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Essentials in Ophthalmology Pediatric Ophthalmology,

Neuro-Ophthalmology, Genetics

B. Lorenz M. C. Brodsky
Editors
Essentials in Ophthalmology Glaucoma

G. K. Krieglstein R. N. Weinreb Cataract and Refractive Surgery

Series Editors
Uveitis and Immunological Disorders

Vitreo-retinal Surgery

Medical Retina

Oculoplastics and Orbit

Pediatric Ophthalmology,
Neuro-Ophthalmology, Genetics

Cornea and External Eye Disease

Editors Birgit Lorenz
Michael C. Brodsky

Pediatric
Ophthalmology,
Neuro-
Ophthalmology,
Genetics
Strabismus - New Concepts in
Pathophysiology, Diagnosis,
and Treatment
Series Editors Volume Editors
Gnter K. Krieglstein, MD Birgit Lorenz, MD
Professor and Chairman Professor of Ophthalmology
Department of Ophthalmology Klinik und Poliklinik fr
University of Cologne Augenheilkunde
Joseph-Stelzmann-Strae 9 Justus-Liebig-University
50931 Kln UKGM GmbH Giessen Campus
Germany Friedrichstrae 18
35392 Giessen
Robert N. Weinreb, MD Germany
Professor and Director
Hamilton Glaucoma Center Michael C. Brodsky, MD
Department of Ophthalmology Professor of Ophthalmology and Neurology
University of California at San Diego Mayo Clinic
9500 Gilman Drive Department of Ophthalmology
La Jolla, CA 92093-0946 200 First Street SW
USA Rochester, MN 55905
USA

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

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 Foreword
The 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 eld
of ophthalmology. This timely transfer of advancements
for the best possible care of our eye patients has proven to
be eective. The initial working hypothesis of providing
new knowledge immediately following publication in the
peer-reviewed journal and not waiting for the textbook
appears to be highly workable.
We are now in the third cycle of the Essentials in
Ophthalmology series, having been encouraged by read-
ership acceptance of the rst two series, each of eight
volumes. This 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. There are many
good reasons to continue and still improve the dissemina-
tion of this didactic and clinically relevant information.
G.K. Krieglstein
R.N. Weinreb
Series Editors
 Preface
The eld of strabismology has long suered 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 scientic
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 unied
philosophy of strabismus that integrates new concepts of
pathogenesis into the clinic.
This book provides a compendium of chapters that
highlight new ideas in the 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 nds
this edition both stimulating and enlightening.
Birgit Lorenz
Michael C. Brodsky
 Contents

Chapter 1 2.1.3 Muscle Length Adaptation . . . . . . . . . . . . . 12

Epidemiology of Pediatric Strabismus 2.2 Modeling the Binocular
Amy E. Green-Simms and Brian G. Mohney Alignment Control System. . . . . . . . . . . . . . 13
2.2.1 Breakdown of the Binocular
1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Alignment Control System. . . . . . . . . . . . . . 14
1.2 Forms of Pediatric Strabismus . . . . . . . . . . 1 2.2.2 Clarication of Unanswered
1.2.1 Esodeviations . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Questions Regarding the
1.2.1.1 Congenital Esotropia . . . . . . . . . . . . . . . . . . . 2 Long-Term Binocular Alignment
1.2.1.2 Accommodative Esotropia. . . . . . . . . . . . . . 2 Control System. . . . . . . . . . . . . . . . . . . . . . . . . 14
1.2.1.3 Acquired Nonaccommodative 2.2.3 Changes in Strabismus as
Esotropia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Bilateral Phenomena . . . . . . . . . . . . . . . . . . . 14
1.2.1.4 Abnormal Central Nervous System 2.2.4 Changes in Basic Muscle Length . . . . . . . . 15
Esotropia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.2.5 Version Stimulation and
1.2.1.5 Sensory Esotropia . . . . . . . . . . . . . . . . . . . . . . 2 Vergence Stimulation . . . . . . . . . . . . . . . . . . 16
1.2.2 Exodeviations . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.2.6 Evidence Against the Final
1.2.2.1 Intermittent Exotropia. . . . . . . . . . . . . . . . . . 3 Common Pathway. . . . . . . . . . . . . . . . . . . . . 17
1.2.2.2 Congenital Exotropia . . . . . . . . . . . . . . . . . . . 3 2.3 Changes in Strabismus . . . . . . . . . . . . . . . . . 18
1.2.2.3 Convergence Insuciency. . . . . . . . . . . . . . 3 2.3.1 Diagnostic Occlusion: And the
1.2.2.4 Abnormal Central Nervous System Hazard of Prolonged Occlusion . . . . . . . . . 19
Exotropia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.3.2 Unilateral Changes in Strabismus . . . . . . . 19
1.2.2.5 Sensory Exotropia . . . . . . . . . . . . . . . . . . . . . . 3 2.3.2.1 Supporting Evidence for Bilateral
1.2.3 Hyperdeviations . . . . . . . . . . . . . . . . . . . . . . . 3 Feedback Control of Muscle Lengths. . . . 19
1.3 Strabismus and Associated 2.4 Applications of Bilateral Feedback
Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Control to Clinical Practice and
1.4 Changing Trends in Strabismus to Future Research . . . . . . . . . . . . . . . . . . . . . 21
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . 4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
1.4.1 Changes in Strabismus Prevalence . . . . . . 4
1.4.2 Changes in Strabismus Surgery Rates . . . 4 Chapter 3
1.5 Worldwide Incidence and Prevalence A Dissociated Pathogenesis
of Childhood Strabismus . . . . . . . . . . . . . . . 4 for Infantile Esotropia
1.6 Incidence of Adult Strabismus . . . . . . . . . . 7 Michael C. Brodsky
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.1 Dissociated Eye Movements . . . . . . . . . . . . 25
Chapter 2 3.2 Tonus and its relationship
Changes in Strabismus Over Time: The Roles of to infantile esotropia . . . . . . . . . . . . . . . . . . . 25
Vergence Tonus and Muscle Length Adaptation 3.3 Esotropia and Exotropia as
David L. Guyton a Continuum . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.4 Distinguishing Esotonus
2.1 Binocular Alignment System. . . . . . . . . . . . 11 from Convergence . . . . . . . . . . . . . . . . . . . . . 28
2.1.1 Long-Term Maintenance 3.5 Pathogenetic Role of Dissociated
of Binocular Alignment . . . . . . . . . . . . . . . . . 11 Eye Movements in Infantile Esotropia . . . 29
2.1.2 Vergence Adaptation. . . . . . . . . . . . . . . . . . . 12 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
x Contents

Chapter 4 5.1.10 Binocular Connections Join

The Monoxation Syndrome: New Monocular Compartments Within
Considerations on Pathophysiology Area V1 (Striate Cortex) . . . . . . . . . . . . . . . . . 44
Kyle Arnoldi 5.1.11 Too Few Cortical Binocular
Connections in Strabismic Primate. . . . . . 46
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 5.1.12 Projections from Striate Cortex
4.2 Normal and Anomalous (Area V1) to Extrastriate Cortex
Binocular Vision . . . . . . . . . . . . . . . . . . . . . . . . 33 (Areas MT/MST) . . . . . . . . . . . . . . . . . . . . . . . . 46
4.2.1 Binocular Correspondence: 5.1.13 Inter-Ocular Suppression
Anomalous, Normal, or Both?. . . . . . . . . . . 34 Rather than Cooperation
4.3 MFS with Manifest Strabismus . . . . . . . . . . 35 in Strabismic Cortex . . . . . . . . . . . . . . . . . . . . 46
4.3.1 Esotropia is the Most Common 5.1.14 Naso-Temporal Inequalities
form of MFS. . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 of Cortical Suppression . . . . . . . . . . . . . . . . . 47
4.3.2 Esotropia Allows for Better 5.1.15 Persistent Nasalward
Binocular Vision . . . . . . . . . . . . . . . . . . . . . . . . 35 Visuomotor Biases in Strabismic
4.3.3 Esotropia is the Most Stable Form. . . . . . . 36 Primate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4.4 Repairing and Producing MFS . . . . . . . . . . 36 5.1.16 Repair of Strabismic Human
4.4.1 Animal Models for the Study Infants: The Historical Controversy . . . . . . 50
of MFS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 5.1.17 Repair of High-grade Fusion
4.5 Primary MFS (Sensory Signs of is Possible. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Infantile-Onset Image Decorrelation) . . . 38 5.1.18 Timely Restoraion of Correclated
4.5.1 Motor Signs of Infantile-Onset Binocular Input: The Key to Repair . . . . . . 50
Image Decorrelation . . . . . . . . . . . . . . . . . . . 38 5.2 Visual Cortex Mechanisms
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 in Micro-Esotropia (Monoxation
Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
5.2.1 Neuroanatomic Findings in
Chapter 5 Area V1 of Micro-Esotropic Primates . . . . 52
Visual Cortex Mechanisms of Strabismus:
5.2.2 Extrastriate Cortex in
Development and Maldevelopment
Micro-Esotropa. . . . . . . . . . . . . . . . . . . . . . . . . 52
Lawrence Tychsen References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
5.1 Esotropia as the Major Type Chapter 6
of Developmental Strabismus . . . . . . . . . . 41 Neuroanatomical Strabismus
5.1.1 Early-Onset (Infantile) Esotropia . . . . . . . . 41
Joseph L. Demer
5.1.2 Early Cerebral Damage as
the Major Risk Factor . . . . . . . . . . . . . . . . . . . 41 6.1 General Etiologies of Strabismus. . . . . . . . 59
5.1.3 Cytotoxic Insults to Cerebral Fibers. . . . . . 42 6.2 Extraocular Myopathy . . . . . . . . . . . . . . . . . . 59
5.1.4 Genetic Inuences on 6.2.1 Primary EOM Myopathy . . . . . . . . . . . . . . . . 59
Formation of Cerebral Connections . . . . . 42 6.2.2 Immune Myopathy . . . . . . . . . . . . . . . . . . . . . 60
5.1.5 Development of Binocular 6.2.3 Inammatory Myositis. . . . . . . . . . . . . . . . . . 61
Visuomotor Behavior 6.2.4 Neoplastic Myositis. . . . . . . . . . . . . . . . . . . . . 61
in Normal Infants. . . . . . . . . . . . . . . . . . . . . . . 42 6.2.5 Traumatic Myopathy . . . . . . . . . . . . . . . . . . . 61
5.1.6 Development of Sensorial 6.3 Congenital Pulley Heterotopy . . . . . . . . . . 62
Fusion and Stereopsis . . . . . . . . . . . . . . . . . . 43 6.4 Acquired Pulley Heterotopy . . . . . . . . . . . . 63
5.1.7 Development of Fusional 6.5 Divergence Paralysis Esotropia . . . . . . . . 64
Vergence and an Innate 6.5.1 Vertical Strabismus Due to
Convergence Bias . . . . . . . . . . . . . . . . . . . . . . 44 Sagging Eye Syndrome . . . . . . . . . . . . . . . . . 65
5.1.8 Development of Motion 6.5.2 Postsurgical and Traumatic Pulley
Sensitivity and Conjugate Heterotopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Eye Tracking (Pursuit/OKN) . . . . . . . . . . . . . 44 6.5.3 Axial High Myopia. . . . . . . . . . . . . . . . . . . . . . 65
5.1.9 Development and 6.6 Congenital Peripheral Neuropathy:
Maldevelopment of Cortical The Congenital Cranial
Binocular Connections . . . . . . . . . . . . . . . . . 44 Dysinnervation Disorders (CCDDs) . . . . . . 66
 Contents xi

6.6.1 Congenital Oculomotor (CN3) Palsy. . . . . 67 Chapter 8

6.6.2 Congenital Fibrosis of the The Value of Screening for Amblyopia Revisited
Extraocular Muscles (CFEOM) . . . . . . . . . . . 67 Jill Carlton and Carolyn Czoski-Murray
6.6.3 Congenital Trochlear (CN4) Palsy. . . . . . . . 69
6.6.4 Duanes Retraction 8.1 Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Syndrome (DRS). . . . . . . . . . . . . . . . . . . . . . . . 69 8.2 What Is Screening? . . . . . . . . . . . . . . . . . . . . . 96
6.6.5 Moebius Syndrome . . . . . . . . . . . . . . . . . . . . 70 8.2.1 Screening for Amblyopia,
6.7 Acquired Motor Neuropathy. . . . . . . . . . . . 71 Strabismus, and/or
6.7.1 Oculomotor Palsy . . . . . . . . . . . . . . . . . . . . . . 71 Refractive Errors. . . . . . . . . . . . . . . . . . . . . . . . 96
6.7.2 Trochlear Palsy . . . . . . . . . . . . . . . . . . . . . . . . . 71 8.2.1.1 Screening for Amblyopia . . . . . . . . . . . . . . . 97
6.7.3 Abducens Palsy . . . . . . . . . . . . . . . . . . . . . . . . 71 8.2.1.2 Screening for Strabismus . . . . . . . . . . . . . . . 97
6.7.4 Inferior Oblique (IO) Palsy . . . . . . . . . . . . . . 71 8.2.1.3 Screening for Refractive Error . . . . . . . . . . . 97
6.8 Central Abnormalities 8.2.1.4 Screening for Other Ocular Conditions . . 97
of Vergence and Gaze . . . . . . . . . . . . . . . . . . 72 8.2.2 Dierence Between a Screening
6.8.1 Developmental Esotropia and Diagnostic Test . . . . . . . . . . . . . . . . . . . . 97
and Exotropia . . . . . . . . . . . . . . . . . . . . . . . . . . 72 8.2.3 Justication for Screening for
6.8.2 Cerebellar Disease. . . . . . . . . . . . . . . . . . . . . . 72 Amblyopia and/or Strabismus . . . . . . . . . . 98
6.8.3 Horizontal Gaze Palsy and 8.2.4 Recent Reports Examining
Progressive Scoliosis . . . . . . . . . . . . . . . . . . . 72 Pre-School Vision Screening . . . . . . . . . . . . 98
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 8.3 Screening Tests for Amblyopia,
Strabismus, and/or
Refractive Error. . . . . . . . . . . . . . . . . . . . . . . . . 100
Chapter 7 8.3.1 Vision Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Congenital Cranial Dysinnervation Disorders: 8.3.2 Cover-Uncover Test. . . . . . . . . . . . . . . . . . . . . 100
Facts and Perspectives to Understand Ocular 8.3.3 Stereoacuity . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Motility Disorders 8.3.4 Photoscreening and/or
Antje Neugebauer and Julia Fricke Autorefraction . . . . . . . . . . . . . . . . . . . . . . . . . 101
8.3.5 What to Do with Those Who
7.1 Congenital Cranial Dysinnervation Are Unable to Perform
Disorders: Facts About Ocular Screening Tests?. . . . . . . . . . . . . . . . . . . . . . . . 102
Motility Disorders . . . . . . . . . . . . . . . . . . . . . . 77 8.3.6 Who Should Administer
7.1.1 The Concept of CCDDs: the Screening Program? . . . . . . . . . . . . . . . . 102
Ocular Motility Disorders as 8.4 Treatment of Amblyopia. . . . . . . . . . . . . . . . 103
Neurodevelopmental Defects . . . . . . . . . . 77 8.4.1 Type of Treatment . . . . . . . . . . . . . . . . . . . . . . 103
7.1.1.1 Brainstem and Cranial 8.4.2 Refractive Adaptation . . . . . . . . . . . . . . . . . . 103
Nerve Development. . . . . . . . . . . . . . . . . . . . 78 8.4.3 Conventional Occlusion . . . . . . . . . . . . . . . . 104
7.1.1.2 Single Disorders 8.4.4 Pharmacological Occlusion . . . . . . . . . . . . . 104
Representing CCDDs . . . . . . . . . . . . . . . . . . . 78 8.4.5 Optical Penalization . . . . . . . . . . . . . . . . . . . . 104
7.1.1.3 Disorders Understood as CCDDs . . . . . . . . 81 8.4.6 Eective Treatment of
7.2 Congenital Cranial Dysinnervation Amblyopia in Older Children
Disorders: Perspectives to Understand (Over the Age of 7 Years). . . . . . . . . . . . . . . . 104
Ocular Motility Disorders . . . . . . . . . . . . . . . 83 8.4.7 Treatment Compliance . . . . . . . . . . . . . . . . . 105
7.2.1 Congenital Ocular 8.4.8 Other Treatment Options
Elevation Deciencies: A for Amblyopia. . . . . . . . . . . . . . . . . . . . . . . . . . 105
Neurodevelopmental View . . . . . . . . . . . . . 83 8.4.9 Recurrence of Amblyopia
7.2.1.1 Brown Syndrome. . . . . . . . . . . . . . . . . . . . . . . 83 Following Therapy . . . . . . . . . . . . . . . . . . . . . 105
7.2.1.2 Congenital Monocular 8.5 Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Elevation Deciency and 8.5.1 The Impact of Amblyopia
Vertical Retraction Syndrome . . . . . . . . . . . 87 Upon HRQoL. . . . . . . . . . . . . . . . . . . . . . . . . . . 106
7.2.2 A Model of some Congenital 8.5.2 Stereoacuity and Motor Skills
Elevation Deciencies as in Children with Amblyopia. . . . . . . . . . . . . 106
Neurodevelopmental Diseases . . . . . . . . . 89 8.5.3 Reading Speed and Reading
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Ability in Children with Amblyopia. . . . . . 106
xii Contents

8.5.4 Impact of Amblyopia 10.2.4 Pharmacological Therapy

Upon Education. . . . . . . . . . . . . . . . . . . . . . . . 106 Combined with a Plano Lens. . . . . . . . . . . . 130
8.5.5 Emotional Well-Being and 10.3 Other Treatment Issues . . . . . . . . . . . . . . . . . 131
Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 10.3.1 Bilateral Refractive Amblyopia . . . . . . . . . . 131
8.5.6 The Impact of Strabismus 10.3.2 Age Eect. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Upon HRQoL. . . . . . . . . . . . . . . . . . . . . . . . . . . 107 10.3.3 Maintenance Therapy . . . . . . . . . . . . . . . . . . 131
8.5.7 Critique of HRQoL Issues 10.3.4 Long-Term Persistence of
in Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . 108 an Amblyopia Treatment Benet. . . . . . . . 132
8.5.8 The Impact of the Condition 10.4 Other Treatments . . . . . . . . . . . . . . . . . . . . . . 132
or the Impact of Treatment? . . . . . . . . . . . . 108 10.4.1 Filters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 10.4.2 Levodopa/Carbidopa
Adjunctive Therapy . . . . . . . . . . . . . . . . . . . . 133
Chapter 9 10.5 Controversy. . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
The Brckner Test Revisited 10.5.1 Optic Neuropathy Rather than
Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Michael Grf
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
9.1 Amblyopia and Amblyogenic
Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Chapter 11
Best Age for Surgery for Infantile Esotropia:
9.1.1 Early Detection of Amblyopia. . . . . . . . . . . 113
Lessons from the Early vs. Late Infantile
9.1.2 Brckners Original Description . . . . . . . . . 114
Strabismus Surgery Study
9.2 Corneal Light Reexes
H. J. Simonsz and G. H. Kolling
(First Purkinje Images) . . . . . . . . . . . . . . . . . . 114
9.2.1 Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
9.2.2 Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 11.1.1 Denition and Prevalence . . . . . . . . . . . . . . 137
9.2.3 Shortcomings and Pitfalls . . . . . . . . . . . . . . 115 11.1.2 Sensory or Motor Etiology . . . . . . . . . . . . . . 137
9.3 Fundus Red Reex (Brckner Reex) . . . . 115 11.1.3 Pathogenesis: Lack of
9.3.1 Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 Binocular Horizontal Connections
9.3.2 Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 in the Visual Cortex. . . . . . . . . . . . . . . . . . . . . 138
9.3.3 Possibilities and Limitations . . . . . . . . . . . . 120 11.1.4 History. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
9.4 Pupillary Light Reexes. . . . . . . . . . . . . . . . . 120 11.1.5 Outcome Parameters . . . . . . . . . . . . . . . . . . . 138
9.4.1 Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 11.2 Outcome of Surgery in the ELISSS. . . . . . . 139
9.4.2 Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 11.2.1 Reasons for the ELISSS. . . . . . . . . . . . . . . . . . 139
9.4.3 Possibilities and Limitations . . . . . . . . . . . . 121 11.2.2 Summarized Methods of the ELISSS. . . . . 139
9.5 Eye Movements with Alternating 11.2.3 Summarized Results of the ELISSS . . . . . . 140
Illumination of the Pupils . . . . . . . . . . . . . . . 122 11.2.4 Binocular Vision at Age Six. . . . . . . . . . . . . . 140
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 11.2.5 Horizontal Angle of
Strabismus at Age Six . . . . . . . . . . . . . . . . . . 140
Chapter 10 11.2.6 Alignment is Associated
Amblyopia Treatment 2009 with Binocular Vision . . . . . . . . . . . . . . . . . . . 141
Michael X. Repka 11.3 Number of Operations and
Spontaneous Reduction into
10.1 Amblyopia Treatment 2009 . . . . . . . . . . . . . 125 Microstrabismus Without Surgery. . . . . . . 142
10.1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 11.3.1 The Number of Operations Per Child and
10.1.2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . 125 the Reoperation Rate in the ELISSS. . . . . . 142
10.1.3 Clinical Features of Amblyopia. . . . . . . . . . 126 11.3.2 Reported Reoperation Rates . . . . . . . . . . . . 142
10.1.4 Diagnosis of Amblyopia . . . . . . . . . . . . . . . . 126 11.3.3 Test-Retest Reliability Studies . . . . . . . . . . . 144
10.1.5 Natural History . . . . . . . . . . . . . . . . . . . . . . . . . 127 11.3.4 Relation Between the Postoperative
10.2 Amblyopia Management . . . . . . . . . . . . . . . 127 Angle of Strabismus and the
10.2.1 Refractive Correction . . . . . . . . . . . . . . . . . . . 127 Reoperation Rate. . . . . . . . . . . . . . . . . . . . . . . 145
10.2.2 Occlusion by Patching. . . . . . . . . . . . . . . . . . 128 11.3.5 Scheduled for Surgery, but no
10.2.3 Pharmacological Treatment Surgery Done at the End of the
with Atropine . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Study at the Age of Six Years . . . . . . . . . . . . 145
 Contents xiii

11.3.6 Spontaneous Reduction 12.3.6.2 Management of Vertical AHP . . . . . . . . . . . 166

of the Angle. . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 12.3.6.3 Management of Head Tilt. . . . . . . . . . . . . . . 167
11.3.7 Predictors of Spontaneous 12.3.6.4 Articial Divergence Surgery . . . . . . . . . . . 167
Reduction into Microstrabismus . . . . . . . . 146 12.3.6.5 Surgery to Decrease the
11.3.8 Random-Eects Model Intensity of Nystagmus . . . . . . . . . . . . . . . . . 168
Predicting the Angle and References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
its Variation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Chapter 13
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Surgical Management of Dissociated Deviations
Susana Gamio
Chapter 12
Management of Congenital Nystagmus 13.1 Dissociated Deviations . . . . . . . . . . . . . . . . . 174
with and without Strabismus 13.2 Surgical Alternatives to Treat
Anil Kumar, Frank A. Proudlock, and Irene Gottlob Patients with DVD . . . . . . . . . . . . . . . . . . . . . . 175
13.2.1 Symmetric DVD with Good Bilateral
12.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 Visual Acuity, with No Oblique
12.1.1 Congenital Nystagmus with Muscles Dysfunction . . . . . . . . . . . . . . . . . . . 175
and Without Sensory Decits . . . . . . . . . . . 154 13.2.2 Bilateral DVD with Deep
12.1.1.1 The Clinical Characteristics Unilateral Amblyopia . . . . . . . . . . . . . . . . . . . 175
of Congenital Nystagmus. . . . . . . . . . . . . . . 156 13.2.3 DVD with Inferior Oblique
12.1.2 Manifest Latent Nystagmus (MLN) . . . . . . 157 Overaction (IOOA) and V Pattern . . . . . . . . 176
12.1.2.1 Clinical Characteristics 13.2.4 DVD with Superior Oblique
of Manifest Latent Nystagmus (MLN). . . . 157 Overaction (SOOA) and A Pattern . . . . . . . 177
12.1.3 Congenital Periodic Alternating 13.2.5 Symmetric vs. Asymmetric
Nystagmus (PAN). . . . . . . . . . . . . . . . . . . . . . . 158 Surgeries for DVD . . . . . . . . . . . . . . . . . . . . . . 178
12.1.3.1 Clinical characteristics 13.2.6 DVD with Hypotropia of the
of congenital periodic Nonxating Eye . . . . . . . . . . . . . . . . . . . . . . . . 178
alternating nystagmus . . . . . . . . . . . . . . . . . 159 13.3 Dissociated Horizontal Deviation . . . . . . . 179
12.2 Compensatory Mechanisms . . . . . . . . . . . . 160 13.4 Dissociated Torsional Deviation.
12.2.1 Dampening by Versions . . . . . . . . . . . . . . . . 160 Head tilts in patients with
12.2.2 Dampening by Vergence . . . . . . . . . . . . . . . 160 Dissociated Strabismus . . . . . . . . . . . . . . . . . 180
12.2.3 Anomalous Head Posture (AHP) . . . . . . . . 160 13.5 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
12.2.3.4 Measurement of AHP. . . . . . . . . . . . . . . . . . . 160 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
12.2.3.5 Eect of Monocular and
Binocular Visual Acuity Chapter 14
Testing on AHP. . . . . . . . . . . . . . . . . . . . . . . . . 161 Surgical Implications of the
12.2.3.6 Testing AHP at Near . . . . . . . . . . . . . . . . . . . . 162 Superior Oblique Frenulum
12.2.3.7 The Eect of Straightening Burton J. Kushner and Megumi Iizuka
the Head in Patients with AHP . . . . . . . . . . 162
12.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 14.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
12.3.1 Optical Treatment . . . . . . . . . . . . . . . . . . . . . . 162 14.2 Clinical and Theoretical
12.3.1.1 Refractive Correction . . . . . . . . . . . . . . . . . . . 162 Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . 186
12.3.1.2 Spectacles and Contact 14.2.1 The Eect of Superior Rectus Muscle
Lenses (CL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Recession on the Location of the
12.3.1.3 Prisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 Superior Oblique Tendon Before
12.3.1.4 Low Visual Aids. . . . . . . . . . . . . . . . . . . . . . . . . 163 and After Cutting the Frenulum. . . . . . . . . 186
12.3.2 Medication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 14.2.2 The Eect of the Frenulum
12.3.3 Acupuncture. . . . . . . . . . . . . . . . . . . . . . . . . . . 164 on Superior Oblique Recession
12.3.4 Biofeedback . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 Using a Suspension Technique. . . . . . . . . . 188
12.3.5 Botulinum Toxin-A (Botox). . . . . . . . . . . . . . 164 14.2.3 The Theoretical Eect of the Superior
12.3.6 Surgical Treatment of Congenital Oblique Frenulum on the Posterior Partial
Nystagmus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 Tenectomy of the Superior Oblique . . . . . . . 189
12.3.6.1 Management of Horizontal AHP . . . . . . . . 165 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
xiv Contents

Chapter 15 16.2 Natural History . . . . . . . . . . . . . . . . . . . . . . . . . 212

Pearls and Pitfalls in Surgical 16.3 Treatment of GO . . . . . . . . . . . . . . . . . . . . . . . 213
Management of Paralytic Strabismus 16.3.1 Active Inammatory Phase . . . . . . . . . . . . . 213
Seyhan B. zkan 16.3.1.1 Glucocorticoid Treatment . . . . . . . . . . . . . . 213
16.3.1.2 Orbital Radiotherapy . . . . . . . . . . . . . . . . . . . 213
15.1 General Principles of Surgical 16.3.1.3 Combined Therapy: Glucocorticoids
Treatment in Paralytic and Orbital Radiotherapy. . . . . . . . . . . . . . . 213
Strabismus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 16.3.1.4 Other Immunosuppressive Treatments
15.1.1 Aims of Treatment. . . . . . . . . . . . . . . . . . . . . . 195 and New Developments . . . . . . . . . . . . . . . . 213
15.1.2 Timing of Surgery . . . . . . . . . . . . . . . . . . . . . . 195 16.3.1.5 Therapy of Dysthyroid Optic
15.1.3 Preoperative Assessment . . . . . . . . . . . . . . . 196 Neuropathy [DON] and
15.1.4 Methods of Surgical Treatment . . . . . . . . . 197 Sight-Threatening Corneal
15.2 Third Nerve Palsy. . . . . . . . . . . . . . . . . . . . . . . 198 Breakdown . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
15.2.1 Complete Third Nerve Palsy . . . . . . . . . . . . 198 16.3.1.6 Other Simple Measures that
15.2.2 Incomplete Third Nerve Palsy . . . . . . . . . . . 199 may Alleviate Symptoms . . . . . . . . . . . . . . . 214
15.3 Fourth Nerve Palsy . . . . . . . . . . . . . . . . . . . . . 200 16.3.2 Inactive Disease Stages. . . . . . . . . . . . . . . . . 215
15.4 Sixth Nerve Palsy . . . . . . . . . . . . . . . . . . . . . . . 204 16.3.2.1 Orbital Decompression . . . . . . . . . . . . . . . . . 215
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 16.3.2.2 Extraocular Muscle Surgery. . . . . . . . . . . . . 216
16.3.2.3 Lid Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Chapter 16
Modern Treatment Concepts 16.4 Thyroid Dysfunction and GO. . . . . . . . . . . . 220
in Graves Disease 16.4.1 Association Between Treatment of
Hyperthyroidism and Course of GO . . . . . 220
Anja Eckstein and Joachim Esser
16.4.2 Relationship Between
16.1 Graves Orbitopathy (GO): TSH-Receptor-Antibody (TRAb)
Pathogenesis and Clinical Signs. . . . . . . . . 207 Levels and Orbitopathy. . . . . . . . . . . . . . . . . 220
16.1.1 Graves Orbitopathy is Part of a Systemic 16.5 Environmental and Genetic
Disease: Graves Disease (GD) . . . . . . . . . . . 207 Inuence on the Course of GO . . . . . . . . . . 221
16.1.2 Graves OrbitopathyClinical Signs . . . . . . 208 16.5.1 Relationship Between Cigarette
16.1.2.1 Clinical Changes Result in Smoking and Graves Orbitopathy. . . . . . . 221
Typical Symptoms. . . . . . . . . . . . . . . . . . . . . . 208 16.5.2 Genetic Susceptibility . . . . . . . . . . . . . . . . . . 221
16.1.3 Clinical Examination of GO . . . . . . . . . . . . . 208 16.6 Special Situations . . . . . . . . . . . . . . . . . . . . . . 222
16.1.3.1 Signs of Activity . . . . . . . . . . . . . . . . . . . . . . . . 208 16.6.1 Euthyroid GO . . . . . . . . . . . . . . . . . . . . . . . . . . 222
16.1.3.2 Assessing Severity of GO . . . . . . . . . . . . . . . 209 16.6.2 Childhood GO. . . . . . . . . . . . . . . . . . . . . . . . . . 222
16.1.3.3 Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 16.6.3 GO and Diabetes . . . . . . . . . . . . . . . . . . . . . . . 222
16.1.4 Classication of GO. . . . . . . . . . . . . . . . . . . . . 211 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
 Contributors

Kyle Arnoldi Susana Gamio

Ross Eye Institute Gallo 1330, Ricardo Gutierrez Childrens Hospital,
Department of Ophthalmology, Matienzo 1731 First Floor E,
University at Bualo, Ross Eye Institute, Buenos Aires, Captial Fedral 1426,
1176 Main Street, NY, 14209, USA Argentina, South America

Michael C. Brodsky Irene Gottlob

Departments of Ophthalmology and Neurology, Department of Ophthalmology,
Mayo Clinic 200 First Street, SW Rochester, Ricardo Gutirrez Childrens Hospital, Buenos Aires,
MN 55905, USA Argentina

Jill Carlton
Health Economics and Decision Science, Michael Grf
CHARR, University of Sheeld, Regent Court, Department of Ophthalmology, Justus-Liebig-University
30 Regent Street, Sheeld, Giessen, Giessen Campus, Friedrichstrae 18, 35385
S1 4DA, UK Giessen, Germany

Carolyn Czoski-Murray Amy E. Greenberg

Leeds Institute of Health Sciences, Department of Ophthalmology, Mayo Clinic,
University of Leeds, 200 First Street Southwest, Rochester, MN 55905, USA
Room 1.26, 6 Charles Thackrah Building,
101 Clarendon Road,
David L. Guyton
Leeds LS2 9LJ, UK
The Krieger Childrens Eye Center at the Wilmer Institute,
The Johns Hopkins University School of Medicine,
Joseph L. Demer
Baltimore, MD 21287-9028, USA
Jules Stein Eye Institute,
100 Stein Plaza, UCLA,
Box 957002, Megumi Iizuka
Los Angeles, CA 90095-7002, USA University of Toronto, St. Michaels Hospital,
61 Queen Street East, 8th Floor, Care of the Eye Clinic,
Anja Eckstein Toronto, ON, Canada M5C 2T2
University Eye Hospital, Hufelandstrae 55, 45122 Essen,
Germany
Gerold H. Kolling
Marinus J.C. Eijkemans Department of Ophthalmology, University Clinic
Department of Public Health, Erasmus Medical Center, Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg,
PO Box 2040, 3000 CA, Rotterdam, Germany
The Netherlands
A. S. Anil Kumar
Julia Fricke Department of Ophthalmology,
Department of Ophthalmology, Kerpener Strae 62, University of Leicester,
50937 Kln, Germany UK
xvi Contributors

Burton J. Kushner Frank A. Proudlock

Department of Ophthalmology and Visual Sciences, Department of Ophthalmology,
2870 University Avenue, Suite 206, Madison, WI 53705, Ricardo Gutirrez Childrens Hospital, Buenos Aires,
USA Argentina

Birgit Lorenz Michael X. Repka

Department of Ophthalmology,
Justus-Liebig-University Giessen
Giessen Campus
Friedrichstrae 18, 35392 Giessen
Germany
Brian G. Mohney
Department of Ophthalmology, Mayo Clinic,
200 First Street Southwest, Rochester, MN 55905, USA
Antje Neugebauer
Department of Ophthalmology,
Kerpener Strae 62, 50937 Kln, Germany
Johns Hopkins University School of Medicine,
Wilmer 233, Johns Hopkins Hospital,
600 North Wolfe Street, Baltimore, MD 21287-9028, USA
Huibert J. Simonsz
Department of Ophthalmology, Erasmus Medical Center,
PO Box 2040, 3000 CA Rotterdam, The Netherlands
Lawrence Tychsen
St Louis Childrens Hospital at Washington University
Medical Center, 1 Childrens Place, St Louis, MO 63110,
USA

Seyhan B. zkan
Guzelhisar Mah. 35. sok. No: 8/A, 09010 Aydin,
Turkey
 Chapter 1
Epidemiology of Pediatric Strabismus
Amy E. Green-Simms and Brian G. Mohney
Core Messages
Recognition and diagnosis of the individual
forms of childhood strabismus are important for
the best preservation of visual function.
Esotropia is the most common form of pediatric
ocular deviation in the West, whereas exotropia
predominates in the East.
Accommodative esotropia is the most prevalent
form of strabismus in the West, comprising half
of all esodeviations.
Congenital, or infantile, esotropia accounts for
less than 10% of all pediatric esotropia, a gure
much smaller than once widely believed.
Intermittent exotropia is the second most com-
mon form of childhood strabismus in the West
1.1 Introduction
Strabismus, or squint, is a disorder of ocular alignment. This
overarching term may be further characterized by the direc-
tion of the misalignment: the prex eso- describes an inward
ocular deviation; exo-, an outward deviation; and hyper-, a
vertical deviation. Descriptive suxes include -tropia, a
manifest deviation in which fusional control is not present,
and -phoria, a latent deviation that is controlled by fusion.
Strabismus detection, classication, 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. This strong connec-
tion with amblyopia dierentiates 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.
This chapter will review recent data on the epidemiol-
ogy of pediatric strabismus. The information will focus
1
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 conrms a more
stable rate.
solely on tropic deviations rather than phorias and will
encompass worldwide incidence and prevalence as well
as clinical characteristics of the various strabismus
subtypes.
1.2 Forms of Pediatric Strabismus
1.2.1 Esodeviations
Esodeviations are characterized by an intermittent or
constant inward deviation of the eye or eyes (Fig. 1.1).
Esotropia comprises approximately 60% of all strabismus
in the West [1] whereas only about 30% in the East [2]. In
the United States, children are diagnosed with esotropia
at a mean age of 3.1 years [3], and 90% of esodeviations
occur by 5 years of age [4]. Esotropia is more commonly
associated with amblyopia than either exo- or hypertro-
pia, occurring in one of three esotropic children vs. 1 of
12 exo- or hypertropic children [5]. There is no signi-
cant gender predilection among any of the following sub-
types of childhood esotropia.
 2 1 Epidemiology of Pediatric Strabismus
1 whose deviation develops after 6 months of age and is not
Fig. 1.1 A child with esotropia
1.2.1.1 Congenital Esotropia
Congenital esotropia, also known as infantile or essential
infantile esotropia, is generally dened as a neurologically
intact child with a constant nonaccommodative esotropia
that develops by 6 months of age. This term is often 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 after wearing hyper-
opic spectacles full time for at least 3 weeks. Patients can
further be classied 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].
This form of esodeviation has been reported to occur in
1 in 92 children [3].
1.2.1.3 Acquired Nonaccommodative
Esotropia
Acquired nonaccommodative esotropia denes children
associated with accommodative eort. This 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 classied under central nervous system
(CNS) defects regardless of the age at onset or form of
esotropia. The most commonly associated conditions
include cerebral palsy, developmental delay, Down 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.
This form of esodeviation is commonly associated with
anisometropic amblyopia as well as with disorders of
deprivation such as cataract, corneal scarring, and retinal
or optic nerve disorders [3].
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 signicantly higher than in chil-
dren with either exotropia or hypertropia.

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 often
in girls compared with boys [10].
1.2.2.2 Congenital Exotropia
Congenital exotropia includes children with a constant
exodeviation that develops by 6 months of age. Although this
condition is rare, many children will have associated neuro-
logic or other disorders and should undergo CNS imaging
[11]. This form of exotropia results in amblyopia much more
often than other subtypes of divergent strabismus.
1.2.2.3 Convergence Insuciency
Convergence insuciency describes children who are
generally orthotropic at distance xation but whose eyes
do not converge suciently at near xation, leaving an
Fig. 1.2 A child with exotropia
1.2 Forms of Pediatric Strabismus 3
exodeviation at near. It is the second most commonly
diagnosed type of exodeviation and comprises approxi-
mately one in 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]. This dier-
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].
Summary for the Clinician
Exotropia is the predominant form of strabismus
among Asian populations; however, it is less
common than esotropia in the West.
Intermittent exotropia is the most commonly
diagnosed form of exodeviation.
Amblyopia is less commonly associated with
exotropia than esotropia.
1.2.3 Hyperdeviations
Hypertropia, or a vertical displacement of one eye relative
to the other, is the least diagnosed form of strabismus [1].
Nearly one-third of all cases are associated with fourth
cranial nerve palsy (Fig. 1.3), corresponding to an
incidence of 1 in 1,264 children [14]. Other causes of
 4 1 Epidemiology of Pediatric Strabismus
a included children with CNS disorders or acquired nonac-
1 esotropia, on the other hand, appears to be relatively
b
Fig. 1.3 A child with left fourth nerve palsy showing, (a) right
head tilt and (b) left hypertropia with left head tilt
hypertropia include primary inferior oblique overaction,
Brown syndrome, and CNS-associated hypertropia [14].
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. Signicant 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 [1520].
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]. The previously
reported higher incidence of infantile esotropia may have
commodative esotropia, distinct forms of early-onset
esotropia that have been shown to occur more frequently
than infantile esotropia. Acquired nonaccommodative
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
There have been several reports from the United Kingdom
describing a decrease in the incidence of strabismus or
strabismus surgery in recent years [2124]. 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 signicant
change in the numbers of children diagnosed with infan-
tile esotropia, and there was no signicant change in the
number of surgeries performed on these children.
Summary for the Clinician
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.
The 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 (19651994).
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
 1.5 Worldwide Incidence and Prevalence of Childhood Strabismus 5

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

Reference Categorical Number Age of Strabismus Esotropia Exotropia Hypertropia
descriptions of subjects prevalence prevalence prevalence prevalence
within the children (years) (%) (%) (%) (%)
study examined

North America

Canada
[31] 946 1.611.6 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 67 1.6
Hispanic 548 67 0.9
[15] All races 39,227 07 4.5 3.2 1.2
Caucasian 17,931 07 5.4 4.1 1.3
African American 19,619 07 3.6 2.3 1.3
[35] Caucasian 119 816 3.4
Asian 310 816 2.9
Hispanic 1,781 816 1.8
Black 9 816 1/9
[27] Hispanic 3,003 0.56 2.4 0.9 1.5
African American 3,005 0.56 2.5 1.1 1.4
([3]a, [9]a, [14]a) Population-based 019 3.9 2.3 1.3 0.3
Mexico [36] 1,035 1213 2.3 1.2 0.8 0.4
[37] 343 36 1.2 0.6 0.6
Europe
England [38] 4,784 56 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 89 4.0 3.4 0.6
Denmark [42] 14,107 019 4.5 3.5 0.9 0.1
Sweden [43] 6,004 07 3.9 3.4 0.4 0.05
[44] 1,046 1213 2.7 1.4 0.7 0.6
[45] 3,126 10 2.7b 1.5 0.6
[46] 143 415 3.5 2.8 0.7
Croatia [47] All children 20,045 Unspecied 4.0 2.1 1.8
Term 17,163 Unspecied 3.3 1.7 1.6
Preterm 2,882 Unspecied 8.0 4.7 3.3
Australia
[20] 1,739 6 2.8 1.6 1.2 0

[48] 2,353 12 2.7c 0.9 1.1

Asia
Malaysia [49] 650 8 2.2 0.2 1.8 0.2
[50] Near xation 4,634 715 0.7 0.5
Distance xation 4,634 715 0.7 0.6

(continued)
 6 1 Epidemiology of Pediatric Strabismus

Table 1.1. (continued)

Reference Categorical Number Age of Strabismus Esotropia Exotropia Hypertropia
descriptions of subjects prevalence prevalence prevalence prevalence
within the children (years) (%) (%) (%) (%)
1 study examined

China [51] Near xation 4,364 515 1.9 1.6

Distance xation 4,364 515 3.0 2.6
[52] 1,084 614 2.5 0.4 2.1
Japan [53] Study year 2003 86,531 612 1.3d 0.3 0.7
e
[54] Study year 2005 84,619 612 1.0 0.2 0.6
[25] Five consecutive 33,929 total 1.5 0.010.1 00.03 00.07
measurements
between years
2000 and 2004
Five consecutive 33,193 total 3 0.20.3 0.020.1 0.20.3
measurements
between years
2000 and 2004
Taiwan [55] 862 6, 8, 11 1.6f 0.5 0.9
Thailand [56] 3,898 1 0.6
India [57] 6,447 515 0.5 0.3 0.2 0.02
[58] 10,605 15 0.4
Nepal [59] 1,100 516 1.6 0.09 1.5
[60] 1,816 516 1.3
Middle East
Israel [61] 38,000 12.5 1.3 0.9 0.3 0.06
Oman [62] 6,292 67, 1112 0.6 0.4 0.2
[63] 143,112 67 0.5
Africa
Cameroon [64] 11,230 26 1.2 0.5 0.8
Nigeria [65] 1,144 424 0.3
Ghana [66] 957 622 0.2
Tanzania [67] 1,386 719 0.5
Madagascar [68] 1,081 814 0.7 0.5 0.3
a
Study of incidence rather than prevalence
b
Strabismus prevalence includes 19 cases of microtropia
c
Strabismus prevalence includes 16 cases of microtropia
d
Strabismus prevalence includes 245 cases of unknown and 20 cases of other types of strabismus
e
Strabismus prevalence includes 110 cases of unknown and 23 cases of other types of strabismus
f
Strabismus prevalence includes two cases of other strabismus

English children [26]. Prevalence studies, reporting on
the number of people with a specic 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
specic 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

Caucasian populations, while exodeviations are more
commonly reported among Asian and African children.
As shown, North American, European, and Australian
data contrast with epidemiologic information gathered
from multiple studies in Asia and Africa. This trend is
additionally evident among non-Caucasians in the US. In
the Multi-Ethnic Pediatric Eye Disease Study groups
work describing strabismus prevalence among Hispanic
and African-American children, for instance, exotropia
was diagnosed more commonly than esotropia [27]. The
basis of this dierence may be in part linked with popula-
tion-based dierences in refractive error. Esotropia is
commonly associated with hyperopia, whereas exotropia
is more often diagnosed in children with myopia [28].
Summary for the Clinician
The prevalence of strabismus subtypes varies
based on racial and ethnic background; Asians
are primarily diagnosed with exotropia whereas
Europeans, Australians, and Americans are pre-
dominantly diagnosed with esotropia.
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].
References
1. Mohney BG (2007) Common forms of childhood strabis-
mus in an incidence cohort. Am J Ophthalmol 144:465467
2. Yu CB, Fan DS, Wong VW, et al (2002) Changing patterns
of strabismus: a decade of experience in Hong Kong. Br J
Ophthalmol 86:854856
3. Greenberg, AE, Mohney BG, Diehl NN, et al (2007)
Incidence and types of childhood esotropia: a population-
based study. Ophthalmology 114:170174
4. Mohney BG, Greenberg AE, Diehl NN (2007) Age at stra-
bismus diagnosis in an incidence cohort of children. Am J
Ophthalmol 144:467469
References 7
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
6. Pediatric eye disease investigator group (2002) Spontaneous
resolution of early-onset esotropia: experience of the
Congenital Esotropia Observational Study.Am J Ophthalmol
133(1):109118
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, 19651994. Arch Ophthalomol 127:200203
8. Mohney BG (2001) Acquired nonaccommodative esotro-
pia in childhood. JAAPOS 5(2):8589
9. Govindan M, Mohney BG, Diehl NN, et al (2005) Incidence
and types of childhood exotropia: a population-based
study. Ophthalmology 112:1046108
10. Nusz KJ, Mohney BG, Diehl NN (2005) Female predominance
in intermittent exotropia. Am J Ophthalmol 140: 546547
11. Hunter DG, Ellis FJ (1999) Prevalence of systemic and
ocular disease in infantile exotropia: comparison with
infantile esotropia. Ophthalmology 106:19511956
12. Mohney BG, Huaker RK (2003) Common forms of child-
hood exotropia. Ophthalmology 110:20932096
13. Havertape SA, Cruz OA, Chu FC (2001) Sensory strabismus
eso or exo? J Pediatr Ophthalmol Strabismus 38: 327330
14. Tollefson, MM, Mohney BG, Diehl NN, et al (2006)
Incidence and types of childhood hypertropia: a popula-
tion-based study. Ophthalmology 113:11421145
15. Chew E, Remaley NA, Tamboli A, et al (1994) Risk
factors for esotropia and exotropia. Arch Ophthalmol 112:
13491354
16. Hakim RB, Tielsch JM (1992) Maternal cigarette smoking
during pregnancy: a risk factor for childhood strabismus.
Arch Ophthalmol 110:14591462
17. Holmstrom G, Rydberg A, Larsson E (2006) Prevalence
and development of strabismus in 10-year-old premature
children: a population-based study. J Pediatr Ophthalmol
Strabismus 43:346352
18. Mohney BG, Erie JC, Hodge DO, et al (1998) Congenital
esotropia in Olmsted County, Minnesota. Ophthalmology
105:846850
19. Pennefather PM, Clarke MP, Strong NP, et al (1999) Risk
factors for strabismus in children born before 32 weeks
gestation. Br J Ophthalmol 83:514518
20. Robaei D, Rose KA, Kiey A, et al (2006) Factors associated
with childhood strabismus: ndings from a population-
based study. Ophthalmology 113:11461153
21. Arora A, Williams B, Arora AK, et al (2005) Decreasing
strabismus surgery. Br J Ophthalmol 89:409412
 8 1 Epidemiology of Pediatric Strabismus
22. Carney CV, Lysons DA, Tapley JV (1995) Is the incidence
of constant esotropia in childhood reducing? Eye 9(Suppl):
4041
23. Ferguson JA, Goldacre MJ, Henderson J, et al (1991)
1 Ophthalmology in the Oxford region: analysis of time
trends from linked statistics. Eye 5(Pt 3):379384
24. MacEwen CJ, Chakrabarti HS (2004) Why is squint sur-
gery in children in decline? Br J Ophthalmol 88:509511
25. Matuso T, Matsuo C, Matsuoka H, et al (2007) Detection of
strabismus and amblyopia in 1.5- and 3-year-old children
by a preschool vision-screening program in Japan. Acta
Med Okayama 61(1):916
26. OConnor AR, Stephenson TJ, Johnson A, et al (2002)
Strabismus in children of birth weight less than 1701 g.
Arch Ophthalmol 120:767773
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 115:12291236
28. Lambert SR (2002) Are there more exotropes than eso-
tropes in Hong Kong? Br J Ophthalmol 86:835836
29. Beauchamp GR, Black BC, Coats DK, et al (2003) The
management of strabismus in adults I. clinical character-
istics and treatment. J AAPOS 7:233240
30. Magramm I, Schlossman A (1991) Strabismus in patients
over the age of 60 years. J Pediatr Ophthalmol Strabismus
28:2831
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
43:8994
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 77:207210
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 77:211214
34. Fischbach LA, Lee DA, Englehardt RF, et al (1993) The
prevalence of ocular disorders among Hispanic and
Caucasian children screened by the UCLA mobile eye
clinic. J Community Health 18(4): 201211
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 69:255261
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 7:4753
37. Juarez-Munoz, IE, Rodriguez-Godoy ME, Guadarrama-
Sotelo ME, et al (1996) Frecuencia de trastornos oftalmo-
logicos comunes en poblacion preescolar de una delegacion
de la Ciudad de Mexico. Salud Publica Mex 38:212216
38. Graham PA (1974) Epidemiology of strabismus. Br J
Ophthalmol 58:224231
39. Stayte M, Johnson A, Wortham C (1990) Ocular and visual
defects in a geographically dened population of 2-year-
old children. Br J Ophthalmol 74:465468
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 92:959964
41. Donnelly UM, Stewart NM, Hollinger M (2005) Prevalence
and outcomes of childhood visual disorders. Ophthalmic
Epidemiol 12:243250
42. Frandsen AD (1960) Occurrence of squint: a clinical-
statistical study on the prevalence of squint and associated
signs in dierent 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:
10151037
44. Ohlsson J, Villarreal G, Sjostrom A, et al (2001) Visual acu-
ity, residual amblyopia and ocular pathology in a screened
population of 1213-year-old children in Sweden. Acta
Ophthalmol Scand 79:589595
45. Kvarnstrom G, Jakobsson P, Lennerstrand G (2001) Visual
screening of Swedish children: an opthalmological evalua-
tion. Acta Ophthalmol Scand 79:240244
46. Gronlund MA, Andersson S, Aring E, et al (2006)
Ophthalmological ndings in a sample of Swedish children
aged 415 years. Acta Ophthalmol Scand 84:169176
47. Karlica D, Galetovic D, Znaor L, et al (2008) Strabismus
incidence in infants born in Split-Dalmatia county 2002
2005. Acta Clin Croat 47:58
48. Robaei D, Kiey 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 142:10851087
49. Teoh GH, Yow CS (1982) Prevalence of squints and visual
defects in Malaysian primary one school children. Med J
Malaysia 37(4):336337
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:
678685
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 45:793799
52. Lu, P, Chen X, Zhang W, et al (2008) Prevalence of ocular
disease in Tibetan primary school children. Can J
Ophthalmol 43:9599
53. Matsuo T, Matsuo C (2005) The prevalence of strabismus
and amblyopia in Japanese elementary school children.
Ophthalmic Epidemiology 12:3136

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):329334
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 19931995. Chang Gung Med J 19: 217224
56. Tengtrisorn S, Singha P, Chuprapawan C (2005) Prevalence
of abnormal vision in one-year-old Thai children, based on
a prospective cohort study of Thai children. J Med Assoc
Thai 88(Suppl 9):S114S120
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 43:623631
58. Nirmalan PK, Vijayalakshmi P, Sheeladevi S, et al
(2003) The Kariapatti pediatric eye evaluation project:
baseline ophthalmic data of children aged 15 years or
younger in southern India. Am J Ophthalmol 136:
703709
59. Nepal BP, Koirala S, Adhikary S, et al (2003) Ocular mor-
bidity in schoolchildren in Kathmandu. Br J Ophthalmol
87:531534
60. Shrestha RK, Joshi MR, Ghising R, et al (2006) Ocular
morbidity among children studying in private schools of
Kathmandu valley: a prospective cross sectional study.
Nepal Medical College Journal 8(1):4346
References 9
61. Friedman Z, Neumann E, Hyams SW, et al (1980)
Ophthalmic screening of 38,000 children, age 1 to 2 years,
in child welfare clinics. J Pediatr Ophthalmol Strabismus
17:261267
62. Lithander J (1998) Prevalence of amblyopia with ani-
sometropia or strabismus among schoolchildren in the
Sultanate of Oman. Acta Ophthalmol Scand 76:658662
63. Khandekar RB, Abdu-Helmi S (2004) Magnitude and
determinants of refractive error in Omani school children.
Saudi Med J 25(10):13881393
64. Ebana Mvogo C, Bella-Hiag AI, Epesse E (1996) Le stra-
bisme au Cameroun. J Fr Ophtalmol 19:705709
65. Ajaiyeoba AI, Isawumi MA, Adeoye AO, et al (2007) Pattern
of eye diseases and visual impairment among students in
southwestern Nigeria. Int Ophthalmol 27:287292
66. Ntim-Amponsah CT, Ofosu-Amaah S (2007) Prevalence
of refractive error and other eye diseases in schoolchildren
in the greater Accra region of Ghana. J Pediatr Ophthalmol
Strabismus 44:294297
67. Wedner SH, Ross DA, Balira R, et al (2000) Prevalence of
eye diseases in primary school children in a rural area of
Tanzania. Br J Ophthalmol 84:12911297
68. Auzemery A, Andriamanamihaja R, Boisier P (1995)
Enquete sur la prevalence et les causes des aections ocu-
laires chez les enfants des ecoles primaries dAntananarivo.
Cahiers Sante 5:163166
 Chapter 2
Changes in Strabismus Over Time:
The Roles of Vergence Tonus and
Muscle Length Adaptation1
David L. Guyton
Core Messages
Patients with long-standing unilateral strabismus,
such as sensory exotropia in the absence of
fusion or esotropia with unilateral amblyopia,
typically show bilateral deviations under anesthe-
sia, often symmetric.
Forced ductions usually show symmetric muscle
tightness. Changes in extraocular muscle lengths
thus appear to occur primarily bilaterally, whether
or not fusion is present.
With skeletal muscles responding to changes in
stimulation by the gain or loss of sarcomeres, it is
likely that abnormal or unguided vergence tonus,
2.1 Binocular Alignment System
A vexing problem in the 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. This 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. This does not refer to strabismus
1
Adapted from [1]. Reprinted with permission of the publisher.
2
which changes the lengths of the extraocular
muscles bilaterally, is largely responsible for
changes in the angle of strabismus over time.
This mechanism helps explain the development of
(1) increasing basic deviations in 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-
ciency in presbyopes, and (5) basic cyclovertical
deviations that mimic superior oblique muscle
paresis.
in terms of the 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. The rst is a neurologic
one, vergence adaptation, and the second is a muscular
one, muscle length adaptation.
 12 2 Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation
2.1.2 Vergence Adaptation
Neurologically, retinal image disparity invokes a fusional
vergence response which moves the eyes in opposite
2 directions to eliminate the retinal image disparity, accu-
rate to within a few minutes of arc, both horizontally and
vertically. This 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
1015 s or less [5].
It is feedback from fast fusional vergence that stimu-
lates changes in tonic vergence, or vergence tonus, over
time [6]. This process is sometimes called slow ver-
gence, or vergence adaptation. Vergence adaptation
occurs selectively for dierent directions of gaze and for
dierent 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]. The eects of vergence adap-
tation can persist for minutes to hours and perhaps much
longer. Vergence adaptation wears o slowly when one
eye is occluded or during sleep, but much faster in the
presence of a competing vergence [6]. This mechanism
was phenomenologically described as long ago as 1868
by Hering (cited in [8]), and in 1893 by Maddox (cited in
[9]). Alfred Bielschowsky actually studied this early in
his career, reporting with Hofmann in 1900 that 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
signicantly eases the burden on sensorimotor fusion,
leaving sensorimotor fusion free to 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 often try to uncover the underlying devia-
tion by occluding one eye. For example, Lancaster red-
green plots of incomitant strabismus with partial fusion
often show best alignment in primary gaze, and in the
reading position, those directions of gaze that are most
used and, therefore, best adapted to. After a 30-min patch
test, the plotted tropia often increases in these directions
of gaze, with increased comitance of the overall pattern of
deviation [13].
However, maximum neuronal 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
The topic of muscle length adaptation does not appear in
most texts on strabismus. The historic assumptions have
been that extraocular muscle lengths are determined
genetically, and that the basic forms of strabismus are due
to primary abnormalities in muscle anatomy, in 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 715 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
myobrils, to maintain the proper overlap of the actin
and myosin myolaments so as to obtain optimal force
generation, velocity, and power output over the range
of motion through which the muscle is most used [17].
The exact biologic mechanism that accomplishes this is
still unknown.
In 1994, Alan Scott [18] showed that the extraocular
muscles can adapt their lengths in the same way as the
other skeletal muscles throughout the body. He sutured
one eye of a monkey to the lateral orbital wall in an exo-
tropic position of approximately 30 prism diopters. After
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 sacriced
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
held in a stretched position, increased stimulation causes
actual loss of sarcomeres with shortening of the basic
muscle length [15, 16, 19]. This change in basic muscle
length in response to the level of stimulation is precisely
in the right direction to help maintain binocular 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.
This further feedback mechanism, that is, vergence
tonus regulating muscle length adaptation, completes the
dynamic feedback system for maintenance of long-term
binocular alignment (Fig. 2.1). Retinal image disparity
elicits fast fusional vergence, which leads in the short
term to vergence adaptation, producing a change in 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
ring rates, and thereby eectively resets vergence adap-
tation so that it can continue to function optimally in
response to input from fast fusional vergence.
Basic muscle lengths
(vergence tonus)
Approx. functional muscle lengths
(acute stimulation)
Exact functional muscle lengths
[perturbation]
Retinal image disparity (diplopia)
Fast fusional vergence
Vergence adaptation
Vergence tonus
Muscle length adaptation
Fig. 2.1 Three-level dynamic feedback system for the mainte-
nance of binocular alignment
13
2.2 Modeling the Binocular Alignment
Control System
The 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
eect, or simply a switch of the object of regard from
the computer screen to the bird out the window. Such a
perturbation requires dierent eye alignment and will
thus result in misaligned eyes for the new task if no
compensation is made. Nevertheless, misaligned eyes
cause retinal image disparity, with a double image of
the bird out the window, which the brain does not
like.
Hence, the brain responds with fast fusional vergence,
changing the acute stimulation levels to the muscles. This
yields new functional muscle lengths in the proper 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.
This is the normal functioning of the long-term (as
well as short-term) binocular alignment control system.
This is the feedback scheme that keeps the eyes aligned
during the growth of the skull in early life, throughout the
development of handeye coordination in oblique direc-
tions of gaze, and throughout the development of presby-
opia, which would otherwise cause a signicant disruption
of near vs. distance alignment.
 14 2 Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation
2.2.1 Breakdown of the Binocular
Alignment Control System
However, what happens when something goes wrong
2 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. The 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 o when their input disappears. They will often con-
tinue to function at a basal level, with a low level of out-
put being generated. This basal output level can be biased
in one direction or the other, and therefore, in this case,
can continue to drive the muscle length adaptation
mechanism slowly in one direction or the other, produc-
ing strabismus that was not there in the 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 drifts outward over time. From
this feedback mechanism, we can begin to understand
that if one eye develops poor vision, and therefore, if the
eyes have no need for convergence, the average vergence
stimulation to the extraocular muscles (which had pre-
viously maintained alignment equilibrium) will shift
slightly to less convergence and more divergence, actively
driving the eyes into a position of exotropia. This sensory
exotropia can thus be seen to be not a passive process
after all, but an active driving of the eyes outward by the
otherwise normal alignment mechanisms that have lost
proper guidance.
2.2.2 Clarication of Unanswered Questions
Regarding the Long-Term Binocular
Alignment Control System
The 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 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]. The model explained how defects
in fusion, or the loss of fusion, which for this purpose
were considered the same as loss of vision in one eye,
could lead to sensory-type changes in strabismus. In
particular, in the torsional dimension, lack of proper 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. That is, will an extraocular muscle adapt its length
for optimal function in the position in which it is held
most of the time by version stimulation? If so, what are
the relative roles of version and vergence stimulation in
the regulation of extraocular muscle length? New obser-
vations have claried these questions. These observations,
the resulting clarication, and the consequences to our
understanding of strabismus are expected benets from
this chapter.
2.2.3 Changes in Strabismus
as a Bilateral Phenomenon
The primary new observation of the author is that changes
in strabismus occur, to a large extent, bilaterally. This is
not speaking of strabismus in terms of the 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 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 often
both the eyes turn out. Figures 2.22.4 show examples
of this bilateral phenomenon in patients with sensory
exotropia.
This observation was rst made by the author 25 years
ago after a recess-resect procedure on a patient with sen-
sory exotropia. The sensory exotropia recurred. When
the patient was put back to sleep for a repeat recess-resect
procedure on the same eye, the previously operated eye
was straight. It was the sound eye that was turning out
signicantly. The muscle changes that caused the original
sensory exotropia had occurred bilaterally. Arthur
Jampolsky [22] reported this phenomenon in 1986, but
he oered no explanation for it.
 2.2 Modeling the Binocular Alignment Control System
Fig. 2.2 Eighty-year-old woman with dense amblyopia in her
left eye since childhood, 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 signicantly farther
than the usual divergence seen under anesthesia
There is more evidence that changes in strabismus
occur bilaterally over time. Infants with esotropia and
amblyopia, where the amblyopic eye is practically 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. They are both abnormally short. These children
sometimes show a small head turn, 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 xation.
There is still further evidence that changes in strabis-
mus occur bilaterally. The 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.
15
Fig. 2.3 Twenty-one-year-old man with left sensory exotropia
(top), from a left macular scar since birth, with counting ngers
vision in his left eye. His eyes also turn out essentially equally
under anesthesia (bottom)
2.2.4 Changes in Basic Muscle Length
These changes in strabismus occur because the muscles
change their basic length, i.e., the number of sarcomeres.
A basically short muscle has fewer sarcomeres than 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, signicantly more
than the usual divergence seen under anesthesia. There
must be another mechanism that causes basic muscle
 16 2 Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation
Fig. 2.4 Thirty-eight-year-old man after a right optic nerve
injury 15 years before, with resulting blindness in his right eye.
The 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
lengths to change bilaterally, and that mechanism is most
surely related to stimulation, given the fact that chronic
electrical stimulation has been shown to shorten muscles
by causing the loss of sarcomeres [15].
2.2.5 Version Stimulation
and Vergence Stimulation
What type of stimulation do the extraocular muscles
normally receive? If one thinks about it, the extraocular
muscles between the two eyes are yoked as much as, or
more than, any other muscles in the body. They are heav-
ily bilaterally innervated. They are linked in versions,
movements of the two eyes in the same directions, and in
vergences, movements of the two eyes in opposite direc-
tions. Versions allow us to look in dierent directions,
while vergences allow us to change our gaze from dis-
tance to near. However, vergences also, and most impor-
tantly, 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
Fig. 2.5 Thirty-four-year-old woman with esotropia since
childhood with xation with her left eye only (top), for many
years. Both eyes turn in signicantly under anesthesia (bottom)
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 eect 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. The same fusional vergence that realigns
the eyes momentarily, leads via vergence adaptation to
changes in vergence tonus. Changes in vergence tonus,
representing chronic changes in the levels of stimulation,
 2.2 Modeling the Binocular Alignment Control System 17

can indeed serve as the necessary and sucient 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 eect of the version stimulation would average
out to zero over time. The vergence stimulation, on the other
hand, would exert a net eect, changing the basic muscle
lengths in the directions necessary to reduce the need for the
vergence stimulation in the rst place a marvelous nega-
tive-feedback servomechanism, as pointed out previously.
The 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 dierence between extraocular muscles and
the other skeletal muscles. The evidence is the same as
that noted earlier simply the observation that chronic
monocular deviations of the eyes, as in sensory exotropia
or in esotropia with unilateral amblyopia, practically
always become binocular deviations under anesthesia,
with bilaterally abnormal basic muscle lengths. Fig. 2.6 Thirty-three-year-old woman with esotropia since
The argument is this: In constant strabismic states birth. Only her right eye was operated for the esotropia at the age
where there is no fusion, there is no signicant fusional of 2 years. She has xed with her LE only (top), as long as she
vergence stimulation, but version stimulation still exists. can remember, because of mild hyperopia and amblyopia in her
right eye. Neither eye has adapted to these positions, because
If the extraocular muscles should adapt their lengths
when she is placed under deep anesthesia (bottom), both the
according to version stimulation, then the muscle lengths eyes deviate rightward. The muscle lengths clearly did not adapt
in the deviating eye in the patient with sensory exotropia in response to chronic everyday version stimulation
would totally adapt to the deviated position.
The sound eye, spending its average time in straight Therefore we must conclude that the stimulation from
ahead gaze, would have normal muscle lengths. However, vergence tonus is the primary regulator of extraocular
this is clearly not the case, because in most cases of sen- muscle length adaptation, and that its eects are bilateral.
sory exotropia, both eyes turn out under anesthesia, and In this regard, the regulation of the extraocular muscle
in most cases of esotropia with unilateral amblyopia, the lengths appears to be fundamentally dierent from the
two eyes are essentially symmetric under anesthesia. By regulation of the lengths of other skeletal muscles. Only
forced duction testing, especially in the cases of esotropia, the extraocular muscles experience this bilateral vergence
the basic muscle lengths are clearly bilaterally abnormal. stimulation. The other skeletal muscles receive primarily
The position of the eyes when asleep probably has little unilateral stimulation, or bilateral stimulation akin to
or no eect on muscle length adaptation, because Breinin version stimulation, and their lengths are responsive to
has shown that electrical activity in the extraocular these forms of stimulation as well as to stretching or
muscles essentially disappears in deep sleep [24], and slackening of the muscles depending on use.
decreased stimulation of skeletal muscles signicantly
slows down muscle length adaptation, as shown by den-
ervation experiments [19].
2.2.6 Evidence Against the
Figure 2.6 shows a patient illustrating the ineective-
Final Common Pathway
ness of version stimulation. The muscle lengths clearly
did not adapt to the positions in which the eyes were held There is a potential problem with the conclusion that
by chronic everyday version stimulation. vergence tonus is the primary regulator of extraocular
 18 2 Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation
muscle length adaptation, and that its eects are bilateral.
Neurophysiologists, with few exceptions [25], have long
believed that version and vergence stimulation, while
arising in dierent centers in the brainstem, are com-
2 bined into a nal common pathway at the motoneu- eye cannot explain the development of esotropia, verti-
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 ber types in the extraocular muscles [28, 29]. It is
tempting to speculate that those 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]. These observa-
tions argue against the 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. The deviation, of course, shows up only in the eye
with poor vision, until the patient is put under anesthesia,
when both the eyes turn out.
Some patients with loss of vision or fusion develop
esotropia, especially when vision is lost in early infancy.
Vertical misalignment can also develop when vision is
lost in one eye. It has been argued before that abnormal
ocular torsion, with associated A and V patterns, are
forms of sensory deviations developing over time when
fusion is faulty or absent [4]. Clearly, the simple decreased
need to converge that occurs when vision is lost in one
cal deviations, or torsional deviations. The many dier-
ent ways that strabismus can change over time, if linked
to changes in vergence tonus, require a more general
explanation.
The explanation, as noted earlier, probably lies in the
very nature of biologic control systems. When input to
such control systems shuts down, the output rarely goes
to zero, but rather goes to a baseline state that may be
biased on either side of zero output. In the case of the
ocular motor control systems, when the eyes become
misaligned enough that fusional vergence cannot 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 often have a stronger
convergence bias than divergence bias, as evidenced by
the relative frequency of esotropia vs. exotropia in infancy.
This may simply be a manifestation of more hyperopia in
childhood, with the attendant increased convergence
tonus from accommodative convergence. If vision is lost
in one eye in early infancy, it is not surprising that a 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. The torsion is often seen at 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, after soft
tissue remodeling occurs in response to the chronic ocu-
lar torsion (the authors interpretation), the eyes move
more along the torted planes dened 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 shifted
[33] (the authors interpretation).
Furthermore, a baseline output bias in the cycloverti-
cal alignment mechanism can drive the eyes into a basic

