2011-2012 Basic and Clinical Science Course, Section 8: External Disease and Cornea (Basic & Clinical Science Course)

External Disease and Cornea Section 8

2011-2012 (Last major revision 2010- 2011)

a~ AMERICAN ACADEMY ~ OF OPHTHALMOLOGY The Eyt M.D. ASSlx;;atio..

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Contents General Introduction

xv

Objectives

.1

1 Structure and Function of the External Eye

2

and Cornea .

.3

The Outer Eye and Cornea in Health and Disease. Development of the Anterior Segment. Anatomy Eyelids. Conjunctiva Cornea Sclera .

3 .4

Examination Techniques for the External Eye and Cornea. Vision . External Examination. Slit-Lamp Biomicroscopy Direct Illumination Methods. Indirect Illumination Methods Clinical Use Stains. Fluorescein. Rose Bengal and Lissamine Green. Clinical Evaluation of Ocular Inflammation Eyelid Signs of Inflammation. Conjunctival Signs of Inflammation Corneal Signs of Inflammation Scleral Signs of Inflammation . Corneal Pachometry Corneal Edema. Esthesiometry Anterior Segment Photography . External and Slit-Lamp Photography. Specular Photomicroscopy . Anterior Segment Fluorescein Angiography. Anterior Segment Imaging. Confocal Microscopy Measurement of Corneal Topography . Zones of the Cornea. Shape, Curvature, and Power.

.4 .4 .4 .6 .9

II 11 11 12 12 14 15 17 17 17 19 19 21 24

28 28 29

30 31 31 31 33 33

35 36 36 37 v

vi • Contents Keratometry ..... . Keratoscopy Computerized Corneal Topog raphy Retinoscopy . . . . Prevention Practices in Ophthalmology Universal Precautions . . .

3

38

39 40 45 45 45

Ocular Surface Disease: Diagnostic Approach.

47

Ocular Cytology . . . Specimen Collection. Interpretation of Ocular Cytology. Dry-Eye Syndrome Mechanism s of Dry Eye . . . . . Classification: Major Etiologic Causes of Dry Eye Tear- Film Evaluation Inspection . . Tests of Tear Production Tear Composition Assays. Newer 1maging Technologies and Dry Eye Aqueous Tear Defi ciency Sjogren Syndrome. Non- Sjogren Syndrome . Evaporative Tear Dysfunction Meibomian Gland Dysfun ction. Rosacea . Sebo rrh eic Blepharitis . Chalazion . Ho rdeolum . . . . . . Sarcoidosis. . Desqu amating Skin Conditions: Ichthyos is. Ectodermal D ysplasia ........ . Xeroderma Pigmentosum . . . Noninflammatory Vascular Anomalies of the Conjunctiva Hereditary Hemorrhagic Telangiectasia Lymphangiectasia. ..... . Nutritional and Ph ys io logic Diso rd ers. Vitamin A Deficiency . Vitamin C Deficiency . . . . Structural and Exogenolls Disorders. Exposure Keratopathy. . . . . Floppy Eyelid Syndrome. Superior Limbic Keratoco njunctivitis Recurrent Corneal Erosion. . Persistent Corneal Epitheli al Defect Trichiasis and Distichiasis . . Factitious Ocular Surface Disorders Dellen. . . . . . ..... Ocu lar Surface Problems Secondary to Contact Lens Wear Limbal Stem CeU Deficiency.

47 47 48 48 49 51

52 52 53 54 55 55

63 65 65 65

69 71 72 73 73

74 74 75 75 76 76 77 77

79

80 80 81 81 83 85

89 89 90 91

92

Contents. vi i

4

Infectious Diseases ofthe External Eye: Basic Concepts and Viral Infections

95

Defense Mechanisms of the External Eye. Normal Ocular Flora Pathogenesis of Ocular Infections. Virulence . Inoculum Host Defense. Ocular Microbiology Diagnostic Laboratory Tech niques Specimen Collection and Culturing Stain ing Methods. . Public Health Ophthalmology Virology and Viral Infections. DNA Vi ruses: Herpesvi ruses . Herpes Simplex Eye Diseases.

95 96 97 98 99 99 100 100 100 103 104 104 105 105

Var icella -Zoster Virus Dermatoblepharitis, Conjunctivitis,

and Keratitis . Epstein-Barr Virus Dacryoadenitis, Conj unctivitis, and Keratitis.

5

. 117 . 122

DNA Viruses: Adenoviruses DNA Viruses: Poxviruses Molluscum Contagiosum Vaccini a . DNA Viruses: Papovaviruses . RNA Viruses.

. 123 127 127 128 128 . 129

Infectious Diseases of the External Eye: Microbial and Parasitic Infections

131

Bacteriology . Gram-positive Cocci.

131 132

Gram-negative Cocci

Gram-positive Rods. Gram-negative Rods. Gram-positive Filaments. Chlamydia Species Spi rochetes. Mycology. Yeasts Septate Filamentous Fungi Nonseptate Filamentous Fungi Parasitology Protozoa. Helminths Arthropods. Prions. . Microbial and Parasitic Infections of the Eyelid Margin and Conjunctiva. Staphylococcal Blepharitis . Fungal and Parasitic Infections of the Eyelid Margin. .

134

. . .

. . .

134 135 136 13 7 137 138 139 139 140 140 140 141 142 143 143 143 148

vii i. Contents Bacterial Conju nctivitis in Children and Adults. Chlamydial Conjunctivitis . . . Parinaud Oculoglandular Synd rome. . Microbial and Parasitic Infections of the Cornea and Sclera. Bacterial Kerat itis. . . Atypical Mycobacteria. Fungal Keratitis. Acanthamoeba Keratitis Corneal Stromal Inflammation Associated With Systemic Infections Microsporidiosis . Loiasis. Microbial Scleritis.

6

149 · 154 · 157 158 158 164 164 167 169 170 170 17 1

Ocular Immunology

173

Cellular Elements of the Ocular Immune Response Lacrimal Fu nctional Unit. . . . The Ocular Surface . . . Soluble Mediators of the Ocular Immu ne Response Tear Film . . ..... Hypersensitivity Reactions of the Ocul ar Surface Anaphylactic or Atopic Reacti ons (Type I) Cytotoxic Hypersensitivity (Type II ) . Immu ne-Complex Reactions (Type 1II ) . Delayed Hype rse nsitivity (Type IV) . Patterns of Immune-Mediated Ocular Disease Conjunctiva Cornea . . Sclera . . Diagnostic Approach to Im mu ne-Mediated Ocular Disorders.

· 173 · 173 173 · 175 175 178 179 180 180 180 180 180 181 18 1 · 181

7 Clinical Approach to Immune-Related Disorders of the External Eye

183

Immune-Mediated Diseases of th e Eyelid Contact Dermatoblepharitis . . Atopic Dermatitis. . . . . . . . . Immune-Mediated Disorders of the Conjunctiva Hay Fever Conjunctivitis a nd Pe ren nial Allergic Conjunctivitis Vernal Keratoconj unctivitis. Atopic Keratoconju nctivitis . . Ligneous Conjunctivitis . . . Contact Lens- Induced Conjunctivitis Stevens-Johnson Syndrome a nd Toxic Epidermal Necrolysis O cular Cicatricial Pe m phigoid . . ......... Ocular Graft-vs-Host Disease. . . Other Immune-Mediated Diseases of the Skin and Mucous Membranes

183 183 185 185 185 187 190 192 193 195 198 . 203 .204

Con tents • ix

Immune-Mediated Diseases of the Cornea. Thygeson Superficial Pu nctate Keratitis Intersti tial Keratitis Associated With Infectious Diseases Reactive Arthritis. . Cogan Syndrome . . . . Marginal Corneal Infiltrates Associated With Blepharoconjunctivitis Peripheral Ulcerative Kerati tis Associated With Systemic lm mu ne-Mediated Diseases . . . Mooren Ulcer.

Immune-Mediated Diseases of the Episclera and Sclera Episcleritis . Scleritis .

8

Clinical Approach to Neoplastic Disorders of the Conjunctiva and Cornea Inclusion Cysts of the Epitheliwl1 . Tumors of Epithelial Origi n Ben ign Epithelial Tumors . . Preinvasive Epithelial Lesions . Malignant Epithelial Lesio ns Glandula r Tu mors of the Conjunctiva. Oncocytoma Sebaceous Gland Carci noma . Tumors of Neuroectoderma l Origin.

Benign Pigmented Lesions Preinvasive Pigmented Lesions Malignant Pigmented Lesions. Neurogenic and Smooth Muscle Tumors. Vasc ular and Mesenchymal Tumors.

Benign Tumors. . . , Malignant Tumors. Lymphatic and Lymphocytic Tumors Lymphangiectasia and Lymphangioma. Lymphoid Hyperplasia. Lymphoma. Metastatic Tumors

Epibulbar Choristoma . Epibulbar Dermoid Dermolipoma Ectopic Lacrimal Gland Other Choristomas

9

.204 .204 .207 · 209 · 209 · 210 · · · · ·

211 213 216 216 217

225 .225 .226 .226 · 228 · 231 · 233 · 233 · 233 · 233 · 233 .237 .238 .240 .240 · 240 · 242 · 242 .243 · 243 .244 · 245 .245 · 245 .246 .246 · 246

Basic and Clinical Concepts of Congenital Anomalies of the Cornea and Sclera .

249

Developmental Anomalies of the Globe and Sclera Cryptophthalmos . Mic rophthalmos

.249 .249 .250

x • Contents Nanophthalmos. Blue Sclera. Developmental Anomalies of the Ante rior Segment. Anomalies of Size and Shape of the Cornea. Abnormalities of Corneal Stru cture and/or Clarity . Congenital Corneal Opacities in Hereditary Syndromes and Chromosomal Aberratio ns. Secondary Abnormalities Affec ting the Fetal Cornea Intrauterine Keratitis: Bacterial and Syphilitic. Congenital Corneal Keloid. Congenital Corneal Anesthesia Congenital Glaucoma Birth Trauma. Arcus Juveni lis

10 Corneal Dystrophies and Ectasias. Corneal Dystrophies . . . . . . . Epithelial and Subepithelial Dystroph ies . Bowman Layer Corneal Dystrophies. Stromal Corneal Dystrophies: TGFBJ Dystrophies. Stromal Dystrophies: Non- TGFBI Dystrophies Endothelial Dystrophies Ectatic Disorders . . . . . . Keratoconus . . . . . Pellucid Marginal Degeneration. Keratoglobus .

11 Metabolic Disorders With Corneal Changes. Disorders of Carbohydrate Metabolism Mucopolysaccharidoses . Diabetes Mellitus . . . Disorders of Lipid Metabolism and Storage. Hyperlipoproteinemias Hypolipoproteinemias . Sphingolipidoses . . . Mucolipidoses . . Bietti Crystalline Corneoretinal Dystrophy. Disorders of Amino Acid Metabolism . Cystinosis . . Tyrosinemia . Alkaptonuria. Disorders of Protein Metabolism AmylOidosis . . . . . . Disorders of Immunoglobulin Synthesis . Noninflammator y Disorders of Connective Tissue Ehlers-Danlos Syndrom e . Marfan Syndrome. . . . .

· 25 1 · 252 · 253 · 253 .255 · 263 .263 .263 · 264 .264 .265 .265 .266

267 .268 .270 · 275 · 278 · 283 · 291 .296 .296 · 30 1 · 302

305 · 305 · 305 · 307 · 308 · 308 .309 · 310 · 3 12 · 313 · 313 .313 · 314 · 3 15 · 3 16 · 316 · 3 19 .320 · 320 · 325

Cont ents • xi

Disorders of Nucleotide Metabolism. Gout . Porphyria . Disorders of Mineral Metabolism. Wilso n D isease .

Hype rcalcemia Hemochromatosi s.

Corneal an d External Disease Signs of System ic Teoplasia En larged Corneal Nerves. . . .

.325 · 325 .326 .327 · 327 · 328 · 328 · 328 · 328

12 Clinical Approach to Depositions and Degenerations of the Conjunctiva, Cornea, and Sclera .

331

Degenerat ive Changes of the Conjunctiva

· 331 · 331 · 331 · 332 · 332 · 333 · 334 · 334 · 334 .336 .344 .345 · 346 · 346 · 348 · 349

Age- related (Involutional) Changes Pinguecula . Pterygium Conjunctival Concretions Conjunctivochalasis .

Degenerative Changes in the Cornea Age- related (Involutional) Changes Epithelial and Subepi thelial Degenerations Stroma l Degenerations. Endoth elial Degenerations

Scleral Degenerations . Drug-Induced Deposition and Pigmentation. Corneal Epithelial Deposits . Stromal and Descemet's Membrane Pigmentation Endo thelial Manifestations. . . . . .

13 Clinical Aspects of Toxic and Traumatic Injuries of the Anterior Segment

351

Injuries Caused by Temperature and Radiation Thermal Burns . Ultraviolet Radiation Ion izing Radiation Chem ical Injuries. Alkali Burns Acid Burns . . Management of Chem ica l Injuries.

· 351 · 351 .352 · 352 · 353 · 353 · 355 · 355 · 359 · 361 · 361 .362 .362 .362 · 363 · 363

Toxic Keratoconjunctiviti s From Medications.

Animal and Plant Substances. Insect Injuries . Vegetation Injuries . . Concussive Trauma.

Conju nctival Hemorrhage Corn eal Changes Traumatic Mydriasis and Miosis.

xii. Contents

Trau matic Irit is . Iridodialysis and Cyclodialysis Traumatic Hyphema . Nonperforating Mechan ical Trauma.

Conjunctival Laceration Conjunctival Foreign Body. Corneal Foreign Body. Corneal Abrasion. Posttraumatic Recu rrent Corneal Erosion

Perforati ng Trauma. Evaluation Management. Surgical Trau ma Corneal Epithelial Changes Fro m Intraocular Surgery Descemet's Membrane Changes During Intraocular Surgery Corneal Endothelial Changes From In traocular Surgery Conjunctival and Corneal Changes From Extraocular Surgery.

14 Surgery of the Ocular Surface . Introduction.

. . . . . . . .

Corneal and Conjunctival Epithelial Wound Healing Role of Stem Cells. Conjunctival Epithelium. Maintenance of the Ocular Surface and Its Response to Wound Healing. Surgical Procedures of the Ocul ar Surface Conjunctival Biopsy. Tarsorrhaphy. Pterygium Excision Conjunctival Transplantation. Li mbal Transplantation Conjunctival Flap. Mucous Nlembrane Grafting Superficial Keratectomy and Corneal Biopsy Management of Descemetocele, Corneal Perforation, and Corneal Edema. Corneal Tattoo

15 Basic Concepts of Corneal Transplantation Transplantat ion Immunobiology

Histocompatibility and Other Antigens. Immune Privilege.

Eye Banking and Donor Selection . Criteria Contraindicating Donor Corn ea Use.

. 363 . 364 . 365 .369

. . . .

369 370 371 372

. 372

. . . . . . . .

373 373 374 382 382 383 383 385

387 .387 .387 · 388 .388 · 388 · 389 · 389 · 390 · 391 · 393 · 395 · 398 · 40 1 .402 .403 .405

407 .407 .407 .407 .408 .409

Contents . xiii

16 Clinical Approach to Corneal Transplantation

4 13

Corneal Transplantation . Surgical App roach to Corneal Disease Preoperative Evaluation and Preparation. Surgical Tech nique for Penet rati ng Kera toplasty . Combined Procedures. Intraoperat ive Complications. Postoperati ve Care and Complications. Control of Postoperative Corneal Astigmatism and Refractive Error . . Diagnosis and Management of Graft Rejection Pediatric Corneal Transplantation. Corneal Autograft Procedures Rotational Autograft. Contralateral Autograft Keratoprosthesis . . La mellar Keratoplasty. Anterior Lamel lar Transplan tation. Surgical Technique Postoperat ive Care and Complications. Descemet Stripping Automated Endoth elial Keratoplasty . Advantages. . . . . . . . Disadvantages . . . . . . . . . . DSAEK Surgical Techn ique. . . . . . Descemet's Membrane Endothelial Keratoplasty.

· · · · · · ·

Basic Texts. Related Academy Materials Credit Reporting Form Study Questions

.447 .449 .453 .457 .466 · 471

Answers.

Index . .

413 413 414 417 419 421 42 1

.426 .427 .430 · 431 .432 .432 .432 .433 · 433 .435 .436 .437 .437 .438 .438 · 445

CHAPTER

1

Structure and Function of the External Eye and Cornea

The Outer Eye and Cornea in Health and Disease The external eye is the most crucial part of the body exposed to the outside world. The no rmal structure and function of the healthy eye rely on homeostasis of the ent ire body for protection agai nst an adverse environment. Ge netics and nutr ition determine the em bryogenesis and growth of the eye. Intact vascu lar and nervous syste ms ensure stabl e metabolism , and the im mune system main tain s su rve illance.

The cushion ing effect of the periocula r tissues and local barr iers such as the orbital ri m are needed to safeguard th e globe. The eyebrows and eyelashes catch sm all particles, and the cilia also work as sensors to stimulate reflex eyelid closure. Blin king augments the lacrimal pum p to ri nse tears over the eye and flush off foreign material. The tea r film also dilutes toxins an d all ergens and contains proteins that control the normal flora. Mucin

stabilizes the tear fil m and dema rcates the living cells of the ocular surface fro m th e surrou nd ing environment.

The epiderm is an d epitheli um of healthy eyelids, conj unctiva, and cornea ad here tightly to their basement membranes. Regulation of cell ular growth and metabolism is cr itical to th e mai ntenance of an intact ocular surface and a transparent cornea. The un derlying extracellular matr ix of the eye's mucous membrane is rich in blood vessels and

conjunctiva-associated lymphOid tissue (CALT). The anterior segment of the eye provides a clear, protected entrance for ligh t that is to be processed by the visual pathways through the central nervous system. Unde rstandi ng the eye's in na te defenses requires study of ocular histology and biochemistry and the observatio n of many people, both healthy and ill. Ophthalmologists who speciali ze in corneal and ex ternal eye disease build on thi s understanding, which extends from clinical exami nat io n to cli nicopathologic problem solving, molecular med ici ne, and microsurgery. Readers should become famil iar with ocular embr yology, anatomy, phYSiology, and biochemist ry (in BCSC Section 2, Fundamentals and Principles oj Ophthalmology); ocular im munology (in BCSC Section 9, Intra ocula>· Infla mmation and Uveitis); and ophthalmic pathology (i n BCSC Section 4, Ophthalmic Pathology and In traocular Tumors).

3

4 • External Disease and Cornea

Development of the Anterior Segment The eye begins to develop during week 4 of gestation as an evagination from the neuroectoderm. Invagination of the optic vesicle fo rms the double-layered optic cup of neuroectoderm at week 5. At th is time, the surface ectoderm forms the lens placode and gives rise to the corneal and conju nctival epithelium and the eyelid epidermis. Also at week 5 to 6, the first wave of mesenchymal cells fro m the neural crest of the surface ectoderm extends under the epithelium from the limbus to begin forming the corneal endothelium. A subsequent wave of mesenchymal cells of neural crest origin at week 7 begins forming the corneal stroma and sclera. Greate r detail is available in BCSC Section 2, Fundamentals and Principles of Ophthalmology. At 2 months' gestation, the eyelids fuse and the conjunctiva begins to develop within the eyelid folds. The ocular surface epithelium differentiates shortly afterward. At 3 months, all corneal components are present except the Bowman layer, which appears in the fourth month as the scleral spur is also forming. The eyelids begin to open between the fifth and seventh months. At birth, the infant's globe is 80% of its adult size. The postnatal sclera and cornea are somewhat distensible, gradually becoming more rigid duri ng the first 2 years of life.

Anatom Eyelids The eyelid skin blends into the surrounding periorbital skin, varying from 0.5 mm thick at the eyelid margin to 1 mm thick at th e orbital rim. Except for fine vellus hairs, the only hairs of the eyelids are the eyelashes, or cilia, which are twice as numerous along the upper eyelid margin as along the lower. Cilia are replaced every 3-5 months; they usually regrow in 2 weeks when cut and within 2 months if pulled out. The epidermis of the eyelids abruptly changes to non keratinized stratified squamous epithelium at the mucocutaneous junction of the eyelid margin, along the row of meibomian gland orifices. Holocrine sebaceous glands and eccrine sweat glands are present in the eyelid skin . Near the eyelid margin are the apocrine sweat glands (the glands of Moll) and numerous sebaceous glands (t he glands of Zeis) (Fig 1-1). Wolfley DE. Eyelids. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol l. Philadelphia: Elsevier/Mosby; 2005:53-58.

Conjunctiva The conjunctival sac includes the bulbar conjunctiva, afornix on 3 sides and a medial semilunar fold, and the palpebral conjunctiva. Smooth-muscle fibe rs from the levator muscle maintain the superior fornix, and fibrous slips extend from the horizontal rectus tendons into the temporal conjunctiva and plica to form cul-de-sacs during horizontal gaze. The caruncle is a fl eshy tissue mass containing hairs and sebaceous glands. The tarsal conjunctiva is tightly adherent to the unde rlying tarsus, and the bulbar conjunctiva is loosely

CHAP.TER 1:

Structu re an d Fu nction of the External Eye and Cornea. 5

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...............

o~~"\ _~..,-b·;P:;==7~~=s:r=::::::=== ocu li m. (orbita l portion) Levator palpebrae m. Orbital septum - ---''-';--,---,--'Orbicularis oculi m. ---'..>-;--'--~--1 (preseptal portion)

Eyelid m'ase- - -- - - - \

'f0.40) might not tolerate in traocular surger y. Percentage of hexagonal cells. The percentage of cells with 6 apices should ideall y approach 100%. Lower percentages indicate a diminishing state of health of the endothelium. Pleomorphism is increased variability in cell shape. Corneas with

Figure 2·16 Confocal videomicrograph of normal corneal endothelium, with cell density

of 2470 cel ls/mm 2

CHAPTE~ 2:

Examination Techniques for the External Eye and Cornea. 33

high pleomorphism (more than 50% nonhexagonal) might not tolerate intraocular surgery. American Academy of Ophthalmology. Corneal Endothelial Photography. Ophthalmic Technology Assessment. San Fran cisco: American Academy of Ophthalmology; 1996. (Reviewed for currency 2003.) Phillips C, Laing R, Vee R. Specular microscopy. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol 1. Philadelphia: Elsevier/Mosby; 2005:261-281.

Anterior Segment Fluorescein Angiography

Anterior segment fluorescein angiography has occasionally been used to study the circulatory dynamics of normal and pathologiC bulbar conjunctival, episcleral, scleral, and iris blood vessels. This technique is particularly applicable to patients who might have areas of vascular nonperfusion, as in necrotizing scleritis and some forms of iritis. Anterior Segment Imaging

Imag ing of the anterior segment has Significantly improved over the past decade, allowing the diagnosis and treatment of various conditions in a more precise and rapid manner. Techniques include the use of high-frequency ultrasound, Scheimpflug analysis, and scanning slit and OCT. The superficial location of the cornea and anterior chamber allows images that can detect foreign bodies, assess iris and ciliary body tumors, evaluate the extent of trauma, assess the anterior chamber angle, and determine the position of the crystalline lens or 10L. Anterior segment echography, or ultrasound biomicroscopy-specifically highfreque ncy ultrasonography-uses a water-bath immersion technique. With this tech nique, the depth of tissue penetration is approximately 5 mm and structures can be viewed through opaque media. Figure 2-17 is an example of ultrahigh frequency biomicroscopy of the normal limbus.

Figure 2·17

Ultrasound bi omicrosco pi c visualization of the entire anterior se gment, including structure s behind the iris pigment epithelium, th ereby perm itting precise determ ination of the sulcus-to-sulcus measu rements prior to pha ki c refract ive implant. (Reprodu ced with permission from Goins KM Wagoner MD. Imaging the anterior segment, Foca l Points : Clinica l Modules for Opht ha lmolog ists, San Francisco: American Academy of Ophthalmology; 2 009, module 11.)

34 • Extern al Disease and Cornea

Techniques involving the Scheimpflug camera, scann ing-slit topography devices, and OCT are non contact, which offers some practical advantages, including less training for image acquisition . The Scheimpflug-based imaging system uses a rotating Scheimpflu g camera that is perpendicular to the slit beam and takes 50 slit images of the anterior segment in less than 2 seconds. A 3-dimensional image is constructed assessing the anterior and posterior corneal curvature, corneal thickness, anterior chamber depth, lens opacification and lens thickness. Pachometry and topography of the entire anterior and posterior surface of the cornea can be displayed (Fig 2-18). The scanning-slit topography devices (eg, Orbscan; Bausch & Lomb, Rochester, NY) assess the cur vature of the anterior and posterior surfaces along with the anterior surface of the lens and iris. T he posterior elevation map created with this instrument is derived mathematically and may overestimate the posterior curvatu re, especially after LASIK procedures (Fig 2-19). The anterior segment OCT devices are analogous to ultrasonographic devices but emit and reflect light rather than sound.The images are obtained in a noncontact, nonin vasive fashion , and high -resolution corneal and angle scans measuring the depth, width, and angle of the anterior chamber can be obtained (Fig 2-20) .

