Essentials in Ophthalmology Pediatric Ophthalmology,...philosophy of strabismus that integrates new...

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Essentials in Ophthalmology Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics

B. Lorenz M. C. Brodsky

Editors

Essentials in Ophthalmology

G. K. Krieglstein R. N. Weinreb

Series Editors

Glaucoma

Cataract and Refractive Surgery

Uveitis and Immunological Disorders

Vitreo-retinal Surgery

Medical Retina

Oculoplastics and Orbit

Pediatric Ophthalmology,Neuro-Ophthalmology, Genetics

Cornea and External Eye Disease

Editors Birgit LorenzMichael C. Brodsky

Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics

Strabismus - New Concepts in Pathophysiology, Diagnosis, and Treatment

ISBN: 978-3-540-85850-8 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

Th is work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lm 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.

Th e use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.

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Series Editors

Günter K. Krieglstein, MDProfessor and ChairmanDepartment of OphthalmologyUniversity of CologneJoseph-Stelzmann-Straße 950931 KölnGermany

Robert N. Weinreb, MDProfessor and DirectorHamilton Glaucoma CenterDepartment of OphthalmologyUniversity of California at San Diego9500 Gilman DriveLa Jolla, CA 92093-0946USA

Volume Editors

Birgit Lorenz, MDProfessor of OphthalmologyKlinik und Poliklinik fürAugenheilkundeJustus-Liebig-UniversityUKGM GmbH Giessen CampusFriedrichstraβe 1835392 GiessenGermany

Michael C. Brodsky, MDProfessor of Ophthalmology and NeurologyMayo ClinicDepartment of Ophthalmology200 First Street SWRochester, MN 55905USA

Foreword

Th e Essentials in Ophthalmology series represents an unique updating publication on the progress in all sub-specialties of ophthalmology.

In a quarterly rhythm, eight issues are published cov-ering clinically relevant achievements in the whole fi eld of ophthalmology. Th is timely transfer of advancements for the best possible care of our eye patients has proven to be eff ective. Th e 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 fi rst two series, each of eight volumes. Th is is a success that was made possible pre-dominantly by the numerous opinion-leading authors and the outstanding section editors, as well as with the constructive support of the publisher. Th ere are many good reasons to continue and still improve the dissemina-tion of this didactic and clinically relevant information.

G.K. KrieglsteinR.N. Weinreb Series Editors

Preface

Th e fi eld of strabismology has long suff ered from a dis-crepancy between its levels of sophistication in practice and theory. Although its diagnostic and therapeutic arma-mentarium has become quite advanced, the scientifi c understanding of disease pathogenesis has remained rudi-mentary. 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 strabis-mus 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 unifi ed

philosophy of strabismus that integrates new concepts of pathogenesis into the clinic.

Th is book provides a compendium of chapters that highlight new ideas in the fi eld of strabismus. We have assembled an international panel of contributors who have advanced our understanding of strabismus patho-genesis. 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 fi nds this edition both stimulating and enlightening.Birgit LorenzMichael C. Brodsky

Contents

Chapter 1Epidemiology of Pediatric Strabismus

Amy E. Green-Simms and Brian G. Mohney

1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 Forms of Pediatric Strabismus . . . . . . . . . . 11.2.1 Esodeviations . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2.1.1 Congenital Esotropia . . . . . . . . . . . . . . . . . . . 21.2.1.2 Accommodative Esotropia. . . . . . . . . . . . . . 21.2.1.3 Acquired Nonaccommodative

Esotropia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.2.1.4 Abnormal Central Nervous System

Esotropia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.2.1.5 Sensory Esotropia . . . . . . . . . . . . . . . . . . . . . . 21.2.2 Exodeviations . . . . . . . . . . . . . . . . . . . . . . . . . . 31.2.2.1 Intermittent Exotropia. . . . . . . . . . . . . . . . . . 31.2.2.2 Congenital Exotropia . . . . . . . . . . . . . . . . . . . 31.2.2.3 Convergence Insuffi ciency. . . . . . . . . . . . . . 31.2.2.4 Abnormal Central Nervous System

Exotropia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.2.2.5 Sensory Exotropia . . . . . . . . . . . . . . . . . . . . . . 31.2.3 Hyperdeviations . . . . . . . . . . . . . . . . . . . . . . . 31.3 Strabismus and Associated

Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.4 Changing Trends in Strabismus

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . 41.4.1 Changes in Strabismus Prevalence . . . . . . 41.4.2 Changes in Strabismus Surgery Rates . . . 41.5 Worldwide Incidence and Prevalence

of Childhood Strabismus . . . . . . . . . . . . . . . 41.6 Incidence of Adult Strabismus . . . . . . . . . . 7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Chapter 2Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation

David L. Guyton

2.1 Binocular Alignment System. . . . . . . . . . . . 112.1.1 Long-Term Maintenance

of Binocular Alignment . . . . . . . . . . . . . . . . . 112.1.2 Vergence Adaptation. . . . . . . . . . . . . . . . . . . 12

2.1.3 Muscle Length Adaptation . . . . . . . . . . . . . 122.2 Modeling the Binocular

Alignment Control System. . . . . . . . . . . . . . 132.2.1 Breakdown of the Binocular

Alignment Control System. . . . . . . . . . . . . . 142.2.2 Clarifi cation of Unanswered

Questions Regarding the Long-Term Binocular Alignment Control System. . . . . . . . . . . . . . . . . . . . . . . . . 14

2.2.3 Changes in Strabismus as Bilateral Phenomena . . . . . . . . . . . . . . . . . . . 14

2.2.4 Changes in Basic Muscle Length . . . . . . . . 152.2.5 Version Stimulation and

Vergence Stimulation . . . . . . . . . . . . . . . . . . 162.2.6 Evidence Against the “Final

Common Pathway”. . . . . . . . . . . . . . . . . . . . . 172.3 Changes in Strabismus . . . . . . . . . . . . . . . . . 182.3.1 Diagnostic Occlusion: And the

Hazard of Prolonged Occlusion . . . . . . . . . 192.3.2 Unilateral Changes in Strabismus . . . . . . . 192.3.2.1 Supporting Evidence for Bilateral

Feedback Control of Muscle Lengths . . . . 192.4 Applications of Bilateral Feedback

Control to Clinical Practice and to Future Research . . . . . . . . . . . . . . . . . . . . . 21

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Chapter 3A Dissociated Pathogenesisfor Infantile Esotropia

Michael C. Brodsky

3.1 Dissociated Eye Movements . . . . . . . . . . . . 253.2 Tonus and its relationship

to infantile esotropia . . . . . . . . . . . . . . . . . . . 253.3 Esotropia and Exotropia as

a Continuum . . . . . . . . . . . . . . . . . . . . . . . . . . . 263.4 Distinguishing Esotonus

from Convergence . . . . . . . . . . . . . . . . . . . . . 283.5 Pathogenetic Role of Dissociated

Eye Movements in Infantile Esotropia . . . 29 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

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Chapter 4The Monofi xation Syndrome: New Considerations on Pathophysiology

Kyle Arnoldi

4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 334.2 Normal and Anomalous

Binocular Vision . . . . . . . . . . . . . . . . . . . . . . . . 334.2.1 Binocular Correspondence:

Anomalous, Normal, or Both?. . . . . . . . . . . 344.3 MFS with Manifest Strabismus . . . . . . . . . . 354.3.1 Esotropia is the Most Common

form of MFS. . . . . . . . . . . . . . . . . . . . . . . . . . . . 354.3.2 Esotropia Allows for Better

Binocular Vision . . . . . . . . . . . . . . . . . . . . . . . . 354.3.3 Esotropia is the Most Stable Form. . . . . . . 364.4 Repairing and Producing MFS . . . . . . . . . . 364.4.1 Animal Models for the Study

of MFS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374.5 Primary MFS (Sensory Signs of

Infantile-Onset Image Decorrelation) . . . 384.5.1 Motor Signs of Infantile-Onset

Image Decorrelation . . . . . . . . . . . . . . . . . . . 38 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Chapter 5Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment

Lawrence Tychsen

5.1 Esotropia as the Major Type of Developmental Strabismus . . . . . . . . . . 41

5.1.1 Early-Onset (Infantile) Esotropia . . . . . . . . 415.1.2 Early Cerebral Damage as

the Major Risk Factor . . . . . . . . . . . . . . . . . . . 415.1.3 Cytotoxic Insults to Cerebral Fibers. . . . . . 425.1.4 Genetic Infl uences on

Formation of Cerebral Connections . . . . . 425.1.5 Development of Binocular

Visuomotor Behavior in Normal Infants. . . . . . . . . . . . . . . . . . . . . . . 42

5.1.6 Development of Sensorial Fusion and Stereopsis . . . . . . . . . . . . . . . . . . 43

5.1.7 Development of Fusional Vergence and an Innate Convergence Bias . . . . . . . . . . . . . . . . . . . . . . 44

5.1.8 Development of Motion Sensitivity and Conjugate Eye Tracking (Pursuit/OKN) . . . . . . . . . . . . . 44

5.1.9 Development and Maldevelopment of Cortical Binocular Connections . . . . . . . . . . . . . . . . . 44

5.1.10 Binocular Connections Join Monocular Compartments Within Area V1 (Striate Cortex) . . . . . . . . . . . . . . . . . 44

5.1.11 Too Few Cortical Binocular Connections in Strabismic Primate. . . . . . 46

5.1.12 Projections from Striate Cortex (Area V1) to Extrastriate Cortex (Areas MT/MST) . . . . . . . . . . . . . . . . . . . . . . . . 46

5.1.13 Inter-Ocular Suppression Rather than Cooperation in Strabismic Cortex . . . . . . . . . . . . . . . . . . . . 46

5.1.14 Naso-Temporal Inequalities of Cortical Suppression . . . . . . . . . . . . . . . . . 47

5.1.15 Persistent Nasalward Visuomotor Biases in Strabismic Primate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

5.1.16 Repair of Strabismic Human Infants: The Historical Controversy . . . . . . 50

5.1.17 Repair of High-grade Fusion is Possible. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

5.1.18 Timely Restoraion of Correclated Binocular Input: The Key to Repair . . . . . . 50

5.2 Visual Cortex Mechanisms in Micro-Esotropia (Monofi xation Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

5.2.1 Neuroanatomic Findings in Area V1 of Micro-Esotropic Primates . . . . 52

5.2.2 Extrastriate Cortex inMicro-Esotropa. . . . . . . . . . . . . . . . . . . . . . . . . 52

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Chapter 6Neuroanatomical Strabismus

Joseph L. Demer

6.1 General Etiologies of Strabismus. . . . . . . . 596.2 Extraocular Myopathy . . . . . . . . . . . . . . . . . . 596.2.1 Primary EOM Myopathy . . . . . . . . . . . . . . . . 596.2.2 Immune Myopathy. . . . . . . . . . . . . . . . . . . . . 606.2.3 Infl ammatory Myositis. . . . . . . . . . . . . . . . . . 616.2.4 Neoplastic Myositis. . . . . . . . . . . . . . . . . . . . . 616.2.5 Traumatic Myopathy . . . . . . . . . . . . . . . . . . . 616.3 Congenital Pulley Heterotopy . . . . . . . . . . 626.4 Acquired Pulley Heterotopy . . . . . . . . . . . . 636.5 “Divergence Paralysis” Esotropia . . . . . . . . 646.5.1 Vertical Strabismus Due to

Sagging Eye Syndrome . . . . . . . . . . . . . . . . . 656.5.2 Postsurgical and Traumatic Pulley

Heterotopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656.5.3 Axial High Myopia. . . . . . . . . . . . . . . . . . . . . . 656.6 Congenital Peripheral Neuropathy:

The Congenital Cranial Dysinnervation Disorders (CCDDs) . . . . . . 66

Contents xi

6.6.1 Congenital Oculomotor (CN3) Palsy. . . . . 676.6.2 Congenital Fibrosis of the

Extraocular Muscles (CFEOM) . . . . . . . . . . . 676.6.3 Congenital Trochlear (CN4) Palsy. . . . . . . . 696.6.4 Duane’s Retraction

Syndrome (DRS). . . . . . . . . . . . . . . . . . . . . . . . 696.6.5 Moebius Syndrome . . . . . . . . . . . . . . . . . . . . 706.7 Acquired Motor Neuropathy. . . . . . . . . . . . 716.7.1 Oculomotor Palsy . . . . . . . . . . . . . . . . . . . . . . 716.7.2 Trochlear Palsy . . . . . . . . . . . . . . . . . . . . . . . . . 716.7.3 Abducens Palsy . . . . . . . . . . . . . . . . . . . . . . . . 716.7.4 Inferior Oblique (IO) Palsy . . . . . . . . . . . . . . 716.8 Central Abnormalities

of Vergence and Gaze . . . . . . . . . . . . . . . . . . 726.8.1 Developmental Esotropia

and Exotropia . . . . . . . . . . . . . . . . . . . . . . . . . . 726.8.2 Cerebellar Disease. . . . . . . . . . . . . . . . . . . . . . 726.8.3 Horizontal Gaze Palsy and

Progressive Scoliosis . . . . . . . . . . . . . . . . . . . 72 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Chapter 7Congenital Cranial Dysinnervation Disorders: Facts and Perspectives to Understand Ocular Motility Disorders

Antje Neugebauer and Julia Fricke

7.1 Congenital Cranial Dysinnervation Disorders: Facts About Ocular Motility Disorders . . . . . . . . . . . . . . . . . . . . . . 77

7.1.1 The Concept of CCDDs: Ocular Motility Disorders as Neurodevelopmental Defects . . . . . . . . . . 77

7.1.1.1 Brainstem and Cranial Nerve Development. . . . . . . . . . . . . . . . . . . . 78

7.1.1.2 Single Disorders Representing CCDDs . . . . . . . . . . . . . . . . . . . 78

7.1.1.3 Disorders Understood as CCDDs . . . . . . . . 817.2 Congenital Cranial Dysinnervation

Disorders: Perspectives to Understand Ocular Motility Disorders . . . . . . . . . . . . . . . 83

7.2.1 Congenital Ocular Elevation Defi ciencies: A Neurodevelopmental View . . . . . . . . . . . . . 83

7.2.1.1 Brown Syndrome. . . . . . . . . . . . . . . . . . . . . . . 837.2.1.2 Congenital Monocular

Elevation Defi ciency and Vertical Retraction Syndrome . . . . . . . . . . . 87

7.2.2 A Model of some Congenital Elevation Defi ciencies as Neurodevelopmental Diseases . . . . . . . . . 89

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Chapter 8The Value of Screening for Amblyopia Revisited

Jill Carlton and Carolyn Czoski-Murray

8.1 Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 958.2 What Is Screening? . . . . . . . . . . . . . . . . . . . . . 968.2.1 Screening for Amblyopia,

Strabismus, and/or Refractive Errors. . . . . . . . . . . . . . . . . . . . . . . . 96

8.2.1.1 Screening for Amblyopia . . . . . . . . . . . . . . . 978.2.1.2 Screening for Strabismus . . . . . . . . . . . . . . . 978.2.1.3 Screening for Refractive Error . . . . . . . . . . . 978.2.1.4 Screening for Other Ocular Conditions . . 978.2.2 Diff erence Between a Screening

and Diagnostic Test . . . . . . . . . . . . . . . . . . . . 978.2.3 Justifi cation for Screening for

Amblyopia and/or Strabismus . . . . . . . . . . 988.2.4 Recent Reports Examining

Pre-School Vision Screening . . . . . . . . . . . . 988.3 Screening Tests for Amblyopia,

Strabismus, and/or Refractive Error. . . . . . . . . . . . . . . . . . . . . . . . . 100

8.3.1 Vision Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008.3.2 Cover-Uncover Test. . . . . . . . . . . . . . . . . . . . . 1008.3.3 Stereoacuity . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018.3.4 Photoscreening and/or

Autorefraction . . . . . . . . . . . . . . . . . . . . . . . . . 1018.3.5 What to Do with Those Who

Are Unable to Perform Screening Tests?. . . . . . . . . . . . . . . . . . . . . . . . 102

8.3.6 Who Should Administer the Screening Program? . . . . . . . . . . . . . . . . 102

8.4 Treatment of Amblyopia. . . . . . . . . . . . . . . . 1038.4.1 Type of Treatment . . . . . . . . . . . . . . . . . . . . . . 1038.4.2 Refractive Adaptation . . . . . . . . . . . . . . . . . . 1038.4.3 Conventional Occlusion . . . . . . . . . . . . . . . . 1048.4.4 Pharmacological Occlusion . . . . . . . . . . . . . 1048.4.5 Optical Penalization . . . . . . . . . . . . . . . . . . . . 1048.4.6 Eff ective Treatment of

Amblyopia in Older Children (Over the Age of 7 Years). . . . . . . . . . . . . . . . 104

8.4.7 Treatment Compliance . . . . . . . . . . . . . . . . . 1058.4.8 Other Treatment Options

for Amblyopia. . . . . . . . . . . . . . . . . . . . . . . . . . 1058.4.9 Recurrence of Amblyopia

Following Therapy . . . . . . . . . . . . . . . . . . . . . 1058.5 Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . 1068.5.1 The Impact of Amblyopia

Upon HRQoL. . . . . . . . . . . . . . . . . . . . . . . . . . . 1068.5.2 Stereoacuity and Motor Skills

in Children with Amblyopia. . . . . . . . . . . . . 1068.5.3 Reading Speed and Reading

Ability in Children with Amblyopia. . . . . . 106

xii Contents

8.5.4 Impact of Amblyopia Upon Education. . . . . . . . . . . . . . . . . . . . . . . . 106

8.5.5 Emotional Well-Being and Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

8.5.6 The Impact of Strabismus Upon HRQoL. . . . . . . . . . . . . . . . . . . . . . . . . . . 107

8.5.7 Critique of HRQoL Issues in Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . 108

8.5.8 The Impact of the Condition or the Impact of Treatment? . . . . . . . . . . . . 108

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

Chapter 9The Brückner Test Revisited

Michael Gräf

9.1 Amblyopia and Amblyogenic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

9.1.1 Early Detection of Amblyopia. . . . . . . . . . . 1139.1.2 Brückner’s Original Description . . . . . . . . . 1149.2 Corneal Light Refl exes

(First Purkinje Images) . . . . . . . . . . . . . . . . . . 1149.2.1 Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149.2.2 Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159.2.3 Shortcomings and Pitfalls . . . . . . . . . . . . . . 1159.3 Fundus Red Refl ex (Brückner Refl ex) . . . . 1159.3.1 Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1169.3.2 Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . 1199.3.3 Possibilities and Limitations . . . . . . . . . . . . 1209.4 Pupillary Light Refl exes. . . . . . . . . . . . . . . . . 1209.4.1 Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1219.4.2 Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . 1219.4.3 Possibilities and Limitations . . . . . . . . . . . . 1219.5 Eye Movements with Alternating

Illumination of the Pupils . . . . . . . . . . . . . . . 122 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Chapter 10Amblyopia Treatment 2009

Michael X. Repka

10.1 Amblyopia Treatment 2009 . . . . . . . . . . . . . 12510.1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 12510.1.2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . 12510.1.3 Clinical Features of Amblyopia . . . . . . . . . . 12610.1.4 Diagnosis of Amblyopia . . . . . . . . . . . . . . . . 12610.1.5 Natural History . . . . . . . . . . . . . . . . . . . . . . . . . 12710.2 Amblyopia Management . . . . . . . . . . . . . . . 12710.2.1 Refractive Correction . . . . . . . . . . . . . . . . . . . 12710.2.2 Occlusion by Patching. . . . . . . . . . . . . . . . . . 12810.2.3 Pharmacological Treatment

with Atropine . . . . . . . . . . . . . . . . . . . . . . . . . . 129

10.2.4 Pharmacological Therapy Combined with a Plano Lens. . . . . . . . . . . . 130

10.3 Other Treatment Issues . . . . . . . . . . . . . . . . . 13110.3.1 Bilateral Refractive Amblyopia . . . . . . . . . . 13110.3.2 Age Eff ect. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13110.3.3 Maintenance Therapy . . . . . . . . . . . . . . . . . . 13110.3.4 Long-Term Persistence of

an Amblyopia Treatment Benefi t. . . . . . . . 13210.4 Other Treatments . . . . . . . . . . . . . . . . . . . . . . 13210.4.1 Filters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13210.4.2 Levodopa/Carbidopa

Adjunctive Therapy . . . . . . . . . . . . . . . . . . . . 13310.5 Controversy. . . . . . . . . . . . . . . . . . . . . . . . . . . . 13310.5.1 Optic Neuropathy Rather than

Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

Chapter 11Best Age for Surgery for Infantile Esotropia: Lessons from the Early vs. Late Infantile Strabismus Surgery Study

H. J. Simonsz and G. H. Kolling

11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 13711.1.1 Defi nition and Prevalence . . . . . . . . . . . . . . 13711.1.2 Sensory or Motor Etiology . . . . . . . . . . . . . . 13711.1.3 Pathogenesis: Lack of

Binocular Horizontal Connections in the Visual Cortex. . . . . . . . . . . . . . . . . . . . . 138

11.1.4 History. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13811.1.5 Outcome Parameters . . . . . . . . . . . . . . . . . . . 13811.2 Outcome of Surgery in the ELISSS. . . . . . . 13911.2.1 Reasons for the ELISSS. . . . . . . . . . . . . . . . . . 13911.2.2 Summarized Methods of the ELISSS. . . . . 13911.2.3 Summarized Results of the ELISSS . . . . . . 14011.2.4 Binocular Vision at Age Six. . . . . . . . . . . . . . 14011.2.5 Horizontal Angle of

Strabismus at Age Six . . . . . . . . . . . . . . . . . . 14011.2.6 Alignment is Associated

with Binocular Vision . . . . . . . . . . . . . . . . . . . 14111.3 Number of Operations and

Spontaneous Reduction into Microstrabismus Without Surgery. . . . . . . 142

11.3.1 The Number of Operations Per Child and the Reoperation Rate in the ELISSS. . . . . . 142

11.3.2 Reported Reoperation Rates . . . . . . . . . . . . 14211.3.3 Test-Retest Reliability Studies . . . . . . . . . . . 14411.3.4 Relation Between the Postoperative

Angle of Strabismus and the Reoperation Rate. . . . . . . . . . . . . . . . . . . . . . . 145

11.3.5 Scheduled for Surgery, but no Surgery Done at the End of the Study at the Age of Six Years . . . . . . . . . . . . 145

Contents xiii

11.3.6 Spontaneous Reduction of the Angle. . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

11.3.7 Predictors of Spontaneous Reduction into Microstrabismus . . . . . . . . 146

11.3.8 Random-Eff ects Model Predicting the Angle and its Variation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

Chapter 12Management of Congenital Nystagmus with and without Strabismus

Anil Kumar, Frank A. Proudlock, and Irene Gottlob

12.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15412.1.1 Congenital Nystagmus with

and Without Sensory Defi cits . . . . . . . . . . . 15412.1.1.1 The Clinical Characteristics

of Congenital Nystagmus. . . . . . . . . . . . . . . 15612.1.2 Manifest Latent Nystagmus (MLN) . . . . . . 15712.1.2.1 Clinical Characteristics

of Manifest Latent Nystagmus (MLN). . . . 15712.1.3 Congenital Periodic Alternating

Nystagmus (PAN). . . . . . . . . . . . . . . . . . . . . . . 15812.1.3.1 Clinical characteristics

of congenital periodic alternating nystagmus . . . . . . . . . . . . . . . . . 159

12.2 Compensatory Mechanisms . . . . . . . . . . . . 16012.2.1 Dampening by Versions . . . . . . . . . . . . . . . . 16012.2.2 Dampening by Vergence . . . . . . . . . . . . . . . 16012.2.3 Anomalous Head Posture (AHP) . . . . . . . . 16012.2.3.4 Measurement of AHP. . . . . . . . . . . . . . . . . . . 16012.2.3.5 Eff ect of Monocular and

Binocular Visual Acuity Testing on AHP. . . . . . . . . . . . . . . . . . . . . . . . . 161

12.2.3.6 Testing AHP at Near . . . . . . . . . . . . . . . . . . . . 16212.2.3.7 The Eff ect of Straightening

the Head in Patients with AHP . . . . . . . . . . 16212.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16212.3.1 Optical Treatment . . . . . . . . . . . . . . . . . . . . . . 16212.3.1.1 Refractive Correction . . . . . . . . . . . . . . . . . . . 16212.3.1.2 Spectacles and Contact

Lenses (CL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16212.3.1.3 Prisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16312.3.1.4 Low Visual Aids. . . . . . . . . . . . . . . . . . . . . . . . . 16312.3.2 Medication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16312.3.3 Acupuncture . . . . . . . . . . . . . . . . . . . . . . . . . . . 16412.3.4 Biofeedback . . . . . . . . . . . . . . . . . . . . . . . . . . . 16412.3.5 Botulinum Toxin-A (Botox) . . . . . . . . . . . . . . 16412.3.6 Surgical Treatment of Congenital

Nystagmus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16412.3.6.1 Management of Horizontal AHP . . . . . . . . 165

12.3.6.2 Management of Vertical AHP . . . . . . . . . . . 16612.3.6.3 Management of Head Tilt. . . . . . . . . . . . . . . 16712.3.6.4 Artifi cial Divergence Surgery . . . . . . . . . . . 16712.3.6.5 Surgery to Decrease the

Intensity of Nystagmus . . . . . . . . . . . . . . . . . 168 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

Chapter 13Surgical Management of Dissociated Deviations

Susana Gamio

13.1 Dissociated Deviations . . . . . . . . . . . . . . . . . 17413.2 Surgical Alternatives to Treat

Patients with DVD . . . . . . . . . . . . . . . . . . . . . . 17513.2.1 Symmetric DVD with Good Bilateral

Visual Acuity, with No Oblique Muscles Dysfunction . . . . . . . . . . . . . . . . . . . 175

13.2.2 Bilateral DVD with Deep Unilateral Amblyopia . . . . . . . . . . . . . . . . . . . 175

13.2.3 DVD with Inferior Oblique Overaction (IOOA) and V Pattern . . . . . . . . 176

13.2.4 DVD with Superior Oblique Overaction (SOOA) and A Pattern . . . . . . . 177

13.2.5 Symmetric vs. Asymmetric Surgeries for DVD . . . . . . . . . . . . . . . . . . . . . . 178

13.2.6 DVD with Hypotropia of the Nonfi xating Eye . . . . . . . . . . . . . . . . . . . . . . . . 178

13.3 Dissociated Horizontal Deviation . . . . . . . 17913.4 Dissociated Torsional Deviation.

Head tilts in patients with Dissociated Strabismus . . . . . . . . . . . . . . . . . 180

13.5 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

Chapter 14Surgical Implications of the Superior Oblique Frenulum

Burton J. Kushner and Megumi Iizuka

14.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 18514.2 Clinical and Theoretical

Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . 18614.2.1 The Eff ect of Superior Rectus Muscle

Recession on the Location of the Superior Oblique Tendon Before and After Cutting the Frenulum. . . . . . . . . 186

14.2.2 The Eff ect of the Frenulum on Superior Oblique Recession Using a Suspension Technique. . . . . . . . . . 188

14.2.3 The Theoretical Eff ect of the Superior Oblique Frenulum on the Posterior Partial Tenectomy of the Superior Oblique . . . . . . . 189

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

xiv Contents

Chapter 15Pearls and Pitfalls in Surgical Management of Paralytic Strabismus

Seyhan B. Özkan

15.1 General Principles of Surgical Treatment in Paralytic Strabismus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

15.1.1 Aims of Treatment. . . . . . . . . . . . . . . . . . . . . . 19515.1.2 Timing of Surgery . . . . . . . . . . . . . . . . . . . . . . 19515.1.3 Preoperative Assessment . . . . . . . . . . . . . . . 19615.1.4 Methods of Surgical Treatment . . . . . . . . . 19715.2 Third Nerve Palsy. . . . . . . . . . . . . . . . . . . . . . . 19815.2.1 Complete Third Nerve Palsy . . . . . . . . . . . . 19815.2.2 Incomplete Third Nerve Palsy . . . . . . . . . . . 19915.3 Fourth Nerve Palsy . . . . . . . . . . . . . . . . . . . . . 20015.4 Sixth Nerve Palsy . . . . . . . . . . . . . . . . . . . . . . . 204 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

Chapter 16Modern Treatment Concepts in Graves Disease

Anja Eckstein and Joachim Esser

16.1 Graves Orbitopathy (GO): Pathogenesis and Clinical Signs. . . . . . . . . 207

16.1.1 Graves Orbitopathy is Part of a Systemic Disease: Graves Disease (GD) . . . . . . . . . . . 207

16.1.2 Graves Orbitopathy−Clinical Signs . . . . . . 20816.1.2.1 Clinical Changes Result in

Typical Symptoms. . . . . . . . . . . . . . . . . . . . . . 20816.1.3 Clinical Examination of GO . . . . . . . . . . . . . 20816.1.3.1 Signs of Activity . . . . . . . . . . . . . . . . . . . . . . . . 20816.1.3.2 Assessing Severity of GO . . . . . . . . . . . . . . . 20916.1.3.3 Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21116.1.4 Classifi cation of GO. . . . . . . . . . . . . . . . . . . . . 211

16.2 Natural History . . . . . . . . . . . . . . . . . . . . . . . . . 21216.3 Treatment of GO . . . . . . . . . . . . . . . . . . . . . . . 21316.3.1 Active Infl ammatory Phase . . . . . . . . . . . . . 21316.3.1.1 Glucocorticoid Treatment . . . . . . . . . . . . . . 21316.3.1.2 Orbital Radiotherapy . . . . . . . . . . . . . . . . . . . 21316.3.1.3 Combined Therapy: Glucocorticoids

and Orbital Radiotherapy. . . . . . . . . . . . . . . 21316.3.1.4 Other Immunosuppressive Treatments

and New Developments . . . . . . . . . . . . . . . . 21316.3.1.5 Therapy of Dysthyroid Optic

Neuropathy [DON] and Sight-Threatening Corneal Breakdown . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

16.3.1.6 Other Simple Measures that may Alleviate Symptoms . . . . . . . . . . . . . . . 214

16.3.2 Inactive Disease Stages. . . . . . . . . . . . . . . . . 21516.3.2.1 Orbital Decompression . . . . . . . . . . . . . . . . . 21516.3.2.2 Extraocular Muscle Surgery . . . . . . . . . . . . . 21616.3.2.3 Lid Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21716.4 Thyroid Dysfunction and GO. . . . . . . . . . . . 22016.4.1 Association Between Treatment of

Hyperthyroidism and Course of GO . . . . . 22016.4.2 Relationship Between

TSH-Receptor-Antibody (TRAb) Levels and Orbitopathy. . . . . . . . . . . . . . . . . 220

16.5 Environmental and Genetic Infl uence on the Course of GO . . . . . . . . . . 221

16.5.1 Relationship Between Cigarette Smoking and Graves Orbitopathy. . . . . . . 221

16.5.2 Genetic Susceptibility . . . . . . . . . . . . . . . . . . 22116.6 Special Situations . . . . . . . . . . . . . . . . . . . . . . 22216.6.1 Euthyroid GO . . . . . . . . . . . . . . . . . . . . . . . . . . 22216.6.2 Childhood GO. . . . . . . . . . . . . . . . . . . . . . . . . . 22216.6.3 GO and Diabetes . . . . . . . . . . . . . . . . . . . . . . . 222 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

Contributors

Kyle ArnoldiRoss Eye InstituteDepartment of Ophthalmology, University at Buff alo, Ross Eye Institute, 1176 Main Street, NY, 14209, USA

Michael C. BrodskyDepartments of Ophthalmology and Neurology, Mayo Clinic 200 First Street, SW Rochester,MN 55905, USA

Jill CarltonHealth Economics and Decision Science,CHARR, University of Sheffi eld, Regent Court,30 Regent Street, Sheffi eld,S1 4DA, UK

Carolyn Czoski-MurrayLeeds Institute of Health Sciences,University of Leeds,Room 1.26, 6 Charles Th ackrah Building,101 Clarendon Road,Leeds LS2 9LJ, UK

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

Anja EcksteinUniversity Eye Hospital, Hufelandstraβe 55, 45122 Essen, Germany

Marinus J.C. EijkemansDepartment of Public Health, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, Th e Netherlands

Julia FrickeDepartment of Ophthalmology, Kerpener Straβe 62,50937 Köln, Germany

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

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

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

Amy E. GreenbergDepartment of Ophthalmology, Mayo Clinic,200 First Street Southwest, Rochester, MN 55905, USA

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

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

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

A. S. Anil KumarDepartment of Ophthalmology,University of Leicester,UK

xvi Contributors

Burton J. KushnerDepartment of Ophthalmology and Visual Sciences,2870 University Avenue, Suite 206, Madison, WI 53705, USA

Birgit LorenzDepartment of Ophthalmology,Justus-Liebig-University GiessenGiessen CampusFriedrichstraβe 18, 35392 GiessenGermany

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

Antje NeugebauerDepartment of Ophthalmology, Kerpener Straβe 62, 50937 Köln, Germany

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

Frank A. ProudlockDepartment of Ophthalmology, Ricardo Gutiérrez Children’s Hospital, Buenos Aires, Argentina

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

Huibert J. SimonszDepartment of Ophthalmology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, Th e Netherlands

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

1.1 Introduction

Strabismus, or squint, is a disorder of ocular alignment. Th is overarching term may be further characterized by the direc-tion of the misalignment: the prefi x eso- describes an inward ocular deviation; exo-, an outward deviation; and hyper-, a vertical deviation. Descriptive suffi xes include -tropia, a manifest deviation in which fusional control is not present, and -phoria, a latent deviation that is controlled by fusion.

Strabismus detection, classifi cation, and treatment are especially important in pediatric populations as strabis-mus is a leading factor in the development of amblyopia, or a loss in visual function resulting from inadequate or abnormal visual system stimulation. Th is strong connec-tion with amblyopia diff erentiates pediatric from adult-onset strabismus, wherein vision and stereopsis are less likely to be irreversibly harmed. In children, strabismus should be corrected to decrease the occurrence of ambly-opia, to maximize the potential for stereopsis, and to straighten the visual axes of the eyes.

Th is chapter will review recent data on the epidemiol-ogy of pediatric strabismus. Th e information will focus

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 hypertro-pia, occurring in one of three esotropic children vs. 1 of 12 exo- or hypertropic children [5]. Th ere is no signifi -cant gender predilection among any of the following sub-types of childhood esotropia.

Epidemiology of Pediatric StrabismusAmy E. Green-Simms and Brian G. Mohney

Chapter 1

1

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 fi gure much smaller than once widely believed.Intermittent exotropia is the second most com- ■

mon form of childhood strabismus in the West

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 confi rms a more stable rate.

2 1 Epidemiology of Pediatric Strabismus

1

1.2.1.1 Congenital Esotropia

Congenital esotropia, also known as infantile or essential infantile esotropia, is generally defi ned as a neurologically intact child with a constant nonaccommodative esotropia that develops by 6 months of age. Th is term is oft en con-fusing 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 esotro-pia 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 popula-tion reported similar results, with infantile esotropia mak-ing up only 8.1% of all forms of esotropia [3].

1.2.1.2 Accommodative Esotropia

Accommodative esotropia is characterized by an acquired constant or intermittent deviation that is cor-rected or reduced 10 PD or more aft er wearing hyper-opic spectacles full time for at least 3 weeks. Patients can further be classifi ed 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 accom-modative 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]. Th is form of esodeviation has been reported to occur in 1 in 92 children [3].

1.2.1.3 Acquired Nonaccommodative Esotropia

Acquired nonaccommodative esotropia defi nes children whose deviation develops aft er 6 months of age and is not associated with accommodative eff ort. Th is subtype has typically been thought of as uncommon and as portend-ing underlying neurological disease. However, a recent population-based study showed that it is the second most common form of childhood esotropia [3], with an inci-dence of 1 in 257 children and is rarely the result of neu-rologic disease [8].

1.2.1.4 Abnormal Central Nervous System Esotropia

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

1.2.1.5 Sensory Esotropia

Sensory esotropia includes patients with a unilateral or bilateral ocular condition that prevents normal fusion. Th is 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].

Fig. 1.1 A child with esotropia

Summary for the Clinician

Accommodative esotropia comprises approxi- ■

mately 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 signifi cantly higher than in chil-dren with either exotropia or hypertropia.

1.2 Forms of Pediatric Strabismus 3

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 com-monly associated with exotropia than esotropia [5].

1.2.2.1 Intermittent Exotropia

Intermittent exotropia is an acquired, intermittent devia-tion of 10 or more PD unassociated with other ocular, paralytic, or neurologic disorders. It is the second most commonly diagnosed form of strabismus (at approxi-mately 17%) in the United States [1] and the most com-monly diagnosed subtype of exodeviation with an incidence of 1 in 155 children [9]. In a recent population-based study, it was reported to occur nearly twice as oft en 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 neuro-logic or other disorders and should undergo CNS imaging [11]. Th is form of exotropia results in amblyopia much more oft en than other subtypes of divergent strabismus.

1.2.2.3 Convergence Insuffi ciency

Convergence insuffi ciency describes children who are generally orthotropic at distance fi xation but whose eyes do not converge suffi ciently at near fi xation, leaving an

exodeviation at near. It is the second most commonly diagnosed type of exodeviation and comprises approxi-mately one in fi ve 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 symp-toms 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 devel-opmental 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 devel-opmental 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]. Th is diff er-ence 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 esotro-pia, whereas those with an acquired visual loss are much more likely to develop sensory exotropia [13].

1.2.3 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


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.

Fig. 1.2 A child with exotropia


1

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

1.3 Strabismus and Associated Conditions

A number of studies have demonstrated an association between prenatal and environmental factors and the devel-opment of strabismus. Signifi cant 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

1.4.1 Changes in Strabismus Prevalence

Our understanding of the prevalence of childhood stra-bismus continues to change. As discussed earlier, con-genital esotropia has recently been reported to occur less commonly than once widely believed, comprising only 8.1% of all diagnosed esodeviations [3]. Th e previously reported higher incidence of infantile esotropia may have

included children with CNS disorders or acquired nonac-commodative 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 treat-ment [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 prev-alent form of strabismus worldwide.

1.4.2 Changes in Strabismus Surgery Rates

Th ere 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 fre-quent 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 signifi cant change in the numbers of children diagnosed with infan-tile esotropia, and there was no signifi cant change in the number of surgeries performed on these children.

1.5 Worldwide Incidence and Prevalence of Childhood Strabismus

Recent reports describe the prevalence of pediatric stra-bismus as ranging from 0.12% in 1.5-year-old Japanese children [25] to 20.1% in a cohort of low birth weight


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 preva- ■

lent form of strabismus worldwide.Th e rate of pediatric strabismus surgery has recently ■

been reported to be in decline; however, data from a population-based cohort of children with con-genital esotropia in the United States found no change in strabismus incidence or surgical rate over a 30-year period (1965–1994).

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

b

a

1.5 Worldwide Incidence and Prevalence of Childhood Strabismus 5

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

Reference Categorical

descriptions

within the

study

Number

of

children

examined

Age of

subjects

(years)

Strabismus

prevalence

(%)

Esotropia

prevalence

(%)

Exotropia

prevalence

(%)

Hypertropia

prevalence

(%)

North America

Canada

[31] 946 1.6–11.6 4.3

[32] 1,074 <3 3.2 2.0 1.0 0.09

[33] 2,619 6 4.5 2.7 1.7 0.08

USA [34] Caucasian 306 6–7 1.6

Hispanic 548 6–7 0.9

[15] All races 39,227 0–7 4.5 3.2 1.2

Caucasian 17,931 0–7 5.4 4.1 1.3

African American 19,619 0–7 3.6 2.3 1.3

[35] 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

[27] 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

([3]a, [9]a, [14]a) Population-based 0–19 3.9 2.3 1.3 0.3

Mexico [36] 1,035 12–13 2.3 1.2 0.8 0.4

[37] 343 3–6 1.2 0.6 0.6Europe

England [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 0.1

Ireland [41] 1,582 8–9 4.0 3.4 0.6

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] 143 4–15 3.5 2.8 0.7

Croatia [47] All children 20,045 Unspecifi ed 4.0 2.1 1.8

Term 17,163 Unspecifi ed 3.3 1.7 1.6

Preterm 2,882 Unspecifi ed 8.0 4.7 3.3Australia

[20] 1,739 6 2.8 1.6 1.2 0

[48] 2,353 12 2.7c 0.9 1.1Asia

Malaysia [49] 650 8 2.2 0.2 1.8 0.2

[50] Near fi xation 4,634 7–15 0.7 0.5

Distance fi xation 4,634 7–15 0.7 0.6

(continued)


1

Table 1.1. (continued)

Reference Categorical

descriptions

within the

study

Number

of

children

examined

Age of

subjects

(years)

Strabismus

prevalence

(%)

Esotropia

prevalence

(%)

Exotropia

prevalence

(%)

Hypertropia

prevalence

(%)

China [51] Near fi xation 4,364 5–15 1.9 1.6

Distance fi xation 4,364 5–15 3.0 2.6

[52] 1,084 6–14 2.5 0.4 2.1

Japan [53] Study year 2003 86,531 6–12 1.3d 0.3 0.7

[54] Study year 2005 84,619 6–12 1.0e 0.2 0.6

[25] Five consecutive

measurements

between years

2000 and 2004

33,929 total 1.5 0.01–0.1 0–0.03 0–0.07

Five consecutive

measurements

between years

2000 and 2004

33,193 total 3 0.2–0.3 0.02–0.1 0.2–0.3

Taiwan [55] 862 6, 8, 11 1.6f 0.5 0.9

Th ailand [56] 3,898 1 0.6

India [57] 6,447 5–15 0.5 0.3 0.2 0.02

[58] 10,605 ≤15 0.4

Nepal [59] 1,100 5–16 1.6 0.09 1.5

[60] 1,816 5–16 1.3Middle East

Israel [61] 38,000 1–2.5 1.3 0.9 0.3 0.06

Oman [62] 6,292 6–7, 11–12 0.6 0.4 0.2

[63] 143,112 6–7 0.5Africa

Cameroon [64] 11,230 ≤26 1.2 0.5 0.8

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 0.5 0.3

aStudy of incidence rather than prevalencebStrabismus prevalence includes 19 cases of microtropiacStrabismus prevalence includes 16 cases of microtropiadStrabismus prevalence includes 245 cases of “unknown” and 20 cases of “other” types of strabismuseStrabismus prevalence includes 110 cases of “unknown” and 23 cases of “other” types of strabismusfStrabismus prevalence includes two cases of “other” strabismus

English children [26]. Prevalence studies, reporting on the number of people with a specifi c disease at a pre-scribed 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

specifi c period of time, may survey any number of char-acteristics 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 dif-fer based on racial and ethnic background. Esodeviations are found with a relatively higher prevalence among

References 7

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. Th is 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]. Th e basis of this diff erence may be in part linked with popula-tion-based diff erences in refractive error. Esotropia is commonly associated with hyperopia, whereas exotropia is more oft en diagnosed in children with myopia [28].

1.6 Incidence of Adult Strabismus

Although there is substantially less epidemiological infor-mation 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].

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5. Greenberg AE, Mohney BG, Diehl NN (2007) Prevalence of amblyopia in an incidence cohort of childhood strabis-mus. In: Transactions of the 31st meeting of the european strabismological association. Editor: Rosario Gomez de Liano. European Strabismological Association. DP- M-8797-2008. Madrid. Spain. Pg 51-54

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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 esotro-pia 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

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13. Havertape SA, Cruz OA, Chu FC (2001) Sensory strabismus – eso or exo? J Pediatr Ophthalmol Strabismus 38: 327–330

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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, Kifl ey A, et al (2006) Factors associated with childhood strabismus: fi ndings from a population-based study. Ophthalmology 113:1146–1153

21. Arora A, Williams B, Arora AK, et al (2005) Decreasing strabismus surgery. Br J Ophthalmol 89:409–412


Th e prevalence of strabismus subtypes varies ■

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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 eso-tropes in Hong Kong? Br J Ophthalmol 86:835–836

29. Beauchamp GR, Black BC, Coats DK, et al (2003) Th e management of strabismus in adults – I. clinical character-istics 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) Th e 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 immi-grant 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-year-old children in northern Mexico. J AAPOS 7:47–53

37. Juarez-Munoz, IE, Rodriguez-Godoy ME, Guadarrama-Sotelo ME, et al (1996) Frecuencia de trastornos oft almo-logicos 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 defi ned population of 2-year-old 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 clinical-statistical study on the prevalence of squint and associated signs in diff erent groups and ages of the Danish popula-tion [dissertation] Acta Ophthalmol 62(Suppl):1

43. Nordlow W (1964) Squint – the frequency of onset at dif-ferent 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 acu-ity, 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 evalua-tion. Acta Ophthalmol Scand 79:240–244

46. Gronlund MA, Andersson S, Aring E, et al (2006) Ophthalmological fi ndings 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, Kifl ey A, Mitchell P (2006) Factors associated with a previous diagnosis of strabismus in a population-based 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

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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 child-hood strabismus: Keelung Ann-Lo community ocular sur-vey 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 Th ai children, based on a prospective cohort study of Th ai children. J Med Assoc Th ai 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

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2.1 Binocular Alignment System

A vexing problem in the fi eld 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 pat-terns [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 under-lying mechanism involved in these changes, we may be able to better guide our research and improve the care we give to our patients. Th is chapter is intended to pro-vide some further insight to this predominant underly-ing mechanism that induces changes in strabismus, to a large extent, bilaterally. Th is does not refer to strabismus

in terms of the fi xation 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 bin-ocular 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 binocu-lar alignment in the long term. Th e fi rst is a neurologic one, “vergence adaptation,” and the second is a muscular one, “muscle length adaptation.”

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

David L. Guyton

Chapter 2

2

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 anesthe-sia, oft en 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,

which changes the lengths of the extraocular muscles bilaterally, is largely responsible for changes in the angle of strabismus over time.Th is mechanism helps explain the development of ■

(1) increasing “basic” deviations in accommoda-tive esotropia, (2) torsional deviations with appar-ent oblique muscle “overaction/underaction” and A and V patterns, (3) recurrent esotropia with early presbyopia, (4) occasional divergence insuf-fi ciency in presbyopes, and (5) basic cyclovertical deviations that mimic superior oblique muscle paresis.

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

12 2 Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation

2

2.1.2 Vergence Adaptation

Neurologically, retinal image disparity invokes a fusional vergence response which moves the eyes in opposite directions to eliminate the retinal image disparity, accu-rate to within a few minutes of arc, both horizontally and vertically. Th is is sometimes called “fast” fusional ver-gence. 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 stimu-lates changes in tonic vergence, or vergence tonus, over time [6]. Th is process is sometimes called “slow” ver-gence, or vergence adaptation. Vergence adaptation occurs selectively for diff erent directions of gaze and for diff erent 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, ver-tically, and torsionally [7]. Th e eff ects of vergence adap-tation 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]. Th is 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 ver-gence adaptation decays slowly, and with an exponential time course (cited in [10]). It has been studied exten-sively 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 signifi cantly eases the burden on sensorimotor fusion, leaving sensorimotor fusion free to fi ne-tune the align-ment of the eyes [6].

Vergence adaptation provides a tonic neural compen-sation 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 oft en try to uncover the underlying devia-tion by occluding one eye. For example, Lancaster red-green plots of incomitant strabismus with partial fusion oft en show best alignment in primary gaze, and in the reading position, those directions of gaze that are most used and, therefore, best adapted to. Aft er a 30-min patch test, the plotted tropia oft en increases in these directions

of gaze, with increased comitance of the overall pattern of deviation [13].

However, maximum neuronal fi ring rates impose lim-its 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 capabili-ties of neurologic adaptation. It is the process of muscle length adaptation that comes to the rescue.

2.1.3 Muscle Length Adaptation

Th e topic of muscle length adaptation does not appear in most texts on strabismus. Th e 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 innerva-tion, 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 addi-tion or subtraction of sarcomeres at the ends of the myofi brils, to maintain the proper overlap of the actin and myosin myofi laments so as to obtain optimal force generation, velocity, and power output over the range of motion through which the muscle is most used [17]. Th e 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 exo-tropic position of approximately 30 prism diopters. Aft er 2 months, when the basic lengths of the extraocular mus-cles were examined, the medial rectus muscle had gained sarcomeres, and the lateral rectus muscle had lost sar-comeres in the experimental animal, compared with con-trol animals operated in the same manner and sacrifi ced immediately.

Change in skeletal muscle length is not only respon-sive to the position in which the muscle is held, but also, and most importantly, in the case of the extraocular mus-cles, to the stimulation that it receives. If a muscle is not

2.2 Modeling the Binocular Alignment Control System 13

held in a stretched position, increased stimulation causes actual loss of sarcomeres with shortening of the basic muscle length [15, 16, 19]. Th is change in basic muscle length in response to the level of stimulation is precisely in the right direction to help maintain binocular align-ment. 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 extraocu-lar muscle length adaptation.

Th is 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 ver-gence 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 feed-back process also works in the direction to ease the bur-den on the level that precedes it. Vergence adaptation frees up fast fusional vergence to be able to respond accu-rately to rapid changes in retinal image disparity. Muscle length adaptation relieves vergence adaptation of exces-sive demands, which would otherwise saturate neuronal fi ring rates, and thereby eff ectively resets vergence adap-tation so that it can continue to function optimally in response to input from fast fusional vergence.

2.2 Modeling the Binocular Alignment Control System

Th e basic components are now in place to model the bin-ocular 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 binocu-lar 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 eff ect, or simply a switch of the object of regard from the computer screen to the bird out the window. Such a perturbation requires diff erent 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. Th is yields new functional muscle lengths in the proper direc-tion 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 hap-pens. 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 mecha-nisms can now be maximally responsive to the next perturbation.

Th is is the normal functioning of the long-term (as well as short-term) binocular alignment control system. Th is 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 direc-tions of gaze, and throughout the development of presby-opia, which would otherwise cause a signifi cant disruption of near vs. distance alignment.

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 Th ree-level dynamic feedback system for the mainte-nance of binocular alignment


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2.2.1 Breakdown of the Binocular Alignment Control System

However, what happens when something goes wrong with this feedback system? Surely it is possible that abnor-malities can be present, or can develop, at various levels within this system, any of which will lead to misalign-ment of the eyes. Th e most common abnormality is prob-ably 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 adapta-tion [20], and muscle length adaptation [4] become free-wheeling – in other words, without guidance.