cyclovertical misalignment, a cyclovertical misalignment
which we often call congenital superior oblique paresis,
probably mistakenly, because we have no other term for
it. Most cases of esotropia are not attributed to sixth nerve
palsy, but we persist in attributing many cyclovertical
deviations of unknown cause to fourth nerve palsy.
Problems at other points in these control mechanisms
can perhaps lead to strabismus in the rst place. An
abnormality in vergence adaptation has been proposed to
cause divergence insuciency 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 suciently 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. This is the nystagmus blockage
or nystagmus compensation mechanism originally
described by Adelstein and Cppers (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 Ciancias 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 eects of muscle length adaptation in the
short term, but will simply reduce the eects of vergence
adaptation over an exponential time course. Thirty to
forty-ve minutes of monocular occlusion are usually
long enough to eliminate most vergence adaptation [13],
although diagnostic monocular occlusion for up to 12
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 710 days to fully uncover latent
2.3 Changes in Strabismus 19
deviations [3941]. By careful study of Marlows published
graphs [40], it is apparent that after 35 days of monocular
occlusion, signicant changes in the monitored deviations
often 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 often developed a hyperdeviation, regardless of
which eye was covered, speaking against the uncovering of
a latent hyperdeviation [4244]. 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. The same may be the case
in more recent studies by Viirre et al. [45] in monkeys, and
by Liesch and Simonsz [46] in normal human subjects. In
these studies, new vertical and torsional deviations were
noted after 7 days of monocular occlusion of the monkeys
and after 3 days of monocular occlusion of the human
subjects.
2.3.2 Unilateral Changes in Strabismus
Clearly, not all changes in strabismus are bilateral.
Patients with loss of fusion from sixth nerve palsy
develop an increasingly short and tight ipsilateral
medial rectus muscle. The contralateral rectus muscle
does not shorten concomitantly. This represents unilat-
eral muscle length adaptation, but from a dierent
mechanism. When a skeletal muscle continues to be
stimulated but is not stretched out from time to time, it
progressively shortens via the active loss of sarcomeres
[16]. This is the mechanism demonstrated by Alan
Scott by suturing his monkeys eye temporally [18], and
is the mechanism determining changes in the medial
and/or lateral rectus muscles in various types of Duanes
syndrome as documented by Collins, Jampolsky, and
Howe [47] and by Castaera de Molina and Gier
Muoz [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 often develop intorsion or
extorsion of the eyes, with accompanying oblique muscle
overaction and A or V patterns, after having lost fusion
for only 1 month [4, 49]. We attribute this to a type of
sensory torsional deviation due to muscle length adap-
tation in the torsional dimension.
 20 2 Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation
Weldon Wright, Katie Gotzler, and the author have
recently collected a large series of patients with early pres-
byopia, mostly with decient or absent fusion, who have
developed progressive esotropia probably from the
2 increased convergence tonus accompanying the increas-
ing eort 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 signicantly increased onset of esotropia in
their 30s and 40s, as expected [21]. This mechanism,
involving muscle length adaptation, is probably
responsible for other reports of esotropia developing in
adulthood [50, 51] and is similar to the mechanism of
hypoaccommodative esotropia occurring in children, as
rst described by Costenbader [52].
Elizabeth Bell, Adam Bowen, and the author have
also identied a series of presbyopic patients, aged 50
years and older, who either had a small amount of uncor-
rected hyperopia, or who often tried to function without
needed correction for near, and developed divergence
insuciency in the later decades of life. They had inter-
mittent or constant esotropia in the distance with diplo-
pia, but could still fuse at near. They are best corrected by
bilateral medial rectus muscle recessions [53, 54], with
the 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 insuciency. Of interest is that the
presbyopic patients identied 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
after 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 [5658]. A
chronic level of cyclovertical vergence might indeed drive
the eyes into a basic cyclovertical deviation, one involving
both the vertical rectus muscles and the oblique muscles.
But what is this basic cyclovertical deviation? We do not
have a name for it. The vast majority of idiopathic 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? After all, we do not speak of patients with
congenital esotropia as having sixth nerve paresis!
Howard Ying, Nicholas Ramey, and the author are
currently investigating the patterns of cyclovertical stra-
bismus that they can create in normal subjects. They have
constructed a special haploscope that allows adaptation
to increasing vertical, torsional, or horizontal disparities,
with near xation, with elds of view of over 50, utilizing
video-oculography for recording. The entire apparatus
can tilt, up to 45, to the right or left.
To conrm 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 3045 min. With adaptation,
we expect to 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.
The 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 Roll
10
Clockwise[deg]
Right Eye
Left Eye
5
0
Counterclockwise
5
STR RHT STR LHT
10
50 100 150
time [s]
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 47
 2.4 Applications of Bilateral Feedback Control to Clinical Practice and to Future Research
Vertical Difference R-L
10
Up[deg]
5 Practically speaking, the consequences of muscle length
Right tilt Left tilt
0 be seen and careful forced ductions can be performed.
Down
5
10
5 10 15
time [s]
Fig. 2.8 Vertical recordings, with head straight and tilted 45 to
either side, after 45 min of adaptation, with head straight, to a
left-over-right vertical disparity of 50+ elds of concentric cir-
cles. The relative positions of the two eyes are shown in the
fusion-free, dissociated state. The negative values correspond to
the induced right hypodeviation
vertical disparity. This arrangement simulated a relative
right hyperdeviation, because the right eye had to move
downward to fuse, and the left eye had to move upward.
After adaptation, the relative positions of the eyes were
measured in the fusion-free, dissociated state. The eyes
had partially adapted to the simulated relative right
hyperdeviation by developing a measured right hypode-
viation. The relative shift of the right eye downward of
3 with head straight increased to 5 with right head tilt
(RHT) and decreased to 0 with left head tilt (LHT)
(see Fig. 2.8). These changes with forced head tilt are in
the directions that are expected from increased tonus
to the normal right superior oblique muscle and to the
normal left inferior oblique muscle. This increased
tonus was produced by vergence adaptation to the rela-
tive right hyperdeviation. The deviations recorded sim-
ply represent a basic cyclovertical deviation induced in
a normal subject by vergence adaptation to a vertical
disparity.
The 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.
21
2.4 Applications of Bilateral Feedback
Control to Clinical Practice
and to Future Research
adaptation are often best appreciated under deep general
anesthesia, when the anatomic positions of the eyes can
The decision about which eye or eyes to operate on, and
which muscles, may best be postponed until obtaining
these intraoperative ndings. This has been advocated by
many, including Roth in Switzerland [61], Jampolsky in
the United States [22], and the author [62].
Because version stimulation is only minimally eec-
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 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 eort 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. The biases
that exist in the unguided vergence and muscle length
adaptation mechanisms may themselves change over
time, altering the angle of strabismus naturally. Waiting
for stabilization of these biases, as reected by stability of
the deviation, may indeed be warranted in such cases.
The 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 after we have achieved it.
For example, selective activation of vergence should
be able to change not only vergence adaptation, but also
 22 2 Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation
muscle lengths over time. This of course is currently the
goal of fusional vergence exercises as part of orthoptic
training. However, eventually we may be able to supply
vergence stimulation from external sources, such as is
2 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 dierences 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.
Summary for the Clinician
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
1. Guyton DL (2006) The 10th Bielschowsky lecture: changes
in strabismus over time: the roles of vergence tonus and
muscle length adaptation. Binocular Vis Strabismus Quart
21:8192
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 90:1118
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 9:209236
5. Ludvigh E, McKinnon P, Zaitze L (1964) Temporal course
of the relaxation of binocular duction (fusion) movements.
Arch Ophthalmol 71:389399
6. Carter DB (1965) Fixation disparity and heterophoria fol-
lowing prolonged wearing of prisms. Am J Optom Arch
Am Acad Optom 42:141152
7. Taylor MJ, Roberts DC, Zee DS (2000) Eect of sustained
cyclovergence on eye alignment: Rapid torsional phoria
adaptation. Invest Ophthalmol Vis Sci 41:10761083
8. Ellerbrock VJ (1950) Tonicity induced by fusional move-
ments. Am J Optom Arch Am Acad Optom 27:820
9. Cooper J (1992) Clinical implications of vergence adapta-
tion. Optom Vis Sci 69:300307
10. Schor CM (1979) The relationship between fusional ver-
gence eye movements and xation disparity. Vis Res
19:13591367
11. Ogle KN, Prangen Ade H (1953) Observations on vertical
divergences and hyperphorias. Arch Ophthalmol 49:
313324
12. Crone RA, Hardjowijoto S (1979) What is normal binocu-
lar vision? Doc Ophthalmol 47(1):163199
13. Hwang J-M, Guyton DL (1999) The Lancaster red-green
test before and after occlusion in the evaluation of incomi-
tant strabismus. J AAPOS 3:151156
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. The Smith-Kettlewell Eye
Research Institute, San Francisco, pp 195206
15. Tabary J-C, Tardieu C, Tardieu G, Tabary C (1981)
Experimental rapid sarcomere loss with concomitant
hypoextensibility. Muscle Nerve 4:198203
16. Williams PE, Catanese T, Lucey EG, Goldspink G (1988)
The importance of stretch and contractile activity in the
prevention of connective tissue accumulation in muscle. J
Anat 158:109114
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 S146S152
18. Scott AB (1994) Change of eye muscle sarcomeres accord-
ing to eye position. J Pediatr Ophthalmol Strabismus
31:8588
19. Hayat A, Tardieu C, Tabary J-C, Tabary C (1978) Efects of
denervation on the reduction of sarcomere number in cat

soleus muscle immobilized in shortened position during
seven days. J Physiol (Paris) 74:563567
20. Schor CM, Maxwell JS, Graf EW (2001) Plasticity of con-
vergence-dependent variations of cyclovergence with ver-
tical gaze. Vis Res 41:33533369
21. Wright WW, Gotzler KC, Guyton DL (2005) Esotropia
associated with early presbyopia caused by inappropriate
muscle length adaptation. J AAPOS 9:563566
22. Jampolsky A (1986) Treatment of exodeviations. In:
Pediatric ophthalmology and strabismus, trans new orleans
acad ophthalmol. Raven, New York, pp 201234
23. Gonzalez C, Jaros PA (1988) Strabismus surgery on the
nonamblyopic eye. Graefes Arch Clin Exp Ophthalmol
226:304308
24. Breinin GM (1957) The position of rest during anesthesia
and sleep. AMA Arch Ophthalmol 57:323326
25. Jampel RS (1967) Multiple motor systems in the extraocu-
lar muscles of man. Invest Ophthalmol 6:288293
26. Keller EL, Robinson DA (1971) Absence of a stretch reex
in extraocular muscles of the monkey. J Neurophysiol
34:908919
27. Scott AB, Collins CC (1973) Division of labor in human
extraocular muscle. Arch Ophthalmol 90:319322
28. Eberhorn AC, Bttner-Ennever JA, Horn AKE (2005)
Identication of motoneurons supplying multiply- or sin-
gly-innervated extraocular muscle bers in the rat.
Neuroscience 137:891903
29. Bttner-Ennever JA (2006) The extraocular motor nuclei:
organization and functional neuroanatomy. Prog Brain Res
151:95125
30. Miller JM (2003) No oculomotor plant, no nal common
path. Strabismus 11:205211
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 33:8588
33. Clark RA, Miller JM, Rosenbaum AL, Demer JL (1998)
Heterotopic muscle pulleys or oblique muscle dysfunc-
tion? J AAPOS 2:1725
34. Schor C, Horner D (1989) Adaptive disorders of accom-
modation and vergence in binocular dysfunction. Ophthal
Physiol Opt 9:264268
35. von Noorden GK (1988) Current concepts of infantile
esotropia. Eye 2:343357
36. von Noorden GK (1976) The nystagmus compensation
(blockage) syndrome. Am J Ophthalmol 82:283290
37. Guyton DL (2000) Dissociated vertical deviation: etiol-
ogy, mechanism, and associated phenomena. J AAPOS
4:131144
References 23
38. Ciancia AO (1995) On infantile esotropia with nystag-
mus in abduction. J Pediatr Ophthalmol Strabismus 32:
280288
39. Marlow FW (1921) Prolonged monocular occlusion as a
test for the muscle balance. Am J Ophthalmol 4:238250
40. Marlow FW (1927) Observations on the prolonged occlu-
sion test. Am J Ophthalmol 10:567574
41. Marlow FW (1938) A tentative interpretation of the nd-
ings of the prolonged occlusion test on an evolutionary
basis. Arch Ophthalmol 19:194204
42. Abraham SV (1931) Bells phenomenon and the fallacy of
the occlusion test. Am J Ophthalmol 14:656664
43. Beisbarth C (1932) Hyperphoria and the prolonged occlu-
sion test. Am J Ophthalmol 15:10131015
44. Holmes JM, Kaz KM (1994) Recovery of phorias following
monocular occlusion. J Pediatr Ophthalmol Strabismus
31:110113
45. Viirre E, Cadera C, Vilis T (1987) The pattern of changes
produced in the saccadic system and vestibuloocular
reex by visually patching one eye. J Neurophysiol 57:
92103
46. Liesch A, Simonsz HJ (1993) Up-and downshoot in adduc-
tion after monocular patching in normal volunteers.
Strabismus 1:2536
47. Collins CC, Jampolsky A, Howe PS (1992) Mechanical
limitations of rotation. In: Proceedings of the mechanics of
strabismus symposium. The Smith-Kettlewell Eye Research
Institute, San Francisco, pp 1940
48. Castaera de Molina A, Gier Muoz ML (1997) Short-
sti extraocular muscles: Mechanisms involved in EOM
adaptations to squint. In: Prieto-Diaz J, Hauviller V (eds)
XII Congreso del Consejo Latinoamericano de Estrabismo
(CLADE). Graca Lifra, La Plata, pp 503508
49. Miller MM, Guyton DL (1994) Loss of fusion and the
development of A or V patterns. J Pediatr Ophthalmol
Strabismus 31:220224
50. Olitsky SE, Juneja RA (1997) Adult onset esotropia with
distance near disparity: a report of two cases. Binocul Vis
Strabismus Q 12:265267
51. Simon AL, Borchert M (1997) Etiology and prognosis
of acute, late-onset esotropia. Ophthalmology 104:
13481352
52. Costenbader FD (1958) Clinical course and management
of esotropia. In: Allen JH (ed) Strabismus ophthalmic
symp II. Mosby, St Louis, pp 325353
53. Thomas AH (2000) Divergence insuciency. J AAPOS
4:359361
54. Bothun ED, Archer SM (2005) Bilateral medial rectus mus-
cle recession for divergence insuciency pattern esotropia.
J AAPOS 9:36
55. Sheedy JE, Saladin JJ (1975) Exophoria at near in presby-
opia. Am J Optom Physiol Optics 53:474481
 24 2 Changes in Strabismus Over Time: The Roles of Vergence Tonus and Muscle Length Adaptation
56. Enright JT (1992) Unexpected role of the oblique muscles
in the human vertical fusion reex. J Physiol 451:
279293
57. van Rijn LJ, Collewijn H (1994) Eye torsion associated with
2 disparity-induced vertical vergence in humans. Vis Res
34:23072316
58. Cheeseman EW Jr, Guyton DL (1999) Vertical fusional
vergence: the key to dissociated vertical deviation. Arch
Ophthalmol 117:11881191
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 303306
60. Sato M, Amano E (2003) Clinical 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, The Netherlands, pp 211214
61. Roth A (1983) Oculomotor asymmetry in concomitant
strabismus and its consequences for the choice of surgical
intervention. In: Castaera de Molina A (ed) Congenital
disorders of ocular motility. Editorial JIMS, Barcelona,
pp 8997
62. Castelbuono AC, White JE, Guyton DL (1999) The use of
(a)symmetry of the rest position of the eyes under general
anesthesia or sedation-hypnosis in the design of strabis-
mus surgery: a favorable pilot study in 51 exotropia cases.
Binocul Vis Strabismus Q 14:285290
63. Gonzalez C, Chen H.H, Ahmadi MA (2005) Sherrington
innervational surgery in the treatment of chronic sixth
nerve paresis. Binocul Vis Strabismus Q 209:159166
64. Fawcett SL, Birch EE (2003) Risk factors for abnormal bin-
ocular vision after successful alignment of accommodative
esotropia. J AAPOS 7:256262
65. Farmer SE, James M (2001) Contractures in orthopaedic
and neurological conditions: a review of causes and treat-
ment. Disabil Rehabil 23:549558
 Chapter 3
A Dissociated Pathogenesis
for Infantile Esotropia
Michael C. Brodsky
Core Messages
Binocular movements that result from unequal
visual input to the two eyes are dened as
dissociated.
Dissociated esotonus, an unrecognized form of
binocular dissociation, underlies dissociated hor-
izontal deviation.
3.1 Dissociated Eye Movements
Although the term dissociated has historically been
restricted to the description of vergence eye movements
[13], 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]. These 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 [68]. It is held that infantile
esotropia disrupts binocular control mechanisms and
thereby engenders these dissociated eye movements [5].
This time-honored notion assumes a distinct and 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.
Summary for the Clinician
Dissociated eye movements include dissociated
vertical divergence, latent nystagmus, and disso-
ciated horizontal deviation.
3
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 eect, of infantile esotropia.
3.2 Tonus and its relationship
to infantile esotropia
Tonus refers to the eects 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.
Thus, while convergence functions to actively alter hori-
zontal eye position, tonus eectively 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 xation (Figs. 3.2 and 3.3) [1117].
These variants of intermittent exotropia are known as
dissociated horizontal deviation. The clinical features
 26 3 A Dissociated Pathogenesis for Infantile Esotropia

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.
Summary for the Clinician
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
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 dierent conditions
with specic diagnostic implications. The intermittent
exodeviation caused by dissociated horizontal deviation
simply constitutes one distinct form of intermittent
exotropia with its own unique pathophysiology.
Many clinicians apply the hybrid term intermittent
exotropia/dissociated horizontal deviation implying that
the two conditions often coexist, and perhaps acknowl-
edging some diagnostic ambiguity [13, 1517, 18, 19]. So
what are the innervational substrates for these distinct but
overlapping categories of intermittent exotropia? Although
Burian believed intermittent exotropia to be caused by an
active divergence mechanism [20], independent studies
have found that these patients are approximately 30 PD
more exotropic when deeply anesthetized than in the
awake state [21, 22], suggesting that intermittent exotropia
 3.3 Esotropia and Exotropia as a Continuum 27

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

actually results from intermittent fusional control of a
large baseline exodeviation [23, 24].
When intermittent exotropia is associated with dis-
sociated horizontal deviation, xation with either
eye superimposes dissociated esotonus on the base-
line exodeviation to produce a variable intermittent
exodeviation (Figs. 3.2 and 3.3) [68]. The distinction
between intermittent exotropia and dissociated
horizontal deviation lies primarily in the relative
activation of binocular fusion (which behaves as an
all-or-nothing phenomenon in most forms of 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 Amplitude of exodeviation is independent

xating eye (i.e., asymmetrical)
Slow velocity of spontaneous exodeviation
Variable amplitude of spontaneous exodeviation
Positive Bielschowsky phenomenon
Associated latent nystagmus and torsional
ocular rotations, prominent dissociated
vertical divergence
Positive reversed xation test
of the xating eye (i.e., symmetrical)
Rapid velocity of spontaneous exodeviation
Constant amplitude of spontaneous exodeviation
Negative Bielschowsky phenomenon
No associated latent nystagmus or torsional ocular
rotations, little if any dissociated vertical
divergence
Negative reversed xation test
 28 3 A Dissociated Pathogenesis for Infantile Esotropia
functions as an open-loop process without reference to
ultimate binocular alignment in dissociated horizontal
deviation). Because xation with the nonpreferred eye
exerts greater esotonus [68], the baseline exodevia-
3 tion can be unilateral, asymmetrical, or associated with
a paradoxical esotropia when the nonpreferred eye is
used for 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
rst glance, it is dicult to imagine how these diametrical
forms of horizontal misalignment are not mutually
exclusive.
The beauty of dissociated horizontal deviation is that
it allows us to recast horizontal strabismus as the relative
balance of mechanical and innervational forces, without
regard to nal eye position. Dissociated esotonus can still
be expressed from an exodeviated position, because it is
generated by unbalanced binocular input that exerts its
inuence 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. The
exotropic form of dissociated horizontal deviation
uniquely embodies the coexistence of the mechanical
exodeviating forces that give rise to intermittent exotropia,
and the dissociated esotonus that may give rise to infantile
esotropia. For example, infantile exotropia is often 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 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 dierent 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.
Summary for the Clinician
Dissociated esotonus can be superimposed upon
the baseline position of the eyes to produce
intermittent esotropia or intermittent exotropia.
3.4 Distinguishing Esotonus
from Convergence
There remains the unfortunate tendency in the strabis-
mus literature to conate 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]. The 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. The distinction between convergence (the eect)
and monocular esotonus (the cause) lies at the heart of
understanding infantile esotropia. Horwood and col-
leagues have recently shown that normal infants display
eeting, large-angle convergent eye movements during
the 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]. This time
course challenges the dubious assumption that infantile
esotropia arises from excessive convergence output. Our
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.
 3.5 Pathogenetic Role of Dissociated Eye Movements in Infantile Esotropia
Summary for the Clinician
Since large convergent movements in early
infancy are predictive of normal binocular align-
ment, infantile esotropia does not result from
excessive convergence.
3.5 Pathogenetic Role of Dissociated
Eye Movements in Infantile Esotropia
Contrary to the stereotype of congenital esotropia as a
large-angle deviation that is present at birth, most cases of
congenital esotropia are acquired (i.e., infantile in ori-
gin) [25, 32]. Furthermore, the eyes do not simply snap in
to their nal esotropic position. Before 12 weeks of age,
nascent infantile esotropia is an intermittent, variable
esodeviation that gradually becomes constant after build-
ing in intensity to a large, 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 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. That this esodeviation appears during
the early period when stereopsis is developing, but before
macular anatomy has matured suciently 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 eort 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 eects of vergence adaptation.
Dissociated esotonus may provide the sensorimotor
substrate for vergence adaptation when binocular cortical
control mechanisms fail to take hold. The nding of a pos-
itive Bielschowsky phenomenon in dissociated horizontal
deviation [15, 17] shows that peripheral luminance reexes
are retained, as in dissociated vertical divergence [37]. In
this setting, both peripheral (luminance and optokinetic)
29
and central (xational) reexes augment dissociated eso-
tonus, and lead over time to infantile esotropia. Subcortical
visual reexes would provide the default system through
which dissociated esotonus operates to re-establish the
baseline horizontal eye position. This process can ulti-
mately lead to loss of sarcomeres and secondary shorten-
ing of the medial rectus muscles. The fact that the eyes
straighten considerably under general anesthesia [18, 22,
29, 38, 39], however, suggests that esotonus is the driving
force for infantile esotropia, and that mechanical eects
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 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 often develop large-angle esotropia, latent nystag-
mus, dissociated vertical divergence, and a head turn to
xate in adduction with the preferred eye [18]. By con-
trast, early infantile esotropia is often characterized by
similar visual acuity in the two eyes, and with alternat-
ing suppression of the nonxating 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.
Summary for the Clinician
Dissociated esotonus may provide the physio-
logic substrate for vergence adaption in infancy.
If so, then dissociated esotonus is the cause,
rather than the eect, of infantile esotropia.
The prevailing concept of infantile esotropia as
the proximate cause of dissociated deviations
may need to be revised.
Acknowledgment Portions of this chapter have 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 figures in this chapter are used with permission from
the American Medical Association and the American
Ophthalmological Society. This chapter is abstracted from
an American Ophthalmological Society thesis [6].
 30 3 A Dissociated Pathogenesis for Infantile Esotropia
References
1. Bielschowsky A (1904) ber die Genese einseitiger
Vertikalbewegungen der Augen. Z Augenheilkd 12: 545557
3 2. Bielschowsky A (1930) Die einseitigen und gegensinnigen
(dissoziierten) Vertikalbewegungen der Augen. Albrecht
Von Graefes Arch Ophthalmol 125:493553
3. Bielschowsky A (1938) Disturbances of the vertical motor
muscles of the eye. Arch Ophthalmol 20:175200
4. Lyle TK (1950) Worth and Chavasses Squint. The binocu-
lar reexes and treatment of strabismus. Blakiston,
Philadelphia, pp 4041
5. Brodsky MC (2005) Visuo-vestibular eye movements.
Infantile Strabismus in Three Dimensions. Arch Oph-
thalmol 123:837842
6. Brodsky MC (2007) Dissociated horizontal deviation: clin-
ical spectrum, pathogenesis, evolutionary underpinnings,
diagnosis, treatment, and potential role in the development
of infantile esotropia. Transact Am Acad Ophthalmol 105:
272293
7. Brodsky MC, Fray KJ (2007) Dissociated horizontal devia-
tion after surgery for infantile esotropia clinical charac-
teristics and proposed pathophysiologic mechanisms. Arch
Ophthalmol 125:16831692
8. Brodsky MC, Fray KJ (2007) Does infantile esotropia arise
from a dissociated deviation? Arch Ophthalmol 125:
16831692.
9. Proceedings of the Smith-Kettlewell Ocular Motor Tonus
Symposium. Tiberon, California, (June 24, 2006) pp 24
10. Spielmann A (1990) Dsquilibres verticaux et torsionnels
dans le strabisme prcoce. Bull Soc Ophtalmol Fr
4: 373384
11. Quintana-Pali L (1990) Desviacion horizontal disociada.
Bol Oftalmol Hosp de la Luz 42:9194
12. Romero-Apis D, Castellanos-Bracamontes A (1990)
Desviacion horizontal disociada (DHD). Rev Mex Oftalmol
64:169173
13. Romero-Apis D, Castellanos-Bracamontes A (1992)
Dissociated Horizontal deviation: clinical ndings and
surgical results in 20 patients. Binoc Vis Q 7:173178
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 173176
15. Wilson ME, McClatchey SK (1991) Dissociated horizontal
deviation. J Pediatr Ophthalmol Strabismus 28:9095
16. Wilson ME (1993) The dissociated strabismus complex.
Binocul Vis Strabismus Q 8:4546
17. Zabalo S, Girett C, Domnguez D, Ciancia A (1993)
Exotropia intermitente con desviacin vertical discodiada.
Arch Oftalmol B Aires 68:1120
18. Thouvenin D, Nogue S, Fontes L, Norbert O (2004)
Strabismus after 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 147152
19. Wilson ME, Hutchinson AK, Saunders RA (2000)
Outcomes from surgical treatment for dissociated hori-
zontal deviation. J AAPOS 4:94101
20. Burian HM (1971) Pathophysiology of exodeviations. In:
Manley DR (ed) Symposium on horizontal ocular devia-
tions. CV Mosby, St Louis, pp 119127
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 226:235240
23. Kushner BK (1992) Exotropic deviations: a functional clas-
sication and approach to treatment. Am Orthop J 38:
8193
24. Kushner BJ, Morton GV (1998) Distance/near dierences
in intermittent exotropia. Arch Ophthalmol 116:478486
25. Pritchard C (1998) Incidence of dissociated vertical
deviation in intermittent exotropia. Am Orthop J 48:
9093
26. Moore S, Cohen RL (1985) Congenital exotropia. Am
Orthop J 35:6870
27. Rubin SE, Nelson LB, Wagner RS, et al (1988) Infantile
exotropia in healthy infants. Ophthalmic Surg 19:
792794
28. Hunter DG, Kelly JB, Ellis FJ (2001) Long-term outcome
of uncomplicated infantile exotropia. J AAPOS 5:
352356
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 10011010
30. Horwood A (2003) Too much or too little: neonatal ocular
misalignment frequency can predict lateral abnormality.
Br J Ophthalmol 87:11421145
31. Horwood AM, Riddell PM (2004) Can misalignments in
typical infants be used as a model for infantile esotropia?
Invest Ophthalmol Vis Sci 45:714720
32. Pediatric eye disease investigator group. (2002) Spontaneous
resolution of early-onset esotropia: Experience of the con-
genital esotropia observational study. Am J Ophthalmol
133:109118
33. Pediatric eye disease investigator group. (2002) The clinical
spectrum of early-onset esotropia: Experience of the con-
genital esotropia observational study. Am J Ophthalmol
133:102108

34. Ing MR (1994) Progressive increase in the quantity of devi-
ation in congenital esotropia. Trans Am Ophthalmol Soc
92:117131
35. Fawcett SL, Wang YZ, Birch EE (2005) The critical period
for susceptibility of human stereopsis. Invest Ophthalmol
Vis Sci 46:521525
36. Guyton DL (2006) Changes in strabismus over time: the
roles of vergence tonus and muscle length adaptation.
Binocul Vis Strabismus Q 21:8192
References 31
37. Brodsky MC (1999) Dissociated vertical divergence. A
righting reex gone wrong. Arch Ophthalmol 117:
12151222
38. Apt L, Isenberg S (1977) Eye position of strabismic
patients under general anesthesia. Am J Ophthalmol 84:
574579
39. Roth A, Speeg-Schatz C (1995) Eye muscle surgery. Basic
data, operative techniques, surgical strategy. Swets and
Zeitlinger, Masson, Paris, pp 283324
 Chapter 4
The Monoxation Syndrome: New
Considerations on Pathophysiology
Kyle Arnoldi
Core Messages
Parks monoxation 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 monoxation 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
monoxation.
4.1 Introduction
In 1969, in his American Ophthalmological Society the-
sis, Marshall Parks described 100 patients with a specic
set of sensory ndings: a foveal suppression scotoma;
peripheral sensory fusion; motor fusion amplitudes
(fusional vergence); and gross stereopsis. He termed this
constellation of ndings the monoxation syndrome
(MFS) to distinguish it from bixation (or bi-foveal 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
4
MFS associated with small angle esotropia is
the most common form, the most stable, and
the form that allows for the best binocular
vision. This may be due to the natural superior-
ity of the nasal retina and its input to the visual
cortex.
Monoxation is a desirable state when bixation
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 monoxation in
favor of bixation.
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 sucient to overcome the
deviation? What is the state of binocular correspondence
in the strabismic and nonstrabismic cases of MFS? Can
monoxation 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
The MFS is an abnormality of binocular vision. In normal
binocular vision, bilateral retinal input from overlapping
visual elds is projected to the same general location in
the visual cortex, stimulating adjacent ocular dominance
columns of opposite ocularity [2]. This close proximity of
input from the two eyes corresponding to the same point
in space facilitates the communication necessary for bin-
ocular single vision. This communication appears to take
 34 4 The Monoxation Syndrome: New Considerations on Pathophysiology
place within a population of binocular cells, neurons that
receive input from both eyes and are sensitive to image
disparity. These cells are prevalent throughout the super-
cial and deep layers of area V1, as well as several areas
4 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 eects on the
population of binocular cells. The supply of binocular
cells throughout area V1 is decimated [3]. Yet objective
evidence of binocular cortical processing has been found
in human subjects with small angle strabismus and MFS
[4, 5]. The question then arises, how is it that these
patients can achieve fusion and stereopsis?
One theory is that the cortical adaptation that occurs
in response to a small angle ocular deviation is limited to
suppression of the foveal ocular dominance columns in
area V1. This would preserve the parafoveal columns and
allow for normal, though limited binocular communica-
tion with gross stereopsis [3]. This theory also implies
that the anomalous motor fusion present in MFS is also
driven by the disparity-sensitive neurons that are located
at this earliest stage of binocular processing [6]. In this
paradigm, retinal correspondence would be considered
normal, as no cortical rewiring would be needed to 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. This adaptation does involve a rewiring that
could be considered the anatomic basis of anomalous
retinal correspondence (ARC) [7, 8]. For example, it has
been demonstrated in esotropic cats that if the angle of
strabismus is small (<10), the binocular neurons in the
lateral suprasylvian cortex (area LS) may be spared,
though their receptive elds are shifted so that normally
noncorresponding retinal elements may communicate
[9, 10]. Area LS of the cat is functionally analogous to area
MT in the primate.
Regardless of where the adaptation takes place, it
appears that the visual cortex may be most successful in
achieving fusion in the presence of a tropia when it can
combine information from cell populations that are no
more than two cortical neurons distant [11]. At approxi-
mately 7 mm in length, the typical cortical neuron is
theoretically capable of joining visual receptive 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
eectively 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 Panums
fusional space in the peripheral eld (Parks conclusion),
or even a combination of the two. Some authors have
found NRC in the central visual 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 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 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 Panums area sur-
rounding the 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?
The state of retinal correspondence has historically been
dened as characteristic responses to specic clinical sen-
sory tests; responses which can be manipulated by many
dierent external factors [14]. Test results are also inu-
enced by both the patients ability to communicate and
the examiners 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, Panums 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,

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
The majority of patients with MFS have a manifest strabis-
mus, and esotropia is the most prevalent form by a wide
margin. The prevalence of micro-esotropia in several large
series of primary and secondary MFS has been reported
from 61 to 90% [1, 15]. MFS with small angle exotropia is
less common, occurring in 821% [1, 15, 16]. The preva-
lence of MFS associated with small angle vertical strabis-
mus is extremely low at 03% 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, monoxation 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 bixation 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
dierent populations of binocular cells within and beyond
area V1 that are sensitive to either relative or absolute reti-
nal image disparity. These cell groups give rise to stereopsis
or fusional vergence, respectively [19]. Vergence neurons
sensitive to crossed disparity (convergence) appear to be
naturally more numerous than those coding for uncrossed
disparity (divergence) in normal monkeys [6]. It is possible
that more convergence neurons survive the early insult sim-
ply because there is a preponderance of them to begin with.
The timing of the insult is probably also contributory
to the prevalence of small angle esotropia in MFS. Eye
4.3 MFS with Manifest Strabismus 35
alignment and fusional vergence is immature in neonates,
but more often results in transient over-convergence as
opposed to over-divergence [20]. Pathways for nasally
directed pursuit are more developed at birth compared
with those for temporally directed pursuit. Interruption of
maturation due to an insult such as early-onset, unrepaired
strabismus, leads to permanent monocular naso-temporal
pursuit asymmetry [21]. It may also lead to latent nystag-
mus, which typically features a pathologic nasally directed
pursuit movement of the xating eye, followed by a physi-
ologic temporal-ward rexation saccade [18]. These motor
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.
The maximum angle of strabismus that still allows for
fusional vergence is not yet known, though the most robust
convergence response to binocular image disparity in
monkeys with MFS occurs at 4.04.5D of crossed disparity
[22], once again corresponding with the length of the aver-
age cortical neuron. The motor fusion amplitudes of
human subjects with MFS have been found to be within
the normal range by some [1, 13, 23], and present but sub-
normal by others [24]. Though patients with MFS often
have fusional vergence sucient to overcome small angles
of strabismus, most patients with MFS maintain a manifest
strabismus. The logical conclusion is that, in patients with
MFS, there is a greater functional benet to keeping the
eyes slightly misaligned, particularly on the esotropic side.
MFS with esotropia diers slightly from MFS with
exo- or hypertropia. Not only is it more common, but it is
the form that allows for the best binocular vision. In a
large series, the micro-ET group out-performed the other
two alignment categories by a wide margin in each of the
three sensory categories: sensory fusion, motor fusion,
and stereopsis [15]. The most striking dierence in the
sensory exam was found in the motor fusion category.
 36 4 The Monoxation Syndrome: New Considerations on Pathophysiology
Both primary and secondary micro-esotropes were sig-
nicantly more likely to have disparity vergence than the
exotropes or hypertropes.
Why might binocular vision be better in MFS with
4 esotropia? In esotropia, the fovea of the xating eye must
communicate with a nonfoveal point on the nasal retina
of the deviating eye to achieve fusion. In exotropia, the
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 [2528]. 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 dierence 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 [3234].
The critical period for the development of the temporal
retina and its connections in the visual cortex begins
later and takes longer to complete than that for nasal
retina [31]. And 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.
This presents a particular problem for exotropia. If
inputs from the temporal retina are less numerous,
delayed in development, relatively suppressed, and more
vulnerable to the deleterious eects 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. The larger the angle of exotropia,
the fewer are the temporal cortical neurons available to
link with the columns of the dominant eye because of the
increase in the ratio of dominance with retinal eccentric-
ity. The relative suppression of these temporal neurons
may result in poor quality communication, even if a link
could be established.
4.3.3 Esotropia is the Most Stable Form
Good binocular vision is associated with stability, but does
not guarantee lasting alignment. Studies have found that
stability of alignment in microtropia is not permanent,
even in the presence of high-quality binocular vision [15,
36, 37]. Twenty-four to 26% of MFS cases deteriorate over
a period of 5.517.5 years [15, 36, 37]. In these studies,
deterioration was not the result of loss of sensory status.
Following treatment, 4880% of subjects were able to
regain monoxation 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 signicant 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 eect. Neither of these factors appears to
have an eect 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 bixation
with fusion and high grade stereopsis, which is consider-
ably more dicult. Most researchers (including Parks)
believe that a patient with MFS cannot be restored to
bixation [1, 13, 38, 39]. There is also very little in the
current literature to suggest that this is possible. A single
study claims to have cured MFS in nine patients [40], and
another reports a spontaneous resolution of MFS and
amblyopia in a small group of older children and teenag-
ers [41]. In the former study, of 30 patients with amblyo-
pia and eccentric 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].

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 monoxation persists and the devia-
tion recurs. Normal or near-normal fusional vergence in
these patients assures that alignment will be maintained
at the visual systems preferred angle, regardless of
attempts at intervention. In addition, patients with MFS
are typically asymptomatic and already enjoy high quality
binocular vision. If bixation could be restored, it may
not result in a signicant 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. The cases in the literature
suggest that suppression cannot be relearned once
unlearned [43]. However, the prognosis may depend on
what caused the loss of suppression, as Case 4.2 shows.
Because MFS cannot or perhaps should not be cured
once established, a better question might be Can MFS be
prevented in favor of bixation? 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. This is a
challenging hypothesis to study in human subjects; such
early intervention is often logistically dicult. An animal
model is better suited to answer this question.
4.4.1 Animal Models for the Study of MFS
There are several valid methods for creating the clinical
conditions associated with the development of MFS.
Large angle esotropia has been surgically induced in
infant monkeys [23], or simulated with the use of prism
glasses [18, 21]. One can create large angle sensory stra-
bismus through monocular or binocular occlusion early
in life [4446]. 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), bixation can result
in some animals [3, 6]. If delayed for up to 24 weeks,
bixation 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
4.4 Repairing and Producing MFS 37
Case 4.1
A 5-year old female was diagnosed with monox-
ation syndrome following a failed pre-school vision
screening. The 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. The patient was
6-years old when presented to the ophthalmologist.
Vsc: 20/20
20/25
Motility:
Dsc
LET 5 with simultaneous prism and cover test
Builds to E 20 with prism and alternate cover
Nsc
LET 5 with simultaneous prism and cover
Builds to E(T) 20 with prism and alternate
cover
Sensory:
Constant, uncrossed diplopia at distance and near,
unrelieved with any combination of prism.
Amblyoscope examination:
Objective angle (Grade I target) = +20
Subjective angle (Grade I target) = +5
Grade II: constant, variable diplopia, no sensory
fusion, no suppression; as image approaches +5
on amblyoscope, diplopia converts from uncrossed
to crossed.
Management:
Bilateral medial rectus recessions were done for the
decompensating near deviation. At the 1-day post-
operative visit, the diplopia was unchanged. Exam-
ination results at that visit are as follows.
Post-op Motility:
Dsc:
LET 5 with simultaneous prism and cover test
Builds to E 20 with prism and alternate cover test
Nsc:
LET 5 with simultaneous prism and cover test
Builds to E 20 with prism and alternate cover test
Post-op Exam 2:
At 1 month following surgery, the motility and sen-
sory examinations were unchanged from presenta-
tion. The patient was oered an occlusion foil to
alleviate the diplopia. The mother declined as she
viewed this as a step backwards after all the vision
therapy that was done.
 38 4 The Monoxation Syndrome: New Considerations on Pathophysiology
Case 4.2
A 16-year old female with a history of monoxation syn-
drome presents with a 3-month history of constant hori-
4 zontal diplopia. The onset of the diplopia was abrupt,
following closed head trauma without loss of conscious-
ness, secondary to a motor vehicle accident. The patient
reports that the diplopic image is always present, but is
not always in the same location relative to xation and
appears to be constantly moving. Previous records doc-
ument a stable RET 6, with a superimposed phoria of
up to 18 in addition to the sensory features of monox-
ation syndrome.
Vcc: 20/20 OD Rx: +0.50 +1.00 090
20/20 OS Plano
Motility:
Dcc:
RET variable from 8 to 25
Ncc:
RET variable from 10 to 25
Sensory:
Constant uncrossed horizontal diplopia of variable
magnitude, unrelieved with prism. The addition of
base-out prism in free space appears to cause an
increase in the esodeviation, with diplopia.
Amblyoscope examination:
Objective angle (Grade I targets) = +25
There was no subjective angle at which the patient
could appreciate sensory fusion with either Grade I
or II targets.
Management:
The patient was prescribed a dense occlusion foil
(Bangerter Light Perception foil) for the right lens
of the glasses. At her 2-week follow-up, the lter
strength was reduced to Bangerter 0.2. Two weeks
later, the strength was reduced again to Bangerter
0.4. The 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.
dissociated vertical deviation [18, 21, 45, 46]. Research
shows that in the animal model, shorter durations of
image decorrelation result in better sensory outcomes.
These results imply that excellent outcomes may be pos-
sible in the human if alignment is restored within 90 days
of the onset of strabismus. This suggests that, if monox-
ation is to be prevented in favor of bixation, very early
detection and intervention is necessary.
4.5 Primary MFS (Sensory Signs
of Infantile-Onset Image Decorrelation)
The problem of primary MFS is one that has perplexed
Parks and others. Primary MFS accounts for 1619% of
all cases of monoxation [1, 15]. This subpopulation is
interesting, as it may represent the visual cortexs active
choice when bifoveal 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-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].
The 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. The 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 often
develop latent nystagmus, dissociated vertical deviation,
and A- or V-pattern incomitance, as well as demonstrate
persistent naso-temporal pursuit and OKN asymmetry
(see Sect. 4.5). The age of onset of binocular decorrelation
appears to determine whether these signs will be present,
and the duration of binocular decorrelation determines
the severity [18, 21, 4446]. 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. The only secondary abnor-
mality that has been found consistently thus far is

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. This is yet another query to be added to Parks
long list of questions about The Monoxation Syndrome.
Summary for the Clinician
The 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.
Monoxation may be preventable if the cause of
the image decorrelation is detected and repaired
promptly, probably within 6090 days of onset.
Once monoxation is present, attempting a cure is
unwise. MFS, particularly with small angle esotro-
pia, is relatively stable and allows for good binocular
vision so there is little to be gained. Antisuppression
and anti-ARC therapies designed to restore bi-
foveal xation typically result in intractable diplo-
pia. Attempted repair of the associated strabismus
with surgery or prism will not create bixation
once monoxation 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.
References
1. Parks MM (1969) The monoxation syndrome. Tr Am
Ophthalm Soc 67:609657
2. Hubel DH, Wiesel TN (1977) Functional architecture of
macaque monkey visual cortex. Philos Trans Roy Soc Lond.
198:159
3. Tychsen L (2005) Can ophthalmologists repair the brain in
infantile esotropia? Early surgery, stereopsis, monoxation
syndrome, and the legacy of Marshall Parks. J AAPOS
9:510521
References 39
4. Fawcett SL, Birch EE (2000) Motion VEPs, stereopsis, and
bifoveal fusion in children with strabismus. Invest
Ophthalmol Vis Sci 41:411416
5. Struck MC, VerHoeve JN, France TD (1996) Binocular cor-
tical interactions in the monoxation syndrome. J Pediatr
Ophthalmol Strabismus 33:291297
6. Tychsen L (2007) Causing and curing infantile esotropia in
primates: the role of decorelated binocular input. Trans
Am Ophthalmol Soc 105:564593
7. McCormack G (1990) Normal retinotopic mapping in
human strabismus with anomalous retinal correspondence.
Invest Ophthalmol Vis Sci 31:559568
8. Sireteanu R, Fronius M (1989) Dierent patterns of retinal
correspondence in the central and peripheral visual eld of
strabismics. Invest Ophthalmol Vis Sci 30:20232033
9. Grant S, Berman NE (1991) Mechanism of anomalous reti-
nal correspondence: maintenance of binocularity with
alteration of receptive-eld position in the lateral suprasyl-
vian (LS) visual area of strabismic cats. Vis Neurosci
7:259281
10. Sireteanu R, Best J (1992) Squint-induced modication of
visual receptive elds in the lateral syprasylvian cortex of
the cat: binocular interaction, vertical eect, and anoma-
lous correspondence. Eur J Neurophysiol 4:235242
11. Wong AMF, Lueder GT, Burkhalter A, Tychsen L (2000)
Anomalous retinal correspondence: neuro-anatomic
mechanism in strabismic monkeys and clinical ndings in
strabismic children. J AAPOS 4:168174
12. Fronius M, Sireteanu R (1989) Monocular geometry is
selectively distorted in the central visual eld of strabismic
amblyopes. Invest Ophthalmol Vis Sci 30:20342044
13. Harwerth RS, Fredenburg PM (2003) Binocular vision
with primary microstrabismus. Invest Ophthalmol Vis Sci
44:42934306
14. Arnoldi K (2004) The VII Burian memorial lecture: factors
contributing to the outcome of sensory testing in patients
with anomalous binocular correspondence. In: Verlohr D,
Georgievski Z, Rydberg A (eds) Global perspectives con-
verge downunder, the transactions of the Xth international
orthoptic congress. International Orthoptic Association,
Melbourne, Australia, pp 7380
15. Arnoldi K (2001) Monoxation with eso-, exo-, or hyper-
tropia: is there a dierence? Am Orthopt J 51:5566
16. Leske DA, Holmes JM (2004) Maximum angle of horizon-
tal strabismus consistent with true stereopsis. J AAPOS
8:2834
17. Choi DG, Isenberg SJ (2001) Vertical strabismus in
monoxation syndrome. J AAPOS 5:58
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 49:18721878
 40 4 The Monoxation Syndrome: New Considerations on Pathophysiology
19. Neri P, Bridge H, Heeger DJ (2004) Stereoscopic processing
of absolute and relative disparity in human visual cortex. J
Neurophysiol 92:18801991
20. Horwood A (2003) Neonatal ocular misalignments reect
4 vergence development but rarely become esotropia. Br
J Ophthalol 87:11461150
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 156:403411
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
44:33583368
23. Harwerth RS, Smith EL, Crawford ML, von Noorden GK
(1997) Stereopsis and disparity vergence in monkeys with
subnormal binocular vision. Vis Res 37:483493
24. Borman DK, Kertesz AE (1985) Fusional responses of stra-
bismics to foveal and extrafoveal stimulation. Invest
Ophthalmol Vis Sci 26:17311739
25. Curcio CA, Allen KA (1990) Topography of ganglion cells
in human retina. J Comp Neurol 300:525
26. Curcio CA, Sloan KR, Kalina RE, Hendrickson AE (1990)
Human photoreceptor topography. J Comp Neurol
292:497523
27. Perry VH, Silveira LC, Cowey A (1990) Pathways mediat-
ing resolution in the primate retina. Cib Found Symp
155:514
28. Wssle H, Grnert U, Rhrenbeck J, Boycott BB (1990)
Retinal ganglion cell density and cortical magnication
factor in the primate. Vis Research 30:18971911
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 388:3246
31. Lewis TL, Maurer D (1992) The development of the tem-
poral and nasal visual elds during infancy. Vis Research
32:903911
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 22:7986
33. Bowering ER, Maurer D, Lewis TL, Brent HP (1993)
Sensitivity in the nasal and temporal hemields in children
treated for cataract. Invest Ophthalmol Vis Sci 34:
35013509
34. Merigan WH, Katz LM (1990) Spatial resolution across the
macaque retina. Vis Research 30:985991
35. Cisarik PM, Harwerth RS (2008) The eects of interocular
correlation and contrast on stereoscopic depth magnitude
estimation. Optom Vis Sci 85:164173
36. Arthur BW, Smith JT, Scott WE (1989) Long-term stability
of alignment in the monoxation syndrome. J Pediatr
Ophthalmol Strabismus 26:224231
37. Hunt MG, Keech RV (2005) Characteristics and course of
patients with deteriorated monoxation syndrome.
J AAPOS 9:533536
38. Pratt-Johnson JA, Tillson G (2001) Management of strabis-
mus and amblyopia, 2nd edn. Thieme, 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
xed phenomenon? Br J Ophthalmol 82:219224
41. Keiner EC (1978) Spontaneous recovery in microstrabis-
mus. Ophthalmologica 177:280283
42. vonNoorden GK, Campos EC (2002) Binocular vision and
ocular motility, 6th edn. Mosby, St. Louis, pp 344345
43. Qur MA, Lavenant G, Pchereau A (1993) Les diplopies
incoercibles post-thrapeutiques. J Fr Orthopt 25:191
44. Das VE, Fu LN, Mustari MJ, Tusa RJ (2005) Incomitance in
monkeys with strabismus. Strabismus 13:3341
45. Fu LN, Tusa RJ, Mustari MJ, Das VE (2007) Horizontal sac-
cade disconjugacy in strabismic monkeys. Invest
Ophthalmol Vis Sci 48:31073114
46. Tusa RJ, Mustari MJ, Das VE, Boothe RG (2002) Animal
models for visual deprivation-induced strabismus and nys-
tagmus. Ann NY Acad Sci 956:346360
47. Wensveen JM, Harwerth RS, Smith EL (2003) Binocular
decits associated with early alternating monocular defocus.
I. Behavioral observations. J Neurophysiol 90: 30013011
48. Zhang B, Matsura K, Mori T, Wensveen JM, Harwerth RS,
Smith EL Chino Y (2003) Binocular decits associated
with early alternating monocular defocus, neurophysiolog-
ical observations. J Neurophysiol 90:30123023
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 102:90269031
 Chapter 5
Visual Cortex Mechanisms
of Strabismus: Development
and Maldevelopment
Lawrence Tychsen
Core Messages
Proper alignment of the eyes requires informa-
tion sharing (fusion) between monocular visual
input channels in the CNS; the 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 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
5.1 Esotropia as the Major Type
of Developmental Strabismus
Esotropia is the leading form of developmental strabismus.
Therefore, unraveling the causal mechanism and response
to treatment is an important public health issue. The 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. The
largest peak (comprising ~40% of all strabismus) occurs
at or before age 1218 months, with a second, smaller
late onset esotropia peak at age 34 years. Children with
5
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/monoxation) 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.
early-onset esotropia are predominantly emmetropic [1],
whereas late-onset esotropia is associated commonly with
a substantial hypermetropic refractive error (accommo-
dative esotropia). The most prevalent form of develop-
mental strabismus in humans is concomitant, constant,
nonaccommodative, early-onset esotropia. Most of these
cases have onset in the 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
 42 5 Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment
mechanisms should begin by asking what factors con-
tribute to its causation. At highest risk are infants who
suer cerebral maldevelopment from a variety of causes
(Table 5.1), especially insults to the parieto-occipital cor-
5 tex and underlying white matter (geniculostriate projec-
tions or optic radiations) [3, 57]. Periventricular and
intraventricular hemorrhage in the neonatal period
increases the prevalence of infantile strabismus 50100-
fold. Less specic 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 2030-fold
[4, 710].
5.1.3 Cytotoxic Insults
to Cerebral Fibers
The occipital lobes in newborns are vulnerable to dam-
age [6, 1214]. Premature infants frequently suer
injury to the optic radiations near the occipital trigone.
Balanced binocular input requires equally strong pro-
jections from each eye through this periventricular
zone. The bers connect the lateral geniculate laminae
to the ocular dominance columns (ODCs) of the striate
cortex. The projections are immature at birth and the
quality of signal ow would be critically dependent
upon the function of oligodendrocytes, which insulate
the visual bers. Neonatal oligodendrocytes are espe-
cially vulnerable to cytotoxic insult [15]. The striate
cortex is also susceptible to hypoxic injury because it
has the highest neuron-to-glia ratio in the entire cere-
brum [16] and the highest regional cerebral glucose
consumption [17].
Table 5.1. Cerebral damage risk factors for infantile-onset strabismus
Type
Intraventricular hemorrhage with hydrocephalus
Cerebral visual pathway white matter injury
Occipitoparietal hemorrhage or leukomalacia
Very low birth weight infants (<1,500 g)
Very low birth weight (<1,251 g) and prethreshold
retinopathy of prematurity
Very low birth weight (<1,251 g) and normal
neuroimaging
Down syndrome
Healthy full-term infants
a
Additional 17% of infants had persistent asymmetric OKN
5.1.4 Genetic Inuences 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]. The 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 dierent
thresholds for expression of each allele. These 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 after a latency of several months,
becoming conspicuous on average between the ages of 2
and 5 months [11, 21, 22]. To understand visuomotor
maldevelopment in strabismic infants during this period, it
is helpful to understand the development of binocular
fusion and vergence in normal infants (Table 5.2) during
the same 25-month postnatal interval.
Prevalence strabismus (%) Author(s)
100 [3]
76 [4]
5457 [5, 6]
33a [7]
30 [8]
17 [4]
2141 [9, 10]
0.51.0 [11]
 5.1 Esotropia as the Major Type of Developmental Strabismus 43

Table 5.2. Binocular development and visuomotor behaviors in infant primate

Immature behavior Chief ndings before onset Investigator(s)

of mature behavior
Binocular disparity Stereo-blindness [23]
sensitivity absent Convergent disparity sensitivity [24, 25]
before ~35 mos emerges earlier than divergent [26]
Binocular sensorial Equal attraction to rivalrous vs. [27, 25]
fusion absent before fusible stimuli [28]
~35 mos
Fusional (binocular) Binocular alignment errors common [29, 30]
vergence unstable despite accommodative capacity [27]
before ~35 mos [31]
[32, 33]
Nasalward bias of vergence Transient convergence errors 4X [34]
pronounced divergence errors
before ~35 mos Convergent disparity sensitivity
present earlier than
divergent
Convergence fusion range exceeds [32, 33]
divergence by 2:1
Nasalward bias of cortically mediated Motion VEP nasotemporal asymmetry [35, 36]
motion sensitivity before ~6 mos Stronger preferential sensitivity [37]
to nasalward motion [38]
[39]
Nasalward bias of pursuit/OKN Nasalward motion evokes stronger [40]
before ~6 mos OKN/pursuit [41]
Nasotemporal asymmetry resolves [42]
after onset binocularity [43]
[44]
[45]
Nasalward bias of gaze-holding Nasalward slow phase drift [42]
before ~6 mos of eye position [46]
Persists as latent xation [47]
nystagmus with binocular
maldevelopment

life, achieving adult-like levels of sensitivity. Sensitivity to

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 [2325,
27, 28]. The FPL studies show that stereopsis emerges
abruptly in humans during the rst 35 months of postnatal
crossed (near) disparity appears on average several weeks
before that to uncrossed (far) disparity [24]. During this
same interval infants begin to display an aversion to stimuli
that cause binocular rivalry (i.e., nonfusable stimuli).
Visually evoked potentials in normal infants, recorded using
dichoptic viewing and dichoptic stimuli, show comparable
results [43, 48, 49]. Onset of binocular signal summation
occurs after, but not before, ~3 months of age.
 44 5 Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment
5.1.7 Development of Fusional
Vergence and an Innate
Convergence Bias
5 Fusional vergence eye movements mature during an
equivalent period in early infancy. In the rst 2 months of
life, alignment is unstable and the responses to step or
ramp changes in disparity are often markedly inaccurate
[32, 33]. The inaccuracy cannot be ascribed to errors of
accommodation. Accommodative precision during this
period consistently exceeds that of fusional (disparity)
vergence [29, 30, 33].
Studies of fusional vergence development in normal
infants reveal an innate bias for convergence [32, 33].
Transient convergence errors of large degree exceed
divergence errors by a ratio of 4:1. The fusional vergence
response to crossed (convergent) disparity is also intact
earlier and substantially more robust than that to diver-
gent disparity. The innate bias favoring fusional conver-
gence in primates persists after full maturation of normal
binocular disparity sensitivity. Fusional convergence
capacity exceeds the range of divergence capacity by a
mean ratio of 2:1 [50, 51].
5.1.8 Development of Motion Sensitivity
and Conjugate Eye Tracking
(Pursuit/OKN)
The innate nasalward bias of the vergence pathway has
analogs in the visual processing of horizontal motion,
both for perception and conjugate eye tracking. In the
rst months of life, VEPs elicited by oscillating grating
stimuli (motion VEPs) show a pronounced nasotempo-
ral asymmetry under conditions of monocular viewing
[3538]. The direction of the asymmetry is inverted
when viewing with the right vs. left eye. Monocular FPL
testing reveals greater sensitivity to nasalward motion
[39]. Monocular pursuit and optokinetic tracking show
strong biases favoring nasalward target motion when
viewing with either eye [40, 41, 4345]. Optokinetic
after-nystagmus (slow phase eye movement in the dark
after extinction of stimulus motion) is characterized by a
consistent nasalward drift of eye position [42]. These
nasalward motion biases are most pronounced before
the onset of sensorial fusion and stereopsis, but system-
atically diminish thereafter.
5.1.9 Development and Maldevelopment
of Cortical Binocular Connections
Knowledge of visual cortex development (Table 5.3) is
important for understanding the neural mechanisms that
could cause strabismus, for several reasons. First, the
visual cortex is the initial locus in the CNS at which visual
signals from the two eyes are combined and a 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. Third,
perinatal insults to the immature visual cortex are linked
strongly to subsequent onset of strabismus. And nally,
the constellation of sensory and motor decits in infantile
strabismus can be explained by known cortical pathway
mechanisms.
5.1.10 Binocular Connections Join Monocular
Compartments Within Area V1 (Striate
Cortex)
Aerents from each eye are segregated in monocular
lamina of the lateral geniculate nucleus (LGN) and at the
input layer (4C) of ODCs of the striate cortex, or visual
area V1 (Fig. 5.1) [52, 53]. The 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 26
[52, 54, 63]. The binocular responses in the neonate are
cruder and weaker than those recorded in normal adult
[58, 59, 77]. Binocular disparity sensitive neurons are
present in the neonatal cortex, but the spatial tuning is
poor and they are characterized by a high binocular sup-
pression (inhibition) index. The immature neuronal
response properties are attributed to unrened, weak
excitatory horizontal binocular connections between
ODCs. These axonal connections help dene the segrega-
tion of ODCs [62, 77]. ODC borders are immature (fuzzy)
at birth but adult-like (sharply dened) by 36 weeks
postnatally [60, 78] (the equivalent of 36 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
Striate cortex (area V1) is the rst
CNS locus for binocular processing
Binocular structure + function in
V1is immature at birth
Maturation of binocular connectivity
in V1 requires correlated RE/LE input
V1 feeds forward to extrastriate visual areas
MT/MST which control ipsiversive eye
tracking and gaze holding
V1 feed forward connections to MT/MST
at birth are monocular from ODCs
driven by the contralateral eye
MST inputs from the ipsilateral eye require
maturation of binocular V1/MT
connections
MST neurons encode both vergence
and pursuit/OKN
Convergence motoneurons are
more numerous
5.1 Esotropia as the Major Type of Developmental Strabismus 45
Physiology/anatomy Investigator(s)
Right and left eye inputs remain [52, 53]
segregated in LGN and input
layer (4C) in V1
Binocular responses recorded from [54]
neurons in V1 lamina beyond layer 4C
Neurons in V1 layers 26 are sensitive [55]
to binocular disparity
Segregation of RE/LE ODCs immature at birth [56]
Binocular (disparity sensitive) neurons [57]
present at birth but tuning poor
Immature binocular neurons have weak [58, 59]
excitatory horizontal connections [60, 61]
between ODCs and high suppression index [62]
Absence of correlation causes lack of disparity [63, 64, 65]
sensitivity and loss of horizontal [66]
connections in V1 [67, 68, 69, 70]
Extrastriate areas MT/MST mediate [71, 72]
pursuit/OKN and recieve feedforward [73, 74]
(binocular)projections from V1 lamina [75]
4B Lesions of MST impair ipsiversive
pursuit/OKN and gaze holding
Before maturation of binocularity, a nasalward [76]
movement bias is apparent when viewing with either
eye (RE viewing evokes leftward pursuit/OKN/gaze
drift; LE viewing evokes rightward
pursuit/OKN/gaze drift)
Nasalward + temporalward neurons are [77]
present in = numbers within V1/MT but [13]
nasalward have innate connectivity advantage
If binocularity matures, monocular viewing [76]
evokes equal nasalward/temporalward eye movement + [13, 47]
stable gaze
Disparity sensitive neurons in MST also [81]
mediate vergence [80]
If binocularity fails to mature, monocular viewing evokes [105]
nasalward pursuit/OKN and inappropriate convergence [82, 47]
Convergence neurons outnumber divergence neurons 3:2 in [122, 123]
the midbrain of normal primates
 46 5 Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment

a 2/3

Fusion/stereopsis 4B
Alignment and 4C
Balanced Gaze
5
Ocular Dominance Columns R L R L
of V1 (Striate Cortex)
Correlated
LGN
2/3 Activity
4B
4C b
Stereo-blindness

R L R L Esotropia and
Gaze Asymmetries
Periventricular
White Matter
R L R L
Projections

Fig. 5.1 Neuroanatomic basis for binocular vision. Monocular
retinogeniculate projections from left eye (temporal retina-nasal
visual hemiled) and right eye (nasal retina-temporal hemield)
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
De-Correlated
Activity
Fig. 5.2 Horizontal connections for binocular vision in V1 of
normal (correlated activity) vs. strabismic (decorrelated) pri-
mate, layer 24B. (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

5.1.12 Projections from Striate Cortex (Area V1)

5.1.11 Too Few Cortical Binocular to Extrastriate Cortex (Areas MT/MST)
Connections in Strabismic
Primate Projections from V1 layer 4B feed forward to regions of
extrastriate visual cortex, in particular the middle tempo-
Maturation of binocular connections in V1 requires
ral and middle superior temporal area (MT/MST) [75].
correlated (synchronous) activity between right and
MT and MST mediate pursuit/OKN and a closely related
left eye inputs (Fig. 5.2a) [66]. Decorrelation of inputs,
type of tracking movement, ocular following [73, 74].
by natural strabismus [68, 70], or as a consequence of
MT/MST neurons are directionally selective and sensi-
experimental manipulations that produce retinal image
tive to binocular disparity, guiding both conjugate and
noncorrespondence [66, 67], causes loss of binocular
disconjugate (near-far) tracking [8082]. In normal pri-
horizontal connections (Fig. 5.2b). Monocular connec-
mates, greater than 90% of MT/MST neurons exhibit bal-
tions between ODCs of the same ocularity are
anced, binocular responses. In strabismic primates, the
maintained. The loss is due to excessive pruning of
responses are predominantly monocular, indicating that
connections, beyond the normal process of axon retrac-
the loss of binocularity found in V1 is passed on in the
tion and renement that takes place within and between
projections to MT/MST.
ODCs in the rst weeks of life. (Captured in the neuro-
science dictum: Cells that re together, wire together.
Cells that re apart, depart.) The paucity of binocular
5.1.13 Inter-Ocular Suppression Rather than
connections is accompanied by loss of binocular
Cooperation in Strabismic Cortex
responsiveness and disparity sensitivity, measured
electrophysiologically, in V1 neurons [55, 63, 64]. The When the eyes are misaligned, suppression is necessary
companion behavioral decits are stereoblindness and to avoid diplopia or visual confusion. Suppression is a
absence of fusional vergence [47, 65]. major sensorial abnormality in humans and monkeys
 5.1 Esotropia as the Major Type of Developmental Strabismus
with infantile strabismus. Visual inputs may be suppressed
from one eye continuously (causing unilateral amblyo-
pia), or commonly in infantile strabismus, from each eye
alternately ~50% of the time (alternate xation) [83, 84].
In normal animals, horizontal connections between
ODCs can mediate suppression when conicting stimuli
activate neurons in neighboring ODCs [85, 86].
The mitochondrial enzyme cytochrome oxidase (CO)
is used to reveal neuronal activity within ODCs [8789].
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), reecting equal activity (absence
of inter-ocular suppression). Unequal CO activity is a gen-
eral nding in area V1 of primates who have strabismus
[78, 90], amblyopia [91], or both [92]. The unequal activity
is seen as reduced CO activity (metabolic suppression) in
the ODCs driven by one eye in each cerebral hemisphere
(Fig. 5.3b). When strabismus is combined with amblyopia,
metabolic suppression is more pronounced.
The CO abnormality in monkey cortex correlates with
clinical observations in strabismic humans. Binocularity
is impaired to a greater degree, and suppression tends to
be more pronounced, in patients who have combined
a 2/3
Equal Neuronal
Metabolic Activity
R L R L
Normal
b be most apparent in ODCs driven by the ipsilateral eye in
Inter-ocular
Metabolic
Suppression
R L R L
Strabismic
Fig. 5.3 Metabolic activity in neighboring ODCs within V1 of
normal vs. strabismic primate. (a) In normal, Layer 4C stains
uniformly for the metabolic enzyme cytochrome oxidase (CO)
(shown as brown), indicating equal activity in right-eye vs. left-eye
columns. (b) In strabismic, a narrow monocular zone within the
dominant ODCs (shown here as left-eye) shows normal 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
47
strabismus and amblyopia, as compared with strabismus
alone (that is, alternating xation). The metabolic abnor-
malities are found throughout V1 when suppression is
widespread; alternatively, suppression is conned to
zones of V1 that match retinotopically the location of a
suppression scotoma. The metabolic suppression is not
found in the LGN, which is composed of neurons driven
monocularly from each eye without binocular interac-
tion. These 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. The abnormalitis
add to our knowledge of the brain damage caused by
unrepaired strabismus. As noted in the preceding sec-
tions, the eects 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
4B
hemields in normal human infants indicate that tempo-
ral retina sensitivity matures slower than nasal retina sen-
4C
sitivity [94, 95]. The 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
[9698] (for review, see [78]).
In strabismic animals, metabolic suppression tends to
V1 of both the right and left hemispheres. Ipsilateral inputs
originate from the temporal hemi-retinae of each eye,
implying that inputs to V1 from the temporal hemiretinae
are at a developmental disadvantage [78, 92, 99]. The
human psychophysical ndings, together with the monkey
anatomic 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
 48 5 Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment

do not resolve they persist and become pronounced [46,
100102]. Normally, area MST in each cerebral hemi-
sphere encodes ipsiversive eye tracking and gaze holding
(Fig. 5.4). Ablations within MST impair ipsiversive pur-
5 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]. The contralateral-

Strabismic Normal

chi

RE LE RE LE RE LE RE LE

call

nasalward gaze stable gaze

instability

Fig. 5.4 Neural network diagrams showing visual signal 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 xation
nystagmus. Note that in all primates, pursuit area neurons in each hemisphere encode ipsilaterally directed pursuit. Signal ow is
initiated by a moving stimulus in the monocular visual 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 eld of right eye. Retinal ganglion cell 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-eld)
occupy slightly more cortical territory than those representing the temporal hemiretinae (nasal hemield), but each ODC contains
neurons sensitive to nasally directed vs. temporally directed motion (half circles shaped like the matching hemield, 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
 5.1 Esotropia as the Major Type of Developmental Strabismus 49

eye-to-MST connectivity advantage is consistent with an
innate, contralateral-eye-to-V1 connectivity advantage.
(Captured in twin dictums: rst come, 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.
The 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. The
left area MST mediates ipsiversive/leftward tracking,
which is nasalward tracking with respect to the viewing
(right) eye. When binocular connections mature, right
eye ODCs gain equal access to neurons within areas MST
of the right and left hemisphere, and the nasalward bias
disappears. (Captured in the dictum: Tracking from ear
to nose will balance as binocularity grows.) If binocular
connections are lost, the nasalward bias persists and is
exaggerated. The bias is evident clinically (Fig. 5.5) as a
pathologic naso-temporal asymmetry of pursuit/OKN
and a nasalward (slow phase) drift of gaze-holding (latent
nystagmus) [103, 104].
Area MST neurons are sensitive to binocular disparity
and also drive fusional vergence eye movements [80, 82].
Eye movement recordings in a primate with infantile
esotropia showed inappropriate activation of 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. The

Fusional Vergence (esotropia)

Fig. 5.5 Nasalward vergence

and gaze asymmetries in
strabismic humans and
monkeys. Fusional vergence:
esodeviation of the
nonxating 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
Tracking (pursuit/OKN)
the visual eld. Pursuit is
cogwheel (low gain-abnor-
mal) when the target moves
temporalward. The
movements of the two eyes
are conjugate, and the
direction of the asymmetry
reverses instantaneously
with a change of xating eye,
so that the direction of
robust pursuit is always for
nasalward motion in the
visual eld. Gaze holding-
latent nystagmus: viewing
Gaze Holding (latent nystagmus)
with the right-eye, both eyes
have a nasalward slow-phase
drift, followed by temporal-
ward refoveating fast-phase
microsaccades. The direction
of the nystagmus reverses
instantaneously when the left
eye is xating, so that the
slow phase is nasalward with
respect to the xating eye
 50 5 Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment
conclusion drawn from these observations was that MST
neurons promote esotropia (i.e., a bias for nasalward ver-
gence) when binocularity fails to develop in V1. The
mechanism is attractive, because it ties together the
5 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?
The 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 suered an
irreparable defect of the fusion faculty [107]. Their 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 reexes 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 reex 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]. The new knowledge prompted
a gradual reexamination of old data and inspired impor-
tant case studies in the 1980 and 1990s on the ecacy
of early strabismus surgery [111114]. These reports
showed that if stable, binocular alignment was not
achieved until age 24 months, the chances of repairing
stereopsis were nil. If stable alignment was achieved by
age 6 months, the chances of repairing stereopsis were
good, and a substantial percentage of the infants regained
robust stereopsis, i.e., random dot stereopsis with thresh-
olds on the order of 60400 arcsec.
Scrutiny of early alignment data in infantile esotropia
has produced more rened and forceful conclusions.
Figure 5.6a is replotted data on stereopsis outcomes in
over 100 consecutive infantile esotropes [112]. The Y-axis
is prevalence of stereopsis after surgical alignment, and
the X-axis is age of onset or duration of misalignment
before surgery. The dashed line at 40% represents the
average prevalence of stereopsis when all infants operated
upon by 2 years of age are grouped together, without
regard to age at correction or duration before correction.
The noise in the data relating age at alignment to 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 26
months of age. There is no systematic relationship between
age of onset of esotropia and subsequent attainment of
stereopsis. However, when the data is reanalyzed with
strict attention to duration of misalignment, a strong 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]. The
clinical dictum that follows is that age at surgery should
be tailored to age of onset and not chronological age.
Esotropic infants who regain high grade stereopsis
also regain robust fusional vergence [112114]. 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 dicult 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 ll gaps in clinical knowledge. The 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 (Monoxation Syndrome) 51

a 100 pursuit/OKN and gaze holding return to normal

% Children with Stereopsis
(Fig. 5.6c). The repair of ocular motor behavior occurs
80 with repair of stereopsis and restoration of normal
motion responses (motion VEPs). If decorrelation per-
60
sists in strabismic monkeys until the equivalent of 12
months duration in humans, esotropia and stereoblind-
40
ness persist. Prolonged-decorrelation animals exhibit
20 latent nystagmus, pursuit/OKN asymmetry, motion VEP
asymmetry, and DVD. The quality of behavioral repair
0 correlates with the quality of neuroanatomic repair in V1
1 2 3 4 5 6
(Fig. 5.6c). Early repair monkeys (i.e., those who have
Age on Onset (months)
shorter durations of decorrelation) have a normal com-
plement of binocular horizontal excitatory connections
b 100 between ODCs of opposite ocularity, and delayed
% Children with Stereopsis

repair (longer durations of decorrelation) monkeys a

80
paucity. The restoration of binocular connections in V1
60 of early repair monkeys appears to have equally bene-
cal eects on downstream areas of extrastriate cortex
40 (MT/MST) driving the ocular motor neurons of the
brainstem. The benet is evident as symmetric naso-
20
temporal eye tracking, stable gaze holding, and more
0 normal fusional vergence.
0-2 3-5 6-8 9-11 12-18 19-24
Duration of Misalignment (months)

5.2 Visual Cortex Mechanisms in Micro-

c 40 Esotropia (Monoxation Syndrome)
Pur Asym
As outlined earlier, recent data on early correction of
30
Magnitude of Deficit

Nyst infantile strabismus suggests that it is a curable disorder.

