not been possible to resolve the controversies regarding … age of intervention in patients with IE. … There is clearly a need for good quality trials to be conducted in various areas of IE, in order to improve the evidence base for the management of this condition.” Indeed, one cannot exclude the possibility that in the retrospective case-series studies, without a control group, an occasional child may have been operated that would have straightened to 60˝ stereopsis without surgery. Three such cases occurred in the ﬁrst prospective study by Birch et al. [27] and two in the ELISSS. Therefore, instead of providing the reader with a quick recipe on whether to operate early or late, it seems more appropriate to list and discuss the outcome measures that should be considered when contemplating early, very early, or late surgery in a speciﬁc child. The primary outcome measures are the following:

1. The binocular vision conserved or regained by early surgery. 2. The angle of strabismus after surgery and the longterm stability of alignment. 3. The number of operations to reach these goals or the chance of spontaneous reduction of the strabismus into a microstrabismus without surgery. There are other outcome parameters that should be considered. For instance, the child’s psychological and motor development, and bonding between infant and parents may be improved by early surgery. These need evaluation within disciplines other than pediatric ophthalmology, however. Endophthalmitis after strabismus surgery [38] occurs preferentially in ﬁrst surgery in children under 6 years of age, but it is not yet clear whether its prevalence in young children diﬀers from that in very young children. Finally, general anesthesia may not be without risk in young children. As a case in point, in a recent population-based, retrospective birth cohort study, general anesthesia before the age of 4 years was signiﬁcantly correlated with learning disability [39].

Outcome of Surgery in the ELISSS

139

Summary for the Clinician ■

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IE may have many causes, ranging from motor to sensory. Whatever its cause, whether sensory or motor, the end state of untreated IE is characterized by lack of binocular vision. If its cause is motor, loss of binocular vision can, in principle, be limited by early surgery. Primary outcome measures of surgery are (1) binocular vision, (2) the angle and long-term stability of alignment, and (3) the number of operations or the chance of spontaneous reduction of the strabismus into microstrabismus without surgery.

11.2 11.2.1

Outcome of Surgery in the ELISSS Reasons for the ELISSS

Early surgery may minimize further loss of the remaining binocular vision. The ﬁrst prospective study of surgery for IE Birch et al. [27] reported 35% random dot stereopsis (disparity 400˝ or better) among 84 children operated at approximately 8.5 months. Sixty-three were aligned within 5.7°. The average number of operations was 1.5. Three were not operated and had full stereopsis. After this ﬁrst prospective study of surgery for IE had been published, the need was felt in Europe for a large, prospective, controlled multicenter trial comparing early surgery for IE with late surgery.

11.2.2

Summarized Methods of the ELISSS

In the ELISSS, all children with IE were included who ﬁrst presented to one of the participating clinics. The ELISSS study committee considered randomization impossible, because it was anticipated that the parents would not cooperate: One ﬁrst would have had to inform the parents of the possibility of surgery next week, only to postpone surgery for 2 years when the randomization procedure prescribed late surgery [40]. Instead, each of the participating clinics chose beforehand whether to operate all of their eligible patients in the recruitment period either early or late. Recruited children received an extensive baseline examination at 6–18 months of age, were assigned to early surgery (6–24 months) or late surgery (32–60 months), and were assessed at the age of 6 years. All children who ﬁrst presented with convergent IE between 5 and 30° were included. However,

11

11

Best Age for Surgery for Infantile Esotropia

children with pre- or dysmaturity, nystagmus, nervous system deﬁcit, retardation, dysmorphia or motility disorders other than up- or downshoot in adduction, V- or A-pattern, or limitation of abduction were excluded. Following recruitment, the angle of strabismus, refraction, degree of amblyopia, and limitation of abduction were assessed in an extensive baseline examination, based on a test–retest reliability study [41]. Orthoptic examinations, including angle and refraction, were repeated every 6 months. Cases with strongly established ﬁxation preference and/or signiﬁcant anisometropia underwent appropriate and eﬀective occlusion therapy to the point of near spontaneous alternation and central ﬁxation of the worse eye. Reoperation was undertaken in cases with a residual esotropia of greater than 10°, or in case of overcorrection. Children were evaluated at the age of 6 years in the presence of independent observers. Endpoints were level of binocular vision, manifest angle of strabismus at distance ﬁxation, remaining amblyopia, number of operations, vertical strabismus, angle at near, and inﬂuence of surgical technique.

11.2.3

Summarized Results of the ELISSS

A total of 58 clinics in 13 countries recruited 532 children: 231 children at the age of 11.1 SD 3.7 months (baseline) for early surgery and 301 at the age of 10.9 SD 3.7 months for late surgery. An additional 442 patients screened for inclusion were excluded for various reasons, like prematurity (32), congenital nystagmus (49), or nervous system deﬁcit (99). No diﬀerences between groups were found in the baseline examination apart from a slightly larger angle in the early group [42]. Of 532 patients, 414 were evaluated at the age of 6 years in the presence of independent observers (82.7% of all forms were signed by the independent observer). Dropout rates were 26.0% in the early and 22.3% in the late group, but no diﬀerences existed between dropouts and completers in the baseline examination, and clinics with many dropouts did not have better results. The ﬁnal examinations were performed at the age of 6.8 SD 0.8 years, on average, in the early group and 6.8 SD 0.7 years in the late group. The interval between the last operation and the ﬁnal examination was 4.4 SD 1.5 years in 157 children from the early group, and 2.3 SD 1.1 years in 187 children from the late group. The number of orthoptic examinations in the early group was 11.3 SD 5.2 per patient, including all children who later became dropouts; in the late group, it was 11.4 SD 4.6.

60

Percentage for unoperated and operated patients

140

50

40

30

20

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0

1

2

3

4

5

6

7

1

2

3

4

5

6

7

early late Degree of binocular vision

Fig. 11.1 Binocular vision at the age of 6 years after early or late surgery, stratiﬁed according to whether the children had been operated (black) or not (white) at the age of 6 years. Categories: (1) Bagolini negative, (2) Bagolini positive, (3) Houseﬂy positive, (4) Titmus circles 200˝–140˝, (5) Titmus circles 100˝–40˝, (6) all ﬁgures of Lang Test or TNO 480˝ and 240˝, (7) TNO 120˝–15˝ (See Ref. [57])

11.2.4

Binocular Vision at Age Six

At the age of 6 years, 51.2% of the early vs. 44.7% of the late group recognized Bagolini striated glasses, and 13.5% of the early vs. 3.9% (P = 0.001) of the late group recognized the Titmus Houseﬂy; 3.0% of the early and 3.9% of the late group had stereopsis beyond Titmus Houseﬂy (Fig. 11.1). Some children had been operated beyond the set time frame (6–18 and 32–60 months), but “as treated” analysis yielded the same result.

11.2.5 Horizontal Angle of Strabismus at Age Six At the age of 6 years, the manifest horizontal angle during ﬁxation at distance was 2.15° SD 5.45° in the early group (N = 167) and 3.21° SD 6.29° in the late group (N = 231), wearing full refractive correction. Surprisingly, 35.1% of

11.2

141

Outcome of Surgery in the ELISSS

40

30

Horizontal angle of strabismus

Percentage for unoperated and operated patients

30

20

10

20

10

0

–10

–20 0 24 > 24 = < 0 =2 < 6 =1 < 2 =1 < 8 = < 4 = < 0 = < −4 = < −8 = 2 < −1 = <

24 > 24 = < 0 =2 < 6 =1 < 2 =1 < 8 = < 4 = < 0 = < −4 = < −8 = 2 < −1 = <

–10

early late Horizontal angle of strabismus (deg)

0

10

20

30

40

Horizontal angle of strabismus at baseline

Fig. 11.2 (Left) Manifest horizontal angle of strabismus in degrees for both groups at the ﬁnal examination at the age of 6 years (N = 414), stratiﬁed according to whether the children had been operated (black) or not (white). (Right) Relationship between horizontal angle at approximately 11 months and horizontal angle at the age of 6 years. Note that the variation of the horizontal angle of strabismus at approximately 11 months was similar to that at the age of 6 years. Note that one dot may represent more children (See Ref. [57])

the early-surgery group and 34.8% of the late-surgery group were not aligned within 0–10°, despite the fact that the protocol prescribed to continue surgery until alignment within 0–10° had been reached. Many children had a small exotropia (especially in the early group), but in other cases, a large esotropia existed that had not been considered a priority by the parents in the period preceding the ﬁnal examination. It was also surprising that the variation of the angle of strabismus at age 6 was equal to its variation at baseline at 11 months (Fig. 11.2). These ﬁndings underscore that surgery for IE is elective and, as clinicians, we primarily see patients while they are being treated by us until they are straight.

IE” [45] among older children, 38.4% of the children had a positive Bagolini test postoperatively, although all children with any form of binocular vision preoperatively had been excluded. These children had signiﬁcantly better ocular alignment, which may have been either a cause or a consequence of the gain of binocular vision.

Summary for the Clinician ■

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11.2.6 Alignment is Associated with Binocular Vision Children with at least Titmus Houseﬂy stereopsis were better aligned (Fig. 11.3). Better alignment in case of better binocular vision has been found by Birch et al. [43] and Fu et al. [44]. In the study “Randomized comparison of bilateral recession vs. unilateral recession-resection for

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In the ELISSS, children with IE operated around the age of 20 months, achieved Bagolini striated glasses or Titmus Houseﬂy stereopsis more frequently as compared to those operated around the age of 49 months. No diﬀerence was found, however, for stereopsis beyond Titmus Houseﬂy. Alignment was similar after early surgery, as compared to that after late surgery, but a large variation of the angle of strabismus was found at the age of 6 years in both groups. Children with stereopsis were aligned better, which may have been either a cause or a consequence of the gain of binocular vision.

142

Best Age for Surgery for Infantile Esotropia

Fig. 11.3 Relation between the level of binocular vision and angle of strabismus at distance ﬁxation for both groups (N=414). Black dots represent the patients who had not been operated at the age of 6 years. One dot may represent more than one child (See Ref. [57])

TNO test 120” or better

Lang test (all) or TNO test 480” to 240”

Titmus circles 100” to 40”

Titmus circles 200” to 140”

Housefly positive

Bagolini positive

Bagolini negative –15

80

11.3 Number of Operations and Spontaneous Reduction into Microstrabismus Without Surgery

70

11.3.1 The Number of Operations Per Child and the Reoperation Rate in the ELISSS In the ELISSS, the number of operations among the children who completed the study was 1.181 SD 0.67 per child in the early group (N = 171) and 0.996 SD 0.64 in the late group (N = 234), including children who were scheduled for surgery, but had not been operated at the age of 6 years. Children scheduled for early surgery had been ﬁrst operated at 20.0 SD 8.4 months, but 8.19% (14) had not been operated at the age of 6 years. Children scheduled for late surgery had been ﬁrst operated at 49.1 SD 12.7 months, but 20.09% (47) had not been operated at the age of 6 years. Accordingly, the reoperation rates were 1.181/(1–0.0819)–1 = 28.7% in the early group and 0.996/(1–0.2009)–1 = 24.6% in the late group, including second and third reoperations. Among the children operated 2 or 3 times, only a few were operated for consecutive divergence, although consecutive divergence occurred frequently (Fig. 11.4).

11.3.2

25

–10 –5 0 5 10 15 20 Horizontal manifest angle of strabismus in degrees at age 6 in degrees for operated (grey circles) and unoperated (black) cases

Reported Reoperation Rates

Reported reoperation rates range from 11% after early surgery to 70% after very early surgery [46–54]. Studies

60

Percent

11

11

50 40 30 20 10 0 0

1

2 early

3

4

0

1

2

3

4

late

Number of operations Surgery Group

Fig. 11.4 Number of operations per child. Among the children operated 2 or 3 times, only a few were operated for consecutive divergence (black), although consecutive divergence occurred frequently. One child from the early group was operated twice for consecutive divergence (striated). Note that 8.2% from the early group and 20.1% from the late group had not been operated at the age of 6 years (See Ref. [57])

11.3 Number of Operations and Spontaneous Reduction into Microstrabismus Without Surgery

with follow-up between 1 and 2 years [7, 48, 51–53] have reported reoperation rates between 8 and 35%. Studies with 7 or 8 years of follow-up have reported 33% for late [47], 11% for early [54], and 70% for very early [49] surgery. In a recent population study by Louwagie et al. [4] over a period of 30 years in Olmsted County, the 130 cases of IE that had occurred underwent a mean of 1.80 operations during a mean follow-up period of 13.5 years from their date of diagnosis, i.e., a 80% reoperation rate, including second and third reoperations. The median age at operation was 14 months, the average age was 18 months. In a multicenter study by Van de Vijver-Reenalda et al. [55], reoperation rates were assessed 6–23 years after ﬁrst surgery had taken place among 181 patients. These patients were consecutive cases of the registries of surgery in each of the seven participating university clinics. Nine patients could not be contacted by telephone, and in six patients, the postoperative angle of strabismus 3 months postoperatively was unknown. Of the remaining 166 patients, on average 4.33 years old at surgery, 32 had a reoperation, in 60% of cases within 2 years after the ﬁrst operation. Average reoperation rate was 19.3%. Logistic

143

regression analysis showed no statistically signiﬁcant difference between clinics concerning chance of reoperation. To test whether the large diﬀerences between reported reoperation rates after early surgery, mentioned earlier, were due to the diﬀerences in the duration of follow-up, a meta-regression was performed. For each study, the mean duration of follow-up, the mean age at operation, and the reoperation rate were obtained from the publication or original data. The mean duration of follow-up and mean age at operation were regressed on the logistically transformed reported reoperation rate. The meta-regression model had an R-squared value of 0.44. The inﬂuence of this confounding factor was estimated in a multivariate logistic model. Reoperation rates were adjusted for duration of follow-up with the meta-regression model and plotted against the mean age at operation for each study (Fig. 11.5). After adjustment of the reoperation rates reported after short follow-up periods, reoperation rates became more similar to the rate reported by Helveston et al. [49] after a long follow-up period. A trend for more reoperations after early surgery when compared with that after late surgery can be noted (Fig. 11.5).

100%

Louwagie [4] 80% Helveston [49] Stager [64] Charles [7] 60%

Keenan [51]

Kushner [52]

Early [57] Nelson [53] 40% Bartley [47] Late [57]

Vijver [55]

Helveston [48]

20%

Tolun [92] Reoperation rate 0% 0

Age in months

12

24

36

48

60

Fig. 11.5 Exploratory meta-analysis of studies reporting reoperation rates (closed circles) after surgery for IE. “Early” and “Late” refer to the early and late groups of the ELISSS. The reoperation rates after shorter follow-up periods were corrected for the duration of follow-up with a multivariate logistic model (closed black squares)

144

11

Best Age for Surgery for Infantile Esotropia

11.3.3 Test-Retest Reliability Studies

50

Angle (degrees) measured by second or third orthoptist

11

One of the reasons contributing to a higher reoperation rate after early surgery is the inaccuracy in measuring the angle of strabismus in young children. In a test-retest reliability study [41] preceding the ELISSS a total of 190 infants of the age of 12.1 SD 2.5 (range 9–15) months were examined in ten university clinics on one day by three orthoptists. Fifteen parameters of the orthoptic examination were assessed that were considered to be of prognostic importance and, hence, suited to detect and correct for disparities between the groups in the ELISSS. In 144 of the 190 infants, the manifest horizontal angle of strabismus was estimated, either with prisms and corneal reﬂexes during ﬁxation of an object with a light at 50 cm or by estimation of the location of the corneal reﬂex relative to the pupil during ﬁxation of an object with a light at 50 cm. The angle of strabismus averaged 21° for the ﬁrst, second, and third examinations, with approximately equal standard deviations for all three examinations. The intraclass correlation coeﬃcient (diﬀerences between

three examiners examining one infant, 1.0 signifying complete agreement) was 0.80. The distribution for the largest diﬀerence between any two of the three measured angles averaged 6.5°. In 10% of the infants, the largest difference between any two of the three measured angles exceeded 10°. Standard deviations and intraclass correlation coeﬃcients were the same for both the methods of measurement (Fig. 11.6). In a recent similar study [56], 143 children aged 22.2 SD 15.0 months (range 2.1–60.2) with esotropia were examined by two masked examiners on one or two occasions yielding 199 test-retest pairs for prism and alternate cover test at distance ﬁxation and 239 at near ﬁxation. For angles greater than 11.3°, the 95% limits of agreement on a measurement and on a diﬀerence between two measurements were ±4.2 and ±5.9° for prism and alternate cover test at distance and ±4.7 and ±6.7° at near. For angles of 5.7–11.3°, they were ±2.3 and ±3.3° at distance and ±1.9 and ±2.7° at near. From these two studies, it is evident that one of the reasons contributing to a higher reoperation rate after

40

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0 0

10 20 30 40 Angle (degrees) measured by first or second orthoptist (N=144 children x 3 pairs of measurements)

50

Fig. 11.6 144 infants at approximately one year of age were examined in ten university clinics on one day by three orthoptists or, rarely, by a strabismologist. The horizontal angle of strabismus was measured, either with prisms and corneal reﬂexes or by estimation of the location of the corneal reﬂex relative to the pupil. Larger circles represent more measurements

145

11.3 Number of Operations and Spontaneous Reduction into Microstrabismus Without Surgery

early surgery is the inaccuracy in measuring the angle of strabismus in young children.

11.3.4

Relation Between the Postoperative Angle of Strabismus and the Reoperation Rate

Variance in the preoperative measurement of the horizontal angle results in variance of the postoperative angle. However, does postoperative variance of the angle cause additional reoperations? In the study by Van de Vijver-Reenalda et al. [55] on reoperation rates 6–23 years after ﬁrst surgery in children operated at 4.33 years, on average, the average reoperation rate was 19.3%. The reoperation rate was only 7.3%, however, for those with a residual angle of −4 to +4° (82, 49.4%), 3 months postoperatively. The reoperation rate was 25% for children who were divergent in excess of 5° and 29% for children between 10 and 14° convergent, 3 months postoperatively. For comparison, eight strabismologists, the heads of the departments where the retrospective study had been done, were asked to give their estimations of the reoperation rate based on the angle of strabismus at distance

ﬁxation, 3 months postoperatively. They estimated the reoperation rate at almost double, probably because of an observer bias, as patients who come for reoperation are more vividly remembered (Fig. 11.7).

11.3.5

Scheduled for Surgery, but no Surgery Done at the End of the Study at the Age of Six Years

In the ELISSS, children scheduled for early surgery had been ﬁrst operated at 20.0 SD 8.4 months, but 8.19% (14) had not been operated at the age of 6 years. Children scheduled for late surgery had been ﬁrst operated at 49.1 SD 12.7 months, but 20.09% (47) had not been operated at the age of 6 years. In his analysis of 500 children with IE [1], Costenbader identiﬁed the size and variability of the angle, onset at birth, duration of strabismus, age at presentation, age at surgery, hypertropia, and amblyopia as “factors that inﬂuence cure”. Ahead of his time, Costenbader included 80 cases in his analysis who had not been operated at all. He analyzed his data truly in accordance with the “intention to treat” principle. These 80 children had “alignment and fusion” in 76% of the cases, when compared with 38.4%

Observed reoperation rate and experts' estimates (%)

90 N=12 80 70 60 50 40 30

N=17 N=4 N=51

20 N=62

10 0

N=20 < -5°

-4 to -1° 0 to 4° 4 to 9° 10 to 14° Postoperative angle of strabismus in degrees, 3 months postoperatively

> 14°

Fig. 11.7 Observed reoperation rate in relation to angle of strabismus 3 months postoperatively in 166 patients operated between 6 and 23 years previously (black) and average estimates by eight strabismologists (white)

146

11

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Best Age for Surgery for Infantile Esotropia

of children operated once and 36% of children operated twice. In the studies by Costenbader [1], by Birch (1990) and in the ELISSS [57], children who had been scheduled for surgery but who had not been operated at ﬁnal assessment had better binocular vision than those who had been operated. Spontaneous resolution of infantile strabismus has ﬁrst been reported by Clarke & Noel [58]. In a study by the Pediatric Eye Disease Investigator Group [59], among 170 children with IE (age ±3 months at recruitment), of those who had had an angle of strabismus >21.8° during two examinations at least one week apart, 2.4% had an angle <4.6° at ±7 months. Among those children who had had an angle of strabismus >11.3° during two examinations at recruitment, 27% had an angle <4.6° at ±7 months. Reduction of the angle within 5° frequently results in microstrabismus with peripheral fusion, central suppression, and a favorable appearance. Due to the peripheral fusion, the strabismus remains stable and rarely needs additional surgery, as has been found for small angles postoperatively in the study by Van de Vijver et al. [55].

11.3.6 Spontaneous Reduction of the Angle In the ELISSS, more than half of the children who were scheduled for surgery, but had not been operated at the age of 6 years, had a spontaneous reduction of the strabismus into a microstrabismus (Fig. 11.8). There are few studies with similar longitudinal measurements of the angle of strabismus in a large group of children. In a recent study by Pediatric Eye Disease Investigator Group [60], the angle of strabismus was measured in 81 children with IE aged 6.0 ± 1.7 months (range 2.4–9.5) at baseline and at 6-week intervals for 18 weeks, using prism and alternate cover test at near (70% of the children) or a modiﬁed Krimsky at near (30%). In 20%, all four measurements were within 2.9° or less than one another. In 46%, any two of the four measurements differed by 8.5° or more. Could we have distinguished the ELISSS children who were scheduled for surgery but, in the end, were never operated, at an early age? In other words, can the reduction of the angle be predicted and, hence, unnecessary operations be avoided in individual cases by waiting? This line of reasoning only pertains to the majority of cases where microstrabismus with peripheral fusion is the best possible result. One cannot exclude the rare possibility that an occasional child, with a pure motor cause of IE, would achieve full binocular vision with 60 arc seconds stereopsis by very early surgery.

11.3.7 Predictors of Spontaneous Reduction into Microstrabismus In the ELISSS, of all parameters assessed in the baseline examination at approximately 11 months, only the angle of strabismus at baseline predicted, to some extent, whether a child had been operated at the age of 6 years or not (Fig. 11.9). Among children with an angle equal or smaller than 13° at baseline at approximately 11 months, 34.9% had not been operated at the age of 6 years. Hypermetropia around spher. + 4 increased the likelihood of regression without surgery, emphasising the need for full refractive correction (there may have been some very early cases of accommodative esotropia). Age at recruitment, age that strabismus reportedly had started and degree of amblyopia at baseline examination seemed not predictive.

11.3.8

Random-Eﬀects Model Predicting the Angle and its Variation

In the 532 children of the ELISSS, the angle of strabismus, refraction, and visual acuity was assessed at baseline at approximately 11 months and every 6 months thereafter, until the ﬁnal evaluation at the age of 6 years. The resulting, slightly more than 6,000, orthoptic exams were used to construct a random-eﬀects model [61] that forecasts the expected angle and its variation years ahead, on the basis of one or more measurements of the angle and refraction in infancy. Angles of strabismus measured at diﬀerent ages and the refraction of the patient can be entered in the model. On entering successive measurements of the angle of strabismus, the model adjusts the slope, i.e., yearly increase or decrease of the expected angle, according to the trend. The uncertainty about the slope decreases with additional measurements because the random eﬀect of the slope of the lines decreases. The uncertainty about the slope is compounded by additional variation of the angle around this slope for an individual child (Fig. 11.10). In simulations with the random-eﬀects model, it was found that the chance of a spontaneous reduction of a strabismus into a microstrabismus is considerable when an angle of strabismus 14° or less is found repeatedly at the age of 1 or 2 years. In the ELISSS, esotropia 13° or less at baseline at approximately 11 months of age had not been operated at the age of 6 years in 35% of the cases (Fig. 11.7). If the angle is large on multiple measurements, the chance that the esotropia will decrease into a microstrabismus spontaneously is very small.

147

11.3 Number of Operations and Spontaneous Reduction into Microstrabismus Without Surgery 30

Horizontal angle of strabismus

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Age at examination (months)

Fig. 11.8 The upper panel shows the 6-monthly measurements of the angle of strabismus in those ELISSS children who had been scheduled for early surgery at baseline at approximately 11 months of age, but had not been operated at the age of 6 years (14, 8.2%). The lower panel shows these measurements for the children who had been scheduled for late surgery, but had not been operated at the age of 6 years (47, 20.1%). These children correspond to the white bars in Figs. 11.1, 11.2, and 11.9

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Best Age for Surgery for Infantile Esotropia

In the model, refractive error exerted its largest inﬂuence, i.e., causing the largest chance of spontaneous reduction into a microstrabismus, at a spher. + 4. Some children in the ELISSS study population may actually have been very early cases of accommodative esotropia. In case of hypermetropia, especially with convergence excess, a large reduction in the angle may occur after ﬁtting full correcting glasses, thereby avoiding surgery.

20

10

Summary for the Clinician ■

0

29 > 29 = £ 25 = £ 21 = £ 17 = £ 13 = £ 9 = £ 5 =

£

29 > 29 = £ 25 = £ 21£ = £ 17 = £ 13 = £ 9 = £ 5 =

£

Early

Late

■

Horizontal angle of strabismus (degrees)

Fig. 11.9 Angle of strabismus at baseline at approximately 11 months for all 414 operated (black) and unoperated (white) patients who underwent the ﬁnal examination at the age of 6 years (same group as in Figs. 11.1 & 11.2). Children who had not been operated at the age of 6 years (white bars) had had smaller angles at baseline (See Ref. [57])

The chance of a spontaneous reduction of the esotropia into microstrabismus is considerable when an angle of strabismus of 13° or less is found repeatedly at the age of 1 year. Fit full-correcting glasses in case of hypermetropia accompanying esotropia at an early age because a large reduction of the angle of strabismus can be achieved without surgery and with better binocular vision.

40

40

35

35

30

30

Measured angle (deg.)

Measured angle (deg.)

11

Percentage for unoperated and operated patients

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25 20 15 10

25 20 15 10 5

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36 48 Age (months)

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72

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36 48 Age (months)

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Fig. 11.10 Random-eﬀects model predicting the angle and its variation based on one or more measurements of the angle and refraction in infancy. For the construction of this model, the random eﬀect for a patient was deﬁned as the deviation of the average angle, the ﬁxed eﬀect. A vector was deﬁned based on age and spherical equivalent of the patient. A covariance matrix of the randomeﬀects estimations was deﬁned and ﬁlled with the values from the approximately 6,000 orthoptic exams in 532 children. The model predicts the average angle in relation to age. A linear relation suﬃced. The variance around the prediction (curved lines represent one and two standard deviations) consists of uncertainty in the estimations, random eﬀects and the residuals. Left: an example prediction based on three increasing angles measured at 9, 12 and 15 months. Right: an example prediction where the angle decreases in successive measurements; the chance that spontaneous reduction into a microstrabismus occurs is considerable

References

Appendix Members of the Early vs. Late Infantile Strabismus Surgery Study Group were: (Austria) A. Langmann, S. Lindner, S. Priglinger, M. Raab, H. Thaller-Antlanger, D. KoschkarMoser, H. Gruber-Luka, R. Führer, S. Harrer, K. Rigal, R. Pelz, B. Puchhammer, A. Thaler, E. Moser, K. Schmidt, (Belgium) M. Spiritus, M. van den Broeck, S.Vandelannoitte, A. Finck, P. Evens, D. Godts, (France) M. BourronMadignier, S. Vettard, O. Benhadj, (Germany)E-Ch. Schwarz, G. Wunsch, C. Jandeck, S. Lutt-Freund, D. JüptnerJohanning, E. Sommer, G. Hochmuth, G. Gusek-Schneider, Schürhoﬀ, A. Boss, A. Zubcov, B. Herrmann, G. Kommerell, B. Lieb, R. Weidlich, U. Wittenbecher, E. Schulz, K. Rettig, G. Kolling, B. Stoll, B. Käsmann, E. Grintschuk, A. Kirsch, T. Schmidt, M. Klopfer, C. Ecker, K.P. Boergen, O. Ehrt, H.D. Schworm, B. Lorenz, B. Derr, (Great Britain) C.J. McEwen, I. Marsh, L. Gannon, C. Timms, D. Taylor, P. Fells, J.P. Lee, (Italy) R. Frosini, L. Campa, F. Carta, A. Carta, (Netherlands) L. Wenniger-Prick, Y EverhardHalm, A.G. Tjiam, M. van Duuren, H.J. Simonsz, H.M. van Minderhout, (Norway) G. Hanken, A. Angermeier, O.H. Haugen, L. Steene Eriksen, B. A. Olsen, E. Dueland, W. Evans Lothe, T. Bulie, H.P. Brinck, T. Kalseth, (Sweden) G. Ladenvall, A.B. Edvinsson, A. Wallin, R. Alvarado, M. Fornander, U. Lidén, L. Lindberg, I. Wiklund, G. Lennerstrand, B. Derouet-Eriksson, B. Sunnqvist, G. Gunnarssen, P. Jakobsson, G. Kvarnström, M. Lindberg, D. Grandell, K. Johansson, A.-L. Galin, I. Axelsson, B.-M. Petersson, (Switzerland) G. Klainguti, J. Strickler, K. Landau, B. Baerlocher, (Turkey) G. Haciyakupoglu, A. Seﬁk Sanaç, E. Cumhur Sener, S. Demirci, N. Erkam, Huban Atilla, N. Erda, A. Tulin Berk. Statististical analysis of the ELISSS was performed by K. Unnebrink of the Coordination Center for Clinical Trials, University Hospital Heidelberg. All other statistical analyses were performed by M.J.C. Eijkemans of the Department of Public Health, Erasmus Medical Center, Rotterdam.

References 1. Costenbader FD (1961) Infantile esotropia. Trans Am Ophthalmol Soc 59:397–429 2. Von Noorden GK. (1988) A reassessment of infantile esotropia. XLIV Edward Jackson memorial lecture. Am J Ophthalmol 105:1–10 3. Greenberg AE, Mohney BG, Diehl NN, Burke JP (2007) Incidence and types of childhood esotropia: a populationbased study. Ophthalmology 114:170–174 4. Louwagie CR, Diehl NN, Greenberg AE (2009) Mohney BG. is the incidence of infantile esotropia declining? A

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population-based study from Olmsted County, Minnesota, 1965 to 1994. Arch Ophthalmol 127:200–203 Mohney BG, Erie JC, Hodge DO, Jacobsen SJ (1998) Congenital esotropia in Olmsted County, Minnesota. Ophthalmology 105:846–850 Mohney BG (2007) Common forms of childhood strabismus in an incidence cohort. Am J Ophthalmol 144: 465–467 Charles S, Moore A (1992) Results of early surgery for infantile esotropia in normal and neurologically impaired infants. Eye 6:603–606 Holman RE, Merritt JC (1986) Infantile esotropia: results in the neurologic impaired and “normal” child at NCMH (six years). J Pediatr Ophthalmol Strabismus 23: 41–45 Surveillance of cerebral palsy in Europe (SCPE) (2002) Prevalence and characteristics of children with cerebral palsy in Europe. Dev Med Child Neurol 44:633–640 Hubel DH, Wiesel TN (1965) Binocular interaction in striate cortex of kittens reared with artiﬁcial squint. J Neurophysiol 28:1041–1059 Tychsen L, Burkhalter A (1995) Neuroanatomic abnormalities of primary visual cortex in macaque monkeys with infantile esotropia: preliminary results. J Pediatr Ophthalmol Strabismus 32:323–328 Tychsen L, Burkhalter A (1997) Nasotemporal asymmetries in V1: ocular dominance columns of infant, adult, and strabismic macaque monkeys. J Comp Neurol 388: 32–46 Tychsen L, Wong AM, Foeller P, Bradley D (2004) Early versus delayed repair of infantile strabismus in macaque monkeys: II. Eﬀects on motion visually evoked responses. Invest Ophthalmol Vis Sci 45:821–827 Hoﬀmann KP (1983) Eﬀects of early monocular deprivation on visual input to cat nucleus of the optic tract. Exp Brain Res 51:236–246 Hoﬀmann KP, Distler C (1986) The role of direction selective cells in the nucleus of the optic tract in the cat and monkey during optokinetic nystagmus. In: Keller EL, Zee DS (eds) Adaptive processes in visual and oculomotor systems. Pergamon: New York, pp 261–266 Hoﬀmann KP, Bremmer F, Thiele A, Distler C (2002) Directional asymmetry of neurons in cortical areas MT and MST projecting to the NOT-DTN in macaques. J Neurophysiol 87:2113–2123 Tychsen L, Lisberger SG (1986) Maldevelopment of visual motion processing in humans who had strabismus with onset in infancy. J Neurosci 6:2495–2508 Hasany A, Wong A, Foeller P, Bradley D, Tychsen L (2008) Duration of binocular decorrelation in infancy predicts the severity of nasotemporal pursuit asymmetries in strabismus macaque monkeys. Neuroscience 156:403–411

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19. Richards M, Wong A, Foeller P, Bradley D, Tychsen L (2008) Duration of binocular decorrelation predicts the severity of latent (fusion maldevelopment) nystagmus in strabismic macaque monkeys. Invest Ophthalmol Vis Sci 49:1872–1878 20. Crawford ML, von Noorden GK (1979) The eﬀect of shortterm experimental strabismus on the visual system in macaca mulatta. Invest Ophthalmol Vis Sci 18:496 21. Crawford ML, von Noorden GK (1980) Optically induced concomitant strabismus in monkeys. Invest Ophthalmol Vis Sci 19:1105–1109 22. Wong AM, Foeller P, Bradley D, Burkhalter A, Tychsen L (2003) Early versus delayed repair of infantile strabismus in macaque monkeys: I. ocular motor eﬀects. J AAPOS 7:200–209 23. Kiorpes L, Boothe R (1981) Naturally occurring strabismus in monkeys (Macaca nemestrina). Invest Ophthalmol Vis Sci 20:257–263 24. Tychsen L, Richards M, Wong A, Foeller P, Burhkalter A, Narasimhan A, Demer J (2008) Spectrum of infantile esotropia in primates: behavior, brains, and orbits. J AAPOS 12:375–380 25. Boothe RG, Quick MW, Joosse MV, Abbas MA, Anderson DC (1990) Accessory lateral rectus orbital geometry in normal and naturally strabismic monkeys. Invest Ophthalmol Vis Sci 31:1168–1174 26. Worth CA (1903) Squint: its causes, pathology and treatment. John Bale, Sons and Danielsson, London 27. Birch EE, Stager DR, Berry P, Everett ME (1990) Prospective assessment of acuity and stereopsis in amblyopic infantile esotropes following early surgery. Invest Ophthalmol Vis Sci 31:758–765 28. Birch EE, Stager DR, Everett ME (1995) Random dot stereoacuity following surgical correction of infantile esotropia. J Pediatr Ophthalmol Strabismus 32:231–235 29. Birch E, Stager D, Wright K, Beck R (1998) The natural history of infantile esotropia during the ﬁrst six months of life. Pediatric eye disease investigator group. J AAPOS 2:325–328 30. Birch EE, Stager DR Sr (2006) Long-term motor and sensory out comes after early surgery for infantile esotropia. J AAPOS 10:409–413 31. Ing MR, Costenbader FD, Parks MM, Albert OO (1966) Early surgical treatment for congenital esotropia. Am J Ophthalmol 652:1419–1427 32. Ing MR (1981) Early surgical alignment for congenital esotropia. Trans Am Ophthalmol Soc 79:625–663 33. Ing MR (1995) Surgical alignment prior to six months of age for congenital esotropia. Trans Am Ophthalmol Soc 93:135–146