Neurologic feedback mechanisms do not necessarily shut off when their input disappears. Th ey will oft en con-tinue to function at a basal level, with a low level of out-put being generated. Th is 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, produc-ing strabismus that was not there in the fi rst place, or causing progressive misalignment if strabismus was already present.

A prime example of this mechanism is the phenome-non 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 drift s 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 pre-viously maintained alignment equilibrium) will shift slightly to less convergence and more divergence, actively driving the eyes into a position of exotropia. Th is sensory exotropia can thus be seen to be not a passive process aft er all, but an active driving of the eyes outward by the otherwise normal alignment mechanisms that have lost proper guidance.

2.2.2 Clarifi cation of Unanswered Questions Regarding the Long-Term Binocular Alignment Control System

Th e description of the above-mentioned three-stage feed-back 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 fi rst described by the author in a paper in Binocular Vision and Eye Muscle Surgery Quarterly in 1994 [4], with further elaboration in 2005 [21]. Th e 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 feed-back to the torsional control mechanism would be expected to produce what we dubbed “sensory torsion,” leading to the development of what is probably errone-ously called primary oblique muscle overaction, or under-action, with accompanying A- or V-pattern strabismus.

It was not clear in 1994, however, whether extraocular muscle length adaptation responds to version stimula-tion. Th at 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 obser-vations have clarifi ed these questions. Th ese observations, the resulting clarifi cation, and the consequences to our understanding of strabismus are expected benefi ts from this chapter.

2.2.3 Changes in Strabismus as a Bilateral Phenomenon

Th e primary new observation of the author is that changes in strabismus occur, to a large extent, bilaterally. Th is is not speaking of strabismus in terms of the fi xation pat-tern, 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 fi x-ing, 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 oft en both the eyes turn out. Figures 2.2–2.4 show examples of this bilateral phenomenon in patients with sensory exotropia.

Th is observation was fi rst made by the author 25 years ago aft er a recess-resect procedure on a patient with sen-sory exotropia. Th e 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 signifi cantly. Th e muscle changes that caused the original sensory exotropia had occurred bilaterally. Arthur Jampolsky [22] reported this phenomenon in 1986, but he off ered no explanation for it.


Th ere is more evidence that changes in strabismus occur bilaterally over time. Infants with esotropia and amblyopia, where the amblyopic eye is practically con-stantly 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 abnor-mally tight. Th ey are both abnormally short. Th ese children sometimes show a small head turn, fi xing 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 fi xation.

Th ere is still further evidence that changes in strabis-mus occur bilaterally. Th e torsional changes that are asso-ciated 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.

2.2.4 Changes in Basic Muscle Length

Th ese 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 nor-mal, and a basically long muscle has more sarcomeres than normal. As noted before, skeletal muscles are con-tinually changing their basic lengths throughout life, by the serial addition or subtraction of sarcomeres, for opti-mal 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 exotro-pia turn out under general anesthesia, signifi cantly more than the usual divergence seen under anesthesia. Th ere must be another mechanism that causes basic muscle

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

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


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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. Th ey are heav-ily bilaterally innervated. Th ey are linked in versions, movements of the two eyes in the same directions, and in vergences, movements of the two eyes in opposite direc-tions. Versions allow us to look in diff erent directions, while vergences allow us to change our gaze from dis-tance to near. However, vergences also, and most impor-tantly, fi ne-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

response which moves the eyes in opposite directions to eliminate image disparity, accurate to within a few min-utes of arc, both horizontally and vertically.

Might one of these types of stimulation, version stim-ulation or vergence stimulation, be involved in the regu-lation 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 eff ect 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 bin-ocular alignment. Th e 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,

Fig. 2.4 Th irty-eight-year-old man aft er a right optic nerve injury 15 years before, with resulting blindness in his right eye. Th e fi xing left eye (top) turns out abnormally under anesthesia (bottom), but not as much as the blind right eye. Not every patient turns out equally

Fig. 2.5 Th irty-four-year-old woman with esotropia since childhood with fi xation with her left eye only (top), for many years. Both eyes turn in signifi cantly under anesthesia (bottom)


can indeed serve as the necessary and suffi cient 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 ver-gence stimulation and not to version stimulation. As both vergence stimulation and version stimulation occur, both could be slowly stimulating muscle length adaptation. However, the eff ect of the version stimulation would average out to zero over time. Th e vergence stimulation, on the other hand, would exert a net eff ect, changing the basic muscle lengths in the directions necessary to reduce the need for the vergence stimulation in the fi rst place – a marvelous nega-tive-feedback servomechanism, as pointed out previously.

Th e mechanism just proposed would work in the nor-mal situation, but there is strong evidence from what hap-pens in strabismic states that extraocular muscle length adaptation responds to vergence stimulation primarily, and only minimally to version stimulation. And that is a fundamental diff erence between extraocular muscles and the other skeletal muscles. Th e 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.

Th e argument is this: In constant strabismic states where there is no fusion, there is no signifi cant 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.

Th e 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 sen-sory 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.

Th e position of the eyes when asleep probably has little or no eff ect 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 signifi cantly slows down muscle length adaptation, as shown by den-ervation experiments [19].

Figure 2.6 shows a patient illustrating the ineff ective-ness of version stimulation. Th e muscle lengths clearly did not adapt to the positions in which the eyes were held by chronic everyday version stimulation.

Th erefore we must conclude that the stimulation from vergence tonus is the primary regulator of extraocular muscle length adaptation, and that its eff ects are bilateral. In this regard, the regulation of the extraocular muscle lengths appears to be fundamentally diff erent from the regulation of the lengths of other skeletal muscles. Only the extraocular muscles experience this bilateral vergence stimulation. Th e 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”

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

Fig. 2.6 Th irty-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 fi xed 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. Th e muscle lengths clearly did not adapt in response to chronic everyday version stimulation


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muscle length adaptation, and that its eff ects are bilateral. Neurophysiologists, with few exceptions [25], have long believed that version and vergence stimulation, while arising in diff erent centers in the brainstem, are com-bined into a “fi nal common pathway” at the motoneu-rons 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 indis-tinguishable by the time the impulses reach the extraoc-ular muscles. If that were the case, extraocular muscle length adaptation could not be preferentially responsive to vergence stimulation. Recent evidence suggests, how-ever, that version and vergence signals may indeed remain segregated in the motor nerves and stimulate dif-ferent fi ber types in the extraocular muscles [28, 29]. It is tempting to speculate that those fi ber 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 demon-strating that measured extraocular muscle tension shows discrepancies with electrical activity [30]. Th ese observa-tions argue against the fi nal common pathway concept and at least allow the thesis that vergence tonus is primar-ily 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 exotro-pia. Th e 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, verti-cal deviations, or torsional deviations. Th e many diff er-ent ways that strabismus can change over time, if linked to changes in vergence tonus, require a more general explanation.

Th e 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 oper-ate, retinal image disparities do not result in corrective vergences. In this case, the fusional vergence control mechanisms for horizontal, vertical, and torsional align-ment probably do not shut down entirely, but rather decrease their outputs to small nonzero levels, with per-sistent weak vergence signals biased in one direction or the other, with the direction of this bias depending upon numerous factors.

For example, young children oft en have a stronger convergence bias than divergence bias, as evidenced by the relative frequency of esotropia vs. exotropia in infancy. Th is 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 non-zero 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 pri-marily or from horizontal misalignment early in life, a baseline output bias in the torsional alignment mecha-nism can drive the eyes into torsional misalignment with apparent oblique muscle dysfunction and accompanying A and V patterns. Th e torsion is oft en seen at fi rst only when awake, disappearing when under anesthesia [31]. Later, as the oblique muscle lengths change, the fundus torsion persists under anesthesia [32]. Still later, aft er soft tissue remodeling occurs in response to the chronic ocu-lar torsion (the author’s interpretation), the eyes move more along the torted planes defi ned by the muscle inser-tions, showing clinical oblique muscle “overaction” (ele-vation or depression in adduction), and on MRI studies, the connective tissue “pulleys” may be seen to have shift ed [33] (the author’s interpretation).

Furthermore, a baseline output bias in the cycloverti-cal alignment mechanism can drive the eyes into a basic

2.3 Changes in Strabismus 19

cyclovertical misalignment, a cyclovertical misalignment which we oft en 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 fi rst place. An abnormality in vergence adaptation has been proposed to cause divergence insuffi ciency 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 progres-sive esotropia, which we would call congenital esotropia. Alternatively, a higher than normal AC/A ratio [35] could strain fusion suffi ciently 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 ini-tial problem, but as fusion deteriorates, the feedback-deprived 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. Th is 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 syn-drome 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 eff ects of muscle length adaptation in the short term, but will simply reduce the eff ects of vergence adaptation over an exponential time course. Th irty to forty-fi ve 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, eliminat-ing 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 advo-cated occlusion for 7–10 days to fully uncover latent

deviations [39–41]. By careful study of Marlow’s published graphs [40], it is apparent that aft er 3–5 days of monocular occlusion, signifi cant changes in the monitored deviations oft en began to appear, and worsen. For example, hyperde-viations and torsional deviations began to appear when there had been none previously. Also, the occluded eye most oft en developed a hyperdeviation, regardless of which eye was covered, speaking against the uncovering of a latent hyperdeviation [42–44]. Rather than the uncover-ing 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. Th e 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 aft er 7 days of monocular occlusion of the monkeys and aft er 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. Th e contralateral rectus muscle does not shorten concomitantly. Th is represents unilat-eral muscle length adaptation, but from a diff erent 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]. Th is 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 con-trol of muscle lengths? We have previously demonstrated that patients with consecutive esotropia following surgery for intermittent exotropia oft en develop intorsion or extorsion of the eyes, with accompanying oblique muscle overaction and A or V patterns, aft er having lost fusion for only 1 month [4, 49]. We attribute this to a type of “sensory torsional” deviation due to muscle length adap-tation in the torsional dimension.


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Weldon Wright, Katie Gotzler, and the author have recently collected a large series of patients with early pres-byopia, mostly with defi cient or absent fusion, who have developed progressive esotropia probably from the increased convergence tonus accompanying the increas-ing eff ort 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 popula-tion showed a signifi cantly increased onset of esotropia in their 30s and 40s, as expected [21]. Th is 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 fi rst described by Costenbader [52].

Elizabeth Bell, Adam Bowen, and the author have also identifi ed a series of presbyopic patients, aged 50 years and older, who either had a small amount of uncor-rected hyperopia, or who oft en tried to function without needed correction for near, and developed divergence insuffi ciency in the later decades of life. Th ey had inter-mittent or constant esotropia in the distance with diplo-pia, but could still fuse at near. Th ey are best corrected by bilateral medial rectus muscle recessions [53, 54], with the fi nding 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 short-ened medial rectus muscles and the characteristic pat-tern of divergence insuffi ciency. Of interest is that the presbyopic patients identifi ed with uncorrected or undercorrected hyperopia showed a somewhat linear increase of distance esotropia with the amount of hyper-opia (Bell, Bowen, and Guyton, unpublished).

In the cyclovertical “plane,” which is not really a plane aft er all, we have long suspected that there should be a thing such as a basic cyclovertical deviation, an analog of straight-forward 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. Th e vast majority of idiopathic cyclover-tical 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 char-acteristics.” Might there be no superior oblique paresis at all in these patients? Aft er 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 stra-bismus that they can create in normal subjects. Th ey have constructed a special haploscope that allows adaptation to increasing vertical, torsional, or horizontal disparities, with near fi xation, with fi elds of view of over 50°, utilizing video-oculography for recording. Th e entire apparatus can tilt, up to 45°, to the right or left .

To confi rm 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 dis-parities increasing to 6° for 30–45 min. With adaptation, we expect to fi nd that the hyperdeviations induced are accompanied by torsional changes, and that the patterns of misalignment induced, especially with forced head tilt-ing, will help explain the patterns that heretofore have been associated with what is called congenital superior oblique paresis.

Th e fi rst 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 Roll10

Right Eye

Left Eye

Clo

ckw

ise[

deg

]C

ou

nte

rclo

ckw

ise

5

0

–5

–10STR RHT

50 100time [s]

150

STR LHT

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 21

vertical disparity. Th is arrangement simulated a relative right hyperdeviation, because the right eye had to move downward to fuse, and the left eye had to move upward. Aft er adaptation, the relative positions of the eyes were measured in the fusion-free, dissociated state. Th e eyes had partially adapted to the simulated relative right hyperdeviation by developing a measured right hypode-viation. Th e 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). Th ese 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. Th is increased tonus was produced by vergence adaptation to the rela-tive right hyperdeviation. Th e deviations recorded sim-ply represent a basic cyclovertical deviation induced in a normal subject by vergence adaptation to a vertical disparity.

Th e demonstration of such head-tilt changes accom-panying the induced cyclovertical deviation is in favor of the belief that many deviations currently called con-genital 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 congeni-tal and acquired forms of apparent superior oblique paresis.

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

Practically speaking, the consequences of muscle length adaptation are oft en best appreciated under deep general anesthesia, when the anatomic positions of the eyes can be seen and careful forced ductions can be performed. Th e decision about which eye or eyes to operate on, and which muscles, may best be postponed until obtaining these intraoperative fi ndings. Th is 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 eff ec-tive 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 fi eld of strabismus to wait for stabilization of the angle of deviation before intervening surgically. However, the consequences of unguided vergence adaptation and muscle length adapta-tion suggest a revision of this teaching. If there is poten-tial for fusion, it now appears that every eff ort should be made to realign the eyes without delay, using glasses, prisms, and surgery when necessary, and not wait for sta-bilization. Waiting for stabilization may actually be harm-ful 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 per-sists. On the other hand, if fusion potential is truly not present, early surgery may best be postponed. Th e 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 refl ected by stability of the deviation, may indeed be warranted in such cases. Th e challenge, therefore, lies in the accurate determina-tion 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 mea-sure 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 aft er we have achieved it.

For example, selective activation of vergence should be able to change not only vergence adaptation, but also

Right tilt

Vertical Difference R-L10

Do

wn

Up

[deg

]

5

0

5 10time [s]

15

–5

–10

Left tilt

Fig. 2.8 Vertical recordings, with head straight and tilted 45° to either side, aft er 45 min of adaptation, with head straight, to a left -over-right vertical disparity of 50+° fi elds of concentric cir-cles. Th e relative positions of the two eyes are shown in the fusion-free, dissociated state. Th e negative values correspond to the induced right hypodeviation


2

muscle lengths over time. Th is 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 stimu-lation used in orthopedic applications to correct or pre-vent scoliosis as well as contractures in cases of hemiplegia or cerebral palsy [65]. To do this, we shall need to dis-cover the diff erences between version and vergence stim-ulation of the extraocular muscles so as to be able to supply vergence stimulation selectively. To be sure, cor-rection of strabismus in the future may possibly be by selective electrical stimulation rather than by surgery.

References

1. Guyton DL (2006) Th e 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 fol-lowing prolonged wearing of prisms. Am J Optom Arch Am Acad Optom 42:141–152

7. Taylor MJ, Roberts DC, Zee DS (2000) Eff ect 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 move-ments. Am J Optom Arch Am Acad Optom 27:8–20

9. Cooper J (1992) Clinical implications of vergence adapta-tion. Optom Vis Sci 69:300–307

10. Schor CM (1979) Th e relationship between fusional ver-gence eye movements and fi xation 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 binocu-lar vision? Doc Ophthalmol 47(1):163–199

13. Hwang J-M, Guyton DL (1999) Th e Lancaster red-green test before and aft er occlusion in the evaluation of incomi-tant 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 mechan-ics of strabismus symposium. Th e 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) Th e 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 expres-sion in response to muscle stretch. In: Clinical orthopae-dics and related research. Lippincott Williams and Wilkins, Philadelphia No. 403S, pp S146–S152

18. Scott AB (1994) Change of eye muscle sarcomeres accord-ing to eye position. J Pediatr Ophthalmol Strabismus 31:85–88

19. Hayat A, Tardieu C, Tabary J-C, Tabary C (1978) Eff fects of denervation on the reduction of sarcomere number in cat


At least a three-level feedback control system ■

exists for the maintenance of binocular align-ment. Of particular interest is the unique regula-tion 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 so-called 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 specula-tion, models such as those formulated here can help in the understanding of not only how stra-bismus 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 23

soleus muscle immobilized in shortened position during seven days. J Physiol (Paris) 74:563–567

20. Schor CM, Maxwell JS, Graf EW (2001) Plasticity of con-vergence-dependent variations of cyclovergence with ver-tical gaze. Vis Res 41:3353–3369

21. Wright WW, Gotzler KC, Guyton DL (2005) Esotropia associated with early presbyopia caused by inappropriate muscle length adaptation. J AAPOS 9:563–566

22. Jampolsky A (1986) Treatment of exodeviations. In: Pediatric ophthalmology and strabismus, trans new orleans acad ophthalmol. Raven, New York, pp 201–234

23. Gonzalez C, Jaros PA (1988) Strabismus surgery on the nonamblyopic eye. Graefe’s Arch Clin Exp Ophthalmol 226:304–308

24. Breinin GM (1957) Th e position of rest during anesthesia and sleep. AMA Arch Ophthalmol 57:323–326

25. Jampel RS (1967) Multiple motor systems in the extraocu-lar muscles of man. Invest Ophthalmol 6:288–293

26. Keller EL, Robinson DA (1971) Absence of a stretch refl ex in extraocular muscles of the monkey. J Neurophysiol 34:908–919

27. Scott AB, Collins CC (1973) Division of labor in human extraocular muscle. Arch Ophthalmol 90:319–322

28. Eberhorn AC, Büttner-Ennever JA, Horn AKE (2005) Identifi cation of motoneurons supplying multiply- or sin-gly-innervated extraocular muscle fi bers in the rat. Neuroscience 137:891–903

29. Büttner-Ennever JA (2006) Th e extraocular motor nuclei: organization and functional neuroanatomy. Prog Brain Res 151:95–125

30. Miller JM (2003) No oculomotor plant, no fi nal common path. Strabismus 11:205–211

31. Guyton DL (1984) Discussion of Paez JH, Isenberg S, Apt L: torsion and elevation under general anesthesia and dur-ing voluntary eyelid closure (Bell phenomenon). J Pediatr Ophthalmol Strabismus 21:78

32. Eustis HS, Nussdorf JD (1966) Inferior oblique overaction in infantile esotropia: Fundus extorsion as a predictive sign. J Pediatr Ophthalmol Strabismus 33:85–88

33. Clark RA, Miller JM, Rosenbaum AL, Demer JL (1998) Heterotopic muscle pulleys or oblique muscle dysfunc-tion? J AAPOS 2:17–25

34. Schor C, Horner D (1989) Adaptive disorders of accom-modation and vergence in binocular dysfunction. Ophthal Physiol Opt 9:264–268

35. von Noorden GK (1988) Current concepts of infantile esotropia. Eye 2:343–357

36. von Noorden GK (1976) Th e nystagmus compensation (blockage) syndrome. Am J Ophthalmol 82:283–290

37. Guyton DL (2000) Dissociated vertical deviation: etiol-ogy, mechanism, and associated phenomena. J AAPOS 4:131–144

38. Ciancia AO (1995) On infantile esotropia with nystag-mus 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 occlu-sion test. Am J Ophthalmol 10:567–574

41. Marlow FW (1938) A tentative interpretation of the fi nd-ings 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 occlu-sion 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) Th e pattern of changes produced in the saccadic system and vestibuloocular refl ex by visually patching one eye. J Neurophysiol 57: 92–103

46. Liesch A, Simonsz HJ (1993) Up-and downshoot in adduc-tion aft er 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. Th e Smith-Kettlewell Eye Research Institute, San Francisco, pp 19–40

48. Castañera de Molina A, Giñer Muñoz ML (1997) Short-stiff extraocular muscles: Mechanisms involved in EOM adaptations to squint. In: Prieto-Diaz J, Hauviller V (eds) XII Congreso del Consejo Latinoamericano de Estrabismo (CLADE). Grafi ca 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. Th omas AH (2000) Divergence insuffi ciency. J AAPOS 4:359–361

54. Bothun ED, Archer SM (2005) Bilateral medial rectus mus-cle recession for divergence insuffi ciency pattern esotropia. J AAPOS 9:3–6

55. Sheedy JE, Saladin JJ (1975) Exophoria at near in presby-opia. Am J Optom Physiol Optics 53:474–481


2

56. Enright JT (1992) Unexpected role of the oblique muscles in the human vertical fusion refl ex. 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 reso-nance imaging. In: Lennerstrand G (ed) Update on stra-bismus and pediatric ophthalmology. CRC, Boca Raton, pp 303–306

60. Sato M, Amano E (2003) Clinical fi ndings and surgical results of true and masquerading congenital superior oblique palsy. In: de Faber J-T (ed) Progress in strabismology. Swets and Zeitlinger, Lisse, Th e 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) Th e use of (a)symmetry of the rest position of the eyes under general anesthesia or sedation-hypnosis in the design of strabis-mus 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 bin-ocular vision aft er 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 treat-ment. Disabil Rehabil 23:549–558

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 bal-ance of visual input to the two eyes [4]. Th ese movements arise almost exclusively in the setting of infantile strabis-mus [5], which has a strong predilection for esotropia over exotropia. Dissociated vertical divergence, latent nystagmus, and dissociated horizontal deviation repre-sent 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]. Th is time-honored notion assumes a distinct and unre-lated pathogenesis for infantile esotropia. It is equally possible, however, that infantile esotropia arises from an unrecognized form of dissociated deviation known as dissociated esotonus.

3.2 Tonus and its relationship to infantile esotropia

Tonus refers to the eff ects 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 physio-logic 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 exo-phoria 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. Th us, while convergence functions to actively alter hori-zontal eye position, tonus eff ectively resets the baseline eye position.

When superimposed upon a baseline orthoposition, dissociated esotonus manifests as an intermittent esotro-pia 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 associ-ated with a paradoxical esodeviation when the nonpre-ferred eye is used for fi xation (Figs. 3.2 and 3.3) [11–17]. Th ese variants of intermittent exotropia are known as dissociated horizontal deviation. Th e clinical features

A Dissociated Pathogenesis for Infantile EsotropiaMichael C. Brodsky

Chapter 3

3

Core Messages

Binocular movements that result from unequal ■

visual input to the two eyes are defi ned as dissociated.Dissociated esotonus, an unrecognized form of ■

binocular dissociation, underlies dissociated hor-izontal deviation.

Because dissociated eye movements arise in the ■

setting of infantile strabismus, they have tradi-tionally been considered to be the result of dis-rupted binocular vision.Dissociated eye movements may be the cause, ■

rather than the eff ect, of infantile esotropia.


Dissociated eye movements include dissociated ■

vertical divergence, latent nystagmus, and disso-ciated horizontal deviation.

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 sum-marized in Table 3.1.

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 inter-mittent exotropia diagnostically, it is ultimately a descrip-tive term that includes a variety of diff erent conditions with specifi c diagnostic implications. Th e 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 oft en coexist, and perhaps acknowl-edging 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


Tonus ■ determines the contractile state of extraoc-ular musculature under baseline conditions.Physiologic tonus maintains normal binocular ■

alignment.

3.3 Esotropia and Exotropia as a Continuum 27

actually results from intermittent fusional control of a large baseline exodeviation [23, 24].

When intermittent exotropia is associated with dis-sociated horizontal deviation, fi xation with either eye superimposes dissociated esotonus on the base-line exodeviation to produce a variable intermittent

exodeviation (Figs. 3.2 and 3.3) [6–8]. Th e 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 inter-mittent 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 fi xating eye (i.e., asymmetrical)

Amplitude of exodeviation is independent of the fi xating 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 fi xation test Negative reversed fi xation test

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


3

functions as an open-loop process without reference to ultimate binocular alignment in dissociated horizontal deviation). Because fi xation with the nonpreferred eye exerts greater esotonus [6–8], the baseline exodevia-tion can be unilateral, asymmetrical, or associated with a paradoxical esotropia when the nonpreferred eye is used for fi xation.

Infantile esotropia and intermittent exotropia are uni-versally regarded as distinct forms of strabismus that occupy opposite points on a clinical spectrum. In con-trast 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 fi rst glance, it is diffi cult to imagine how these diametrical forms of horizontal misalignment are not mutually exclusive.

Th e 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 fi nal eye position. Dissociated esotonus can still be expressed from an exodeviated position, because it is generated by unbalanced binocular input that exerts its infl uence upon any baseline deviation. Consequently, intermittent exotropia is a common clinical manifesta-tion of dissociated esotonus. Mechanistically, there is nothing sacred about orthotropia as a clinical demarca-tion, and nothing signatory about the direction of hori-zontal misalignment.

In this light, dissociated horizontal deviation is trans-formed from a clinical curiosity to a fundamental piece of the puzzle for understanding horizontal strabismus. Th e 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 oft en accom-panied by dissociated eye movements such as latent nys-tagmus and dissociated vertical divergence [26, 27]. Some infants exhibit an intermittent form of exotropia with other dissociated eye movements [28], suggesting a com-ponent of dissociated horizontal deviation. Patients with primary dissociated horizontal deviation also display an intermittent exodeviation of one or both eyes with disso-ciated ocular signs [13].

All of these conditions share a common pathophysi-ology wherein dissociated esotonus is superimposed upon a baseline exodeviation to produce an intermit-tent exodeviation, which varies in size depending upon which eye is used for fi xation. In patients without bin-ocular fusion, dissociated esotonus can cause a constant exodeviation to appear intermittent. In patients who

retain binocular fusion, it can produce a combined clin-ical picture of intermittent exotropia (with intermittent fusion), an asymmetrical exodeviation of the two eyes, or an exodeviation of the nonpreferred eye with a para-doxical esodeviation of the preferred eye. In classifying these disorders pathogenetically, it becomes critically important to distinguish sensory motor factors from the diff erent forms of ocular misalignment that they ultimately produce. Dissociated horizontal deviation shows us how it is only the resultant horizontal devia-tions, and not the underlying conditions, that are dia-metrically opposed.

3.4 Distinguishing Esotonus from Convergence

Th ere remains the unfortunate tendency in the strabis-mus literature to confl ate esotonus of the eyes as a base-line 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]. Th e importance of this distinction lies in the understanding that conver-gence implies a deviation from baseline under normal conditions of sensory input, whereas tonus implies a return to baseline under altered conditions of sensory input. Th e distinction between convergence (the eff ect) and monocular esotonus (the cause) lies at the heart of understanding infantile esotropia. Horwood and col-leagues have recently shown that normal infants display fl eeting, large-angle convergent eye movements during the fi rst 2 months of life, and that these convergent movements are ultimately predictive of normal binocu-lar alignment [30]. By contrast, infantile esotropia tends to increase over the period when this excessive conver-gence is disappearing in normal infants [31]. Th is time course challenges the dubious assumption that infantile esotropia arises from excessive convergence output. Our fi nding 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 “con-vergent” position.


Dissociated esotonus can be superimposed upon ■

the baseline position of the eyes to produce intermittent esotropia or intermittent exotropia.

3.5 Pathogenetic Role of Dissociated Eye Movements in Infantile Esotropia 29

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 ori-gin) [25, 32]. Furthermore, the eyes do not simply snap in to their fi nal esotropic position. Before 12 weeks of age, nascent infantile esotropia is an intermittent, variable esodeviation that gradually becomes constant aft er build-ing in intensity to a large, fi xed-angle of horizontal mis-alignment [32, 33]. Ing has noted that 50% of patients with infantile esotropia show an increase in the measured angle between the time of fi rst 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. Th at this esodeviation appears during the early period when stereopsis is developing, but before macular anatomy has matured suffi ciently 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 pro-duced by increased accommodative eff ort in the presby-ope) 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 condi-tions [36]. Muscle length adaptation refers to the change in extraocular muscle length due to gain or loss of sar-comeres. Muscle length adaption is driven in part by the physiologic eff ects of vergence adaptation.

Dissociated esotonus may provide the sensorimotor substrate for vergence adaptation when binocular cortical control mechanisms fail to take hold. Th e fi nding of a pos-itive Bielschowsky phenomenon in dissociated horizontal deviation [15, 17] shows that peripheral luminance refl exes are retained, as in dissociated vertical divergence [37]. In this setting, both peripheral (luminance and optokinetic)

and central (fi xational) refl exes augment dissociated eso-tonus, and lead over time to infantile esotropia. Subcortical visual refl exes would provide the default system through which dissociated esotonus operates to re-establish the baseline horizontal eye position. Th is process can ulti-mately lead to loss of sarcomeres and secondary shorten-ing of the medial rectus muscles. Th e 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 eff ects play a secondary role in its pathogenesis. It is possible that stable, large-angle esodeviation that we recognize as infan-tile esotropia simply represents the fi nal stage of dissoci-ated 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 dis-sociated eye movements that accompany infantile esotropia [18]. Patients with unilateral congenital cata-ract oft en develop large-angle esotropia, latent nystag-mus, dissociated vertical divergence, and a head turn to fi xate in adduction with the preferred eye [18]. By con-trast, early infantile esotropia is oft en characterized by similar visual acuity in the two eyes, and with alternat-ing suppression of the nonfi xating eye. So perhaps dis-sociated horizontal deviation is not an epiphenomenon of infantile esotropia, but a “footprint in the snow” of the horizontal tonus imbalance that is actually respon-sible for its inception.

Acknowledgment Portions of this chapter have previ-ously 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 fi gures 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].


Since large convergent movements in early ■

infancy are predictive of normal binocular align-ment, infantile esotropia does not result from excessive convergence.


Dissociated esotonus may provide the physio- ■

logic substrate for vergence adaption in infancy.If so, then dissociated esotonus is the cause, ■

rather than the eff ect, of infantile esotropia.Th e prevailing concept of infantile esotropia as ■

the proximate cause of dissociated deviations may need to be revised.


3

References

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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. Th e binocu-lar refl exes and treatment of strabismus. Blakiston, Philadelphia, pp 40–41

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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 Oft almol Hosp de la Luz 42:91–94

12. Romero-Apis D, Castellanos-Bracamontes A (1990) Desviacion horizontal disociada (DHD). Rev Mex Oft almol 64:169–173

13. Romero-Apis D, Castellanos-Bracamontes A (1992) Dissociated Horizontal deviation: clinical fi ndings 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) Th e 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 Oft almol B Aires 68:11–20

18. Th ouvenin D, Nogue S, Fontes L, Norbert O (2004) Strabismus aft er treatment of unilateral congenital cata-racts. A clinical model for strabismus physiopathogenesis? In: de Faber (ed) Transactions 28th European strabismologi-cal 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 hori-zontal deviation. J AAPOS 4:94–101

20. Burian HM (1971) Pathophysiology of exodeviations. In: Manley DR (ed) Symposium on horizontal ocular devia-tions. 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 intra-operative 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 clas-sifi cation and approach to treatment. Am Orthop J 38: 81–93

24. Kushner BJ, Morton GV (1998) Distance/near diff erences 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 con-genital esotropia observational study. Am J Ophthalmol 133:109–118

33. Pediatric eye disease investigator group. (2002) Th e clinical spectrum of early-onset esotropia: Experience of the con-genital esotropia observational study. Am J Ophthalmol 133:102–108

References 31

34. Ing MR (1994) Progressive increase in the quantity of devi-ation in congenital esotropia. Trans Am Ophthalmol Soc 92:117–131

35. Fawcett SL, Wang YZ, Birch EE (2005) Th e 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

37. Brodsky MC (1999) Dissociated vertical divergence. A righting refl ex 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

4.1 Introduction

In 1969, in his American Ophthalmological Society the-sis, Marshall Parks described 100 patients with a specifi c set of sensory fi ndings: a foveal suppression scotoma; peripheral sensory fusion; motor fusion amplitudes (fusional vergence); and gross stereopsis. He termed this constellation of fi ndings the monofi xation syndrome (MFS) to distinguish it from bifi xation (or bi-foveal fi xa-tion) [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 ani-sometropia 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

raised in his original manuscript. Why would an ortho-tropic patient with no history of strabismus or ani-sometropia have primary MFS? Is the foveal suppression the cause or the result of MFS? Why do some cases mani-fest a small tropia in the presence of motor fusion ampli-tudes that are more than suffi cient to overcome the deviation? What is the state of binocular correspondence in the strabismic and nonstrabismic cases of MFS? Can monofi xation be prevented? Can it be cured? And if so, should a cure be attempted? Recent clinical and labora-tory 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

Th e MFS is an abnormality of binocular vision. In normal binocular vision, bilateral retinal input from overlapping visual fi elds is projected to the same general location in the visual cortex, stimulating adjacent ocular dominance columns of opposite ocularity [2]. Th is close proximity of input from the two eyes corresponding to the same point in space facilitates the communication necessary for bin-ocular single vision. Th is communication appears to take

The Monofi xation Syndrome: New Considerations on PathophysiologyKyle Arnoldi

Chapter 4

4

Core Messages

Parks’ monofi xation 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 monofi xation and not characteristics of the syndrome.Animal studies have begun to clarify the path- ■

ways for normal binocular vision, and anatomic and metabolic adaptations which may result in monofi xation.

MFS associated with small angle esotropia is ■

the most common form, the most stable, and the form that allows for the best binocular vision. Th is may be due to the natural superior-ity of the nasal retina and its input to the visual cortex.Monofi xation is a desirable state when bifi xation ■

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 monofi xation in favor of bifi xation.

34 4 The Monofi xation Syndrome: New Considerations on Pathophysiology

4

place within a population of binocular cells, neurons that receive input from both eyes and are sensitive to image disparity. Th ese cells are prevalent throughout the super-fi cial 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 supe-rior temporal visual area), and play a major role in the appreciation of stereopsis and in generating disparity ver-gence (motor fusion).

In the presence of strabismus, inputs from the same point in space will stimulate nonadjacent ocular domi-nance columns, cells that would ordinarily not communi-cate with each other horizontally, or synapse with the same binocular cell further downstream in visual pro-cessing. Unrepaired, large angle infantile-onset strabis-mus has been shown to have devastating eff ects on the population of binocular cells. Th e 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]. Th e 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. Th is would preserve the parafoveal columns and allow for normal, though limited binocular communica-tion with gross stereopsis [3]. Th is 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 main-tain fusion in the presence of a small deviation.

Other researchers have found evidence of an adapta-tion that results in binocular vision in MFS; one that occurs further downstream from area V1, in areas V2, V3, and beyond. Th is 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 fi elds are shift ed 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 approxi-mately 7 mm in length, the typical cortical neuron is

theoretically capable of joining visual receptive fi elds 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 eff ectively communicate with a peripheral retinal ele-ment 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, nor-mal correspondence (NRC) with an expansion of Panum’s fusional space in the peripheral fi eld (Parks’ conclusion), or even a combination of the two. Some authors have found NRC in the central visual fi eld, 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 fi elds 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 fi ne as 70 seconds of arc, which has been found in MFS, could be consistent with a foveal suppres-sion scotoma of up to 5° with NRC. Perhaps stereoacuity at this level is the result of an expansion of Panum’s area sur-rounding the fi xation 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? Th e state of retinal correspondence has historically been defi ned as characteristic responses to specifi c clinical sen-sory tests; responses which can be manipulated by many diff erent external factors [14]. Test results are also infl u-enced 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 charac-teristic 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 corre-spondence are simply geometric and psychophysical con-structs used to describe binocular vision. Until we know how this binocular vision is achieved in the visual cortex,

4.3 MFS with Manifest Strabismus 35

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 dis-cussed earlier, animal studies are beginning to reveal a possible anatomical basis for the clinical observations described in MFS. Until these anomalous neural connec-tions can be shown in a human subject with the clinical features of MFS, the debate remains unresolved.

4.3 MFS with Manifest Strabismus

Th e majority of patients with MFS have a manifest strabis-mus, and esotropia is the most prevalent form by a wide margin. Th e 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]. Th e preva-lence of MFS associated with small angle vertical strabis-mus is extremely low at 0–3% in large series [1, 15, 16]. Choi and Isenberg described 40 cases of MFS with a ver-tical 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, monofi xation can be achieved and main-tained with any type of strabismus. However, the esotro-pic variety of MFS is so prevalent it is unlikely that this occurs by chance. New evidence suggests that a conver-gent deviation may be the default position if orthotropia with bifi xation is not possible [6].

As discussed in Sect. 4.2, studies comparing normal and strabismic monkeys have found that an early onset unre-paired strabismus will deplete the supply of binocular con-nections in area V1, as well as cause low metabolic activity (suppression) in ocular dominance columns correspond-ing 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 diff erent populations of binocular cells within and beyond area V1 that are sensitive to either relative or absolute reti-nal image disparity. Th ese 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 sim-ply because there is a preponderance of them to begin with.

Th e timing of the insult is probably also contributory to the prevalence of small angle esotropia in MFS. Eye

alignment and fusional vergence is immature in neonates, but more oft en 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 nystag-mus, which typically features a pathologic nasally directed pursuit movement of the fi xating eye, followed by a physi-ologic temporal-ward refi xation saccade [18]. Th ese motor fi ndings associated with infantile esotropia seem to sug-gest 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 con-sistent with true stereopsis was found to be only 4D [16], which happens to correspond with the approximate length of one cortical neuron.

Th e 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 aver-age cortical neuron. Th e 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 sub-normal by others [24]. Th ough patients with MFS oft en have fusional vergence suffi cient to overcome small angles of strabismus, most patients with MFS maintain a manifest strabismus. Th e logical conclusion is that, in patients with MFS, there is a greater functional benefi t to keeping the eyes slightly misaligned, particularly on the esotropic side.

MFS with esotropia diff ers 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]. Th e most striking diff erence in the sensory exam was found in the motor fusion category.


4

Both primary and secondary micro-esotropes were sig-nifi cantly 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 fi xating eye must communicate with a nonfoveal point on the nasal retina of the deviating eye to achieve fusion. In exotropia, the fi xating 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 competi-tive 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 terri-tory than nasal columns, with the diff erence 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]. Th e 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 fi nally, the neural mechanisms underly-ing 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.

Th is 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 eff ects of image decorrela-tion, the foveal cortical neurons of the dominant eye would have comparatively few neurons from the deviated eye with which to work. Th e 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 eccentric-ity. Th e 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 monofi xation 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 signifi cant change in the refractive error over time [15]. Dense amblyopia appears to be dis-ruptive to an already fragile binocular connection in exotropia, and may contribute to instability in the major-ity of exotropic patients. Drastic changes in refractive error in MFS with exotropia appear to have a similar destabilizing eff ect. Neither of these factors appears to have an eff ect on long-term stability in micro-esotropia, however.

Instability of alignment in MFS is also associated with the presence of vertically incomitant horizontal strabis-mus, 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 bifi xation with fusion and high grade stereopsis, which is consider-ably more diffi cult. Most researchers (including Parks) believe that a patient with MFS cannot be restored to bifi xation [1, 13, 38, 39]. Th ere 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 teenag-ers [41]. In the former study, of 30 patients with amblyo-pia and eccentric fi xation, 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 Repairing and Producing MFS 37

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 monofi xation persists and the devia-tion 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 bifi xation could be restored, it may not result in a signifi cant improvement in quality of life.

Can MFS be restored once deconstructed? If it is pos-sible to lose the suppression ability due to trauma, occlu-sion 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. Th e 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 bifi xation?” Parks hypothesized that, for those cases of secondary MFS, correction of the underlying pathology, whether strabismus or anisometro-pia, before 6 months of age may be the answer. Th is is a challenging hypothesis to study in human subjects; such early intervention is oft en logistically diffi cult. An animal model is better suited to answer this question.

4.4.1 Animal Models for the Study of MFS

Th ere 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 stra-bismus 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 deter-mines the sensory outcome. If the image decorrelation is repaired in the infant monkey by 3 weeks of age (corre-lates to 3 months in human infants), bifi xation can result in some animals [3, 6]. If delayed for up to 24 weeks, bifi xation 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 pur-suit and OKN, A- and V- pattern incomitance, and

Case 4.1

A 5-year old female was diagnosed with monofi x-ation syndrome following a failed pre-school vision screening. Th e patient completed a course of optom-etric 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 ophthalmolo-gist for the management of diplopia. Th e patient was 6-years old when presented to the ophthalmologist.Vsc: 20/20 20/25Motility: 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

coverSensory: 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 post-operative visit, the diplopia was unchanged. Exam-ination 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 testPost-op Exam 2: At 1 month following surgery, the motility and sen-

sory examinations were unchanged from presenta-tion. Th e patient was off ered an occlusion foil to alleviate the diplopia. Th e mother declined as she viewed this as “a step backwards” aft er all the vision therapy that was done.


4

dissociated vertical deviation [18, 21, 45, 46]. Research shows that in the animal model, shorter durations of image decorrelation result in better sensory outcomes. Th ese results imply that excellent outcomes may be pos-sible in the human if alignment is restored within 90 days of the onset of strabismus. Th is suggests that, if monofi x-ation is to be prevented in favor of bifi xation, very early detection and intervention is necessary.

4.5 Primary MFS (Sensory Signs of Infantile-Onset Image Decorrelation)

Th e problem of primary MFS is one that has perplexed Parks and others. Primary MFS accounts for 16–19% of all cases of monofi xation [1, 15]. Th is subpopulation is interesting, as it may represent the visual cortex’s active choice when bifoveal fi xation is not possible for some rea-son. But what is that reason? One theory that has been debated for decades is the possibility that some individu-als have an inherent inability to bi-fi xate. 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 demon-strated 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 decorre-lation 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]. Th e fi rst 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 meta-bolic activity spreads quickly. Th e longer the period of image decorrelation, the more prevalent the suppression becomes in all layers of V1. Once suppression is estab-lished, the developing cortex may have no choice but to work around it to achieve the best binocular vision pos-sible 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 oft en 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). Th e 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 par-ticularly rare in primary MFS. Th e only secondary abnor-mality that has been found consistently thus far is

Case 4.2

A 16-year old female with a history of monofi xation syn-drome presents with a 3-month history of constant hori-zontal diplopia. Th e onset of the diplopia was abrupt, following closed head trauma without loss of conscious-ness, secondary to a motor vehicle accident. Th e patient reports that the diplopic image is always present, but is not always in the same location relative to fi xation and appears to be constantly moving. Previous records doc-ument a stable RET 6Δ, with a superimposed phoria of up to 18Δ in addition to the sensory features of monofi x-ation syndrome.Vcc: 20/20 OD Rx: +0.50 +1.00 ´ 090 20/20 OS PlanoMotility: Dcc: RET variable from 8Δ to 25Δ Ncc: RET variable from 10Δ to 25ΔSensory: Constant uncrossed horizontal diplopia of variable

magnitude, unrelieved with prism. Th e 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

Th ere was no subjective angle at which the patient could appreciate sensory fusion with either Grade I or II targets.

Management: Th e 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 fi lter strength was reduced to Bangerter 0.2. Two weeks later, the strength was reduced again to Bangerter 0.4. Th e fi lter 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.

References 39

asymmetry of the motion VEP response, which appears to be associated with foveal suppression [4].

One possible explanation for this lack of motor evi-dence of the long-term image decorrelation in MFS is that the motor signs such as pursuit asymmetry are pres-ent, 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 path-ways 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. Th is is yet another query to be added to Parks’ long list of questions about Th e Monofi xation Syndrome.

References

1. Parks MM (1969) Th e monofi xation 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, monofi xation syndrome, and the legacy of Marshall Parks. J AAPOS 9:510–521

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 cor-tical interactions in the monofi xation 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) Diff erent patterns of retinal correspondence in the central and peripheral visual fi eld of strabismics. Invest Ophthalmol Vis Sci 30:2023–2033

9. Grant S, Berman NE (1991) Mechanism of anomalous reti-nal correspondence: maintenance of binocularity with alteration of receptive-fi eld position in the lateral suprasyl-vian (LS) visual area of strabismic cats. Vis Neurosci 7:259–281

10. Sireteanu R, Best J (1992) Squint-induced modifi cation of visual receptive fi elds in the lateral syprasylvian cortex of the cat: binocular interaction, vertical eff ect, and anoma-lous 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 fi ndings in strabismic children. J AAPOS 4:168–174

12. Fronius M, Sireteanu R (1989) Monocular geometry is selectively distorted in the central visual fi eld 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) Th e 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 con-verge downunder, the transactions of the Xth international orthoptic congress. International Orthoptic Association, Melbourne, Australia, pp 73–80

15. Arnoldi K (2001) Monofi xation with eso-, exo-, or hyper-tropia: is there a diff erence? Am Orthopt J 51:55–66

16. Leske DA, Holmes JM (2004) Maximum angle of horizon-tal strabismus consistent with true stereopsis. J AAPOS 8:28–34

17. Choi DG, Isenberg SJ (2001) Vertical strabismus in monofi xation 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


Th e MFS has much to teach us about both nor- ■

mal and abnormal binocular vision. Even as some answers begin to reveal themselves, more questions arise.Monofi xation may be preventable if the cause of ■

the image decorrelation is detected and repaired promptly, probably within 60–90 days of onset. Once monofi xation is present, attempting a cure is ■

unwise. MFS, particularly with small angle esotro-pia, is relatively stable and allows for good bin ocular vision so there is little to be gained. Antisuppression and anti-ARC therapies designed to restore bi-foveal fi xation typically result in intractable diplo-pia. Attempted repair of the associated strabismus with surgery or prism will not create bifi xation once monofi xation 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 dete-rioration with loss of binocular vision.


4

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 refl ect 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 strabis-mic 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 stra-bismics 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 mediat-ing 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 magnifi cation 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) Th e development of the tem-poral and nasal visual fi elds during infancy. Vis Research 32:903–911

32. Beirne RO, Zlatkova MB, Anderson RS (2005) Changes in human short-wavelenth-sensitive and achromatic resolu-tion 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 hemifi elds in children

treated for cataract. Invest Ophthalmol Vis Sci 34: 3501–3509

34. Merigan WH, Katz LM (1990) Spatial resolution across the macaque retina. Vis Research 30:985–991

35. Cisarik PM, Harwerth RS (2008) Th e eff ects of interocular correlation and contrast on stereoscopic depth magnitude estimation. Optom Vis Sci 85:164–173

36. Arthur BW, Smith JT, Scott WE (1989) Long-term stability of alignment in the monofi xation syndrome. J Pediatr Ophthalmol Strabismus 26:224–231

37. Hunt MG, Keech RV (2005) Characteristics and course of patients with deteriorated monofi xation syndrome. J AAPOS 9:533–536

38. Pratt-Johnson JA, Tillson G (2001) Management of strabis-mus and amblyopia, 2nd edn. Th ieme, New York, Stuttgart, pp 113

39. vonNoorden GK, Campos EC (2002) Binocular vision and ocular motility, 6th edn. Mosby, St. Louis, pp 544

40. Houston CA, Cleary M, Dutton GN, McFadsean RM (1998) Clinical characteristics of microtropia – is microtropia a fi xed phenomenon? Br J Ophthalmol 82:219–224

41. Keiner EC (1978) Spontaneous recovery in microstrabis-mus. Ophthalmologica 177:280–283

42. vonNoorden GK, Campos EC (2002) Binocular vision and ocular motility, 6th edn. Mosby, St. Louis, pp 344–345

43. Quéré MA, Lavenant G, Péchereau A (1993) Les diplopies incoercibles post-thérapeutiques. J Fr Orthopt 25:191

44. Das VE, Fu LN, Mustari MJ, Tusa RJ (2005) Incomitance in monkeys with strabismus. Strabismus 13:33–41

45. Fu LN, Tusa RJ, Mustari MJ, Das VE (2007) Horizontal sac-cade disconjugacy in strabismic monkeys. Invest Ophthalmol Vis Sci 48:3107–3114

46. Tusa RJ, Mustari MJ, Das VE, Boothe RG (2002) Animal models for visual deprivation-induced strabismus and nys-tagmus. Ann NY Acad Sci 956:346–360

47. Wensveen JM, Harwerth RS, Smith EL (2003) Binocular defi cits associated with early alternating monocular defocus. I. Behavioral observations. J Neurophysiol 90: 3001–3011

48. Zhang B, Matsura K, Mori T, Wensveen JM, Harwerth RS, Smith EL Chino Y (2003) Binocular defi cits associated with early alternating monocular defocus, neurophysiolog-ical observations. J Neurophysiol 90:3012–3023

49. 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

5.1 Esotropia as the Major Type of Developmental Strabismus

Esotropia is the leading form of developmental strabismus. Th erefore, unraveling the causal mechanism and response to treatment is an important public health issue. Th e pur-pose of this chapter is to review knowledge gained over the last two decades that: (a) implicates cerebral cortex malde-velopment as the cause, and (b) explains how repair of cor-tical circuits may be the key to functional cures.

5.1.1 Early-Onset (Infantile) Esotropia

Esotropia has a bimodal, age-of-onset distribution. Th e 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

early-onset esotropia are predominantly emmetropic [1], whereas late-onset esotropia is associated commonly with a substantial hypermetropic refractive error (accommo-dative esotropia). Th e most prevalent form of develop-mental strabismus in humans is concomitant, constant, nonaccommodative, early-onset esotropia. Most of these cases have onset in the fi rst 12 months of life, i.e., infan-tile-onset. Infantile esotropia may be considered the para-digmatic form of strabismus in all primates, as it is also the most frequent type of natural strabismus observed in monkeys [2].

5.1.2 Early Cerebral Damage as the Major Risk Factor

If infantile esotropia is a paradigmatic form of strabis-mus, investigations designed to reveal pathophysiologic

Visual Cortex Mechanisms of Strabismus: Development and MaldevelopmentLawrence Tychsen

Chapter 5

5

Core Messages

Proper alignment of the eyes requires informa- ■

tion sharing (fusion) between monocular visual input channels in the CNS; the fi rst locus for fusion in the CNS of primates is the striate cere-bral cortex (area V1).Fusion behaviors and V1 binocular connections ■

are immature at birth, maturing during a critical period in the fi rst months of life; maturation of fusion and V1 binocular connections requires correlated (synchronized) input from each eye.Nasalward biases are present innately in the neu- ■

ral pathways of normal primates before matura-tion of binocularity.Esotropia and the associated nasalward gaze ■

biases of infantile strabismus can be produced

reliably in normal primates by impeding the mat-uration 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 criti- ■

cal period of normal binocular maturation may achieve functional sensory and motor cures.If surgery fails to restore bifoveal fusion, subnor- ■

mal fusion (micro-esotropia/monofi xation) may be achieved within boundaries set by the proper-ties 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.