(SD multiples)

20
10
0 rescuing bifoveal fusion after this interval are slim. Most
0 3 6 9 12
Duration of Decorrelation (weeks)
Fig. 5.6 Repair of random-dot stereopsis after surgical
realignment of the eyes in children with infantile esotropia,
and analogous 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 decits 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 decit; 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)
Stereo
But early surgery is the exception rather than the rule of
Eso current clinical practice in the U.S. and Europe. The
DVD majority of infants who have esotropia are corrected 6 or
V1 binoc more months after onset of misalignment. The chances of
infants are aligned to within 8 PD of orthotropia (microe-
24 sotropia) and regain a degree of subnormal stereopsis and
motor fusion, i.e., monoxation syndrome.
Monoxation syndrome occurs as a primary disor-
der (prevalence 1%) or, more commonly, as a secondary
phenomenon, after delayed treatment of large magni-
tude strabismus [116, 117]. The syndrome also occurs
in monkeys [118]. The major sensory and motor fea-
tures of monoxation syndrome are listed in Table 5.4.
Neural mechanisms for the rst two features listed in
Table 5.4 are not dicult to explain. Receptive elds in
V1 representing the fovea are tiny and have narrow
tolerances. Any defocusing or other decorrelation of
one eyes inputs would produce a conict in neighboring
V1 columns and promote suppression of ODCs corre-
sponding to the weaker eye. The fovea subtends ~5 of
the retinotopic map of V1, thus a suppression scotoma
of 5 makes sense. Feature two, subnormal stereopsis,
 52 5 Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment
Table 5.4. Monoxation (Microstrabismus) Syndrome
Clinical Feature
1. Foveal suppression scotoma of 3-5 deg in the
5 non-preferred eyea when viewing binocularly
2. Subnormal stereopsis (threshold 60-3000 arc sec)
3. Stable microesotropiab less than ~ 4-8 PD (~2.5-5 deg)
4. Fusional vergence amplitudes intact for disparities
>2.5-5 deg (>4-8 PD)
a
subnormal acuity (amblyopia) in the non-preferred eye in 34% of corrected infantile esotropes and 100% of anisometropes.
b
microexotropia in 10%
could be explained along similar lines. Stereoscopic
thresholds increase exponentially from the fovea to more
eccentric positions along the retinotopic map of the visual
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
monoxation syndrome, the visuomotor signs, that are
most intriguing. If binocular development is perturbed so
that right and left eye foveal ODCs (receptive elds) do
not enjoy perfectly correlated activity, why should the fall
back position of visual cortex be set so predictably ~24
(~48 prism diopters or PD) of micro-esotropia (Fig. 5.7)?
And if the heterotropia exceeds that range, why is fusional
vergence typically absent?
5.2.1 Neuroanatomic Findings in Area V1
of Micro-Esotropic Primates
Studies of ODCs and neuronal axons in area V1 have
revealed a possible mechanism. The overall pattern and
width of ODCs in V1 (~400 mm [0.40 mm]) is the same in
normal and strabismic monkeys [70, 78]. Horizontal axon
length was measured for neurons within the V1 region
corresponding to visual eld eccentricities of 010 (i.e.,
the representation of the fovea, parafovea and macula).
The 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. The
side-by-side arrangement of the foveolar columns in
normal V1 is well within the range of horizontal axonal
connections needed to allow those ODCs to communi-
cate for high-grade binocular fusion.
Possible Neural Mechanism
Inhibitory-connection-mediated metabolic suppression of
decorrelated activity in V1 foveal ODCs of non-preferred eye
Broader disparity tuning of parafoveal neurons in V1/MT (foveal
neurons suppressed)
Small angle average horizontal neuron length in V1, eso by
default to convergent disparity coding of major MST population
V1 excitatory horizontal binocular connections (and V1/MT/
MST disparity neurons) intact beyond region of foveal
suppression
In a primate with microesotropia and a right eye xa-
tion preference (Fig. 5.7), a neuron within a foveolar (0)
column of the 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 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-eld) of a microesotropic macaque. The sulci
and gyri have been unfolded and the visual eld represen-
tation superimposed using standard retinotopic land-
marks. One horizontal axon, originating within the foveal
representation at 01 eccentricity, could link to a recep-
tive eld shifted 2.5 or 4.4 PD distant (Fig. 5.7). Two neu-
rons strung together could join receptive elds 5 or 8.7
PD apart. The conclusion that emerges is that the 48 PD
rule of the monoxation syndrome is explicable as a
combination of innate V1 neuron size and V1 topography.
The visuomotor system of the strabismic primate appears
to achieve subnormal, but stable binocular fusion so long
as the angle of deviation is conned 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 monoxation
syndrome. MST receives downstream projections from
disparity-sensitive cells, both in V1 and in MT. The
majority of binocular neurons in V1, MT and MST
encode absolute disparity [82, 120]. Absolute disparity
 5.2 Visual Cortex Mechanisms in Micro-Esotropia (Monoxation Syndrome) 53

Fig. 5.7 (a) Monoxator/ a

microesotrope exhibits a
deviation of the visiual axes
on cover testing of approxi-
mately 4 PD (~2.5), which in 2.5 (4.4 PD)
Left Esotropia
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 0 2.5 0
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-eld) of a
microesotropic primate. The
sulci and gyri have been
unfolded and the visual eld
representation superimposed
b Right V-1 Left Visual Field
using standard retinotopic
landmarks. One horizontal
axon (average length ~7 mm), D
originating within the foveal Monocular 135 180
Region 10 5 2.5
representation at 01 80
eccentricity, could link to a 20 0
40 40
receptive eld shifted 2.5 or
80 20
4.4 PD distant. Two neurons 4.5
strung together could join 10
M FOVEA H.M.
receptive elds 5 or 8.7 PD
L
apart. The conclusion that H.M.
emerges is that the 48 PD
rule of monoxation/ 135
microesotropia syndrome is
explicable as a combination 180 45
of innate V1 neuron size V 0
(one to two axon lengths)
4.4 PD 1axon
and V1 topography
7 mm
8.7 PD 2axon
14 mm

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. The largest
population of vergence-related neurons in MST of nor-
mal monkeys drives the eyes to ~2.5 of convergent
(crossed) disparity [82]. (The next largest population
encodes ~2.5 of divergence.) Normal primates have the
strongest short-latency vergence responses to 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. The 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. These 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.
 54 5 Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment
References
1. Graham PA (1974) Epidemiology of strabismus. Br
J Ophthalmol 58:224231
5 2. Kiorpes L, Boothe RG, Carlson MR, et al (1985) Frequency
of naturally occurring strabismus in monkeys. J Pedriatr
Ophthalmol Strabismus 22:6064
3. Tamura EE, Hoyt CS (1987) Oculomotor consequences of
intraventricular hemorrhages in premature infants. Arch
Ophthalmol 105:533535
4. Khanna S, Sharma A, Ghasia F, et al (2009) Prevalence of
the ocular motor signs of the infantile strabismus complex
in children with and without cerebral visual pathway white
matter injury. Invest Ophthalmol Vis Sci Abstracts 09-A-
5876
5. Pike MG, Holmstrom G, de Vries LS, et al (1994) Patterns
of visual impairment associated with lesions of the preterm
infant brain. Dev Med Child Neurol 36:849862
6. Hoyt CS (2003) Visual function in the brain-damaged
child. Eye 17:369384
7. van Hof-van Duin J, Evenhuis-van Leunen A, Mohn G, et
al (1989) Eects of very low birth weight (VLBW) on visual
development during the rst year after term. Early Hum
Dev 20:255266
8. VanderVeen DK, Coats DK, Dobson V, et al (2006)
Prevalence and course of strabismus in the rst year of life
for infants with prethreshold retinopathy of prematurity.
Arch Ophthalmol 124:766773
9. Hiles DA, Hoyme SH, McFarlane F (1974) Downs syn-
drome and strabismus. Am Orthopt J 24:6368
10. Shapiro MB, France TD (1985) The ocular features of
Downs syndrome. Am J Ophthalmol 99:659663
11. Pediatric eye disease investigator group (2002) The clinical
spectrum of early-onset esotropia: experience of the con-
genital esotropia observational study. Am J Ophthalmol
133:102108
12. Bailey P, von Bonin G (1951) The isocortex of man.
University of Illinois, Urbana
13. Tychsen L (1999) Infantile esotropia: current neurophysio-
logic concepts. In: Rosenbaum AL, Santiago AP (eds) Clinical
strabismus management. WB Saunders, Philadephia
14. Volpe JJ (1987) Hypoxic-ischemic encephalopathy: neuro-
pathology and pathogenesis. In: Volpe JJ, Markowitz M
(eds) Neurology of the newborn. W.B.Saunders Company,
Philadelphia
15. Noetzel MJ, Brunstrom JE (2001) The vulnerable oligoden-
drocyte. Inammatory observations on a cause of cerebral
palsy. Neurology 56:12541255
16. Huttenlocher P, de Courten C, Garey L, et al (1982)
Synaptogenesis in human visual cortex: evidence for syn-
apse elimination during normal development. Neurosci
Lett 33:247252
17. Phelps M, Mazziotta J, Kuhl D, et al (1981) Tomographic
mapping of human cerebral metabolism: visual stimula-
tion and deprivation. Neurology 31:517529
18. Lorenz B (2002) Genetics of isolated and syndromic stra-
bismus: facts and perspectives. Strabismus 10:147156
19. Paul TO, Hardage LK (1994) The heritability of strabismus.
Ophthalmic Genet 15:118
20. Maumenee IH, Alston A, Mets MB, et al (1986) Inheritance
of congenital esotropia. Tr Am Ophthalmol Soc 84:
8593
21. Archer SM, Sondhi N, Helveston EM (1989) Strabismus in
infancy. Ophthalmology 96:133137
22. Birch E, Stager D, Wright K, et al (1998) The natural his-
tory of infantile esotropia during the rst six months of life.
J AAPOS 2:325328
23. Fox R, Aslin RN, Shea SL, et al (1980) Stereopsis in human
infants. Science 207:323324
24. Birch EE, Gwiazda J, Held R (1982) Stereoacuity develop-
ment for crossed and uncrossed disparities in human
infants. Vision Res 22:507513
25. Birch EE, Shimojo S, Held R (1985) Preferential-looking
assessment of fusion and stereopsis in infants aged 1 to 6
months. Invest Ophthalmol Vis Sci 26:366370
26. ODell C, Boothe RG (1997) The development of
stereoacuity in infant rhesus monkeys. Vision Res 37:
26752684
27. Birch EE, Gwiazda J, Held R (1983) The development of
vergence does not account for the onset of stereopsis.
Perception 12:331336
28. Gwiazda J, Bauer JAJ, Held R (1989) Binocular function
in human infants: correlation of stereoptic and fusion-
rivalry discriminations. J Pediatr Ophthalmol Strabismus
26:128132
29. Aslin RN (1977) Development of binocular xation in
human infants. J Exp Child Psychol 23:133-150.
30. Aslin RN, Jackson RW (1979) Accommodative-convergence
in young infants: development of a synergistic sensory-
motor system. Can J Psychol 33:222231
31. Hainline L, Riddell PM (1995) Binocular alignment and
vergence in early infancy. Vision Res. 35:32293236
32. Horwood AM (1993) Maternal observations of ocular
alignment in infants. J Pediatr Ophthalmol Strabismus
30:100105
33. Horwood AM, Riddell PM (2004) Can misalignments in
typical infants be used as a model for infantile esotropia?
Invest Ophthalmol Vis Sci 45:714720
34. Riddell PM, Horwood AM, Houston SM, et al (1999) The
response to prism deviations in human infants. Curr Biol
9:10501052
35. Norcia AM, Garcia H, Humphry R, et al (1991) Anomalous
motion VEPs in infants and in infantile esotropia. Invest
Ophthalmol Vis Sci 32:436439

36. Norcia AM (1996) Abnormal motion processing and bin-
ocularity: infantile esotropia as a model system for eects
of early interruptions of binocularity. Eye 10:259265
37. Brown RJ, Norcia AM (1997) A method for investigating
binocular rivalry in real-time with the steady-state VEP.
Vision Res 37:24012408
38. Birch EE, Fawcett S, Stager D (2000) Co-development of
VEP motion response and binocular vision in normal
infants and infantile esotropes. Invest Ophthalmol Vis Sci
41:17191723
39. Bosworth RG, Birch EE (2007) Direction-of-motion detec-
tion and motion VEP asymmetries in normal children and
children with infantile esotropia. Invest Ophthalmol Vis
Sci 48:55235531
40. Atkinson J (1979) Development of optokinetic nystagmus
in the human infant and monkey infant: an analogue to
development in kittens. In: Freeman RD (ed) Developmental
neurobiology of vision. Plenum, New York
41. Naegele JR, Held R (1982) The postnatal development of
monocular optokinetic nystagmus in infants. Vision Res
22:341346
42. Schor CM, Narayan V, Westall C (1983) Postnatal develop-
ment of optokinetic after nystagmus in human infants.
Vision Res. 23:16431647
43. Wattam-Bell J, Braddick O, Atkinson J, et al (1987)
Measures of infant binocularity in a group at risk for stra-
bismus. Clin Vis Sci 4:327336
44. Jacobs M, Harris C, Taylor D (1994) The Development of
eye movements in infancy. In: Lennerstrand G (ed) Update
on strabismus and pediatric ophthalmology. Proceedings
of the Joint ISA and AAPO&S Meeting. Vancouver,
Canada. June 19 to 23, 1994. CRC, Boca Raton
45. Tychsen L (2001) Critical periods for development of
visual acuity, depth perception and eye tracking. In: Bailey
DB Jr, et al (ed) Critical thinking about critical periods.
Paul H. Brookes, Baltimore
46. Tychsen L, Hurtig RR, Scott WE (1985) Pursuit is impaired
but the vestibulo-ocular reex is normal in infantile stra-
bismus. Arch Ophthalmol 103:536539
47. Wong AMF, Foeller P, Bradley D, et al (2003) Early versus
delayed repair of infantile stabismus in macaque monkeys:
I. Ocular motor eects. J AAPOS 7:200209
48. Birch E, Petrig B (1996) FPL and VEP measures of fusion,
stereopsis and stereoacuity in normal infants. Vision Res.
36:13211327
49. Skarf B, Eizenman M, Katz LM, et al (1993) A new VEP
system for studying binocular single vision in human
infants. J Pediatr Ophthalmol Strabismus 30:237242
50. Mellick A (1949) Convergence. An investigation into the nor-
mal standards of age groups. Br J Ophthalmol 33: 755763
51. Tait EF (1949) Fusional vergence. Am J Ophthalmol
32:12231230
References 55
52. Hubel DH, Wiesel TN (1977) Ferrier lecture. Functional
architecture of macaque monkey visual cortex. Proc R Soc
Lond Biol Sci 198:159
53. Hubel DH (1982) Exploration of the primary visual cortex,
195578. Nature 299:515524
54. Poggio GF, Fischer B (1977) Binocular interaction and
depth sensitivity in striate and prestriate cortex of behav-
ing rhesus monkey. J Neurophysiol 40:13921405
55. Wiesel TN (1982) Postnatal development of the visual
cortex and the inuence of environment. Nature 299:
583591
56. Hubel DH, Wiesel TN, LeVay S (1977) Plasticity of ocular
dominance columns in monkey striate cortex. Philos Trans
R Soc Lond B Biol Sci 278:377409
57. LeVay S, Wiesel TN, Hubel DH (1980) The development of
ocular dominance columns in normal and visually deprived
monkeys. J Comp Neurol 191:151
58. Chino Y, Smith EL, Hatta S, et al (1996) Suppressive bin-
ocular interactions in the primary visual cortex (V1) of
infant rhesus monkeys, Society for Neuroscience.
Washington, D.C
59. Chino YM, Smith IIIEL, Hatta S, et al (1997) Postnatal
development of binocular disparity sensitivity in neurons
of the primate visual cortex. J Neurosci 17:296307
60. Horton JC, Hocking DR (1996) An adult-like pattern of
ocular dominance columns in striate cortex of newborn
monkeys prior to visual experience. J Neurosci 16:
17911807
61. Horton JC, Hocking DR (1997) Timing of the critical
period for plasticity of ocular dominance columns in
macaque striate cortex. J Neurosci 17:36843709
62. Endo M, Kaas JH, Jain N, et al (2000) Binocular cross-ori-
entation suppression in the primary visual cortex (V1) of
infant rhesus monkeys. Invest Ophthalmol Vis Sci
41:40224031
63. Crawford MLJ, von Noorden GK (1979) The eects of
short-term experimental strabismus on the visual system
in Macaca mulatta. Invest Ophthalmol Vis Sci 18:496505
64. Crawford MLJ, Smith IIIEL, Harwerth RS, et al (1984)
Stereoblind monkeys have few binocular neurons. Invest
Ophthalmol Vis Sci 25:779781
65. Crawford ML, Harwerth RS, Smith EL, et al (1996) Loss of
stereopsis in monkeys following prismatic binocular dis-
sociation during infancy. Behav Brain Res 79:207218
66. Lowel S, Singer W (1992) Selection of intrinsic horizontal
connections in the visual cortex by correlated neuronal
activity. Science 255:209212
67. Trachtenberg JT, Stryker MP (2001) Rapid anatomical
plasticity of horizontal connections in the developing
visual cortex. J Neurosci 21:34763482
68. Tychsen L, Burkhalter A (1995) Neuroanatomic abnor-
malities of primary visual cortex in macaque monkeys
 56 5 Visual Cortex Mechanisms of Strabismus: Development and Maldevelopment
with infantile esotropia: preliminary results. J Pediatr
Ophthalmol Strabismus 32:323328
69. Tychsen L, Yildirim C, Anteby I, et al (2000) Macaque
monkey as an ocular motor and neuroanatomic model of
5 human infantile strabismus. In: Lennerstrand G, Ygge J
(eds) Advances in strabismus research: basic and clinical
aspects. Wenner-Gren International Series. Portland,
London, U.K
70. Tychsen L, Wong AMF, Burkhalter A (2004) Paucity of
horizontal connections for binocular vision in V1 of natu-
rally-strabismic macaques: cytochrome-oxidase compart-
ment specicity. J Comp Neurol 474:261275
71. Pasik T, Pasik P (1964) Optokinetic nystagmus: an
unlearned response altered by section of chiasma and cor-
pus callosum in monkeys. Nature 203:609611
72. Pasik P, Pasik T (1977) Ocular movements in split-brain
monkeys. Adv Neurol 18:125135
73. Drsteler MR, Wurtz RH, Newsome WT (1987) Directional
pursuit decits following lesions of the foveal representa-
tion within the superior temporal sulcus of the macaque
monkey. J Neurophysiol 57:12621287
74. Drsteler MR, Wurtz RH (1988) Pursuit and optokinetic
decits following chemical lesions of cortical areas MT and
MST. J Neurophysiol 60:940965
75. Ungerleider LG, Desimone R (1986) Cortical connections
of visual area MT in the macaque. J Comp Neurol 248:
190222
76. Kiorpes L, Walton PJ, OKeefe LP, et al (1996) Eects of
articial early-onset strabismus on pursuit eye movements
and on neuronal responses in area MT of macaque mon-
keys. J Neurosci 16:65376553
77. Hatta S, Kumagami T, Qian J, et al (1998) Nasotemporal
directional bias of V1 neurons in young infant monkeys.
Invest Ophthalmol Vis Sci 39:22592267
78. Tychsen L, Burkhalter A (1997) Nasotemporal asymme-
tries in V1: ocular dominance columns of infant, adult, and
strabismic macaque monkeys. J Comp Neurol 388:3246
79. Boothe RG, Dobson V, Teller DY (1985) Postnatal develop-
ment of vision in human and nonhuman primates. Ann
Rev Neurosci 8:495546
80. Kawano K (1999) Ocular tracking: behavior and neuro-
physiology. Curr Opin Neurobiol 9:467473
81. Maunsell JHR, Van Essen DC (1983) Functional properties
of neurons in middle temporal visual area of the macaque
monkey. II. Binocular interactions and sensitivity to bin-
ocular disparity. J Neurophysiol 49:11481167
82. Takemura A, Inoue Y, Kawano K, et al (2001) Single-unit
activity in cortical area MST associated with disparity-
vergence eye movements: evidence for population coding.
J Neurophysiol 85:22452266
83. Jampolsky A (1955) Characteristics of suppression in stra-
bismus. Arch Ophthalmol 54:683
84. Pratt-Johnson JA, Tillson G (1984) Suppression in strabis-
mus an update. Br J Ophthalmol 68:174178
85. Hirsch JA, Gilbert CD (1991) Synaptic physiology of hori-
zontal connections in primary visual cortex. J Neurosci
11:18001809
86. Weliky M, Kandler K, Fitzpatrick D, et al (1995) Patterns of
excitation and inhibition evoked by horizontal connec-
tions in visual cortex share a common relationship to ori-
entation columns. Neuron 15:541552
87. Deyoe EA, Trusk TC, Wong-Riley MT (1995) Activity cor-
relates of cytochrome oxidase-dened compartments in
granular and supragranular layers of primary visual cortex
of the macaque monkey. Vis Neurosci 12:629639
88. Horton JC (1984) Cytochrome oxidase patches: a new
cytoarchitectonic feature of monkey visual cortex. Philos
Trans R Soc Lond B Biol Sci 304:199253
89. Wong-Riley MTT (1994) Primate visual cortex: dynamic
metabolic organization and plasticity revealed by cyto-
chrome oxidase. In: Peters A, Rockland KS (eds) Cerebral
cortex. Plenum, New York
90. Fenstemaker SB, Kiorpes L, Movshon JA (2001) Eects of
experimental strabismus on the architecture of macaque
monkey striate cortex. J Comp Neurol 438:300317
91. Horton JC, Hocking DR, Kiorpes L (1997) Pattern of ocu-
lar dominance columns and cytochrome oxidase activity
in a macaque monkey with naturally occurring anisome-
tropic amblyopia. Vis Neurosci 14:681689
92. Wong AMF, Burkhalter A, Tychsen L (2005) Suppression
of metabolic activity caused by infantile strabismus and
strabismic amblyopia in striate visual cortex of macaque
monkeys. J AAPOS 9:3747
93. Tychsen L (2007) Causing and curing infantile eostropia in
primates: the role of de-correlated binocular input (an
American ophthalmological society thesis). Trans Am
Ophthalmol Soc 105:564593
94. Lewis TL, Maurer D (1992) The development of the tem-
poral and nasal visual elds during infancy. Vision Res
32:903911
95. Lewis TL, Maurer D, Blackburn K (1985) The development
of young infants ability to detect stimuli in the nasal visual
eld. Vision Res. 25:943950
96. Bowering ER, Maurer D, Lewis TL, et al (1993) Sensitivity
in the nasal and temporal hemields in children treated for
cataract. Invest Ophthalmol Vis Sci 34:35013509
97. Sireteanu R, Fronius M (1982) Naso-temporal asymme-
tries in human amblyopia: consequence of long-term
interocular suppression. Vision Res 21:10551063
98. Sireteanu R, Fronius M (1989) Visual eld losses in strabis-
mic amblyopes. Klin Monatsbl Augenheilkd 194:261269
99. Horton JC, Hocking DR, Adams DL (1999) Metabolic map-
ping of suppression scotomas in striate cortex of macaques
with experimental strabismus. J Neurosci 19:71117129

100. Schor CM, Levi DM (1980) Disturbances of small-eld
horizontal and vertical optokinetic nystagmus in amblyo-
pia. Invest Ophthalmol Vis Sci 19:668683
101. Tychsen L, Lisberger SG (1986) Maldevelopment of visual
motion processing in humans who had strabismus with
onset in infancy. J Neurosci 6:24952508
102. Tychsen L, Rastelli A, Steinman S, et al (1996) Biases of
motion perception revealed by reversing gratings in
humans who had infantile-onset strabismus. Dev Med
Child Neurol 38:408422
103. Hasany A, Wong A, Foeller P, et al (2008) Duration of bin-
ocular decorrelation in infancy predicts the severity of
nasotemporal pursuit asymmetries in strabismic macaque
monkeys. Neuroscience 156:403411
104. Richards M, Wong A, Foeller P, et al (2008) Duration of
binocular decorrelation predicts the severity of latent
(fusion maldevelopment) nystagmus in strabismic
macaque monkeys. Invest Ophthalmol Vis Sci 49:
18721878
105. Yildirim C, Tychsen L (2000) Disjunctive optokinetic nys-
tagmus in a naturally esotropic macaque monkey: interac-
tions between nasotemporal asymmetries of versional eye
movement and convergence. Ophthalmic Res 32:172180
106. Leigh RJ, Zee DS (1999) The neurology of eye movements.
Oxford University, New York
107. Worth C (1903) Squint. Its causes, pathology, and treat-
ment. Blakiston, Philadelphia
108. Chavasse F (1939) Worths squint or the binocular reexes
and the treatment of strabismus. 7th Bailliere Tindall and
Cox, London
109. Costenbader FD (1961) Infantile esotropia. Trans Am
Ophthalmol Soc 59:397429
110. Ing M, Costenbader FD, Parks MM, et al (1966) Early sur-
gery for congenital esotropia. Am J Ophthalmol
61:14191427
111. Birch EE, Stager DR, Everett ME (1995) Random dot stere-
oacuity following surgical correction of infantile esotropia.
J Pediatr Ophthalmol Strabismus 32:231235
References 57
112. Birch EE, Fawcett S, Stager DR (2000) Why does early sur-
gical alignment improve stereopsis outcomes in infantile
esotropia? J AAPOS 4:1014
113. Ing MR (1995) Surgical alignment prior to six months of
age for congenital esotropia. Trans Am Ophthalmol Soc
93:135146
114. Wright KW, Edelman PM, McVey JH, et al (1994) High-
grade stereo acuity after early surgery for congenital
esotropia. Arch Ophthalmol 112:913919
115. Tychsen L, Wong AMF, Foeller P, et al (2004) Early versus
delayed repair of infantile strabismus in macaque mon-
keys: II. Eects on motion visually evoked responses. Invest
Ophthalmol Vis Sci 45:821827
116. Lang J (1968) Evaluation in small angle strabismus or
microtopia, Strabismus symposium Gieben. Karger, Basel
117. Parks MM (1969) The monoxation syndrome. Tr Am
Ophthalmol Soc 67:609657
118. Tychsen L, Scott C (2003) Maldevelopment of convergence
eye movements in macaque monkeys with small and large-
angle infantile esotropia. Invest Ophthalmol Vis Sci
44:33583368
119. Wong AMF, Lueder GT, Burkhalter A, et al (2000)
Anomalous retinal correspondence: neuroanatomic mech-
anism in strabismic monkeys and clinical ndings in stra-
bismic children. J AAPOS 4:168174
120. Cumming BG, Parker AJ (1999) Binocular neurons in V1
of awake monkeys are selective for absolute, not relative,
disparity. J Neurosci 19:56026218
121. Masson GS, Busettini C, Miles FA (1997) Vergence eye
movements in response to binocular disparity without
depth perception. Nature 389:283286
122. Mays LE (1983) Neurophysiological correlates of vergence
eye movements. In: Schor CM, Ciureda KJ (eds) Vergence
eye movements: basic and clinical aspects. Butterworths,
Boston
123. Mays LE (1984) Neural control of vergence eye move-
ments: convergence and divergence neurons in midbrain. J
Neurophysiol 51:10911108
 Chapter 6
Neuroanatomical Strabismus
Joseph L. Demer
Core Messages
Strabismus may arise from identiable structural
abnormalities of the extraocular muscles (EOMs)
or their innervation. Congenital or acquired
myopathies aect 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 inuence 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.
6.1 General Etiologies of Strabismus
Strabismus, dened as misalignment of the visual direc-
tions of the two eyes, may arise from several general
causes. These include primary myopathies of extraocu-
lar muscles (EOMs), disorders of the connective tissues
that comprise the globes gimbal system, peripheral dis-
orders of nerves controlling the EOMs, and central dis-
orders of fusional vergence commands (Table 6.1). This
chapter emphasizes causes of strabismus that can be
characterized as mechanistically specic 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
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
insuciently innervated EOMs, with contracture
of their more normally innervated antagonists.
High resolution imaging can directly demonstrate
hypoplastic and misdirected motor nerves to the
EOMs in the CCDDs, sometimes with additional
abnormalities of the optic or other cranial nerves.
Some forms of strabismus may be associated with
abnormalities of the brainstem or cerebellum that
are demonstrable by clinical imaging. However,
typical forms of developmental strabismus such
as concomitant esotropia and exotropia are not
associated with EOM abnormalities.
6.2 Extraocular Myopathy
6.2.1 Primary EOM Myopathy
Primary EOM myopathy may be due to congenital meta-
bolic disorder, acquired inammation, 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 aected [2]. The asso-
ciation between CPEO and heart block is called Kearns
Sayre syndrome [3]. Ragged red bers, as demonstrated
on modied trichrome stain, can be seen in limb and
EOMs in nearly all cases of KearnsSayre syndrome and
occasionally in isolated CPEO [3]. Molecular diagnosis of
 60 6 Neuroanatomical Strabismus

Table 6.1. Etiologies of strabismus

Category Examples

Primary myopathies Mitochondrial myopathy,

6 endocrine myopathy, traumatic
myopathy
Orbital connective Pulley heterotopy, pulley
tissue disorders instability, pulley hindrance
Peripheral motor Congenital cranial dysinnervation
neuropathies disorders (CCDDs), acquired
peripheral ocular motor
neuropathy
Subcortical vergence Horizontal gaze palsy and
disorders progressive scoliosis, cerebellar
disease
Cortical disorders Infantile strabismus, intermittent
of vergence 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
CPEO is problematic, since most cases are caused by spo- bright signal within extraocular muscles that are of generally
radic mitochondrial DNA deletions. More clinically use- normal size. IR inferior rectus muscle; LR lateral rectus muscle;
ful may be T1-weighted magnetic resonance imaging ON optic nerve; SO superior oblique muscle; SR superior
rectus muscle
(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, 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 inammation
and inltration of EOMs, orbital connective tissues, or
both. A classical presentation of TED involves inamma-
tory enlargement of EOMs producing upper eyelid retrac-
tion, proptosis, and restrictive ophthalmoplegia. Chronic
EOM enlargement and brosis persists following resolu-
tion of inammation. 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
Fig. 6.2 Coronal T1-weighted MRI of both orbits of a patient
the most common clinical involvement, although all
with thyroid eye disease (TED) demonstrating enlargement and
EOMs, including the obliques (Fig. 6.2), may be involved. in all rectus and the SO muscles. IR inferior rectus muscle; LR
Restrictive strabismus is typical in TED, most commonly lateral rectus muscle; MR medial rectus muscle; ON optic nerve;
involving limitation of supraduction. SO superior oblique muscle; SR superior rectus muscle
 6.2 Extraocular Myopathy 61

Table 6.2. Types of extraocular myopathy

Cause Main clinical features Imaging ndings Laboratory diagnostic tests

Metabolic Progressive weakness Normal EOM size, bright T1 MRI Muscle biopsy for ragged red
signal bers, electrocardiogram
Immune Restriction, EOM belly enlargement Thyroid function tests
myopathy inammatory signs and/or orbital fat enlargement
Inammatory Restriction and/or weakness, EOM belly and tendon Tests for vasculitis,
myositis inammatory signs enlargement inammation, sarcoidosis
Neoplastic Restriction and/or weakness, Nodular EOM enlargement, Metastatic evaluation, EOM
myopathy and/or inammatory signs or orbital mass biopsy
Mechanical Weakness or restriction EOM discontinuity or displace-
ment, possible orbital fracture

Another presentation in TED is inammatory 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 xed structures such as the xed anchors of
the trochlea and the soft pulley system of the other EOMs.
6.2.3 Inammatory 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.
Summary for the Clinician
Old orbital fractures may complicate the presen-
tation of strabismus of recent origin.
Patients may not recall old orbital fractures.
6.2.5 Traumatic Myopathy
Direct trauma to EOMs may compromise their function
and produce strabismus. Sharp objects penetrating the
orbit may disinsert EOM tendons from the globe,
transect or avulse EOM bellies, or avulse motor nerves to
EOMs. Clinically unrecognized penetration of the orbit
by thin, sharp objections may occur in the setting of
more widespread facial trauma, since entry wounds
through the eyelid crease or conjunctival fornix are 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 often
with strabismus unless there is direct EOM trauma. Smaller
orbital fractures may exhibit a trap-door mechanism, with
a displaced bone fragment trapping an EOM or part of the
connective tissue pulley system. Especially in children in
whom inammatory 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
 62 6 Neuroanatomical Strabismus
may be associated with the clinical ndings of limitation
of active duction in the EOMs eld of action due to pulley
hindrance (discussed below), as well as mechanical restric-
tion to the opposite direction of passive rotation using for-
6 ceps. In the usual clinical setting of generalized orbital and
eyelid edema, these clinical 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].
Summary for the Clinician
Orbital pulley disorders can cause strabismus.
Strabismus due to pulley disorders can clinically
mimic restrictive or paralytic strabismus.
6.3 Congenital Pulley Heterotopy
The direction of ocular rotation imparted by any EOM is
dened by the relative locations of its scleral insertion
and pulley; EOM path direction posterior to the pulley is
not directionally important [1214]. Every EOM can
produce horizontal, vertical, and torsional actions, in
relative proportions depending on pulley and insertion
locations. Thus, alterations in positions of the horizontal
rectus pulleys can impart substantial vertical and 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).
The MR and LR pulleys are directly suspended by
broelastic connective tissues from anteriorly located
entheses, or anchors, on the orbital bones [15]. The medial
enthesis is at the posterior lacrimal crest, while the lateral
enthesis is at Whitnalls tubercle. The inferior (IR) and
superior rectus (SR) pulleys are somewhat indirectly
supported by, in both cases, the medial and lateral enthe-
Table 6.3. Pattern strabismus associated with pulley heterotopy and eyelid conguration
Incomitance Horizontal Vertical pulleys
pulleys
LR MR IR
A pattern Superior Inferior Temporal
V pattern Inferior Superior Nasal
ses. Malpositioning of the entheses, or malpositioning of
the orbital bones to which the entheses join, can therefore
cause signicant alterations in rectus EOM pulling direc-
tions. More signicant still, the pulling directions of the
four horizontal rectus EOMs can be purely horizontal
only if their respective pulleys all lie on a horizontal line
exactly transverse to the mid-sagittal plane of the skull.
Any other orientation of the horizontal rectus pulleys in
the two orbits will impart vertically imbalanced actions to
the binocularly yoked agonist pairs: the MR in one orbit
and the LR in the opposite orbit. This eect 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 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]. The 95% condence 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. The expected eect 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 xate a target in this
position. This heterotopic pulley conguration 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
Lateral canthal
inclination
SR
Nasal Superior
Temporal Inferior

Fig. 6.3 Coronal T2 fast
spin echo MRI showing
typical pulley congurations
of both orbits for (a) A and
V (b) pattern strabismus
center. In supraversion, the SR exerts an adducting action,
while in infraversion, the IR exerts an abducting action.
Binocular alignment is consequently more divergent in
infraversion than in supraversion, constituting an A 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 xate a target in this
position. This heterotopic pulley conguration 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
6.4 Acquired Pulley Heterotopy 63
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 signicant inclination to one or
both the palpebral apertures [12, 23]. The medial and
lateral canthal tendons normally insert on the orbital
bones near the medial and lateral entheses of the pulley
system, respectively. A superior (mongoloid) 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
The inferior obliques (IOs) orbital layer inserts partly on
the conjoined IOIR pulleys, partly on the IO sheath
temporally and partly on the LR pulleys inferior aspect
 64 6 Neuroanatomical Strabismus
[15, 24]. Consequently, the IO exerts a tonic nasalward
force on the IR pulley, and a tonic inferior force on the LR
pulley [24]. In youth, these active muscular forces are bal-
anced by the elastic stiness of the pulley connective tis-
6 sue suspensions, particularly by the elasticity of a ligament
connecting the LR with the SR pulleys that is termed the
LRSR band [15, 25]. The suspensory tissues of the orbital
pulleys become gradually attenuated during normal aging
[15, 25], causing predictable inferior shifts in horizontal
rectus pulley positions [26], and making the pulleys of
order people more susceptible to the eects of trauma
and surgery.
Summary for the Clinician
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.
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 23 mm
by the seventh decade of life [26]. This converts some of
the horizontal force of the horizontal rectus EOMs to
infraducting force, without any abducens neuropathy or
deciency of the magnitude of LR force generation.
Abducting saccades maintain normal peak velocities [27].
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 LRSR band with inferior sag of the LR pulley relative to the center of the medial rectus
pulley (denoted by the yellow horizontal line). Massons trichrome stains collagen blue and muscle dark red. (Copyright nonexclu-
sively assigned to American Academy of Ophthalmology, 2008.)
When horizontal pulley sag occurs symmetrically, there
is no eect on horizontal binocular alignment, since the
MR and LR muscles experience balanced force reduc-
tions [25]. The additional infraducting force contributed
by the horizontal rectus EOMs is most likely to be the
cause of the predictably reduced supraducting ability of
older people [28].
More severe LRSR 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. The 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. This 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 eect 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

Table 6.4. Alignment eect of LRSR band degeneration
Symmetry Resulting strabismus
Bilaterally symmetric Divergence paralysis
esotropia
Asymmetric Hypotropia Esotropia
very successfully treated by multiple conventional stra-
bismus surgical approaches that counteract esodeviation
(e.g., MR recession or LR resection), it is the authors
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
LRSR band may suddenly impart a marked infraduct-
ing action to the involved LR muscle, even creating
restriction to passive supraduction [25] (Fig. 6.5). The
clinical presentation may be acute onset of hypotropia
with deciency of supraduction that might be mistaken
for SR paralysis or IR restriction in the absence of ade-
quate orbital imaging. Orbital imaging secures the
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
6.5 Divergence Paralysis Esotropia 65
diagnosis of sagging eye syndrome (Fig. 6.5). While it
may sometimes be possible to surgically repair the rup-
tured or stretched LRSR 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
eect of aggressive anterior dissection at strabismus, reti-
nal, or orbital surgery. For instance, damage to the LRSR
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 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 LRSR 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 conrms the diagnosis of LR displacement, and
excludes alternative or coexisting conditions that may
require dierent surgical treatment, or preclude treat-
ment altogether. For example, with or without inferior
displacement of the LR pulley, a severely staphyomatous
globe may ll the bony orbit so completely that duction is
limited [32], or the LR muscle may have suered neuro-
pathic paralysis and have become atrophic. If the cause of
the esotropia is simply inferior displacement of the LR
pulley due to LRSR band degeneration, an eective
treatment may be identical to that used in the sagging eye
 66 6 Neuroanatomical Strabismus

Summary for the Clinician 6.6 Congenital Peripheral Neuropathy:

Numerous structural abnormalities of extraocu-
lar muscles and associated connective tissues
6 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.
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.
The Congenital Cranial Dysinnervation
Disorders (CCDDs)
Certain congenital forms of strabismus occur despite
normal orbital connective tissues and pulleys, as the result
of deciency or misdirection of motor nerves to the
EOMs. Genetic causes of many of the CCDDs are described
in chapter 7 in this volume by Antje Neugebauer and Julia Fricke,
and will not be discussed here in this chapter that emphasizes
the pathophysiology of strabismus. It is useful to under-
stand two general principles in the functional anatomy of
these CCDDs. First, EOMs with insucient motor innerva-
tion are hypoplastic and hypofunctional. Second, eectively
innervated antagonists of congenitally noninnervated EOMs
exhibit contracture and increased stiness (Table 6.5).

Table 6.5. Main imaging ndings in CCDDs

Disorder Orbital ndings Skull base ndings

Congenital oculomotor Variable hypoplasia of inferior oblique Profound hypoplasia of oculomotor

palsy
Congenital brosis
of extraocular muscles
Congenital trochlear palsy
Duane syndrome
Moebius syndrome
Horizontal gaze palsy with
progressive scoliosis
(IO), IR, medial rectus (MR), SR, and LPS; nerves
hypoplasia of intraorbital
oculomotor nerve branches
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
Aected SO hypoplasia None (normal trochlear nerve usually
too small to image)
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
Hypoplasia of deep portions Normal subarachnoid cranial nerves
of all myopathies of extraocular innervating orbit
muscles (EOMs);
curvature of anterior rectus EOMs;
narrowing of deep bony orbits;
ON straightening;
Intraorbital motor nerve hypoplasia
Normal Hypoplastic and ssured medulla and
pons
 6.6 Congenital Peripheral Neuropathy: The Congenital Cranial Dysinnervation Disorders (CCDDs)
6.6.1 Congenital Oculomotor (CN3) Palsy
Congenital oculomotor (CN3) palsy is typically partial.
It may appear clinically bilateral or unilateral, although
on careful evaluation apparently unilateral cases may be
discovered to be bilateral albeit highly asymmetrical
[33]. Patients may present with variable deciencies of
adduction, supraduction, and infraduction, along with
variable mydriasis and blepharoptosis. Aected EOMs
are hypoplastic, corresponding to their functional de-
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 bers, more
profoundly aecting the superior than inferior division
of CN3. Three distinct phenotypes, CFEOM13, are rec-
ognized. The classic form, CFEOM1 (MIM 135700), is
Fig. 6.6 FIESTA MRI
demonstrating hypoplasia
of the subarachnoid
oculomotor nerve (CN3).
(a) Normal subject. (b)
Dominant Duane retraction
syndrome (DRS) linked to
chromosome 2 (DURS2).
(c) Congenital oculomotor
palsy. (d) Congenital brosis
of the extraocular muscles
type 1 (CFEOM1)
67
typied 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 [3537]. 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
 68 6 Neuroanatomical Strabismus

Table 6.6. Imaging features in acquired neuropathic extraocular muscle palsy

Muscle Size Contractility Path

Inferior oblique Reduced 40% Reduced Normal

6 IR Small posteriorly Reduced Centrifugal inection
Lateral rectus Reduced 5090% posteriorly Reduced Centrifugal inection
Levator palpebrae superioris Small Cannot evaluate Normal
Medial rectus Small posteriorly Reduced Normal
SO Reduced 4050% Reduced Normal
SR Small posteriorly Reduced Normal

and blepharoptosis (Fig. 6.7a, b) [38]. Intraorbital motor
branches of CN3 are also hypoplastic (Fig. 6.7c).
MRI in CFEOM1 demonstrates marked hypoplasia of
the subarachnoid CN3. Signicant but usually subclinical
optic nerve (ON) hypoplasia occurs in CFEOM1, as may
superior oblique (SO) muscle hypoplasia presumably due
to trochlear nerve (CN4) hypoplasia. The posterior parts
of multiple EOMs may be dysplastic in CFEOM, although
their anterior portions generally appear normal both by
MRI and at EOM surgery.
The frequent occurrence of synergistic eye movements
and the Marcus Gunn jaw winking phenomenon in
CFEOM1 [39, 40] suggests motor axonal misrouting.
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. This rare recessive disorder occurs in consan
guineous pedigrees. The orbital and cranial nerve pheno-
type of CFEOM2 have not been studied in detail.

Fig. 6.7 Typical orbital MRI 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)
The third CFEOM variant, CFEOM3, encompasses
patients with CFEOM not classiable as either CFEOM1
or CFEOM2. This atypical group includes unilateral
cases who have orthotropic central gaze, or whose central
gaze is hypotropic but who can supraduct above the 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 decient 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.
Summary for the Clinician
CFEOM is not a primary muscle disorder, but
rather a cranial nerve disorder.
6.6.3 Congenital Trochlear (CN4) Palsy
While SO hypoplasia may coexist with other CCDDs
such as CFEOM, SO dysfunction may not be clinically
evident in the setting of diuse external ophthalmople-
gia or anomalous innervation of other EOMs. Isolated
congenital CN4 palsy is often suspected in the presence
of clinical evidence of ipsilateral hypertropia increasing
on contralateral gaze, and with head tilt toward the 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 after many years of compensation
for what the history suggests has been a progressive
condition without identiable 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.
69
6.6.4 Duanes 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 decit, narrowing
of the palpebral 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 conrmed in one sporadic unilateral
[46] and another bilateral autopsy case of DRS [47]. Parsa
et al. rst used MRI to demonstrate absence of the suba-
rachnoid portion of CN6 in DRS [48], a nding that has
been conrmed 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 decient 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 often nondetectable. Lateral
rectus (LR) muscles are often structurally abnormal, often
with MRI and motility evidence of oculomotor nerve
(CN3) innervation from vertical rectus EOMs leading to
A or V patterns of strabismus. Cases may include SO, SR,
and LPS hypoplasia, sparing only the MR, IR, and IO
EOMs. The subarachnoid CN3 may be small. Therefore,
DURS2-linked DRS is a diuse CCDD involving but not
limited to CN6.
Summary for the Clinician
CCDDs are nonprogressive developmental
disorders featuring reduced and aberrant
innervation.
Subnormal innervation of some EOMs in
CCDDs leads to secondary EOM hypoplasia,
dysplasia, and weakness.
 70 6 Neuroanatomical Strabismus
Antagonists of hypoplastic EOMs become sec-
ondarily sti.
Neuromuscular features may vary between orbits
of the same patient, and among patients with
6 identical genetic CCDDs.
High-resolution imaging of EOMs and their
peripheral innervation can be clinically valuable
for strabismus management in CCDDs.
6.6.5 Moebius Syndrome
Moebius syndrome typically presents as a sporadic trait
with congenital facial (CN7) palsy and abduction
Fig. 6.8 Coronal T2-weighted MRI of both orbits in
left SO palsy demonstrating marked reduction in SO
cross-section, as well as reduction in normal contrac-
tile increase in cross-section from up to down gaze
impairment. Moebius syndrome is a heterogeneous
clinical disorder whose clinical denition has evolved in
the recent literature. Minimum criteria include congeni-
tal facial palsy with impairment of ocular abduction
[5456]. The 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.

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 EOMs 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
Theoretical, 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]. The basis of this three-step test is traditionally
believed to be related to Ocular Counter Rolling (OCR),
so that the eye ipsilateral to head tilt is normally intorted
by the SO and SR muscles whose vertical actions cancel
[59]. However, ipsilateral to a palsied SO, unopposed SR
elevating action is supposed to create hypertropia. The
three-step test has been the cornerstone of diagnosis and
classication 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 tests
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 eects head tilt
in SO palsy suggests that SO weakness alone cannot
account for typical three-step test ndings [64].
6.7 Acquired Motor Neuropathy 71
Summary for the Clinician
The three-step test is not specic for trochlear
palsy.
Orbital imaging conrms neurogenic atrophy of
the SO muscle.
High-resolution MRI has quantied normal changes in SO
cross-section with vertical gaze, and SO atrophy and loss of
gaze-related contractility typical of SO palsy [23, 6567].
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 ber size is reduced by 80%,
sparing the orbital layer [68]. A striking and consistent
MRI nding has been nonspecicity 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 signicant 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 inection 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 IOs motor nerve follows a relatively
lengthy isolated course along the lateral margin of the IR
 72 6 Neuroanatomical Strabismus
Fig. 6.9 Orbital T2-weighted
MRI in chronic left abducens
palsy. Axial view above
shows thinning and lateral
inection of palsied LR
6 muscle, which in coronal
view below is seen to have
reduced cross-section
muscle, entering the IO in the EOMs posterior surface
relatively supercially 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. The forms of strabismus arise from
abnormalities in the central nervous system, some of
which are structural lesions that may be imaged.
Summary for the Clinician
Developmental esotropia and exotropia are not
associated with structural abnormalities in the
orbit.
6.8.1 Developmental Esotropia and Exotropia
Human infantile and accommodative esotropia are not
known to be associated with anatomic abnormalities in
the orbit. Naturally and articially 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
The cerebellum contributed toward binocular alignment
[81]. Hereditary cerebellar degeneration is often associ-
ated with convergence insuciency, and in advanced
cases often produces cerebellar atrophy [82]. Cerebellar
or brainstem tumors may be associated with acute onset
of concomitant esotropia in children [83]. Acquired 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 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 ssure
interrupting decussating white matter tracts [84].
References
1. Ortube MC, Bhola R, Demer JL (2006) Orbital magnetic
resonance imaging of extraocular muscles in chronic pro-
gressive external ophthalmoplegia: Specic diagnostic
ndings. J AAPOS 10:414418
2. Biousse V, Newman NJ (2001) Neuro-ophthalmology of
mitochondrial diseases. Semin Neurol 3:275291
3. Vilarinho L, Santorelli FM, Cardoso ML, et al (1998)
Mitochondrial DNA analysis in ocular myopathy.Observations
in 29 portuguese patients. Euro Neurol 39: 148153
4. Kuriyan AE, Phipps RP, Feldon SE (2008) The eye and thy-
roid disease. Cur Opin Ophthalmol 19:499506

5. Wolf AB, Yang MB, Archer SM (2007) Postoperative myosi-
tis in reoperated extraocular muscles. J AAPOS 11: 373376
6. Capone AJ, Slamovits TL (1990) Discrete metastasis of
solid tumors to extraocular muscles. Arch Ophthalmol
108:237243
7. Demer JL (2003) A 12 year, prospective study of extraocu-
lar muscle imaging in complex strabismus. J AAPOS
6:337347
8. Koornneef L (1982) Current concepts on the management
of orbital blow-out fractures. Ann Plast Surg 9:185200
9. Wojno TH (1987) The incidence of extraoular muscle and
cranial nerve palsy in orbital oor blow-out fractures.
Ophthalmol 94:682687
10. Ortube MC, Rosenbaum AL, Goldberg RA, et al (2004)
Orbital imaging demonstrates occult blow out fracture in
complex strabismus. J AAPOS 8:264273
11. Tse R, Allen L, Matic D (2007) The white-eyed medial
blowout fracture. Plast Reconstr Surg 119:277286
12. Demer JL (2004) Pivotal role of orbital connective tissues
in binocular alignment and strabismus. The Friedenwald
lecture. Invest Ophthalmol Vis Sci 45:729738
13. Demer JL (2006) Current concepts of mechanical and neu-
ral factors in ocular motility. Cur Opin Neurol 19:413
14. Demer JL (2006) Ocular motility in a time of revolutionary
paradigm shift. Invest Ophthalmol Vis Sci
15. Kono R, Poukens V, Demer JL (2002) Quantitative analysis
of the structure of the human extraocular muscle pulley
system. Invest Ophthalmol Vis Sci 43:29232932
16. Clark RA, Miller JM, Rosenbaum AL, et al (1998)
Heterotopic muscle pulleys or oblique muscle dysfunc-
tion? J AAPOS 2:1725
17. Miller JM, Demer JL Biomechanical modeling in strabis-
mus surgery. In: Rosenbaum AL, Santiago P (eds) (1999)
Clinical strabismus management: principles and tech-
niques. Mosby, St. Louis
18. Clark RA, Miller JM, Demer JL (1997) Location and stabil-
ity of rectus muscle pulleys inferred from muscle paths.
Invest Ophthalmol Vis Sci 38:227240
19. Miller JM (2007) Understanding and misunderstanding
extraocular muscle pulleys. J Vision 7:115
20. Miller JM, Pavlovski DS, Shaemeva I (1999). Orbit 1.8 gaze
mechanics simulation. Eidactics, San Francisco
21. Clark RA, Miller JM, Demer JL (1998) Displacement of the
medial rectus pulley in superior oblique palsy. Invest
Ophthalmol Vis Sci 39:207212
22. Demer JL, Clark RA, Miller JM (1999) Heterotopy of
extraocular muscle pulleys causes incomitant strabismus.
In: Lennerstrand G (ed) Advances in strabismology.
Aeolus, Buren, The Netherlands
23. Velez FG, Clark RA, Demer JL (2000) Facial asymmetry in
superior oblique palsy and pulley heterotopy. J AAPOS
4:233239
References 73
24. Demer JL, Oh SY, Clark RA, et al (2003) Evidence for a
pulley of the inferior oblique muscle. Invest Ophthalmol
Vis Sci 44:38563865
25. Rutar T, Demer JL (2009) Heavy eye syndrome in the
absence of high myopia: A connective tissue degeneration
in elderly strabismic patients. J AAPOS 13(1):3644
26. Clark RA, Demer JL (2002) Eect of aging on human rec-
tus extraocular muscle paths demonstrated by magnetic
resonance imaging. Am J Ophthalmol 134:872878
27. Lim L, Rosenbaum AL, Demer JL (1995) Saccadic velocity
analysis in patients with digergence paralysis. J Pediatr
Ophthalmol Strabismus 32:7681
28. Clark RA, Isenberg SJ (2001) The range of ocular move-
ments decreases with aging. J AAPOS 5:2630
29. Krzizok TH, Schroeder BU (1999) Measurement of recti
eye muscle paths by magnetic resonance imaging in highly
myopic and normal subjects. Invest Ophthalmol Vis Sci
40:25542560
30. Kowal L, Troski M, Gilford E (1994) MRI in the heavy eye
phenomenon. Aust N Zeal J Ophthalmol 22:125126
31. Ward DM (1956) The heavy eye phenomenon. Trans
Ophthalmol Soc U K 87:717726
32. Demer JL, von Noorden GK (1989) High myopia as an
unusual cause of restrictive motility disturbance. Surv
Ophthalmol 33:281284
33. Wu J, Isenberg S, DJ L (2006) Magnetic resonance imaging
demonstrates neuropathology in congenital inferior divi-
sion oculomotor palsy. J AAPOS 10:473475
34. Engle EC, Goumnerov BC, McKeown CA, et al (1997)
Oculomotor nerve and muscle abnormalities in congeni-
tal brosis of the extraocular muscles. Ann Neurol
41:314325
35. Apt L, Axelrod N (1978) Generalized brosis of the
extraocular muscles. Am J Ophthalmol 85:822829
36. Brodsky MC, Pollock SC, Buckley EG (1989) Neural misdi-
rection in congenital ocular brosis syndrome: Implications
and pathogenesis. J Pediatr Ophthalmol Strabismus
26:159161
37. Harley RD, Rodrigues MM, Crawford JS (1978) Congenital
brosis of the extraocular muscles. Trans Am Ophtlalmol
Soc 76:197226
38. Demer JL, Clark RA, Engle EC (2005) Magnetic resonance
imaging evidence for widespread orbital dysinnervation in
congenital brosis of extraocular muscles due to mutations
in KIF21A. Invest Ophthalmol Vis Sci 46:530539
39. Brodsky MC (1998) Hereditary external ophthalmoplegia,
synergistic divergence, jaw winking, and oculocutaneous
hypopigmentation. Ophthalmology 105:717725
40. Yamada K, Andrews C, Chan W-M, et al (2003)
Heterozygous mutations of the kinesin KIF21A in congen-
ital brosis of the extraocular muscles type 1 (CFEOM1).
Nat Genet 35:318321
 74 6 Neuroanatomical Strabismus
41. Demer JL, Clark RA, Engle EC (2009) Magnetic resonance
imaging evidence of an asymmetrical endophenotype in
congenital brosis of extraocular muscles type 3. Invest
Ophthalmol Vis Sci (in preparation)
6 42. Clark RA, Engle EC, Demer JL (2009) Magnetic resonance
imaging (MRI) of the endophenotype of congenital brosis
of the extraocular muscles type 3 (CFEOM3). Abstracts of
35th Annual Meeting of the American Association for
Pediatric Ophthalmology and Strabismus. J Am Assoc
Pediatr Ophthmol Strabismus 13(1):e13
43. Duane A (1905) Congenital deciency of abduction asso-
ciated with impairment of adduction, retraction move-
ments, contraction of the palpebral ssure and oblique
movements of the eye. Arch Ophthalmol 34:133159
44. Huber A (1974) Electrophysiology of the retraction syn-
dromes. Br J Ophthalmol 58:293300
45. Strachan IM, Brown BH (1972) Electromyography of
extraocular muscles in Duanes syndrome. Br J Ophthalmol
56:594599
46. Miller NR, Kiel SM, Green WR, et al (1982) Unilateral
Duanes retraction syndrome (type 1). Arch Ophthalmol
100:14681472
47. Hotchkiss MG, Miller NR, Clark AW, et al (1980) Bilateral
Duanes retraction syndrome. A clinical-pathologic case
report. Archives of Ophthalmology 98:870874
48. Parsa CF, Grant E, Dillon WP, et al (1998) Absence of the
abducens nerve in Duane syndrome veried by magnetic
resonance imaging. Am J Ophthalmol 125:399401
49. Ozkurt H, Basak M, Oral Y, et al (2003) Magnetic reso-
nance imaging in Duanes retraction syndrome. J Pediatr
Ophthalmol Strabismus 40:1922
50. Kim JH, Hwang J-M (2005) Hypoplastic oculomotor nerve
and absent abducens nerve in congenital brosis syndrome
and synergistic divergence with magnetic resonance imag-
ing. Ophthalmology 112:728732
51. Kim JH, Hwang JM (2005) Presence of abducens nerve
according to the type of Duanes retraction syndrome.
Ophthalmology 112:109113
52. DeRespinis PA, Caputo AR, Wagner RS, et al (1993) Duanes
Retraction Syndrome. Surv Ophthalmol 38:257288
53. Demer JL, Clark RA, Lim KH, et al (2007) Magnetic reso-
nance imaging evidence for widespread orbital dysinner-
vation in dominant Duanes retraction syndrome linked to
the DURS2 locus. Invest Ophthalmol Vis Sci 48:194202
54. Kumar D (1990) Moebius syndrome. J Med Genet 27:
122126
55. MacDermot KD, Winter RM, Taylor D, et al (1991)
Oculofacialbulbar palsy in mother and son: review of 26
reports of familial transmission within the Mobius spec-
trum of defects. J Med Genet 28:1826
56. Verzijl HT, van der Zwaag B, Cruysberg JR, et al (2003)
Mobius syndrome redened: a syndrome of rhomben-
cephalic maldevelopment. Neurology 61:327333
57. Bielschowsky A (1939) Lectures on motor anomalies. XI.
Etiology, prognosis, and treatment of ocular paralyses. Am
J Ophthalmol 22:723734
58. von Noorden GK, Murray E, Wong SY (1986) Superior
oblique paralysis. A review of 270 cases. Arch Ophthalmol
104:17711776
59. Adler FE (1946) Physiologic factors in dierential diagno-
sis of paralysis of superior rectus and superior oblique
muscles. Arch Ophthalmol 36:661673
60. Scott WE, Kraft SP (1986) Classication 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, Steen H, Landau K, et al (2003) Primary
position and Listings law in acquired and congenital tro-
chlear nerve palsy. Invest Ophthalmol Vis Sci 44:42824292
62. Kushner BJ (2004) Ocular torsion: Rotations around the
WHY axis. J AAPOS 8:112
63. Kushner BJ (1988) The diagnosis and treatment of bilateral
masked superior oblique palsy. Am J Ophthalmol
105:186194
64. Robinson DA (1985) Bielschowsky head-tilt testII.
Quantitative mechanics of the Bielschowsky head-tilt test.
Vision Res 25:19831988
65. Chan TK, Demer JL (1999) Clinical features of congenital
absence of the superior oblique muscle as demonstrated by
orbital imaging. J AAPOS 3:143150
66. Demer JL, Miller JM (1995) Magnetic resonance imaging
of the functional anatomy of the superior oblique muscle.
Invest Ophthalmol Vis Sci 36:906913
67. Kono R, Demer JL (2003) Magnetic resonance imaging of
the functional anatomy of the inferior oblique muscle in
superior oblique palsy. Ophthalmology 110:12191229
68. Demer JL, Poukens V, Ying H, et al (2008) Eects of acute
trochlear denervation on primate superior oblique (SO)
muscle: dierential sparing of orbital layer. ARVO
Abstracts: #4495
69. Demer JL, Miller MJ, Koo EY, et al (1995) True versus mas-
querading superior oblique palsies: muscle mechanisms
revealed by magnetic resonance imaging. In: Lennerstrand
G (ed) Update on strabismus and pediatric ophthalmology.
CRC, Boca Raton (FL)
70. Kushner BJ (1987) Errors in the three-step test in the diag-
nosis of vertical strabismus. Ophthalmology 96:127132
71. Brodsky ME (2003) Three dimensions of skew deviation.
Br J Ophthalmol 87:14401441

72. Donahue SP, Lavin PJ, Hamed LM (1999) Tonic ocular tilt
reaction simulating a superior oblique palsy: diagnostic con-
fusion with the 3-step test. Arch Ophthalmol 117:347352
73. Kono R, Okanobu H, Ohtsuki H, et al (2008) Displacement
of the rectus muscle pulleys simulating superior oblique
palsy. Jpn J Ophthalmol 52:3643
74. Clark RA, Rosenbaum AL, Demer JL (1999) Magnetic
resonance imaging after surgical transposition denes the
anteroposterior location of the rectus muscle pulleys.
J AAPOS 3:914
75. Clark RA, Demer JL (2002) Rectus extraocular muscle pul-
ley displacement after surgical transposition and posterior
xation for treatment of paralytic strabismus. Am
J Ophthalmol 133:119128
76. Demer JL (2008) Inection in inactive lateral rectus mus-
cle: Evidence suggesting focal mechanical eects of con-
nective tissues. Invest Ophthalmol Vis Sci 49:48584864
77. Clark RA, Demer JL (2008) Posterior inection of weak-
ened lateral rectus path: Connective tissue factors reduce
response to lateral rectus recession. Am J Ophthalmol
147(1):127133.e2
78. Ela-Dalman N, Velez FG, Demer JL, et al (2008) High reso-
lution MRI demonstrates reduced inferior oblique muscle
References 75
size in isolated inferior oblique palsy. J AAPOS 12(6):
602607
79. Narasimhan A, Tychsen LT, Poukens V, et al (2007)
Horizontal rectus muscle anatomy in naturally and arti-
cially strabismic monkeys. Invest Ophthalmol Vis Sci
48:25762588
80. Tychsen L, Wong AM, Burkhalter A (2004) Paucity of hori-
zontal connections for binocular vision in V1 of naturally
strabismic macaques: Cytochrome oxidase compartment
specicity. J Comp Neurol 474:261275
81. Takagi M, Tamargo R, Zee DS (2003) Effects of lesions
of the cerebellar oculomotor vermis on eye move-
ments in primate: binocular control. Prog Brain Res
142: 1933
82. Durig JS, Jen JC, Demer JL (2002) Ocular motility in
genetically dened autosomal dominant cerebellar ataxia.
Am J Ophthalmol 133:718721
83. Williams AS, Hoyt CS (1989) Acute comitant esotropia in
children with brain tumors. Arch Ophthalmol 107:
376378
84. Jen JC, Chan WM, Bosley TM, et al (2004) Mutations in a
human ROBO gene disrupt hindbrain axon pathway cross-
ing and morphogenesis. Science 304:15091513
 Chapter 7
Congenital Cranial Dysinnervation
Disorders: Facts and Perspectives to
Understand Ocular Motility Disorders
Antje Neugebauer and Julia Fricke
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 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 brosis of
the extraocular muscles (CFEOM), isolated and
7.1 Congenital Cranial Dysinnervation
Disorders: Facts About Ocular Motility
Disorders
Electromyographic, clinicopathologic, neuroradiologic
and genetic studies changed the view upon some con-
genital ocular motor disorders dramatically during the
last decades [18].
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 brosis of the
extraocular muscles (CFEOM) and Duane retraction
syndrome [2, 3, 6, 1015, 21, 22]. In familial cases,
mutations were found in genes that play crucial roles in
7
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, Mbius syndrome and Marcus Gunn
jaw winking phenomenon are understood as
CCDDs.
Other congenital disturbances of ocular motility
with brotic features such as congenital Brown
syndrome, congenital monocular elevation palsy
and vertical retraction syndrome may be discussed
as CCDDs.
cranial nerve development. The typical motility patterns
in these diseases and the muscular anomalies can now be
explained as changes secondary to incomplete, absent or
paradoxical innervation of the eye muscles.
7.1.1 The Concept of CCDDs: Ocular Motility
Disorders as Neurodevelopmental Defects
With the term congenital cranial dysinnervation disor-
ders (CCDDs) coined in 2002 [16] a new entity was estab-
lished that convincingly encompasses dierent congenital,
nonprogressive diseases sharing etiopathologic features.
The 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 inu-
ences are a possibility.
 78 7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives
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
7 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 brotic changes in the tar-
get muscles. Substitutional innervation of the target mus-
cles by cranial nerve 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 dierent stages at which hazardous
inuences can induce specic lesions.
7.1.1.1 Brainstem and Cranial Nerve Development
From the 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 anteriorposterior patterning of the
neural system as well as dorsalventral 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.
That is why insight into the developmental plans of inver-
tebrates helps us to understand the developmental steps
in mammals.
The role of so called homeobox genes that form a
genomic sequence that is encoding developmental steps
in anteriorposterior patterning and segmentation is a
prominent example for this. The hox homeobox cluster
encoding sequential processes of dierentiation both in
time and space has been studied in the genome of
Drosophila melanogaster. In mammals related sequences
that encode dierent steps in hindbrain dierentiation
are identied on four chromosomes thus multiplying the
information for single developmental steps [1719].
Genes for axonal guidance are preserved through the
species as well and that is why basic research in this 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 [1720].
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 identied 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]. The example of the dierent mutated genes causing
Duane retraction syndrome shows that the interference
with dierent 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].
This disorder drew the attention of Elizabeth Engle to the
 7.1 Congenital Cranial Dysinnervation Disorders: Facts About Ocular Motility Disorders
entity of ocular motility disorders [2] and in 2001 it was
the rst congenital eye motility disorder in which a gene
relevant in cranial nerve development was identied to
be mutated in familial cases [21].
Clinically, CFEOM is characterized by gross motility
disorders and sometimes paradoxical motility [2628] 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 de-
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
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. Thus clinic, pathologic
and genetic 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. The brous changes in the
noninnervated muscles can be understood as secondary
changes due to noninnervation of the muscle bers.
Fig. 7.1 Patient with bilateral congenital brosis of the extraoc-
ular muscles (CFEOM). After bilateral inferior rectus recession,
the patient still adopts a 10 chin-up head posture to xate due
to ptosis and residual elevation deciency
79
CFEOM2 is inherited in an autosomal recessive mode;
features are bilateral ptosis and an exotropia with adduc-
tion deciency 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 deciencies 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 dierent families also indicate other
genetic loci. Clinical overlap with congenital motility dis-
orders classied as vertical retraction syndrome is possi-
ble [31, 32].
Duane Retraction Syndrome
Duane 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 deciency of abduction,
associated with impairment of adduction, retraction
movements, contraction of the palpebral ssure and
oblique movements of the eye [33]. This title still gives
the full description of the main features of the syndrome
known today as Duane or retraction syndrome (Fig. 7.2).
In primary gaze, esotropia is the most common 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.
The early etiopathologic theories put forward mainly
focused on mechanical changes in the horizontal rectus
muscles. In 1959, Breinin performed electromyographic
examinations in Duane retraction syndrome and found
no potential in the lateral rectus muscle on abduction but
a response in the lateral rectus on intended adduction [1].
Thus a paradoxical innervation of the lateral rectus was
realized. A further milestone were clinicopathologic stud-
ies by Hotchkiss and Miller who found absent sixth nerves
in Duane retraction syndrome and conrmed pathologic
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 bers of the third nerve [4, 7, 8].
 80 7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives
Fig. 7.2 Patient with Duane a d
syndrome in the left eye.
Near alignment in primary
gaze (b), adduction
deciency and downward
7 movement on right gaze (a),
abduction deciency on left
gaze (c). Lateral view of the
b
globe on left gaze (d),
retraction of the globe on
right gaze (e)
Neuroradiologic studies later on also diagnosed hypopla-
sia of the sixth nerve in Duane syndrome [3537].
In a thorough review De Respinis [34] gives data on
demographic and epidemiologic features of the disease.
Duane syndrome is estimated to account for 14% of
strabismus cases. Pooled data of major studies showed a
predilection of left eyes with 59%; 23% occurred in the
right eye and 18% were bilateral cases. Sixty percent of
the patients were female.
The spectrum of associated nonocular 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
suer from uni- or bilateral Duane syndrome [34, 86].
The rst mutation to be identied 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. The molecular mechanisms by which Duane
syndrome and radial anomalies are induced are not yet
clear. In sporadic cases of Duane syndrome up to now no
mutations in SALL4 were found [39].
In the recently described Bosley-Salih-Alorainy syn-
drome (BSAS), bilateral Duane syndrome combines
variably with sensorineural deafness, carotid artery
malformations, delayed motor development and some-
times autistic disorders. The syndrome is inherited in an
autosomal recessive mode. In dierent pedigrees, mutations
e
in HOXA1 were found to be causative [2, 38, 40, 41].
HOXA1 encodes one homeobox gene that is important for
hindbrain segmentation. Individuals suering 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].
The 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 often bilat-
eral Duane syndrome but also some abnormalities in the
vertically acting eye muscles innervated by the third
nerve. The gene CHN1 encodes a2-Chimaerin, a protein
that plays a role in the information ow induced by eph-
rin and ephrin-receptor interaction that leads to growth
cone changes inuencing the guidance of a growing axon
[44]. In a chick in ovo model, it could be shown that
changes comparable with those induced by the gain of
function mutations found in CHN1 lead to incomplete
outgrowth of ocular motoneurons [23].
The current pathophysiologic concept for Duane syn-
drome putting together clinical, electrophysiologic, clini-
copathologic, neuroradiologic and genetic ndings looks
upon the disorder as a CCDD in which innervation of the
lateral rectus by sixth nerve bers is not full or absent and
third nerve bers, mainly those primarily intended for
the medial rectus take over some innervation of the lat-
eral rectus. Thus, in primary position the underlying
paresis is partly or fully compensated for the lateral rectus
 7.1 Congenital Cranial Dysinnervation Disorders: Facts About Ocular Motility Disorders 81

receives nerve impulses of the third nerve, thus keeping a

the angle of squint in primary gaze relatively small with
regard to the motility deciency in abduction. Sometimes
even overcompensation with a divergent angle in primary
position or synergistic divergence on adduction occurs.
The most common pattern of motility in Duane syn-
drome is an abduction deciency, accompanied by a
slighter adduction deciency that results from the lateral
rectus cocontracting on intended adduction. This cocon- b
traction results in retraction of the globe and narrowing
of the palpebral 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 c
leads to a horizontal gaze palsy with unaected vertical
eye movements. In the entity of so-called HGPPS hind-
brain anomalies and ocular motor anomalies can be
explained by disorders of the pathnding of 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 identied in d
patients with HGPPS [15, 45]. The 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 bers of ascending and descending tracts
[4648]. Neurologic examinations conrm that atypical e
lack of crossing bers exists [49]. The nature of the pro-
gressive scoliosis which means a signicant impairment
to the patients may be to be neurogenic.