34. Ing MR, Okino LM (2002) Outcome study of stereopsis in relation to duration of misalignment in congenital esotropia. J AAPOS 6:3–8 35. Wright KW, Edelman PM, McVey JH, Terry AP, Lin M (1994) Highgrade stereo acuity after early surgery for congenital esotropia. Arch Ophthalmol 112:913–919 36. Tychsen L (2005) Can ophthalmologists repair the brain in infantile esotropia? Early surgery, stereopsis, monoﬁxation syndrome, and the legacy of Marshall Parks. J AAPOS 9:510–521 37. Elliott S, Shaﬁq A (2005) Interventions for infantile esotropia. Cochrane Database of Systematic Reviews Issue 1. Art. No.: CD004917. DOI: 10.1002/14651858.CD004917.pub2 38. Simonsz HJ, Batstra MR, Mooy CM, van Leeuwen WB, Löﬄer KU, Hartwig NG (2009) Age-related immune defects causing endophthalmitis after strabismus surgery in young children or in elderly. Invest Ophthalmol Vis Sci 50:ARVO E-Abstract 1134 39. Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO (2009) Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 110:796–804 40. Early vs late infantile strabismus surgery study group (1993a) The protocol for the Early vs. Late infantile strabismus surgery study. Strabismus 1:135–157. 41. Early vs late infantile strabismus surgery study group (1993b) How accurate is orthoptic examination at age one? Strabismus 1:75–83 42. Meyer K, Breitschwerdt H, Kolling GH, Simonsz HJ (1998) The early vs. late infantile strabismus surgery study: do sources for bias exist in this non-randomized trial? Br J Ophthalmol 82:934–938 43. Birch EE, Felius J, Stager DR Sr, Weakley DR Jr, Bosworth RG (2004) Pre-operative stability of infantile esotropia and post-operative outcome. Am J Ophthalmol 138: 1003–1009 44. Fu VL, Stager DR, Birch EE (2007) Progression of intermittent, small angle, and variable esotropia in infancy. Invest Ophthalmol Vis Sci 48:661–664 45. Polling JR, Eijkemans MJ, Esser J, Gilles U, Kolling GH, Schulz E, Lorenz B, Roggenkämper P, Herzau V, Zubcov A, Ten Tusscher MP, Wittebol-Post D, Gusek-Schneider GC, Cruysberg JR, Simonsz HJ (2009) A randomised comparison of bilateral recession vs. unilateral recession-resection as surgery for infantile esotropia. Br J Ophthalmol 93:954–957 46. Arnoult JB, Yeshurun O, Mazow ML (1976) Comparative study of the surgical management of congenital esotropia of 50 prism diopter or less. J Pediatr Ophthalmol 13:129–131

References 47. Bartley GB, Dyer JA, Ilstrup DM (1985) Characteristics of recession-resection and bimedial recession for childhood esotropia. Arch Ophthalmol 103:190–195 48. Helveston EM, Ellis FD, Schott J, Mitchelson J, Weber JC, Taube S, Miller K (1983) Surgical treatment of congenital esotropia. Am J Ophthalmol 96:218–228 49. Helveston EM, Neely FN, Stidham DB, Wallace DK, Plager DA, Sprunger DT (1999) Results of early alignment of congenital esotropia. Ophthalmology 106:1716–1726 50. Hiles DA, Watson BA, Biglan AW (1980) Characteristics of infantile esotropia following early bimedial rectus recession. Arch Ophthalmol 98:697–703 51. Keenan JM, Willshaw HE (1992) Outcome of strabismus surgery in congenital esotropia. Br J Ophthalmol 76: 342–345 52. Kushner BJ, Morton GV (1984) A randomized comparison of surgical procedures for infantile esotropia. Am J Ophthalmol 98:50–61 53. Nelson LB, Calhoun JH, Sion JW, Wilson T, Harley RD (1987) Surgical management of large angle congenital esotropia. Br J Ophthalmol 71:380–383 54. Tolun H, Dikici K, Ozkiris A (1999) Long-term results of bimedial rectus recessions in infantile esotropia: J Pediatr Ophthalmol Strabismus 36:201–205 55. Van de Vijver-Reenalda H, Polling JR, Simonsz HJ, Cruysberg JRM, Kommerell G, Schulz E, Wenniger-Prick LJJM (1999) Cumulatieve kans op heroperatie gerelateerd aan de postoperatieve scheelzienshoek bij congenitaal

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scheelzien: een retrospectief onderzoek. Ned Tijdschr Geneesk 143:2121 Pediatric Eye Disease Investigator Group (2009) Interobserver reliability of the prism and alternate cover test in children with esotropia. Arch Ophthalmol 127: 59–65 Simonsz HJ, Kolling GH, Unnebrink K (2005) Final report of the early vs. late infantile strabismus surgery study (ELISSS), a controlled, prospective, multicenter study. Strabismus 13:169–199, Erratum (2006) Strabismus 14: 127–128 Clarke WN, Noel LP (1982) Vanishing infantile esotropia. Can J Ophthalmol 17:100–102 Pediatric Eye Disease Investigator Group (2002) Spontaneous resolution of early onset-esotropia: experience of the congenital esotropia observational study. Am J Ophthalmol 133:109–118 Pediatric Eye Disease Investigator Group, Christiansen SP, Chandler DL, Holmes JM, Arnold RW, Birch E, Dagi LR, Hoover DL, Klimek DL, Melia BM, Paysse E, Repka MX, Suh DW, Ticho BH, Wallace DK, Weaver RG Jr (2008) Instability of ocular alignment in childhood esotropia. Ophthalmology. 115:2266–2274 Simonsz HJ, Eijkemans MJC, Early vs Late Strabismus Surgery Study Group (2006). Natural course of infantile esotropia: angle of strabismus and refraction in the Early vs. Late Strabismus Surgery Study. Invest Ophthalmol Vis Sci 47:ARVO E-Abstract 2934

Chapter 12

Management of Congenital Nystagmus with and without Strabismus

12

Anil Kumar, Frank A. Proudlock, and Irene Gottlob

Core Messages ■

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Congenital nystagmus consists of involuntary periodic to-and-fro oscillations of the eye, which are usually horizontal and present within the ﬁrst 3 months of life. Congenital nystagmus can be idiopathic or occur in association with defects in the aﬀerent visual system such as albinism, congenital retinal dystrophies or congenital retinal dysfunction disorders (such as achromatopsia and congenital stationary night blindness (CSNB) ), congenital optic atrophy, optic nerve hypoplasia, and congenital cataracts. Congenital nystagmus need to be diﬀerentiated from manifest latent nystagmus (MLN) and congenital periodic alternating nystagmus (PAN) as the management of these conditions diﬀers. Several compensatory mechanisms exist in congenital nystagmus, which tend to decrease the nystagmus and thus improve the visual acuity. These mechanisms need to be analyzed carefully because their understanding is important for the patient’s management. Various modes of management are available for patients with congenital nystagmus such as optical, medical, and surgical treatment. A combination of treatment options might be helpful to achieve the best outcome. The incidence of signiﬁcant refractive errors in patients with congenital nystagmus is around 85%. Hence, correcting refractive errors improves visual acuity and is important at an early age to prevent ambylopia. Optical treatment can involve

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spectacles, contact lenses (CL), or low visual aids. Recently, medical treatment for congenital nystagmus with memantine and gabapentin has been shown to reduce nystagmus intensity and to increase visual acuity. Baclofen is beneﬁcial in the management of congenital PAN. Surgery in congenital nystagmus is used to correct the anomalous head posture (AHP) and to dampen the nystagmus. For Anderson−Kestenbaum- like procedures various extents of surgery have been proposed by diﬀerent surgeons. However, if the head turn is signiﬁcant, only limitation of motility due to a large extent of surgery will correct the head turn. If the patient has a squint, care needs to be taken that Anderson−Kestenbaum-like procedures are performed on the dominant or ﬁxing eye. Strabismus correction is best planned during the same surgical session on the non-ﬁxing eye. Surgery causing artiﬁcial divergence (exophoria) is beneﬁcial in patients with binocular vision and damping of nystagmus on convergence. Combination of Anderson−Kestenbaum-like procedures and artiﬁcial divergence surgeries have been shown to be beneﬁcial. Recently, tenotomies of extraocular muscles have been advocated for dampening nystagmus and for increasing the null region. However, the exact mechanism is not fully understood and further studies are needed.

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The management of congenital nystagmus presents a complex problem, which requires the accurate diagnosis of the underlying causes of congenital nystagmus and an understanding of the compensatory mechanisms used. Diagnosis can involve detailed clinical examination with ancillary testing such as the eye movement recordings and electrodiagnostics. It is important to delineate between the diﬀerent forms of congenital nystagmus such as congenital periodic alternating nystagmus (PAN) and manifest latent nystagmus (MLN) before treatment is considered. Treatment of congenital nystagmus is rapidly evolving, with new methods of treatment emerging which are now proving to be beneﬁcial. The armamentarium of treatment of congenital nystagmus includes optical, medical, and surgical treatments. Currently, in most nystagmus forms there is no deﬁnite answer as to which is the best treatment option. This chapter highlights the diﬀerent modes of treatment. The ﬁrst section of this chapter discusses in detail the clinical characteristics of patients with congenital nystagmus with and without sensory deﬁcit, MLN, and PAN. In the second section, the compensatory mechanism involved and methods to identify them are considered. The third section discusses the treatment options available for congenital nystagmus.

During Treatment

Before Treatment

Overview

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12.1

12 Management of Congenital Nystagmus with and without Strabismus

SN

12.1.1

Congenital Nystagmus with and Without Sensory Deﬁcits

Congenital nystagmus consists of involuntary periodic to-and-fro oscillations of the eye. It usually presents within the ﬁrst 3 months of life; however, onset as late as 12 months to 10 years has been reported [1]. The incidence of congenital nystagmus is estimated to be 1 in 2,000, in a population-based survey done in UK. The eye movements in congenital nystagmus are mainly in the horizontal plane, although they can be vertical or torsional, or in a combination of diﬀerent planes. Congenital nystagmus is often described in the literature as being a jerk nystagmus with accelerating slow phase; however, IIN may show diﬀerent waveforms that usually vary with eccentricity. Frequently, congenital nystagmus consists of underlying pendular oscillations interrupted by regularly occurring foveating saccades (quick phases) as shown in Fig. 12.1. Nystagmus intensity often changes with the direction of gaze. The region of lowest nystagmus intensity and longest foveation periods is known as the “null region.” This is often the preferred region of

3º 1sec

Fig. 12.1 Original horizontal eye movement recordings of right eyes of (ﬁrst row) a patient with congenital idiopathic nystagmus (CIN) and (second row) a patient with secondary nystagmus (SN) associated with albinism before and during memantine treatment; (third row) a patient with CIN and (fourth row) a patient with SN associated with achromatopsia before and during gabapentin treatment; (ﬁfth row) a patient with SN and (sixth row) a patient with SN associated with albinism before and during placebo treatment at examinations one and four. Eye movements to the right are represented by an upward deﬂection, and eye movements to the left by a downward deﬂection. The eye movement recordings show the variability in waveforms with the common occurrence of an underlying pendular waveform. They also show reduction of intensity after treatment with memantine and gabapentin but not with placebo

ﬁxation for optimal vision with the head position being used to maintain vision in the null region. Consequently, patients often exhibit an anomalous head posture (AHP)

12.1 Overview

if the null region is eccentric. Typically, the oscillation drifts toward the null region with the drift becoming accentuated further away from the null region. This results in the quick phases usually beating away from the null region with slow phases often accelerating toward the null region. Congenital nystagmus can be idiopathic with the most likely cause being abnormal development of the brain areas controlling eye movements and gaze stability. It can also occur in association with defects in the aﬀerent visual system such as albinism, congenital optic atrophy, optic nerve hypoplasia, congenital retinal dystrophies or

retinal dysfunction disorders (such as achromatopsia and congenital stationary night blindness (CSNB) ), and congenital cataracts. To assess visual potential when treating a patient, it is important to carefully diagnose whether an aﬀerent visual defect is present. Ocular albinism is frequently misdiagnosed as idiopathic nystagmus as the phenotypical characteristics might be subtle. Figure 12.2 shows clinical signs seen in a patient with oculocutaneous albinism as well as in a patient with ocular albinism. The patient with ocular albinism has dark hair and skin, very mild iris transillumination, but a hypopigmented fundus. Both patients have foveal hypoplasia to varying

Oculocutaneous Albinism (OCA)

Ocular Albinism (OA)

a

b

c

d

e

f

g

h

Appearance

Iris transillumination

Fig. 12.2 Phenotypical characteristics of patients with oculocutaneous (a, c, e, g) and ocular (b, d, f, h) albinism. The patient with oculocutaneous albinism has light hair and more prominent iris transillumination than the patient with ocular albinism. Both patients have fundus hypopigmentation, macular hypoplasia, and small optic nerves. Optical coherence tomography (OCT) shows foveal thickening in both patients (g, h) with total absence of foveal pit in the patient with oculocutaneous albinism (g)

Fundoscopy

Optical Coherence Tomography

155

156

degrees as shown using optical coherence tomography (OCT). Both patients had increased crossing of optical nerve ﬁbers in the chiasm shown on visual evoked potential examination (see Fig. 12.3d). The diﬀerent causes of nystagmus can be diagnosed by detailed clinical examination aided by electrodiagnostics (electroretinograms (ERGs) and visual evoked potentials (VEPs) ) (Fig. 12.3).

12.1.1.1 ■ ■ ■

The Clinical Characteristics of Congenital Nystagmus

Onset in infancy Nystagmus is mainly horizontal and conjugate Eye movement recordings are usually horizontal waveforms (both pendular and jerk) that vary with eccentricity

Electroretinogram

a

b

c

Scotopic

Flicker

20µv 20ms

10µv 20ms

Achromatopsia

500µv 20ms

d

Photopic

Congenital Stationary Night Blindness

Fz

Visual Evoked Potentials Albinism

Normal O 1 - Fz

Right Eye Open

Fig. 12.3 Examples of scotopic, photopic, and ﬂicker electroretinograms (ERGs) of (a) a normal subject, (b) a patient with congenital stationary night blindness (CSNB) with a negative scotopic ERG, and (c) a patient with achromatopsia with extinguished photopic ERG and ﬂicker ERG. (d) Visual evoked potential of a patient with albinism showing asymmetry between recording from the right and left hemisphere (see placements of electrodes on scalp in upper right corner) when the right and left eye are individually stimulated. Owing to increased crossing of optic nerve ﬁbers in the chiasm, the evoked potentials are more pronounced in the contralateral hemisphere (O1, O2, and O3 are electrodes placed over the back of the head (near the occipital pole of the cortex) in left, central, and right positions, respectively; FZ is the reference electrode)

Normal

O z - Fz

O1

Oz

O2

O1 - Fz Oz - Fz

O 2 - Fz O2 - Fz O1 - O2

O 1 - Fz Left Eye Open

12

12 Management of Congenital Nystagmus with and without Strabismus

O z - Fz O 2 - Fz

O1 - O2

O1 - O2

O1 - Fz Oz - Fz O2 - Fz

O1 - O2

157

12.1 Overview

Possible presence of AHP, strabismus, and refractive errors Decreased amplitude of nystagmus in null point Dampening of nystagmus on convergence The intensity of nystagmus increases with ﬁxation, decreases with sleep or inattention

■ ■ ■ ■

12.1.2

Manifest Latent Nystagmus (MLN)

MLN is most commonly associated with infantile or childhood onset esotropia as well as ambylopia. MLN is deﬁned as jerk nystagmus that develops at an early age and increases with monocular viewing, triggered by occlusion of one eye. Previously latent nystagmus was distinguished from MLN where no nystagmus was detected when both eyes were open. However, it has been shown that in cases clinically diagnosed as “latent nystagmus,” nystagmus is seen on eye movement recordings even when both eyes are open. Hence MLN/latent nystagmus is considered as a single entity (MLN). Characteristically, the amplitude of MLN decreases in adduction and increases in abduction, with the fast phase of the nystagmus beating toward the side of the ﬁxating eye or open eye. MLN has a distinctive slow phase with an exponentially decreasing or linear velocity in all positions of gaze as shown in Fig. 12.4. As nystagmus decreases in adduction in patients with MLN, they frequently develop an AHP toward the side of the ﬁxating eye when the fellow RIGHT EYE COVERED

12.1.2.1 ■ ■ ■

Clinical Characteristics of Manifest Latent Nystagmus (MLN)

Onset in infancy Nystagmus is horizontal and conjugate Associated with strabismus and amblyopia

LEFT EYE COVERED

BOTH EYES UNCOVERED

Right Eye

LEFT EYE COVERED

eye is occluded. The AHP changes to the other side in an alternating monocular occlusion, which helps in the diagnosis of MLN. If patients with MLN have alternating ﬁxation the head turn can change spontaneously, depending on which eye is ﬁxing. Figure 12.5e, f shows an alternating AHP to the right and left in one of our patients who had fusional maldevelopment syndrome with latent nystagmus conﬁrmed on eye movement recordings. The patient has exotropia and is freely alternating. He is always keeping the ﬁxing eye in adduction and therefore his head posture is alternating with a turn to the right with the right eye ﬁxing and left with the left eye ﬁxing. When one eye was patched his head turn was unidirectional in the direction of the open eye. The cause of MLN appears to be due to disruption of binocular vision during visual development, especially when the motion sensitive areas of the middle temporal and medial superior temporal cortex do not develop binocular function. Patients can have a combination of congenital and latent nystagmus. According to Dell’Osso [2], 80% of nystagmus is congenital nystagmus, 15% is MLN, and 5% is a combination of both forms.

Left Eye

RIGHT BEATING

R 10º 0.5 sec L

Fig. 12.4 Original horizontal eye movement recordings of both eyes of a patient with manifest latent nystagmus (MLN) and exotropia during an alternating cover test. Eye movements to the right are represented by an upward deﬂection, and eye movements to the left by a downward deﬂection. The fast phase is always beating toward the open eye (to the right with the left eye covered and to the left with the right eye covered). When both eyes are open the direction of the fast phase is toward the dominant left eye. The velocity of the slow phase is decelerating or linear. Arrows indicate blinks

158

12

Management of Congenital Nystagmus with and without Strabismus

Anomalous Head Posture in Idiopathic Infantile Nystagmus

12

Child

Correction of Anomalous Head Posture in Idiopathic Infantile Nystagmus with AndersonKesternbaum Surgery Horizontal head turn

Without visual effort

With visual effort

Before surgery

a

b

g

Adult

After surgery

h

Vertical and horizontal head turn with esotropia

Without visual effort

With visual effort

Before surgery

c

d

i

Bi-directional Alternating Head Turn in MLN Right head turn

Left head turn

e

f

After surgery

j

Measurement of head turn using Harms wall

k

Fig. 12.5 Abnormal head posture (AHP) of a child with idiopathic congenital nystagmus (a) without visual eﬀort and (b) with increased head turn while pointing at pictures on the Lang stereo test. Panel (c) shows a patient with idiopathic congenital nystagmus without head posture when there is no visual eﬀort and (d) a prominent abnormal head posture when reading at distance. Spontaneous alternating head turn to the right (e) and left (f) in a patient with MLN. Panel (g) shows a patient with idiopathic congenital nystagmus with approximately 45° head turn to the left before surgery and with straight head position (h) after Anderson– Kestenbaum procedure. A patient with oculo-cutaneous albinism and chin depression, face turn to the right and left esotropia before surgery (i) and after surgery (j). An accurate method of measuring AHP is achieved by using the Harms Wall (k) where the degree of head turn is measured by the amount of displacement of the cross observed on the tangent screen. The cross is projected from a light source ﬁxed on the head

■

■

Eye movement recordings have a characteristic slow phase with exponentially decreasing or linear velocity Amplitude of nystagmus decreases in adduction and increases in abduction, with the fast phase of nystagmus toward the side of ﬁxating eye

12.1.3 Congenital Periodic Alternating Nystagmus (PAN) Congenital PAN is classiﬁed as a variant of congenital nystagmus according to the CEMAS classiﬁcation. Congenital PAN is discussed as a separate entity because

12.1 Overview

it has speciﬁc implications for management which are diﬀerent from other forms of nystagmus. The frequency of congenital PAN is variably reported in the literature. Gradstein et al. [3] in a retrospective analysis of approximately 200 congenital nystagmus patients with and without sensory deﬁcits found 18 patients (9%) with a diagnosis of PAN. Five of these 18 patients had albinism. AHP was seen in 16 of the 18 patients. Shallo-Hoﬀman et al. [4] in a prospective study involving 18 patients with congenital nystagmus without sensory deﬁcits found that seven patients (39%) had PAN. Abadi and Pascal [5] found 12 patients with PAN in 32 patients with oculocutaneous albinism (37.5%). These 12 patients did not exhibit AHP nor had dampening of nystagmus on convergence (Fig. 12.6). Congenital PAN is most often missed or misdiagnosed if not properly investigated. The main reasons for diﬃculties in recognizing PAN are: ■

PAN. Absence of alternating AHP in congenital PAN is possibly due to the asymmetry of the PAN cycle, nystagmus beating longer in one direction than the other, and also the unequal intensities of nystagmus in the two phases.

12.1.3.1 ■ ■ ■

■

Clinical characteristics of congenital periodic alternating nystagmus

Onset in infancy. Nystagmus horizontal and conjugate. Eye movement recording shows a characteristic active phase with right/left beating nystagmus followed by a quite transition phase and then an active left/right beating nystagmus. The AHP is usually bidirectional.

Summary for the Clinician ■

■

■

Familiarity with the clinical characteristics of congenital nystagmus, MLN, and congenital PAN will minimize the chances of misdiagnosing these conditions and plan proper management of these conditions. Electrodiagnostics: both ERG and VEP should be done in all patients with congenital nystagmus to ﬁnd a cause for the congenital nystagmus. Eye movement recording aids in diﬀerentiating congenital nystagmus from MLN and congenital PAN.

Right Eye

■

Long cycle duration: The cycle duration of the congenital PAN is variable lasting mostly between 2 and 7 min. Thus, ocular motility examination (clinical or with eye movement recordings) must extend over a prolonged time period. The absence of alternating head turn: Classically, a clinical sign assisting in the diagnosis of congenital PAN is the alternating or bidirectional head turn. Gradstein et al. [3], on the contrary, have reported that the majority of patients with congenital PAN used a predominant head posture rather than an alternating head posture. Abadi and Pascal [5] also reported the absence of AHP in all the 12 patients diagnosed with congenital

159

R

Left Eye

LEFT BEATING

5º

3 sec

RIGHT BEATING

L

Fig. 12.6 Original eye movement recordings of a patient with idiopathic congenital periodic alternating nystagmus (PAN) of the right and left eye showing left beating nystagmus, a quiet phase and right beating nystagmus. Eye movements to the right are represented by an upward deﬂection, and eye movements to the left by a downward deﬂection. Arrows indicate blinks

160 12.2

12

12 Management of Congenital Nystagmus with and without Strabismus

Compensatory Mechanisms

Several compensatory mechanisms exist in congenital nystagmus which tend to decrease the nystagmus and thus improve the visual acuity. These compensatory mechanisms are achieved with superimposed vergence and version movements. Diﬀerent compensatory mechanisms may coexist in the same patient with congenital nystagmus. These mechanisms need to be analyzed carefully both to plan the treatment and also to make prognostic predictions.

NBS occurs with the waveform characteristics of increasing velocity slow phase and variable angle esotropia (Fig. 12.7a–d). MLN is also frequently associated with infantile esotropia. Most cases diagnosed as nystagmus blockage syndrome in the past probably corresponded to infantile esotropia associated with MLN.

Summary for the Clinician ■

■

12.2.1

Dampening by Versions

Version eye movements are used in some patients as a compensatory mechanism to reduce congenital nystagmus. Sustained contractions of yoke muscles help maintain the eyes in a peripheral lateral, vertical, or oblique gaze, depending on the position of the null region, leading to dampening of nystagmus. These versions are often accompanied, and consequently identiﬁed, by an AHP. An eccentric horizontal null zone leads to horizontal head turn and an eccentric vertical null zone leads to chin elevation or depression. For example, in a patient who has null position in the laevoversion, the compensatory head position is face turn to right, for null zone in elevation the compensatory mechanism is chin down position. Compensatory cycloversion leads to head tilt. A right head tilt corresponds to blocking incyclotorsion of the right eye and excyclotorsion of the left eye.

12.2.2

Dampening by Vergence

There are two distinct clinical conditions which use dampening by convergence as a compensatory mechanism to reduce the amplitude and frequency of nystagmus. These are MLN and nystagmus blockade syndrome (NBS). Adelstein and Cüppers [6] coined the term “nystagmus blockage syndrome” as having the following clinical features: ■ ■ ■ ■

Esotropia with sudden onset in early infancy, often preceded by nystagmus Pseudoparalysis of both abducens nerves The appearance of manifest nystagmus as the ﬁxating eye moves from adduction toward abduction Increase in the angle of the convergent squint when a base-out prism is put in front of the ﬁxating eye

■

Compensatory mechanisms are seen in patients with congenital nystagmus to increase visual acuity by decreasing the intensity of nystagmus. Compensatory mechanism can be achieved by convergence or version movements in case of eccentric null region. Compensatory mechanisms by versions lead to AHP. Several compensatory mechanisms usually exist in the same patient.

12.2.3 Anomalous Head Posture (AHP) AHP in children could be due to abnormalities of the oculomotor system, neck muscles, or the central nervous system. The ocular causes of AHP include strabismus, nystagmus, refractive errors, and ptosis. Although clinical diﬀerentiation of these disorders is accurately accomplished after thorough history and ocular examination, the exact mechanism of AHP is often diﬃcult to determine in patients with combination of strabismus and nystagmus. It is important to delineate the cause of AHP and the amount of AHP before considering treatment in patients with congenital nystagmus.

12.2.3.4 Measurement of AHP An AHP typically becomes progressively larger with increased visual eﬀort. Hence, quantiﬁcation of the surgery must be based on an appropriate eﬀort of ﬁxation, usually achieved by testing visual acuity at distance and near. Figures 12.5a, b show a child with no AHP when no visual eﬀort is needed. However, when he identiﬁes a stereoptic stimulus on the Lang test at near he is using a head turn to the right. Similarly, Figs. 12.5c, d show a patient with no head turn without visual eﬀort. However, he uses a very large chin elevation and head turn to the right when he is asked to read small letters at distance. AHP can be measured objectively, while reading small optotypes at distance and near, using calipers or the Harms wall (Fig. 12.5k). For diﬀerential diagnosis, it is important to record visual acuity with both eyes open as well as with each eye occluded. It is also useful

12.2 Compensatory Mechanisms Fig. 12.7 A patient with nystagmus blockage syndrome (a) with straight eyes, (b) when dampening nystagmus with right esotropia, (c) wearing Fresnel prisms for surgical evaluation, which showed dampening of nystagmus and (d) after bimedial medial rectus recessions. Original eye movement recordings show periodic convergence to dampen the nystagmus before surgery and quieter eye movements after surgery (e)

During nystagmus

Blocking with convergence

a

b

With prisms

After surgery

c

e

161

d

Eye movement recordings BEFORE SURGERY

AFTER SURGERY

Right Eye

nystagmus blockage

R 10º

2 sec

Left Eye

L

clinically to look at the eﬀects of straightening the head on nystagmus.

12.2.3.5

■

Eﬀect of Monocular and Binocular Visual Acuity Testing on AHP ■

Testing Visual Acuity with Both Eyes Open AHP should be ﬁrst assessed testing visual acuity with both eyes open to determine the existence and the type of AHP naturally adopted by the patient. The patient could have one of the following:

■ ■ ■ ■

No AHP: This could indicate that either the patient is using vergence as a compensatory mechanism, that the null region is in the primary position, or that no compensatory mechanism is being used by the patient A horizontal AHP consisting of a face turn to the right or left A vertical AHP consisting of a chin elevation or depression A bidirectional or alternating AHP A head tilt to the right or left A combination of AHP in diﬀerent planes

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12 Management of Congenital Nystagmus with and without Strabismus

Testing Visual Acuity with Either Eye Covered Testing AHP under monocular conditions using occlusion helps to diﬀerentiate between congenital nystagmus and MLN, since in congenital nystagmus the AHP is usually concordant (i.e., usually does not change position when covering one eye), whereas in MLN nystagmus the AHP is discordant. This is because in MLN the intensity of the nystagmus tends to be least in adduction. Consequently, in MLN the head turn and the nystagmus direction reverse when ﬁxation shifts from one eye to the other (Fig. 12.5e, f). 12.2.3.6

Testing AHP at Near

Since convergence has an eﬀect on nystagmus, AHP should also be tested when measuring visual acuity or reading at near (e.g. at 33 cm). All the observations noted regarding the position of AHP and the nystagmus intensity for distance should also be evaluated for near vision.

12.2.3.7

The Eﬀect of Straightening the Head in Patients with AHP

On straightening the head, if the nystagmus increases, then the cause of the AHP is almost certainly due to the nystagmus. If there is no change in the nystagmus, the AHP is either due to other ocular causes, a structural anomaly of the head or neck, CNS anomalies, or because of strabismus. Since strabismus in presence of nystagmus can be responsible for AHP thorough examination for comitant or incomitant squint is important in all patients with nystagmus. If the strabismus increases with head straightening, it indicates that an incomitant deviation is responsible for the AHP. However, if the strabismus improves with straightening of the head, the AHP is more likely associated with the nystagmus or some other cause.

Summary for the Clinician ■

■

■

It is important to delineate the cause of AHP and the amount of AHP before considering treatment in patients with congenital nystagmus. AHP typically becomes progressively larger with increased visual eﬀort. Hence quantiﬁcation of the head turn for surgical assessment must be based on measurement during maximal visual eﬀort. In patients with combination of strabismus and nystagmus, the cause of AHP needs to be carefully analyzed.

12.3 Treatment Various modes of treatment are available for patients with congenital nystagmus. However, it is necessary to decide the best method to treat these patients in the light of understanding the type of congenital nystagmus and the compensatory mechanism being used. Sometimes a combination of treatment options might be needed to achieve a better outcome. The main aim of treatment of congenital nystagmus is: 1. To improve visual acuity 2. To diminish the amplitude and frequency of nystagmus 3. To shift the null position to primary position with the aim of correcting an AHP 4. To correct the strabismus if present The main categories of treatment of nystagmus are optical, medical, and surgical although other forms of treatment have been attempted such as acupuncture, biofeedback, and use of botulinum toxin-A.

12.3.1 Optical Treatment The incidence of signiﬁcant refractive errors in patients with congenital nystagmus has been estimated to be as high as 85% [7]. The importance of correcting refractive errors besides improving visual acuity is to prevent ambylopia and to treat the associated strabismus, commonly seen in patients with congenital nystagmus. Optical treatment can involve spectacles, contact lenses (CL), or low visual aids.

12.3.1.1 Refractive Correction A full cycloplegic refraction should be performed in children. A simple correction of refraction is the easiest way of improving the visual acuity in congenital nystagmus. Hence, all patients with congenital nystagmus should have precise refraction with appropriate correction before attempting other modalities of treatment.

12.3.1.2

Spectacles and Contact Lenses (CL)

Several studies have suggested that CL improve visual function better than spectacles in patients with congenital nystagmus [8, 9]. The possible mechanisms underlying this are that CL reduces the chromatic and spherical

12.3

aberration, together with the prismatic eﬀect, compared to spectacles [8–10]. Since CL move with the eyes, the patient permanently looks along the visual axis of the correcting lens unlike with spectacles. CL also have the additional advantage of inducing convergence and accommodative eﬀort, which both decrease congenital nystagmus in some patients [8, 11]. It has been suggested that CL reduce the intensity of the nystagmus by providing sensory feedback through the eye lid [8, 11]. Tinted CL have also been used to reduce photophobia in patients with achromatopsia [12].

12.3.1.4

Low Visual Aids

Summary for the Clinician ■

Prisms

In 1950, Metzger [13] was the ﬁrst to describe the treatment of congenital nystagmus by using prisms in spectacles in four patients with nystagmus. Prisms are used to improve visual acuity by reducing the intensity of nystagmus and also to correct the AHP. Base-out prisms are prescribed to induce fusional convergence, which may be eﬀective in decreasing the amplitude of nystagmus, thus improving visual acuity [13]. Presence of binocular vision is a prerequisite for the use of base-out prisms since fusional convergence in response to prism-induced retinal disparity cannot be expected in patients without fusion. Prism adaptation for both distant and near vision helps to determine the largest amount of prism-induced convergence that dampens nystagmus without creating diplopia. Prisms can also be used in preoperative evaluation or as a non-surgical treatment to correct AHP in patients with congenital nystagmus and eccentric null points. The base of the prism is inserted opposite to the preferred direction of gaze. For instance, in patients with head turn to right, the null zone is in laevoversion, and prisms baseout in front of right eye and base-in in front of left eye will correct the head turn. Likewise, chin elevation or depression can be corrected by prism base-up or prism basedown, respectively, in front of both eyes. Godde-Jolly and Larmande [14] advocate the use of a combination of horizontal and vertical prisms when the null zone is in an oblique position of gaze. Since the visual acuity is often decreased with the use of Fresnel prisms and prisms incorporated in glasses, this method is not eﬀective to treat larger compensatory head posture in patients with congenital nystagmus. Nonetheless, it can be useful for preoperative assessment of the amount of AHP in terms of prism diopters, and also the response of the patients to prisms, which form a guide for planning the surgical treatment of nystagmus.

163

The use of telescope, magniﬁcation glasses, large print books, computer with large fonts, and other low vision aids are valuable refractive adjuncts that can be used in patients with low vision associated with congenital nystagmus.

■

12.3.1.3

Treatment

■ ■

All children with congenital nystagmus must have cycloplegic refraction and appropriate full refractive correction. The importance of correcting refractive errors besides improving visual acuity is to prevent ambylopia and to treat the associated strabismus commonly seen in patients with congenital nystagmus. Refractive correction could be achieved by glasses, CL, or low visual aids. A trial of CL should be oﬀered to suitable patients as they have shown to improve visual acuity better than spectacles.