42 5 Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment

5

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

5.1.3 Cytotoxic Insults to Cerebral Fibers

Th e occipital lobes in newborns are vulnerable to dam-age [6, 12–14]. Premature infants frequently suff er injury to the optic radiations near the occipital trigone. Balanced binocular input requires equally strong pro-jections from each eye through this periventricular zone. Th e fi bers connect the lateral geniculate laminae to the ocular dominance columns (ODCs) of the striate cortex. Th e projections are immature at birth and the quality of signal fl ow would be critically dependent upon the function of oligodendrocytes, which insulate the visual fi bers. Neonatal oligodendrocytes are espe-cially vulnerable to cytotoxic insult [15]. Th e striate cortex is also susceptible to hypoxic injury because it has the highest neuron-to-glia ratio in the entire cere-brum [16] and the highest regional cerebral glucose consumption [17].

5.1.4 Genetic Infl uences on Formation of Cerebral Connections

Genetic factors also play a causal role. Large-scale studies have documented that ~30% of children born to a strabis-mic parent will themselves develop strabismus [18]. Twin studies reveal a concordance rate for monozygous twins of 73% [19]. Less than 100% concordance implies that intra-uterine 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]. Th e results sug-gested a multifactorial or Mendelian codominant inheri-tance pattern. Codominant means that both alleles of a single gene contribute to the phenotype but with diff erent thresholds for expression of each allele. Th ese genes could conceivably encode cortical neurotrophins, or axon guid-ance and maturation. Any of these genetically modulated factors could increase the susceptibility to disruption of visual cortical connections in otherwise healthy infants.

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 aft er 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

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]aAdditional 17% of infants had persistent asymmetric OKN

5.1 Esotropia as the Major Type of Developmental Strabismus 43

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 demon-strated by several methods, most notably studies that have used forced preferential looking (FPL) techniques [23–25, 27, 28]. Th e FPL studies show that stereopsis emerges abruptly in humans during the fi rst 3–5 months of postnatal

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 aft er, but not before, ~3 months of age.

Table 5.2. Binocular development and visuomotor behaviors in infant primate

Immature behavior Chief fi ndings before onset of mature behavior

Investigator(s)

Binocular disparity sensitivity absent before ~3–5 mos

Stereo-blindnessConvergent 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

Transient convergence errors 4X divergence errors

Convergent disparity sensitivity present earlier than divergent

[34]

Convergence fusion range exceeds divergence by 2:1

[32, 33]

Nasalward bias of cortically mediated motion sensitivity before ~6 mos

Motion VEP nasotemporal asymmetryStronger 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 aft er onset binocularity

[42][43]

[44]

[45]

Nasalward bias of gaze-holding before ~6 mos

Nasalward slow phase drift of eye position

Persists as latent fi xation nystagmus with binocular maldevelopment

[42][46][47]


5

5.1.7 Development of Fusional Vergence and an Innate Convergence Bias

Fusional vergence eye movements mature during an equivalent period in early infancy. In the fi rst 2 months of life, alignment is unstable and the responses to step or ramp changes in disparity are oft en markedly inaccurate [32, 33]. Th e 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. Th e fusional vergence response to crossed (convergent) disparity is also intact earlier and substantially more robust than that to diver-gent disparity. Th e innate bias favoring fusional conver-gence in primates persists aft er 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)

Th e 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 fi rst months of life, VEPs elicited by oscillating grating stimuli (motion VEPs) show a pronounced nasotempo-ral asymmetry under conditions of monocular viewing [35–38]. Th e 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 aft er-nystagmus (slow phase eye movement in the dark aft er extinction of stimulus motion) is characterized by a consistent nasalward drift of eye position [42]. Th ese nasalward motion biases are most pronounced before the onset of sensorial fusion and stereopsis, but system-atically diminish thereaft er.

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 combina-tion 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, bin-ocular, sensorimotor behaviors in normal infants. Th ird, perinatal insults to the immature visual cortex are linked strongly to subsequent onset of strabismus. And fi nally, the constellation of sensory and motor defi cits in infantile strabismus can be explained by known cortical pathway mechanisms.

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

Aff erents 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]. Th e fi rst stage of binocular processing in the primate CNS is made possible by hori-zontal 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]. Th e 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 sup-pression (inhibition) index. Th e immature neuronal response properties are attributed to unrefi ned, weak excitatory horizontal binocular connections between ODCs. Th ese axonal connections help defi ne the segrega-tion of ODCs [62, 77]. ODC borders are immature (fuzzy) at birth but adult-like (sharply defi ned) by 3–6 weeks postnatally [60, 78] (the equivalent of 3–6 months in humans, 1 week of monkey visual development is compa-rable with 1 month in humans [79]).


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

Neurobiological principle Physiology/anatomy Investigator(s)

Striate cortex (area V1) is the fi rst 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]

Binocular structure + function in V1is immature at birth

Segregation of RE/LE ODCs immature at birthBinocular (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 left ward 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]


5

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 connec-tions between ODCs of the same ocularity are maintained. Th e loss is due to excessive pruning of connections, beyond the normal process of axon retrac-tion and refi nement that takes place within and between ODCs in the fi rst weeks of life. (Captured in the neuro-science dictum: “Cells that fi re together, wire together. Cells that fi re apart, depart.”) Th e paucity of binocular connections is accompanied by loss of binocular responsiveness and disparity sensitivity, measured electrophysiologically, in V1 neurons [55, 63, 64]. Th e companion behavioral defi cits are stereoblindness and absence of fusional vergence [47, 65].

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 tempo-ral 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 sensi-tive to binocular disparity, guiding both conjugate and disconjugate (near-far) tracking [80–82]. In normal pri-mates, greater than 90% of MT/MST neurons exhibit bal-anced, 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

Ocular Dominance Columnsof V1 (Striate Cortex)

LGN2/3

4B

4C

PeriventricularWhite MatterProjections

R RL L

Fig. 5.1 Neuroanatomic basis for binocular vision. Monocular retinogeniculate projections from left eye (temporal retina-nasal visual hemifi led) and right eye (nasal retina-temporal hemifi eld) remain segregated up to and within the input layer of ocular dominance columns (ODCs) in V1, layer 4C (striate visual cor-tex). Binocular vision is made possible by horizontal connec-tions 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

Fusion/stereopsisAlignment and

Balanced Gaze

CorrelatedActivity

De-CorrelatedActivity

Stereo-blindness

Esotropia andGaze Asymmetries

2/3

4B

4C

R RL L

R RL L

a

b

Fig. 5.2 Horizontal connections for binocular vision in V1 of normal (correlated activity) vs. strabismic (decorrelated) pri-mate, 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 mon-ocular (i.e., a paucity of binocular connections). RE inputs red; LE blue; binocular violet


with infantile strabismus. Visual inputs may be suppressed from one eye continuously (causing unilateral amblyo-pia), or commonly in infantile strabismus, from each eye alternately ~50% of the time (alternate fi xation) [83, 84]. In normal animals, horizontal connections between ODCs can mediate suppression when confl icting stimuli activate neurons in neighboring ODCs [85, 86].

Th e 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), refl ecting equal activity (absence of inter-ocular suppression). Unequal CO activity is a gen-eral fi nding in area V1 of primates who have strabismus [78, 90], amblyopia [91], or both [92]. Th e 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.

Th e 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

strabismus and amblyopia, as compared with strabismus alone (that is, alternating fi xation). Th e metabolic abnor-malities are found throughout V1 when suppression is widespread; alternatively, suppression is confi ned to zones of V1 that match retinotopically the location of a suppression scotoma. Th e metabolic suppression is not found in the LGN, which is composed of neurons driven monocularly from each eye without binocular interac-tion. Th ese fi ndings imply that abnormal binocular inter-action in V1 leads to heightened competition between ODCs of opposite ocularity, with suppression of meta-bolic activity in opposite-eye ODCs. Th e abnormalitis add to our knowledge of the brain damage caused by unrepaired strabismus. As noted in the preceding sec-tions, the eff ects include an ~50% reduction in long-range, excitatory binocular horizontal connections joining ODCs of opposite ocularity [70, 93]. In the pres-ence of strabismus, the remaining 50% of binocular con-nections (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 hemifi elds in normal human infants indicate that tempo-ral retina sensitivity matures slower than nasal retina sen-sitivity [94, 95]. Th e nasotemporal asymmetry in sensitivity diminishes if the infant develops normal vision, but lower temporal sensitivity remains permanently if early binocu-lar 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]. Th e human psychophysical fi ndings, together with the monkey anatomic fi ndings, reinforce the conclusion that abnormal binocular experience in early infancy unfairly punishes visual neurons that are slow to develop and fewer in num-ber, 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

Equal NeuronalMetabolic Activity

Normal

Strabismic

Inter-ocularMetabolic

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2/3

4B

4C

R RL L

R RL L

a

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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 meta-bolic 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


5

do not resolve – they persist and become pronounced [46, 100–102]. Normally, area MST in each cerebral hemi-sphere encodes ipsiversive eye tracking and gaze holding (Fig. 5.4). Ablations within MST impair ipsiversive pur-suit/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 connec-tion – through area V1 of both hemispheres – to area MST of the left hemisphere) [13, 76]. Th e contralateral-

nasalward gazeinstability

stable gaze

call

RE RELE LE RE RELE LE

chi

Strabismic Normal

Fig. 5.4 Neural network diagrams showing visual signal fl ow 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 fi xation nystagmus. Note that in all primates, pursuit area neurons in each hemisphere encode ipsilaterally directed pursuit. Signal fl ow is initiated by a moving stimulus in the monocular visual fi eld, 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 hemi-sphere. 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 fi eld of right eye. Retinal ganglion cell fi bers 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-fi eld) occupy slightly more cortical territory than those representing the temporal hemiretinae (nasal hemifi eld), but each ODC contains neurons sensitive to nasally directed vs. temporally directed motion (half circles shaped like the matching hemifi eld, arrows indicate directional preference). Visual area neurons (including those beyond V1 in area MT) are sensitive to both nasally directed and tem-porally 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 prefer-ences 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 binocu-lar connections. Call corpus callosum, through which visual area neurons in each hemisphere project to opposite pursuit area. Bold lines active neurons and neuronal projections


eye-to-MST connectivity advantage is consistent with an innate, contralateral-eye-to-V1 connectivity advantage. (Captured in twin dictums: “fi rst come, fi rst served ”and “majority rules.”) V1 neurons in each hemisphere, driven by the nasal hemiretinae (contralateral eye), develop ear-lier and outnumber (by a ratio of ~53:47 in primate) neu-rons 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.

Th e contralateral eye-to-MST connectivity bias pro-vides a mechanism for the nasalward tracking bias, evi-dent 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. Th e left area MST mediates ipsiversive/left ward 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. Th e 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 conver-gence 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. Th e

Fusional Vergence (esotropia)

Tracking (pursuit/OKN)

Gaze Holding (latent nystagmus)

Fig. 5.5 Nasalward vergence and gaze asymmetries in strabismic humans and monkeys. Fusional vergence: esodeviation of the nonfi xating 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 fi eld. Pursuit is cogwheel (low gain-abnor-mal) when the target moves temporalward. Th e movements of the two eyes are conjugate, and the direction of the asymmetry reverses instantaneously with a change of fi xating eye, so that the direction of robust pursuit is always for nasalward motion in the visual fi eld. Gaze holding-latent nystagmus: viewing with the right-eye, both eyes have a nasalward slow-phase drift , followed by temporal-ward refoveating fast-phase microsaccades. Th e direction of the nystagmus reverses instantaneously when the left eye is fi xating, so that the slow phase is nasalward with respect to the fi xating eye


5

conclusion drawn from these observations was that MST neurons promote esotropia (i.e., a bias for nasalward ver-gence) when binocularity fails to develop in V1. Th e 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 sys-tem is unbalanced, favoring convergence. Midbrain pre-motor 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 revers-ing the constellation of ocular motor maldevelopments? Th e answer to this question is rooted in a debate between two competing twentieth century schools of treatment philosophy, derived from the eminent British strabismol-ogists, Claude Worth and Bernard Chavasse. Worth pos-tulated in 1903 that esotropic infants suff ered “an irreparable defect of the fusion faculty” [107]. Th eir brain was congenitally incapable of achieving substantial bin-ocular 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 refl exes” 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 refl ex 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 articu-lated by disciples of Chavasse in the U.S., most notably August Costenbader, Marshall Parks, and a series of Parks’ trainees [109, 110]. Th e new knowledge prompted a gradual reexamination of old data and inspired impor-tant case studies – in the 1980 and 1990s – on the effi cacy of early strabismus surgery [111–114]. Th ese 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 thresh-olds on the order of 60–400 arcsec.

Scrutiny of early alignment data in infantile esotropia has produced more refi ned and forceful conclusions. Figure 5.6a is replotted data on stereopsis outcomes in over 100 consecutive infantile esotropes [112]. Th e Y-axis is prevalence of stereopsis aft er surgical alignment, and the X-axis is age of onset or duration of misalignment before surgery. Th e 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. Th e noise in the data – relating age at alignment to stere-opsis outcome – is related to the fact that onset of strabis-mus is idiosyncratic, varying considerably from infant to infant, and distributed randomly in the interval 2–6 months of age. Th ere 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 cor-relation is evident between shorter durations of misalign-ment 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]. Th e 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 preva-lence of recurrent esotropia (or exotropia), pursuit/OKN asymmetry, motion VEP asymmetry, latent nystagmus, and dissociated vertical deviation (DVD). However, ocu-lar motor recording is diffi cult 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 fi ll gaps in clinical knowledge. Th e studies have shown that normal motor and sensory pathway develop-ment can be restored when the timeliness of therapy con-forms 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 (Monofi xation Syndrome) 51

pursuit/OKN and gaze holding return to normal (Fig. 5.6c). Th e repair of ocular motor behavior occurs with repair of stereopsis and restoration of normal motion responses (motion VEPs). If decorrelation per-sists in strabismic monkeys until the equivalent of 12 months’ duration in humans, esotropia and stereoblind-ness persist. Prolonged-decorrelation animals exhibit latent nystagmus, pursuit/OKN asymmetry, motion VEP asymmetry, and DVD. Th e 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 com-plement of binocular horizontal excitatory connections between ODCs of opposite ocularity, and “delayed repair” (longer durations of decorrelation) monkeys a paucity. Th e restoration of binocular connections in V1 of “early repair” monkeys appears to have equally benefi -cal eff ects on downstream areas of extrastriate cortex (MT/MST) driving the ocular motor neurons of the brainstem. Th e benefi t is evident as symmetric naso-temporal eye tracking, stable gaze holding, and more normal fusional vergence.

5.2 Visual Cortex Mechanisms in Micro-Esotropia (Monofi xation Syndrome)

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. Th e majority of infants who have esotropia are corrected 6 or more months aft er onset of misalignment. Th e chances of rescuing bifoveal fusion aft er this interval are slim. Most infants are aligned to within 8 PD of orthotropia (microe-sotropia) and regain a degree of subnormal stereopsis and motor fusion, i.e., monofi xation syndrome.

Monofi xation syndrome occurs as a primary disor-der (prevalence 1%) or, more commonly, as a secondary phenomenon, aft er delayed treatment of large magni-tude strabismus [116, 117]. Th e syndrome also occurs in monkeys [118]. Th e major sensory and motor fea-tures of monofi xation syndrome are listed in Table 5.4. Neural mechanisms for the fi rst two features listed in Table 5.4 are not diffi cult to explain. Receptive fi elds in V1 – representing the fovea – are tiny and have narrow tolerances. Any defocusing or other decorrelation of one eye’s inputs would produce a confl ict in neighboring V1 columns and promote suppression of ODCs corre-sponding to the weaker eye. Th e fovea subtends ~5° of the retinotopic map of V1, thus a suppression scotoma of ≤5° makes sense. Feature two, subnormal stereopsis,

Fig. 5.6 Repair of random-dot stereopsis aft er surgical realignment of the eyes in children with infantile esotropia, and analogous fi ndings 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 defi cits 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 defi cit; 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)

% C

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ren

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5

could be explained along similar lines. Stereoscopic thresholds increase exponentially from the fovea to more eccentric positions along the retinotopic map of the visual fi eld. 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 monofi xation syndrome, the visuomotor signs, that are most intriguing. If binocular development is perturbed so that right and left eye foveal ODCs (receptive fi elds) 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. Th e 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 fi eld eccentricities of 0–10° (i.e., the representation of the fovea, parafovea and macula). Th e length is similar in both normal and strabismic mon-keys, on average ~7 mm [70, 119]. In a primate with nor-mal 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. Th e 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 communi-cate for high-grade binocular fusion.

In a primate with microesotropia and a right eye fi xa-tion preference (Fig. 5.7), a neuron within a foveolar (0°) column of the fi xating, right eye must link up with a non-adjacent 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 fi elds) 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-fi eld) of a microesotropic macaque. Th e sulci and gyri have been unfolded and the visual fi eld represen-tation superimposed using standard retinotopic land-marks. One horizontal axon, originating within the foveal representation at 0–1° eccentricity, could link to a recep-tive fi eld shift ed 2.5° or 4.4 PD distant (Fig. 5.7). Two neu-rons strung together could join receptive fi elds 5° or 8.7 PD apart. Th e conclusion that emerges is that the 4–8 PD “rule” of the monofi xation syndrome is explicable as a combination of innate V1 neuron size and V1 topography. Th e visuomotor system of the strabismic primate appears to achieve subnormal, but stable binocular fusion so long as the angle of deviation is confi ned to a distance corre-sponding 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 monofi xation syndrome. MST receives downstream projections from disparity-sensitive cells, both in V1 and in MT. Th e majority of binocular neurons in V1, MT and MST encode absolute disparity [82, 120]. Absolute disparity

Table 5.4. Monofi xation (Microstrabismus) Syndrome

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

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

5.2 Visual Cortex Mechanisms in Micro-Esotropia (Monofi xation Syndrome) 53

sensitivity (the location of an image on each retina with respect to the foveola, or 0° eccentricity) guides ver-gence, as opposed to relative disparity sensitivity (the location of an image in depth with respect to other images), which is necessary for stereopsis. Th e largest population of vergence-related neurons in MST of nor-mal monkeys drives the eyes to ~2.5° of convergent (crossed) disparity [82]. (Th e next largest population encodes ~2.5° of divergence.) Normal primates have the strongest short-latency vergence responses to conver-gent disparities of ~2.5° [121].

Insults that impair the development of binocular con-nections in immature V1 would be expected to impair the (downstream) development of the entire population of

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

Fig. 5.7 (a) Monofi xator/microesotrope exhibits a deviation of the visiual axes on cover testing of approxi-mately 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 persis-tently return to that 2.3° angle. (b) Two-dimensional map representing V1 from the right cerebral hemisphere (left visual hemi-fi eld) of a microesotropic primate. Th e sulci and gyri have been unfolded and the visual fi eld 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 fi eld shift ed 2.5° or 4.4 PD distant. Two neurons strung together could join receptive fi elds 5° or 8.7 PD apart. Th e conclusion that emerges is that the 4–8 PD “rule” of monofi xation/microesotropia syndrome is explicable as a combination of innate V1 neuron size (one to two axon lengths) and V1 topography

a

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6.1 General Etiologies of Strabismus

Strabismus, defi ned as misalignment of the visual direc-tions of the two eyes, may arise from several general causes. Th ese include primary myopathies of extraocu-lar muscles (EOMs), disorders of the connective tissues that comprise the globe’s gimbal system, peripheral dis-orders of nerves controlling the EOMs, and central dis-orders of fusional vergence commands (Table 6.1). Th is chapter emphasizes causes of strabismus that can be characterized as mechanistically specifi c pathologies of the subcortical nervous system, EOMs, and associated connective tissues. Such pathologies are termed neuro-anatomical 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.

6.2 Extraocular Myopathy

6.2.1 Primary EOM Myopathy

Primary EOM myopathy may be due to congenital meta-bolic disorder, acquired infl ammation, 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 aff ected [2]. Th e asso-ciation between CPEO and heart block is called Kearns–Sayre syndrome [3]. Ragged red fi bers, as demonstrated on modifi ed 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

Neuroanatomical StrabismusJoseph L. Demer

Chapter 6

6

Core Messages

Strabismus may arise from identifi able structural ■

abnormalities of the extraocular muscles (EOMs) or their innervation. Congenital or acquired myopathies aff ect EOM function or structure to impair normal relaxation and force generation. Abnormalities of EOM paths may produce stra-bismus by altering EOM pulling directions. Path abnormalities arise from abnormalities of the location and stability of the connective tissue pul-leys that infl uence EOM paths. Pulley disorders may be congenital or acquired, and produce pat-tern strabismus, divergence paralysis esotropia, and horizontal or vertical incomitant strabismus. Structural abnormalities of EOMs or their associ-ated connective tissues may be demonstrated by clinical orbital imaging.

Strabismus may also arise from abnormalities of ■

peripheral innervation of the EOMs. Congenital cranial dysinnervation disorders (CCDDs) typi-cally produce hypoplasia and loss of function of insuffi ciently 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.

60 6 Neuroanatomical Strabismus

6

CPEO is problematic, since most cases are caused by spo-radic mitochondrial DNA deletions. More clinically use-ful may be T1-weighted magnetic resonance imaging (MRI), which in CPEO demonstrates abnormal bright signal within clinically weak EOMs having generally nor-mal size [1] (Fig. 6.1). Other cases of chronic, fi xed EOM weakness are associated with obvious EOM atrophy (Table 6.2).

6.2.2 Immune Myopathy

Immune EOM myopathy, also known as endocrine myo-pathy or thyroid eye disease (TED), is typically associated with immune dysthyroidism but may follow an indepen-dent temporal course [4]. TED begins with infl ammation and infi ltration of EOMs, orbital connective tissues, or both. A classical presentation of TED involves infl amma-tory enlargement of EOMs producing upper eyelid retrac-tion, proptosis, and restrictive ophthalmoplegia. Chronic EOM enlargement and fi brosis persists following resolu-tion of infl ammation. Orbital imaging by MRI or com-puted X-ray tomography (CT) typically demonstrates enlargement of EOM bellies, sparing the terminal ten-dons. 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.

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

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

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

Another presentation in TED is infl ammatory enlarge-ment of the nonmuscular orbital connective tissues, par-ticularly orbital fat. Proptosis is the main feature, but strabismus may arise due to forward displacement of the globe relative to fi xed structures such as the fi xed anchors of the trochlea and the soft pulley system of the other EOMs.

6.2.3 Infl ammatory 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 enlarge-ment or a contiguous orbital mass [6]. Biopsy of the involved EOM may be helpful for diagnosis if likely meta-static source is not already known.

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 con-cealed 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 oft en 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 infl ammatory 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

Table 6.2. Types of extraocular myopathy

Cause Main clinical features Imaging fi ndings Laboratory diagnostic tests

Metabolic Progressive weakness Normal EOM size, bright T1 MRI signal

Muscle biopsy for ragged red fi bers, electrocardiogram

Immune myopathy

Restriction, infl ammatory signs

EOM belly enlargement and/or orbital fat enlargement

Th yroid function tests

Infl ammatory myositis

Restriction and/or weakness, infl ammatory signs

EOM belly and tendon enlargement

Tests for vasculitis, infl ammation, sarcoidosis

Neoplastic myopathy

Restriction and/or weakness, and/or infl ammatory signs

Nodular EOM enlargement, or orbital mass

Metastatic evaluation, EOM biopsy

Mechanical Weakness or restriction EOM discontinuity or displace-ment, possible orbital fracture


Old orbital fractures may complicate the presen- ■

tation of strabismus of recent origin.Patients may not recall old orbital fractures. ■


6

may be associated with the clinical fi ndings of limitation of active duction in the EOM’s fi eld of action due to pulley hindrance (discussed below), as well as mechanical restric-tion to the opposite direction of passive rotation using for-ceps. In the usual clinical setting of generalized orbital and eyelid edema, these clinical fi ndings can be indistinguish-able 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].

6.3 Congenital Pulley Heterotopy

Th e direction of ocular rotation imparted by any EOM is defi ned 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. Th us, alterations in positions of the horizontal rectus pulleys can impart substantial vertical and tor-sional 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).

Th e MR and LR pulleys are directly suspended by fi broelastic connective tissues from anteriorly located entheses, or anchors, on the orbital bones [15]. Th e medial enthesis is at the posterior lacrimal crest, while the lateral enthesis is at Whitnall’s tubercle. Th e 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 signifi cant alterations in rectus EOM pulling direc-tions. More signifi cant 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. Th is eff ect 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 fi ndings: imbalanced ver-sions in oblique gaze directions (formerly but incorrectly attributed to oblique EOM dysfunction) and vertically incomitant horizontal strabismus [16, 17]. MRI has dem-onstrated the coronal plane locations of rectus EOM pul-leys to be stereotypic in normal [17, 18] and most strabismic subjects [18]. Th e 95% confi dence intervals of coronal plane pulley coordinates are less than ±1 mm [18]. A computer model of binocular alignment incorpo-rates passive elastic pulleys [19] and is now available as the application Orbit. Th e expected eff ect 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 sim-ulation 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 infra-ducting action in adduction relative to that of the LR, causing excessive infraduction in extreme adduction, since only the abducting eye can fi xate a target in this position. Th is heterotopic pulley confi guration is typi-cally 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 confi guration

Incomitance Horizontal pulleys

Vertical pulleys Lateral canthal inclination

LR MR IR SR

A pattern Superior Inferior Temporal Nasal Superior

V pattern Inferior Superior Nasal Temporal Inferior


Orbital pulley disorders can cause strabismus. ■

Strabismus due to pulley disorders can clinically ■

mimic restrictive or paralytic strabismus.

6.4 Acquired Pulley Heterotopy 63

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 pat-tern strabismus.

When the LR pulley is located inferiorly to the MR pulley in both orbits (Fig. 6.3b), the MR exerts a supra-ducting action in adduction relative to that of the LR, causing excessive supraduction in extreme adduction, since only the abducting eye can fi xate a target in this position. Th is heterotopic pulley confi guration is typi-cally associated with a temporal placement of the SR pul-ley 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 con-vergent 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 asymmetri-cal, or when there is a signifi cant inclination to one or both the palpebral apertures [12, 23]. Th e 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”) inclina-tion 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

Th e 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

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


6

[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 bal-anced by the elastic stiff ness of the pulley connective tis-sue suspensions, particularly by the elasticity of a ligament connecting the LR with the SR pulleys that is termed the LR–SR band [15, 25]. Th e suspensory tissues of the orbital pulleys become gradually attenuated during normal aging [15, 25], causing predictable inferior shift s in horizontal rectus pulley positions [26], and making the pulleys of order people more susceptible to the eff ects of trauma and surgery.

6.5 “Divergence Paralysis” Esotropia

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

When horizontal pulley sag occurs symmetrically, there is no eff ect on horizontal binocular alignment, since the MR and LR muscles experience balanced force reduc-tions [25]. Th e 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 con-verted to infraducting force than is the corresponding situation for MR adducting force. Th e imbalance leads to a convergent shift in alignment most evident during dis-tance viewing when the visual axes of the eyes should be parallel, while there may be little or no esodeviation dur-ing near viewing where physiologic convergence is required. Th is situation has been described as “diver-gence 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 sac-cadic velocities and abduction range are normal [27]. When bilaterally symmetrical, the vertical eff ect 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


Pulley connective tissue degeneration in older ■

people can cause horizontal or vertical stra-bismus.Involutional eyelid changes and blepharopto- ■

sis suggest that pulley tissues may also be degenerating.

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 nonexclu-sively assigned to American Academy of Ophthalmology, 2008.)

6.5 “Divergence Paralysis” Esotropia 65

very successfully treated by multiple conventional stra-bismus 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 infraduct-ing action to the involved LR muscle, even creating restriction to passive supraduction [25] (Fig. 6.5). Th e clinical presentation may be acute onset of hypotropia with defi ciency of supraduction that might be mistaken for SR paralysis or IR restriction in the absence of ade-quate orbital imaging. Orbital imaging secures the

diagnosis of sagging eye syndrome (Fig. 6.5). While it may sometimes be possible to surgically repair the rup-tured 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 eff ect of aggressive anterior dissection at strabismus, reti-nal, 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-rec-ognized cause of strabismus in high myopes [29]. Known as “heavy eye” syndrome or myopic strabismus fi xus, 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 degen-eration 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 syn-drome” 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 confi rms the diagnosis of LR displacement, and excludes alternative or coexisting conditions that may require diff erent surgical treatment, or preclude treat-ment altogether. For example, with or without inferior displacement of the LR pulley, a severely staphyomatous globe may fi ll the bony orbit so completely that duction is limited [32], or the LR muscle may have suff ered neuro-pathic 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 eff ective treatment may be identical to that used in the sagging eye

Table 6.4. Alignment eff ect of LR–SR band degeneration

Symmetry Resulting strabismus

Bilaterally symmetric Divergence paralysis esotropia

Asymmetric Hypotropia ± Esotropia

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


6

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

6.6 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 defi ciency 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 patho physiology of strabismus. It is useful to under-stand two general principles in the functional anatomy of these CCDDs. First, EOMs with insuffi cient motor innerva-tion are hypoplastic and hypofunctional. Second, eff ectively innervated antagonists of congenitally noninnervated EOMs exhibit contracture and increased stiff ness (Table 6.5).

Table 6.5. Main imaging fi ndings in CCDDs

Disorder Orbital fi ndings Skull base fi ndings

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 fi brosis 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 Aff ected 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 fi ssured medulla and pons


Numerous structural abnormalities of extraocu- ■

lar muscles and associated connective tissues may cause strabismus.Structural causes of strabismus may mimic neu- ■

rological causes of strabismus.High-quality orbital imaging is generally neces- ■

sary to diagnose structural abnormalities of extraocular muscles and associated connective tissues that cause strabismus.

6.6 Congenital Peripheral Neuropathy: The Congenital Cranial Dysinnervation Disorders (CCDDs) 67

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 defi ciencies of adduction, supraduction, and infraduction, along with variable mydriasis and blepharoptosis. Aff ected EOMs are hypoplastic, corresponding to their functional defi -ciencies. 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 fi bers, more profoundly aff ecting the superior than inferior division of CN3. Th ree distinct phenotypes, CFEOM1–3, are rec-ognized. Th e classic form, CFEOM1 (MIM 135700), is

typifi ed by bilateral congenital blepharoptosis and oph-thalmoplegia, 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 speci-mens of resected EOMs in CFEOM suggested replace-ment by fibrous tissue [35–37]. The classic concept of CFEOM as a primary myopathy, however, was chal-lenged by autopsy findings in a subject from a pedigree with the KIF21A mutation [34]. Engle et al. alterna-tively suggested that CFEOM1 is a primary disorder of EOM motor neuron development, leading to hypopla-sia or atrophy of the EOMs they innervate, and sec-ondary contracture of their antagonists [34]. Older reports of “fibrosis” in EOM tendons are likely to have been artifacts of inadvertent biopsy of distal EOM ten-dons [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

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 fi brosis of the extraocular muscles type 1 (CFEOM1)


6

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. Signifi cant but usually subclinical optic nerve (ON) hypoplasia occurs in CFEOM1, as may superior oblique (SO) muscle hypoplasia presumably due to trochlear nerve (CN4) hypoplasia. Th e posterior parts of multiple EOMs may be dysplastic in CFEOM, although their anterior portions generally appear normal both by MRI and at EOM surgery.

Th e frequent occurrence of synergistic eye movements and the Marcus Gunn jaw winking phenomenon in CFEOM1 [39, 40] suggests motor axonal misrouting.

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 congeni-tally bilateral exotropic ophthalmoplegia and blepharop-tosis. Th is rare recessive disorder occurs in consan guineous pedigrees. Th e orbital and cranial nerve pheno-type of CFEOM2 have not been studied in detail.

Table 6.6. Imaging features in acquired neuropathic extraocular muscle palsy

Muscle Size Contractility Path

Inferior oblique Reduced 40% Reduced Normal

IR Small posteriorly Reduced Centrifugal infl ection

Lateral rectus Reduced 50–90% posteriorly Reduced Centrifugal infl ection

Levator palpebrae superioris Small Cannot evaluate Normal

Medial rectus Small posteriorly Reduced Normal

SO Reduced 40–50% Reduced Normal

SR Small posteriorly Reduced Normal

Fig. 6.7 Typical orbital MRI fi ndings 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)

6.6 Congenital Peripheral Neuropathy: The Congenital Cranial Dysinnervation Disorders (CCDDs) 69

Th e third CFEOM variant, CFEOM3, encompasses patients with CFEOM not classifi able as either CFEOM1 or CFEOM2. Th is “atypical” group includes unilateral cases who have orthotropic central gaze, or whose central gaze is hypotropic but who can supraduct above the cen-tral position. Subjects with CFEOM3 have asymmetrical blepharoptosis, limited supraduction, variable ophthal-moplegia, and are usually exotropic. MRI demonstrates asymmetrical levator palpebrae superioris and SR atro-phy correlating with blepharoptosis and defi cient supra-duction, and small orbital motor nerves [41]. While at least one subarachnoid CN is hypoplastic, ophthalmople-gia occurs only when subarachoid CN3 width is less than the 2.5th percentile of normal. Multiple EOMs exhibit variable hypoplasia, correlating with duction in individ-ual orbits. A-pattern exotropia is frequent in CFEOM3, correlating with LR misinnervation by CN3. ON cross-sections are slightly subnormal, but rectus pulley loca-tions are normal [42]. Some cases of CFEOM3 are associated with brain abnormalities including corpus cal-losum hypoplasia.

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 diff use external ophthalmople-gia or anomalous innervation of other EOMs. Isolated congenital CN4 palsy is oft en suspected in the presence of clinical evidence of ipsilateral hypertropia increasing on contralateral gaze, and with head tilt toward the ipsi-lateral shoulder. While the congenital nature of the dis-order appears clear when there is a history of lifelong spontaneous head tilt to the contralateral shoulder, in many cases present aft er many years of compensation for what the history suggests has been a progressive condition without identifi able 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 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 defi cit, narrowing of the palpebral fi ssure on adduction, and globe retrac-tion 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 confi rmed in one sporadic unilateral [46] and another bilateral autopsy case of DRS [47]. Parsa et al. fi rst used MRI to demonstrate absence of the suba-rachnoid portion of CN6 in DRS [48], a fi nding that has been confi rmed 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 defi cient 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 struc-tural abnormalities of all EOMs except those innervated by the inferior division of CN3 [53]. Orbital motor nerves are typically small, with CN6 oft en nondetectable. Lateral rectus (LR) muscles are oft en structurally abnormal, oft en 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. Th e subarachnoid CN3 may be small. Th erefore, DURS2-linked DRS is a diff use CCDD involving but not limited to CN6.


CFEOM is not a primary muscle disorder, but ■

rather a cranial nerve disorder.


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.


6

6.6.5 Moebius Syndrome

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

impairment. Moebius syndrome is a heterogeneous clinical disorder whose clinical defi nition has evolved in the recent literature. Minimum criteria include congeni-tal facial palsy with impairment of ocular abduction [54–56]. Th e wide clinical spectrum and multiple areas of brainstem involvement in patients with Moebius syn-drome have led to its early conceptualization as a devel-opmental 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 suba-rachnoid portions of motor cranial nerves innervating the orbit, but marked hypoplasia of the deep portions of the EOMs.

Antagonists of hypoplastic EOMs become sec- ■

ondarily 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.

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 contrac-tile increase in cross-section from up to down gaze

6.7 Acquired Motor Neuropathy 71

6.7 Acquired Motor Neuropathy

On orbital imaging, the hallmarks of EOM denervation are atrophy of the EOM belly, and loss of normal contrac-tile increase in EOM cross-section in the EOM’s fi eld 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 inner-vation 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 nor-mally 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

Th eoretical, experimental, and much clinical evidence support the idea that acute, unilateral SO palsy produces a small ipsilateral hypertropia that increases with contral-ateral gaze, and with head tilt to the ipsilateral shoulder [57, 58]. Th e 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. Th e three-step test has been the cornerstone of diagnosis and classifi cation cyclovertical strabismus for generations of clinicians [60]. When the three-step test is positive, clini-cians 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 inconsisten-cies with common clinical observations [62], bilateral should cause greater head-tilt-dependent change in hypertropia than unilateral SO palsy; however, the oppo-site is found [63]. Simulation of putative eff ects head tilt in SO palsy suggests that SO weakness alone cannot account for typical three-step test fi ndings [64].

High-resolution MRI has quantifi ed 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 fi ber size is reduced by 80%, sparing the orbital layer [68]. A striking and consistent MRI fi nding has been nonspecifi city 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” pat-tern of incomitant hypertropia [70]. Vestibular lesions produce head-tilt-dependent hypertropia, also known as skew deviation [71] that can mimic SO palsy by the three-step test [72]. Pulley heterotopy can simulate SO palsy [16, 73], and is probably not its result, since SO atrophy is not associated with signifi cant alterations in pulley posi-tion 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 infl ection 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 para-lyzed 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


Th e three-step test is not specifi c for trochlear ■

palsy.Orbital imaging confi rms neurogenic atrophy of ■

the SO muscle.


6

muscle, entering the IO in the EOM’s posterior surface relatively superfi cially in the orbit when compared with innervation to the other EOMs. Isolated acquired neuro-pathic 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. Th e forms of strabismus arise from abnormalities in the central nervous system, some of which are structural lesions that may be imaged.

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 artifi cially esotropic and exo-tropic 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

Th e cerebellum contributed toward binocular alignment [81]. Hereditary cerebellar degeneration is oft en associ-ated with convergence insuffi ciency, and in advanced cases oft en produces cerebellar atrophy [82]. Cerebellar or brainstem tumors may be associated with acute onset of concomitant esotropia in children [83]. Acquired cer-ebellar 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 reces-sive disorder of axon path fi nding in the central nervous system. Patients have essentially complete horizontal ophthalmoplegia despite intact EOMs and peripheral motor innervation to them, but MRI demonstrates dys-plasia of the hindbrain suggestive of a sagittal fi ssure interrupting decussating white matter tracts [84].

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


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41. Demer JL, Clark RA, Engle EC (2009) Magnetic resonance imaging evidence of an asymmetrical endophenotype in congenital fi brosis of extraocular muscles type 3. Invest Ophthalmol Vis Sci (in preparation)

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45. Strachan IM, Brown BH (1972) Electromyography of extraocular muscles in Duane’s syndrome. Br J Ophthalmol 56:594–599

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59. Adler FE (1946) Physiologic factors in diff erential diagno-sis of paralysis of superior rectus and superior oblique muscles. Arch Ophthalmol 36:661–673

60. Scott WE, Kraft SP (1986) Classifi cation and treatment of superior oblique palsies: II. Bilateral superior oblique pal-sies. In: Caldwell D (ed) Pediaric ophthalmology and stra-bismus: transactions of the New Orleans academy of ophthalmology. Raven, New York

61. Straumann D, Steff en H, Landau K, et al (2003) Primary position and Listing’s law in acquired and congenital tro-chlear nerve palsy. Invest Ophthalmol Vis Sci 44:4282–4292

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63. Kushner BJ (1988) Th e diagnosis and treatment of bilateral masked superior oblique palsy. Am J Ophthalmol 105:186–194

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7.1 Congenital Cranial Dysinnervation Disorders: Facts About Ocular Motility Disorders

Electromyographic, clinicopathologic, neuroradiologic and genetic studies changed the view upon some con-genital ocular motor disorders dramatically during the last decades [1–8].

Many of them that were formerly understood as con-genital 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 fi brosis 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

cranial nerve development. Th e 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 disor-ders (CCDDs) coined in 2002 [16] a new entity was estab-lished that convincingly encompasses diff erent congenital, nonprogressive diseases sharing etiopathologic features.

Th e underlying concept postulates a defect in the pre-natal development of the neuronal structures supplying innervation of the cranial region.

As to the nature of this defect, primary genetic disor-ders in the neurodevelopmental plan or exogenic infl u-ences are a possibility.

Congenital Cranial Dysinnervation Disorders: Facts and Perspectives to Understand Ocular Motility DisordersAntje Neugebauer and Julia Fricke

Chapter 7

7

Core Messages

Congenital cranial dysinnervation disorders ■

(CCDDs) are a group of neurodevelopmental dis-eases of the brainstem and the cranial nerves.Endogenic or exogenic disturbances lead to a pri- ■

mary dysinnervation of structures supplied by cranial nerves. Motility disturbances and poten-tially structural changes occur.Secondary dysinnervation occurs if fi bers of other ■

cranial nerves innervate the primarily misinner-vated structures. Synkinetic movements or cocontractions of antagonists result and may lead to structural changes in the muscles involved.Neurogenetic studies proved congenital fi brosis of ■

the extraocular muscles (CFEOM), isolated and

syndromic forms of Duane syndrome and horizon-tal 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 fi brotic features such as congenital Brown syndrome, congenital monocular elevation palsy and vertical retraction syndrome may be discussed as CCDDs.

78 7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives

7

So it has to be stressed that although by genetic inves-tigations in familial cases of congenital cranial dysinner-vation 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 nec-essarily genetic. Nevertheless, the proof that mutations in genes playing a role in brainstem development are caus-ative 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 fea-tures: the underaction of the non- or underdeveloped cranial nerve is referred to as primary dysinnervation, which may lead to secondary fi brotic changes in the tar-get muscles. Substitutional innervation of the target mus-cles by cranial nerve fi bers 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 for-mation of brainstem structures involved in ocular motor control are of interest.

A brief summary of the steps involved in proper devel-opment of the brainstem structures supplying ocular motility may indicate diff erent stages at which hazardous infl uences can induce specifi c lesions.

7.1.1.1 Brainstem and Cranial Nerve Development

From the fi rst 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, segmen-tation 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. Th at is why insight into the developmental plans of inver-tebrates helps us to understand the developmental steps in mammals.

Th e 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. Th e hox homeobox cluster encoding sequential processes of diff erentiation both in time and space has been studied in the genome of Drosophila melanogaster. In mammals related sequences that encode diff erent steps in hindbrain diff erentiation are identifi ed 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 fi eld 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 can-didate genes are likely to elucidate the role of further genes in these processes.

Hitherto mutations in six genes are identifi ed as caus-ative 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 dif-ferent subgroups of Duane retraction syndrome [6, 10, 23, 24]. Th e example of the diff erent mutated genes causing Duane retraction syndrome shows that the interference with diff erent 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 pre-sumed 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]. Th is disorder drew the attention of Elizabeth Engle to the

7.1 Congenital Cranial Dysinnervation Disorders: Facts About Ocular Motility Disorders 79

entity of ocular motility disorders [2] and in 2001 it was the fi rst congenital eye motility disorder in which a gene relevant in cranial nerve development was identifi ed 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 charac-terized by bilateral ptosis and bilateral elevation defi -ciency 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 fi brous changes in the eye muscles that formerly led to the assumption that the disorder was primarily myogenic. More recent neuropathologic studies revealed abnormali-ties 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 disor-der, it could be shown that alterations in a kinesin pro-moting axonal transport processes in neurons play an etiopathologic role in CFEOM1. Th us clinic, pathologic and genetic fi ndings are consistent in this disorder with the notion of a primary defective innervation in the mus-cles usually supplied by the superior part of the third nerve, stemming from neurons located in the inferior part of the third nerve nucleus. Th e fi brous changes in the noninnervated muscles can be understood as secondary changes due to noninnervation of the muscle fi bers.

CFEOM2 is inherited in an autosomal recessive mode; features are bilateral ptosis and an exotropia with adduc-tion defi ciency 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 defi ciencies 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 diff erent families also indicate other genetic loci. Clinical overlap with congenital motility dis-orders classifi ed as vertical retraction syndrome is possi-ble [31, 32].

Duane Retraction SyndromeDuane retraction syndrome represents the most frequent and the most prominent congenital cranial dysinnerva-tion disorder (CCDD). In 1905 Alexander Duane pub-lished a paper titled “Congenital defi ciency of abduction, associated with impairment of adduction, retraction movements, contraction of the palpebral fi ssure and oblique movements of the eye” [33]. Th is 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 fi nd-ing 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 pub-lished cases, thus accumulating the data of 54 patients.

Th e 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]. Th us a paradoxical innervation of the lateral rectus was realized. A further milestone were clinicopathologic stud-ies by Hotchkiss and Miller who found absent sixth nerves in Duane retraction syndrome and confi rmed pathologic fi ndings by Mantucci dating from 1946 where a hypoplas-tic sixth nerve nucleus and absence of the sixth nerve were described. Miller showed that lateral rectus innerva-tion was taken over by fi bers of the third nerve [4, 7, 8].

Fig. 7.1 Patient with bilateral congenital fi brosis of the extraoc-ular muscles (CFEOM). Aft er bilateral inferior rectus recession, the patient still adopts a 10° chin-up head posture to fi xate due to ptosis and residual elevation defi ciency


7

Neuroradiologic studies later on also diagnosed hypopla-sia 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.

Th e spectrum of associated nonocular fi ndings encompasses miswiring syndromes as Marcus Gunn phe-nomenon and crocodile tears, vertebral anomalies as the Klippel-Feil anomaly and hearing problems. Syndromes encompassing Duane syndrome are Wildervanck or cer-vico-oculo-acoustic syndrome with Duane syndrome, sensorineural deafness and the Klippel-Feil anomaly as traits and Okihiro syndrome that combines Duane syn-drome with radial ray anomalies.

An induction of Duane syndrome by teratogens is possible; some patients with thalidomide embryopathy suff er from uni- or bilateral Duane syndrome [34, 86].

Th e fi rst mutation to be identifi ed 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 transcrip-tion factor. Th e 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 syn-drome (BSAS), bilateral Duane syndrome combines variably with sensorineural deafness, carotid artery malformations, delayed motor development and some-times autistic disorders. Th e syndrome is inherited in an autosomal recessive mode. In diff erent 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 suff ering 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 abnor-malities in the HOXA1 gene were found [38, 42].

Th e third gene involved in the genesis of Duane syn-drome 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 oft en bilat-eral Duane syndrome but also some abnormalities in the vertically acting eye muscles innervated by the third nerve. Th e gene CHN1 encodes a2-Chimaerin, a protein that plays a role in the information fl ow induced by eph-rin and ephrin-receptor interaction that leads to growth cone changes infl uencing 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].

Th e current pathophysiologic concept for Duane syn-drome putting together clinical, electrophysiologic, clini-copathologic, neuroradiologic and genetic fi ndings looks upon the disorder as a CCDD in which innervation of the lateral rectus by sixth nerve fi bers is not full or absent and third nerve fi bers, mainly those primarily intended for the medial rectus take over some innervation of the lat-eral rectus. Th us, in primary position the underlying paresis is partly or fully compensated for the lateral rectus

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

a d

e

b

c

7.1 Congenital Cranial Dysinnervation Disorders: Facts About Ocular Motility Disorders 81

receives nerve impulses of the third nerve, thus keeping the angle of squint in primary gaze relatively small with regard to the motility defi ciency in abduction. Sometimes even overcompensation with a divergent angle in primary position or synergistic divergence on adduction occurs. Th e most common pattern of motility in Duane syn-drome is an abduction defi ciency, accompanied by a slighter adduction defi ciency that results from the lateral rectus cocontracting on intended adduction. Th is cocon-traction results in retraction of the globe and narrowing of the palpebral fi ssure 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 unaff ected vertical eye movements. In the entity of so-called HGPPS hind-brain anomalies and ocular motor anomalies can be explained by disorders of the pathfi nding of fi bers that normally cross the midline in the hindbrain. Mutations in the ROBO3 gene that encodes a transmembrane recep-tor molecule that normally seems to promote midline crossing of some hindbrain axons were identifi ed in patients with HGPPS [15, 45]. Th e neuroanatomic corre-lates 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 non-crossing fi bers of ascending and descending tracts [46–48]. Neurologic examinations confi rm that atypical lack of crossing fi bers exists [49]. Th e nature of the pro-gressive scoliosis which means a signifi cant impairment to the patients may be to be neurogenic.

7.1.1.3 Disorders Understood as CCDDs

Th e 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, defi cient 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 identifi ed.

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

Fig. 7.3 Patient with familial horizontal gaze palsy and progres-sive scoliosis (HGPPS). Patient aft er bilateral medial rectus reces-sion 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)

b

d

a

c

e


7

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

ba

displays lid opening on intended downgaze on adduc-tion, hinting to a possible miswiring of fourth nerve neu-rons 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 adduc-tion (Fig. 7.6). Th e disorder was put into the context with

CCDDs by Traboulsi [52, 53]. Familial cases are described [54, 55] but an associated gene locus is not yet identifi ed. In a study targeting on ARIX as a candidate gene in con-genital trochlear palsy, no mutation was identifi ed 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].

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

cba

fed

ihg

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

ba

7.2 Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders 83

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. Th us Möbius syn-drome covers features of a more generalized developmen-tal brainstem syndrome [56, 57].

Isolated uni- or bilateral facial palsy is described as a familial disorder; gene loci are mapped [16, 53].

7.2 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.

In 1949, H.W. Brown (1898–1978) at the First Strabismus Symposium in Iowa City gave a lecture on congenital struc-tural muscle anomalies. In this talk and in the subsequent publication, he discussed congenital motility disorders with fi brotic features such as retraction syndrome, strabismus fi xus, vertical retraction syndrome and general fi brosis syn-drome. Furthermore, under the name of superior oblique tendon sheath syndrome, he introduced a special form of congenital elevation defi ciency 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 ver-tical retraction syndrome represent congenitial cranial dysinnervation disorders.

7.2.1 Congenital Ocular Elevation Defi ciencies: A Neurodevelopmental View

7.2.1.1 Brown Syndrome

Motility FindingsBrown syndrome is an oculomotor disturbance charac-terized by an elevation defi ciency on adduction, normal or near normal elevation on abduction, mild elevation defi ciency 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 aff ected eye in primary position may occur, a relative divergence of the eyes in upgaze may exist and sometimes widening of the lid fi ssure on adduc-tion can be observed [59, 60] (Fig. 7.7).

