The Sclera, 2nd Edition

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Maite Sainz de la Maza • Joseph Tauber
C. Stephen Foster

The Sclera
Second Edition
Maite Sainz de la Maza, MD, PhD Joseph Tauber, MD
Clinical Associate Professor Tauber Eye Center
of Ophthalmology 4400 Broadway, Suite 202
Clinical Institute of Ophthalmology Kansas City, MO 64111, USA
Hospital Clinic of Barcelona [email protected]
Urgel 224, Barcelona 08036, Spain
[email protected]

C. Stephen Foster, MD
Professor of Ophthalmology
Harvard Medical School
Massachusetts Eye Research
and Surgery Institution
Cambridge, MA 02142, USA
[email protected]

ISBN 978-1-4419-6501-1 e-ISBN 978-1-4419-6502-8

DOI 10.1007/978-1-4419-6502-8
Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2012930382

© Springer Science+Business Media, LLC 2012

All rights reserved. This work may not be translated or copied in whole or in part without the
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To our children:
Alejandro and Eduardo Zaballos Sainz de la Maza
Allyson, Jessica, and David Tauber
Marc Foster

And our grandchildren:

Abigail, Carson, and Charles Foster
Preface

Dr. Sainz de la Maza published the first edition of this text on the sclera over
18 years ago, as a consequence of Dr. Sainz de la Maza being unable to find
a copy of a monograph on the subject by Dr. Hazleman and Mr. Watson upon
her return to Spain after her fellowship in Boston with me in Ocular
Immunology and Uveitis. She had fallen in love with my copy of that book,
and was stunned and depressed when she discovered that it was out of print
and that none of the libraries in Barcelona possessed a copy of the book.
Cunning catalan that she is, she connived to obtain a Fulbright scholarship to
return to Boston for another year of fellowship with me, with the prime objec-
tive of exploiting my collection of patients with scleritis (and me) for the
production of a book on the sclera. The text turned out to be a huge success,
selling out, and hence the invitation from Springer Verlag was forthcoming
for us to produce a second edition of this work. It has been a pleasure to work
once more with Dr. Sainz de la Maza on this project, producing this updated
work on a subject which is widely neglected and for which, therefore, there is
need for such a work.
The sclera composes 80% of the geographic extent of the exterior confines
or wall of the eyeball, yet it receives relatively little attention in the ophthal-
mic literature. This is understandable, given the fact that disorders of the
sclera are not common and the fact that, when relatively minor problems of
the sclera do develop, healing without consequence is the usual outcome.
After all, a scar in the sclera is of little importance, because the sclera is an
opaque structure. Such a scar in the cornea, or an opacity in the lens or vitre-
ous, or a scar in the macula, of course, carries infinitely more visual signifi-
cance. But it is exactly this rarity of significant sclera problems, coupled with
the profound systemic implications that some inflammatory disorders of the
sclera carry, that makes studies of the sclera and its disorders important.
Indeed, a substantial proportion of individuals who develop serious sclera
inflammation are discovered to have an occult systemic disease; in The Sclera
and Systemic Disorders, Watson and Hazleman1 emphasized that 27% of
patients who develop necrotizing scleritis are dead within 5 years from a
systemic, vasculitic lesion. Watson and Hazleman also emphasized that
because of the comparative rarity of sclera disease, the diagnosis is often

1
Watson PG, Hazleman BL: The Sclera and Systemic Disorders, WB Saunders, Philadelphia,
1976.

vii
viii Preface

missed, and 40% of eyes reported in one series of enucleated eyes had had a
primary diagnosis of scleritis.
We began with all that we had learned from Watson and Hazleman and
built on that excellent foundation. The basis of our current experience springs
from the Massachusetts Eye Research and Surgery Institution (MERSI) in
Cambridge, Massachusetts, and from the Hospital Clinic of Barcelona, Spain,
dating from 2005, both devoted to the study and care of patients with any
inflammatory problem related to the eye, from the lids to the optic nerve. The
first Research Fellow joined the service of Dr. Foster in 1980, and the first
Clinical Fellow arrived in 1984. Between 1977 and 2011 approximately
150,000 patient visits have occurred, approximately 10,000 new patients have
been evaluated, and 110 Ocular Immunology Fellows have been trained in the
service. Dr. Sainz de la Maza was one of those Fellows, and in the course of
training she developed a special interest in and affinity for patients with
scleritis. It was her initiative that was at the heart of the genesis of this project,
and it is entirely through her efforts that this project has been successfully
completed.
Our hope is that this book will serve as a resource for residents in ophthal-
mology, for cornea and immunology fellows in training, and for those oph-
thalmologists in practice and on faculties who have an interest in patients
with diseases of the sclera. The majority of the book is devoted to sclera
inflammation because scleritis represents, by far, the most common sclera
disorder encountered in ophthalmic practice, and because of the profound
systemic implications of scleritis. The references at the end of each chapter,
although not exhaustive, are generous in number and should provide the
reader with more than enough original source material for further reading.
Finally, we would enthusiastically encourage you to read the book The Sclera
and Systemic Disorders, second edition2 as well as this one.