12.3.2

Medication

Medications such as baclofen, cannabis, gabapentin, or memantine were ﬁrst trialed in acquired nystagmus. These studies led to the use of several of these drugs for congenital nystagmus as well. However, most of the reports in the literature consist of single cases or small case series. Because of the prolonged treatment required and the side eﬀects of medications, one needs to weigh the beneﬁts of pharmacological treatment in comparison with the other treatment modalities. Hertle et al. [15] reported a case study of a patient with congenital nystagmus, who showed improvement in foveation time with broadening of null zone and increased visual acuity after the use of an anti-anorexic drug (diethyl proprionate). Pradeep et al. [16] reported reduction in nystagmus intensity and improvement in visual acuity in a patient with congenital nystagmus after smoking cannabis. There are a number of other reports suggesting the use of tranquilizers and the anti-epileptic phenobarbital in the treatment of congenital nystagmus with reported improvement in the visual acuity. Sarvananthan et al. [17] reported a case study of a patient, with congenital nystagmus and corneal dystrophy being treated with gabapentin, which showed decrease in nystagmus and improvement in visual acuity. Shery et al. [18] showed a reduction in nystagmus amplitude and increase in visual acuity in

164

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12 Management of Congenital Nystagmus with and without Strabismus

seven patients (three with congenital idiopathic nystagmus and ﬁve with associated ocular defects) treated with gabapentin. McLean et al. [19] conducted the ﬁrst randomized, controlled, double-masked trial of memantine and gabapentin in the treatment of congenital nystagmus. A total of 48 patients with congenital nystagmus with and without sensory deﬁcits were included in the study. Sixteen patients in each group received memantine, gabapentin, or placebo treatment. The maximum dose of memantine was up to 40 mg/day and gabapentin up to 2,400 mg/day. Results showed reduction in nystagmus using eye movement recordings (see Fig. 12.4) and increase in visual acuity in both treatment groups with memantine and gabapentin showing a signiﬁcant improvement compared with the placebo-controlled group. There are several case reports of patients with congenital PAN being treated with baclofen with some success [4, 20]. In 2002, Solomon et al. [21] reported a reduction in nystagmus with improved reading ability in a single case of congenital PAN treated with baclofen. Comer et al. [22] did a retrospective review of eight patients diagnosed with congenital PAN and treated with baclofen. AHP improved in four of the eight patients treated with four patients improving in Snellen visual acuity by one line. The dose of baclofen was initially started at 15 mg/day with a weekly increase in the dose to up to 120 mg/day.

Summary for the Clinician ■ ■

■

■

Recently, medical treatment has been used for congenital nystagmus. In an RCT [19] of medical treatment of congenital nystagmus, both memantine and gabapentin showed reduction in nystagmus and improvement in visual acuity. The dosage of memantine used to treat congenital nystagmus was up to 40 mg/day, and that of Gabapentin 2,400 mg/day. The decision to treat patients medically should be individualized given the long-term treatment, the beneﬁts, and side eﬀects of medications.

12.3.3

Acupuncture

Acupuncture of the sternoclenoidmastoid muscle of the neck has been shown to reduce the frequency of nystagmus and improve the visual acuity by increasing the length of foveations, although the exact mechanism is not known. In a case series of six patients with congenital

nystagmus who underwent acupuncture, Blekher et al. [23] showed an increased foveation time in four patients.

12.3.4

Biofeedback

Auditory feedback is a method that was ﬁrst introduced to treat patients with congenital nystagmus in 1980 in which the patient hears a sound cue representing the intensity of the nystagmus [24]. Auditory feedback has been shown to be eﬀective in decreasing the amplitude of nystagmus in patients with congenital nystagmus; however, Sharma et al. [25] have shown that the action is not sustained being present only during the duration of the biofeedback therapy.

12.3.5

Botulinum Toxin-A (Botox)

Carruthers et al. [26] studied four patients with congenital nystagmus treated by botox injected into multiple horizontal rectus muscles. Three of the four patients were reported to have achieved a signiﬁcant improvement in the visual acuity. However, the botox injection needs to be repeated every 3–4 months. Oleszczynska-Prost et al. [27] in a case series of 32 patients with congenital nystagmus treated with botox showed an improvement in visual acuity in all the patients. The amplitude of nystagmus decreased by 29–50%. The head turn was corrected in few patients. The common complications of repeated botox injection are ptosis, retrobulbar hemorrhage, and spread of the toxin to other horizontal or vertical muscles resulting in palsies of these muscles.

12.3.6 Surgical Treatment of Congenital Nystagmus The surgical principles for correction of the AHP and dampening of nystagmus uses the basic strabismus procedure involving either the recession, resection procedures, or both. The aim is to move the eyes conjugately in the opposite direction to the gaze angle of the null region, or to artiﬁcially create an exotropia in patients with good binocular fusion in the presence of convergence null. Newer surgical procedures such as tenotomy of extraocular muscles have now been developed based on the beneﬁcial secondary eﬀects noted in patients who were earlier treated with the strabismus procedure (Anderson−Kestenbaum procedure) to dampen the congenital nystagmus.

12.3

The importance of diagnosing congenital PAN and MLN preoperatively is crucial as the surgical management diﬀers from congenital nystagmus in these cases. In addition to the nystagmus, a detailed examination evaluating the presence or absence of strabismus is also important. The common strabismus forms seen in association with nystagmus are esotropia, exotropia, dissociated vertical deviation, and dissociated horizontal deviation. A proper surgical plan should be made to either correct this strabismus along with the nystagmus as a single procedure or in two stages. The patient should, however, be informed that a second procedure might be necessary in case of residual strabismus or AHP, which needs to be addressed.

12.3.6.1 Management of Horizontal AHP A face turn to right or left is the most common compensatory posture encountered in patients with nystagmus with an eccentric null position. Various surgical procedures are used to correct this AHP and shift the null zone into primary position. Anderson, Goto, and Kestenbaum in 1950s independently reported the surgical procedures for the correction of AHP in patients with congenital nystagmus [20, 28, 29]. Anderson postulated that the muscles acting during the slow phase of the nystagmus were overacting. He consequently treated the nystagmus using a recession or weakening procedure of the two yoke muscles involved. Goto, on the contrary, believed that there was underaction of the muscles acting during the fast phase of the nystagmus, and advocated strengthening or resection of these two muscles. Kestenbaum advocated a combined resection and recession procedure on all the four horizontal rectus muscles. He recessed or resected the two horizontal muscles of each eye. He also suggested performing the same quantity of surgery for both weakening and strengthening procedures (5 mm). Parks [30] made modiﬁcations in the Kestenbaum technique and proposed that, to obtain symmetrical horizontal ductions of the two eyes, surgery should be a 5 mm recession of medial rectus and a 8 mm resection of the lateral rectus for the eyes in adduction, and 6 mm resection of medial rectus and a 7 mm recession of the lateral rectus of the fellow eye. This became the classical “5, 6, 7, 8” measurements for the Kestenbaum procedure modiﬁed by Parks. Because of the high rates of recurrence and undercorrection following the modiﬁed Kestenbaum procedure, Calhoun and Harley [31] recommended augmentation of the original Parks modiﬁcation of Kestenbaum procedure by 40–60% depending on the amount of head turn. For

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example, 40% augmentation of the Parks procedure corresponds to 7, 8.4, 9.8, and 11.2 mm. Nelson et al. [32] found that a more sustained correction of the AHP in congenital nystagmus was obtained by an augmented modiﬁed Kestenbaum procedure. They suggested 40% augmentation of modiﬁed Kestenbaum procedure for patients with 30° of head turn, and 60% augmentation for patients with 45° of head turn. Taylor recommended that recession of 8–9 mm of the lateral rectus muscle and 6 mm recession of the medial rectus muscle be performed in conjunction with 6 mm resections of the respective antagonists [33]. De Decker [34] advocated the modiﬁcation of Anderson procedure to correct the AHP. In this procedure, only the yoke muscles are recessed, to as much as 10–12 mm, rather than 4–5 mm as suggested by Anderson. Since the recession of medial rectus is more eﬀective than recession of lateral rectus, the medial rectus is recessed 2 mm less than the lateral rectus muscle. For example, in patients with a face turn to right, the right medial rectus is recessed 10 mm, and the left lateral rectus is recessed 12 mm. As only the two yoke muscles are operated on, it spares the other two horizontal muscles, which could be available if further surgery is required. Flynn and Dell’Osso [35] conﬁrmed the initial ﬁndings described by Kestenbaum of an increase in the visual acuity after the Kestenbaum-type procedure. They also demonstrated that the Anderson-Kestenbaum procedure does not alter the binocular function in those patients with intact binocular function before surgery. It is very diﬃcult to advocate a rigid dosage scheme for all patients. Each surgeon adopts his own nomogram to correct the amount of AHP. With very large head turns of 40–45°, in our experience, very large amounts of surgery is needed. Restriction of eye movements is often a necessary consequence of large Kestenbaum procedures but is necessary to reduce large AHPs. In Fig. 12.5g, h an example of a child who underwent horizontal Anderson−Kestenbaum procedure is shown. She was ﬁrst examined at 1 year of age because of nystagmus since birth. A diagnosis of congenital idiopathic nystagmus (CIN) was made after detailed clinical examination and electrodiagnostic tests. At 2 years of age, she started to develop an AHP. A refractive error of −4D cyl. in the right eye and −2D cyl. in the left eye was detected, but she was unable to wear glasses owing to the large AHP. The child was reassessed at the age of 3 years. Her visual acuity was 6/24 with both eyes open. She had an AHP of about 45° (Fig. 12.5g). No squint was detected. We performed an augmented Anderson−Kestenbaum procedure to correct the AHP (recession of right lateral rectus and

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left medial rectus and resection of right medial rectus and left lateral rectus by 12 mm each). Postoperatively, the AHP was corrected without residual AHP. The child was able to wear glasses, which improved the visual acuity to 6/9 with both eyes open (Fig. 12.5h). Postoperatively, the child had limitation on right gaze, which is necessary to avoid recurrence of head turn. In the presence of strabismus, the amount of the surgery performed on each muscle is modiﬁed to correct the strabismus in addition to the head turn. In patients with strabismus or amblyopia, the surgery for AHP must be planned on the ﬁxing eye or non-amblyopic eye. If necessary, eso- or exotropia can be corrected by performing diﬀerent amounts of recess–resect procedures on the non-ﬁxing eye simultaneously. For example, in a patient with a head turn to the right and left esotropia, surgery for the AHP needs to be performed on the right eye (medial rectus recess and lateral rectus resect). This will reduce the esotropia. Depending on the amount corrected for the AHP, the amount of surgery on the left eye needs to be reduced (i.e., smaller than the amount corrected for AHP on the right eye) to correct the squint. If the esotropia and the head turn are approximately of equal size, it is suﬃcient to correct the head position on the ﬁxating eye. If a patient has a right AHP with left exotropia, the amount of the left squint surgery needs to be increased (i.e., larger than the surgery for AHP on the right eye). Surgical decision for the child shown in Fig. 12.5e, f was a challenge. Since he adducted each eye to dampen his latent nystagmus, bimedial rectus recession would have been the ideal surgery. However, he also had a large exotropia, which would have increased with bimedial recessions. We performed, therefore, large bilateral medial rectus recessions (12 mm) and even larger bilateral rectus recessions (16 mm). Postoperatively, the head turn was improved signiﬁcantly and he remained with moderate exotropia. Alternatively, one could have performed a Faden procedure on both medial recti combined with lateral recti recessions. NBS can also be treated surgically. Figure 12.7 shows an example of a patient with congenital nystagmus and NBS before surgery. The patient complained of one eye moving inward intermittently. To dampen his nystagmus, he developed large intermittent right esotropia (Fig. 12.7a, b). Eye movement recordings (Fig. 12.7e) show large convergent movements in the right eye which dampened the nystagmus. With a trial of Fresnel prisms (20 base out on each side), the eyes remained esotropic and the nystagmus dampened. After bimedial rectus recession, he developed a small constant esotropia (Fig. 12.7d). The nystagmus was signiﬁcantly reduced (Fig. 12.7e).

12.3.6.2

Management of Vertical AHP

Chin elevation or chin depression are compensatory mechanisms for a null position with eyes in down or upgaze, respectively. Vertical or torsional AHP to dampen the nystagmus is seen less frequently than horizontal AHP. Pierse [36] in 1959 was the ﬁrst to attempt to correct vertical AHP. He reported two cases with chin-up position for which he did bilateral inferior rectus recession and superior oblique tenectomies, with marked improvement of vision in primary position and improvement in the AHP. Schlossman [37] reported a patient with chin-down posture for which he resected the inferior rectus and recessed the inferior oblique. Parks [30] suggested operation on all four vertical rectus muscles for chin elevation or depression greater than 25°. He recommended 4 mm resection and recession for these patients. For patients with chin elevation or depression less than 25°, only 4 mm recession of the appropriate vertical muscle without resection was recommended. Taylor and Jesse [38] recommended superior rectus recession and inferior oblique myectomy for chin-down posture, inferior rectus recession and superior oblique tenotomy for chin-up position. In 1990, Sigal et al. [39] conducted a poll of AAPOS members to ﬁnd the methods used to correct vertical AHP. Two surgical procedures were used by most of the respondents to correct vertical AHP. While 44% of the respondents preferred recession surgery alone, 55% preferred both recession and resection procedure on all four vertical rectus muscles. Recession only consisted of bilateral average vertical muscle recession of 4.8 mm for 10°, 5.9 mm for 20°, and 7.3 mm for 30° AHP. Average amount of surgery for both recession and resection of bilateral vertical rectus muscle were 4.5 mm recession and 4.3 mm resection for 10° AHP, 5.3 mm recession and resection for 20° AHP, 7.7 mm recession and 6.4 mm resection for 30° AHP. Robert and colleagues [40] described a series of seven patients with vertical AHP, three of whom underwent combined bilateral inferior rectus recession and bilateral superior rectus resection for chin-up AHP. Four patients underwent superior rectus recession and inferior oblique anteriorization for chin-down AHPs. Based on their results, they recommended a minimum combined bilateral 8 mm recession and 8 mm resection of the vertical rectus muscles, should be performed for chin-up AHP greater than 30°. Yang et al. [41] conducted a retrospective review of 20 patients who underwent surgery for vertical AHP. They found that recession alone caused either no change or worsening of the vertical AHP, while the recessionresection procedure of all four vertical rectus muscle produced excellent results in correcting the vertical AHP. They recommended 12 mm of combined recession and

12.3

resection for each pair of vertical rectus muscles for 10–15° AHP, 16 mm for 20–25°, and 20 mm for more than 30° AHP. For example, for 10° chin-down posture, 6 mm resection of inferior rectus and 6 mm recession of superior rectus should be performed of both eyes. In Fig. 12.5i, j an example of a patient who underwent simultaneous Anderson procedure for vertical and horizontal AHP and correction of squint is shown. This patient was diagnosed as having oculocutaneous albinism with nystagmus. She had a visual acuity of 6/36 with both eyes open. She had a chin-down position of approximately 20° and face turn to right of approximately 20°, more at near than at distance (Fig. 12.5i shows head position at distance). She had left esotropia of 35 prism diopters. She underwent Anderson procedure (bilateral superior rectus recession of 12 mm) and correction of squint on the dominant right eye to correct simultaneously the horizontal AHP and the squint (right eye medial rectus recession of 9 mm). Postoperatively, her AHP and squint were well corrected (Fig. 12.5j). Operating on the oblique muscles to correct the vertical AHP harbors a potential complication of iatrogenic cyclotropia in patients with binocularity. As the vertical muscles also contribute to the torsional status of the eye, one could expect torsional problems with large amounts of surgery on the vertical muscles as well. This can be counteracted by shifting the insertion of the vertical rectus muscles laterally. For example, a large recession of the superior rectus causes excylcotropia. Moving the insertion of the superior rectus temporally reduces the induced excylcotropia.

12.3.6.3

Management of Head Tilt

Head tilt is due to compensatory cycloversion. A right head tilt corresponds to blocking incyclotorsion in the right eye and of excyclotorsion in the left eye. Based on the Kestenbaum principle to shift the muscle in the direction of the AHP, Conrad and de Decker [42, 43] in a review of 66 cases with head tilt suggested rotating both eyes around the sagittal axis toward the shoulder to which the head is tilted. They combined a recession−resection procedure at the anterior portions of the oblique muscles with transpositions of their insertion toward the posterior−anterior pole. They had a success rate of 54%; while some improvement was seen in 25% of cases, 21% of cases showed no improvement. Although surgery of oblique muscles is technically more complex than surgery of horizontal muscles, De Decker advocated this surgery because it avoids disturbing the vascular supply through horizontal muscles. In cases where horizontal surgery is also necessary for strabismus or horizontal AHP, De Decker [44] suggested

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vertical transposition of the horizontal rectus muscles to correct the head tilt. For example, transposing the medial rectus downward and the lateral rectus upward causes excycloduction in the right eye. Von Noorden et al. [45] proposed the horizontal transposition of the vertical rectus muscles to correct the head tilt. For example, to achieve excyclotorsion of the right eye and incyclotorsion of the left eye in case of right head tilt, the right superior rectus muscle is transposed nasally, and the right inferior muscle inferiorly, and in the left eye, the superior rectus muscle is transposed temporally, and the left inferior muscle nasally. This surgery has been found to be eﬀective when operated on both eyes, in patients with no ﬁxation preferences or with binocularity and also on the ﬁxating eye alone in monocular ﬁxation. Spielmann [46] recommended slanting the insertions of all four rectus muscles. For example, excycloduction of the right eye can be achieved by recessing the temporal part of the superior rectus, inferior part of the lateral, nasal part of the inferior and superior part of the medial rectus muscle insertions. Sigal et al. [39] found ﬁve diﬀerent surgical procedures used by AAPOS members to treat torsional AHP: 1. 2. 3. 4. 5.

Bilateral vertical rectus muscle recession Bilateral vertical rectus muscle recess−resect Bilateral oblique muscle weakening Bilateral oblique muscle recess−resect Bilateral oblique muscle weakening and vertical rectus muscle recession

When dealing with moderate to severe AHP, 88% of surgeons preferred operating on at least one oblique muscle.

12.3.6.4

Artiﬁcial Divergence Surgery

Patients suitable for artiﬁcial divergence surgery should be orthotropic with convergence as the compensatory mechanism used to dampen the nystagmus. Binocular fusion is necessary to achieve this eﬀect. The vergence dampens the nystagmus regardless of the stimulus inducing the convergence. This principle has been used optically (base-out prisms) and surgically (artiﬁcial divergence) to dampen the nystagmus. Cüppers [47] proposed the concept of artiﬁcial divergence in patients with convergence dampening of nystagmus. In this procedure, an exodeviation is induced, which can be compensated by fusional convergence. This causes the patients to have convergence innervations even at distance. The acceptability and eﬀectiveness of artiﬁcial divergence surgery should be evaluated

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preoperatively by using the prism adaptation test. A base-out prism is prescribed to induce artiﬁcial divergence. Inducing divergence with a base-out prism causes the patient to converge, and therefore decreases the nystagmus, which can then be followed by the corresponding amount of recession−resection procedure [48]. The amount of surgery is based on the prism diopters tolerated by the patient preoperatively. Spielmann [49] in a retrospective study of 120 patients who underwent artiﬁcial divergence surgery found 93 (77.5%) of the patients were orthophoric, 18 patients had exophoria postoperatively, and 9 patients had exotropia. Exotropia was found to be associated with hypermetropia. Spielmann proposed bilateral recession of medial rectus muscle by 5–13 mm depending on the amount of prism determined preoperatively by the prism adaptation test. She recommended 5 mm recession if the fusion was tolerated with 30–40 PD, 7 mm for 50–60 PD, and 8 mm if fusion exceeds 60 PD. Some patients have a convergence null in addition to the gaze angle null causing the AHP. If the amount of divergence induced by base-out prisms did not satisfactorily correct the AHP, these patients beneﬁtted by a combination of artiﬁcial divergence and Anderson–Kestenbaum procedure [48, 50]. The amount of surgery is done for the total prism diopters tolerated by artiﬁcial divergence procedure and then the remaining AHP is corrected using the Anderson–Kestenbaum procedure. Zubcov et al. [48] compared pre- and postoperative eye movement recording and binocular visual acuities of patients who underwent the Anderson−Kestenbaum procedure (n = 7), artiﬁcial divergence procedure (n = 6), and a combination of both procedures (n = 5) in patients with congenital nystagmus. In patients who underwent artiﬁcial divergence surgery, only one patient developed 4 PD esophoria postoperatively. Stereopsis improved in four patients. Four patients had a head turn of less than 5°. Binocular visual acuity improved in 50% of the patients by 1–2 Snellen lines. Eye movement recordings showed broadening of the null zone. In patients who underwent a combined procedure, stereopsis improved in two patients and no residual head turn greater than 5° was found. Binocular visual acuity improved by two or more Snellen lines in four of the ﬁve patients. Broadening of the null zone was noticed in all patients. Graf et al. [51] in a retrospective study to analyze the eﬀects of Kestenbaum surgery and artiﬁcial divergence surgery found that artiﬁcial divergence surgery when performed alone oﬀers better correction of AHP than with the Kestenbaum surgery. However, in patients with large AHP, combining both artiﬁcial divergence surgery and Kestenbaum surgery gives better results.

12.3.6.5 Surgery to Decrease the Intensity of Nystagmus In patients who do not exhibit any compensatory mechanism to dampen the nystagmus, various surgeries have been done to dampen the congenital nystagmus. These procedures were referred by Crone [52] as immobilization procedures. Various surgical procedures have been mentioned in the literature. Von Noorden summarized these surgical principles, including large recession of all horizontal rectus muscles, the tenotomy procedure, ﬁxation of the extraocular muscles to the periosteum of the lateral orbital wall, retro-equatorial myopexy of all horizontal rectus muscles, placement of retro-equatorial encircling silicone band over rectus muscles in both eyes and extirpation of horizontal rectus muscles. Both retro equatorial recession of horizontal rectus muscle and tenotomy procedure have been used more frequently and will be discussed in detail.

Retro-Equatorial Recession of Horizontal Rectus Muscles Bietti and Bagolini [53], in 1956, ﬁrst described retroequatorial recession of all four horizontal rectus muscles. Von Noorden and Sprunger [54] performed this procedure on three patients and reported increased acuity in two patients and correction of head posture in one patient. Helveston et al. [55] performed this procedure in ten patients and reported dampening of nystagmus and improvement of visual acuity in 80% of patients. All his patients also reported improvement in visual acuity and head posture. Datta et al. [56] performed surgery on nine patients and reported decreased amplitude in 15 eyes and increased visual acuity in 12 eyes. Boyle et al. [57] in a retrospective review of 18 patients who underwent retro-equatorial recession surgery of horizontal muscle, 50% of patients showed improvement in visual acuity by at least one Snellen line. All patients underwent medial rectus recession of 8–10 mm, and bilateral lateral rectus muscle recession of 8–12 mm. Bagheri et al. [58] reported results of 20 patients who underwent horizontal rectus recession surgery. Thirteen patients (76.5%) improved in visual acuity from one to three Snellen lines. AHP improved in most of the patients. Similar results were also documented by other authors, Davis et al. [59] and Atilla et al. [60]. They calculated the amount of recession individually depending on the angle of deviation, head position, and amount of strabismus if present. Recessions performed on the medial rectus were more eﬀective than recession on the lateral rectus. Thus surgery is planned based on the eﬀect of recession of the medial rectus muscle rather than the lateral rectus recession. To correct the associated strabismus, the surgical plan is

References

revised by increasing the recession of medial rectus muscles in case of esotropia, and recession of lateral rectus muscles in case of exotropia. Similar adjustments can be made to correct the AHP for example in patients with left face turn, the right lateral rectus and left medial rectus is recessed more than the right medial rectus and left lateral rectus.

The Tenotomy Procedure Advancements in understanding secondary mechanisms involved in the reducing nystagmus amplitude in patients who underwent recession−resection surgery for congenital nystagmus mainly to correct the AHP has led to a new surgical procedure “tenotomy” of extraocular muscle. This procedure has been reported to be beneﬁcial in patients without compensatory mechanisms, also in patients with a null region at or near primary position and in patients with a non-stationary null region (PAN) [61].The tenotomy procedure can be done on both horizontal and vertical rectus muscles based on the dominant plane of the nystagmus. Following the initial success of the tenotomy procedure in an animal model [62], clinical trials [63, 64] were performed on patients with congenital nystagmus with and without sensory deﬁcits including asymmetric congenital PAN. In the ﬁrst trial, involving ten patients, binocular visual acuity increased in ﬁve patients and remained unchanged in the remaining patients. The eye movement recording data showed an increase in the average foveation times in all nine patients’ ﬁxating eyes. In the second trial, tenotomy was performed on ﬁve patients with congenital nystagmus. Visual acuity improved in four of the ﬁve patients, but did not improve in a patient with retinal dystrophy.

Summary for the Clinician ■

■

Various surgical procedures are used to treat both the AHP and strabismus seen in patients with congenital nystagmus. Surgical consists mostly of recessions alone or the combination of recessions and resections depending on the amount of head turn and strabismus. The surgical plan depends on whether patient has horizontal or vertical AHP or head tilt and the presence or absence of strabismus. Other compensatory need to be taken into consideration before deciding on the type of surgery. For example, if there is dampening of nystagmus mechanisms on convergence, artiﬁcial divergence surgery alone can be performed, or it can be combined with Anderson−Kestenbaum like procedures.

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Acknowledgments We acknowledge support from Shery Thomas, Chris Degg, Nagini Sarvananthan, Rebecca McLean, Mervyn Thomas, Mylvaganam Surendran, and Shegufta Farooq. We thank the Nystagmus Network for their continued interest in and support for nystagmus research. We acknowledge the financial support of Ulverscroft Foundation, Medisearch, National Eye Research Centre, and Nystagmus Network.

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15. Hertle RW, Maybodi M, Mellow SD, Yang D (2002) Clinical and oculographic response to Tenuate Dospan (diethylpropionate) in a patient with congenital nystagmus. Am J Ophthalmol 133:159–160 16. Pradeep A, Thomas S, Roberts EO et al (2008) Reduction of congenital nystagmus in a patient after smoking cannabis. Strabismus 16:29–32 17. Sarvananthan N, Proudlock FA, Choudhuri I et al (2006) Pharmacologic treatment of congenital nystagmus. Arch Ophthalmol 124:916–918 18. Shery T, Proudlock FA, Sarvananthan N et al (2006) The eﬀects of gabapentin and memantine in acquired and congenital nystagmus: a retrospective study. Br J Ophthalmol 90:839–843 19. McLean R, Proudlock F, Thomas S et al (2007) Congenital nystagmus: randomized, controlled, double-masked trial of memantine/gabapentin. Ann Neurol 61:130–138 20. Anderson JR (1953) Causes and treatment of congenital eccentric nystagmus. Br J Ophthalmol 37:267–281 21. Solomon D, Shepard N, Mishra A (2002) Congenital periodic alternating nystagmus: response to baclofen. Ann N Y Acad Sci 956:611–615 22. Comer RM, Dawson EL, Lee JP (2006) Baclofen for patients with congenital periodic alternating nystagmus. Strabismus 14:205–209 23. Blekher T, Yamada T, Yee RD, Abel LA (1998) Eﬀects of acupuncture on foveation characteristics in congenital nystagmus. Br J Ophthalmol 82:115–120 24. Abadi RV, Carden D, Simpson J (1980) A new treatment for congenital nystagmus. Br J Ophthalmol 64:2–6 25. Sharma P, Tandon R, Kumar S, Anand S (2000) Reduction of congenital nystagmus amplitude with auditory biofeedback. J AAPOS 4:287–290 26. Carruthers J (1995) The treatment of congenital nystagmus with Botox. J Pediatr Ophthalmol Strabismus 32: 306–308 27. Oleszczynska-Prost E (2004) Botulinum toxin A in the treatment of congenital nystagmus in children. Klin Oczna 106:625–628 28. Goto N (1954) A study of optic nystagmus by the electrooculogram. Acta Soc Ophthalmol Jap 58:851–865 29. Kestenbaum A (1953) New operation for nystagmus. Bull Soc Ophtalmol Fr 6:599–602 30. Parks MM (1973) Symposium: nystagmus. Congenital nystagmus surgery. Am Orthopt J 23:35–39 31. Calhoun JH, Harley RD (1973) Surgery for abnormal head position in congenital nystagmus. Trans Am Ophthalmol Soc 71:70–83; discussion 84–77 32. Nelson LB, Ervin-Mulvey LD, Calhoun JH et al (1984) Surgical management for abnormal head position in nystagmus: the augmented modiﬁed Kestenbaum procedure. Br J Ophthalmol 68:796–800

33. Taylor JN (1973) Surgery for horizontal nystagmus– Anderson-Kestenbaum operation. Aust J Ophthalmol 1:114–116 34. De Decker W (1987) Kestenbaum transposition in nystagmus theraphy. Transposition in horizontal and torsional plane. Bull soc Belge Ophthalmol 221–222 35. Flynn JT, Dell’Osso LF (1979) The eﬀects of congenital nystagmus surgery. Ophthalmology 86:1414–1427 36. Pierse D (1959) Operation on the vertical muscles in cases of nystagmus. Br J Ophthalmol 43:230–233 37. Schlossman A (1972) Nystagmus with strabismus: surgical management. Trans Am Acad Ophthalmol Otolaryngol 76:1479–1486 38. Taylor JN, Jesse K (1987) Surgical management of congenital nystagmus. Aust N Z J Ophthalmol 15:25–34 39. Sigal MB, Diamond GR (1990) Survey of management strategies for nystagmus patients with vertical or torsional head posture. Ann Ophthalmol 22:134–138 40. Roberts EL, Saunders RA, Wilson ME (1996) Surgery for vertical head position in null point nystagmus. J Pediatr Ophthalmol Strabismus 33:219–224 41. Yang MB, Pou-Vendrell CR, Archer SM et al (2004) Vertical rectus muscle surgery for nystagmus patients with vertical abnormal head posture. J AAPOS 8:299–309 42. Conrad HG, de Decker W (1978) “Kestenbaum’s surgical rotation of the eyes” in patients with head tipped to the shoulder (author’s transl). Klin Monatsbl Augenheilkd 173:681–690 43. De Decker W, Conrad HG (1988) Torsional shift operation, a tool in complete early childhood strabismus. Klin Monatsbl Augenheilkd 193:615–621 44. De Decker W (1990) Rotatorischer Kestenbaum an geraden Augenmuskeln. Z Prakt Augenheilkd 11:111 45. von Noorden GK, Jenkins RH, Rosenbaum AL (1993) Horizontal transposition of the vertical rectus muscles for treatment of ocular torticollis. J Pediatr Ophthalmol Strabismus 30:8–14 46. Spielmann A (1987) The “oblique” Kestenbaum procedure revisited. In: Lenk-Schafer M (ed) Orthoptic horizons. Transactions of the sixth international orthoptic congress. Harrogate, UK, pp 433 47. Cuppers C (1971) Problems in the surgery for ocular nystagmus. Klin Monatsbl Augenheilkd 159:145–157 48. Zubcov AA, Stark N, Weber A et al (1993) Improvement of visual acuity after surgery for nystagmus. Ophthalmology 100:1488–1497 49. Spielmann A (1993) La mise en divergence artiﬁcielle dans les nystagmus congénitaux. A propos de 120 cas. Bull Soc Fr Ophtalmol 6/7:571–578 50. Sendler S, Shallo-Hoﬀmann J, Muhlendyck H (1990) Artiﬁcial divergence surgery in congenital nystagmus. Fortschr Ophthalmol 87:85–89

References 51. Graf M, Droutsas K, Kaufmann H (2001) Surgery for nystagmus related head turn: Kestenbaum procedure and artiﬁcial divergence. Graefes Arch Clin Exp Ophthalmol 239:334–341 52. Crone RA (1971) The operative treatment of nystagmus. Ophthalmologica 163:15–20 53. Bietti GB (1956) Notes on ophthalmological surgical technics. Boll Ocul 35:642–656 54. von Noorden GK, Sprunger DT (1991) Large rectus muscle recessions for the treatment of congenital nystagmus. Arch Ophthalmol 109:221–224 55. Helveston EM, Ellis FD, Plager DA (1991) Large recession of the horizontal recti for treatment of nystagmus. Ophthalmology 98:1302–1305 56. Datta H, Prasad S (1994) Postequatorial horizontal rectus recession in the management of congenital nystagmus. Indian J Ophthalmol 42:203–206 57. Boyle NJ, Dawson EL, Lee JP (2006) Beneﬁts of retroequatorial four horizontal muscle recession surgery in congenital idiopathic nystagmus in adults. J AAPOS 10:404–408 58. Bagheri A, Farahi A, Yazdani S (2005) The eﬀect of bilateral horizontal rectus recession on visual acuity, ocular devia-

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tion or head posture in patients with nystagmus. J AAPOS 9:433–437 Davis PL, Baker RS, Piccione RJ (1997) Large recession nystagmus surgery in albinos: eﬀect on acuity. J Pediatr Ophthalmol Strabismus 34:279–283; discussion 283–275 Atilla H, Erkam N, Isikcelik Y (1999) Surgical treatment in nystagmus. Eye 13(Pt 1):11–15 Dell’Osso LF (1998) Extraocular muscle tenotomy, dissection, and suture: a hypothetical therapy for congenital nystagmus. J Pediatr Ophthalmol Strabismus 35:232–233 Dell’Osso LF, Hertle RW, Williams RW, Jacobs JB (1999) A new surgery for congenital nystagmus: eﬀects of tenotomy on an achiasmatic canine and the role of extraocular proprioception. J AAPOS 3:166–182 Hertle RW, Dell’Osso LF, FitzGibbon EJ et al (2004) Horizontal rectus muscle tenotomy in children with infantile nystagmus syndrome: a pilot study. J AAPOS 8: 539–548 Hertle RW, Dell’Osso LF, FitzGibbon EJ et al (2003) Horizontal rectus tenotomy in patients with congenital nystagmus: results in 10 adults. Ophthalmology 110: 2097–2105

Chapter 13

Surgical Management of Dissociated Deviations

13

Susana Gamio

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Dissociated deviation (DD) manifests as a slow, intermittent, and variable vertical (DVD), horizontal (DHD), and torsional (DTD) movement. It is usually found in patients with early onset strabismus and profound sensorial anomalies. The treatment for patients with DD requires a speciﬁc surgical approach to improve the vertical, horizontal, and torsional misalignment simultaneously. DVD neither disappears nor improves over time; the aim of treatment is to obtain a latent deviation. Symmetric dissociated vertical deviation (DVD), with good bilateral visual acuity (VA), without oblique muscle dysfunction: four surgical alternatives: (1) Bilateral large superior rectus (SR) recession. (2) Bilateral retroequatorial myopexy (posterior ﬁxation) of the SR combined with or without recession of these muscles. (3) Four oblique muscles weakening procedure. (4) Bilateral inferior rectus (IR) resection. Bilateral DVD with deep unilateral amblyopia: three available procedures: (1) Unilateral SR recession, (2) Unilateral inferior oblique anterior transposition (IOAT), and (3) Unilateral IR resection or tucking. DVD with inferior oblique overaction (IOOA) and V pattern: (1) Bilateral IOAT. (2) Bilateral SR recession added to bilateral inferior oblique (IO) recession. DVD with superior oblique overaction (SOOA) and A pattern: (1) Bilateral SR recession, (2) Bilateral SR recession + superior oblique (SO) posterior tenectomy, or (3) Four oblique muscles weakening procedure. Symmetric vs. Asymmetric surgeries for DVD: Bilateral symmetric procedures are performed

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for cases with bilaterally symmetric DVD. Cases with asymmetric DVD are more common. These cases require asymmetrical techniques. Dissociated horizontal deviation (DHD): The main diagnostic sign of DHD is the presence of a horizontal deviation, esotropia (ET), or exotropia (XT) that changes with ﬁxation of each eye, unrelated to diﬀerent accommodation, muscle weakness, or restriction. The technique most used for DHD is unilateral lateral rectus (LR) recession. Retroequatorial myopexy (posterior ﬁxation) of the LR with recession of this muscle is recommended by certain authors. Bilateral LR recession is indicated when XT is bilateral; unilateral or bilateral medial rectus (MR) recession when the patient exhibits ET instead of XT. Performing an LR recession added to MR advancement is a valid alternative in cases with previous surgery on the medials. Dissociated torsional deviation (DTD): Children with DD frequently have head turn but they also have head tilt. The head tilt can be toward the shoulder of the ﬁxing eye (direct tilt) or toward the contralateral side (inverse tilt). We have to take into account the head tilt to attempt to improve the head position when performing surgery. Obtaining long-term control of the deviation in patient with DD is diﬃcult; a successful outcome in the postoperative period does not guarantee the ﬁnal alignment. In treated patients with DD, some kind of movement is always detected when performing the cover test. DVD never disappears completely and the dissociated behavior in DHD also persists when testing under slow cover test.