7.1.1.3 Disorders Understood as CCDDs

The pathophysiological concept of CCDDs also helps to
understand other congenital, nonprogressive disorders
and syndromes in which the proper motor innervation of
cranial muscles is lacking, decient 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 identied.
Fig. 7.3 Patient with familial horizontal gaze palsy and progres-
sive scoliosis (HGPPS). Patient after 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)
Congenital synkinetic movements of the lid on jaw
movements often with congenital ptosis are referred to as
Marcus Gunn phenomenon and hint to a paradoxical
innervation in the levator palpebrae by bers of the motor
portion of the fth nerve (Fig. 7.4). Misrouting of sixth
and seventh nerve bers into the levator palpebrae also
has been described [28, 47, 50, 51]. One of our patients
 82 7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives

a b

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

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). The 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 identied.
In a study targeting on ARIX as a candidate gene in con-
genital trochlear palsy, no mutation was identied 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].

a b c

d e f

g h i

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

a b

Fig. 7.6 Patient with congenital fourth nerve palsy in the right eye. Normal right gaze (a), elevation on adduction on left gaze (b)
7.2 Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders
Some more descriptions of single synkinetic disorders
concerning the sixth nerve and its target muscle such as
abduction of the globe on mouth opening, upgaze and
drinking exist [47].
A typical combination of mostly bilateral sixth nerve
and seventh nerve underaction can be observed in Mbius
syndrome. Recent publications hint to the total spectrum
of Mbius syndrome that is broader and encompasses
also combinations of horizontal gaze palsies or bilateral
Duane syndrome and facial weakness and presumably
lower brainstem disorders such as pharyngeal and tongue
anomalies. But also third nerve anomalies reminding of
CFEOM are described. Furthermore limb anomalies and
problems of motor coordination occur. Thus Mbius 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].
Summary for the Clinician
A group of congenital ocular motility disorders
are caused by developmental disturbances. These
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.
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.
a b
d e
Fig. 7.7 Patient with right-sided Brown syndrome. Minimal hypotropia in primary gaze (e). Slight elevation deciency in right
upgaze (a), marked elevation deciency in left upgaze (c). Slight depression on adduction in left gaze (f)
83
In 1949, H.W. Brown (18981978) 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
brotic features such as retraction syndrome, strabismus
xus, vertical retraction syndrome and general brosis syn-
drome. Furthermore, under the name of superior oblique
tendon sheath syndrome, he introduced a special form of
congenital elevation deciency 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 Deciencies:
A Neurodevelopmental View
7.2.1.1 Brown Syndrome
Motility Findings
Brown syndrome is an oculomotor disturbance charac-
terized by an elevation deciency on adduction, normal
or near normal elevation on abduction, mild elevation
deciency 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 aected eye in primary position may
occur, a relative divergence of the eyes in upgaze may
exist and sometimes widening of the lid 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. The pathogenesis in congenital
cases is not completely understood [6063].
Browns initial assumption that a congenital palsy
of the inferior oblique leads to secondary changes in the
superior oblique tendon sheath was disproven by
c
f
 84 7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives
electromyography, which showed normal innervation in
the inferior oblique. Brown subsequently regarded the
disorder to be caused by a structural anomaly in a supe-
rior oblique tendon sheath [59, 64]. Many studies report
7 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 [6063].
The notion of Brown syndrome as a misinnervation
syndrome was put forward already in 1969 by Papst and
Stein who in an electromyographic study demonstrated
paradoxical innervation of the superior oblique muscle on
intended elevation in adduction of the globe. The authors
interpreted this nding in analogy to the paradoxical
coinnervation found in Duane retraction syndrome and
postulated a neurodevelopmental origin of the syndrome.
Other authors conrmed the results by electromyography,
so that a total of ve cases with electromyographic record-
ing of paradoxical innervation to the superior oblique are
reported by three dierent 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 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
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 denes 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.
The 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 bers
of the third nerve.
Up to now CCDDs with secondary dysinnervation of
ocular target muscles by nerve 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 bers normally intended for the
antagonists of the primary dysinnervated muscles occurs
in Duane syndrome and often keeps the deviation of the
eyes in primary position remarkably small.
A misinnervation of a non- or underinnervated supe-
rior oblique muscle by 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 bers normally running to the inferior
oblique muscle. First, because the antagonist of the pri-
marily paretic superior oblique muscle might receive less
nerve 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
bers intended for the inferior oblique would result in
blockage of elevation in adduction by cocontraction of
the two muscles. This could be the explanation for the
elevation deciency 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 ssure on adduction. This would be an eect reverse to
the narrowing of the lid 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 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
7.2 Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders 85

superior oblique by bers primarily destined to the a

medial rectus would be possible [68].
At last even a miswiring of bers prone to the supe-
rior rectus could be discussed. This would explain why
many patients show also a minor elevation deciency in
abduction.
Thus, the motility ndings of Brown syndrome could b
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 19952007 for information supporting
or contradicting the hypothesis that the typical features of c
congenital Brown syndrome result from primary and sec-
ondary misinnervation.

Saccadic Eye Movements

Barton [69] in a study on vertical saccades described the
eye tracking of vertical saccades in a patient with Brown
syndrome. Reproducibly, there occurred a marked and
punctuated lateral shift, described as a horizontal 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 eld of action of the inferior oblique.
The authors compare the ip movement of the eye to
that in horizontal saccades in Duane syndrome. With the
onset of cocontraction, a ip could occur by the sudden
action of the antagonist.
Comorbidity
In 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 [7173]. 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.
The coincidence with CCDDs could be caused by
common pathogenetic mechanisms interfering with
brainstem and cranial nerve development.
The high incidence of contralateral fourth nerve
palsies also is of interest with regard to a potential
d
Fig. 7.8 Patient with right-sided Duane and left-sided Brown syn-
drome. Right upgaze (a) shows abduction deciency in the right
eye and elevation deciency on adduction on the left side. Right
gaze (b) shows abduction deciency in the right eye and widening
of the palpebral ssure in the left eye. Eyes shown in primary gaze
(c). Left gaze (d) shows narrowing of the right lid ssure
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 Features
Under the hypothesis of a similar etiology, we compared
epidemiologic data for Brown and Duane syndrome
because both the fourth and sixth cranial nerves have
developmentally an origin of rhombomeres which is dif-
ferent from the third nerve [52].
Laterality
De Respinis [34] reviewed publications on Duane syn-
drome and gured out side distribution from pooled data
of dierent studies. We pooled the data of ten studies on
Brown syndrome [60, 65, 7481] and of our own series.
In a total of 11 studies, including 246 patients with con-
genital Brown syndrome the right side was aected in
53%, the left side in 38% and both sides in 9%.
 86 7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives
In the series on Duane syndrome [34], a total of 835
cases were analyzed.
In 59% the left eye was aected, in 23% the right eye
and in 18% bilaterality was found.
7 Assuming that in Duane syndrome the pathophysio-
logic mechanism has a tendency to aect rather the left eye,
these data seem contradictory to a common pathogenesis.
This contradiction resolves because the bers of the
fourth nerve are crossing and the nucleus of the fourth
nerve lies contralaterally. The hypothesis stating a primary
brainstem related pathophysiologic mechanism of Brown
syndrome, the data concerning laterality show an 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 signicantly.
Sex Distribution
Pooled data of ten and our own studies [60, 65, 7481]
encompassing 246 patients showed the aection of 55%
females and 45% males. For Duane syndrome de Respinis
[34] found in pooled data of 835 patients, 58% were
women and 42% were men. Again, an analogy between
the entities of Brown and Duane syndrome under the
hypothesis of a similar pathophysiologic mechanism
could be drawn.
Incidence
Incidence of Brown syndrome is estimated to be 1 per
430450 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 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 gure out the incidence of the
underlying pathophysiologic entity of a developmental
fourth nerve disorder.
Heredity
In 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 conrmed 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.
Three of the reports of familial Brown syndrome
involve monocygotic twins with mirror images. In Duane
syndrome, mirror images in twins are also described.
But, although there are as in Brown syndrome far
more sporadic than familial cases, the amount of 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 aection [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. Thus, this paper in our
opinion does not contradict the hypothesis in question.
Of our 87 patients, 21 patients had a positive family
history in regard to strabismus or amblyopia (24.1%).
Three patients (3.4%) had relatives with Brown syn-
drome: two pairs of brothers, amongst them one pair
of twins with mirror images and one parent child
constellation.
One patients grandfather was reported to us to be
unable to move the eyes to the right or left. We had no
opportunity to examine the patient but a video of him
showed a condition that might represent bilateral Duane
syndrome or horizontal gaze palsy.
Potential Induction of the Syndrome
Among the developmental defects caused by thalidomide
there are also cranial miswiring syndromes. We 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 suered from gaze
paresis, isolated abduction weakness, aberrant lacrimation
and facial nerve palsy.
7.2 Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders
It could be discussed whether the patients described
with inferior oblique underaction were patients with a
paradoxical coinnervation in fourth nerve hypo- or
aplasia.
Saito in a neurological work-up of the data of 137
patients with thalidomide embryopathy described three
patients with disturbances of the fourth nerve [87].
Radiologic Findings
Imaging studies in Brown syndrome displayed dierent
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
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 deciency a nding in
favor of the hypothesis. Muscular anomalies were not
found in these patients [80, 88].
Natural Course in Brown Syndrome
As to the natural course of the disease, reports are incon-
sistent. Whereas Wright states that congenital Brown
syndrome yields rather stable ndings, many authors
report spontaneous improvement or even resolution
[8991]. In most of our patients 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 signicant
spontaneous improvement.
The nding of spontaneous resolutions challenges
the hypothesis of a dysinnervation. But one has to con-
sider that the hypothesis states secondary 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
brotic tissues would serve under both assumptions. In
the setting of cocontraction, changes in 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].
87
Intra-and Postoperative Findings
Structural changes in the superior oblique tendon in
Brown syndrome have been described by many surgeons
[79, 92, 103]. In our series, 28 patients underwent 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 brotic
changes in this muscle were reported.
Surgical results are often disappointing as indicated by
the multitude of approaches suggested. Surgeons often
recognize a disappointing discrepancy between intraop-
erative ndings after interventions on the superior oblique
in that passive motility is improved after the procedure
but active motility in the postoperative course is still not
improved signicantly.
Papst and Stein in their thorough early discussion of a
potential misinnervation already hinted to this 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 veried or falsied.
7.2.1.2 Congenital Monocular Elevation
Deciency and Vertical Retraction
Syndrome
While in congenital Brown syndrome an elevation de-
ciency of the eye exists if the globe is adducted, in con-
genital monocular elevation deciency 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. Often 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 after
operation. Often Bells 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 deciency in which they reg-
istered pseudptosis in 90%, true ptosis in 64%, chin-up
head position in 77%, hypotropia in primary gaze in 97%
 88 7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives
a
7 exclude a nuclear disorder: for the third nerve, the sub-
b Remarkably, as in Brown syndrome, which was ini-
c adduction and that an inferior oblique palsy not neces-
d
Fig. 7.9 Patient with congenital monocular elevation deciency
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, Bells phenomenon, (d) than
on elevation (b)
with a mean of 20 PD, Marcus Gunn jaw winking in 28%,
reduced or absent Bells 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 Bells phenomenon was positive.
The fact that in some cases elevation of the globe is
preserved under the conditions of Bells 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 nding that elevation is hindered in
abduction, which means in the eld of action of the supe-
rior rectus, and in adduction, which means in the eld of
action of the inferior oblique, led many observers to
nucleus for the innervation of the superior rectus lies
contralaterally, and for the inferior oblique, it lies ipsilat-
erally in the mesencephalon.
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
sarily is required to produce the typical motility pattern,
[62, 94] thus a nuclear origin conned to the subnucleus
of the superior rectus was not out of discussion.
In cases with resistance to forced duction, impairment
of Bells phenomenon also exists, where sometimes a pri-
marily brotic origin is presumed.
Thus supranuclear, nuclear, fascicular and muscular
etiologies are discussed for the rare disorder of congenital
monocular elevation deciency.
With the Marcus Gunn phenomenon, ptosis and
restriction as accompanying signs some features exist that
could be compatible with a neurodevelopmental origin of
double elevator palsy. A case with the combination of
Duane syndrome and double elevator palsy has been
reported [99]. In our series of 23 patients, two showed
contralateral fourth nerve palsy.
Three of our patients showed retraction of the globe
on vertical eye movements.
This leads to similarities with vertical retraction 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 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 deciency.
A secondary misinnervation as cause for the retrac-
tion of the globe on vertical movements would be a pos-
sible explanation.
The view upon congenital double elevator palsy and
vertical retraction syndrome as neurodevelopmental dis-
orders would require a model that solves the question
why Bells phenomenon remains intact in some cases.
7.2 Congenital Cranial Dysinnervation Disorders: Perspectives to Understand Ocular Motility Disorders 89

sequential activation of genes and the building up of

7.2.2 A Model of some Congenital Elevation
Deciencies as Neurodevelopmental
Diseases
Our inquiries into the eld of congenital elevation de-
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 dierentiate
between a Brown syndrome and a congenital monocular
elevation deciency. Wright in his review hinted to 70%
of patients that had been operated and that demon-
strated signicant elevation deciency 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 aected side. Patients with congeni-
tal monocular elevation deciency may display retrac-
tion on up- or downgaze so that clear dierentiation
from vertical retraction syndrome may be dicult. At
last even dierentiation between a unilateral congenital
brosis syndrome and these disturbances may be di-
cult. Thus one might ask for an explanation taking into
account that borders are not clear cut.
In prenatal development segmentation, anterior
posterior and dorsoventral patterning is achieved by
gradients of mediators for developmental steps.
The crossing of 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. The muta-
tions in the ROBO3 gene leading to HGPPS are an exam-
ple of a locally dened 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 bers of the third nerve e.g., 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
bers of the third nerve, the subnucleus sending bers
across the midline that lies next to the fourth nerve and
innervates the levator palpebrae muscle would be aected
and fourth nerve palsy or Brown syndrome accompanied
by ptosis would result. A substitutional innervation, e.g.,
by bers of the motor portion of the fth 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 ssure.

superior rectus, MIF

superior rectus, SIF

Fig. 7.10 Model of N. III-
congenital Brown syndrome nucleus
as a neurodevelopmental
disorder. A schematic levator palpebrae, SIF
drawing shows the third and
N. IV-nucleus
fourth nerve nuclei in the
brainstem. A unilateral
superior oblique, SIF
gradual disturbance exists
that mostly aects the fourth
nerve nucleus or its crossing
x
neurons. An x indicates N.IV
disruption of normal fourth
nerve innervation. Dashed
lines indicate secondary
misinnervation of the
superior oblique by third
nerve bers. Note that this
misinnervation does not run
topographically in the way N.III-
shown. The lines just indicate fibers
which muscles might share
innervation
 90 7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives

Further extension would encompass the subnucleus
for the superior rectus. Brown syndrome and ptosis would
be accompanied by an elevation deciency in abduction,
thus completing the image of congenital monocular ele-
7 vation deciency. If the superior rectus is innervated by
bers of its main antagonist, retraction movements as
well as depression deciency 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
bers (SIF) and multiple innervated muscle bers (MIF)
receive input each from a special subset of motoneurons
that dier in their histologic appearance from neurons
innervating SIF bers. These are located in distinct
regions of the third nerve nucleus [100, 101].
Such a dual innervation would make it necessary to
reconsider the presumption of a nal common path in eye
muscle innervation. The principle itself as introduced by
Sherrington referred to the motoneuron as the 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.
The motoneuron group innervating the MIF of the
superior rectus is found in the so-called S-group, which in
man lies in the cranial part of the nucleus. The functional
role of the MIF 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 Bells phenomenon and further that these
neurons either by their special cytologic features or just by
their cranial position are not reached by the pathologic
process hindering midline crossing. This would explain
why Bells phenomenon remains intact in some cases of
monocular elevation deciency. Thus the concept of a
supranuclear disorder would not be necessary.
This model would explain Brown syndrome, congeni-
tal monocular elevation deciency and vertical retraction
syndrome as disorders of mesencephalic disturbance of
midline crossing of fourth and third nerve bers with
dysinnervation (Fig. 7.11).

superior rectus, MIF

N.III

superior rectus, SIF

N. III-
nucleus

N. IV-
levator palpebrae, SIF
nucleus

N.V- superior oblique, SIF

fibers
x
x
x

N.IV

N.III-
fibers

Fig. 7.11 Model of congenital monocular elevation deciency as a neurodevelopmental disorder. A schematic drawing shows
the third and fourth nerve nuclei in the brainstem. A unilateral gradual disturbance exists that mostly aects the fourth and third
nerve nuclei or their crossing neurons. An x indicates disruption of normal fourth nerve innervation and disruption
of the crossing 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 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. The lines just indicate which muscles might share innervation. Green line indicates multiple innervated muscle
bers (MIF) for tonic innervation of the superior rectus not aected by the lesion

The clinical ndings seem consistent, future studies
namely genetic studies in familial cases or on candidate
genes will help to test this model.
Summary for the Clinician
Congenital Brown syndrome, congenital mon-
ocular elevation deciency and vertical retrac-
tion syndrome as nonprogressive forms of
strabismus with brotic changes share features
with CCDDs and are found to be accompanied
intraindividually or familial by other CCDDs.
Electromyographic, neuroradiologic and surgi-
cal 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.
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.
References
1. Breinin GM (1957) Electromyography: a tool in ocular and
neurologic diagnosis. II. Muscle palsy. Arch Ophthalmol
57:165175
2. Engle EC (2007) Oculomotility disorders arising from dis-
ruptions in brainstem motor neuron development. Arch
Neurol 64(5):633637
3. Engle EC, Leigh RJ (2002) Genes, brainstem development,
and eye movements. Neurology 59(3):304305
4. Hotchkiss MG, Miller NR, Clark AW, et al (1980) Bilateral
Duanes retraction syndrome. A clinical-pathologic case
report. Arch Ophtalmol 98:870874
5. Huber A, Esslen E (1969) Duanes syndrome; observa-
tions on the pathogenesis and etiology of dierent formes
of the Stilling-Duane-Turk-retraction syndrome. Doc
Ophthalmol 26:619628
6. Kohlhase J, Heinrich M, Schubert L, Liebers M, et al (2002)
Okihiro syndrome is caused by SALL4 mutations. Hum
Mol Genet 11(23):29792987
7. Miller NR (2005) Strabismus syndromes: the congenital
cranial dysinnervation disorders (CCDDs). In: Taylor D,
Hoyt CS (eds) Pediatric ophthalmology and strabismus.
Elsevier, Saunders, Edinburgh, London
References 91
8. Miller NR, Kiel SM, Green WR, et al (1982) Unilateral
Duanes retraction syndrome (TypI). Arch Ophthalmol
100(9):14681472
9. Brown HW (1950) Congenital structural muscle anoma-
lies. In: Allen JH (ed) Strabismus ophthalmic symposium I.
VC Mosby, St. Louis
10. Al-Baradie R, Yamada K, St Hilaire C, et al (2002) Duane
radial ray syndrome (Okihiro syndrome) maps to 20q13
and results from mutations in SALL4, a new member of the
SALL family. Am J Hum Genet 71(5):11951199 Epub
2002 Oct 22
11. Engle EC (2002) Applications of molecular genetics to the
understanding of congenital ocular motility disorders.
Ann N Y Acad Sci 956:5563
12. Engle EC (2006) The genetic basis of complex strabismus.
Pediatr Res 59(3):343348
13. Engle EC (2007) Genetic basis of congenital strabismus.
Arch Ophthalmol 125(2):189195
14. Engle EC, Goumnerov BC, McKeown CA, et al (1997)
Oculomotor nerve and muscle abnormalities in congenital
brosis of the extraocular muscles. Ann Neurol 41(3):
314325
15. Jen JC, Chan WM, Bosley TM, et al (2004) Mutations in a
human ROBO gene disrupt hindbrain axon pathway cross-
ing and morphogenesis. Science 304(5676):15091513.
Epub 2004 Apr 22
16. Gutowski NJ, Bosley TM, Engle EC (2003) The congenital
cranial dysinnervation disorders. Neuromuscul Disord
13:573578
17. Hans ten Donkelaar J, Lammens M, Hori A (2006) Clinical
neuroembryology. Springer, Berlin
18. Purves D (ed) (2008) Neuroscience, 4th edn. Sinauer
Associates, Massachusetts
19. Sanes DH (ed) (2006) Development of the nervous system,
2nd edn. Elsevier, Amsterdam
20. Woods CG (2004) Crossing the Midline. Science 304:
14551456
21. Nakano M, Yamada K, Fain J, et al (2001) Homozygous
mutations in ARIX(PHOX2A) result in congenital brosis of
the extraocular muscles type 2. Nat Genet 29(3): 315320
22. Yamada K, Andrews C, Chan WM, et al (2003)
Heterozygous mutations of the kinesin KIF21A in congen-
ital brosis of the extraocular muscles type 1 (CFEOM1).
Nat Genet 35(4):318321. Epub 2003 Nov 2
23. Miyake N, Chilton J, Psatha M, et al (2008) Human CHN1
mutations hyperactivate alpha2-chimaerin and cause
Duanes retraction syndrome. Science 321(5890):839843.
Epub 2008 Jul 24
24. Tischeld MA, Bosley TM, Salih MA (2005) Homozygous
HOXA1 mutations disrupt human brainstem, inner ear,
cardiovascular and cognitive development. Nat Genet 37
(10):10351037. Epub 2005 Sep 11
 92 7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives
25. Heuck G (1879) ber angeborenen vererbten Beweglich-
keitsdefect der Augen. Klin Monatsbl Augenheilkd 17:
253278
26. Brodsky MC, Pollock SC, Buckley EG (1989) Neural
7 misdirection in congenital ocular brosis syndrome:
implications and pathogenesis. Pediatr Ophthalmol
Strabismus 26(4):159161
27. Cibis GW (1984) Congenital familial external ophthal-
moplegia with co-contraction. Ophthalmic Paediatr Genet
4:163167
28. Yamada K, Hunter DG, Andrews C, et al (2005) A novel
KIF21A mutation in a patient with congenital brosis of
the extraocular muscles and Marcus Gunn jaw-winking
phenomenon. Arch Ophthalmol 123(9):12541259
29. Heidary G, Engle EC, Hunter DG (2008) Congenital brosis
of the extraocular muscles. Semin Ophthalmol 23(1):38
30. Yazdani A, Chung DC, Abbaszadegan, et al (2005) A novel
PHOX2A/ARIX mutation in an Iranian family with con-
genital brosis of extraocular muscles type 2 (CFEOM2).
Am J Ophthalmol 136(5):861865
31. Hanisch F, Bau V, Zierz S (2005) Congenital brosis of
extraocular muscles (CFEOM) and other phenotypes of
congenital cranial dysinnervation syndromes (CCDD).
Nervenarzt 76(4):395402
32. Yamada K, Chan WM, Andrews C, et al (2004) Identication
of KIF21A mutations as a rare cause of congenital brosis
of the extraocular muscles type 3 (CFEOM3). Invest
Ophthalmol Vis Sci 45(7):22182223
33. Duane A (1905) Congenital deciency of abduction, asso-
ciated with impairment of adduction, retraction move-
ments, contraction of the palpebral ssure and oblique
movements of the eye. Arch Ophthalmol 34:139159
34. De Respinis PA, Caputo AR, Wagner RS, et al (1993) Duanes
retraction syndrome. Surv Ophthalmol 38: 257288
35. Kim HJ, Hwang JM (2005) Presence of the abducens nerve
according to the type of Duanes retraction syndrome.
Ophthalmology 112(1):109113
36. Ozkurt H, Basak M, Oral Y, et al (2003) Magnetic reso-
nance imaging in Duanes retraction syndrome. J Pediatr
Ophthalmol Strabismus 40(1):1922
37. Parsa CF, Grant E, Dillon WP Jr (1998) Absence of the
abducens nerve in Duane syndrome veried by magnetic
resonance imaging. Am J Ophthalmol 125(3):399401
38. Tischeld 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):900902
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):216218
40. Bosley TM, Salih MA, Alorainy IA, et al (2007) Clinical
characterization of the HOXA1 syndrome BSAS variant.
Neurology 69(12):12451253
41. Bosley TM, Alorainy IA, Salih MA, et al (2008) The clinical
spectrum of homozygous HOXA1 mutations. Am J Med
Genet A 146A(10):12351240
42. Holve S, Friedman B, Hoyme HE, et al (2003) Athabascan
brainstem dysgenesis syndrome. Am J Med Genet A
120A(2):169173
43. Stein HJ, Papst W (1969) Elektromyographische Unter-
suchungen zur Pathogenese und Therapie des Musculus
obliquus superior-Sehnenscheidensyndroms (Brown-
Syndrom). Ber Zusammenkunft Dtsch Ophthalmol Ges
69:618624
44. Wegmeyer H, Egea J, Rabe N, et al (2007) EphA4-dependent
axon guidance is mediated by the RacGAP a2-Chimaerin.
Neuron 55:756767
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, Ltschg J (2008) Functional MRI, DTI
and neurophysiology in horizontal gaze palsy with pro-
gressive scoliosis. Neuroradiology 50:453459
47. Pieh C, Lagrze WA (2007) Angeborene Fehlinnerva-
tionssyndrome. Ophthalmologe 104:10831096
48. Sicotte NL, Salamon G, Shattuck DW, et al (2006) Diusion
tensor MRI shows abnormal brainstem crossing bers
associated with ROBO3 mutations. Neurology 67(3):
519521
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 77:10471053; 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 105:717725
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 102:373389
53. Traboulsi EI (2007) Congenital cranial dysinnervation dis-
orders and more. J AAPOS 11(3):215217
54. Astle WF, Rosenbaum AL (1985) Familial congenital
fourth cranial nerve palsy. Arch Ophthalmol 103:532535
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):
5562

56. De Souza-Dias CR, Goldchmitt M (2007) Further consider-
ations about the ophthalmic features of the Mbius sequence,
with data of 28 cases. Arq Bras Oftalmol 70(3): 451457
57. Verzijl HT, van der Zwaag B, Cruysberg JR, et al (2003)
Mbius syndrome redened: a syndrome of rhomben-
cephalic maldevelopment. Neurology 61(3):327333
58. Von Noorden GK (2002) The history of strabismology.
Wayenborgh, Ostende
59. Brown HW (1973) True and simulated superior oblique
tendon sheath syndromes. Doc Ophthalmol 34:123136
60. Wright KW (1999) Browns syndrome: diagnosis and man-
agement. Trans Am Ophthalmol Soc 47:10231107
61. Esser J, Mhlendyck H (2004) Jaensch-Brown-Syndrom.
In: Kaufmann H (ed) Strabismus. Georg Thieme, Stuttgart,
New York
62. Von Noorden GK, Campos EC (2002) Binocular vision
and ocular motility, 6th edn. Mosby, St. Louis
63. Wright KW (ed) (2003) Pediatric ophthalmology and stra-
bismus, 2nd edn. Springer, New York
64. DEsposito M, Cotticelli L, Caccia-Perugini G, et al (1974)
La Pseudoparalisis delloblique inferiore. Acta Neurol
(Napoli) 29(6):625658
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 354359
66. Papst W, Stein HJ (1969) Zur tiologie des Musculus-
obliquus-superior-Sehnenscheidensyndroms. Klin Monatsbl
Augenheilkd 154:506518
67. Catford GV, Hart JCD (1971) Superior oblique tendon
sheath syndrome. An electromyographical study. Brit J
Ophthalmol 55:155160
68. Clarke WN, Nol LP (1985) Depression in adduction syn-
drome. Can J Ophthalmol 20:2328
69. Barton JJ, Intriligator JM (2001) Vertical saccades in supe-
rior oblique palsy and Browns syndrome.J Neuroophthalmol
21:250255
70. Wilson ME, Eustis HS, Parks MM (1989) Browns syn-
drome. Surv Ophthalmol 34:153172
71. Bhola R, Sharma P, Saxena R, et al (2004) Magnetic reso-
nance imaging of an unusual case of Browns Syndrome with
contralteral superior oblique palsy. J AAPO 8(2): 196197
72. Castanera de Molina A, Munoz GL (1991) Brown syndrome
associated with contralateral superior oblique palsy: a case
report. J Pediatr Ophthalmol Strabismus 28: 310313
73. Clarke WN, Nol LP (1993) Browns syndrome with con-
tralateral inferior oblique overaction: a possible mecha-
nism. Can J Ophthalmol 28(5):213216
74. Berk AT, Erkan D, Sener C, et al (1994) Congenital Browns
syndrome: clinical and surgical approach. Eur J Ophthalmol
4:138143
References 93
75. Crawford JS, Orton RB, Labow-Daily L (1980) Late results
of superior oblique muscle tenotomy in true Browns syn-
drome. Am J Ophthalmol 89:824829
76. Eustis HS, OReilly C, Crawford JS (1987) Management of
superior oblique palsy after surgery for true Browns syn-
drome. J Pediatr Ophthalmol Strabismus 24:1016
77. Hadjadj E, Conrath J, Ridings B, et al (1998) Syndrome de
Brown: actualits. J Fr Optalmol 21:276282
78. Maggi R, Maggi C (2002) Tendon surgery in Browns syn-
drome. J Pediatr Opthalmol Strabismus 39:3338
79. Parks MM, Eustis HS (1987) Simultaneous superior
oblique tenotomy and inferior oblique recession in Browns
syndrome. Ophthalmology 94:10431048
80. Sener EC, zkan SB, Aribal ME, et al (1996) Evaluation of
congenital Browns syndrome with magnetic resonance
imaging. Eye 10:492496
81. Von Noorden GK, Olivier P (1982) Superior oblique tenec-
tomy in Browns syndrome. Ophthalmology 89:303309
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): 233241
83. Mc Kusick VA (1990). Mendelian inheritance in Man, 9th
edn. John Hopkins Univ, Baltimore
84. Paul OT, Hardage LK (1994) The heritability of strabismus.
Ophthalmic Genet 15(1):118
85. Iannaccone A, McIntosh N, Ciccarelli ML (2002) Familial
unilateral Brown syndrome. Ophthalmic Genet 23(3):
175184
86. Miller MT (1991) Thalidomide embryopathy: a model for
the study of congenital incomitant horizontal strabismus.
Trans Am Ophthalmol Soc 89:623674
87. Kida M (ed) (1987) Thalidomide 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): 438448
89. Capasso L, Torre A, Gagliardi V (2001) Spontaneous
resolution of congenital bilateral Browns Syndrome.
Ophthalmologica 215:372375
90. Gregersen E, Rindziunski E (1993) Browns syndrome.
Acta Ophthalmol 71:371376
91. Kaban TJ, Smith K, Orton RB, et al (1993) Natural history
of presumed congenital Brown syndrome. Arch
Ophthalmol 111:943946
92. Mhlendyck H (1996) Jaensch-Brown-Syndrom Ursache
und operatives Vorgehen. Klin Monatsbl Augenheilkd
208:3747
93. Crawford JS (1976) Surgical treatment of true Browns syn-
drome. Am J Ophthalmol 81:289296
94. White JW (1942) Paralysis of the superior rectus and infe-
rior oblique muscles in the same eye. Arch Ophthalmol
27:366371
 94 7 Congenital Cranial Dysinnervation Disorders: Facts and Perspectives
95. Olson RJ, Scott WE (1998) Dissociative phenomena in con-
genital monocular elevation deciency. J AAPOS 2:728
96. Mims JL 3rd (2005) Double elevator palsy eye supraducts
during stage II general anesthesia supporting hypothesis of
7 (supra)nuclear etiology. Binocul Vis Strabismus Q 20(4):
199204
97. Leigh RJ, Zee DS (2006) The neurology of eye movements,
4th edn. Oxford University, Oxford, New York
98. Bell J A, Fielder A, Viney S (1990) Congenital double ele-
vator palsy in identical twins. J Clin Neuro-ophthalmol
10(1):3234
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
syndromea case report. Indian J Ophthalmol 40(2):6162
100. Bttner-Ennever JA (2006) The extraocular motor nuclei:
organization and functional neuroanatomy. In: Bttner-
Ennever JA (ed) Neuroanatomy of the oculomotor system.
Elsevier, Amsterdam
101. Horn AK, Eberhorn A, Hrtig W, et al (2008)
Perioculomotor cell groups in monkey and man dened by
their histochemical and functional properties: reappraisal
of the Edinger-Westphal nucleus. J Comp Neurol 507(3):
13171335
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):
8286
 Chapter 8
The Value of Screening
for Amblyopia Revisited
Jill Carlton and Carolyn Czoski-Murray
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.
The justications 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-eective, 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
after glasses are prescribed. Most improvement
8.1 Amblyopia
Amblyopia is a sensory anomaly dened as defective uni-
lateral or bilateral visual acuity (VA). There are a number
of classications of amblyopia based on the etiological
cause(s). The reported prevalence of amblyopia varies
widely, from 15%. Dierences in prevalence can be
attributed to the population studied (e.g. ethnicity), and
8
occurs in weeks 412. In some cases, further
amblyopia therapy may not be required.
Children who undergo amblyopia therapy at an
early age have been found to respond more
quickly to occlusion than older children, and
require less occlusion in total. There is evidence
to suggest that successful treatment of children
aged over 7 years can be achieved in cases of
anisometropic, strabismic, and mixed etiology
amblyopia.
Atropine has been found to be as eective as
patching in the treatment of both moderate and
severe amblyopia.
Recurrence of amblyopia may occur following
treatment, with reported rates of 727%. Factors
inuencing 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; ne motor skills;
reading speed; and interpersonal relationships.
The reported HRQoL implications of strabismus
are related to physical appearance, particularly
upon self-image and interpersonal relationships.
Surgical correction of strabismus has been
reported to improve HRQoL.
whether the study sample was taken from a clinical cohort
(where a greater prevalence would be expected), or a pop-
ulation-based study. However, the most important factor
that can account for the dierences in the reported preva-
lence rates is that of amblyopia denition. Over the recent
years, a denition of amblyopia based upon a dierence
in VA of two or more Snellen or logMAR lines between
eyes has been adopted. However, there is no universally
 96 8 The Value of Screening for Amblyopia Revisited

accepted denition of amblyopia in terms of VA decit.

Studies that report on amblyopia prevalence, diagnosis,
and/or treatment must be interpreted carefully, and often
cannot be directly compared. Nonetheless, amblyopia is
8 considered to be a common condition which occurs in
childhood, and if left untreated, will remain present
throughout adult life. This chapter will explore what is
meant by screening; detection of amblyopia and 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?
The purpose of screening is to identify persons as being
at greater or lesser risk of developing, or having, a par-
ticular condition. The United Kingdom (UK) National
Screening Committee (NSC) dened screening as a
public health service in which members of a dened
population, who do not necessarily perceive that they
are at risk of, or are already aected by, a disease or its
complications, are asked a question or oered a test to
identify those individuals who are more likely to be
helped than harmed by further tests or treatment to
reduce the risk of a disease or its complications [1].
There are recognized criteria for screening relating to
the condition itself, diagnosis, treatment, and cost. These
are summarized in Table 8.1.
8.2.1 Screening for Amblyopia,
Strabismus, and/or Refractive Errors
Screening for amblyopia, strabismus, and/or refractive
errors has long been an emotive and contentious issue.
Dierences in health care provision from one country to
another can make it dicult to draw inferences on the
possible benets 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.
The appropriateness of such programs was called into
question following a systematic review of their eective-
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]. This recommenda-
tion has been adopted regionally in the UK, although not
universally.
Within the USA, there are also widespread dier-
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 The condition should be an important health problem, whose epidemiology and natural history are
understood. There should be a recognizable risk factor or early symptomatic stage
Diagnosis There should be a simple, safe, precise, and validated screening test which is acceptable to the
population. There should be an agreed policy on further investigation of individuals with a positive
test result
Treatment There should be an eective treatment or intervention for those identied as having the disease or
condition, with evidence of early treatment leading to better outcome than late treatment. There
should be agreed evidence-based policies regarding which individuals should be oered treatment
Program There should be evidence from high-quality randomized controlled trials (RCTs) that the screening
program is eective in reducing mortality or morbidity. There should be evidence that the
complete screening program (including the test, diagnostic procedures, and treatment) is clinically,
socially, and ethically acceptable. The benet of the program should outweigh the physical and
psychological harm. The cost of the program should be economically balanced in relation to
expenditure on medical care as a whole (i.e. value for money)

(AAPOS), and the American Academy of Pediatrics
(AAP) are that vision screening should be performed on
children between the ages of 3 and 3 years [5]. Despite
the existence of such recommendations, current practice
within the USA is totally non-standardized, with much
variability by state and locality. This was highlighted by
Ciner et al. [6], who recommended that specic 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 often driven by political rather
than clinical factors.
8.2.1.1 Screening for Amblyopia
The 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. The 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
The purpose or value for pre-school vision screening for
strabismus alone could be questioned. It may be argued
that large, cosmetically apparent strabismus would be
observed by parents or guardians and/or health care
practitioners. Once noted, appropriate referral to an
ophthalmologist would be initiated. Therefore, the jus-
tication of pre-school vision screening for large-angled
strabismus may not be valid. The detection of small-
angle strabismus, however, is not as easy and requires
expert testing from orthoptists and ophthalmologists.
The value of such detection remains under debate. If the
strabismus is so small that it is not cosmetically obvious,
then it is unlikely that surgical treatment for the 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
8.2 What Is Screening? 97
of the strabismus would be suggestive that amblyopia is
likely to develop within the critical period of vision
development.
8.2.1.3 Screening for Refractive Error
Screening for refractive error alone is not commonplace.
The justication would be that the presence of signi-
cant refractive error may impact upon educational prog-
ress and daily living. The existence of unequal refractive
error (anisometropia) could be deemed an amblyogenic
risk factor. Indeed, the correction of any clinically sig-
nicant 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. These may include
ocular pathologies such as cataract or retinoblastoma; or
may be related to motility, such as Duanes or Browns
syndrome. Whilst such conditions are of great clinical
importance, not least because of their association with
systemic health problems, the justication of screening
for detection of these conditions alone cannot be justi-
ed. To screen for such conditions in isolation is neither
practical nor appropriate. The economic benet of adding
such conditions to a screening program for amblyopia
and/or strabismus is negligible.
8.2.2 Dierence Between a Screening
and Diagnostic Test
There is dierence 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 decit 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 inuence the management plan of the
condition. A diagnostic test often quanties the extent or
severity of the condition. For example, photoscreening is
used to detect refractive error (screening test); however,
the results would not be used to diagnose the extent of
the refractive error present or indeed for the prescription
of glasses. This would be achieved through refraction
(diagnostic test).
 98 8 The Value of Screening for Amblyopia Revisited
8.2.3 Justication for Screening
for Amblyopia and/or Strabismus
The justication of pre-school vision screening for ambly-
8 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.
The evidence relating to the conditions 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 eect 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 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.
The authors were able to report on the total population
lifetime risk and annual rate of permanent visual
impairment or blindness attributable to loss of vision in
the non-amblyopic eye. In addition, the projected 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 [4.337.01 CI] compared
with 32.98, [29.0636.89 CI]). This can be attributed to
the increased prevalence of other ocular disorders that
occur with increasing age (such as cataract and age-
related macular degeneration). The authors stated that
every year as a result of disease aecting 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
after disease in the non-amblyopic eye being reported.
The authors stated that the lifetime risk of serious vision
loss for an individual with amblyopia was substantial
and in the region of 1.23.3%. This was supported by
Chua and Mitchell [9], who found that people with
amblyopia had almost three times the risk of visual
impairment in their better-seeing eye compared with
people without amblyopia.
More recently, Van Leeuwen et al. [10] examined
the excess risk of bilateral visual impairment among
individuals with amblyopia as part of the Rotterdam
study (a population-based prospective cohort study of
the frequency and determinants of common 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 eect on the individual is often devastating.
There have been reported cases of plasticity in the visual
system, even in adulthood, whereby improvements in VA
in the amblyopic eye have been observed [11].
Another argument for the notion of pre-school
vision screening for amblyopia and/or strabismus is the
impact of having either condition on quality of life. This
will be examined in more detail towards the end of the
chapter.
8.2.4 Recent Reports Examining
Pre-School Vision Screening
The scarcity of evidence that would allow decision makers
in the UK NHS to fund screening programs with con-
dence that it is an ecient use of limited health care
resources has made screening for amblyopia problematic.
To be cost-eective, a program has to demonstrate that it
is rst clinically eective. 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. The
problems associated with older established programs
relate mainly to the reality that often 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. The
recent review of screening for amblyopia is one such area.

In 2008, the Health Technology Assessment report on
pre-school vision screening was updated, examining both
the clinical and cost eectiveness of screening programs
for amblyopia and strabismus in children up to the ages of
45 years [12].
A systematic review of the literature examining the
clinical and cost eectiveness of screening children for
amblyopia and strabismus before the age of 5 years was
undertaken. Cost eectiveness and expected value of per-
fect information (EVPI) modeling was reported. EVPI
modeling is used in cost-eectiveness analysis to attempt
to establish the benets of undertaking research that
would reduce the costs of uncertainty. The 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 eects of amblyopia over an individuals remain-
ing lifetime was also constructed. These models were
incorporated into a separate screening model that repre-
sented the potential impact of treatment. The expected
health outcome for the individual was dened 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 eects of childhood amblyopia on a cohort
of individuals who would have bilateral or unilateral
vision loss over a 93-year time horizon. The costs associ-
ated with the screening program and the benets
(expressed as utility weights) were applied to both vision
loss across the models time horizon, which allowed us to
give the estimated costs, and to the consequences of
amblyopia.
The model population was informed by the literature
reviews. It was identied during the data extraction pro-
cess that there was a signicant lack of quantitative data
available which could be used in the model. This 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 conrm 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 eectiveness of treat-
ment for amblyogenic factors. It was assumed that by
removing the risk factor for refractive error, the out-
come would be 100% eective. Strabismus treatment
is acknowledged to be less successful; therefore, the
8.2 What Is Screening? 99
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-eective use of resources.
Analysis of cost eectiveness using the available research
data found that screening was not cost-eective 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. The 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-eective. 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 persons
quality of life (in the short or long term) is still unknown,
and guesstimates of such impact lead only to more
uncertainty.
These ndings may not provide the ideal result for
decision makers, as the answers are not clear cut. Cost
eectiveness 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.
This is particularly relevant in communities where there
may be a greater prevalence of amblyopia or strabismus
which could not be detected or acted upon by parental
observation alone. The gures reported earlier, linking
the cost per QALY, are those which are applied to new
technologies. The QALY threshold for disinvestment is
undened at present.
The German Institute for Quality and Eciency in
Healthcare (IQWIG) is an independent scientic institute
that investigates the benets 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 benets of screening for visual
impairment in children up to the age of 6 years [14]. They
concluded that no robust conclusions could be directly
inferred from the studies identied in their review. To
that end, the notion of pre-school vision screening could
neither be supported nor rejected.
 100 8 The Value of Screening for Amblyopia Revisited
Summary for the Clinician
The purpose of screening is to identify persons
as being at greater or lesser risk of developing, or
8 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.
The justications 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
The accurate detection of amblyopia, strabismus, and/or
refractive error undoubtedly forms a critical factor in the
reported success of any pre-school vision screening pro-
gram. However, much variation exists both within and
between countries as to the content of vision screening
programs. This includes the age at which the child is
screened, referral criteria of the screening program, and
indeed, the personnel administering the tests that form
the screening program. Owing to such dierences, it is
often dicult 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 eectively in pre-
school vision testing.
The eectiveness of a screening test in detecting a con-
dition is considered in terms of sensitivity, specicity, and
positive and negative predictive values. Sensitivity is
dened as the proportion of individuals with the target
condition in a population who are correctly identied by
a screening test. Specicity is the proportion of individu-
als free of the target condition in a population who are
correctly identied 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
The use of crowded logMAR acuity is the gold-standard
VA measure in adults both within clinical and research
settings. This is also becoming the case with VA mea-
surement in children. Steps have been made to identify
normative values of pediatric VA using dierent vision
tests, protocols of testing, and repeatability of testing
[1519]. The preference as to which vision test that is to
be included in a screening program is not always clear.
Often a number of vision tests may be included within
the one screening program to incorporate factors such
as a childs comprehension and ability to perform a test.
It is outside the scope of this chapter to report upon the
relative sensitivity and specicity of each vision test.
However, it should be noted that the cut-o points used
for referral within a screening program should be
directly related to the specic 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 dierent from that achieved using an
alternative vision test. The referral criteria should be
stipulated for each vision test that could be used within
the screening program.
8.3.2 Cover-Uncover Test
The cover-uncover test is used to detect the presence of
strabismus, and is deemed to be the gold standard for
detecting strabismus. However, there are few studies that
report on the sensitivity and specicity of the test itself.
Williams et al. [20] were able to report on the sensitivity
and specicity 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, 0.5770.899%), with a speci-
city of 100%.
The VIP study also assessed the eectiveness of the
cover-uncover test in detecting strabismus, amblyopia,
reduced VA, and refractive error [21]. The results are
 8.3 Screening Tests for Amblyopia, Strabismus, and/or Refractive Error 101

Table 8.2. Sensitivity of cover-uncover test when specicity was set to 0.94 [21]
Test Amblyopia n = 75 Strabismus n = 48 Refractive error Reduced VA n = 132
(95% CI) (95% CI) n = 240 (95% CI) (95% CI)
Cover-uncover 0.27 (0.170.37) 0.60 (0.460.74) 0.16 (0.110.21) 0.06 (0.020.10)
n = number of children

summarized in Table 8.2. The results of this study indicated
that the cover-uncover test is more sensitive at detecting
the presence of strabismus compared with detecting the
presence of amblyopia, refractive error, or reduced VA.
8.3.3 Stereoacuity
The inclusion of stereoacuity tests within pre-school
vision screening programs could be considered as a 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 signicant 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 identied for some of these tests. In the
absence of such data, the appropriateness of inclusion of
such tests could be questioned. Stereotests that involve a
pass/fail response could be deemed as more appropriate
for the purpose of screening for vision problems.
The VIP has reported on the testability of two dierent
stereotests used to screen for vision disorders, the Random
Dot E and the Stereo Smile test [21, 23]. The results
reported by condition type are summarized in Table 8.3.
The results indicated that both the stereotests are more
accurate at detecting the presence of amblyopia and 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 specicity was set at 0.94. The
results are summarized in Table 8.4, and show that
the Stereo Smile test was more accurate than the Random
Dot E in detecting most target conditions of screening.
8.3.4 Photoscreening and/or Autorefraction
The use of photoscreeners and/or autorefractors in
pre-school vision screening is extremely varied. Within
the USA, they are commonplace, and the variety of dif-
ferent makes and models make summarizing literature
extremely dicult. The use of such instruments within

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

Stereotest Amblyopia Reduced VA Strabismus Refractive error Specicity

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

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

Test Amblyopia Strabismus Refractive error Reduced VA

(95% CI) (95% CI) (95% CI) (95% CI)

Random Dot E 0.28 (0.180.38) 0.29 (0.160.42) 0.23 (0.180.23) 0.24 (0.170.31)
Stereo smile 0.61 (0.510.71) 0.58 (0.460.70) 0.37 (0.320.42) 0.20 (0.130.27)
a
May have more than one condition
 102 8 The Value of Screening for Amblyopia Revisited
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
8 when compared with a gold standard (usually a refrac-
tion performed under full cycloplegia). There are notable
advantages and disadvantages of photoscreening when
compared with autorefraction. One of the main dier-
ences is that of cost. After the initial expense of purchase,
there is minimal additional cost to autorefraction.
Photoscreening, however, requires printing of the image,
and depending upon who is administering the test, inter-
pretation of the results. The 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. That 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 specicity 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 specic 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 specicity
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
childs cooperation and compliance. The decision about
whether to refer those children who are unable to per-
form screening tests is dicult. 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. The 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, signicant refractive error, or
unexplained low VA compared with those who had
passed the screening test [24]. This led the authors to
recommend that these children ought to be referred or
retested at a later date possibly with a dierent test. The
impact of recall and re-testing, or automatic referral will
undoubtedly aect the overall clinical and cost eective-
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. The 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? This question was addressed
by VIP, who assessed the performance of lay screeners in
administering pre-school vision screening tests compared
to nurse screeners [25]. In this study, the screening tests
conducted included assessment of refractive error, VA,
and stereoacuity. Two hand-held autorefractors were used
to detect the presence of refractive error. VA was assessed
at two dierent testing distances; a linear test was per-
formed at 10 feet, and a single, crowded test administered
at 5 feet. The results of the study demonstrated that
although nurse screeners appeared to have slightly higher
sensitivities in the assessment of refractive error and pres-
ence of stereoacuity compared with lay screeners, the dif-
ferences were not statistically signicant.
However, when examining the results of VA testing,
the authors reported that nurse screeners achieved sig-
nicantly 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. The lack of sta-
tistically signicant dierences 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 dierences
observed in VA testing between lay screeners and nurse
screeners could suggest that nurse screeners would be
more eective in detecting vision anomalies. Dierences
in screening programs between countries will undoubt-
edly continue to exist; however, recommendations as to

who should conduct screening based upon personnel
costs alone may not be appropriate.
Summary for the Clinician
Content of vision screening programs vary widely.
Most involve assessment of VA for which a large
number of tests are available. The gold standard is
a crowded logMAR-based test. Referral criteria
should be specic for the test used.
The use of photoscreeners and/or autorefractors
in vision screening programs is not universal.
The use of photoscreeners and/or autorefractors
will have an impact upon the cost eectiveness
of screening.
The inclusion of stereotests in pre-school vision
screening programs could be questioned.
Recommendations state that pre-school vision
screening programs be conducted by orthoptists
or by professionals trained and supported by
orthoptists.
8.4 Treatment of Amblyopia
The clinical management of amblyopia is determined
following careful consideration on a case-per-case basis,
taking into account a number of factors including the
type of amblyopia present, the patients 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. The
Pediatric Eye Disease Investigator Group (PEDIG),
based in the USA, is a multi-centre group dedicated to
clinical research in strabismus, amblyopia and other eye
disorders aecting children. Funded by the National
Eye Institute (NEI), this group has investigated many
aspects of the clinical course of amblyopia and its treat-
ment. The 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. They 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 Treatment of Amblyopia 103
8.4.1 Type of Treatment
Amblyopia is treated by obscuring the image from the
good eye to promote the use of the amblyopic eye. This
can be achieved through occlusion treatment (patching
or pharmacological occlusion, in the form of atropine), or
through optical penalization. There are notable advan-
tages and disadvantages to dierent treatment modalities
in terms of compliance, ease of administration, and VA
outcome. Comparison of studies investigating the eec-
tiveness of treatment of amblyopia is hindered, due to dif-
fering denitions 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 dier. 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]. There 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 [2629]. These
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. The
time taken to reach this period, however, remains under
debate. The MOTAS studies utilized a period of 18-week
observation [2729]; however, the PEDIG reported that
83% of their study group demonstrated stability of
improvement in VA before 15 weeks, but one patient
improved in 30 weeks [26]. Improvements in VA have
been described to occur after 20 weeks, but not consider-
ably, with the majority of improvement having occurred
in weeks 412 [30].
One of the arguments supporting the notion of vision
screening is the detection of bilateral refractive error.
 104 8 The Value of Screening for Amblyopia Revisited
Wallace et al. [31], as part of the PEDIG study, examined
the improvements in VA in children with bilateral refrac-
tive amblyopia aged between 3 and 10 years. They reported
that correction of refractive error improved VA, with only
8 12% of the cohort requiring additional amblyopia therapy
in the form of occlusion or atropine.
8.4.3 Conventional Occlusion
Patching treatment is often initiated as the rst-line
approach in amblyopia therapy. One advantage of patching
treatment is that the eects 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 conrm that occlusion therapy is also eective in
the management of amblyopia. PEDIG compared the eect
of daily patching vs. a control group of amblyopes in chil-
dren aged 37 years, following a period of refractive adap-
tation. An improvement in VA was observed in both the
groups after 5 weeks, and as expected, a greater improve-
ment was reported in the patched group [32].
The MOTAS Cooperative investigated the amount of
occlusion required to improve VA and explored the dose-
response relationship in amblyopia therapy [28]. They
found that most children required between 150 and 250 h
of occlusion, irrespective of the type of amblyopia present.
Specic characteristics were observed to aect 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 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. The
PEDIG investigated whether performing such activities
inuenced 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
benets; 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 eects are not readily reversible; it can take several
weeks for the eects of atropine to wear o. Concerns
also exist regarding its ecacy as a treatment modality,
with some clinicians believing it to be a less eective
treatment when compared with conventional occlusion.
Studies conducted by PEDIG examined the eectiveness
of conventional occlusion vs. pharmacological occlusion
in the treatment of moderate amblyopia (20/4020/80)
[34] and severe amblyopia (20/10020/400) [35]. Either
treatment modality was found to be appropriate with
similar improvements in VA in either group. The decision
towards which therapy should be adopted may now be
based on other factors. One such factor may be the instil-
lation of the atropine itself. The eect of dierent atropine
regimens in the treatment of moderate amblyopia (20/40
20/80) was investigated. Comparisons were made between
the observed eects 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. This in itself
may encourage parents and/or clinicians to adopt this
treatment modality.
8.4.5 Optical Penalization
Another treatment option in the management of amblyo-
pia is that of optical penalization. This is where lenses are
used to induce a defocused image of the non-amblyopic
eye. Tejedor and Ogallar [37] directly compared the
eects of atropine vs. optical penalization in the treat-
ment of mild to moderate amblyopia (VA of at least
20/60). This small study found greater improvements in
VA in the atropine group after 6 months of therapy, which
may be attributed to the child peeking over or around the
glasses and thereby not achieving the desired eect of
optical penalization. Although optical penalization
remains a useful treatment option in specic clinical situ-
ations, it is often not considered as an appropriate rst-
line choice of therapy in the management of amblyopia.
8.4.6 Eective Treatment of Amblyopia
in Older Children (Over the Age of 7 Years)
There has been strong evidence that treatment for
amblyopia is more eective prior to the age of 7 years.
Despite this, amblyopia therapy has been reported to be
successful in older children with either anisometropic
[3842] and/or strabismic amblyopia [4042]. Treatment

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-eects had been observed [4042]. 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
The successful management of amblyopia is intrinsically
linked to treatment compliance and adherence to ther-
apy. This in itself is multi-factorial in nature. The 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 often
falls short of their recommended treatment plan. Stewart
et al. [29] reported on the eect of 6 h a day occlusion
compared with 12 h a day occlusion in the treatment of
strabismic and/or anisometropia amblyopia. They found
that the amount of occlusion received was 66 and 50% of
their prescribed 6 and 12 h a day, respectively. Such
information ought to be taken into account when pre-
scribing occlusion therapy.
Loudon et al. [43] examined some of the limiting fac-
tors of occlusion therapy for amblyopia and reported that
parental 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 signicant pre-
dictors of compliance with occlusion therapy. They
reported that self-ecacy (the belief in the ability to patch
their child) was positively associated with treatment com-
pliance. The parental belief that occlusion therapy inhib-
its the childs activities was negatively associated with
treatment compliance.
8.4 Treatment of Amblyopia 105
8.4.8 Other Treatment Options for Amblyopia
The use of photorefractive keratectomy (PRK) for the
treatment of anisometropia in children has not been fully
investigated and concerns exist surrounding the 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 unaected in this study group fol-
lowing treatment. The use of refractive surgery in children
is not commonplace and there remains a need for a large
randomized clinical trial to fully investigate the possible
benets 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 inuence whether recurrence is likely to
occur [4649]. These 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 727%, with a low reported recurrence in chil-
dren who underwent treatment after the age of 7 years
[49]. Age of the child at the cessation of treatment does
appear to be a factor, with recurrence inversely correlated
with patient age [46].
Summary for the Clinician
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 after glasses are pre-
scribed, but most improvement occurs in weeks
412. In some cases, further amblyopia therapy
may not be required.
There is evidence to suggest that children who
undergo amblyopia therapy at an early age
respond more quickly to occlusion than older
children, and require less occlusion in total.
 106 8 The Value of Screening for Amblyopia Revisited
Pharmacological occlusion, in the form of atro-
pine, has been found to be as eective as conven-
tional occlusion (patching) in the treatment of
both moderate and severe amblyopia. Weekend-
8 only atropine instillation has been shown to pro-
duce similar improvements in VA as daily
atropine instillation in the treatment of moder-
ate amblyopia.
There 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.
The 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 inuence treatment
outcome.
Recurrence of amblyopia may occur following
treatment, with reported rates of 727%. Factors
inuencing 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
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 persons
physical and emotional well-being.
8.5.1 The Impact of Amblyopia
Upon HRQoL
There have been a number of studies that have investi-
gated the impact of amblyopia upon HRQoL. These have
examined the eect of amblyopia upon stereoacuity and
motor skills [50, 51], reading speed ability [52], educa-
tional attainment [9], and emotional well-being [44,
5358].
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 ne motor skills of those with
amblyopia compared with age-matched control subjects.
It was noted that the subjects with amblyopia performed
signicantly worse in most of the ne motor skills tests
conducted as part of the study, particularly in the tasks
related to time. The results were even more noticeable in
those children with a diagnosis of amblyopia and strabis-
mus. Hrisos et al. [51] investigated the inuence of VA
and stereoacuity on the performance of pre-school chil-
dren undertaking tasks that required visuomotor skills
and visuospatial ability. The authors reported that reduced
monocular VA itself did not relate to any ability of task
performance, but stereoacuity was found to aect 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. Stifter et al. [52] reported that
maximum reading speed was signicantly reduced in
those with the condition. Therefore, they could be deemed
to have a functional reading impairment when compared
with normal-sighted controls. It is recognized that read-
ing ability is multi-factorial in nature, and is inuenced
by comprehension. The 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 signicantly associated
with lifetime occupational class. However, fewer people
with amblyopia were found to have completed higher
university degrees. This nding was supported by Rahi

et al. [59], who reported on ndings of the 1958 British
birth cohort with respect to any association of amblyopia
with diverse educational, health, and social outcomes.
The authors could nd no statistical evidence between
the presence of amblyopia and educational attainment or
paid employment.
8.5.5 Emotional Well-Being
and Amblyopia
The psychosocial impact of amblyopia and its treatment
has been explored from both the parental and child per-
spective [56]. Children have reported feelings of shame
and negativity associated with amblyopia, particularly
following the start of treatment. The initiation of therapy
can draw adverse attention from others, and children
have reported that they felt interrogated by others about
their treatment (particularly if their treatment involved
the wearing of glasses and a patch).
It is important to recognize that the impact of ambly-
opia therapy may be experienced not only by the child,
but also by family members [54]. This could result in
impaired relationships between the child and parent/
guardian, but also between siblings. Parents often state
that their child may be more clingy or demanding when
occlusion is worn; that the childs compliance with occlu-
sion can lead to negative behavioral changes or that their
child appears to be less condent when wearing their
patch or glasses [56].
The issue of peer victimization and bullying associated
with amblyopia has been recognized [55, 56, 58]. This
may be in response to the wearing of glasses and/or 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. The authors
reported that those children who wore glasses or had a
history of wearing an eye patch were 3537% more likely
to be victims of physical or verbal bullying (after 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
8.5 Quality of Life 107
adverse reactions from their peers. They compared two
groups that had been oered pre-school vision screening
at the age of 3 years with those who had not; and asked
the children at age 8 years whether they had been bullied
through a standard structured interview. The authors
reported an almost 50% reduction in children who
reported having been bullied in the group that had been
oered pre-school screening, compared with the group
who had not.
Not all children undertaking amblyopia therapy nd
the treatment a negative experience. Indeed, in a study by
Choong et al. [53], the authors found no signicant
changes in parental (carers) stress or the childs 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 signicant dierence 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 carers perspective.
Conicting 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 nd no evidence for an association
between the presence of amblyopia and participation in
social activities in either childhood or adult life. The
authors also stated that those with amblyopia were no
more likely to report depression or psychological distress
in adult life.
This 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. The
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 eect of
impaired reading, motor skills, and psychosocial impact
of amblyopia, for example, might inuence HRQoL to a
greater degree.
8.5.6 The Impact of Strabismus Upon HRQoL
The psychosocial implications of strabismus are more
accepted and recognized, particularly in cases of cos-
metically obvious strabismus. Detrimental implications
of strabismus include a negative self-image, reduced
 108 8 The Value of Screening for Amblyopia Revisited
self-condence, low self-esteem, and poor interpersonal
relationships [60]. The presence of a cosmetically notice-
able strabismus has also been reported to impact upon a
persons ability to gain employment [61, 62], and in a
8 persons ability to attract a partner [63]. Furthermore,
the presence of strabismus does not only aect those in
adulthood. Uretman et al. [64] determined that children
with strabismus were perceived in a negative light by
adults. The age at which the emergence of negative 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 benets, and thus improves HRQoL.
Improvements in quality of life following strabis-
mus surgery are well documented in adults [6669];
however, its eect on children is not as extensively
researched. Archer et al. [70] reported on a group of 98
children who underwent strabismus surgery (although
it is unclear whether the purpose of surgery was purely
cosmetic or functional in nature). The authors stated
that following surgery, there were signicant improve-
ments in a number of quality of life dimensions, includ-
ing those of anxiety, social relations, and developmental
satisfaction (parental response). The results concur
with those found in an adult population, and it can
therefore be deemed that the psychosocial benets
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 dier 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 ndings are of great clini-
cal importance, it can be dicult to compare one study
with another due to dierences in methodologies.
One key component that must be considered when
addressing the issue of HRQoL and amblyopia and/or
strabismus is that of the perspective from which the
results are taken. That is, are the results taken from
responses from the parent, the child, or from an adult
with a history of amblyopia and/or strabismus? The
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. They 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 dicult to fully distinguish whether any
reported detriment to HRQoL in amblyopia is due to
the condition itself or its treatment. This is not a factor
when considering strabismus. Strabismus (particularly
that of large angle strabismus) is cosmetically notice-
able and it is the impact that that has upon the person
which can aect HRQoL. Therefore, it can be said that
any study that reports on HRQoL and strabismus is
reporting on the eect that the condition has upon a
persons well-being. With amblyopia, this is not the
case. The condition itself cannot be identied by peers.
What is noted is the eect 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, 5355,
5557]. 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 identied studies are so dierent.
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.