In acquired cases, Brown syndrome results from dam-age that hinders the passage of the superior oblique ten-don through the trochlea. Th e 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 group of congenital ocular motility disorders ■

are caused by developmental disturbances. Th ese are nonprogressive, incomitant forms of strabis-mus 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.

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

ba c

d e f


7

electromyography, which showed normal innervation in the inferior oblique. Brown subsequently regarded the disorder to be caused by a structural anomaly in a supe-rior 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 tis-sues [60–63].

Th e 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. Th e authors interpreted this fi nding in analogy to the paradoxical coinnervation found in Duane retraction syndrome and postulated a neurodevelopmental origin of the syndrome. Other authors confi rmed the results by electromyography, so that a total of fi ve cases with electromyographic record-ing of paradoxical innervation to the superior oblique are reported by three diff erent 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 para-doxical innervation refers to an electromyographic study by Catford and Hart [67] who could not fi nd 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 fi nding 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 mis-innervation, one has to consider that a misinnervation could lead to secondary changes in the muscle, tendon, trochlea and surrounding connective tissues. In the publi-cation by Gutowski that defi nes CCDDs it is summarized that “dysinnervation may be associated with secondary muscle pathology and/or other orbital and bony struc-tural 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.

Th e hypothesis is that a primary developmental dysin-nervation of the superior oblique muscle as it occurs in congenital fourth nerve palsy is accompanied by a sec-ondary dysinnervation of the superior oblique by fi bers of the third nerve.

Up to now CCDDs with secondary dysinnervation of ocular target muscles by nerve fi bers 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 fi bers normally intended for the antagonists of the primary dysinnervated muscles occurs in Duane syndrome and oft en keeps the deviation of the eyes in primary position remarkably small.

A misinnervation of a non- or underinnervated supe-rior oblique muscle by fi bers intended for the inferior oblique or the medial rectus would eliminate the eleva-tion on adduction found in congenital fourth nerve palsy. Furthermore, the vertical and torsional angles of devia-tion in primary position would be kept small by a coin-nervation by fi bers normally running to the inferior oblique muscle. First, because the antagonist of the pri-marily paretic superior oblique muscle might receive less nerve fi bers and second, because its tone now simultane-ously is antagonized by a tone in the superior oblique.

An aberrant innervation in the superior oblique by fi bers intended for the inferior oblique would result in blockage of elevation in adduction by cocontraction of the two muscles. Th is could be the explanation for the elevation defi ciency on adduction. Primary dysinnerva-tion 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 fi ssure on adduction. Th is would be an eff ect reverse to the narrowing of the lid fi ssure on adduction by retraction of the globe in Duane syndrome. A paradoxical coinnerva-tion 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 fi bers originally destined for the medial rectus would explain depression of the globe on adduction. Moreover, an overcompensation of the pri-mary 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


superior oblique by fi bers primarily destined to the medial rectus would be possible [68].

At last even a miswiring of fi bers prone to the supe-rior rectus could be discussed. Th is would explain why many patients show also a minor elevation defi ciency in abduction.

Th us, the motility fi ndings 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 sec-ondary misinnervation.

Saccadic Eye MovementsBarton [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 fl ip,” 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 fi eld of action of the inferior oblique.

Th e authors compare the fl ip movement of the eye to that in horizontal saccades in Duane syndrome. With the onset of cocontraction, a fl ip could occur by the sudden action of the antagonist.

ComorbidityIn the majority of cases Brown syndrome represents an iso-lated disease. Among the diseases reported to accompany Brown syndrome interestingly CCDDs such as Duane syn-drome, 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 clo-sure 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.

Th e coincidence with CCDDs could be caused by common pathogenetic mechanisms interfering with brainstem and cranial nerve development.

Th e high incidence of contralateral fourth nerve palsies also is of interest with regard to a potential

misinnervation disorder in Brown syndrome. In these cases a bilateral disturbance of trochlear nerve develop-ment could be postulated that in the side with Brown syn-drome 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 FeaturesUnder 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 dif-ferent from the third nerve [52].

LateralityDe Respinis [34] reviewed publications on Duane syn-drome and fi gured out side distribution from pooled data of diff erent 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 con-genital Brown syndrome the right side was aff ected in 53%, the left side in 38% and both sides in 9%.

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

a

d

c

b


7

In the series on Duane syndrome [34], a total of 835 cases were analyzed.

In 59% the left eye was aff ected, in 23% the right eye and in 18% bilaterality was found.

Assuming that in Duane syndrome the pathophysio-logic mechanism has a tendency to aff ect rather the left eye, these data seem contradictory to a common pathogenesis.

Th is contradiction resolves because the fi bers of the fourth nerve are crossing and the nucleus of the fourth nerve lies contralaterally. Th e hypothesis stating a primary brainstem related pathophysiologic mechanism of Brown syndrome, the data concerning laterality show an interest-ing 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 signifi cantly.

Sex DistributionPooled data of ten and our own studies [60, 65, 74–81] encompassing 246 patients showed the aff ection 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.

IncidenceIncidence of Brown syndrome is estimated to be 1 per 430–450 strabismus cases, i.e., 0.22% [60]. Duane syn-drome occurs in at least 1% of strabismus cases [34].

Both syndromes are rare but a 4 times greater inci-dence of Duane syndrome remains to be explained. Stating a failed innervation of the superior oblique mus-cle by fi bers of the fourth nerve and paradoxical innerva-tion of the superior oblique in Brown syndrome one would have to add the cases of uni- or bilateral congenital fourth nerve palsy to fi gure out the incidence of the underlying pathophysiologic entity of a developmental fourth nerve disorder.

HeredityIn Brown syndrome, most cases seem to occur spontane-ously. Of the 126 cases in the 1973 report of Brown [59] 2 are familial, although it cannot be confi rmed 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 lit-erature with a total of 23 involved patients, he himself add-ing another one [60]. Lobefalo [82] reported a family with autosomal distal arthrogryposis multiplex congenita and Brown syndrome; thus, we overlook a total of ten descrip-tions of familial Brown syndrome.

Th ree 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 heredi-tary 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 aff ection [85]. ARIX was not found to be mutated. But the case reports of the patients should be read carefully for the late onset of symp-toms in the teenage years should also let an acquired pathol-ogy maybe on the basis of a familial rheumatic disposition being taken into consideration. Th us, 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%).

Th ree patients (3.4%) had relatives with Brown syn-drome: 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 SyndromeAmong the developmental defects caused by thalidomide there are also cranial miswiring syndromes. We investi-gated 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 infe-rior oblique; furthermore, patients suff ered from gaze paresis, isolated abduction weakness, aberrant lacrimation and facial nerve palsy.


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 FindingsImaging studies in Brown syndrome displayed diff erent pathologies. Enlargement and irregularities in the tro-chlear 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 fi nding with regard to the hypothesis of a primary devel-opmental disorder in the fourth nerve underlying Brown syndrome.

To test the hypothesis of a fourth nerve dysinnerva-tion in Brown syndrome, Kolling and coworkers exam-ined 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 defi ciency a fi nding in favor of the hypothesis. Muscular anomalies were not found in these patients [80, 88].

Natural Course in Brown SyndromeAs to the natural course of the disease, reports are incon-sistent. Whereas Wright states that congenital Brown syndrome yields rather stable fi ndings, many authors report spontaneous improvement or even resolution [89–91]. In most of our patients fi ndings 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 signifi cant spontaneous improvement.

Th e fi nding of spontaneous resolutions challenges the hypothesis of a dysinnervation. But one has to con-sider that the hypothesis states secondary fi brotic changes. Also under the assumption of a mere mechan-ical cause of Brown syndrome, spontaneous improve-ments remain to be explained. Any explanation such as growth changes of the orbital anatomy or changes in fi brotic tissues would serve under both assumptions. In the setting of cocontraction, changes in fi brous strands even may be more probable. Furthermore, the postna-tal 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].

Intra-and Postoperative FindingsStructural changes in the superior oblique tendon in Brown syndrome have been described by many surgeons [79, 92, 103]. In our series, 28 patients underwent oper-ation, 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 fi brotic changes in this muscle were reported.

Surgical results are oft en disappointing as indicated by the multitude of approaches suggested. Surgeons oft en recognize a disappointing discrepancy between intraop-erative fi ndings aft er interventions on the superior oblique in that passive motility is improved aft er the procedure but active motility in the postoperative course is still not improved signifi cantly.

Papst and Stein in their thorough early discussion of a potential misinnervation already hinted to this fi nding 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 verifi ed or falsifi ed.

7.2.1.2 Congenital Monocular Elevation Defi ciency and Vertical Retraction Syndrome

While in congenital Brown syndrome an elevation defi -ciency of the eye exists if the globe is adducted, in con-genital monocular elevation defi ciency 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 pseu-doptosis in the majority of cases. In a considerable number of cases restriction of the globe to forced duc-tion into elevation is found. Oft en the lid shows para-doxical movements on yaw movements, i.e., the Marcus Gunn phenomenon. Furthermore dissociated vertical deviation (DVD) is present, sometimes it occurs aft er operation. Oft en 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 con-genital monocular elevation defi ciency in which they reg-istered pseudptosis in 90%, true ptosis in 64%, chin-up head position in 77%, hypotropia in primary gaze in 97%


7

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 supra-nuclear disorder and seemed to exclude an infranuclear disorder. Some authors discuss a fascicular lesion [62, 94, 97].

Further, the fi nding that elevation is hindered in abduction, which means in the fi eld of action of the supe-rior rectus, and in adduction, which means in the fi eld of action of the inferior oblique, led many observers to exclude a nuclear disorder: for the third nerve, the sub-nucleus for the innervation of the superior rectus lies contralaterally, and for the inferior oblique, it lies ipsilat-erally in the mesencephalon.

Remarkably, as in Brown syndrome, which was ini-tially 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 electromyo-graphic 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 neces-sarily is required to produce the typical motility pattern, [62, 94] thus a nuclear origin confi ned 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 pri-marily fi brotic origin is presumed.

Th us supranuclear, nuclear, fascicular and muscular etiologies are discussed for the rare disorder of congenital monocular elevation defi ciency.

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.

Th ree of our patients showed retraction of the globe on vertical eye movements.

Th is leads to similarities with vertical retraction syn-drome 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 anoma-lies in vertical eye movements with retraction of the globe with narrowing of the lid fi ssure; others describe vertical motility disorders with retraction combined with hori-zontal abnormalities that resemble Duane syndrome.

Vertical retraction syndrome seems to be even rarer than congenital monocular elevation defi ciency.

A secondary misinnervation as cause for the retrac-tion of the globe on vertical movements would be a pos-sible explanation.

Th e view upon congenital double elevator palsy and vertical retraction syndrome as neurodevelopmental dis-orders would require a model that solves the question why Bell’s phenomenon remains intact in some cases.

a

b

c

d

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


7.2.2 A Model of some Congenital Elevation Defi ciencies as Neurodevelopmental Diseases

Our inquiries into the fi eld of congenital elevation defi -ciencies lead us to hypothesize that these disorders might represent rather a continuum of developmental disorders than distinct diseases.

Clinically, it is sometimes hard to diff erentiate between a Brown syndrome and a congenital monocular elevation defi ciency. Wright in his review hinted to 70% of patients that had been operated and that demon-strated signifi cant elevation defi ciency 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 aff ected side. Patients with congeni-tal monocular elevation defi ciency may display retrac-tion on up- or downgaze so that clear diff erentiation from vertical retraction syndrome may be diffi cult. At last even diff erentiation between a unilateral congenital fi brosis syndrome and these disturbances may be diffi -cult. Th us 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

sequential activation of genes and the building up of gradients of mediators for developmental steps.

Th e crossing of fi bers in certain segments of the brain-stem depends on the integrity of the cascade of interac-tions between substances mediating attraction to and repulsion from the midline and their receptors. Th e muta-tions in the ROBO3 gene leading to HGPPS are an exam-ple of a locally defi ned 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 fi bers of the third nerve e.g., fi bers 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 fi bers of the third nerve, the subnucleus sending fi bers across the midline that lies next to the fourth nerve and innervates the levator palpebrae muscle would be aff ected and fourth nerve palsy or Brown syndrome accompanied by ptosis would result. A substitutional innervation, e.g., by fi bers of the motor portion of the fi ft h nerve or of the third nerve would compensate the primary dysinnerva-tion 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 fi ssure.

superior rectus, SIF

superior rectus, MIF

levator palpebrae, SIF

superior oblique, SIF

N.III-fibers

N.IV

N. III-nucleus

N. IV-nucleus

x

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 aff ects 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 fi bers. Note that this misinnervation does not run topographically in the way shown. Th e lines just indicate which muscles might share innervation


7

Further extension would encompass the subnucleus for the superior rectus. Brown syndrome and ptosis would be accompanied by an elevation defi ciency in abduction, thus completing the image of congenital monocular ele-vation defi ciency. If the superior rectus is innervated by fi bers of its main antagonist, retraction movements as well as depression defi ciency result.

Interestingly, recent studies on the functional neuro-anatomy of the third nerve nucleus state a dual innerva-tion of the eye muscles. So called single innervated muscle fi bers (SIF) and multiple innervated muscle fi bers (MIF) receive input each from a special subset of motoneurons that diff er in their histologic appearance from neurons innervating SIF fi bers. Th ese 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 fi nal common path in eye muscle innervation. Th e principle itself as introduced by Sherrington referred to the motoneuron as the fi nal 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 supra-nuclear disorders in general have to be reconsidered.

Th e 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. Th e functional role of the MIF fi bers 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. Th is would explain why Bell’s phenomenon remains intact in some cases of monocular elevation defi ciency. Th us the concept of a supranuclear disorder would not be necessary.

Th is model would explain Brown syndrome, congeni-tal monocular elevation defi ciency and vertical retraction syndrome as disorders of mesencephalic disturbance of midline crossing of fourth and third nerve fi bers with dysinnervation (Fig. 7.11).

Fig. 7.11 Model of congenital monocular elevation defi ciency as a neurodevelopmental disorder. A schematic drawing shows the third and fourth nerve nuclei in the brainstem. A unilateral gradual disturbance exists that mostly aff ects the fourth and third nerve nuclei or their crossing neurons. An x indicates disruption of normal fourth nerve innervation and disruption of the crossing fi bers 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 fi bers 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. Th e lines just indicate which muscles might share innervation. Green line indicates multiple innervated muscle fi bers (MIF) for tonic innervation of the superior rectus not aff ected by the lesion

x xx

superior rectus, SIF

superior rectus, MIF

levator palpebrae, SIF

superior oblique, SIFN.V-fibers

N.III-fibers

N.III

N.IV

N. III-nucleus

N. IV-nucleus

References 91

Th e clinical fi ndings seem consistent, future studies namely genetic studies in familial cases or on candidate genes will help to test this model.

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

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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. Tischfi eld 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


Congenital Brown syndrome, congenital mon- ■

ocular elevation defi ciency and vertical retrac-tion syndrome as nonprogressive forms of strabismus with fi brotic changes share features with CCDDs and are found to be accompanied intraindividually or familial by other CCDDs.Electromyographic, neuroradiologic and surgi- ■

cal fi ndings support the hypothesis that Brown syndrome represents a CCDD.Genetic linkage analysis or examination of candi- ■

date genes might prove or disprove a model that hypothesizes a continuous spectrum of congenital neurodevelopmental elevation disorders.


7

25. Heuck G (1879) Über angeborenen vererbten Beweglich-keitsdefect der Augen. Klin Monatsbl Augenheilkd 17: 253–278

26. Brodsky MC, Pollock SC, Buckley EG (1989) Neural misdirection in congenital ocular fi brosis syndrome: implications and pathogenesis. Pediatr Ophthalmol Strabismus 26(4):159–161

27. Cibis GW (1984) Congenital familial external ophthal-moplegia 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 fi brosis 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 fi brosis 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 con-genital fi brosis of extraocular muscles type 2 (CFEOM2). Am J Ophthalmol 136(5):861–865

31. Hanisch F, Bau V, Zierz S (2005) Congenital fi brosis 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) Identifi cation of KIF21A mutations as a rare cause of congenital fi brosis of the extraocular muscles type 3 (CFEOM3). Invest Ophthalmol Vis Sci 45(7):2218–2223

33. Duane A (1905) Congenital defi ciency of abduction, asso-ciated with impairment of adduction, retraction move-ments, contraction of the palpebral fi ssure 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 reso-nance 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 verifi ed by magnetic resonance imaging. Am J Ophthalmol 125(3):399–401

38. Tischfi eld 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) Th e 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 Unter-suchungen zur Pathogenese und Th erapie des Musculus obliquus superior-Sehnenscheidensyndroms (Brown-Syndrom). 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 com-pound 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 pro-gressive scoliosis. Neuroradiology 50:453–459

47. Pieh C, Lagrèze WA (2007) Angeborene Fehlinnerva-tionssyndrome. Ophthalmologe 104:1083–1096

48. Sicotte NL, Salamon G, Shattuck DW, et al (2006) Diff usion tensor MRI shows abnormal brainstem crossing fi bers 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 con-genital 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 syn-dromes with congenital limitation of eye movements. Trans Am Ophthalmol Soc 102:373–389

53. Traboulsi EI (2007) Congenital cranial dysinnervation dis-orders 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 supe-rior oblique muscle palsy. Acta Med Okayama 59(2): 55–62

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56. De Souza-Dias CR, Goldchmitt M (2007) Further consider-ations about the ophthalmic features of the Möbius sequence, with data of 28 cases. Arq Bras Oft almol 70(3): 451–457

57. Verzijl HT, van der Zwaag B, Cruysberg JR, et al (2003) Möbius syndrome redefi ned: a syndrome of rhomben-cephalic maldevelopment. Neurology 61(3):327–333

58. Von Noorden GK (2002) Th e 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 man-agement. Trans Am Ophthalmol Soc 47:1023–1107

61. Esser J, Mühlendyck H (2004) Jaensch-Brown-Syndrom. In: Kaufmann H (ed) Strabismus. Georg Th ieme, 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 stra-bismus, 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 syn-drome. 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 Musculus-obliquus-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 syn-drome. Can J Ophthalmol 20:23–28

69. Barton JJ, Intriligator JM (2001) Vertical saccades in supe-rior oblique palsy and Brown’s syndrome. J Neuroophthalmol 21:250–255

70. Wilson ME, Eustis HS, Parks MM (1989) Brown’s syn-drome. Surv Ophthalmol 34:153–172

71. Bhola R, Sharma P, Saxena R, et al (2004) Magnetic reso-nance 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 con-tralateral inferior oblique overaction: a possible mecha-nism. 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

75. Crawford JS, Orton RB, Labow-Daily L (1980) Late results of superior oblique muscle tenotomy in true Brown’s syn-drome. Am J Ophthalmol 89:824–829

76. Eustis HS, O’Reilly C, Crawford JS (1987) Management of superior oblique palsy aft er surgery for true Brown’s syn-drome. 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 syn-drome. 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 tenec-tomy 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 congen-ita 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) Th e 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) Th alidomide embryopathy: a model for the study of congenital incomitant horizontal strabismus. Trans Am Ophthalmol Soc 89:623–674

87. Kida M (ed) (1987) Th alidomide embryopathy in Japan. Kodansha, Tokyo

88. Bhola R, Rosenbaum AL, Ortube MC, et al (2005) High-resolution 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 syn-drome. Am J Ophthalmol 81:289–296

94. White JW (1942) Paralysis of the superior rectus and infe-rior oblique muscles in the same eye. Arch Ophthalmol 27:366–371


7

95. Olson RJ, Scott WE (1998) Dissociative phenomena in con-genital monocular elevation defi ciency. 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) Th e neurology of eye movements, 4th edn. Oxford University, Oxford, New York

98. Bell J A, Fielder A, Viney S (1990) Congenital double ele-vator 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) Th e extraocular motor nuclei: organization and functional neuroanatomy. In: Büttner-Ennever 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 defi ned 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

8.1 Amblyopia

Amblyopia is a sensory anomaly defi ned as defective uni-lateral or bilateral visual acuity (VA). Th ere are a number of classifi cations of amblyopia based on the etiological cause(s). Th e reported prevalence of amblyopia varies widely, from 1–5%. Diff erences in prevalence can be attributed to the population studied (e.g. ethnicity), and

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

The Value of Screening for Amblyopia RevisitedJill Carlton and Carolyn Czoski-Murray

Chapter 8

8

Core Messages

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 con-ducted by orthoptists or by professionals trained and supported by orthoptists.Th e justifi cations 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 amblyo- ■

pia could not be considered as cost-eff ective, but acknowledged that much uncertainty exists sur-rounding the short- and long-term implications of the condition(s). Further research is needed to provide such evidence.Treatment of amblyopia associated with refrac- ■

tive error should incorporate a period of observa-tion 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 aft er glasses are prescribed. Most improvement

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. Th ere 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 eff ective 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 infl uencing 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; fi ne motor skills; reading speed; and interpersonal relationships.Th e 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.

96 8 The Value of Screening for Amblyopia Revisited

8

accepted defi nition of amblyopia in terms of VA defi cit. Studies that report on amblyopia prevalence, diagnosis, and/or treatment must be interpreted carefully, and oft en 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. Th is chapter will explore what is meant by screening; detection of amblyopia and strabis-mus through screening programs; amblyopia treatment; and consequences of amblyopia and its treatment (both in the long and short term).

8.2 What Is Screening?

Th e purpose of screening is to identify persons as being at greater or lesser risk of developing, or having, a par-ticular condition. Th e United Kingdom (UK) National Screening Committee (NSC) defi ned screening as “a public health service in which members of a defi ned population, who do not necessarily perceive that they are at risk of, or are already aff ected by, a disease or its complications, are asked a question or off ered 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]. Th ere are recognized criteria for screening relating to the condition itself, diagnosis, treatment, and cost. Th ese 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. Diff erences in health care provision from one country to another can make it diffi cult to draw inferences on the possible benefi ts and risks associated with the implemen-tation or withdrawal of such programs. For example, dif-ferences exist between the UK and the United States of America (USA). Within the UK, vision screening of chil-dren was developed as part of the child health surveil-lance programs established during the 1960s and 1970s. Th e appropriateness of such programs was called into question following a systematic review of their eff ective-ness [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 ambly-opia 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]. Th is recommenda-tion has been adopted regionally in the UK, although not universally.

Within the USA, there are also widespread diff er-ences 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 Th e condition should be an important health problem, whose epidemiology and natural history are understood. Th ere should be a recognizable risk factor or early symptomatic stage

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

Treatment Th ere should be an eff ective treatment or intervention for those identifi ed as having the disease or condition, with evidence of early treatment leading to better outcome than late treatment. Th ere should be agreed evidence-based policies regarding which individuals should be off ered treatment

Program Th ere should be evidence from high-quality randomized controlled trials (RCTs) that the screening program is eff ective in reducing mortality or morbidity. Th ere should be evidence that the complete screening program (including the test, diagnostic procedures, and treatment) is clinically, socially, and ethically acceptable. Th e benefi t of the program should outweigh the physical and psychological harm. Th e 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 What Is Screening? 97

(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. Th is was highlighted by Ciner et al. [6], who recommended that specifi c compo-nents 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 oft en driven by political rather than clinical factors.

8.2.1.1 Screening for Amblyopia

Th e purpose of pre-school vision screening for amblyopia is to detect children with unilateral or bilateral amblyo-pia. Accurate detection of amblyopia is primarily achieved through VA testing. Th e value of conducting other tests for the purpose of screening for amblyopia alone is mini-mal; some would argue additional tests could be included in the screening program to detect amblyogenic factors (e.g. strabismus or refractive error).

8.2.1.2 Screening for Strabismus

Th e 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. Th erefore, the jus-tifi cation of pre-school vision screening for large-angled strabismus may not be valid. Th e detection of small-angle strabismus, however, is not as easy and requires expert testing from orthoptists and ophthalmologists. Th e 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 condi-tion would be undertaken. To that end, the value of screening may be questioned. An argument for screen-ing could be that the presence of a small-angle strabis-mus is an amblyogenic factor: amblyopia may not be present at the time of screening; however, the existence

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. Th e justifi cation would be that the presence of signifi -cant refractive error may impact upon educational prog-ress and daily living. Th e existence of unequal refractive error (anisometropia) could be deemed an amblyogenic risk factor. Indeed, the correction of any clinically sig-nifi cant 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

Any form of pre-school vision screening is likely to result in detection of other ocular conditions. Th ese 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 justifi cation of screening for detection of these conditions alone cannot be justi-fi ed. To screen for such conditions in isolation is neither practical nor appropriate. Th e economic benefi t of adding such conditions to a screening program for amblyopia and/or strabismus is negligible.

8.2.2 Diff erence Between a Screening and Diagnostic Test

Th ere is diff erence between a screening test and a diag-nostic 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 defi cit 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 infl uence the management plan of the condition. A diagnostic test oft en quantifi es 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. Th is would be achieved through refraction (diagnostic test).


8

8.2.3 Justifi cation for Screening for Amblyopia and/or Strabismus

Th e justifi cation of pre-school vision screening for ambly-opia 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. Th e 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 eff ect 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 fi ndings 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 indi-viduals with unilateral amblyopia with a newly acquired loss of vision in the non-amblyopic eye was recorded. Th e 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 life-time risk and annual rate of permanent visual impair-ment 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]). Th is can be attributed to the increased prevalence of other ocular disorders that occur with increasing age (such as cataract and age-related macular degeneration). Th e authors stated that every year as a result of disease aff ecting the non-amblyopic eye, at least 185 people in the UK with uni-lateral 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 aft er disease in the non-amblyopic eye being reported. Th e 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%. Th is 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 cardiovas-cular, 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 impair-ment is 12.5.

When vision loss in the non-amblyopic eye in the presence of amblyopia does occur (through injury or dis-ease), the eff ect on the individual is oft en devastating. Th ere 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. Th is will be examined in more detail towards the end of the chapter.

8.2.4 Recent Reports Examining Pre-School Vision Screening

Th e scarcity of evidence that would allow decision makers in the UK NHS to fund screening programs with confi -dence that it is an effi cient use of limited health care resources has made screening for amblyopia problematic. To be cost-eff ective, a program has to demonstrate that it is fi rst clinically eff ective. 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 man-dated 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. Th e problems associated with older established programs relate mainly to the reality that oft en these were imple-mented many years ago when evidence was limited, or they were never subject to the level of scrutiny that is cur-rently expected for any new technology or program. Th e recent review of screening for amblyopia is one such area.

8.2 What Is Screening? 99

In 2008, the Health Technology Assessment report on pre-school vision screening was updated, examining both the clinical and cost eff ectiveness 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 eff ectiveness of screening children for amblyopia and strabismus before the age of 5 years was undertaken. Cost eff ectiveness and expected value of per-fect information (EVPI) modeling was reported. EVPI modeling is used in cost-eff ectiveness analysis to attempt to establish the benefi ts of undertaking research that would reduce the costs of uncertainty. Th e cost of uncer-tainty in this case is that the wrong disinvestment deci-sion 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 eff ects of amblyopia over an individual’s remain-ing lifetime was also constructed. Th ese models were incorporated into a separate screening model that repre-sented the potential impact of treatment. Th e expected health outcome for the individual was defi ned 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 eff ects of childhood amblyopia on a cohort of individuals who would have bilateral or unilateral vision loss over a 93-year time horizon. Th e costs associ-ated with the screening program and the benefi ts (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.

Th e model population was informed by the literature reviews. It was identifi ed during the data extraction pro-cess that there was a signifi cant lack of quantitative data available which could be used in the model. Th is prob-lem was addressed by having a pragmatic approach to estimate the transitions in the model for which amblyo-genic factors translated into a number of VA states. A number of experts, who were able to confi rm 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 eff ectiveness of treat-ment for amblyogenic factors. It was assumed that by removing the risk factor for refractive error, the out-come would be 100% eff ective. Strabismus treatment is acknowledged to be less successful; therefore, the

outcomes for removing the amblyogenic risk were con-sidered 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-eff ective use of resources. Analysis of cost eff ectiveness using the available research data found that screening was not cost-eff ective at cur-rently 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. Th e lack of evi-dence surrounding the long-term impact of amblyopia increased the level of uncertainty in the model. By mak-ing a number of assumptions on utility loss (i.e. the impact on quality of life), the model demonstrated that screening could become highly cost-eff ective. EVPI mod-eling 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.

Th ese fi ndings may not provide the ideal result for decision makers, as the answers are not clear cut. Cost eff ectiveness alone should not be the deciding factor in the provision of pre-school vision screening. For exam-ple, the issue of equity may also need to be considered. Th is 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. Th e fi gures reported earlier, linking the cost per QALY, are those which are applied to new technologies. Th e QALY threshold for disinvestment is undefi ned at present.

Th e German Institute for Quality and Effi ciency in Healthcare (IQWIG) is an independent scientifi c institute that investigates the benefi ts and harms of medical inter-ventions. In producing reports on the assessment of an intervention (such as screening), IQWIG adheres to strict inclusion and exclusion criteria in the reviewing of exist-ing literature surrounding the given subject. In 2008, IQWIG assessed the benefi ts of screening for visual impairment in children up to the age of 6 years [14]. Th ey concluded that “no robust conclusions” could be directly inferred from the studies identifi ed in their review. To that end, the notion of pre-school vision screening could neither be supported nor rejected.


8

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

Th e accurate detection of amblyopia, strabismus, and/or refractive error undoubtedly forms a critical factor in the reported success of any pre-school vision screening pro-gram. However, much variation exists both within and between countries as to the content of vision screening programs. Th is 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 diff erences, it is oft en diffi cult to make direct comparisons between stud-ies 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 eff ectively in pre-school vision testing.

Th e eff ectiveness of a screening test in detecting a con-dition is considered in terms of sensitivity, specifi city, and positive and negative predictive values. Sensitivity is defi ned as the proportion of individuals with the target

condition in a population who are correctly identifi ed by a screening test. Specifi city is the proportion of individu-als free of the target condition in a population who are correctly identifi ed by a screening test. Positive predictive values describe the proportion of individuals with a posi-tive result who have a target condition; and negative pre-dictive value is the proportion of individuals who test negative and who do not have a target condition.

8.3.1 Vision Tests

Th e use of crowded logMAR acuity is the gold-standard VA measure in adults both within clinical and research settings. Th is is also becoming the case with VA mea-surement in children. Steps have been made to identify normative values of pediatric VA using diff erent vision tests, protocols of testing, and repeatability of testing [15–19]. Th e preference as to which vision test that is to be included in a screening program is not always clear. Oft en 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 specifi city 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 specifi c vision tests used within that screening program. In other words, it should not be generic, with an arbitrary referral point (such as 0.2 log-MAR or worse). A VA level that is achieved using one vision test may be diff erent from that achieved using an alternative vision test. Th e referral criteria should be stipulated for each vision test that could be used within the screening program.

8.3.2 Cover-Uncover Test

Th e 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 specifi city of the test itself. Williams et al. [20] were able to report on the sensitivity and specifi city 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 cal-culated to be 75% (95% CI, 0.577–0.899%), with a speci-fi city of 100%.

Th e VIP study also assessed the eff ectiveness of the cover-uncover test in detecting strabismus, amblyopia, reduced VA, and refractive error [21]. Th e results are


Th e 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, diagno-sis, 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 screen-ing for children in terms of program content, referral criteria, and personnel.Th e justifi cations 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 exam-ining diagnosis, treatment, and consequence of amblyopia, strabismus, and/or refractive error.

8.3 Screening Tests for Amblyopia, Strabismus, and/or Refractive Error 101

summarized in Table 8.2. Th e 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

Th e inclusion of stereoacuity tests within pre-school vision screening programs could be considered as a con-tentious issue. VIP [22] stated that most guidelines rec-ommend a test of stereopsis. However, if a child was found to have normal VA, no strabismus, and no clini-cally signifi cant 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 stereop-sis have not been identifi ed 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.

Th e VIP has reported on the testability of two diff erent stereotests used to screen for vision disorders, the Random Dot E and the Stereo Smile test [21, 23]. Th e results reported by condition type are summarized in Table 8.3. Th e results indicated that both the stereotests are more accurate at detecting the presence of amblyopia and stra-bismus compared with that for reduced VA or refractive error.

In a further study, VIP examined the sensitivity of the same stereotests when the specifi city was set at 0.94. Th e 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

Th e use of photoscreeners and/or autorefractors in pre-school vision screening is extremely varied. Within the USA, they are commonplace, and the variety of dif-ferent makes and models make summarizing literature extremely diffi cult. Th e 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 Specifi city

Year 1 n = 796 n = 75 n = 132 n = 48 n = 240

Random Dot E 0.63 0.38 0.60 0.47 0.90

Year 2 n = 1037 n = 88 n = 114 n = 62 n = 299

Stereo smile 0.77 0.30 0.68 0.51 0.91

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

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)aMay have more than one condition

Table 8.2. Sensitivity of cover-uncover test when specifi city 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

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


8

UK pre-school vision screening programs is much less frequent. When considering the appropriateness of pho-toscreeners and/or autorefractors in pre-school vision screening, it is important to recognize their accuracy when compared with a gold standard (usually a refrac-tion performed under full cycloplegia). Th ere are notable advantages and disadvantages of photoscreening when compared with autorefraction. One of the main diff er-ences is that of cost. Aft er 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, inter-pretation of the results. Th e implications of both these factors lead to a higher overall expense when incorpo-rated 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. Th at is, it may detect an amblyogenic fac-tor, but not amblyopia itself. Similarly, the presence of strabismus may also be detected, although understand-ably, the sensitivity and specifi city rates of these are con-siderably lower than those of detecting refractive error.

It is beyond the scope of this chapter to review and appraise literature describing specifi c 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 specifi city 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. Th e decision about whether to refer those children who are unable to per-form screening tests is diffi cult. Some would argue that such children ought to be referred for further investiga-tion, 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. Th e prevalence of ocu-lar conditions amongst children who were unable to per-form 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, signifi cant refractive error, or unexplained low VA compared with those who had passed the screening test [24]. Th is led the authors to

recommend that these children ought to be referred or retested at a later date possibly with a diff erent test. Th e impact of recall and re-testing, or automatic referral will undoubtedly aff ect the overall clinical and cost eff ective-ness 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 con-ducted by nurses and lay people. Th e use of lay people to administer screening tests does have advantages, particu-larly when considering the economic burden of a screen-ing 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, strabis-mus, and/or refractive error? Th is 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 diff erent testing distances; a linear test was per-formed at 10 feet, and a single, crowded test administered at 5 feet. Th e results of the study demonstrated that although nurse screeners appeared to have slightly higher sensitivities in the assessment of refractive error and pres-ence of stereoacuity compared with lay screeners, the dif-ferences were not statistically signifi cant.

However, when examining the results of VA testing, the authors reported that nurse screeners achieved sig-nifi cantly higher sensitivity than lay screeners with the linear VA test. Whilst the authors made no recommen-dations for future screening protocol strategies, their results could be interpreted in two ways. Th e lack of sta-tistically signifi cant diff erences 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 diff erences observed in VA testing between lay screeners and nurse screeners could suggest that nurse screeners would be more eff ective in detecting vision anomalies. Diff erences in screening programs between countries will undoubt-edly continue to exist; however, recommendations as to

8.4 Treatment of Amblyopia 103

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

8.4 Treatment of Amblyopia

Th e 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 clini-cal practice in the management of this condition. Th e 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 aff ecting children. Funded by the National Eye Institute (NEI), this group has investigated many aspects of the clinical course of amblyopia and its treat-ment. Th e Monitored Occlusion Treatment of Amblyopia Study Cooperative (MOTAS Cooperative) is a multi-disciplinary group of ophthalmologists, orthoptists, basic scientists, and statisticians dedicated to investigat-ing amblyopia treatment. Based in London (UK), it is funded by the charities Guide Dogs for the Blind Association, and Fight for Sight. Th ey have conducted two clinical trials to identify the response of amblyopia to occlusion therapy. Data from both the studies con-ducted by PEDIG and the MOTAS Cooperative have contributed to our understanding of the management of amblyopia.

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. Th is can be achieved through occlusion treatment (patching or pharmacological occlusion, in the form of atropine), or through optical penalization. Th ere are notable advan-tages and disadvantages to diff erent treatment modalities in terms of compliance, ease of administration, and VA outcome. Comparison of studies investigating the eff ec-tiveness of treatment of amblyopia is hindered, due to dif-fering defi nitions 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 diff er. Objective mea-surement of the amount of occlusion worn has been made possible with the introduction of occlusion dose moni-tors (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 adapta-tion (or “optical treatment of amblyopia” as it is some-times known [26]. Th ere has been increasing evidence to suggest that the treatment of amblyopia in the presence of refractive error should incorporate observation of VA fol-lowing the prescription of glasses alone [26–29]. Th ese studies report increases in VA in subjects such that some did not require any additional treatment for their ambly-opia. 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 adap-tation is a recognized period in amblyopia therapy. Th e time taken to reach this period, however, remains under debate. Th e 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 aft er 20 weeks, but not consider-ably, 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.


Content of vision screening programs vary widely. ■

Most involve assessment of VA for which a large number of tests are available. Th e gold standard is a crowded logMAR-based test. Referral criteria should be specifi c for the test used.Th e use of photoscreeners and/or autorefractors ■

in vision screening programs is not universal. Th e use of photoscreeners and/or autorefractors will have an impact upon the cost eff ectiveness of screening.Th e 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

Wallace et al. [31], as part of the PEDIG study, examined the improvements in VA in children with bilateral refrac-tive amblyopia aged between 3 and 10 years. Th ey 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 oft en initiated as the fi rst-line approach in amblyopia therapy. One advantage of patching treatment is that the eff ects 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 nec-essary to confi rm that occlusion therapy is also eff ective in the management of amblyopia. PEDIG compared the eff ect of daily patching vs. a control group of amblyopes in chil-dren aged 3–7 years, following a period of refractive adap-tation. An improvement in VA was observed in both the groups aft er 5 weeks, and as expected, a greater improve-ment was reported in the patched group [32].

Th e MOTAS Cooperative investigated the amount of occlusion required to improve VA and explored the dose-response relationship in amblyopia therapy [28]. Th ey found that most children required between 150 and 250 h of occlusion, irrespective of the type of amblyopia present. Specifi c characteristics were observed to aff ect 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 fi nal 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. Th e PEDIG investigated whether performing such activities infl uenced 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 pre-scribed only 2 h of patching per day, and that the authors made no inference as to whether the results would be simi-lar in subjects patched for a greater or lesser time.

8.4.4 Pharmacological Occlusion

Pharmacological occlusion (i.e. atropine) has notable benefi ts; 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 eff ects are not readily reversible; it can take several weeks for the eff ects of atropine to wear off . Concerns also exist regarding its effi cacy as a treatment modality, with some clinicians believing it to be a less eff ective treatment when compared with conventional occlusion. Studies conducted by PEDIG examined the eff ectiveness 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. Th e decision towards which therapy should be adopted may now be based on other factors. One such factor may be the instil-lation of the atropine itself. Th e eff ect of diff erent atropine regimens in the treatment of moderate amblyopia (20/40–20/80) was investigated. Comparisons were made between the observed eff ects 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 improv-ing the therapeutic experience for the child. Th is 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 amblyo-pia is that of optical penalization. Th is is where lenses are used to induce a defocused image of the non-amblyopic eye. Tejedor and Ogallar [37] directly compared the eff ects of atropine vs. optical penalization in the treat-ment of mild to moderate amblyopia (VA of at least 20/60). Th is small study found greater improvements in VA in the atropine group aft er 6 months of therapy, which may be attributed to the child peeking over or around the glasses and thereby not achieving the desired eff ect of optical penalization. Although optical penalization remains a useful treatment option in specifi c clinical situ-ations, it is oft en not considered as an appropriate fi rst-line choice of therapy in the management of amblyopia.

8.4.6 Eff ective Treatment of Amblyopia in Older Children (Over the Age of 7 Years)

Th ere has been strong evidence that treatment for amblyopia is more eff ective 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 Treatment of Amblyopia 105

of strabismic amblyopia in the older child should be pursued with caution, as there is a notable risk of reduc-ing the density of suppression, and thereby inducing intractable diplopia in these patients. A number of stud-ies that reported on improvements in VA in older chil-dren 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-eff ects had been observed [40–42]. Despite some evidence to suggest that successful treatment of amblyopia in the older child is possible, earlier inter-vention is more advantageous, and to that end supports the notion of pre-school vision screening.

8.4.7 Treatment Compliance

Th e successful management of amblyopia is intrinsically linked to treatment compliance and adherence to ther-apy. Th is in itself is multi-factorial in nature. Th e devel-opment and application of ODMs has meant that reasons for non-compliance can be more thoroughly investi-gated. In particular, ODMs have highlighted the dis-crepancy between the amount of occlusion prescribed and the amount administered. Clinicians have long rec-ognized that the amount of occlusion carried out oft en falls short of their recommended treatment plan. Stewart et al. [29] reported on the eff ect of 6 h a day occlusion compared with 12 h a day occlusion in the treatment of strabismic and/or anisometropia amblyopia. Th ey 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 pre-scribing occlusion therapy.

Loudon et al. [43] examined some of the limiting fac-tors of occlusion therapy for amblyopia and reported that parental fl uency 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 advo-cated by the ophthalmologist and/or orthoptist. Searle et al. [44] found two variables that were signifi cant pre-dictors of compliance with occlusion therapy. Th ey reported that self-effi cacy (the belief in the ability to patch their child) was positively associated with treatment com-pliance. Th e parental belief that occlusion therapy inhib-its the child’s activities was negatively associated with treatment compliance.

8.4.8 Other Treatment Options for Amblyopia

Th e use of photorefractive keratectomy (PRK) for the treatment of anisometropia in children has not been fully investigated and concerns exist surrounding the long-term 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 ambly-opia would be reduced. Paysse et al. [45] reported the results of a small study of children with high anisometro-pia, and found improvements in both VA and stereopsis following treatment. However, compliance with amblyo-pia therapy remained unaff ected in this study group fol-lowing treatment. Th e 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 benefi ts 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 fac-tors that may infl uence whether recurrence is likely to occur [46–49]. Th ese include age of termination of treat-ment, 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 chil-dren who underwent treatment aft er 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].


Treatment of amblyopia associated with refrac- ■

tive error should incorporate a period of obser-vation 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 aft er glasses are pre-scribed, but most improvement occurs in weeks 4–12. In some cases, further amblyopia therapy may not be required.Th ere 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.


8

8.5 Quality of Life

When considering the application of any screening pro-gram, 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 subse-quent 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.

8.5.1 The Impact of Amblyopia Upon HRQoL

Th ere have been a number of studies that have investi-gated the impact of amblyopia upon HRQoL. Th ese have examined the eff ect of amblyopia upon stereoacuity and motor skills [50, 51], reading speed ability [52], educa-tional attainment [9], and emotional well-being [44, 53–58].

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 chil-dren by assessing the fi ne motor skills of those with amblyopia compared with age-matched control subjects. It was noted that the subjects with amblyopia performed signifi cantly worse in most of the fi ne motor skills tests conducted as part of the study, particularly in the tasks related to time. Th e results were even more noticeable in those children with a diagnosis of amblyopia and strabis-mus. Hrisos et al. [51] investigated the infl uence of VA and stereoacuity on the performance of pre-school chil-dren undertaking tasks that required visuomotor skills and visuospatial ability. Th e authors reported that reduced monocular VA itself did not relate to any ability of task performance, but stereoacuity was found to aff ect 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

Reading speed and reading ability has been assessed in children with amblyopia. Stift er et al. [52] reported that maximum reading speed was signifi cantly reduced in those with the condition. Th erefore, they could be deemed to have a functional reading impairment when compared with normal-sighted controls. It is recognized that read-ing ability is multi-factorial in nature, and is infl uenced by comprehension. Th e study does not imply that chil-dren 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

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 signifi cantly associated with lifetime occupational class. However, fewer people with amblyopia were found to have completed higher university degrees. Th is fi nding was supported by Rahi

Pharmacological occlusion, in the form of atro- ■

pine, has been found to be as eff ective as conven-tional occlusion (patching) in the treatment of both moderate and severe amblyopia. Weekend-only atropine instillation has been shown to pro-duce similar improvements in VA as daily atropine instillation in the treatment of moder-ate amblyopia.Th ere is evidence to suggest that successful treat- ■

ment of children aged over 7 years can be achieved in cases of anisometropic, strabismic, and mixed etiology amblyopia.Th e development of ODM has informed not only ■

the occlusion-dose response of amblyopia treat-ment, but also reasons for poor treatment com-pliance. Parental understanding of the condition and belief in therapy may infl uence treatment outcome.Recurrence of amblyopia may occur following ■

treatment, with reported rates of 7–27%. Factors infl uencing recurrence include age of the child at cessation of treatment, VA at the time of cessa-tion of treatment, and the type of amblyopia present.

8.5 Quality of Life 107

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

8.5.5 Emotional Well-Being and Amblyopia

Th e psychosocial impact of amblyopia and its treatment has been explored from both the parental and child per-spective [56]. Children have reported feelings of shame and negativity associated with amblyopia, particularly following the start of treatment. Th e 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 ambly-opia therapy may be experienced not only by the child, but also by family members [54]. Th is could result in impaired relationships between the child and parent/guardian, but also between siblings. Parents oft en state that their child may be more clingy or demanding when occlusion is worn; that the child’s compliance with occlu-sion can lead to negative behavioral changes or that their child appears to be less confi dent when wearing their patch or glasses [56].

Th e issue of peer victimization and bullying associated with amblyopia has been recognized [55, 56, 58]. Th is may be in response to the wearing of glasses and/or occlu-sion 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 chil-dren 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-to-face 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. Th e 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 (aft er adjust-ment 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 ther-apy early (i.e. before school starts), and thus would avoid

adverse reactions from their peers. Th ey compared two groups that had been off ered 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. Th e authors reported an almost 50% reduction in children who reported having been bullied in the group that had been off ered pre-school screening, compared with the group who had not.

Not all children undertaking amblyopia therapy fi nd the treatment a negative experience. Indeed, in a study by Choong et al. [53], the authors found no signifi cant changes in parental (carer’s) stress or the child’s psycho-social 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 signifi cant diff erence 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.

Confl icting 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 fi nd no evidence for an association between the presence of amblyopia and participation in social activities in either childhood or adult life. Th e authors also stated that those with amblyopia were no more likely to report depression or psychological distress in adult life.

Th is fi nding 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. Th e authors reported that those with amblyopia experienced more distress in several areas of psychological well-being, including somatization, obsession-compulsion, interper-sonal sensitivity, anxiety, and depression.

Taken in isolation, the impact of any one of the afore-mentioned problems may be minimally associated with detriment to HRQoL. However, the cumulative eff ect of impaired reading, motor skills, and psychosocial impact of amblyopia, for example, might infl uence HRQoL to a greater degree.

8.5.6 The Impact of Strabismus Upon HRQoL

Th e psychosocial implications of strabismus are more accepted and recognized, particularly in cases of cos-metically obvious strabismus. Detrimental implications of strabismus include a negative self-image, reduced


8

self-confi dence, low self-esteem, and poor interpersonal relationships [60]. Th e presence of a cosmetically notice-able 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 aff ect those in adulthood. Uretman et al. [64] determined that children with strabismus were perceived in a negative light by adults. Th e age at which the emergence of negative atti-tudes 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 atti-tude 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 psy-chosocial benefi ts, and thus improves HRQoL.

Improvements in quality of life following strabis-mus surgery are well documented in adults [66–69]; however, its eff ect 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). Th e authors stated that following surgery, there were signifi cant improve-ments in a number of quality of life dimensions, includ-ing those of anxiety, social relations, and developmental satisfaction (parental response). Th e results concur with those found in an adult population, and it can therefore be deemed that the psychosocial benefi ts 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 diff er 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 fi ndings are of great clini-cal importance, it can be diffi cult to compare one study with another due to diff erences 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. Th at is, are the results taken from responses from the parent, the child, or from an adult with a history of amblyopia and/or strabismus? Th e

fi ndings 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 perspec-tive [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 exaggerat-ing or diminishing the true changes in HRQoL experi-enced as a child. Perhaps, studies that report from the child perspective [55, 56, 58] could be considered the most valid. Th ey deliver insight into what is experienced at the time. However, they are not without their weak-nesses. 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 diffi cult to fully distinguish whether any reported detriment to HRQoL in amblyopia is due to the condition itself or its treatment. Th is is not a factor when considering strabismus. Strabismus (particularly that of large angle strabismus) is cosmetically notice-able and it is the impact that that has upon the person which can aff ect HRQoL. Th erefore, it can be said that any study that reports on HRQoL and strabismus is reporting on the eff ect that the condition has upon a person’s well-being. With amblyopia, this is not the case. Th e condition itself cannot be identifi ed by peers. What is noted is the eff ect 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, educa-tional attainment, and risk of losing vision in the non-amblyopic eye) [9, 59]. It is not possible to determine whether the same HRQoL changes that occur in child-hood are appreciated in adulthood, because the mea-sures used in the identifi ed studies are so diff erent. Nonetheless, it can be concluded that there is evidence to suggest that there are HRQoL issues related to ambly-opia and/or strabismus and its treatment.

References 109

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Th ere have been a number of studies investigat- ■

ing HRQoL implications of amblyopia and/or strabismus over recent years. Th ese have involved studies with children who have the condition, or adults who had previously undergone treatment.Studies have reported amblyopia to impact upon ■

stereoacuity, fi ne motor skills, and reading speed.Th e presence of amblyopia does not appear to ■

have any impact on educational attainment or paid employment in adult life.Amblyopia (more specifi cally amblyopia treat- ■

ment) has been shown to impact negatively upon a child’s emotional well-being; and may also aff ect relationships between the child and par-ent/guardian.Th e 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 eff ect of impaired reading, motor skills, and psychosocial impact of amblyopia, for example, might infl uence HRQoL to a greater degree.Th e 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.