CornaoFrcnt

..

-.~

..

c..'~

,

~.~

-""" """""

• '" '" r'" r'" r

r

'"fFOi'" fW:;J

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Figure 2-18 Scheimpflug image of a 55-year-old patient with Fuchs endothelial dystrophy and cataract. The general display clearly depicts epithelial and endothelial opactiy of the cornea with a densitometry measurement of 49.7 (normal 22-30) and the lenticular opacity with a

densitometry reading of 37.0. In addition, keratometry, axis of astigmatism, corneal thickn ess, and anterior chamber depth are provided. (Reproduced with permission from Goins KM, Wagoner MD. Imagmg the anterior segment Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2009, module 11.)

CHAPTER 2:

Examination Techn iques for the Externa l Eye and Cornea • 35

---,-- ---=-..._. .. ... - ..... ....... --_ --...-.... _ _ ......... _.........

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os

Figure 2-19

Orbscan scanning-si lt top ography of a keratoconus patient. (Courtesv of James J

Reidy, MD.)

Figure 2-20 Anterior segment OCT image in a phakic eye. The central anterior chamber depth is 2.73 mm, and there is moderate narrowing of the anterior chamber angle. (Reproduced with permission from Goins KM Wagoner MO. Imaging the anterior segment. Foca l Points Cl inical Modu les for Ophtha lmologists. San Francisco: American Academy of Ophthalmology; 2009, module 11.)

Goins KM , Wagoner MD. Imagi ng th e anterior segment. Focal Points: Clinical Modules for Ophthalmologists. San Fra ncisco: Am erican Academy of Ophthalmology; 2009, module II. Konstantopouios A, Hossain P, Anderson OF. Recent advances in ophthalmic anterior segment imaging: a new era for ophtha lmic d iagnosis? BrJ Ophthalmol. 2007;91(4):55 1-557.

Confocal Microscopy

The scanning confocal microscope can be used to study cell layers of the cornea even in cases with edema and scarring_ Compared with ultrasonography or OCT, confocal

36 • External Disease and Cornea

Figure 2-21 Confocal microscopic imag e at th e level of deep stroma demonstrates fun gal hyphae . Carets denote branch ing hyphae (bh). (Reproduced with permission from Goins KM Wagoner MD. Imaging the anterior segment. Focal Points: Clinical Modules for Ophthalmologists. San Francisco. American Academy of Ophrhalmology; 2009. module 11.)

microscopy provides more spatial resolution and magnification, particularly in the z-axis. This allows in vivo optical sections of the cornea with a resolution at cellula r and subcel lular levels. Confocal microscopy can detect infectious crystalline keratopathy, fun gal keratitis, and amebic keratitis. It has also been used to follow refractive surgery patients to anal yze haze formation and the complications of LAS IK flaps, such as epithelial ingrowth. Four types of confocal microscopes have been described for clin ical use: (I ) the tandem-scanning (TSCM), (2) the scanning-slit (SSCM), (3) the laser scanning (LSCM), and (4) a single-sided disk design that is not commercially available. The first 3 are approved by the FDA in the United States. They differ in several ways, but, in general, the TSCM provides a shallower depth of field and better anterior-posterior localization and reconstruction. The SSCM is more user-fri endly and, as a result, is the most used technique. The LSCM provides the highest resolution: to approximately 1- 2 ~m (Fig 2-2 1). Cavanagh HD, Petro!! WM, Jester IV. Confocal microscopy. In: Krachmer JH, Ma nn is MJ, Holland EJ, eds. Cornea. 2nd ed. Voll. Ph iladelphia: Elsevier/Mosby; 2005:283-297. Ch iou AG, Kaufma n SC, Kaufman HE, Beuerma n RW. Clinical corneal confocal microscopy. Surv Ophthalmol. 2006;S l (S)A82-S00. Goins K~'l , Wagoner MD. Imaging the anterior segment. Focal Points: Clinical Modu les Jar Ophthalmologists. San Francisco: Amer ican Academy of Ophthalmology; 2009, module 11.

Measurement of Corneal Topography Zones of the Cornea For more than 100 years, the corneal shape has been known to be aspheric. Typically, the cent ral cornea is about 3 D steeper than the periphery, a positive shape factor. Clini ca ll y, the cornea is di vided into zones that surround ftxation and blend into one another.

CHAPTER 2:

Exami natio n Techn iques for the External Eye and Cornea .

37

The central zone of 1- 2 mm closely fits a spheri cal surface. Adjacent to the central zone is a 3- 4-mm doughnut with an outer diameter of 7-8 mm. Called the paracentral zone, th is doughnut represents an area of progress ive flatten ing from the center. Together, the paracentral and central zones constitute the apical zone, as used in contact le ns fitting. The central and paracentral zones are pri marily responsible for the refractive power of the cornea (Fig 2-22). Adjacent to the paracentra l zone is the peripheral zone, with an outer diameter of approximately 11 mm, and adjoin ing this is the limbus, with an outer diam eter that averages 12 mm. The peripheral zone is also kn own as th e transitional zon e, as it is the area of greatest flatten ing and asphericity of the no rmal corn ea. The limbus is adjacent to the sclera and is the area where the cornea steepens prior to join ing the sclera at the limbal sulcus. The optical zone is the portion of the cornea that overlies the entrance pupil of the iriS; it is phYSiologically limited to approxi mately 5.4 m m because of the Stiles-Crawford effect. The corneal apex is the point of maximu m curvature, typically temporal to the center of the pupil. The corneal vertex is the point located at the intersection of the patient's line of fixation and the corneal surface. It is represented by the corneal light reflex when the cornea is illuminated coaxially with fixat ion. The corneal vertex is the center of the kera toscopic image and does not necessarily correspond to the pOint of maximum curvature at the corneal apex (Fig 2-23).

Shape, Curvature, and Power Three topographic properties of the corn ea are important to its optical function: the underlying shape, which dete rmines its curvature and hence its refractive power. Shape and curvature are geom etric properties of the cornea, whereas power is a functional property. Historically, power was the first paramete r of the cornea to be described, and a unit representing the refracti ve power of the central cornea, the diopter, was accepted as the basic unit of measurement. However, with th e advent of contact lenses and refractive surgery,

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Figure 2-22 Topogra phic zones of the corn ea. (Illustration by Christine Gralapp.)

38 • Externa l Disease and Cornea

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knowing the overall shape and the related property of curvature has become increasingly important. The refractive powe r of the cornea is determined by Snell's law, the law of refraction. Snell's law is based on the difference between 2 refractive indices (in this case, of the cornea and of air), divided by the radius of curvature. The anterior corneal power using air and corneal stromal refractive indices is higher than cl inically useful because it does not take into accou nt the negative contrib ution of the posterior cornea. Thus, for most clinical purposes, a derived corneal refractive index of 1.3375 is used in calculating central corneal power. This value was chosen to allow 45 D to equate to a 7.5-mm radius of cu rvature. Average refractive power of the central cornea is about +43 D, which is the sum of the refract ive power at the air-stroma interface of +49 D minus the endothelium-aqueous power of 6 D. The refractive index of air is 1.000; aqueous and tears, 1.336; and corneal stroma, 1.376. Although the air-tear inte rface of the corn ea is responsible for most of the eye's refraction, the difference between total corneal power based on stroma alone and with tears is only - 0.06 D. BCSC Section 3, ClinicaL Optics, covers these topi cs in greater depth. Keratometry

The ophthalmometer (keratometer) empiricall y estimates corneal power by reading 4 points of the central 2.8 - to 4.0-mm zo ne. These points do not represent the corn ea l apex or vertex but are a clinicall y useful estimat ion of centra l corneal power. The radius of curvatu re is calculated fro m the simple vergence formula using the known circular object size and measuring the distance with doubling prisms to stabilize the image. The

CHA PTER 2: Exam inatio n Te chnique s fo r th e Exte rna l Ey e and Co rne a . 39

longe r axis of the elliptical image is produced by the fl attest portion of the cornea (ie, that part of the cent ra l cornea that has the longest radius of curvature and the lowest dioptric power). The ax ial radiu s of curvature is th en used in compu ting the corneal power in this region . Results are repo rted as radius of curvature in millimeters o r refra cting power in

diopters. For most normal corneas, keratometry is sufficiently accurate for contact lens fitting or IOL power ca lc ulatio n. Keratometry is also useful in detecting irregular ast igmatism, in which keratometric Lmages cannot be superimposed or are not regular ovals. However, in some circumstances, such as with keratoconus or after radial keratotom y, th e optical

properties of the cornea are affected by zo nes other than those measured by keratometry. Topographic keratometry can be performed with a special attachment to th e keratometer. See also BCSC Section 3, Clinical Optics.

Keratoscopv Information about cornea l curvature can be obtained with a variety of instruments that

reflect the images of multiple concentric circles from the corneal surface. These devices allow analysis of corneal curvatu re in zones both central and peripheral to those measured by kerato metr y. In general, on steeper parts of the cornea, the reflected mires appear closer together and th in ner, and the axis of the central mi re is shorter (Fig 2-24). Conversely, along the flat axis, the mi res are far ther apart and th icker, and the central mire is longer. The ha ndheld Placido disk is a keratoscope with a flat target. Collimating keratoscopes use rings inside a column or a curve to maxim ize the area of th e ocular surface that can reflect the target mires. Photo keratoscopy preserves the virtual image of concentric circles on

film, and video ke ratoscopy stores the images on video.

Figure 2-24

Videokeratoscopic mires are closer together in the axis of steep curvature (arrow),

and farther apart in the flat axis (arrowhead) in this post-penetrating ke ratoplasty patient. Maj or axes are not orthogona l. (Courtesy of John E. Su tphin, MD.)

40 • Exte rn al Diseas e and Co rn ea

Computerized Corneal Topography See BeSe Section 13, Refractive Surgery, fo r a more detailed discussion of computerized corneal topography. Ke ratosco py images can be digitall y captured and analyzed by com puters. Placido disk- based computeri zed topographers have been the type most commonly available. These units assume the angle of incidence to be nearly perpendicula r and the radius of curvature to be the distance from the surface to the intersection wi th the li ne of sight or visual axis of the patient (axial distance) (Fig 2-25). However, the ass umption that the visual axis is coincident to the cornea l apex may lead to some misinterpretations, such as the overdiag nosis of keratoconus. Axial curvature closely approximates the power of the central \ -2 mm of the cornea but fa ils to describe the true shape and power of the peripheral cornea. Another metho d of describing the corneal curvature uses the instan taneous radius of curvature (also called tangential power) at a certain point. This radiu s is determined by taking a perpendicula r path through the point in question from a plane that intersects the point and the visual axis but allowing the radius to be the length necessary to correspond to a sphere with the same curvature at that point. The instantaneous radius of curvature, with curvature given in diopters, is estimated by the difference between th e corneal index of refraction and 1.000 divided by th is tange ntially determined rad ius. The tangential map typically shows better sensitivity to peripheral changes with less "smoothing" of the curvature than the axial maps (Fig 2-26) . (In these maps, diopters are relative un its of curvature and not the equivalent of diopters of corneal poweLl

Line of sight Normal of the videokeratoscope

Placido cu rvature maps are computed from the normal of the videokeratoscope, not fro m any accepted optical pathway.

Corneal apex

Figure 2-25 Placido imagery for ca lcul ating the corneal curva ture. The assumption that th e perpendicular to the videokeratograph, th e patient's line of si ght, and the corneal apex are coincident is ra rely corre ct. (Courtesy of Michael W Belin MD; rendered by C. H. Wooley.)

CHAPTER ·2:

Exa mi nation Techn iques for the Externa l Eye and Cornea.

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A third map, the mean curvature map, does not require the perpendicular ray to cross the visual axis. It uses an infinite number of spheres to fit the curvature at that point. The algorithm dete rmines a minimum and maximum size best-fit sphere and, from their radii, determines an average curvature (arithmetic mean of principal curvatures) known as the mean curvature for that point. These powers are then mapped using standard colors to represent diopter changes, alloWing for more sensitivity to peripheral changes of curvature (Fig 2-27). In addition to power maps, computerized topographic systems may display other data: pupil size and location, indexes estimating regular and irregular astigmatism, estimates of the probability of having keratoconus, simulated keratometry, and more.

42 • Exte rnal Di sease and Cornea Mean Power

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All of these maps attempt to depict the underlying shape of the cornea by scaling curvature through the familiar dioptric notation instead of the less fam il iar millimeters of radius. A more accurate way to describe curvature wou ld be to use th e true shape of the cornea; some systems directly derive corneal shape by means of scanning slits or rectan gular grids and then determine power from that shape. To represent shape directly, maps may display a z-height from an arbit rar y plane (iris plane, limbal plane, or frontal plane) using color maps. Just as viewing the curvature of the earth in an appropriate scale fails to show the details of mountains and basins, these

CHAPTER 2:

Examination Techn iques for the Externa l Eye and Cornea. 43

z maps do not show clinically important variations. Geographic maps show land elevation relative to sea level. Similarly, corneal surface maps are plotted to show differences from best-fit spheres or other objects that closely mimic the normal corneal shape. The American National Standards Institute (ANSI) in the United States is currently developing standards for the corneal topography industry that will make the comparison of maps more uniform and clarify the confusion of terminology.

Indications About two thirds of patients with normal corneas have a symmetric pattern that is round, oval, or bowtie-shaped, as in Figure 2-28. The others are classified as having an asymmetric pattern: inferior steepening, superior steepening, asymmetric bowtie patterns, or nonspecific irregularity. However, many corneas are found to have a complex shape that is oversimplified by the use of such qualitative pattern descriptions. Corneal topography detects irregular astigmatism from contact lens warpage, keratoconus and other thinning disorders, corneal surgery, trauma, and postinflammatory and degenerative conditions. Different values obtained at subsequent examinations can Signal a change in corneal contour if the alignment of the eye and the instrument is the same. Computer-assisted topographiC modeling systems allow the clinician to detect subtle and minor variations in power distribution of the anterior corneal surface. Corneal topography is important in the preoperative evaluation of cataract and refractive surgery patients. Patients with corneal warpage (irregular astigmatism andlor peripheral steepening, distorted keratoscopic mires) should discontinue contact lens wear and allow the corneal map and refraction to stabilize prior to undergoing surgery. Patients with keratoconus are not routinely considered for LASIK surgery, as the thin cornea has an unpredictable response and red ucing its thickness may lead to progression of the condition. The forme fruste, or subclinical, keratoconus recognized by Placido disk-based topography

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44 • External Disease and Cornea

requires caution on the part of the ophthalmologist and is now considered to be a contraindication to LASIK and possibly surface ablation. Forme fruste keratoconus or early pellucid marginal degeneration may show a peripheral steepening or "crab claw" configuration (Fig 2-29). Furthermore, topographic corneal abnormalities may preclude the use of advanced IOL technologies such as toric, multi focal, or pseudoaccommodative IOLs. Corneal topography can also be used to show the effects of keratorefractive procedures. Pre- and postoperative maps may be algebraically subtracted to determine whether the desired effect was achieved. Corneal mapping may help to explain unexpected results, including undercorrections, aberrations, induced astigmatism, or glare and halos, by detecting decentered surgery or inadequa te surgery, such as shallow incisions in radial kera-

totomy. Corneal topography also confirms the expected phYSiologic effects of refractive surgery. For example, in LASIK for myopia, the ablation profile leads to flattening of the central cornea and a relative periph eral steepening.

Corneal topography is useful in managing congenital and postoperative astigmatism, particularly following penetrating keratoplasty. Complex peripheral patterns may result in a refractive axis of astigmatism that is not aligned with topographic axes. Failure to correct

the underl ying shape by removing appropriate sutures or operating on the appropriate axis may lead to unexpected results. The appropriate axis depends on the type of surgery (incisional surgery is done on the steep axis, compression sutures on the flat axis, and

minus cylinder ablation on the flat axis). Finally, detection of irregular astigmatism by means of corneal topography can be used in managing ocular surface disorders such as map-dot-fingerprint dystrophy.

Limitations Besides the limitations of the algorith ms and variation in terminology by manufacturer, the accuracy of corneal topography may be affected by various other potential problems: misalignment

stability (test-to-test variation)

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Figure 2-29 Keratography of a patient with pellucid marginal degeneration . The "crab claw" appeara nce is fully developed , with ce ntral flattening and inferior steepening; forme fruste keratoconus may have a similar but less definite appearance . (Courtesy of John E Sutphm, MD.)

CHAPTE,R 2:

Exa mination Techniques for the External Eye and Corn ea.

45

sensitivity to focus errors tear-film effects distortions area of coverage (central and limbal) nonstandardized data maps colors that may be absolute or varied (normalized) Corbett MC, O' Brart DPS, Rosen E, et a1. Corneal Topography: Principles and Applications. London: BM) Books; 1999. Courville CB, Klyce SD. Corneal topography. In: Foster CS, Azar DT, Dohlman CH, eds. Smolin and Thoft's The Cornea: SCientific Foundation s and Clinical Practice. 4th ed. Philadelphia: Lippincott vVilliams & Wilkins; 2004:175-1 85. Maguire LJ. Keratometry, photokeratoscopy, and computer-assisted topographic analysis . In: Krachmer JH , Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol 1. Philadelphia: Elsevier! Mosby; 2005:171-184. Roberts C. Principles of corneal topography. In: Elander RE, Rich LF, Robin JB, ed s. Principles and Practice of Refractive Surgery. Philadelphia: Saunders; 1997:475- 497.

Retinoscopy

Retinoscopy can detect irregular astigmatism by showing nonlinear or multiple reflexes that cannot be completely neutralized with a spherocylindrical lens. With a multifocal cornea, retinoscopy reveals multiple regular reflexes that move in different directions. Irregular astigmatism and multifocal cornea can occur in keratoconus and after keratorefractive surgery. Abnormalities found with retinoscopy can help explain why a patient with a clear cornea cannot see well. In addition, retinoscopy can disclose disrupted light reflexes caused by disturbances of the corneal surface. In cases where reti noscopic findings exceed the corresponding slit-lamp findings, retinoscopy can help gauge the relative effect of corneal surface changes on vision. See also BCSC Section 3, Clinical Optics. Krachmer JH, Mannis MJ. Refraction of the abnormal cornea. Tn: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol l. Philadelphia: Elsevier!Mosby; 2005:167-170.

Prevention Practices in Ophthalmology Some corneal and external eye diseases can be prevented. Strategies for prevention include adequate hygiene and nutrition, aseptic surgical techniques, protective spectacles to minimize ocular trauma, and prophylactic antibiotics. Prevention begins with imn1unization. Practicing ophthalmologists should provide their office staff with an opportunity for hepatitis B vaccination and follow other regulations of the Occupational Safety and Health Administration. Universal precautions that safeguard the health of patients' eyes, as well as the health of the ophthalmologist's and staff's eyes, should be a part of daily practice. Universal Precautions

Optimal infection control is based on the assumption that all specified human body fluids are potentially infectious. Many transmissible diseases of the external eye, such as adenoviral conjunctivitis, cause redness that immediately indicates infection. Other infectious

46 • External Disease and Co rn ea

agents, hmvever, can be present o n the ocular surface without causing inflammation. Human inlmu nodeficiency virus (HI V), hepa ti tis B virus, hepatitis C vi rus, rabies virus, and the agent of ereutzfe ldt-Jakob disease are not immediately obvious without systemic clues or laboratory testing. Every patient must be approached as potentially contagious. Guidelines for ro utine ophthalmic examinations include the following:

Wash hands between patient examinations. Use d isposable gloves if an open sore, blood, or blood -contaminated fl uid is present. Using cotton -tipped applicators to manipulate the eyelids can also minimi ze direct contact. Avoid unnecessar y contact. Eyedropper bottles used in the offi ce should not directly touch the eyelids, eyelashes, or ocu lar surface of any pati ent. Individual sterile strips impregnated with dye are preferred whe re available. D isinfect all contact instruments after each use. Tonometer tips and pachometer tips should be soaked in diluted bleach or hydrogen peroxide after every use. Trial contact lenses must be disin fected between patients. BeSe Section la, Glaucoma, discusses in fectio n control in cl in ical to no metry in greater detail. Handle sharp devices carefu ll y. Needles must always be discarded into punctureresistant (sharps) containers. Universal precautions are also discussed in BeSe Section 9, Intraocular Inflammation and Uveitis. Minimizing transm iss ion of bloodbo rne pathoge ns and surface infectious agents in ophthalmic offices and ope rati ng rooms. Information Statement. San Francisco: American Acad emy of Ophthalmology; 2002. Segal WA, Pirnazar JR, Arens M, Pepose ]S. Disinfection of Gold mann tonometers after co ntamination with hepatitis C virus. Am J Ophth(llmol. 2001; 131 (2): 184- 187. Smith CA, Pepose ]S. Disinfection of tonometers and contact lenses in the office setting: are current techniques adequate? Am } Oph thalmol. 1999;127( 1):77-84 .

CHAPTER

3

Ocular Surface Disease: Diagnostic Approach

Ocular Cytology An important step in the diagnosis of m any in fect io us and infla m matory conditions of th e ocu lar surface is the examination of conjunctival or corneal specimens by light micros-

copy. Standard stain ing procedures are widely used to faci litate the detection of microbial and human cells. This section d iscusses the procedures used in these investigat ions and the implications that can be drawn from their results. See also BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors.

Specimen Collection Scraping or swabbing Conjunctival scrap ing is generally preferred to swabbing because it yields more epithelial cell s and causes less contamination due to inflammatory debr is from the ocular surface. To obtain a conjunct ival specimen for cytologic examination, th e clinician applies a topi-

cal anesthetic and everts the upper eyelid. The ta rsal conjunctiva is lightly scraped with a sterile spatula. When epithelial cells are removed du rin g scrap ing, the conjunctival surfa ce should bl anch slightly, but not bleed excessively. An alternative method of gathering conjun ctival cells involves the use of a cytobrush. After the conjunctiva is rubbed, the brush is dipped into buffer solution, and the cells that float to the surface are concentrated on a Millipore filter. Rap id imme rsion into fixative avoids excessive air dry ing of material on a

glass slide or fi lter paper. Conjunctival swabbing for culture should be done before a topical anesthetic is in stilled. Calci um alginate or Dacro n swabs, slightl y moistened with liquid broth, are preferable for collecting speci mens of epithelial cells and microfl ora; cotton swabs may inhibit bacte ri al and viral growth. Specimens can also be obtained from the contralateral con jun ctiva for comparison. Procedures for obtaining and cult uring speci mens for suspected infect io us conditions

are discussed further in Chapter 4.

Impression cytology Imp ression cytology is primarily a research tool, but it allows fo r precise assessment of the ocular surface epithelium. A piece of filter paper is pressed against a specific area of the 47

48 • Externa l Dis ease and Cornea

conj unctival (or, in rare cases, the corneal) surface to lift off epithelial cells. This procedure can be considered a noninvasive superficial biopsy that provides a means for mapping specific cell changes topographicall y and quantifying surface abnormalities. Cells thus harvested can be examined directly as attached epithelial sheets for morphologic and histologic studies or may be processed as free cells for flow cytometry; the latter technique allows quantification of the expression of specific proteins (eg, cytokines, receptors, and so on) by the epithelial cells. The technique is both powerful and quantitative, and it precludes the need for a biopsy, which is not always convenient in a clin ic setting. Baudouin C, Hamard P, Liang H, Creuzot-Garcher C, Bensoussan L, Brignole F. Conjunctival epithelial cell expression of interleukins and inflammatory markers in glaucoma patients treated over the long term. Ophthalmology. 2004;111(12) ,21 86-2192. Koh S, Maeda N, Hirohara Y, et aL Serial measuremen ts of higher-order aberrations after blinking in patients with dry eye. Invest Ophtha/mol Vis Sci. 200S;49( 1): 133-13S. Preferred Practice Patterns Committee, Cornea/External Disease Panel. Conjunctivitis . San Francisco: American Academy of Ophthalmology; 200S. Tseng Sc. Staging of conjunctival squamous metaplasia by impression cytology. Ophthalmology. 1985;92(6P28-733.

Interpretation of Ocular Cytology Microscopic examination of material collected from the ocular surface can reveal ceils, cell ular elements, and microorganisms that can be helpful in diagnostic evaluation; such examination is perhaps best carried out in conjunction with a laboratory experienced in these evaluations.