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13 Surgical Management of Dissociated Deviations

Dissociated Deviations

Dissociated deviation (DD) Represents a Challenge for Diagnosis and Surgical Treatment. It is known to exhibit a slow, variable, and intermittent movement with vertical, horizontal, and torsional components. It is commonly found in patients with early onset strabismus and profound sensorial anomalies [1–5]. Diagnosis is not easy because the movement is slow and needs a more prolonged occlusion to appear; the amount of deviation is variable, intermittent, and depends on attention. These patients usually show horizontal, vertical, and torsional movements when performing the cover test and have diﬀerent amounts of deviation when ﬁxing with each eye. They also have latent nystagmus (LN), head tilt, and associated oblique muscles dysfunction in many cases. A distinctive feature of dissociated strabismus is the response to changes in light density; these changes impact on the deviation amount. When neutral ﬁlters of increasing density (bagolini ﬁlter bar) are placed before the ﬁxating eye, the hypertropic eye falls (Bielschowsky’s phenomenon) [6]. Conversely, increasing light in the hypertropic eye will cause an increase in upward deviation. A further peculiar behavior of patients with DD is evidenced by Posner’s maneuver [7]: when occluding one eye, the eye moves upwards, when occluding the contralateral eye (keeping the other eye occluded), the second eye moves upwards and the ﬁrst one downwards, becoming aligned in the vertical plane (Fig. 13.1). Red glass testing yields particular results in dissociated vertical deviation (DVD). Regardless of whether the red ﬁlter is placed before the right eye or the left one, the patient sees the red light below the white one. These maneuvers attest to the tight interocular interrelation of this particular form of strabismus.

Vertical manifestation of DD is known as DVD and is characterized for being a slow, intermittent, variable, and bilateral movement of elevation, abduction, and extorsion of the nonﬁxating eye. The downward vertical drift of the hypertropic eye takes place together with intorsion and adduction. The horizontal component has recently been described and is called dissociated horizontal deviation (DHD) [5, 8–10]. Even though most papers consider DHD as a variable, intermittent exodeviation with a different magnitude according to ﬁxating eye, there exist cases that exhibit an esodeviation with the same characteristics of variability and intermittence [11, 12]. There are also patients who manifest esotropia (ET) when ﬁxating with one eye and exotropia (XT) when ﬁxating with the other eye [9]. The torsional component of this entity, named dissociated torsional deviation (DTD), occurs simultaneously with vertical movement: extorsion of the elevating eye and intorsion of the ﬁxating eye. The vertical movement always cooccurs with extorsion of the elevating eye and intorsion of the descending eye. This is inﬂuenced by oblique muscles dysfunction also causing incomitance of vertical and torsional deviation in lateroversions [11, 13, 14]. Measuring horizontal and vertical DD is complicated because we need to superimpose horizontal and vertical prisms over each eye. In addition, it is necessary to measure DVD and DHD with each eye ﬁxating in all gaze positions (including head tilts) to have the necessary panorama to choose the best surgical procedure for each case. Therefore, surgical treatment of patients with DD requires a speciﬁc surgical approach. Long-term surgical results and recommendations for these cases remain sparse in literature. The purpose of this chapter is to mention the surgical alternatives tailored to treat each particular case.

Fig. 13.1 Posner’s maneuver: when occluding one eye, the eye moves upwards; when occluding the contralateral eye (keeping the other eye occluded), the second eye moves upwards and the ﬁrst one downwards, becoming aligned in the vertical plane

13.2 Surgical Alternatives to Treat Patients with DVD

Summary for the clinician ■ ■

DD have three components: vertical (DVD), horizontal (DHD), and torsional (DTD) movements. Surgical plan requires taking into account the three components and must be tailored to treat each particular case.

13.2 Surgical Alternatives to Treat Patients with DVD Patients with DVD are usually asymptomatic, but in those cases where signiﬁcant hypertropia is manifested spontaneously, or those associated with horizontal misalignment, surgical treatment should be considered knowing that the problem will not always be completely solved. DVD neither disappears nor improves over time [15]. Treatment is focused on obtaining a latent vertical deviation, only present with occlusion and to a lesser amount. Multiple techniques have been developed for DVD treatment; the most successful ones are those that limit elevation to a greater degree. To choose the surgical procedure, the following should be taken into account: (1) visual acuity (VA) (2) degree of non-DVD incomitance (3) oblique muscles dysfunction with A or V pattern (4) Degree of DVD symmetry.

13.2.1

Symmetric DVD with Good Bilateral Visual Acuity, with No Oblique Muscles Dysfunction

The following are the most used procedures in these cases: 1. Bilateral large superior rectus (SR) recession (7–12 mm) [16–20] 2. Bilateral retro-equatorial myopexy (posterior ﬁxation) of the SR combined with or without recession of these muscles [18, 21–24] 3. Four oblique muscles weakening procedure (superior oblique (SO) recession or tenectomy and inferior oblique (IO) recession or anterior transposition (IOAT) ) [25–28] 4. Bilateral inferior rectus (IR) resection [16, 29–32] Large SR recession with hang-loose technique is one of the mostly used in these cases. Extensive dissection is required to clean attachments oﬀ the SR to avoid

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retraction and lid ﬁssure asymmetry. This technique may limit elevation, especially in abduction (Pseudo inferior oblique over action (IOOA) ). It should be noted that weakening of SR modiﬁes horizontal deviation in PP, causing a 6 PD exodeviation, which should be taken into account when planning surgery. Conventional recession (3–5 mm) of SR together with retroequatorial myopexy (12–15 mm of original insertion) is used by several author successfully [64]. The posterior ﬁxation suture must be placed at least 20 mm, and preferably 23–25 mm from the limbus, which often is technically troublesome. The four oblique weakening procedures proved to be an eﬀective technique to treat these cases. This procedure is especially useful in cases that underwent surgery on two horizontal rectus muscles in each eye and in those where operating on the SR implies a risk of anterior segment ischemia. IR resection: Although this technique has been proposed as a primary procedure, we believe that it should be reserved for reoperation in the case of failure of SR recession. It creates a marked restriction of elevation and in some cases alterations in the lid ﬁssures. Its additional horizontal eﬀect, ET on PP, should also be considered.

13.2.2

Bilateral DVD with Deep Unilateral Amblyopia

DVD cases with deep monocular amblyopia are usually characterized by great asymmetry in vertical deviation, even simulating monocular DVD. Monocular surgery is possible in patients with a deviating eye with no possibilities of becoming ﬁxating eye due to deep amblyopia. There are four procedures that may be used in these cases: 1. Unilateral SR recession [16, 33]. 2. Unilateral inferior oblique anterior transposition (IOAT) [34, 35]. 3. Unilateral IR resection or tucking [36]. 4. Unilateral SR retroequatorial myopexy (posterior ﬁxation) combined with or without recession of this muscle [18]. When unilateral SR recess is decided, the amount of such must be moderate (5–7 mm) to avoid postoperative hypotropia. This technique is chosen in cases showing comitant vertical deviation in lateroversions.

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Many authors express concern that unilateral SR recession might also result in an unacceptable postoperative hypotropia in the operated eye or in a large hypertropia in the contralateral eye, if the patient were to switch ﬁxation [20]. For this reason, unilateral surgery is reserved for patients with dense amblyopia, who would have little or no chance of changing ﬁxation after surgery. In Schwartz and Scott’s paper [33], postoperative hypotropia developed in the operated eye in 12 patients (21%). Nine of these patients had deviations less than 10 PD. In Helveston’s study [3], only 5 out of 33 patients undergoing unilateral surgical correction of DVD developed a signiﬁcant deviation in the unoperated eye. Duncan and von Noorden [21] demonstrated the development of contralateral DVD postoperatively in 8/35 cases. In those cases manifesting incomitance in lateroversions: greater hypertropia in adduction, unilateral IOAT is chosen. Bothun and Summers [34] proved that unilateral IOAT is an eﬀective treatment for unilateral or markedly asymmetric DVD in patients with a strong, contralateral ﬁxation preference. This surgery reduces IOOA, but may also cause an ipsilateral hypotropia. Ipsilateral DVD in PP decreased from a mean of 20.2 to 3.7 PD in their series. Ninety percent of the patients had an excellent postoperative result. Goldchmit et al. [35] found that the unilateral IOAT produces a mean correction of 18.1 PD (range, 4–33) in PP, directly proportional to the size of the hypertropia before surgery.

IOAT remained with postoperative vertical deviation. 10/20 of such cases had preoperative asymmetric DVD. Although late development of a postoperative A pattern strabismus does not appear to be a problem even in patients with modest preoperative V patterns, the true incidence of the development of A pattern have not been addressed to date. Bradley Black [39] reported that after the operation, 50% of his patients had experienced neither A nor V pattern. Thirty-three percent had a V pattern averaging 4 PD (2–8 PD). Seventeen percent had a postoperative A pattern. In our series, 4/20 patients with bilateral IOAT had postoperative A pattern (20%) over 36-month follow-up on average. When there is a remaining postoperative vertical deviation after the IOAT, a unilateral SR recession can be performed according to the amount of vertical deviation in PP. This procedure proved eﬀective in obtaining good vertical alignment and has apparently given a predictable and stable result with low incidence of postoperative complications. Several studies have attempted to obtain better surgical outcomes in asymmetric DVD with IOOA by performing asymmetric procedures. There are several surgical alternatives: ■ ■ ■ ■

13.2.3

DVD with Inferior Oblique Overaction (IOOA) and V Pattern

When DVD is associated with IOOA, the hypertropia is greater in adduction and a V pattern may be observed. In extreme adduction, a true hypertropia may be seen in addition to the DVD. 1. Bilateral IOAT has become a popular surgical treatment for DVD with IOOA. 2. The second alternative is to perform a bilateral SR recession added to bilateral IO recession [37]. The IOAT reduces the hypertropia to an acceptable amount, and eliminates the IOOA and the V pattern with a low incidence of recurrence. However, this surgical procedure has yielded poor results in patients with asymmetric DVD and IOOA [38]. Nine out of 20 consecutive patients in our series with DVD and IOOA who underwent bilateral and symmetric

Combined unilateral IO resection and bilateral IOAT. Graded bilateral IOAT (1, 2, or 3 mm anterior to the IR muscle insertion). Graded bilateral IOAT (1, 2, or 3 mm posterior to the IR muscle insertion). Symmetric and bilateral IOAT + SR recession of the most hypertropic eye.

Burke et al. [40] suggested a graded procedure to eﬀectively treat coexisting DVD and IOOA. It has signiﬁcantly reduced the mean DVD from 13.4 PD to 6.7 PD. In cases of asymmetric DVD, unequal transpositions were performed: IOAT in the eye with the larger DVD can be placed up to 2 mm anterior to the temporal pole of the IR. The DVD remained controlled in 86% of their cases after a 2-year follow-up. The best results were obtained in those patients with a preoperative DVD of less than 15 PD. Mims and Wood [41] also performed bilateral graded displacement of the IO tendon, attaching the muscle at a point 2–4 mm anterior to the lateral end of the IR insertion. These authors reported low residual IOOA in 11/61 patients. Only one patient required reoperation for manifest DVD. Kratz et al. [42] compared two groups of patients with DVD who underwent standard or graded IOAT. In the graded group, the IO tendon was placed in one of the

13.2 Surgical Alternatives to Treat Patients with DVD

three stations: 1 mm posterior or 1 mm anterior to the IR insertion or at the level of the IR insertion. In the standard group, the IO tendon was positioned 1 mm anterior to the IR insertion for all degrees of DVD. The residual postoperative DVD was 1.15 PD in the graded group compared with 2.44 PD in the standard group. This difference was statistically signiﬁcant. Finally, Snir et al. [43], to improve the postoperative outcome in patients with asymmetric DVD with IOOA, augmented the functional change in the IO induced by IOAT by resecting the IO muscle in the eye with greater vertical deviation before displacing it anterior to the IR insertion. The IO resection was graded according to the diﬀerence in the preoperative vertical deviation between the eyes: 3 mm for a diﬀerence of up to 10 PD and 5 mm for a diﬀerence of 11–20 PD. These authors compared the postoperative outcomes of six consecutive patients who underwent combined graded monocular resection and bilateral ATIO with six consecutive historical control patients who underwent equal IOAT. The mean diﬀerence of the asymmetric DVD in the primary position was reduced from 13.3 to 2.2 PD in the study group and from 13.3 to 10.2 PD in the control group (P = 0.004). In conclusion, for patients with asymmetric DVD and coexisting IOOA and V pattern, we recommend bilateral IOAT combined with monocular graded IO resection in the eye with greater DVD or bilateral but graded IOAT to prevent the postoperative vertical deviation.

Fig. 13.2 Dissociated vertical deviation (DVD) with SOOA and A pattern: DVD is greater in abduction of the nonﬁxating eye

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The weakening of both elevators (IO and SR) always results in an elevation deﬁciency, that could be acceptable in cases with large hypertropia, but it could induce a noticeable and undesirable chin-up head position.

13.2.4

DVD with Superior Oblique Overaction (SOOA) and A Pattern

In these cases, DVD is greater in abduction of the nonﬁxating eye than in PP. The SOOA causes incomitance in DVD and A pattern [14, 44, 45] (Fig. 13.2). In this group, when A pattern anisotropia is small not over 14 PD 1. Bilateral SR improves DVD and controls A pattern [46]. If the A pattern is larger, undercorrection is obtained; therefore, other alternatives should be used. 2. Bilateral SR recession + bilateral SO posterior tenectomy or [44, 47, 48]. 3. Four oblique weakening procedure [27, 28]. Simultaneous weakening of SO and SR may cause an inversion of vertical incomitance, transforming the A pattern into V pattern. Thus, it is beneﬁcial to carry out the four oblique weakening procedure in these patients [28, 44].

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It may be a quite complex and lengthy procedure for nonexperienced surgeons; it produces a symmetric outcome and so it is not the preferred option in a markedly asymmetrical case. It could also produce a vertical deviation. When this complication occurs, a simple SR recession of the hypertropic eye can be performed according to the hypertropia amount in PP, thus solving the problem. There are several surgical alternatives to treat asymmetric cases with A pattern. A graded bilateral IOAT or a SR recession of the most hypertropic eye can be added to the usual SO weakening. The size of the A pattern and the presence of asymmetry are important when deciding the technique to be employed.

13.2.5 Symmetric vs. Asymmetric Surgeries for DVD DVD is often perceived as a bilateral condition; however, many cases are markedly asymmetric. These cases are usually found associated with unilateral deep amblyopia. Just as oblique muscle dysfunction makes DVD incomitant in diﬀerent gaze positions, the presence of a true vertical deviation (hypo or hypertropia) makes it asymmetric. The nondissociated vertical tropia can be lesser or larger than the amplitude of the DVD. When the nondissociated hypertropia is larger than the magnitude of the DVD, the hypotropic eye is never the higher eye. Despite the fact that the greater amplitude of DVD is usually seen in the nonﬁxating eye, cases with greater DVD in the ﬁxating eye do exist and may show hypotropia of the fellow eye in binocular conditions. When the cover test is performed, this hypotropic eye can either become hypertropic if DVD is larger than the vertical

Fig. 13.3 Bilateral DVD with left hypotropia in primary position

tropia, or it can remain aligned when the DVD is of a similar magnitude to that of the vertical tropia. This situation may be erroneously interpreted as monocular DVD. Asymmetric DVD will often appear to be unilateral. However, by performing the proper maneuvers, the bilaterality of most cases can be detected. The objective eye movement recording clearly demonstrates that DVD is bilateral in almost all cases. Bilateral symmetric procedures are performed for cases of bilaterally symmetric DVD (within ± 7 PD), but asymmetric DVD is more common, and larger DVD can be found in the nonﬁxating eye or even in the ﬁxating eye. Determining the diﬀerence in the amount of SR recession in these asymmetric cases remains challenging. The maximum diﬀerence allowed to obtain a good outcome remains controversial.

13.2.6

DVD with Hypotropia of the Nonﬁxating Eye

DVD usually manifests as an intermittent hypertropia, but there are certain cases with hypotropia of the nonﬁxating eye. Although rare, these cases are identiﬁed in different reports under the labels of Dissociated hypotropia [49, 50], Hypotropic DVD, Hypotropic Dissociated Deviation [51], or Inverse DVD (Fig. 13.3). Yet, we are not going to refer to patients with this condition, but to those with DVD and a hypotropic nonﬁxating eye. We can distinguish two groups: 1. Consecutive cases: cases secondary to surgical overcorrection (previous vertical acting muscles surgery). 2. Primitive cases: patients with asymmetric DVD (greater in the ﬁxating eye), with associated nondissociated vertical tropia or with unilateral deep amblyopia.

13.3

Three situations can lead to hypotropia of the nonﬁxating eye in a patient with DVD: 1. Hypertropia in the nondominant eye: the patient appears to have greater DVD amplitude in the nondominant eye: when he changes the ﬁxation and ﬁxates with that eye, despite its own DVD, hypotropia in the other one becomes evident. 2. True hypotropia of the nondominant eye. When the occlusion of this eye is performed, the magnitude of DVD will determine the position reached by the eye: it can be aligned, hypo, or hypertropic. 3. Nondissociated hypertropia in the dominant eye leading to hypotropia of the fellow eye in binocular conditions. These patients seem to have greater DVD amplitude in the dominant eye. Most cases of DVD that show hypotropia are due to surgical overcorrection, but other causes such as asymmetric DVD associated with vertical deviation or deep unilateral amblyopia may be responsible for this clinical feature. Accurate diagnosis is essential for correct surgical management [52].

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To choose the surgical procedure for DVD, we need to take into account: (1) VA; (2) vertical deviation incomitance; (3) oblique muscles dysfunction with A or V pattern; (4) DVD symmetry. Symmetric DVD with good bilateral VA, without oblique muscle dysfunction: four surgical alternatives: (1) Bilateral large SR recession. (2) Bilateral retroequatorial myopexy (posterior ﬁxation) of the SR combined with or without recession of these muscles. (3) Four oblique muscles weakening procedure. (4) Bilateral IR resection. Bilateral DVD with deep unilateral amblyopia: three available procedures: (1) Unilateral SR recession. (2) Unilateral IOAT. (3) Unilateral IR resection or tucking. DVD with IOOA and V pattern: (1) Bilateral IOAT. (2) Bilateral SR recession added to bilateral IO recession. DVD with SOOA and A pattern: (1) Bilateral SR recession. (2) Bilateral SR recession + SO posterior tenectomy. (3) Four oblique weakening procedure. Symmetric vs. Asymmetric surgeries for DVD: Bilateral symmetric procedures are performed for cases with bilaterally symmetric DVD.Asymmetric DVD is more common and these cases require asymmetrical techniques.

Dissociated Horizontal Deviation

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13.3 Dissociated Horizontal Deviation DHD has become a more recognized entity in the last few years and is usually related to the horizontal deviation associated with DVD in patients with early onset strabismus history. The main diagnostic sign of DHD is the presence of a horizontal variable deviation, ET, or XT that changes with ﬁxation of each eye, unrelated to diﬀerent accommodation or presence of primary and secondary deviation due to weakness or restriction. It is a slow and variable horizontal movement, similar to the intermittent hypertropia that characterized the DVD. Commonly both conditions coexist; both are variable and diﬃcult to measure and are also more prominent during inattention. In DHD, we cannot neutralize the horizontal deviation by the classical prism and alternating cover test. Alternate cover testing must be performed slowly allowing the nonﬁxating eye time for the slow drift to fully manifest. It is also necessary to make the right eye ﬁxate ﬁrst and neutralize with prism the left eye deviation, and then let the left eye ﬁxate and neutralize the right eye deviation. The reversed ﬁxation test (RFT) [53] is useful to diagnose DHD. During this test, the patient is asked to ﬁxate through the prism that neutralizes the deviation of one of his eyes and then the occluder is shifted to the uncovered eye without the prism and it is observed for any reﬁxation movement when the cover test is performed. The test is positive when a reﬁxation movement which can be measured placing prisms in front of this eye is observed. Brodsky et al. [54] found that 50% of his patients with consecutive XT had DHD demonstrated by a positive RFT. Seven of the 14 patients with DHD had a greater exodeviation when ﬁxating with the preferred eye. In our series, seven patients had greater exodeviation when ﬁxating with the dominant eye, seven patients had greater esodeviation when ﬁxating with the nondominant eye, and three cases had XT when ﬁxating with the dominanteye and ET when ﬁxating with the nonpreferred eye. Only one patient had greater ET when ﬁxating with the dominant eye. These ﬁndings seem to support his hypothesis that the exodeviation is usually smaller with the nonpreferred eye ﬁxating (Fig. 13.4). DHD is often observed to be larger with visual inattention than when the prisms measurements are done, and the eye position under general anesthesia (GA) usually shows greater deviation than the measured angle in the awake state. Examining the patient under GA [55] is extremely useful to decide the amount of surgery to be done. The

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13

Fig. 13.4 Dissociated horizontal deviation (DHD). She has greater exodeviation when ﬁxating with the dominant eye

eye position under GA used to show greater exodeviation when the innervational forces are abolished. The forced duction can diagnose a restriction and the spring back test can determine a medial rectus (MR) muscle weakness when it was previously recessed. Wilson and McClatchey, in 1991 [5], recommended graded unilateral lateral rectus (LR) recession for the treatment of DHD, and this was the most common method to treat it when surgery is indicated. It was said that bilateral surgery is less often required for DHD than for DVD. However, DHD is almost always associated with DVD, so we consider that bilateral surgery to treat both is a good option in many patients [56]. All our patients had DHD coexisting with DVD; ten cases received bilateral surgery to treat both conditions, ﬁve underwent surgery just for the DVD because the horizontal deviation was small, and two patients received surgery for the horizontal deviation alone despite having DVD as well. The most used technique for DHD was unilateral LR recession. Retroequatorial myopexy (posterior ﬁxation) of the LR with a recession of this muscle is recommended by certain authors [12]. Bilateral LR recession is indicated when XT is bilateral, unilateral, or bilateral MR recession when the patient exhibits ET instead of XT. Performing a LR recession added to MR advancement is a valid alternative in cases with previous surgery on the medials. DVD and DHD usually coexist. When the vertical or the horizontal deviation manifests frequently, a surgical plan to ﬁx the drift of the eyes is needed. Bilateral surgery is proposed to address both conditions simultaneously [57].

Summary for the Clinician ■

■

The main diagnostic sign of DHD is the presence of a horizontal variable deviation, ET, or XT that changes with ﬁxation of each eye, unrelated to diﬀerent accommodation or presence of primary and secondary deviation due to weakness or restriction. The technique most used for DHD was unilateral LR recession. Bilateral LR recession is indicated when XT is bilateral; unilateral or bilateral MR recession when the patient exhibits ET instead of XT. Performing a LR recession added to an MR advancement is a valid alternative in cases with previous surgery on the medials.

13.4

Dissociated Torsional Deviation. Head tilts in patients with Dissociated Strabismus

There is very little information on DTD in literature. Torsional movements are involved in the genesis of this form of strabismus and oblique muscles are the main oculomotor muscles with torsional action [2, 58, 59]. DVD mechanism has been elucidated recently by means of ocular movement recording techniques. DVD would be mediated primarily by the SO in the ﬁxating eye and the IO in the fellow eye, added to a bilateral supraversion required for the maintenance of ﬁxation with the ﬁxating eye. In the latter eye, only an intorsional movement is observed, because the vertical components of SO and SR are annulled. A movement of elevation, abduction and

13.4

Dissociated Torsional Deviation. Head tilts in patients with Dissociated Strabismus

extorsion characteristic of DVD produced by SR and OI is observed in the fellow eye. In this case, the vertical vectors would be added while the extorsion and abduction produced by the IO in upgaze would prevail on intorsion and adduction of the SR. Children with DD frequently have head turn; they usually ﬁxate in adduction but they also have head tilts. The head tilt can be toward the shoulder of the ﬁxating eye (direct tilt) or toward the contralateral side (inverse tilt) [60, 61]. This head tilt has been thought to be related to the presence of DVD, but there is no evidence conﬁrming the relationship between these two ﬁndings. Guyton [58] claims that adopting an anomalous head posture can inﬂuence latent and manifest LN in some cases. The head tilt would damp the pattern of LN associated with the ﬁxing eye, and therefore, surgery on the ﬁxing eye is practically always necessary to abolish head tilts. Brodsky et al. [62] proposed that direct tilt is not compensatory for binocular vision, while a head tilt toward the hyperdeviated eye (inverse tilt) serves to neutralize the hyperdeviation and stabilizes binocular vision. According to Jampolsky’s description of Bielschowsky head tilt test (BHTT) response in DVD [63], there is an increased hyperdeviation of the contralateral eye on tilting to either side, the exactly inverse behavior to that of SO palsy or SR overaction/contracture syndrome (Fig. 13.5).

Fig. 13.5 Bielschowsky head tilt test (BHTT) response in DVD: there is an increased hyperdeviation of the contralateral eye on tilting to either side

181

Direct tilt is observed in patients without horizontal alignment and with a head turn and fixation in adduction. On tilting the head toward the fixating eye side, they are demanding more vestibular innervation to increase adduction and therefore, they could improve their monocular fixation. The most patients who adopt inverse tilt can obtain better vertical alignment in that position. Out of 50 consecutive patients in our series who underwent surgical treatment for DVD, only 54% (27/50) had head tilt. Of 27 cases, 14 had direct tilt (51%); the head tilt did not improve vertical alignment. They usually obtain improvement of the head position by means of the bilateral SR recession surgery. Direct tilt improves the vertical alignment in two situations: when a contracture of the SR of the nonﬁxating eye exists or in asymmetric DVD cases, larger in the ﬁxating eye. We found inverse head tilt, which improved the vertical alignment, in 13/27 (49%) cases. Many of these patients had vertical deviation in PP and it was not rare to ﬁnd SR contracture of the ﬁxating eye. When ﬁxing with either eye, the head tilt improved the vertical alignment. When we have a patient with DD who needs surgery, the head tilt should be taken into account to attempt to improve the head position.

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Finally, we want to point out that a great number of patients with DD do not have head tilt. This fact makes evident that there are other nonelucidated factors that determine such a particular clinical sign.

13 Summary for the Clinician ■

■

When we have a patient with DD who need surgery, we have to take into account the presence of head tilt to attempt to improve the head position. Direct tilt (toward the ﬁxing eye) is not compensatory for binocular vision, while a head tilt toward the hyperdeviated eye (inverse tilt) serves to improve the vertical alignment.

13.5

Conclusions

Obtaining long-term control of the deviation in patient with dissociated strabismus is diﬃcult; a successful outcome in the postoperative period does not guarantee the ﬁnal alignment. In treated patients with DD, we will always see some kind of movement when performing the cover test. DVD never disappears completely and the dissociated behavior in DHD also persists when testing under slow cover test.

References 1. Guyton DL (2000) Dissociated vertical deviation: etiology, mechanism, and associated phenomena. J AAPOS 4: 131–144 2. Guyton DL, Cheeseman EW Jr., Ellis FJ, Straumann D, Zee DS (1998) Dissociated vertical deviation: an exaggerated normal eye movement used to damp cyclovertical latent nystagmus. Trans Am Ophthalmol Soc 96:389–429 3. Helveston EM (1980) Dissociated vertical deviation: a clinical and laboratory study. Trans Am Ophthalmol Soc 78: 734–779 4. Raab EL (1970) Dissociative vertical deviation. J Pediatr Ophthalmol Strabismus 7:146–151 5. Wilson ME, McClatchey SK (1991) Dissociated horizontal deviation. J Pediatr Ophthalmol Strabismus 28:90–95 6. Bielschowsky A (1938) Lectures on motor anomalies: II. The theory of heterophoria. Am J Ophtahlmol 21:1129 7. Posner A (1944) Noncomitant hyperphorias: considered as aberrations of the postural tonus of the muscular apparatus Am J Ophtahlmol 27:1275

8. Romero-Apis D, Castellanos-Bracamontes A (1992) Dissociated horizontal deviation: clinical ﬁndings and surgical results in 20 patients. Binocul Vis 7:135–138 9. Wilson ME, Saunders RA, Berland JE (1995) Dissociated horizontal deviation and accomodative esotropia: treatment options when an eso and exodeviation co-exist. J Pediatr Ophtahlmol Strabismus 32:228 10. Zubcov AA, Reinecke RD, Calhoun JH (1990) Asymmetric horizontal tropias, DVD, and manifest laternt nystagmus: an explanation of dissociated horizontal deviation. J Pediatr Ophtahlmol Strabismus 27:59 11. Spielmann A (1990) Vertical and torsional deviations in early strabismus. Bull Soc Ophtalmol Fr. 90(4):373–378; 381–384 12. von Noorden GK (1996) Cyclovertical deviations. In: Binocular vision and ocular motility: theory and management of strabismus, 5th edn. Mosby-Year Book, St Louis, pp 360 13. Berard PV, Reydy R, Berard PV Jr (1990) Symptomatologic value of dissociated vertical divergence in concomitant strabismus. Bull Soc Ophtahlmol Fr 90(1):31–38 14. McCall LC, Rosenbaum AL (1991) Incomitant dissociated vertical deviation and superior oblique overaction. Ophthalmolgy 98:911 15. Harcourt B, Mein J, Johnson F (1980) Natural history and associations of dissociated vertical divergence. Trans Ophtahlmol Soc UK 100:495 16. Braverman DE Scott WE (1977) Surgical correction of dissociated vertical deviations. J Pediatr Ophtahlmol Strabismus 14:337–342 17. Jampolsky A (1986) Management of vertical strabismus. Trans New Orleans Acad Ophtahlmol 34:141 18. Lorenz B, Raab I, Boergen KP (1992) Dissociated vertical deviation: what is the most eﬀective surgical approach? J Pediatr Ophtahlmo Strabismus 29:21 19. Magoon E, Cruciger M, Jampolsky A (1982) Dissociated vertical deviation: an asymmetric condition treated with large bilateral superior rectus recession. J Pediatr Ophtahlmol Strabismus 19:152 20. Scott WE, Sutton VJ, Thalacker JA (1982) Superior rectus recessions for dissociated vertical deviation.Ophtahlmology 89:317–322 21. Duncan LF, von Noorden GK (1984) Surgical results in dissociated vertical deviations J Pediatr Ophthalmol Strabismus 21:25–27 22. Hiles DA, Baybars I, Biglan AW (1986) Long-term stability of the superior rectus recession Faden operation for dissociative vertical deviation. In: Campos ED (ed) Proceedings of ISA V. Athena Scientiﬁc, Rome, Modena, Italy, pp 403–412 23. Sprague JB, Moore S, Eggers H et al (1980) Dissociated vertical deviation: treatment with the fadenoperation of Cuppers. Arch Ophtahlmol 98:465

References 24. von Noorden GK (1978) Posterior ﬁxation suture in strabismus surgery. In: Symposium on strabismus. Trans new Orleans acad ophtahlmol. CV Mosby, St. Louis, pp 307 25. Acosta Silva MA, Campomanes G (2000) Cirugia de cuatro oblicuos para Desviacion Vertical Disociada y sindrome em A. CLADE anais 2000 del XIV Congreso del CLADE. São Paulo, pp 359–360 26. Gamio S (2002) A surgical alternative for dissociated vertical deviation based on new pathologic concepts: weakening all four oblique eye muscles. Outcome and results in 9 cases. Binocul Vis Strabismus Q 17(1):15–24 27. Gamio S (2006) Weakening the four oblique muscles in the tereatment of DVD. In: Proceedings of the joint congress: the Xth meeting of ISA and the ﬁrst extraordinary meeting of CLADE. São Paulo, Brazil pp 97–100 28. Texeira Krieger F, Caron Lambert A (2000) Efeito do debilitamento do músculo Oblicuo superior hiperfuncionante associado a anteriorizacao do músculo oblicuo inferior na Divergencia Vertical Dissociada. CLADE anais 2000 del XIV Congreso del CLADE. Sao Paulo, pp 447–450 29. Esswein Kapp MB, von Noorden GK (1994) Treatment of residual dissociated vertical deviation with inferior rectus resection. J Pediatr Ophtahlmol Strabismus 31:262 30. Noel LP, Parks MM (1982) Dissociated vertical deviation: associated ﬁndings and results of surgical treatment. Can J Ophtahlmol 17:10 31. Parks MM (1975) Dissociated hyperdevitions. In: Ocular motility and strabismus. Harper and Row, Hagerstown, MD, pp 149 32. Sargent RA (1979) Dissociated hypertropia: surgical treatment. Ophtahlmology 86:1428 33. Schwartz T, Scott W (1991) Unilateral superior rectus recession for the treatment of dissociated vertical deviation. J Pediatr Ophtahlmol Strabismus 28:219 34. Bothun ED, Summers CG (2004) Unilateral inferior oblique anterior transposition for dissociated vertical deviation. JAAPOS 8(3):259–263 35. Goldchmit M, Felberg S, Souza-Dias C (2003) Unilateral anterior transposition of the inferior oblique muscle for correction of hypertropia in primary position. JAAPOS 7(4):241–243 36. Arroyo Yllanes ME, Escanio Cortes ME, Perez Perez JF, Murillo Murillo L (2007) Unilateral tucking of the inferior rectus muscles for dissociated vertical deviation. Cir Cir 75(1):7–12 37. Varn MM, Saunders RA, Wilson ME (1997) Combined bilateral superior rectus muscle recession and inferior oblique muscle weakening for dissociated vertical deviation. J Am Assoc Pediatr Ophthalmol Strabismus 1:134 38. Del Monte MP (1993) Atlas of pediatric ophthalmology and strabismus surgery. Churchill-Livingstone, New York, pp 9

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39. Black BC (1997) Results of anterior transposition of the inferior oblique muscle in incomitant dissociated vertical deviation. JAAPOS 1(2):83–87 40. Burke JP, Scott WE, Kutshke PJ (1993) Anterior transposition of the inferior oblique muscle for dissociated vertical deviation. Ophthalmology 100:245–250 41. Mims JLIII, Wood RC (1989) Bilateral anterior transposition of the inferior obliques. Arch Ophthalmol 107:41–44 42. Kratz RE, Rogers GL, Bremer DL, Leguire LE (1989) Anterior tendon displacement of the inferior oblique for DVD J Pediatr Ophtahlmol Strabisumus 26:212–217 43. Snir M, Axer-Siegel R, Cotlear D, Sherf I, Yassur Y (1999) Combined resection and anterior transposition of the inferior oblique muscle for asymmetric double dissociated vertical deviation. Ophtahlmology 106(12):2372–2376 44. Velez G, Velez F, Ela-Dalman N (2008) Surgical management of dissociated vertical deviation associated with A pattern strabismus. Poster presented at the 34th AAPOS Annual Meeting. Washington 45. Velez G (2000) A clinical classiﬁcation of DVD for a better surgical approach. Fetscrif for Arthur Jampolsky. The Smith Kettlewell Eye Research Institute, pp 59–63 46. Melek N, Mendoza JC, Ciancia AO (1998) Bilateral recession of the superior rectus: its inﬂuence in A and V pattern strabismus. J AAPOS 2:61 47. Prieto-Diaz J (1979) Posterior tenectomy of the superior oblique. J Pediatr Ophtahlmol Strabismus 16:321 48. Shin GS, Elliott RL, Rosenbaum AL (1996) Posterior superior oblique tenectomy at the scleral insertion for collapse of A pattern strabismus. J Pediatr Ophthalmol Strabismus 33:211 49. Kraft SP Long QB, Irving EL (2006) Dissociated hypotropia: clinical features and surgical management of two cases. JAAPOS 10(5):389–393 50. Greenberg MF, Pollard ZF (2001) A rare case of bilateral dissociated hypotropia and unilateral dissociated esotropia. JAAPOS 5(2):123–125 51. Kraft SP, Irving EL, Steinbach MJ, Levin AV (2000) A case of hypotropic dissociated vertical deviation: surgical management. In: Spiritus M (ed) Transactions of the 25th meeting of the European strabismological association. Aeolus, Lisse, The Netherlands, pp 93–95 52. Gamio S (2007) Hypotropia in patients with dissociated vertical deviation. Transactions of the 31th ESA meeting. Mykonos, Greece, pp 337–340 53. Brodsky MC, Gräf MH, Kommerell G (2005) The reversed ﬁxation test: a diagnostic test for dissociated horizontal deviation. Arch Ophthalmol 123(8):1083–1087 54. Brodsky MC, Fray KJ (2007) Dissociated horizontal deviation after surgery for infantile esotropia: clinical characteristics and proposed pathophysiologic mechanisms. Arch Ophthalmol 125(12):1683–1692

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55. Apt L, Isenberg S (1977) Eye position of strabismus patients under general anesthesia. Am J Ophthalmol 84(4): 574–579 56. Wilson ME, Hutchinson AK, Saunders R (2000) Outcomes from surgical treatment for dissociated horizontal deviation. J AAPOS 4(2):94–101 57. S. Gamio, MD (2008) Diagnosis and surgical treatment of dissociated horizontal deviation (DHD). In: Transactions of the 32nd Meeting of the European Strabismological Association. Edited Rosario Gomez de Liano. European Strabismological association. Depósito legal: M-141742009. Madrid, Spain, 37 pp 113–115 58. Guyton DL (2004) Dissociated vertical deviation: an acquired nystagmus-blockage phenomenon. Am Orthoptic Journal 54:77–87 59. Guyton DL (2008) Ocular torsion reveals the mechanisms of cyclovertical strabismus: the Weisenfeld lecture. Invest Ophthalmol Vis Sci 49(3):847–857; 846

60. Bechtel RT, Kushner BJ, Morton GV (1996) The relationship between dissociated vertical divergence (DVD) and head tilts. J Pediatr Ophtahlmol Strabismus 33:303 61. Santiago AP, Rosenbaum AL (1998) Dissociated vertical deviation and head tilts. J Am Assoc Pediatr Ophtahlmol Strabismus 2:5 62. Brodsky MC, Jenkins R, Nucci P (2004) Unexplained head tilt following surgical treatment of congenital esotropia A postural manifestation of DVD. Br J Ophthalmol 88(2): 268–272. Erratum in: Br J Ophthalmol 2004 Apr;88 (4):599 63. Jampolsky A (1994) A new look at the head tilt test In: Fuchs AF, Brandt TH, Buttner U, Zee DS (eds) Contemporary ocular motor and vestibular research A tribute to David A Robinson. Springer, Sttuttgart, pp 432–439 64. De Decker W, Conrad HG (1975) Fadenoperation nach Cuppers bei komplizierten Augenmuskelstorungen und nichtakkommodativem Konvergenzexzess. Klin Monatsbl Augenheilkd 167:217

Chapter 14

Surgical Implications of the Superior Oblique Frenulum

14

Burton J. Kushner and Megumi Iizuka

Core Messages ■

■

The superior oblique (SO) tendon is attached to the undersurface of the superior rectus muscle by an areolar frenulum. The frenulum, if left intact, causes the SO tendon to move posteriorly with the superior rectus muscle when it is recessed. This can prevent the SO from becoming scarred into the superior rectus insertion when the latter is recessed. It can, however, prevent the superior rectus muscle from taking up slack when recessed with a suspension technique.