Summary for the Clinician
There have been a number of studies investigat-
ing HRQoL implications of amblyopia and/or
strabismus over recent years. These have involved
studies with children who have the condition, or
adults who had previously undergone treatment.
Studies have reported amblyopia to impact upon
stereoacuity, ne motor skills, and reading speed.
The presence of amblyopia does not appear to
have any impact on educational attainment or
paid employment in adult life.
Amblyopia (more specically amblyopia treat-
ment) has been shown to impact negatively upon
a childs emotional well-being; and may also
aect relationships between the child and par-
ent/guardian.
The issue of bullying and amblyopia treatment
requires further investigation. Some studies
reported that children who had glasses or had a
history of occlusion therapy were more likely to
be victims of bullying. However, other studies
refuted this.
Taken in isolation, the impact of any one of the
aforementioned problems may be minimally
associated with detriment to HRQoL. However,
the cumulative eect of impaired reading, motor
skills, and psychosocial impact of amblyopia, for
example, might inuence HRQoL to a greater
degree.
The reported HRQoL implications of strabismus
are related to physical appearance and the impact
of strabismus upon self-image and interpersonal
relationships. Surgical correction of strabismus
has been reported to improve HRQoL.
References
1. Health departments of the United Kingdom (2000) Second
report of the National Screening Committee
2. Snowdon SK, Stewart-Brown SL (1997) Pre-school vision
screening. Health Technol Assess 1:198
3. Hall DMB, Elliman D (2003) Health for all children, 4th
edn. Oxford University, Oxford
4. Department of health (2008) Updated child health promo-
tion programme
5. A Joint Statement of the American Association for Pediatric
Ophthalmology and Strabismus and the American
Academy of Ophthalmology. Vision screening for infants
and children (2007)
References 109
6. Ciner E, Dobson V, Schmidt P, Allen D, Cyert L, Maguire M,
et al (1999) A survey of vision screening policy of pre-
school children in the United States. Surv Ophthalmol
43(5):445457
7. Brown MM, Grown GC, Sharma S, Busbee B, Brown H
(2001) Quality of life associated with unilateral and bilat-
eral good vision. Ophthalmology 108:643648
8. Rahi JS, Logan S, Timms C, Russell-Eggitt I, Taylor D
(2002) Risk, causes, and outcomes of visual impairment
after loss of vision in the non-amblyopic eye: a population-
based study. Lancet 360:597602
9. Chua B, Mitchell P (2004) Consequences of amblyopia on
education, occupation, and long term vision loss. Br
J Ophthalmol 88:11191121
10. Van Leeuwen RE (2007) Risk of bilateral visual impair-
ment in individuals with amblyopia: the rotterdam study.
Br J Ophthalmol 91(11):14501451
11. Rahi JS, Logan S, Borja MC, Timms C, Russell-Eggitt I,
Taylor D (2002) Prediction of improved vision in the
amblyopic eye after visual loss in the non-amblyopic eye.
Lancet 360:621622
12. Carlton J, Karnon J, Czoski-Murray C, Smith KJ, Marr J
(2008) The clinical eectiveness and cost-eectiveness of
screening programmes for amblyopia and strabismus in
children up to the age of 45 years: a systematic review and
economic evaluation. Health Technol Assess 12(25):iii-194
13. Gold M, Siegel J, Russell L, Weinstein M (1996) Cost-
eectiveness in health and medicine. Oxford University,
New York
14. IQWiG (2008) Screening for visual impairment in chil-
dren: executive summary (translation of the executive
summary of the nal report). IQWiG Reports
Commission No S0502
15. Drover JR, Felius J, Cheng CS, Morale SE, Wyatt L, Birch
EE (2008) Normative pediatric visual acuity using single
surrounded HOTV optotypes on the electronic visual acu-
ity tester following the amblyopia treatment study proto-
col. J AAPOS 12(2):145149
16. Sonksen PMW (2008) The Sonksen logMAR test of visual
acuity: II. Age norms from 2 years 9 months to 8 years.
J AAPOS 12(1):1822
17. Shea SJ, Gaccon L (2006) In the absence of strabismus what
constitutes a visual decit in children? Br J Ophthalmol
90(1):4043
18. Birch EE, Strauber SF, Beck RW, Holmes JM, Pediatric eye
disease investigator group (2008) Comparison of the
amblyopia treatment study HOTV and the electronic-early
treatment of diabetic retinopathy study visual acuity pro-
tocols in amblyopic children aged 5 to 11 years. J AAPOS
13(1):7578
19. Chen SI, Chandna A, Norcia AM, Pettet M, Stone D (2006)
The repeatability of best corrected acuity in normal and
 110 8 The Value of Screening for Amblyopia Revisited
amblyopic children 4 to 12 years of age. Invest Ophthalmol
Vis Sci 47(2):614619
20. Williams C, Harrad RA, Harvey I, Sparrow JM, ALSPAC
study group (2001) Screening for amblyopia in preschool
8 children: results of a population-based randomised con-
trolled trial. Ophthalmic Epidemiol 8:279295
21. The vision in preschoolers study group (2005) Sensitivity
of screening tests for detecting vision in preschoolers-
targeted vision disorders when specicity is 94%. Optom
Vis Sci 82:432438
22. Vision in preschoolers study group (2006) Random Dot E
stereotest: testability and reliability in 3- to 5-year-old
children. J AAPOS 10(6):507514
23. The vision in preschoolers study group (2004) Comparison
of preschool vision screening tests as administered by
licensed eye care professionals in the vision in preschoolers
study. Ophthalmology 111:637650
24. Maguire MG, Vision in preschoolers study group (2007)
Children unable to perform screening tests in vision in
preschoolers study: proportion with ocular conditions and
impact on measures of test accuracy. Invest Ophthalmol
Vis Sci 48(1):8387
25. Vision in preschoolers study group (2005) Preschool vision
screening tests administered by nurse screeners compared
with lay screeners in the vision in preschoolers study.
Invest Ophthalmol Vis Sci 46:26392648
26. Cotter SA, Pediatric eye disease investigator group,
Edwards AR, Wallace DK, Beck RW, Arnold RW, et al
(2006) Treatment of anisometropic amblyopia in children
with refractive correction. Ophthalmology 113(6):
895903
27. Stewart CE, Moseley MJ, Stephens DA, Fielder AR (2005)
On behalf of the MOTAS Cooperative. Refractive adapta-
tion in amblyopia: quantication of eect and implications
for practice. Br J Ophthalmol 88:15521556
28. Stewart CE, Stephens DA, Fielder AR, Moseley MJ (2007)
Modeling dose-response in amblyopia: toward a child-
specic treatment plan. Invest Ophthalmol Vis Sci
48(6):25892594
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):5460
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):487496
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):904912
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):20712078
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 120:268278
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 110:20752087
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):20762085
37. Tejedor J, Ogallar C (2008) Comparative ecacy of penal-
ization methods in moderate to mild amblyopia. Am
J Ophthalmol 145(3):562569
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 12:493497
39. Patwardhan NA (2007) Is age relevant for the success
of treatment of anisometropic amblyopia? Indian
J Ophthalmol 55(6):469470
40. Brar GS, Bandyopadhyay S, Kaushik S, Raj S (2006)
Eciency of occlusion therapy for management of ambly-
opia in older children. Indian J Ophthalmol 54:257260
41. Park KH, Hwang J-M, Ahn JK (2004) Ecacy of amblyo-
pia therapy initiated after 9 years of age. Eye 18:571574
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):581583
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):43934400
44. Searle A, Norman P, Harrad R, Vedhara K (2002)
Psychosocial and clinical determinants of compliance with
occlusion therapy for amblyopic children. Eye 16:150155
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):169176
46. Bhola R, Keech RV, Kutschke P, Pfeifer W, Scott WE (2006)
Recurrence of amblyopia after occlusion therapy.
Ophthalmology 113:20972100
47. Holmes JM, Melia M, Bradeld YS, Cruz OA, Forbes B,
Pediatric eye disease investigator group (2007) Factors

associated with recurrence of amblyopia on cessation of
patching. Ophthalmology 114(8):14271432
48. Tacagni DJ, Stewart CE, Moseley MJ, Fielder AR (2007)
Factors aecting the stability of visual function following
cessation of occlusion therapy for amblyopia. Graefes Arch
Clin Exp Ophthalmol 245(6):811816
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):
655659
50. Webber AL, Wood JM, Gole GA, Brown B (2008) The
eect of amblyopia on ne motor skills in children. Invest
Ophthalmol Vis Sci 49(2):594603
51. Hrisos Clarke S (2006) Unilateral visual impairment and
neurodevelopmental performance in preschool children.
Br J Ophthalmol 90(7):836838
52. Stifter E, Burggasser G, Hirmann E, Thaler A, Radner W
(2005) Monocular and binocular reading performance in
children with microstrabismic amblyopia. Br J Ophthalmol
89:13241329
53. Choong YF, Lukman H, Martin S, Laws DE (2004)
Childhood amblyopia treatment: psychosocial implica-
tions for patients and primary carers. Eye 18:369375
54. Parkes LC (2001) An investigation of the impact of occlusion
therapy on children with amblyopia, its eect on their fami-
lies, and compliance with treatment. Br Orthopt J 58:3037
55. Williams C, Horwood J, Northstone K, Herrick D, Waylen
A, Wolke D, et al (2006) The timing of patching treatment
and a childs wellbeing.[see comment]. Br J Ophthalmol
90(6):670671
56. Koklanis K, Abel LA, Aroni R (2006) Psychosocial impact
of amblyopia and its treatment: a multidisciplinary study.
Clin Exp Ophthalmol 34:743750
57. Packwood EA, Cruz OA, Rychwalski P, Keech RV (1999) The
psychosocial eects of amblyopia study. J AAPOS 3:1517
58. Horwood J, Waylen A, Herrick D, Williams C, Wolke D,
Avon longitudinal study of parents and children study team
(2005) Common visual defects and peer victimization in
children. Invest Ophthalmol Vis Sci 46(4):11771181
59. Rahi JS, Cumberland PM, Peckham CS (2006) Does
amblyopia aect educational, health, and social outcomes?
References 111
Findings from 1958 British birth cohort. BMJ 332(7545):
820825
60. Sattereld D, Keltner JL, Morrison TL (1993) Psychosocial
aspects of strabismus study. Arch Ophthalmol 111:
11001105
61. Coats DK, Paysse EA, Towler AJ, Dipboy RL (2000) Impact
of large angle horizontal strabismus on ability to obtain
employment. Ophthalmology 107:402405
62. Mojon-Azzi SM, Mojon DS (2008) Strabismus and employ-
ment: the opinion of headhunters. Acta Ophthalmol epub
ahead of print
63. Mojon-Azzi SM, Potnik W, Mojon DS (2008) Opinions of
dating agents about strabismic subjects ability to nd a
partner. Br J Ophthalmol 92:765769
64. Uretmen O, Egrilmez S, Kose S, Pamukcu K, Akkin C,
Palamar M (2003) Negative social bias against children
with strabismus. Acta Ophthalmol Scand 81:138142
65. Paysse EA, Steele EA, Brady McCreery KM, Wilhelmus
KR, Coats DK (2001) Age of the emergence of negative
attitudes toward strabismus. J AAPOS 5:361366
66. Jackson S, Harrad R, Morris M, Rumsey N (2006) The psy-
chosocial benets of corrective surgery for adults with
strabismus. Br J Ophthalmol 90:883888
67. Nelson BA, Gunton KB, Lasker JN, Nelson LB, Drohan LA
(2008) The psychosocial aspects of strabismus in teenagers
and the impact of surgical correction. J AAPOS 12:7276
68. Burke J, Leech C, Davis H (1997) Psychosocial implica-
tions of strabismus surgery in adults. J Pediatr Ophthalmol
Strabismus 34:159164
69. Menon V, Saha J, Tandon R, Mehta M, Kokhar S (2002)
Study of psychosocial aspects of strabismus. J Pediatr
Ophthalmol Strabismus 39:203208
70. Archer SM, Musch DC, Wren PA, Guire KE, Del Monte MA
(2005) Social and emotional impact of strabismus surgery
on quality of life in children. J AAPOS 9:148151
71. van de Graaf ES, van der Sterre GW, Polling JR, van
Kempen H, Simonsz B, Simonsz HJ (2004) Amblyopia and
Strabismus Questionnaire: design and initial validation.
Strabismus 12:181193
72. UK National screening committee (2003) Criteria for
appraising the viability, eectiveness and appropriateness
of a screening programme
 Chapter 9
The Brckner Test Revisited
Michael Grf
Core Messages
The Brckner test is useful to detect various
amblyogenic disorders. After a short training,
every physician can perform the test.
The test as originally described consists of four
elements to observe: (1) the position of the rst
Purkinje images (corneal light reexes), (2) the
fundus red reex in the pupil, (3) pupillary light
reexes, and (4) any movement of the eyes when
illumination alters from one eye to the other.
Asymmetry in corneal light reexes on both eyes
may indicate strabismus. However, small devia-
tions are not reliably detected, and asymmetry
can also be caused by dierent angle kappa in
both eyes.
Performance of the red reex test requires a direct
ophthalmoscope. Substitution by an otoscope,
indirect ophthalmoscope, or any other light
source causes loss of test validity.
The red reex 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.
9.1 Amblyopia and Amblyogenic Disorders
Amblyopia is estimated to aect approximately 25% of
the population in Western countries and is a signicant
preventable cause of vision loss in children and adults
[18]. Amblyogenic risk factors include ptosis, media
opacity, fundus pathologies, strabismus and refractive
error [911]. When these risk factors are detected at an
early age, amblyopia can be prevented or minimized more
eectively [3, 1214]. One signicant limiting factor of
most amblyopia screening programs is the reliance on the
subjective responses of the child being tested.
9
Any optically relevant opacity will be apparent by
a shadow in the red reex.
Detection of refractive error can be improved by
extending the test distance up to 4 m and observ-
ing the brightness of the red reex in both eyes
simultaneously. While usually at a distance of 1 m,
the red reex is brighter in the more ametropic
eye, the reex 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 signicant dimming, and anisometropia
causes increasing asymmetry.
The test sensitivity to detect microstrabismus by
asymmetric fundus red reex is low.
Testing pupillary light reexes is recommendable
to assess visual aerence, pupillomotor eerence
and pupil responsiveness. It is hardly suitable to
diagnose or exclude amblyopia and amblyogenic
disorders.
Testing for 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.
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 specicity. 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. These
 114 9 The Brckner Test Revisited
conditions as well as parental readiness are often lacking.
Non-cycloplegic photorefractive screening is not a tanta-
mount substitute of refractometry in cycloplegia [15, 16].
Besides, the technical equipment is relatively expensive,
9 and therefore hardly any paediatrician or general practi-
tioner performs photorefractometry. Even the Brckner
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]. The Brckner test is a readily available
screening tool that can be used with newborns, infants
and preverbal children by non-ophthalmologists [18, 19].
The test requires not more than a direct ophthalmoscope
and only few seconds for performance.
9.1.2 Brckners Original Description
In 1962, Roland Brckner (19121996), an ophthalmolo-
gist in Basel, Switzerland, reported on Exact strabismus
diagnostic in - to 3-year-old children by a simple proce-
dure, the transillumination test [18]. Brckner illumi- movements induce parallel shift of the images in both
nated both pupils from a distance of 1 m and assessed the
following criteria:
Position of rst Purkinje images relative to the pupil
Colour of the fundus red reex in the pupil
Size and constriction of the pupils
Eye movements with and illumination of the pupils
Assessment of the rst two criteria requires simultaneous
illumination of both eyes, whereas assessment of the fol-
lowing two criteria requires alternate illumination. Three
years later, Brckner 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 reex of the fun-
dus when the pupil is lighted and viewed with a direct
ophthalmoscope [19]. This particular component was
new concerning strabismus diagnostic and in the after-
math called Brckner test in the closer sense. It has also
been called the Brckner reex [3, 20].
9.2 Corneal Light Reexes
(First Purkinje Images)
Assessment of the 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 ssure. The latter depends on the conguration 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 ssure can be suggestive of esotropia.
9.2.1 Physiology
Purkinje described that when the eye is being illumi-
nated by an examination light, reexes appear from the
corneal surface, the corneal endothelium, and both the
anterior and posterior surface of the lens. The rst
Purkinje image coming from the corneal tear lm is
brightest. Usually it appears slightly nasally of the centre
of the cornea and the pupil, when the eye is xating a
light source which is held directly below the pupil of the
observer. Slight eccentricity of the corneal light reex is
caused by the dierence 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 reex relative to the pupil
will shift to the opposite direction. Conjugate gaze
eyes. This causes asymmetry in the two images, if their
positions were symmetric at 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. The same will
happen, when the light source is moved to the right-
hand side from the observers 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 xates the light and the right
eye is esotropic, then the rst Purkinje image on the
right eye will be temporally dislocated. So, this method
in principle allows for detection of strabismus.
The idea to measure squint angles by using corneal
light reexes arose at the end of the nineteenth century
[22, 23]. Hirschberg assumed that 1-mm shift of the cor-
neal light reex 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-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 eective 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 rst and the fourth
Purkinje images due to deviation of the visual axis have

been studied [11, 2832]. However, the fourth Purkinje
image is not visible clearly enough by performing the
Brckner test.
9.2.2 Performance
Assessment of the corneal light reex for symmetry on
both eyes requires a small light source, which must be
xated by the patient. To avoid glaring the patient, the
light should not be too bright. The observer compares
the position of the corneal reex images in the two eyes
in relation to the pupils. Physiologically, the images
appear approximately 0.5 mm nasal to the centre of the
pupil. The eccentricity depends on the individual angle k.
The images may be better visible when the observer
looks above the ophthalmoscope. Then the pupils
appear black and there is more luminance contrast of
the images. If the iris is dark brown with low contrast to
the black pupil, looking through the ophthalmoscope is
advantageous. Favourite test distances are around
0.5 m. Closer test distance may cause defence in chil-
dren and also adequate convergence might not be war-
ranted. Larger distance makes it dicult to detect small
asymmetry.
9.2.3 Shortcomings and Pitfalls
False-negative 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 reexes, it is evident that small angle strabismus can
hardly be identied 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 nding of strabismus can be caused
by parallel shift of the reex images in the two eyes when
the light is horizontally displaced. The light source must
be exactly beneath (not beside!) the visual axis of the
observers xating eye. Severe bias occurs when the light
is hold under one eye while the other eye is 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 ashlight
photographs, which were recorded with the ashlight
beside the objective (Fig. 9.1). With the ashlight coaxi-
ally or above the objective, this bias can be avoided, but it
cannot be assured that the child was really xating the
camera [33].
9.3 Fundus Red Reex (Brckner Reex) 115
Fig. 9.1 Corneal light reexes in a 12-month-old girl. In this
case, asymmetry of the corneal light reex between both eyes is
caused by ashlight position beside the objective of the camera.
So, the image of the ashlight on the right eye is more and the
image on the left eye is less nasally decentred. At 9 oclock in
front of both pupils, images of a window
Summary for the Clinician
Evaluating the corneal light reexes 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 xates a point
beside the examination light or when the light is
not on the examiners visual line.
9.3 Fundus Red Reex (Brckner Reex)
Performing the transillumination test requires a direct
ophthalmoscope. Looking through the ophthalmoscope,
the examiner can see the patients pupil shining red,
caused by the light reected by the choroid and the retinal
surface of the eye. The fundus reex was also called
Brckner reex [3, 20]. Colour and brightness of the fun-
dus reex 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 reex 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
Brckner test will probably detect every optically relevant
cataract, albeit we are not aware of any scientic study on
 116 9 The Brckner Test Revisited

Fig. 9.2 Visualization of organic pathologies in the fundus reex 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 signicant 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 ndings are better visible with magnication by shorter distance compared to armlength
distance

the sensitivity of the Brckner test to detect media opac-

ity. Visualizing media opacity and pathologies of the fun-
dus the Brckner reex 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 reex can also be caused by the optic nerve
head and by pathologies of the fundus, such as coloboma,
retinoblastoma, toxoplasmosis scars and medullated
nerve bres.
When the patient takes up central xation of the oph-
thalmoscope light, there is normally a constriction of the
pupils and dimming of both fundus reexes [18]. By
interfering with this dimming phenomenon, manifest
strabismus and anisometropia can produce asymmetry in
the brightness and colour of the fundus reexes in both
eyes. Brckner 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 reex [9, 18]. Regarding ametropia, however,
examination distance is a decisive factor. At larger dis-
tance, the more ametropic eye yields the darker fundus
reex [34].
9.3.1 Physiology
Examination of the fundus red reex 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 xation of the patient, the fun-
dus red reex represents the patients fovea. To explain
the dimming of the red reex when the patient takes up
xation, Brckner discussed various factors [18].
Pupillary constriction, dierent reectivity 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, 3537]. Backscattering of the
light by the retinal nerve 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 diuse reector, 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
eects of defocus and retinal reectivity. Brckners idea
that dierence in reectivity between the central and
para-central or peripheral retinal surface contribute to

the dimming phenomenon was refreshed by Roe and
Guyton who described specular reection of the retina
from the internal limiting membrane that changes slope
with ocular rotation [35, 36]. The fundus reex is not
solely caused by reection from the choroid and the reti-
nal pigment epithelium but, to a minor part, also by
reection from the retinal surface. If signicant light were
reected from the internal limiting membrane of the ret-
ina, the slope of the foveal pit would reect enough light
away from the pupil. Because this part of light would not
be reected back to the observer, the red reex would
appear darkened [35, 36]. Misalignment of one eye with
light being reected from the para-foveal retinal surface,
which is rather perpendicular to the direction of the
incoming light, increases coaxial reection and thus the
brightness of the fundus reex (Fig. 9.3).
This 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 reexes in both
eyes occurring with central xation, neonates and most
infants younger than 2 months of age do not show dim-
ming of the fundus reex with xation and between 2 and
8 months of age up to 28% of infants have asymmetric
dimming of the fundus reexes 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 o-axis aberration
resulting in poor image formation on the retina. Roe and
Guyton believed the fundus reex would appear darker in
an eye that is 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.
200 m
Fig. 9.3 Optic coherence tomography (spectralis OCT) of the normal central fundus. Part of the light is already reected from the
surface of the retina. Due to the slope of the foveal pit part of the light is reected away from the pupil. This might in part explain
that the red reex darkens when the patient takes up central xation of the ophthalmoscope light
9.3 Fundus Red Reex (Brckner Reex) 117
If an eye is deviated, o-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 examiners eye, increasing the brightness
of the red reex [35, 36]. This hypothesis might t with
the observation that at the traditional examination dis-
tance of 1 m the fundus red reex in the (more) ame-
tropic eye is usually brighter compared to an emmetropic
eye. The hypothesis corresponds to the assumption that
accuracy of accommodation is one reason of dimming.
Foveal dimming of the red reex allows for sensitive
discrimination between subsequent central and eccentric
illumination of the same eye. Dimming occurred in 97.2%
of trials with xation of the light compared with xation of
a target between 2.5 and 10 beside the light, regardless of
the angle of eccentricity. This rate did not decrease when
the pupil was dilated by mydriatic eye drops (Grf et al.,
MS in preparation). However, the static inter-ocular dif-
ference in the reexes due to strabismus was less apparent.
In young adults, simulated esotropia with squint angles up
to 5 was detected in not more than 62%. The deviated eye
was identied by the brighter red reex in 48%. Esotropia
of 7.5 and 10 was detected in 85 and 97% with identica-
tion of the deviated eye in 75 and 86% (Table 9.1). To
achieve these rates, very discreet red reex asymmetry
was considered. The rate of false-positive ndings was
36% (Grf et al., MS in preparation). These results con-
rm prior ndings [38]. When esotropia of, for example,
8 prism dioptres was simulated by 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 specic-
ity in young children compared with highly cooperative
 118 9 The Brckner Test Revisited

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

Simulated esotropia Number of trials Test negative (%) Test positive (%) Correct localization (%)

Esotropia 25 100 38 62 48
9 Esotropia 7.5 100 15 85 76
Esotropia 10 100 3 97 86
Orthotropia 300 64 36
Test negative symmetric red reex; test positive inter-ocular asymmetry in red reex; correct localization brighter red reex in the
deviated eye Grf et al., (in preparation)

adults is rather unlikely. Strabismus detection will hardly
improve by extending the test distance, except indirectly,
by detection of anisometropia which frequently accom-
panies esotropia [35]. There might be a chance to improve
test sensitivity and specicity by using a short-pass lter
that blocks the reexes coming from the retinal pigment
epithelium and the choroid and thus augments asymme-
try caused by asymmetric light reection from the inter-
nal limiting membrane.
Considering optical basics, examination distance
must be an essential factor inuencing the red reex 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 reected light bundle reaching the observers
pupil decreases. So, when the observer moves back-
wards, the brighter reex, which at a distance of 1 m,
usually corresponds to the (more) ametropic eye,
becomes darker (Fig. 9.4) [34]. The test sensitivity to
detect unilateral refractive error by the weak reex 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 14 diopters was detected in 6082% of trials at 1 m
but in 100% of trials at 4 m (Table 9.2). Unilateral hyper-
metropia of 14 diopters was detected in 3480% of tri-
als at 1 m but in 5298% of trials at 4 m. Compared with
experts, results of students were weaker at 1 m but
equivalent at 4 m [34]. The low rate of false-positive
ndings shows that rather discreet asymmetry was not
considered pathologic in that study, in contrast to the
study on simulated strabismus, (Fig. 9.5).

Fig. 9.4 Anisometropia of 5 dioptres (emmetropia OD, hypermetropia OS). Fundus red reex recorded at distances of 1 m (top) and
4 m (bottom). This amount of anisometropia causes red reex asymmetry already at the traditional distance with the reex from the
more ametropic eye being somewhat brighter. At the extended distance the red reex of the (more) ametropic eye is much darker
 9.3 Fundus Red Reex (Brckner Reex) 119

Table 9.2. Sensitivity (50 trials for each condition) and false-positive ndings (in 225 trials) of the Brckner reex to detect
unilateral spherical ametropia [34]

Simulated unilateral Experts 1 m (%) Experts 4 m (%) Students 1 m (%) Students 4 m (%)
ametropia

Hypermetropia 1 diopters 34 52 8 60
Hypermetropia 2 diopters 58 94 40 100
Hypermetropia 3 diopters 76 96 56 100
Hypermetropia 4 diopters 80 98 64 100
Myopia 1 diopters 60 100 32 68
Myopia 2 diopters 80 100 28 100
Myopia 3 diopters 74 98 40 100
Myopia 4 diopters 82 100 36 100
False-positive tests 3.1 4.0 1.5 3.0

Results for unilateral astigmatism showed also the
higher detection rates at 4 m distance (Table 9.3).
On the basis of these results, it is recommendable to 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 dierentiate asymmetric from symmetric red
reex in ten patients and six control subjects. Four
patients were anisometropic by 2.255.5 dioptres without
strabismus. In the entire group, paediatric residents
achieved a test sensitivity of 61% and a specicity of 71%
[3]. Gole and Douglas reported a test sensitivity of 86%
and a specicity of not more than 65%. The Brckner 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 specicity of 93.3%. At a distance of 4 m,
sensitivity increased to 77.5% and specicity was 80%
[34]. These rates that depend on patient selection and
observer experience are not representative for a real
screening situation in early infancy.
9.3.2 Performance
It is commonly recommended to perform the test at a dis-
tance of about 1 m or less (arms length distance) by
simultaneously illuminating both eyes of a patient, and to
compare colour and brightness of the pupillary red
reexes for symmetry [3, 18, 19, 35, 37, 38, 40, 41]. The
room light should be dimmed but the room should not be
completely dark [18].
Using a direct ophthalmoscope is mandatory. Otoscope
or ashlight illumination will not yield the same optical
phenomena because the characteristic of the emitted light
is dierent. The light beam must be directed simultaneous

Table 9.3. Sensitivity (50 trials for each condition) and false-positive ndings (in 400 trials) of the Brckner reex to detect uni-
lateral astigmatismus simplex [30]

Simulated astigmatism With the rule Against rule With the rule Against rule
1 m (%) 1 m (%) 4 m (%) 4 m (%)

Hypermetropic 1 diopters 44 44 62 46
Hypermetropic 2 diopters 58 60 88 72
Hypermetropic 3 diopters 76 66 100 82
Hypermetropic 4 diopters 88 72 100 100
Myopic 1 diopters 50 22 44 74
Myopic 2 diopters 60 48 74 98
Myopic 3 diopters 60 70 86 100
Myopic 4 diopters 70 80 92 100
False-positive tests 5.5 5.25
 120 9 The Brckner Test Revisited

into both eyes to enable accurate comparison of the red

reexes. 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 0.50.1 m, examining each a
9 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 reexes. By the same way, it is possible to
check for correct spectacle correction.
b

9.3.3 Possibilities and Limitations

Severe media opacity is visible by lacking or dark fun-
dus red reex, regardless of distance. Small media opac-
ity and pathologies of the fundus are best visible at a
c
short distance. Any asymmetry in brightness and colour
of the reexes 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- d
ertheless, isometropic hypermetropia cannot be detected
reliably. Inter-ocular asymmetry in the red reex can be
caused by anisocoria and is also frequent in the age range
below 8 months.

Summary for the Clinician

e
The fundus red reex 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 f
the red reex. Testing for refractive error is better
performed at an extended distance. Uni- or
bilateral partially or completely weak or lacking
red reex is always pathological. Fig. 9.5 Brckner reex at 4 m distance in case of emmetropia
OU (a) and simulated hypermetropia OS (anisometropia) of 1
diopter (b), 2 diopters (c), 3 diopters (d), and 4 diopters (e). For
comparison, simulated myopia OS of 1 diopter (f) [34]
9.4 Pupillary Light Reexes
Pupillary light reexes are being tested to detect patholo- 1. Dimming of the red reex when the child is centrally
gies in the iris, in the eerent branch of the pupillary light xating the ophthalmoscope light.
reex loop, in the midbrain, or in the aerent branch of 2. Reduced direct pupillary light reex in the amblyopic
the reex loop. Regarding strabismus diagnostic, Brckner eye compared with the direct light reex in the non-
described two criteria: amblyopic eye.
 9.4 Pupillary Light Reexes 121

This step requires monocular illumination of the pupils.
Brckner reported pupillary constriction in the deviated
eye when the light beam was changed from the xating
eye onto the strabismic eye, as soon as this eye took up
xation. Permanent 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
eect 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 aerent pupillomotor decit or dimming of the
red reex in the amblyopic eye occurs after some latency
when the amblyopic eye takes up xation.
9.4.1 Physiology
Illumination of one eye causes symmetric constriction of
both pupils [4246]. 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
aerent disorders show a similar pattern except residual
reaction to illumination of the (more severely) concerned
eye. Discreet aerent disorders can be found by the swing-
ing ash light test [4244]. Aiming at strabismus diagnos-
tic, the observer has to watch any eye movement occurring
after the change of the illumination to the other eye. If the
previously deviated eye which is now being illuminated
takes up xation, the movement of this eye may be visible,
and the pupils will constrict because foveal illumination
has a stronger pupillomotor eect 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 xation, an aerent pupillomotor defect
component may be simulated when this eye is being illumi-
nated or there is in fact a relative aerent pupillary defect
(RAPD) due to amblyopia [4750]. Figure 9.6 shows that
already minimal eccentricity of illumination reduces pupil-
lary constriction compared with a central illumination.
9.4.2 Performance
The examiner directs the light cone on the patients right
eye and observes constriction of each pupil. The proce-
dure is repeated illuminating the patients left eye. If both
pupils are normally reactive, which is mostly the case,
comparison of the direct light reexes of both eyes will be
sucient [5152]. If only one pupil is reactive, this pupil
can be used to compare the constriction with subsequent
illumination of the right and the left eye. The pupillary
constriction has to be equal in latency, speed and 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,

gaze direction

10

5
Fig. 9.6 Video-oculographic
registration of the change in 10
pupil diameter with
alternating xation of the pupil diameter
ophthalmoscope light and
low illuminated visual 6 mm
targets 2.5, 5, 7.5, and 10
right (positive values) and 4 mm
left (negative values) of the
ophthalmoscope light. 2 mm
Fixation of the ophthalmo-
scope light induced more 0 mm
pupillary constriction than
xation of a target as few as 0 5 10 15 20 25 30 35 40 45 50 55 60
2.5 beside time / seconds
 122 9 The Brckner Test Revisited
media opacity or any other pre-retinal disorder, gener-
ally do not cause an apparent RAPD. Thompson reported
that a careful look revealed small RAPD in less than half
of amblyopic eyes. This defect was generally less than 0.5
9 log units [46], and the size of possible RAPD did not cor-
relate well with the visual acuity of the amblyopic eye
[4750]. 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 xation. However, it is hardly
possible to detect strabismus by RAPD.
Summary for the Clinician
Severe unilateral amblyopia might be detected
by RAPD in the amblyopic eye, but usually, the
pupillary light reexes are hardly suitable to
detect strabismus or amblyopia.
9.5 Eye Movements with Alternating
Illumination of the Pupils
Provided central 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 xa-
tion is identical with the angle of abnormal retinal corre-
spondence, there will also be no xation movement
[53, 54]. These patterns are well known from cover test-
ing. Since it is possible that the child keeps 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.
Summary for the Clinician
Brckners transillumination test allows for very
sensitive detection of media opacity. Therefore,
every ophthalmologic examination in early
childhood should include the Brckner test. The
test is suitable to detect strabismus but it does
not allow for sucient detection of small angle
strabismus. Reliable strabismus diagnostic in
childhood requires additional cover testing and
testing of random dot stereopsis. The transillu-
mination test allows for detection of refractive
error, particularly at an extended test distance.
Nevertheless, reliable detection of amblyogenic
ametropia requires refractometry or retinoscopy
in cycloplegia.
References
1. Ehrlich MI, Reinecke RD, Simons K (1983) Preschool
vision screening for amblyopia and strabismus. Programs,
methods, guidelines. Surv Ophthalmol 28:145163
2. Flynn JT (1991) Amblyopia revisited. J Pediatr Ophthalmol
Strabismus 28:183201
3. Paysse EA, Williams GC, Coats DK, Williams EA (2001)
Detection of red reex asymmetry by pediatric residents
using the Brckner reex versus the MTI photoscreener.
Pediatrics 108:E74
4. Tychsen L (1992) Binocular vision. In: Hart WM Jr (ed)
Adlers physiology of the eye: clinical application. Mosby,
St Louis, pp 837838
5. Rahi J, Logan S, Timms C (2002) Risk, causes and out-
comes of visual impairment after loss of vision in the non-
amblyopic eye. Lancet 360:597602
6. Rahi J S, Logan S, Borja MC, Timms C, Russell-Eggitt,
Taylor D (2002) Prediction of improved vision in the
amblyopic eye after visual loss in the non-amblyopic eye.
Lancet 360:621622
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 91:14501451
8. Webber AL, Wood JM, Gole GA, Brown B (2008) The
eect of amblyopia on ne motor skills in children. Invest
Ophthalmol Vis Sci 49:594603
9. Archer SM (1988) Developmental aspects of the Brckner
test. Ophthalmology 95:10961101
10. Barry JC (1999) Hier irrte Hirschberg: Der richtige
Winkelfaktor betrgt 12/mm Hornhautreexdezentrierung.
Geometrisch-optische Analyse verschiedener Methoden der
Strabismometrie. Klin Monatsbl Augenheilkd 215: 104113
11. Barry JC, Eert R, Homann N (1996) Detection and diag-
nosis of small ocular misalignment with the Purkinje reex
pattern method. Klin Monatsbl Augenheilkd 208:167180
12. Coats D, Jenkins R (1997) Vision assessment of the pediat-
ric patient. Renements. Am Acad Ophthalmol 1:1
13. Donahue SP (2006) Relationship between anisometropia,
patient age, and the development of amblyopia. Am
J Ophthalmol 142:132140
14. Sjstrand J, Abrahamsson M (1990) Risk factors in ambly-
opia. Eye 4:787793

15. Ehrt O, Weber A, Boergen KP (2007) Screening for refrac-
tive errors in preschool children with the vision screener.
Strabismus 15:1319
16. Schaeel F, Mathis U, Brggemann G (2007) Noncycloplegic
refractive screening in pre-school children with the
power-refractor in a pediatric practice. Optom Vis Sci
84:630639
17. Zentralinstitut fr kassenrztliche Versorgung (1991)
Hinweise zur Durchfhrung der Frherkennungsunter-
suchungen im Kindesalter. Deutscher rzte Verlag, Kln
18. Brckner R (1962) Exakte Strabismusdiagnostik bei 1/2-
bis 3jhrigen Kindern mit einem einfachen Verfahren, dem
Durchleuchtungstest. Ophthalmologica 144: 184198
19. Brckner R (1965) Praktische bungen mit dem
Durchleuchtungstest zur Frhdiagnose des Strabismus.
Ophthalmologica 149:497503
20. Gole GM, Douglas LM (1995) Validity of the Brckner
reex in the detection of amblyopia. Aust N Z J Ophthalmol
23:281285
21. Kaufmann H (1995) Strungen des Binokularsehens.
Terminologie. In Kaufmann H (ed) Strabismus. Enke,
Stuttgart, pp 162165
22. Hirschberg J (1886) Beitrge zur Lehre vom Schielen
und von der Schieloperation. Zbl prakt Augenheilkd
10:59
23. Smith P (1892) On the corneal reex of the ophthalmo-
scope as a test of xation and deviation. Ophthalmic Rev
11:3742
24. Brodie SE (1987) Photographic calibration of the
Hirschberg test. Invest Ophthalmol Vis Sci 28:736742
25. DeRespinis PA, Naidu E, Brodie SE (1989) Calibration of
Hirschberg test photographs under clinical conditions.
Ophthalmology 96:944949
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 reexes. Acta Ophthalmol 57:600611
27. Grin JR, McLin LN, Schor CM (1989) Photographic
method for Brckner and Hirschberg testing. Optom Vis
Sci 66:474479
28. Barry JC, Eert R, Kaupp A (1992) Objective measurement
of small angles of strabismus in infants and children with
photographic refection pattern evaluation. Ophthalmology
99:320328
29. Barry JC, Eert R, Kaupp A, Burho A (1994) Measurement
of ocular alignment with photographic Purkinje I and IV
reection pattern evaluation. Invest Ophthalmol Vis Sci
35:42194235
30. Barry JC, Eert R, Reim M, Meyer-Ebrecht D (1994)
Computational principles in Purkinje I and IV reection
pattern evaluation for the assessment of ocular alignment.
Invest Ophthalmol Vis Sci 35:42054218
References 123
31. Eert R, Barry JC, Colberg R, Kaupp A, Scherer G (1995)
Self-assessment of angles of strabismus with photographic
Purkinje I and IV reection pattern evaluation. Graefes
Arch Clin Exp Ophthalmol 233:494506
32. Eert 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:
284289
33. Becker R, Grf M (2006) Systematische Fehler bei der
fotograschen Beurteilung der Hornhautspiegelbilder.
Klin Monatsbl Augenheilkd 223:294296
34. Grf M, Jung A (2008) The Brckner test: extended dis-
tance improves sensitivity for ametropia. Graefes Arch
Clin Exp Ophthalmol 246:135141
35. Roe LD, Guyton DL (1984) Perspectives in refraction. Surv
Ophthalmol 28:405408
36. Roe LD, Guyton DL (1984) The light that leaks: Brckner
and the red reex. Surv Ophthalmol 28:655670
37. Tongue AC, Cibis GW (1981) Brckner test. Ophthalmology
88:10411044
38. Grin JR, Cotter SA (1986) The Brckner test: evaluation
of clinical usefulness. Am J Optom Physiol Opt 63:
957961
39. Leertstra LJ (1977) Vergleichende Untersuchungen auf
unterschiedliche Refraktionsnderungen beider Augen bei
Patienten mit Strabismus convergens. Klin Monatsbl
Augenheilkd 170:7479
40. Carrera A, Saornil MA, Zamora MI, Maderuelo A,
Canamares S, Pastor JC (1993) Detecting amblyogenic dis-
eases with the photographic Brckner test. Strabismus
1:39
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 62:768779
43. Loewenfeld IE (1993) The pupil. Wayne State University,
Detroit
44. Miller, NR (1995) Walsh and Hoyths clinical neuro-
ophthalmology, Vol. I-V. Williams and Wilkins, Baltimore
45. Miller JM, Leising Hall H, Greivenkamp JE, Guyton DL
(1994) Quantication of the Brckner test for strabismus.
Invest Ophthalmol Vis Sci 36:897905
46. Thompson HS (1992) The pupil. In Hart WM Jr (ed) Adlers
physiology of the eye. Mosby, St. Louis, pp 412441
47. Firth AY (1990) Pupillary responses in amblyopia. Br J
Ophthalmol 74:676680
48. Greenwald MJ, Folk ER (1983) Aerent pupillary defects
in amblyopia. J Pediatr Ophthalmol Strabismus 20:
6367
49. Kase M, Nagata R, Yoshida A, Hanada I (1984) Pupillary
light reex in amblyopia. Invest Ophthalmol Vis Sci 25:
467471
 124 9 The Brckner Test Revisited
50. Portnoy JZ, Thompson HS, Lennarson L, Corbett JJ (1983)
Pupillary defects in amblyopia. Am J Ophthalmol 96: 609614
51. Gruber H, Lessel MR (1982) Modikation des swinging
ashlight tests. Klin Monatsbl Augenheilkd 181: 402403
9 52. Jiang MQ, Thompson HS, Lam BL (1989) Kestenbaums
number as an indicator of pupillomotor input asymmetry.
Am J Ophthalmol 107:528530
53. Rssmann W, Fricke J, Neugebauer A (2004) Nachweis der
Fehlstellung mit dem Ab- und Aufdecktest. In: Kaufmann
H (ed) Strabismus. Thieme, Stuttgart, pp 341344
54. Rssmann W, Kaufmann H (2008) Augenbewegungs-
strungen. In: Straub W, Kroll P, Kchle J (eds)
Augenrztliche Untersuchungsmethoden. Enke, Stuttgart,
pp 637643
 Chapter 10
Amblyopia Treatment 2009
Michael X. Repka
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. This improvement may facili-
tate subsequent treatment.
For initial therapy of moderate anisometropic
and strabismic amblyopia among children
37 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
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.
These 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 eective as initial
management of moderate amblyopia. Initial dosages of
2 h daily of patching or twice weekly atropine have been
shown to be eective and can be considered suitable for
initial therapy. Severe amblyopia may be initially man-
aged with 6 h of patching. Intensied treatment for
patients who are incompletely treated is logical to pre-
scribe, yet not proven in clinical trials.
10
administered to the sound eye are equally
eective.
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 eective.
Amblyopia therapy can be benecial for older
children up to 17 years of age, especially if they
have not been previously treated.
There have not been any studies to date which
demonstrate the best therapy for patients with
residual amblyopia following initial therapy.
There are also no studies that have identied the
best treatments for deprivation amblyopia.
The strict age cut-o 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 dicult, frustrating to the families, and often
unsuccessful. There 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 2070-year-old age group [4]. These
 126 10 Amblyopia Treatment 2009
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-
10 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]. The authors extrapolated their nding to
suggest that there are approximately 271,000 cases of
amblyopia among children 3071 months of age in the
United States. The second study, completed in Los Angeles,
California, detected amblyopia in 2.6% of Hispanic/Latino
children and 1.5% of African-American children, with 78%
of cases of amblyopia attributable to refractive error [8].
A study of a birth cohort at age 7 years in the United
Kingdom found 3.6% of children to have amblyopia [9].
There was a suggestion in this latter study that amblyopia
prevalence correlated mildly with lower socioeconomic
status.
Whatever the actual percentage of amblyopia in a
population, this disease remains a common ocular prob-
lem among children. The causes of amblyopia depend on
the population studied. In one treatment trial, amblyopia
was associated with strabismus (37%), Anisometropia
(38%) or both combined (24%) [10]. In another 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. The 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]. The 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 dicult 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 [1416], whereas
minimal loss has been reported with Pelli-Robson charts,
which test intermediate spatial frequencies [16, 17].
Detection of a decit of contrast sensitivity after 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 conrmed this nding of only a minimal decit
with Pelli-Robson charts 37 years after 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 aected
[21]. PEDIG recently reported the monocular oral read-
ing speed, accuracy, 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 patients binocular reading ability
remains to be thoroughly explored.
10.1.4 Diagnosis of Amblyopia
The diagnosis of amblyopia requires detection of a dier-
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.
The test should employ either crowded or line optotypes.
The clinician should exercise caution when interpreting
the results of optotype testing. The variability of the
instrument needs to be considered. Specically, what is
the expected variability of a second measurement when
there has been no actual change in the visual acuity? For
the Amblyopia Treatment Study Visual acuity testing
protocol of single surrounded HOTV, we found high
testability after age 3 years, with 93% of retests within 0.1
logMAR. More importantly, the visual acuity needs to
dier by more than 0.18 logMAR for the dierence to
likely be true [23]. In my experience a one-line change
from a prior visit nearly always led to a change in therapy
prescribed, usually an escalation. In children the test
retest variability is very high. For children 7<13 years, a
change in visual acuity must be at least 0.2 logMAR (ten
letters) from a previous acuity measure to be unlikely
resulting from measurement variability [24]. These two
studies of rigorously administered visual acuity testing
protocols remind clinicians that substantial variability of
visual acuity results is present in children and careful

consideration of testing results before adjusting therapy
is warranted.
A recent article has also conrmed that the visual acu-
ity may vary from test strategy to test strategy. The 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.
The examiner determines the preference for 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 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. These research groups
tested children 30 to less than 72 months with xation
preference testing and optotype acuity. Fixation prefer-
ence testing identied only 15% of preschool children
who had an IOD of two lines or more on visual acuity
testing and 25% of those with an IOD of three lines or
more [26]. There were an insucient number of children
with strabismus to comment on that subgroup.
In the Multiethnic Pediatric Eye Disease Study
(MEPEDS), the authors reported sensitivity of xation
preference testing for amblyopia among children with
anisometropia was 20% (9/44), although specicity was
94% (102/109). Among strabismic children, sensitivity
was 69% (9/13; worse in children 3047 than 4872
months old), and specicity was 79% (70/89) [27].
Hakim found that 75% of strabismic children had
positive test results by xation preference testing, but
only 13% had an IOD of two lines or more [28]. The obvi-
ous, albeit controversial confusion, is that xation prefer-
ence testing misses most cases of amblyopia when used in
a screening setting. In addition, the use of 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
10.2 Amblyopia Management 127
suggested a tendency to spontaneous improvement of
the visual acuity decit 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.
Summary for the Clinician
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 suciently reliable to guide
amblyopia therapy in many children.
Care is needed when interpreting sequential
measurements of visual acuity when made with
dierent instruments or testing paradigms.
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
The value of an accurate refraction can not be underesti-
mated in the management of amblyopia. These 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. The 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 lm.
 128 10 Amblyopia Treatment 2009
Prescribed glasses for ametropia are not controversial.
The prescription for an esotropia patient should be full
plus power [32]. Even if this power slightly blurs distance
vision, it will not have a deleterious eect at the childs
10 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,
specically 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 38 years
of age were treated with spectacles, taking an average of
14 weeks to reach best visual acuity [33]. Surprisingly,
improvement was noted among both anisometropic and
strabismic patients. These authors have termed this eect
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 strabismicanisometropic 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 after instituting the glasses
were not available. Improvement in the visual acuity of
amblyopic strabismic patients was not expected to occur
so often so PEDIG has launched an adequately powered
prospective study of the impact of spectacle correction
alone to explore this result.
10.2.2 Occlusion by Patching
The benecial eect 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 eects or possibly the benets 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. They
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].
Thus, occlusion was better but surprisingly there was con-
tinuing benet of the spectacles alone, reinforcing how
important this aspect of therapy must be.
The 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 eective
[38]. Subgroup analysis of diering dosages from 6 h
daily to full time (all waking hours less one daily) found
no advantage of prescribing more hours [39]. This led us
to design two studies directed at exploring occlusion dos-
age. In the rst trial, we compared 2 with 6 h daily for the
initial treatment of moderate amblyopia, 20/4020/80,
for a period of 4 months [40]. Visual acuity in the ambly-
opic eye improved a similar amount in both groups. The
improvement in the amblyopic eye from baseline to 4
months averaged 2.40 lines in each group (P = 0.98). The
4-month visual acuity was 20/30 and/or improved from
baseline by 3 lines in 62% in each group (P = 1.00). We
did not follow and treat these patients after 4 months so
we do not know if a dierence 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,
20/10020/400 [41]. VA in the amblyopic eye improved
to a similar extent in both groups. The improvement in

the amblyopic eye acuity from the baseline to 17 weeks
averaged 4.8 lines in the 6-h group and 4.7 lines in the
full-time group (P = 0.45). However, 75% of patients in
both groups were 20/40 or worse after therapy. There is a
natural concern about amblyopia therapy, particularly
with higher dosages, causing loss of vision in the sound
eye. The sound eye lost two or more lines in 4% of the 6-h
group and in 11% of the full-time group. Nearly all
patients returned to their baseline level with follow-up,
typically by just stopping all patching.
These patching dosage data show that for initial 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.
These studies have taught much about initial patching
therapy, but they have left substantial uncertainty about
what to do for those children who are not completely 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 nd an eective, yet easy to administer, treatment of
amblyopia has been a goal pursued by clinicians treating
amblyopia in response to the complaints and diculties
associated with occlusion therapy. This 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 eectiveness, but the common belief was that
this was an inferior treatment. The largest prospective
study was completed in 2002, comparing once daily atro-
pine to patching 6 or more hours per day for moderate
amblyopia 20/3020/100 [38]. Visual acuity improved in
10.2 Amblyopia Management 129
both groups: 2.84 lines in the atropine group and 3.16
lines in the patching group. The patching group did get
better faster, but by 6 months, the dierence of 0.034 was
clinically inconsequential. Both treatments were well tol-
erated, although the atropine was easier to administer
based on parental questionnaires.
These 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. This dif-
ference in visual acuity between treatment groups was
small: 0.01 logMAR (95% condence interval, 0.02 to
0.04). Thus, the relative equivalence of the techniques and
the persistence of the treatment benet were rearmed.
Stereoacuity outcomes were similar suggesting no untow-
ard relative eect 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. This 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. These data show that strabismus may
develop or resolve with amblyopia therapy in about equal
proportions.
The dosage of atropine in the original PEDIG trial
was once daily. This design was consistent with the
desire to maximize the likelihood of nding benet if
there was one. While that study was underway, the ben-
et of less frequent administration was suggested by
Simons and coworkers [44]. They reported reasonable
improvement from less frequent administration. This
was plausible since the duration of cycloplegia was often
more than 1 day. This nding led PEDIG to develop a
clinical trial, which compared daily atropine to weekend
atropine.
 130 10 Amblyopia Treatment 2009
The atropine dosage treatment trial included 168 chil-
dren younger than 7 years with amblyopia in the range of
20/4020/80 associated with strabismus, anisometropia
or both. They were randomized to either daily or week-
10 end atropine [45]. The improvement of the amblyopic eye
from baseline to 4 months averaged 2.3 lines in each
group. The visual acuity of the amblyopic eye at study
completion was either (1) at least 20/25 or (2) better than
or equal to the sound eye in 39 children (47%) in the daily
group and 45 children (53%) in the weekend group. The
visual acuity of the sound eye at the end of follow-up was
reduced by two lines in one patient in each group.
Stereoacuity outcomes were similar in the two groups.
Patients who were not cured continued on the ran-
domized treatment beyond the 4-month outcome exam.
They improved an average of 0.8 additional lines (0.7 lines
among the 22 daily group patients and 0.8 lines among
the 31 weekend group patients).
At the time of study completion, 39 (47%) of the
patients in the daily group and 45 (53%) in the weekend
group had an amblyopic eye acuity that was either (1)
20/25 or better or (2) the same or better than the sound
eye acuity, provided that the sound eye acuity had not
decreased from enrollment. The mean amblyopic eye
acuity at study completion was 0.23 logMAR in the daily
group and 0.21 logMAR in the weekend group (approxi-
mately 20/32). The 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. These
results were similar in the two atropine treatment groups.
Thus, a 4-month treatment period with atropine will
treat most patients but is not sucient to complete treat-
ment for all. Thus, treatment should be continued until
there is good evidence that a plateau in improvement has
been achieved.
There is a chance of visual impairment of the sound
eye so care needs to be taken. In this study 1% of sound
eyes lost two or more lines of acuity at last follow up. As
expected, light sensitivity was common, reported by 16%
of children. Facial ushing and fever, a more worrisome
side eect, was reported by 1% of the children.
Summarizing, weekend atropine for moderate ambly-
opia is eective in improving visual acuity. The amount of
improvement was comparable with that seen with 4
months of 2 or 6 h of daily patching [40]. Parents need to
realize that most children will need at least 4 months of
treatment irrespective of which therapy and dosage.
Twice weekly atropine is fairly unobtrusive for preschool
children, should easily be incorporated into a childs 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. The eectiveness 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 eect. 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 after 10 weeks
of treatment with atropine and a plano lens to the sound
eye. This was a remarkable achievement. However,
Morrison and colleagues cautioned that this treatment
resulted in a case of severe treatment-related amblyopia in
the sound eye when parental noncompliance occurs [47].
To explore the value of this augmented atropine
approach, PEDIG randomized 180 children with moder-
ate amblyopia (visual acuities of 20/4020/100) 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 dierence between groups
adjusted for baseline acuity, 0.3 line; 95% condence
interval, 0.20.8 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. The important conclusion
is that in spite of intuition, augmentation of weekend
atropine use with a plano lens does not substantially
improve amblyopic eye visual acuity when compared
with weekend atropine use alone.

Summary for the Clinician
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 signicantly more eective than
spectacles alone.
Atropine and patching are equally eective 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 eectiveness to more
intensive therapy as initial treatment.
Expect that about 80% of the children will be
20/30 (6/9, 0.66) or better in the sound eye after
treatment completion.
Augmented pharmacological treatment with a
plano lens for the sound eye is not associated
with substantial benet as initial therapy, but is
associated with a risk of visual loss in the sound
eye.
10.3 Other Treatment Issues
10.3.1 Bilateral Refractive Amblyopia
The management of bilateral amblyopia from hyper-
metropia and/or astigmatism has been the subject of sev-
eral reports. The incidence was 4 of 830 (0.5%) children at
entry into school in an older report [49]. Small case series
have found substantial benet 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 sucient 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 20/4020/400 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% condence interval, 3.54.2). Mean improve-
ment was 3.4 lines (95% CI, 3.23.7) for children with
10.3 Other Treatment Issues 131
moderate amblyopia (20/4020/80) and 6.3 lines (95%
CI, 5.17.5) for children with severe amblyopia (20/100
20/320). Maximum improvement was achieved after 13
weeks for some, yet only after a year for others. The 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 Eect
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 eect
identied [53]. This nding along with case reports of
ecacy in older children, teens and even adults led
PEDIG to undertake a treatment trial of subjects 717
years of age [3]. In the 7 to 12-year-olds (n = 404), treat-
ment was 26 h of patching daily plus daily atropine.
Fifty-three percent of the treatment group improved at
least ten letters compared with 25% of the optical correc-
tion group (P < 0.001). In the 13 to 17-year-olds (n = 103)
treatment was 26 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 decit. This 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]. This approach was indirectly studied by
taking some patients from some of the early PEDIG trials
and whose therapy was being stopped or maintained on a
low dose of occlusion [54]. The recurrence rate was 24%
(35 of 145) (95% condence interval 1732%). There was
no dierence between patching and atropine. In patients
treated with patching of 68 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% condence interval
1.018.7). Absent additional data seems prudent to mon-
itor all patients and to taper occlusion therapy (6 or more
hours) and daily atropine therapy.
 132 10 Amblyopia Treatment 2009
10.3.4 Long-Term Persistence of an
Amblyopia Treatment Benet
The longevity of the improvement in VA achieved with
10 amblyopia treatment has been questioned. Short-term
recurrence and the need to repeat therapy is well known.
The best estimates are about 25% will recur during the
rst year after cessation of therapy [5557]. Most of these
cases will occur in the rst 6 months after cessation of
therapy. Based on clinical experience most of the recur-
rences can be successfully treated, but prospective data
are needed.
The long-term benet of amblyopia therapy would
only be proven if the improvement in acuity experienced
by the amblyopic eye is maintained. There are substantial
data published in this area, which is quite troublesome.
The extent of deterioration reported in retrospective out-
come studies of children treated for amblyopia to be as
high as 58% in spite of interim treatment, thereby reduc-
ing the actual benet of therapy [5863]. To address this
question, prospectively, children 3<8 years enrolled in
our trial comparing patching to atropine were followed at
2 years after randomization, and a subgroup reexamined
at age 10 years, 37 years after randomization [64]. Two
years after randomization visual acuity in the amblyopic
eye improved a mean of 3.7 lines in the patching group
and 3.6 lines in the atropine group. In both treatment
groups, the mean amblyopic eye acuity was approximately
20/32, 1.8 lines worse than the mean sound eye.
At age 10 years, 169 patients had an amblyopic eye
VA of 0.17 logMAR (approximately 20/32), and 46% of
amblyopic eyes had an acuity of 20/25 or better [65]. Age
younger than 5 years at entry into the randomized trial
was associated with a better visual acuity outcome
(P < 001). Mean amblyopic and sound eye visual acuities
at age 10 years were similar in the original treatment
groups (P = 0.56 and P = 0.80, respectively). The good
news here is that the visual acuity improvement was
maintained. However, 88% of all of these patients were
treated at least once between the primary 6-month 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-eective
among the spectrum of eye and health care interven-
tions [66, 67]. However, there is substantial uncertainty
concerning the eect 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 nd signicant dierences 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 benets as perceived
by those patients [69].
Summary for the Clinician
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 eect
of amblyopia on patient outcomes.
10.4 Other Treatments
Clinicians have long known that the standard treatment
of patching and even atropine were not always successful.
They have therefore sought alternatives to occlusion 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]. The eight lter densities were designed to reduce
visual acuity of the sound eye to a range of 20/2520/300.
Selecting the proper blur level would force the patient to
use the amblyopic eye. The 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, lters do not
cause skin irritation. Finally, one could postulate that
Bangerter foils are less disruptive to binocular function
during treatment compared with patching. The key 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]. They treated
15 children, 38 years old, with amblyopia of 20/3020/60
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 ve
patients, four attained amblyopic eye acuity of 20/25 or

20/30 or within a half line of the sound eye. Bangerter
lters, as in this study, are prescribed for longer periods
than either patching or atropine because they are well
tolerated.
Bangerter lters have not been compared with patch-
ing or atropine. PEDIG has completed a clinical trial com-
paring Bangerter lters (0.2 and 0.3 densities) to 2 h of
daily occlusion. The results are currently being analyzed.
10.4.2 Levodopa/Carbidopa
Adjunctive Therapy
Levodopa is used to treat adults with Parkinson disease
and children with dopamine responsive dystonia.
Dopamine is a neurotransmitter that does not cross the
bloodbrain barrier. However, levodopa administered
orally crosses the bloodbrain 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. This reduces the dose of levodopa and thereby
reduces the primary side eects of nausea and emesis.
A randomized longitudinal double masked placebo
control trial of ten amblyopic children aged 614 years
[72]. The dosing averaged 0.5 mg/kg/tid and lasted for 3
weeks. Visual acuity of the amblyopic eyes improved by
2.7 lines in the levodopa treated group, and by 1.6 lines in
the subjects treated with placebo. One month after the
termination of treatment, the levodopa-carbidopa group
maintained a 1.2-line improvement in visual acuity.
A 1-week, randomized, placebo-controlled study was
performed with 62 children with amblyopia who were
between 7 and 17 years of age. Subjects were instructed to
occlude the dominant eye for 3 h per day. Visual acuity
improved from 0.59 to 0.45 in the levodopacarbidopa
group (average dose 0.51 mg/kg/tid) and from 0.69 to
0.63 in the control group (P = 0.023) [73].
In a prospective randomized trial, 72 subjects with
amblyopia were distributed into three groups [74]. Group
A subjects received levodopa alone, group B received
levodopa (0.50 mg/kg/t.i.d.) and part-time occlusion (3 h/
day), and group C received levodopa and all waking horus
occlusion of the sound eye. Although 53/72 subjects
(74%) had an improvement in visual acuity (maximum =
4.6 Snellen lines; mean 1.6 Snellen lines, 10 years; mean
1.1 Snellen lines, >10 years) after treatment, 52% of those
who improved had regression in visual acuity when mea-
sured after 1 year.
A follow-up report of three longitudinal studies (927
months) using levodopa (0.55 mg/kg/t.i.d.) plus occlu-
sion for treatment of amblyopia included 30/33 (91%) of
10.5 Controversy 133
participating subjects. Subjects who received levodopa
plus occlusion demonstrated signicant regression of
visual acuity after stopping the medication. On average,
the amount of regression over 6 months of follow-up
averaged 1.4 lines, similar to that experienced by those
receiving occlusion only [75].
Forty children 6<18 years were randomized to 4
weeks of levodopa (1.86 mg/kg/day (1.332.36 mg/kg/
day) plus full-time occlusion or full-time occlusion only
[76]. No dierence in visual acuity outcome was found.
Summary for the Clinician
Bangerter 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 eect and a comparison with patching
alone needs to be completed.
10.5 Controversy
10.5.1 Optic Neuropathy Rather
than Amblyopia
Every clinician managing a child with amblyopia must be
aware of the masquerade of an optic neuropathy as an
amblyopia. Careful attention to pupillary signs, 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 aerent 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
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
ber layer thickness would be reduced. Such investiga-
tions based on optical coherence tomography have not
 134 10 Amblyopia Treatment 2009
found any substantive dierence among amblyopic, fel-
low, and normal eyes [8082]. In addition, it has never
been clear why patients with an optic neuropathy would
show the substantial improvement in visual acuity seen
10 during management of most cases of amblyopia.
Summary for the Clinician
The presence of an optic nerve abnormality in
typical amblyopia remains controversial.
The value of optic nerve head analysis in the
management of most cases of amblyopia is not
claried.
References
1. American Academy of Ophthalmology pediatric ophthal-
mology panel (2002) Preferred practice pattern guidelines:
amblyopia. American Academy of Ophthalmology, San
Francisco, pp 125
2. American Optometric Association (1994) Care of the
patient with amblyopia, optometric clinical practice guide-
line. American Optometric Association, St. Louis, pp 151
3. Pediatric eye disease investigator group (2005) Randomized
trial of treatment of amblyopia in children aged 7 to 17
years. Arch Ophthalmol 123:437447
4. Simons K (1996) Preschool vision screening, methodology
and outcome. Surv Ophthalmol 41:330
5. Williamson TH, Andrews R, Dutton GN, et al (1995)
Assessment of an inner city visual screening programme
for preschool children. Br J Ophthalmol 79:10681073
6. National eye institute oce of biometry and epidemiology
(1984) Report on the national eye institutes visual acuity
impairment survey pilot study. Department of Health and
Human Services, Washington, DC
7. Friedman DA, Repka MX, Katz J, et al (2009) Prevalence of
amblyopia and strabismus in white and African-American
children aged 6 through 71 months: the Baltimore pediat-
ric eye disease study. Ophthalmology 116:(in press)
8. Multi-ethnic pediatric eye disease study group (2008)
Prevalence of amblyopia and strabismus in African
American and hispanic children ages 6 to 72 months the
multi-ethnic pediatric eye disease study. Ophthalmology
115:12291236
9. 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
92:959964
10. Pediatric eye disease investigator group (2002) The clinical
prole of moderate amblyopia in children younger than 7
years. Arch Ophthalmol 120:281287
11. Woodru G, Hiscox F, Thompson JR, et al (1994) The pre-
sentation of children with amblyopia. Eye 8:623626
12. Bray LC, Clarke MP, Jarvis SN, et al (1996) Preschool vision
screening: a prospective comparative evaluation. Eye
10:714718
13. Khler L, Stigmar G (1973) Vision screening of four-year-
old children. Acta Paediatr Scand 62:1727
14. Hess RF, Howell ER (1977) The threshold contrast sensitiv-
ity function in strabismic amblyopia: evidence for a two
type classication. Vision Res 17:10491055
15. Howell ER, Mitchell DE, Keith CG (1983) Contrast thresh-
olds for sine gratings of children with amblyopia. Invest
Ophthalmol Vis Sci 24:782787
16. McKee SP, Levi DM, Movshon JA (2003) The pattern of
visual decits in amblyopia. J Vis 3:380405
17. Moseley MJ, Stewart CE, Fielder AR, et al (2006)
Intermediate spatial frequency letter contrast sensitivity:
its relation to visual resolution before and during amblyo-
pia treatment. Ophthalmic Physiol Opt 26:14
18. Repka MX, Kraker RT, Beck RW, et al (2009) Contrast sen-
sitivity following amblyopia treatment in children. Arch
Ophthalmol 127:12251227
19. Stifter E, Burggasser G, Hirmann E, et al (2005) Monocular
and binocular reading performance in children with
microstrabismic amblyopia. Br J Opthalmol 89:13241329
20. Zurcher B, Lang J (1980) Reading capacity in cases of
cured strabismic amblyopia. Trans Ophthalmol Soc U K
100:501503
21. Koklanis K, Georgievski Z, Brassington K, et al (2006) The
prevalence of specic reading disability in an amblyopic
population: a preliminary report. Binocul Vis Strabismus
Q 21:2732
22. Repka MX, Kraker RT, Beck RW, et al (2008) Monocular
oral reading performance after amblyopia treatment in
children. Am J Ophthalmol 146:942947
23. Holmes JM, Beck RW, Repka MX, et al (2001) The amblyo-
pia treatment study visual acuity testing protocol. Arch
Ophthalmol 119:13451353
24. Cotter SA, Chu RH, Chandler DL, et al (2003) Reliability
of the electronic early treatment diabetic retinopathy study
testing protocol in children 7 to <13 years old. Am
J Ophthalmol 136:655661
25. Birch EE, Strauber SF, Beck RW, et al (2009) Comparison
of the amblyopia treatment study HOTV and the elec-
tronic-early treatment of diabetic retinopathy study visual
acuity protocols in amblyopic children aged 5 to 11 years.
J AAPOS 13:7578
26. Friedman DS, Katz J, Repka MX, et al (2008) Lack of con-
cordance between xation preference and HOTV optotype
visual acuity in preschool children: the Baltimore pediatric
eye disease study. Ophthalmology 115:17961799
27. Cotter SA, Tarczy-Hornoch K, Song E, et al (2009) Fixation
preference and visual acuity testing in a population-based