Cambridge, MA, USA C. Stephen Foster

2
Watson PG, Hazleman BL, Pavesio CE, Green WR: The Sclera and Systemic Disorders,
Elsevier Limited, Philadelphia, 2004.
Contents

1 Structural Considerations of the Sclera....................................... 1

1.1 Introduction ............................................................................. 1
1.2 Development of the Sclera ...................................................... 1
1.2.1 Prenatal Development: Ultrastructural Studies ........... 1
1.2.2 Prenatal Development: Immunohistochemical
Studies ......................................................................... 7
1.2.3 Postnatal Development and Age-Related
Changes ....................................................................... 8
1.3 Anatomy.................................................................................. 9
1.3.1 Gross and Microscopic Anatomy ................................ 9
1.3.2 Ultramicroscopic Anatomy ......................................... 19
1.4 Biochemistry ........................................................................... 22
1.5 Immunohistochemistry ........................................................... 22
1.6 Biomechanics .......................................................................... 23
1.7 Molecular Structure ................................................................ 23
1.7.1 Collagen ....................................................................... 23
1.7.2 Elastin .......................................................................... 24
1.7.3 Proteoglycans .............................................................. 24
1.7.4 Glycoproteins .............................................................. 25
1.7.5 Matrix-Degrading Enzymes ........................................ 25
1.7.6 Fibroblast Growth Regulation ..................................... 26
1.8 Summary ................................................................................. 26
References ........................................................................................ 27
2 Immunologic Considerations of the Sclera .................................. 31
2.1 General Immune Response Considerations ............................ 32
2.1.1 Components of the Adaptive Immune Response......... 32
2.1.2 Immunoregulation ....................................................... 40
2.1.3 Abnormalities of the Immune Response ..................... 41
2.2 Connective Tissue and the Immune Response ........................ 45
2.2.1 Fibroblast Functions and the Immune Response ......... 45
2.3 The Sclera and the Immune Response: Scleritis ..................... 46
2.3.1 Immune Characteristics of the Sclera .......................... 46
2.3.2 The Susceptible Host: Immunogenetics ...................... 46

ix
x Contents

2.3.3 Etiology ....................................................................... 47

2.3.4 Pathogenesis ................................................................ 49
2.4 Summary ................................................................................. 50
References ........................................................................................ 51
3 Diagnostic Approach of Episcleritis and Scleritis ....................... 57
3.1 Investigation of the Illness ...................................................... 58
3.1.1 Major Complaint and History of Present Illness ......... 59
3.1.2 Past History.................................................................. 60
3.1.3 Family History ............................................................. 60
3.1.4 Past and Present Therapy History ................................ 60
3.1.5 Review of Systems ...................................................... 60
3.1.6 Systemic Examination ................................................. 62
3.1.7 Ocular Examination ..................................................... 64
3.2 Diagnostic Tests ...................................................................... 71
3.2.1 Blood Tests .................................................................. 71
3.2.2 Anterior Chamber Polymerase Chain
Reaction Testing .......................................................... 79
3.2.3 Smears and Cultures .................................................... 79
3.2.4 Skin Testing ................................................................. 80
3.2.5 Radiologic Studies ....................................................... 80
3.2.6 Anterior Segment Fluorescein Angiography ............... 80
3.2.7 Anterior Segment Indocyanine Green Angiography ... 84
3.2.8 Other Imaging Studies ................................................. 85
3.3 Biopsy ..................................................................................... 88
3.3.1 Biopsy for Suspected Systemic
Vasculitic Disease ........................................................ 88
3.3.2 Biopsy for Suspected Local or Systemic
Infectious Disease ........................................................ 89
3.4 Data Integration: Diagnosis .................................................... 89
3.5 Therapeutic Plan ..................................................................... 89
3.6 Summary ................................................................................. 89
References ........................................................................................ 90
4 Clinical Considerations of Episcleritis and Scleritis ................... 95
4.1 Episcleritis............................................................................... 96
4.1.1 Introduction ................................................................. 96
4.1.2 Patient Characteristics ................................................. 96
4.1.3 Clinical Manifestations ................................................ 97
4.1.4 Classification of Episcleritis ........................................ 99
4.1.5 Associated Diseases..................................................... 100
4.1.6 Precipitating Factors .................................................... 100
4.2 Scleritis ................................................................................... 102
4.2.1 Introduction ................................................................. 102
4.2.2 Patient Characteristics ................................................. 102
4.2.3 Clinical Manifestations ................................................ 102
4.2.4 Classification ............................................................... 105
Contents xi