14.1

Introduction

The superior oblique (SO) muscle is adherent to the undersurface of the superior rectus muscle by an areolar connective tissue. Jampolsky was the ﬁrst to describe the surgical signiﬁcance of this local adherence, which he referred to as a frenulum [1]. The term frenulum can be deﬁned as a membranous fold of skin that supports or restricts the movement of an organ, such as the small band of tissue connecting the tongue to the ﬂoor of the mouth. Jampolsky stated that when the frenulum is left intact, the SO tendon moves with the superior rectus muscle. Hence, when the superior rectus muscle is recessed, the SO tendon will not only retract with it but may also constrain the posterior movement of the muscle if the superior rectus is recessed, using an adjustable suture or suspension (A.K.A. hang-back) technique. He found that if the frenulum is left intact, the SO tendon via the frenulum will prevent the superior rectus muscle from achieving a recession of greater than 10 mm. Therefore, Jampolsky recommended severing the frenulum if a recession of greater than 10 mm of the superior rectus is desired to obtain the desired amount of recession. He also recommended cutting the frenulum during superior rectus resections, so as to avoid pulling the SO tendon forward with the resection, resulting in the

■

■

An intact frenulum can result in the SO tendon scarring into the superior rectus insertion when the latter is resected. The posterior SO tenectomy procedure is eﬀective in collapsing small A patterns but often does not eliminate overdepression in adduction. This apparent contradiction can be explained by the change in SO vector force that results from cutting the frenulum, which is unavoidable with this surgical procedure.

potential complication of the SO tendon becoming scarred into the insertion of the superior rectus muscle. Recently, studies have suggested that scarring of the SO muscle in this way can produce a complication referred to as the SO tendon incarceration syndrome [2]. This syndrome is a restrictive strabismus characterized by a hypertropia with incyclotropia of the aﬀected eye that is associated with scarring of the SO tendon to the nasal corner of the insertion of the superior rectus muscle. It is a very diﬃcult surgical problem to correct and hence should be avoided if possible. The frenulum may also be an important structure to consider during SO surgery as well. Prieto Diaz advocated cutting the frenulum to obtain maximal weakening of the SO muscle by the temporal approach [3, 4]. On the other hand, excessive stripping of the frenulum may also be an additional cause of SO tendon incarceration syndrome when weakening procedures are performed on the SO tendon [2, 5]. Several authors, cited above, have alluded to the importance of the proper handling of the frenulum for both superior rectus surgery and SO surgery. Their statements appear logical, but it is only recently that the eﬀect of severing the frenulum on the position of both the SO tendon and superior rectus muscle at surgery has been quantiﬁed [2]. In addition, it has been observed that the

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Surgical Implications of the Superior Oblique Frenulum

posterior partial tenectomy procedure on the SO tendon is eﬀective in collapsing of A patterns that measure less than 20 PD (prism diopters); however, it is less eﬀective in decreasing the overdepression in adduction [3, 5]. This residual overdepression in adduction has been described as pseudo-SO overaction (pseudo-SOOA) [3, 5]. It appears that the inevitable severing of the SO frenulum that occurs with this surgical procedure can explain the persistence of the overdepression in adduction in spite of its eﬀectiveness in collapsing the pattern, as described in Sect. 10.2.3 of this chapter.

14.2

Clinical and Theoretical Investigations

A series of clinical in vivo investigations of the eﬀect of diﬀerent methods of handling the SO tendon frenulum, as well as some theoretical calculations made from scale modeling shed important light on how the SO frenulum should be handled when surgery is performed on the SO tendon or superior rectus muscle.

14.2.1 The Eﬀect of Superior Rectus Muscle Recession on the Location of the Superior Oblique Tendon Before and After Cutting the Frenulum This experiment consisted of measuring the posterior displacement of the SO tendon with recession of the superior rectus muscle before and after cutting the SO frenulum in three patients (2, 8, and 25 years of age) who were undergoing enucleation for unrelated reasons [6]. At the time of surgery but before the globe was enucleated, the position of the SO tendon was measured before and after cutting the frenulum in the eye undergoing enucleation while suspending the superior rectus muscle at various distances. This was performed as follows: The superior rectus muscle was isolated on a muscle hook, imbricated with two double-armed 6–0 Polyglactin 910 sutures, the check ligaments were cut in the usual manner, and the superior rectus muscle was disinserted. The underlying SO tendon insertion was identiﬁed without cutting the frenulum. A single-armed 6–0 Polyglactin 910 suture was sewn into the anterior aspect of the SO tendon midway between the nasal and temporal edge of the superior rectus muscle and knotted in place (Fig. 14.1). A reference knot was tied in this suture approximately 15–20 mm from the knot placed in the SO tendon. Next, with the superior rectus held at the original insertion, the distance between the reference knot and the superior rectus muscle insertion was recorded. This distance was referred to as the initial

Fig. 14.1 Photograph of right eye at surgery as seen from below. The needle of a 6–0 Polyglactin 910 suture is being passed through anterior aspect of the superior oblique (SO) tendon midway between the nasal and temporal edge of the superior rectus muscle with the superior rectus muscle disinserted and reﬂected upward. The small arrow denotes the SO tendon; the large arrow denotes the reﬂected superior rectus muscle. (Reprinted from [6] Elsevier Press)

reference knot distance. The superior rectus muscle was then suspended 6, 8, 10, 12, and 14 mm for a total of three recessions at each distance in a randomly generated order to avoid any inﬂuence of tissue hysteresis or tissue memory. The temporary suspension of the muscle was accomplished by grasping the sutures in the superior rectus with forceps at the desired distance from the superior rectus and then holding this point on the sutures at the superior rectus insertion. The eye was then rotated to the primary position and the conjunctiva was lifted to verify if the muscle had completely taken up the slack in the suspension suture. If the slack had not been spontaneously taken up for the desired amount of recession, the superior rectus muscle was reposited with instruments and the occurrence thereof noted. The eﬀect of the superior rectus suspension on the position of the SO tendon was recorded using calipers to measure the distance from the reference knot to the insertion of the superior rectus muscle. This was referred to as the second reference knot distance. A masked assistant (resident, fellow, or scrub nurse) then read the caliper distance using a straight ruler to the nearest 0.5 mm. By subtracting the second reference knot distance from the initial reference knot distance, the amount of posterior movement of the SO tendon was calculated for each successive suspension of the superior rectus muscle (Fig. 14.2). The SO frenulum was then completely severed under direct visualization by elevating the superior rectus muscle and lysing the connection between it and the underlying SO tendon using sharp and blunt dissection.

14.2 Clinical and Theoretical Investigations

187

Fig. 14.2 Axial view of the left eye as viewed from superiorly in the orbit illustrating location of SO tendon before cutting the frenulum while suspending the superior rectus muscle at various distances. Superior rectus suspended at (a) Original insertion, (b) 6 mm, (c) 14 mm. (Reprinted from [6] Elsevier Press)

All the above measurements were repeated, again with three measurements for each superior rectus suspension distance performed in a randomly determined sequence. There was essentially a one-to-one correlation between the amount of superior rectus recession and posterior movement of the SO tendon for superior rectus recessions up to 10 mm. After severing the frenulum, there was negligible movement of the SO tendon reaching a maximum of only 1.7 mm in only one patient for a superior rectus recession of 14 mm. For superior rectus recessions between 10 and 14 mm, the suspended superior rectus typically would not take up the slack to achieve the desired amount of recession prior to severing the frenulum without being manually reposited. This conﬁrms that the frenulum intimately links the superior rectus muscle and the SO tendon. The fact that the superior rectus muscle did not consistently take up the slack for large suspension recessions (10–14 mm) with the frenulum intact, but did so more often when the frenulum was severed, is probably due to a constraining eﬀect of the frenulum. The frenulum is attached to the SO tendon, which in turn has limited amount of slack to allow the tendon to continue to move freely posteriorly. Hence, at these large recession values, the frenulum may prevent adequate weakening unless the superior rectus muscle is sutured in place. We therefore advocate cutting the frenulum for superior rectus muscle recessions that are larger than 10 mm, especially when using a suspension technique. In theory, when the frenulum is intact the orientation of the SO tendon would bow backwards as illustrated in Fig. 14.2c when a large recession of the superior rectus muscle is performed. This graphically illustrates why an intact frenulum will limit the amount the superior rectus

muscle can be recessed using a suspension. It appears, however, that this should result in a substantial alteration of the force of the SO muscle. Yet clinically, we do not observe such a profound change in the SO muscle function. One explanation may be that the frenulum allows some movement of the SO tendon relative to the superior rectus muscle during active contraction. Our studies were all done with the patients anesthetized and consequently did not address that possibility. After cutting the frenulum, the SO muscle moved minimally when the superior rectus muscle was recessed. Because the anterior border of the SO tendon is approximately 8 mm posterior to the superior rectus when the globe is rotated in the downward position, an 8 mm recession of the superior rectus muscle would place its new insertion overlying the SO tendon if the frenulum is severed. The SO insertion is broad and underlies a relatively large area beneath the superior rectus muscle. Consequently, cutting the frenulum may result in diﬃculty with suturing the superior rectus to the sclera without incorporating some of the SO insertion whose diaphanous nature can make it diﬃcult to visualize. We therefore agree with Jampolsky’s recommendations to preserve the frenulum for superior rectus recessions that are 10 mm or less to insure that the SO tendon will move posteriorly with the recessed superior rectus muscle and not get scarred into the new superior rectus insertion [1, 7]. Furthermore, for recessions greater than 10 mm we advocate lysing this areolar connection owing to its constraining eﬀect [6]. Although we did not study superior rectus resections [6], we speculate that with the frenulum intact, the SO tendon would be pulled anteriorly with the superior rectus muscle as previously stated by Jampolsky, and the SO

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Surgical Implications of the Superior Oblique Frenulum

tendon may therefore be at risk of being sutured into the insertion site of the superior rectus muscle [1, 7]. Consequently, for superior rectus resections, we also advocate separating the frenulum.

14 14.2.2 The Eﬀect of the Frenulum on Superior Oblique Recession Using a Suspension Technique This experiment consisted of assessing how far the SO tendon retracted (recessed) after disinsertion to simulate what happens with either a recession with a suspension technique or a free disinsertion. This was done both before and after separating the frenulum in a second series of four patients (ages 8, 17, 22, and 47 years) who were undergoing bilateral SO recession using a suspension technique. The position of the SO was measured before and after cutting the frenulum in the following manner: The SO tendon’s insertion was isolated through a superotemporal incision after ﬁrst hooking the superior rectus muscle. The SO tendon was hooked at its insertion with care to avoid pulling the tendon from under the superior rectus muscle, thus preserving the frenulum. This was done by reﬂecting the superior rectus nasally as minimally as possible but suﬃcient to allow for visualization of the insertion of the SO tendon. A 6–0 Polyglactin 910 suture was woven through the tendon near the insertion and knotted (Fig. 14.3). A reference knot was tied in the suture 15–20 mm from the distal end of the SO tendon and the superior rectus muscle was set back in its unreﬂected position. The distance from the reference knot to the temporal edge of the superior rectus muscle

was measured and recorded in the aforementioned masked manner. This was recorded as the initial reference knot distance. The SO tendon was then disinserted, and two successive forced ductions to rotate the eye maximally up and in were performed. With the eye returned to the primary position, the distance between the initial reference knot and the temporal superior rectus edge was remeasured with calipers to give the second reference knot distance. The masked assistant then read the caliper distance using a straight ruler to the nearest 0.5 mm. The amount of recession of the SO tendon was calculated to the nearest 0.5 mm by subtracting the second reference knot distance from the initial reference knot distance. This was repeated for three sets of measurements. Traction was then placed on the SO tendon, to pull it approximately 12–14 mm out from under the superior rectus muscle temporally (Fig. 14.4). This movement essentially brought all of the tendon that is normally under the superior rectus muscle out temporal to it, and eﬀectively severed the frenulum connection. This maneuver is similar to what frequently occurs if one just exerts substantial traction on the SO tendon when weakening it at the insertion or during a SO tendon tucking procedure. Two forced ductions were again performed to rotate the eye up and in. The distance between the knot and the superior rectus edge was measured with calipers in the same manner as when the frenulum was intact. Again, using simple subtraction, the amount of recession of the SO tendon after the frenulum was stripped was calculated using our masked measurement technique for three successive measurements. To control the possibility that the amount of recession simply increased with the multiple forced ductions that were needed to obtain multiple measurements, a single set of

Fig. 14.3 Axial view of the right eye viewed from superiorly in the orbit illustrating movement of the SO tendon. (a) A 6–0 Polyglactin 910 suture woven through the insertion, just after hooking the SO tendon. The frenulum is intact. (b) The SO tendon disinserted with the frenulum intact. A relatively small amount of recession occurs. (c) After stripping the frenulum a much larger amount of recession of the SO tendon occurs than prior to stripping the frenulum. (Reprinted from [6] Elsevier Press)

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achieved by cutting the frenulum [4]. It also suggests that asymmetric eﬀects may occur with bilateral SO recession using a suspension technique, if there is asymmetric stripping of the frenulum. On the other hand, stripping the frenulum may allow the disinserted SO tendon to migrate forward resulting in the SO tendon incarceration syndrome [2]. Thus how the frenulum is handled with these procedures may be a matter of tradeoﬀs.

14.2.3 The Theoretical Eﬀect of the Superior Oblique Frenulum on the Posterior Partial Tenectomy of the Superior Oblique

Fig. 14.4 Surgical photograph of the right eye rotated downward as viewed from below; superior muscles are at the top in the photograph. Traction is placed on the SO tendon pulling it 12–14 mm out from under the superior rectus muscle temporally to eﬀectively sever the frenulum. Small arrow denotes SO tendon; large arrow denotes suture tied to the cut end of the SO tendon. (Reprinted from [6] Elsevier Press)

measurements was taken prior to and after stripping the frenulum on the other (control) eye in the same manner as in the ﬁrst (study) eye. In two patients, the study procedure was performed in the right eye ﬁrst, and in the other two patients, the study procedure was performed in left eye ﬁrst. The mean distance that the SO tendon recessed was 2.4 ± 0.4 mm before cutting the frenulum and 8.5 ± 0.7 mm after cutting the frenulum. There was a statistically signiﬁcant diﬀerence between the two measurements (P = 0.0011, paired two-tailed student’s t-test). The same procedure was followed in the fellow control eye for one set of measurement. For the control eyes the mean recession prior to stripping the frenulum was 2.4 ± 0.3 mm and after stripping the frenulum was 8.0 ± 0.8 mm (P = 0.0004, paired two-tailed student’s t-test). These values for the amount of recession obtained in the control eyes before and after stripping the frenulum were essentially identical to the values for the study eyes, despite the control eyes only having a single measurement. This conﬁrms that taking multiple measurements prior to stripping the frenulum was not a confounding factor on the amount that the SO moved after stripping the frenulum. The results of this experiment are consistent with the observation that the maximal eﬀect of a recession of the SO tendon using a suspension technique can only be

The threefold function of the SO muscle includes intorsion, depression, and to a lesser degree, abduction. These actions are uniquely related to its anatomy and the angle the tendon makes with the anterior–posterior axis. The SO tendon makes an angle of approximately 54° with the anterior–posterior axis. The anterior ﬁbers of the SO tendon make a relatively large angle with the anterior–posterior axis and therefore are thought to primarily have a torsional action, and only a small vertical action. Prieto Diaz calculated the relative vertical and torsional actions of the anterior and posterior ﬁbers of the SO tendon using computer-aided design software and determined that the vertical action is approximately 1/3 of the torsional action [8]. The posterior ﬁbers of the SO tendon make a smaller angle with the anterior–posterior axis than the anterior ﬁbers. He concluded they therefore contribute approximately 50% less torsion than the anterior ﬁbers but twice as much vertical action. These anatomic considerations of the differential effects of the anterior and posterior fibers of the SO tendon have given rise to different surgical procedures depending on whether one wants more torsion vs. vertical correction. For example, the Harada–Ito operation tightens the anterior fibers and primarily provides torsional changes [9]. Conversely, the posterior partial tenectomy primarily weakens the more posterior fibers of the SO tendon and thus gives more vertical correction with minimal change in torsion. Prieto–Diaz first described this procedure, which consists of cutting the posterior 4/5 or 7/8 of the SO tendon at its insertion and then excising a posterior triangle of tendon extending about 8–12 mm toward the trochlea [10, 11]. He proposed this operation to surgically treat A-patterns without affecting torsion. It has been reported to be effective in collapsing A patterns of up to 20 PD; however, it is not effective in decreasing the overdepression in adduction resulting

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14

Fig. 14.5 This patient underwent bilateral posterior tenectomy of the SO tendon combined with bilateral 5 mm lateral rectus muscle recessions to treat an exotropia associated with 18PD of A pattern. Before surgery he had +2 bilateral SO overaction. The surgery not only eliminated the A pattern but overcorrected it resulting in a small V pattern, yet his SO overaction persisted

in a pseudo-SOOA [3, 5] (Fig. 14.5). Why this procedure fails to address the overdepression in adduction has not been adequately explained. We feel that some unique considerations about the SO frenulum as well as some anatomic considerations of the SO tendon explain why the posterior partial tenectomy operation does not eliminate the overdepression in adduction. To study this, we used scale ﬁgures of the anatomy of the SO and SR obtained from Orbit™1.8 (Eidactics, San Francisco, CA) to determine the angles made by the anterior and posterior ﬁbers of the SO tendon with the anterior–posterior axis when the eye was in the primary position, as well as in adduction. We then modiﬁed those ﬁgures to assume that the frenulum constrained the SO tendon to the SR muscle and recalculated the same angles. The contribution of the net force directed parallel to the anterior–posterior axis represents the force that creates depression, and the contribution of the net force directed perpendicular to the anterior–posterior axis represents the torsional force. The percentage of original SO force that is directed vertically and torsionally is the cosine and sine of the angle made by the SO tendon and the anterior–posterior axis, respectively, multiplied by 100. Figure 14.6a shows the eye in primary position. The anterior ﬁbers of the SO tendon make an angle of 75° with the anterior–posterior axis. Thus, the torsional force vector of these ﬁbers is the sine of 75°, or 0.97 times the magnitude of the net force. Or in other words, the torsional force vector equals 97% of the net force. Similarly, the vertical force vector is the cosine of 75° multiplied by 100, or 26% of the net force. When the eye is adducted 35°, and if one assumes the frenulum constrains the tendon to the SR muscle, the tendon will bow backwards as shown in Fig. 14.6b. In this picture, which is modiﬁed from the Orbit™1.8 model, we

have kept the distance between the anterior edge of the SO tendon and the SR insertion the same, implying that the constraining property of the frenulum completely prevents the SO tendon from slipping anteriorly. In this scenario, the original angle made by the anterior ﬁbers of the SO tendon and the anterior–posterior axis is approximately the same. As seen in Fig. 14.6b, the anterior ﬁbers of the SO tendon still make an angle of 75° with the anterior–posterior axis. Consequently, in the normal nonoperated eye, the contribution of the SO forces of intorsion, abduction, and depression remain relatively unchanged in adduction compared with the primary position. Figure 14.6c illustrates the situation after a posterior partial tenectomy procedure. The excised portion of the posterior four ﬁfths of the SO tendon insertion is outlined in black. This surgical procedure necessitates that the frenulum be excised, which allows the SO tendon to move forward. This substantially decreases the angle between the anterior ﬁbers of the SO tendon and the anterior–posterior axis. In Fig. 14.6c, we measured this angle to be approximately 40°. In this position, the depressor action of the SO tendon is increased compared with that found in the unoperated state. The magnitude of depression is the sine of 40° or 77% of the total net force as compared with only 26% prior to the surgical procedure. This may be one explanation why overdepression in adduction persist after posterior partial tenectomy. This residual abnormality of versions may be due to the unavoidable excision of the SO frenulum, which occurs with this surgical procedure, and the eﬀect this has on the subsequent distribution of vertical force of the SO tendon. Persistent overdepression in adduction has been reported as occurring in 40.4% [12]–57% [5] of patients after posterior partial SO tenectomy. Despite this unwanted overdepression in adduction, weakening of the

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Fig. 14.6 Three-dimensional scale ﬁgure of the anatomy of the SO modiﬁed from Orbit™1.8 program seen from above. (a) Representation of an unoperated eye in the primary position. The anterior ﬁbers of the SO tendon make an angle of 75° with the anterior–posterior axis. The magnitude of the force vector for depression of the SO tendon is 26% of the total net force. (b) Representation of an unoperated eye in adduction. This is modiﬁed from Orbit™1.8 to assume the frenulum completely constrains the tendon to the SR muscle. The original angle made by the anterior ﬁbers of the SO tendon and the anterior–posterior axis is preserved measuring 75°. The magnitude of the force vector for depression of the SO tendon remains unchanged at 26% C) Representation of the eye in adduction following posterior partial tenectomy procedure of the SO tendon. Th e absence of the constraining eﬀect of the frenulum allows the SO tendon to slide forward. Th is decreases the angle between the anterior ﬁbers of the SO tendon and the anterior–posterior axis to 40°. The magnitude of the force vector for depressor of the SO tendon increases to 77% of the total net force

SO with posterior partial tenectomy eﬀectively reduces the exo-shift in down gaze and thus reduces the A pattern [5, 10–12]. This may be due to the ability of the adducting power of the inferior rectus muscle to prevail over any residual abducting power of the weakened SO in the adducted and depressed position (unpublished written personal communication from A. Castanera de Molina, July 18, 2007). However, overdepression occurs even when the A-pattern is eﬀectively collapsed, suggesting that this motility pattern is not simply due to a surgical undercorrection. Castanera considers this common postoperative complication of downshoot in adduction to be a direct consequence of the surgery itself (unpublished written personal communication from A Castanera de Molina, July 18, 2007). This would be consistent with our hypothesis that excision of the frenulum can result in forward slippage of the remaining ﬁbers of the SO when the eye is adducted, thus increasing their vertical force. Some investigators have speculated that the downshoot in adduction seen after partial posterior SO tenectomy occurs secondary to a limitation of depression in abduction of the contralateral eye after bilateral surgery.

This results in a pseudo-SOOA in the ipsilateral eye by Herring’s law [5, 8]. There are several theories as to the cause of this limitation. For example, anteriorization of the SO tendon insertion to a preequatorial location after a posterior partial tenectomy has been theorized. Using the Orbit™ 1.8 model, Castanera simulated that an anterior shift of the muscle insertion centroid of 4.45 mm after a posterior partial tenectomy would cause a reduction in the vertical force of the SO tendon [13]. He also modeled the situation in which the cut end of the SO tendon could inadvertently be reattached to the sclera, thus simulating a recession plus resection procedure. Both simulations show a similar change in the vertical force component such that the SO tendon becomes an elevator in abduction with no change of depression in adduction. Another cause of the limitation to depression in abduction of the contralateral eye may due to iatrogenic incarceration of the SO tendon to the SR insertion [2, 5, 13]. This complication also places the eﬀective insertion of the SO tendon to a preequatorial position. One further mechanism could be the presence of underlying occult SR contracture [7]. We feel that

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contralateral restriction of depression in abduction cannot fully account for the persistence of overdepression in adduction after partial posterior SO tenectomy, because we have seen this occur in the operated eye after unilateral surgery. Also, we have observed that this ﬁnding is often present immediately after surgery. This would tend to rule out postoperative iatrogenic mechanical restriction in the contralateral eye as the cause. We do recognize, however, that since most SO weakening procedures are bilateral, both residual overdepression in adduction of the ipsilateral eye and limitation to depression in abduction of the contralateral eye could occur. Furthermore, these two conditions would be additive with respect to their eﬀect on versions in adduction. We considered the anatomical eﬀects of the SO frenulum on the vertical and torsional force vectors of the SO tendon using basic two-dimensional trigonometry. We recognize that there are some obvious oversimpliﬁcations in our theoretical analysis. The geometric angles drawn on the scaled model are somewhat arbitrary. For example, our modeling of the anterior ﬁbers of the unoperated SO tendon when the eye is adducted (see again Fig. 14.6b) assumes that the frenulum completely constrains the tendon. In reality, there is probably some elasticity of the frenulum that allows at least some forward slippage [6]. We assume this to be the case as common clinical observations conﬁrm that the SO has a greater vertical and lesser torsional action in adduction than in the primary position. Nevertheless, prior investigation on the constraining eﬀect of the SO tendon frenulum suggests that our model is at least qualitatively sound, even if it is not exactly quantitatively accurate [6, 7]. In addition, we reduced a complex three-dimensional situation into a two-dimensional construct, and the abducting contribution of the SO tendon was ignored. We feel, however, that this would have minimal impact on our conclusions, as the abducting force of the SO muscle is relatively small. Thus, although the actual numbers we calculated are approximate, our qualitative analysis conﬁrms what seems logical. Speciﬁcally, if we assume that the SO tendon is constrained by the frenulum in the primary and adducted ﬁelds of gaze, cutting the frenulum after a procedure such as a partial posterior tenectomy would collapse the angle the anterior ﬁbers make with the anterior–posterior axis. This reduction in the angle makes the SO tendon a more eﬀective depressor in the adducted position. This may be an explanation for the residual overdepression in adduction in the ipsilateral eye after posterior partial tenectomy of the SO tendon.

Summary for Clinicians ■

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The SO frenulum is an important structure. How it is handled with superior rectus and SO surgery may aﬀect the surgical outcome. The frenulum should be severed for superior rectus recessions that exceed 10 mm, to allow for the desired recession eﬀect. The frenulum should be severed for all superior rectus resections to prevent the SO tendon incarceration syndrome. The frenulum should be left intact for superior rectus recessions that are less than 10 mm to prevent the SO tendon incarceration syndrome. With SO recessions using a suspension technique the handling of the frenulum is a matter of tradeoﬀs. Severing the frenulum will involve a greater amount of recession, but may predispose to the SO tendon incarceration syndrome. Leaving the frenulum intact will prevent that restrictive strabismic syndrome but will limit the amount of recession obtained. Asymmetric handling of the frenulum with bilateral SO recession may predispose to an asymmetric response. The posterior tenectomy operation of the SO is eﬀective in collapsing up to 20 PD of A pattern but is less eﬀective in eliminating the overdepression in adduction.

References 1. Jampolsky A (1981) Superior rectus revisited. Tr Am Ophth Soc 79:233 2. Kushner BJ (2007) Superior oblique tendon incarceration syndrome. Arch Ophthalmol 125:1070–1076 3. Prieto-Diaz J (1988) Management of superior oblique overaction in A-pattern deviations. Graefes Arch Clin Exp Ophthalmol 226:126–131 4. Prieto-Diaz J (1989) Superior oblique overaction. Int Ophthalmol Clin 29:43–50 5. Castanera de Molina A, Fabiani R, Giner MG (1998) Downshoot in infra-adduction following selected superior oblique surgical weakening procedures for A-pattern strabismus. Binocul Vis Strabismus Q 13:17–28 6. Iizuka M, Kushner B (2008) Surgical implications of the superior oblique frenulum. J AAPOS 12:27–32 7. Jampolsky A (1986) Management of vertical strabismus. Symposium on pediatric ophthalmology: transactions of the new Orleans acad ophthalmol. Raven, New York, pp 141–171

References 8. Prieto-Diaz J (1996) Selective and moderated weakening of the superior oblique muscle. Memorias del IV Congresso del Consejo Latinoamericano de Estrabismus. Mayo, Buenos Aires, pp. 535–541 9. Harada M, Ito Y (1964) Surgical correction of cyclotropia. Jap J Ophthalmol 8:88–96 10. Prieto-Diaz J (1976) Tenectomia parcial posterior del oblicuo superior. Arch Oftalmol B Aires 51:267–271 11. Prieto-Diaz J (1979) Poseterior partial tenectomy of the SO. J Pediatr Ophthalmol Strabismus 16:321–323

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12. Shin GS, Elliott RL, Rosenbaum AL (1996) Posterior superior oblique tenectomy at the scleral insertion for collapse of A-pattern strabismus. J Pediatr Ophthalmol Strabismus 33:211–218 13. Castanera de Molina A, ML GM (1997) Persistent SO “overaction” after surgical treatment of A-pattern anisotropies. In: M. Spiritus (ed) Transactions 24th meeting European strabismological association; Vilamoura, Portugal. Aeolus, Buren, The Netherlands

Chapter 15

Pearls and Pitfalls in Surgical Management of Paralytic Strabismus

15

Seyhan B. Özkan

Core Messages ■

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Careful preoperative assessment and a correct diagnosis of the problem are the essential factors for a successful outcome of surgical treatment. The pearl to go through the correct route in surgical management of paralytic strabismus is to know the questions that need to be answered during the preoperative assessment. The correct answers for these questions clarify the method of appropriate surgical treatment. During the preoperative assessment, the potential for fusion must be carefully evaluated. Acquired loss of fusion or, in other words, central fusion disruption may coexist in acquired paralytic ocular motility problems. In such cases, restoration of the ocular alignment may make the symptoms worse because of the increased awareness of diplopia with two overlapping images. The aims of surgical treatment are primarily to obtain a diplopia-free ﬁeld, to achieve symmetric ocular motility and a good looking eye that will allow eye contact, and to correct the abnormal head posture, if any.

15.1 General Principles of Surgical Treatment in Paralytic Strabismus Paralytic strabismus is one of the most challenging areas in strabismus practice. In other types of strabismus, the ophthalmic surgeon considers to operate six muscles for each eye to restore the ocular alignment. However, in paralytic strabismus, the ocular alignment needs to be restored with limited number of muscles, sometimes even with only one functioning extraocular muscle (EOM). In this chapter, the general principles of surgical treatment will be reviewed ﬁrst and then the treatment strategies in third, fourth, and sixth cranial nerves will be evaluated.

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The major pitfall in paralytic strabismus is the coexistence of a restrictive element. The secondary restrictions may mask the partial functional recovery in a paretic extraocular muscle (EOM), and sometimes they may become a more prominent problem than the paralytic condition itself. The restoration of ocular alignment should be planned to create a new balance in both eyes. Paralytic strabismus is a binocular problem even in cases with unilateral involvement. There should be no hesitation to operate the sound eye where necessary. The methods of surgical treatment primarily aim to weaken the unopposed overaction of the antagonist, then to strengthen the paretic muscle where possible or to create a mechanical eﬀect by transposition, and ﬁnally to weaken the yoke muscle in the sound eye. In certain cases like complete third nerve palsy, creating a restriction with surgery may be required to keep the eye in primary position.

15.1.1 Aims of Treatment The major aims of treatment are enlargement of diplopiafree ﬁeld, restoration of ocular alignment, and restoration of the appearance of the patient, to correct abnormal head posture, and to improve the ductions. The last one is the concern of the strabismus surgeon, and the patients usually do not complain of limited ductions and are mostly not even aware of the limitation of their ductions if it is not very severe.