cohort of preschool children with amblyopia risk factors.
Ophthalmology 116:145153
28. Hakim OM (2007) Association between xation prefer-
ence testing and strabismic pseudoamblyopia. J Pediatr
Ophthalmol Strabismus 44:174177
29. Clarke MP, Wright CM, Hrisos S, et al (2003) Randomised
controlled trial of treatment of unilateral visual impairment
detected at preschool vision screening. BMJ 327:1251
30. Hard AL, Williams P, Sjostrand J (1995) Do we have opti-
mal screening limits in sweden for vision testing at the age
of four years? Acta Ophthalmol 73:483485
31. Simons K, Preslan M (1999) Natural history of amblyopia
untreated owing to lack of compliance. Br J Ophthalmol
83:582587
32. American academy of ophthalmology pediatric ophthal-
mology/strabismus panel (2007) Preferred practice pattern
guidelines: pediatric eye evaluations. American Academy
of Ophthalmology, San Francisco, California
33. Stewart CE, Moseley MJ, Fielder AR, et al (2004) Refractive
adaptation in amblyopia: quantication of eect and impli-
cations for practice. Br J Ophthalmol 88:15521556
34. Pediatric eye disease investigator group (2006) Treatment
of anisometropic amblyopia in children with refractive
correction. Ophthalmology 113:895903
35. Cotter SA, Edwards AE, Arnold RW, et al (2007) Treatment
of strabismic amblyopia with refractive correction. Am
J Ophthalmol 143:10601063
36. Lempert P (2004) The eectiveness of patching for ambly-
opia should be tested with untreated control subjects (let-
ter to editor). Arch Opthalmol 122:423424
37. Pediatric eye disease investigator group (2006) A random-
ized trial to evaluate 2 hours of daily patching for strabismic
and anisometropic amblyopia in children. Ophthalmology
113:904912
38. Pediatric eye disease investigator group (2002) A random-
ized trial of atropine vs patching for treatment of moderate
amblyopia in children. Arch Ophthalmol 120:268278
39. Pediatric eye disease investigator group (2003) The course
of moderate amblyopia treated with patching in children:
experience of the amblyopia treatment study. Am
J Ophthalmol 136:620629
40. Pediatric eye disease investigator group (2003) A random-
ized trial of patching regimens for treatment of moderate
amblyopia in children. Arch Ophthalmol 121:603611
41. Pediatric eye disease investigator group (2003) A random-
ized trial of prescribed patching regimens for treatment
of severe amblyopia in children. Ophthalmology 110:
20752087
42. Pediatric eye disease investigator group (2005) Two-year
follow up of a six-month randomized trial of atropine ver-
sus patching for treatment of moderate amblyopia in chil-
dren (reply to letter to editor). Arch Ophthalmol 123:
285287
References 135
43. Repka MX, Holmes JM, Melia BM, et al (2005) The eect
of amblyopia therapy on ocular alignment. J AAPOS
9:542545
44. Simons K, Stein L, Sener EC, et al (1997) Full-time atro-
pine, intermittent atropine, and optical penalization and
binocular outcome in treatment of strabismic amblyopia.
Ophthalmology 104:21432155
45. Pediatric eye disease investigator group (2004) A ran-
domized trial of atropine regimens for treatment of
moderate amblyopia in children. Ophthalmology 111:
20762085
46. Kaye SB, Chen SI, Price G, et al (2002) Combined optical
and atropine penalization for the treatment of strabismic
and anisometropic amblyopia. J AAPOS 6:289293
47. Morrison DG, Palmer NJ, Sinatra RB, et al (2005) Severe
amblyopia of the sound eye resulting from atropine
therapy combined with optical penalization. J Pediatr
Ophthalmol Strabismus 42:5253
48. Pediatric eye disease investigator group (2009)
Pharmacological plus optical penalization treatment for
amblyopia: results of a randomized trial. Arch Ophthalmol
127:2230
49. Haase W (1978) Visual acuity in cases of monocular and
bilateral amblyopia: treatment during school age. Metabolic
Ophthalmology 2:147148
50. Schoenleber DB, Crouch ER (1987) Bilateral hyperme-
tropic amblyopia. J Pediatr Ophthalmol Strabismus 24:
7577
51. Klimek DL, Cruz OA, Scott WE, et al (2004) Isoametropic
amblyopia due to high hyperopia in children. J AAPOS
8:310313
52. Pediatric eye disease investigator group (2007) Treatment
of bilateral refractive amblyopia in children three to less
than 10 years of age. Am J Ophthalmol 144:487496
53. Pediatric eye disease investigator group (2003) A compari-
son of atropine and patching treatments for moderate
amblyopia by patient age, cause of amblyopia, depth
of amblyopia, and other factors. Ophthalmology 110:
16321638
54. Pediatric eye disease investigator group (2004) Risk of
amblyopia recurrence after cessation of treatment.
J AAPOS 8:420428
55. Bhola R, Keech RV, Kutschke P, et al (2006) Recurrence of
amblyopia after occlusion therapy. Ophthalmology
113(11):20972100
56. Flynn JT, Schiman J, Feuer W, et al (1998) The therapy of
amblyopia: an analysis of the results of amblyopia therapy
utilizing the pooled data of published studies. Trans Am
Ophthalmol Soc 96:431453
57. Pediatric eye disease investigator group (2007) Stability of
visual acuity improvement following discontinuation of
amblyopia treatment in children aged 7 to 12 years. Arch
Ophthalmol 125:655659
 136 10 Amblyopia Treatment 2009
58. Fletcher MC, Silverman SJ, Boyd J, et al (1969) Biostatistical
studies: comparison of the management of suppression
amblyopia by conventional patching, intensive hospital
pleoptics, and intermittent oce pleoptics. Am Orthopt
10 J 19:404407
59. Gregersen E, Rindziunski E (1965) Conventional occlu-
sion in the treatment of squint amblyopia. a 10-year fol-
lowup. Acta Ophthalmol (Copenh) 43:462474
60. Leiba H, Shimshoni M, Oliver M, et al (2001) Long-term
follow-up of occlusion therapy in amblyopia. Ophthal-
mology 108:15521555
61. Levartovsky S, Oliver M, Gottesman N, et al (1995) Factors
aecting long term results of successfully treated amblyo-
pia: initial visual acuity and type of amblyopia. Br
J Ophthalmol 79:225228
62. Rutstein RP, Fuhr PS (1992) Ecacy and stability of ambly-
opia therapy. Optom Vis Sci 69:747754
63. Sparrow JC, Flynn JT (1977) Amblyopia: a long-term fol-
lowup. J Pediatr Ophthalmol 14:333336
64. Pediatric eye disease investigator group (2005) Two-year
follow-up of a 6-month randomized trial of atropine vs
patching for treatment of moderate amblyopia in children.
Arch Ophthalmol 123:149157
65. Pediatric eye disease investigator group (2008) A random-
ized trial of atropine versus patching for treatment of mod-
erate amblyopia: follow-up at 10 years of age. Arch
Ophthalmol 126:10391044
66. Konig HH, Barry JC (2004) Cost eectiveness of treatment
for amblyopia: an analysis based on a probabilistic Markov
model. Br J Ophthalmol 88:606612
67. Membreno JH, Brown MM, et al (2002) A cost-utility
analysis of therapy for amblyopia. Ophthalmology 109:
22652271
68. Rahi JS, Cumberland PM, Peckham CS (2006) Does
amblyopia aect educational, health, and social outcomes?
Findings from 1958 British birth cohort. BMJ 332:
820825
69. van de Graaf ES, van der Sterre GW, van Kempen-du Saar
H, et al (2007) Amblyopia and strabismus questionnaire
(A&SQ): clinical validation in a historic cohort. Graefes
Arch Clin Exp Ophthalmol 245:15891595
70. Bangerter (1958) Orthoptische Behandlung des Begleit
schielens. pleoptik (monokulare orthoptik). Acta XVIII
concilium ophthalmologica, Excerpta Medica Foundation
1:105128
71. Iacobucci IL, Archer SM, Furr BA, et al (2001) Bangerter
foils in the treatment of moderate amblyopia. Am Orthopt
J 54:8491
72. Leguire LE, Rogers GL, Bremer DL, et al (1993) Levodopa/
carbidopa for childhood amblyopia. Invest Ophthalmol
Vis Sci 34:30903095
73. Procianoy E, Fuchs FD, Procianoy L, et al (1999) The eect
of increasing doses of levodopa on children with strabis-
mic amblyopia. J AAPOS 3:337340
74. Mohan K, Dhankar V, Sharma A (2001) Visual acuities
after levodopa adminstration in amblyopia. J Pediatr
Ophthalmol Strabismus 38:6267
75. Leguire LE, Komaromy KL, Nairus TM, et al (2002) Long-
term follow-up of l-dopa treatment in children with
amblyopia. J Pediatr Ophthalmol Strabismus 39: 326330
76. Bhartiya P, Sharma P, Biswas NR, et al (2002) Levodopa-
carbidopa with occlusion in older children with amblyo-
pia. J AAPOS 6:368372
77. Lempert P (2000) Optic nerve hypoplasia and small eyes in
presumed amblyopia. J AAPOS 4:258266
78. Lempert P, Porter L (1998) Dysversion of the optic disc and
axial length measurements in a presumed amblyopic pop-
ulation. J AAPOS 2:207213
79. Lempert P (2008) Retinal area and optic disc rim area in
amblyopic, fellow, and normal hyperopic eyes: a hypothesis
for decreased acuity in amblyopia. Ophthalmology
115:22592261
80. Altintas O, Yuksel N, Ozkan B, et al (2005) Thickness of the
retinal nerve ber layer, macular thickness, and macular
volume in patients with strabismic amblyopia. J Pediatr
Ophthalmol Strabismus 42:216221
81. Repka MX, Goldenberg-Cohen N, Edwards AR (2006)
Retinal nerve ber layer thickness in amblyopic eyes. Am
J Ophthalmol 142:247251
82. Yen M, Cheng C, Wang A (2004) Retinal nerve ber layer
thickness in unilateral amblyopia. Invest Ophthalmol Vis
Sci 45:22242230
 Chapter 11
Best Age for Surgery for Infantile
Esotropia: Lessons from the Early vs.
Late Infantile Strabismus Surgery Study
H.J. Simonsz, G. H. Kolling, and the Early vs. Late Infantile Strabismus Surgery Study Group
Core Messages
The result of surgery for infantile esotropia (IE)
can be described by the following outcome
parameters: (1) the binocular vision conserved
or regained by early surgery, (2) the 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 specic child with IE,
the expected outcome of surgery should be esti-
mated according to these parameters.
There have been no studies with prospectively
assigned early- and late-surgery groups and an
evaluation according to intention-to-treat, other
than the Early vs. Late Infantile Strabismus
Surgery Study (ELISSS). The primary outcome of
that study was that 13.5% of those operated at
approximately 20 months of age against 3.9% (P =
11.1 Introduction
11.1.1 Denition and Prevalence
Infantile esotropia (IE) is dened 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 aects approximately 0.25% of the population
[35]. A higher prevalence has been found previously in
studies where little distinction was made between
11
0.001) of those operated at approximately 49
months recognized the Titmus Housey at the
age of 6 years; there was no dierence in stereop-
sis beyond Titmus Housey.
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 ner stereopsis after very
early surgery await conrmation in a randomized
controlled trial.
esotropia with and without nervous system impairment.
In a recent study among 627 consecutive strabismus
patients younger than 19 years [6], 4.8% had congenital
esotropia without and 7.0% congenital esotropia with
nervous system impairment, including any nervous sys-
tem impairment except speech delay.
11.1.2 Sensory or Motor Etiology
IE may have dierent causes, ranging from sensory to
motor defects. Prematurity, low birth weight, and low
Apgar scores are signicant risk factors for IE [5]. Motor
fusion, i.e., translating image disparity information into a
 138 11 Best Age for Surgery for Infantile Esotropia
vergence command to facilitate stereopsis, is a complex
cerebral function that may well falter in nervous system
damage, explaining the bad outcome of early surgery in
such cases [7, 8]. On the other hand, if esotropia results
11 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 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 ner distinction among the sub-
types of IE.
IE should be considered, similar to the working de-
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 dierentiated according
to location, extent, and timing of the period of develop-
ment. Such an open matrix 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). They develop if the inputs from the right and left
eye are obtained from corresponding images, facilitating
fusional vergence and stereopsis [1113].
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. The 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 [1417]. The 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 after birth by cutting the medial rectus muscles
[10], cutting the lateral rectus muscles [20], or 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].
The restoration of binocular vision by removal of the
prism goggles, simulating early surgery, demonstrated
in these animals [18, 22], stresses the feasibility of early
surgery in IE cases when its cause is motor. In another
animal model, esotropia was found to occur naturally
in macaque monkeys [23]. This seems more like IE in
children than surgically induced esotropia [24], but
many of the macaques had high hypermetropia [23,
24], their accessory lateral rectus muscle was absent
[25], or their horizontal recti were twice as large as
those of, albeit younger, controls [24].
11.1.4 History
Whatever its cause, whether sensory or motor, the end
state of IE is characterized by lack of binocular vision,
first described by Claud Alley Worth in 1903 [26] when
he wrote: In the human infant the motor 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 3580% after surgery at the age of 06
months [2735]. Current US standard age of rst surgery

is approximately 1218 months of age, and in many
European countries, surgery for IE is performed at the
age of 2 or 3 years. There has been a call recently for
surgery within 2 months of the onset of esotropia [36].
However, there have been no randomized studies with
prospectively assigned early-surgery and late-surgery
groups and an evaluation according to intention-to-
treat. Elliot and Shaq [37] concluded in their Cochrane
review: As there are no randomised controlled trials in
the area at present, it has not been possible to resolve
the controversies regarding age of intervention in
patients with IE. There is clearly a need for good
quality trials to be conducted in various areas of IE, in
order to improve the evidence base for the management
of this condition.
Indeed, one cannot exclude the possibility that in the
retrospective case-series studies, without a control group,
an occasional child may have been operated that would
have straightened to 60 stereopsis without surgery. Three
such cases occurred in the rst prospective study by Birch
et al. [27] and two in the ELISSS.
Therefore, instead of providing the reader with a quick
recipe on whether to operate early or late, it seems more
appropriate to list and discuss the outcome measures that
should be considered when contemplating early, very
early, or late surgery in a specic child. The primary out-
come measures are the following:
1. The binocular vision conserved or regained by early
surgery.
2. The angle of strabismus after surgery and the long-
term stability of alignment.
3. The number of operations to reach these goals or the
chance of spontaneous reduction of the strabismus
into a microstrabismus without surgery.
There are other outcome parameters that should be con-
sidered. For instance, the childs psychological and motor
development, and bonding between infant and parents
may be improved by early surgery. These need evaluation
within disciplines other than pediatric ophthalmology,
however.
Endophthalmitis after strabismus surgery [38] occurs
preferentially in rst surgery in children under 6 years of
age, but it is not yet clear whether its prevalence in young
children diers 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 signicantly correlated with learn-
ing disability [39].
11.2 Outcome of Surgery in the ELISSS 139
Summary for the Clinician
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.
11.2 Outcome of Surgery in the ELISSS
11.2.1 Reasons for the ELISSS
Early surgery may minimize further loss of the remaining
binocular vision. The 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. The average number of operations was 1.5.
Three were not operated and had full stereopsis. After this
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
rst presented to one of the participating clinics. The
ELISSS study committee considered randomization
impossible, because it was anticipated that the parents
would not cooperate: One 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 618 months of
age, were assigned to early surgery (624 months) or
late surgery (3260 months), and were assessed at the
age of 6 years. All children who rst presented with con-
vergent IE between 5 and 30 were included. However,
 140 11 Best Age for Surgery for Infantile Esotropia

children with pre- or dysmaturity, nystagmus, nervous 60

system decit, retardation, dysmorphia or motility dis-
orders other than up- or downshoot in adduction, V- or

Percentage for unoperated and operated patients

A-pattern, or limitation of abduction were excluded. 50
11 Following recruitment, the angle of strabismus, refrac-
tion, degree of amblyopia, and limitation of abduction
were assessed in an extensive baseline examination,
40
based on a testretest reliability study [41]. Orthoptic
examinations, including angle and refraction, were
repeated every 6 months. Cases with strongly estab-
lished xation preference and/or signicant anisometro- 30
pia underwent appropriate and eective occlusion
therapy to the point of near spontaneous alternation
and central xation of the worse eye. Reoperation was 20
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- 10
pendent observers. Endpoints were level of binocular
vision, manifest angle of strabismus at distance xation,
remaining amblyopia, number of operations, vertical
0
strabismus, angle at near, and inuence of surgical 1 2 3 4 5 6 7 1 2 3 4 5 6 7
technique.
early late
Degree of binocular vision

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 decit (99). No dierences 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 dierences existed between dropouts and completers
in the baseline examination, and clinics with many drop-
outs did not have better results. The 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. The interval between the last operation and the
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. The 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.
Fig. 11.1 Binocular vision at the age of 6 years after early or late
surgery, stratied 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) Housey positive, (4) Titmus cir-
cles 200140, (5) Titmus circles 10040, (6) all gures of Lang
Test or TNO 480 and 240, (7) TNO 12015 (See Ref. [57])
11.2.4 Binocular Vision at Age Six
At the age of 6 years, 51.2% of the early vs. 44.7% of the
late group recognized Bagolini striated glasses, and 13.5%
of the early vs. 3.9% (P = 0.001) of the late group recog-
nized the Titmus Housey; 3.0% of the early and 3.9% of
the late group had stereopsis beyond Titmus Housey
(Fig. 11.1). Some children had been operated beyond the
set time frame (618 and 3260 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
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
 11.2 Outcome of Surgery in the ELISSS 141

40

30
Percentage for unoperated and operated patients

30
20

Horizontal angle of strabismus

10
20

10
10

20
0
10 0 10 20 30 40
> 24

> 24
< 4
< 0
< 4

< 4
< 0
< 4
< 8
< 2
< 6
< 0

< 8
< 2
< 6
< 0
< 1
< 8

< 1
< 8
<

<
24

24
=
=
=

=
=
=
=1
=1
=2
=

=1
=1
=2
=
= 2
=

= 2
=
=

early late Horizontal angle of strabismus at baseline

Horizontal angle of strabismus (deg)

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

the early-surgery group and 34.8% of the late-surgery
group were not aligned within 010, despite the fact that
the protocol prescribed to continue surgery until align-
ment within 010 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 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). These
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 Housey 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. These children had signicantly bet-
ter ocular alignment, which may have been either a cause
or a consequence of the gain of binocular vision.
Summary for the Clinician
In the ELISSS, children with IE operated around
the age of 20 months, achieved Bagolini striated
glasses or Titmus Housey stereopsis more fre-
quently as compared to those operated around
the age of 49 months.
No dierence was found, however, for stereopsis
beyond Titmus Housey.
Alignment was similar after early surgery, as
compared to that after late surgery, but a large
variation of the angle of strabismus was found at
the age of 6 years in both groups.
Children with stereopsis were aligned better, which
may have been either a cause or a consequence of
the gain of binocular vision.
 142 11 Best Age for Surgery for Infantile Esotropia

Fig. 11.3 Relation between TNO test 120 or better

the level of binocular vision
and angle of strabismus at
distance xation for both
groups (N=414). Black dots Lang test (all) or TNO test 480 to 240
11 represent the patients who
had not been operated at the
age of 6 years. One dot may
represent more than one Titmus circles 100 to 40
child (See Ref. [57])

Titmus circles 200 to 140

Housefly positive

Bagolini positive

Bagolini negative
15 10 5 0 5 10 15 20 25
Horizontal manifest angle of strabismus in degrees at age 6 in degrees
for operated (grey circles) and unoperated (black) cases

80
11.3 Number of Operations and Spontaneous
Reduction into Microstrabismus
Without Surgery 70

11.3.1 The Number of Operations Per Child 60

and the Reoperation Rate in the ELISSS
In the ELISSS, the number of operations among the chil- 50
Percent

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 40
group (N = 234), including children who were scheduled
for surgery, but had not been operated at the age of 6 years. 30
Children scheduled for early surgery had been rst oper-
ated at 20.0 SD 8.4 months, but 8.19% (14) had not been 20
operated at the age of 6 years. Children scheduled for late
surgery had been rst operated at 49.1 SD 12.7 months, but
10
20.09% (47) had not been operated at the age of 6 years.
Accordingly, the reoperation rates were 1.181/(10.0819)1
= 28.7% in the early group and 0.996/(10.2009)1 = 24.6% 0
0 1 2 3 4 0 1 2 3 4
in the late group, including second and third reoperations.
early late
Among the children operated 2 or 3 times, only a few were
Number of operations Surgery Group
operated for consecutive divergence, although consecutive
divergence occurred frequently (Fig. 11.4).
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
11.3.2 Reported Reoperation Rates frequently. One child from the early group was operated twice
for consecutive divergence (striated). Note that 8.2% from the
Reported reoperation rates range from 11% after early early group and 20.1% from the late group had not been oper-
surgery to 70% after very early surgery [4654]. Studies 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, 5153] 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. The median age at
operation was 14 months, the average age was 18 months.
In a multicenter study by Van de Vijver-Reenalda
et al. [55], reoperation rates were assessed 623 years after
rst surgery had taken place among 181 patients. These
patients were consecutive cases of the registries of surgery
in each of the seven participating university clinics. Nine
patients could not be contacted by telephone, and in six
patients, the postoperative angle of strabismus 3 months
postoperatively was unknown. Of the remaining 166
patients, on average 4.33 years old at surgery, 32 had a
reoperation, in 60% of cases within 2 years after the rst
operation. Average reoperation rate was 19.3%. Logistic
regression analysis showed no statistically signicant dif-
ference between clinics concerning chance of reoperation.
To test whether the large dierences between reported
reoperation rates after early surgery, mentioned earlier,
were due to the dierences in the duration of follow-up, a
meta-regression was performed. For each study, the mean
duration of follow-up, the mean age at operation, and the
reoperation rate were obtained from the publication or
original data. The mean duration of follow-up and mean
age at operation were regressed on the logistically trans-
formed reported reoperation rate. The meta-regression
model had an R-squared value of 0.44. The inuence 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).
After adjustment of the reoperation rates reported
after short follow-up periods, reoperation rates became
more similar to the rate reported by Helveston et al. [49]
after a long follow-up period. A trend for more reopera-
tions after early surgery when compared with that after
late surgery can be noted (Fig. 11.5).

100%

Louwagie [4]
80%

Helveston [49]
Stager [64]
Charles [7]
Keenan [51]
60%
Kushner [52]

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

Helveston [48] Vijver [55]

20%
Tolun [92]
Reoperation
rate

0%
0 Age in months 12 24 36 48 60

Fig. 11.5 Exploratory meta-analysis of studies reporting reoperation rates (closed circles) after surgery for IE. Early and Late refer
to the early and late groups of the ELISSS. The reoperation rates after shorter follow-up periods were corrected for the duration of
follow-up with a multivariate logistic model (closed black squares)
 144 11 Best Age for Surgery for Infantile Esotropia

three examiners examining one infant, 1.0 signifying

11.3.3 Test-Retest Reliability Studies
complete agreement) was 0.80. The distribution for the
One of the reasons contributing to a higher reoperation largest dierence between any two of the three measured
rate after early surgery is the inaccuracy in measuring the angles averaged 6.5. In 10% of the infants, the largest dif-
11 angle of strabismus in young children. In a test-retest reli- ference between any two of the three measured angles
ability study [41] preceding the ELISSS a total of 190 exceeded 10. Standard deviations and intraclass correla-
infants of the age of 12.1 SD 2.5 (range 915) months tion coecients were the same for both the methods of
were examined in ten university clinics on one day by measurement (Fig. 11.6).
three orthoptists. Fifteen parameters of the orthoptic In a recent similar study [56], 143 children aged 22.2
examination were assessed that were considered to be of SD 15.0 months (range 2.160.2) with esotropia were
prognostic importance and, hence, suited to detect and examined by two masked examiners on one or two occa-
correct for disparities between the groups in the ELISSS. sions yielding 199 test-retest pairs for prism and alternate
In 144 of the 190 infants, the manifest horizontal angle of cover test at distance xation and 239 at near xation. For
strabismus was estimated, either with prisms and corneal angles greater than 11.3, the 95% limits of agreement on
reexes during xation of an object with a light at 50 cm a measurement and on a dierence between two mea-
or by estimation of the location of the corneal reex rela- surements were 4.2 and 5.9 for prism and alternate
tive to the pupil during xation of an object with a light at cover test at distance and 4.7 and 6.7 at near. For
50 cm. The angle of strabismus averaged 21 for the rst, angles of 5.711.3, they were 2.3 and 3.3 at distance
second, and third examinations, with approximately and 1.9 and 2.7 at near.
equal standard deviations for all three examinations. The From these two studies, it is evident that one of the
intraclass correlation coecient (dierences between reasons contributing to a higher reoperation rate after

50
Angle (degrees) measured by second or third orthoptist

40

30

20

10

0
0 10 20 30 40 50
Angle (degrees) measured by first or second orthoptist (N=144 children x 3 pairs of measurements)

Fig. 11.6 144 infants at approximately one year of age were examined in ten university clinics on one day by three orthoptists or,
rarely, by a strabismologist. The horizontal angle of strabismus was measured, either with prisms and corneal reexes or by estima-
tion of the location of the corneal reex relative to the pupil. Larger circles represent more measurements
 11.3 Number of Operations and Spontaneous Reduction into Microstrabismus Without Surgery
early surgery is the inaccuracy in measuring the angle of
strabismus in young children.
11.3.4
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 623 years after rst surgery in children
operated at 4.33 years, on average, the average reoperation
rate was 19.3%. The reoperation rate was only 7.3%, how-
ever, for those with a residual angle of 4 to +4 (82,
49.4%), 3 months postoperatively. The reoperation rate
was 25% for children who were divergent in excess of 5
and 29% for children between 10 and 14 convergent, 3
months postoperatively.
For comparison, eight strabismologists, the heads of
the departments where the retrospective study had been
done, were asked to give their estimations of the reopera-
tion rate based on the angle of strabismus at distance
90
Observed reoperation rate and experts' estimates (%)
80
70
60
50
40
30
20
10
0
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)
145
xation, 3 months postoperatively. They estimated the
reoperation rate at almost double, probably because of an
observer bias, as patients who come for reoperation are
more vividly remembered (Fig. 11.7).
Relation Between the Postoperative
Angle of Strabismus and
the Reoperation Rate 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 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 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
identied 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 inu-
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. These 80 children had alignment and
fusion in 76% of the cases, when compared with 38.4%
N=12
N=17
N=4
N=51
N=62
N=20
< -5 -4 to -1 0 to 4 4 to 9 10 to 14 > 14
Postoperative angle of strabismus in degrees, 3 months postoperatively
 146 11 Best Age for Surgery for Infantile Esotropia
of children operated once and 36% of children operated
twice. In the studies by Costenbader [1], by Birch (1990)
and in the ELISSS [57], children who had been scheduled
for surgery but who had not been operated at nal assess-
11 ment had better binocular vision than those who had
been operated.
Spontaneous resolution of infantile strabismus has 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).
There 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
2.49.5) at baseline and at 6-week intervals for 18 weeks,
using prism and alternate cover test at near (70% of the
children) or a modied 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? This
line of reasoning only pertains to the majority of cases
where microstrabismus with peripheral fusion is the best
possible result. One cannot exclude the rare possibility
that an occasional child, with a pure motor cause of IE,
would achieve full binocular vision with 60 arc seconds
stereopsis by very early surgery.
11.3.7 Predictors of Spontaneous
Reduction into Microstrabismus
In the ELISSS, of all parameters assessed in the baseline
examination at approximately 11 months, only the angle
of strabismus at baseline predicted, to some extent,
whether a child had been operated at the age of 6 years or
not (Fig. 11.9). Among children with an angle equal or
smaller than 13 at baseline at approximately 11 months,
34.9% had not been operated at the age of 6 years.
Hypermetropia around spher. + 4 increased the 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-Eects Model Predicting
the Angle and its Variation
In the 532 children of the ELISSS, the angle of strabismus,
refraction, and visual acuity was assessed at baseline at
approximately 11 months and every 6 months thereafter,
until the nal evaluation at the age of 6 years. The result-
ing, slightly more than 6,000, orthoptic exams were used
to construct a random-eects 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 dierent ages and
the refraction of the patient can be entered in the model.
On entering successive measurements of the angle of
strabismus, the model adjusts the slope, i.e., yearly
increase or decrease of the expected angle, according to
the trend. The uncertainty about the slope decreases
with additional measurements because the random
eect of the slope of the lines decreases. The uncertainty
about the slope is compounded by additional variation
of the angle around this slope for an individual child
(Fig. 11.10).
In simulations with the random-eects 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.
 11.3 Number of Operations and Spontaneous Reduction into Microstrabismus Without Surgery 147

30

20
Horizontal angle of strabismus

10

10
0 12 24 36 48 60 72 84 96
Age at examination (months)

30

20
Horizontal angle of strabismus

10

10
0 12 24 36 48 60 72 84 96
Age at examination (months)

Fig. 11.8 The upper panel shows the 6-monthly measurements of the angle of strabismus in those ELISSS children who had been
scheduled for early surgery at baseline at approximately 11 months of age, but had not been operated at the age of 6 years (14, 8.2%).
The lower panel shows these measurements for the children who had been scheduled for late surgery, but had not been operated at
the age of 6 years (47, 20.1%). These children correspond to the white bars in Figs. 11.1, 11.2, and 11.9
 148 11 Best Age for Surgery for Infantile Esotropia

30 In the model, refractive error exerted its largest

inuence, i.e., causing the largest chance of spontane-
Percentage for unoperated and operated patients

ous reduction into a microstrabismus, at a spher. + 4.

Some children in the ELISSS study population may
11 actually have been very early cases of accommodative
20 esotropia. In case of hypermetropia, especially with
convergence excess, a large reduction in the angle may
occur after tting full correcting glasses, thereby avoid-
ing surgery.

10

Summary for the Clinician

The chance of a spontaneous reduction of the
esotropia into microstrabismus is considerable
0 when an angle of strabismus of 13 or less is

5
9
13
17
21
25

5
9
13
17
21
25

> 29 found repeatedly at the age of 1 year.

> 29

=
=
=
=
=
=
=
=
=
=
=
=
=
=

29
29

Early Late Fit full-correcting glasses in case of hypermetropia

Horizontal angle of strabismus (degrees)
accompanying esotropia at an early age because
a large reduction of the angle of strabismus can
Fig. 11.9 Angle of strabismus at baseline at approximately 11 be achieved without surgery and with better bin-
months for all 414 operated (black) and unoperated (white) ocular vision.
patients who underwent the 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])

40 40

35 35

30 30
Measured angle (deg.)
Measured angle (deg.)

25 25

20 20

15 15

10 10

5 5

0 0
0 12 24 36 48 60 72 0 12 24 36 48 60 72
Age (months) Age (months)

Fig. 11.10 Random-eects 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 eect for a patient was dened as the deviation of the average
angle, the xed eect. A vector was dened based on age and spherical equivalent of the patient. A covariance matrix of the random-
eects estimations was dened and lled with the values from the approximately 6,000 orthoptic exams in 532 children. The model
predicts the average angle in relation to age. A linear relation suced. The variance around the prediction (curved lines represent
one and two standard deviations) consists of uncertainty in the estimations, random eects 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

Appendix
Members of the Early vs. Late Infantile Strabismus Surgery
Study Group were: (Austria) A. Langmann, S. Lindner,
S. Priglinger, M. Raab, H. Thaller-Antlanger, D. Koschkar-
Moser, H. Gruber-Luka, R. Fhrer, S. Harrer, K. Rigal,
R. Pelz, B. Puchhammer, A. Thaler, E. Moser, K. Schmidt,
(Belgium) M. Spiritus, M. van den Broeck, S.Vandelannoitte,
A. Finck, P. Evens, D. Godts, (France) M. Bourron-
Madignier, S. Vettard, O. Benhadj, (Germany)E-Ch.
Schwarz, G. Wunsch, C. Jandeck, S. Lutt-Freund, D. Jptner-
Johanning, E. Sommer, G. Hochmuth, G. Gusek-Schneider,
Schrho, A. Boss, A. Zubcov, B. Herrmann, G. Kommerell,
B. Lieb, R. Weidlich, U. Wittenbecher, E. Schulz, K. Rettig,
G. Kolling, B. Stoll, B. Ksmann, 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. Lidn, L. Lindberg, I. Wiklund,
G. Lennerstrand, B. Derouet-Eriksson, B. Sunnqvist,
G. Gunnarssen, P. Jakobsson, G. Kvarnstrm, 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. Sek Sana, 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
1. Costenbader FD (1961) Infantile esotropia. Trans Am
Ophthalmol Soc 59:397429
2. Von Noorden GK. (1988) A reassessment of infantile
esotropia. XLIV Edward Jackson memorial lecture. Am
J Ophthalmol 105:110
3. Greenberg AE, Mohney BG, Diehl NN, Burke JP (2007)
Incidence and types of childhood esotropia: a population-
based study. Ophthalmology 114:170174
4. Louwagie CR, Diehl NN, Greenberg AE (2009) Mohney
BG. is the incidence of infantile esotropia declining? A
References 149
population-based study from Olmsted County, Minnesota,
1965 to 1994. Arch Ophthalmol 127:200203
5. Mohney BG, Erie JC, Hodge DO, Jacobsen SJ (1998)
Congenital esotropia in Olmsted County, Minnesota.
Ophthalmology 105:846850
6. Mohney BG (2007) Common forms of childhood strabis-
mus in an incidence cohort. Am J Ophthalmol 144:
465467
7. Charles S, Moore A (1992) Results of early surgery for
infantile esotropia in normal and neurologically impaired
infants. Eye 6:603606
8. Holman RE, Merritt JC (1986) Infantile esotropia:
results in the neurologic impaired and normal child at
NCMH (six years). J Pediatr Ophthalmol Strabismus 23:
4145
9. Surveillance of cerebral palsy in Europe (SCPE) (2002)
Prevalence and characteristics of children with cerebral
palsy in Europe. Dev Med Child Neurol 44:633640
10. Hubel DH, Wiesel TN (1965) Binocular interaction in
striate cortex of kittens reared with articial squint.
J Neurophysiol 28:10411059
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 32:323328
12. Tychsen L, Burkhalter A (1997) Nasotemporal asymme-
tries in V1: ocular dominance columns of infant, adult,
and strabismic macaque monkeys. J Comp Neurol 388:
3246
13. Tychsen L, Wong AM, Foeller P, Bradley D (2004) Early
versus delayed repair of infantile strabismus in macaque
monkeys: II. Eects on motion visually evoked responses.
Invest Ophthalmol Vis Sci 45:821827
14. Homann KP (1983) Eects of early monocular depriva-
tion on visual input to cat nucleus of the optic tract. Exp
Brain Res 51:236246
15. Homann KP, Distler C (1986) The role of direction selec-
tive cells in the nucleus of the optic tract in the cat and
monkey during optokinetic nystagmus. In: Keller EL, Zee
DS (eds) Adaptive processes in visual and oculomotor sys-
tems. Pergamon: New York, pp 261266
16. Homann KP, Bremmer F, Thiele A, Distler C (2002)
Directional asymmetry of neurons in cortical areas MT
and MST projecting to the NOT-DTN in macaques.
J Neurophysiol 87:21132123
17. Tychsen L, Lisberger SG (1986) Maldevelopment of visual
motion processing in humans who had strabismus with
onset in infancy. J Neurosci 6:24952508
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 156:403411
 150 11 Best Age for Surgery for Infantile Esotropia
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
11 49:18721878
20. Crawford ML, von Noorden GK (1979) The eect 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 19:11051109
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 eects. J AAPOS
7:200209
23. Kiorpes L, Boothe R (1981) Naturally occurring strabis-
mus in monkeys (Macaca nemestrina). Invest Ophthalmol
Vis Sci 20:257263
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 12:375380
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 31:11681174
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 31:758765
28. Birch EE, Stager DR, Everett ME (1995) Random dot stere-
oacuity following surgical correction of infantile esotropia.
J Pediatr Ophthalmol Strabismus 32:231235
29. Birch E, Stager D, Wright K, Beck R (1998) The natural his-
tory of infantile esotropia during the rst six months of
life. Pediatric eye disease investigator group. J AAPOS
2:325328
30. Birch EE, Stager DR Sr (2006) Long-term motor and sen-
sory out comes after early surgery for infantile esotropia.
J AAPOS 10:409413
31. Ing MR, Costenbader FD, Parks MM, Albert OO (1966)
Early surgical treatment for congenital esotropia. Am J
Ophthalmol 652:14191427
32. Ing MR (1981) Early surgical alignment for congenital
esotropia. Trans Am Ophthalmol Soc 79:625663
33. Ing MR (1995) Surgical alignment prior to six months of
age for congenital esotropia. Trans Am Ophthalmol Soc
93:135146
34. Ing MR, Okino LM (2002) Outcome study of stereopsis in
relation to duration of misalignment in congenital esotro-
pia. J AAPOS 6:38
35. Wright KW, Edelman PM, McVey JH, Terry AP, Lin M
(1994) Highgrade stereo acuity after early surgery for con-
genital esotropia. Arch Ophthalmol 112:913919
36. Tychsen L (2005) Can ophthalmologists repair the brain in
infantile esotropia? Early surgery, stereopsis, monoxation
syndrome, and the legacy of Marshall Parks. J AAPOS
9:510521
37. Elliott S, Shaq 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,
Ler KU, Hartwig NG (2009) Age-related immune
defects causing endophthalmitis after strabismus surgery
in young children or in elderly. Invest Ophthalmol Vis Sci
50:ARVO E-Abstract 1134
39. Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ,
Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner
DO (2009) Early exposure to anesthesia and learning dis-
abilities in a population-based birth cohort. Anesthesiology
110:796804
40. Early vs late infantile strabismus surgery study group
(1993a) The protocol for the Early vs. Late infantile strabis-
mus surgery study. Strabismus 1:135157.
41. Early vs late infantile strabismus surgery study group
(1993b) How accurate is orthoptic examination at age one?
Strabismus 1:7583
42. Meyer K, Breitschwerdt H, Kolling GH, Simonsz HJ (1998)
The early vs. late infantile strabismus surgery study: do
sources for bias exist in this non-randomized trial? Br
J Ophthalmol 82:934938
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:
10031009
44. Fu VL, Stager DR, Birch EE (2007) Progression of inter-
mittent, small angle, and variable esotropia in infancy.
Invest Ophthalmol Vis Sci 48:661664
45. Polling JR, Eijkemans MJ, Esser J, Gilles U, Kolling GH,
Schulz E, Lorenz B, Roggenkmper 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 93:954957
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
13:129131

47. Bartley GB, Dyer JA, Ilstrup DM (1985) Characteristics of
recession-resection and bimedial recession for childhood
esotropia. Arch Ophthalmol 103:190195
48. Helveston EM, Ellis FD, Schott J, Mitchelson J, Weber JC,
Taube S, Miller K (1983) Surgical treatment of congenital
esotropia. Am J Ophthalmol 96:218228
49. Helveston EM, Neely FN, Stidham DB, Wallace DK, Plager
DA, Sprunger DT (1999) Results of early alignment of con-
genital esotropia. Ophthalmology 106:17161726
50. Hiles DA, Watson BA, Biglan AW (1980) Characteristics of
infantile esotropia following early bimedial rectus reces-
sion. Arch Ophthalmol 98:697703
51. Keenan JM, Willshaw HE (1992) Outcome of strabismus
surgery in congenital esotropia. Br J Ophthalmol 76:
342345
52. Kushner BJ, Morton GV (1984) A randomized comparison
of surgical procedures for infantile esotropia. Am J
Ophthalmol 98:5061
53. Nelson LB, Calhoun JH, Sion JW, Wilson T, Harley RD
(1987) Surgical management of large angle congenital
esotropia. Br J Ophthalmol 71:380383
54. Tolun H, Dikici K, Ozkiris A (1999) Long-term results of
bimedial rectus recessions in infantile esotropia: J Pediatr
Ophthalmol Strabismus 36:201205
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
References 151
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:
5965
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 13:169199, Erratum (2006) Strabismus 14:
127128
58. Clarke WN, Noel LP (1982) Vanishing infantile esotropia.
Can J Ophthalmol 17:100102
59. Pediatric Eye Disease Investigator Group (2002)
Spontaneous resolution of early onset-esotropia: experi-
ence of the congenital esotropia observational study. Am J
Ophthalmol 133:109118
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. 115:22662274
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
 Chapter 12
Management of Congenital
Nystagmus with and without
Strabismus
Anil Kumar, Frank A. Proudlock, and Irene Gottlob
Core Messages
Congenital nystagmus consists of involuntary
periodic to-and-fro oscillations of the eye, which
are usually horizontal and present within the rst
3 months of life.
Congenital nystagmus can be idiopathic or occur
in association with defects in the aerent 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 dierentiated
from manifest latent nystagmus (MLN) and con-
genital periodic alternating nystagmus (PAN) as
the management of these conditions diers.
Several compensatory mechanisms exist in con-
genital nystagmus, which tend to decrease the
nystagmus and thus improve the visual acuity.
These mechanisms need to be analyzed carefully
because their understanding is important for the
patients 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.
The incidence of signicant 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
12
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 benecial 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 AndersonKestenbaum- like procedures var-
ious extents of surgery have been proposed by
dierent surgeons. However, if the head turn is
signicant, 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 AndersonKestenbaum-like procedures are
performed on the dominant or xing eye.
Strabismus correction is best planned during the
same surgical session on the non-xing eye.
Surgery causing articial divergence (exophoria)
is benecial in patients with binocular vision
and damping of nystagmus on convergence.
Combination of AndersonKestenbaum-like pro-
cedures and articial divergence surgeries have
been shown to be benecial.
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

Before During
12.1 Overview Treatment Treatment
The management of congenital nystagmus presents a
complex problem, which requires the accurate diagnosis
CIN
12 of the underlying causes of congenital nystagmus and an

Memantine
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
SN
between the dierent 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 CIN

Gabapentin
now proving to be benecial. The armamentarium of
treatment of congenital nystagmus includes optical, med-
ical, and surgical treatments. Currently, in most nystag-
mus forms there is no denite answer as to which is the SN
best treatment option. This chapter highlights the dier-
ent modes of treatment.
The rst section of this chapter discusses in detail the
clinical characteristics of patients with congenital nystag-
mus with and without sensory decit, MLN, and PAN. In
the second section, the compensatory mechanism CIN
involved and methods to identify them are considered.
The third section discusses the treatment options avail-
Placebo

able for congenital nystagmus.

12.1.1 Congenital Nystagmus with
and Without Sensory Decits
Congenital nystagmus consists of involuntary periodic
to-and-fro oscillations of the eye. It usually presents
within the rst 3 months of life; however, onset as late as
12 months to 10 years has been reported [1]. The inci-
dence of congenital nystagmus is estimated to be 1 in
2,000, in a population-based survey done in UK.
The eye movements in congenital nystagmus are
mainly in the horizontal plane, although they can be ver-
tical or torsional, or in a combination of dierent planes.
Congenital nystagmus is often described in the literature
as being a jerk nystagmus with accelerating slow phase;
however, IIN may show dierent waveforms that usually
vary with eccentricity. Frequently, congenital nystagmus
consists of underlying pendular oscillations interrupted
by regularly occurring foveating saccades (quick phases)
as shown in Fig. 12.1. Nystagmus intensity often changes
with the direction of gaze. The region of lowest nystag-
mus intensity and longest foveation periods is known as
the null region. This is often the preferred region of
SN
3
1sec
Fig. 12.1 Original horizontal eye movement recordings of right
eyes of (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; (fth 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 deection, and eye movements to the left by a
downward deection. The eye movement recordings show the vari-
ability in waveforms with the common occurrence of an underly-
ing pendular waveform. They also show reduction of intensity after
treatment with memantine and gabapentin but not with placebo
xation for optimal vision with the head position being
used to maintain vision in the null region. Consequently,
patients often exhibit an anomalous head posture (AHP)
 12.1 Overview 155

if the null region is eccentric. Typically, the oscillation
drifts toward the null region with the drift becoming
accentuated further away from the null region. This
results in the quick phases usually beating away from the
null region with slow phases often accelerating toward
the null region.
Congenital nystagmus can be idiopathic with the most
likely cause being abnormal development of the brain
areas controlling eye movements and gaze stability. It can
also occur in association with defects in the aerent
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
aerent 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.
The patient with ocular albinism has dark hair and skin,
very mild iris transillumination, but a hypopigmented
fundus. Both patients have foveal hypoplasia to varying

Oculocutaneous Ocular
Albinism (OCA) Albinism (OA)

a b

Appearance

c d

Iris trans-
illumination

Fig. 12.2 Phenotypical

characteristics of patients e f
with oculocutaneous
(a, c, e, g) and ocular (b, d, f,
h) albinism. The patient with Fundoscopy
oculocutaneous albinism has
light hair and more
prominent iris transillumina-
tion than the patient with
ocular albinism. Both
patients have fundus g h
hypopigmentation, macular
hypoplasia, and small optic
nerves. Optical coherence Optical
Coherence
tomography (OCT) shows
Tomography
foveal thickening in both
patients (g, h) with total
absence of foveal pit in the
patient with oculocutaneous
albinism (g)
 156 12 Management of Congenital Nystagmus with and without Strabismus

degrees as shown using optical coherence tomography

12.1.1.1 The Clinical Characteristics
(OCT). Both patients had increased crossing of optical
of Congenital Nystagmus
nerve bers in the chiasm shown on visual evoked poten-
tial examination (see Fig. 12.3d). Onset in infancy
12 The dierent causes of nystagmus can be diagnosed by Nystagmus is mainly horizontal and conjugate
detailed clinical examination aided by electrodiagnostics Eye movement recordings are usually horizontal
(electroretinograms (ERGs) and visual evoked potentials waveforms (both pendular and jerk) that vary with
(VEPs) ) (Fig. 12.3). eccentricity

Electroretinogram

a Normal Scotopic Photopic Flicker

b Congenital
Stationary
Night Blindness

Fig. 12.3 Examples of c Achromatopsia

scotopic, photopic, and
icker electroretinograms
(ERGs) of (a) a normal 500v 20v 10v
subject, (b) a patient with
20ms 20ms 20ms
congenital stationary night
blindness (CSNB) with a
negative scotopic ERG, and
Fz
(c) a patient with achro- d Visual Evoked Potentials
matopsia with extinguished
photopic ERG and icker Albinism Normal O1 O2
ERG. (d) Visual evoked Oz
potential of a patient with
albinism showing asymme- O 1 - Fz O1 - Fz
Right Eye Open

try between recording from O z - Fz

the right and left hemisphere Oz - Fz
(see placements of electrodes O 2 - Fz
on scalp in upper right O2 - Fz
corner) when the right and
left eye are individually
stimulated. Owing to O1 - O2 O1 - O2
increased crossing of optic
nerve bers in the chiasm,
the evoked potentials are O 1 - Fz
more pronounced in the O1 - Fz
contralateral hemisphere
Left Eye Open

O z - Fz
(O1, O2, and O3 are Oz - Fz
electrodes placed over the
back of the head (near the O 2 - Fz
O2 - Fz
occipital pole of the cortex)
in left, central, and right
positions, respectively; FZ is
O1 - O2 O1 - O2
the reference electrode)
 12.1 Overview 157

Possible presence of AHP, strabismus, and refractive
errors
Decreased amplitude of nystagmus in null point
Dampening of nystagmus on convergence
The intensity of nystagmus increases with 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
dened 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 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 xating eye when the fellow
eye is occluded. The 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 xa-
tion the head turn can change spontaneously, depending
on which eye is 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 conrmed on eye movement recordings. The patient
has exotropia and is freely alternating. He is always keep-
ing the xing eye in adduction and therefore his head pos-
ture is alternating with a turn to the right with the right
eye xing and left with the left eye xing. When one eye
was patched his head turn was unidirectional in the direc-
tion of the open eye. The 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 DellOsso [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 EYE RIGHT EYE LEFT EYE BOTH EYES

COVERED COVERED COVERED UNCOVERED
Right Eye

RIGHT BEATING
Left Eye

10
0.5 sec
L

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 deection, and eye movements to the
left by a downward deection. The fast phase is always beating toward the open eye (to the right with the left eye covered and to the
left with the right eye covered). When both eyes are open the direction of the fast phase is toward the dominant left eye. The velocity
of the slow phase is decelerating or linear. Arrows indicate blinks
 158 12 Management of Congenital Nystagmus with and without Strabismus

Anomalous Head Posture in Idiopathic Correction of Anomalous Head Posture in

Infantile Nystagmus Idiopathic Infantile Nystagmus with Anderson-
Kesternbaum Surgery

Child Horizontal head turn

12 Without visual effort With visual effort Before surgery After surgery
a b g h

Adult Vertical and horizontal head turn with esotropia

Without visual effort With visual effort Before surgery After surgery

c d i j

Bi-directional Alternating Head Turn in MLN

Measurement of head turn using Harms wall
Right head turn Left head turn

e f k

Fig. 12.5 Abnormal head posture (AHP) of a child with idiopathic congenital nystagmus (a) without visual eort 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 eort 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) after Anderson
Kestenbaum procedure. A patient with oculo-cutaneous albinism and chin depression, face turn to the right and left esotropia before
surgery (i) and after surgery (j). An accurate method of measuring AHP is achieved by using the Harms Wall (k) where the degree
of head turn is measured by the amount of displacement of the cross observed on the tangent screen. The cross is projected from a
light source xed on the head

Eye movement recordings have a characteristic

slow phase with exponentially decreasing or linear
velocity
Amplitude of nystagmus decreases in adduction and
increases in abduction, with the fast phase of nystag-
mus toward the side of xating eye
12.1.3 Congenital Periodic Alternating
Nystagmus (PAN)
Congenital PAN is classied as a variant of congenital
nystagmus according to the CEMAS classication.
Congenital PAN is discussed as a separate entity because

it has specic implications for management which are
dierent from other forms of nystagmus.
The frequency of congenital PAN is variably reported
in the literature. Gradstein et al. [3] in a retrospective
analysis of approximately 200 congenital nystagmus
patients with and without sensory decits 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-Homan et al. [4] in a prospective study
involving 18 patients with congenital nystagmus without
sensory decits found that seven patients (39%) had PAN.
Abadi and Pascal [5] found 12 patients with PAN in 32
patients with oculocutaneous albinism (37.5%). These 12
patients did not exhibit AHP nor had dampening of nys-
tagmus on convergence (Fig. 12.6).
Congenital PAN is most often missed or misdiagnosed
if not properly investigated. The main reasons for dicul-
ties in recognizing PAN are:
Long cycle duration: The cycle duration of the congeni-
tal PAN is variable lasting mostly between 2 and 7 min.
Thus, ocular motility examination (clinical or with eye
movement recordings) must extend over a prolonged
time period.
The absence of alternating head turn: Classically, a 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
Right Eye
LEFT BEATING
5
3 sec
L
Left Eye
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 deection, and eye movements to the left by a downward deection. Arrows indicate blinks
12.1 Overview 159
PAN. Absence of alternating AHP in congenital PAN
is possibly due to the asymmetry of the PAN cycle,
nystagmus beating longer in one direction than the
other, and also the unequal intensities of nystagmus in
the two phases.
12.1.3.1 Clinical characteristics of congenital
periodic alternating nystagmus
Onset in infancy.
Nystagmus horizontal and conjugate.
Eye movement recording shows a characteristic active
phase with right/left beating nystagmus followed by a
quite transition phase and then an active left/right
beating nystagmus.
The AHP is usually bidirectional.
Summary for the Clinician
Familiarity with the clinical characteristics of
congenital nystagmus, MLN, and congenital
PAN will minimize the chances of 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 nd a cause for the congenital nystagmus.
Eye movement recording aids in dierentiating
congenital nystagmus from MLN and congenital
PAN.
RIGHT BEATING
 160 12 Management of Congenital Nystagmus with and without Strabismus
12.2 Compensatory Mechanisms
Several compensatory mechanisms exist in congenital
nystagmus which tend to decrease the nystagmus and
12 thus improve the visual acuity. These compensatory
mechanisms are achieved with superimposed vergence
and version movements.
Dierent compensatory mechanisms may coexist in
the same patient with congenital nystagmus. These 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. These versions are
often accompanied, and consequently identied, 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
There are two distinct clinical conditions which use
dampening by convergence as a compensatory mecha-
nism to reduce the amplitude and frequency of nystag-
mus. These are MLN and nystagmus blockade syndrome
(NBS).
Adelstein and Cppers [6] coined the term nystag-
mus blockage syndrome as having the following clinical
features:
Esotropia with sudden onset in early infancy, often
preceded by nystagmus
Pseudoparalysis of both abducens nerves
The appearance of manifest nystagmus as the xating
eye moves from adduction toward abduction
Increase in the angle of the convergent squint when a
base-out prism is put in front of the xating eye
NBS occurs with the waveform characteristics of increas-
ing velocity slow phase and variable angle esotropia
(Fig. 12.7ad). MLN is also frequently associated with
infantile esotropia. Most cases diagnosed as nystagmus
blockage syndrome in the past probably corresponded
to infantile esotropia associated with MLN.
Summary for the Clinician
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.
12.2.3 Anomalous Head Posture (AHP)
AHP in children could be due to abnormalities of the
oculomotor system, neck muscles, or the central nervous
system. The ocular causes of AHP include strabismus,
nystagmus, refractive errors, and ptosis. Although clini-
cal dierentiation of these disorders is accurately accom-
plished after thorough history and ocular examination,
the exact mechanism of AHP is often dicult 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 eort. Hence, quantication of the sur-
gery must be based on an appropriate eort of xation,
usually achieved by testing visual acuity at distance and
near. Figures 12.5a, b show a child with no AHP when no
visual eort is needed. However, when he identies 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 eort. 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 dierential diagnosis, it
is important to record visual acuity with both eyes open
as well as with each eye occluded. It is also useful
 12.2 Compensatory Mechanisms 161

Fig. 12.7 A patient with During nystagmus Blocking with convergence

nystagmus blockage
syndrome (a) with straight a b
eyes, (b) when dampening
nystagmus with right
esotropia, (c) wearing Fresnel
prisms for surgical evalua-
tion, which showed
dampening of nystagmus and
(d) after bimedial medial
rectus recessions. Original
eye movement recordings
show periodic convergence to
dampen the nystagmus before
surgery and quieter eye With prisms After surgery
movements after surgery (e)
c d

e Eye movement recordings

BEFORE SURGERY AFTER SURGERY
nystagmus
blockage
Right Eye

10
2 sec
L
Left Eye

clinically to look at the eects of straightening the head No AHP: This could indicate that either the patient is
on nystagmus. using vergence as a compensatory mechanism, that
the null region is in the primary position, or that no
12.2.3.5 Eect of Monocular and Binocular compensatory mechanism is being used by the
Visual Acuity Testing on AHP patient
A horizontal AHP consisting of a face turn to the right
or left
Testing Visual Acuity with Both
A vertical AHP consisting of a chin elevation or
Eyes Open
depression
AHP should be rst assessed testing visual acuity with
A bidirectional or alternating AHP
both eyes open to determine the existence and the type of
A head tilt to the right or left
AHP naturally adopted by the patient. The patient could
A combination of AHP in dierent planes
have one of the following:
 162 12 Management of Congenital Nystagmus with and without Strabismus
Testing Visual Acuity with Either
Eye Covered
Testing AHP under monocular conditions using occlusion
helps to dierentiate between congenital nystagmus and
12 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. This 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 xation shifts from one eye to the other (Fig. 12.5e, f).
12.2.3.6 Testing AHP at Near
Since convergence has an eect 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 Eect of Straightening the
Head in Patients with AHP
On straightening the head, if the nystagmus increases,
then the cause of the AHP is almost certainly due to the
nystagmus. If there is no change in the nystagmus, the
AHP is either due to other ocular causes, a structural
anomaly of the head or neck, CNS anomalies, or because
of strabismus. Since strabismus in presence of nystagmus
can be responsible for AHP thorough examination for
comitant or incomitant squint is important in all patients
with nystagmus. If the strabismus increases with head
straightening, it indicates that an incomitant deviation is
responsible for the AHP. However, if the strabismus
improves with straightening of the head, the AHP is more
likely associated with the nystagmus or some other cause.
Summary for the Clinician
It is important to delineate the cause of AHP
and the amount of AHP before considering
treatment in patients with congenital nysta-
gmus.
AHP typically becomes progressively larger with
increased visual eort. Hence quantication of
the head turn for surgical assessment must be
based on measurement during maximal visual
eort.
In patients with combination of strabismus and
nystagmus, the cause of AHP needs to be carefully
analyzed.
12.3 Treatment
Various modes of treatment are available for patients with
congenital nystagmus. However, it is necessary to decide
the best method to treat these patients in the light of
understanding the type of congenital nystagmus and the
compensatory mechanism being used. Sometimes a com-
bination of treatment options might be needed to achieve
a better outcome.
The main aim of treatment of congenital nystagmus is:
1. To improve visual acuity
2. To diminish the amplitude and frequency of nysta-
gmus
3. To shift the null position to primary position with the
aim of correcting an AHP
4. To correct the strabismus if present
The main categories of treatment of nystagmus are 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
The incidence of signicant refractive errors in patients
with congenital nystagmus has been estimated to be as
high as 85% [7]. The importance of correcting refractive
errors besides improving visual acuity is to prevent 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]. The possible mechanisms underly-
ing this are that CL reduces the chromatic and spherical

aberration, together with the prismatic eect, compared
to spectacles [810]. 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 eort, 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 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 eective 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. The
base of the prism is inserted opposite to the preferred
direction of gaze. For instance, in patients with head turn
to right, the null zone is in laevoversion, and prisms 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 often decreased with the
use of Fresnel prisms and prisms incorporated in
glasses, this method is not eective 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 Treatment 163
12.3.1.4 Low Visual Aids
The use of telescope, magnication 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.
Summary for the Clinician
All children with congenital nystagmus must
have cycloplegic refraction and appropriate full
refractive correction.
The importance of correcting refractive errors
besides improving visual acuity is to prevent
ambylopia and to treat the associated strabismus
commonly seen in patients with congenital
nystagmus.
Refractive correction could be achieved by
glasses, CL, or low visual aids.
A trial of CL should be oered to suitable patients
as they have shown to improve visual acuity better
than spectacles.
12.3.2 Medication
Medications such as baclofen, cannabis, gabapentin, or
memantine were rst trialed in acquired nystagmus.
These studies led to the use of several of these drugs for
congenital nystagmus as well. However, most of the
reports in the literature consist of single cases or small
case series. Because of the prolonged treatment required
and the side eects of medications, one needs to weigh
the benets 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 after the use of an anti-anorexic drug (diethyl
proprionate). Pradeep et al. [16] reported reduction in
nystagmus intensity and improvement in visual acuity in
a patient with congenital nystagmus after smoking can-
nabis. There are a number of other reports suggesting the
use of tranquilizers and the anti-epileptic phenobarbital
in the treatment of congenital nystagmus with reported
improvement in the visual acuity. Sarvananthan et al. [17]
reported a case study of a patient, with congenital 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
 164 12 Management of Congenital Nystagmus with and without Strabismus
seven patients (three with congenital idiopathic nystag-
mus and ve with associated ocular defects) treated with
gabapentin.
McLean et al. [19] conducted the rst randomized,
12 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 decits were included in the study. Sixteen
patients in each group received memantine, gabapentin,
or placebo treatment. The maximum dose of memantine
was up to 40 mg/day and gabapentin up to 2,400 mg/day.
Results showed reduction in nystagmus using eye move-
ment recordings (see Fig. 12.4) and increase in visual
acuity in both treatment groups with memantine and
gabapentin showing a signicant improvement compared
with the placebo-controlled group.
There 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. The dose of baclofen was initially
started at 15 mg/day with a weekly increase in the dose to
up to 120 mg/day.
Summary for the Clinician
Recently, medical treatment has been used for
congenital nystagmus.
In an RCT [19] of medical treatment of congeni-
tal nystagmus, both memantine and gabapentin
showed reduction in nystagmus and improve-
ment in visual acuity.
The dosage of memantine used to treat congeni-
tal nystagmus was up to 40 mg/day, and that of
Gabapentin 2,400 mg/day.
The decision to treat patients medically should
be individualized given the long-term treatment,
the benets, and side eects of medications.
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 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 eective 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. Three of the four patients were
reported to have achieved a signicant improvement in
the visual acuity. However, the botox injection needs to
be repeated every 34 months.
Oleszczynska-Prost et al. [27] in a case series of 32
patients with congenital nystagmus treated with botox
showed an improvement in visual acuity in all the patients.
The amplitude of nystagmus decreased by 2950%. The
head turn was corrected in few patients. The 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
The 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. The aim is to move the eyes conjugately
in the opposite direction to the gaze angle of the null
region, or to articially 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 benecial secondary eects noted in patients who
were earlier treated with the strabismus procedure
(AndersonKestenbaum procedure) to dampen the
congenital nystagmus.

The importance of diagnosing congenital PAN and
MLN preoperatively is crucial as the surgical manage-
ment diers 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. The 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. The patient should, however, be
informed that a second procedure might be necessary in
case of residual strabismus or AHP, which needs to be
addressed.
12.3.6.1 Management of Horizontal AHP
A face turn to right or left is the most common 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-
ications in the Kestenbaum technique and proposed
that, to obtain symmetrical horizontal ductions of the
two eyes, surgery should be a 5 mm recession of medial
rectus and a 8 mm resection of the lateral rectus for the
eyes in adduction, and 6 mm resection of medial rectus
and a 7 mm recession of the lateral rectus of the fellow
eye. This became the classical 5, 6, 7, 8 measurements
for the Kestenbaum procedure modied by Parks.
Because of the high rates of recurrence and undercor-
rection following the modied Kestenbaum procedure,
Calhoun and Harley [31] recommended augmentation of
the original Parks modication of Kestenbaum procedure
by 4060% depending on the amount of head turn. For
12.3 Treatment 165
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
modied Kestenbaum procedure. They suggested 40%
augmentation of modied Kestenbaum procedure for
patients with 30 of head turn, and 60% augmentation for
patients with 45 of head turn. Taylor recommended that
recession of 89 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 modication of
Anderson procedure to correct the AHP. In this proce-
dure, only the yoke muscles are recessed, to as much as
1012 mm, rather than 45 mm as suggested by Anderson.
Since the recession of medial rectus is more eective 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 DellOsso [35] conrmed the initial nd-
ings described by Kestenbaum of an increase in the visual
acuity after the Kestenbaum-type procedure. They also
demonstrated that the Anderson-Kestenbaum procedure
does not alter the binocular function in those patients
with intact binocular function before surgery.
It is very dicult 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 4045, in our experi-
ence, very large amounts of surgery is needed. Restriction
of eye movements is often a necessary consequence of
large Kestenbaum procedures but is necessary to reduce
large AHPs.
In Fig. 12.5g, h an example of a child who underwent
horizontal AndersonKestenbaum procedure is shown.
She was rst examined at 1 year of age because of nystag-
mus since birth. A diagnosis of congenital idiopathic nys-
tagmus (CIN) was made after detailed clinical examination
and electrodiagnostic tests. At 2 years of age, she started
to develop an AHP. A refractive error of 4D cyl. in the
right eye and 2D cyl. in the left eye was detected, but she
was unable to wear glasses owing to the large AHP. The
child was reassessed at the age of 3 years. Her visual 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 AndersonKestenbaum procedure
to correct the AHP (recession of right lateral rectus and
 166 12 Management of Congenital Nystagmus with and without Strabismus
left medial rectus and resection of right medial rectus and
left lateral rectus by 12 mm each). Postoperatively, the
AHP was corrected without residual AHP. The child was
able to wear glasses, which improved the visual acuity to
12 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 modied 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 xing eye or non-amblyopic eye. If neces-
sary, eso- or exotropia can be corrected by performing
dierent amounts of recessresect procedures on the
non-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). This 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 sucient to correct the head position on
the 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 signicantly 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. The 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. After bimedial rectus recession, he developed
a small constant esotropia (Fig. 12.7d). The nystagmus
was signicantly 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 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 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. They
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.
They recommended 12 mm of combined recession and

resection for each pair of vertical rectus muscles for 1015
AHP, 16 mm for 2025, 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. This
patient was diagnosed as having oculocutaneous albinism
with nystagmus. She had a visual acuity of 6/36 with both
eyes open. She had a chin-down position of 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. This can be counter-
acted by shifting 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.
They combined a recessionresection procedure at the
anterior portions of the oblique muscles with transposi-
tions of their insertion toward the posterioranterior pole.
They 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
12.3 Treatment 167
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. This surgery has been
found to be eective when operated on both eyes, in
patients with no xation preferences or with binocularity
and also on the xating eye alone in monocular 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 ve dier-
ent surgical procedures used by AAPOS members to treat
torsional AHP:
1. Bilateral vertical rectus muscle recession
2. Bilateral vertical rectus muscle recessresect
3. Bilateral oblique muscle weakening
4. Bilateral oblique muscle recessresect
5. 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 Articial Divergence Surgery
Patients suitable for articial divergence surgery should be
orthotropic with convergence as the compensatory mech-
anism used to dampen the nystagmus. Binocular fusion is
necessary to achieve this eect. The vergence dampens the
nystagmus regardless of the stimulus inducing the conver-
gence. This principle has been used optically (base-out
prisms) and surgically (articial divergence) to dampen
the nystagmus.
Cppers [47] proposed the concept of articial diver-
gence in patients with convergence dampening of nys-
tagmus. In this procedure, an exodeviation is induced,
which can be compensated by fusional convergence. This
causes the patients to have convergence innervations
even at distance. The acceptability and eectiveness
of articial divergence surgery should be evaluated
 168 12 Management of Congenital Nystagmus with and without Strabismus
preoperatively by using the prism adaptation test. A
base-out prism is prescribed to induce articial diver-
gence. Inducing divergence with a base-out prism causes
the patient to converge, and therefore decreases the nys-
12 tagmus, which can then be followed by the correspond-
ing amount of recessionresection procedure [48]. The
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 articial 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 513 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 3040 PD, 7 mm for 5060 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 benetted by a combi-
nation of articial divergence and AndersonKestenbaum
procedure [48, 50]. The amount of surgery is done for the
total prism diopters tolerated by articial divergence pro-
cedure and then the remaining AHP is corrected using
the AndersonKestenbaum procedure.
Zubcov et al. [48] compared pre- and postoperative
eye movement recording and binocular visual acuities of
patients who underwent the AndersonKestenbaum
procedure (n = 7), articial divergence procedure (n = 6),
and a combination of both procedures (n = 5) in patients
with congenital nystagmus. In patients who underwent
articial 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 12 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 ve patients. Broadening
of the null zone was noticed in all patients.
Graf et al. [51] in a retrospective study to analyze the
eects of Kestenbaum surgery and articial divergence
surgery found that articial divergence surgery when
performed alone oers better correction of AHP than
with the Kestenbaum surgery. However, in patients with
large AHP, combining both articial 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. These
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, 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 Muscles
Bietti and Bagolini [53], in 1956, 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 810 mm, and bilat-
eral lateral rectus muscle recession of 812 mm.
Bagheri et al. [58] reported results of 20 patients who
underwent horizontal rectus recession surgery. Thirteen
patients (76.5%) improved in visual acuity from one to
three Snellen lines. AHP improved in most of the patients.
Similar results were also documented by other authors,
Davis et al. [59] and Atilla et al. [60]. They calculated the
amount of recession individually depending on the angle of
deviation, head position, and amount of strabismus if pres-
ent. Recessions performed on the medial rectus were more
eective than recession on the lateral rectus. Thus surgery
is planned based on the eect of recession of the medial
rectus muscle rather than the lateral rectus recession. To
correct the associated strabismus, the surgical plan is

revised by increasing the recession of medial rectus muscles
in case of esotropia, and recession of lateral rectus muscles
in case of exotropia. Similar adjustments can be made to
correct the AHP for example in patients with left face turn,
the right lateral rectus and left medial rectus is recessed
more than the right medial rectus and left lateral rectus.
The Tenotomy Procedure
Advancements in understanding secondary mechanisms
involved in the reducing nystagmus amplitude in patients
who underwent recessionresection surgery for congeni-
tal nystagmus mainly to correct the AHP has led to a new
surgical procedure tenotomy of extraocular muscle.
This procedure has been reported to be benecial in
patients without compensatory mechanisms, also in
patients with a null region at or near primary position
and in patients with a non-stationary null region (PAN)
[61].The tenotomy procedure can be done on both 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 decits including asymmetric con-
genital PAN. In the rst trial, involving ten patients, bin-
ocular visual acuity increased in ve patients and
remained unchanged in the remaining patients. The eye
movement recording data showed an increase in the aver-
age foveation times in all nine patients xating eyes. In
the second trial, tenotomy was performed on ve patients
with congenital nystagmus. Visual acuity improved in
four of the ve patients, but did not improve in a patient
with retinal dystrophy.
Summary for the Clinician
Various surgical procedures are used to treat
both the AHP and strabismus seen in patients
with congenital nystagmus. Surgical consists
mostly of recessions alone or the combination of
recessions and resections depending on the
amount of head turn and strabismus.
The surgical plan depends on whether patient has
horizontal or vertical AHP or head tilt and the
presence or absence of strabismus. Other compen-
satory need to be taken into consideration before
deciding on the type of surgery. For example, if
there is dampening of nystagmus mechanisms on
convergence, articial divergence surgery alone
can be performed, or it can be combined with
AndersonKestenbaum like procedures.
References 169
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 financial support of Ulverscroft Foundation,
Medisearch, National Eye Research Centre, and Nystagmus
Network.
References
1. Gresty MA, Bronstein AM, Page NG, Rudge P (1991)
Congenital-type nystagmus emerging in later life. Neurology
41:653656
2. DellOsso LF (1985) Congenital, latent and manifest latent
nystagmussimilarities, dierences and relation to strabis-
mus. Jpn J Ophthalmol 29:351368
3. Gradstein L, Reinecke RD, Wizov SS, Goldstein HP (1997)
Congenital periodic alternating nystagmus. Diagnosis and
management. Ophthalmology 104:918928; discussion
928919
4. Shallo-Homann J, Riordan-Eva P (2001) Recognizing
periodic alternating nystagmus. Strabismus 9:203215
5. Abadi RV, Pascal E (1994) Periodic alternating nystagmus
in humans with albinism. Invest Ophthalmol Vis Sci 35:
40804086
6. Adelstein F, Cuppers C (1966) On the problem of true and
apparent abducens paralysis (so-called blocking syn-
drome). Buch Augenarzt 46:271278
7. Hertle RW, Zhu X (2000) Oculographic and clinical char-
acterization of thirty-seven children with anomalous head
postures, nystagmus, and strabismus: the basis of a clinical
algorithm. J AAPOS 4:2532
8. Abadi RV (1979) Visual performance with contact lenses
and congenital idiopathic nystagmus. Br J Physiol Opt 33:
3237
9. Allen ED, Davies PD (1983) Role of contact lenses in the
management of congenital nystagmus. Br J Ophthalmol
67:834836
10. Hertle RW (2000) Examination and refractive manage-
ment of patients with nystagmus. Surv Ophthalmol 45:
215222
11. DellOsso LF (2002) Development of new treatments for
congenital nystagmus. Ann N Y Acad Sci 956:361379
12. Schornack MM, Brown WL, Siemsen DW (2007) The use
of tinted contact lenses in the management of achromatop-
sia. Optometry 78:1722
13. Metzger EL (1950) Correction of congenital nystagmus.
Am J Ophthalmol 33:17961797
14. Godd-Jolly D, Larmande A (1973) Les nystagmus. Paris,
Masson
 170 12 Management of Congenital Nystagmus with and without Strabismus
15. Hertle RW, Maybodi M, Mellow SD, Yang D (2002) Clinical
and oculographic response to Tenuate Dospan (diethyl-
propionate) in a patient with congenital nystagmus. Am
J Ophthalmol 133:159160
12 16. Pradeep A, Thomas S, Roberts EO et al (2008) Reduction
of congenital nystagmus in a patient after smoking canna-
bis. Strabismus 16:2932
17. Sarvananthan N, Proudlock FA, Choudhuri I et al (2006)
Pharmacologic treatment of congenital nystagmus. Arch
Ophthalmol 124:916918
18. Shery T, Proudlock FA, Sarvananthan N et al (2006) The
eects of gabapentin and memantine in acquired and con-
genital nystagmus: a retrospective study. Br J Ophthalmol
90:839843
19. McLean R, Proudlock F, Thomas S et al (2007) Congenital
nystagmus: randomized, controlled, double-masked trial
of memantine/gabapentin. Ann Neurol 61:130138
20. Anderson JR (1953) Causes and treatment of congenital
eccentric nystagmus. Br J Ophthalmol 37:267281
21. Solomon D, Shepard N, Mishra A (2002) Congenital peri-
odic alternating nystagmus: response to baclofen. Ann N Y
Acad Sci 956:611615
22. Comer RM, Dawson EL, Lee JP (2006) Baclofen for patients
with congenital periodic alternating nystagmus. Strabismus
14:205209
23. Blekher T, Yamada T, Yee RD, Abel LA (1998) Eects of
acupuncture on foveation characteristics in congenital
nystagmus. Br J Ophthalmol 82:115120
24. Abadi RV, Carden D, Simpson J (1980) A new treatment
for congenital nystagmus. Br J Ophthalmol 64:26
25. Sharma P, Tandon R, Kumar S, Anand S (2000) Reduction
of congenital nystagmus amplitude with auditory biofeed-
back. J AAPOS 4:287290
26. Carruthers J (1995) The treatment of congenital nystag-
mus with Botox. J Pediatr Ophthalmol Strabismus 32:
306308
27. Oleszczynska-Prost E (2004) Botulinum toxin A in the
treatment of congenital nystagmus in children. Klin Oczna
106:625628
28. Goto N (1954) A study of optic nystagmus by the electro-
oculogram. Acta Soc Ophthalmol Jap 58:851865
29. Kestenbaum A (1953) New operation for nystagmus. Bull
Soc Ophtalmol Fr 6:599602
30. Parks MM (1973) Symposium: nystagmus. Congenital
nystagmus surgery. Am Orthopt J 23:3539
31. Calhoun JH, Harley RD (1973) Surgery for abnormal head
position in congenital nystagmus. Trans Am Ophthalmol
Soc 71:7083; discussion 8477
32. Nelson LB, Ervin-Mulvey LD, Calhoun JH et al (1984)
Surgical management for abnormal head position in nys-
tagmus: the augmented modied Kestenbaum procedure.
Br J Ophthalmol 68:796800
33. Taylor JN (1973) Surgery for horizontal nystagmus
Anderson-Kestenbaum operation. Aust J Ophthalmol
1:114116
34. De Decker W (1987) Kestenbaum transposition in nystag-
mus theraphy. Transposition in horizontal and torsional
plane. Bull soc Belge Ophthalmol 221222
35. Flynn JT, DellOsso LF (1979) The eects of congenital nys-
tagmus surgery. Ophthalmology 86:14141427
36. Pierse D (1959) Operation on the vertical muscles in cases
of nystagmus. Br J Ophthalmol 43:230233
37. Schlossman A (1972) Nystagmus with strabismus: surgical
management. Trans Am Acad Ophthalmol Otolaryngol
76:14791486
38. Taylor JN, Jesse K (1987) Surgical management of congeni-
tal nystagmus. Aust N Z J Ophthalmol 15:2534
39. Sigal MB, Diamond GR (1990) Survey of management
strategies for nystagmus patients with vertical or torsional
head posture. Ann Ophthalmol 22:134138
40. Roberts EL, Saunders RA, Wilson ME (1996) Surgery for
vertical head position in null point nystagmus. J Pediatr
Ophthalmol Strabismus 33:219224
41. Yang MB, Pou-Vendrell CR, Archer SM et al (2004) Vertical
rectus muscle surgery for nystagmus patients with vertical
abnormal head posture. J AAPOS 8:299309
42. Conrad HG, de Decker W (1978) Kestenbaums surgical
rotation of the eyes in patients with head tipped to the
shoulder (authors transl). Klin Monatsbl Augenheilkd
173:681690
43. De Decker W, Conrad HG (1988) Torsional shift opera-
tion, a tool in complete early childhood strabismus. Klin
Monatsbl Augenheilkd 193:615621
44. De Decker W (1990) Rotatorischer Kestenbaum an geraden
Augenmuskeln. Z Prakt Augenheilkd 11:111
45. von Noorden GK, Jenkins RH, Rosenbaum AL (1993)
Horizontal transposition of the vertical rectus muscles for
treatment of ocular torticollis. J Pediatr Ophthalmol
Strabismus 30:814
46. Spielmann A (1987) The oblique Kestenbaum procedure
revisited. In: Lenk-Schafer M (ed) Orthoptic horizons.
Transactions of the sixth international orthoptic congress.
Harrogate, UK, pp 433
47. Cuppers C (1971) Problems in the surgery for ocular nys-
tagmus. Klin Monatsbl Augenheilkd 159:145157
48. Zubcov AA, Stark N, Weber A et al (1993) Improvement of
visual acuity after surgery for nystagmus. Ophthalmology
100:14881497
49. Spielmann A (1993) La mise en divergence articielle dans
les nystagmus congnitaux. A propos de 120 cas. Bull Soc
Fr Ophtalmol 6/7:571578
50. Sendler S, Shallo-Homann J, Muhlendyck H (1990)
Articial divergence surgery in congenital nystagmus.
Fortschr Ophthalmol 87:8589