Dry-Eye Syndrome The term dry-eye syndrome has been defined as "a multifactorial disease of the tears and ocular surface that results in symptoms of d iscomfort, visual disturbance, and tear-ftlm instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface" (DEWS, 2007) . Dry eye represents a disturbance of the la crimal functional unit (LFU), an integrated system comprising the lacrimal glands, ocular surface (cornea, conjunctiva, and meibomian glands), and eyelids, as well as the sensory and motor nerves that connect them (Fig 3-1 ). The LFU regulates the major components of the tear film and responds to environmental, endocrinologic, and cortical in fl uences. Its overall functions are to preserve tear-film integrity: lubricating, ant imicrobial, and nutritional roles ocular surface health: maintaining corneal transpare ncy and surface stem cell population quality of image projected onto the retina

Tear-film stability is threate ned when the interactions among stabilizing tear-film constituents are compromised by decreased tear secretion, delayed clearance, and altered tear composition. A consequence of such compromise is ocular surface inflammation. Although the initial reaction to ocular irritation may be reflex tear secretion, eventuall y

50 • Externa l Disease and Cornea

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center of Fig 3-2). Low humidity and high air now help increase evaporative loss, which may be caused clinically, in particular, by meibomian gland dysfunction (MGD), which leads to an unstable teadilm lipid layer. The quality of eyelid oil is modified by the action of esterases and li pases released by normal eyelid commensals, whose numbers are increased in blepharitis. Reduced aqueous tear now is due to impaired delivery of lacrimal nuid into the conjunctival sac. It is unclear whether this is a feature of normal aging, but it may be induced by some systemic drugs, such as certain antihypertensive agents, antihistamines, and antimusca rinic agents. The most common cause is inflammatory lacrimal damage, which is seen in autoimmune disorders such as Sjogren syndrome and also in non-Sjogren syndrome dry eye (NSSDE). Inflammation causes both tissue destruction and a potentially reversible neurosecretory block. A receptor block may also be caused by circulating antibodies to the M3 receptor. Inflammation is favored by low tissue androgen levels. Tear delive ry may be obstructed by cicatricial conjunctival scarrin g or reduced by a loss of sensory reflex drive to the lacrimal gland from the ocular surface. Eventually, the chronic surface damage of dry eye leads to a reduction in corneal sensitivity and renex tear secretion. Various etiologies, acting, at teast in part, by the mechani sm of reflex secretory block, may cause dry eye, including refractive surgery (LASIK dry eye), contact lens

CHAPTER 3:

Ocu lar Surface Disea se: Diagnostic Approach. 51

wear, and the chronic abuse of topical anesthetics. Individual etiologies often cause dry eye by several interacting mechanisms.

Classification: Major Etiologic Causes of Dry Eye Interpret ing studies that investigate the ris k factors, pathogenesis, and therapy of dryeye cond itions has been complicated in the past by a lack of accepted d iagnostic criteria and standardized, specific diagnostic tests. However, a diagnostic classification scheme fo r dry-eye disorders has now been estab li shed, along with uniform guidelines for evaluating both the disorder and its response to therapy. The major subclassification in this scheme, shown in Figure 3-3, separates dry-eye patients into those with ATD and those with evaporati ve tear dysfunction (ETD). The term environment is used broadly to include bod ily states habituall y experienced by an ind ividual both internall y and externally.

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Diagnostic classification scheme for dry-eye disorders. (Courtesy of Minas T. Coroneo. MD.}

52 • Externa l Di sease and Cornea

This background may infl uence the onset and type of dry-eye d isease in an individual, which may be aqueous-deficient or evaporative in nature. Aqueous-deficient dry eye has 2 major gro upings: Sjogren syndrome dry eye and nonSjogren syndrome dr y eye. Evaporati ve dry eye may be intrinsic, where the regulation of evaporative loss fro m the tear film is directly affected (eg, by meibomian lipid deficiency; poor lid congruity and lid dynamics; low blink rate; and the effects of drug action, such as that of systemic retinoids). Extrinsic evaporative dry eye is caused by conditions that are associated with evaporation through pathologic effects on the ocula r surface. These in clude vitamin A deficiency; the action of toxic topical agents such as preservatives; contact lens wear; and a range of ocular surface diseases, including allergic eye disease. Dry-eye syndrome is one of th e commonest reasons for ophthalmic consultation and becomes increasingly prevalent with age, affecting approximately 10% of those aged 30- 60 and increasing to 15% of adults over the age of 65. Most epidemiologic studies have demonstrated a higher prevalence among women, and it seems to occur with equal preva lence in all racial and ethnic groups. There has been renewed interest in dr y eye with the growth and development of refrac tive procedures, which demand high ocular surface quality on the one hand, yet interfere with ocular surface innervation and shape on the other. Related technologies (such as double-pass ret ina l image- based scatter indices) may allow more sensitive measures of tear-film failure.

Tear-Film Evaluation Tests for dry eye lend some degree of obj ectivity to what is essentiall y a clinical diagnosis, although no one test is sufficiently specific to permit an absolute diagnosis. The best approach is to combine information from th e history and exam inat ion with the results of one or more of the following diagnostic tests. The tests described may be performed in the following sequence to minimize the potential fo r alterat io n of subsequent test resu lts by preceding procedu res. However, any of the tests may affect the outcome of subsequent ones. An ongoing issue in assessing patients with dry eye is th e frequent lack of correlation between symptoms and signs.

Inspection A "foot-of-the- bed" inspection may reveal signs of associated systemic disease (such as rheumatoid arth rit is), indications of personal habits (eg, smoking), or signs of associated ocular disease (pseudoptosis, blepharospasm), as well as eyelid malpos ition. External exam ination may also revea l the characteristic facia l telangiectasia and eyelid margin hyperemia associated with ocular rosacea. Inspection of the tear meniscus between the globe and the lower eyelid (no rmall y 1.0 mm in height and convex) is essentia l. A tear men iscus 0.3 mm or less is cons idered abnormal. Tear breakup is a functio nal measure of tear stabili ty; if stability is perturbed (as in lipid or mucin deficiency), the tear breakup time (TBUT) can become more rapid (lower). TBUT is determined by instilling nuorescein and then evaluating the stability of

CHAPTER 3 :

Ocular Surfa ce Disease: Diagnostic Approach . 53

the tear film. The examiner moistens a fluorescein strip with sterile saline and applies it to the tarsal conjunctiva (fluorescein-anesthetic combination drops are not suitable for this purpose). After several blinks, the tear film is exam ined using a broad beam of the slit lamp with a blue filter. The time lapse between the last blink and the appearance of the first randomly distributed dry spot on the cornea is the tear breakup time. Dry spots appearing in less than 10 seconds are considered abnormal. Noninvasive assessment of the TBUT (without applyi ng any fluorescein to the ocular surface) can also be made by using optical (eg, videokeratoscopic) imaging devices that can similarly detect a break in the tear film. TBUT should be measured before any eyedrops are instilled and before the eyelids are man ipulated in any way. It is best to wait at least 1 minute after fluorescein instillation to eva luate the corneal su rface for fluorescein staining. Afterward, an additional dye, such as lissamine green or rose bengal, can be used to evaluate bulbar conjunctival staining. Evidence of tear-fUm debris should be sought. The eye should be carefully inspected for conjunctivochalasis, especially in patients with poor-quality tear film who complain of epiphora (Fig 3-4). Also, besides an assessment of staining, a complete inspection of the ocular surface, including eversion of the eyelids, must be performed. Evaluation of eyelid laxity in floppy eyelid syndrome can be done at this time. Some of the symptomatology of dry eye can occur in patients with multi ple concret ions. often seen in patients with chronic blepharitis (Fig 3-5; see also Chapter 5).

Tests of Tear Production Aqueous tear production can be assessed in a variety of ways (Table 3-1). Schirmer testing is performed by plaCing a thin strip of filter paper in the inferior cul-de-sac (Fig 3-6). The amount of wetting can be measured to quanti fy aqueous tear production. There are several variations of the Schirmer test. The basic secretion test is performed following the instillation of a topical anesthetic, followed by lightly blotting residual fluid out of the

Figure 3-4 Conjunctivochalasis is frequently seen in dry-eye patients and may require repair. (Courtesy of Robert W Weisenrhal, MD.)

Figure 3-5

Multiple concretions in a patient

with dry eye and chronic blepharitis . Symptoms were more easily controlled after the concretions were removed. (Courtesy of Minas r Coroneo, MD.)

54 • Externa l Disease and Cornea

Table 3-' Assessment of Aqueous Tear Production Test

Topical Anesthesia

Time

+

5 min 5 min 5 min

Basic tear secretion Schirmer I Schirmer II

Nasal Stimul ation

Normal Va lue

;,:>:lQmm

+

.?:10mm .?: 15 mm

Figure 3-6 The Schirmer test uses the amount of wett ing of the paper strips as a measure of tear flow. (Reproduced with permission from Carr 1; ed. Ophthalmic Medical Assisting. 3rd ed, rev. San Francisco: American

Academy of Ophthalmology; 2003:93.)

inferior fornix. A thin filter-pa per strip (5 mm wide, 35 mm long) is placed at the junction of the middle and lateral thirds of the lower eyelids to minimize irri tation to the cornea during the test. The test can be performed with open or closed eyes, although some recom mend the eyes be closed to limit the effect of blinking. Although normal measurements are quite variable, repeated measurements of less than 5 mm of wetting, with anesthetic, are highly suggestive of aqueous tea r deficiency (ATD), whe reas 5- 10 mm is equivoca l. The Schirmer I test, which is si milar to the basic secretion test but without topical anesthetic, measu res both basic and reflex tearing combined. Less than 10 mm of wetting after 5 minutes is diagnostic of ATD. Although th is test is relatively speciflc, the level of sensitivity is poor. Using lower cutoff measurements increases the specificity of these tests but decreases their sensitivity. The Schirmer II test, wh ich measures reflex secretion, is performed in a similar manner wit hout topical anesthe ti c. However, after the filter-paper strips have been inserted into the in ferior fornices, a cotto n-tipped applicator is used to irritate the nasal mucosa. 'Aletting ofless than 15 mm after 5 minutes is consistent with a defect in reflex secretion. Although an isolated abnormal result for any of these tests can be mislead ing, serially consistent results are highly suggestive. Schirmer testing is also useful in demonstrating to patients the presence of an ATD. An alternative to classic Schirmer strips is the phenol red-impregnated cotton thread test, which allows for qu icker assessment of tear secret ion but has not been full y validated.

Tear Composition Assays Other procedures may be useful in helping diagnose ATD. Cultures of the eyelid margins are rarely helpful, but they may provide useful information in selected cases. Additional tests include tear-film osmolarity (virtually all forms of dry eye are associated with increased osmolarity; benchtop osmometers are becoming more available), tear lysozyme, and tear lactoferrin. In lacrimal gland dysfunction states, the normal production of

CHAPTER 3:

Ocular Surface Di sease: Diagnosti c Approach .

55

proteins by the lacrimal gland is dim in ished, so a decreased tear lysozyme or lactoferrin level is high ly suggestive of dry eye. A commercial assay is available for measuring lactoFerrin in tears. Many of these tests have been used in clinical tr ials assessing the efficacy of novel treatments for dr y eye. At the present ti me, no consensus has been reached as to which of these tests is most sensitive an d/or specific for the di agnosis of ATD, and some are not readily ava ilable.

Newer Imaging Technologies and Dry Eye An important symptom of d ry eye is red uced qua li ty of vision, and many new technologies brought about by refractive surgery may prove useful in functional assessments of d ry eye. Wavefront sensing, fo r example, appears to be a useful objective method for evaluating sequential changes in visual performance related to tear- film dynamiCS. Serial measurement of higher. order aberrations, increased in some fo rms of dr y eye, may show a relationship between tea r dynamiCS and quali ty of vision. More recently, retinal image double-pass-based scattering indices have been developed as an objective means of assessing the tear film . Confocal m icroscopy has been used to image the tear film and assess dry-eyeassociated corneal neu ropathy. It has also been used to assess meibomian gland morphology; mean acinar unit diameter is sign ificantly larger in patients wit h meibomian gland disease. Both the denSity and diameter of acinar units has been shmvn to be associated with the severity of meibom ian gland dropout.

Aqueous Tear Deficiency Findings that are particularly indicative of ATD incl ude, by definition, decreased aqueous tear production, as measured by Schirmer testi ng. In add ition, the characteristic exposure pattern of conjunctival and/o r corneal stain ing with either lissaJnine green or rose bengal, corn eal stai ning by fluo rescein, and filamentary keratopathy support a diagnOSiS of ATD. Pat ients who display signs and symptoms of ATD can be subdivided into those who have Sjogren syndrome and those who do not (non-Sjogren syndro me) . The spectrum of ATD ranges from mild irr itation wi th min imal ocular surface disease to severe and disabli ng irritation. occaSiona ll y associated with Sight-threateni ng corn eal complications. Advanced stages can incl ude the development of corneal calcification , particularly in association with certain topical medications (es peCially anti glaucoma medicatio ns); band keratopathy; and keratinization of the cornea and conj unctiva. Symptoms tend to be worse toward the end of the day, with prolonged use of the eyes. or with exposure to environmental extremes. Patients who live in temperate climates and are exposed to the lower levels of hu mid ity assoc iated with indoor heating systems during the winter months tend to become particularly symptomatic. Foreign-body sen sation is a symptom frequently associated with punctate epithelial keratopathy. Associated complaints include burning, a d ry sensation, photophobia, and blurred vision. Rapid

CLINICA L PRESENTATION

56 • External Disease and Cornea

assessment of dry eye can be achieved by the "stare test": after a few blinks, a patient is asked to look at a visual acuity chart; the time until the image blurs should be more than 8 seconds. Signs of a dry eye include bulbar conjunctival hyperemia, conjunctivochalasis (redundancy of the bulbar conjunctiva), a decreased tear meniscus, irregular corneal surface, and debris in the tear film. Epithelial kerato pathy, which can be fine and granular, coarse, or confluent, is best demonstrated following the instillation of lissamine green, rose bengal, or fluorescein. Fluorescein stains epithelial erosions and exposed basement membrane and may produce fine or coarse granular staining of the inferior or central cornea. Rose bengal and lissamine green stain not only dead and devitalized cells and mucus but also epithelial cells that are inadequately protected by ocular surface mucins. Rose bengal and lissamine green staining can be more sensitive than fluorescein in revealing early or mild cases of keratoconjunctivitis sicca (KCS); the staining may be seen at the nasal and temporal limbus and/or inferior paracentral cornea (exposure staining) (Fig 3-7; see also Fig 2-12C, in Chapter 2). Alternatively, it can be most prominent along the inferior cornea and inferior conjunctiva (linear staining), as seen in MGD. Lissamine green has some advantages over rose bengal: it does not stain healthy conjunctival epithelium, it is far less irritating, and it does not inhibit viral growth. In more severe dry-eye states, filaments and mucous plaques may be seen. Filaments represent strands of epithelial cells attached to the surface of the cornea over a core of mucus. Filamentar y keratopathy can be qui te pain ful, as these strands are firmly attached to the richly innervated surface epithelium (Fig 3-8). Marginal or paracentral thinning and even perforation can occur in more severe disease. Incomplete blinking is frequently noted. Associated local eye disease, such as blepharitis, MGD, and eyelid abnormalities, can contribute significantly to the patient's level of discomfort. Clinicians may find useful a classification based on disease severity (Table 3-2). A reliable means of assessing cl inical disease severity by questionnaire is the Ocular Surface Disease Index (OSDJ). The question naire is useful in evaluating the effects of various treatment regimes, and the scoring system allows patients to follow their progress. In some patients, although ocular surface health improves, discomfort does not (this is thought to be due to corneal neuropathy).

Figure 3-7 Ke ratoconjunct ivitis sicca with punctate epithelial erosions, shown by rose benga l stain. (Courtes y of Vincent P deLuise, MD.)

CHAPTER 3:

Figure 3-8

Ocular Surfac e Disease: Diagnostic Approach.

57

Fil am enta ry ke ratopathy in a vascu larized cornea . (Courtesy of Minas T Coroneo. MD)

Although lacrimal gland biopsy is rarely performed to help diagnose Sjogren syndrome, minor (labial) salivary gland biopsy is easily carried out (Fig 3-9). After local anesthetic gel is applied, followe d by local infiltration, a chalazion clamp is applied to the buccal mucosa inside the lower lip. A 1- to 2-mm incision is made with a 30' blade, and tissue deep to this is grasped, teased through the incision, and excised. Clumps of glands usually emerge, 2- 3 clumps per incision site. Patients are warned of the possibility of localized labial numbness, although with this small incision technique, it is rare. Conjunctival impression cytology can be used to monitor the progression of ocular surface changes, beginning with decreased goblet cell density, followed by squamous metaplasia and, in later stages, keratinization. Patients with ATD may have circulating autoantibodies, including antinuclear antibody (ANA), rheumatoid factor (RF ), or SS antibodies (SS-A and SS-B). The presence of these antibodies has been correlated with the severity of symptoms and ocular surface changes, including a higher incidence of sterile and bacterial keratitis, suggesting that a disturbance in immune regulation may playa role in pathogenesis. As previously noted, many systemic diseases have been associated with ATD (Table 3-3).

LABORATORY EVALUATION

MEDICAL MA NAG EMENT The selection of treatment modalities for patients with dry eye depends largely on the severity of their disease (Table 3-4). Mild cases of dry eye may require no more than the use of artificial tear solutions. Preservative-free lubricants can be useful, even at early stages of the disease. Changing or discontinuing any topical or systemic medications that contribute to the condition should be considered, although it is not always practical. Smoking is a risk factor, and advice regarding cessation should be sought. Warm compresses with eyelid massage can also help by bolstering the lipid layer. If the condition is not suffiCiently managed with artificial tears, the use of sustained-release ocular lubricants may be considered. 11 may also be appropriate to modify the patient's environment in an effort to reduce evaporation of the tear film; a humidifier and/or moisture shields on glasses can be helpfuL Therapy for patients with severe dry-eye syndrome

58 • Exte rnal Di sea se and Co rn ea

Table 3-2 Dry-Eye Severity Grading Scheme Dry-Eye Severity level Discomfort, severity & frequency

2 Mi ld and/or episod ic; occurs unde r environmental stress None or episodic mild fatigue

Conjun ctiva l injection Conjunctival staining Cornea l sta ining (severity/ locat ion) Cornea l/tear signs

N one to mild

Mo derate episodic or chronic. stress or no stress Annoying an d/ or activitylimit ing episod ic None to mild

None to m ild

Va ri able

None to mi ld

Va riable

None to m ild

Mild debris, t meniscus

Filamentary keratitis, mucus clu m ping, i tear debris

Li d/meibomian glands

MGO va riably present

MGD variably present

Frequent

TBUT (sec)

Variable Va riable

5 10 5 10

\Tegener granulomatosis. Patients receiving systemic immunosuppressive therapy for scleritis should be monitored closely for systemic complications associated with these drugs. Antituberculosis and anti-Pneumocystis coverage may be necessary for at-risk patients. Both the treatment and long- term management of these patients are best done as a collaborative effort between the ophthalmologist and rheumatologist. In patients whose systemic evaluation is initially negative, it is important to repeat the vmrkup annually. Albert DM, Miller JW, Azar DT, Blodi EA, eds. Albert 6- Jakobiec's Principles and Practice of Ophthalmology. 3rd ed. 4 vols. Philadelphia: Elsevier/Saunders; 2008. Jabs DA, Mudun A, Dunn JP, Marsh MJ. Episcleritis and scleritis: clinical features and treatment results. Am J Ophthalmol. 2000:130(4):469-476 .

CHAPTER

8

Clinical Approach to Neoplastic Disorders of the Conjunctiva and Cornea

In the United States, approximately 1 person in 2500 seeks ophthalmic care for a tumor of the eyelid or ocular surface each year, about 100,000 total. Benign neoplasms are at least 3 times more frequent than malignant lesions. Most of these tumors arise from the eyelid

skin and are discussed in BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors, and Section 7, Orbit, Eyelids, and Lacrimal System. Neoplastic tumors of the conjunctiva and cornea are considered together because the

lesions often affect both tissues in a similar fashion. These lesions are classified by cell type: epithelium, melanocytes and nevus cel ls, vascular endothelium, mesenchymal cells,

and lymphocytes. Many are analogous to lesions affecting the eyelid. See also BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors. Shields JA, Shields CL. Atlas of Eyelid and Conjunctival Tumors. Philadelphia: Lippincott Wil liams & Wilkins; 1999.

Inclusion Cysts of the Epithelium Inclusion cysts of the conjunctival epithelium are typically asymptomatic and are commonly found during routine ophthalmic examination (Fig 8-1). PATHOGENESIS

Like epidermal cysts of the eyelids, cysts of conjunctival epithelium can

be congenital or acquired. Most acquired cysts of the conjunctiva are derived from an

inclusion of conjunctival epithelium into the substantia propria. As nests of epithelial cells proliferate, a central cavity forms lined by nonkeratinized conjunctival epithelium. The

central cavity is filled with clear fluid. Conjunctival cysts may also form from ductal epithelium of the accessory lacrimal glands and are lined by a double layer of epithelium . Stimuli for cyst formation include chronic inflammation, trauma, and surgery. Conjunctival inclusion cysts typically appear clear and i110st commonly occur in either the bulbar conjunctiva or the conj unctival fornix. A corneal epithelial inclusion cyst is rare, but it can occur if trauma, surgery, or chronic inflammation results in

CLINICAL FINDINGS

conjunctival overgrowth onto the surface of the cornea. Dilated lymphatic channels may mimic an inclusion cyst of the bulbar conjunct iva.

225

226 • External Di sease and Cornea

Figure 8-1

Large conjunctival epithel ial inclusion cyst.

Epithelial inclusion cysts are most commonly asymptomatic and therefore may be simply observed. Cysts will usually re-form after simple drainage because the inner epithelial cell wall remai ns. Complete excision is necessary to prevent recurrence.

MA NAGEME NT

Tumors of Epithelial Origin Table B-1 lists the epithelial tumors of the conjunctiva and cornea. \'Varner MA, Jakobiec FA. Squamous neoplasms of the conjunctiva. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol 2. Philadelphia: Elsevier/ Mosby; 2005:557-570.

Benign Epithelial Tumors

Conjunctival papilloma The 2 form s of conjunctival papi lloma, sessile and pedunculated, have etiologic, h istologic, and clinical differences. Human papilloma virus (HPV), subtype 6 (in children) or 16 (i n ad ults), initiates a neoplastic growth of epithelial cells with vascular proliferation that gives rise

PATHOGE N ES IS

Table 8·1 Neoplastic Tumors of Ocular Surface Epithelium Beni gn

Preinvas ive

Malignant

Papilloma

Conjunct ival and corneal intraepit helial neopl asi a

Squamous cell carc in oma

Pseudoepitheliomatous hyperplasia Benign hereditary intraep ithelial dyskeratosis

Mucoepidermoid carcinoma

CHAPTER 8:

Cli nica l Ap proach to Neopl astic Disorders of the Conjunctiva and Corn ea.

2 27

to a pedunculated papilloma of the conju nctiva. Although also usually benign, a sessile conjunctival lesion may represent a dysplastic or carcinomatous lesion, especially when caused by HPV- 16 or HPV-18 . A pedunculated conjunctival papilloma is a fleshy, exophytic growth with a fibrovascular core (Fig 8-2A). It often arises in the inferior fornix but can also present on the tarsal or bulbar conjunctiva or along the semilunar fold. The lesion emanates from a stalk and has a multilobulated appearance with smooth, clear epithelium and numerous underlying, small corkscrew blood vessels. Multiple lesions sometimes occur, and the lesion may be extensive in patients with compromised im munity. A sessile papilloma is more typically found at the limbus and has a flat base (Fig 8-2B). The glistening surface and numerous red dots resemble a strawberry. The lesion may spread onto the corn ea. Signs of dysplasia include ke ratinization (leukoplakia), symblepharon for mation, inflammation, and invasion. A very rare variant is an inverted papilloma.

CLIN ICAL FI NDI NGS

Many conjunctival papillomas regress spontaneously. A pedunculated papilloma that is small, cosmetically acceptable, and nonirritating may be observed.

MANAGEM ENT

A

8 Fi gur e8-2

Conjunct iva l squamous papillom a. A, Peduncu lated. 8 , Sessile.

(Reproduced withpermis-

sion from Krachmer JH, Mannis MJ, Holland E), eds. Cornea . 2nd ed. Vol 1. Philadelphia: Elsevier/Mosby, 2005'559.)

228 • External Disease and Cornea Spontaneous resolution may take months to years. An incomplete excision, however, can stimulate growth and lead to a worse cosmetic outcome. Cryotherapy alone, excision with cryotherapy to th e base, or excision with adjunctive application of inte rfero n-a 2b is sometimes curative, but recurrences are frequent. Surgical manipulation should be minimized to reduce the risk of virus dissem ination to uninvolved healthy conjunctiva. Oral cimetidine (Tagam et) may be a systemic adju nct acting as an immunomodulator. A sessi le Ii mbal papilloma must be observed closely or excised. If the lesion enlarges or shows clinical features suggesti ng dysp lastic or carcinomatous growth, then excisional biopsy with adj unctive cryotherapy is indicated.