4.2.5 Associated Diseases..................................................... 125

4.2.6 Complications of Scleritis ........................................... 126
4.3 Summary ................................................................................. 132
References ........................................................................................ 133
5 Pathology in Scleritis ..................................................................... 137
5.1 General Considerations of Connective Tissue
Inflammation ........................................................................... 137
5.1.1 Chronic Nongranulomatous Inflammation .................. 138
5.1.2 Chronic Granulomatous Inflammation ........................ 138
5.1.3 Fibrinoid Necrosis ....................................................... 138
5.1.4 Vascular Inflammation ................................................. 139
5.2 Specific Considerations of Scleral Tissue Inflammation ........ 139
5.2.1 Pathology of Episcleritis.............................................. 141
5.2.2 Pathology of Scleritis................................................... 141
5.3 Biopsy ..................................................................................... 164
5.3.1 Noninfectious Necrotizing Scleritis .......................... 164
5.3.2 Noninfectious Recurrent Diffuse or Nodular
(Nonnecrotizing) Scleritis ......................................... 164
5.3.3 Infectious Scleritis (Diffuse, Nodular,
or Necrotizing Scleritis) ............................................ 165
5.3.4 Biopsy Technique ...................................................... 165
5.4 Summary ................................................................................. 166
References ........................................................................................ 167
6 Noninfectious Scleritis ................................................................... 173
6.1 Systemic Immune-Mediated Disease-Associated Scleritis:
Vasculitides ............................................................................. 174
6.1.1 Adult Rheumatoid Arthritis ....................................... 174
6.1.2 Systemic Lupus Erythematosus ................................ 189
6.1.3 Ankylosing Spondylitis ............................................. 194
6.1.4 Reactive Arthritis (Reiter) ......................................... 199
6.1.5 Psoriatic Arthritis ...................................................... 203
6.1.6 Inflammatory Bowel Disease-Associated
Arthritis ..................................................................... 206
6.1.7 Relapsing Polychondritis........................................... 208
6.1.8 Polyarteritis Nodosa .................................................. 211
6.1.9 Allergic Granulomatous Angiitis (Churg–Strauss
Syndrome) ................................................................. 213
6.1.10 Granulomatosis with Polyangiitis (Wegener) ............ 214
6.1.11 Adamantiades–Behçet’s Disease ............................... 217
6.1.12 Giant-Cell Arteritis .................................................... 220
6.1.13 Cogan’s Syndrome .................................................... 222
6.1.14 Systemic Immune-Mediated Diseases Associated
with Scleritis: Atopy.................................................. 223
6.1.15 Other Systemic Immune-Mediated Diseases
That Rarely May Be Associated with Scleritis
and Episcleritis .......................................................... 224
6.1.16 Systemic Immune-Mediated Disease-Associated
Scleritis After Ocular Surgery ................................... 225
xii Contents