15.1.2 Timing of Surgery In all types of paralytic strabismus, the stability of the deviation must be observed before considering any surgical

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intervention. The time period that the spontaneous recovery occurs is usually accepted as 6 months; however, this period may last longer, especially in third nerve palsies. A waiting period of 12 months is recommended for third nerve palsies and spontaneous recovery may occur even in a longer period of time in some cases [1]. As a general rule, one must consider that if the deviation is still unstable following consecutive examinations after 6 months, surgical treatment must be postponed till the deviation becomes stable.

15.1.3 Preoperative Assessment Prior to any treatment, one must be sure about the diagnosis. Restrictive motility problems may simulate paralytic conditions and sometimes both restrictive and paralytic problems occur at the same time making the clinical picture more complicated. The combination of restrictive and paralytic problems mostly occurs in orbital blow-out fractures and in long-standing paralytic problems. The combination of restrictive element has a negative eﬀect on the predictability of surgical results, so the presence of any restrictive factors must be carefully evaluated in all cases with paralytic strabismus. For a correct surgical planning, the following questions need to be answered preoperatively in cases with paralytic strabismus: 1. 2. 3. 4.

Is the problem partial (paresis) or total (paralysis)? Are there any restrictive factors? Is the problem congenital or acquired? Is there “acquired loss of fusion” or in other words “central fusion disruption?”

The answers for the ﬁrst two questions will be discussed together. ■ ■

Is the paralytic problem partial or total? Are there any restrictive factors?

If there are no restrictive forces, it is not diﬃcult to assess whether the paralytic condition is partial or total. These factors may be primary as it is the case in blow-out fracture or secondary as the contracture of the antagonist muscle(s) in long-standing paralytic problems. For a correct evaluation of the role of accompanying restrictive factors and the residual function of the paretic EOM, the following tests may be used: ■ ■ ■ ■

Measurement of the deviation in nine positions of gaze Assessment of the ocular rotations Traction test Active forced generation test

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Electromyography (EMG) Increase of intraocular pressure with positions of gaze Measurement of saccadic eye movements Botulinum toxin A (BTXA) injection into the antagonist EOM

Among those methods, the saccadic eye movement recordings provide very reliable information. However, in most of the clinics, saccadic eye movement recording is not available as a routine clinical method. BTXA may also be used as a diagnostic tool in paralytic strabismus [2]. The secondary unopposed contracture of the antagonist EOM may not allow the eye to move toward the direction of the aﬀected muscle despite some spontaneous recovery. For diagnostic purpose, BTXA is injected into the antagonist EOM. An improvement of the movement toward the functional area of the paretic muscle indicates that there is some residual function of the paretic muscle [3] (Figs. 15.1 and 15.2). However, it must be kept in mind that in presence of severe contracture with ﬁbrosis BTXA injection does not give reliable results, as BTXA cannot eliminate the ﬁbrotic tissue eﬀect. Despite the numerous methods for preoperative assessment of the restrictive forces, the surgeon may have to change the surgical plan depending upon the traction test results under general anesthesia. In long-standing paralytic strabismus, the contracture and ﬁbrosis may not only aﬀect the EOMs but also the fascial structures and EOM pulleys and an orbital ﬁbrosis develops [4, 5]. In such cases, the traction test will be found positive despite the disinsertion of the EOM. These cases represent the most challenging paralytic ocular motility problems. ■

Is the problem congenital or acquired?

In congenital paralytic disorders, there may be some developmental abnormalities like the tendon abnormalities in congenital superior oblique palsy, EOM ﬁbrosis, or orbital ﬁbrosis. Most of the congenital cases do not complain of diplopia. The exception of this is decompensated congenital fourth nerve palsy presenting with vertical diplopia. ■

Is there “acquired loss of fusion (central fusion disruption)?”

Acquired loss of fusion or central fusion disruption may occur in paralytic strabismus cases especially the posttraumatic ones. In these cases, because of the involvement of the fusional areas which are supposed to be located in the midbrain, the previously healthy fusional ability is lost causing intractable diplopia. When the

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Fig. 15.1 Use of botulinum toxin A (BTXA) for assessment of the function of the paretic muscle. If the paretic muscle has some residual function the eye moves toward the functional area of the paretic extraocular muscle (EOM) following injection of BTXA into the antagonist muscle [3] Paretic EOM

Partially recovered paretic EOM

Contracture of the antagonist

Paralysis of the antagonist with BTXA

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b

Fig. 15.2 In a patient with left sixth nerve palsy (a) the improvement of abduction of the left eye after injection of BTXA into the medial rectus muscle is shown (b) [3]

deviation is neutralized by prisms or synoptophor, these patients typically describes a vertical sliding of the images when the two images were overlapped and were just about to appear single. The diagnosis of this challenging problem preoperatively is very important. If the patient has an acquired loss of fusion and intractable diplopia, the deviation should better be corrected temporarily by prisms or BTXA to allow the assessment of the tolerance of diplopia [2, 6]. In some cases during this period, the fusional ability may be regained and in those ones surgery may be performed safely. Our preferred method is BTXA injection in such cases to provide a temporary period of orthophoria under real-life conditions. The decreased contrast sensitivity and the loss of image quality related to Fresnel prisms may have a negative eﬀect on recovery of fusion. If the patient cannot overcome or tolerate diplopia with the use of BTXA or prisms, surgical correction of the deviation may cause an increase of the complaint of diplopia. Orthophoria in a patient with intractable diplopia is much more bothersome compared with the diplopia with a large deviation. The overlapping

two close images cannot be tolerated and cause more symptoms compared with the two far away images in a patient with a large deviation.

15.1.4 Methods of Surgical Treatment ■

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Decreasing the strength of the antagonist: Recession or disinsertion of the antagonist is the preferred method. If it will be combined with full tendon transposition, BTXA injection instead of surgical recession should be preferred for the risk of anterior segment ischemia. Strengthening the paretic EOM: Resection or tendon tuck could be performed. For strengthening procedures, the paretic muscle is preferred to have some residual function. The exception of this is superior oblique palsy. Because of the tendon length and the anatomical characteristics, superior oblique tendon tuck may be performed in a superior oblique muscle with no residual function.

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Weakening the yoke muscle in the sound eye: Recession or faden operation of the yoke muscle in the unaﬀected eye is the preferred method to increase the ﬁeld of binocular diplopia-free ﬁeld.

15 These are the general principles that the strabismus surgeon needs to consider in all types of paralytic strabismus cases. The cranial nerve palsies will be evaluated individually during the rest of the manuscript.

15.2 Third Nerve Palsy Third nerve palsy may aﬀect the third nerve in total, or the superior or inferior branches of the nerve as well as the isolated EOM involvement. All these types of third nerve palsy may present with a total or partial involvement, and they represent a wide range of ocular motility problems. The involvement of the inferior branch of the third nerve aﬀects medial rectus, inferior rectus, and inferior oblique muscles, whereas the superior branch aﬀects the superior rectus and levator palpebrae superioris muscle.

15.2.1

Complete Third Nerve Palsy

In complete third nerve palsy, the major problem is the unopposed contracture of the antagonist lateral rectus muscle. There is a small hypotropia with a large angle exodeviation and ptosis due to the involvement of levator palpebrae superioris muscle. If the pupillary ﬁbers are aﬀected, a mydriatic pupilla will be observed. In congenital and long-standing cases, ﬁbrosis of the intraorbital structures develops. The aims of treatment in complete third nerve palsy are to obtain an improvement of the appearance of the patient, orthophoria in primary position, and a ﬁeld of binocular single vision in a very limited area. Prior to any surgical intervention, the patient must be informed about the goals of surgery and the possibility of a more bothersome diplopia with the decrease of the proximity of the two images in primary position. The surgical treatment modalities in complete third nerve palsy may be summarized as follows: ■ ■ ■ ■

Weakening of the lateral rectus muscle. Resection of the medial rectus muscle. Superior oblique tendon transposition. The procedures that keep the eye in passive adduction.

Weakening of the lateral rectus muscle: The methods of weakening are supramaximal recession, hang back

recession enough to allow the passive adduction of the eye, orbital wall periost ﬁxation of the lateral rectus muscle, and BTXA injection in residual deviations [7–9]. Orbital wall periost ﬁxation is a recently described method for the inactivation of lateral rectus muscle that we found useful in our clinical practice. Posterior Tenon ﬁxation is proposed to be an alternative method to periost ﬁxation [10]. The potential reversibility of the procedure is the advantage of both of these methods. Medial rectus resection: Although the resection of a paralytic muscle is not so eﬀective, some authors prefer to perform a large resection to obtain a mechanical resistance against abduction. In our experience, this eﬀect does not last long and we do not prefer to resect medial rectus muscle. Superior oblique tendon transposition: The aims of superior oblique tendon transposition is to correct the hypotropia, making the superior oblique an adductor, creating a mechanical barrier against abduction, and thus preventing the recurrence of the exodeviation. Superior oblique tendon transposition may work if and only if the superior oblique muscle has some function. Especially, in long-standing ones, it may be diﬃcult to assess the function of the superior oblique muscle while the eye is ﬁxated in an abducted position. In such patients with no apparent hypotropia or intorsion in ocular motility examination, slit lamp observation may be very helpful. Any attempt of intorsion of the eye can easily be observed under slit lamp. Superior oblique tendon transposition may be performed by trochlear luxation and superior oblique tendon resection or with Scott’s method by cutting the superior oblique tendon via nasal approach and suturing the tendon 2 mm anterior and nasal to the superior rectus tendon without destroying the trochlea [7, 11]. The latter is our preferred method for superior oblique tendon transposition, which is a less invasive one. The procedures to keep the eye in passive adduction: For a permanent eﬀect fascia lata, silicone band or superior oblique tendon may be used to ﬁxate the globe to the orbital periosteum [12, 13]. Traction sutures are used to keep the eye in passive adduction for a transient period to increase the eﬀect of surgery [14, 15]. These sutures are kept in place for 6 weeks. This is our method of choice in total third nerve palsy [3] (Figs. 15.3–15.5). The other methods are usually performed in secondary cases with a failure of a previous operation. The major problems in total third nerve palsy are lateral rectus contracture that cannot be overcome by any methods, orbital ﬁbrosis in long-standing cases, recurrence of exodeviation, and the more bothersome diplopia following a successful surgery that provides orthophoria in a very limited area.

15.2 Third Nerve Palsy

199

Fig. 15.3 Preoperative right exo and hypotropia in a patient with right congenital third nerve palsy [3]

and in that case, the treatment should be modiﬁed depending upon the severity of the involvement of the EOM(s). As the goal is to enlarge the diplopia-free ﬁeld, the sound eye may be operated where necessary. In that case, faden operation or recession of the yoke muscle in the sound eye may be used.

Summary for the Clinician ■

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Fig. 15.4 In the case with congenital third nerve palsy traction sutures are seen in upper and lower eyelid to keep the eye in adducted position [3] ■

15.2.2

Incomplete Third Nerve Palsy

In incomplete third nerve palsy with a superior or inferior branch or isolated EOM involvement, the treatment should be planned depending upon the aﬀected EOM(s). Recess-resect or transposition with a recession or BTXA injection may be preferred. In isolated inferior oblique palsy, transposition of horizontal recti perfectly works without weakening the superior rectus muscle. Complete third nerve palsy may present with partial involvement

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The correct evaluation of a complete or incomplete third nerve palsy (to diagnose the number of aﬀected muscles) and assessment of a total or partial involvement (the residual function of the aﬀected muscles) are the pearls for an appropriate surgical planning. In complete third nerve palsy, superior oblique function may easily be overlooked. The pearl is to use slit lamp for a precise evaluation to see the tiny intorsion. In incomplete or partial third nerve palsy, the aim is to provide a functional diplopia-free area; however, in complete third nerve palsy, the aim is to ﬁxate the aﬀected eye in primary position. Orbital ﬁbrosis is the bad prognostic sign for any type of surgery. The pearl is to create surgically induced restriction that provides a mechanical pulling eﬀect. A temporary pulling by traction sutures is very eﬀective that allows the development of the scar tissue while the globe was ﬁxated on adduction.

200

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15

Fig. 15.5 Postoperative appearance of the patient after removal of the traction sutures 6 weeks after surgery. Orthophoria is obtained in primary position [3]

15.3

Fourth Nerve Palsy

In fourth nerve palsy hypertropia, inferior oblique overaction and superior oblique underaction is observed in the aﬀected eye. In long-standing unilateral cases, a secondary contracture of the superior rectus develops and a pseudo overaction of the superior oblique muscle in the sound eye is observed. Abnormal head posture and a positive Bielschowsky head tilt test are the other ﬁndings of fourth nerve palsy. In unilateral cases, the typically observed abnormal head posture is chin down with head tilt toward the unaﬀected side. In bilateral cases, the abnormal head posture may be as in unilateral cases if there is marked asymmetry. If the bilaterality is symmetrical, then the abnormal head posture aims to compensate the “V” pattern. In acquired cases, vertical or torsional diplopia is the main complaint of the patients. Congenital cases do not usually complain about diplopia; however, in decompensated congenital fourth nerve palsy, the patient has vertical diplopia. Some patients may beneﬁt from prisms but most of the patients require surgical treatment. For a correct surgical plan, one needs to have the correct answers for the following questions: ■ ■ ■ ■ ■ ■ ■

What is the amount of deviation in primary position? What is the position of gaze with the largest deviation? Is it congenital or acquired? Is there any superior oblique tendon laxity? Is there any superior rectus contracture? Is it unilateral or bilateral? Is there any torsional diplopia?

What is the amount of the deviation in primary position? If the vertical deviation in primary position is exceeding 15 prism diopters, two muscle surgeries need to be considered. What is the position of gaze with the largest deviation? The surgical treatment should be planned on the EOMs functioning in the ﬁeld of gaze with the largest deviation. To obtain a reliable data, the measurement of the deviation should be done in nine diagnostic positions of gaze. Is it congenital or acquired? The reply to this question has a speciﬁc importance in fourth nerve palsy. Congenital cases may present with superior oblique tendon abnormalities, such as abnormal tendon laxity, tendon insertion abnormalities, and sometimes even agenesis of the tendon [16–19]. Because of the frequent tendon abnormalities in congenital cases, it was proposed that these cases might have primary developmental abnormality of the superior oblique tendon rather than fourth nerve palsy [16]. However, in a previous MRI study where we looked for the superior oblique muscle size in congenital and acquired cases, we demonstrated that congenital cases with abnormal tendon laxity may have denervation atrophy in the superior oblique muscle bulk and our ﬁndings were conﬁrmed in other recent studies [20, 21]. If the abnormality would only be limited with the tendon itself, denervation atrophy would not be expected to develop in those cases with congenital fourth nerve palsy. The differential diagnosis in congenital and acquired cases is not only important for the etiological investigation but also for surgical planning. The clinical clues suggesting that the patient has a congenital superior oblique palsy may be summarized as follows:

15.3 ■ ■ ■ ■ ■ ■ ■ ■ ■

History, old photos Absence of a preceding event Prominent abnormal head posture Facial asymmetry Coexistence of amblyopia Signiﬁcant superior oblique underaction Large vertical fusional amplitude Coexisting horizontal deviation Absence of subjective torsion

Is there any superior oblique tendon laxity? Superior oblique tendon laxity can be assessed prior to surgery with traction test that was described by Guyton [22] and modiﬁed by Plager [17]. The globe is ﬁxated by two forceps at inferior nasal and superior temporal areas and with retropulsion the globe is elevated on adduction. With this maneuver, the globe is pushed against the superior oblique tendon, and with back and forth movements, the globe the tendon can easily be felt (Fig. 15.6). If there is an agenesis of the superior oblique tendon, the tendon cannot be felt and the globe is totally free with back and forth movements. As an additional ﬁnding when the globe is elevated on adduction cornea disappears in total if there is a tendon laxity. Is there any superior rectus contracture? Superior rectus contracture may develop in long-standing fourth nerve

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201

palsy. In these cases, traction test is positive in depression on adduction. In motility examination, a limitation of depression on adduction and a pseudo overaction of the superior oblique muscle in the sound eye are the clues for superior rectus contracture (Fig. 15.7). Recession of superior rectus muscle is advised in those cases with superior rectus contracture [23, 24] (Fig. 15.8). Is it unilateral or bilateral? Especially in traumatic cases, masked bilaterality is very common. All of the cases with fourth nerve palsy should be carefully evaluated for the clues of bilateral involvement [25, 26]. The bilateral involvement may be asymmetric but even with marked asymmetry surgery should be planned in both eyes. The clinical clues suggesting bilateral involvement are as follows: ■ ■ ■

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Bilateral inferior oblique overaction. Bilateral superior oblique underaction. Positive Bielschowsky head tilt test with the head tilted on both sides. In case of a marked asymmetry, Bielschowsky head tilt test may be positive on the side with marked involvement. “V” pattern deviation. Abnormal head posture to compensate the “V” pattern. Objective torsion exceeding 10° [40].

Fig. 15.6 Steps of superior oblique tendon tuck in abnormally lax superior oblique tendon in the right eye. (1) The globe is grasped with retropulsion. (2)The globe is moved superonasally and the cornea disappears in total, the back and forth movements indicate superior oblique tendon laxity. (3) Superior oblique muscle is found abnormally lax. (4)Tucking is performed with non absorbable sutures. (5) Superior oblique tendon is ﬁxated on the sclera. (6) Traction test is repeated after tucking. Note the diﬀerence of the position of the cornea

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15

Fig. 15.7 Preoperative appearance of a patient with right long-standing fourth nerve palsy with ipsilateral superior rectus contracture. Note the limitation of depression in the right eye and the pseudo overaction of the left superior oblique muscle

Fig. 15.8 Postoperative appearance of the patient with right long-standing fourth nerve palsy following inferior oblique disinsertion and adjustable superior rectus recession of the right eye

Is there any torsional diplopia? Torsional diplopia is a symptom that occurs in acquired fourth nerve palsy. The patients with a decompensated congenital fourth nerve palsy has vertical diplopia without a torsional element,

although an excyclotorsion is observed in fundus examination, and this is one of the clues for diﬀerential diagnosis of a congenital and acquired fourth nerve palsy. Some patients may not describe torsional diplopia properly

15.3

unless asked speciﬁcally and may complain about “blurring” in certain gaze positions. Surgical methods of treatment may be summarized as follows: ■ ■ ■ ■

Inferior oblique weakening procedures Superior oblique strengthening procedures Superior rectus recession in the aﬀected eye Inferior rectus recession in the contralateral eye

Inferior oblique weakening procedures: Inferior oblique weakening procedures are the most commonly performed operations for treatment of fourth nerve palsy [41, 42]. The weakening procedures are disinsertion, myectomy, recession, and anteroposition of the inferior oblique muscle. Inferior oblique weakening should be performed in all cases with inferior oblique overaction. Our preferred method for inferior oblique weakening is disinsertion. If the deviation in primary position is more than 15 prism diopters, inferior oblique weakening will not be enough to correct the deviation [27]. Anteroposition of inferior oblique muscle should be regarded with caution as it may cause asymmetrical results because of the limitation of elevation and it is not recommended in unilateral cases [24]. Anterior and nasal transposition of inferior oblique muscle is a recently described method to be used in ones with congenital absence of superior oblique tendon [28]. Superior oblique strengthening procedures: Superior oblique strengthening procedures are superior oblique tendon tuck and Fells modiﬁed Harada-Ito operation. Superior oblique tendon tuck has a high risk of iatrogenic Brown syndrome in acquired cases with a normal tendon. However, it is a safe and very eﬀective procedure in congenital cases with abnormal tendon laxity [18, 29]. In cases with marked hypertropia and marked abnormal head posture, superior oblique tendon tuck may be performed alone or usually in combination with inferior oblique weakening. If there is no apparent inferior oblique overaction, superior oblique tendon tuck may be performed without weakening the inferior oblique muscle. To reduce the risk of iatrogenic Brown syndrome, traction test must be performed after tucking with loop sutures (Fig. 15 6). If the traction test is positive then the amount of tuck should be reduced. The triad of indications for superior oblique tendon tuck is large angled vertical deviation, prominent abnormal head posture, and superior oblique tendon laxity. In acquired cases with marked torsional diplopia, Fells modiﬁed Harada-Ito procedure is the method of choice that strengthens the anterior torsional ﬁbers. The anterior ﬁbers of superior oblique muscle are transposed lateral and anteriorly at the upper border of the lateral rectus

Fourth Nerve Palsy

203

muscle [26, 30]. This procedure is usually performed bilaterally and has a minimal eﬀect on the vertical deviation in primary position and does not alter the esodeviation on downgaze. So, it is only indicated if there is subjective torsional complaint that need to be corrected. Superior rectus recession in the aﬀected eye: The indication for superior rectus recession is a vertical deviation exceeding 15 prism diopters in combination with superior rectus contracture [23, 24]. It should be considered as an additional surgery with inferior oblique weakening. The predictability of the recession in a restricted superior rectus muscle will be low and adjustable recession should better be preferred in those cases. In cases with agenesis of the superior oblique tendon, superior rectus recession is the procedure of choice with inferior oblique weakening. Inferior rectus recession of the contralateral eye: The cases that do not ﬁt any of the indications speciﬁed above and where there is a vertical deviation exceeding 15 prism diopters are the candidates for contralateral inferior rectus recession. It can be performed in combination with inferior oblique weakening of the aﬀected eye or as a secondary procedure in cases with residual deviation. Progressive overcorrection and lower eyelid retraction are well recognized problems with inferior rectus recession [31]. In summary for an appropriate surgical plan for the individual patient, the diagnosis of a congenital or acquired palsy, the deviation in nine positions of gaze, abnormal head posture, the subjective characteristics of diplopia, and the traction test results are required. In some particular cases BTXA may be used. Some authors reported encouraging results with BTXA injection of ipsilateral inferior oblique muscle [32]. Contralateral inferior rectus injection may be performed during acute or chronic superior oblique palsies. Botulinum toxin is helpful to control postoperative over and undercorrections; ipsilateral inferior rectus injection in the former and contralateral inferior rectus injection in the latter [33]. In our clinical practice, we use BTXA only for inferior rectus muscle in fourth nerve palsy and the patient beneﬁts with BTXA injection if there is no signiﬁcant torsional element.

Summary for the Clinician ■

The pearl is the correct evaluation of a congenital and acquired case. Large vertical fusional amplitudes, facial asymmetry, and absence of torsional diplopia are the major clues for congenital fourth nerve palsy.

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The major pitfall is to overlook masked bilaterality. Presence of a “V” pattern and a large extorsion indicates bilaterality. Consider bilateral surgery in such cases despite the absence of apparent inferior oblique overaction and superior oblique underaction. Inferior oblique weakening alone provides satisfactory outcome in most of the cases if the vertical deviation does not exceed 15 prism diopters. Ipsilateral superior rectus and contralateral inferior rectus weakening procedures should always be considered in combination with inferior oblique weakening. Do not consider superior oblique tuck surgery in acquired ones. The risk for symptomatic iatrogenic Brown syndrome is very high. Superior oblique tendon tuck should be reserved for congenital cases with abnormal tendon laxity and a large vertical deviation. Fells modiﬁed Harada-Ito procedure is a surgery for acquired bilateral cases with marked torsional component.

15.4

Sixth Nerve Palsy

Lateral rectus underaction, esotropia, and a horizontal diplopia, which is more prominent at distance, and abnormal head posture in unilateral cases keeping the aﬀected eye in adduction are the clinical features of sixth nerve palsy. Lateral rectus underaction may be very subtle in partially aﬀected cases and it is essential to measure the deviation in nine positions of gaze. Partially aﬀected cases beneﬁt from prisms. Addition of prisms only on distance glasses are enough in most of the cases. Botulinum toxin has a major role in treatment of sixth nerve palsy both for diagnostic and therapeutic purposes. During acute stage, injection of BTXA into the medial rectus muscle of the aﬀected eye provides a symptomatic relief. Although it was previously proposed that BTXA increased the possibility of spontaneous recovery, randomized clinical trials demonstrated that BTXA injection does not alter the chance of spontaneous recovery, but provides a rapid symptomatic relief of diplopia [34–38]. In chronic stage in mild partial cases BTXA injection alone may provide a satisfactory improvement of the deviation. For a correct surgical plan, one needs to have the correct answers for the following questions:

■ ■ ■

What is the amount of the measurement of the deviation in primary position? Is the paralysis total or partial? Are there any medial rectus contracture?

Surgical methods of treatment may be summarized as follows: ■ ■ ■ ■

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Medial rectus recession and lateral rectus resection. Medial rectus weakening of the sound eye. BTXA injection into the medial rectus muscle + vertical rectus muscle transposition. Medial rectus recession + vertical rectus muscle transposition: This method carries a risk of anterior segment ischemia. That risk may be reduced by ciliary artery preserved full tendon transposition, performing the surgery in two divided sessions leaving at least 3 months between two operations, or by performing a partial vertical rectus transposition. If there is bilateral involvement, surgery should be performed in both eyes.

Medial rectus recession and lateral rectus resection: Recess–resect should be reserved only for those with a good residual function of the aﬀected lateral rectus muscle. If the residual function of the lateral rectus muscle is very limited, then transposition will work better than recess–resect procedure. The correct surgical decision for a recess–resect or a transposition procedure is highly important. A wrong decision for a recess–resect procedure in an old patient makes the patient lose his or her chance to have a transposition procedure because of the signiﬁcant risk of anterior segment ischemia. To obtain a more reliable assessment for the residual lateral rectus function, BTXA injection is recommended as a ﬁrst line treatment and the rest of the treatment plan is made according to the results that are obtained by BTXA injection [3, 39] (Fig. 15.9). In cases with a signiﬁcant limitation of ocular motility, BTXA provides the assessment of the residual function of the paretic muscle in the absence of secondary ﬁbrotic changes in medial rectus muscle. If there is no improvement in abduction following a relaxation of the medial rectus muscle by BTXA, it indicates that lateral rectus muscle is totally dead and a transposition is required. We evaluate the ocular motility 1 week after the BTXA injection and if there is no improvement on abduction, we perform full tendon width vertical rectus muscle transposition during the maximal BTXA eﬀect. This method reduces the risk for anterior segment ischemia. Medial rectus weakening of the sound eye: Medial rectus recession or faden operation of the medial rectus muscle

References

• Botulinum toxin injection as the first line treatment

• Cure-no further treatment • Patient satisfied regular injections

• Unsatisfactory result necessary information for recess-resect or transposition surgery

Fig 15.9 The use of BTXA for planning of treatment in sixth nerve palsy [3]

of the sound eye increases the area of binocular diplopiafree ﬁeld. A combination of recession and resection of the medial rectus muscle provides an adjustable faden eﬀect in the medial rectus muscle and may prove to be useful to reduce the symptoms of the patient with more control compared with conventional faden operation [43]. The problems of treatment in sixth nerve palsy are the anterior segment ischemia risk and the insuﬃcient correction because of a recess–resect procedure in a non functioning lateral rectus muscle.

Summary for the Clinician ■

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The correct diagnosis of partial and total sixth nerve palsy is the pearl for a successful outcome of surgery. The major pitfall is the misinterpretation of the lateral muscle function because of the secondary medial rectus restriction in long-standing cases. BTXA has major role both for surgical planning and as an adjunct to surgery. Recess–resect procedure works only in ones with good residual function of the lateral rectus muscle. Consider vertical rectus transposition without augmentation sutures in ones with very limited evidence of lateral rectus muscle function. Augmentation sutures increases the eﬀect of transposition and should better be used in ones with a totally dead lateral rectus muscle. To reduce the problems of vertical rectus muscle transposition procedure keep parallel to the spiral of Tillaux.

205

References 1. Golnik KC, Miller NR (1991) Late recovery of function after oculomotor nerve palsy. Am J Ophthalmol 111: 566–570 2. Ansons AM, Davis H (2001) Diagnosis and management of ocular motility disorders, 3rd edn. Oxford, Blackwell Science, Paris Berlin Tokyo, pp 143–162 3. Özkan SB (2006) Strategies of treatment in paralytic strabismus. Türkiye Klinikleri J Surg Med Sci 2:58–65 4. Demer JL, Miller JM, Poukens V, et al (1995) Evidence for ﬁbromuscular pulleys of the recti extraocular muscles. Invest Ophthalmol Vis Sci 36:1125–1136 5. Demer JL, Miller JM, Poukens V (1996) Surgical implications of the rectus extraocular muscle pulleys. J Pediatr Ophthalmol Strabismus 33:208–218 6. Özkan SB, Dayanir V, Kir E, et al (2001) Role of botulinum toxin A in management of acquired loss of fusion. In: de Faber JT (ed) Transactions 27th meeting of the European strabismological association. Swets and Zeitlinger, The Netherlands, pp 195–198 7. Gottlob IG, Catalano R, Reinecke RD (1991) Surgical management of oculomotor nerve palsy. Am J Ophthalmol 111:71–76 8. Morad Y, Kowal L, Scott AB (2005) Lateral rectus muscle disinsertion and reattachment to the lateral orbital wall. Br J Ophthalmol 89:983–985 9. Velez FG, Thacker N, Britt MT, et al (2004) Rectus muscle orbital wall ﬁxation: a reversible profound weakening procedure. J AAPOS 8:473–480 10. Heo H, Park SW (2008) Rectus muscle posterior tenon ﬁxation as an inactivation procedure. Am J Ophthalmol 146:310–317 11. Young TL, Conahan BM, Summers CG, et al (2000) Anterior transposition of the superior oblique tendon in the treatment of oculomotor nerve palsy and its inﬂuence on postoperative hypertropia. J Pediatr Ophthalmol Strabismus 37:149–155 12. Salazar Leon JA, Ramirez-Ortiz MA, Salas-Vargas M (1998) The surgical correction of paralytic strabismus using fascia lata. J Pediatr Ophthalmol Strabismus 35: 27–32 13. Villasenor Solares J, Riemann BI, Romanelli Zuazo AC, et al (2000) Ocular ﬁxation to nasal periosteum with a superior oblique tendon in patients with third nerve palsy. J Pediatr Ophthalmol Strabismus 37:260–265 14. Daniell MD, Gregson RM, Lee JP (1996) Management of ﬁxed divergent squint in third nerve palsy using traction sutures. Aust N Z J Ophthalmol 24:261–265 15. Khaier A, Dawson E, Lee J (2008) Traction sutures in the management of long standing third nerve palsy. Strabismus 16:77–83

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16. Helveston EM, Krach D, Plager DA, et al (1992) A new classiﬁcation of superior oblique palsy based on congenital variations of the tendon. Ophthalmology 99:1609–1615 17. Plager DA (1990) Traction testing in superior oblique palsy. J Pediatr Ophthalmol Strabismus 27:136–140 18. Plager DA (1992) Tendon laxity in superior oblique palsy. Ophthalmology 99:1032–1038 19. Wallace DK, von Noorden GK (1994) Clinical characteristics and surgical management of congenital absence of the superior oblique tendon. Am J Ophthalmol 118:63–69 20. Özkan SB, Aribal ME, Sener EC, et al (1997) Magnetic resonance imaging in evaluation of congenital and acquired superior oblique palsy. J Pediatr Ophthalmol Strabismus 34:29–34 21. Sato M. Magnetic resonance imaging and tendon anomaly associated with congenital superior oblique palsy (1999) Am J Ophthalmol 127:379–387 22. Guyton DL (1981) Exaggerated traction test for the oblique muscles. Ophthalmology 88:1035–1040 23. Aseﬀ AJ, Munoz M (1998) Outcome of surgery for superior oblique palsy with contracture of ipsilateral superior rectus treated by superior rectus recession. Binocul Vis Strabismus Q 13:177–180 24. Mims JL (2003) The triple forced duction test(s) for diagnosis and treatment of superior oblique palsy with an updated ﬂow chart for unilateral superior oblique palsy. Binocul Vis Strabismus Q18:15–24 25. Kushner BJ (1988) The diagnosis and treatment of bilateral masked superior oblique palsy. Am J Ophthalmol 105: 186–194 26. Price NC, Vickers S, Lee JP, et al (1987) The diagnosis and surgical management of acquired bilateral superior oblique palsy. Eye 1:78–85 27. Hatz KB, Brodsky MC, Killer HE (2006) When is isolated inferior oblique muscle surgery an appropriate treatment for superior oblique palsy? Eur J Ophthalmol 16:10–16 28. Hussein MA, Stager DRSr, Beauchamp GR, et al (2007) Anterior and nasal transposition of the inferior oblique muscle. J AAPOS 11:29–33 29. Özkan SB, Can D, Demirci S, et al (1995) Surgical treatment in congenital superior oblique palsy. Türkiye Klinikleri. J Surg Med Sci 4:223–226

30. Roberts C, Dawson E, Lee J (2002) Modiﬁed Harada-Ito procedure in bilateral superior oblique paresis. Strabismus 10:211–214 31. Sprunger DT, Helveston EM (1993) Progressive overcorrection after inferior rectus recession. J Pediatr Ophthalmol Strabismus 30:145–148 32. Lozano-Pratt A, Estanol B (1994) Treatment of acute paralysis of the fourth cranial nerve by botulinum toxin A chemodenervation. Binocul Vis Strabismus Q 9:155–168 33. Garnham L, Lawson JM, O’Neill D, et al (1997) Botulinum toxin in fourth nerve palsies. Aust N Z J Ophthalmol 25:31–35 34. Holmes JM, Beck RW, Kip KE, et al (2000) Botulinum toxin treatment versus conservative management in acute traumatic sixth nerve palsy or paresis. J AAPOS 4:145–149 35. Lee J, Haris S, Cohen J, et al (1994) Results of a prospective randomized trial of botulinum toxin therapy in acute unilateral sixth nerve palsy. J Pediatr Ophthalmol Strabismus 31:283–286 36. Metz HS, Masow M (1988) Botulinum toxin treatment of acute sixth and third nerve palsy. Graefe’s Arch Clin Exp Ophthalmol 226:141–144 37. Murray ADN (1991) Early botulinum toxin treatment of acute sixth nerve palsy. Eye 5:45–47 38. Repka MX, Lam GC, Morrison NA (1994) The eﬃcacy of botulinum neurotoxin A for the treatment of complete and partially recovered chronic sixth nerve palsy. J Pediatr Ophthalmol Strabismus 31:79–83 39. Riordian PR, Lee JP (1992) Management of VIth nerve palsy – avoiding unnecessary surgery. Eye 386–390 40. Kraft SP, O’Reilly C, Quigley PL, et al (1993) Cyclotorsion in unilateral and bilateral superior oblique paresis. J Pediatr Ophthalmol Strabismus 30:361–367 41. von Noorden GK, Murray E, Wong SY (1986) Superior oblique paralysis: a review of 270 cases. Arch Ophthalmol 104:1771–1776 42. von Noorden GK, Campos EC (2002) Binocular vision and ocular motility, 6th edn. Mosby, St. Louis, USA pp 559–565 43. Dawson E, Boyle N, Taherian K, et al (2007) Use of a combined recession and resection of a rectus muscle procedure in the management of incomitant strabismus. J AAPOS 11:131–134

Chapter 16

Modern Treatment Concepts in Graves Disease

16

Anja Eckstein and Joachim Esser

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Graves orbitopathy (GO) is part of an autoimmune systemic disease, which is composed of hyperthyroidism, orbitopathy, dermopathy, and acropachy. Stimulating antibodies against the TSH receptor are directly involved in the pathogenesis of hyperthyroidism; their role is less clear with regard to the other manifestations. However, high TSH receptor antibody concentrations are associated with a higher prevalence and more severe course of extra-thyroidal symptoms. Main symptoms of GO are orbital soft tissue inﬂammation, proptosis due to increase (mainly through adipogenesis) of orbital volume and impairment of ocular and lid motility due to inﬂammation, and scarring of chieﬂy the levator, inferior, and medial rectus muscles. In severe cases, vision-threatening compression of the optic nerve can occur. Inﬂammatory phase is self-limiting but may relapse, in most cases, owing to insuﬃciently controlled thyroid disease, but also indepen-

16.1

16.1.1

Graves Orbitopathy (GO): Pathogenesis and Clinical Signs Graves Orbitopathy is Part of a Systemic Disease: Graves Disease (GD)

Graves orbitopathy is a part of a systemic autoimmune disease. The full clinical picture is composed of hyperthyroidism, orbitopathy, pretibial myxedema, and acropachy. The full symptom complex is very rare – Myxedema and acropachy occur only in 3–5%. With a prevalence of 0.5–2%, GD is a relatively common autoimmune disease [1]. In nearly all patients, antibodies against the TSH

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dently. To restrict damage, anti-inﬂammatory therapy (e.g., systemic steroids or orbital radiotherapy) is indicated in moderate to severe active disease stages. Patients with sight-threatening GO should be treated with i.v. steroids as ﬁrst-line treatment; if the response is poor after 1 to 2 weeks, they should be immediately referred for surgical decompression. In patients with mild GO, local measures and an expectant strategy are usually suﬃcient, but treatment may be justiﬁed if quality of life is reduced signiﬁcantly. In the inactive disease stages, proptosis can be alleviated through orbital decompression; restricted ocular and lid motility can be improved by muscle recession and appearance can be improved by blepharoplasty of lower and upper lids. Important for the successful treatment of GO is continuous and stable sustenance of euthyroidism and smoking cessation.

receptor (TSHR) can be measured in the serum as indicators of the failed immune system. Those antibodies stimulate the TSHR in an uncontrolled manner and are directly responsible for the development of hyperthyroidism. Whether the TSHR alone or in combination with other antigens is responsible for the extra-thyroidal aspects of GD is of considerable research interest. Symptoms of GO are caused by inﬂammation in the connective tissue of the orbit, an increase of intraorbital volume due to enhanced adipogenesis, overproduction of glycosaminoglycanes (GAG), and ﬁbrosis of the extraocular muscles [2]. Orbital ﬁbroblasts are pivotal to these pathologic processes. Cultured orbital ﬁbroblasts can be

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16

Modern Treatment Concepts in Graves Disease

stimulated by patient IgG, several cytokines, and autologous lymphocytes. Stimulation by autologous lymphocytes is antigen-dependent, as direct cell−cell contact, MHC class II, and CD40–CD154 signaling are necessary [3]. In addition, orbital ﬁbroblasts may diﬀerentiate to preadipocytes, which are accompanied by an increase in TSHR expression [4]. Thus, the shared candidate autoantigen between thyroid and orbita is the TSHR. Clinically, high serum levels of TSHR antibodies (TRAb) are associated with higher prevalence and increased severity of GO. However, presence of TRAb alone does not cause the complete symptom complex. Neonates of mothers with TRAb positive GD usually develop hyperthyroidism, which gradually dwindles as antibodies are cleared from the child’s body, yet only few develop eye signs (mainly proptosis). Immunization of mice against the TSHR does generate TRAb and hyperthyroidism but no associated orbital inﬂammation [5]. Thus, factors other than the presence of TRAb are probably involved in the development of GD. In GD, there is a strong genetic component [see Chap. 16.5.2] involving immunoregulatory and thyroid-speciﬁc genes [6]. In most patients, there is a close temporal relationship between the onset of hyperthyroidism and orbitopathy. Orbitopathy usually manifests within 6 months before or after the ﬁrst clinical signs of hyperthyroidism. MRI images of patients who suﬀer from hyperthyroidism but not from clinically overt orbitopathy reveal orbital manifestation in more than two-thirds of those patients [7]. The development of GO is a marker for a more severe course of GD and associated with signiﬁcantly lower remission rates of hyperthyroidism [8]. However, GO can also occur many years after the onset of thyroid disease or − in rare cases − long before or even without overt thyroid disease [9]. In 75% of euthyroid GO patients, thyroid-speciﬁc antibodies can be detected as indicators of associated thyroid disease [10]. About half of those patients will develop thyroid dysfunction within the following 18 months [11].