51. Graf M, Droutsas K, Kaufmann H (2001) Surgery for nys-
tagmus related head turn: Kestenbaum procedure and arti-
cial divergence. Graefes Arch Clin Exp Ophthalmol
239:334341
52. Crone RA (1971) The operative treatment of nystagmus.
Ophthalmologica 163:1520
53. Bietti GB (1956) Notes on ophthalmological surgical tech-
nics. Boll Ocul 35:642656
54. von Noorden GK, Sprunger DT (1991) Large rectus muscle
recessions for the treatment of congenital nystagmus. Arch
Ophthalmol 109:221224
55. Helveston EM, Ellis FD, Plager DA (1991) Large recession
of the horizontal recti for treatment of nystagmus.
Ophthalmology 98:13021305
56. Datta H, Prasad S (1994) Postequatorial horizontal rectus
recession in the management of congenital nystagmus.
Indian J Ophthalmol 42:203206
57. Boyle NJ, Dawson EL, Lee JP (2006) Benets of retroequa-
torial four horizontal muscle recession surgery in congeni-
tal idiopathic nystagmus in adults. J AAPOS 10:404408
58. Bagheri A, Farahi A, Yazdani S (2005) The eect of bilateral
horizontal rectus recession on visual acuity, ocular devia-
References 171
tion or head posture in patients with nystagmus. J AAPOS
9:433437
59. Davis PL, Baker RS, Piccione RJ (1997) Large recession
nystagmus surgery in albinos: eect on acuity. J Pediatr
Ophthalmol Strabismus 34:279283; discussion 283275
60. Atilla H, Erkam N, Isikcelik Y (1999) Surgical treatment in
nystagmus. Eye 13(Pt 1):1115
61. DellOsso LF (1998) Extraocular muscle tenotomy, dissec-
tion, and suture: a hypothetical therapy for congenital nys-
tagmus. J Pediatr Ophthalmol Strabismus 35:232233
62. DellOsso LF, Hertle RW, Williams RW, Jacobs JB (1999) A
new surgery for congenital nystagmus: eects of tenotomy
on an achiasmatic canine and the role of extraocular prop-
rioception. J AAPOS 3:166182
63. Hertle RW, DellOsso LF, FitzGibbon EJ et al (2004)
Horizontal rectus muscle tenotomy in children with infan-
tile nystagmus syndrome: a pilot study. J AAPOS 8:
539548
64. Hertle RW, DellOsso LF, FitzGibbon EJ et al (2003)
Horizontal rectus tenotomy in patients with congenital
nystagmus: results in 10 adults. Ophthalmology 110:
20972105
 Chapter 13
Surgical Management
of Dissociated Deviations
Susana Gamio
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.
The treatment for patients with DD requires a
specic 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 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
13
for cases with bilaterally symmetric DVD. Cases
with asymmetric DVD are more common. These
cases require asymmetrical techniques.
Dissociated horizontal deviation (DHD): The
main diagnostic sign of DHD is the presence of a
horizontal deviation, esotropia (ET), or exotropia
(XT) that changes with xation of each eye, unre-
lated to dierent accommodation, muscle weak-
ness, or restriction. The technique most used for
DHD is unilateral lateral rectus (LR) recession.
Retroequatorial myopexy (posterior 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. The head tilt can be toward the
shoulder of the 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 dicult; a successful out-
come in the postoperative period does not guar-
antee the 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
13.1 Dissociated Deviations
Dissociated deviation (DD) Represents a Challenge for
Diagnosis and Surgical Treatment. It is known to exhibit
13 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 [15].
Diagnosis is not easy because the movement is slow
and needs a more prolonged occlusion to appear; the
amount of deviation is variable, intermittent, and depends
on attention. These patients usually show horizontal, ver-
tical, and torsional movements when performing the
cover test and have dierent amounts of deviation when
xing with each eye. They 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 lters of increasing
density (bagolini lter bar) are placed before the xating
eye, the hypertropic eye falls (Bielschowskys 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 Posners
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 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 lter is placed before the right eye or the left one, the
patient sees the red light below the white one.
These maneuvers attest to the tight interocular inter-
relation of this particular form of strabismus.
Fig. 13.1 Posners 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 rst one downwards, becoming aligned in the vertical plane
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 nonxating eye. The downward vertical drift
of the hypertropic eye takes place together with intorsion
and adduction.
The horizontal component has recently been
described and is called dissociated horizontal deviation
(DHD) [5, 810]. Even though most papers consider
DHD as a variable, intermittent exodeviation with a dif-
ferent magnitude according to xating eye, there exist
cases that exhibit an esodeviation with the same charac-
teristics of variability and intermittence [11, 12]. There
are also patients who manifest esotropia (ET) when x-
ating with one eye and exotropia (XT) when xating
with the other eye [9].
The 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 xating eye. The vertical movement always
cooccurs with extorsion of the elevating eye and intorsion
of the descending eye. This is inuenced 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 xating in all gaze posi-
tions (including head tilts) to have the necessary panorama
to choose the best surgical procedure for each case.
Therefore, surgical treatment of patients with DD
requires a specic surgical approach. Long-term surgical
results and recommendations for these cases remain
sparse in literature. The purpose of this chapter is to men-
tion the surgical alternatives tailored to treat each partic-
ular case.
 13.2 Surgical Alternatives to Treat Patients with DVD
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.
13.2 Surgical Alternatives to Treat
Patients with DVD
Patients with DVD are usually asymptomatic, but in those
cases where signicant 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
The following are the most used procedures in these cases:
1. Bilateral large superior rectus (SR) recession (712 mm)
[1620]
2. Bilateral retro-equatorial myopexy (posterior xation)
of the SR combined with or without recession of these
muscles [18, 2124]
3. Four oblique muscles weakening procedure (superior
oblique (SO) recession or tenectomy and inferior
oblique (IO) recession or anterior transposition
(IOAT) ) [2528]
4. Bilateral inferior rectus (IR) resection [16, 2932]
Large SR recession with hang-loose technique is one
of the mostly used in these cases. Extensive dissection
is required to clean attachments o the SR to avoid
175
retraction and lid ssure asymmetry. This technique
may limit elevation, especially in abduction (Pseudo
inferior oblique over action (IOOA) ). It should be noted
that weakening of SR modies horizontal deviation in
PP, causing a 6 PD exodeviation, which should be taken
into account when planning surgery.
Conventional recession (35 mm) of SR together with
retroequatorial myopexy (1215 mm of original inser-
tion) is used by several author successfully [64]. The pos-
terior xation suture must be placed at least 20 mm, and
preferably 2325 mm from the limbus, which often is
technically troublesome.
The four oblique weakening procedures proved to be
an eective technique to treat these cases. This procedure
is especially useful in cases that underwent surgery on
two horizontal rectus muscles in each eye and in those
where operating on the SR implies a risk of anterior 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 ssures. Its additional
horizontal eect, 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 xating eye
due to deep amblyopia.
There are four procedures that may be used in these
cases:
1. Unilateral SR recession [16, 33].
2. Unilateral inferior oblique anterior transposition
(IOAT) [34, 35].
3. Unilateral IR resection or tucking [36].
4. Unilateral SR retroequatorial myopexy (posterior xa-
tion) combined with or without recession of this
muscle [18].
When unilateral SR recess is decided, the amount of such
must be moderate (57 mm) to avoid postoperative
hypotropia. This technique is chosen in cases showing
comitant vertical deviation in lateroversions.
 176 13 Surgical Management of Dissociated Deviations
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
13 xation [20]. For this reason, unilateral surgery is reserved
for patients with dense amblyopia, who would have little
or no chance of changing xation after surgery. In
Schwartz and Scotts paper [33], postoperative hypotropia
developed in the operated eye in 12 patients (21%). Nine
of these patients had deviations less than 10 PD. In
Helvestons study [3], only 5 out of 33 patients undergo-
ing unilateral surgical correction of DVD developed a
signicant 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 eective treatment for unilateral or markedly
asymmetric DVD in patients with a strong, contralateral
xation preference. This surgery reduces IOOA, but may
also cause an ipsilateral hypotropia. Ipsilateral DVD in
PP decreased from a mean of 20.2 to 3.7 PD in their
series. Ninety percent of the patients had an excellent
postoperative result.
Goldchmit et al. [35] found that the unilateral IOAT
produces a mean correction of 18.1 PD (range, 433) 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. The second alternative is to perform a bilateral SR
recession added to bilateral IO recession [37].
The IOAT reduces the hypertropia to an acceptable
amount, and eliminates the IOOA and the V pattern with
a low incidence of recurrence. However, this surgical
procedure has yielded poor results in patients with
asymmetric DVD and IOOA [38].
Nine out of 20 consecutive patients in our series with
DVD and IOOA who underwent bilateral and symmetric
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 after the operation, 50%
of his patients had experienced neither A nor V pattern.
Thirty-three percent had a V pattern averaging 4 PD (28
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 after the IOAT, a unilateral SR recession can be per-
formed according to the amount of vertical deviation in
PP. This procedure proved eective in obtaining good
vertical alignment and has apparently given a predictable
and stable result with low incidence of postoperative
complications.
Several studies have attempted to obtain better
surgical outcomes in asymmetric DVD with IOOA by
performing asymmetric procedures. There are several
surgical alternatives:
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 eec-
tively treat coexisting DVD and IOOA. It has signicantly
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.
The DVD remained controlled in 86% of their cases after
a 2-year follow-up. The best results were obtained in those
patients with a preoperative DVD of less than 15 PD.
Mims and Wood [41] also performed bilateral graded
displacement of the IO tendon, attaching the muscle at a
point 24 mm anterior to the lateral end of the IR inser-
tion. These 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
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. The residual
postoperative DVD was 1.15 PD in the graded group
compared with 2.44 PD in the standard group. This dif-
ference was statistically signicant.
Finally, Snir et al. [43], to improve the postoperative
outcome in patients with asymmetric DVD with IOOA,
augmented the functional change in the IO induced by
IOAT by resecting the IO muscle in the eye with greater
vertical deviation before displacing it anterior to the IR
insertion. The IO resection was graded according to the
dierence in the preoperative vertical deviation between
the eyes: 3 mm for a dierence of up to 10 PD and 5 mm
for a dierence of 1120 PD. These authors compared the
postoperative outcomes of six consecutive patients who
underwent combined graded monocular resection and
bilateral ATIO with six consecutive historical control
patients who underwent equal IOAT. The mean dier-
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.
Fig. 13.2 Dissociated
vertical deviation (DVD) with
SOOA and A pattern: DVD
is greater in abduction of the
nonxating eye
177
The weakening of both elevators (IO and SR) always
results in an elevation deciency, 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 nonx-
ating eye than in PP. The SOOA causes incomitance in
DVD and A pattern [14, 44, 45] (Fig. 13.2).
In this group, when A pattern anisotropia is small not
over 14 PD
1. Bilateral SR improves DVD and controls A pattern
[46].
If the A pattern is larger, undercorrection is obtained;
therefore, other alternatives should be used.
2. Bilateral SR recession + bilateral SO posterior 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. Thus, it is benecial to carry out
the four oblique weakening procedure in these patients
[28, 44].
 178 13 Surgical Management of Dissociated Deviations
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-
13 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.
There 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.
The 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 dierent gaze positions, the presence of a
true vertical deviation (hypo or hypertropia) makes it
asymmetric.
The nondissociated vertical tropia can be lesser or
larger than the amplitude of the DVD.
When the nondissociated hypertropia is larger than
the magnitude of the DVD, the hypotropic eye is never
the higher eye.
Despite the fact that the greater amplitude of DVD is
usually seen in the nonxating eye, cases with greater
DVD in the 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
Fig. 13.3 Bilateral DVD with left hypotropia in primary position
tropia, or it can remain aligned when the DVD is of a
similar magnitude to that of the vertical tropia. This
situation may be erroneously interpreted as monocular
DVD.
Asymmetric DVD will often appear to be unilateral.
However, by performing the proper maneuvers, the bilat-
erality of most cases can be detected. The objective eye
movement recording clearly demonstrates that DVD is
bilateral in almost all cases.
Bilateral symmetric procedures are performed for
cases of bilaterally symmetric DVD (within 7 PD), but
asymmetric DVD is more common, and larger DVD can
be found in the nonxating eye or even in the xating
eye.
Determining the dierence in the amount of SR reces-
sion in these asymmetric cases remains challenging. The
maximum dierence allowed to obtain a good outcome
remains controversial.
13.2.6 DVD with Hypotropia
of the Nonxating Eye
DVD usually manifests as an intermittent hypertropia,
but there are certain cases with hypotropia of the nonx-
ating eye. Although rare, these cases are identied 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 nonxat-
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 xating eye), with associated nondissociated verti-
cal tropia or with unilateral deep amblyopia.

Three situations can lead to hypotropia of the nonxating
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 xation and 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. These 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].
Summary for the clinician
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 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.
13.3 Dissociated Horizontal Deviation 179
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. The main diagnostic sign of DHD is the
presence of a horizontal variable deviation, ET, or XT that
changes with xation of each eye, unrelated to dierent
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 dicult 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 nonxating eye time for the slow drift to fully
manifest. It is also necessary to make the right eye xate
rst and neutralize with prism the left eye deviation, and
then let the left eye xate and neutralize the right eye
deviation.
The reversed xation test (RFT) [53] is useful to
diagnose DHD. During this test, the patient is asked to
xate through the prism that neutralizes the deviation
of one of his eyes and then the occluder is shifted to the
uncovered eye without the prism and it is observed for
any rexation movement when the cover test is per-
formed. The test is positive when a rexation 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 xating with the preferred eye. In our
series, seven patients had greater exodeviation when x-
ating with the dominant eye, seven patients had greater
esodeviation when xating with the nondominant eye,
and three cases had XT when xating with the dominant-
eye and ET when xating with the nonpreferred eye. Only
one patient had greater ET when xating with the domi-
nant eye. These ndings seem to support his hypothesis
that the exodeviation is usually smaller with the nonpre-
ferred eye xating (Fig. 13.4).
DHD is often 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. The
 180 13 Surgical Management of Dissociated Deviations
13
Fig. 13.4 Dissociated horizontal deviation (DHD). She has greater exodeviation when xating with the dominant eye
eye position under GA used to show greater exodeviation
when the innervational forces are abolished. The forced
duction can diagnose a restriction and the spring back
test can determine a medial rectus (MR) muscle 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 often 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,
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.
The most used technique for DHD was unilateral LR
recession. Retroequatorial myopexy (posterior 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 x the drift of the eyes is needed. Bilateral sur-
gery is proposed to address both conditions simultane-
ously [57].
Summary for the Clinician
The main diagnostic sign of DHD is the presence
of a horizontal variable deviation, ET, or XT that
changes with xation of each eye, unrelated to
dierent accommodation or presence of primary
and secondary deviation due to weakness or
restriction.
The 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
There is very little information on DTD in literature.
Torsional movements are involved in the genesis of this
form of strabismus and oblique muscles are the main
oculomotor muscles with torsional action [2, 58, 59].
DVD mechanism has been elucidated recently by means
of ocular movement recording techniques. DVD would
be mediated primarily by the SO in the xating eye and
the IO in the fellow eye, added to a bilateral supraversion
required for the maintenance of xation with the 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
 13.4 Dissociated Torsional Deviation. Head tilts in patients with Dissociated Strabismus
extorsion characteristic of DVD produced by SR and OI
is observed in the fellow eye. In this case, the vertical 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 xate in adduction but they also have head tilts. The
head tilt can be toward the shoulder of the xating eye (direct
tilt) or toward the contralateral side (inverse tilt) [60, 61].
This head tilt has been thought to be related to the
presence of DVD, but there is no evidence conrming the
relationship between these two ndings.
Guyton [58] claims that adopting an anomalous head
posture can inuence latent and manifest LN in some
cases. The head tilt would damp the pattern of LN associ-
ated with the xing eye, and therefore, surgery on the 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 Jampolskys description of Bielschowsky
head tilt test (BHTT) response in DVD [63], there is an
increased hyperdeviation of the contralateral eye on
tilting to either side, the exactly inverse behavior to that
of SO palsy or SR overaction/contracture syndrome
(Fig. 13.5).
Fig. 13.5 Bielschowsky
head tilt test (BHTT)
response in DVD: there is an
increased hyperdeviation of
the contralateral eye on
tilting to either side
181
Direct tilt is observed in patients without 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.
The most patients who adopt inverse tilt can obtain
better vertical alignment in that position.
Out of 50 consecutive patients in our series who
underwent surgical treatment for DVD, only 54% (27/50)
had head tilt. Of 27 cases, 14 had direct tilt (51%); the
head tilt did not improve vertical alignment. They usually
obtain improvement of the head position by means of the
bilateral SR recession surgery.
Direct tilt improves the vertical alignment in two
situations: when a contracture of the SR of the nonxat-
ing eye exists or in asymmetric DVD cases, larger in the
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 nd SR contracture of the xating eye. When 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.
 182 13 Surgical Management of Dissociated Deviations
Finally, we want to point out that a great number of
patients with DD do not have head tilt. This fact makes
evident that there are other nonelucidated factors that
determine such a particular clinical sign.
13
Summary for the Clinician
When we have a patient with DD who need sur-
gery, we have to take into account the presence
of head tilt to attempt to improve the head
position.
Direct tilt (toward the 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.
13.5 Conclusions
Obtaining long-term control of the deviation in patient
with dissociated strabismus is dicult; a successful out-
come in the postoperative period does not guarantee the
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:
131144
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 96:389429
3. Helveston EM (1980) Dissociated vertical deviation: a clin-
ical and laboratory study. Trans Am Ophthalmol Soc 78:
734779
4. Raab EL (1970) Dissociative vertical deviation. J Pediatr
Ophthalmol Strabismus 7:146151
5. Wilson ME, McClatchey SK (1991) Dissociated horizontal
deviation. J Pediatr Ophthalmol Strabismus 28:9095
6. Bielschowsky A (1938) Lectures on motor anomalies: II.
The theory of heterophoria. Am J Ophtahlmol 21:1129
7. Posner A (1944) Noncomitant hyperphorias: considered as
aberrations of the postural tonus of the muscular apparatus
Am J Ophtahlmol 27:1275
8. Romero-Apis D, Castellanos-Bracamontes A (1992)
Dissociated horizontal deviation: clinical ndings and sur-
gical results in 20 patients. Binocul Vis 7:135138
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):373378;
381384
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):3138
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 14:337342
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 eective surgical approach?
J Pediatr Ophtahlmo Strabismus 29:21
19. Magoon E, Cruciger M, Jampolsky A (1982) Dissociated
vertical deviation: an asymmetric condition treated
with large bilateral superior rectus recession. J Pediatr
Ophtahlmol Strabismus 19:152
20. Scott WE, Sutton VJ, Thalacker JA (1982) Superior rectus
recessions for dissociated vertical deviation.Ophtahlmology
89:317322
21. Duncan LF, von Noorden GK (1984) Surgical results in
dissociated vertical deviations J Pediatr Ophthalmol
Strabismus 21:2527
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 Scientic, Rome, Modena, Italy, pp 403412
23. Sprague JB, Moore S, Eggers H et al (1980) Dissociated ver-
tical deviation: treatment with the fadenoperation of
Cuppers. Arch Ophtahlmol 98:465

24. von Noorden GK (1978) Posterior 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. So Paulo, pp 359360
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):1524
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 rst extraordinary meeting
of CLADE. So Paulo, Brazil pp 97100
28. Texeira Krieger F, Caron Lambert A (2000) Efeito do debili-
tamento do msculo Oblicuo superior hiperfuncionante
associado a anteriorizacao do msculo oblicuo inferior na
Divergencia Vertical Dissociada. CLADE anais 2000 del
XIV Congreso del CLADE. Sao Paulo, pp 447450
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 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):259263
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):241243
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):712
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
References 183
39. Black BC (1997) Results of anterior transposition of the
inferior oblique muscle in incomitant dissociated vertical
deviation. JAAPOS 1(2):8387
40. Burke JP, Scott WE, Kutshke PJ (1993) Anterior transposi-
tion of the inferior oblique muscle for dissociated vertical
deviation. Ophthalmology 100:245250
41. Mims JLIII, Wood RC (1989) Bilateral anterior transposi-
tion of the inferior obliques. Arch Ophthalmol 107:4144
42. Kratz RE, Rogers GL, Bremer DL, Leguire LE (1989)
Anterior tendon displacement of the inferior oblique for
DVD J Pediatr Ophtahlmol Strabisumus 26:212217
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):23722376
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 classication of DVD for a better
surgical approach. Fetscrif for Arthur Jampolsky. The
Smith Kettlewell Eye Research Institute, pp 5963
46. Melek N, Mendoza JC, Ciancia AO (1998) Bilateral reces-
sion of the superior rectus: its inuence 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):389393
50. Greenberg MF, Pollard ZF (2001) A rare case of bilateral
dissociated hypotropia and unilateral dissociated esotro-
pia. JAAPOS 5(2):123125
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, The Netherlands, pp 9395
52. Gamio S (2007) Hypotropia in patients with dissociated
vertical deviation. Transactions of the 31th ESA meeting.
Mykonos, Greece, pp 337340
53. Brodsky MC, Grf MH, Kommerell G (2005) The reversed
xation test: a diagnostic test for dissociated horizontal
deviation. Arch Ophthalmol 123(8):10831087
54. Brodsky MC, Fray KJ (2007) Dissociated horizontal devia-
tion after surgery for infantile esotropia: clinical character-
istics and proposed pathophysiologic mechanisms. Arch
Ophthalmol 125(12):16831692
 184 13 Surgical Management of Dissociated Deviations
55. Apt L, Isenberg S (1977) Eye position of strabismus patients
under general anesthesia. Am J Ophthalmol 84(4):
574579
56. Wilson ME, Hutchinson AK, Saunders R (2000) Outcomes
13 from surgical treatment for dissociated horizontal devia-
tion. J AAPOS 4(2):94101
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. Depsito legal: M-14174-
2009. Madrid, Spain, 37 pp 113115
58. Guyton DL (2004) Dissociated vertical deviation: an
acquired nystagmus-blockage phenomenon. Am Orthoptic
Journal 54:7787
59. Guyton DL (2008) Ocular torsion reveals the mechanisms
of cyclovertical strabismus: the Weisenfeld lecture. Invest
Ophthalmol Vis Sci 49(3):847857; 846
60. Bechtel RT, Kushner BJ, Morton GV (1996) The 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):
268272. 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 432439
64. De Decker W, Conrad HG (1975) Fadenoperation nach
Cuppers bei komplizierten Augenmuskelstorungen und
nichtakkommodativem Konvergenzexzess. Klin Monatsbl
Augenheilkd 167:217
 Chapter 14
Surgical Implications
of the Superior Oblique Frenulum
Burton J. Kushner and Megumi Iizuka
Core Messages
The superior oblique (SO) tendon is attached to
the undersurface of the superior rectus muscle by
an areolar frenulum.
The frenulum, if left intact, causes the SO tendon to
move posteriorly with the superior rectus muscle
when it is recessed. This can prevent the SO from
becoming scarred into the superior rectus insertion
when the latter is recessed. It can, however, prevent
the superior rectus muscle from taking up slack
when recessed with a suspension technique.
14.1 Introduction
The superior oblique (SO) muscle is adherent to the
undersurface of the superior rectus muscle by an areolar
connective tissue. Jampolsky was the rst to describe the
surgical signicance of this local adherence, which he
referred to as a frenulum [1]. The term frenulum can be
dened 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 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.
Therefore, 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
14
An intact frenulum can result in the SO tendon
scarring into the superior rectus insertion when
the latter is resected.
The posterior SO tenectomy procedure is eec-
tive in collapsing small A patterns but often does
not eliminate overdepression in adduction. This
apparent contradiction can be explained by the
change in SO vector force that results from cut-
ting the frenulum, which is unavoidable with this
surgical procedure.
potential complication of the SO tendon becoming
scarred into the insertion of the superior rectus muscle.
Recently, studies have suggested that scarring of the SO
muscle in this way can produce a complication referred to
as the SO tendon incarceration syndrome [2]. This syn-
drome is a restrictive strabismus characterized by a
hypertropia with incyclotropia of the aected 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 dicult surgical problem to correct and hence
should be avoided if possible.
The frenulum may also be an important structure to
consider during SO surgery as well. Prieto Diaz 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. Their state-
ments appear logical, but it is only recently that the eect
of severing the frenulum on the position of both the SO
tendon and superior rectus muscle at surgery has been
quantied [2]. In addition, it has been observed that the
 186 14 Surgical Implications of the Superior Oblique Frenulum
posterior partial tenectomy procedure on the SO tendon
is eective in collapsing of A patterns that measure less
than 20 PD (prism diopters); however, it is less eective
in decreasing the overdepression in adduction [3, 5]. This
14 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 eectiveness 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 eect of
dierent 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 Eect of Superior Rectus Muscle
Recession on the Location of the
Superior Oblique Tendon Before
and After Cutting the Frenulum
This experiment consisted of measuring the posterior dis-
placement of the SO tendon with recession of the superior
rectus muscle before and after cutting the SO frenulum in
three patients (2, 8, and 25 years of age) who were 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 after cutting
the frenulum in the eye undergoing enucleation while
suspending the superior rectus muscle at various dis-
tances. This was performed as follows: The superior rectus
muscle was isolated on a muscle hook, imbricated with
two double-armed 60 Polyglactin 910 sutures, the check
ligaments were cut in the usual manner, and the superior
rectus muscle was disinserted. The underlying SO tendon
insertion was identied without cutting the frenulum. A
single-armed 60 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 1520 mm from the knot placed
in the SO tendon. Next, with the superior rectus held at
the original insertion, the distance between the reference
knot and the superior rectus muscle insertion was
recorded. This distance was referred to as the initial
Fig. 14.1 Photograph of right eye at surgery as seen from below.
The needle of a 60 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
reected upward. The small arrow denotes the SO tendon; the
large arrow denotes the reected superior rectus muscle.
(Reprinted from [6] Elsevier Press)
reference knot distance. The superior rectus muscle was
then suspended 6, 8, 10, 12, and 14 mm for a total of three
recessions at each distance in a randomly generated order
to avoid any inuence of tissue hysteresis or tissue mem-
ory. The 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. The eye was then rotated to the primary
position and the conjunctiva was lifted to verify if the
muscle had completely taken up the slack in the 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. The eect of the superior rectus
suspension on the position of the SO tendon was recorded
using calipers to measure the distance from the reference
knot to the insertion of the superior rectus muscle. This
was referred to as the second reference knot distance. A
masked assistant (resident, fellow, or scrub nurse) then
read the caliper distance using a straight ruler to the 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).
The SO frenulum was then completely severed under
direct visualization by elevating the superior rectus
muscle and lysing the connection between it and the
underlying SO tendon using sharp and blunt dissection.

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)
All the above measurements were repeated, again with
three measurements for each superior rectus suspension
distance performed in a randomly determined sequence.
There was essentially a one-to-one correlation between
the amount of superior rectus recession and posterior
movement of the SO tendon for superior rectus reces-
sions up to 10 mm. After 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. This conrms that the frenulum intimately links the
superior rectus muscle and the SO tendon. The fact that
the superior rectus muscle did not consistently take up
the slack for large suspension recessions (1014 mm)
with the frenulum intact, but did so more often when the
frenulum was severed, is probably due to a constraining
eect of the frenulum. The frenulum is attached to the SO
tendon, which in turn has limited amount of slack to
allow the tendon to continue to move freely posteriorly.
Hence, at these large recession values, the frenulum may
prevent adequate weakening unless the superior rectus
muscle is sutured in place. We therefore advocate cutting
the frenulum for superior rectus muscle recessions that
are larger than 10 mm, especially when using a 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. This graphically illustrates why an
intact frenulum will limit the amount the superior rectus
14.2 Clinical and Theoretical Investigations 187
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.
After cutting the frenulum, the SO muscle moved
minimally when the superior rectus muscle was recessed.
Because the anterior border of the SO tendon is 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. The SO insertion is broad and underlies a
relatively large area beneath the superior rectus muscle.
Consequently, cutting the frenulum may result in di-
culty with suturing the superior rectus to the sclera
without incorporating some of the SO insertion whose
diaphanous nature can make it dicult to visualize. We
therefore agree with Jampolskys 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 eect [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
 188 14 Surgical Implications of the Superior Oblique Frenulum

tendon may therefore be at risk of being sutured into
the insertion site of the superior rectus muscle [1, 7].
Consequently, for superior rectus resections, we also
advocate separating the frenulum.
14
14.2.2 The Eect of the Frenulum
on Superior Oblique Recession
Using a Suspension Technique
This experiment consisted of assessing how far the SO
tendon retracted (recessed) after disinsertion to simulate
what happens with either a recession with a suspension
technique or a free disinsertion. This was done both
before and after separating the frenulum in a second
series of four patients (ages 8, 17, 22, and 47 years) who
were undergoing bilateral SO recession using a suspen-
sion technique. The position of the SO was measured
before and after cutting the frenulum in the following
manner: The SO tendons insertion was isolated through
a superotemporal incision after rst hooking the superior
rectus muscle. The SO tendon was hooked at its insertion
with care to avoid pulling the tendon from under the
superior rectus muscle, thus preserving the frenulum.
This was done by reecting the superior rectus nasally as
minimally as possible but sucient to allow for visualiza-
tion of the insertion of the SO tendon. A 60 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 1520 mm from the distal end of the SO ten-
don and the superior rectus muscle was set back in its
unreected position. The distance from the reference
knot to the temporal edge of the superior rectus muscle
was measured and recorded in the aforementioned
masked manner. This was recorded as the initial reference
knot distance. The SO tendon was then disinserted, and
two successive forced ductions to rotate the eye 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. The masked assistant then read the caliper
distance using a straight ruler to the nearest 0.5 mm. The
amount of recession of the SO tendon was calculated to
the nearest 0.5 mm by subtracting the second reference
knot distance from the initial reference knot distance.
This was repeated for three sets of measurements.
Traction was then placed on the SO tendon, to pull it
approximately 1214 mm out from under the superior rec-
tus muscle temporally (Fig. 14.4). This movement essen-
tially brought all of the tendon that is normally under the
superior rectus muscle out temporal to it, and eectively
severed the frenulum connection. This 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. The
distance between the knot and the superior rectus edge was
measured with calipers in the same manner as when the
frenulum was intact. Again, using simple subtraction,
the amount of recession of the SO tendon after the 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 60
Polyglactin 910 suture woven through the insertion, just after hooking the SO tendon. The frenulum is intact. (b) The SO tendon
disinserted with the frenulum intact. A relatively small amount of recession occurs. (c) After stripping the frenulum a much larger
amount of recession of the SO tendon occurs than prior to stripping the frenulum. (Reprinted from [6] Elsevier Press)

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
1214 mm out from under the superior rectus muscle tempo-
rally to eectively sever the frenulum. Small arrow denotes SO
tendon; large arrow denotes suture tied to the cut end of the SO
tendon. (Reprinted from [6] Elsevier Press)
measurements was taken prior to and after stripping the
frenulum on the other (control) eye in the same manner as
in the rst (study) eye. In two patients, the study procedure
was performed in the right eye rst, and in the other two
patients, the study procedure was performed in left eye rst.
The mean distance that the SO tendon recessed was
2.4 0.4 mm before cutting the frenulum and 8.5
0.7 mm after cutting the frenulum. There was a statisti-
cally signicant dierence between the two measure-
ments (P = 0.0011, paired two-tailed students t-test).
The same procedure was followed in the fellow control
eye for one set of measurement. For the control eyes the
mean recession prior to stripping the frenulum was 2.4
0.3 mm and after stripping the frenulum was 8.0
0.8 mm (P = 0.0004, paired two-tailed students t-test).
These values for the amount of recession obtained in the
control eyes before and after stripping the frenulum
were essentially identical to the values for the study eyes,
despite the control eyes only having a single measure-
ment. This conrms that taking multiple measurements
prior to stripping the frenulum was not a confounding
factor on the amount that the SO moved after stripping
the frenulum.
The results of this experiment are consistent with the
observation that the maximal eect of a recession of
the SO tendon using a suspension technique can only be
14.2 Clinical and Theoretical Investigations 189
achieved by cutting the frenulum [4]. It also suggests that
asymmetric eects may occur with bilateral SO recession
using a suspension technique, if there is asymmetric
stripping of the frenulum. On the other hand, stripping
the frenulum may allow the disinserted SO tendon to
migrate forward resulting in the SO tendon incarceration
syndrome [2]. Thus how the frenulum is handled with
these procedures may be a matter of tradeos.
14.2.3 The Theoretical Eect of the Superior
Oblique Frenulum on the Posterior
Partial Tenectomy of the
Superior Oblique
The threefold function of the SO muscle includes intor-
sion, depression, and to a lesser degree, abduction. These
actions are uniquely related to its anatomy and the angle
the tendon makes with the anteriorposterior axis. The
SO tendon makes an angle of approximately 54 with the
anteriorposterior axis. The anterior bers of the SO ten-
don make a relatively large angle with the anteriorposte-
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 bers of the SO tendon using
computer-aided design software and determined that the
vertical action is approximately 1/3 of the torsional action
[8]. The posterior bers of the SO tendon make a smaller
angle with the anteriorposterior axis than the anterior
bers. He concluded they therefore contribute approxi-
mately 50% less torsion than the anterior 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 HaradaIto
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.
PrietoDiaz 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 812 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
 190 14 Surgical Implications of the Superior Oblique Frenulum
14
Fig. 14.5 This 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. The surgery
not only eliminated the A pattern but overcorrected it resulting in a small V pattern, yet his SO overaction persisted
in a pseudo-SOOA [3, 5] (Fig. 14.5). Why this 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 gures of the anatomy of
the SO and SR obtained from Orbit1.8 (Eidactics, San
Francisco, CA) to determine the angles made by the ante-
rior and posterior bers of the SO tendon with the ante-
riorposterior axis when the eye was in the primary
position, as well as in adduction. We then modied those
gures to assume that the frenulum constrained the SO
tendon to the SR muscle and recalculated the same angles.
The contribution of the net force directed parallel to the
anteriorposterior axis represents the force that creates
depression, and the contribution of the net force directed
perpendicular to the anteriorposterior axis represents
the torsional force. The percentage of original SO force
that is directed vertically and torsionally is the cosine and
sine of the angle made by the SO tendon and the ante-
riorposterior axis, respectively, multiplied by 100.
Figure 14.6a shows the eye in primary position. The
anterior bers of the SO tendon make an angle of 75 with
the anteriorposterior axis. Thus, the torsional force vec-
tor of these 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 modied from the Orbit1.8 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 bers of
the SO tendon and the anteriorposterior axis is approxi-
mately the same. As seen in Fig. 14.6b, the anterior bers
of the SO tendon still make an angle of 75 with the ante-
riorposterior 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 after a posterior
partial tenectomy procedure. The excised portion of the
posterior four fths of the SO tendon insertion is out-
lined in black. This surgical procedure necessitates that
the frenulum be excised, which allows the SO tendon to
move forward. This substantially decreases the angle
between the anterior bers of the SO tendon and the
anteriorposterior axis. In Fig. 14.6c, we measured this
angle to be approximately 40. In this position, the
depressor action of the SO tendon is increased compared
with that found in the unoperated state. The magnitude
of depression is the sine of 40 or 77% of the total net
force as compared with only 26% prior to the surgical
procedure. This may be one explanation why overdepres-
sion in adduction persist after posterior partial tenec-
tomy. This residual abnormality of versions may be due
to the unavoidable excision of the SO frenulum, which
occurs with this surgical procedure, and the eect this
has on the subsequent distribution of vertical force of the
SO tendon. Persistent overdepression in adduction has
been reported as occurring in 40.4% [12]57% [5] of
patients after posterior partial SO tenectomy. Despite this
unwanted overdepression in adduction, weakening of the
 14.2 Clinical and Theoretical Investigations 191

Fig. 14.6 Three-dimensional scale gure of the anatomy of the SO modied from Orbit1.8 program seen from above. (a)
Representation of an unoperated eye in the primary position. The anterior bers of the SO tendon make an angle of 75 with the
anteriorposterior axis. The magnitude of the force vector for depression of the SO tendon is 26% of the total net force. (b)
Representation of an unoperated eye in adduction. This is modied from Orbit1.8 to assume the frenulum completely con-
strains the tendon to the SR muscle. The original angle made by the anterior bers of the SO tendon and the anteriorposterior
axis is preserved measuring 75. The magnitude of the force vector for depression of the SO tendon remains unchanged at 26% C)
Representation of the eye in adduction following posterior partial tenectomy procedure of the SO tendon. Th e absence of the
constraining eect of the frenulum allows the SO tendon to slide forward. Th is decreases the angle between the anterior bers
of the SO tendon and the anteriorposterior axis to 40. The magnitude of the force vector for depressor of the SO tendon
increases to 77% of the total net force

SO with posterior partial tenectomy eectively reduces
the exo-shift in down gaze and thus reduces the A pattern
[5, 1012]. This may be due to the ability of the adducting
power of the inferior rectus muscle to prevail over any
residual abducting power of the weakened SO in the
adducted and depressed position (unpublished written
personal communication from A. Castanera de Molina,
July 18, 2007). However, overdepression occurs even
when the A-pattern is eectively 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). This would be consistent with our
hypothesis that excision of the frenulum can result in for-
ward slippage of the remaining 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 after partial posterior SO tenec-
tomy occurs secondary to a limitation of depression in
abduction of the contralateral eye after bilateral surgery.
This results in a pseudo-SOOA in the ipsilateral eye by
Herrings law [5, 8]. There are several theories as to the
cause of this limitation. For example, anteriorization of
the SO tendon insertion to a preequatorial location after
a posterior partial tenectomy has been theorized. Using
the Orbit 1.8 model, Castanera simulated that an ante-
rior shift of the muscle insertion centroid of 4.45 mm
after 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]. This complication also places the
eective 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
 192 14 Surgical Implications of the Superior Oblique Frenulum
contralateral restriction of depression in abduction can-
not fully account for the persistence of overdepression
in adduction after partial posterior SO tenectomy,
because we have seen this occur in the operated eye
14 after unilateral surgery. Also, we have observed that this
nding is often present immediately after surgery. This
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 eect on versions in
adduction.
We considered the anatomical eects 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-
plications in our theoretical analysis. The geometric
angles drawn on the scaled model are somewhat arbi-
trary. For example, our modeling of the anterior 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 conrm that the SO
has a greater vertical and lesser torsional action in
adduction than in the primary position. Nevertheless,
prior investigation on the constraining eect 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. Thus,
although the actual numbers we calculated are approxi-
mate, our qualitative analysis conrms what seems logi-
cal. Specically, if we assume that the SO tendon is
constrained by the frenulum in the primary and
adducted elds of gaze, cutting the frenulum after a pro-
cedure such as a partial posterior tenectomy would col-
lapse the angle the anterior bers make with the
anteriorposterior axis. This reduction in the angle
makes the SO tendon a more eective depressor in the
adducted position. This may be an explanation for the
residual overdepression in adduction in the ipsilateral
eye after posterior partial tenectomy of the SO tendon.
Summary for Clinicians
The SO frenulum is an important structure. How
it is handled with superior rectus and SO surgery
may aect the surgical outcome.
The frenulum should be severed for superior
rectus recessions that exceed 10 mm, to allow for
the desired recession eect.
The frenulum should be severed for all superior
rectus resections to prevent the SO tendon incar-
ceration syndrome.
The 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-
os. 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.
The posterior tenectomy operation of the SO is
eective in collapsing up to 20 PD of A pattern but
is less eective in eliminating the overdepression
in adduction.
References
1. Jampolsky A (1981) Superior rectus revisited. Tr Am
Ophth Soc 79:233
2. Kushner BJ (2007) Superior oblique tendon incarceration
syndrome. Arch Ophthalmol 125:10701076
3. Prieto-Diaz J (1988) Management of superior oblique
overaction in A-pattern deviations. Graefes Arch Clin Exp
Ophthalmol 226:126131
4. Prieto-Diaz J (1989) Superior oblique overaction. Int
Ophthalmol Clin 29:4350
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 13:1728
6. Iizuka M, Kushner B (2008) Surgical implications of the
superior oblique frenulum. J AAPOS 12:2732
7. Jampolsky A (1986) Management of vertical strabismus.
Symposium on pediatric ophthalmology: transactions of
the new Orleans acad ophthalmol. Raven, New York, pp
141171

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. 535541
9. Harada M, Ito Y (1964) Surgical correction of cyclotropia.
Jap J Ophthalmol 8:8896
10. Prieto-Diaz J (1976) Tenectomia parcial posterior del obli-
cuo superior. Arch Oftalmol B Aires 51:267271
11. Prieto-Diaz J (1979) Poseterior partial tenectomy of the
SO. J Pediatr Ophthalmol Strabismus 16:321323
References 193
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
33:211218
13. Castanera de Molina A, ML GM (1997) Persistent SO
overaction after surgical treatment of A-pattern anisot-
ropies. In: M. Spiritus (ed) Transactions 24th meeting
European strabismological association; Vilamoura,
Portugal. Aeolus, Buren, The Netherlands
 Chapter 15
Pearls and Pitfalls in Surgical
Management of Paralytic Strabismus
Seyhan B. zkan
Core Messages
Careful preoperative assessment and a correct
diagnosis of the problem are the essential factors
for a successful outcome of surgical treatment.
The pearl to go through the correct route in surgi-
cal management of paralytic strabismus is to
know the questions that need to be answered dur-
ing the preoperative assessment. The correct
answers for these questions clarify the method of
appropriate surgical treatment.
During the preoperative assessment, the potential
for fusion must be carefully evaluated. Acquired
loss of fusion or, in other words, central fusion
disruption may coexist in acquired paralytic 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.
The aims of surgical treatment are primarily to
obtain a diplopia-free 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.
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 rst and then the treat-
ment strategies in third, fourth, and sixth cranial nerves
will be evaluated.
15
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.
The restoration of ocular alignment should be
planned to create a new balance in both eyes.
Paralytic strabismus is a binocular problem even
in cases with unilateral involvement. There should
be no hesitation to operate the sound eye where
necessary.
The methods of surgical treatment primarily aim
to weaken the unopposed overaction of the
antagonist, then to strengthen the paretic muscle
where possible or to create a mechanical eect by
transposition, and 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.
15.1.1 Aims of Treatment
The major aims of treatment are enlargement of diplopia-
free eld, restoration of ocular alignment, and restoration of
the appearance of the patient, to correct abnormal head pos-
ture, and to improve the ductions. The last one is the concern
of the strabismus surgeon, and the patients usually do not
complain of limited ductions and are mostly not even aware
of the limitation of their ductions if it is not very severe.
15.1.2 Timing of Surgery
In all types of paralytic strabismus, the stability of the devi-
ation must be observed before considering any surgical
 196 15 Pearls and Pitfalls in Surgical Management of Paralytic Strabismus
intervention. The time period that the spontaneous recovery
occurs is usually accepted as 6 months; however, this period
may last longer, especially in third nerve palsies. A waiting
period of 12 months is recommended for third nerve palsies
15 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 after 6 months, surgical treatment must be
postponed till the deviation becomes stable.
15.1.3 Preoperative Assessment
Prior to any treatment, one must be sure about the 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. The combination of
restrictive and paralytic problems mostly occurs in orbital
blow-out fractures and in long-standing paralytic prob-
lems. The combination of restrictive element has a nega-
tive eect 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?
The answers for the 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 dicult to assess
whether the paralytic condition is partial or total. These
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
gaze
Assessment of the ocular rotations
Traction test
Active forced generation test
Electromyography (EMG)
Increase of intraocular pressure with positions of
gaze
Measurement 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]. The secondary unopposed contrac-
ture of the antagonist EOM may not allow the eye to move
toward the direction of the aected 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 brosis BTXA injection does not give reliable results,
as BTXA cannot eliminate the brotic tissue eect.
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 brosis may not
only aect the EOMs but also the fascial structures and
EOM pulleys and an orbital brosis develops [4, 5]. In
such cases, the traction test will be found positive despite
the disinsertion of the EOM. These cases represent the
most challenging paralytic ocular motility problems.
Is the problem congenital or acquired?
In congenital paralytic disorders, there may be some
developmental abnormalities like the tendon abnormali-
ties in congenital superior oblique palsy, EOM brosis, or
orbital brosis. Most of the congenital cases do not com-
plain of diplopia. The exception of this is decompensated
congenital fourth nerve palsy presenting with vertical
diplopia.
Is there acquired loss of fusion (central fusion
disruption)?
Acquired loss of fusion or central fusion disruption may
occur in paralytic strabismus cases especially the 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

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]

Paretic EOM Partially recovered Contracture of

paretic EOM the antagonist Paralysis of the
antagonist with BTXA

Fig. 15.2 In a patient with left sixth nerve palsy (a) the improvement of abduction of the left eye after injection of BTXA into the
medial rectus muscle is shown (b) [3]

deviation is neutralized by prisms or synoptophor, these
patients typically describes a vertical sliding of the images
when the two images were overlapped and were just
about to appear single. The diagnosis of this challenging
problem preoperatively is very important. If the patient
has an acquired loss of fusion and intractable diplopia,
the deviation should better be corrected temporarily by
prisms or BTXA to allow the assessment of the tolerance
of diplopia [2, 6]. In some cases during this period, the
fusional ability may be regained and in those ones 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. The
decreased contrast sensitivity and the loss of image qual-
ity related to Fresnel prisms may have a negative eect 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. The overlapping
two close images cannot be tolerated and cause more
symptoms compared with the two far away images in a
patient with a large deviation.
15.1.4 Methods of Surgical Treatment
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. The exception of this is superior
oblique palsy. Because of the tendon length and the
anatomical characteristics, superior oblique tendon
tuck may be performed in a superior oblique muscle
with no residual function.
 198 15 Pearls and Pitfalls in Surgical Management of Paralytic Strabismus
Weakening the yoke muscle in the sound eye:
Recession or faden operation of the yoke muscle in the
unaected eye is the preferred method to increase the
eld of binocular diplopia-free eld.
15
These are the general principles that the strabismus sur-
geon needs to consider in all types of paralytic strabismus
cases. The cranial nerve palsies will be evaluated individ-
ually during the rest of the manuscript.
15.2 Third Nerve Palsy
Third nerve palsy may aect the third nerve in total, or the
superior or inferior branches of the nerve as well as the
isolated EOM involvement. All these types of third nerve
palsy may present with a total or partial involvement, and
they represent a wide range of ocular motility problems.
The involvement of the inferior branch of the third nerve
aects medial rectus, inferior rectus, and inferior oblique
muscles, whereas the superior branch aects the superior
rectus and levator palpebrae superioris muscle.
15.2.1 Complete Third Nerve Palsy
In complete third nerve palsy, the major problem is the
unopposed contracture of the antagonist lateral rectus
muscle. There is a small hypotropia with a large angle
exodeviation and ptosis due to the involvement of levator
palpebrae superioris muscle. If the pupillary bers are
aected, a mydriatic pupilla will be observed. In congeni-
tal and long-standing cases, brosis of the intraorbital
structures develops. The aims of treatment in complete
third nerve palsy are to obtain an improvement of the
appearance of the patient, orthophoria in primary posi-
tion, and a 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.
The surgical treatment modalities in complete third
nerve palsy may be summarized as follows:
Weakening of the lateral rectus muscle.
Resection of the medial rectus muscle.
Superior oblique tendon transposition.
The procedures that keep the eye in passive
adduction.
Weakening of the lateral rectus muscle: The methods
of weakening are supramaximal recession, hang back
recession enough to allow the passive adduction of the
eye, orbital wall periost xation of the lateral rectus mus-
cle, and BTXA injection in residual deviations [79].
Orbital wall periost xation is a recently described
method for the inactivation of lateral rectus muscle that
we found useful in our clinical practice. Posterior Tenon
xation is proposed to be an alternative method to periost
xation [10]. The potential reversibility of the procedure
is the advantage of both of these methods.
Medial rectus resection: Although the resection of a
paralytic muscle is not so eective, some authors prefer to
perform a large resection to obtain a mechanical resis-
tance against abduction. In our experience, this eect
does not last long and we do not prefer to resect medial
rectus muscle.
Superior oblique tendon transposition: The aims of
superior oblique tendon transposition is to correct the
hypotropia, making the superior oblique an adductor,
creating a mechanical barrier against abduction, and thus
preventing the recurrence of the exodeviation. Superior
oblique tendon transposition may work if and only if the
superior oblique muscle has some function. Especially, in
long-standing ones, it may be dicult to assess the func-
tion of the superior oblique muscle while the eye is 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 Scotts 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].
The latter is our preferred method for superior oblique
tendon transposition, which is a less invasive one.
The procedures to keep the eye in passive adduction: For
a permanent eect fascia lata, silicone band or superior
oblique tendon may be used to 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 eect of surgery [14, 15]. These sutures are
kept in place for 6 weeks. This is our method of choice in
total third nerve palsy [3] (Figs. 15.315.5). The other
methods are usually performed in secondary cases with a
failure of a previous operation.
The major problems in total third nerve palsy are lat-
eral rectus contracture that cannot be overcome by any
methods, orbital 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]

and in that case, the treatment should be modied

depending upon the severity of the involvement of the
EOM(s). As the goal is to enlarge the diplopia-free 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.

Summary for the Clinician

Fig. 15.4 In the case with congenital third nerve palsy traction
sutures are seen in upper and lower eyelid to keep the eye in
adducted position [3]
15.2.2 Incomplete Third Nerve Palsy
In incomplete third nerve palsy with a superior or infe-
rior branch or isolated EOM involvement, the treatment
should be planned depending upon the aected 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
The correct evaluation of a complete or incom-
plete third nerve palsy (to diagnose the number
of aected muscles) and assessment of a total or
partial involvement (the residual function of the
aected muscles) are the pearls for an appropri-
ate surgical planning.
In complete third nerve palsy, superior oblique
function may easily be overlooked. The pearl is to
use slit lamp for a precise evaluation to see the
tiny intorsion.
In incomplete or partial third nerve palsy, the
aim is to provide a functional diplopia-free area;
however, in complete third nerve palsy, the aim
is to xate the aected eye in primary position.
Orbital brosis is the bad prognostic sign for any
type of surgery. The pearl is to create surgically
induced restriction that provides a mechanical
pulling eect. A temporary pulling by traction
sutures is very eective that allows the develop-
ment of the scar tissue while the globe was xated
on adduction.
 200 15 Pearls and Pitfalls in Surgical Management of Paralytic Strabismus
15
Fig. 15.5 Postoperative appearance of the patient after removal of the traction sutures 6 weeks after surgery. Orthophoria is obtained
in primary position [3]
15.3 Fourth Nerve Palsy
In fourth nerve palsy hypertropia, inferior oblique overac-
tion and superior oblique underaction is observed in the
aected 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 ndings of fourth
nerve palsy. In unilateral cases, the typically observed
abnormal head posture is chin down with head tilt toward
the unaected 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 benet 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?
The surgical treatment should be planned on the EOMs
functioning in the 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? The reply to this question
has a specic 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 [1619]. 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 nd-
ings were conrmed in other recent studies [20, 21]. If the
abnormality would only be limited with the tendon itself,
denervation atrophy would not be expected to develop in
those cases with congenital fourth nerve palsy. The dif-
ferential diagnosis in congenital and acquired cases is not
only important for the etiological investigation but also
for surgical planning. The clinical clues suggesting that
the patient has a congenital superior oblique palsy may be
summarized as follows:
 15.3 Fourth Nerve Palsy 201

History, old photos
Absence of a preceding event
Prominent abnormal head posture
Facial asymmetry
Coexistence of amblyopia
Signicant 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
modied by Plager [17]. The globe is 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 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]. The bilateral
involvement may be asymmetric but even with marked
asymmetry surgery should be planned in both eyes. The
clinical clues suggesting bilateral involvement are as
follows:
Bilateral inferior oblique overaction.
Bilateral superior oblique underaction.
Positive Bielschowsky head tilt test with the head tilted
on both sides. In case of a marked asymmetry,
Bielschowsky head tilt test may be positive on the side
with marked involvement.
V pattern deviation.
Abnormal head posture to compensate the V
pattern.
Objective torsion exceeding 10 [40].

Fig. 15.6 Steps of superior oblique tendon tuck in abnormally lax superior oblique tendon in the right eye. (1) The globe is
grasped with retropulsion. (2)The globe is moved superonasally and the cornea disappears in total, the back and forth 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 xated on the sclera. (6) Traction test is repeated after tucking. Note
the dierence of the position of the cornea
 202 15 Pearls and Pitfalls in Surgical Management of Paralytic Strabismus

15

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

Is there any torsional diplopia? Torsional diplopia is a although an excyclotorsion is observed in fundus exami-
symptom that occurs in acquired fourth nerve palsy. The nation, and this is one of the clues for dierential diagno-
patients with a decompensated congenital fourth nerve sis of a congenital and acquired fourth nerve palsy. Some
palsy has vertical diplopia without a torsional element, patients may not describe torsional diplopia properly

unless asked specically 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 aected eye
Inferior rectus recession in the contralateral eye
Inferior oblique weakening procedures: Inferior oblique
weakening procedures are the most commonly performed
operations for treatment of fourth nerve palsy [41, 42].
The weakening procedures are disinsertion, myectomy,
recession, and anteroposition of the inferior oblique 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 modied 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 eective 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 after tucking with loop
sutures (Fig. 15 6). If the traction test is positive then the
amount of tuck should be reduced. The triad of 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
modied Harada-Ito procedure is the method of choice
that strengthens the anterior torsional bers. The anterior
bers of superior oblique muscle are transposed lateral
and anteriorly at the upper border of the lateral rectus
15.3 Fourth Nerve Palsy 203
muscle [26, 30]. This procedure is usually performed
bilaterally and has a minimal eect 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 aected eye: The 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. The 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: The
cases that do not t any of the indications specied 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 aected 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 benets with
BTXA injection if there is no signicant torsional
element.
Summary for the Clinician
The 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.
 204 15 Pearls and Pitfalls in Surgical Management of Paralytic Strabismus
The 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
15 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. The 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 modied Harada-Ito procedure is a surgery
for acquired bilateral cases with marked torsional
component.
15.4 Sixth Nerve Palsy
Lateral rectus underaction, esotropia, and a horizontal
diplopia, which is more prominent at distance, and abnor-
mal head posture in unilateral cases keeping the aected
eye in adduction are the clinical features of sixth nerve
palsy. Lateral rectus underaction may be very subtle in
partially aected cases and it is essential to measure the
deviation in nine positions of gaze. Partially aected cases
benet 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 aected 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 [3438].
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: This method carries a risk of anterior seg-
ment ischemia. That 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:
Recessresect should be reserved only for those with a
good residual function of the aected lateral rectus mus-
cle. If the residual function of the lateral rectus muscle is
very limited, then transposition will work better than
recessresect procedure. The correct surgical decision
for a recessresect or a transposition procedure is highly
important. A wrong decision for a recessresect proce-
dure in an old patient makes the patient lose his or her
chance to have a transposition procedure because of the
signicant risk of anterior segment ischemia. To obtain
a more reliable assessment for the residual lateral rectus
function, BTXA injection is recommended as a 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 signicant limitation of ocular motility,
BTXA provides the assessment of the residual function of
the paretic muscle in the absence of secondary 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 after 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 eect. This method
reduces the risk for anterior segment ischemia.
Medial rectus weakening of the sound eye: Medial rectus
recession or faden operation of the medial rectus muscle

Botulinum toxin injection
as the first line treatment
Cure-no further
treatment
Patient satisfied -
regular injections Unsatisfactory result -
necessary information
for recess-resect or
transposition surgery
Fig 15.9 The use of BTXA for planning of treatment in sixth
nerve palsy [3]
of the sound eye increases the area of binocular diplopia-
free eld. A combination of recession and resection of the
medial rectus muscle provides an adjustable faden eect in
the medial rectus muscle and may prove to be useful to
reduce the symptoms of the patient with more control
compared with conventional faden operation [43].
The problems of treatment in sixth nerve palsy are the
anterior segment ischemia risk and the insucient cor-
rection because of a recessresect procedure in a non
functioning lateral rectus muscle.
Summary for the Clinician
The correct diagnosis of partial and total sixth
nerve palsy is the pearl for a successful outcome
of surgery.
The major pitfall is the misinterpretation of the
lateral muscle function because of the second-
ary medial rectus restriction in long-standing
cases.
BTXA has major role both for surgical planning
and as an adjunct to surgery.
Recessresect 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
eect 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.
References 205
References
1. Golnik KC, Miller NR (1991) Late recovery of function
after oculomotor nerve palsy. Am J Ophthalmol 111:
566570
2. Ansons AM, Davis H (2001) Diagnosis and management
of ocular motility disorders, 3rd edn. Oxford, Blackwell
Science, Paris Berlin Tokyo, pp 143162
3. zkan SB (2006) Strategies of treatment in paralytic stra-
bismus. Trkiye Klinikleri J Surg Med Sci 2:5865
4. Demer JL, Miller JM, Poukens V, et al (1995) Evidence for
bromuscular pulleys of the recti extraocular muscles.
Invest Ophthalmol Vis Sci 36:11251136
5. Demer JL, Miller JM, Poukens V (1996) Surgical implica-
tions of the rectus extraocular muscle pulleys. J Pediatr
Ophthalmol Strabismus 33:208218
6. zkan SB, Dayanir V, Kir E, et al (2001) Role of botulinum
toxin A in management of acquired loss of fusion. In: de
Faber JT (ed) Transactions 27th meeting of the European
strabismological association. Swets and Zeitlinger, The
Netherlands, pp 195198
7. Gottlob IG, Catalano R, Reinecke RD (1991) Surgical man-
agement of oculomotor nerve palsy. Am J Ophthalmol
111:7176
8. Morad Y, Kowal L, Scott AB (2005) Lateral rectus muscle
disinsertion and reattachment to the lateral orbital wall. Br
J Ophthalmol 89:983985
9. Velez FG, Thacker N, Britt MT, et al (2004) Rectus muscle
orbital wall xation: a reversible profound weakening pro-
cedure. J AAPOS 8:473480
10. Heo H, Park SW (2008) Rectus muscle posterior tenon
xation as an inactivation procedure. Am J Ophthalmol
146:310317
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 inuence
on postoperative hypertropia. J Pediatr Ophthalmol
Strabismus 37:149155
12. Salazar Leon JA, Ramirez-Ortiz MA, Salas-Vargas M
(1998) The surgical correction of paralytic strabismus
using fascia lata. J Pediatr Ophthalmol Strabismus 35:
2732
13. Villasenor Solares J, Riemann BI, Romanelli Zuazo AC,
et al (2000) Ocular xation to nasal periosteum with a
superior oblique tendon in patients with third nerve palsy.
J Pediatr Ophthalmol Strabismus 37:260265
14. Daniell MD, Gregson RM, Lee JP (1996) Management of
xed divergent squint in third nerve palsy using traction
sutures. Aust N Z J Ophthalmol 24:261265
15. Khaier A, Dawson E, Lee J (2008) Traction sutures in the
management of long standing third nerve palsy. Strabismus
16:7783
 206 15 Pearls and Pitfalls in Surgical Management of Paralytic Strabismus
16. Helveston EM, Krach D, Plager DA, et al (1992) A new
classication of superior oblique palsy based on congenital
variations of the tendon. Ophthalmology 99:16091615
17. Plager DA (1990) Traction testing in superior oblique
15 palsy. J Pediatr Ophthalmol Strabismus 27:136140
18. Plager DA (1992) Tendon laxity in superior oblique palsy.
Ophthalmology 99:10321038
19. Wallace DK, von Noorden GK (1994) Clinical characteris-
tics and surgical management of congenital absence of the
superior oblique tendon. Am J Ophthalmol 118:6369
20. zkan SB, Aribal ME, Sener EC, et al (1997) Magnetic
resonance imaging in evaluation of congenital and acquired
superior oblique palsy. J Pediatr Ophthalmol Strabismus
34:2934
21. Sato M. Magnetic resonance imaging and tendon anomaly
associated with congenital superior oblique palsy (1999)
Am J Ophthalmol 127:379387
22. Guyton DL (1981) Exaggerated traction test for the oblique
muscles. Ophthalmology 88:10351040
23. Ase 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 13:177180
24. Mims JL (2003) The triple forced duction test(s) for diag-
nosis and treatment of superior oblique palsy with an
updated ow chart for unilateral superior oblique palsy.
Binocul Vis Strabismus Q18:1524
25. Kushner BJ (1988) The diagnosis and treatment of bilateral
masked superior oblique palsy. Am J Ophthalmol 105:
186194
26. Price NC, Vickers S, Lee JP, et al (1987) The diagnosis and
surgical management of acquired bilateral superior oblique
palsy. Eye 1:7885
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 16:1016
28. Hussein MA, Stager DRSr, Beauchamp GR, et al (2007)
Anterior and nasal transposition of the inferior oblique
muscle. J AAPOS 11:2933
29. zkan SB, Can D, Demirci S, et al (1995) Surgical treat-
ment in congenital superior oblique palsy. Trkiye
Klinikleri. J Surg Med Sci 4:223226
30. Roberts C, Dawson E, Lee J (2002) Modied Harada-Ito
procedure in bilateral superior oblique paresis. Strabismus
10:211214
31. Sprunger DT, Helveston EM (1993) Progressive overcor-
rection after inferior rectus recession. J Pediatr Ophthalmol
Strabismus 30:145148
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 9:155168
33. Garnham L, Lawson JM, ONeill D, et al (1997) Botulinum
toxin in fourth nerve palsies. Aust N Z J Ophthalmol
25:3135
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 4:145149
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
31:283286
36. Metz HS, Masow M (1988) Botulinum toxin treatment of
acute sixth and third nerve palsy. Graefes Arch Clin Exp
Ophthalmol 226:141144
37. Murray ADN (1991) Early botulinum toxin treatment of
acute sixth nerve palsy. Eye 5:4547
38. Repka MX, Lam GC, Morrison NA (1994) The ecacy of
botulinum neurotoxin A for the treatment of complete and
partially recovered chronic sixth nerve palsy. J Pediatr
Ophthalmol Strabismus 31:7983
39. Riordian PR, Lee JP (1992) Management of VIth nerve
palsy avoiding unnecessary surgery. Eye 386390
40. Kraft SP, OReilly C, Quigley PL, et al (1993) Cyclotorsion
in unilateral and bilateral superior oblique paresis. J Pediatr
Ophthalmol Strabismus 30:361367
41. von Noorden GK, Murray E, Wong SY (1986) Superior
oblique paralysis: a review of 270 cases. Arch Ophthalmol
104:17711776
42. von Noorden GK, Campos EC (2002) Binocular vision and
ocular motility, 6th edn. Mosby, St. Louis, USA pp 559565
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
11:131134
 Chapter 16
Modern Treatment Concepts
in Graves Disease
Anja Eckstein and Joachim Esser
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
inammation, proptosis due to increase (mainly
through adipogenesis) of orbital volume and
impairment of ocular and lid motility due to
inammation, and scarring of chiey the levator,
inferior, and medial rectus muscles. In severe
cases, vision-threatening compression of the optic
nerve can occur.
Inammatory phase is self-limiting but may
relapse, in most cases, owing to insuciently
controlled thyroid disease, but also indepen-
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. The full clinical picture is composed of hyperthy-
roidism, orbitopathy, pretibial myxedema, and acropachy.
The full symptom complex is very rare Myxedema and
acropachy occur only in 35%. With a prevalence of
0.52%, GD is a relatively common autoimmune disease
[1]. In nearly all patients, antibodies against the TSH
16
dently. To restrict damage, anti-inammatory
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 rst-line treatment; if
the response is poor after 1 to 2 weeks, they
should be immediately referred for surgical
decompression.
In patients with mild GO, local measures and an
expectant strategy are usually sucient, but treat-
ment may be justied if quality of life is reduced
signicantly.
In the inactive disease stages, proptosis can
be alleviated through orbital decompression;
restricted ocular and lid motility can be improved
by muscle recession and appearance can be
improved by blepharoplasty of lower and upper
lids.
Important for the successful treatment of GO is
continuous and stable sustenance of euthyroidism
and smoking cessation.
receptor (TSHR) can be measured in the serum as indica-
tors of the failed immune system. Those 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 inammation in the con-
nective tissue of the orbit, an increase of intraorbital vol-
ume due to enhanced adipogenesis, overproduction of
glycosaminoglycanes (GAG), and brosis of the extraoc-
ular muscles [2]. Orbital broblasts are pivotal to these
pathologic processes. Cultured orbital broblasts can be
 208 16 Modern Treatment Concepts in Graves Disease
stimulated by patient IgG, several cytokines, and autolo-
gous lymphocytes. Stimulation by autologous lymphocytes
is antigen-dependent, as direct cellcell contact, MHC
class II, and CD40CD154 signaling are necessary [3]. In
16 addition, orbital broblasts may dierentiate to preadi-
pocytes, which are accompanied by an increase in TSHR
expression [4]. Thus, the shared candidate autoantigen
between thyroid and orbita is the TSHR.
Clinically, high serum levels of TSHR antibodies
(TRAb) are associated with higher prevalence and
increased severity of GO. However, presence of TRAb
alone does not cause the complete symptom complex.
Neonates of mothers with TRAb positive GD usually
develop hyperthyroidism, which gradually dwindles as
antibodies are cleared from the childs 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 inammation [5].
Thus, 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-specic genes [6].
In most patients, there is a close temporal relationship
between the onset of hyperthyroidism and orbitopathy.
Orbitopathy usually manifests within 6 months before or
after the rst clinical signs of hyperthyroidism. MRI
images of patients who suer from hyperthyroidism but
not from clinically overt orbitopathy reveal orbital mani-
festation in more than two-thirds of those patients [7]. The
development of GO is a marker for a more severe course of
GD and associated with signicantly lower remission rates
of hyperthyroidism [8]. However, GO can also occur many
years after the onset of thyroid disease or in rare cases
long before or even without overt thyroid disease [9]. In
75% of euthyroid GO patients, thyroid-specic 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 OrbitopathyClinical Signs
Graves Orbitopathy is typically characterized by the fol-
lowing clinical characteristics (Fig. 16.1) [12, 13]:
Most frequent sign (in 9098% of patients): upper lid
retraction, often with lateral are and lid lag on verti-
cal downward pursuit, lagophthalmos (due to 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 inammation)
Proptosis (exophthalmos) with possible concomitant
lower lid retraction (mainly due to increased adipo-
genesis, but also due to enlargement of extraocular
muscles and inammatory swelling)
Ocular surface lesions (due to lagophthalmos,
increased lid width, impaired Bells phenomenon, and
reduced tear secretion and deteriorated composition)
Restriction of ocular excursions most often upgaze
and abduction (due to 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 inammation: painful, oppres-
sive feeling on or behind the globe, pain of attempted
up-, lateral, or downgaze
Symptoms related to ocular surface irritation: gritty
sensation, light sensitivity, excess tearing, and reduced
visual acuity
Symptoms related to restricted ocular motility: diplo-
pia, abnormal head positure
Symptoms related to DON: reduced visual acuity,
restricted visual 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 eective in the presence of active
inammation. Certain surgical treatments, on the other
hand, (orbital, lid, or strabism surgery) should only be
performed when GO has been constantly inactive for at
least 6 months.
16.1.3.1 Signs of Activity
The active phase of the disease is the period when the
patient is most likely to be symptomatic: gaze evoked or
spontaneous grittiness, light sensitivity, and excessive
orbital aching gaze evoked or spontaneous. Patients
notice change of severity over the previous 3 months.
Classical signs of inammation are used as surrogate
markers to evaluate the degree of orbital inammation:
 16.1 Graves Orbitopathy (GO): Pathogenesis and Clinical Signs 209

a b c

d e f

g h i

Fig. 16.1 Patient examples of typical symptoms of GO: 1A1C Patient with mild GO, the only sign is upper lid retraction at the right
eye. 1D1F Patient with typical impairment of motility: 1D the patients developed a vertical squint of 22 (+VD), the upgaze of the
left eye with 0, 1E the coronary MRI scans show the enlargement of the inferior rectus muscle of the left eye. The other muscles are
almost normal. 1G1I Patients with full picture of GO with DON: marked signs of soft tissue inammation (conjunctival injection
and chemosis, caruncle inammation, redness and swelling of the lids), marked proptosis, severe impairment of ocular motility right
and dysthyroid optic neuropathy both eyes. Enlargement of all extraocular muscles was seen in the coronary MRI apical crowding
in the orbital apex and intracranial fat prolapse in the axial MRI