Preinvasive Epithelial Lesions

Conjunctival intraepithelial neoplasia Conjunctival in traepi thelial neoplasia (CIN), or dysplasia, is analogous to actinic keratosis of the eyelid skin. In CIN, the dysplastic process does not invade the un derlying basement membrane and is refe rred to as mild (CIN I), moderate (CIN TI ), or severe (CIN III), depending on the extent of involvement of the epithelium with atypical cells. Related terms include squamous dysplasia, if atypical cells involve only part of th e epithelium, and carcinoma in situ, when cellular atypia involves the entire thickness of the epithelial layer. See also BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors. The relative contributions to this condition ofHPV infection, sunlight exposure, and host fac to rs have not been determined. The lesion most commonly develops on exposed areas of the bulbar conjunctiva, at or near the limbus, in older male smokers with light complexions who may have been exposed to petroleum products or to the sun over long periods of time. Rapid growth may occur when th e lesion is present in a person with AIDS. SystemiC immunosuppression appears to potentiate sq uamous neoplasia. In a young adult, CIN should instigate a serologic test for HIV infection.

PATHOGE NESIS

Macarez R, Boss is S. Robinet A, Le Collonnec A, Charlin ]F, Colin J. Conj unctival epithelial neoplasias in organ transplant patients receiving cyclosporine therapy. Comca. 1999;18(4 ): 495-497.

CIN is usually found at the limbus in the inte rpalpebral zone. There are 3 principal cl inical variants (Fig 8-3):

CLINICA L FINDING S

I. papilliform, in which a sessile papilloma harbors dysplastic cells 2. gelati nous, as a result of acanthosis and dysplasia 3. leukoplakic, caused by hyperkeratosis, parakeratosis, and dyskeratosis

Mild inflam mation and various degrees of abnormal vascularization may accompany CIN lesions, but large feeder blood vessels indicate a higher probabil ity of invasion beneath the epithelial basement membrane. CIN lesions are slow-growing tumo rs nearly always centered at the limbus but wit h the potential to spread to other areas of the ocular surface, includi ng th e cornea. The surgical management of CIN is the same as for squamous cell carci noma of the conjunctiva and cornea. Excision should include 3-4 mm of surrounding,

MANAGE M ENT

CHAPTER 8:

Clinical Approach to Neoplastic Disorders ofthe Conjunctiva and Cornea •

229

Figure 8-3 Conjunctiva l intraepi thelia l neoplasia: A, Papilliform. B, Ge latinous . C, Leukoplaki c. (Part A courtesy of James Chodosh, MD; parts Band C courtes y of James J. Reid v, MO .)

clinically uninvolved, tissue. Rose bengal or lissamine green staining is useful to help delineate tumor margins. CIN has been reported to recur in approximately one third of eyes with negative surgical margins within 10 years and in one half of eyes with positive surgical margins. Lesions with dysplastic cells at the excision edge recur sooner than lesions that have been completely excised. Therefore, although excisional biopsy with adjunctive cryotherapy is still recommended, recent reports have focused on topical chemotherapeutic agents with the potential to treat the entire ocular surface without regard to surgical margins. Interferon-a'b, mitomycin e , and 5-fluorouracil applied topically as eyedrops appear in some cases to completely eradicate CIN lesions. Long-term studies of newer therapies are still pending. Figure 8-4 summarizes the various treatment options for CIN and invasive squamous cell carcinoma. Hardten DR, Samuelson TvV. Ocular toxicity of mitomycin-Co Int Ophtha/mol Clin. 1999;39(2) : 79-90. Koreishi AF, Karp CL. Ocular surface neoplasia. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalm ology; 2007, module I.

Corneal intraepithelial neoplasia The cornea adjacent to intraepithelial neoplasia of the conjunctiva can also be affected. Sometimes, the conjunctival or limbal component is not clinically apparent, and only a sheet or individual islands of well-demarcated, geographic, epithelial granularity are seen. Corneal intra epithelial neoplasia is associated with the same risk factors as e IN and presumably shares the same pathogenesis.

PATHOG EN ESIS

230 • External Disease and Cornea

Alcohol corneal epithelialectomy +

Lr~~~~~~~~~~

L~ ~ ~B~e~a~v~e~,b~l~ad~e~s~c~,a~p~;"~g~ ~ ~

--------- r

____________ +1- Rose bengal

Beaver blade scraping alone

3-4 mm tumor-free margins

/

l[s~u~,~g~;c~a~l~ex~c~;s~;~o~"JI ~----___ ~

Cryotherapy at limbus

L=~LL.J _ _ _ _

~I

I Stromal bed

.. ;---+-I---L-a-m-e-'Ia-'-s-cl-e-'e-c-'o-m-y-----,

_ _ _ _ _. ..

1------1/ 1 ----""1 0.04% OlD I Punctalocclusion ~

Cryotherapy at excisional margins

~========~==i +/- Cryotherapy

Daily until clinical re solution (generally not more than 14 days)

0.02%010

1MMC

; -____________

Cycle 14 days on, 2-4 weeks off repeated until clinical resolution

Steroid as needed

Cycle 1 week on, 1 week off until cl inical resolution

~ _______ I

Daily for 4 weeks

1 m I---+LI_ _ '% _0_10_ -.-11 ___---.... i===~=======i . .. . Cycle on 2-4 days, off 30-45 days unti l clinical resolution

I plus topical aiD "" . ____ ~ ----""' 1 TopicalO ID 1 --------._ 1 . . .

Subconjunctivallintralesiona I ---+- 0.5 mL 3 mill ion IU/O.S mL

/'

I

1 mi llion IU/mL aiD

Repeated 1- 3 x per week

until clinical resolution I---+- ;:::=======:::=~ Drops tapered over 1 ---+- months or stopped after . clinical resolution

8-4 Treatment opt ions for conjunct ival intraep ithelia l neoplasia and invasive squamous ce ll carc inoma. (Reproduced from Koreishi At=, Karp CL. Ocular surface neoplasia. Focal Points Clinica l Modules for

Figure

Ophthalmologists . San Fra ncisco: American Academy of Ophthalmolog y; 2007, module1.J

A granular, translucent, gray epithelial sheet broadly based at the limbus extends onto the cornea. Occasionally, free islands of punctate granular epitheliUlll are present on the cornea. The edges of corneal lesions have characteristic fimbriated margins and pseudopodia-like extensions (Fig 8-5) . Rose bengal and lissamine green staining help define the edges of the lesion. Corneal neovascularization does not typically occur, which helps to differentiate CIN lesions fro mlim bal stem cell failure. CLIN ICA L FIN DING S

Corneal involvement may be treated by applying absolute alcohol for 30- 40 seconds to the affected part of the cornea and extending 1- 2 mm into the normal cornea, followed by copious irrigation with balanced salt solution. The devitalized epithelium is then gently removed from the underlying Bowman layer with a surgical sponge, a blunt spatula, or a No. 64 Beaver blade. Care should be taken not to penetrate the Bowm an layer. Excision of the grossly normal but often histologically abnormal adjacent Iimbal tissue is important, even if the lesion appears to be primarily corneal. Cryotherapy of the excisional margins of the conjunctiva, using a double rapid-freeze-slow-thaw technique, MANA GEMENT

CHAPTER 8:

Clinical Approach to Neoplastic Disorders of the Conjunctiva and Cornea.

Figure 8-5

231

Cornea l intraepithel ial neoplasia. (Courtesy of James Chodosh, M O)

can destroy any residual abnormal cells and possibly reduce the likelihood of recurrence. In cases where extensive surgical excision may lead to future ocular surface disease, or in cases of recurrent tumor, topical chemotherapy using mitomycin C, 5-fluorouracil, or interferon-a2b has successfully eradicated ocular surface neoplasia. See the references in "Conjunctival intraepithelial neoplasia:'

Malignant Epithelial Lesions

Squamous cell carcinoma Squamous cell carcinoma, a plaquelike, gelatinous, or papilliform growth, occurs in limbal and bulbar conjunctiva in the interpalpebral fissure zone of older individuals. Ultraviolet radiation is an important influence on the development of squamous cell carcinoma, but viral and genetic factors probably also playa role. Squamous cell carcinoma is more common and more aggressive in patients with compromised immunity and in those with xeroderma pigmentosum.

PATHOGENESIS

A broad base is usually present along the limbus. The lesion tends to grow outward with sharp borders and may appear leukoplakic (Fig 8-6). Although histologic invasion beneath the epithelial basement membrane is present, growth usually remains superficial, infrequently penetrating the sclera or Bowman layer. Pigmentation can occur in dark-skinned patients. Engorged conjunctival vessels feed the tumor.

CLINICAL FINDINGS

When possible, complete local excision of the tumor, accompanied by adjunctive cryotherapy, is suggested. The treatment of choice includes excision of conjunctiva 4 mm beyond the clinically apparent margins of the tumor, along with a thin lamellar scleral flap beneath the tumor; treatment of the remaining sclera with absolute alcohol; and cryotherapy applied to the conjunctival margins. As with CIN, the risk of recurrence depends on the status of the surgical margins. If neglected, squamous cell carcinoma can

MANAGEMENT

232 • Externa l Disease and Cornea

Figure 8-6

Limbal squamous cell carcinoma.

eventuall y invade the interior of the eye, where the tum or can exhibit vigorous growth. Invasion of the iris or trabecular meshwork provides th e tumor with access to the systemic circulati on and may be the ro ute by which metastases occur. Orbital invasion may necessitate orbital exenteration. Radiatio n therapy mal' be indicated as adjunctive th erapy in select cases. The area of surgical resection may be closed pri marily or left open to heal if the area of resection is small in size. An amniotic membrane graft may be Llsed to cover larger defects. Amniotic membrane facil itates reepithelialization and minimizes postoperative innammation. The graft should be cut slightly larger th an the defect and may be fixated with either absorbable (9-0 or 10-0 pol yglactin) o r nonabsorbable suture (10-0 nylon). Tissue adhesive (eg, Tisseel; Baxter Healthcare, Dearfield, IL) may also be used to fixate the graft, thereby avoiding th e need for suture removal and possible com plications related to the presence of the sutures. If greater than two th irds of the limbus is removed, stem cell transplantation may be required. Nordlund ML, Brilakis HS, Holland EJ. Surgical techniques for ocular surface reconstruction. Focal Points: Clinical Modules jar Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2006, module 12. Sh ields CL, Shields JA. Tumors of the conj unctiva and cornea. SIlTV Ophthalmol. 2004;49: 3-24. Tse ng SCG, Tsubota K. Amniotic membrane transpla ntation for ocular surface reconstruction. In: Holland El, Mannis MJ, eds. Ocular Surjace Disease: Medical arId Surgical Man agement. New York: Springer-Verlag; 2002: 226-231 . Warner MA, Jakobiec FA. Squamous neoplasia of the conjunctiva . In: Krachmer ]H, Manni s MJ. Holland EJ, eds. Comea. 2nd ed. Vol l. Ph iladelphia: Elsevier/ Mosby; 2005:557-570.

Mucoepidermoid carcinoma Mucoepidermoid carcinoma, a very rare carcinoma of the limbal conjun ctiva, fornix, or caru ncle, clinically rese mbles an aggressive variant of squamous ceLl carcinoma. In

CHAPTER 8:

Clinical Approach to Neoplastic Disorders of the Conjunctiva and Cornea.

233

addition to neoplastic epithelial cells, malignant goblet cells can be shown with mucin stains. Compared to squamous cell carcinoma, mucoepidermoid carcinoma is more likely to invade the globe or orbit. Treatment is wide surgical excision; adjuvant therapy can include cryotherapy and radiotherapy.

Spindle cell carcinoma Spindle cell carcinoma is a rare, highly malignant tumor of the bulbar or limbal conjunctiva in which the anaplastic cells appear spindle-shaped like fibroblasts.

Glandular Tumors of the Conjunctiva Oncocytoma A slow-growing cystadenoma, an oncocytoma arises from ductal and acinar cells of main and accessory lacrimal glands. 1n older individuals, an oncocytoma may present as a reddish brown nodule on the surface of the caruncle.

Sebaceous Gland Carcinoma Sebaceous gland carcinomas account for approximately 1% of all eyelid tumors and 5% of eyelid malignancies. They affect older individuals but may be seen in younger individuals after radiation the rapy. They may masquerade as chalazia or as chronic unilateral blepharoconjunctivitis (Fig 8-7). See also BCSC Section 7, Orbit, Eyelids, and Lacrimal System.

Tumors of Neuroectodermal Origin Table 8-2 lists the ocular surface tumors that arise from melanocytes, nevus cells, and other neuroectodermal cells. Some pigmented lesions of the globe are normal. For example, a pigment spot of the sclera is a collection of melanocytes associated with an intrascleral nerve loop or perforating anterior ciliary vessel. The term melanosis refers to excessive pigmentation without an elevated mass that may be congenital (whether epithelial or subepithelial) or acquired (whether primary or secondary). Conjunctival pigmentation can also occur from chronic exposure to epinephrine, silver, or mascara. McLean IW Melanocytic neoplasms of the conjunctiva. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Voll. Philadelphia: Elsevier/Mosby; 2005:571- 578. Shields CL, Demirci H, Karatza E, Shields JA. Clinical survey of 1643 meianocytic and non melanocytic conjunctival tumors. Ophthalmology. 2004;111(9}:1747 -1754.

Benign Pigmented Lesions

Congenital epithelial melanosis A conjunctival freckle, or ephelis, is a flat brown patch, usually of the bulbar conjunctiva near the limbus. It is more common in darkly pigmented individuals and is present at an early age.

234 • External Disease and Cornea

B

D Figure 8-7

Sebaceous gland carcino ma: variou s presentations. A, Presents as a un ilatera l bl epharoconjunctivitis with injection, pannus, thickened lid margin, and eyelash loss. B, White nodules composed of neoplastic sebaceous cells may be present near the limbus. C, Neo-

plastic symblepharon is present nasa lly. 0 , Upper palpebral conjunctival thickening. Papillary frending may be present.

(Reproduced wlrh permission from Krachmer JH, Mannis MJ, Holland fJ, eds. Cornea

2nd ed. Vol 1. Philadelphia: Elsevier/Mosby; 2005:568.)

Table 8·2 Neoplastic Tumors and Related Conditions of Neuroectodermal Cells of the Ocular Surface Cell of Ori gin

Benign

Preinvasive/Malignant

Epithelial melanocytes

Freckle Benign acquired melanosis

Prim ary acqu ired melanosis Melanoma

Subepithelial melanocytes

Ocular melanocytosis Blue nevus Melanocytoma

Melan oma

Nevus cells

Intraepithelia l nevus Compound nevus Su bepithelial nevus

Melanoma

Neural and other cells

Neurofibroma

Leiomyosarcoma

Benign melanosis Increasing pigmentation of the conjunctiva of both eyes is a common occurrence in middle-aged individuals with dark skin . This pigmentation is often most apparent in the bulbar conjunctiva. The stimulus to melanocytic hyperplasia is unknown but may be reo lated to sunlight exposure. Benign melanosis is characterized by light brown pigmentation of the perilimbal (Fig 8-8) and inter palpebral bulbar conjunctiva. Streaks and whorls called striate melarlOkeratosis sometimes extend into the peripheral corneal epithelium.

CHAPTERS: Clinical Approa ch to Neoplastic Disorders of th e Conjunctiva and Corne a. 235

Figure 8-8

Benign acquired melanosis in a patient with corneal arcus. (Counesyof James Chodosh, MD.J

Ocular melanocytosis Congenital melanosis of the episclera occurs in about I in every 2500 individuals and is more common in the black. Hispan ic. and Asian populations.

Ocular melanocytosis consists of focal proliferation of subepithelial melanocytes (blue nevus).

PATH OG ENESIS

Patches of episcleral pigmentatio n appear slate gray through the normal conjunctiva (Fig 8-9) and are immobile and us ually unilateral. Affec ted patients may have a diffuse nevus of the uvea evident as increased pigmentation of the iris and choroid. About one half of patients with ocular melanocytosis have ipsilateral dermal melanocytosis (nevus of Ota) and a proliferation of dermal melanocytes in the periocular ski n of

CLINICAL FINDINGS

Figure 8-9

Episcleral pigmentation in a patien t with congenita l ocular melanocytos is.

236 • External Di sease and Cornea

the fi rst and second dermatomes of cranial nerve V. The combined ocular and cutaneous pigmentations are referred to as oculodennal melanGeytosis. App roximately 5% of cases are bilateral.

Secondary glaucoma occurs in the affected eye in 10% of patients. Malignant transformation is possible but rare and seems to occur on ly in patients with a fair complexion. Malignant melanoma can develop in the skin, conj unctiva, uvea, or orbit. The li fetime risk of uveal melanoma in a patient with ocular melanocytosis is about 1 in 400, significantly greater than the approximate 6 per million risk of the general population. MANAGEMENT

Nevus Nevocellular nevi of the conjunctiva are hamartias that arise during childhood and adolescence. A nevus can be junctiona l, compound, o r subepithelial. Pure intraepithelial nevi are rare except in children, and these junctional nevi may be difficult to distinguish histopathologically from primary acquired melanosis. The subepithelial nevus of the conjunctiva is the equi valent of the intradermal nevus of the skin.

PATHOGENESIS

A nevus near the limbus is usually almost flat. Those appearing elsewhere on the bulbar conjunctiva, semilunar fold, caruncle, or eyelid margin tend to be elevated. Pigmentation of conjunctival nevi is vari able; they may be light tan in color or amelanotic (Fig 8-10). A subepithelial nevus often has a cobblestone appearance. Small epithelial inclusion cysts occur within about half of all conjunctival nevi, partic ularly the compound or subepithelial varieties. Secretion of mucin by goblet cells in the inclus ion cysts can cause a nevus to en large, producing a false impression of malignant change. Cellular proliferation may induce secondary lymphocytic inflammation. Rapid enlargement can occur at puberty, giving rise to a clinical impressio n of conjunct ival melanoma. When inflamed, an amelanotic, vascularized nevus may resem ble an angioma.

CLINICAL FINDINGS

Figure 8-10

Amelanotic conjunctival nevu s.

CHAPT ER 8:

Clinical A ppro ach to Neop lastic Disorders of the Conjunctiva and Cornea. 237

Conjunctival nevi rarely become malignant and can be followed every 6-12 months with serial photography or detailed slit-lamp drawings that include dimensional measurements. Excisional biopsy should be performed on lesions that change. Because nevi are rare on the palpebral conjunctiva, pigmented lesions on the tarsal conjunctiva, the caruncle, or plica semilunaris, or in the fornix should be biopsied rather than observed. MANAGEMENT

Shields CL, Fasiudden A, Mashayekhi A, Shields JA. Conjunctival nevi: clinical features and natural course in 410 consecutive patients. Arch Ophthalmol. 2004;122 (2):167-175.

Preinvasive Pigmented lesions

Primary acquired melanosis Primary acquired melanosis (PAM), an acquired pigmentation of the conjunctival epithelium, may be analogous to lentigo maligna of the skin (Hutchinson freckle), a preinvasive intraepidermallesion of sun-exposed skin. It is usually unilateral and most often seen in light-skinned individuals. The term primary acquired melanosis refers to flat, brown lesions of the conjunctival epithelium (Fig 8-11 ). By defini tion, the condition diffe rs from congenital pigmented lesions and from secondary acquired melanosis, such as that caused by Addison disease, radiation, or pregnancy. Table 8-3 compares the various pigmentary lesions of the conjunctiva. Most types of acquired melanosis remain benign, but in one study, PAM associated Vo,'ith cellular atypia progressed to conjunctival melanoma in 46% of cases. See BeSe Section 4, OphthalmiC Pathology and Intraocular Tum01's. Folberg R, McLean rw, Zimmerman LE. Pri mary acquired melanosis of the conjunc tiva. Hum Patlwl. 1985;16(2P 29 - 135.

Abnormal melanocytes proliferate in the basal conjunctival epitheliu m of middle-aged, light-skinned individuals for reasons that are unknown . Pigmentation in an individual with dark skin is called benign acquired melanosis rather than PAM, but the 2 conditions may be related.

PATHOGENESIS

B A, Prim ary acqui red melanosis of t he bulbar co njunctiva. S, Pri ma ry acqu ired melanosis of the palpebral conju nctiva. (Part A courtesy of Jam es Chodosh, MD; part B courtesy of James Figure 8·"

J. Reidy, MD.}

238 • External Disease and Cornea

Tab le 8-3

Clinical Comparison of Conjunctival Pigmentary Lesions Malignant Potential

Les ion

Onset

Appe arance

Location

Nevus

1st or 2nd decade Adulthood, dark-skinned , bilateral Congenital

Conj unctival epithelium! stroma Conjunctival epithelium

1.8 mm; involvement of the eyelid margin; pagetoid or full -thickness intraepithelial spread; lymphatic invasion; or mixed cell type. Conjunctival melanomas may metastasize to reg ional lymph nodes, the brain, lungs, liver, and bone.

CLI NICAL FINDI NGS

An excisionai biopsy should be considered for any suspicious pigmented epibulbar lesions; biopsy seems not to increase the risk of metastasis. The recommended treatment comprises excision of conjunctiva 4 mm beyond the clinically apparent margins of the tumor, along with a thin lamellar scleral fl ap beneath the tumo r; treatment of the remaining sclera with absolute alcohol; and cryotherapy applied to the conjunctival margins. Primary closure is performed when feas ible, but conjunctival or amniotic men1brane grafts are necessary for large excisions. Sentinel lymph node biopsy performed prior to

MANAG EM ENT

Fi gure 8-1 2 Ma lignant melanoma of t he limba l conj unctiva. (Reproduced with permission from Helm CJ Melanoma and other pigmen ted leSIOns bf the ocular surface. Foca l Points: Clinical Modules for Op hthalmologists. San Francisco: American Academy of Ophthalmology; 1996, module 11. Photograph courtesy of Thomas Pettit MD l

240 • Externa l Disease and Cornea

surgical excision may be helpful in establishing prognosis. Topical m itomyc in e has been used after excision and cryotherapy to treat residual d isease. Orbital exenteration is performed fo r advanced disease when local excision or enucleation wou ld be insufficient to completely excise the tumor (when metastases have been excluded) or as palliative treatment for advanced, aggressive tumors. Conj unctival malignant melanomas are potentially deadly tumors. In one study, metastasis was detected in 26% of patients, and death occurred in 13% of patients 10 years after surgical excision. Melanomas aris ing de novo (not in preexisting nevi or from PAM), tumors not involving the limbus, and residual involvement at the surgical margins v,re re especially poor prognostic factors. The ro le of adjunctive radiotherapy has not been determi ned. Ge ne expression profiling is currently being evaluated to determine prognosis and m ight be beneficial in the future to determine response to ta rgeted chemotherapies that are under development. Esmaeli B. Regional lymph node assessment for conjun cti val melanoma: sentinel lymph node biopsy and positron em ission tomography. Br J Ophthalmol. 2008;92( 4}:443-445. Finge r PT, Sedeek RW, Chi n KJ. Top ical interferon alfa in the treatment of conjunctival melanoma and primary acquired melanosis complex. Am J Ophthalmol. 2008; 145 (1):124-129. Seregard S. Conjunctival melanoma. Surv Ophthalmol. 1998;42(4):32 1-350. Shields Cl, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol. 2004;49(1 ): 3-24. Sh ields CL, Shields lA, GUn dUz K, et aL Conjunctival melanoma: risk fac to rs for recurrence, exenteratio n, metastasis, and death in I SO consecutive patients. Arch Ophthalmol. 2000; 118( II P497-1507.

Neurogenic and Smooth Muscle Tumors Subconjun ctival peripheral nerve sheath tum ors such as neurofibromas, schwannomas, and neuromas have been reported, especially in multiple endocri ne neoplasia (MEN) . A neurofibroma of th e conjunctiva or eyelid is almost always a m anifestation of neurofibromatosis, an autosomal dominant phakomatosis (see sese Section 6, Pediatric Ophthalmology and Strabismus). A neurilemoma is a very rare tumor of th e conjunctiva that originates fro m Schwann cells of a peripheral nerve sheath. A leiomyosarcoma is a very rare limballesion with the potential for orbital invasion.

Vascular and Mesenchymal Tumors Vascula r lesions of the eyelid margin or conjun ctiva generally are ben ign hamartomas or secondary reactions to infection or other stimuli (Table 8-4).