6.2 Dermatological Disease-Associated Scleritis ......................... 226

6.2.1 Rosacea ........................................................................ 226
6.3 Metabolic Disease-Associated Scleritis .................................. 226
6.3.1 Gout ............................................................................. 226
6.4 Foreign Body Granuloma-Associated Scleritis ...................... 227
6.5 Chemical Injury-Associated Scleritis ..................................... 227
6.6 Summary ................................................................................. 228
References ........................................................................................ 228
7 Infectious Scleritis .......................................................................... 241
7.1 Bacterial Scleritis .................................................................... 242
7.1.1 Gram-Positive Coccus and Gram-Negative
Rod Scleritis ................................................................ 242
7.1.2 Mycobacterial Scleritis ................................................ 245
7.1.3 Spirochetal Scleritis ..................................................... 250
7.1.4 Chlamydial Scleritis .................................................... 254
7.1.5 Actinomycetic Scleritis ............................................... 254
7.2 Fungal Scleritis ....................................................................... 255
7.2.1 Filamentous and Dimorphic Fungal Scleritis .............. 255
7.3 Viral Scleritis .......................................................................... 258
7.3.1 Herpes Scleritis ............................................................ 258
7.3.2 Mumps Scleritis ........................................................... 265
7.4 Parasitic Scleritis ..................................................................... 265
7.4.1 Protozoal Scleritis ........................................................ 266
7.4.2 Helminthic Scleritis ..................................................... 268
7.5 Summary ................................................................................. 269
References ........................................................................................ 270
8 Noninflammatory Diseases of the Sclera...................................... 277
8.1 Scleral Deposits ...................................................................... 277
8.1.1 Scleral Protein Deposition ........................................... 277
8.1.2 Scleral Lipid Deposition .............................................. 281
8.1.3 Scleral Carbohydrate Deposition ................................. 281
8.1.4 Scleral Mineral Deposition: Calcium .......................... 281
8.1.5 Scleral Pigment Deposition: Bilirubin......................... 282
8.2 Scleral Thinning (Blue Sclerae) .............................................. 283
8.2.1 Scleral Thinning in Inherited or Congenital
Diseases ....................................................................... 283
8.2.2 Scleral Thinning in Acquired Diseases ....................... 286
8.3 Scleral Thickening .................................................................. 287
8.3.1 Nanophthalmos ............................................................ 287
8.3.2 Scleropachynsis ........................................................... 287
8.3.3 Phthisis Bulbi............................................................... 287
8.4 Scleral Tumors ........................................................................ 288
8.4.1 Dermoid Choristomas .................................................. 288
8.4.2 Epithelial Tumors ........................................................ 288
8.4.3 Dense Connective Tissue Tumors................................ 289
8.4.4 Vascular Tumors .......................................................... 289
8.4.5 Blood Cell Tumors ...................................................... 290
Contents xiii

8.4.6 Nervous Tumors .......................................................... 290

8.4.7 Pigmented Tumors ....................................................... 291
8.4.8 Secondary Tumors ....................................................... 292
8.5 Summary ................................................................................. 292
References ........................................................................................ 292
9 Treatment of Episcleritis and Scleritis ......................................... 299
9.1 Treatment of Episcleritis ......................................................... 299
9.2 Treatment of Scleritis .............................................................. 300
9.2.1 Medical Treatment ....................................................... 300
9.2.2 Ancillary Therapy ........................................................ 304
9.2.3 Drug Management Responsibility ............................... 304
9.2.4 Surgical Treatment....................................................... 305
9.3 Summary ................................................................................. 307
References ........................................................................................ 307

Index ...................................................................................................... 309