8

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28. Stewart CE, Stephens DA, Fielder AR, Moseley MJ (2007) Modeling dose-response in amblyopia: toward a child-specifi c treatment plan. Invest Ophthalmol Vis Sci 48(6):2589–2594

29. Stewart CE, Stephens DA, Fielder AR, Moseley MJ, ROTAS C (2007) Objectively monitored patching regi-mens for treatment of amblyopia: randomised trial. BMJ 335(7622): 707

30. Chen PL, Chen JT, Tai MC, Fu JJ, Chang CC, Lu DW (2007) Anisometropic amblyopia treated with spectacle correc-tion alone: possible factors predicting success and time to start patching. Am J Ophthalmol 143(1):54–60

31. Wallace DK, Chandler DL, Beck RW, Arnold RW, Bacal DA, Birch EE, et al (2007) Treatment of bilateral refractive amblyopia in children three to less than 10 years of age. Am J Ophthalmol 144(4):487–496

32. Wallace DK, Pediatric eye disease investigator group, Edwards AR, Cotter SA, Beck RW, Arnold RW, et al (2006)

A randomized trial to evaluate 2 hours of daily patching for strabismic and anisometropic amblyopia in children. Ophthalmology 113(6):904–912

33. Pediatric eye disease investigator group (2008) A random-ized trial of near versus distance activities while patching for amblyopia in children aged 3 to less than 7 years. Ophthalmology 115(11):2071–2078

34. Pediatric eye disease investigator group (2002) A random-ized trial of atropine vs. patching for treatment of moder-ate amblyopia in children. Arch Ophthalmol 120:268–278

35. Holmes JM, Kraker RT, Beck RW, Birch EE, Cotter SA, Everett DF, et al (2003) A randomized trial of prescribed patching regimens for treatment of severe amblyopia in children. Ophthalmology 110:2075–2087

36. Repka MX, Cotter SA, Beck RW, Kraker RT, Birch EE, Everett DF, et al (2004) A randomized trial of atropine regimens for treatment of moderate amblyopia in children. Ophthalmology 111(11):2076–2085

37. Tejedor J, Ogallar C (2008) Comparative effi cacy of penal-ization methods in moderate to mild amblyopia. Am J Ophthalmol 145(3):562–569

38. Menon V, Shailesh G, Sharma P, Saxena R (2008) Clinical trial of patching versus atropine penalization for the treat-ment of anisometropic amblyopia in older children. J AAPOS 12:493–497

39. Patwardhan NA (2007) Is age relevant for the success of treatment of anisometropic amblyopia? Indian J Ophthalmol 55(6):469–470

40. Brar GS, Bandyopadhyay S, Kaushik S, Raj S (2006) Effi ciency of occlusion therapy for management of ambly-opia in older children. Indian J Ophthalmol 54:257–260

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42. Pediatric eye disease investigator group (2004) A prospec-tive, pilot study of treatment of amblyopia in children 10 to <18 years old. Am J Ophthalmol 137(3):581–583

43. Loudon SE, Fronius M, Looman CW, Awan M, Simonsz B, van der Maas PJ, et al (2006) Predictors and a remedy for noncompliance with amblyopia therapy in children mea-sured with the occlusion dose monitor. Invest Ophthalmol Vis Sci 47(10):4393–4400

44. Searle A, Norman P, Harrad R, Vedhara K (2002) Psychosocial and clinical determinants of compliance with occlusion therapy for amblyopic children. Eye 16:150–155

45. Paysse EA, Coats DK, Hussein MA, Hamill MB, Koch DD (2006) Long-term outcomes of photorefractive keratectomy for anisometropic amblyopia in children. Ophthalmology 113(2):169–176

46. Bhola R, Keech RV, Kutschke P, Pfeifer W, Scott WE (2006) Recurrence of amblyopia aft er occlusion therapy. Ophthalmology 113:2097–2100

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48. Tacagni DJ, Stewart CE, Moseley MJ, Fielder AR (2007) Factors aff ecting the stability of visual function following cessation of occlusion therapy for amblyopia. Graefes Arch Clin Exp Ophthalmol 245(6):811–816

49. Hertle RW, Scheiman MM, Beck RW, Chandler DL, Bacal DA, Birch E, et al (2007) Stability of visual acuity improve-ment following discontinuation of amblyopia treatment in children aged 7 to 12 years. Arch Ophthalmol 125(5): 655–659

50. Webber AL, Wood JM, Gole GA, Brown B (2008) Th e eff ect of amblyopia on fi ne motor skills in children. Invest Ophthalmol Vis Sci 49(2):594–603

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52. Stift er E, Burggasser G, Hirmann E, Th aler A, Radner W (2005) Monocular and binocular reading performance in children with microstrabismic amblyopia. Br J Ophthalmol 89:1324–1329

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54. Parkes LC (2001) An investigation of the impact of occlusion therapy on children with amblyopia, its eff ect on their fami-lies, and compliance with treatment. Br Orthopt J 58:30–37

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72. UK National screening committee (2003) Criteria for appraising the viability, eff ectiveness and appropriateness of a screening programme

9.1 Amblyopia and Amblyogenic Disorders

Amblyopia is estimated to aff ect approximately 2–5% of the population in Western countries and is a signifi cant 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 eff ectively [3, 12–14]. One signifi cant limiting factor of most amblyopia screening programs is the reliance on the subjective responses of the child being tested.

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 strabis-mus are the most frequent causes of amblyopia. So, meth-ods are necessary that indicate ametropia and strabismus with a high sensitivity and specifi city. 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 possibil-ity to perform both cycloplegia and measurement. Th ese

The Brückner Test RevisitedMichael Gräf

Chapter 9

9

Core Messages

Th e Brückner test is useful to detect various ■

amblyogenic disorders. Aft er a short training, every physician can perform the test.Th e test as originally described consists of four ■

elements to observe: (1) the position of the fi rst Purkinje images (corneal light refl exes), (2) the fundus red refl ex in the pupil, (3) pupillary light refl exes, and (4) any movement of the eyes when illumination alters from one eye to the other.Asymmetry in corneal light refl exes on both eyes ■

may indicate strabismus. However, small devia-tions are not reliably detected, and asymmetry can also be caused by diff erent angle kappa in both eyes.Performance of the red refl ex test requires a direct ■

ophthalmoscope. Substitution by an otoscope, indirect ophthalmoscope, or any other light source causes loss of test validity.Th e red refl ex test allows for detection of refrac- ■

tive 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.

Any optically relevant opacity will be apparent by a shadow in the red refl ex.Detection of refractive error can be improved by ■

extending the test distance up to 4 m and observ-ing the brightness of the red refl ex in both eyes simultaneously. While usually at a distance of 1 m, the red refl ex is brighter in the more ametropic eye, the refl ex in this eye becomes increasingly darker with increasing test distance. With increas-ing test distance, myopia and hypermetropia, which are not compensated by accommodation, cause signifi cant dimming, and anisometropia causes increasing asymmetry.Th e test sensitivity to detect microstrabismus by ■

asymmetric fundus red refl ex is low.Testing pupillary light refl exes is recommendable ■

to assess visual aff erence, pupillomotor eff erence and pupil responsiveness. It is hardly suitable to diagnose or exclude amblyopia and amblyogenic disorders.Testing for fi xation movements caused by switch- ■

ing illumination from one eye to the other is sim-ilar to the cover test. Data on diagnostic validity of this procedure are lacking.

114 9 The Brückner Test Revisited

9

conditions as well as parental readiness are oft en lacking. Non-cycloplegic photorefractive screening is not a tanta-mount substitute of refractometry in cycloplegia [15, 16]. Besides, the technical equipment is relatively expensive, and therefore hardly any paediatrician or general practi-tioner performs photorefractometry. Even the Brückner test is not routinely used by paediatricians, although pre-conditions for performance are ideal and the test is rec-ommended for paediatric screening examinations in Germany [17]. Th e Brückner test is a readily available screening tool that can be used with newborns, infants and preverbal children by non-ophthalmologists [18, 19]. Th e 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 ophthalmolo-gist in Basel, Switzerland, reported on ‘Exact strabismus diagnostic in ½- to 3-year-old children by a simple proce-dure, the “transillumination test” ’ [18]. Brückner illumi-nated both pupils from a distance of 1 m and assessed the following criteria:

Position of fi rst Purkinje images relative to the pupil ■

Colour of the fundus red refl ex in the pupil ■

Size and constriction of the pupils ■

Eye movements with and illumination of the pupils ■

Assessment of the fi rst two criteria requires simultaneous illumination of both eyes, whereas assessment of the fol-lowing two criteria requires alternate illumination. Th ree years later, Brückner added an article on ‘Practical exer-cises with the transillumination test for early diagnosis of strabismus’, emphasizing the essential component of the test, which is the assessment of the red refl ex of the fun-dus when the pupil is lighted and viewed with a direct ophthalmoscope [19]. Th is particular component was new concerning strabismus diagnostic and in the aft er-math called Brückner test in the closer sense. It has also been called the Brückner refl ex [3, 20].

9.2 Corneal Light Refl exes (First Purkinje Images)

Assessment of the fi rst Purkinje images in the two eyes allows for more exact strabismus diagnostic than mere assessment of the position of the cornea within the palpe-bral fi ssure. Th e latter depends on the confi guration 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 fi ssure can be suggestive of esotropia.

9.2.1 Physiology

Purkinje described that when the eye is being illumi-nated by an examination light, refl exes appear from the corneal surface, the corneal endothelium, and both the anterior and posterior surface of the lens. Th e fi rst Purkinje image coming from the corneal tear fi lm is brightest. Usually it appears slightly nasally of the centre of the cornea and the pupil, when the eye is fi xating a light source which is held directly below the pupil of the observer. Slight eccentricity of the corneal light refl ex is caused by the diff erence 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 refl ex relative to the pupil will shift to the opposite direction. Conjugate gaze movements induce parallel shift of the images in both eyes. Th is causes asymmetry in the two images, if their positions were symmetric at fi rst. For instance, right gaze induces nasal shift of the image in the right eye and temporal shift of the image in the left eye. Th e same will happen, when the light source is moved to the right-hand 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 fi xates the light and the right eye is esotropic, then the fi rst Purkinje image on the right eye will be temporally dislocated. So, this method in principle allows for detection of strabismus.

Th e idea to measure squint angles by using corneal light refl exes arose at the end of the nineteenth century [22, 23]. Hirschberg assumed that 1-mm shift of the cor-neal light refl ex 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-fi rst century, the wrong ratio of 7°/mm is still wide spread. Recognition of asym-metry in the Purkinje images can be improved by evalu-ating photographs [26]. In laboratory trials, photographic Hirschberg testing was eff ective 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 fi rst and the fourth Purkinje images due to deviation of the visual axis have

9.3 Fundus Red Refl ex (Brückner Refl ex) 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 refl ex for symmetry on both eyes requires a small light source, which must be fi xated by the patient. To avoid glaring the patient, the light should not be too bright. Th e observer compares the position of the corneal refl ex 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. Th e eccentricity depends on the individual angle k. Th e images may be better visible when the observer looks above the ophthalmoscope. Th en 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 chil-dren and also adequate convergence might not be war-ranted. Larger distance makes it diffi cult to detect small asymmetry.

9.2.3 Shortcomings and Pitfalls

False-negative fi ndings 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 refl exes, it is evident that small angle strabismus can hardly be identifi ed by this method. Asymmetry in the angle k between both eyes can veil strabismus.

Ectopia and anomalies of the pupil have to be consid-ered. False-positive fi nding of strabismus can be caused by parallel shift of the refl ex images in the two eyes when the light is horizontally displaced. Th e light source must be exactly beneath (not beside!) the visual axis of the observer’s fi xating eye. Severe bias occurs when the light is hold under one eye while the other eye is fi xating: 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 fl ashlight photographs, which were recorded with the fl ashlight beside the objective (Fig. 9.1). With the fl ashlight coaxi-ally or above the objective, this bias can be avoided, but it cannot be assured that the child was really fi xating the camera [33].

9.3 Fundus Red Refl ex (Brückner Refl ex)

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 refl ected by the choroid and the retinal surface of the eye. Th e fundus refl ex was also called Brückner refl ex [3, 20]. Colour and brightness of the fun-dus refl ex 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 refl ex 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 scientifi c study on


Evaluating the corneal light refl exes in both eyes ■

for symmetry allows to detect manifest strabis-mus and to estimate its size. Exclusion of strabis-mus 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 fi xates a point beside the examination light or when the light is not on the examiner’s visual line.

Fig. 9.1 Corneal light refl exes in a 12-month-old girl. In this case, asymmetry of the corneal light refl ex between both eyes is caused by fl ashlight position beside the objective of the camera. So, the image of the fl ashlight 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


9

the sensitivity of the Brückner test to detect media opac-ity. Visualizing media opacity and pathologies of the fun-dus the Brückner refl ex 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 refl ex can also be caused by the optic nerve head and by pathologies of the fundus, such as coloboma, retinoblastoma, toxoplasmosis scars and medullated nerve fi bres.

When the patient takes up central fi xation of the oph-thalmoscope light, there is normally a constriction of the pupils and dimming of both fundus refl exes [18]. By interfering with this dimming phenomenon, manifest strabismus and anisometropia can produce asymmetry in the brightness and colour of the fundus refl exes 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 refl ex [9, 18]. Regarding ametropia, however, examination distance is a decisive factor. At larger dis-tance, the more ametropic eye yields the darker fundus refl ex [34].

9.3.1 Physiology

Examination of the fundus red refl ex 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 fi xation of the patient, the fun-dus red refl ex represents the patient’s fovea. To explain the dimming of the red refl ex when the patient takes up fi xation, Brückner discussed various factors [18]. Pupillary constriction, diff erent refl ectivity of the central and peripheral retinal surface and accuracy of accommo-dation were assumed to be the major causes of dimming and change in colour [18, 35–37]. Backscattering of the light by the retinal nerve fi bre layer proportional to the thickness of the layer and changes arising from variation in retinal pigment epithelium density, with the retina dis-playing the characteristics of a diff use refl ector, were fur-ther discussed but not as primary factors of dimming [35]. Mere pupillary constriction does not explain asym-metric dimming due to strabismus, but it may amplify eff ects of defocus and retinal refl ectivity. Brückner’s idea that diff erence in refl ectivity between the central and para-central or peripheral retinal surface contribute to

Fig. 9.2 Visualization of organic pathologies in the fundus refl ex 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 signifi cant central shadow. Bottom (better right), large peripheral retinoblastoma OS already visible by partial leukocoria when looking above the ophthalmo-scope. Both examples show that organic fi ndings are better visible with magnifi cation by shorter distance compared to “armlength” distance


the dimming phenomenon was refreshed by Roe and Guyton who described specular refl ection of the retina from the internal limiting membrane that changes slope with ocular rotation [35, 36]. Th e fundus refl ex is not solely caused by refl ection from the choroid and the reti-nal pigment epithelium but, to a minor part, also by refl ection from the retinal surface. If signifi cant light were refl ected from the internal limiting membrane of the ret-ina, the slope of the foveal pit would refl ect enough light away from the pupil. Because this part of light would not be refl ected back to the observer, the red refl ex would appear darkened [35, 36]. Misalignment of one eye with light being refl ected from the para-foveal retinal surface, which is rather perpendicular to the direction of the incoming light, increases coaxial refl ection and thus the brightness of the fundus refl ex (Fig. 9.3).

Th is might also explain the lack of dimming in new-borns and young infants as a consequence of develop-ment of the foveal pit. While most infants 8 months of age and older show dimming of the fundus refl exes in both eyes occurring with central fi xation, neonates and most infants younger than 2 months of age do not show dim-ming of the fundus refl ex with fi xation and between 2 and 8 months of age up to 28% of infants have asymmetric dimming of the fundus refl exes 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 refl ex would appear darker in an eye that is fi xating and focusing on the ophthalmo-scope light because the light source in the ophthalmo-scope and its retinal image are conjugate to one another.

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 refl ex [35, 36]. Th is hypothesis might fi t with the observation that – at the traditional examination dis-tance of 1 m – the fundus red refl ex in the (more) ame-tropic eye is usually brighter compared to an emmetropic eye. Th e hypothesis corresponds to the assumption that accuracy of accommodation is one reason of dimming.

Foveal dimming of the red refl ex allows for sensitive discrimination between subsequent central and eccentric illumination of the same eye. Dimming occurred in 97.2% of trials with fi xation of the light compared with fi xation of a target between 2.5 and 10° beside the light, regardless of the angle of eccentricity. Th is rate did not decrease when the pupil was dilated by mydriatic eye drops (Gräf et al., MS in preparation). However, the static inter-ocular dif-ference in the refl exes due to strabismus was less apparent. In young adults, simulated esotropia with squint angles up to 5° was detected in not more than 62%. Th e deviated eye was identifi ed by the brighter red refl ex in 48%. Esotropia of 7.5 and 10° was detected in 85 and 97% with identifi ca-tion of the deviated eye in 75 and 86% (Table 9.1). To achieve these rates, very discreet red refl ex asymmetry was considered. Th e rate of false-positive fi ndings was 36% (Gräf et al., MS in preparation). Th ese results con-fi rm prior fi ndings [38]. When esotropia of, for example, 8 prism dioptres was simulated by fi xating a near target, not more than two thirds of strabismus conditions were detected [27]. One might argue that these were only labo-ratory studies, but an increase in sensitivity and specifi c-ity in young children compared with highly cooperative

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

200 µm


9

adults is rather unlikely. Strabismus detection will hardly improve by extending the test distance, except indirectly, by detection of anisometropia which frequently accom-panies esotropia [35]. Th ere might be a chance to improve test sensitivity and specifi city by using a short-pass fi lter that blocks the refl exes coming from the retinal pigment epithelium and the choroid and thus augments asymme-try caused by asymmetric light refl ection from the inter-nal limiting membrane.

Considering optical basics, examination distance must be an essential factor infl uencing the red refl ex 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 bun-dle 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 por-tion of the refl ected light bundle reaching the observer’s pupil decreases. So, when the observer moves back-wards, the brighter refl ex, which at a distance of 1 m, usually corresponds to the (more) ametropic eye, becomes darker (Fig. 9.4) [34]. Th e test sensitivity to detect unilateral refractive error by the weak refl ex in the ametropic eye at a test distance of 4 m is better com-pared 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 hyper-metropia of 1–4 diopters was detected in 34–80% of tri-als 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]. Th e low rate of false-positive fi ndings shows that rather discreet asymmetry was not considered pathologic in that study, in contrast to the study on simulated strabismus, (Fig. 9.5).

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

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 refl ex; test positive inter-ocular asymmetry in red refl ex; correct localization brighter red refl ex in the deviated eye Gräf et al., (in preparation)

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


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 per-form the test also at a distance of 4 m to detect refractive error more sensitively [34].

Paysse et al. compared the ability of paediatric resi-dents to diff erentiate asymmetric from symmetric red refl ex 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 specifi city of 71% [3]. Gole and Douglas reported a test sensitivity of 86% and a specifi city of not more than 65%. Th e Brückner test was performed by a medical student [20]. In these two studies, the test distance was 1 m. In a group of anisome-tropic patients, we achieved a sensitivity of 32.5% at that distance, and a specifi city of 93.3%. At a distance of 4 m, sensitivity increased to 77.5% and specifi city was 80%

[34]. Th ese 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 dis-tance 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 refl exes for symmetry [3, 18, 19, 35, 37, 38, 40, 41]. Th e room light should be dimmed but the room should not be completely dark [18].

Using a direct ophthalmoscope is mandatory. Otoscope or fl ashlight illumination will not yield the same optical phenomena because the characteristic of the emitted light is diff erent. Th e light beam must be directed simultaneous

Table 9.2. Sensitivity (50 trials for each condition) and false-positive fi ndings (in 225 trials) of the Brückner refl ex 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




Myopia 1 diopters 60 100 32 68




False-positive tests 3.1 4.0 1.5 3.0

Table 9.3. Sensitivity (50 trials for each condition) and false-positive fi ndings (in 400 trials) of the Brückner refl ex to detect uni-lateral 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




Myopic 1 diopters 50 22 44 74




False-positive tests 5.5 5.25


9

into both eyes to enable accurate comparison of the red refl exes. Light intensity can be varied during the examina-tion. 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 ophthalmo-scope, if necessary. To improve detection of refractive error, the examiner should then go 4 m backwards con-tinuously observing the pupils simultaneously for lumi-nance of the red refl exes. By the same way, it is possible to check for correct spectacle correction.

9.3.3 Possibilities and Limitations

Severe media opacity is visible by lacking or dark fun-dus red refl ex, regardless of distance. Small media opac-ity and pathologies of the fundus are best visible at a short distance. Any asymmetry in brightness and colour of the refl exes 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 nev-ertheless, isometropic hypermetropia cannot be detected reliably. Inter-ocular asymmetry in the red refl ex can be caused by anisocoria and is also frequent in the age range below 8 months.

9.4 Pupillary Light Refl exes

Pupillary light refl exes are being tested to detect patholo-gies in the iris, in the eff erent branch of the pupillary light refl ex loop, in the midbrain, or in the aff erent branch of the refl ex loop. Regarding strabismus diagnostic, Brückner described two criteria:

1. Dimming of the red refl ex when the child is centrally fi xating the ophthalmoscope light.

2. Reduced direct pupillary light refl ex in the amblyopic eye compared with the direct light refl ex in the non-amblyopic eye.


Th e fundus red refl ex test is an excellent comple- ■

ment and a possibility for ophthalmologists, orthoptists, paediatricians, and general practitio-ners 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 refl ex. Testing for refractive error is better performed at an extended distance. Uni- or bilateral partially or completely weak or lacking red refl ex is always pathological. Fig. 9.5 Brückner refl ex 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]

a

b

c

d

e

f

9.4 Pupillary Light Refl exes 121

Th is step requires monocular illumination of the pupils. Brückner reported pupillary constriction in the deviated eye when the light beam was changed from the fi xating eye onto the strabismic eye, as soon as this eye took up fi xation. Permanent fi xation with the previously illumi-nated dominant eye yields an eccentric retinal image of the ophthalmoscope light in the deviated eye. Despite dark adaptation of the deviated eye, the pupillomotor eff ect 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 aff erent pupillomotor defi cit or dimming of the red refl ex in the amblyopic eye occurs aft er some latency when the amblyopic eye takes up fi xation.

9.4.1 Physiology

Illumination of one eye causes symmetric constriction of both pupils [42–46]. In unilateral amaurosis, pupillary con-striction 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 aff erent disorders show a similar pattern except residual reaction to illumination of the (more severely) concerned eye. Discreet aff erent disorders can be found by the swing-ing fl ash light test [42–44]. Aiming at strabismus diagnos-tic, the observer has to watch any eye movement occurring aft er the change of the illumination to the other eye. If the previously deviated eye which is now being illuminated takes up fi xation, the movement of this eye may be visible, and the pupils will constrict because foveal illumination

has a stronger pupillomotor eff ect compared with para-central 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 fi xation, an aff erent pupillomotor defect component may be simulated when this eye is being illumi-nated or there is in fact a relative aff erent pupillary defect (RAPD) due to amblyopia [47–50]. Figure 9.6 shows that already minimal eccentricity of illumination reduces pupil-lary constriction compared with a central illumination.

9.4.2 Performance

Th e examiner directs the light cone on the patient’s right eye and observes constriction of each pupil. Th e proce-dure is repeated illuminating the patient’s left eye. If both pupils are normally reactive, which is mostly the case, comparison of the direct light refl exes of both eyes will be suffi cient [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. Th e pupillary constriction has to be equal in latency, speed and ampli-tude, 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,

Fig. 9.6 Video-oculographic registration of the change in pupil diameter with alternating fi xation 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 ophthalmo-scope light induced more pupillary constriction than fi xation of a target as few as 2.5° beside

gaze direction

10º

5º

0º

–5º

–10º

6 mm

4 mm

2 mm

0 mm

0 5 10 15 20 25 30time / seconds

50 55 6035 40 45

pupil diameter


9

media opacity or any other pre-retinal disorder, gener-ally do not cause an apparent RAPD. Th ompson reported that a careful look revealed small RAPD in less than half of amblyopic eyes. Th is defect was generally less than 0.5 log units [46], and the size of possible RAPD did not cor-relate 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 move-ment when illumination changes from one eye to the other and the child changes fi xation. However, it is hardly possible to detect strabismus by RAPD.

9.5 Eye Movements with Alternating Illumination of the Pupils

Provided central fi xation 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 fi xa-tion is identical with the angle of abnormal retinal corre-spondence, there will also be no fi xation movement [53, 54]. Th ese patterns are well known from cover test-ing. Since it is possible that the child keeps fi xation of the ophthalmoscope with the dominant eye because this eye is not occluded, cover testing is safer and certainly more sensitive to detect strabismus.

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 refl ex asymmetry by pediatric residents using the Brückner refl ex 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 out-comes of visual impairment aft er loss of vision in the non-amblyopic 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 aft er 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) Th e eff ect of amblyopia on fi ne 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 Hornhautrefl ex dezentrierung. Geometrisch-optische Analyse verschiedener Methoden der Strabismometrie. Klin Monatsbl Augenheilkd 215: 104–113

11. Barry JC, Eff ert R, Hoff mann N (1996) Detection and diag-nosis of small ocular misalignment with the Purkinje refl ex pattern method. Klin Monatsbl Augenheilkd 208:167–180

12. Coats D, Jenkins R (1997) Vision assessment of the pediat-ric patient. Refi nements. 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 ambly-opia. Eye 4:787–793


Severe unilateral amblyopia might be detected ■

by RAPD in the amblyopic eye, but usually, the pupillary light refl exes are hardly suitable to detect strabismus or amblyopia.


Brückner’s transillumination test allows for very ■

sensitive detection of media opacity. Th erefore, every ophthalmologic examination in early childhood should include the Brückner test. Th e test is suitable to detect strabismus but it does not allow for suffi cient detection of small angle strabismus. Reliable strabismus diagnostic in childhood requires additional cover testing and testing of random dot stereopsis. Th e 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 123

15. Ehrt O, Weber A, Boergen KP (2007) Screening for refrac-tive errors in preschool children with the vision screener. Strabismus 15:13–19

16. Schaeff el 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 Früherkennungsunter-suchungen im Kindesalter. Deutscher Ärzte Verlag, Köln

18. Brückner R (1962) Exakte Strabismusdiagnostik bei 1/2- bis 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 refl ex 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 refl ex of the ophthalmo-scope as a test of fi xation 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 refl exes. Acta Ophthalmol 57:600–611

27. Griffi n JR, McLin LN, Schor CM (1989) Photographic method for Brückner and Hirschberg testing. Optom Vis Sci 66:474–479

28. Barry JC, Eff ert 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, Eff ert R, Kaupp A, Burhoff A (1994) Measurement of ocular alignment with photographic Purkinje I and IV refl ection pattern evaluation. Invest Ophthalmol Vis Sci 35:4219–4235

30. Barry JC, Eff ert R, Reim M, Meyer-Ebrecht D (1994) Computational principles in Purkinje I and IV refl ection pattern evaluation for the assessment of ocular alignment. Invest Ophthalmol Vis Sci 35:4205–4218

31. Eff ert R, Barry JC, Colberg R, Kaupp A, Scherer G (1995) Self-assessment of angles of strabismus with photographic Purkinje I and IV refl ection pattern evaluation. Graefes Arch Clin Exp Ophthalmol 233:494–506

32. Eff ert R, Barry JC, Dahm M, Kaupp A (1991) A new pho-tographic 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 fotografi schen Beurteilung der Hornhautspiegelbilder. Klin Monatsbl Augenheilkd 223:294–296

34. Gräf M, Jung A (2008) Th e Brückner test: extended dis-tance 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) Th e light that leaks: Brückner and the red refl ex. Surv Ophthalmol 28:655–670

37. Tongue AC, Cibis GW (1981) Brückner test. Ophthalmology 88:1041–1044

38. Griffi n JR, Cotter SA (1986) Th e Brückner test: evaluation of clinical usefulness. Am J Optom Physiol Opt 63: 957–961

39. Leff ertstra 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 dis-eases 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) Th e pupil. Wayne State University, Detroit

44. Miller, NR (1995) Walsh and Hoyth’s clinical neuro-ophthalmology, Vol. I-V. Williams and Wilkins, Baltimore

45. Miller JM, Leising Hall H, Greivenkamp JE, Guyton DL (1994) Quantifi cation of the Brückner test for strabismus. Invest Ophthalmol Vis Sci 36:897–905

46. Th ompson HS (1992) Th e 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) Aff erent pupillary defects in amblyopia. J Pediatr Ophthalmol Strabismus 20: 63–67

49. Kase M, Nagata R, Yoshida A, Hanada I (1984) Pupillary light refl ex in amblyopia. Invest Ophthalmol Vis Sci 25: 467–471


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50. Portnoy JZ, Th ompson HS, Lennarson L, Corbett JJ (1983) Pupillary defects in amblyopia. Am J Ophthalmol 96: 609–614

51. Gruber H, Lessel MR (1982) Modifi kation des swinging fl ashlight tests. Klin Monatsbl Augenheilkd 181: 402–403

52. Jiang MQ, Th ompson 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. Th ieme, Stuttgart, pp 341–344

54. Rüssmann W, Kaufmann H (2008) Augenbewegun gs-störungen. In: Straub W, Kroll P, Küchle J (eds) Augenärztliche Untersuchungsmethoden. Enke, Stuttgart, pp 637–643

10.1 Amblyopia Treatment 2009

10.1.1 Introduction

Amblyopia management, long based on consensus or clinical wisdom [1, 2], has been developing an evidence-based 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. Th ese studies have dealt solely with the most common forms of amblyopia, those due to anisometropia, strabis-mus or a combination. Spectacle correction is the base on which all treatment for amblyopia must be built. Both patching and atropine penalization are eff ective as initial management of moderate amblyopia. Initial dosages of 2 h daily of patching or twice weekly atropine have been shown to be eff ective and can be considered suitable for initial therapy. Severe amblyopia may be initially man-aged with 6 h of patching. Intensifi ed treatment for patients who are incompletely treated is logical to pre-scribe, yet not proven in clinical trials.

Th e 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 amblyo-pia, such as seen with unilateral aphakia or trauma, remains diffi cult, frustrating to the families, and oft en unsuccessful. Th ere is little new information on manage-ment 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 individu-als [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]. Th ese

Amblyopia Treatment 2009Michael X. Repka

Chapter 10

10

Core Messages

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. Th is improvement may facili-tate subsequent treatment.For initial therapy of moderate anisometropic ■

and strabismic amblyopia among children 3–7 years of age, patching and atropine are equiv-alent. Atropine is slightly more acceptable than patching on the basis of parental ques-tioning.For initial therapy of moderate amblyopia, 2 h of ■

daily patching or twice weekly topical atropine

administered to the sound eye are equally eff ective.For initial therapy of severe amblyopia for chil- ■

dren 3 to less than 7 years of age, 6 h of daily patching and full-time patching appear to be equally eff ective.Amblyopia therapy can be benefi cial for older ■

children up to 17 years of age, especially if they have not been previously treated.Th ere have not been any studies to date which ■

demonstrate the best therapy for patients with residual amblyopia following initial therapy. Th ere are also no studies that have identifi ed the best treatments for deprivation amblyopia.

126 10 Amblyopia Treatment 2009

10

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 ambly-opia 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 African-Americans [7]. Th e authors extrapolated their fi nding to suggest that there are approximately 271,000 cases of amblyopia among children 30–71 months of age in the United States. Th e 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]. Th ere 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 prob-lem among children. Th e 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 retro-spective 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. Th e literature sug-gests 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]. Th e more common causes of amblyo-pia are strabismus and moderate anisometropia, each accounting for about 35%, with 25% having both ani-sometropia 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 treat-ment, these cases are typically more diffi cult to treat successfully.

Other features of amblyopia include a reduction in contrast sensitivity and possibly reading ability. Most stud-ies 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 defi cit of contrast sensitivity aft er treatment

of strabismic and anisometropic amblyopia is slight in the intermediate spatial frequencies tested with the low-con-trast letters of the Pelli-Robson charts [16, 17]. We have recently confi rmed this fi nding of only a minimal defi cit with Pelli-Robson charts 3–7 years aft er enrollment in an amblyopia treatment trial [18].

Most studies of reading ability of amblyopic patients have tested the subjects binocularly, rather than monocu-larly, 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 aff ected [21]. PEDIG recently reported the monocular oral read-ing speed, accuracy, fl uency 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 monocu-lar loss of vision on the patient’s binocular reading ability remains to be thoroughly explored.

10.1.4 Diagnosis of Amblyopia

Th e diagnosis of amblyopia requires detection of a diff er-ence 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. Th e test should employ either crowded or line optotypes. Th e clinician should exercise caution when interpreting the results of optotype testing. Th e variability of the instrument needs to be considered. Specifi cally, 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 aft er age 3 years, with 93% of retests within 0.1 logMAR. More importantly, the visual acuity needs to diff er by more than 0.18 logMAR for the diff erence 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]. Th ese 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 Amblyopia Management 127

consideration of testing results before adjusting therapy is warranted.

A recent article has also confi rmed that the visual acu-ity may vary from test strategy to test strategy. Th e ATS-HOTV 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. Th e examiner determines the preference for fi xation 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 fi xation preference is again made. If the patient alternated or at least could hold with the less-preferred 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. Th ese research groups tested children 30 to less than 72 months with fi xation preference testing and optotype acuity. Fixation prefer-ence testing identifi ed 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]. Th ere were an insuffi cient number of children with strabismus to comment on that subgroup.

In the Multiethnic Pediatric Eye Disease Study (MEPEDS), the authors reported sensitivity of fi xation preference testing for amblyopia among children with anisometropia was 20% (9/44), although specifi city was 94% (102/109). Among strabismic children, sensitivity was 69% (9/13; worse in children 30–47 than 48–72 months old), and specifi city was 79% (70/89) [27].

Hakim found that 75% of strabismic children had positive test results by fi xation preference testing, but only 13% had an IOD of two lines or more [28]. Th e obvi-ous, albeit controversial confusion, is that fi xation prefer-ence testing misses most cases of amblyopia when used in a screening setting. In addition, the use of fi xation prefer-ence 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 ther-apy. Although compliance is quite variable, most children receive some intervention. Some authors have

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

10.2 Amblyopia Management

Best practice for management of amblyopia had been based on clinician consensus [1]. However, no random-ized 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 evidence-based information into the practice of amblyopia care based on the earlier guidelines.

10.2.1 Refractive Correction

Th e value of an accurate refraction can not be underesti-mated in the management of amblyopia. Th ese data are essential for both the diagnosis of amblyopia and the sub-sequent optimum treatment of the amblyopia. For secu-rity of the amblyopia diagnosis, the presence of an anisometropia helps substantiate the presence of amblyo-pia. Th e refractive error requires a measurement obtained under adequate cycloplegia, usually 1% cyclopentolate or similar cycloplegic. Many clinicians instill a topical anes-thetic before the cycloplegic agent to prolong the reten-tion of the cycloplegic drug in the tear fi lm.


Current estimates of the prevalence of amblyo- ■

pia 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 refrac-tive error.Fixation preference testing for amblyopia is ■

unreliable for the detection of amblyopia. It also appears to not be suffi ciently reliable to guide amblyopia therapy in many children.Care is needed when interpreting sequential ■

measurements of visual acuity when made with diff erent instruments or testing paradigms.


10

Prescribed glasses for ametropia are not controversial. Th e 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 eff ect at the child’s usual working distance. For the microstrabismic or ortho-tropic child, under correcting the hypermetropia sym-metrically by up to 1.50 diopters avoids the problem of distance blur and does not seem to detract from the treat-ment outcome. For the exotropic patient, the anisometro-pia 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 writ-ten and spectacles obtained. Some clinicians have rou-tinely 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, specifi cally 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. Th ese authors have termed this eff ect 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 ani-sometropic amblyopia ranging from 20/40 to 20/250 [34]. Optimal refractive correction was provided in accor-dance 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 pro-tocol to determine if such patients could respond to spectacle correction alone [35]. Twelve patients with pre-viously 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 aft er instituting the glasses were not available. Improvement in the visual acuity of

amblyopic strabismic patients was not expected to occur so oft en 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

Th e benefi cial eff ect 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 eff ects or possibly the benefi ts of spectacles alone as noted earlier [36]. To address that issue, PEDIG conducted a RCT comparing occlusion to specta-cles only. Before enrollment, the patients wore glasses until their vision stabilized between two consecutive visits. Th ey were then randomized to continue spectacles alone com-pared 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 mea-sured VA at any visit averaged 2.2 lines in the patching group and 1.3 lines in the control group (P < 0.001) [37]. Th us, occlusion was better but surprisingly there was con-tinuing benefi t of the spectacles alone, reinforcing how important this aspect of therapy must be.

Th e dosage of occlusion therapy prescribed has his-torically 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 patch-ing, both treatments were found to be equally eff ective [38]. Subgroup analysis of diff ering dosages from 6 h daily to full time (all waking hours less one daily) found no advantage of prescribing more hours [39]. Th is led us to design two studies directed at exploring occlusion dos-age. In the fi rst 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 ambly-opic eye improved a similar amount in both groups. Th e improvement in the amblyopic eye from baseline to 4 months averaged 2.40 lines in each group (P = 0.98). Th e 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 aft er 4 months so we do not know if a diff erence might develop. In the sec-ond 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. Th e improvement in

10.2 Amblyopia Management 129

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 aft er therapy. Th ere is a natural concern about amblyopia therapy, particularly with higher dosages, causing loss of vision in the sound eye. Th e 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.

Th ese patching dosage data show that for initial treat-ment 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.

Th ese 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 cor-rected. 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 com-plete 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 discon-tinuing treatment.

10.2.3 Pharmacological Treatment with Atropine

To fi nd an eff ective, yet easy to administer, treatment of amblyopia has been a goal pursued by clinicians treating amblyopia in response to the complaints and diffi culties associated with occlusion therapy. Th is pursuit has led to many failed treatments that were launched with great fan-fare, but ultimate abandonment.

For more than a century, clinicians have used pharma-cological penalization of the sound eye to make the child use the amblyopic eye and thereby improve the visual acu-ity of that eye. Most clinicians typically used this treat-ment for patching failures or noncompliance. Case series reported eff ectiveness, but the common belief was that this was an inferior treatment. Th e largest prospective study was completed in 2002, comparing once daily atro-pine to patching 6 or more hours per day for moderate amblyopia 20/30–20/100 [38]. Visual acuity improved in

both groups: 2.84 lines in the atropine group and 3.16 lines in the patching group. Th e patching group did get better faster, but by 6 months, the diff erence of 0.034 was clinically inconsequential. Both treatments were well tol-erated, although the atropine was easier to administer based on parental questionnaires.

Th ese children were followed in the study for an addi-tional 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 atro-pine group and 3.7 lines in the patching group. Th is dif-ference in visual acuity between treatment groups was small: 0.01 logMAR (95% confi dence interval, −0.02 to 0.04). Th us, the relative equivalence of the techniques and the persistence of the treatment benefi t were reaffi rmed. Stereoacuity outcomes were similar suggesting no untow-ard relative eff ect of either of the two treatments.

One concern regarding amblyopia therapy is the potential for inducing or worsening a strabismus. In addi-tion, most authors have suggested treating amblyopia before undertaking strabismus surgery. Th is study evalu-ated the chance of inducing a strabismus, but also the chance of improving a strabismus with amblyopia treat-ment. Of the 161 patients with no strabismus, similar proportions initially assigned to the patching and atro-pine groups developed new strabismus by 2 years (18 vs. 16%, P < 0.84) [43]. Of the new cases of strabis-mus, 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 stra-bismus surgery. Th ese data show that strabismus may develop or resolve with amblyopia therapy in about equal proportions.

Th e dosage of atropine in the original PEDIG trial was once daily. Th is design was consistent with the desire to maximize the likelihood of fi nding benefi t if there was one. While that study was underway, the ben-efi t of less frequent administration was suggested by Simons and coworkers [44]. Th ey reported reasonable improvement from less frequent administration. Th is was plausible since the duration of cycloplegia was oft en more than 1 day. Th is fi nding led PEDIG to develop a clinical trial, which compared daily atropine to weekend atropine.


10

Th e atropine dosage treatment trial included 168 chil-dren younger than 7 years with amblyopia in the range of 20/40–20/80 associated with strabismus, anisometropia or both. Th ey were randomized to either daily or week-end atropine [45]. Th e improvement of the amblyopic eye from baseline to 4 months averaged 2.3 lines in each group. Th e 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. Th e 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 ran-domized treatment beyond the 4-month outcome exam. Th ey 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. Th e mean amblyopic eye acuity at study completion was 0.23 logMAR in the daily group and 0.21 logMAR in the weekend group (approxi-mately 20/32). Th e mean sound eye visual acuity at enroll-ment 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. Th ese results were similar in the two atropine treatment groups. Th us, a 4-month treatment period with atropine will treat most patients but is not suffi cient to complete treat-ment for all. Th us, treatment should be continued until there is good evidence that a plateau in improvement has been achieved.

Th ere 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 fl ushing and fever, a more worrisome side eff ect, was reported by 1% of the children.

Summarizing, weekend atropine for moderate ambly-opia is eff ective in improving visual acuity. Th e 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 propor-tion of parents. However, as with patching if the visual acuity improvement is not complete increasing the dos-age or changing to an alternative therapy should be con-sidered. Th e eff ectiveness 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 eff ect. For atro-pine penalization of the sound eye, it has been long noted that adding optical penalization, by removing all hyper-metropic correction from the sound eye, would add opti-cal blur at distance to complement the cycloplegic blur provided at near. A retrospective report included 42 chil-dren (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 ambly-opic eye visual acuity from 20/113 to 20/37 aft er 10 weeks of treatment with atropine and a plano lens to the sound eye. Th is 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 moder-ate amblyopia (visual acuities of 20/40–20/100) to week-end 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 diff erence between groups adjusted for baseline acuity, 0.3 line; 95% confi dence 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 atro-pine plus a plano lens had reduced sound eye visual acu-ity at 18 weeks; fortunately, there were no cases of persistent reverse amblyopia. Th e 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 131

10.3 Other Treatment Issues

10.3.1 Bilateral Refractive Amblyopia

Th e management of bilateral amblyopia from hyper-metropia and/or astigmatism has been the subject of sev-eral reports. Th e incidence was 4 of 830 (0.5%) children at entry into school in an older report [49]. Small case series have found substantial benefi t 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 suffi cient 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 astig-matism, or both in each eye. Mean binocular visual acu-ity improved from 0.50 logMAR (20/63) at baseline to 0.11 logMAR (20/25) at 1 year (mean improvement, 3.9 lines; 95% confi dence interval, 3.5–4.2). Mean improve-ment was 3.4 lines (95% CI, 3.2–3.7) for children with

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 aft er 13 weeks for some, yet only aft er a year for others. Th e obvi-ous 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 Eff ect

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 eff ect identifi ed [53]. Th is fi nding along with case reports of effi cacy 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), treat-ment was 2–6 h of patching daily plus daily atropine. Fift y-three percent of the treatment group improved at least ten letters compared with 25% of the optical correc-tion 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 defi cit. Th is means that older chil-dren 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]. Th is 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]. Th e recurrence rate was 24% (35 of 145) (95% confi dence interval 17–32%). Th ere was no diff erence 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% confi dence interval 1.0–18.7). Absent additional data seems prudent to mon-itor all patients and to taper occlusion therapy (6 or more hours) and daily atropine therapy.


A series of trials has shown that for amblyopia ■

from anisometropia, strabismus or both com-bined, initial therapy should be refractive cor-rection with the expectation of substantial improvement.Occlusion is signifi cantly more eff ective than ■

spectacles alone.Atropine and patching are equally eff ective for ■

initial treatment of mild amblyopia among chil-dren 3 to less than 7 years of age.Initial dosages of 2 h of patching and weekend ■

atropine are similar in eff ectiveness 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 aft er treatment completion.Augmented pharmacological treatment with a ■

plano lens for the sound eye is not associated with substantial benefi t as initial therapy, but is associated with a risk of visual loss in the sound eye.


10

10.3.4 Long-Term Persistence of an Amblyopia Treatment Benefi t

Th e 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. Th e best estimates are about 25% will recur during the fi rst year aft er cessation of therapy [55–57]. Most of these cases will occur in the fi rst 6 months aft er cessation of therapy. Based on clinical experience most of the recur-rences can be successfully treated, but prospective data are needed.

Th e long-term benefi t of amblyopia therapy would only be proven if the improvement in acuity experienced by the amblyopic eye is maintained. Th ere are substantial data published in this area, which is quite troublesome. Th e extent of deterioration reported in retrospective out-come studies of children treated for amblyopia to be as high as 58% in spite of interim treatment, thereby reduc-ing the actual benefi t 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 aft er randomization, and a subgroup reexamined at age 10 years, 3–7 years aft er randomization [64]. Two years aft er 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). Th e 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 out-come 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-eff ective among the spectrum of eye and health care interven-tions [66, 67]. However, there is substantial uncertainty concerning the eff ect 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 fi nd signifi cant diff erences in educational, social, or employment attainment between amblyopic and control subjects [68]. Conversely, a questionnaire-based study of adults with amblyopia and strabismus on their quality of life found lifelong benefi ts as perceived by those patients [69].

10.4 Other Treatments

Clinicians have long known that the standard treatment of patching and even atropine were not always successful. Th ey have therefore sought alternatives to occlusion ther-apy 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]. Th e eight fi lter 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. Th e fi lters 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, fi lters do not cause skin irritation. Finally, one could postulate that Bangerter foils are less disruptive to binocular function during treatment compared with patching. Th e key dis-advantage 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]. Th ey 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 bet-ter or equal to that of the sound eye. Of the remaining fi ve patients, four attained amblyopic eye acuity of 20/25 or


Amblyopia therapy appears to lead to a persis- ■

tent improvement in visual acuity of the ambly-opic 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 eff ect ■

of amblyopia on patient outcomes.

10.5 Controversy 133

20/30 or within a half line of the sound eye. Bangerter fi lters, as in this study, are prescribed for longer periods than either patching or atropine because they are well tolerated.

Bangerter fi lters have not been compared with patch-ing or atropine. PEDIG has completed a clinical trial com-paring Bangerter fi lters (0.2 and 0.3 densities) to 2 h of daily occlusion. Th e 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 con-verted to dopamine. Levodopa is typically used in combi-nation with carbidopa, a peripheral decarboxylase inhibitor that prevents the peripheral breakdown of levodopa. Th is reduces the dose of levodopa and thereby reduces the primary side eff ects of nausea and emesis.

A randomized longitudinal double masked placebo control trial of ten amblyopic children aged 6–14 years [72]. Th e 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 aft er 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) aft er treatment, 52% of those who improved had regression in visual acuity when mea-sured aft er 1 year.

A follow-up report of three longitudinal studies (9–27 months) using levodopa (0.55 mg/kg/t.i.d.) plus occlu-sion for treatment of amblyopia included 30/33 (91%) of

participating subjects. Subjects who received levodopa plus occlusion demonstrated signifi cant regression of visual acuity aft er 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 diff erence in visual acuity outcome was found.

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, appear-ance 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 neu-ropathy. Such a situation might be an optic neuropathy related to compression or other progressive damage of the aff erent 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 fi ndings are very common. He has reported termed “dys-version” 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 ambly-opic 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 fi ber layer thickness would be reduced. Such investiga-tions based on optical coherence tomography have not


Bangerter fi lters appear to be a useful option but ■

data compared with those of other treatments are not yet available.Many pilot studies have shown some improve- ■

ment when patching is combined with levodopa/carbidopa for about 8 weeks. Durability of the treatment eff ect and a comparison with patching alone needs to be completed.


10

found any substantive diff erence among amblyopic, fel-low, 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.

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80. Altintas O, Yuksel N, Ozkan B, et al (2005) Th ickness of the retinal nerve fi ber 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 fi ber layer thickness in amblyopic eyes. Am J Ophthalmol 142:247–251

82. Yen M, Cheng C, Wang A (2004) Retinal nerve fi ber layer thickness in unilateral amblyopia. Invest Ophthalmol Vis Sci 45:2224–2230

11.1 Introduction

11.1.1 Defi nition and Prevalence

Infantile esotropia (IE) is defi ned 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 disor-ders [1, 2].

IE aff ects approximately 0.25% of the population [3–5]. A higher prevalence has been found previously in studies where little distinction was made between

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 sys-tem impairment except speech delay.

11.1.2 Sensory or Motor Etiology

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

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

Chapter 11

11

Core Messages

Th e 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 postopera-tive angle of strabismus and the long-term stabil-ity 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 specifi c child with IE, the expected outcome of surgery should be esti-mated according to these parameters.Th ere 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). Th e primary outcome of that study was that 13.5% of those operated at approximately 20 months of age against 3.9% (P =

0.001) of those operated at approximately 49 months recognized the Titmus Housefl y at the age of 6 years; there was no diff erence in stereop-sis beyond Titmus Housefl y.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 fi ner stereopsis aft er very ■

early surgery await confi rmation in a randomized controlled trial.

138 11 Best Age for Surgery for Infantile Esotropia

11

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 fi ne 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 fi ner distinction among the sub-types of IE.

IE should be considered, similar to the working defi -nition formulated for congenital cerebral palsy [9], as a group of permanent, but not unchanging, disorders with strabismus and disability of fusional vergence and bin-ocular vision, due to a nonprogressive interference, lesion, or maldevelopment of the immature brain, the orbit, the eyes, or its muscles, that can be diff erentiated according to location, extent, and timing of the period of develop-ment. Such an open matrix fi ts 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 ocu-lar dominance columns of the right and left eyes [10], do not develop (sensory cause) or cannot develop (motor cause). Th ey 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, ver-gence, and gaze holding. Accordingly, infants can follow objects moving towards the nose more easily, the so called nasotemporal OKR and pursuit bias. Th e ipsilat-eral 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 per-sists and latent nystagmus develops [14–17]. Th e dura-tion 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 aft er birth by cutting the medial rectus muscles [10], cutting the lateral rectus muscles [20], or fi tting 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]. Th e 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]. Th is 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 coordina-tions 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 main-tain 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 hyper-metropia, nor anisometropia, nor heterophoria can cause squint. … Sometimes, however, owing to a con-genital 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 rela-tive directions of the eyes, and anything which disturbs the balance of these coordinations will cause a perma-nent squint.”

11.1.5 Outcome Parameters

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

11.2 Outcome of Surgery in the ELISSS 139

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. Th ere 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-to-treat. Elliot and Shafi q [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. … Th ere 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. Th ree such cases occurred in the fi rst prospective study by Birch et al. [27] and two in the ELISSS.

Th erefore, 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 specifi c child. Th e primary out-come measures are the following:

1. Th e binocular vision conserved or regained by early surgery.

2. Th e angle of strabismus aft er surgery and the long-term stability of alignment.

3. Th e number of operations to reach these goals or the chance of spontaneous reduction of the strabismus into a microstrabismus without surgery.