Benign Tumors

Hemangioma Isolated capillary and cavernous hemangiomas of the bulbar conjunctiva are rare an d are more likely to represent extension from adjacent structures. The palpebral conjunctiva is frequently involved with an eyelid capillary hemangioma. The presence of diffuse hemangiomatosis of the palpebral conjunctiva or conjunctival fornix indicates an orbital

CHAPTER8: Cl inica l Approach to Neop la stic Diso rders of th e Conju nctiva and Co rn ea . 241

Table 8-4 Neoplastic Tumors of Blood Vessels of the Eyelid and Conjunctiva> Hamartoma

-- ---

Nevus fl am m eus Capil lary hema ng iom a Cavern ous hem angioma

Reacti ve

Malignant

Pyoge ni c gran uloma Glomus tumor Intrava scular papillary en dothelia l hyperp las ia

Kaposi sarcoma A ng iosarcoma

* Tumors are not listed in a particular orde r. and lesio ns in 1 column do not necessarily correspond to th ose in pa rallel columns.

capillary hemangio ma_A cavern ous hemangioma of the orbit may present initially und er the conjunctiva. Nevus Jlammeus, a congenital lesion described as a port-wine stain, may occur alone or as part of Sturge- Webe r syndrome, associated with vascular ham artomas, secondary glaucoma, andlor leptomeni ngeal angiomatosis. Some cases result from a ge netic mutation coding for the vascular endothelial protein receptor for angiopoietin I , which con trols the assemb ly of perivascular smooth muscle. Ataxia- telangiectasia is a synd rom e of epibulbar telangiectasis, cerebellar abnormalities, and immu ne alterations. Inflammatory vascular tumors

Inflammatory conjunctival lesions often show vascular proliferation. Pyogenic granuloma, a common type of reactive hemangioma, is misnamed because it is not suppurative and does not contain giant cells. The lesion may occur over a chalazion or when minor trauma or surgery stim ulates exuberant healing tissue with fi broblasts (granulation tissue) and proliferating capillaries that grow in a radiating pattern. This rapidly growing lesion is red, peduncu lated, and smooth (Fig 8- 13), bleeds easily, and stains with fluo rescein dye.

Fi gure 8-13

Pyogenic granuloma (in association w ith a chronically inflamed chalazion) . (Reproduced with permission from Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea . 2nd ed. Vol 1. Philadelphia: Elsevier/ Mosby; 2005:452.)

242 • External Disease and Cornea

Topical or intralesional corticosteroids may be curative. Excision with cauterization to the base, primary closure of the wound, and generous postoperative topical corticosteroids may minim ize recurrences. Subconjunctival granulomas may form around parasitic and mycotic infectious foci. They have also occurred with connective tissue diseases such as rheumatoid arthritis. Sarcoid nodules appear as tan-yellow elevations that can resemble follicles. Juvenile xanthogranuloma is a histiocytic disorder that can present as a conjunctival mass. A fibrous histiocytoma, composed of fibroblasts and histiocytes with lipid vac uoles, arises on rare occasions on the conjunctiva or limbus. Nodular jasciitis is a very rare benign tumor of fibrovasc ular tissue in the eyelid or under the conjunctiva; it may originate at the insertion site of a rectus muscle. Necrobiotic xanthogranuloma is a very rare tumor that may affect the anterior orbit and eyelids. These lesions can present as subconjunctival or subdermal nodular fibrovascular tissue. Biopsy is essential to establish the diagnosis because it is often associated with paraproteinemias, multiple myeloma, or lymphoma.

Malignant Tumors

Kaposi sarcoma Kaposi sarcoma, a malignant neoplasm of vascular endothelium , involves the skin and mucous membranes. Internal organs are occasionally involved as welL Infection with Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV) is responsible for this disease. In young patients, it occurs most often in the setting of AIDS. PATHOGENESIS

On the eyelid skin, Kaposi sarcoma presents as a purplish nodule. Orbital involvement may produce eyelid and conjunctival edema. In the conjunctiva, Kaposi sarcoma presents as a reddish, highly vascular subconjunctival lesion that may simulate a subconjunctival hemorrhage. Lesions are most often found in the inferior fornix and may be nodular or diffuse (Fig 8-14). Nodular lesions may be relatively less responsive to therapy. CLINICAL FIND INGS

MANAG EM ENT Treatment may not be curative. Options for controlling symptoms include surgical debulking, cryotherapy, and radiotherapy. Local or systemic chemotherapy may be required. Intrales ional interferon-a2a has been reported to be effective.

Other malignant tumors Malignant mesenchymal lesions that rarely involve the conjunctiva include malignant fibrous histiocytoma, liposarcoma, leiomyosarcoma, and rhabdomyosarcoma.

lymphatic and lymphocytic Tumors LymphOid tumors of the conjunctiva may be benign, malignant, or indeterminate. Many of these lesions have overlapping clinical and pathologiC features. About 20% of patients with a conjunctival lymphoid tumor have detectable extraocular lymphoma.

CHAPTER 8:

Figure 8-14

Clinical Approach to Neoplastic Disorders of the Conjunctiva and Cornea.

Kaposi sarcoma of t he co njunctiva.

243

(Reproduced with permission from Holland GN, PeposeJS,

Pettit TH, Go ttlieb M S, Yee RD, Foos RY Acquired immune deficiency syndrome Ocular manifestation s. Opht hal mology. 1983;90(8):859-873. Ph otograph cou rtesy of Gary N. Holland, M D.)

Lymphangiectasia and Lymphangioma Lymphangiectasia appears on the eye as irregularly dilated lymphatic channels in the bulbar conjunctiva. It may be a developmental anomaly or can follow trauma or inflammation. Anomalous communication with a venule can lead to spontaneous filling of the lymphatic vessels with blood. Lymphangiomas are proliferations oflymphatic channel elements. Like a capillary hemangioma, lympha ngiomas are usually present at birth and may enlarge slowly. The lesion ap.pears as a patch of vesicles with edema. Intralesional hemorrhage, producing a "chocolate cyst;' makes differentiation from a hemangioma difficult. Lymphoid Hyperplasia

Formerly called reactive hyperplasia, this benign-appearing accumulation of lymphocytes and other leukocytes may represent a low-grade B-ceillymphoma. Most patients are older than 40 years, although, in rare instances, extranodallymphoid hyperplasia has occurred in children. PATHOGENESIS

This mass presents as a minimally elevated, salmon-colored subepithelial tumor with a pebbly appea rance corresponding to follicle formation (Fig 8-1 5); it is clinically indistinguishable from conjunctival lymphoma. It is often moderately or highly vascularized. Primary localized amyloidosis can have a similar appearance. CLINICAL FINDINGS

Lymphoid hyperplasia may reso lve spontaneously, but these lesions have been treated with local excision, topical corticosteroids, or radiation. Biopsy specimens require special handling to complete many of the histochemical and immunologic studies. Fresh tissue is required for immunohistochemistry, flow cytometry, and gene rearrangement studies. Because a patient w,ith an apparently benign polyclonallymphoid lesion has the potential to develop a systemic lymphoma, general medical consultation is advisable. MANAGEMENT

244 • Ext ernal Dise ase and Corn ea

Figure 8-15

Conjunctival lymphoid hyperplasia.

Lymphoma A neoplastic lymphoid lesion of the conjun ctiva is generally a monoclo nal proliferatio n of B lymp hocytes. A lymphoma can arise in conjunctival lymphoid follicles_ Some lymphomas are li mited to th e conjunctiva; oth ers occur in conjunction with systemic malignant lymp homa. Some are polyclonal, but most conjunctival lymphomas are monoclonal B-cell lymphom as. Conjunctival plasmaC)1oma, Hodgkin lymphoma, an d T-cell lymphomas are less common.

PATHOGENESIS

Non- Hodgkin B-cell lymphoma has essentia lly the sam e cl inical appearan ce as benign lymphoid hyperplasia. It appears as a salmon pink, mobile m ass on the conjunctiva (Fig 8- 16). The lesions are usuall y u nilateral; however, 20% are bi lateral. A di ffuse lesio n may masquerade as chronic co njunctivitis. An epibulbar mass fixed to the und erlying sclera may be a sign of extrascle ral exte nsion of uveal lymphoid neoplasia. Most patients with conjunctival lympho ma are either over 50 years of age or immunosuppressed.

CLINICAL FINDINGS

Pati ents should be referred to an oncologist for systemic evaluation. Unless a tumor is small enough to be removed completel y, incisionai biopsy is indicated for histopathologic diagnosis. Local external beam radiation therapy is usually cu rati ve for lesions confined to the conjun cti va, but system ic chemotherapy is required fo r the treatment of system ic lymphoma. Cryotherapy and chemotherapy with inte rferon-a ' b have also been described. LABORATORY EVALUATION AND MANAGEMENT

Warner MA , Jakobiec FA. Subepithe lia l neoplasms of the conju nctiva . In: Krachmer ]H, Mannis M], Holland El. eds. Cort/ea. 2nd ed. Vol I. Philadelphia: Elsevier/Mosby; 2005:579- 600 .

CHAPTER 8:

Clinical Approach to Neoplastic Disorders ofthe Conjunctiva and Cornea • 245

Figure 8-16

Conj unctival lymphoma .

Metastatic Tumors Metastatic tumors to the conjunctiva are much less common than those to the uveal tract and orbit, but such tumors have arisen from cancer of the breast, lung, kidney, and elsewhere, including cutaneous melanoma. Metastatic lesions to the uveal tract, orbit, or paranasal sinuses can extend into the conjunctiva. Metastases or leukemic infiltrates to the limbus or cornea also occur.

Epibulbar Choristoma Epibulbar Dermoid The congenital epibulbar dermoid typ ically occurs on the inferotemporal globe or temporallimbus as a smooth, elevated, solid mass embedded in the superficial sclera and/or cornea (Fig 8-17). About 1 in 10,000 individuals is affected. An epibulbar dermoid results from faulty development of the eyelid folds and consists of displaced embryonic tissue that was destined to become skin. Dermoids are composed of fibrous tissue and occasionally hair with sebaceous glands; they are covered by conjunctival epithelium. Epibulbar dermoids are solid rather than cystic and are not fully entrapped beneath the surface, unlike derm oid cysts.

PATHOGENESIS

CLI NICAL FIND INGS Dermoids are well circumscribed, porcelain white, round to oval lesions that occur most often at the inferotemporal limbus, but they can also be found on the central cornea, in the subconjunctival space, or in the orbit. Fine hairs may pro trude from some dermoids. A limbal dermoid often has an arcuslike deposition oflipid along its anterior corneal border. Corneal astigmatism caused by a dermoid can lead to

246 • Externa l Disease and Corn ea

B Figure 8-17 A, Limbal dermoid; note the fine hairs. B, Lamellar keratoplasty following resection of a limbal dermoid. (Courtesy ofJames J Reidy, MD.)

anisometropic amblyopia. The flattest meridian of the cornea is adjacent to the limbal dermoid. Dermoids are often associated wi th a congenital malformation kno\.... n as Goldenhar syndrome (oculoauriculovertebral dysplasia), a sporadic or autosomal dominant syndrome of the firs t branchial arch, characterized by the presence of epibulbar dermoid, coloboma of the upper eyelid, preauricular skin tags, aural fistulae, and vertebral anomalies. BeSe Section 6, Pediatric Ophthalmology and Strabismus, discusses and illustrates Goldenhar syndrome in greater detail. Dermoids grow along with the child and the eye and have virtually no malignant potential. The elevated portion of a dermoid may be excised, but the lesion often extends deep into underlying tissues. Some cornea l astigmatism often remains after a shaVing dissection of a limbal dermoid. Often , however, excision or shaving allows the fitting of a rigid contact lens. A relaxing incision or other corrective measure may also be considered. Lamellar keratoplasty can improve the cosmetic appearance and may reduce postoperative astigmatism.

MANAG EM ENT

Dermolipoma A dermolipoma is a pale yellow dermoid containing adipose tissue that should be distinguished from herniation of orbital fat. It typically occurs superotemporally and may extend posteriorly.

Ectopic lacrimal Gland Lacrimal gland tissue occurring outside of the lacrimal fossa may be associated with a complex choristoma (see the following section ), or it may occur alone as a round, pink, vascularized mass at the limbus.

Other Choristomas A complex choristoma, usually on the superotemporal globe, consists of multiple tissues, including cartilage, bone, lacrimal gland lobules, hair follicles, hair, sebaceous glands, and

CHAPTER 8: Clinica l Approac h to Neoplastic Dis orders of the Conju nctiva and Cornea. 247

Figure 8-18 Complex choristoma showing rose coloring caused by the presence of richly vascularized ectopic lacrim al gland ti ssue. (Reproduced wirh permission from Margo CE. Nonpigmenred lesIons of the ocular surface. Focal Points: Clinical Modules for Ophthalmologists . San FranCISCO: American Academy of

Ophthalmology; 1996, module 9)

adipose tissue (Fig 8-18). An osseous choristoma is a solitary nodule of bone surrounded by fibrous tissue that is also located superotemporally. A neuroglial choristoma is more diffuse. A phakomatous choristoma is a subcutaneous nodule in the inferomedial eyelid composed of disorgani zed lens cells.

CHAPTER

9

Basic and Clinical Concepts of Congenital Anomalies of the Cornea and Sclera

Congenital anomalies are also discussed in depth in BCSC Section 6. Pediatric Ophthalmology and Strabismus. Chapter 18 of that volu me covers diseases of the cornea and anterior segment. See also BCSC Section 2. Fundamentals and Principles of Ophthalmology.

Develo mental Anomalies of the Globe and Sclera Cryptophtha Imos Cryptophthalmos. or "hidden eye;' is a very rare condition. with fewer than 150 reported cases. It is usually bilateral. The eyelids and associated structures of the brows and lashes fail to form (ablepharon ). The cornea is merged with the epidermiS. and the anterior cham ber. iris. and lens are variably formed or are absent (Fig 9-1 ). The conjunctiva is typically absent. Pseudocryptophthalmos occurs when the eyelids and associated structures form but fail to separate (ankyloblepharon). Cryptophthalmos occurs in both isolated and syndromic form . The principal syndromic form is Fraser syndrome, a recessive disorder with a combination of acrofacial and urogenital malformations with or without cryptophthalmos. The disorder

PATHOGEN ESI S

A

B

Fi gure 9-' A , Compl ete cryptophtha lmos, both eyes. B, Incomplete cryptoph thalmos of the right eye, w ith eyelid fus ed to corn ea superonasally.

249

250 • Externa l Disease and Cornea

results fro m mu tati ons in the FRASl gene located at 4q21 , which encodes a putative extracell ular matr ix (ECM ) protein. Cryptophthalmos demonstrates equal sex distribution and equal occurrence in male and female siblings. consanguinity in families with more than I affected child, and lack of ve rtical transmission-strongly suggesting autosomal recessive inheritance. Associated ocular findings include corneal and conjunctival dermoid. absence of the lacrimal glands and canaliculi, and anterior segment dysgenes is.

CLINICAL FI NDIN GS

Cryptophthalmos requires surgical intervention onl y for cosmesis or re lief of pai n from absolute glaucoma. Pseud ocryptophthalmos may benefit from fornix reconstruction using buccal mucosa l and amniotic membrane grafts. but ongoing man agemen t of the reconstructed eyelids to prevent secondary complications is necessary. See also BCSC Section 6, Pediatric Oph thalmology and Strabismus.

MANAG EM ENT

McGregor L. Makela V, Darling SM. et a1. Fraser syndrome and mouse blebbed phenotype caused by mutations in FRASl/Fras l en codi ng a putative extrace!lular matrix protein. Nat Gellet.2003;34(2):203-208. Stewart ]M. David S, SeiffSR. Amniotic memb rane graft in the surgical management of cryptophthahnos. Ophthal Plast Recollstr Surg. 2002;18(5):378-3 80. Thomas IT, Frias ]L, Felix V, Sanchez de Leon L, Hern andez RA, Jones MC Isolated and syndromic cryplophthal mos. Am JNJed Ge1let. 1986;25(1 ):85-98.

Microphthalmos Microphthalmos is a small disorganized globe (Fig 9-2) . There is often an associated cystic outpollching of the posteroinferior sclera. This condition has been associated with failure of the fetal fissure to close properly, and colobomatous defects of the iris, Ciliary body, uvea, and optic nerve are often present. Normal embryonic development proceeds th rough at least th e forma tion of the optic vesicle. Multiple associat ions have been made with microphthalmos,

PATH OG ENESIS

Fi gu re 9-2

Microphthalmos 00 (Counesy ofJeffr8y Nerad. MD.)

CHAPTER 9: Congenita l Anomal ies of the Cornea and Sclera. 251

including trisomies of almost every chromosome (typically, trisomy 13), maternal in fections, and exposure to toxins and rad iation. Most cases of nonsyndromic microphthalmos are sporadic, although autosomal dominant, autosomal recessive, and X-linked forms have been reported. Isolated, nonsyndromic microphthalmos has been reported to map to the 14q23-q24.3 and 2qll-14 gene loci. Synd romic microphthalmos has been reported to map to the following gene loci: Xp22, 15q24. 1, and 14q-22-q23. Mutations in the autosomal CHXJO, MAE, PAX6, PAX2, RAX, SHH, SIX3, and SOX2 genes have all been shown to be involved in the development of various forms of microphthalmos. Associated ocular abno rma li ties may include leukomas, an terior segment disorders, retinal dysplas ia, colobomas, cysts, marked internal dysgenesis, persistent fetal vasculature (PFV), small orbit, ptosis, and blepharophimosis. Systemic associations are numerous, including menta l retardation and dwarfism among many others. CLINICAL FINDINGS

Associated conditions should be sought and managed appropriately, and genetic counseling should be considered. A cosmetic sheil or contact lens may be indicated in selected patients.

MANAGEMENT

Fe rda Percin E, Ploder LA, Yu JJ, et a1. Human microphthalmia associated with mutations in the retinal homeobox gene CHX IO. Nat Genet. 2000;25 (4):397-401. Li H, Wang IX, Wang CY, et at. Localization of a novel gene for congenital nonsyndromic

simple microphthalmia to chromosome 2q ll - 14. Hum Geflet. 2008;122(6) :589- 593. Verma AS, FitzPatrick DR. Anophthalmia and mic rophthalm ia. Orpha1let ] Rare Dis. 2007;2:47.

Nanophthalmos Nanophthalmos is characterized by a small, func tio nal eye with relativel y normal internal organization and proportions. Patients have a high degree of hyperopia (7-15 diopters [D)) due to a short axial length (15-20 m m ). Patients also have a high lens-to-eye volume ratio that can lead to crowding of the anterior segment and angle-closure glaucoma. Nanophthalmos may be sporadic or hereditary, and both autosomal dominant (nanophthalmos 1) and autosomal recessive (nanophthalmos 2) inheritance patterns have been reported. One gene locus for the autosomal dominant form has been mapped to chromosome arm 11 p. The recessive fo rm of the disease is caused by a mutation in the gene encoding membrane-type frizzled protein (MFRP).

PATHOGENESIS

Patients have high hyperopia due to short axial length, high lens- eye volume ratio, thickened sclera, steep corneal cu rvature, narrow palpebral fissures, and crowded anterior segments associated with angle-closure glaucoma. Many patients have strabismus. Histopathologic examination of the sclera from nanophthalmos patients has revealed frayed collagen fibrils and glycogen-like deposits. These findin gs might contribute to scleral inelasticity, which in turn leads to reduced intraocular volume, choroidal congestion, choroidal detachment, andlor exudative retinal detachment. Peripheral choroidal effusion can occur spontaneously. Large choroidal effusions or hemorrhage has been frequently encountered during anterior segment su rgery.

CLINICAL FINDINGS

252 • External Di sease and Cornea

Hyperopia and glaucoma are managed medically. Peripheral laser iri dotomy, sometimes combined with peripheral laser iridoplasty, may be effective treatment of the angle-closure component. Cataract surgery may be complicated by uveal effusion or hemorrhage and exudative retinal detachment, although advances in small-incision surgery have reduced the frequency of these complications. Extremely high intraocular lens powers are required to achieve emmetropia. MANAGEMENT

Faucher A, Hasanee K, Rootman DS. Phacoemul sificat ion an d intraocular lens implantation in nan ophthalm ic eyes: report of a medium -size series.

J Cmaract Refract SlIrg. 2002;28(5):

837-842. Othman MI, Sullivan SA, Skuta GL, et a!. Autosomal dominant nanophthalmos (NNOl) with high hyperopia and angle-closure glaucoma maps to chromosome II. Am

J Hum Genet.

1998;63(5) : 1411-1418. Yamani A, vVood I. Sugino I, Wan ner M. Zarbi n MA. Abnormal collagen fibrils in nanophthal mQs: a clinical and hi stologic study. Am JOphtlw/11Iol. 1999; 127( I): I06- 108.

Blue Sclera The striking clinical picture of blue sclera is related to generalized scleral thinning, with increased visibility of underlying uvea. This anomaly must be distinguished from the slate-gray appearance of ocular melanosis bulbi and from acquired causes of scleral thinning such as rheumatoid arthri tis or staining from minocycline treatment . Genetic mutations and altered proteins have been identified for 2 syndromes associated with blue sclera:

PATHOGENESI S

1. Osteogenesis imperfecta type I is a somewhat common, dominantly inherited , gen eralized connective tissue disorder characterized mainly by bone fragility and blue sclerae. "Functional nuLl" alleles of COLlA 1 on chromosome 17q21.31 or COLlA2 on chromosome 7q22.llead to reduced amounts of normal type I collagen in most cases. 2. Ehlers-Danlos syndrome type VI (EDS VI) is a somewhat rare syndrome with autosomal recessive inheritance characterized by joint hyperextensibility. moderate to severe kyphoscoliosis, cardiac anomalies, and skin abnormalities of easy bruisability, abnormal scarring, and soft distensibility. EDS VI is associated with molecular defects in the gene for Iysyl hydroxylase located on Ip36.3 -p36.2 in some patients. A third syndrome of brittle cornea, blue sclera, keratoglobus, and joint hyperextensibility may be the same as EDS VI but wi th a normal level oflysyl hydroxylase. AU 3 syndromes may share similar manifestations of fractures from minor trauma in childhood, kyphosco liosis, joint extensibility, and elastic skin. Decreased hearing and tinnitus may also occur.

CLINICAL FINDINGS

Regular hearing evaluations after adolescence are recommended. Oral bisphosphonate therapy may be specificall y indicated for these patients. Postmenopausal

MANAGEM ENT

:CHAPTER 9:

Congenita l Anomalies of

the

Cornea and Sclera.

253

women should engage in a long-term physical therapy program to strengthen the paraspinal muscles. Estrogen and progesterone replacement and adequate calcium and vi tamin D intake are indicated. Fractures are treated with standard methods. Future therapies may include stem cell transplantation and gene therapy. See also Chapter 15.

Develo pmental Anomalies of the Anterior Segment Anoma lies of Size and Shape of the Cornea Microcornea Microcornea is a somewhat common condition that refers to a clear cornea of normal thickness whose diameter is less than 10 mm (or 9 mm in a newborn). If the whole anterior segment is small, the term anterior microphthalmos applies. [f the entire eye is small and malformed, the term microphthalmos is used in contrast to nanophthalmos, in which the eye is small but otherwise normal.

The cause is unknown and may be related to fetal arrest of growth of the cornea in the fifth month. Alternatively, it may be related to overgro'01h of the anterior tips of the optic cup, which leaves less space for the cornea to develop.

PATHOGE N ESIS

CLIN ICA L FI NDI NG S Microcornea may be transmitted as an autosomal dom inant or recessive trait with equal sex predilection. Dominant transmission is more common. Because their corneas are relatively flat, patients with microcornea are usually hyperopic and have a higher incidence of angle-closure glaucoma. Of patients who avoid angle-closure glaucoma, 20% develop open-angle glaucoma later in life. Important ocular anomalies often associated with microcornea include PFV, congenital cataracts, anterior segment dysgenesis, and optic nerve hypoplasia. Significant systemic associations include myotonic dystrophy, fetal alcohol syndrome, achondroplasia, and Ehlers-Danlos syndrome.

If microcornea occurs as an isolated finding, the patient has an excellent visual prognosis with spectacles to treat the hyperopia resulting from the flat cornea. Concurrent ocular pathology such as cataract, PFV, and glaucoma may requi re treatment following the usual procedures for those conditions. MAN AG EM ENT

Mega/ocornea Megalocornea is a bilateral, nonprogressive corneal enlargement with an X-linked recessive inheritance pattern. Rare cases of autosomal recessive inheritance have been re ported. Affected subjects have histologically normal corneas measuring 13.0-16.5 mm in diameter (Fig 9-3). Males are more typically affected, but heterozygo us women may demonstrate a slight increase in corneal diameter.