16.1.2 Graves Orbitopathy−Clinical Signs Graves Orbitopathy is typically characterized by the following clinical characteristics (Fig. 16.1) [12, 13]: ■

■

Most frequent sign (in 90–98% of patients): upper lid retraction, often with lateral ﬂare and lid lag on vertical downward pursuit, lagophthalmos (due to ﬁbrosis of the levator palpebrae muscle) Other common signs: soft tissue signs, e.g., periorbital swelling and redness, conjunctival swelling and injection, prominent glabellar rhytids (due to inﬂammation)

■

■

■

■

Proptosis (exophthalmos) with possible concomitant lower lid retraction (mainly due to increased adipogenesis, but also due to enlargement of extraocular muscles and inﬂammatory swelling) Ocular surface lesions (due to lagophthalmos, increased lid width, impaired Bell’s phenomenon, and reduced tear secretion and deteriorated composition) Restriction of ocular excursions – most often upgaze and abduction (due to ﬁbrosis of inferior and medial rectus muscles) In rare cases (about 5%), dysthyroid optic neuropathy (DON) (due to apical crowding)

16.1.2.1 ■ ■

■

■ ■

Clinical Changes Result in Typical Symptoms

Change of facial appearance Symptoms related to inﬂammation: painful, oppressive feeling on or behind the globe, pain of attempted up-, lateral, or downgaze Symptoms related to ocular surface irritation: gritty sensation, light sensitivity, excess tearing, and reduced visual acuity Symptoms related to restricted ocular motility: diplopia, abnormal head positure Symptoms related to DON: reduced visual acuity, restricted visual ﬁeld, and desaturated color perception

16.1.3

Clinical Examination of GO

Determining the phase of GO at each clinical assessment [14] is fundamental to the establishment of an appropriate management plan (Fig. 16.2). Immunomodulatory therapies can only be eﬀective in the presence of active inﬂammation. Certain surgical treatments, on the other hand, (orbital, lid, or strabism surgery) should only be performed when GO has been constantly inactive for at least 6 months.

16.1.3.1

Signs of Activity

The active phase of the disease is the period when the patient is most likely to be symptomatic: gaze evoked or spontaneous grittiness, light sensitivity, and excessive orbital aching – gaze evoked or spontaneous. Patients notice change of severity over the previous 3 months. Classical signs of inﬂammation are used as surrogate markers to evaluate the degree of orbital inﬂammation:

16.1

Graves Orbitopathy (GO): Pathogenesis and Clinical Signs

a

b

c

d

e

f

g

h

i

209

Fig. 16.1 Patient examples of typical symptoms of GO: 1A–1C Patient with mild GO, the only sign is upper lid retraction at the right eye. 1D–1F Patient with typical impairment of motility: 1D the patients developed a vertical squint of 22° (+VD), the upgaze of the left eye with 0°, 1E the coronary MRI scans show the enlargement of the inferior rectus muscle of the left eye. The other muscles are almost normal. 1G–1I Patients with full picture of GO with DON: marked signs of soft tissue inﬂammation (conjunctival injection and chemosis, caruncle inﬂammation, redness and swelling of the lids), marked proptosis, severe impairment of ocular motility right and dysthyroid optic neuropathy both eyes. Enlargement of all extraocular muscles was seen in the coronary MRI apical crowding in the orbital apex and intracranial fat prolapse in the axial MRI ■ ■ ■ ■ ■

Eyelid redness Conjunctival injection Chemosis (conjunctival edema) Eyelid swelling Inﬂammation of caruncle or plica

All features of soft tissue inﬂammation can be assessed by comparison with standard patient photographs available at www.eugogo.eu. Studies show that reproducibility of patient assessment can be improved by the use of this atlas and careful methodology (interobserver agreement − 86%). Photographic documentation is a reliable method for assessing soft tissue signs for follow-up. Signs of activity are summarized in the clinical activity score (CAS) (maximal seven points at the ﬁrst visit and maximal ten points at follow-up) (Table 16.1) [16]. Using a cut-oﬀ of at least four (ﬁrst visit three), the positive predictive value

was 80% in estimating the response to immunomodulation. Patients with disease duration of more than 18 months are less likely to respond to immunomodulation. A-mode ultrasound, T2 weighted or STIR sequence MRI images, and serum or urine levels of a number of inﬂammatory markers including IL-6, and urine GAG excretion provide only little additional beneﬁt in predicting the response to anti-inﬂammatory therapy [17].

16.1.3.2

Assessing Severity of GO

The following features are quantiﬁed to assess severity: ■

■

Lid ﬁssure width (distance between the lid margins in mm with the patient in primary position; sitting, relaxed, with distant ﬁxation) Swelling of the eyelids (absent/moderate/severe)

210

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Modern Treatment Concepts in Graves Disease

All patients with GO • Restore euthyroidism • Urge smoking withdrawal • Refer to specialist centers, except for the mildest cases • Local measures

16

Moderate to severe

Mild

Sight-threatening (DON)

i.v. GCs Local measures wait and see

Progression

Active

Inactive Poor response (2 weeks)

Stable and inactive

i.v. GCS (± OR)

Rehabilitative surgery (if needed)

Stable and inactive

Prompt decompression

Rehabilitative surgery

Still active

Stable and inactive

i.v. GCs (± OR)

Rehabilitative surgery

Fig. 16.2 Management of Graves’ orbitopathy. Anti-inﬂammatory therapy in the active phase includes: intravenous glucocorticoids (i.v. GCs) and orbital radiotherapy (OR); Rehabilitative surgery includes orbital decompression, squint surgery, lid lengthening, and blepharoplasty/browplasty. Sight threatening GO (with dysthyroid optic neuropathy (DON) demands rapid decompression in case of poor response to i.v. GCs within 2 weeks. For the deﬁnitions of GO severity and activity, see Chap. 16.1.3 ■ ■ ■ ■ ■

■

■ ■ ■

Redness of the eyelids (absent/present) Conjunctival injection (absent/present) Conjunctival chemosis (absent/present) Inﬂammation of the caruncle or plica (absent, present) Exophthalmos (measured in mm using the same Hertel exophthalmometer and same intercanthal distance for an individual patient) Subjective diplopia score (0 no diplopia; 1 intermittent, i.e., diplopia in primary position of gaze, when tired or when ﬁrst awakening; 2 inconstant, i.e., diplopia at extremes of gaze; 3 constant, i.e., continuous diplopia in primary or reading position) Eye muscle involvement (duction in degrees) Corneal involvement (absent/punctate lesions/corneal ulcer) Dysthyroid optic neuropathy (DON) (best-corrected visual acuity, color (de-) saturation, optic disk, relative aﬀerent pupillary defect (absent/present), visual ﬁelds, visually evoked potentials)

Examination of lid ﬁssure width should be performed with the head in a stationary position and under ﬁxation.

If vertical strabism is present, the contralateral eye should be occluded. To evaluate upper and lower lid retraction, eyelid position is measured in relation to the respective limbus. Proptosis is usually measured with an exophthalmometer. Numerous diﬀerent makes are available with diﬀerent scales, so for each patient the same exophthalmometer with identical intercanthal distance should always be used for follow-up. Proptosis is deﬁned as a reading 2 mm greater than the upper normal limit for that patient’s age, gender, and “race.” More important, however, is the measured change during follow-up. There are numerous ways of assessing extraocular muscles. Subjective diplopia scores are simple but only of limited help, since signiﬁcant changes in limitation of motility may go unnoticed, when bilateral symmetrical reduction of upgaze results in no noticeable double vision. The measurement of monocular excursions is a more exact way to assess restricted excursions of each eye separately. Excursions are best measured using a bowl or arc perimeter, but so-called “Kestenbaum glasses” or the position of light reﬂexes may be used as well. Normal

16.1

Graves Orbitopathy (GO): Pathogenesis and Clinical Signs

Table 16.1. Clinical activity score (CAS), maximal 7 points at the ﬁrst visit and maximal 10 points at follow-up, active disease CAS ≥4 (three ﬁrst visits) Clinical activity score CAS (one point is given for each feature) Subjective signs of activity Painful, oppressive feeling on or behind the globe

1

Pain of attempted up-, side-, or downgaze

1

Objective signs of activity Redness of the eyelids

1

Redness of the conjunctiva

1

Chemosis

1

Inﬂammatory eyelid swelling

1

Inﬂammation of the caruncle or plica

1

Sum score (at ﬁrst consultation no evaluation of progression possible)

Maximal 7

Signs of progression Increase of 2 mm or more in proptosis in the last 1–3 months

1

Decrease in eye movements of 5° or more in the last 1–3 months

1

Decrease in visual acuity in the last 1–3 months

1

Sum score

Maximal 10

values are given in Table 16.2. The prism cover test (separate measurement of the squint angles in primary position for far and near distances) and the ﬁeld of binocular single vision are used to ﬁt corrective prisms and to plan squint surgery. Of outstanding importance is the evaluation of the corneal surface. This requires slit lamp examination to detect punctate ﬂuoresceine staining or ulceration; the latter constitutes an ophthalmologic emergency. There is no single test that proves DON. DON occurs bilateral in 70% of the patients. Anatomical indicators are Table 16.2. Normal values for monocular excursions (after Mourits et al. [18]) Direction of gaze

Monocular excursion (°)

Abduction

46

Upgaze 90°

34

Adduction

47

Downgaze 270°

58

211

very large muscles in the orbital apex, fat herniation through the superior orbital ﬁssure, and tense ballottement of the globe and venous stasis. DON is insidious as its onset is rarely obvious and visual acuity is long preserved. Color vision disturbances are present in most patients. Only 30–40% of the patients present with swelling of the optic disc. Visual ﬁeld defects are most commonly paracentral or inferior. VEP amplitudes are reduced and latency periods can be delayed [14]. Severity can be scored using the NOSPECS classiﬁcation, which provides in its slightly modiﬁed version a maximal score of 14 (Table 16.3) for patients with all manifestations of GO in its most active stage [19].

16.1.3.3

Imaging

Orbital imaging can be necessary for diﬀerential diagnosis as well as, in special situations, to facilitate treatment decisions. If the patient presents with asymmetrical symptoms (usually unilateral proptosis), inﬂammatory orbital disease of nonthyroidal etiology or orbital tumors have to be ruled out. Orbital imaging is necessary for all clinical treatment decisions in Dysthyroid optic neuropathy. Signal intensity in T2-weighted MRI scans corresponds to inﬂammatory edema and can be used to ease treatment decisions in diﬃcult clinical situations. Orbital ultrasound is only informative if performed and evaluated by experienced clinicians [20].

16.1.4

Classiﬁcation of GO

Members of EUGOGO recommend to classify patients according to activity (active disease CAS ≥ 4, inactive disease CAS < 4) and according to severity to manage patients with GO [21]. Severity classiﬁcation: 1. Sight-threatening GO: Patients with dysthyroid optic neuropathy (DON) or corneal breakdown. This category warrants immediate intervention. 2. Moderate-to-severe GO: Patients without sight-threatening GO whose eye disease has suﬃcient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate-to-severe GO usually present with one or more of the following: lid retraction >2 mm, moderate or severe soft tissue involvement, exophthalmos >3 mm above normal for “race” and gender, intermittent, or constant diplopia.

212

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Modern Treatment Concepts in Graves Disease

Table 16.3. Modiﬁed NOSPECS score for quantiﬁcation of severity, maximal score of 14 NOSPECS score Lid retraction

16

a

a

0

1

2

No

Yes

3

Soft tissue inﬂammation

0

1–4

5–8

>8

Proptosis and or Site Diﬀerence

<17 mm

17–18 mm

19–22 mm

>22 mm

<1 mm

1–2 mm

Extraocular muscle involvement

No

Corneal defects

No

Optic nerve compression

No

3–4 mm

>4 mm

>20° upgaze

≤20° upgaze

>35°abduction but not normal

≤35°abduction

Yes Yes

Upper lid edema 0–2; Lower lid edema 0–2; conjunctival injection 1; conjunctival chemosis 1

3. Mild GO: patients whose features of GO have only a minor impact on daily life, insuﬃcient to justify immunosuppressive or surgical treatment. They usually have only one or more of the following: minor lid retraction (<2 mm), mild soft tissue involvement, exophthalmos <3 mm above normal for “race” and gender, transient or no diplopia, and corneal exposure responsive to lubricants.

■

Treatment decision can be made with the help of a detailed management plan (see Fig. 16.2)

the active phase and rehabilitative surgical treatments in the inactive phase of the disease. According to its grade, GO can be classiﬁed as mild, moderate to severe, and sight threatening. Mild GO permits a “wait and see” approach, moderateto-severe GO requires immunosuppressive treatment in the active phase, and sight-threatening GO demands immediate treatment with i.v. steroids/ orbital decompression/treatment of ocular surface damage.

Summary for the clinician ■

■

■

Graves’ Orbitopathy is part of an autoimmune systemic disease encompassing hyperthyroidism, orbitopathy, dermatopathy, and acropachy. TSHR receptor antibodies (TRAb) are indicators of the failed immune system and direct pathomechanism for hyperthyroidism. Their role in the pathogenesis of orbitopathy is less clear, though patients with high serum TRAb levels have a higher prevalence of GO and develop more severe disease stages. Orbital ﬁbroblasts play a pivotal role in the pathologic changes in the orbit (release of chemokines, production of glycoseaminoglycanes/ﬁbrosis, and diﬀerentiation into adipose tissue). Assessment of activity (clinical activity score) and severity is necessary for disease management: immunomodulation is performed during

16.2

Natural History

Control of thyroid function inﬂuences the course of GO (see Chap. 4). Patient with mild-to-moderate GO, monitored over 1 year without treatment, improved in 22%, showed minor improvement or no change in 42 and 22%, respectively, and deteriorated in 14% [22]. With or without treatment, there are often residual symptoms of GO in the form of lid retraction, proptosis, and muscle dysfunction. The outcome is signiﬁcantly better in patients who have been diagnosed early and treatment started promptly.

Summary for the Clinician ■

Spontaneous improvement of GO with restoration of euthyroidism occurs in more than 60% of the patients.

16.3 Treatment of GO

16.3 Treatment of GO 16.3.1

Active Inﬂammatory Phase

Treatment is indicated in patients mainly with active moderate-to-severe GO with a clinical activity score of four or more.

16.3.1.1

Glucocorticoid Treatment

Glucocorticoids (GC) have been used in the management of GO administered locally, orally, or through i.v. [23]. Oral GC therapy (starting dose, 80–100 mg or 1 mg/kg body weight) requires high doses for prolonged periods of time. No randomized, placebo-controlled study, evaluating oral glucocorticoid treatment was ever performed. Open trials or randomized studies, in which oral GC were compared with other treatments, show a favorable response in about 33–63% of patients, particularly concerning soft tissue signs, eye muscle involvement of recent onset, and DON. Eye disease frequently ﬂares up on tapering out or withdrawing of oral GC therapy. Side eﬀects are frequent. Local retrobulbar or subconjunctival administration of glucocorticoids is less eﬀective than oral GC. Intravenous GC pulse therapy is more eﬀective than oral GC (dose: 250 mg–1 g/week, over 6–12 weeks or 500 mg–1 g for 3 consecutive days, followed by oral GCs); response rates of about 80% are reported [24]. Evidence for the superiority of any of the diﬀerent i.v. GC schedules as well as studies on the optimal cumulative dose is still lacking. Although i.v. GCs are tolerated better than oral GCs, life-threatening liver failure has been reported in association with very high cumulative doses in 0.8% of patients. Intravenous administration appears to be safe, if the cumulative dose is below 8 g methylprednisolone in each course of therapy.

16.3.1.2

Orbital Radiotherapy

The reported response rate to orbital radiotherapy (OR) in open trials is about 60%. Total doses between 10 and 20 Gy are commonly absorbed per orbit, fractionated in single doses between 1 and 2 Gy over a 2–20 week period. Higher doses are no more eﬀective. The response to OR did not diﬀer from oral prednisone in a randomized controlled trial (RCT), but glucocorticoids are faster acting. Two recent RCTs have shown that OR is more eﬀective than sham irradiation in improving diplopia and eye muscle motility [25, 26]. OR is usually well tolerated, but may cause transient exacerbation of ocular symptoms,

213

which is preventable if corticosteroids are administered simultaneously. Data on long-term safety are reassuring, but theoretical concerns about carcinogenesis remain for younger patients, particularly those under the age of 35 years. Retinal microvascular abnormalities have been detected in a minority of patients, mostly in those with concomitant severe hypertension or diabetic retinopathy. Consequently, these two comorbidities are considered absolute contraindications to OR. It is possible that diabetes, even in the absence of retinopathy, represents a risk factor for the development of retinal changes after OR, but the evidence is less persuasive [21, 27].

16.3.1.3

Combined Therapy: Glucocorticoids and Orbital Radiotherapy

Combination of systemic GC (either orally or locally) with OR is more eﬀective than either treatment alone. It is unclear whether combining i.v. GCs with OR is more eﬀective than i.v. GCs alone [28]. Representative studies are summarized in Table 16.4.

16.3.1.4 Other Immunosuppressive Treatments and New Developments One major problem is recurrent activity of GO after maximal doses of i.v. glucocorticoid therapy and orbital radiotherapy. In most of the cases, poor control of thyroid function, high TSH-receptor-antibody levels, and nicotine abuse are among the underlying reasons. A thyroid specialist should always be consulted. In cases of expected low chance of remission or uncontrolled thyroid function, deﬁnitive therapy of the thyroid has to be initiated. Thyroidectomy is preferred because radioiodine therapy carries a risk of deterioration of active GO. In patients with marked proptosis, orbital decompression has to be considered because apart from proptosis reduction, decompression may also silence orbital inﬂammation − probably due to improvement of orbital lymphatic and venous drainage. If activity still does not decline, other immunomodulatory agents have to be considered. Two studies have shown the superiority of the combination of oral GCs and cyclosporine over either treatment alone. Recent treatment studies of GO patients with the B-lymphocyte depleting monoclonal antibody Rituximab have shown promising results. Administered together with standard methimazole-therapy, it prolongs remission of thyroid function in comparison with methimazole monotherapy. Also, the stimulatory capacity of TRAbs was reduced markedly. Clinical activity of GO signiﬁcantly decreased after injection of 1,000 mg i.v. Rituximab

214

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Modern Treatment Concepts in Graves Disease

Table 16.4. Representative results of randomized clinical trails of anti-inﬂammatory therapy for active GO Randomization

Response rates

i.v. methylprednisoloned (n = 35)

Group A c

Oral Prednisonec Radiotherapyb (n = 41)

88%

oral prednisonee (n = 35)

77%

Authors

<0.02

Marcocci

<0.01

Kahaly

Group B «

63%

«

51%

«

i.v. methylprednisolone Radiotherapyb (n = 41)

Group B a

«

Group A

16

P values

Comparison between i.v. and oral glucorticoid therapy is marked with horizontal arrows and comparison of single vs. combined (with orbital radiotherapy) therapy is marked with vertical arrows ([24, 29] Doses for glucocorticoid and radiotherapy: a

15 mg/kgKG for four cycles, then 7.5 mg/kgKG for four cycles; each cycle consisted of two infusions on alternate days at 2-week intervals b

20 Gy in ten daily doses of 2 Gy over 2 weeks

c

100 mg daily for 1 week, then weekly reduction until 25 mg daily, and then tapering by 5 mg every 2 weeks

d

500 mg once weekly for 6 weeks, 250 mg once weekly for 6 weeks, total treatment period: 12 weeks

e

100 mg daily starting dose, tapering by 10 mg/week, total treatment period: 12 weeks

twice at 2-week interval. Even proptosis was signiﬁcantly reduced. Subsequent randomized controlled trials with Rituximab need to be performed [30–32]. The anti-TNF a drug Etanercept is described as eﬀective as well in an open trial [33]. Treatments of marginal or unproven value include somatostatin analogs, azathioprine, ciamexone, and i.v. immunoglobulins.

16.3.1.5 Therapy of Dysthyroid Optic Neuropathy (DON) and Sight-Threatening Corneal Breakdown High-dose i.v. GCs are the preferred ﬁrst-line treatment for DON (3 × 500 mg–1 g at consecutive days within 1 week, if necessary repeated the following week). If the response to i.v. GCs is absent or poor after 1–2 weeks, or the dose/duration of steroid required induces signiﬁcant side eﬀects, orbital decompression should be carried out promptly. Orbital decompression should be recommended promptly to patients with DON or corneal breakdown who cannot tolerate glucocorticoids. Both i.v. GC therapy and orbital decompression surgery should only be performed in clinical centers with the appropriate expertise. Sight-threatening corneal breakdown must be treated as an emergency as well.

Frequent topical lubricants, moisture chambers, tarsorrhaphy, amnion epithelium membrane as shield, and botulinum toxin injections in the levator muscle (doses for therapeutic ptosis: e.g., 30 IE Dysport®) should be applied immediately. Surgical decompression or lid lenghthening a chaud should be considered when the above measures alone are ineﬀective [21].

16.3.1.6 Other Simple Measures that may Alleviate Symptoms The symptoms of corneal exposure (grittiness, watering, and photophobia) should be treated with lubricant eyedrops. Nocturnal ointment is of great beneﬁt if eyelid closure is incomplete. Prisms may correct intermittent or constant diplopia. Sleeping with the head in an upright position may improve lymphatic drainage and alleviate early morning eyelid swelling. Diuretics are rarely useful. Upper lid retraction can be reduced by injecting botulinum toxin (e.g., 5–15 IU Dysport®) subconjunctivally in the tarsal muscle (Mueller muscle). Full eﬀect is evident after 2–3 days and persists for about 4–6 weeks. The outcome is variable and the dose of botulinum toxin must be adjusted individually. Transient double vision and ptosis may occur in 10–20%. This procedure should be carried out in specialized centers [34].

16.3 Treatment of GO

Summary for the Clinician ■

■

■

■

■

■

■

Patients with active moderate-to-severe GO or active mild GO with suﬃcient impairment on daily life should receive anti-inﬂammatory treatment. Glucocorticoids are applied most eﬃciently i.v. 250 mg–1 g weekly over 6–12 weeks or at consecutive days within 1 week (cumulative dose: 1.5–3g) followed by an oral regime (response rate about 80%). Cumulative doses of 8 g should not be exceeded to prevent liver damage and other severe side eﬀects. Orbital radiotherapy is indicated primarily for patients with impaired motility. Fractionated doses between 10 and 20 Gy are applied to each orbit (response rate about 60%). Combined therapy (glucocorticoids and orbital radiotherapy) is more eﬃcient than each therapy alone. Patients with dysthyroid optic neuropathy should be treated with i.v. steroids as ﬁrst-line treatment; if the response is poor after 1–2 weeks, they should be referred for immediate surgical decompression. In case of marked proptosis or severe corneal exposure, surgical decompression can be immediately performed. New therapeutic strategies for patients with severe GO are being tested – most promising is B cell depletion, which inactivates GO and supports remission of thyroid dysfunction. Simple measures like topical lubricants, botulinum toxin for retracted lids and prisms for compensation of double vision are important for the quality of life of the patients.

16.3.2 Inactive Disease Stages Rehabilitative surgery includes one or more of the following procedures: (a) orbital decompression, the usual indication for surgery being disﬁguring exophthalmos with or without keratopathy; (b) squint correction; (c) lid lengthening; and (d) blepharoplasty/browplasty. Prerequisite for successful surgery is a minimum of 6 months of stable inactive ophthalmologic and thyroid disease. Concerning thyroid disease, this means either constant doses of Levothyroxin after deﬁnitive therapy (thyroidectomy/ radioiodine therapy) or stable remission at least 6 months

215

after cessation of antithyroid drug therapy. Because of its inﬂuence on ocular motility and lid width, decompression surgery should be performed ﬁrst. Vertical squint correction may then be performed. Pseudoretraction will resolve postoperatively but lower lid retraction can occur after inferior rectus recession. Small medial rectus recessions can be combined with lid surgery; larger recessions should be performed separately [35, 36].

16.3.2.1

Orbital Decompression

A wide range of surgical approaches is used to reduce disﬁguring proptosis in patients with GO. The amount of proptosis reduction depends on the number of walls removed and whether or not fatty tissue is removed. Serious complications are rare. Common surgical approaches for orbital decompression are: coronal, via the upper skin crease, the lateral canthus, or the inferior fornix (both together = swinging eyelid), sub-ciliary, directly through the lower lid, transcaruncular, transnasal, and transanthral. Further restriction of ocular motility is still a major complication; this mainly occurs with medial wall decompression. The risk is much lower with removal of the lateral wall alone. Clinically obvious impairment of motility increases the risk of postoperative diplopia signiﬁcantly. At present, the medial, inferior, and lateral walls are addressed during bony orbital decompression (Fig. 16.3), while the orbital roof is neglected due to potential complications. Minimally invasive approaches and hidden incisions are preferred. Decompression of the medial orbital wall is necessary to decompress the optic nerve in patients with DON. The transnasal endoscopic procedure addresses the medial and inferior orbital walls. The advantage of a convenient scarless procedure is opposed by the relative high risk of decreased ocular motility and inferior and nasal dislocation of the globe. Proptosis may be reduced by 2–5 mm. With the coronary approach, all orbital walls can be accessed and proptosis reduction up to 10 mm can be achieved. This is, however, an elaborate procedure. To enhance the eﬀect of lateral wall decompression, the procedure can be combined with removal of its deep portion or with additional fat removal (Fig. 16.3). The lateral wall has, due to a very low risk of diplopia, increasingly become the ﬁrst choice for orbital decompression (traditional concept – inferior-medial decompression ﬁrst) in cases of rehabilitative surgery. The approach to the lateral wall is variable via the upper skin crease,

216

16

Modern Treatment Concepts in Graves Disease

a

b

16

1 3

1 2 2 3

Fig. 16.3 Surgical approaches for orbital decompression in coronar and axial view. All orbital walls except the roof are addressed. The lateral wall can be removed conservatively (A1), until is deep portion (A2) or completely (A3). Various surgical approaches are possible to decompress the inferior (B2) and medial (B1) orbita. The inferior-lateral region of the orbit is the most common zone for fat removal (B3)

swinging eyelid, sub-ciliary, or directly through the lower lid. Average proptosis reduction ranges between 2 and 5 mm. (Literature is reviewed in [37].)

■

■

16.3.2.2

Extraocular Muscle Surgery

The basic concept for eye muscle surgery in GO is recession of the ﬁbrotic muscle. The approach is diﬀerent for inferior and medial rectus muscles. Vertical deviation increases with side diﬀerences in monocular upward excursions. Bilateral symmetric restrictions of inferior rectus muscles cancel each other out and cases with abnormal head posture need to be corrected by symmetric inferior rectus recession. Bilateral restriction of abduction adds up. Diﬀerent concepts for surgical strabism correction are available: preoperatively determined recession distances according to dose eﬀect curves, and intraoperative determination of recession distance via active or passive motility and adjustable sutures (literature is reviewed in [38]). Principles for extraocular muscle surgery in patients with GO: ■

■

Vertical squint – no head tilt when covering the eye with more limited upgaze: Recession of inferior rectus muscle: dose: 1 mm recession per 2° of intended squint angle reduction, maximal recession distance 7–8 mm, persisting vertical squint: second step: recession of the contralateral superior rectus muscle dose 1 mm/per 2° of intended squint angle reduction Vertical squint – head tilt when covering the eye with more limited upgaze: asymmetric bilateral inferior rectus recession (side diﬀerence in mm depends on the squint angle, measured with head tilt: 1 mm recession per 2° of intended squint angle reduction)

■

■

■

Horizontal squint <10°: unilateral medial rectus recession (side: eye with least abduction), dose 1 mm recession per 1.75° of intended squint angle reduction, maximal recession distance 6–7 mm Horizontal squint ≥10°: bilateral medial rectus recession, dose 1 mm recession per 1.6° of intended squint angle reduction (dose side diﬀerent, when side diﬀerence in monocular abduction), maximal recession distance per eye 6–7 mm Combined horizontal and vertical squint: small vertical angles disappear after correction of horizontal squint; a two-step procedure (large angle ﬁrst) is more precise; if all in one procedure is preferred (only recommended for unilateral procedures): consider higher dose eﬀect for vertical squint 2.1° per mm recession Lower lid retraction after inferior recession can be prevented through dissection of the capsulopalpebral ligament. Upper lid retraction of the eye with elevation deﬁcit (“pseudoretraction”) will disappear after inferior recession Convergent squint correction after decompression: consider lower dose eﬀects: unilateral medial rectus recession: 1 mm recession per 1.2° of intended squint angle reduction; bilateral rectus recession: 1 mm recession per 1.0° of intended squint angle reduction; consider medial rectus tendon elongation with a spacer for very large angles: 1 mm elongation per 0.9° of intended squint angle reduction

Dose eﬀect data are summarized in Table 16.5 [38, 40–42]. In most cases, it is possible to improve the ﬁeld of binocular single vision. Over-corrections occur more often when the muscle is not directly ﬁxed to the sclera but is

16.3 Treatment of GO

217

Table 16.5. Extraocular muscle surgery: dose eﬀect coeﬃcients: squint angle reduction (°)/per mm muscle recession (source: [38–41]) Muscle

Dose eﬀect: angle [°] reduction/ mm recession

Authors

Inferior rectus muscle

2.0

Esser et al., 1999

2.1

Krizok et al., 1993

Medial rectus muscle unilateral

1.75

Eckstein et al., 2004

Medial rectus muscle bilateral

1.6

Combined unilateral inferior rectus muscle

2.1

unilateral medial rectus muscle

1.9

Eckstein et al., 2004 Eckstein et al., 2004

After orbital decompression

Eckstein et al., 2008

Medial rectus muscle unilateral

1.2

Medial rectus muscle bilateral

1.0

Tendon elongation with interponate

0.9

adjusted on the following day. This probably occurs due to adaptation of the muscles to changed tension during the operation. Post-operative tone increase occurs in structures that were previously relaxed, e.g., the antagonist and the “passive orbital tissue.” They return to their original tension, which leads to a further globe rotation against the direction of the recession. Therefore, the eﬀect of squint angle reduction increases signiﬁcantly within the ﬁrst postoperative month. Persistent diplopia in extreme gaze is common, which is usually tolerable in upgaze, since the used gaze ﬁeld is larger in downgaze than in upgaze. Success rates (ocular alignment within about 2–3° in primary position) are similar for the diﬀerent approaches and vary mainly between 60 and 80% for horizontal squint and up to 90% for vertical squint.