Th ere are other outcome parameters that should be con-sidered. For instance, the child’s psychological and motor development, and bonding between infant and parents may be improved by early surgery. Th ese need evaluation within disciplines other than pediatric ophthalmology, however.

Endophthalmitis aft er strabismus surgery [38] occurs preferentially in fi rst surgery in children under 6 years of age, but it is not yet clear whether its prevalence in young children diff ers from that in very young children. Finally, general anesthesia may not be without risk in young chil-dren. As a case in point, in a recent population-based, ret-rospective birth cohort study, general anesthesia before the age of 4 years was signifi cantly correlated with learn-ing disability [39].

11.2 Outcome of Surgery in the ELISSS

11.2.1 Reasons for the ELISSS

Early surgery may minimize further loss of the remaining binocular vision. Th e fi rst prospective study of surgery for IE Birch et al. [27] reported 35% random dot stereop-sis (disparity 400˝ or better) among 84 children operated at approximately 8.5 months. Sixty-three were aligned within 5.7°. Th e average number of operations was 1.5. Th ree were not operated and had full stereopsis. Aft er this fi rst prospective study of surgery for IE had been pub-lished, 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 fi rst presented to one of the participating clinics. Th e ELISSS study committee considered randomization impossible, because it was anticipated that the parents would not cooperate: One fi rst 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 fi rst presented with con-vergent IE between 5 and 30° were included. However,


IE may have many causes, ranging from motor ■

to sensory. Whatever its cause, whether sensory or motor, the end state of untreated IE is charac-terized 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) bin- ■

ocular vision, (2) the angle and long-term stability of alignment, and (3) the number of operations or the chance of spontaneous reduction of the stra-bismus into microstrabismus without surgery.


11

children with pre- or dysmaturity, nystagmus, nervous system defi cit, retardation, dysmorphia or motility dis-orders other than up- or downshoot in adduction, V- or A-pattern, or limitation of abduction were excluded. Following recruitment, the angle of strabismus, refrac-tion, 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 estab-lished fi xation preference and/or signifi cant anisometro-pia underwent appropriate and eff ective occlusion therapy to the point of near spontaneous alternation and central fi xation 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 inde-pendent observers. Endpoints were level of binocular vision, manifest angle of strabismus at distance fi xation, remaining amblyopia, number of operations, vertical strabismus, angle at near, and infl uence of surgical technique.

11.2.3 Summarized Results of the ELISSS

A total of 58 clinics in 13 countries recruited 532 chil-dren: 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 ner-vous system defi cit (99). No diff erences 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 diff erences existed between dropouts and completers in the baseline examination, and clinics with many drop-outs did not have better results. Th e fi nal examinations were performed at the age of 6.8 SD 0.8 years, on aver-age, in the early group and 6.8 SD 0.7 years in the late group. Th e interval between the last operation and the fi nal examination was 4.4 SD 1.5 years in 157 children from the early group, and 2.3 SD 1.1 years in 187 chil-dren from the late group. Th e number of orthoptic examinations in the early group was 11.3 SD 5.2 per patient, including all children who later became drop-outs; in the late group, it was 11.4 SD 4.6.

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 recog-nized the Titmus Housefl y; 3.0% of the early and 3.9% of the late group had stereopsis beyond Titmus Housefl y (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 fi xation 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

Fig. 11.1 Binocular vision at the age of 6 years aft er early or late surgery, stratifi ed according to whether the children had been oper-ated (black) or not (white) at the age of 6 years. Categories: (1) Bagolini negative, (2) Bagolini positive, (3) Housefl y positive, (4) Titmus cir-cles 200˝–140˝, (5) Titmus circles 100˝–40˝, (6) all fi gures of Lang Test or TNO 480˝ and 240˝, (7) TNO 120˝–15˝ (See Ref. [57])

60

50

40

30

20

10

Per

cent

age

for

unop

erat

ed a

nd o

pera

ted

patie

nts

01 2 3 4

early lateDegree of binocular vision

5 6 7 1 2 3 4 5 6 7

11.2 Outcome of Surgery in the ELISSS 141

Fig. 11.2 (Left ) Manifest horizontal angle of strabismus in degrees for both groups at the fi nal examination at the age of 6 years (N = 414), stratifi ed 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])

30

20

10

–10

–10

–20

0

0 10 20 30 40

Hor

izon

tal a

ngle

of s

trab

ism

us

Horizontal angle of strabismus at baseline

40

30

20

10

0

Per

cent

age

for

unop

erat

ed a

nd o

pera

ted

patie

nts

early late

Horizontal angle of strabismus (deg)

< = − 12

< = − 8

< = − 4

< = 0< = 4

< = 8< =12

< =16< =20

< =24> 24

< = − 12

< = − 8

< = − 4

< = 0< = 4

< = 8< =12

< =16< =20

< =24> 24

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 align-ment 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 preced-ing the fi nal 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). Th ese fi ndings 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.

11.2.6 Alignment is Associated with Binocular Vision

Children with at least Titmus Housefl y stereopsis were better aligned (Fig. 11.3). Better alignment in case of bet-ter 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

IE” [45] among older children, 38.4% of the children had a positive Bagolini test postoperatively, although all chil-dren with any form of binocular vision preoperatively had been excluded. Th ese children had signifi cantly bet-ter ocular alignment, which may have been either a cause or a consequence of the gain of binocular vision.


In the ELISSS, children with IE operated around ■

the age of 20 months, achieved Bagolini striated glasses or Titmus Housefl y stereopsis more fre-quently as compared to those operated around the age of 49 months.No diff erence was found, however, for stereopsis ■

beyond Titmus Housefl y.Alignment was similar aft er early surgery, as ■

compared to that aft er 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.


11

11.3 Number of Operations and Spontaneous Reduction into Microstrabismus Without Surgery

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 chil-dren 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 fi rst oper-ated 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 fi rst 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 Reported Reoperation Rates

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

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 –10 –5 0Horizontal manifest angle of strabismus in degrees at age 6 in degrees

for operated (grey circles) and unoperated (black) cases

5 10 15 20 25

Fig. 11.3 Relation between the level of binocular vision and angle of strabismus at distance fi xation 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])

80

70

60

50

40Per

cent

30

20

10

00 1 2

early late

Number of operations Surgery Group

3 4 0 1 2 3 4

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 oper-ated at the age of 6 years (See Ref. [57])

11.3 Number of Operations and Spontaneous Reduction into Microstrabismus Without Surgery 143

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] sur-gery. 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 opera-tions during a mean follow-up period of 13.5 years from their date of diagnosis, i.e., a 80% reoperation rate, includ-ing second and third reoperations. Th e 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 aft er fi rst surgery had taken place among 181 patients. Th ese 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 aft er the fi rst operation. Average reoperation rate was 19.3%. Logistic

regression analysis showed no statistically signifi cant dif-ference between clinics concerning chance of reoperation.

To test whether the large diff erences between reported reoperation rates aft er early surgery, mentioned earlier, were due to the diff erences 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. Th e mean duration of follow-up and mean age at operation were regressed on the logistically trans-formed reported reoperation rate. Th e meta-regression model had an R-squared value of 0.44. Th e infl uence of this confounding factor was estimated in a multivariate logistic model. Reoperation rates were adjusted for duration of fol-low-up with the meta-regression model and plotted against the mean age at operation for each study (Fig. 11.5).

Aft er adjustment of the reoperation rates reported aft er short follow-up periods, reoperation rates became more similar to the rate reported by Helveston et al. [49] aft er a long follow-up period. A trend for more reopera-tions aft er early surgery when compared with that aft er late surgery can be noted (Fig. 11.5).

0%

20%

40%

60%

80%

100%

Age in months

Reoperationrate

Louwagie [4]

Helveston [49]

Helveston [48]

Stager [64]

Nelson [53]

Kushner [52]

Charles [7]

Early [57]

Keenan [51]

Tolun [92]

Late [57]Bartley [47]

Vijver [55]

0 12 24 36 48 60

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


11

11.3.3 Test-Retest Reliability Studies

One of the reasons contributing to a higher reoperation rate aft er early surgery is the inaccuracy in measuring the angle of strabismus in young children. In a test-retest reli-ability 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. Fift een 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 refl exes during fi xation of an object with a light at 50 cm or by estimation of the location of the corneal refl ex rela-tive to the pupil during fi xation of an object with a light at 50 cm. Th e angle of strabismus averaged 21° for the fi rst, second, and third examinations, with approximately equal standard deviations for all three examinations. Th e intraclass correlation coeffi cient (diff erences between

three examiners examining one infant, 1.0 signifying complete agreement) was 0.80. Th e distribution for the largest diff erence between any two of the three measured angles averaged 6.5°. In 10% of the infants, the largest dif-ference between any two of the three measured angles exceeded 10°. Standard deviations and intraclass correla-tion coeffi cients 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 occa-sions yielding 199 test-retest pairs for prism and alternate cover test at distance fi xation and 239 at near fi xation. For angles greater than 11.3°, the 95% limits of agreement on a measurement and on a diff erence between two mea-surements 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 aft er

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. Th e horizontal angle of strabismus was measured, either with prisms and corneal refl exes or by estima-tion of the location of the corneal refl ex relative to the pupil. Larger circles represent more measurements

0

10

20

30

40

50

50403020100Angle (degrees) measured by first or second orthoptist (N=144 children x 3 pairs of measurements)

Ang

le (

degr

ees)

mea

sure

d by

sec

ond

or th

ird o

rtho

ptis

t


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)

N=4

N=20N=62

N=51

N=17

N=12

0

10

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30

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50

60

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Postoperative angle of strabismus in degrees, 3 months postoperatively

Obs

erve

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te a

nd e

xper

ts' e

stim

ates

(%

)

< -5° -4 to -1° 0 to 4° 4 to 9° 10 to 14° > 14°

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 hori-zontal 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 aft er fi rst surgery in children operated at 4.33 years, on average, the average reoperation rate was 19.3%. Th e reoperation rate was only 7.3%, how-ever, for those with a residual angle of −4 to +4° (82, 49.4%), 3 months postoperatively. Th e 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 reopera-tion rate based on the angle of strabismus at distance

fi xation, 3 months postoperatively. Th ey 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 fi rst 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 fi rst 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 identifi ed 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 infl u-ence 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. Th ese 80 children had “alignment and fusion” in 76% of the cases, when compared with 38.4%


11

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 fi nal assess-ment had better binocular vision than those who had been operated.

Spontaneous resolution of infantile strabismus has fi rst 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 sup-pression, and a favorable appearance. Due to the periph-eral 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 strabis-mus into a microstrabismus (Fig. 11.8).

Th ere are few studies with similar longitudinal mea-surements 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 mea-sured 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 modifi ed 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 dif-fered 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 reduc-tion of the angle be predicted and, hence, unnecessary operations be avoided in individual cases by waiting? Th is 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 likeli-hood 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-Eff ects 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 thereaft er, until the fi nal evaluation at the age of 6 years. Th e result-ing, slightly more than 6,000, orthoptic exams were used to construct a random-eff ects 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 diff erent 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. Th e uncertainty about the slope decreases with additional measurements because the random eff ect of the slope of the lines decreases. Th e 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-eff ects 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.


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Fig. 11.8 Th e 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%). Th e 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%). Th ese children correspond to the white bars in Figs. 11.1, 11.2, and 11.9


11

In the model, refractive error exerted its largest infl uence, i.e., causing the largest chance of spontane-ous 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 aft er fi tting full correcting glasses, thereby avoid-ing surgery.


Th e 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 bin-ocular vision.

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Fig. 11.10 Random-eff ects 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 eff ect for a patient was defi ned as the deviation of the average angle, the fi xed eff ect. A vector was defi ned based on age and spherical equivalent of the patient. A covariance matrix of the random-eff ects estimations was defi ned and fi lled with the values from the approximately 6,000 orthoptic exams in 532 children. Th e model predicts the average angle in relation to age. A linear relation suffi ced. Th e variance around the prediction (curved lines represent one and two standard deviations) consists of uncertainty in the estimations, random eff ects and the residuals. Left : an example pre-diction 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

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Fig. 11.9 Angle of strabismus at baseline at approximately 11 months for all 414 operated (black) and unoperated (white) patients who underwent the fi nal 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])

References 149

Appendix

Members of the Early vs. Late Infantile Strabismus Surgery Study Group were: (Austria) A. Langmann, S. Lindner, S. Priglinger, M. Raab, H. Th aller-Antlanger, D. Koschkar-Moser, H. Gruber-Luka, R. Führer, S. Harrer, K. Rigal, R. Pelz, B. Puchhammer, A. Th aler, E. Moser, K. Schmidt, (Belgium) M. Spiritus, M. van den Broeck, S. Vandelannoitte, A. Finck, P. Evens, D. Godts, (France) M. Bourron-Madignier, S. Vettard, O. Benhadj, (Germany)E-Ch. Schwarz, G. Wunsch, C. Jandeck, S. Lutt-Freund, D. Jüptner-Johanning, 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 Everhard-Halm, 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. Sefi k Sanaç, E. Cumhur Sener, S. Demirci, N. Erkam, Huban Atilla, N. Erda, A. Tulin Berk. Statististical analy-sis 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

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11. Tychsen L, Burkhalter A (1995) Neuroanatomic abnor-malities of primary visual cortex in macaque monkeys with infantile esotropia: preliminary results. J Pediatr Ophthalmol Strabismus 32:323–328

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16. Hoff mann KP, Bremmer F, Th iele 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

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18. 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 strabis-mus macaque monkeys. Neuroscience 156:403–411


11

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) Th e eff ect of short-term 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 eff ects. J AAPOS 7:200–209

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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 nor-mal and naturally strabismic monkeys. Invest Ophthalmol Vis Sci 31:1168–1174

26. Worth CA (1903) Squint: its causes, pathology and treat-ment. 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 stere-oacuity following surgical correction of infantile esotropia. J Pediatr Ophthalmol Strabismus 32:231–235

29. Birch E, Stager D, Wright K, Beck R (1998) Th e natural his-tory of infantile esotropia during the fi rst 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 sen-sory out comes aft er 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 esotro-pia. J AAPOS 6:3–8

35. Wright KW, Edelman PM, McVey JH, Terry AP, Lin M (1994) Highgrade stereo acuity aft er early surgery for con-genital esotropia. Arch Ophthalmol 112:913–919

36. Tychsen L (2005) Can ophthalmologists repair the brain in infantile esotropia? Early surgery, stereopsis, monofi xation syndrome, and the legacy of Marshall Parks. J AAPOS 9:510–521

37. Elliott S, Shafi q A (2005) Interventions for infantile esotro-pia. 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, Löffl er KU, Hartwig NG (2009) Age-related immune defects causing endophthalmitis aft er 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 dis-abilities in a population-based birth cohort. Anesthesiology 110:796–804

40. Early vs late infantile strabismus surgery study group (1993a) Th e protocol for the Early vs. Late infantile strabis-mus 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) Th e 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 inter-mittent, 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 compari-son 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

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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 con-genital esotropia. Ophthalmology 106:1716–1726

50. Hiles DA, Watson BA, Biglan AW (1980) Characteristics of infantile esotropia following early bimedial rectus reces-sion. 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

scheelzien: een retrospectief onderzoek. Ned Tijdschr Geneesk 143:2121

56. Pediatric Eye Disease Investigator Group (2009) Interobserver reliability of the prism and alternate cover test in children with esotropia. Arch Ophthalmol 127: 59–65

57. 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

58. Clarke WN, Noel LP (1982) Vanishing infantile esotropia. Can J Ophthalmol 17:100–102

59. Pediatric Eye Disease Investigator Group (2002) Spontaneous resolution of early onset-esotropia: experi-ence of the congenital esotropia observational study. Am J Ophthalmol 133:109–118

60. 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

61. 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

Management of Congenital Nystagmus with and without StrabismusAnil Kumar, Frank A. Proudlock, and Irene Gottlob

Chapter 12

12

Core Messages

Congenital nystagmus consists of involuntary ■

periodic to-and-fro oscillations of the eye, which are usually horizontal and present within the fi rst 3 months of life.Congenital nystagmus can be idiopathic or occur ■

in association with defects in the aff erent visual system such as albinism, congenital retinal dystro-phies 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 diff erentiated ■

from manifest latent nystagmus (MLN) and con-genital periodic alternating nystagmus (PAN) as the management of these conditions diff ers.Several compensatory mechanisms exist in con- ■

genital nystagmus, which tend to decrease the nystagmus and thus improve the visual acuity. Th ese 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 opti-cal, medical, and surgical treatment. A combina-tion of treatment options might be helpful to achieve the best outcome.Th e incidence of signifi cant 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

spectacles, contact lenses (CL), or low visual aids.Recently, medical treatment for congenital nys- ■

tagmus with memantine and gabapentin has been shown to reduce nystagmus intensity and to increase visual acuity. Baclofen is benefi cial in the management of congenital PAN.Surgery in congenital nystagmus is used to cor- ■

rect the anomalous head posture (AHP) and to dampen the nystagmus.For Anderson−Kestenbaum- like procedures var- ■

ious extents of surgery have been proposed by diff erent surgeons. However, if the head turn is signifi cant, 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 fi xing eye. Strabismus correction is best planned during the same surgical session on the non-fi xing eye.Surgery causing artifi cial divergence (exophoria) ■

is benefi cial in patients with binocular vision and damping of nystagmus on convergence. Combination of Anderson−Kestenbaum-like pro-cedures and artifi cial divergence surgeries have been shown to be benefi cial.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.

154 12 Management of Congenital Nystagmus with and without Strabismus

12

12.1 Overview

Th e 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 diff erent 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 evolv-ing, with new methods of treatment emerging which are now proving to be benefi cial. Th e armamentarium of treatment of congenital nystagmus includes optical, med-ical, and surgical treatments. Currently, in most nystag-mus forms there is no defi nite answer as to which is the best treatment option. Th is chapter highlights the diff er-ent modes of treatment.

Th e fi rst section of this chapter discusses in detail the clinical characteristics of patients with congenital nystag-mus with and without sensory defi cit, MLN, and PAN. In the second section, the compensatory mechanism involved and methods to identify them are considered. Th e third section discusses the treatment options avail-able for congenital nystagmus.

12.1.1 Congenital Nystagmus with and Without Sensory Defi cits

Congenital nystagmus consists of involuntary periodic to-and-fro oscillations of the eye. It usually presents within the fi rst 3 months of life; however, onset as late as 12 months to 10 years has been reported [1]. Th e inci-dence of congenital nystagmus is estimated to be 1 in 2,000, in a population-based survey done in UK.

Th e eye movements in congenital nystagmus are mainly in the horizontal plane, although they can be ver-tical or torsional, or in a combination of diff erent planes. Congenital nystagmus is oft en described in the literature as being a jerk nystagmus with accelerating slow phase; however, IIN may show diff erent 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 oft en changes with the direction of gaze. Th e region of lowest nystag-mus intensity and longest foveation periods is known as the “null region.” Th is is oft en the preferred region of

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

BeforeTreatment

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Fig. 12.1 Original horizontal eye movement recordings of right eyes of (fi rst 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 treat-ment; (fi ft h 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 repre-sented by an upward defl ection, and eye movements to the left by a downward defl ection. Th e eye movement recordings show the vari-ability in waveforms with the common occurrence of an underly-ing pendular waveform. Th ey also show reduction of intensity aft er treatment with memantine and gabapentin but not with placebo

12.1 Overview 155

if the null region is eccentric. Typically, the oscillation drift s toward the null region with the drift becoming accentuated further away from the null region. Th is results in the quick phases usually beating away from the null region with slow phases oft en 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 aff erent 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 con-genital cataracts. To assess visual potential when treating a patient, it is important to carefully diagnose whether an aff erent visual defect is present. Ocular albinism is fre-quently misdiagnosed as idiopathic nystagmus as the phenotypical characteristics might be subtle. Figure 12.2 shows clinical signs seen in a patient with oculocutane-ous albinism as well as in a patient with ocular albinism. Th e patient with ocular albinism has dark hair and skin, very mild iris transillumination, but a hypopigmented fundus. Both patients have foveal hypoplasia to varying

Appearance

OculocutaneousAlbinism (OCA)

OcularAlbinism (OA)

Iris trans-illumination

Fundoscopy

OpticalCoherence

Tomography

a b

c d

e f

g h

Fig. 12.2 Phenotypical characteristics of patients with oculocutaneous (a, c, e, g) and ocular (b, d, f, h) albinism. Th e patient with oculocutaneous albinism has light hair and more prominent iris transillumina-tion 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)


12

degrees as shown using optical coherence tomography (OCT). Both patients had increased crossing of optical nerve fi bers in the chiasm shown on visual evoked poten-tial examination (see Fig. 12.3d).

Th e diff erent 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

Scotopic Photopic FlickerNormal

CongenitalStationary

Night Blindness

Achromatopsia

500µv 20µv 10µv20ms20ms20ms

Visual Evoked Potentials

Albinism

O1 - Fz

Oz - Fz

O2 - Fz

O1 - O2

O1 - Fz

Oz - Fz

O2 - Fz

O1 - O2

O1 - Fz

OzO2

Fz

O1

Oz - Fz

O2 - Fz

O1 - O2

O1 - Fz

Oz - Fz

O2 - Fz

O1 - O2

Normal

Rig

ht

Eye

Op

enL

eft

Eye

Op

en

a

b

c

d

Fig. 12.3 Examples of scotopic, photopic, and fl icker 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 achro-matopsia with extinguished photopic ERG and fl icker ERG. (d) Visual evoked potential of a patient with albinism showing asymme-try 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 fi bers 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)

12.1 Overview 157

Possible presence of AHP, strabismus, and refractive ■

errorsDecreased amplitude of nystagmus in null point ■

Dampening of nystagmus on convergence ■

Th e intensity of nystagmus increases with fi xation, ■

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 defi ned 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 nystag-mus,” nystagmus is seen on eye movement recordings even when both eyes are open. Hence MLN/latent nys-tagmus 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 fi xating 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 fi xating eye when the fellow

eye is occluded. Th e AHP changes to the other side in an alternating monocular occlusion, which helps in the diag-nosis of MLN. If patients with MLN have alternating fi xa-tion the head turn can change spontaneously, depending on which eye is fi xing. 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 nystag-mus confi rmed on eye movement recordings. Th e patient has exotropia and is freely alternating. He is always keep-ing the fi xing eye in adduction and therefore his head pos-ture is alternating with a turn to the right with the right eye fi xing and left with the left eye fi xing. When one eye was patched his head turn was unidirectional in the direc-tion of the open eye. Th e cause of MLN appears to be due to disruption of binocular vision during visual develop-ment, 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 nys-tagmus is congenital nystagmus, 15% is MLN, and 5% is a combination of both forms.

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 EYECOVERED

Rig

ht E

yeLe

ft E

ye

RIGHT EYECOVERED

LEFT EYECOVERED

BOTH EYESUNCOVERED

RIGHT BEATING

R

L

10º0.5 sec

Fig. 12.4 Original horizontal eye movement recordings of both eyes of a patient with manifest latent nystagmus (MLN) and exotro-pia during an alternating cover test. Eye movements to the right are represented by an upward defl ection, and eye movements to the left by a downward defl ection. Th e 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. Th e velocity of the slow phase is decelerating or linear. Arrows indicate blinks


12

Eye movement recordings have a characteristic ■

slow phase with exponentially decreasing or linear velocityAmplitude of nystagmus decreases in adduction and ■

increases in abduction, with the fast phase of nystag-mus toward the side of fi xating eye

12.1.3 Congenital Periodic Alternating Nystagmus (PAN)

Congenital PAN is classifi ed as a variant of congenital nystagmus according to the CEMAS classifi cation. Congenital PAN is discussed as a separate entity because

Anomalous Head Posture in IdiopathicInfantile Nystagmus

Without visual effort

Child

Adult

Without visual effort

Bi-directional Alternating Head Turn in MLN

Right head turn Left head turn

With visual effort

With visual effort

Correction of Anomalous Head Posture inIdiopathic Infantile Nystagmus with Anderson-Kesternbaum Surgery

Vertical and horizontal head turn with esotropia

Before surgery After surgery

Horizontal head turn

Before surgery After surgery

Measurement of head turn using Harms wall

a b g h

i j

k

c d

e f

Fig. 12.5 Abnormal head posture (AHP) of a child with idiopathic congenital nystagmus (a) without visual eff ort and (b) with increased head turn while pointing at pictures on the Lang stereo test. Panel (c) shows a patient with idiopathic congenital nystag-mus without head posture when there is no visual eff ort 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 con-genital nystagmus with approximately 45° head turn to the left before surgery and with straight head position (h) aft er Anderson–Kestenbaum procedure. A patient with oculo-cutaneous albinism and chin depression, face turn to the right and left esotropia before surgery (i) and aft er 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. Th e cross is projected from a light source fi xed on the head

12.1 Overview 159

it has specifi c implications for management which are diff erent from other forms of nystagmus.

Th e 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 defi cits 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-Hoff man et al. [4] in a prospective study involving 18 patients with congenital nystagmus without sensory defi cits found that seven patients (39%) had PAN. Abadi and Pascal [5] found 12 patients with PAN in 32 patients with oculocutaneous albinism (37.5%). Th ese 12 patients did not exhibit AHP nor had dampening of nys-tagmus on convergence (Fig. 12.6).

Congenital PAN is most oft en missed or misdiagnosed if not properly investigated. Th e main reasons for diffi cul-ties in recognizing PAN are:

Long cycle duration: ■ Th e cycle duration of the congeni-tal PAN is variable lasting mostly between 2 and 7 min. Th us, ocular motility examination (clinical or with eye movement recordings) must extend over a prolonged time period.Th e absence of alternating head turn: ■ Classically, a clin-ical 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 major-ity of patients with congenital PAN used a predomi-nant 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

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.Th e AHP is usually bidirectional. ■

R

L

5º3 sec

Rig

ht E

yeLe

ft E

ye

LEFT BEATINGRIGHT BEATING

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 repre-sented by an upward defl ection, and eye movements to the left by a downward defl ection. Arrows indicate blinks


Familiarity with the clinical characteristics of ■

congenital nystagmus, MLN, and congenital PAN will minimize the chances of misdiagnos-ing these conditions and plan proper manage-ment of these conditions.Electrodiagnostics: both ERG and VEP should ■

be done in all patients with congenital nystagmus to fi nd a cause for the congenital nystagmus.Eye movement recording aids in diff erentiating ■

congenital nystagmus from MLN and congenital PAN.


12

12.2 Compensatory Mechanisms

Several compensatory mechanisms exist in congenital nystagmus which tend to decrease the nystagmus and thus improve the visual acuity. Th ese compensatory mechanisms are achieved with superimposed vergence and version movements.

Diff erent compensatory mechanisms may coexist in the same patient with congenital nystagmus. Th ese mech-anisms need to be analyzed carefully both to plan the treatment and also to make prognostic predictions.

12.2.1 Dampening by Versions

Version eye movements are used in some patients as a compensatory mechanism to reduce congenital nystag-mus. Sustained contractions of yoke muscles help main-tain the eyes in a peripheral lateral, vertical, or oblique gaze, depending on the position of the null region, lead-ing to dampening of nystagmus. Th ese versions are oft en accompanied, and consequently identifi ed, by an AHP. An eccentric horizontal null zone leads to hori-zontal 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

Th ere are two distinct clinical conditions which use dampening by convergence as a compensatory mecha-nism to reduce the amplitude and frequency of nystag-mus. Th ese are MLN and nystagmus blockade syndrome (NBS).

Adelstein and Cüppers [6] coined the term “nystag-mus blockage syndrome” as having the following clinical features:

Esotropia with sudden onset in early infancy, oft en ■

preceded by nystagmusPseudoparalysis of both abducens nerves ■

Th e appearance of manifest nystagmus as the fi xating ■

eye moves from adduction toward abductionIncrease in the angle of the convergent squint when a ■

base-out prism is put in front of the fi xating eye

NBS occurs with the waveform characteristics of increas-ing 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.

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. Th e ocular causes of AHP include strabismus, nystagmus, refractive errors, and ptosis. Although clini-cal diff erentiation of these disorders is accurately accom-plished aft er thorough history and ocular examination, the exact mechanism of AHP is oft en diffi cult to deter-mine in patients with combination of strabismus and nys-tagmus. 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 eff ort. Hence, quantifi cation of the sur-gery must be based on an appropriate eff ort of fi xation, usually achieved by testing visual acuity at distance and near. Figures 12.5a, b show a child with no AHP when no visual eff ort is needed. However, when he identifi es a ste-reoptic 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 eff ort. 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 diff erential diagnosis, it is important to record visual acuity with both eyes open as well as with each eye occluded. It is also useful


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 mecha-nisms by versions lead to AHP.Several compensatory mechanisms usually exist ■

in the same patient.

12.2 Compensatory Mechanisms 161

clinically to look at the eff ects of straightening the head on nystagmus.

12.2.3.5 Eff ect of Monocular and Binocular Visual Acuity Testing on AHP

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

No AHP: Th is 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 patientA horizontal AHP consisting of a face turn to the right ■

or left A vertical AHP consisting of a chin elevation or ■

depressionA bidirectional or alternating AHP ■

A head tilt to the right or left ■

A combination of AHP in diff erent planes ■

During nystagmus

With prisms After surgery

Blocking with convergence

Eye movement recordings

BEFORE SURGERY AFTER SURGERY

nystagmusblockage

R

L

10º2 sec

Rig

ht E

yeLe

ft E

ye

a

c d

e

b

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 evalua-tion, which showed dampening of nystagmus and (d) aft er bimedial medial rectus recessions. Original eye movement recordings show periodic convergence to dampen the nystagmus before surgery and quieter eye movements aft er surgery (e)


12

Testing Visual Acuity with Either Eye CoveredTesting AHP under monocular conditions using occlusion helps to diff erentiate between congenital nystagmus and MLN, since in congenital nystagmus the AHP is usually con-cordant (i.e., usually does not change position when cover-ing one eye), whereas in MLN nystagmus the AHP is discordant. Th is is because in MLN the intensity of the nys-tagmus tends to be least in adduction. Consequently, in MLN the head turn and the nystagmus direction reverse when fi xation shift s from one eye to the other (Fig. 12.5e, f).

12.2.3.6 Testing AHP at Near

Since convergence has an eff ect 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 inten-sity for distance should also be evaluated for near vision.

12.2.3.7 The Eff ect 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.

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 com-bination of treatment options might be needed to achieve a better outcome.

Th e main aim of treatment of congenital nystagmus is:

1. To improve visual acuity2. To diminish the amplitude and frequency of nysta-

gmus3. To shift the null position to primary position with the

aim of correcting an AHP4. To correct the strabismus if present

Th e main categories of treatment of nystagmus are opti-cal, medical, and surgical although other forms of treat-ment have been attempted such as acupuncture, biofeedback, and use of botulinum toxin-A.

12.3.1 Optical Treatment

Th e incidence of signifi cant refractive errors in patients with congenital nystagmus has been estimated to be as high as 85% [7]. Th e importance of correcting refractive errors besides improving visual acuity is to prevent amby-lopia and to treat the associated strabismus, commonly seen in patients with congenital nystagmus. Optical treat-ment can involve spectacles, contact lenses (CL), or low visual aids.

12.3.1.1 Refractive Correction

A full cycloplegic refraction should be performed in chil-dren. 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 congeni-tal nystagmus [8, 9]. Th e possible mechanisms underly-ing this are that CL reduces the chromatic and spherical


It is important to delineate the cause of AHP ■

and the amount of AHP before considering treatment in patients with congenital nysta-gmus.AHP typically becomes progressively larger with ■

increased visual eff ort. Hence quantifi cation of the head turn for surgical assessment must be based on measurement during maximal visual eff ort.In patients with combination of strabismus and ■

nystagmus, the cause of AHP needs to be carefully analyzed.

12.3 Treatment 163

aberration, together with the prismatic eff ect, 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 eff ort, which both decrease congenital nystagmus in some patients [8, 11]. It has been suggested that CL reduce the intensity of the nystagmus by provid-ing sensory feedback through the eye lid [8, 11]. Tinted CL have also been used to reduce photophobia in patients with achromatopsia [12].

12.3.1.3 Prisms

In 1950, Metzger [13] was the fi rst to describe the treat-ment of congenital nystagmus by using prisms in specta-cles in four patients with nystagmus. Prisms are used to improve visual acuity by reducing the intensity of nystag-mus and also to correct the AHP.

Base-out prisms are prescribed to induce fusional convergence, which may be eff ective 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 larg-est 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. Th e 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 base-out in front of right eye and base-in in front of left eye will correct the head turn. Likewise, chin elevation or depres-sion can be corrected by prism base-up or prism base-down, respectively, in front of both eyes. Godde-Jolly and Larmande [14] advocate the use of a combination of hori-zontal and vertical prisms when the null zone is in an oblique position of gaze.

Since the visual acuity is oft en decreased with the use of Fresnel prisms and prisms incorporated in glasses, this method is not eff ective to treat larger com-pensatory head posture in patients with congenital nys-tagmus. 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.

12.3.1.4 Low Visual Aids

Th e use of telescope, magnifi cation 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.

12.3.2 Medication

Medications such as baclofen, cannabis, gabapentin, or memantine were fi rst trialed in acquired nystagmus. Th ese 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 eff ects of medications, one needs to weigh the benefi ts 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 fove-ation time with broadening of null zone and increased visual acuity aft er 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 aft er smoking can-nabis. Th ere 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 nystag-mus 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


All children with congenital nystagmus must ■

have cycloplegic refraction and appropriate full refractive correction.Th e 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 off ered to suitable patients ■

as they have shown to improve visual acuity better than spectacles.


12

seven patients (three with congenital idiopathic nystag-mus and fi ve with associated ocular defects) treated with gabapentin.

McLean et al. [19] conducted the fi rst randomized, controlled, double-masked trial of memantine and gaba-pentin in the treatment of congenital nystagmus. A total of 48 patients with congenital nystagmus with and with-out sensory defi cits were included in the study. Sixteen patients in each group received memantine, gabapentin, or placebo treatment. Th e 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 move-ment recordings (see Fig. 12.4) and increase in visual acuity in both treatment groups with memantine and gabapentin showing a signifi cant improvement compared with the placebo-controlled group.

Th ere are several case reports of patients with con-genital PAN being treated with baclofen with some suc-cess [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. Th e dose of baclofen was initially started at 15 mg/day with a weekly increase in the dose to up to 120 mg/day.

12.3.3 Acupuncture

Acupuncture of the sternoclenoidmastoid muscle of the neck has been shown to reduce the frequency of nystag-mus 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 fi rst 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 eff ective in decreasing the amplitude of nystagmus in patients with congenital nystagmus; how-ever, 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 congeni-tal nystagmus treated by botox injected into multiple horizontal rectus muscles. Th ree of the four patients were reported to have achieved a signifi cant 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. Th e amplitude of nystagmus decreased by 29–50%. Th e head turn was corrected in few patients. Th e common complications of repeated botox injection are ptosis, ret-robulbar 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

Th e surgical principles for correction of the AHP and dampening of nystagmus uses the basic strabismus pro-cedure involving either the recession, resection proce-dures, or both. Th e aim is to move the eyes conjugately in the opposite direction to the gaze angle of the null region, or to artifi cially create an exotropia in patients with good binocular fusion in the presence of conver-gence null. Newer surgical procedures such as tenotomy of extraocular muscles have now been developed based on the benefi cial secondary eff ects noted in patients who were earlier treated with the strabismus procedure (Anderson−Kestenbaum procedure) to dampen the congenital nystagmus.


Recently, medical treatment has been used for ■

congenital nystagmus.In an RCT [19] of medical treatment of congeni- ■

tal nystagmus, both memantine and gabapentin showed reduction in nystagmus and improve-ment in visual acuity.Th e dosage of memantine used to treat congeni- ■

tal nystagmus was up to 40 mg/day, and that of Gabapentin 2,400 mg/day.Th e decision to treat patients medically should ■

be individualized given the long-term treatment, the benefi ts, and side eff ects of medications.

12.3 Treatment 165

Th e importance of diagnosing congenital PAN and MLN preoperatively is crucial as the surgical manage-ment diff ers from congenital nystagmus in these cases. In addition to the nystagmus, a detailed examination evalu-ating the presence or absence of strabismus is also impor-tant. Th e common strabismus forms seen in association with nystagmus are esotropia, exotropia, dissociated ver-tical deviation, and dissociated horizontal deviation. A proper surgical plan should be made to either correct this strabismus along with the nystagmus as a single proce-dure or in two stages. Th e 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 compen-satory posture encountered in patients with nystagmus with an eccentric null position. Various surgical proce-dures are used to correct this AHP and shift the null zone into primary position.

Anderson, Goto, and Kestenbaum in 1950s indepen-dently 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 conse-quently treated the nystagmus using a recession or weak-ening 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 nystag-mus, and advocated strengthening or resection of these two muscles. Kestenbaum advocated a combined resec-tion and recession procedure on all the four horizontal rectus muscles. He recessed or resected the two horizon-tal muscles of each eye. He also suggested performing the same quantity of surgery for both weakening and strengthening procedures (5 mm). Parks [30] made mod-ifi cations 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. Th is became the classical “5, 6, 7, 8” measurements for the Kestenbaum procedure modifi ed by Parks.

Because of the high rates of recurrence and undercor-rection following the modifi ed Kestenbaum procedure, Calhoun and Harley [31] recommended augmentation of the original Parks modifi cation of Kestenbaum procedure by 40–60% depending on the amount of head turn. For

example, 40% augmentation of the Parks procedure cor-responds 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 modifi ed Kestenbaum procedure. Th ey suggested 40% augmentation of modifi ed 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 modifi cation of Anderson procedure to correct the AHP. In this proce-dure, 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 eff ective 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] confi rmed the initial fi nd-ings described by Kestenbaum of an increase in the visual acuity aft er the Kestenbaum-type procedure. Th ey 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 diffi cult 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 experi-ence, very large amounts of surgery is needed. Restriction of eye movements is oft en 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 fi rst examined at 1 year of age because of nystag-mus since birth. A diagnosis of congenital idiopathic nys-tagmus (CIN) was made aft er 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. Th e child was reassessed at the age of 3 years. Her visual acu-ity was 6/24 with both eyes open. She had an AHP of about 45° (Fig. 12.5g). No squint was detected. We per-formed an augmented Anderson−Kestenbaum procedure to correct the AHP (recession of right lateral rectus and


12

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. Th e 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 sur-gery performed on each muscle is modifi ed 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 fi xing eye or non-amblyopic eye. If neces-sary, eso- or exotropia can be corrected by performing diff erent amounts of recess–resect procedures on the non-fi xing 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). Th is will reduce the esotropia. Depending on the amount cor-rected for the AHP, the amount of surgery on the left eye needs to be reduced (i.e., smaller than the amount cor-rected for AHP on the right eye) to correct the squint. If the esotropia and the head turn are approximately of equal size, it is suffi cient to correct the head position on the fi xating 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 signifi cantly and he remained with moderate exotropia. Alternatively, one could have performed a Faden procedure on both medial recti combined with lat-eral recti recessions.

NBS can also be treated surgically. Figure 12.7 shows an example of a patient with congenital nystagmus and NBS before surgery. Th e patient complained of one eye moving inward intermittently. To dampen his nystagmus, he devel-oped 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 nystag-mus. With a trial of Fresnel prisms (20 base out on each side), the eyes remained esotropic and the nystagmus dampened. Aft er bimedial rectus recession, he developed a small constant esotropia (Fig. 12.7d). Th e nystagmus was signifi cantly 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 fi rst to attempt to correct verti-cal AHP. He reported two cases with chin-up position for which he did bilateral inferior rectus recession and supe-rior oblique tenectomies, with marked improvement of vision in primary position and improvement in the AHP. Schlossman [37] reported a patient with chin-down pos-ture 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 depres-sion 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 supe-rior 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 fi nd the methods used to correct vertical AHP. Two surgical procedures were used by most of the respon-dents to correct vertical AHP. While 44% of the respon-dents preferred recession surgery alone, 55% preferred both recession and resection procedure on all four vertical rectus muscles. Recession only consisted of bilateral aver-age 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 com-bined bilateral inferior rectus recession and bilateral supe-rior 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. Th ey found that recession alone caused either no change or worsening of the vertical AHP, while the recession-resection procedure of all four vertical rectus muscle pro-duced excellent results in correcting the vertical AHP. Th ey recommended 12 mm of combined recession and

12.3 Treatment 167

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 hori-zontal AHP and correction of squint is shown. Th is 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 approxi-mately 20° and face turn to right of approximately 20°, more at near than at distance (Fig. 12.5i shows head posi-tion 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 simultane-ously 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 sur-gery on the vertical muscles as well. Th is can be counter-acted by shift ing the insertion of the vertical rectus muscles laterally. For example, a large recession of the superior rec-tus causes excylcotropia. Moving the insertion of the supe-rior 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. Th ey combined a recession−resection procedure at the anterior portions of the oblique muscles with transposi-tions of their insertion toward the posterior−anterior pole. Th ey had a success rate of 54%; while some improvement was seen in 25% of cases, 21% of cases showed no improve-ment. 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

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 trans-position 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. Th is surgery has been found to be eff ective when operated on both eyes, in patients with no fi xation preferences or with binocularity and also on the fi xating eye alone in monocular fi xation.

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 fi ve diff er-ent surgical procedures used by AAPOS members to treat torsional AHP:

1. Bilateral vertical rectus muscle recession2. Bilateral vertical rectus muscle recess−resect3. Bilateral oblique muscle weakening4. Bilateral oblique muscle recess−resect5. Bilateral oblique muscle weakening and vertical rectus

muscle recession

When dealing with moderate to severe AHP, 88% of sur-geons preferred operating on at least one oblique muscle.

12.3.6.4 Artifi cial Divergence Surgery

Patients suitable for artifi cial divergence surgery should be orthotropic with convergence as the compensatory mech-anism used to dampen the nystagmus. Binocular fusion is necessary to achieve this eff ect. Th e vergence dampens the nystagmus regardless of the stimulus inducing the conver-gence. Th is principle has been used optically (base-out prisms) and surgically (artifi cial divergence) to dampen the nystagmus.

Cüppers [47] proposed the concept of artifi cial diver-gence in patients with convergence dampening of nys-tagmus. In this procedure, an exodeviation is induced, which can be compensated by fusional convergence. Th is causes the patients to have convergence innervations even at distance. Th e acceptability and eff ectiveness of artifi cial divergence surgery should be evaluated


12

preoperatively by using the prism adaptation test. A base-out prism is prescribed to induce artifi cial diver-gence. Inducing divergence with a base-out prism causes the patient to converge, and therefore decreases the nys-tagmus, which can then be followed by the correspond-ing amount of recession−resection procedure [48]. Th e amount of surgery is based on the prism diopters toler-ated by the patient preoperatively.

Spielmann [49] in a retrospective study of 120 patients who underwent artifi cial 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 hypermetro-pia. 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 satisfacto-rily correct the AHP, these patients benefi tted by a combi-nation of artifi cial divergence and Anderson–Kestenbaum procedure [48, 50]. Th e amount of surgery is done for the total prism diopters tolerated by artifi cial divergence pro-cedure 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), artifi cial divergence procedure (n = 6), and a combination of both procedures (n = 5) in patients with congenital nystagmus. In patients who underwent artifi cial 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 fi ve patients. Broadening of the null zone was noticed in all patients.

Graf et al. [51] in a retrospective study to analyze the eff ects of Kestenbaum surgery and artifi cial divergence surgery found that artifi cial divergence surgery when performed alone off ers better correction of AHP than with the Kestenbaum surgery. However, in patients with large AHP, combining both artifi cial 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 mecha-nism to dampen the nystagmus, various surgeries have been done to dampen the congenital nystagmus. Th ese procedures were referred by Crone [52] as immobiliza-tion 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, fi xa-tion of the extraocular muscles to the periosteum of the lateral orbital wall, retro-equatorial myopexy of all hori-zontal 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 MusclesBietti and Bagolini [53], in 1956, fi rst described retro-equatorial 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 bilat-eral lateral rectus muscle recession of 8–12 mm.

Bagheri et al. [58] reported results of 20 patients who underwent horizontal rectus recession surgery. Th irteen 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]. Th ey calculated the amount of recession individually depending on the angle of deviation, head position, and amount of strabismus if pres-ent. Recessions performed on the medial rectus were more eff ective than recession on the lateral rectus. Th us surgery is planned based on the eff ect of recession of the medial rectus muscle rather than the lateral rectus recession. To correct the associated strabismus, the surgical plan is

References 169

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 ProcedureAdvancements in understanding secondary mechanisms involved in the reducing nystagmus amplitude in patients who underwent recession−resection surgery for congeni-tal nystagmus mainly to correct the AHP has led to a new surgical procedure “tenotomy” of extraocular muscle. Th is procedure has been reported to be benefi cial 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].Th e tenotomy procedure can be done on both hori-zontal and vertical rectus muscles based on the dominant plane of the nystagmus.

Following the initial success of the tenotomy proce-dure in an animal model [62], clinical trials [63, 64] were performed on patients with congenital nystagmus with and without sensory defi cits including asymmetric con-genital PAN. In the fi rst trial, involving ten patients, bin-ocular visual acuity increased in fi ve patients and remained unchanged in the remaining patients. Th e eye movement recording data showed an increase in the aver-age foveation times in all nine patients’ fi xating eyes. In the second trial, tenotomy was performed on fi ve patients with congenital nystagmus. Visual acuity improved in four of the fi ve patients, but did not improve in a patient with retinal dystrophy.

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 acknowl-edge the fi nancial support of Ulverscroft Foundation, Medisearch, National Eye Research Centre, and Nystagmus Network.

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tion or head posture in patients with nystagmus. J AAPOS 9:433–437

59. Davis PL, Baker RS, Piccione RJ (1997) Large recession nystagmus surgery in albinos: eff ect on acuity. J Pediatr Ophthalmol Strabismus 34:279–283; discussion 283–275

60. Atilla H, Erkam N, Isikcelik Y (1999) Surgical treatment in nystagmus. Eye 13(Pt 1):11–15

61. Dell’Osso LF (1998) Extraocular muscle tenotomy, dissec-tion, and suture: a hypothetical therapy for congenital nys-tagmus. J Pediatr Ophthalmol Strabismus 35:232–233

62. Dell’Osso LF, Hertle RW, Williams RW, Jacobs JB (1999) A new surgery for congenital nystagmus: eff ects of tenotomy on an achiasmatic canine and the role of extraocular prop-rioception. J AAPOS 3:166–182

63. Hertle RW, Dell’Osso LF, FitzGibbon EJ et al (2004) Horizontal rectus muscle tenotomy in children with infan-tile nystagmus syndrome: a pilot study. J AAPOS 8: 539–548

64. 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

Surgical Management of Dissociated DeviationsSusana Gamio

Chapter 13

13

Core Messages

Dissociated deviation (DD) manifests as a slow, ■

intermittent, and variable vertical (DVD), hori-zontal (DHD), and torsional (DTD) movement. It is usually found in patients with early onset strabismus and profound sensorial anomalies.Th e treatment for patients with DD requires a ■

specifi c surgical approach to improve the vertical, horizontal, and torsional misalignment simulta-neously.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 alter-natives: (1) Bilateral large superior rectus (SR) recession. (2) Bilateral retroequatorial myopexy (posterior fi xation) 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 resec-tion 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

for cases with bilaterally symmetric DVD. Cases with asymmetric DVD are more common. Th ese cases require asymmetrical techniques.Dissociated horizontal deviation (DHD): Th e ■

main diagnostic sign of DHD is the presence of a horizontal deviation, esotropia (ET), or exotropia (XT) that changes with fi xation of each eye, unre-lated to diff erent accommodation, muscle weak-ness, or restriction. Th e technique most used for DHD is unilateral lateral rectus (LR) recession. Retroequatorial myopexy (posterior fi xation) of the LR with recession of this muscle is recom-mended 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. Th e head tilt can be toward the shoulder of the fi xing 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 diffi cult; a successful out-come in the postoperative period does not guar-antee the fi nal 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.

174 13 Surgical Management of Dissociated Deviations

13

13.1 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 pro-found 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. Th ese patients usually show horizontal, ver-tical, and torsional movements when performing the cover test and have diff erent amounts of deviation when fi xing with each eye. Th ey also have latent nystagmus (LN), head tilt, and associated oblique muscles dysfunc-tion 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 fi lters of increasing density (bagolini fi lter bar) are placed before the fi xating 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 fi rst one downwards, becoming aligned in the ver-tical plane (Fig. 13.1).

Red glass testing yields particular results in dissoci-ated vertical deviation (DVD). Regardless of whether the red fi lter is placed before the right eye or the left one, the patient sees the red light below the white one.

Th ese maneuvers attest to the tight interocular inter-relation 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 extor-sion of the nonfi xating eye. Th e downward vertical drift of the hypertropic eye takes place together with intorsion and adduction.

Th e 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 dif-ferent magnitude according to fi xating eye, there exist cases that exhibit an esodeviation with the same charac-teristics of variability and intermittence [11, 12]. Th ere are also patients who manifest esotropia (ET) when fi x-ating with one eye and exotropia (XT) when fi xating with the other eye [9].

Th e torsional component of this entity, named dissoci-ated torsional deviation (DTD), occurs simultaneously with vertical movement: extorsion of the elevating eye and intorsion of the fi xating eye. Th e vertical movement always cooccurs with extorsion of the elevating eye and intorsion of the descending eye. Th is is infl uenced by oblique mus-cles 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 mea-sure DVD and DHD with each eye fi xating in all gaze posi-tions (including head tilts) to have the necessary panorama to choose the best surgical procedure for each case.

Th erefore, surgical treatment of patients with DD requires a specifi c surgical approach. Long-term surgical results and recommendations for these cases remain sparse in literature. Th e purpose of this chapter is to men-tion the surgical alternatives tailored to treat each partic-ular 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 fi rst one downwards, becoming aligned in the vertical plane

13.2 Surgical Alternatives to Treat Patients with DVD 175

13.2 Surgical Alternatives to Treat Patients with DVD

Patients with DVD are usually asymptomatic, but in those cases where signifi cant hypertropia is manifested sponta-neously, or those associated with horizontal misalign-ment, 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 devia-tion, 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

Th e 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 fi xation) 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

retraction and lid fi ssure asymmetry. Th is technique may limit elevation, especially in abduction (Pseudo inferior oblique over action (IOOA) ). It should be noted that weakening of SR modifi es 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 inser-tion) is used by several author successfully [64]. Th e pos-terior fi xation suture must be placed at least 20 mm, and preferably 23–25 mm from the limbus, which oft en is technically troublesome.