The etiology may be related to failure of the optic cup to grow and of its anterior tips to close, leaving a larger space for the cornea to fill. Alternatively, megalocornea may represent arrested buphthalmos and exaggerated growth of the cornea in relation to the rest of the eye. An abnormality in collagen production is suggested by the association

PATH OG EN ESI S

254 • Exte rnal Disease and Cornea

Figure 9·3

Megalocornea.

of megalocorn ea with systemic diso rd ers of collagen synthesis (Ma rfan synd rome). The ge ne locus has been identified at Xq21.3-q22. Mega locornea may be associated with iris translucency (d iapha ny), miosis, goniodysgenesis, cataract, ectopia len tis, arcus juvenilis, mosaic corneal dystrophy (central cloudy dystroph y of Franc;ois), and glaucoma (but not congenital glaucoma). Systemk associations include craniosynostosis, fro ntal bossing, hypertelorism, facial anom alies, dwarfism, facial hemiatrophy, mental retardation, hypotonia, Down syndrome, Marfan syndrome, Alpo rt syndrome, osteogenesis imperfecta, Illucolipidosis type ll, or occasionally other genetic synd romes. CLINICAL FINDINGS

Congenital gla ucoma Illust be rul ed out by lOP testin g and ca reful biomicroscopy. Ultrasonography may be of value in determinin g the short vitreous length, deep lens and iris position, and normal axial length that distingu ish megalocornea from buphthalmos caused by congenital glaucoma. Myopia and with -the-rule astigmatism are managed as in unaffected patients. Care must be taken during cataract surgery to implant the in traocular lens into the lens capsu lar bag. Standard -sized posterior chamber lenses are typically too short to be fixated in the ciliary sulcus, and anterior chamber lenses are Similarly problematic in the enlarged anterior chamber. MANAGEMENT

Mackey DA, Buttery RG, Wise GM, Denlon MJ. Descr iption of X-l inked megalocornea wi th identification of the gene locus. Arch Ophthalmol. 1991 ;109(6}:829-833.

Cornea plana Cornea plana is a rare condition that refers to a flat cornea, where the radius of curvature is less than 43 D, and readings of30-35 D are common. Corneal curvature that is the same as that of the adjacent sclera is pathognomonic. Sclerocornea also features flat corneas, but it is di stingUished by the loss of transparency as well (see Fig 9-8), Both autosomal recessive and dominant forms of cornea plana have been associated with mutations of the KERA gene (I2q22), wh ich codes fo r keratan sulfate

PATHOGENESIS

CHAPTER 9:

Congenital Anom alies of the Cornea and Sclera. 255

proteoglycans (keratocan, lumican, and mi mecan). These proteins are thought to play an important role in the regular spacing of corneal collagen fibrils. Investigators have speculated that mutatio ns in the KERA gene cause an alteration of the tertiary stru cture of the keratan sulfate proteoglyca ns that leads to the cornea plana phenotype. CLIN ICAL FINDINGS Cornea plana is often seen in association with sclerocornea or m icrocornea. Other associated ocular or systemic abnormalities include cataracts, anterior and

posterior colobomas, and Ehlers-Danlos synd rome. Cornea plana usually produces hyperopia, but any type of refractive error may be present because of variations in globe size.

Angle-closure glaucoma occurs because of a morphologically shallow anterior chamber, and open-angle glaucoma occurs because of angle abnormalities. The majority of isolated cases appear in patients of Finnish ancestry. MANAGEMENT

Refractive errors are corrected and glaucoma must be controlled either

medically or surgically. Loss of central clarity may indicate penetrating keratoplasty (PK), but cornea plana increases the risk of graft rejection and postkeratoplasty glaucoma. Lehman n OJ, EI -Ashry MF, Ebenezer ND, et al. A novel keratocan mutation causing autosomal recessive cornea plana. Invest Ophthalmol Vis Sci. 200 1;42(13):3118-3122. Tahvanainen E, Villanueva AS, Forsius H, Salo p, and de la Chapelle A. Dominantly and receSSively inherited cornea plana congenita map to same small region of ch romosome 12. Genome Res. 1996:6(4):249-254.

Abnormalities of Corneal Structure and/or Clarity The following group of conditions is associated with various congenital and/or developmental anomalies of the cornea and anterior segment. Reese and Ellsworth were among the first to link many of these conditions together, based on proposed anomalies during embryologiC development, under the designation of anterior chamber cleavage syndrome. Other terms used in the past include mesodermal dysgenesis, mesellchymal dysgenesis, iridogoniodysgenesis, and neurocristopathy. Because of advances in our understanding of genetic control of embryonic development) these classification systems have become less useful. MihelecM, St Heaps L, Fl aherty M, et a1. Chromosomal rearrangements and novel genes in disorders of eye development, cataract and glaucoma . Twill Res Hum Genet. 2008; II (4):4 12- 421. Reese AB, Ellsworth RM. The anterior chambe r cleavage syndrome. Arch Ophthalmol. 1966; 7S(3P07-3 JS.

Posterior embryotoxon Posterior embryotoxon involves a thickened and centrally displaced anterior border ring of Schwalbe. The Schwalbe ring represents the junction of the trabecular meshwork with the termination ofDescemet's membrane. and it is vi sibl e in 8%-30% of normal eyes as an irregular, opaque ridge 0.5-2.0 mm central to the limbus. The term posterior embryotoxon is used when the Schwalbe ring is visible by external examination (Fig 9-4). Posterior embryotoxon is usually inherited as a domi nant trait. The eye is usually normal but can manifest a number of other anterior segment anomalies that are part of ocular or systemic

syndromes, such as Alagille syndrome (arteriohepatic dysplasia), X-linked ichthyosis, and fa m ilial aniridia.

256 • External Disease and Cornea

./

Figure 9·4

Posterior em bryotoxon displaying a prominent and ante riorly displaced Schw albe

ring .

Axenfeld-Rieger syndrome The conditions previously referred to as Axenfeld anomaly and syndrome and Rieger anomaly and syndrome have overlapping findings and have now been grouped into a single entity known as Axenfeld-Rieger syndrom e. This syndrome represents a spectrum of disorders characterized by an anteriorly displaced Schwalbe ring (posterior embryotoxon) with attached iris strands, iris hypoplasia, and glaucoma in 50% of the cases occurring in late childhood or in adulthood (Fig 9-5). Associated skeletal, cranial, facial, and dental abnormalities are often present.

Transmission is usually dominant (75%) for the Axenfeld-Ri eger group, but it can be sporadic. Evidence suggests that a spectru m of mutations of transcription factors located in chromosome region 6p25, known as forkhead gelles, are responsible for many developmental defects of the an terior chamber of the eye. Nishimura DY, Searby CC, Alward WL, et al. A spectrum of FOXCI mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet. 2001 ;68(2):364-372.

Peters anomaly Pete rs anomaly is a central corneal opacity present at birth that may be associated wit h variable degrees of iridocorneal adhesion extendi ng from the region of the iris collarette

CHAPTER 9: Congenital Anomalies of the Cornea and Sclera. 257

Fi gure 9-5

Axenfeld-Rieger syndrome exh ibiting iris atrophy, corectopia, and pseudopolycoria,

(Counesy of V!'ncent P deLUise, MD.)

to the border of the opacity (Fig 9-6). Approximately 60% of cases are bilateral. Associated ocular ab normalities are present in approximately 50% of cases. Ocular abnormalities include keratolenticular touch, cataract, congenital gla ucoma, microcornea, aniridia, and

PFY. Characteristic histopathologic findin gs in Peters anomaly include a localized absence of the corneal endothelium and Descemet's membrane beneath the area of opacity. Peters an o maly has been associated with systemic malformations in up to 60% of

patients. These abnorm alities include developmental delay, heart defec ts, external ear abnormalities, hearing loss, CNS deficits, spinal defects, gastrointestinal and genitourinary defects, facial clefts, and skeletal anomalies. Although systemic malformations may

Figure 9-6

Peters anomaly.

258 • External Disease and Cornea

be associated with genetically transmitted syndromes (trisomy 13- \5, Peters-plus syndrome, Kivlin syndrome, Pfeiffer syndrome), these associations are the exception rather than the rule. Most cases of Peters anomaly occur sporadically; however, both autosomal recessive and dominant modes of inheritance have been reported. Peters anomaly can be caused

by mutations in the PAX6 gene (llp13), the PITX2 gene (4q25-26), the CYPIBI gene (2p22-2l), and the FOXCI gene (6p25). Kivlin JD, Apple D], Olson RJ, Manthey R. Dominantly inherited keratitis. Arch Ophthalmol. 1986; 104( II), 1621-1623. Traboulsi E1, Maumenee IH. Peters' anomaly and associated congenital malformations. Arch Ophthalmol. 1992;110(12) ,1739- 1742.

Circumscribed posterior keratoconus The presence of a localized central or paracentral indentation of the posterior cornea without any protrusion of the anterior surface, as is seen in typical keratoconus, characterizes circumscribed posterior keratoconus. A variable amount of overlying stromal haze is also usually present. Loss of stromal substance can lead to corneal thinning approaching

one third of normal (Fig 9-7A, B). Descemet's membrane and endothelium are usually present in the area of defect. Focal deposits of pigmentation and guttae are often present at the margins of the opacity. Most cases are unilateral, non progressive, and sporadic. Irregular astigmatism and/or amblyopia may occur. An autosomal recessive form of disease is associated with bilateral corneal changes, short stature, mental retardation, cleft lip and palate, and vertebral anomalies. Young ID, Macrae WG, Hughes HE, Crawford IS. Keratoconus posticus circumscriptus, cleft lip and palate, genitourinary abnormalities, short stature, and mental retardation in sibs.

J Med Genet. 19S2; 19(5)m2 - 336.

Sclerocornea Sclerocornea, a non progressive, noninflammatory sclerahzation of the cornea, may be limited to the corneal periphery, or the entire cornea may be involved. The limbus is usu -

ally ill-defined, and superficial vessels that are extensions of normal scleral, episcleral, and conjunctival vessels cross the cornea (Fig 9-8). The most common associated ocular finding is cornea plana, which occurs in 80% of cases. Angle structures are also commonly

malformed. No sex predilection is evident, and 90% of cases are bilateral. Multiple systemic anomalies have been reported in association with sclerocornea.

Sclerocornea is usually sporadic, but both autosomal dominant and recessive patterns of inheritance have been reported.

Keratectasia and congenital anterior staphyloma Keratectasia and congenital anterior staphyloma are very rare unilateral conditions that

are both characterized by protrusion of the opaque cornea between the eyelids at birth. They differ only in the presence of a uveal lining of the cornea in congenital anterior staphyloma. See Table 9-\ for a summary of developmental anomalies of the anterior segment.

CHAPTER 9:

Congenital Anomalies of the Cornea and Sclera • 259

Figure 9·7 Circumscribed posterior ke ratoconus . A, Scanning-slit corn eal topography shows a nasally displaced anterior corn eal apex (top left), tempora l paracentra l posterior corneal vault-

ing (top right), no rmal anterio r keratometry (bottom left), and significant loss of stroma l thickness (bottom right). B, A slit-lamp photograph shows loss of stromal th ic kness, stromal ha ze, and posterior corneal crater.

(Counesy of Kenneth M. Goins, MD.)

Intrauterine perforation from an infection or from thi nning following secondary failure of neural crest cell migration results in dermoid transformation of the cornea to stratified squamous epithelium, sparing the eyelids and conjunctiva. Keratectasia is probably not the result of abnormal development but rather of intrauterine keratitis or vitamin defiCiency and subsequent corneal perforation. Histopathologically, Descemet's membrane and endothelium are absent, and a uveal lining is present (except in keratectasia). The cornea is variably thinned and scarred and the anterior segment disorganized, with the lens occasionally adherent to the posterior cornea, resembling unilateral Peters anomaly.

PATHOGENESIS

An opaque, bulging cornea (Fig 9-9) is accompanied by a deep anterior segment. These cases are typically un ilateral, and all are sporadic, with no familial or systemic association.

CLINICAL FINDINGS

260 • Externa l Disease and Cornea

Figure 9-8

Sclerocorn ea.

MANAGE MENT Except in very mild cases, visual prognosis is poor because of associated severe damage to the anterior segment. Penetrating keratoplasty and sderokeratoplasty techniques may be useful to preserve the globe and improve cosmesis; however, enucleation may be required for a blind, glaucom atous, painful eye.

Other congenital corneal opacities Congenital hereditary stromal dystrophy (CHSD) This extremely ra re dominant stationary dystrophy presents at birth with bilateral central superficial corn eal clouding. The anterior corneal stroma exhibits an ill-defi ned flaky or feathery appearance. The cornea is dear peripherally. No edema, photophobia, or tearing occurs, but the opacities can be sufficiently dense to cause a reduction in vision. Congenital hereditary endothelial dystrophy (CHED) CHED is a cause of bilateral congenital corneal edema, but more com mon causes, such as birth trauma, posterior polymorphous corneal dystrophy (PPMD), an d congenital glaucoma, m ust be ruled out. Two forms of CHED are recognized. The dom inant form (CHED 1) presents in the first or second year of life, although expressivity is variable. It is slowly progressive and accompanied by pain, photophobia, and tearing, but nystagmus is not present. The cornea exhibits a diffuse, blue-gray, ground-glass appearance. The primary abnormality is thought to be a degeneration of endothelial cells during or after the fifth month of gestation . The more common autosomal recessive type (CHED 2) presents at birth, remains stationary, and is accompanied by nystagmus. The bluish white cornea may be 2-3 times no[mal thickness and have a ground-glass appearance, but this finding is not associated with tearing or photophobia. There may be diffuse non bullous epithelial edema. A uniform

Table 9-1 Developmental Anom alies of the Ant erior Segment Anomaly

Unilateral! Bilate ral

--------- - -

----

Associated Oc" I,..· 4 nnm"li ....

Associated Systemic Ano malies

Corneal diam right

Pierre Robin malformation

Megaloco rnea (rare)

Enophthalmos. ocu lomotor palsies, pupillary abno rmalities, Horne r syndrome, heterochromia, intraocular inflammation, optic nerve hypoplasia, choroidal atrophy Congenital glaucoma, high myopia, vitreoretin al degeneration, retina l detachme nt, esotrop ia, conge nital ca taracts, microphthalmia

(261800)

Rothmund -Thomson syndrome (268400 )

Degenerative lesions of cornea

Cataracts

Treacher Col lins syn drom e; mandibulofacia l dysostosis

Microco rnea

Coloboma of lowe r li ds, dysplasia of bo ny orbit, absent lower lid cilia, absent lowe r lid lacrima l punctae, iris co loboma, microphth almia, strabismus, ant im ongoloid slant Prese n ile posterio r subcapsu lar cataracts (205- 305). proptosis, b lue sc lerae Rare: nystagmus, astigmatism, telangiectasia of iri s, macular degen eration, pigmentary retinopat hy

(154500)

Werne r syndrome (277700)

Cornea l edema seco ndary to endothelia l d ecompensat ion following cata ract surgery Poor wo un d healing

Spora dic Stickler synd rom e in 1/3 of cases Other syndromes NB: increased anestheti c risk secondary to glossoptosis

AR 70% female Mutations in DNA heli case (RECQL4) on 8q24.3

AD Mutations in treacle (TCOF1) gene on 5q32-q33.1

AR Mutations in DNA helica se (RECQL2) gene on 8p 12-pl1

For more informa ti on and bibliography on di sorders li sted in this table, cons ult On li ne Mendelian Inherita nce in Man {O M 1M) at http://www.ncbi. nl m.nih.gov/ omimJ. The numbers given in colum n 1 after th e di sease name{ s) are the OMIM entry numbers. AD", autosomal dom inant, AR '" autosomal recessive. Reprod uced with permission from Krachmer JH, Man nis MJ, Holland EJ, eds. Cornea. 2nd ed. Vo l 1. Phi ladelphia: Elsevier/Mosby; 2005:779- 780.

CHAPTER 11: Metabolic Di sorders W ith Cornea l Changes. 325

have been identified . Specific defects occur in collagen type I and III synthesis, and there can be Iysyl hydroxylase deficiency. CLINICAL FINDINGS Ehlers-Danlos syndrome VI (E DS VI), or the ocular-scoliotic type, is autoso mal recessive and associated with only moderate joint and skin extensibility, brittle cornea easily ruptured on minor trauma, blue sclera, keratoconus and keratoglobus, and severe scoliosis. Type VIA shows lysyl hydroxylase deficiency, but type VIE shows normal production oflysyl hydroxylase.

Traditionally, the cl inical diagnosis is confirmed by an insufficiency of hydroxylysine on analysis of hydrol yzed dermis and/o r reduced enzyme activi ty in cultured skin fibroblasts. However, it can also be confirmed by the altered urinary ratio of Iysyl pyrid inoline to hydroxylysyl pyridi noline that is characteristic for EDS VI.

LABORATORY EVALUATION

Recognition of the syndrome and awareness of its association with mitral valve prolapse, spontaneous bowel rupture, and complications of strabismus surgery. and of potential confusion of the brittle cornea with child abuse, are essential. Scleral patch grafts for ruptures have been successful. Genetic counseling should be considered. MANAGEMENT

Marfan Syndrome Marfan syndrome is a common autosomal dominan t disorder associated with disorders of the eye (ectopia lentis), heart (dilation of the ao rtic root and aneurysms of the aorta), and skeletal system (a rachnodactyly, pectus excavatum, and kyphosco liosis) . It maps to chromosome 15q21.1 (fi brillin gene). PATHOGENESIS Fibrillin and glycoprotein make up the microfibrillar system of the extracellular matrix. Fibrill in is fou nd in corneal basement membrane, zonular fibers of the lens and capsule, and sclera. Defects in fi bri llin synthesis lead to thi nn ing of the sclera (bl ue sclera), lens subluxation, and flattening of the cornea. BCSC Section II , Lens and Cataract, discusses and illustrates the lens subluxation caused by Marfan syndrome.

Megalocornea and keratoconus are uncommon, but excessive flattening (35 D range) occurs in up to 20% of patients.

CLINICAL FINDINGS

Cardiac evaluation should be completed, as premature mortality is associated with aortic complications. Open-angle glaucoma and cataract occur at a higher rate and earlier age than in the normal population. Lens subluxation may require advanced cataract techniques such as corneal tension rings or scleral fixation.

MANAGEMENT

Disorders of Nucleotide Metabolism Gout Hyperuricemia is a heterogeneous group of disorders of purine metabolism that result in increased uric acid. Discrete deposits of urate crystals into the joints or kidney is called gout.

326 • External Disease and Cornea

PATHOGENESIS Hyperuri cemia may be fam ilial, as a result of an enzyme deficiency (eg, hypoxanthine phosphoribosyltransfe rase in Lesch-Nyhan syndrome). More commonly, it is polygenic or secondary to obesity, cytotoxic chemotherapy, myelop roliferative disease, diuretic therapy, or excessive alcohol consumption. Acute inflammation of the sclera, episclera. or conjunctiva can occur. Fine corneal epithelial and stromal depOSits may appear in the absence of inflammation. See Table 11-5 for differential diagnosis of corneal deposits. An orange-brown band keratopathyor a typical whitish band keratopathy is seen in rare cases. CLI NICAL FIN DINGS

Seru m uric acid level is typically elevated. However, in urate keratopathy, uric acid level may be normal in the presence of keratopathy if there is no concurrent inflammation.

LABORATORY EVALUATION

Acute treatment is with indo methacin, colchicine. or phenylbutazone; long-term reduction in uric acid levels shou ld be pursued with drugs such as allopurinol. Superficial deposits can be removed mechanically with scraping or keratecto my. MANAG EM ENT

Porphyria The porphyrias are a group of disorders characterized by excess production and excretion of porphyrins, pigments involved in the synthesis of heme.

Porphyria cutanea tarda, the fo rm most commonly associated with ocular surface problems, is either sporadically o r autosomal dominantly inherited (chromosome 1p34). The enzyme uroporphyrinogen decarboxylase is defi cient, resulting in an accumulation of porphyrins in the liver and in the circulation. Typically, a second insult to the liver such as alcoholism or drug metabolism brings on the condition in late middle age. The pathogenesis is related to porphyri n acc umulation in the skin and mucous mem branes and to significant iron overload. A severe form of porphyria, called hepatoerythropoietic porphyria (HEP), is a homozygous presentation of the same enzymatic defect, but the onset of the disease occurs in infancy.

PATHOGENESIS

CLINICAL FINDINGS Sun-exposed surfaces develop hyperpigmentation, erythema, sclerodermalike changes, increased fragility, and vesicular and ulcerative lesions. Interpalpebral injection occurs, and the conjunctiva may develop vesicles. necrosis, scarring, and symblepharon minlicking bullous pemphigOid. Necrotizing scieritis has been reported. The cornea may be affected by exposure or by th in ni ng and perforation at the limbus. Skin and ocular lesions may fluoresce. Urine turns dark on standing. Reduced li ver and red cell uroporphyrinogen decarboxylase is confirmatory, and hepatic biopsy shows liver parenchym a cells filled with porph yr ins that fluoresce bright red in ultraviolet light.

LABORATORY EVALUATION

MANAGEMENT Protection from ultraviolet light and reduction of iron by phlebotomy are the principal treatments. No speCific ocular treatment is available, and corneal thin n ing and perforation are treated in standard ways.

CHAPTER 11:

Meta bolic Di sorders With Corneal Changes.

327

Disorders of Mineral Metabolism Wilson Disease Inherited as an autosomal recessive metabol ic defect linked to chromosome 13qI4.3q21.1, Wilson disease, or hepatolenticular degeneration, is caused by multiple allelic substitutions or deletions in DNA coding for an ATPase, Cu" -transporting, ~-polypeptide. PATHOGENESIS Copper is deposited in the liver, then in the kidneys, and eventually in the brain and the cornea at Descemet's membrane. Muscular rigidity in creases, and tremor and involuntary movement gradually occur in a fluctuating course resembli ng parkinsonism. Unintelligible speech and mild dementia usually occur concomitantly. Equal numbers of patients (40%) present with hepatic or nervous system symptoms. In the cornea, a golden brown, ruby red, or green pigment ring (Kayser-Fleischer ring) ap pears in peripheral Descemet's membrane (Fig 11-5). Not all patients with bona fide Wi lson disease will manifest a Kayser-Fleischer ring, which appears fi rst superiorly, gradua ll y spreading and widening to meet depOSits inferio rly. It consists of depOSits of copper in the posterior lamella of Descemet's membrane. Gonioscopy may assist in visualizing the ring. A "sunflower" cataract may be present. The differential diagnosis includes primary biliary cirrhosis, chronic active hepati tis, exogenous chalcosis, and progressive intrahepatic cholestasis of ch ildhood. These and other non- Wilsonian hepatic disorders can also be associated with Kayser- Fleischer rings, but only Wilson disease has decreased seru m ceruloplasmin and neurologiC symptoms. CLINICAL FINDINGS

LABORATORY EVALUATION Patients with Wilson disease can be di fferent iated from patients with other diseases that show Kayser-Fleischer rings by their inability to incorporate radioactive copper into ceruloplasmin. Low serum ceruloplasmin, high nonceruloplasminbound serum copper, and high urinary copper suggest the diagnos is, which can be established with li ve r biopsy. onspecific findings of proteinuria, aminoaciduria, glycosuria, uricaciduria, hyperphosphaturia, and hypercalciuria are seen.

MANAGEMENT Wilson disease can be treated with penicillamine. The Kayser-Fleischer ring disappears graduall y with therapy, including liver transplantation, and the disappearance

Figure 11-5 Deposits of copper in Oescemet's membrane in Kayser-Fleischer ring of Wilson hepatole nticular degeneration. (Reproduced with permiSSion from Kr8chmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Vol 1. Philadelphia: Elsevier/Mosby; 2005:375.)

328 • External Disease and Cornea

of the rings can be used to help monitor therapy. Recently, electrophysiologic abnormalities from retinal dysfunction have been shown to reverse after disease treatment.

Hypercalcemia Disorders of calcium and phosphate metabolism are associated with formation of band keratopathy. See Chapter 12.

Hemochromatosis Systemic iron overload is not associated with corneal deposits or changes. In rare cases, congenital spherocytosis has been associated with deep intraepithelial reddish brown deposits in an oval shape of unknown pathogenesis. Iron depositions are discussed further in Chapter 12.

Corneal and External Disease Signs of Systemic Neoplasia Chapter 8 discusses neoplastic disorders in greater depth. See also BCSC Section 7, Orbit, Eyelids, and Lacrimal System.

En larged Corneal Nerves Several conditions feature enlarged corneal nerves (Fig 11-6). The most important is multiple endocrine neoplasia (MEN) type 2B. This autosomal dominant (chromosome IOq 1l.2) disease is characterized by medullary carcinoma of the thyroid gland,

Figu re " ·6

Promin ent corneal nerve.

(Repro-

duced with permission from Krachm er JH, Mannis MJ, Hal/and EJ, eds. Cornea. 2nd ed. Vol 1. Philadelphia: Elsevier/Mosby; 2005:836,)

CHAPTER 11:

Metabolic Disorders With Corneal Changes.

329

Table 11-7 Prominent Corneal Nerves Enlarged Corneal Nerves

More Visible Corneal Nerves

Multiple endocrine neoplasia type liB (Sipple-Gorlin syndrome) Phytanic acid storage disease (Refsum syndrome) Hansen disease (leprosy, beading of nerves) Familial dysautonomia (Riley-Day syndrome) Neurofib romatos is Acanthamoeba perineuritis

Keratoconus Ichthyosis Fuchs corneal dystrophy Corneal edema Congenital glaucoma

pheochromocytoma, and mucosal neuromas in patients who frequently have a marfanoid habitus. Besides the thickened corneal nerves, conjunctival and eyelid neuromas and keratoconjunctivitis sicca may occur. Patients with MEN type 2A also have been noted to have enlarged corneal nerves. Other causes of prominent corneal nerves from either true enlargement or increased visibility are listed in Table 11 -7.