16.3.2.3 Lid Surgery The most common indication for lid surgery in GO is upper lid retraction due to levator muscle ﬁbrosis. Genuine lid retraction has to be discriminated from pseudo-lid retraction due to ﬁbrosis of the inferior rectus muscle. The latter resolves after inferior rectus recession. Lower lid lengthening is indicated in lower lid retraction following inferior rectus recession. Bilateral lower lid retraction with proptosis should primarily be referred for orbital decompression. Another indication for eyelid surgery is increased preaponeurotic and subdermal fat, resulting in bulging eye lids. This may be treated during blepharoplasty when redundant lid skin is excised (review of the literature: [35, 43]).

Upper lid lengthening: Many diﬀerent techniques for lenghthening the upper eyelids have been described. Among these are techniques with or without implants. In most cases, use of implants is not necessary. These are Müllerotomy or recession, medial or lateral levator aponeurosis recession, lateral horn cut (important for lateral ﬂare), medial and lateral full thickness levator-, Müller-muscle-, and conjunctival recession. Since lateral retraction (temporal ﬂare) is the most important aspect of upper lid retraction in patients with Graves orbitopathy, division of the lateral horn of the aponeurosis is necessary in most cases. Sutures may be placed between the tarsal plate and the detached aponeurosis to prevent spontaneous disinsertion. When sutures are used, it is important to protect the cornea, e.g., using the conjunctiva as a cover. Myotomies without spacers (grafts) require patient cooperation. If compliance is poor or marked ﬁbrosis is present, spacers may be used. The vertical height of the implant should be approximately twice the measured eyelid retraction or measured eyelid retraction +2 mm, respectively. Patients examples before and after upper lid lengthening without and with implant are shown in Fig. 16.4. The implant is used in a patient with severe GO (after three wall decompression for DON) with marked ﬁbrosis of levator palpebrae muscle. Correction of upper lid retraction is successful when 1–2 mm of the superior cornea is covered, the lid margin contour is smooth, when upper lid skin crease is between 7 and 10 mm, and lids are symmetric. Most of the surgical procedures are ascribed success rates of about 70–80%. Asymmetry can occur due to over- or undercorrection, lid crease recession, and a thickened eyelid after use of a graft.

218

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Modern Treatment Concepts in Graves Disease

a

e

16 b f

c g

d

Fig. 16.4 Upper lid lenghthening in GO. 4A–4D In most of the cases upper lid retraction does not exceed 2 mm and levator muscle desinsertion (4D scheme from [15]) will suﬃce. Patient example with upper lid retraction right eye in primary position (4A), in downgaze showing the lid lag on vertical downward pursuit (4B) and after lid lenghthening (4C). In rare cases with marked retraction (especially after decompression), the use of an implant is necessary (4E–4G). Patient example before (4E) and after lid lengthening with an implant (5 mm Tutopatch®) (4F) and intraoperative situation (4G)

Lower lid lengthening: To correct lid retraction exceeding 1 mm, a “spacer” between lower lid retractors and tarsus is required (Fig. 16.5). Various organic and anorganic materials have been used as spacers. These include auricular cartilage, hard palate mucosa, expanded polyethylene Medpor microplates, autogenous tarsus transplants, porcine acellular dermal matrix, and donor sclera or pericardium. The vertical expansion of the spacer should amount to 3 times the lid retraction in mm. Most spacers, except hard palate mucosa, need to be covered with conjunctiva. The lower lid retractors are accessible either by anterior subciliary or posterior subtarsal transconjunctival approach. The eﬀect of lower lid lengthening can be increased by

lateral tarsal strip or tarsorrhaphy. Undercorrection is common. Upper and lower lid blepharoplasty: Upper lid debulking and blepharoplasty is the ﬁnal surgical procedure in the functional and cosmetic rehabilitation of the GO patient. Redundant skin and fat can be excised using scissors and bipolar cauterant, laser, or monopolar cauterization needle. In the lower lid, the skin excision should be modest to avoid lower lid retraction or ectropion. It is important to remove preaponeurotic fat (Fig. 16.6) and even subdermal fat together with the orbicularis muscle. Prolapsing lower lid fat can also be removed transconjunctivally in patients without excess skin.

16.3

Treatment of GO

219

a

Sutures for stabilisation of the interponate

c

d

b

e

Tarsus

f

Interponate Lid retractors Lig. capsulopalp.

Inferior rectus muscle

Fig. 16.5 Lower lid lengthening in GO. Lower lid retraction can occur after large inferior rectus muscle recession if the ligamentum capsulopalpebrale cannot be suﬃciently detached from the inferior rectus muscle. Patient example: 5A before inferior rectus muscle recession of 7.5 mm, vertical squint: −VD15°. 5B lower lid retraction after inferior recession. 5C intraoperative situation: size and position of the implant. 5D patient situation 1 day postoperative. 5E cross section of the lower lid with implant (black), F ﬁnal result after lower lid lengthening with an implant and lateral tarsorrhaphy of 5 mm 40,0 35,0 30,0 TBII [IU/l]

25,0 20,0

grey Zone: no prediction possible

15,0

TBII values below: 2.3-15.6x better chance for a good course of GO

Summary for the Clinician

TBII values above: 8.7-31.1x higher risk of a severe course

■

8,8

10,0

5,1

4,8

2,6

1,5

5-8

9-12

2,9

2,8

1,5

1,5

1,5

13-16

17-20

20-24

5,0 0,0

5,7

-5,0 1-4

Months after first symptoms of GO

■

Fig. 16.6 Cut oﬀ TBII levels for the prediction of a good course of GO (grey line) and for the prediction of a severe course of GO (black line). For patients with TBII level within the grey zone no prognostic statement for the course of their GO is possible. Example: A GO patient presenting at 1–4 months after onset of the disease with TBII values below 5.7 IU/L has a 13.9-fold higher chance of a mild curse of GO than a patient with TBII values above this cut oﬀ. Otherwise, when TRAb are still above 8.8 IU/l 6 months after the beginning of GO the odds ratio to develop a severe course of GO is 18

Disﬁguring proptosis can be reduced through orbital decompression. Various surgical techniques are available. The amount of reduction depends on the number of walls removed and whether or not fat is removed. Removal of the medial wall is accompanied with the highest and removal of the lateral wall with the lowest risk of postoperative diplopia. If muscle restriction is present preoperatively, the risk of postoperatively deteriorated ocular motility is increased. The basic concept for eye muscle surgery in GO is recession of the ﬁbrotic muscle. Diﬀerent approaches are possible: preoperatively determined recession distances according to dose– eﬀect curves and intraoperative determination of recession distance via active or passive motility and adjustable sutures. Success rates are high.

220 ■

16

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Modern Treatment Concepts in Graves Disease

Upper lid retraction can be corrected in most patients without the use of a spacer through recession of levator palpebrae and Müller muscle. Implants have to be inserted for successful lower lid lengthening. The eﬀect can be enhanced with a lateral tarsal strip or tarsorrhaphy. The last step in surgical rehabilitation is blepharoplasty of upper and lower lids.

16.4 Thyroid Dysfunction and GO 16.4.1 Association Between Treatment of Hyperthyroidism and Course of GO The main goal during the early stage of thyroid disease is to achieve euthyroidism. Not only does this alleviate most thyroid symptoms, it is also beneﬁcial for the further course of GO. Antithyroid drug therapy seems to prevent most eﬃciently further deterioration of GO in comparison with thyroidectomy and radioiodine therapy [44]. Observational trials showed that thyroidectomy in the intermediate phase (6–12 months after ﬁrst symptoms of GO) may positively inﬂuence the clinical course of GO. In later, inactive stages, this beneﬁcial eﬀect is lost [45]. Leaving too large thyroid remnants increases the risk of recurrence of hyperthyroidism and reactivation of GO [46]. Radioiodine therapy carries a small but not inconsiderable (about 15%) risk of inducing or worsening GO in the intermediate phase [47]. Radiogenic inﬂammation of the thyroid during and after radioiodine application may reinforce the autoimmune reaction in the thyroid and activate or induce GO. It does not, however, inﬂuence inactive GO [48]. Patients with poor prognosis for remission should receive deﬁnitive therapy as a prerequisite for surgical rehabilitation of GO. Poor prognosis for hyperthyroidism can be expected with persisting high TSH-receptorantibodies (TRAb) during the course of antithyroid drug therapy. Remission rates are about 3% if TRAb are still above 10 IU/l after 6 months, above 7.5 IU/l after 12 months, and 3.9 IU/l after 15 months of antithyroid drug therapy (TRAb levels must be measured with a second generation assay for these statements to be valid). Remission rates are low (about 8%) in cases of moderate-to-severe GO [8, 49, 50]. Patients with a chance for remission of thyroid disease (non-smoker, low TRAb levels, small thyroid, mild hyperthyroidism at manifestation) should be followed for at least 6 months after cessation of antithyroid drug therapy before surgical rehabilitation (if necessary) is initiated. The overall relapse rate for hyperthyroidism is about 50%

[51] and relapse of hyperthyroidism can be accompanied by worsening/reactivation of pre-existing GO. Regular consultations with a thyroid specialist are necessary.

16.4.2

Relationship Between TSH-Receptor-Antibody (TRAb) Levels and Orbitopathy

The relation between TRAb and GO was for a long time subject to debate and became evident with modern, more sensitive second-generation TRAb assays. The prevalence of GO among patients with Graves’ hyperthyroidism increases with higher serum TRAb levels [52]. There is a signiﬁcant correlation of clinical activity [53] and severity [54] with TRAb levels in untreated individuals. In late stages, non-responders to anti-inﬂammatory therapy reveal higher TRAb levels [55]. Patients with moderate-to-severe GO have signiﬁcantly higher TRAb levels over the whole course of the disease (24 months follow-up) (Fig. 16.6). Cox regression analysis 6 months after disease onset revealed a hazard ratio of 1.27 to incur severe GO per every unit increase of TRAb [56]. When TRAb are still above 8.8 IU/l 6 months after beginning of GO, the odds ratio to develop a severe course of GO is 18. Patients with TRAb levels in the risk zone (see Fig. 16.6) should have short control intervals, treated with anti-inﬂammatory therapy in cases of doubt and treated longer with higher doses.

Summary for the Clinician ■ ■

■

■

■

Restoration of euthyroidism is beneﬁcial for the course of GO. Radioiodine therapy carries a small but not considerable (about 15%) risk of inducing or worsening GO. Patients with poor prognosis for remission of hyperthyroidism should receive deﬁnitive therapy as a perquisite for surgical rehabilitation of GO. The overall relapse rate of hyperthyroidism after cessation of antithyroid drug therapy is 50%. Therefore, surgical rehabilitation of GO should only be started after a 6 months period of stable remission. Relapses of hyperthyroidism can be accompanied by worsening or reactivation of GO. TSH-receptor autoantibodies are independent risk factors for GO and help to predict severity and outcome of the disease. Certain cut oﬀ levels can be used for treatment decisions.

16.5 Environmental and Genetic Inﬂuence on the Course of GO

16.5 Environmental and Genetic Inﬂuence on the Course of GO 16.5.1

Relationship Between Cigarette Smoking and Graves Orbitopathy

There is a strong and consistent association between smoking and GO. Smoking increases the prevalence of GO among patients with Graves’ hyperthyroidism. Smokers suﬀer from more severe GO than non-smokers. A dose– response relationship between the amount of cigarettes smoked daily and the risk of developing GO has been demonstrated (Fig. 16.7). Smoking increases the risk of extraocular muscle ﬁbrosis sevenfold [57]. Smoking increases the likelihood of progression of GO after radioiodine therapy. There is also evidence that smoking either delays response or impairs the outcome of treatment for GO [58]. As to the thyroid, smoking is a similarly independent risk factor for relapse of hyperthyroidism after antithyroid drug treatment [51]. In vitro models (orbital ﬁbroblast cell cultures) have been used to illustrate the impact of smoke constituents on GO, which were found to enhance two of the central processes in GO: adipogenesis and GAG production in a dose-dependent manner [59]. The eﬀect is markedly enhanced in the presence of the proinﬂammatory cytokine IL-1. The synergy between cigarette smoke and cytokine action may have potential for therapeutic implications.

16.5.2

Genetic Susceptibility

There are a number of epidemiological and twin studies which clearly indicate that autoimmune thyroid disease is

221

genetically inﬂuenced. The concordance rate for clinically overt Graves disease is 35% for monozygotic twins (MZ) and 3% for dizygotic twins (DZ). Model-ﬁtting analysis on the pooled twin data showed that 79% of the disposition for the development of GD is attributable to genetic factors [60]. Approximately, half of the patients show a positive family history of thyroid dysfunction with a higher frequency among females in comparison with males. Positive family history is also more common in maternal than in paternal relatives. The reporting of a parent with thyroid dysfunction is associated with a lower median age at diagnosis for GD. There is an inverse relationship between the number of relatives with thyroid dysfunction and age at diagnosis [61]. Frequently, identical susceptibility genes are designated for Graves and Hashimoto’s disease (summarized in [6, 62]). Within monozygotic twins, it is possible for one twin to develop typical Graves disease while the other suﬀers from Hashimoto’s thyroiditis without orbitopathy [63]. Thus, there is clear evidence for genetic susceptibility to develop thyroid autoimmunity. The disease phenotype, however, appears to be determined by environmental factors, for instance, smoking behavior. In the meantime, linkage and candidate gene analyses have revealed more than 50 genes, which may contribute to autoimmune thyroid disease. However, essential genes which are crucial for disease development remain to be identiﬁed. The genes identiﬁed to this day comprise thyroid speciﬁc genes (TSHR, Thyroglobulin) and immune modulating genes (among them: HLA class II, CTLA-4, PTPN22, CD40). Important for the disease phenotype are functional consequences of these gene variants. Table 16.6 displays the most important susceptibility genes, including possible functional consequences (modiﬁed from Jacobson et al. [6]).

Summary for the Clinician

% of the GO patients

Severity of GO and Smoking 100 90 80 70 60 50 40 30 20 10 0

■

Prevalence of GO

■

Proptosis Diplopia

■ Nonsmoker

1-10 Cigarettes

10-20 Cigarettes

> als 20 Cigarettes

Fig. 16.7 Association of GO symptoms with the number of smoked cigarettes

Graves’ disease arises owing to interaction between environmental and genetic factors. Smoking is associated with a higher prevalence of GO, the development of more severe disease stages of GO, reduced eﬀectiveness of treatments for GO, and with the progression of GO after radioiodine treatment. Therefore, the patient should be advised to stop smoking. Immune regulatory and thyroid-speciﬁc genes contribute to the disease. The risk for ﬁrst-degree relatives is 3%. About 50% of patients report a positive family history, more common in the maternal than in the paternal trait.

222

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Modern Treatment Concepts in Graves Disease

Table 16.6. Susceptibility genes and possible functional consequences in Graves’ disease (slightly modiﬁed from Jacobson et al. [6]) Gene

16

Associated variants

Potential mechanisms

HLA DR

DR3

Alteration in autoantigen presentation

CTLA-4

Several SNP’s (A/G49, CT60, 3’UTR AT)

Reduction of suppression of T-cell activation (CTLA-4 = negative regulator of T-cells)

CD 40

Kozak sequence SNP

Alteration of translational eﬃciency of CD40 in CD40 expressing tissues (APC, thyrocytes, orbital ﬁbroblasts)

PTPN22

R620W

Inhibition of T-cell activation

IL23R

Several SNP (rs11209026, rs7530511, rs2201841, rs10889677)

Reduction of activation of T cells, natural killer (NK) cells, monocytes, and dendritic cells “protecting factor”, expansion of Th17 subset

Thyroglobulin

Several SNP

Alteration in thyroglobulin peptide presentation by HLA DR to T-cells

TSHR

28 SNPs revealed association

Alteration in TSHR peptide presentation by HLA DR to T-cells, alterations in Auto AB binding

Immune response modulating genes

Thyroid speciﬁc genes

16.6 16.6.1

Special Situations Euthyroid GO

Patients with euthyroid GO developed less severe symptoms, especially fewer soft tissue signs and more asymmetric disease (unilateral proptosis) than hyperthyroid patients. Levels of thyroid-speciﬁc antibodies are lower and less prevalent. However, they occur in at least 75% of the patients; therefore, the application of sensitive assay technology is of utmost concern [64].

16.6.2

Childhood GO

GO is rare in childhood because of the low incidence of Graves disease in this age group. The eye disease is usually milder in children than in adults and often stabilizes and eventually resolves without intervention. Soft tissue inﬂammation is rare in childhood GO. Achieving and maintaining euthyroidism are as important objectives as in adult patients. Exposure to smoking (active and, possibly even passive) is probably as detrimental as in adults. Because of their eﬀect on growth,

glucocorticoids should be avoided unless the patient suﬀers from optic neuropathy. Orbital radiotherapy is contraindicated in children. Orbital surgery may be necessary in cases of severe exophthalmos, but for most patients a conservative and expectant approach is most appropriate [65].

16.6.3

GO and Diabetes

Systemic glycocorticoids may induce or exacerbate diabetes or hypertension. However, indications for glucocorticoid use in patients with diabetes or hypertension are no diﬀerent than in other patients. Close monitoring of blood sugar levels and blood pressure is important. Thiazide or loop diuretics should be used cautiously during high-dose steroid therapy to avoid hypokalemia. The same principle applies to surgical treatment. Orbital radiotherapy may increase the risk of retinopathy in diabetic and hypertensive patients. Diabetes or hypertension are no contraindication to surgical orbital decompression or other surgical treatments. Optic neuropathy occurs signiﬁcantly more often in diabetic patients (reviewed in [21]).

References

Summary for the Clinician ■ ■ ■

Patient with euthyroid GO develop less active/ severe and more asymmetric GO symptoms. If present at all GO is mild in childhood and rarely needs treatment. Orbital irradiation is possibly contraindicated in patients with diabetic retinopathy and DON occurs more often.

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Index

A

Abducens palsy, 71 Abnormal central nervous system (CNS) esotropia, 2 Abnormal central nervous system (CNS) exotropia, 3 Acquired motor neuropathy, 71–72 Acquired nonaccommodative esotropia, 2 Acquired pulley heterotopy, 63–64 Amblyopia treatment 2009 age eﬀect, 131 amblyopia management patch occlusion, 128–129 pharmacological therapy, plano lens, 130 pharmacological treatment, atropine, 129–130 refractive correction, 127–128

Bangerter ﬁlters, 132–133 bilateral refractive amblyopia, 131 clinical features, 126 deep unilateral amblyopia, 175–176

diagnosis, 126–127 epidemiology, 125–126 levodopa/carbidopa adjunctive therapy, 133 long-term persistence, 132 maintenance therapy, 131 natural history data, 127 optic neuropathy, 133–134 spectacle correction, 125 Amblyopia, screening Child Health Promotion Program (CHPP), 96 classiﬁcation, 95 conventional occlusion, 104 cover-uncover test, 100–101 deﬁnition, 95–96 Duane’s/Brown’s syndrome, 97 justiﬁcation, 98 lay screeners, 102 older children, 104–105 optical penalization, 104 orthoptists, 102 pharmacological occlusion, 104 photorefractive keratectomy (PRK), 105 photoscreening/autorefraction, 101–102 pre-school vision screening, 98–99 quality of life emotional well-being, 107 impact of treatment, 108 impact on education, 106–107 reading speed and ability, 106 strabismus impact, 107–108

recurrence, 105

refractive adaptation, 103–104 refractive error, 97 sensitivity, 100 stereoacuity test, 101 strabismus, 97 treatment compliance, 105 type of treatment, 103 vision in preschoolers study (VIP), 100, 101 vision tests, 100 vs. diagnostic test, 97 Anisometropia, 33 Anisometropic amblyopia, 2, 3 Anomalous head posture (AHP) Anderson–Kesternbaum surgery, 158 binocular visual acuity testing, 161–162 horizontal management, 165–166 idiopathic infantile nystagmus, 158 measurement, 160–161 monocular eﬀect, 161–162 straightening eﬀect, head, 162 testing, near vision, 162 vertical management, 166–167 Anomalous retinal correspondence (ARC), 34 Atropine, 129–130 B

Bagolini test, 141 Bangerter foils, 132 Bell’s phenomenon, 88 Bielschowsky head tilt test (BHTT), 181 Bilateral feedback control applications, 21–22 muscle lengths, 19–21 Bilateral posterior tenectomy, 190 Bilateral refractive amblyopia, 131 Binocular alignment system control system A-/V-pattern strabismus, 14 basic muscle length, 15–16 bilateral phenomena, 14–15 breakdown, 14 final common pathway, 17–18 perturbation, 13 sensory torsion, 14 version and vergence stimulation, 16–17

deviation and ﬁxation pattern, 11 long-term maintenance, 11 muscle length adaptation, 12–13

228

Index

vergence adaptation, 12 Binocular vision angle of strabismus, 140–141 at age six, 140 bilateral recession vs. unilateral recession-resection, 141 Blood–brain barrier, 133 Botulinum toxin A (BTXA), 197, 203, 204 Brown syndrome, 4, 203 Brückner test amblyopia and amblyogenic disorders, 113–114 corneal light reﬂex, 114–115 eye movements, alternating illumination, 122 fundus red reﬂex ametropia, 116, 118 anisometropia, 118 esotropia, 117–118 foveal dimming, 117 hypermetropia, 118 Mittendorf’s spot, 115 optic coherence tomography, 117 paediatric residents, 119 possibilities and limitations, 120 pupillary constriction, 116 test performance, 119–120 transillumination test, 115 uncorrected ametropia, 118 uni-lateral astigmatismus, 119 uni-lateral spherical ametropia, 118, 119

pupillary light reﬂex eccentric vs. central illumination, 121 iris pathology, 120 monocular illumination, 121 possibilities and limitations, 121–122 strabismus diagnostics, 120 test performance, 121 C

Cataract, 2, 3 Child Health Promotion Program (CHPP), 96 Chronic progressive external ophthalmoplegia (CPEO), 59–60 CNS-associated hypertropia, 4 Complete third nerve palsy hypertropia, 198–199 Congenital cranial dysinnervation disorders (CCDDs), 66 brainstem and cranial nerve development, 77, 78 Brown syndrome comorbidity, 85 epidemiologic features, 85 incidence and heredity, 86 intra-and postoperative findings, 87 laterality, 85–86 motility findings, 83–85 natural course, 87 neurodevelopmental disorder, 89–90 potential induction, 86–87 radiologic findings, 87 saccadic eye movements, 85 sex distribution, 86

CFEOM, 78–79 congenital fourth nerve palsy, 82 congenital monocular elevation deﬁciency, 87–89 congenital ptosis, 81

congenital trochlear palsy, 82 Duane retraction syndrome, 79–81 HGPPS, 81 isolated uni-/bilateral facial palsy, 83 vertical retraction syndrome, 88 Congenital esotropia, 2 Congenital exotropia, 3 Congenital ﬁbrosis of the extraocular muscles (CFEOM), 78–79 A-pattern exotropia, 69 motor axonal misrouting, 67 MRI, 67–68 phenotypes, 67 Congenital nystagmus clinical characteristics, 156–157 compensatory mechanisms AHP, 160–162 versions and vergence, 160

manifest latent nystagmus (MLN) clinical characteristics, 157–158 slow phase, 157

periodic alternating nystagmus (PAN), 158–159 sensory deﬁcits afferent visual defect, 155 causes, 156 horizontal eye movement, 154 idiopathy, 155 phenotypical characteristics, 155

treatment acupuncture, 164 artiﬁcial divergence surgery, 167–168 botulinum toxin-A (Botox), 164 head tilt, 167 horizontal AHP, 165–167 medications, 162–163 prisms, 163 refractive correction, 162 retro-equatorial recession, 168–169 spectacles and contact lenses (CL), 162–163 surgical principles, 164–165 tenotomy procedure, 169 vertical AHP, 166–167 Congenital oculomotor (CN3) palsy, 67 Congenital pulley heterotopy, 62–63 Congenital superior oblique paresis, 20, 21 Congenital trochlear (CN4) palsy, 69 Convergence insuﬃciency, 3 Cycloplegic drug, 127 Cyclovertical misalignment, 19 D

Diagnostic occlusion, 19 Dissociated eye movements pathogenetic role, 29 vergence eye movements, 25 dissociated horizontal deviation (DHD), 25–29, 179–180 dissociated torsional deviation (DTD) inverse and direct head tilt, 181 strabismus, 180

dissociated vertical deviation (DVD) asymmetric vs. symmetric surgeries, 178 bilateral, 175–176

Index hypotropia, nonfixating eye, 178–179 IOOA and V pattern, 176–177 SOOA and A pattern, 177–178 symmetric, 175

Divergence paralysis esotropia, 64–65 Double elevator palsy, 83, 87, 88 Duane’s retraction syndrome (DRS), 69, 79–81 Duane’s syndrome, 19 Dysthyroid optic neuropathy (DON), 214

G

German Institute for Quality and Eﬃciency in Healthcare (IQWIG), 99 Glucocorticoids (GC), 213 Graves orbitopathy active inﬂammatory phase combined therapy, 213 dysthyroid optic neuropathy (DON), 214 glucocorticoids (GC), 213 immunosuppressive treatments, 213–214 orbital radiotherapy (OR), 213 sight-threatening corneal breakdown, 214 symptoms, 214–215

E

EOM surgery, 216–217 Esotropia (ET) DHD, 179–180 monoﬁxation syndrome, 35–36 visual cortex mechanisms binocular input correlation, 50–51 binocular visuomotor behavior development, 42, 43 cerebral damage risk factors, 41–42 cortical binocular connections, 44–46 cytotoxic insult, cerebral fibers, 42 early-onset (infantile) esotropia, 41 extrastriate cortex, striate cortex, 46 fusional vergence and innate convergence bias, 44 genetic influence, cerebral connection, 42 high-grade fusion repair, 50 inter-ocular suppression, 46–47 monocular compartments, striate cortex, 44, 46 motion sensitivity and conjugate eye tracking, 44 naso-temporal inequalities, cortical suppression, 47 persistent nasalward visuomotor bias, 47–50 sensorial fusion and stereopsis development, 43 strabismic human infant repair, 50

Essential infantile esotropia. See Congenital esotropia Exotropia (XT) DHD, 179–180 infantile esotropia active divergence mechanism, 26 binocular fusion vs. dissociated esotonus, 27, 28 clinical signs, 27 horizontal strabismus, 28

Expected value of perfect information (EVPI), 99 Extraocular muscle (EOM), 196, 197 Eye lid surgery lower lid lengthening, 218, 219 upper and lower lid blepharoplasty, 218 upper lid lengthening, 217 F

First Purkinje images, 114–115 Fourth nerve palsy hypertropia bilateral involvement, 201 congenital superior oblique palsy, 200 inferior oblique weakening procedure, 203 superior and inferior rectus recession, 209 superior oblique strengthening procedure, 209 superior oblique tendon laxity, 201 superior rectus contracture, 201 surgical plan, 200 torsional diplopia, 202–203

childhood, 222 classiﬁcation, 211–212 clinical assessment activity signs, 208–209 assess severity, 209–211 orbital imaging, 211

clinical characteristics, 208 diabetes, 222 environmental and genetic inﬂuence cigarette smoking, 221 susceptibility genes, 221–222 euthyroid, 222 Graves disease (GD), 207–208 inactive disease stages extraocular muscle surgery, 216–217 lid surgery, 217–220 orbital decompression, 215–216 management plan, 208, 210 thyroid dysfunction, 220 H

Health-related quality of life (HRQoL), 98, 99, 106–108 Horizontal gaze palsy with progressive scoliosis (HGPPS), 81 Hypertropia, 3–4, 179 I

Immune myopathy, 60–61 Incomplete third nerve palsy hypertropia, 199 Infantile esotropia (IE) deﬁnition and prevalence, 137 dissociated eye movements pathogenetic role, 29 vergence eye movements, 25

early vs. late infantile strabismus surgery study (ELISSS) alignment and fusion, 145 binocular vision, 140 horizontal angle of strabismus, 140–141 methods and results, 139–140 postoperative angle of strabismus, 145 prospective study, 139 random-effects model, 146, 148 reoperation rate, 142–143 spontaneous reduction, 146–148 spontaneous resolution, 146 test-retest reliability, 144–145

esotonus vs. convergence, 28 exotropia

229

230

Index active divergence mechanism, 26 binocular fusion vs. dissociated esotonus, 27, 28 clinical signs, 27 horizontal strabismus, 28

outcome parameters, 138–139 pathogenesis, 138 sensory/motor etiology, 137–138 tonus, 25–26 Infantile-onset image decorrelation, 38–39 Inferior oblique (IO) palsy, 71–72 Inferior oblique overaction (IOOA), 4, 176–177 Inﬂammatory myositis, 61 Intermittent exotropia, 3, 4

N

Neoplastic myositis, 61 Neuroanatomical strabismus acquired motor neuropathy, 71–72 acquired pulley heterotopy, 63–64 congenital peripheral neuropathy congenital cranial dysinnervation disorders (CCDDs), 66 congenital fibrosis of the extraocular muscles (CFEOM), 67–69 congenital oculomotor (CN3) palsy, 67 congenital trochlear (CN4) palsy, 69 Duane’s retraction syndrome (DRS), 69 Moebius syndrome, 70

congenital pulley heterotopy, 62–63 divergence paralysis esotropia, 64–65 etiology, 59 extraocular myopathy

L

Levodopa, 133 Logistic regression analysis, 143 Long-term binocular alignment control system, 14

immune myopathy, 60–61 inflammatory myositis, 61 neoplastic myositis, 61 primary EOM myopathy, 59–60 traumatic myopathy, 61–62

M

Manifest latent nystagmus (MLN) Anderson–Kesternbaum surgery, 158 clinical characteristics, 157–158 idiopathic infantile nystagmus, 158 slow phase, 157 Marcus-Gunn phenomenon, 80–82, 85, 87–89 Marlow occlusion, 19 Meta-regression model, 143 Microstrabismus number of operations postoperative angle of strabismus, 145 reoperation rate, 142–143 test-retest reliability, 144–145

random-eﬀects model, 146, 148 spontaneous reduction, 146–148 spontaneous resolution, 146 Mittendorf ’s spot, 115 Möbius syndrome, 83 Moebius syndrome, 70 Monoﬁxation syndrome (MFS) animal models, 37 anisometropia, 33 bi-ﬁxation, 36–37 causes, 33 foveal suppression scotoma elimination, 36 manifest strabismus, 35–36 micro-esotropia extrastriate cortex, 52–53 neural mechanism, 51 neuroanatomic findings, 52, 53 stereoscopic threshold, 52 subnormal stereopsis and motor fusion, 51

normal and anomalous binocular vision anomalous retinal correspondence (ARC), 34 binocular correspondence, 34–35 communication, 33 cortical adaptation, 34 ocular dominance column, 33, 34

normal/near-normal fusional vergence, 37 primary MFS, 38–39 Motor skills, 106 Muscle length adaptation, 11–13

vergence and gaze abnormalities, 72 Normal correspondence (NRC), 34 O

Ocular albinism (OA), 155 Ocular motility disorders, CCDD brainstem and cranial nerve development, 77, 78 Brown syndrome comorbidity, 85 epidemiologic features, 85 incidence and heredity, 86 intra-and postoperative findings, 87 laterality, 85–86 motility findings, 83–85 natural course, 87 neurodevelopmental disorder, 89–90 potential induction, 86–87 radiologic findings, 87 saccadic eye movements, 85 sex distribution, 86

CFEOM, 78–79 congenital fourth nerve palsy, 82 congenital monocular elevation deﬁciency, 87–89 congenital ptosis, 81 congenital trochlear palsy, 82 Duane retraction syndrome, 79–81 HGPPS, 81 isolated uni-/bilateral facial palsy, 83 vertical retraction syndrome, 88 Ocular motor control system, 18 Oculocutaneous albinism (OCA), 155 Oculomotor palsy, 71 Optic neuropathy, 133–134 Optical coherence tomography (OCT), 155, 156 Orbital radiotherapy (OR), 213 P

Paralytic strabismus complete third nerve palsy, 198–199

Index

fourth nerve palsy hypertropia

measurement technique, 188 superior rectus muscle recession effects, 186–188 suspension technique, 188–189 tendon incarceration syndrome, 185

bilateral involvement, 201 congenital superior oblique palsy, 200 inferior oblique weakening procedure, 203 superior and inferior rectus recession, 209 superior oblique strengthening procedure, 209 superior oblique tendon laxity, 201 superior rectus contracture, 201 surgical plan, 200 torsional diplopia, 202–203

frenulum, 185 theoretical eﬀect anterior–posterior axis, 189 posterior tenectomy, 190 SO anatomy, 190, 191 SO tendon, 189, 192 threefold function, 189 two-dimensional trigonometry, 192

incomplete third nerve palsy, 199 principles preoperative assessment, 196–197 surgery timing, 195–196 surgical treatment, 197–198

sixth nerve palsy hypertropia lateral and medial rectus resection, 204 medial rectus weakening, sound eye, 204–205

Pediatric strabismus adult strabismus, 7 associated conditions, 4 esodeviation, 1–2 exodeviation, 3 hyperdeviation, 3–4 surgery rates, 4 worldwide incidence and prevalence, 4–7 Periodic alternating nystagmus (PAN), 158–159 Pharmacological occlusion, 104 Photorefractive keratectomy (PRK), 105 Plano lens, 130 Posner’s maneuver, 174 Posterior partial tenectomy, 190 Primary extraocular muscle (EOM) myopathy, 59–60 Primary oblique muscle overaction, 14 Prism adaptation, 12 Q

Quality adjusted life years (QALY), 99 R

Reversed ﬁxation test (RFT), 179 S

Sensory esotropia, 2, 3 Sensory exotropia, 3 Sixth nerve palsy hypertropia lateral and medial rectus resection, 204 medial rectus weakening, sound eye, 204–205 Stereoacuity skills, 106 Superior oblique overaction (SOOA), 176–177 Superior oblique (SO) surgery clinical investigation 6–0 Polyglactin 910 sutures, 186 asymmetric effects, 189 enucleation, 186 Jampolsky’s recommendations, 187

T

Thyroid-stimulating hormone receptor (TSHR), 208 Traumatic myopathy, 61–62 Trochlear palsy, 71 TSHR antibodies (TRAb), 208 Two-dimensional trigonometry, 192 U

Unilateral strabismus changes cyclovertical deviation, 20, 21 head-tilt changes, 21 ipsilateral medial and contralateral rectus muscle, 19 torsional position, 20 vertical recordings, 21 V

Vergence adaptation, 11, 12 Vertical retraction syndrome, 88 Visual cortex mechanisms esotropia binocular input correlation, 50–51 binocular visuomotor behavior development, 42, 43 cerebral damage risk factors, 41–42 cortical binocular connections, 44–46 cytotoxic insult, cerebral ﬁbers, 42 early-onset (infantile) esotropia, 41 extrastriate cortex, striate cortex, 46 fusional vergence and innate convergence bias, 44 genetic inﬂuence, cerebral connection, 42 high-grade fusion repair, 50 inter-ocular suppression, 46–47 monocular compartments, striate cortex, 44, 46 motion sensitivity and conjugate eye tracking, 44 naso-temporal inequalities, cortical suppression, 47 persistent nasalward visuomotor bias, 47–50 sensorial fusion and stereopsis development, 43 strabismic human infant repair, 50 micro-esotropia extrastriate cortex, 52–53 neural mechanism, 51 neuroanatomic ﬁndings, 52, 53 stereoscopic threshold, 52 subnormal stereopsis and motor fusion, 51

231

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