Th e four oblique weakening procedures proved to be an eff ective technique to treat these cases. Th is 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 seg-ment ischemia.

IR resection: Although this technique has been pro-posed as a primary procedure, we believe that it should be reserved for reoperation in the case of failure of SR reces-sion. It creates a marked restriction of elevation and in some cases alterations in the lid fi ssures. Its additional horizontal eff ect, 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 devi-ating eye with no possibilities of becoming fi xating eye due to deep amblyopia.

Th ere 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 fi xa-

tion) 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. Th is technique is chosen in cases showing comitant vertical deviation in lateroversions.

Summary for the clinician

DD have three components: vertical (DVD), hori- ■

zontal (DHD), and torsional (DTD) movements.Surgical plan requires taking into account the ■

three components and must be tailored to treat each particular case.


13

Many authors express concern that unilateral SR recession might also result in an unacceptable postopera-tive hypotropia in the operated eye or in a large hypertro-pia in the contralateral eye, if the patient were to switch fi xation [20]. For this reason, unilateral surgery is reserved for patients with dense amblyopia, who would have little or no chance of changing fi xation aft er 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 undergo-ing unilateral surgical correction of DVD developed a signifi cant deviation in the unoperated eye. Duncan and von Noorden [21] demonstrated the development of con-tralateral DVD postoperatively in 8/35 cases.

In those cases manifesting incomitance in laterover-sions: greater hypertropia in adduction, unilateral IOAT is chosen.

Bothun and Summers [34] proved that unilateral IOAT is an eff ective treatment for unilateral or markedly asymmetric DVD in patients with a strong, contralateral fi xation preference. Th is 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.

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 treat-ment for DVD with IOOA.

2. Th e second alternative is to perform a bilateral SR recession added to bilateral IO recession [37].

Th e 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

IOAT remained with postoperative vertical deviation. 10/20 of such cases had preoperative asymmetric DVD.

Although late development of a postoperative A pat-tern 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 aft er the operation, 50% of his patients had experienced neither A nor V pattern. Th irty-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 devi-ation aft er the IOAT, a unilateral SR recession can be per-formed according to the amount of vertical deviation in PP. Th is procedure proved eff ective 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. Th ere are several surgical alternatives:

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 eff ec-tively treat coexisting DVD and IOOA. It has signifi cantly reduced the mean DVD from 13.4 PD to 6.7 PD. In cases of asymmetric DVD, unequal transpositions were per-formed: IOAT in the eye with the larger DVD can be placed up to 2 mm anterior to the temporal pole of the IR. Th e DVD remained controlled in 86% of their cases aft er a 2-year follow-up. Th e 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 inser-tion. Th ese authors reported low residual IOOA in 11/61 patients. Only one patient required reoperation for mani-fest 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 177

three stations: 1 mm posterior or 1 mm anterior to the IR insertion or at the level of the IR insertion. In the stan-dard group, the IO tendon was positioned 1 mm anterior to the IR insertion for all degrees of DVD. Th e residual postoperative DVD was 1.15 PD in the graded group compared with 2.44 PD in the standard group. Th is dif-ference was statistically signifi cant.

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. Th e IO resection was graded according to the diff erence in the preoperative vertical deviation between the eyes: 3 mm for a diff erence of up to 10 PD and 5 mm for a diff erence of 11–20 PD. Th ese 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. Th e mean diff er-ence 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.

Th e weakening of both elevators (IO and SR) always results in an elevation defi ciency, 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 nonfi x-ating eye than in PP. Th e 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 tenec-tomy 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. Th us, it is benefi cial to carry out the four oblique weakening procedure in these patients [28, 44].

Fig. 13.2 Dissociated vertical deviation (DVD) with SOOA and A pattern: DVD is greater in abduction of the nonfi xating eye


13

It may be a quite complex and lengthy procedure for nonexperienced surgeons; it produces a symmetric out-come and so it is not the preferred option in a markedly asymmetrical case. It could also produce a vertical devi-ation. When this complication occurs, a simple SR reces-sion of the hypertropic eye can be performed according to the hypertropia amount in PP, thus solving the problem.

Th ere are several surgical alternatives to treat asym-metric 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.

Th e size of the A pattern and the presence of asym-metry 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; how-ever, many cases are markedly asymmetric. These cases are usually found associated with unilateral deep amblyopia.

Just as oblique muscle dysfunction makes DVD incomitant in diff erent gaze positions, the presence of a true vertical deviation (hypo or hypertropia) makes it asymmetric.

Th e 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 nonfi xating eye, cases with greater DVD in the fi xating eye do exist and may show hypotro-pia 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

tropia, or it can remain aligned when the DVD is of a similar magnitude to that of the vertical tropia. Th is situation may be erroneously interpreted as monocular DVD.

Asymmetric DVD will oft en appear to be unilateral. However, by performing the proper maneuvers, the bilat-erality of most cases can be detected. Th e 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 nonfi xating eye or even in the fi xating eye.

Determining the diff erence in the amount of SR reces-sion in these asymmetric cases remains challenging. Th e maximum diff erence allowed to obtain a good outcome remains controversial.

13.2.6 DVD with Hypotropia of the Nonfi xating Eye

DVD usually manifests as an intermittent hypertropia, but there are certain cases with hypotropia of the nonfi x-ating eye. Although rare, these cases are identifi ed in dif-ferent 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 con-dition, but to those with DVD and a hypotropic nonfi xat-ing 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 fi xating eye), with associated nondissociated verti-cal tropia or with unilateral deep amblyopia.

Fig. 13.3 Bilateral DVD with left hypotropia in primary position

13.3 Dissociated Horizontal Deviation 179

Th ree situations can lead to hypotropia of the nonfi xating eye in a patient with DVD:

1. Hypertropia in the nondominant eye: the patient appears to have greater DVD amplitude in the non-dominant eye: when he changes the fi xation and fi x-ates 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 lead-ing to hypotropia of the fellow eye in binocular condi-tions. Th ese patients seem to have greater DVD amplitude in the dominant eye.

Most cases of DVD that show hypotropia are due to sur-gical 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 man-agement [52].

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 strabis-mus history. Th e main diagnostic sign of DHD is the presence of a horizontal variable deviation, ET, or XT that changes with fi xation of each eye, unrelated to diff erent 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 vari-able and diffi cult to measure and are also more prominent during inattention.

In DHD, we cannot neutralize the horizontal devia-tion by the classical prism and alternating cover test. Alternate cover testing must be performed slowly allow-ing the nonfi xating eye time for the slow drift to fully manifest. It is also necessary to make the right eye fi xate fi rst and neutralize with prism the left eye deviation, and then let the left eye fi xate and neutralize the right eye deviation.

Th e reversed fi xation test (RFT) [53] is useful to diagnose DHD. During this test, the patient is asked to fi xate through the prism that neutralizes the deviation of one of his eyes and then the occluder is shift ed to the uncovered eye without the prism and it is observed for any refi xation movement when the cover test is per-formed. Th e test is positive when a refi xation 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 fi xating with the preferred eye. In our series, seven patients had greater exodeviation when fi x-ating with the dominant eye, seven patients had greater esodeviation when fi xating with the nondominant eye, and three cases had XT when fi xating with the dominant-eye and ET when fi xating with the nonpreferred eye. Only one patient had greater ET when fi xating with the domi-nant eye. Th ese fi ndings seem to support his hypothesis that the exodeviation is usually smaller with the nonpre-ferred eye fi xating (Fig. 13.4).

DHD is oft en observed to be larger with visual inat-tention than when the prisms measurements are done, and the eye position under general anesthesia (GA) usu-ally 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. Th e


To choose the surgical procedure for DVD, we ■

need to take into account: (1) VA; (2) vertical devi-ation incomitance; (3) oblique muscles dysfunc-tion with A or V pattern; (4) DVD symmetry.Symmetric DVD with good bilateral VA, with- ■

out oblique muscle dysfunction: four surgical alternatives: (1) Bilateral large SR recession. (2) Bilateral retroequatorial myopexy (posterior fi x-ation) of the SR combined with or without reces-sion 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 bilat-eral 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.


13

eye position under GA used to show greater exodeviation when the innervational forces are abolished. Th e forced duction can diagnose a restriction and the spring back test can determine a medial rectus (MR) muscle weak-ness 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 oft en required for DHD than for DVD. However, DHD is almost always associated with DVD, so we consider that bilat-eral 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, fi ve underwent surgery just for the DVD because the hor-izontal deviation was small, and two patients received surgery for the horizontal deviation alone despite having DVD as well.

Th e most used technique for DHD was unilateral LR recession. Retroequatorial myopexy (posterior fi xation) of the LR with a recession of this muscle is recom-mended 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 advance-ment 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 fi x the drift of the eyes is needed. Bilateral sur-gery is proposed to address both conditions simultane-ously [57].

13.4 Dissociated Torsional Deviation. Head tilts in patients with Dissociated Strabismus

Th ere 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 fi xating eye and the IO in the fellow eye, added to a bilateral supraversion required for the maintenance of fi xation with the fi xating 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

Fig. 13.4 Dissociated horizontal deviation (DHD). She has greater exodeviation when fi xating with the dominant eye


Th e main diagnostic sign of DHD is the presence ■

of a horizontal variable deviation, ET, or XT that changes with fi xation of each eye, unrelated to diff erent accommodation or presence of primary and secondary deviation due to weakness or restriction.Th e technique most used for DHD was unilat- ■

eral LR recession. Bilateral LR recession is indi-cated 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 181

extorsion characteristic of DVD produced by SR and OI is observed in the fellow eye. In this case, the vertical vec-tors 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 usu-ally fi xate in adduction but they also have head tilts. Th e head tilt can be toward the shoulder of the fi xating eye (direct tilt) or toward the contralateral side (inverse tilt) [60, 61].

Th is head tilt has been thought to be related to the presence of DVD, but there is no evidence confi rming the relationship between these two fi ndings.

Guyton [58] claims that adopting an anomalous head posture can infl uence latent and manifest LN in some cases. Th e head tilt would damp the pattern of LN associ-ated with the fi xing eye, and therefore, surgery on the fi x-ing eye is practically always necessary to abolish head tilts.

Brodsky et al. [62] proposed that direct tilt is not com-pensatory 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).

Direct tilt is observed in patients without horizon-tal 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.

Th e 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. Th ey 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 nonfi xat-ing eye exists or in asymmetric DVD cases, larger in the fi xating eye.

We found inverse head tilt, which improved the ver-tical alignment, in 13/27 (49%) cases. Many of these patients had vertical deviation in PP and it was not rare to fi nd SR contracture of the fi xating eye. When fi xing 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.

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


13

Finally, we want to point out that a great number of patients with DD do not have head tilt. Th is fact makes evident that there are other nonelucidated factors that determine such a particular clinical sign.

13.5 Conclusions

Obtaining long-term control of the deviation in patient with dissociated strabismus is diffi cult; a successful out-come in the postoperative period does not guarantee the fi nal 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 dis-sociated 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 clin-ical 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. Th e 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 fi ndings and sur-gical results in 20 patients. Binocul Vis 7:135–138

9. Wilson ME, Saunders RA, Berland JE (1995) Dissociated horizontal deviation and accomodative esotropia: treat-ment 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 man-agement 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 eff ective 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, Th alacker 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 dissocia-tive vertical deviation. In: Campos ED (ed) Proceedings of ISA V. Athena Scientifi c, Rome, Modena, Italy, pp 403–412

23. Sprague JB, Moore S, Eggers H et al (1980) Dissociated ver-tical deviation: treatment with the fadenoperation of Cuppers. Arch Ophtahlmol 98:465


When we have a patient with DD who need sur- ■

gery, we have to take into account the presence of head tilt to attempt to improve the head position.Direct tilt (toward the fi xing eye) is not compen- ■

satory for binocular vision, while a head tilt toward the hyperdeviated eye (inverse tilt) serves to improve the vertical alignment.

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24. von Noorden GK (1978) Posterior fi xation suture in stra-bismus 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 cua-tro oblicuos para Desviacion Vertical Disociada y sin-drome em A. CLADE anais 2000 del XIV Congreso del CLADE. São Paulo, pp 359–360

26. Gamio S (2002) A surgical alternative for dissociated verti-cal deviation based on new pathologic concepts: weaken-ing 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 fi rst extraordinary meeting of CLADE. São Paulo, Brazil pp 97–100

28. Texeira Krieger F, Caron Lambert A (2000) Efeito do debili-tamento 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 fi ndings 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 treat-ment. Ophtahlmology 86:1428

33. Schwartz T, Scott W (1991) Unilateral superior rectus recession for the treatment of dissociated vertical devia-tion. J Pediatr Ophtahlmol Strabismus 28:219

34. Bothun ED, Summers CG (2004) Unilateral inferior oblique anterior transposition for dissociated vertical devi-ation. 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 devia-tion. 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

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 transposi-tion of the inferior oblique muscle for dissociated vertical deviation. Ophthalmology 100:245–250

41. Mims JLIII, Wood RC (1989) Bilateral anterior transposi-tion 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 infe-rior oblique muscle for asymmetric double dissociated ver-tical deviation. Ophtahlmology 106(12):2372–2376

44. Velez G, Velez F, Ela-Dalman N (2008) Surgical manage-ment of dissociated vertical deviation associated with A pattern strabismus. Poster presented at the 34th AAPOS Annual Meeting. Washington

45. Velez G (2000) A clinical classifi cation of DVD for a better surgical approach. Fetscrif for Arthur Jampolsky. Th e Smith Kettlewell Eye Research Institute, pp 59–63

46. Melek N, Mendoza JC, Ciancia AO (1998) Bilateral reces-sion of the superior rectus: its infl uence 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 supe-rior 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 hypotro-pia: 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 esotro-pia. JAAPOS 5(2):123–125

51. Kraft SP, Irving EL, Steinbach MJ, Levin AV (2000) A case of hypotropic dissociated vertical deviation: surgical man-agement. In: Spiritus M (ed) Transactions of the 25th meet-ing of the European strabismological association. Aeolus, Lisse, Th e 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) Th e reversed fi xation test: a diagnostic test for dissociated horizontal deviation. Arch Ophthalmol 123(8):1083–1087

54. Brodsky MC, Fray KJ (2007) Dissociated horizontal devia-tion aft er surgery for infantile esotropia: clinical character-istics 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 devia-tion. 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-14174-2009. 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) Th e relation-ship 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

14.1 Introduction

Th e superior oblique (SO) muscle is adherent to the undersurface of the superior rectus muscle by an areolar connective tissue. Jampolsky was the fi rst to describe the surgical signifi cance of this local adherence, which he referred to as a frenulum [1]. Th e term frenulum can be defi ned 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 fl oor 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. Th erefore, Jampolsky recommended severing the frenu-lum if a recession of greater than 10 mm of the superior rectus is desired to obtain the desired amount of reces-sion. 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

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]. Th is syn-drome is a restrictive strabismus characterized by a hypertropia with incyclotropia of the aff ected 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 diffi cult surgical problem to correct and hence should be avoided if possible.

Th e frenulum may also be an important structure to consider during SO surgery as well. Prieto Diaz advo-cated 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 syn-drome 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. Th eir state-ments appear logical, but it is only recently that the eff ect of severing the frenulum on the position of both the SO tendon and superior rectus muscle at surgery has been quantifi ed [2]. In addition, it has been observed that the

Surgical Implications of the Superior Oblique FrenulumBurton J. Kushner and Megumi Iizuka

Chapter 14

14

Core Messages

Th e superior oblique (SO) tendon is attached to ■

the undersurface of the superior rectus muscle by an areolar frenulum.Th e frenulum, if left intact, causes the SO tendon to ■

move posteriorly with the superior rectus muscle when it is recessed. Th is 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.

An intact frenulum can result in the SO tendon ■

scarring into the superior rectus insertion when the latter is resected.Th e posterior SO tenectomy procedure is eff ec- ■

tive in collapsing small A patterns but oft en does not eliminate overdepression in adduction. Th is apparent contradiction can be explained by the change in SO vector force that results from cut-ting the frenulum, which is unavoidable with this surgical procedure.

186 14 Surgical Implications of the Superior Oblique Frenulum

14

posterior partial tenectomy procedure on the SO tendon is eff ective in collapsing of A patterns that measure less than 20 PD (prism diopters); however, it is less eff ective in decreasing the overdepression in adduction [3, 5]. Th is 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 eff ectiveness 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 eff ect of diff erent 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 Eff ect of Superior Rectus Muscle Recession on the Location of the Superior Oblique Tendon Before and After Cutting the Frenulum

Th is experiment consisted of measuring the posterior dis-placement of the SO tendon with recession of the superior rectus muscle before and aft er cutting the SO frenulum in three patients (2, 8, and 25 years of age) who were under-going 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 aft er cutting the frenulum in the eye undergoing enucleation while suspending the superior rectus muscle at various dis-tances. Th is was performed as follows: Th e 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. Th e underlying SO tendon insertion was identifi ed 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. Th is distance was referred to as the initial

reference knot distance. Th e 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 infl uence of tissue hysteresis or tissue mem-ory. Th e temporary suspension of the muscle was accom-plished 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. Th e eye was then rotated to the primary position and the conjunctiva was lift ed to verify if the muscle had completely taken up the slack in the suspen-sion suture. If the slack had not been spontaneously taken up for the desired amount of recession, the superior rec-tus muscle was reposited with instruments and the occur-rence thereof noted. Th e eff ect 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. Th is 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 near-est 0.5 mm. By subtracting the second reference knot dis-tance 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 mus-cle (Fig. 14.2).

Th e 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.

Fig. 14.1 Photograph of right eye at surgery as seen from below. Th e 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 refl ected upward. Th e small arrow denotes the SO tendon; the large arrow denotes the refl ected superior rectus muscle. (Reprinted from [6] Elsevier Press)

14.2 Clinical and Theoretical Investigations 187

All the above measurements were repeated, again with three measurements for each superior rectus suspension distance performed in a randomly determined sequence.

Th ere was essentially a one-to-one correlation between the amount of superior rectus recession and posterior movement of the SO tendon for superior rectus reces-sions up to 10 mm. Aft er severing the frenulum, there was negligible movement of the SO tendon reaching a maxi-mum 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 repos-ited. Th is confi rms that the frenulum intimately links the superior rectus muscle and the SO tendon. Th e 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 oft en when the frenulum was severed, is probably due to a constraining eff ect of the frenulum. Th e 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 suspen-sion 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. Th is 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 func-tion. 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.

Aft er cutting the frenulum, the SO muscle moved minimally when the superior rectus muscle was recessed. Because the anterior border of the SO tendon is approx-imately 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. Th e SO insertion is broad and underlies a relatively large area beneath the superior rectus muscle. Consequently, cutting the frenulum may result in diffi -culty with suturing the superior rectus to the sclera without incorporating some of the SO insertion whose diaphanous nature can make it diffi cult 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 mus-cle 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 eff ect [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 rec-tus muscle as previously stated by Jampolsky, and the SO

Fig. 14.2 Axial view of the left eye as viewed from superiorly in the orbit illustrating location of SO tendon before cutting the frenu-lum 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)


14

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.

14.2.2 The Eff ect of the Frenulum on Superior Oblique Recession Using a Suspension Technique

Th is experiment consisted of assessing how far the SO tendon retracted (recessed) aft er disinsertion to simulate what happens with either a recession with a suspension technique or a free disinsertion. Th is was done both before and aft er 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 suspen-sion technique. Th e position of the SO was measured before and aft er cutting the frenulum in the following manner: Th e SO tendon’s insertion was isolated through a superotemporal incision aft er fi rst hooking the superior rectus muscle. Th e SO tendon was hooked at its insertion with care to avoid pulling the tendon from under the superior rectus muscle, thus preserving the frenulum. Th is was done by refl ecting the superior rectus nasally as minimally as possible but suffi cient to allow for visualiza-tion of the insertion of the SO tendon. A 6–0 Polyglactin 910 suture was woven through the tendon near the inser-tion and knotted (Fig. 14.3). A reference knot was tied in the suture 15–20 mm from the distal end of the SO ten-don and the superior rectus muscle was set back in its unrefl ected position. Th e distance from the reference knot to the temporal edge of the superior rectus muscle

was measured and recorded in the aforementioned masked manner. Th is was recorded as the initial reference knot distance. Th e SO tendon was then disinserted, and two successive forced ductions to rotate the eye maxi-mally 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. Th e masked assistant then read the caliper distance using a straight ruler to the nearest 0.5 mm. Th e 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. Th is 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 rec-tus muscle temporally (Fig. 14.4). Th is movement essen-tially brought all of the tendon that is normally under the superior rectus muscle out temporal to it, and eff ectively severed the frenulum connection. Th is maneuver is similar to what frequently occurs if one just exerts substantial trac-tion on the SO tendon when weakening it at the insertion or during a SO tendon tucking procedure. Two forced duc-tions were again performed to rotate the eye up and in. Th e 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 aft er the frenu-lum was stripped was calculated using our masked mea-surement 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 aft er hooking the SO tendon. Th e frenulum is intact. (b) Th e SO tendon disinserted with the frenulum intact. A relatively small amount of recession occurs. (c) Aft er 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)


measurements was taken prior to and aft er stripping the frenulum on the other (control) eye in the same manner as in the fi rst (study) eye. In two patients, the study procedure was performed in the right eye fi rst, and in the other two patients, the study procedure was performed in left eye fi rst.

Th e mean distance that the SO tendon recessed was 2.4 ± 0.4 mm before cutting the frenulum and 8.5 ± 0.7 mm aft er cutting the frenulum. Th ere was a statisti-cally signifi cant diff erence between the two measure-ments (P = 0.0011, paired two-tailed student’s t-test). Th e 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 aft er stripping the frenulum was 8.0 ± 0.8 mm (P = 0.0004, paired two-tailed student’s t-test). Th ese values for the amount of recession obtained in the control eyes before and aft er stripping the frenulum were essentially identical to the values for the study eyes, despite the control eyes only having a single measure-ment. Th is confi rms that taking multiple measurements prior to stripping the frenulum was not a confounding factor on the amount that the SO moved aft er stripping the frenulum.

Th e results of this experiment are consistent with the observation that the maximal eff ect of a recession of the SO tendon using a suspension technique can only be

achieved by cutting the frenulum [4]. It also suggests that asymmetric eff ects 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]. Th us how the frenulum is handled with these procedures may be a matter of tradeoff s.

14.2.3 The Theoretical Eff ect of the Superior Oblique Frenulum on the Posterior Partial Tenectomy of the Superior Oblique

Th e threefold function of the SO muscle includes intor-sion, depression, and to a lesser degree, abduction. Th ese actions are uniquely related to its anatomy and the angle the tendon makes with the anterior–posterior axis. Th e SO tendon makes an angle of approximately 54° with the anterior–posterior axis. Th e anterior fi bers of the SO ten-don make a relatively large angle with the anterior–poste-rior 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 fi bers of the SO tendon using computer-aided design soft ware and determined that the vertical action is approximately 1/3 of the torsional action [8]. Th e posterior fi bers of the SO tendon make a smaller angle with the anterior–posterior axis than the anterior fi bers. He concluded they therefore contribute approxi-mately 50% less torsion than the anterior fi bers 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 poste-rior 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 pat-terns of up to 20 PD; however, it is not effective in decreasing the overdepression in adduction resulting

Fig. 14.4 Surgical photograph of the right eye rotated down-ward 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 tempo-rally to eff ectively 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)


14

in a pseudo-SOOA [3, 5] (Fig. 14.5). Why this proce-dure 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 fi gures of the anatomy of the SO and SR obtained from Orbit™1.8 (Eidactics, San Francisco, CA) to determine the angles made by the ante-rior and posterior fi bers of the SO tendon with the ante-rior–posterior axis when the eye was in the primary position, as well as in adduction. We then modifi ed those fi gures to assume that the frenulum constrained the SO tendon to the SR muscle and recalculated the same angles. Th e 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. Th e 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 ante-rior–posterior axis, respectively, multiplied by 100.

Figure 14.6a shows the eye in primary position. Th e anterior fi bers of the SO tendon make an angle of 75° with the anterior–posterior axis. Th us, the torsional force vec-tor of these fi bers is the sine of 75°, or 0.97 times the mag-nitude 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 ten-don will bow backwards as shown in Fig. 14.6b. In this picture, which is modifi ed 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 fi bers of the SO tendon and the anterior–posterior axis is approxi-mately the same. As seen in Fig. 14.6b, the anterior fi bers of the SO tendon still make an angle of 75° with the ante-rior–posterior axis. Consequently, in the normal nonop-erated 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 aft er a posterior partial tenectomy procedure. Th e excised portion of the posterior four fi ft hs of the SO tendon insertion is out-lined in black. Th is surgical procedure necessitates that the frenulum be excised, which allows the SO tendon to move forward. Th is substantially decreases the angle between the anterior fi bers 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. Th e 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. Th is may be one explanation why overdepres-sion in adduction persist aft er posterior partial tenec-tomy. Th is residual abnormality of versions may be due to the unavoidable excision of the SO frenulum, which occurs with this surgical procedure, and the eff ect 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 aft er posterior partial SO tenectomy. Despite this unwanted overdepression in adduction, weakening of the

Fig. 14.5 Th is patient underwent bilateral posterior tenectomy of the SO tendon combined with bilateral 5 mm lateral rectus mus-cle recessions to treat an exotropia associated with 18PD of A pattern. Before surgery he had +2 bilateral SO overaction. Th e surgery not only eliminated the A pattern but overcorrected it resulting in a small V pattern, yet his SO overaction persisted


SO with posterior partial tenectomy eff ectively reduces the exo-shift in down gaze and thus reduces the A pattern [5, 10–12]. Th is 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 eff ectively collapsed, suggesting that this motility pattern is not simply due to a surgical undercorrection. Castanera considers this common post-operative 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). Th is would be consistent with our hypothesis that excision of the frenulum can result in for-ward slippage of the remaining fi bers of the SO when the eye is adducted, thus increasing their vertical force.

Some investigators have speculated that the down-shoot in adduction seen aft er partial posterior SO tenec-tomy occurs secondary to a limitation of depression in abduction of the contralateral eye aft er bilateral surgery.

Th is results in a pseudo-SOOA in the ipsilateral eye by Herring’s law [5, 8]. Th ere are several theories as to the cause of this limitation. For example, anteriorization of the SO tendon insertion to a preequatorial location aft er a posterior partial tenectomy has been theorized. Using the Orbit™ 1.8 model, Castanera simulated that an ante-rior shift of the muscle insertion centroid of 4.45 mm aft er a posterior partial tenectomy would cause a reduc-tion 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 depres-sion in abduction of the contralateral eye may due to iatrogenic incarceration of the SO tendon to the SR insertion [2, 5, 13]. Th is complication also places the eff ective 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

Fig. 14.6 Th ree-dimensional scale fi gure of the anatomy of the SO modifi ed from Orbit™1.8 program seen from above. (a) Representation of an unoperated eye in the primary position. Th e anterior fi bers of the SO tendon make an angle of 75° with the anterior–posterior axis. Th e 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. Th is is modifi ed from Orbit™1.8 to assume the frenulum completely con-strains the tendon to the SR muscle. Th e original angle made by the anterior fi bers of the SO tendon and the anterior–posterior axis is preserved measuring 75°. Th e 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 eff ect of the frenulum allows the SO tendon to slide forward. Th is decreases the angle between the anterior fi bers of the SO tendon and the anterior–posterior axis to 40°. Th e magnitude of the force vector for depressor of the SO tendon increases to 77% of the total net force


14

contralateral restriction of depression in abduction can-not fully account for the persistence of overdepression in adduction aft er partial posterior SO tenectomy, because we have seen this occur in the operated eye aft er unilateral surgery. Also, we have observed that this fi nding is oft en present immediately aft er surgery. Th is would tend to rule out postoperative iatrogenic mechan-ical 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 eff ect on versions in adduction.

We considered the anatomical eff ects of the SO frenulum on the vertical and torsional force vectors of the SO tendon using basic two-dimensional trigonom-etry. We recognize that there are some obvious oversim-plifi cations in our theoretical analysis. Th e geometric angles drawn on the scaled model are somewhat arbi-trary. For example, our modeling of the anterior fi bers of the unoperated SO tendon when the eye is adducted (see again Fig. 14.6b) assumes that the frenulum com-pletely constrains the tendon. In reality, there is proba-bly some elasticity of the frenulum that allows at least some forward slippage [6]. We assume this to be the case as common clinical observations confi rm that the SO has a greater vertical and lesser torsional action in adduction than in the primary position. Nevertheless, prior investigation on the constraining eff ect of the SO tendon frenulum suggests that our model is at least qualitatively sound, even if it is not exactly quantita-tively 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 abduct-ing force of the SO muscle is relatively small. Th us, although the actual numbers we calculated are approxi-mate, our qualitative analysis confi rms what seems logi-cal. Specifi cally, if we assume that the SO tendon is constrained by the frenulum in the primary and adducted fi elds of gaze, cutting the frenulum aft er a pro-cedure such as a partial posterior tenectomy would col-lapse the angle the anterior fi bers make with the anterior–posterior axis. Th is reduction in the angle makes the SO tendon a more eff ective depressor in the adducted position. Th is may be an explanation for the residual overdepression in adduction in the ipsilateral eye aft er posterior partial tenectomy of the SO tendon.

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 stra-bismus. 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

Summary for Clinicians

Th e SO frenulum is an important structure. How ■

it is handled with superior rectus and SO surgery may aff ect the surgical outcome.Th e frenulum should be severed for superior ■

rectus recessions that exceed 10 mm, to allow for the desired recession eff ect.Th e frenulum should be severed for all superior ■

rectus resections to prevent the SO tendon incar-ceration syndrome.Th e frenulum should be left intact for superior ■

rectus recessions that are less than 10 mm to pre-vent the SO tendon incarceration syndrome.With SO recessions using a suspension technique ■

the handling of the frenulum is a matter of trade-off s. 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 stra-bismic syndrome but will limit the amount of recession obtained. Asymmetric handling of the frenulum with bilateral SO recession may predis-pose to an asymmetric response.Th e posterior tenectomy operation of the SO is ■

eff ective in collapsing up to 20 PD of A pattern but is less eff ective in eliminating the overdepression in adduction.

References 193

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 obli-cuo superior. Arch Oft almol B Aires 51:267–271

11. Prieto-Diaz J (1979) Poseterior partial tenectomy of the SO. J Pediatr Ophthalmol Strabismus 16:321–323

12. Shin GS, Elliott RL, Rosenbaum AL (1996) Posterior supe-rior 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” aft er surgical treatment of A-pattern anisot-ropies. In: M. Spiritus (ed) Transactions 24th meeting European strabismological association; Vilamoura, Portugal. Aeolus, Buren, Th e Netherlands

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 surgi-cal treatment will be reviewed fi rst and then the treat-ment strategies in third, fourth, and sixth cranial nerves will be evaluated.

15.1.1 Aims of Treatment

Th e major aims of treatment are enlargement of diplopia-free fi eld, restoration of ocular alignment, and restoration of the appearance of the patient, to correct abnormal head pos-ture, and to improve the ductions. Th e 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 devi-ation must be observed before considering any surgical

Pearls and Pitfalls in Surgical Management of Paralytic StrabismusSeyhan B. Özkan

Chapter 15

15

Core Messages

Careful preoperative assessment and a correct ■

diagnosis of the problem are the essential factors for a successful outcome of surgical treatment.Th e pearl to go through the correct route in surgi- ■

cal management of paralytic strabismus is to know the questions that need to be answered dur-ing the preoperative assessment. Th e 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 ocu-lar 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.Th e aims of surgical treatment are primarily to ■

obtain a diplopia-free fi eld, to achieve symmetric ocular motility and a good looking eye that will allow eye contact, and to correct the abnormal head posture, if any.

The major pitfall in paralytic strabismus is the ■

coexistence of a restrictive element. The sec-ondary restrictions may mask the partial func-tional recovery in a paretic extraocular muscle (EOM), and sometimes they may become a more prominent problem than the paralytic condition itself.Th e 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. Th ere should be no hesitation to operate the sound eye where necessary.Th e 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 eff ect by transposition, and fi nally 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.

196 15 Pearls and Pitfalls in Surgical Management of Paralytic Strabismus

15

intervention. Th e 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 con-sider that if the deviation is still unstable following consecu-tive examinations aft er 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 diag-nosis. Restrictive motility problems may simulate para-lytic conditions and sometimes both restrictive and paralytic problems occur at the same time making the clinical picture more complicated. Th e combination of restrictive and paralytic problems mostly occurs in orbital blow-out fractures and in long-standing paralytic prob-lems. Th e combination of restrictive element has a nega-tive eff ect on the predictability of surgical results, so the presence of any restrictive factors must be carefully evalu-ated in all cases with paralytic strabismus.

For a correct surgical planning, the following ques-tions need to be answered preoperatively in cases with paralytic strabismus:

1. Is the problem partial (paresis) or total (paralysis)?2. Are there any restrictive factors?3. Is the problem congenital or acquired?4. Is there “acquired loss of fusion” or in other words

“central fusion disruption?”

Th e answers for the fi rst 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 diffi cult to assess whether the paralytic condition is partial or total. Th ese factors may be primary as it is the case in blow-out frac-ture 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 ■

gazeAssessment of the ocular rotations ■

Traction test ■

Active forced generation test ■

Electromyography (EMG) ■

Increase of intraocular pressure with positions of ■

gazeMeasurement of saccadic eye movements ■

Botulinum toxin A (BTXA) injection into the antago- ■

nist 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 para-lytic strabismus [2]. Th e secondary unopposed contrac-ture of the antagonist EOM may not allow the eye to move toward the direction of the aff ected 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 mus-cle 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 fi brosis BTXA injection does not give reliable results, as BTXA cannot eliminate the fi brotic tissue eff ect.

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 fi brosis may not only aff ect the EOMs but also the fascial structures and EOM pulleys and an orbital fi brosis develops [4, 5]. In such cases, the traction test will be found positive despite the disinsertion of the EOM. Th ese 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 abnormali-ties in congenital superior oblique palsy, EOM fi brosis, or orbital fi brosis. Most of the congenital cases do not com-plain of diplopia. Th e 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 post-traumatic ones. In these cases, because of the involve-ment 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

15.1 General Principles of Surgical Treatment in Paralytic Strabismus 197

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. Th e 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 sur-gery may be performed safely. Our preferred method is BTXA injection in such cases to provide a temporary period of orthophoria under real-life conditions. Th e decreased contrast sensitivity and the loss of image qual-ity related to Fresnel prisms may have a negative eff ect on recovery of fusion. If the patient cannot overcome or tol-erate 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. Th e 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

Decreasing the strength of the antagonist: Recession ■

or disinsertion of the antagonist is the preferred method. If it will be combined with full tendon trans-position, 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 proce-dures, the paretic muscle is preferred to have some residual function. Th e 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.

Paretic EOM Partially recoveredparetic EOM

Contracture ofthe antagonist Paralysis of the

antagonist with BTXA

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 extraocu-lar muscle (EOM) following injection of BTXA into the antagonist muscle [3]

a

b

Fig. 15.2 In a patient with left sixth nerve palsy (a) the improvement of abduction of the left eye aft er injection of BTXA into the medial rectus muscle is shown (b) [3]


15

Weakening the yoke muscle in the sound eye: ■

Recession or faden operation of the yoke muscle in the unaff ected eye is the preferred method to increase the fi eld of binocular diplopia-free fi eld.

Th ese are the general principles that the strabismus sur-geon needs to consider in all types of paralytic strabismus cases. Th e cranial nerve palsies will be evaluated individ-ually during the rest of the manuscript.

15.2 Third Nerve Palsy

Th ird nerve palsy may aff ect 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. Th e involvement of the inferior branch of the third nerve aff ects medial rectus, inferior rectus, and inferior oblique muscles, whereas the superior branch aff ects 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. Th ere is a small hypotropia with a large angle exodeviation and ptosis due to the involvement of levator palpebrae superioris muscle. If the pupillary fi bers are aff ected, a mydriatic pupilla will be observed. In congeni-tal and long-standing cases, fi brosis of the intraorbital structures develops. Th e aims of treatment in complete third nerve palsy are to obtain an improvement of the appearance of the patient, orthophoria in primary posi-tion, and a fi eld of binocular single vision in a very lim-ited area. Prior to any surgical intervention, the patient must be informed about the goals of surgery and the pos-sibility of a more bothersome diplopia with the decrease of the proximity of the two images in primary position.

Th e 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. ■

Th e procedures that keep the eye in passive ■

adduction.

Weakening of the lateral rectus muscle: Th e methods of weakening are supramaximal recession, hang back

recession enough to allow the passive adduction of the eye, orbital wall periost fi xation of the lateral rectus mus-cle, and BTXA injection in residual deviations [7–9]. Orbital wall periost fi xation is a recently described method for the inactivation of lateral rectus muscle that we found useful in our clinical practice. Posterior Tenon fi xation is proposed to be an alternative method to periost fi xation [10]. Th e 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 eff ective, some authors prefer to perform a large resection to obtain a mechanical resis-tance against abduction. In our experience, this eff ect does not last long and we do not prefer to resect medial rectus muscle.

Superior oblique tendon transposition: Th e 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 diffi cult to assess the func-tion of the superior oblique muscle while the eye is fi x-ated in an abducted position. In such patients with no apparent hypotropia or intorsion in ocular motility exam-ination, 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 cut-ting the superior oblique tendon via nasal approach and suturing the tendon 2 mm anterior and nasal to the supe-rior rectus tendon without destroying the trochlea [7, 11]. Th e latter is our preferred method for superior oblique tendon transposition, which is a less invasive one.

Th e procedures to keep the eye in passive adduction: For a permanent eff ect fascia lata, silicone band or superior oblique tendon may be used to fi xate 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 eff ect of surgery [14, 15]. Th ese sutures are kept in place for 6 weeks. Th is is our method of choice in total third nerve palsy [3] (Figs. 15.3–15.5). Th e other methods are usually performed in secondary cases with a failure of a previous operation.

Th e major problems in total third nerve palsy are lat-eral rectus contracture that cannot be overcome by any methods, orbital fi brosis in long-standing cases, recur-rence 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]

15.2.2 Incomplete Third Nerve Palsy

In incomplete third nerve palsy with a superior or infe-rior branch or isolated EOM involvement, the treatment should be planned depending upon the aff ected 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

and in that case, the treatment should be modifi ed depending upon the severity of the involvement of the EOM(s). As the goal is to enlarge the diplopia-free fi eld, 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.

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]


Th e correct evaluation of a complete or incom- ■

plete third nerve palsy (to diagnose the number of aff ected muscles) and assessment of a total or partial involvement (the residual function of the aff ected muscles) are the pearls for an appropri-ate surgical planning.In complete third nerve palsy, superior oblique ■

function may easily be overlooked. Th e 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 fi xate the aff ected eye in primary position.Orbital fi brosis is the bad prognostic sign for any ■

type of surgery. Th e pearl is to create surgically induced restriction that provides a mechanical pulling eff ect. A temporary pulling by traction sutures is very eff ective that allows the develop-ment of the scar tissue while the globe was fi xated on adduction.


15

15.3 Fourth Nerve Palsy

In fourth nerve palsy hypertropia, inferior oblique overac-tion and superior oblique underaction is observed in the aff ected 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 fi ndings of fourth nerve palsy. In unilateral cases, the typically observed abnormal head posture is chin down with head tilt toward the unaff ected 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” pat-tern. In acquired cases, vertical or torsional diplopia is the main complaint of the patients. Congenital cases do not usually complain about diplopia; however, in decompen-sated congenital fourth nerve palsy, the patient has vertical diplopia. Some patients may benefi t from prisms but most of the patients require surgical treatment.

For a correct surgical plan, one needs to have the cor-rect 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? Th e surgical treatment should be planned on the EOMs functioning in the fi eld of gaze with the largest deviation. To obtain a reliable data, the measurement of the devia-tion should be done in nine diagnostic positions of gaze.

Is it congenital or acquired? Th e reply to this question has a specifi c importance in fourth nerve palsy. Congenital cases may present with superior oblique tendon abnor-malities, such as abnormal tendon laxity, tendon inser-tion abnormalities, and sometimes even agenesis of the tendon [16–19]. Because of the frequent tendon abnor-malities 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 fi nd-ings were confi rmed 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. Th e dif-ferential diagnosis in congenital and acquired cases is not only important for the etiological investigation but also for surgical planning. Th e clinical clues suggesting that the patient has a congenital superior oblique palsy may be summarized as follows:

Fig. 15.5 Postoperative appearance of the patient aft er removal of the traction sutures 6 weeks aft er surgery. Orthophoria is obtained in primary position [3]

15.3 Fourth Nerve Palsy 201

History, old photos ■

Absence of a preceding event ■

Prominent abnormal head posture ■

Facial asymmetry ■

Coexistence of amblyopia ■

Signifi cant 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 modifi ed by Plager [17]. Th e globe is fi xated by two for-ceps 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 supe-rior 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 fi nding 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

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 supe-rior 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]. Th e bilateral involvement may be asymmetric but even with marked asymmetry surgery should be planned in both eyes. Th e clinical clues suggesting bilateral involvement are as follows:

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) Th e globe is grasped with retropulsion. (2)Th e globe is moved superonasally and the cornea disappears in total, the back and forth move-ments 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 fi xated on the sclera. (6) Traction test is repeated aft er tucking. Note the diff erence of the position of the cornea


15

Is there any torsional diplopia? Torsional diplopia is a symptom that occurs in acquired fourth nerve palsy. Th e patients with a decompensated congenital fourth nerve palsy has vertical diplopia without a torsional element,

although an excyclotorsion is observed in fundus exami-nation, and this is one of the clues for diff erential diagno-sis of a congenital and acquired fourth nerve palsy. Some patients may not describe torsional diplopia properly

Fig. 15.7 Preoperative appearance of a patient with right long-standing fourth nerve palsy with ipsilateral superior rectus contrac-ture. 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 disinser-tion and adjustable superior rectus recession of the right eye

15.3 Fourth Nerve Palsy 203

unless asked specifi cally and may complain about “blur-ring” 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 aff ected 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]. Th e weakening procedures are disinsertion, myectomy, recession, and anteroposition of the inferior oblique mus-cle. 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 modifi ed 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 eff ective procedure in con-genital cases with abnormal tendon laxity [18, 29]. In cases with marked hypertropia and marked abnormal head posture, superior oblique tendon tuck may be per-formed alone or usually in combination with inferior oblique weakening. If there is no apparent inferior oblique overaction, superior oblique tendon tuck may be per-formed without weakening the inferior oblique muscle. To reduce the risk of iatrogenic Brown syndrome, trac-tion test must be performed aft er tucking with loop sutures (Fig. 15 6). If the traction test is positive then the amount of tuck should be reduced. Th e triad of indica-tions for superior oblique tendon tuck is large angled ver-tical deviation, prominent abnormal head posture, and superior oblique tendon laxity.

In acquired cases with marked torsional diplopia, Fells modifi ed Harada-Ito procedure is the method of choice that strengthens the anterior torsional fi bers. Th e anterior fi bers of superior oblique muscle are transposed lateral and anteriorly at the upper border of the lateral rectus

muscle [26, 30]. Th is procedure is usually performed bilaterally and has a minimal eff ect on the vertical devia-tion in primary position and does not alter the esodevia-tion on downgaze. So, it is only indicated if there is subjective torsional complaint that need to be corrected.

Superior rectus recession in the aff ected eye: Th e indica-tion for superior rectus recession is a vertical deviation exceeding 15 prism diopters in combination with supe-rior rectus contracture [23, 24]. It should be considered as an additional surgery with inferior oblique weaken-ing. Th e predictability of the recession in a restricted superior rectus muscle will be low and adjustable reces-sion 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: Th e cases that do not fi t any of the indications specifi ed above and where there is a vertical deviation exceeding 15 prism diopters are the candidates for contralateral inferior rec-tus recession. It can be performed in combination with inferior oblique weakening of the aff ected eye or as a sec-ondary procedure in cases with residual deviation. Progressive overcorrection and lower eyelid retraction are well recognized problems with inferior rectus reces-sion [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 injec-tion 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 undercorrec-tions; 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 benefi ts with BTXA injection if there is no signifi cant torsional element.


Th e pearl is the correct evaluation of a congenital ■

and acquired case. Large vertical fusional ampli-tudes, facial asymmetry, and absence of torsional diplopia are the major clues for congenital fourth nerve palsy.


15

15.4 Sixth Nerve Palsy

Lateral rectus underaction, esotropia, and a horizontal diplopia, which is more prominent at distance, and abnor-mal head posture in unilateral cases keeping the aff ected eye in adduction are the clinical features of sixth nerve palsy. Lateral rectus underaction may be very subtle in partially aff ected cases and it is essential to measure the deviation in nine positions of gaze. Partially aff ected cases benefi t 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 aff ected eye provides a symptomatic relief. Although it was previously proposed that BTXA increased the possibility of spontaneous recovery, ran-domized 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 cor-rect answers for the following questions:

What is the amount of the measurement of the devia- ■

tion in primary position?Is the paralysis total or partial? ■

Are there any medial rectus contracture? ■

Surgical methods of treatment may be summarized as follows:

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 trans- ■

position: Th is method carries a risk of anterior seg-ment ischemia. Th at risk may be reduced by ciliary artery preserved full tendon transposition, perform-ing 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 aff ected lateral rectus mus-cle. If the residual function of the lateral rectus muscle is very limited, then transposition will work better than recess–resect procedure. Th e correct surgical decision for a recess–resect or a transposition procedure is highly important. A wrong decision for a recess–resect proce-dure in an old patient makes the patient lose his or her chance to have a transposition procedure because of the signifi cant risk of anterior segment ischemia. To obtain a more reliable assessment for the residual lateral rectus function, BTXA injection is recommended as a fi rst 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 signifi cant limitation of ocular motility, BTXA provides the assessment of the residual function of the paretic muscle in the absence of secondary fi brotic changes in medial rectus muscle. If there is no improve-ment 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 aft er the BTXA injec-tion and if there is no improvement on abduction, we perform full tendon width vertical rectus muscle transpo-sition during the maximal BTXA eff ect. Th is 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

Th e major pitfall is to overlook masked bilateral- ■

ity. Presence of a “V” pattern and a large extor-sion indicates bilaterality. Consider bilateral surgery in such cases despite the absence of apparent inferior oblique overaction and supe-rior oblique underaction.Inferior oblique weakening alone provides satis- ■

factory outcome in most of the cases if the verti-cal deviation does not exceed 15 prism diopters.Ipsilateral superior rectus and contralateral infe- ■

rior rectus weakening procedures should always be considered in combination with inferior oblique weakening.Do not consider superior oblique tuck surgery in ■

acquired ones. Th e risk for symptomatic iatro-genic Brown syndrome is very high. Superior oblique tendon tuck should be reserved for con-genital cases with abnormal tendon laxity and a large vertical deviation.Fells modifi ed Harada-Ito procedure is a surgery ■

for acquired bilateral cases with marked torsional component.

References 205

of the sound eye increases the area of binocular diplopia-free fi eld. A combination of recession and resection of the medial rectus muscle provides an adjustable faden eff ect 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].

Th e problems of treatment in sixth nerve palsy are the anterior segment ischemia risk and the insuffi cient cor-rection because of a recess–resect procedure in a non functioning lateral rectus muscle.

References

1. Golnik KC, Miller NR (1991) Late recovery of function aft er 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 stra-bismus. Türkiye Klinikleri J Surg Med Sci 2:58–65

4. Demer JL, Miller JM, Poukens V, et al (1995) Evidence for fi bromuscular pulleys of the recti extraocular muscles. Invest Ophthalmol Vis Sci 36:1125–1136

5. Demer JL, Miller JM, Poukens V (1996) Surgical implica-tions 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, Th e Netherlands, pp 195–198

7. Gottlob IG, Catalano R, Reinecke RD (1991) Surgical man-agement 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, Th acker N, Britt MT, et al (2004) Rectus muscle orbital wall fi xation: a reversible profound weakening pro-cedure. J AAPOS 8:473–480

10. Heo H, Park SW (2008) Rectus muscle posterior tenon fi xation 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 infl uence on postoperative hypertropia. J Pediatr Ophthalmol Strabismus 37:149–155

12. Salazar Leon JA, Ramirez-Ortiz MA, Salas-Vargas M (1998) Th e 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 fi xation 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 fi xed 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

•Botulinum toxin injectionas the first line treatment

•Cure-no furthertreatment

•Patient satisfied -regular injections •Unsatisfactory result -

necessary informationfor recess-resect ortransposition surgery

Fig 15.9 Th e use of BTXA for planning of treatment in sixth nerve palsy [3]


Th e correct diagnosis of partial and total sixth ■

nerve palsy is the pearl for a successful outcome of surgery.Th e major pitfall is the misinterpretation of the ■

lateral muscle function because of the second-ary 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 eff ect 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.