CHAPTER

12

Clinical Approach to Depositions and Degenerations of the Conjunctiva, Cornea, and Sclera

Degeneration of a tissue refers to decomposition of tissue elements and deterioration of tissue functions. Degenerations of the ocular surface may occur from physiologic changes associated with aging, or they may follow chronic environmental insults to the eye, such as exposure to ultraviolet light.

Degenerative Changes of the Conjunctiva Age-related (Involutional) Changes As a result of aging, the conjunctiva loses transparency. The epithelium thickens and may become keratinized in exposed zones. The substantia propria (stroma) becomes thinner and less elastic. In older persons, the conjunctival vessels can become more prominent. Saccular telangiectasias, fusiform dilatory clianges, or tortuosities may appear in the vessels. These changes are not necessarily uniform and tend to be more pronounced in the

area of the interpalpebral fissure, corresponding to the area most commonly exposed to the environmental elements.

Pinguecula A pinguecula is a common conjunctival condition that occurs typically at the nasal and temporal anterior bulbar conjunctiva as a result of the effects of ultraviolet (UV) light (actinic exposure), although it may also be related to other insults, such as welding. The epithelium overlying a pinguecula may be normal, thick, or thin. Calcification occurs occasionally. Pingueculae appear adjacent to the limbus in the interpalpebral zone, more often nasally, and have the appearance of yellow-white, amorphous subepithelial deposits. They may enlarge gradually over long periods of time. Recurrent inflammation and ocular irritation may be encountered. Lubricant therapy to alleviate ocular irritation is the mainstay of treatment. Excision is indicated only when pinguec~lae cause cosmetic problems or in the rare instances in 331

332 • Ext erna l Disease and Cornea

which they become chronically inflamed o r interfere with successful contact lens wear. Judicious use of topical corticosteroids can be considered in pati ents with chronic inflammatio n, but they are strongly discouraged as a chron ic therapy for pinguec ulae due to their side effects.

Pterygium A pterygium is a wing-shaped fold of conjunctiva and fibrovascular tissue that has invaded the superficial cornea (Fig 12-1). As with a pinguecula, the path ogenesis of a pterygium is strongly correlated with UV exposure) alth ough dryness, inflammation, and exposure to wind and dust or other irritants may also be fac tors. T he histopathology of pterygium shows elastotic degeneration of the stromal collagen with sub epithelial fibrovascular tissue. Further discussion of the histopathology of both pinguecula and pterygium ca n be found in BCSC Section 4, Ophthalmic Pathology and Intraocular TunlO rs. Pterygia are nearl y always preceded and accompanied by pingueculae, although why some patients develop pterygia wh ereas oth ers have onl y pingueculae is not kn own. The prevalence of pterygia increases steadi ly with proximity to the equator. Regular and irregular astigmatism occurs in proportion to pterygium size. A pigmented iron line (Stocker line) may be seen at the central anterior edge of the pterygium on the cornea when longstanding and stable. Excision is indicated if the pterygium approaches the visual ax is, causing loss of vision from irregular astigmatism or in cases of considerable irritat ion . See Chapter 15.

Conjunctival Concretions Concretions appear histopath ologicall y to be epithelial inclusion cysts filled with epithelial and keratin debris. Yellow-white deposits are sometimes found in the palpebral conjunctiva of older patients or patients who have had chronic co njunctivitis. Secondar y caJcification occurs occaSionally, in which case the lesions are sometimes referred to as

Figure 12-1

Slit-lamp photograph of a pterygium. (CounesyofRoben

w. Weisenrhal, MD.)

CHAPTER 12:

Depositions and Degenerations.

333

conjunctival lithiasis. The subconjunctival deposition of oral tetracyclines mimics concretions. Concretions are almost always asymptomatic but may erode the overlying epithelium to cause foreign- body sensation. If symptomatic, concretions can be easily removed under topical anesthesia.

Conjunctivochalasis Conjunctivochalasis is a loose adherence of the lower conjunctiva; it occurs commonly with chronic inflammation or agi ng and is often overlooked and asymptomatic. Occasionally, the redundant conjunctiva overlies the lower eyelid margin to such an extent that various clinical problems appear (Fig 12-2A, B). These range from the aggravation of dry eye in the mild stages (from exposure of the redundant conjunctiva due to uneven wetting), to secondary tearing due to occlusion of the lower punctum when the chalasis is prominent medially, to exposure-related pain and irritation in its severe stages. Lubricants, anti-inflammatory agents, antihistamines, and nocturnal patching have been offered as treatments, although none besides lubrication is offered as a long-term potential solution. If these modalities fail, then cautious surgical excision, conjunctival fixation to the sclera, amniotic membrane grafts, or cauterization of the redundant folds may be required. Di Pascuale MA, Espana EM, Kawakita T, Tseng Sc. Clinical characteristics of conjunctivochalasis with or without aqueous tear deficiency. Br J Ophthalmol. 2004;88 (3} :388-392. Haefliger 10, Vysniauskiene I, Figueiriedo AR, Piffaretti JM. Superficial conjunctiva cauterization to reduce moderate conjunctivochalasis. Klin Monatsbl Augellheilkd. 2007;224{4): 237- 239. Maskin SL. Effect of ocular surface deconstruction by using amniotic membrane transplant for symptomatic conjunctivochalasis on fluorescein clearance test results. Cornea. 2008,27(6),644 - 649. Meller D, Tseng Sc. Conjunctivochalasis: literature review and possible pathophysiology. Surv Ophthalmol.1998;43(3) ,225- 232 . Otaka I, Kyu N. A new surgical technique fo r management of conjunctivochalasis. Am } Ophthalmol.2000;129(3)385-387.

A

B

Figure 12-2 A and B, "Redundant," or extra, conjunctiva l tissue inferotemporaliy overlying t he lid, caus ing foreign-body sensation due to interruption of the tear fi lm, highlighted with f luorescein. (Courtesy of Robert W. Weisen rha l, MD.)

334 • Extern al Disease and Corn ea

Degenerative Changes in the Cornea Age-related (Involutional) Changes As a resu lt of aging, the cornea gradually becomes flatter, thin ner, and slightly less tra nsparent. Its refractive index increases, and Descemet's membrane becomes thicker, increasing fro m 3 ~m at birth to 10 ~m in ad ults as a result of the increased thickness of its posterior nonbanded zone. Occasional peripheral endothelial guttae, sometimes known as Hassall-Henle bodies, can form with age (see the discussion later in the chapter). Agerelated attrition of corneal endothelial cells results in a loss of about 100,000 cells during the first 50 years of li fe, from a cell density of about 4000 cells/mm' at birth to a dens ity of 2500-3000 cells/mm' in older adults. The ave rage rate of endothelial cell de nsity decrease throughout adult life is approxi mately 0.6% per year. It is important to differentiate corneal degenerations from corneal dystroph ies (Table 12 -1). Bourne WM, Nelson LR, Hodge DO. Central corneal endothelial cell changes over a ten -year period. lllvest Ophthalmol Vis Sci. 1997;38(3),77 9- 782.

Epithelial and Subepithelial Degenerations Coats white ring A sm all (I mm or less in diameter) circle or oval-shaped area of discrete gray-white dots is sometimes seen in the superficial stroma. Referred to as Coa ts white ring, it represents iron-containing fibrotic remnants of a metall ic fore ign body; once these lesions matu re and are free of any associated infl am mation, they do not change; hence, therapy with corticosteroids or other anti-inflammato ries is not indicated (Fig 12-3) . Spheroidal degeneration Spheroidal degeneration is a common degeneration; it is often bilateral and interpalpebral and is more common in males. It is characterized by the appearance in the cornea, and sometimes in the conjunctiva, of translucent, golden brown, spheroidlike deposits in the superficial stroma (Fig 12-4) . The condition has been reported under different names, including corneal elastosis, keratinoid degeneration, climatic droplet keratopathy, Bietti nodular dystrophy, proteinaceous degeneration, and Labrador keratopathy. [n primary spherOidal degeneration, the deposits are bilateral and initially located in the nasal and temporal cornea. With advanCing age, they can extend onto the conju nctiva. The degenerat ion is unrelated to the coexistence of other ocular disease. In rare cases,

Table 12-1 Differences Between Corneal Degenerations and Corneal Dystrophies Degeneration

Dystrophy

Opacity often peripherally located May be asymmetric Presents later in life, associated w ith aging Prog ress ion can be very slow or rapid

Often centrally located Bil ate ral and symmetric Presents early in life, hereditary Progression usuall y slow

CHAPTER 12:

Figure 12-3

Depositions and Degenerations. 335

Coats w hi te ring (arrow) (n ot to be co nfused w it h ma p-dot-fin gerprint dystroph y).

(Courtesy of W Craig Fowler, MD.}

Figure 12-4 Spheroidal degeneration at th e corn eal limbus (Courtesy of Robert W Weisenthal M D.)

generally in childhood, the spheroidal deposits extend across the interpalpebral zone of the cornea, producing a noncalcific band-shaped keratopathy. Secondary spheroidal degeneration is associated with ocular injury or inflammation. The deposits aggregate near the area of corneal scarring or vascularization. All cases show extracellular proteinaceous deposits with characteristics of e1astotic degeneration, which are thought to be secondary to the combined effects of genetic predisposition, actinic exposure, age, and perhaps various kinds of environmental trauma other than sunlight, such as wind. The pattern is similar to that of other UV light-associated degenerations, such as pingueculae. The composition is not lipid despite its "oil droplet" appearance. No medical therapy is of much value, although lubrication is recommended to address uneven layering of the tear film over affected areas. In cases of central involvement, superficial keratectomy or excimer excision may be indicated. Recurrence after conjunctival resection is common.

Iron deposition A Fleischer ring, representing iron deposition in keratoconus, is one of many corneal iron lines associated with epithelial irregularities (see Fig 10-28). This sign is extremely useful in the diagnosis of mild or early cases of keratoconus. Often it can be seen only by using

336 • Extern a l Disease and Cornea

red-free or cobalt blue illumination prior to instilling fluorescein. The Hudson-Stahli line, generally located at the junction of the upper two thirds and lower third of the cornea, is ubiquitous. Most iron lines are related to ab normalities of tear pooling related to su rface irregularities (Fig 12-5). [ron li nes are also associated with keratorefractive procedu res. Following rad ial keratotomy, visually insignificant iron lines are noted centrall y in approximately 80% of patients and are commonly characterized as a "tear star." Common conditions associated wi th corneal iron li nes are listed in Table 12-2. Palay DA. Corn ea l deposits. In: Krachmer JH, Mannis MJ. Holland EJ. Comea. 2nd ed. Vol I. Philadelphia: Elsevier/Mosby; 2005:chap 26, pp 365- 378.

Stromal Degenerations Age-related (involutional) changes

White limbal girdle Two forms of the white limbal girdle of Vogt have been described. Type I is a narrow, concentric, whitish superficial band runni ng along the limbus in the palpebral fissure. A lucid interval appears between the li mbus and the girdle. This girdle is a degenerative change of the anterior li miti ng membrane, with chalklike opacities and small clear areas li ke the holes in Swiss cheese. Type [] consists of small white, fleckJike, and needlelike deposits that are often seen at the nasal and temporal limbus in older patients. No clear interval separates this girdle from the limbus. The histopathologic picture represents epithelial elastotic degeneration of collagen, sometimes with particles of calcium . Corneal arcus Corneal arcus, or arcus senilis, is most often an involutional change modified by genetic factors. HO\vever, arcus is sometimes indicati ve of a hyperlipoproteine-

mia (involving low-density lipoproteins) with elevated serum cholesterol, especially in patients under 40 years of age (see Chapter 11 ). It can be a prognostic factor for coronary artery disease in this age group. Arcus occurs occasionally as a congen ital anomal y (arcus juvenilis), us ually involVi ng only a sector of the peripheral corn ea and not associated with abnormalities of serum lipid.

Figure 12-5 Iron deposition (iron line) (arrow) due to irregu larity of the tear fi lm from subepithelial fibrosis . (Courtesy of Robert W Weisenthal. MDJ

CHAPTER 12:

Table 12·2

Depositions and Degenerations.

337

Corneal Pigmentations

Pigment

Clinical Condition

Location in Cornea

Melanin

Kruken berg spind le

Melan in-like pigment (oxidized epinephrine) Melanin-li ke pigment (alkapton) Iron

Adrenoc hrome deposition

Endoth elium, in a vertically oriented ellipse; sometimes associated with pigmentary glaucoma Between basement memb rane and Bowman layer or in conjunctival cysts; occurs in patients using topica l epineph rine compo unds for glaucoma

Iron (foreign body) Iron Iron

Siderosis

Iron Iron Copper Copper Silver Gold Carbon

Ochronosis

Epithe lium and superfic ial stroma, peripherally; occurs in the metabo li c disease alkaptonu ria

Blood sta ining

Ch iefly stroma; epithelium in some cases; occurs in some cases of hyphema Chi efly stroma; epithe lium in some cases

Ferry line Fle ische r ring (or l ine) Hudson-Stahli li ne Stocker line Kayser-F leischer ring Chal cosis Argyriasis Chrysiasis Corneal tattoo

Corneal epithelium anterior to filtering bleb Corneal epithelium surrounding base of co ne in keratoconus Corneal epithelium at junction o f upper two t hird s w ith lower one third of the aging cornea Corneal epith elium anterior to head of pterygium Descemet's membrane peripherally, in patients w ith W il son hepatolenticula r degeneration Descemet's membrane Deep stroma and Descemet's membrane Deep stroma (mo re in periphery) Stroma

Arcus is a deposition of lipid in the peripheral corn eal stroma. It starts at the inferior and superior poles of the cornea and in the late stages encircles the enti re circumference. The incidence is 60% in individuals between the ages of 50 and 60; it approaches 100% in individuals over 80. The frequency is higher in the black population. The arcus has a hazy white appearance, a sharp outer border, an d an indisti nct central border; it is denser superi orly and inferiorly (Fig 12·6) . A lucid in terval is usually present between the peripheral edge of the arcus and the limbus. The lipid is fo und to be concent rated mai nly in 2 areas of the peripheral corneal stroma: one adjacent to Bowman layer and another near Descemet's membran e. Unilateral arcus is a rare condition associated with contralateral carotid artery disease or ocular hypotony. Arcus is also seen in Schn yder centra l crystalline dystrophy. Crocodile shagreen Ante rior crocodile shagreen, or mosaic degeneration, is a central corneal opacity at the level of Bowman layer characterized by mosaic, polygonal, gray opacities separated by clear zones. Histologically, th e Bowman layer is thrown into ridges and may be calcified. Posterior crocodile shagreen shows similar changes in the deep strorna near Descemet's membrane. The posterior variety of crocodile shagreen resembles central cloudy dystrophy ofFran~oi s (see Fig 10· 17). Cornea ialinala Corn ea farinata, an involutional change, probably depends on a domi· nantly transmitted genetic predisposition. The deep corneal stroma shows many dot· and com ma·shaped opacities (Fig 12·7). They are very nebulous and subtle and often are best

338 • Externa l Disease and Cornea

Figure 12·6

Figure 12·7

Cornea l arcus. (Courtesy of Robert W Welsenthal, MO)

Corneal fari nata. (Courtesy of Robert

W Weisenthal, MDJ

seen with retroiliumination. The condition does not affect vision and has no clinical significance, except that it is sometimes mistaken for a progressive dystrophy. The deposits may consist of li pofuscin. a degenerative pigment that appears in some aged cells. PreDescemet's dystrophy is probably a morphologic variant of cornea farinata. Although these conditions are most likely related, it is unclear whether they are degenerations or dystrophies.

Polymorphic amyloid degeneration Polymorphic amylOid degeneration is a bilate rally symmetric, slowly progressive corneal degeneration that appears late in life. The corneal opacities emerge as either stellate fl ecks in mid- to deep stroma or irregular fil aments. Both forms may occur together, but usually 1 predominates. These deposits are usuaUy axial, polymorphic, and filamentou s. The opacities are gray to white and somewhat refractile but appear transl ucent in retroillumination (Fig 12-8). The interveni ng stroma appears clear, and visual acu ity is usually normal. The corneal depOSits consist of amylOid and can resem ble some of the deposits seen in early lattice corneal dyst rophy type III.

CHAPTER 12:

Figure 12·8

Depositions and Degenerations . 339

Polymorphic amyloid degeneration.

(Courtesy of Robert WWeisenrhal, MD.)

Peripheral cornea The peripheral cornea differs from the central cornea in several unique anatomical and physiologic features. Contiguity with the Iimbal vasculature is the most important difference. Thus, compared to the central cornea, the peripheral cornea is much more susceptible to the adverse effects of pathologies associated with blood vessels, such as inflammatory infiltrations and depositions of serum proteins or other substances. Because

of this proximity to Iimbal vessels, the peripheral cornea is also inevitably involved in the early stage of any condition causing corneal vascu larization. The peripheral cornea is also close to the surrounding conjunctiva, episclera, and

sclera and is thus secondarily affected by primary diseases of these adjacent tissues. For example, conjunctival inflammatory conditions such as pterygium and trachoma often in -

volve the peripheral cornea. Mechanical disruption of normal corneal wetting by the adjacent swollen conjunctiva can lead to drying of the peripheral cornea and dellen for mation. Autoimmune scleral inflammation (eg, scleritis) may be seen contiguous with peripheral

corneal ulceration, in a process called peripheral ulcerative keratitis (PUK). Senile furrow degeneration Senile furrow degeneration is an appearance of thinning that is seen in older people in the lucid interval of a corneal arcus. There is no inflammation, vascu lari zation, or tendency to perforate. Vision is rarely affected unless astigmatism occurs because of the thinning. Although slight thi nning is occasionally present, it is usually more apparent than real. The epithelium is intact. No treatment is required. Terrien marginal degeneration The cause of Terrien marginal degeneration is unknown. This condition is a quiet, essentially noninflammatory, unilateral or asymmetrically bilat-

eral, slowly progressive thinning of the peripheral cornea. Sex prevalence is roughly equal, and cases usually occur in the second or third decade of life. The corneal thinning can be localized or involve extensive portions of the peripheral cornea. Terrien marginal degener~tion begins superiorly, spreads circumferentially, and rarely involves the inferior limbus. The central wall is steep, and the peripheral wall slopes

340 • External Disease and Cornea

Figure 12-9

Terrien margina l degeneration wi th superior thinning .

(Courtes yofJ. Jude/son, MD.J

gradually. The epithelium remains intact, and a fine vascular pannus traverses the area of stromal thinning. A line of lipid deposits appears at the leading edge of the pannus (central edge of the furrow) (Fig 12-9). Spontaneous perforation is rare, although perforation can easily occur with minor trauma. Corneal topography reveals flattening of the peripheral thinned cornea, with steepening of the corneal surface approximately 90° away from the midpoint of the th inned area. This pattern usually results in high against-the-rule or oblique astigmatism. Spontaneous ruptures in Descemet's membrane can result in interlamellar fluid or even a corneal cyst. An inflammatory condition of the peripheral cornea that may resemble Terrien marginal degeneration occurs, in rare instances, in children and young adults. Also known as Fuchs superficial marginal keratitis, it features progressive thinning without epithelial ulceration and can lead to perforation. Surgical correction is indicated when perforation is imminent due to progressive thinning or when marked astigmatism Significantly limits visual acuity. Crescent-shaped lamellar or full-thickness corneoscleral patch grafts may be used and have been reported to arrest the progression of severe against-the-rule astigmatism for up to 20 years. Annular lamellar keratoplasty grafts may be required in severe cases of 360" marginal degeneration. Postinflammatory changes

Salzmann nodular degeneration Salzmann nodular degeneration is a noninflammatory corneal degeneration that sometimes occurs as a late sequela to old, long-standing keratitis, or it may often be idiopathic. Causes include phlyctenulosis, trachoma, and interstitial keratitis. The degeneration may not appear until years after the active keratitis has subsided. It can be bilateral and is more common in middle-aged and older women. The nodules are gray-white or blue-white and elevated (Fig 12-10), and they may be associated with recurrent erosion. They often develop in a roughly circular configuration in the central or paracentral cornea and at the ends of vessels of a pannus. Histopathologic examination

CHAPTER 12:

Figure 12-10

Deposi tions and Degenerations . 341

Salzmann corneal nodules in the superonasal periphery of the cornea. (Counesyof

Robert W Welsenthaf, MD.}

reveals localized replacement of Bowman layer by hyaline and fibrillar material, probably representing basement membrane and material si milar to that found in spheroidal degeneration. Treatment for mild cases is lubrication, although superficial keratectomy may be indicated in more severe cases causing decreased vision secondary to irregular astigmatism. This degeneration may recur after removal; however, treatment with mitomyci n Cat the tim e of surgery has been shown to reduce the incidence of recurrence. Bowers PJ Jr, Price MO, Zel des SS, Price FW Jr. Superfi Cial keratectomy with mitomycin C for the treatment of Salzmann's nodules. ] Cataract Refract Surg 2003;29(7): 1302-1306.

Amvloid degeneration Acquired (secondary localized) corneal amylOidoSiS may be associated with corneal inflanunation (such as trachoma, keratoconus, Hansen disease [leprosy], or phlyctenulosis) or intraocular disease (such as uveitis, retinopathy of prematurity, or glaucoma) or may be secondary to trauma. Clinica lly, amylOid deposits LlSUall y occur as raised, yellow-pink nodu lar masses in the cornea. Less commonly, they may appear as perivascular deposits, In most cases, corneal vascularization is associated with the amylOid. The depOSits may be refractile with retroillumination. See the discussion on amylOidOSiS in Chapter II. Amyloid depOS its of the conjunctiva are described in BCSC Section 4, OphthalmiC Pathology and Intmocular Tumo rs. Corneal keloid Corneal keloids are white, sometimes protuberant, glistening corneal masses that often resemble dermoids and can involve the entire corneal surface. They are thought to be secondary to a vigorous fibrotic response to corneal perforation or injury. The resemblance to corneal dermoids can make diagnosis difficult. Subtle differences between corneal keloids and dermoids include the glistening and jellylike quality of the keloids. Definitive diagnosiS can be made by corn eal biopsy. Study of enucleation specimens has revealed associated find ings, includi ng cataract, anterior staphyloma, ruptured lens capsule with lens fragments in the wound, buphthalmos, chronic glaucoma, and angleclosure glaucoma.

342 • External Disease and Cornea

Lipid keratopathy In lipid keratopathy, yellow or cream-colored lipids containing cholesterol, neutral fats, and glycoproteins are deposited in the superficial or deeper cornea, usually in areas of vascularized corneal scars. The epithelium is involved secondarily, after prolonged corneal inflammation with corneal vascularization (eg, herpes simplex or herpes zoster keratitis or trachoma). This form is best described as secondary lipid keratopathy (Fig 12-11 ). Argon laser treatment with and without fluorescein and subconjunctival and topical bevacizumab have been reported to reduce corneal neovascularization and lipid deposition. Lipid keratopathy has been reported, in rare instances, with no evidence of an antecedent infection, inflammatory process, or corneal damage. These cases are best described as primary lipid keratopathy. Do ctor PP, Bhat PV, Foster CS. Subconjunctival bevacizumab for corneal neovascularization. Cornea. 2008;27(9),992 - 995. Gordon YJ, Mann RK, Mah TS, Gorin ME. Fluorescein-potentiated argon laser therapy improves symptoms and appearance of corneal neovascularization. Cornea. 2002;2l(8): 770-773. You Ie, Kang IS, Lee SH, Yoon KC. Therapeutic effect of subconjunctival injection of bevacizumab in the treatment of corneal neovascularization. Acta OphthalmoL 2009;87(6): 653-658.

Calcific band keratopathy Calcific band keratopathy (calcium hydroxyapatite deposi tion) is a calcific degeneration of the superficial cornea that involves mainly Bowman layer. It is often idiopathic. There are 6 main known causes: 1. chronic ocular disease (usually inflammatory) such as uveitis in children, intersti-

2. 3. 4. 5.

6.

tial keratitis, severe superficial keratitis, and phthisis bulbi hypercalcemia caused by hyperparathyrOidism, vitamin D toxicity, milk- alkali syndrome, sarcoidosis, and other systemic disorders hereditary transmission (primary hereditary band keratopathy, with or without other anomalies) elevated serum phosphorus with normal serum calcium, which sometimes occurs in patients with renal failure chronic exposure to mercurial vapors or to mercurial preservatives (phenylmercuric nitrate or acetate) in ophthalmic medications (the mercury causes changes in corneal collagen that result in the deposition of calcium) silicone oil instillation in an aphakic eye

Figure 12-11

Lipid keratopathy secondary to cornea l vascu larization (arrow points to lipid).

(Courtesy of Robert W. Weisenrhal, MD.) .