Eyelid redness was 80% in estimating the response to immunomodula-

Conjunctival injection
Chemosis (conjunctival edema)
Eyelid swelling
Inammation of caruncle or plica
All features of soft tissue inammation 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 rst visit and maximal ten
points at follow-up) (Table 16.1) [16]. Using a cut-o of at
least four (rst visit three), the positive predictive value
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 inam-
matory markers including IL-6, and urine GAG excretion
provide only little additional benet in predicting the
response to anti-inammatory therapy [17].
16.1.3.2 Assessing Severity of GO
The following features are quantied to assess severity:
Lid ssure width (distance between the lid margins in
mm with the patient in primary position; sitting,
relaxed, with distant xation)
Swelling of the eyelids (absent/moderate/severe)
 210 16 Modern Treatment Concepts in Graves Disease

All patients with GO

Restore euthyroidism
Urge smoking withdrawal
16 Refer to specialist centers, except for the mildest cases
Local measures

Mild Moderate to severe Sight-threatening (DON)

i.v. GCs
Local measures Active Inactive
wait and see Progression

Poor response (2 weeks)

Stable and i.v. GCS

inactive ( OR) Prompt decompression

Still active Stable and inactive

Rehabilitative
Stable and Rehabilitative
surgery
inactive surgery
(if needed)
i.v. GCs Rehabilitative
( OR) surgery

Fig. 16.2 Management of Graves orbitopathy. Anti-inammatory 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 denitions of GO severity and activity, see Chap. 16.1.3

Redness of the eyelids (absent/present)
Conjunctival injection (absent/present)
Conjunctival chemosis (absent/present)
Inammation 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 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
aerent pupillary defect (absent/present), visual elds,
visually evoked potentials)
Examination of lid ssure width should be performed
with the head in a stationary position and under 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 dierent makes are available with dier-
ent scales, so for each patient the same exophthalmometer
with identical intercanthal distance should always be used
for follow-up. Proptosis is dened as a reading 2 mm
greater than the upper normal limit for that patients age,
gender, and race. More important, however, is the mea-
sured change during follow-up.
There are numerous ways of assessing extraocular
muscles. Subjective diplopia scores are simple but only of
limited help, since signicant changes in limitation of
motility may go unnoticed, when bilateral symmetrical
reduction of upgaze results in no noticeable double vision.
The measurement of monocular excursions is a more
exact way to assess restricted excursions of each eye
separately. Excursions are best measured using a bowl
or arc perimeter, but so-called Kestenbaum glasses or
the position of light reexes may be used as well. Normal
 16.1 Graves Orbitopathy (GO): Pathogenesis and Clinical Signs 211

Table 16.1. Clinical activity score (CAS), maximal 7 points at
the rst visit and maximal 10 points at follow-up, active disease
CAS 4 (three 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
Pain of attempted up-, side-,
or downgaze
Objective signs of activity
Redness of the eyelids
Redness of the conjunctiva
Chemosis
Inammatory eyelid swelling
Inammation of the caruncle
or plica
Sum score (at rst consultation no
evaluation of progression possible)
Signs of progression
Increase of 2 mm or more in
proptosis in the last 13 months
Decrease in eye movements of 5
or more in the last 13 months
Decrease in visual acuity in the
last 13 months
Sum score
very large muscles in the orbital apex, fat herniation
through the superior orbital 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 3040% of the patients present with swell-
ing of the optic disc. Visual eld defects are most com-
1 monly paracentral or inferior. VEP amplitudes are
reduced and latency periods can be delayed [14].
1 Severity can be scored using the NOSPECS classica-
tion, which provides in its slightly modied version a
maximal score of 14 (Table 16.3) for patients with all
manifestations of GO in its most active stage [19].
1
1
1
16.1.3.3 Imaging
1
1 Orbital imaging can be necessary for dierential diag-
nosis as well as, in special situations, to facilitate treat-
Maximal 7 ment decisions. If the patient presents with asymmetrical
symptoms (usually unilateral proptosis), inammatory
orbital disease of nonthyroidal etiology or orbital
tumors have to be ruled out. Orbital imaging is neces-
1
sary for all clinical treatment decisions in Dysthyroid
optic neuropathy. Signal intensity in T2-weighted MRI
1 scans corresponds to inammatory edema and can be
used to ease treatment decisions in dicult clinical
1 situations. Orbital ultrasound is only informative if
performed and evaluated by experienced clinicians
Maximal 10 [20].

values are given in Table 16.2. The prism cover test (sepa-
rate measurement of the squint angles in primary posi- 16.1.4 Classication of GO
tion for far and near distances) and the eld of binocular
single vision are used to t corrective prisms and to plan Members of EUGOGO recommend to classify patients
squint surgery. according to activity (active disease CAS 4, inactive dis-
Of outstanding importance is the evaluation of the ease CAS < 4) and according to severity to manage
corneal surface. This requires slit lamp examination to patients with GO [21].
detect punctate uoresceine staining or ulceration; the Severity classication:
latter constitutes an ophthalmologic emergency.
There is no single test that proves DON. DON occurs 1. Sight-threatening GO: Patients with dysthyroid optic
bilateral in 70% of the patients. Anatomical indicators are neuropathy (DON) or corneal breakdown. This cate-
gory warrants immediate intervention.
Table 16.2. Normal values for monocular excursions (after
2. Moderate-to-severe GO: Patients without sight-threat-
Mourits et al. [18]) ening GO whose eye disease has sucient impact on
daily life to justify the risks of immunosuppression (if
Direction of gaze Monocular excursion ()
active) or surgical intervention (if inactive). Patients
Abduction 46 with moderate-to-severe GO usually present with one
Upgaze 90 34 or more of the following: lid retraction >2 mm, mod-
Adduction 47 erate or severe soft tissue involvement, exophthalmos
>3 mm above normal for race and gender, intermit-
Downgaze 270 58
tent, or constant diplopia.
 212 16 Modern Treatment Concepts in Graves Disease

Table 16.3. Modied NOSPECS score for quantication of severity, maximal score of 14
NOSPECS score 0 1 2 3

Lid retraction No Yes

16 Soft tissue inammation a
0 14 58 >8
Proptosis and or Site Dierence <17 mm 1718 mm 1922 mm >22 mm
<1 mm 12 mm 34 mm >4 mm
Extraocular muscle involvement No >20 upgaze 20 upgaze
>35abduction but not 35abduction
normal
Corneal defects No Yes
Optic nerve compression No Yes
a
Upper lid edema 02; Lower lid edema 02; conjunctival injection 1; conjunctival chemosis 1

3. Mild GO: patients whose features of GO have only a
minor impact on daily life, insucient to justify
immunosuppressive or surgical treatment. They 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)
the active phase and rehabilitative surgical treat-
ments in the inactive phase of the disease.
According to its grade, GO can be classied 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.

Summary for the clinician

Graves Orbitopathy is part of an autoimmune
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. Their role
in the pathogenesis of orbitopathy is less clear,
though patients with high serum TRAb levels
have a higher prevalence of GO and develop more
severe disease stages. Orbital broblasts play a
pivotal role in the pathologic changes in the orbit
(release of chemokines, production of glycoseam-
inoglycanes/brosis, and dierentiation into adi-
pose tissue).
Assessment of activity (clinical activity score)
and severity is necessary for disease manage-
ment: immunomodulation is performed during
16.2 Natural History
Control of thyroid function inuences 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 often residual symptoms of GO
in the form of lid retraction, proptosis, and muscle dys-
function. The outcome is signicantly better in patients
who have been diagnosed early and treatment started
promptly.
Summary for the Clinician
Spontaneous improvement of GO with restora-
tion of euthyroidism occurs in more than 60% of
the patients.

16.3 Treatment of GO
16.3.1 Active Inammatory 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, 80100 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 3363% of patients, particularly con-
cerning soft tissue signs, eye muscle involvement of recent
onset, and DON. Eye disease frequently ares up on
tapering out or withdrawing of oral GC therapy. Side
eects are frequent.
Local retrobulbar or subconjunctival administration
of glucocorticoids is less eective than oral GC.
Intravenous GC pulse therapy is more eective than
oral GC (dose: 250 mg1 g/week, over 612 weeks or
500 mg1 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 dierent i.v. GC schedules
as well as studies on the optimal cumulative dose is still
lacking. Although i.v. GCs are tolerated better than oral
GCs, life-threatening liver failure has been reported in
association with very high cumulative doses in 0.8% of
patients. Intravenous administration appears to be safe, if
the cumulative dose is below 8 g methylprednisolone in
each course of therapy.
16.3.1.2 Orbital Radiotherapy
The reported response rate to orbital radiotherapy (OR)
in open trials is about 60%. Total doses between 10 and
20 Gy are commonly absorbed per orbit, fractionated in
single doses between 1 and 2 Gy over a 220 week period.
Higher doses are no more eective. The response to OR
did not dier from oral prednisone in a randomized con-
trolled trial (RCT), but glucocorticoids are faster acting.
Two recent RCTs have shown that OR is more eective
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,
16.3 Treatment of GO 213
which is preventable if corticosteroids are administered
simultaneously. Data on long-term safety are reassuring,
but theoretical concerns about carcinogenesis remain for
younger patients, particularly those under the age of 35
years. Retinal microvascular abnormalities have been
detected in a minority of patients, mostly in those with
concomitant severe hypertension or diabetic retinopathy.
Consequently, these two comorbidities are considered
absolute contraindications to OR. It is possible that dia-
betes, even in the absence of retinopathy, represents a risk
factor for the development of retinal changes after OR,
but the evidence is less persuasive [21, 27].
16.3.1.3 Combined Therapy: Glucocorticoids
and Orbital Radiotherapy
Combination of systemic GC (either orally or locally)
with OR is more eective than either treatment alone. It is
unclear whether combining i.v. GCs with OR is more
eective than i.v. GCs alone [28]. Representative studies
are summarized in Table 16.4.
16.3.1.4 Other Immunosuppressive
Treatments and New Developments
One major problem is recurrent activity of GO after 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, denitive therapy of the thyroid has to be initiated.
Thyroidectomy is preferred because radioiodine therapy
carries a risk of deterioration of active GO. In patients
with marked proptosis, orbital decompression has to be
considered because apart from proptosis reduction,
decompression may also silence orbital inammation
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 signi-
cantly decreased after injection of 1,000 mg i.v. Rituximab
 214 16 Modern Treatment Concepts in Graves Disease

Table 16.4. Representative results of randomized clinical trails of anti-inammatory therapy for active GO

Randomization Response rates P values Authors

Group A Group B Group A Group B

16 i.v. methylprednisolone a
Oral Prednisonec c
88% 63% <0.02 Marcocci
Radiotherapyb Radiotherapyb

(n = 41) (n = 41)

i.v. methylprednisoloned oral prednisonee 77% 51% <0.01 Kahaly
(n = 35) (n = 35)

Comparison between i.v. and oral glucorticoid therapy is marked with horizontal arrows and comparison of single vs. combined
(with orbital radiotherapy) therapy is marked with vertical arrows ([24, 29]
Doses for glucocorticoid and radiotherapy:
a
15 mg/kgKG for four cycles, then 7.5 mg/kgKG for four cycles; each cycle consisted of two infusions on alternate days at 2-week
intervals
b
20 Gy in ten daily doses of 2 Gy over 2 weeks
c
100 mg daily for 1 week, then weekly reduction until 25 mg daily, and then tapering by 5 mg every 2 weeks
d
500 mg once weekly for 6 weeks, 250 mg once weekly for 6 weeks, total treatment period: 12 weeks
e
100 mg daily starting dose, tapering by 10 mg/week, total treatment period: 12 weeks

twice at 2-week interval. Even proptosis was signicantly
reduced. Subsequent randomized controlled trials with
Rituximab need to be performed [3032]. The anti-TNF
a drug Etanercept is described as eective as well in an
open trial [33].
Treatments of marginal or unproven value include
somatostatin analogs, azathioprine, ciamexone, and i.v.
immunoglobulins.
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 ineective [21].

16.3.1.6 Other Simple Measures

16.3.1.5 Therapy of Dysthyroid Optic Neuropathy
(DON) and Sight-Threatening Corneal
Breakdown
High-dose i.v. GCs are the preferred rst-line treatment
for DON (3 500 mg1 g at consecutive days within 1
week, if necessary repeated the following week). If the
response to i.v. GCs is absent or poor after 12 weeks, or
the dose/duration of steroid required induces signicant
side eects, 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.
that may Alleviate Symptoms
The symptoms of corneal exposure (grittiness, watering,
and photophobia) should be treated with lubricant eye-
drops. Nocturnal ointment is of great benet 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., 515 IU Dysport) subconjunctivally in the tarsal
muscle (Mueller muscle). Full eect is evident after 23
days and persists for about 46 weeks. The outcome is
variable and the dose of botulinum toxin must be adjusted
individually. Transient double vision and ptosis may
occur in 1020%. This procedure should be carried out in
specialized centers [34].

Summary for the Clinician
Patients with active moderate-to-severe GO or
active mild GO with sucient impairment
on daily life should receive anti-inammatory
treatment.
Glucocorticoids are applied most eciently i.v.
250 mg1 g weekly over 612 weeks or at con-
secutive days within 1 week (cumulative dose:
1.53g) 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 eects.
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 ecient than each therapy
alone.
Patients with dysthyroid optic neuropathy should
be treated with i.v. steroids as rst-line treat-
ment; if the response is poor after 12 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.
16.3.2 Inactive Disease Stages
Rehabilitative surgery includes one or more of the follow-
ing procedures: (a) orbital decompression, the usual indi-
cation for surgery being disguring 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 after denitive therapy (thyroidectomy/
radioiodine therapy) or stable remission at least 6 months
16.3 Treatment of GO 215
after cessation of antithyroid drug therapy. Because of its
inuence on ocular motility and lid width, decompression
surgery should be performed rst. Vertical squint correc-
tion may then be performed. Pseudoretraction will resolve
postoperatively but lower lid retraction can occur after
inferior rectus recession. Small medial rectus recessions
can be combined with lid surgery; larger recessions should
be performed separately [35, 36].
16.3.2.1 Orbital Decompression
A wide range of surgical approaches is used to reduce
disguring proptosis in patients with GO. The amount of
proptosis reduction depends on the number of walls
removed and whether or not fatty tissue is removed.
Serious complications are rare. Common surgical
approaches for orbital decompression are: coronal, via
the upper skin crease, the lateral canthus, or the inferior
fornix (both together = swinging eyelid), sub-ciliary,
directly through the lower lid, transcaruncular, transna-
sal, and transanthral. Further restriction of ocular motil-
ity is still a major complication; this mainly occurs with
medial wall decompression. The risk is much lower with
removal of the lateral wall alone. Clinically obvious
impairment of motility increases the risk of postopera-
tive diplopia signicantly.
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.
The transnasal endoscopic procedure addresses the
medial and inferior orbital walls. The 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 25 mm.
With the coronary approach, all orbital walls can be
accessed and proptosis reduction up to 10 mm can be
achieved. This is, however, an elaborate procedure.
To enhance the eect of lateral wall decompression,
the procedure can be combined with removal of its deep
portion or with additional fat removal (Fig. 16.3). The lat-
eral wall has, due to a very low risk of diplopia, increas-
ingly become the rst choice for orbital decompression
(traditional concept inferior-medial decompression
rst) in cases of rehabilitative surgery. The approach to
the lateral wall is variable via the upper skin crease,
 216 16 Modern Treatment Concepts in Graves Disease

a b

16 1
3
1
2

Fig. 16.3 Surgical approaches for orbital decompression in coronar and axial view. All orbital walls except the roof are addressed.
The lateral wall can be removed conservatively (A1), until is deep portion (A2) or completely (A3). Various surgical approaches are
possible to decompress the inferior (B2) and medial (B1) orbita. The inferior-lateral region of the orbit is the most common zone for
fat removal (B3)

swinging eyelid, sub-ciliary, or directly through the lower
lid. Average proptosis reduction ranges between 2 and
5 mm. (Literature is reviewed in [37].)
16.3.2.2 Extraocular Muscle Surgery
The basic concept for eye muscle surgery in GO is reces-
sion of the brotic muscle. The approach is dierent for
inferior and medial rectus muscles. Vertical deviation
increases with side dierences 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.
Dierent concepts for surgical strabism correction are
available: preoperatively determined recession distances
according to dose eect 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 78 mm,
persisting vertical squint: second step: recession of the
contralateral superior rectus muscle dose 1 mm/per 2
of intended squint angle reduction
Vertical squint head tilt when covering the eye with
more limited upgaze: asymmetric bilateral inferior
rectus recession (side dierence 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 67 mm
Horizontal squint 10: bilateral medial rectus reces-
sion, dose 1 mm recession per 1.6 of intended squint
angle reduction (dose side dierent, when side dier-
ence in monocular abduction), maximal recession
distance per eye 67 mm
Combined horizontal and vertical squint: small verti-
cal angles disappear after correction of horizontal
squint; a two-step procedure (large angle rst) is more
precise; if all in one procedure is preferred (only rec-
ommended for unilateral procedures): consider higher
dose eect for vertical squint 2.1 per mm recession
Lower lid retraction after inferior recession can be
prevented through dissection of the capsulopalpebral
ligament. Upper lid retraction of the eye with eleva-
tion decit (pseudoretraction) will disappear after
inferior recession
Convergent squint correction after decompression:
consider lower dose eects: 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 eect data are summarized in Table 16.5 [38,
4042].
In most cases, it is possible to improve the eld of bin-
ocular single vision. Over-corrections occur more often
when the muscle is not directly xed to the sclera but is

Table 16.5. Extraocular muscle surgery: dose eect coecients: squint angle reduction ()/per mm muscle recession (source: [3841])
Muscle Dose eect: angle []
reduction/ mm recession
Inferior rectus muscle 2.0
2.1
Medial rectus muscle unilateral 1.75
Medial rectus muscle bilateral 1.6
Combined
unilateral inferior rectus muscle 2.1
unilateral medial rectus muscle 1.9
After orbital decompression
Medial rectus muscle unilateral 1.2
Medial rectus muscle bilateral 1.0
Tendon elongation with interponate 0.9
adjusted on the following day. This probably occurs due
to adaptation of the muscles to changed tension during
the operation. Post-operative tone increase occurs in
structures that were previously relaxed, e.g., the antago-
nist and the passive orbital tissue. They return to their
original tension, which leads to a further globe rotation
against the direction of the recession. Therefore, the eect
of squint angle reduction increases signicantly within
the rst postoperative month.
Persistent diplopia in extreme gaze is common, which
is usually tolerable in upgaze, since the used gaze eld is
larger in downgaze than in upgaze.
Success rates (ocular alignment within about 23 in
primary position) are similar for the dierent approaches
and vary mainly between 60 and 80% for horizontal
squint and up to 90% for vertical squint.
16.3.2.3 Lid Surgery
The most common indication for lid surgery in GO is
upper lid retraction due to levator muscle brosis.
Genuine lid retraction has to be discriminated from
pseudo-lid retraction due to brosis of the inferior rectus
muscle. The latter resolves after inferior rectus recession.
Lower lid lengthening is indicated in lower lid retraction
following inferior rectus recession. Bilateral lower lid
retraction with proptosis should primarily be referred for
orbital decompression. Another indication for eyelid sur-
gery is increased preaponeurotic and subdermal fat,
resulting in bulging eye lids. This may be treated during
blepharoplasty when redundant lid skin is excised (review
of the literature: [35, 43]).
16.3 Treatment of GO 217
Authors
Esser et al., 1999
Krizok et al., 1993
Eckstein et al., 2004
Eckstein et al., 2004
Eckstein et al., 2004
Eckstein et al., 2008
Upper lid lengthening: Many dierent techniques for
lenghthening the upper eyelids have been described.
Among these are techniques with or without implants.
In most cases, use of implants is not necessary. These are
Mllerotomy or recession, medial or lateral levator
aponeurosis recession, lateral horn cut (important for
lateral are), medial and lateral full thickness levator-,
Mller-muscle-, and conjunctival recession. Since lateral
retraction (temporal 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 (grafts)
require patient cooperation. If compliance is poor or
marked brosis is present, spacers may be used. The 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 after upper lid lengthening without and with implant
are shown in Fig. 16.4. The implant is used in a patient
with severe GO (after three wall decompression for
DON) with marked brosis of levator palpebrae muscle.
Correction of upper lid retraction is successful when
12 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
7080%. Asymmetry can occur due to over- or under-
correction, lid crease recession, and a thickened eyelid
after use of a graft.
 218 16 Modern Treatment Concepts in Graves Disease

a e

16

b
f

Fig. 16.4 Upper lid lenghthening in GO. 4A4D In most of the cases upper lid retraction does not exceed 2 mm and levator muscle
desinsertion (4D scheme from [15]) will suce. Patient example with upper lid retraction right eye in primary position (4A), in
downgaze showing the lid lag on vertical downward pursuit (4B) and after lid lenghthening (4C). In rare cases with marked retrac-
tion (especially after decompression), the use of an implant is necessary (4E4G). Patient example before (4E) and after lid lengthen-
ing with an implant (5 mm Tutopatch) (4F) and intraoperative situation (4G)

Lower lid lengthening: To correct lid retraction
exceeding 1 mm, a spacer between lower lid retrac-
tors and tarsus is required (Fig. 16.5). Various organic
and anorganic materials have been used as spacers.
These include auricular cartilage, hard palate mucosa,
expanded polyethylene Medpor microplates, autoge-
nous tarsus transplants, porcine acellular dermal
matrix, and donor sclera or pericardium. The vertical
expansion of the spacer should amount to 3 times the
lid retraction in mm. Most spacers, except hard palate
mucosa, need to be covered with conjunctiva. The lower
lid retractors are accessible either by anterior subciliary
or posterior subtarsal transconjunctival approach. The
eect 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 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.
 16.3 Treatment of GO 219

a
Sutures for
stabilisation of the
interponate

d c

e Tarsus
f
Interponate

Lid retractors
Lig. capsulopalp.

Inferior rectus
muscle

Fig. 16.5 Lower lid lengthening in GO. Lower lid retraction can occur after large inferior rectus muscle recession if the ligamentum
capsulopalpebrale cannot be suciently detached from the inferior rectus muscle. Patient example: 5A before inferior rectus muscle
recession of 7.5 mm, vertical squint: VD15. 5B lower lid retraction after inferior recession. 5C intraoperative situation: size and
position of the implant. 5D patient situation 1 day postoperative. 5E cross section of the lower lid with implant (black), F nal result
after lower lid lengthening with an implant and lateral tarsorrhaphy of 5 mm

40,0
grey TBII values below: 2.3-15.6x better Summary for the Clinician
35,0 Zone: chance for a good course of GO
no
30,0
pre- TBII values above: 8.7-31.1x higher Disguring proptosis can be reduced through
25,0 diction risk of a severe course orbital decompression. Various surgical tech-
TBII [IU/l]

20,0 possible niques are available. The amount of reduction

15,0 depends on the number of walls removed and
8,8
10,0 5,1 4,8
whether or not fat is removed. Removal of the
2,9 2,8 medial wall is accompanied with the highest and
5,0
5,7 removal of the lateral wall with the lowest risk of
0,0 2,6 1,5 1,5 1,5 1,5
-5,0
postoperative diplopia. If muscle restriction is
1-4 5-8 9-12 13-16 17-20 20-24 present preoperatively, the risk of postopera-
Months after first symptoms of GO tively deteriorated ocular motility is increased.
The basic concept for eye muscle surgery in GO
Fig. 16.6 Cut o TBII levels for the prediction of a good course of
is recession of the brotic muscle. Dierent
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 approaches are possible: preoperatively deter-
statement for the course of their GO is possible. Example: A GO mined recession distances according to dose
patient presenting at 14 months after onset of the disease with TBII eect curves and intraoperative determination of
values below 5.7 IU/L has a 13.9-fold higher chance of a mild curse recession distance via active or passive motility
of GO than a patient with TBII values above this cut o. Otherwise,
and adjustable sutures. Success rates are high.
when TRAb are still above 8.8 IU/l 6 months after the beginning of
GO the odds ratio to develop a severe course of GO is 18
 220 16 Modern Treatment Concepts in Graves Disease
Upper lid retraction can be corrected in most
patients without the use of a spacer through
recession of levator palpebrae and Mller mus-
cle. Implants have to be inserted for successful
16 lower lid lengthening. The eect can be enhanced
with a lateral tarsal strip or tarsorrhaphy. The last
step in surgical rehabilitation is blepharoplasty
of upper and lower lids.
16.4 Thyroid Dysfunction and GO
16.4.1 Association Between Treatment
of Hyperthyroidism and Course of GO
The main goal during the early stage of thyroid disease is to
achieve euthyroidism. Not only does this alleviate most
thyroid symptoms, it is also benecial for the further course
of GO. Antithyroid drug therapy seems to prevent most
eciently further deterioration of GO in comparison with
thyroidectomy and radioiodine therapy [44]. Observational
trials showed that thyroidectomy in the intermediate phase
(612 months after rst symptoms of GO) may positively
inuence the clinical course of GO. In later, inactive stages,
this benecial eect 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 inammation of the thyroid during and after
radioiodine application may reinforce the autoimmune
reaction in the thyroid and activate or induce GO. It does
not, however, inuence inactive GO [48].
Patients with poor prognosis for remission should
receive denitive 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 after 6 months, above 7.5 IU/l after 12
months, and 3.9 IU/l after 15 months of antithyroid
drug therapy (TRAb levels must be measured with a
second generation assay for these statements to be
valid). Remission rates are low (about 8%) in cases of
moderate-to-severe GO [8, 49, 50].
Patients with a chance for remission of thyroid disease
(non-smoker, low TRAb levels, small thyroid, mild hyper-
thyroidism at manifestation) should be followed for at
least 6 months after cessation of antithyroid drug therapy
before surgical rehabilitation (if necessary) is initiated.
The overall relapse rate for hyperthyroidism is about 50%
[51] and relapse of hyperthyroidism can be accompanied
by worsening/reactivation of pre-existing GO.
Regular consultations with a thyroid specialist are
necessary.
16.4.2 Relationship Between
TSH-Receptor-Antibody (TRAb)
Levels and Orbitopathy
The relation between TRAb and GO was for a long time
subject to debate and became evident with modern, more
sensitive second-generation TRAb assays. The prevalence
of GO among patients with Graves hyperthyroidism
increases with higher serum TRAb levels [52]. There is a
signicant correlation of clinical activity [53] and severity
[54] with TRAb levels in untreated individuals. In late
stages, non-responders to anti-inammatory therapy reveal
higher TRAb levels [55]. Patients with moderate-to-severe
GO have signicantly higher TRAb levels over the whole
course of the disease (24 months follow-up) (Fig. 16.6). Cox
regression analysis 6 months after disease onset revealed a
hazard ratio of 1.27 to incur severe GO per every unit
increase of TRAb [56]. When TRAb are still above 8.8 IU/l
6 months after beginning of GO, the odds ratio to develop a
severe course of GO is 18. Patients with TRAb levels in the
risk zone (see Fig. 16.6) should have short control intervals,
treated with anti-inammatory therapy in cases of doubt
and treated longer with higher doses.
Summary for the Clinician
Restoration of euthyroidism is benecial 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 denitive therapy
as a perquisite for surgical rehabilitation of GO.
The overall relapse rate of hyperthyroidism after
cessation of antithyroid drug therapy is 50%.
Therefore, surgical rehabilitation of GO should
only be started after a 6 months period of stable
remission. Relapses of hyperthyroidism can be
accompanied by worsening or reactivation of GO.
TSH-receptor autoantibodies are independent
risk factors for GO and help to predict severity
and outcome of the disease. Certain cut o levels
can be used for treatment decisions.

16.5 Environmental and Genetic
Inuence on the Course of GO
16.5.1 Relationship Between Cigarette
Smoking and Graves Orbitopathy
There is a strong and consistent association between smok-
ing and GO. Smoking increases the prevalence of GO
among patients with Graves hyperthyroidism. Smokers
suer 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 brosis sevenfold [57]. Smoking
increases the likelihood of progression of GO after radio-
iodine therapy. There is also evidence that smoking either
delays response or impairs the outcome of treatment for
GO [58]. As to the thyroid, smoking is a similarly inde-
pendent risk factor for relapse of hyperthyroidism after
antithyroid drug treatment [51]. In vitro models (orbital
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].
The eect is markedly enhanced in the presence of the
proinammatory cytokine IL-1. The synergy between cig-
arette smoke and cytokine action may have potential for
therapeutic implications.
16.5.2 Genetic Susceptibility
There are a number of epidemiological and twin studies
which clearly indicate that autoimmune thyroid disease is
Severity of GO and Smoking
100
90 Prevalence of GO
80 Proptosis
% of the GO patients
70 Diplopia
60
50
40
30
20
10
0 contribute to the disease. The risk for rst-degree
Nonsmoker 1-10
Cigarettes Cigarettes
Fig. 16.7 Association of GO symptoms with the number of
smoked cigarettes
16.5 Environmental and Genetic Inuence on the Course of GO 221
genetically inuenced. The concordance rate for clinically
overt Graves disease is 35% for monozygotic twins (MZ)
and 3% for dizygotic twins (DZ). Model-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. The reporting of a parent with thyroid
dysfunction is associated with a lower median age at diag-
nosis for GD. There is an inverse relationship between the
number of relatives with thyroid dysfunction and age at
diagnosis [61]. Frequently, identical susceptibility genes
are designated for Graves and Hashimotos disease (sum-
marized in [6, 62]). Within monozygotic twins, it is possi-
ble for one twin to develop typical Graves disease while the
other suers from Hashimotos thyroiditis without orbit-
opathy [63]. Thus, there is clear evidence for genetic sus-
ceptibility to develop thyroid autoimmunity. The 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
identied. The genes identied to this day comprise thy-
roid specic genes (TSHR, Thyroglobulin) and immune
modulating genes (among them: HLA class II, CTLA-4,
PTPN22, CD40). Important for the disease phenotype
are functional consequences of these gene variants. Table
16.6 displays the most important susceptibility genes,
including possible functional consequences (modied
from Jacobson et al. [6]).
Summary for the Clinician
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 eectiveness of treatments
for GO, and with the progression of GO after
radioiodine treatment. Therefore, the patient
should be advised to stop smoking.
Immune regulatory and thyroid-specic genes
10-20 > als 20
Cigarettes relatives is 3%. About 50% of patients report a
positive family history, more common in the
maternal than in the paternal trait.
 222 16 Modern Treatment Concepts in Graves Disease

Table 16.6. Susceptibility genes and possible functional consequences in Graves disease (slightly modied from Jacobson et al. [6])

Gene Associated variants Potential mechanisms

Immune response
16 modulating genes
HLA DR DR3 Alteration in autoantigen presentation
CTLA-4 Several SNPs (A/G49, Reduction of suppression of T-cell activation
CT60, 3UTR AT) (CTLA-4 = negative regulator of T-cells)
CD 40 Kozak sequence SNP Alteration of translational eciency of CD40
in CD40 expressing tissues (APC,
thyrocytes, orbital broblasts)
PTPN22 R620W Inhibition of T-cell activation
IL23R Several SNP (rs11209026, rs7530511, Reduction of activation of T cells, natural
rs2201841, rs10889677) killer (NK) cells, monocytes, and
dendritic cells protecting factor,
expansion of Th17 subset
Thyroid specic genes
Thyroglobulin Several SNP Alteration in thyroglobulin peptide
presentation by HLA DR to T-cells
TSHR 28 SNPs revealed association Alteration in TSHR peptide presentation by
HLA DR to T-cells, alterations in Auto AB
binding

glucocorticoids should be avoided unless the patient

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-specic antibodies are lower
and less prevalent. However, they occur in at least 75% of
the patients; therefore, the application of sensitive assay
technology is of utmost concern [64].
16.6.2 Childhood GO
GO is rare in childhood because of the low incidence of
Graves disease in this age group. The eye disease is usu-
ally milder in children than in adults and often stabi-
lizes and eventually resolves without intervention. Soft
tissue inammation 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 eect on growth,
suers 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 dierent than in other patients. Close monitoring
of blood sugar levels and blood pressure is important.
Thiazide or loop diuretics should be used cautiously dur-
ing high-dose steroid therapy to avoid hypokalemia. The
same principle applies to surgical treatment. Orbital
radiotherapy may increase the risk of retinopathy in
diabetic and hypertensive patients. Diabetes or hyper-
tension are no contraindication to surgical orbital
decompression or other surgical treatments. Optic neu-
ropathy occurs signicantly more often in diabetic
patients (reviewed in [21]).

Summary for the Clinician
Patient with euthyroid GO develop less active/
severe and more asymmetric GO symptoms.
If present at all GO is mild in childhood and
rarely needs treatment.
Orbital irradiation is possibly contraindicated in
patients with diabetic retinopathy and DON
occurs more often.
References
1. Wiersinga WM, Bartalena L (2002) Epidemiology
and prevention of Graves ophthalmopathy. Thyroid 12:
855860
2. Gianoukakis AG, Smith TJ (2008) Recent insights into the
pathogenesis and management of thyroid-associated oph-
thalmopathy. Curr Opin Endocrinol Diabetes Obes
15:446452
3. Feldon SE, Park DJ, OLoughlin CW, et al (2005) Autologous
T-lymphocytes stimulate proliferation of orbital broblasts
derived from patients with Graves ophthalmopathy. Invest
Ophthalmol Vis Sci 46:39133921
4. Smith TJ (2004) Novel aspects of orbital broblast pathol-
ogy. J Endocrinol Invest 27:246253
5. McLachlan SM, Nagayama Y, Rapoport B (2005) Insight
into Graves hyperthyroidism from animal models. Endocr
Rev 26:800832
6. Jacobson EM, Tomer Y (2007) The genetic basis of thyroid
autoimmunity. Thyroid 17:949961
7. Villadolid MC, Yokoyama N, Izumi M, et al (1995)
Untreated Graves disease patients without clinical ophthal-
mopathy demonstrate a high frequency of extraocular
muscle (EOM) enlargement by magnetic resonance. J Clin
Endocrinol Metab 80:28302833
8. Eckstein AK, Lax H, Losch C, et al (2007) Patients with
severe Graves ophthalmopathy have a higher risk of relaps-
ing hyperthyroidism and are unlikely to remain in remis-
sion. Clin Endocrinol (Oxf) 67:607612
9. Bartley GB, Fatourechi V, Kadrmas EF, et al (1996)
Chronology of Graves ophthalmopathy in an incidence
cohort. Am J Ophthalmol 121:426434
10. Eckstein AK, Loesch C, Okundia H, et al (2009) Patients
with euthyroid and primarily hypothyroid status have low
TRAb levels and develop a tendentious milder and signi-
cantly more asymmetric Graves Ophthalmopathy. Br J
Ophthalmol in print
11. Khoo DH, Eng PH, Ho SC, et al (2000) Graves ophthal-
mopathy in the absence of elevated free thyroxine and
triiodothyronine levels: prevalence, natural history, a
References 223
nd thyrotropin receptor antibody levels. Thyroid 10:
10931100
12. Bartley GB, Fatourechi V, Kadrmas EF, et al (1996) Clinical
features of Graves ophthalmopathy in an incidence cohort.
Am J Ophthalmol 121:284290
13. Wiersinga W, Kahaly G (2007) Gravess ophthalmopathy. A
multidisciplinary approach. Karger
14. Wiersinga WM, Perros P, Kahaly GJ, et al (2006) Clinical
assessment of patients with Graves orbitopathy: the
European Group on Graves Orbitopathy recommenda-
tions to generalists, specialists and clinical researchers. Eur
J Endocrinol 155:387389
15. Hintschich C, Haritoglou C (2005) Full thickness eyelid
transsection (blepharotomy) for upper eyelid lengthening
in lid retraction associated with Graves disease. Br J
Ophthalmol 89:413416
16. Mourits MP, Prummel MF, Wiersinga WM, et al (1997)
Clinical activity score as a guide in the management of
patients with Graves ophthalmopathy. Clin Endocrinol
(Oxf) 47:914
17. Terwee CB, Prummel MF, Gerding MN, et al (2005)
Measuring disease activity to predict therapeutic outcome
in Graves ophthalmopathy. Clin Endocrinol (Oxf)
62:145155
18. Mourits MP, Prummel MF, Wiersinga WM, et al (1994)
Measuring eye movements in Graves ophthalmopathy.
Ophthalmology 101:13411346
19. Eckstein AK, Plicht M, Lax H, et al (2006) Thyrotropin
receptor autoantibodies are independent risk factors for
Graves ophthalmopathy and help to predict severity and
outcome of the disease. J Clin Endocrinol Metab
91:34643470
20. Kahaly GJ (2004) Recent developments in Graves ophthal-
mopathy imaging. J Endocrinol Invest 27:254258
21. Bartalena L, Baldeschi L, Dickinson A, et al (2008)
Consensus statement of the European Group on Graves
orbitopathy (EUGOGO) on management of GO. Eur J
Endocrinol 158:273285
22. Perros P, Crombie AL, Kendall-Taylor P (1995) Natural
history of thyroid associated ophthalmopathy. Clin
Endocrinol (Oxf) 42:4550
23. Kahaly G (2007) Management of moderately severe Graves
orbitopathy. In: Wiersinga WM, Kahaly GJ (eds) Graves
orbitopathy: a multidiscplinary approach. Karger, Basel, pp
120152
24. Kahaly GJ, Pitz S, Hommel G, et al (2005) Randomized,
single blind trial of intravenous versus oral steroid mono-
therapy in Graves orbitopathy. J Clin Endocrinol Metab
90:52345240
25. Mourits MP, van Kempen-Harteveld ML, Garcia MB, et al
(2000) Radiotherapy for Graves orbitopathy: randomised
placebo-controlled study. Lancet 355:15051509
 224 16 Modern Treatment Concepts in Graves Disease
26. Prummel MF, Terwee CB, Gerding MN, et al (2004) A ran-
domized controlled trial of orbital radiotherapy versus
sham irradiation in patients with mild Graves ophthalmo-
pathy. J Clin Endocrinol Metab 89:1520
16 27. Bradley EA, Gower EW, Bradley DJ, et al (2008) Orbital
radiation for graves ophthalmopathy: a report by the
American academy of ophthalmology. Ophthalmology
115:398409
28. Marcocci C, Bartalena L, Panicucci M, et al (1987) Orbital
cobalt irradiation combined with retrobulbar or systemic
corticosteroids for Graves ophthalmopathy: a comparative
study. Clin Endocrinol (Oxf) 27:3342
29. Marcocci C, Bartalena L, Tanda ML, et al (2001) Comparison
of the eectiveness and tolerability of intravenous or oral
glucocorticoids associated with orbital radiotherapy in the
management of severe Graves ophthalmopathy: results of a
prospective, single-blind, randomized study. J Clin
Endocrinol Metab 86:35623567
30. El Fassi D, Banga JP, Gilbert JA, et al (2009) Treatment of
Graves disease with rituximab specically reduces the pro-
duction of thyroid stimulating autoantibodies. Clin
Immunol 130:252258
31. Heemstra KA, Toes RE, Sepers J, et al (2008) Rituximab in
relapsing Graves disease, a phase II study. Eur J Endocrinol
159:609615
32. Salvi M, Vannucchi G, Campi I, et al (2007) Treatment of
Graves disease and associated ophthalmopathy with the
anti-CD20 monoclonal antibody rituximab: an open study.
Eur J Endocrinol 156:3340
33. Paridaens D, van den Bosch WA, van der Loos TL, et al
(2005) The eect of etanercept on Graves ophthalmopa-
thy: a pilot study. Eye 19:12861289
34. Traisk F, Tallstedt L (2001) Thyroid associated ophthalmo-
pathy: botulinum toxin A in the treatment of upper eyelid
retractiona pilot study. Acta Ophthalmol Scand
79:585588
35. Baldeschi L (2008) Correction of lid retraction and
exophthalmos. Dev Ophthalmol 41:103126
36. Garrity JA, Bahn RS (2006) Pathogenesis of graves oph-
thalmopathy: implications for prediction, prevention, and
treatment. Am J Ophthalmol 142:147153
37. Mourits MP, Bijl HM, Baldeschi L, et al (2008) Outcome of
orbital decompression for disguring proptosis in patients
with Graves orbitopathy using various surgical procedures.
Br J Ophthalmol
38. Esser J, Eckstein A (1999) Ocular muscle and eyelid sur-
gery in thyroid-associated orbitopathy. Exp Clin Endocrinol
Diabetes 107(Suppl 5):S214S221
39. Eckstein A, Holdt M, Johnson KTM, et al (2008) Tendon
elongation: a new surgical technique for large convergent
squint after three wall orbital decompression in thyroid
associated ophthalmopathy. ESA proceedings
40. Eckstein A, Schulz S, Esser J (2004) Is combined surgical
correction of horizontal and vertical squint of value in
graves ophthalmopathy? Klin Monatsbl Augenheilkd
221:769775
41. Krzizok T, Enger K, Kaufmann H (1993) Dosierbarkeit
von Augenmuskeloperationen bei endokriner Orbitopathie.
Z prakt Augenheilk 14:273279
42. Schittkowski M, Fichter N, Gutho R (2004) Strabismus
surgery in Graves diseasedose-eect relationships and
functional results. Klin Monatsbl Augenheilkd 221:
941947
43. Neoh C, Eckstein A (2007) Eyelid surgery. In: Wiersinga
WM, Kahaly GJ (eds) Graves orbitopathy: a multidisc-
plinary approach. Karger, Basel, pp 188198
44. Tallstedt L, Lundell G, Torring O, et al (1992) Occurrence
of ophthalmopathy after treatment for Graves hyperthy-
roidism. The thyroid study group. N Engl J Med 326:
17331738
45. Marcocci C, Bruno-Bossio G, Manetti L, et al (1999) The
course of Graves ophthalmopathy is not inuenced by
near total thyroidectomy: a case-control study. Clin
Endocrinol (Oxf) 51:503508
46. Dralle H, Sekulla C (2004) Morbidity after subtotal and
total thyroidectomy in patients with Graves disease: the
basis for decision-making regarding surgical indication
and extent of resection. Z Arztl Fortbild Qualitatssich
98(Suppl 5):4553
47. Bartalena L, Marcocci C, Bogazzi F, et al (1998) Relation
between therapy for hyperthyroidism and the course of
Graves ophthalmopathy. N Engl J Med 338:7378
48. Perros P, Kendall-Taylor P, Neoh C, et al (2005) A pro-
spective study of the effects of radioiodine therapy for
hyperthyroidism in patients with minimally active
graves ophthalmopathy. J Clin Endocrinol Metab 90:
53215323
49. Carella C, Mazziotti G, Sorvillo F, et al (2006) Serum thy-
rotropin receptor antibodies concentrations in patients
with Graves disease before, at the end of methimazole
treatment, and after drug withdrawal: evidence that the
activity of thyrotropin receptor antibody and/or thyroid
response modify during the observation period. Thyroid
16:295302
50. Schott M, Morgenthaler NG, Fritzen R, et al (2004) Levels
of autoantibodies against human TSH receptor predict
relapse of hyperthyroidism in Graves disease. Horm Metab
Res 36:9296
51. Orgiazzi J, Madec AM (2002) Reduction of the risk of
relapse after withdrawal of medical therapy for Graves dis-
ease. Thyroid 12:849853
52. Khoo DH, Ho SC, Seah LL, et al (1999) The combination of
absent thyroid peroxidase antibodies and high thyroid-
stimulating immunoglobulin levels in Graves disease iden-

ties a group at markedly increased risk of ophthalmopathy.
Thyroid 9:11751180
53. Gerding MN, van der Meer JW, Broenink M, et al (2000)
Association of thyrotrophin receptor antibodies with
the clinical features of Graves ophthalmopathy. Clin
Endocrinol (Oxf) 52:267271
54. Noh JY, Hamada N, Inoue Y, et al (2000) Thyroid-
stimulating antibody is related to Graves ophthalmopathy,
but thyrotropin-binding inhibitor immunoglobulin is
related to hyperthyroidism in patients with Graves disease.
Thyroid 10:809813
55. Eckstein AK, Plicht M, Lax H, et al (2004) Clinical results
of anti-inammatory therapy in Graves ophthalmopa-
thy and association with thyroidal autoantibodies. Clin
Endocrinol (Oxf) 61:612618
56. Eckstein AK, Plicht M, Lax H, et al (2006) TSH-receptor
autoantibodies are independent risk factors for Graves
ophthalmopathy and help to predict severity and outcome
of the disease. J Clin Endocrinol Metab 91(9):34643470
57. Pfeilschifter J, Ziegler R (1996) Smoking and endocrine
ophthalmopathy: impact of smoking severity and current
vs lifetime cigarette consumption. Clin Endocrinol (Oxf)
45:477481
58. Eckstein A, Quadbeck B, Mueller G, et al (2003) Impact of
smoking on the response to treatment of thyroid associ-
ated ophthalmopathy. Br J Ophthalmol 87:773776
References 225
59. Cawood TJ, Moriarty P, OFarrelly C, et al (2007) Smoking
and thyroid-associated ophthalmopathy: a novel explana-
tion of the biological link. J Clin Endocrinol Metab
92:5964
60. Brix TH, Kyvik KO, Christensen K, et al (2001) Evidence
for a major role of heredity in Graves disease: a population-
based study of two Danish twin cohorts. J Clin Endocrinol
Metab 86:930934
61. Manji N, Carr-Smith JD, Boelaert K, et al (2006) Inuences
of age, gender, smoking, and family history on autoim-
mune thyroid disease phenotype. J Clin Endocrinol Metab
91:48734880
62. Ban Y, Tomer Y (2005) Genetic susceptibility in thyroid
autoimmunity. Pediatr Endocrinol Rev 3:2032
63. Aust G, Krohn K, Morgenthaler NG, et al (2006) Graves
disease and Hashimotos thyroiditis in monozygotic twins:
case study as well as transcriptomic and immunohistologi-
cal analysis of thyroid tissues. Eur J Endocrinol 154:1320
64. Eckstein A, Loesch C, Glowacka D, et al (2009) Euthyroid
and primarily hypothyroid patients develop milder and
signicantly more asymmetric Graves ophthalmopathy. Br
J Ophthalmol 93:10521056
65. Krassas GE, Gogakos A (2006) Thyroid-associated oph-
thalmopathy in juvenile Graves diseaseclinical, endocrine
and therapeutic aspects. J Pediatr Endocrinol Metab
19:11931206
 Index
A refractive adaptation, 103104
Abducens palsy, 71
Abnormal central nervous system (CNS) esotropia, 2
Abnormal central nervous system (CNS) exotropia, 3
Acquired motor neuropathy, 7172
Acquired nonaccommodative esotropia, 2
Acquired pulley heterotopy, 6364
Amblyopia treatment 2009
age eect, 131
amblyopia management
patch occlusion, 128129
pharmacological therapy, plano lens, 130
pharmacological treatment, atropine, 129130
refractive correction, 127128
Bangerter lters, 132133
bilateral refractive amblyopia, 131
clinical features, 126
deep unilateral amblyopia, 175176
diagnosis, 126127
epidemiology, 125126
levodopa/carbidopa adjunctive therapy, 133
long-term persistence, 132
maintenance therapy, 131
natural history data, 127
optic neuropathy, 133134
spectacle correction, 125
Amblyopia, screening
Child Health Promotion Program (CHPP), 96
classication, 95
conventional occlusion, 104
cover-uncover test, 100101
denition, 9596
Duanes/Browns syndrome, 97
justication, 98
lay screeners, 102
older children, 104105
optical penalization, 104
orthoptists, 102
pharmacological occlusion, 104
photorefractive keratectomy (PRK), 105
photoscreening/autorefraction, 101102
pre-school vision screening, 9899
quality of life
emotional well-being, 107
impact of treatment, 108
impact on education, 106107
reading speed and ability, 106
strabismus impact, 107108
recurrence, 105
refractive error, 97
sensitivity, 100
stereoacuity test, 101
strabismus, 97
treatment compliance, 105
type of treatment, 103
vision in preschoolers study
(VIP), 100, 101
vision tests, 100
vs. diagnostic test, 97
Anisometropia, 33
Anisometropic amblyopia, 2, 3
Anomalous head posture (AHP)
AndersonKesternbaum surgery, 158
binocular visual acuity testing, 161162
horizontal management, 165166
idiopathic infantile nystagmus, 158
measurement, 160161
monocular eect, 161162
straightening eect, head, 162
testing, near vision, 162
vertical management, 166167
Anomalous retinal correspondence (ARC), 34
Atropine, 129130
B
Bagolini test, 141
Bangerter foils, 132
Bells phenomenon, 88
Bielschowsky head tilt test (BHTT), 181
Bilateral feedback control
applications, 2122
muscle lengths, 1921
Bilateral posterior tenectomy, 190
Bilateral refractive amblyopia, 131
Binocular alignment system
control system
A-/V-pattern strabismus, 14
basic muscle length, 1516
bilateral phenomena, 1415
breakdown, 14
final common pathway, 1718
perturbation, 13
sensory torsion, 14
version and vergence stimulation, 1617
deviation and xation pattern, 11
long-term maintenance, 11
muscle length adaptation, 1213
228 Index

vergence adaptation, 12 congenital trochlear palsy, 82

Binocular vision Duane retraction syndrome, 7981
angle of strabismus, 140141 HGPPS, 81
at age six, 140 isolated uni-/bilateral facial palsy, 83
bilateral recession vs. unilateral recession-resection, 141 vertical retraction syndrome, 88
Bloodbrain barrier, 133 Congenital esotropia, 2
Botulinum toxin A (BTXA), 197, 203, 204 Congenital exotropia, 3
Brown syndrome, 4, 203 Congenital brosis of the extraocular muscles (CFEOM),
Brckner test 7879
amblyopia and amblyogenic disorders, 113114 A-pattern exotropia, 69
corneal light reex, 114115 motor axonal misrouting, 67
eye movements, alternating illumination, 122 MRI, 6768
fundus red reex phenotypes, 67
ametropia, 116, 118 Congenital nystagmus
anisometropia, 118 clinical characteristics, 156157
esotropia, 117118 compensatory mechanisms
foveal dimming, 117 AHP, 160162
hypermetropia, 118 versions and vergence, 160
Mittendorfs spot, 115 manifest latent nystagmus (MLN)
optic coherence tomography, 117 clinical characteristics, 157158
paediatric residents, 119 slow phase, 157
possibilities and limitations, 120 periodic alternating nystagmus (PAN), 158159
pupillary constriction, 116 sensory decits
test performance, 119120 afferent visual defect, 155
transillumination test, 115 causes, 156
uncorrected ametropia, 118 horizontal eye movement, 154
uni-lateral astigmatismus, 119 idiopathy, 155
uni-lateral spherical ametropia, 118, 119 phenotypical characteristics, 155
pupillary light reex treatment
eccentric vs. central illumination, 121 acupuncture, 164
iris pathology, 120 articial divergence surgery, 167168
monocular illumination, 121 botulinum toxin-A (Botox), 164
possibilities and limitations, 121122 head tilt, 167
strabismus diagnostics, 120 horizontal AHP, 165167
test performance, 121 medications, 162163
prisms, 163
C refractive correction, 162
Cataract, 2, 3 retro-equatorial recession, 168169
Child Health Promotion Program (CHPP), 96 spectacles and contact lenses (CL), 162163
Chronic progressive external ophthalmoplegia (CPEO), surgical principles, 164165
5960 tenotomy procedure, 169
CNS-associated hypertropia, 4 vertical AHP, 166167
Complete third nerve palsy hypertropia, 198199 Congenital oculomotor (CN3) palsy, 67
Congenital cranial dysinnervation disorders (CCDDs), 66 Congenital pulley heterotopy, 6263
brainstem and cranial nerve development, 77, 78 Congenital superior oblique paresis, 20, 21
Brown syndrome Congenital trochlear (CN4) palsy, 69
comorbidity, 85 Convergence insuciency, 3
epidemiologic features, 85 Cycloplegic drug, 127
incidence and heredity, 86 Cyclovertical misalignment, 19
intra-and postoperative findings, 87
laterality, 8586 D
motility findings, 8385 Diagnostic occlusion, 19
natural course, 87 Dissociated eye movements
neurodevelopmental disorder, 8990 pathogenetic role, 29
potential induction, 8687 vergence eye movements, 25
radiologic findings, 87 dissociated horizontal deviation (DHD), 2529, 179180
saccadic eye movements, 85 dissociated torsional deviation (DTD)
sex distribution, 86 inverse and direct head tilt, 181
CFEOM, 7879 strabismus, 180
congenital fourth nerve palsy, 82 dissociated vertical deviation (DVD)
congenital monocular elevation deciency, 8789 asymmetric vs. symmetric surgeries, 178
congenital ptosis, 81 bilateral, 175176
 Index 229

hypotropia, nonfixating eye, 178179 G

IOOA and V pattern, 176177 German Institute for Quality and Eciency in Healthcare
SOOA and A pattern, 177178 (IQWIG), 99
symmetric, 175 Glucocorticoids (GC), 213
Divergence paralysis esotropia, 6465 Graves orbitopathy
Double elevator palsy, 83, 87, 88 active inammatory phase
Duanes retraction syndrome (DRS), 69, 7981 combined therapy, 213
Duanes syndrome, 19 dysthyroid optic neuropathy (DON), 214
Dysthyroid optic neuropathy (DON), 214 glucocorticoids (GC), 213
immunosuppressive treatments, 213214
E orbital radiotherapy (OR), 213
EOM surgery, 216217 sight-threatening corneal breakdown, 214
Esotropia (ET) symptoms, 214215
DHD, 179180 childhood, 222
monoxation syndrome, 3536 classication, 211212
visual cortex mechanisms clinical assessment
binocular input correlation, 5051 activity signs, 208209
binocular visuomotor behavior assess severity, 209211
development, 42, 43 orbital imaging, 211
cerebral damage risk factors, 4142 clinical characteristics, 208
cortical binocular connections, 4446 diabetes, 222
cytotoxic insult, cerebral fibers, 42 environmental and genetic inuence
early-onset (infantile) esotropia, 41 cigarette smoking, 221
extrastriate cortex, striate cortex, 46 susceptibility genes, 221222
fusional vergence and innate euthyroid, 222
convergence bias, 44 Graves disease (GD), 207208
genetic influence, cerebral connection, 42 inactive disease stages
high-grade fusion repair, 50 extraocular muscle surgery, 216217
inter-ocular suppression, 4647 lid surgery, 217220
monocular compartments, striate cortex, 44, 46 orbital decompression, 215216
motion sensitivity and conjugate eye tracking, 44 management plan, 208, 210
naso-temporal inequalities, cortical suppression, 47 thyroid dysfunction, 220
persistent nasalward visuomotor bias, 4750
sensorial fusion and stereopsis development, 43 H
strabismic human infant repair, 50 Health-related quality of life (HRQoL), 98, 99, 106108
Essential infantile esotropia. See Congenital esotropia Horizontal gaze palsy with progressive scoliosis
Exotropia (XT) (HGPPS), 81
DHD, 179180 Hypertropia, 34, 179
infantile esotropia
active divergence mechanism, 26 I
binocular fusion vs. dissociated esotonus, 27, 28 Immune myopathy, 6061
clinical signs, 27 Incomplete third nerve palsy hypertropia, 199
horizontal strabismus, 28 Infantile esotropia (IE)
Expected value of perfect information (EVPI), 99 denition and prevalence, 137
Extraocular muscle (EOM), 196, 197 dissociated eye movements
Eye lid surgery pathogenetic role, 29
lower lid lengthening, 218, 219 vergence eye movements, 25
upper and lower lid blepharoplasty, 218 early vs. late infantile strabismus
upper lid lengthening, 217 surgery study (ELISSS)
alignment and fusion, 145
F binocular vision, 140
First Purkinje images, 114115 horizontal angle of strabismus, 140141
Fourth nerve palsy hypertropia methods and results, 139140
bilateral involvement, 201 postoperative angle of strabismus, 145
congenital superior oblique palsy, 200 prospective study, 139
inferior oblique weakening procedure, 203 random-effects model, 146, 148
superior and inferior rectus recession, 209 reoperation rate, 142143
superior oblique strengthening procedure, 209 spontaneous reduction, 146148
superior oblique tendon laxity, 201 spontaneous resolution, 146
superior rectus contracture, 201 test-retest reliability, 144145
surgical plan, 200 esotonus vs. convergence, 28
torsional diplopia, 202203 exotropia
230 Index

active divergence mechanism, 26 N

binocular fusion vs. dissociated esotonus, 27, 28 Neoplastic myositis, 61
clinical signs, 27 Neuroanatomical strabismus
horizontal strabismus, 28 acquired motor neuropathy, 7172
outcome parameters, 138139 acquired pulley heterotopy, 6364
pathogenesis, 138 congenital peripheral neuropathy
sensory/motor etiology, 137138 congenital cranial dysinnervation disorders
tonus, 2526 (CCDDs), 66
Infantile-onset image decorrelation, 3839 congenital fibrosis of the extraocular muscles
Inferior oblique (IO) palsy, 7172 (CFEOM), 6769
Inferior oblique overaction (IOOA), 4, 176177 congenital oculomotor (CN3) palsy, 67
Inammatory myositis, 61 congenital trochlear (CN4) palsy, 69
Intermittent exotropia, 3, 4 Duanes retraction syndrome (DRS), 69
Moebius syndrome, 70
L congenital pulley heterotopy, 6263
Levodopa, 133 divergence paralysis esotropia, 6465
Logistic regression analysis, 143 etiology, 59
Long-term binocular alignment control system, 14 extraocular myopathy
immune myopathy, 6061
M inflammatory myositis, 61
Manifest latent nystagmus (MLN) neoplastic myositis, 61
AndersonKesternbaum surgery, 158 primary EOM myopathy, 5960
clinical characteristics, 157158 traumatic myopathy, 6162
idiopathic infantile nystagmus, 158 vergence and gaze abnormalities, 72
slow phase, 157 Normal correspondence (NRC), 34
Marcus-Gunn phenomenon, 8082, 85, 8789
Marlow occlusion, 19 O
Meta-regression model, 143 Ocular albinism (OA), 155
Microstrabismus Ocular motility disorders, CCDD
number of operations brainstem and cranial nerve development, 77, 78
postoperative angle of strabismus, 145 Brown syndrome
reoperation rate, 142143 comorbidity, 85
test-retest reliability, 144145 epidemiologic features, 85
random-eects model, 146, 148 incidence and heredity, 86
spontaneous reduction, 146148 intra-and postoperative findings, 87
spontaneous resolution, 146 laterality, 8586
Mittendorf s spot, 115 motility findings, 8385
Mbius syndrome, 83 natural course, 87
Moebius syndrome, 70 neurodevelopmental disorder, 8990
Monoxation syndrome (MFS) potential induction, 8687
animal models, 37 radiologic findings, 87
anisometropia, 33 saccadic eye movements, 85
bi-xation, 3637 sex distribution, 86
causes, 33 CFEOM, 7879
foveal suppression scotoma elimination, 36 congenital fourth nerve palsy, 82
manifest strabismus, 3536 congenital monocular elevation deciency, 8789
micro-esotropia congenital ptosis, 81
extrastriate cortex, 5253 congenital trochlear palsy, 82
neural mechanism, 51 Duane retraction syndrome, 7981
neuroanatomic findings, 52, 53 HGPPS, 81
stereoscopic threshold, 52 isolated uni-/bilateral facial palsy, 83
subnormal stereopsis and motor fusion, 51 vertical retraction syndrome, 88
normal and anomalous binocular vision Ocular motor control system, 18
anomalous retinal correspondence (ARC), 34 Oculocutaneous albinism (OCA), 155
binocular correspondence, 3435 Oculomotor palsy, 71
communication, 33 Optic neuropathy, 133134
cortical adaptation, 34 Optical coherence tomography (OCT), 155, 156
ocular dominance column, 33, 34 Orbital radiotherapy (OR), 213
normal/near-normal fusional vergence, 37
primary MFS, 3839 P
Motor skills, 106 Paralytic strabismus
Muscle length adaptation, 1113 complete third nerve palsy, 198199

fourth nerve palsy hypertropia
bilateral involvement, 201
congenital superior oblique palsy, 200
inferior oblique weakening procedure, 203
superior and inferior rectus recession, 209
superior oblique strengthening procedure, 209
superior oblique tendon laxity, 201
superior rectus contracture, 201
surgical plan, 200
torsional diplopia, 202203
incomplete third nerve palsy, 199
principles
preoperative assessment, 196197
surgery timing, 195196
surgical treatment, 197198
sixth nerve palsy hypertropia
lateral and medial rectus resection, 204
medial rectus weakening, sound eye, 204205
Pediatric strabismus
adult strabismus, 7
associated conditions, 4
esodeviation, 12
exodeviation, 3
hyperdeviation, 34
surgery rates, 4
worldwide incidence and prevalence, 47
Periodic alternating nystagmus (PAN), 158159
Pharmacological occlusion, 104
Photorefractive keratectomy (PRK), 105
Plano lens, 130
Posners maneuver, 174
Posterior partial tenectomy, 190
Primary extraocular muscle (EOM) myopathy, 5960
Primary oblique muscle overaction, 14
Prism adaptation, 12
Q cortical binocular connections, 4446
Quality adjusted life years (QALY), 99
R extrastriate cortex, striate cortex, 46
Reversed xation test (RFT), 179
S high-grade fusion repair, 50
Sensory esotropia, 2, 3
Sensory exotropia, 3
Sixth nerve palsy hypertropia
lateral and medial rectus resection, 204
medial rectus weakening, sound eye, 204205
Stereoacuity skills, 106
Superior oblique overaction (SOOA), 176177
Superior oblique (SO) surgery
clinical investigation
60 Polyglactin 910 sutures, 186
asymmetric effects, 189
enucleation, 186
Jampolskys recommendations, 187
Index 231
measurement technique, 188
superior rectus muscle recession effects, 186188
suspension technique, 188189
tendon incarceration syndrome, 185
frenulum, 185
theoretical eect
anteriorposterior axis, 189
posterior tenectomy, 190
SO anatomy, 190, 191
SO tendon, 189, 192
threefold function, 189
two-dimensional trigonometry, 192
T
Thyroid-stimulating hormone receptor (TSHR), 208
Traumatic myopathy, 6162
Trochlear palsy, 71
TSHR antibodies (TRAb), 208
Two-dimensional trigonometry, 192
U
Unilateral strabismus changes
cyclovertical deviation, 20, 21
head-tilt changes, 21
ipsilateral medial and contralateral rectus muscle, 19
torsional position, 20
vertical recordings, 21
V
Vergence adaptation, 11, 12
Vertical retraction syndrome, 88
Visual cortex mechanisms
esotropia
binocular input correlation, 5051
binocular visuomotor behavior development, 42, 43
cerebral damage risk factors, 4142
cytotoxic insult, cerebral bers, 42
early-onset (infantile) esotropia, 41
fusional vergence and innate convergence bias, 44
genetic inuence, cerebral connection, 42
inter-ocular suppression, 4647
monocular compartments, striate cortex, 44, 46
motion sensitivity and conjugate eye tracking, 44
naso-temporal inequalities, cortical suppression, 47
persistent nasalward visuomotor bias, 4750
sensorial fusion and stereopsis development, 43
strabismic human infant repair, 50
micro-esotropia
extrastriate cortex, 5253
neural mechanism, 51
neuroanatomic ndings, 52, 53
stereoscopic threshold, 52
subnormal stereopsis and motor fusion, 51