15

16. Helveston EM, Krach D, Plager DA, et al (1992) A new classifi cation 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 characteris-tics 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 supe-rior oblique palsy with contracture of ipsilateral superior rectus treated by superior rectus recession. Binocul Vis Strabismus Q 13:177–180

24. Mims JL (2003) Th e triple forced duction test(s) for diag-nosis and treatment of superior oblique palsy with an updated fl ow chart for unilateral superior oblique palsy. Binocul Vis Strabismus Q18:15–24

25. Kushner BJ (1988) Th e 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) Th e 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 treat-ment in congenital superior oblique palsy. Türkiye Klinikleri. J Surg Med Sci 4:223–226

30. Roberts C, Dawson E, Lee J (2002) Modifi ed Harada-Ito procedure in bilateral superior oblique paresis. Strabismus 10:211–214

31. Sprunger DT, Helveston EM (1993) Progressive overcor-rection aft er inferior rectus recession. J Pediatr Ophthalmol Strabismus 30:145–148

32. Lozano-Pratt A, Estanol B (1994) Treatment of acute paral-ysis 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 trau-matic 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 uni-lateral 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) Th e effi cacy 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 com-bined recession and resection of a rectus muscle procedure in the management of incomitant strabismus. J AAPOS 11:131–134

16.1 Graves Orbitopathy (GO): Pathogenesis and Clinical Signs

16.1.1 Graves Orbitopathy is Part of a Systemic Disease: Graves Disease (GD)

Graves orbitopathy is a part of a systemic autoimmune disease. Th e full clinical picture is composed of hyperthy-roidism, orbitopathy, pretibial myxedema, and acropachy. Th e 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

receptor (TSHR) can be measured in the serum as indica-tors of the failed immune system. Th ose antibodies stim-ulate the TSHR in an uncontrolled manner and are directly responsible for the development of hyperthyroid-ism. 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 infl ammation in the con-nective tissue of the orbit, an increase of intraorbital vol-ume due to enhanced adipogenesis, overproduction of glycosaminoglycanes (GAG), and fi brosis of the extraoc-ular muscles [2]. Orbital fi broblasts are pivotal to these pathologic processes. Cultured orbital fi broblasts can be

Modern Treatment Concepts in Graves DiseaseAnja Eckstein and Joachim Esser

Chapter 16

16

Core messages

Graves orbitopathy (GO) is part of an autoim- ■

mune systemic disease, which is composed of hyperthyroidism, orbitopathy, dermopathy, and acropachy.Stimulating antibodies against the TSH receptor ■

are directly involved in the pathogenesis of hyper-thyroidism; 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 ■

infl ammation, proptosis due to increase (mainly through adipogenesis) of orbital volume and impairment of ocular and lid motility due to infl ammation, and scarring of chiefl y the levator, inferior, and medial rectus muscles. In severe cases, vision-threatening compression of the optic nerve can occur.Infl ammatory phase is self-limiting but may ■

relapse, in most cases, owing to insuffi ciently controlled thyroid disease, but also indepen-

dently. To restrict damage, anti-infl ammatory therapy (e.g., systemic steroids or orbital radio-therapy) is indicated in moderate to severe active disease stages.Patients with sight-threatening GO should be ■

treated with i.v. steroids as fi rst-line treatment; if the response is poor aft er 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 suffi cient, but treat-ment may be justifi ed if quality of life is reduced signifi cantly.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.

208 16 Modern Treatment Concepts in Graves Disease

16

stimulated by patient IgG, several cytokines, and autolo-gous 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 fi broblasts may diff erentiate to preadi-pocytes, which are accompanied by an increase in TSHR expression [4]. Th us, 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 hyper-thyroidism but no associated orbital infl ammation [5]. Th us, factors other than the presence of TRAb are prob-ably involved in the development of GD. In GD, there is a strong genetic component [see Chap. 16.5.2] involving immunoregulatory and thyroid-specifi c 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 aft er the fi rst clinical signs of hyperthyroidism. MRI images of patients who suff er from hyperthyroidism but not from clinically overt orbitopathy reveal orbital mani-festation in more than two-thirds of those patients [7]. Th e development of GO is a marker for a more severe course of GD and associated with signifi cantly lower remission rates of hyperthyroidism [8]. However, GO can also occur many years aft er 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-specifi c antibodies can be detected as indicators of associated thyroid disease [10]. About half of those patients will develop thyroid dys-function within the following 18 months [11].

16.1.2 Graves Orbitopathy−Clinical Signs

Graves Orbitopathy is typically characterized by the fol-lowing clinical characteristics (Fig. 16.1) [12, 13]:

Most frequent sign (in 90–98% of patients): upper lid ■

retraction, oft en with lateral fl are and lid lag on verti-cal downward pursuit, lagophthalmos (due to fi brosis of the levator palpebrae muscle)Other common signs: soft tissue signs, e.g., periorbital ■

swelling and redness, conjunctival swelling and injec-tion, prominent glabellar rhytids (due to infl ammation)

Proptosis (exophthalmos) with possible concomitant ■

lower lid retraction (mainly due to increased adipo-genesis, but also due to enlargement of extraocular muscles and infl ammatory 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 oft en upgaze ■

and abduction (due to fi brosis 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 infl ammation: painful, oppres- ■

sive feeling on or behind the globe, pain of attempted up-, lateral, or downgazeSymptoms related to ocular surface irritation: gritty ■

sensation, light sensitivity, excess tearing, and reduced visual acuitySymptoms related to restricted ocular motility: diplo- ■

pia, abnormal head positureSymptoms related to DON: reduced visual acuity, ■

restricted visual fi eld, and desaturated color percep-tion

16.1.3 Clinical Examination of GO

Determining the phase of GO at each clinical assessment [14] is fundamental to the establishment of an appropri-ate management plan (Fig. 16.2). Immunomodulatory therapies can only be eff ective in the presence of active infl ammation. 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

Th e 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 infl ammation are used as surrogate markers to evaluate the degree of orbital infl ammation:

16.1 Graves Orbitopathy (GO): Pathogenesis and Clinical Signs 209

Eyelid redness ■

Conjunctival injection ■

Chemosis (conjunctival edema) ■

Eyelid swelling ■

Infl ammation of caruncle or plica ■

All features of soft tissue infl ammation 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 activ-ity are summarized in the clinical activity score (CAS) (maximal seven points at the fi rst visit and maximal ten points at follow-up) (Table 16.1) [16]. Using a cut-off of at least four (fi rst visit three), the positive predictive value

was 80% in estimating the response to immunomodula-tion. 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 infl am-matory markers including IL-6, and urine GAG excretion provide only little additional benefi t in predicting the response to anti-infl ammatory therapy [17].

16.1.3.2 Assessing Severity of GO

Th e following features are quantifi ed to assess severity:

Lid fi ssure width (distance between the lid margins in ■

mm with the patient in primary position; sitting, relaxed, with distant fi xation)Swelling of the eyelids (absent/moderate/severe) ■

a b c

d e f

g h i

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. Th e other muscles are almost normal. 1G–1I Patients with full picture of GO with DON: marked signs of soft tissue infl ammation (conjunctival injection and chemosis, caruncle infl ammation, 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

www.eugogo.eu


16

Redness of the eyelids (absent/present) ■

Conjunctival injection (absent/present) ■

Conjunctival chemosis (absent/present) ■

Infl ammation of the caruncle or plica (absent, present) ■

Exophthalmos (measured in mm using the same ■

Hertel exophthalmometer and same intercanthal dis-tance for an individual patient)Subjective diplopia score ( ■ 0 no diplopia; 1 intermit-tent, i.e., diplopia in primary position of gaze, when tired or when fi rst awakening; 2 inconstant, i.e., diplo-pia 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 aff erent pupillary defect (absent/present), visual fi elds, visually evoked potentials)

Examination of lid fi ssure width should be performed with the head in a stationary position and under fi xation.

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 exophthalmom-eter. Numerous diff erent makes are available with diff er-ent scales, so for each patient the same exophthalmometer with identical intercanthal distance should always be used for follow-up. Proptosis is defi ned as a reading 2 mm greater than the upper normal limit for that patient’s age, gender, and “race.” More important, however, is the mea-sured change during follow-up.

Th ere are numerous ways of assessing extraocular muscles. Subjective diplopia scores are simple but only of limited help, since signifi cant changes in limitation of motility may go unnoticed, when bilateral symmetrical reduction of upgaze results in no noticeable double vision. Th e 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 refl exes may be used as well. Normal

All patients with GO

Moderate to severe

• Restore euthyroidism• Urge smoking withdrawal• Refer to specialist centers, except for the mildest cases• Local measures

Mild

Local measureswait and see Progression Active Inactive

i.v. GCs

Poor response (2 weeks)

Prompt decompression

Still active Stable and inactive

i.v. GCs(± OR)

Rehabilitativesurgery


i.v. GCS(± OR)

Stable andinactive

Stable andinactive


(if needed)

Sight-threatening (DON)

Fig. 16.2 Management of Graves’ orbitopathy. Anti-infl ammatory 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 defi nitions of GO severity and activity, see Chap. 16.1.3

16.1 Graves Orbitopathy (GO): Pathogenesis and Clinical Signs 211

values are given in Table 16.2. Th e prism cover test (sepa-rate measurement of the squint angles in primary posi-tion for far and near distances) and the fi eld of binocular single vision are used to fi t corrective prisms and to plan squint surgery.

Of outstanding importance is the evaluation of the corneal surface. Th is requires slit lamp examination to detect punctate fl uoresceine staining or ulceration; the latter constitutes an ophthalmologic emergency.

Th ere is no single test that proves DON. DON occurs bilateral in 70% of the patients. Anatomical indicators are

very large muscles in the orbital apex, fat herniation through the superior orbital fi ssure, and tense ballotte-ment of the globe and venous stasis. DON is insidious as its onset is rarely obvious and visual acuity is long pre-served. Color vision disturbances are present in most patients. Only 30–40% of the patients present with swell-ing of the optic disc. Visual fi eld defects are most com-monly paracentral or inferior. VEP amplitudes are reduced and latency periods can be delayed [14].

Severity can be scored using the NOSPECS classifi ca-tion, which provides in its slightly modifi ed 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 diff erential diag-nosis as well as, in special situations, to facilitate treat-ment decisions. If the patient presents with asymmetrical symptoms (usually unilateral proptosis), infl ammatory orbital disease of nonthyroidal etiology or orbital tumors have to be ruled out. Orbital imaging is neces-sary for all clinical treatment decisions in Dysthyroid optic neuropathy. Signal intensity in T2-weighted MRI scans corresponds to infl ammatory edema and can be used to ease treatment decisions in diffi cult clinical situations. Orbital ultrasound is only informative if performed and evaluated by experienced clinicians [20].

16.1.4 Classifi cation of GO

Members of EUGOGO recommend to classify patients according to activity (active disease CAS ≥ 4, inactive dis-ease CAS < 4) and according to severity to manage patients with GO [21].

Severity classifi cation:

1. Sight-threatening GO: Patients with dysthyroid optic neuropathy (DON) or corneal breakdown. Th is cate-gory warrants immediate intervention.

2. Moderate-to-severe GO: Patients without sight-threat-ening GO whose eye disease has suffi cient 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, mod-erate or severe soft tissue involvement, exophthalmos >3 mm above normal for “race” and gender, intermit-tent, or constant diplopia.

Table 16.1. Clinical activity score (CAS), maximal 7 points at the fi rst visit and maximal 10 points at follow-up, active disease CAS ≥4 (three fi rst 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

Infl ammatory eyelid swelling 1

Infl ammation of the caruncle or plica

1

Sum score (at fi rst 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

Table 16.2. Normal values for monocular excursions (aft er Mourits et al. [18])

Direction of gaze Monocular excursion (°)

Abduction 46

Upgaze 90° 34

Adduction 47

Downgaze 270° 58


16

3. Mild GO: patients whose features of GO have only a minor impact on daily life, insuffi cient to justify immunosuppressive or surgical treatment. Th ey usu-ally 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)

16.2 Natural History

Control of thyroid function infl uences the course of GO (see Chap. 4). Patient with mild-to-moderate GO, moni-tored 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 with-out treatment, there are oft en residual symptoms of GO in the form of lid retraction, proptosis, and muscle dys-function. Th e outcome is signifi cantly better in patients who have been diagnosed early and treatment started promptly.

Table 16.3. Modifi ed NOSPECS score for quantifi cation of severity, maximal score of 14

NOSPECS score 0 1 2 3

Lid retraction No Yes

Soft tissue infl ammationa 0 1–4 5–8 >8

Proptosis and or Site Diff erence <17 mm 17–18 mm 19–22 mm >22 mm

<1 mm 1–2 mm 3–4 mm >4 mm

Extraocular muscle involvement No >20° upgaze ≤20° upgaze

>35°abduction but not normal

≤35°abduction

Corneal defects No Yes

Optic nerve compression No YesaUpper lid edema 0–2; Lower lid edema 0–2; conjunctival injection 1; conjunctival chemosis 1


Graves’ Orbitopathy is part of an autoi mmune ■

systemic disease encompassing hyperthyroid-ism, orbitopathy, dermatopathy, and acropachy.TSHR receptor antibodies (TRAb) are indica- ■

tors of the failed immune system and direct pathomechanism for hyperthyroidism. Th eir 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 fi broblasts play a pivotal role in the pathologic changes in the orbit (release of chemokines, production of glycoseam-inoglycanes/fi brosis, and diff erentiation into adi-pose tissue).Assessment of activity (clinical activity score) ■

and severity is necessary for disease manage-ment: immunomodulation is performed during


Spontaneous improvement of GO with restora- ■

tion of euthyroidism occurs in more than 60% of the patients.

the active phase and rehabilitative surgical treat-ments in the inactive phase of the disease.According to its grade, GO can be classifi ed as mild, ■

moderate to severe, and sight threatening. Mild GO permits a “wait and see” approach, moderate-to-severe GO requires immunosuppressive treat-ment in the active phase, and sight-threatening GO demands immediate treatment with i.v. steroids/orbital decompression/treatment of ocular surface damage.

16.3 Treatment of GO 213

16.3 Treatment of GO

16.3.1 Active Infl ammatory 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, evalu-ating 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 con-cerning soft tissue signs, eye muscle involvement of recent onset, and DON. Eye disease frequently fl ares up on tapering out or withdrawing of oral GC therapy. Side eff ects are frequent.

Local retrobulbar or subconjunctival administration of glucocorticoids is less eff ective than oral GC.

Intravenous GC pulse therapy is more eff ective 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 diff erent 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

Th e 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 eff ective. Th e response to OR did not diff er from oral prednisone in a randomized con-trolled trial (RCT), but glucocorticoids are faster acting. Two recent RCTs have shown that OR is more eff ective 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,

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 dia-betes, even in the absence of retinopathy, represents a risk factor for the development of retinal changes aft er 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 eff ective than either treatment alone. It is unclear whether combining i.v. GCs with OR is more eff ective 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 aft er max-imal doses of i.v. glucocorticoid therapy and orbital radio-therapy. In most of the cases, poor control of thyroid function, high TSH-receptor-antibody levels, and nico-tine abuse are among the underlying reasons. A thyroid specialist should always be consulted. In cases of expected low chance of remission or uncontrolled thyroid func-tion, defi nitive therapy of the thyroid has to be initiated. Th yroidectomy 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 infl ammation − 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 remis-sion of thyroid function in comparison with methimazole monotherapy. Also, the stimulatory capacity of TRAbs was reduced markedly. Clinical activity of GO signifi -cantly decreased aft er injection of 1,000 mg i.v. Rituximab


16

twice at 2-week interval. Even proptosis was signifi cantly reduced. Subsequent randomized controlled trials with Rituximab need to be performed [30–32]. Th e anti-TNF a drug Etanercept is described as eff ective 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 fi rst-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 aft er 1–2 weeks, or the dose/duration of steroid required induces signifi cant side eff ects, orbital decompression should be carried out promptly. Orbital decompression should be recom-mended 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 appropri-ate expertise.

Sight-threatening corneal breakdown must be treated as an emergency as well.

Frequent topical lubricants, moisture chambers, tars-orrhaphy, 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 ineff ective [21].

16.3.1.6 Other Simple Measures that may Alleviate Symptoms

Th e symptoms of corneal exposure (grittiness, watering, and photophobia) should be treated with lubricant eye-drops. Nocturnal ointment is of great benefi t if eyelid clo-sure 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 eff ect is evident aft er 2–3 days and persists for about 4–6 weeks. Th e outcome is variable and the dose of botulinum toxin must be adjusted individually. Transient double vision and ptosis may occur in 10–20%. Th is procedure should be carried out in specialized centers [34].

Table 16.4. Representative results of randomized clinical trails of anti-infl ammatory therapy for active GO

Randomization Response rates P values Authors

Group A Group B Group A Group B

i.v. methylprednisolonea Radiotherapyb (n = 41)

Oral Prednisonecc Radiotherapyb (n = 41)

88% « 63% <0.02 Marcocci

i.v. methylprednisoloned (n = 35)

oral prednisonee (n = 35)

77% « 51% <0.01 Kahaly

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:a15 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 intervalsb20 Gy in ten daily doses of 2 Gy over 2 weeksc100 mg daily for 1 week, then weekly reduction until 25 mg daily, and then tapering by 5 mg every 2 weeksd500 mg once weekly for 6 weeks, 250 mg once weekly for 6 weeks, total treatment period: 12 weekse100 mg daily starting dose, tapering by 10 mg/week, total treatment period: 12 weeks

« «


16.3.2 Inactive Disease Stages

Rehabilitative surgery includes one or more of the follow-ing procedures: (a) orbital decompression, the usual indi-cation for surgery being disfi guring exophthalmos with or without keratopathy; (b) squint correction; (c) lid length-ening; 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 aft er defi nitive therapy (thyroidectomy/radioiodine therapy) or stable remission at least 6 months

aft er cessation of antithyroid drug therapy. Because of its infl uence on ocular motility and lid width, decompression surgery should be performed fi rst. Vertical squint correc-tion may then be performed. Pseudoretraction will resolve postoperatively but lower lid retraction can occur aft er 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 disfi guring proptosis in patients with GO. Th e 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, transna-sal, and transanthral. Further restriction of ocular motil-ity is still a major complication; this mainly occurs with medial wall decompression. Th e risk is much lower with removal of the lateral wall alone. Clinically obvious impairment of motility increases the risk of postopera-tive diplopia signifi cantly.

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 com-plications. 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.

Th e transnasal endoscopic procedure addresses the medial and inferior orbital walls. Th e advantage of a con-venient 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. Th is is, however, an elaborate procedure.

To enhance the eff ect of lateral wall decompression, the procedure can be combined with removal of its deep portion or with additional fat removal (Fig. 16.3). Th e lat-eral wall has, due to a very low risk of diplopia, increas-ingly become the fi rst choice for orbital decompression (traditional concept – inferior-medial decompression fi rst) in cases of rehabilitative surgery. Th e approach to the lateral wall is variable via the upper skin crease,


Patients with active moderate-to-severe GO or ■

active mild GO with suffi cient impairment on daily life should receive anti-infl ammatory treatment.Glucocorticoids are applied most effi ciently i.v. ■

250 mg–1 g weekly over 6–12 weeks or at con-secutive 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 eff ects.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 effi cient than each therapy alone.Patients with dysthyroid optic neuropathy should ■

be treated with i.v. steroids as fi rst-line treat-ment; if the response is poor aft er 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 sup-ports remission of thyroid dysfunction.Simple measures like topical lubricants, botuli- ■

num toxin for retracted lids and prisms for com-pensation of double vision are important for the quality of life of the patients.


16

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

Th e basic concept for eye muscle surgery in GO is reces-sion of the fi brotic muscle. Th e approach is diff erent for inferior and medial rectus muscles. Vertical deviation increases with side diff erences in monocular upward excursions. Bilateral symmetric restrictions of inferior rec-tus 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. Diff erent concepts for surgical strabism correction are available: preoperatively determined recession distances according to dose eff ect curves, and intraoperative deter-mination of recession distance via active or passive motil-ity 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 reductionVertical squint – head tilt when covering the eye with ■

more limited upgaze: asymmetric bilateral inferior rectus recession (side diff erence in mm depends on the squint angle, measured with head tilt: 1 mm reces-sion per 2° of intended squint angle reduction)

Horizontal squint <10°: unilateral medial rectus reces- ■

sion (side: eye with least abduction), dose 1 mm reces-sion per 1.75° of intended squint angle reduction, maximal recession distance 6–7 mmHorizontal squint ■ ≥10°: bilateral medial rectus reces-sion, dose 1 mm recession per 1.6° of intended squint angle reduction (dose side diff erent, when side diff er-ence in monocular abduction), maximal recession distance per eye 6–7 mmCombined horizontal and vertical squint: small verti- ■

cal angles disappear aft er correction of horizontal squint; a two-step procedure (large angle fi rst) is more precise; if all in one procedure is preferred (only rec-ommended for unilateral procedures): consider higher dose eff ect for vertical squint 2.1° per mm recessionLower lid retraction aft er inferior recession can be ■

prevented through dissection of the capsulopalpebral ligament. Upper lid retraction of the eye with eleva-tion defi cit (“pseudoretraction”) will disappear aft er inferior recessionConvergent squint correction aft er decompression: ■

consider lower dose eff ects: unilateral medial rectus recession: 1 mm recession per 1.2° of intended squint angle reduction; bilateral rectus recession: 1 mm reces-sion per 1.0° of intended squint angle reduction; con-sider medial rectus tendon elongation with a spacer for very large angles: 1 mm elongation per 0.9° of intended squint angle reduction

Dose eff ect data are summarized in Table 16.5 [38, 40–42].

In most cases, it is possible to improve the fi eld of bin-ocular single vision. Over-corrections occur more oft en when the muscle is not directly fi xed to the sclera but is

a

1

2

3

b

1

2

3

Fig. 16.3 Surgical approaches for orbital decompression in coronar and axial view. All orbital walls except the roof are addressed. Th e 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. Th e inferior-lateral region of the orbit is the most common zone for fat removal (B3)


adjusted on the following day. Th is 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 antago-nist and the “passive orbital tissue.” Th ey return to their original tension, which leads to a further globe rotation against the direction of the recession. Th erefore, the eff ect of squint angle reduction increases signifi cantly within the fi rst postoperative month.

Persistent diplopia in extreme gaze is common, which is usually tolerable in upgaze, since the used gaze fi eld is larger in downgaze than in upgaze.

Success rates (ocular alignment within about 2–3° in primary position) are similar for the diff erent approaches and vary mainly between 60 and 80% for horizontal squint and up to 90% for vertical squint.

16.3.2.3 Lid Surgery

Th e most common indication for lid surgery in GO is upper lid retraction due to levator muscle fi brosis. Genuine lid retraction has to be discriminated from pseudo-lid retraction due to fi brosis of the inferior rectus muscle. Th e latter resolves aft er 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 sur-gery is increased preaponeurotic and subdermal fat, resulting in bulging eye lids. Th is may be treated during blepharoplasty when redundant lid skin is excised (review of the literature: [35, 43]).

Upper lid lengthening: Many diff erent 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. Th ese are Müllerotomy or recession, medial or lateral levator aponeurosis recession, lateral horn cut (important for lateral fl are), medial and lateral full thickness levator-, Müller-muscle-, and conjunctival recession. Since lateral retraction (temporal fl are) is the most important aspect of upper lid retraction in patients with Graves orbitopa-thy, division of the lateral horn of the aponeurosis is nec-essary 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 conjunc-tiva as a cover. Myotomies without spacers (graft s) require patient cooperation. If compliance is poor or marked fi brosis is present, spacers may be used. Th e ver-tical height of the implant should be approximately twice the measured eyelid retraction or measured eyelid retraction +2 mm, respectively. Patients examples before and aft er upper lid lengthening without and with implant are shown in Fig. 16.4. Th e implant is used in a patient with severe GO (aft er three wall decompression for DON) with marked fi brosis 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 surgi-cal procedures are ascribed success rates of about 70–80%. Asymmetry can occur due to over- or under-correction, lid crease recession, and a thickened eyelid aft er use of a graft .

Table 16.5. Extraocular muscle surgery: dose eff ect coeffi cients: squint angle reduction (°)/per mm muscle recession (source: [38–41])

Muscle Dose eff ect: 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 Eckstein et al., 2004

Combinedunilateral inferior rectus muscle 2.1

Eckstein et al., 2004

unilateral medial rectus muscle 1.9

Aft er orbital decompression Eckstein et al., 2008

Medial rectus muscle unilateral 1.2

Medial rectus muscle bilateral 1.0

Tendon elongation with interponate 0.9


16

Lower lid lengthening: To correct lid retraction exceeding 1 mm, a “spacer” between lower lid retrac-tors and tarsus is required (Fig. 16.5). Various organic and anorganic materials have been used as spacers. Th ese include auricular cartilage, hard palate mucosa, expanded polyethylene Medpor microplates, autoge-nous tarsus transplants, porcine acellular dermal matrix, and donor sclera or pericardium. Th e 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. Th e lower lid retractors are accessible either by anterior subciliary or posterior subtarsal transconjunctival approach. Th e eff ect of lower lid lengthening can be increased by

lateral tarsal strip or tarsorrhaphy. Undercorrection is common.

Upper and lower lid blepharoplasty: Upper lid deb-ulking and blepharoplasty is the fi nal surgical proce-dure in the functional and cosmetic rehabilitation of the GO patient. Redundant skin and fat can be excised using scissors and bipolar cauterant, laser, or monopo-lar cauterization needle. In the lower lid, the skin exci-sion 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.

a

b

c

d

e

f

g

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 suffi ce. Patient example with upper lid retraction right eye in primary position (4A), in downgaze showing the lid lag on vertical downward pursuit (4B) and aft er lid lenghthening (4C). In rare cases with marked retrac-tion (especially aft er decompression), the use of an implant is necessary (4E–4G). Patient example before (4E) and aft er lid lengthen-ing with an implant (5 mm Tutopatch®) (4F) and intraoperative situation (4G)


a

b

Tarsus

Interponate

Lid retractors

Lig. capsulopalp.

Inferior rectusmuscle

ef

Sutures forstabilisation of theinterponate

cd

Fig. 16.5 Lower lid lengthening in GO. Lower lid retraction can occur aft er large inferior rectus muscle recession if the ligamentum capsulopalpebrale cannot be suffi ciently 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 aft er 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 fi nal result aft er lower lid lengthening with an implant and lateral tarsorrhaphy of 5 mm


Disfi guring proptosis can be reduced through ■

orbital decompression. Various surgical tech-niques are available. Th e 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 postopera-tively deteriorated ocular motility is increased.Th e basic concept for eye muscle surgery in GO ■

is recession of the fi brotic muscle. Diff erent approaches are possible: preoperatively deter-mined recession distances according to dose–eff ect curves and intraoperative determination of recession distance via active or passive motility and adjustable sutures. Success rates are high.

greyZone:nopre-dictionpossible

5,72,6 1,5 1,5 1,5 1,5

8,85,1 4,8

2,9 2,8

-5,0

0,0

5,0

10,0

15,0

20,0

25,0

30,0

35,0

40,0

1-4 5-8 9-12 13-16 17-20 20-24

Months after first symptoms of GO

TB

II [I

U/l]

TBII values below: 2.3-15.6x betterchance for a good course of GO

TBII values above: 8.7-31.1x higherrisk of a severe course

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 aft er 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 aft er the beginning of GO the odds ratio to develop a severe course of GO is 18


16

16.4 Thyroid Dysfunction and GO

16.4.1 Association Between Treatment of Hyperthyroidism and Course of GO

Th e main goal during the early stage of thyroid disease is to achieve euthyroidism. Not only does this alleviate most thyroid symptoms, it is also benefi cial for the further course of GO. Antithyroid drug therapy seems to prevent most effi ciently further deterioration of GO in comparison with thyroidectomy and radioiodine therapy [44]. Observational trials showed that thyroidectomy in the intermediate phase (6–12 months aft er fi rst symptoms of GO) may positively infl uence the clinical course of GO. In later, inactive stages, this benefi cial eff ect is lost [45]. Leaving too large thyroid remnants increases the risk of recurrence of hyperthyroid-ism and reactivation of GO [46]. Radioiodine therapy car-ries a small but not inconsiderable (about 15%) risk of inducing or worsening GO in the intermediate phase [47]. Radiogenic infl ammation of the thyroid during and aft er radioiodine application may reinforce the autoimmune reaction in the thyroid and activate or induce GO. It does not, however, infl uence inactive GO [48].

Patients with poor prognosis for remission should receive defi nitive therapy as a prerequisite for surgical rehabilitation of GO. Poor prognosis for hyperthyroid-ism can be expected with persisting high TSH-receptor-antibodies (TRAb) during the course of antithyroid drug therapy. Remission rates are about 3% if TRAb are still above 10 IU/l aft er 6 months, above 7.5 IU/l aft er 12 months, and 3.9 IU/l aft er 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 hyper-thyroidism at manifestation) should be followed for at least 6 months aft er cessation of antithyroid drug therapy before surgical rehabilitation (if necessary) is initiated. Th e 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

Th e relation between TRAb and GO was for a long time subject to debate and became evident with modern, more sensitive second-generation TRAb assays. Th e prevalence of GO among patients with Graves’ hyperthyroidism increases with higher serum TRAb levels [52]. Th ere is a signifi cant correlation of clinical activity [53] and severity [54] with TRAb levels in untreated individuals. In late stages, non-responders to anti-infl ammatory therapy reveal higher TRAb levels [55]. Patients with moderate-to-severe GO have signifi cantly higher TRAb levels over the whole course of the disease (24 months follow-up) (Fig. 16.6). Cox regression analysis 6 months aft er 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 aft er 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-infl ammatory therapy in cases of doubt and treated longer with higher doses.

Upper lid retraction can be corrected in most ■

patients without the use of a spacer through recession of levator palpebrae and Müller mus-cle. Implants have to be inserted for successful lower lid lengthening. Th e eff ect can be enhanced with a lateral tarsal strip or tarsorrhaphy. Th e last step in surgical rehabilitation is blepharoplasty of upper and lower lids.


Restoration of euthyroidism is benefi cial for the ■

course of GO.Radioiodine therapy carries a small but not con- ■

siderable (about 15%) risk of inducing or wors-ening GO.Patients with poor prognosis for remission of ■

hyperthyroidism should receive defi nitive therapy as a perquisite for surgical rehabilitation of GO.Th e overall relapse rate of hyperthyroidism aft er ■

cessation of antithyroid drug therapy is 50%. Th erefore, surgical rehabilitation of GO should only be started aft er 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 Infl uence on the Course of GO 221

16.5 Environmental and Genetic Infl uence on the Course of GO

16.5.1 Relationship Between Cigarette Smoking and Graves Orbitopathy

Th ere is a strong and consistent association between smok-ing and GO. Smoking increases the prevalence of GO among patients with Graves’ hyperthyroidism. Smokers suff er 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 fi brosis sevenfold [57]. Smoking increases the likelihood of progression of GO aft er radio-iodine therapy. Th ere 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 inde-pendent risk factor for relapse of hyperthyroidism aft er antithyroid drug treatment [51]. In vitro models (orbital fi broblast 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]. Th e eff ect is markedly enhanced in the presence of the proinfl ammatory cytokine IL-1. Th e synergy between cig-arette smoke and cytokine action may have potential for therapeutic implications.

16.5.2 Genetic Susceptibility

Th ere are a number of epidemiological and twin studies which clearly indicate that autoimmune thyroid disease is

genetically infl uenced. Th e concordance rate for clinically overt Graves disease is 35% for monozygotic twins (MZ) and 3% for dizygotic twins (DZ). Model-fi tting 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 fre-quency among females in comparison with males. Positive family history is also more common in maternal than in paternal relatives. Th e reporting of a parent with thyroid dysfunction is associated with a lower median age at diag-nosis for GD. Th ere 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 (sum-marized in [6, 62]). Within monozygotic twins, it is possi-ble for one twin to develop typical Graves disease while the other suff ers from Hashimoto’s thyroiditis without orbit-opathy [63]. Th us, there is clear evidence for genetic sus-ceptibility to develop thyroid autoimmunity. Th e disease phenotype, however, appears to be determined by environ-mental 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 identifi ed. Th e genes identifi ed to this day comprise thy-roid specifi c genes (TSHR, Th yroglobulin) 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 (modifi ed from Jacobson et al. [6]).


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 eff ectiveness of treatments for GO, and with the progression of GO aft er radioiodine treatment. Th erefore, the patient should be advised to stop smoking.Immune regulatory and thyroid-specifi c genes ■

contribute to the disease. Th e risk for fi rst-degree relatives is 3%. About 50% of patients report a positive family history, more common in the maternal than in the paternal trait.

Severity of GO and Smoking

0102030405060708090

100

Nonsmoker 1-10Cigarettes

10-20Cigarettes

> als 20Cigarettes

% o

f the

GO

pat

ient

s

Prevalence of GO

Proptosis

Diplopia

Fig. 16.7 Association of GO symptoms with the number of smoked cigarettes


16

16.6 Special Situations

16.6.1 Euthyroid GO

Patients with euthyroid GO developed less severe symp-toms, especially fewer soft tissue signs and more asym-metric disease (unilateral proptosis) than hyperthyroid patients. Levels of thyroid-specifi c 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. Th e eye disease is usu-ally milder in children than in adults and oft en stabi-lizes and eventually resolves without intervention. Soft tissue infl ammation is rare in childhood GO. Achieving and maintaining euthyroidism are as important objec-tives as in adult patients. Exposure to smoking (active and, possibly even passive) is probably as detrimental as in adults. Because of their eff ect on growth,

glucocorticoids should be avoided unless the patient suff ers 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 dia-betes or hypertension. However, indications for gluco-corticoid use in patients with diabetes or hypertension are no diff erent than in other patients. Close monitoring of blood sugar levels and blood pressure is important. Th iazide or loop diuretics should be used cautiously dur-ing high-dose steroid therapy to avoid hypokalemia. Th e same principle applies to surgical treatment. Orbital radiotherapy may increase the risk of retinopathy in diabetic and hypertensive patients. Diabetes or hyper-tension are no contraindication to surgical orbital decompression or other surgical treatments. Optic neu-ropathy occurs signifi cantly more oft en in diabetic patients (reviewed in [21]).

Table 16.6. Susceptibility genes and possible functional consequences in Graves’ disease (slightly modifi ed from Jacobson et al. [6])

Gene Associated variants Potential mechanisms

Immune response modulating genes

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 effi ciency of CD40 in CD40 expressing tissues (APC, thyrocytes, orbital fi broblasts)

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 Th 17 subset

Th yroid specifi c genes

Th yroglobulin 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

References 223

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Index

AAbducens palsy, 71Abnormal central nervous system (CNS) esotropia, 2Abnormal central nervous system (CNS) exotropia, 3Acquired motor neuropathy, 71–72Acquired nonaccommodative esotropia, 2Acquired pulley heterotopy, 63–64Amblyopia treatment 2009

age eff ect, 131amblyopia management

patch occlusion, 128–129pharmacological therapy, plano lens, 130pharmacological treatment, atropine, 129–130refractive correction, 127–128

Bangerter fi lters, 132–133bilateral refractive amblyopia, 131clinical features, 126

deep unilateral amblyopia, 175–176 diagnosis, 126–127epidemiology, 125–126levodopa/carbidopa adjunctive therapy, 133long-term persistence, 132maintenance therapy, 131natural history data, 127optic neuropathy, 133–134spectacle correction, 125

Amblyopia, screeningChild Health Promotion Program (CHPP), 96classifi cation, 95conventional occlusion, 104cover-uncover test, 100–101defi nition, 95–96Duane’s/Brown’s syndrome, 97justifi cation, 98lay screeners, 102older children, 104–105optical penalization, 104orthoptists, 102pharmacological occlusion, 104photorefractive keratectomy (PRK), 105photoscreening/autorefraction, 101–102pre-school vision screening, 98–99quality of life

emotional well-being, 107impact of treatment, 108impact on education, 106–107reading speed and ability, 106strabismus impact, 107–108

recurrence, 105

refractive adaptation, 103–104refractive error, 97sensitivity, 100stereoacuity test, 101strabismus, 97treatment compliance, 105type of treatment, 103vision in preschoolers study

(VIP), 100, 101vision tests, 100vs. diagnostic test, 97

Anisometropia, 33Anisometropic amblyopia, 2, 3Anomalous head posture (AHP)

Anderson–Kesternbaum surgery, 158binocular visual acuity testing, 161–162horizontal management, 165–166idiopathic infantile nystagmus, 158measurement, 160–161monocular eff ect, 161–162straightening eff ect, head, 162testing, near vision, 162vertical management, 166–167

Anomalous retinal correspondence (ARC), 34Atropine, 129–130

BBagolini test, 141Bangerter foils, 132Bell’s phenomenon, 88Bielschowsky head tilt test (BHTT), 181Bilateral feedback control

applications, 21–22muscle lengths, 19–21

Bilateral posterior tenectomy, 190Bilateral refractive amblyopia, 131Binocular alignment system

control systemA-/V-pattern strabismus, 14basic muscle length, 15–16bilateral phenomena, 14–15breakdown, 14fi nal common pathway, 17–18perturbation, 13sensory torsion, 14version and vergence stimulation, 16–17

deviation and fi xation pattern, 11long-term maintenance, 11muscle length adaptation, 12–13

228 Index

vergence adaptation, 12Binocular vision

angle of strabismus, 140–141at age six, 140bilateral recession vs. unilateral recession-resection, 141

Blood–brain barrier, 133Botulinum toxin A (BTXA), 197, 203, 204Brown syndrome, 4, 203Brückner test

amblyopia and amblyogenic disorders, 113–114corneal light refl ex, 114–115eye movements, alternating illumination, 122fundus red refl ex

ametropia, 116, 118anisometropia, 118esotropia, 117–118foveal dimming, 117hypermetropia, 118Mittendorf’s spot, 115optic coherence tomography, 117paediatric residents, 119possibilities and limitations, 120pupillary constriction, 116test performance, 119–120transillumination test, 115uncorrected ametropia, 118uni-lateral astigmatismus, 119uni-lateral spherical ametropia, 118, 119

pupillary light refl execcentric vs. central illumination, 121iris pathology, 120monocular illumination, 121possibilities and limitations, 121–122strabismus diagnostics, 120test performance, 121

CCataract, 2, 3Child Health Promotion Program (CHPP), 96Chronic progressive external ophthalmoplegia (CPEO),

59–60CNS-associated hypertropia, 4Complete third nerve palsy hypertropia, 198–199Congenital cranial dysinnervation disorders (CCDDs), 66

brainstem and cranial nerve development, 77, 78Brown syndrome

comorbidity, 85epidemiologic features, 85incidence and heredity, 86intra-and postoperative fi ndings, 87laterality, 85–86motility fi ndings, 83–85natural course, 87neurodevelopmental disorder, 89–90potential induction, 86–87radiologic fi ndings, 87saccadic eye movements, 85sex distribution, 86

CFEOM, 78–79congenital fourth nerve palsy, 82congenital monocular elevation defi ciency, 87–89congenital ptosis, 81

congenital trochlear palsy, 82Duane retraction syndrome, 79–81HGPPS, 81isolated uni-/bilateral facial palsy, 83vertical retraction syndrome, 88

Congenital esotropia, 2Congenital exotropia, 3Congenital fi brosis of the extraocular muscles (CFEOM),

78–79A-pattern exotropia, 69motor axonal misrouting, 67MRI, 67–68phenotypes, 67

Congenital nystagmusclinical characteristics, 156–157compensatory mechanisms

AHP, 160–162versions and vergence, 160

manifest latent nystagmus (MLN)clinical characteristics, 157–158slow phase, 157

periodic alternating nystagmus (PAN), 158–159sensory defi cits

afferent visual defect, 155causes, 156horizontal eye movement, 154idiopathy, 155phenotypical characteristics, 155

treatmentacupuncture, 164artifi cial divergence surgery, 167–168botulinum toxin-A (Botox), 164head tilt, 167horizontal AHP, 165–167medications, 162–163prisms, 163refractive correction, 162retro-equatorial recession, 168–169spectacles and contact lenses (CL), 162–163surgical principles, 164–165tenotomy procedure, 169vertical AHP, 166–167

Congenital oculomotor (CN3) palsy, 67Congenital pulley heterotopy, 62–63Congenital superior oblique paresis, 20, 21Congenital trochlear (CN4) palsy, 69Convergence insuffi ciency, 3Cycloplegic drug, 127Cyclovertical misalignment, 19

DDiagnostic occlusion, 19Dissociated eye movements

pathogenetic role, 29vergence eye movements, 25dissociated horizontal deviation (DHD), 25–29, 179–180dissociated torsional deviation (DTD)

inverse and direct head tilt, 181strabismus, 180

dissociated vertical deviation (DVD)asymmetric vs. symmetric surgeries, 178bilateral, 175–176

Index 229

hypotropia, nonfi xating eye, 178–179IOOA and V pattern, 176–177SOOA and A pattern, 177–178symmetric, 175

Divergence paralysis esotropia, 64–65Double elevator palsy, 83, 87, 88Duane’s retraction syndrome (DRS), 69, 79–81Duane’s syndrome, 19Dysthyroid optic neuropathy (DON), 214

EEOM surgery, 216–217Esotropia (ET)

DHD, 179–180monofi xation syndrome, 35–36visual cortex mechanisms

binocular input correlation, 50–51binocular visuomotor behavior

development, 42, 43cerebral damage risk factors, 41–42cortical binocular connections, 44–46cytotoxic insult, cerebral fi bers, 42early-onset (infantile) esotropia, 41extrastriate cortex, striate cortex, 46fusional vergence and innate

convergence bias, 44genetic infl uence, cerebral connection, 42high-grade fusion repair, 50inter-ocular suppression, 46–47monocular compartments, striate cortex, 44, 46motion sensitivity and conjugate eye tracking, 44naso-temporal inequalities, cortical suppression, 47persistent nasalward visuomotor bias, 47–50sensorial fusion and stereopsis development, 43strabismic human infant repair, 50

Essential infantile esotropia. See Congenital esotropiaExotropia (XT)

DHD, 179–180infantile esotropia

active divergence mechanism, 26binocular fusion vs. dissociated esotonus, 27, 28clinical signs, 27horizontal strabismus, 28

Expected value of perfect information (EVPI), 99Extraocular muscle (EOM), 196, 197Eye lid surgery

lower lid lengthening, 218, 219upper and lower lid blepharoplasty, 218upper lid lengthening, 217

FFirst Purkinje images, 114–115Fourth nerve palsy hypertropia

bilateral involvement, 201congenital superior oblique palsy, 200inferior oblique weakening procedure, 203superior and inferior rectus recession, 209superior oblique strengthening procedure, 209superior oblique tendon laxity, 201superior rectus contracture, 201surgical plan, 200torsional diplopia, 202–203

GGerman Institute for Quality and Effi ciency in Healthcare

(IQWIG), 99Glucocorticoids (GC), 213Graves orbitopathy

active infl ammatory phasecombined therapy, 213dysthyroid optic neuropathy (DON), 214glucocorticoids (GC), 213immunosuppressive treatments, 213–214orbital radiotherapy (OR), 213sight-threatening corneal breakdown, 214symptoms, 214–215

childhood, 222classifi cation, 211–212clinical assessment

activity signs, 208–209assess severity, 209–211orbital imaging, 211

clinical characteristics, 208diabetes, 222environmental and genetic infl uence

cigarette smoking, 221susceptibility genes, 221–222

euthyroid, 222Graves disease (GD), 207–208inactive disease stages

extraocular muscle surgery, 216–217lid surgery, 217–220orbital decompression, 215–216

management plan, 208, 210thyroid dysfunction, 220

HHealth-related quality of life (HRQoL), 98, 99, 106–108Horizontal gaze palsy with progressive scoliosis

(HGPPS), 81Hypertropia, 3–4, 179

IImmune myopathy, 60–61Incomplete third nerve palsy hypertropia, 199Infantile esotropia (IE)

defi nition and prevalence, 137dissociated eye movements

pathogenetic role, 29vergence eye movements, 25

early vs. late infantile strabismus surgery study (ELISSS)

alignment and fusion, 145binocular vision, 140horizontal angle of strabismus, 140–141methods and results, 139–140postoperative angle of strabismus, 145prospective study, 139random-effects model, 146, 148reoperation rate, 142–143spontaneous reduction, 146–148spontaneous resolution, 146test-retest reliability, 144–145

esotonus vs. convergence, 28exotropia

230 Index

active divergence mechanism, 26binocular fusion vs. dissociated esotonus, 27, 28clinical signs, 27horizontal strabismus, 28

outcome parameters, 138–139pathogenesis, 138sensory/motor etiology, 137–138tonus, 25–26

Infantile-onset image decorrelation, 38–39Inferior oblique (IO) palsy, 71–72Inferior oblique overaction (IOOA), 4, 176–177Infl ammatory myositis, 61Intermittent exotropia, 3, 4

LLevodopa, 133Logistic regression analysis, 143Long-term binocular alignment control system, 14

MManifest latent nystagmus (MLN)

Anderson–Kesternbaum surgery, 158clinical characteristics, 157–158idiopathic infantile nystagmus, 158slow phase, 157

Marcus-Gunn phenomenon, 80–82, 85, 87–89Marlow occlusion, 19Meta-regression model, 143Microstrabismus

number of operationspostoperative angle of strabismus, 145reoperation rate, 142–143test-retest reliability, 144–145

random-eff ects model, 146, 148spontaneous reduction, 146–148spontaneous resolution, 146

Mittendorf ’s spot, 115Möbius syndrome, 83Moebius syndrome, 70Monofi xation syndrome (MFS)

animal models, 37anisometropia, 33bi-fi xation, 36–37causes, 33foveal suppression scotoma elimination, 36manifest strabismus, 35–36micro-esotropia

extrastriate cortex, 52–53neural mechanism, 51neuroanatomic fi ndings, 52, 53stereoscopic threshold, 52subnormal stereopsis and motor fusion, 51

normal and anomalous binocular visionanomalous retinal correspondence (ARC), 34binocular correspondence, 34–35communication, 33cortical adaptation, 34ocular dominance column, 33, 34

normal/near-normal fusional vergence, 37primary MFS, 38–39

Motor skills, 106Muscle length adaptation, 11–13

NNeoplastic myositis, 61Neuroanatomical strabismus

acquired motor neuropathy, 71–72acquired pulley heterotopy, 63–64congenital peripheral neuropathy

congenital cranial dysinnervation disorders (CCDDs), 66

congenital fi brosis of the extraocular muscles (CFEOM), 67–69

congenital oculomotor (CN3) palsy, 67congenital trochlear (CN4) palsy, 69Duane’s retraction syndrome (DRS), 69Moebius syndrome, 70

congenital pulley heterotopy, 62–63divergence paralysis esotropia, 64–65etiology, 59extraocular myopathy

immune myopathy, 60–61infl ammatory myositis, 61neoplastic myositis, 61primary EOM myopathy, 59–60traumatic myopathy, 61–62

vergence and gaze abnormalities, 72Normal correspondence (NRC), 34

OOcular albinism (OA), 155Ocular motility disorders, CCDD

brainstem and cranial nerve development, 77, 78Brown syndrome

comorbidity, 85epidemiologic features, 85incidence and heredity, 86intra-and postoperative fi ndings, 87laterality, 85–86motility fi ndings, 83–85natural course, 87neurodevelopmental disorder, 89–90potential induction, 86–87radiologic fi ndings, 87saccadic eye movements, 85sex distribution, 86

CFEOM, 78–79congenital fourth nerve palsy, 82congenital monocular elevation defi ciency, 87–89congenital ptosis, 81congenital trochlear palsy, 82Duane retraction syndrome, 79–81HGPPS, 81isolated uni-/bilateral facial palsy, 83vertical retraction syndrome, 88

Ocular motor control system, 18Oculocutaneous albinism (OCA), 155Oculomotor palsy, 71Optic neuropathy, 133–134Optical coherence tomography (OCT), 155, 156Orbital radiotherapy (OR), 213

PParalytic strabismus

complete third nerve palsy, 198–199

Index 231

fourth nerve palsy hypertropiabilateral involvement, 201congenital superior oblique palsy, 200inferior oblique weakening procedure, 203superior and inferior rectus recession, 209superior oblique strengthening procedure, 209superior oblique tendon laxity, 201superior rectus contracture, 201surgical plan, 200torsional diplopia, 202–203

incomplete third nerve palsy, 199principles

preoperative assessment, 196–197surgery timing, 195–196surgical treatment, 197–198

sixth nerve palsy hypertropialateral and medial rectus resection, 204medial rectus weakening, sound eye, 204–205

Pediatric strabismusadult strabismus, 7associated conditions, 4esodeviation, 1–2exodeviation, 3hyperdeviation, 3–4surgery rates, 4worldwide incidence and prevalence, 4–7

Periodic alternating nystagmus (PAN), 158–159Pharmacological occlusion, 104Photorefractive keratectomy (PRK), 105Plano lens, 130Posner’s maneuver, 174Posterior partial tenectomy, 190Primary extraocular muscle (EOM) myopathy, 59–60Primary oblique muscle overaction, 14Prism adaptation, 12

QQuality adjusted life years (QALY), 99

RReversed fi xation test (RFT), 179

SSensory esotropia, 2, 3Sensory exotropia, 3Sixth nerve palsy hypertropia

lateral and medial rectus resection, 204medial rectus weakening, sound eye, 204–205

Stereoacuity skills, 106Superior oblique overaction (SOOA), 176–177Superior oblique (SO) surgery

clinical investigation6–0 Polyglactin 910 sutures, 186asymmetric effects, 189enucleation, 186Jampolsky’s recommendations, 187

measurement technique, 188superior rectus muscle recession effects, 186–188suspension technique, 188–189tendon incarceration syndrome, 185

frenulum, 185theoretical eff ect

anterior–posterior axis, 189posterior tenectomy, 190SO anatomy, 190, 191SO tendon, 189, 192threefold function, 189two-dimensional trigonometry, 192

TTh yroid-stimulating hormone receptor (TSHR), 208Traumatic myopathy, 61–62Trochlear palsy, 71TSHR antibodies (TRAb), 208Two-dimensional trigonometry, 192

UUnilateral strabismus changes

cyclovertical deviation, 20, 21head-tilt changes, 21ipsilateral medial and contralateral rectus muscle, 19torsional position, 20vertical recordings, 21

VVergence adaptation, 11, 12Vertical retraction syndrome, 88Visual cortex mechanismsesotropia

binocular input correlation, 50–51binocular visuomotor behavior development, 42, 43cerebral damage risk factors, 41–42cortical binocular connections, 44–46cytotoxic insult, cerebral fi bers, 42early-onset (infantile) esotropia, 41extrastriate cortex, striate cortex, 46fusional vergence and innate convergence bias, 44genetic infl uence, cerebral connection, 42high-grade fusion repair, 50inter-ocular suppression, 46–47monocular compartments, striate cortex, 44, 46motion sensitivity and conjugate eye tracking, 44naso-temporal inequalities, cortical suppression, 47persistent nasalward visuomotor bias, 47–50sensorial fusion and stereopsis development, 43strabismic human infant repair, 50

micro-esotropiaextrastriate cortex, 52–53neural mechanism, 51neuroanatomic fi ndings, 52, 53stereoscopic threshold, 52subnormal stereopsis and motor fusion, 51

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