 Structural Considerations
of the Sclera 1

into the tissues of the embryo. The cells of the

1.1 Introduction outer cell mass become flattened; they eventually
develop into the trophoblast. The space between
The sclera, the dense connective tissue that
inner and outer cell mass forms a central cavity,
encloses about five-sixths of the eye, is remark-
the blastocystic cavity, after which the embryo is
able for its strength and the firmness with which
called a blastocyst.
it maintains the shape of the globe. It aids in the
maintenance of intraocular pressure, provides
1.2.1.2 Second Week
attachment sites for the extraocular muscles, and
During the second week of development, some of
protects the intraocular structures from trauma
the cells of the inner cell mass become detached
and mechanical displacement.
from the inner surface and give rise to a cavity, the
To appreciate these normal functions and
primitive yolk sac. The remaining cells give rise to
understand the pathogenesis of inflammatory and
another cavity, the amniotic cavity, and to a bilam-
noninflammatory diseases of the sclera, one must
inar embryonic disk, consisting of a single upper
acquire some knowledge of the development,
layer of columnar cells, the epiblast, and a single
anatomy, and physiology of the sclera. A brief
lower layer of flattened cells, the hypoblast. The
description of these areas follows.
cells of the outer cell mass form the trophoblast
which divides into two layers, the inner cytotro-
phoblast and the outer syncytiotrophoblast.
1.2 Development of the Sclera
1.2.1.3 Third Week
1.2.1 Prenatal Development: Early in the third week, a thick linear band of
Ultrastructural Studies epiblast, called the primitive streak, appears cau-
dally in the midline of the dorsal aspect of the
1.2.1.1 First Week embryonic disk. The cranial end of the primitive
In placental mammals, the fertilized zygote is streak is swollen and is known as the primitive
transformed by cleavage cell division into a solid knot. The primitive streak gives rise to the meso-
mass of cells with the appearance of a mulberry blast, which spreads to form a layer between the
called morula. The cells are then rearranged, epiblast and hypoblast. This new layer is called
becoming organized as a group of centrally the embryonic mesoderm, and the process by
placed cells, the inner cell mass, completely sur- which the bilaminar embryonic disk becomes tri-
rounded by a layer of cells, the outer cell mass. laminar is called gastrulation. At the end of gas-
The cells of the inner cell mass are attached at trulation, the cells that remain in the epiblast form
one pole of the morula; they eventually develop the outer layer or embryonic ectoderm. Some

M. Sainz de la Maza et al., The Sclera, DOI 10.1007/978-1-4419-6502-8_1, 1

© Springer Science+Business Media, LLC 2012
2 1 Structural Considerations of the Sclera

Fig. 1.1 Diagrams of longitudinal and transverse sec- neural tube at the level of the forebrain in the diencepha-
tions of the fourth-week embryo, showing the neuroecto- lon to form the optic vesicle
dermal evagination from the ventrolateral aspect of the

mesoblastic cells displace the hypoblastic cells The mesoderm in the head and neck areas (cra-
laterally, forming the layer known as the embry- nial mesoderm) also undergoes differentiation,
onic endoderm. Hence, the epiblast is the source but the segmentation results in contiguous loose
of embryonic ectoderm, embryonic mesoderm, condensations or somitomeres [1, 2]. These
and most, if not all, of embryonic endoderm. mesodermal condensations are located close to
A solid cord of cells grows cranially from the neural crest cell population forming a neural
primitive knot to the prochordal plate between crest–mesoderm interface [1, 2]. The neural crest
ectoderm and endoderm forming a midline cord and mesoderm form the mesenchyme, which is a
known as the notochord. The notochord induces population of loosely arrayed stellate or fibro-
the thickening of the overlying ectoderm between blast-shaped cells.
the prochordal plate and the primitive knot form-
ing the neural plate. Shortly after its appearance, 1.2.1.4 Fourth Week
the neural plate invaginates along the long axis of The eye develops early in the fourth week as an
the embryo to form the neural groove. The lateral evagination from the ventrolateral aspect of the
walls of the groove are called the neural folds and neural tube or neuroectoderm, at the level of
the edges of the folds form the neural crest. By the forebrain in the diencephalon (Fig. 1.1) [3].
the end of the third week, the inner neural folds The end of the evagination becomes slightly
begin to fuse, forming the neural tube which dilated to form the optic vesicle. Neural crest
gives rise to the central nervous system. The pro- cells cover the convex surface of the vesicles or
cess of fusion starts in the future embryonic neck neuroectoderm and partially isolate them from
and extends toward the cranial and caudal ends of the dorsal, cranial, lateral, and ventral surface
the embryo. The cranial end of the neural tube ectoderm, and from the caudomedial paraxial
forms the forebrain, midbrain, and hindbrain; the mesoderm. At the same time, a small area of sur-
remainder of the tube forms the spinal cord. face ectoderm, overlying each optic vesicle thick-
The mesoderm down the center of the embryo ens, forms the lens placode (Fig. 1.2), which
differentiates into the paraxial mesoderm, the invaginates to become the lens vesicle.
intermediate mesoderm, and the lateral meso-
derm; the paraxial mesoderm divides into dense 1.2.1.5 Fifth Week
condensations or somites, each of which differen- Each optic vesicle then invaginates to form the
tiates into sclerotome, dermatome, and myotome. double-layered optic cup of neuroectoderm