CHAPTER 12:

Depositi ons and Degenerations.

343

Other rare assoc iated disorders have been reporled, including iris mel anoma. Band keratopathy may also result fro m the deposition in th e cornea of urates, which appear brown, unlike the gray-white calcific deposits, and may be associated with gout or hyperuricemia. Calcific band keratopathy begins as fine, dustl ike, basophilic deposits in Bowman layer. These changes are usually fi rst seen peripherally. A peripheral clear zone representing a lucid interval is seen between the limbus and the peripheral edge of the keratopathy. Event ually, the deposits may coalesce to form a hor izo ntal band of dense calcific plaques across the interpalpebral zone of the cornea (Fig 12- 12). A reasonable first step in managing this condition would be a workup (eg, serum electrolytes and urin alys is) to rule out associated metabolic!renal disease. Underlying conditions, such as keratoconjunctivitis sicca or renal failure, should be treated or controlled as much as possible, which may reduce or control the deposition of calcium o r at least help redu ce the rec urrence of band keratopathy. The calciu m can usually be removed from Bowman layer by chelation with a neutral solution of disodium ethylenediaminetetraacetic acid (E DTA; usual concentration 0.5%- 1.5%), which can be warmed to speed up the chemical chelation of calcium. (Disodium EDTA is no longer commercially available but can be obtained through a compounding pharmacy.) The epithelium overlying the calcium needs to be removed prior to applying the chelating solution. Any cylindrical tube that approximates the corneal diameter can facilitate the process by acting as a reservoir to confine the chelating sol ution to th e desired treatment area, althoug h this is not always necessary. With the reservoir in place. very gentle surface agitation with truncated Weck-Cel sponges may furt her enhance the release of th e impregnated calcium. If used at all, scraping should be gentle so as to prevent damage to Bowman layer. A fibrous pannus may be present along with extensive calcific band keratopathy, especially if silicone oil is responsible, and neither EDTA nor scraping will remove such fibro us tissue. A soft contact lens can be helpful postoperatively until the epithelium has healed. The problem can recur but may not do so for years, at which time the treatment may be repeated.

Figure 12-12

Band keratopathy.

344 • External Disease and Cornea

Phototherapeutic keratectomy (PTK) usi ng excimer laser is not advised as a primary treatment because calcium ablates at a different rate from stroma, which could produce a severely irregular surface. If residual opacification remains after the initial EDTA chelation, then PTK may be employed. Roy FH. Corneal and conjunctival calcification. In: Roy FH , Fraunfelder FW, Fraunfelder FT. Roy and Fraunfelder's Current Ocular Therapy. 6th ed . Current Therapy series. Philadelphia: Elsevier/Saunders; 2008:337-338.

Endothelial Degenerations Iridocorneal endothelial syndrome Iridocorneal endothelial (ICE) syndrome is a spectrum of disorders characterized by varying degrees of corneal edema, glaucoma, and iris abnormalities (Fig 12-13). The pathogenesis of ICE syndrome is unknown but appears to involve an abnormal clone of endothelial cells that takes on the ultrastructural characteristics of epithelial cells. The condition appears to represent an acqu ired maldifferentiation of a group of endothelial cells, although the abnormal clone could originate at birth or before. Varying degrees of endothelialization take place in the anterior chamber angle and on the iris surface. Herpesvirus DNA has been identified in some corneal specimens following keratoplasty and in the aqueous humor of some patients. This raises the in triguing possibility that a herpes Simplex virus infection may induce these changes. When the pathology is confined to the inner corneal surface, corneal edema may result from subnormal endothelial pump function, produCing the Chandler variant of ICE syndrome. Frequently, the border between the abnormal and normal endothelium can be seen at the slit lamp using specular reflection. When the abnormal endothelium migrates over the anterior chamber angle, the resu ltant peripheral anterior synechiae and outflow obstruction produce glaucoma. When the abnormal endothelium spreads onto the surface of the iris, the resulting contractile membrane may produce iris atrophy) corectopia, and

polycoria, hallmarks of the essential iris atrophy variant of ICE syndrome (see Fig 12-1 3).

Figure 12·13

Iridocorneal endothelial syndrome with corectopia. (Counesyof Srephen Orlin, MD.)

CHAPTER 12: Depositions and Degenerations . 345

The Cogan -Reese (or iris nevus) variant shows multiple pigmented iris nodules, also produced by the contracting endothelial membrane. This syndrome becomes ap parent most commonly in middle-aged females and is almost always unilateral. Asymmetric posterior polymorphous dystrophy, as well as other causes of un ilateral corneal edema, must be included in the differential diagnosis of ICE syndrome. Penetrating keratoplasty and endothelial keratoplasty are effective treatments for the corneal component of this syndrome. Glaucoma is an important feature of the ICE syndrome. Long-term graft clarity depends on the successful control of lOP, which can be dim cult (see BCSC Section 10, Glau coma ). Alvarado lA, Underwood IL, Green WR, et al. Detection of herpes simplex viral DNA in the iridocorneal endothelial syndrome. Arch Ophtl/almol. 1994;112(12):1601-1609. Carpel EF. Iridocorneal endothelial syndrome. In: Krachmer JH, Mannis MJ, Holland EJ. COTnea. 2nd ed. Vall. Philadelphia: Elsevier/Mosby; 2005:chap 79, pp 975-985. Groh MJ, Seitz B, Schumacher S, Naumann GO. Detection of herpes simplex virus in aqueous humor in iridocorneal endothelial (ICE) synd rome. Cornea. 1999;18(3):359-360. Herde]. Iridocorneal endothelial syndrome (ICE-S): classification, clinical picture, diagnosis. Klin Monatsbl Al 168 herpes simplex keratitis differentiated from,

168-169 isolation techniques for diagnosis of, 103

polyplwga, 140/ stains and culture media for identification of, !O3!

ACD. See Granular corneal d ystrophy, type 2 Acet)'lcysteine. for filamentar y keratopathy, 60 Add, ocular injuries caused by, 355 ACid-fast stain, 131

ACL syndrome, congenital corneal keloids in, 264 Acne rosacea. See Rosacea AcqUired immunodetlciency syndrome. See HIV infection/AIDS Acrocephalopolysyndactyly type II. 3221 Actinomyces. 137 Acute hemorrhagic conju ncti vitis. 130 AcyclOVir. 109t for epithelial keratitis. 113 for herpes zoster ophthalm icus. 121 for iridocyclitis. 116 for stromal keratitis. 108t. 11 5. 116 ADCC See Antibody-dependent cel1ular cytotoxicity Adenoviruses/adenoviral infection. 123-127 acute hemorrhagiC conjunctivitis. 130 epidemic keratoconjunctivitis. 124. 125, 125f, 126f follicular conjunc ti vitis, 124 herpes simplex infection differentiated from, 107 pharyngoconjunctival fever. 124 Adherence. as microbial virulence factor. 98.159 Adhesins.98. 132 Adolescents. cystinosis in . 313 Adrenochrome deposition. corneal pigmentation caused by, 3371, 348, 348/ Advancement flaps. 400 Age/aging aqueous tear deficiencyfdry eye and. 50 of conjunctiva. 331 of cornea, 334 donor corneas and. 4 11 stromal corneal degenerations and, 336- 338. 338f, 339/ of sclera. 9. 345-346, 346f Aggrecan,9 AHC See Acute hemorrhagic conjunctivitis AIDS. See HI V infectionfAIDS Air, refractive index of, 38 AK. See Astigmatic keratotomy AKC See Atopic keratoconjunctivitis Albright hereditary osteodystrophy, 322t Alcohol, vitamin A deficiency and, 78

Alkalis (alkaline solutions), ocular inj uries caused by, 353-355, 353t, 354f vitamin C and, 79 Alkapton, corneal pigmentation caused by, 3 15-316, 337t Alkaptonuria, 3141 Allergic conjunctivitis, 185-187 Allergic reactionsfallergies anaphylaxis, 178f, 179-180, 1791, 183, 184f conjunctivitis, 185-187 contact lens wear and, 92 in eyelid atopic dermatitis, 185 contact dermatoblepharitis, 183-185, 184/ keratoconjunctivitis atopic, 190- 192, 191f vernal, 187-190. IS8f, 189f, 191f to topical medications, 183-185, 184/ Allografts corneal, 413. See also Keratoplasty rejection of, 407, 408, 427-430, 428f, 429J, 436. See also Rejection limbal, 94, 398 for chemical injuries, 94 indications for, 3871 ALMDI (anterior limiting membrane dystrophy type 1). See Reis-Biicklers corneal dystrophy ALMD2 (an terior limiting membrane dystrophy type 2). See Thiel -Behnke corneal dystrophy Alpha (a)-agonists, for hyphema, 368 Alpha (a)-melanocyte-stimulating hormone (a-MSH),

177t AlphaCor keratoprosthesis, 432 Amblyopia, corneal transplantation and, 430, 431 Amebae, 140, 140/ Amebiccysts, 140, 140J, 169 Amebic keratitis, 167- 169, 168/ See also Acanthamoeba, ke ratitisfocular infection caused by Ame1anotic conjunctival nevus, 236, 236/ American Standards Institute (ANSI), on corneal topography standards, 43 Amicar. See Aminocaproic acid Amino acids, disorders of metabolism of, 313- 316, 314t.

See a/so specific disorder corneal changes and, 313-3 16, 3141 Aminocaproic acid, for hyphema, 368 Aminoglycosides, for Acantllamoeba keratitis, 169 Amiodarone, cornea vert ici llata caused by, 346 Amitriptyline, for postherpetic neuralgia, 121 Amniotic membrane transplantation, 389 for chemical injuries, 358 as cyanoacr ylate alternative, 404 for graft-vs-host disease. 203 for herpetic eye disease complications, 117 indications for, 387t for ligneous conjunctivitis, 193 for neurotrophic keratopathy, 88 for pseudocryptophthalmos. 250

471

472 • Index for pterygium, 394 for squamous cell carcinoma of conjunctiva, 232 for Slevens-Johnson syndrome, \9i Amorphous corneal dystrophy, posterior, 268/, 2701, 288-289,288/ genetics of, 269t, 288 Amphoterici n S, for fungal keratitis, 166 AMT. See Amniotic membrane transplantation Amyloid AA, 316, 319 Amyloid AL, 316 . Amyloid degeneration, 341. See also Am)'loidosisf amyloid deposits polymorphic, 338, 339/ Amyloid SA A, 316 Amyloidosis/amyloid deposits, 316-319, 317t, 318/ conjunctival, 317/, 318, 318! corneal, 317t, 318-319, 318! in gelatinous droplike dystrophy, 274-275, 275/, 3I7t, 318, 318! in lattice dystrophy, 278, 280

familial Finnish-type (amylOidosis V/gelsolin-type lattice corneal dystrophy), 2681, 2701, 280, 280f, 3171, 319 genetics of, 2691, 2BO, 317t primary of cornea (subepithelial amyloidosis/ gelatinous droplike dystrophy), 268t, 2701, 274- 275, 275j, 317t, 318, 318f genetics of, 269t, 274, 317t primary localized, 317t, 3IB-319, 318j primary systemic, 317t, 319 secondary localized, 317t, 319, 341 secondary systemic, 317t, 319 ANA. See Antinuclear (anti neutrophil) antibodies Anaerobes, as normal ocular flora, 971 Anaphylactic hypersensitivity (type I) reaction, 17Bf, 179-180, 1791 allergic conjunctivitis and, 185 topical medications/substances and, 183, 184, 184/ Anaphylaxis, 178j, 179-180, 179t slow-reacting substance of, 179t ANCA. See Antinuclear (antineutrophil) antibodies Androgens, in tear secretion/Sjogren syndrome, 63-64 Anesthesia, corneal congenital,264-265 herpes simplex epithelial keratitis and, 110 neurotrophic keratopathy/persistent corneal defects and, 86, 87 Anesthesia (anesthetics) for corneal transplantation in children, 430 local (topical/regional) abuse of, 90, 9 1j, 359 keratoconjunctivitis caused by, 359, 359t for perforating injury repair, 376 tear production affected by, 661 Angioedema, 1961 Angiokeratoma corporis diffusum universale (Fabry disease), 3\0, 311 Angiopoietin 1, nevus flarnmeus and, 241 Angle closure/angle-closure glaucoma cornea plana and, 255 microcornea and, 253 nanophthalmos and, 251,252

Anhidrotic ectodermal dysplasia, 75 Ankyloblepharon, 249, 249j Annular keratopathy, traumatic, 363 ANSI (American Standards Institute), on corneal topography standards, 43 Anterior basement membrane dystrophy. See Epithelial/ subepithelial dystrophies, basement membrane Anterior chamber, flat or sha llmv, penetrating keratoplasty and, 421 Anterior chamber-associated immune deviation (ACAID), corneal grafl tolerance and, 408 Anterior chamber cleavage syndrome, 255-263. See also specific disorder Anterior crocodile shagreen (mosaic degeneration), 337 Anterior limiting membrane dystrophy type 1. See ReisBucklers corneal dystrophy Anterior limiting membrane dystrophy type 2. See Thiel -Behnke corneal dystrophy Anterior microphthalmos, 253 Anterior segment. See also specific structure and under Anterior chamber development of, 4 disorders of developmental anomalies, 249- 253 toxic keratoconjunctivitis from medications, 359- 361,3591,361/ traumatic, 351-385. See also Anterior segment, trauma to examination of fluorescein angiography in, 33 imaging in, 33-35, 33j, 34f, 35f photography in, 31-36, 32f, 33j, 34f, 35f, 36f function of, 3 surgery on, traumatic injury and, 382-385, 384f trauma to, 351-385 animal and plant substances causing, 361 -362 chemical injuries, 353-359. See also Chemical injury concussive, 362-369, 364j, 365j, 366f, 367f, 369t nonperforating mechanical, 369-372, 370j, 371j perforating, 3i3-382, 373t, 374t, 376j, 377t, 378j, 379f, 38tf, 382f See also Perforating injuries surgical, 382-385, 384j temperature and radiation causing, 351 -353 Anterior stroma! micrOpU!1Cture, for recurrent corneal erosions, 84, 85j Antiarrhythmic drugs, tear production affected by, 66t Antibiotics for Acanthamoeba keratitis, 169 for acute purulent conjunctivitis, 150- 151 for bacterial keratitis, 161 - 163, 162t for corneal abrasion, 372 for gonococcal conjunctivitis, 152 for meibomian gland dysfunction, 68 for perforating injury, 375, 380 , 381 for recurrent corneal erosions, 84 for scleritis, 171 for seborrheic blepharitis, 72 for staphylococcal blepharitis/blepharoconjunctivitis, 147

Antibody·dependent cellular cytotoxicity, 180 AnticholinergiC agents, dry eye caused by, 66t Antidepressants, tear production affected by, 66t

In dex. 473 Antiftbrinolytic agents, for hyphema, 368 Antifibrotic agents, toxic keratoconjunctivitis caused by, 360 Antifungal agents, for keratitis, 166~ 167 Antigen ~ antibody (immune) complexes, in type III hypersensitivity reaction, 178j, 179t, 180 Antigen-presenting cells in conjunctiva, 173 in cornea, 174 in external eye defense, 96 Ahtigens endogenous, 407 histocompatibility, 407 homologous, 407 transplantation, 407 Antiglaucoma agents, dry eye and, 61 Antihistamines for ocular allergies conjunctivitis, 186 vernal keratoconjunctivitis, 188 tear production affected by, 66t Antihypertensive drugs for hyphema, 368 tear production affected by, 66t Antinuclear (antineutrophil) antibodies in aqueous tear deficiency, 57 in Sjogren syndrome, 57 testing for, 182l Anti-Parkinson agents, tear production affected by, 66t Antispasmodics, tear production affected by, 66t Anti-SS-A autoantibodies in aqueous tear deficiency, 57 in Sjogren syndrome, 57, 64t Anti-SS-8 autoantibodies in aqueous tear deficiency, 57 in Sjogren syndrome, 57, 64t Antiulcer agents, tear prod uction affected by, 66t Antiviral agents, for herpetic eye disease, 109, 109! epitheliopathy caused by, 116~ 117 herpes simplex epithelial keratitis, 111-113 herpes zoster ophthalmicus, 121 stromal keratitis, 108t, 115 -1 16 Anwar big-bubble technique, 435 -436 Apert syndrome, 322t Apical zone, 37 Apocrine glands of eyelid, 4 Apolipoprotein E mutation, in hyperlipoproteinemia, 308 Applanation tonometer/tonometry, fluorescein for, 17 Aqueous humor, refractive index of, 38 Aqueous layer (component) of tear film, tests of secretion of, 53-54, 54f, 54l Aqueous tear deficiency, 49- 50, 50/. 51, 511, 52, 55 ~ 65 blepharitis and, 144/, 145 clinical presentation of, 55-56, 56/. 57/, 58t laboratory evaluation of, 57, 59f, 59t medications causing, 55, 61, 661 non-Sjogren syndrome, 50, 51j, 52, 65 Sjogren syndrome, 50, 51f, 52, 63-65, 64t in staphylococcal blepharitis, 14M, 145 systemic diseases associated with, 59t tear composition assays in, 54-55 tests of, 53-54, 54J, 54t

treatment of medical management, 57 ~ 61, 60t surgical management, 61 ~ 63, 61j, 621 Ara-C. See Cytarabine Arcus (corneal), 336- 337, 338f in dyslipoproteinemia/hyperlipoproteinemia, 308, 309(,336 juvenilis, 266, 336 Iipoides, in Schnyder corneal dystrophy, 285, 2851 senilis, 336- 337, 338f Argon laser therapy, ocular damage (laser burns) caused by, 385 Argyriasis, corneal pigmentation in, 337/, 349 Arlt line, 154, ISS Arthritis reactive (Reiter syndrome), 209 rheumatoid peripheral ulcerative keratitis and, 211, 212, 2121 scleritis/scleromalacia perforans and, 220, 220j, 222 Arthropods, 142 - 143, 1421 Arthus reaction, 180, 181 Artificial tears for allergic conjunctivitis, 186 for dry eye, 57, 58, 60t for exposure keratopathy, 80 for Stevens-Johnson syndrome, 196 for Thygeson superficial punctate keratitis, 206 Ascorbic acid (vitami n C) for chemical injuries, 79, 358 deficiency of (scu r vy), 79 Aspergillus (aspergi!losis), ocular infection/keratitis caused by, 139, 166 Astigmatic keratotomy, for astigmatismlrefractive errors after penetrating keratoplasty, 427 Astigmatism corneal topography in detection/management of, 43, 43J, 44 after penetrating keratoplasty, 426, 4271 in keratoconus, 297 after penetrating keratoplasty, management of, 426- 427,427/ corneal topographyin,426,4271 retinoscopy in detection of, 45 Ataxia-telangiectasia (Louis-Bar syndrome), 77, 241 ATD. See Aqueous tear deficiency Atopic dermatitis, 185 keratoconjunctivitis and, 190-1 92, 191f Atopic hypersensitivity (immedi ate/type I) reaction, l78j, 179- 180, 1791 allergic conjunctivitis and, 185 topical medications/substances and, 183, 184, 18'if Atopic keratoconjunctivitis, 190-192, 19 1f Atopy. See under Atopic Atypical granular corneal dystrophy_ See Reis-Bticklers corneal dystrophy Atypical mycobacteria, 164 Autoantibodies in aqueous tear deficiency, 57 in Sjogren syndrome, 57, 64t Autografts conjunctival, 94, 392f, 393-395 for chemical injuries, 358 indications for, 387(, 395

474 • Index for wound closure after pterygium excision, 392f,

393, 393-395 corneal, 413, 431 - 432. See also Keratoplasty limbal, 94, 389, 395-398, 396-397/ for chemical injuries, 94, 358 indications for. 3871

Autoimmune diseases Mooreo ulcer as, 21 3-216. 215/ peripheral keratitis as, 211-213, 21 1t, 212/ scleritis in, 222 AveUino (granular-lattice) corneal dystrophy, 2681, 2701. 278t, 182, 282f genetics of, 269t, 282 Axenfeld anomaly/syndrome. See Axenfeld-Rieger syndrome Axenfeld loop. 9 Axenfeld-Rieger syndrome, 256, lS7/. 2611 Axial curvature, 40, 41f Axial distance, 40 Azithrom},cin for chlamydial conjunctivitis, 157 for trachoma, 156 B-ceU!ymphomas, conjunctival, 244, 245/ B cells (8 lymphocytes) in external eye, 1741 monoclonal proliferation of, corneal deposits and. 319-320 in Sjogren syndrome. 63 Bacillus. 135

cereus, 135 as normal ocular flora, 97r ocular infection caused by. 135 after perforating injury, 375 Bacteria, 131-137, 132t, See a/50 specific organism or

type of infection classification of, 131, 132r conjunctivitis caused by. 149-154. ISOt in children, 149-152 classification of, 149. ISOr in neonates, 152- 154 keratitis caused by, 158- 164, 1601. 160t, 162t. See a/so Keratitis, bacterial as normal flora, 96-97, 97t ocula r infection caused by, 13 1- 137, 132(, 143-164 adherence and, 98, 159 of cornea and sclera, 158- 164, 160f, 160t, 1621, 171 evasion and, 98 of eyelid margin and conjunctiva, 143 - 148 invasion and, 98-99 specimen collection/isolation techniques for diagnosis of, 10 It , 103 scleritis caused by, 17 1, 171f Bacterial cell wall , J31 - [32 Bacteriology, 131 - 137, 1321. See also Bacteria Band keratopathy, calcific (calcium hydroxyapatite deposition), 328, 342-344, 343f in sarcoidosis, 73 Bandage contact lenses, 403 for chemical inju ries, 358 contraindications to in exposure keratopathy, 80 for corneal abrasion, 372 •

for dry eye, 60t, 61,403 for graft-vs-host disease, 203 for perfo rating injury, 375 for peripheral ulcerative keratitis, 213 for recurrent corneal erosions, 84, 403 for Thygeson superficial punctate keratitis, 206 Bare sclera, wound closure afte r pterygium excision and, 391, 39 If Bartonella liellSefae, 136. 157, 158 Basement membrane dystrophies. epithelial (mapdot -fmgerprint/Cogan microcystic/anterior basement membrane), 268/, 270-272, 2701, 271f genetics of, 2691, 270 recurrent corneal erosion and, 83, 271, 272 Basement membrane zone, in cicatricial pemphigoid, 198,201,202/ Basic secretion test, 53-54, 541 Basophils, cytologiC identification of. in immunemediated keratoconjunctivitis, 182t Bee stings, ocular injury caused by, 361-362 Bence Jones protein, corneal deposition of, 319-320 Benign hereditaT)' intraepithelial dyskeratosis, 2261 Benign lymphoid folliculosis, 24, 24f Benign melanosis, 234, 235f acquired,237 Benign monoclonal gam mopathy, corneal deposits in, 320 Be nzalkonium, toxic reactions to, 359, 360 Beta (f3)-blockers dry eye and, 61 for hyphema, 368 Beta (p)-hemolytic group A streptococci (Streptococcus pyogenes), 133, 149 Beta (P)-Iysin, in ex ternal eye defense, 95 Biber-Haab-Dimmer (classic lattice) dystrophy, 268t,

270t, 278-279,279f genetics of, 2691, 278 Bietti crystalline corneoreti nal d ystroph},. 313 Bielli nodular dystrophy, 334-335, 335f See also Spheroidal degeneration Big-H3 gene. See TGFBI gene Biglycan,9 Biguanides, for ACOIlllwlltoeba keratitis, 169 Binary fission, in bacterial replication, 132 Biofilm, microbial, 98. 132 staphylococci forming, 132- 133 Biomechanics of cornea, 9 Biomicroscopy slit-lamp. See Slit-lamp biomicroscopy/examination ultrasound, 33, 33f before corneal transplantation. 417 Bioterrorism, smallpox vaccinatio n and, ocular complications of, 128 Bipedicle (bucket handle) flap, 400 Birth trauma, corneal edema caused by, 265-266, 266/ Bitot spot, 77, 78, 78f Corynebacterium xerosis and, 134 Blepharitis,l44t dry eye and, 53, 53f infectious, IOlt, 143- 149, 14'if 144/, 146/ meibomian gland dysfunction and, 68.143,1441 in rosacea, 69,1441 seborrheic, 71-72.143, 144t

Index. 475 staphylococcal, 143- 148, 14' block, after Descemet stripping automated endothelial keratoplasty, 442 Pupillar y examination, after perforating injury, 374 Purine metabolism, hyperuricemia caused by disorders of,325 Pustule, of eyelid, 201 Pyogenic granuloma, 241 - 242, 241f Rabies virus, ocular infection caused by, \30 Race ocular melanosis and, 238t vernal keratoconjunctivitis and, 187 Racquet (single-pedicle) flaps, 400 Radial keratotomy (RK), iron lines associated with, 336 Radial perineuritis, AWllthamoeba keratitis and, 167 Radiation, anterior segment injury caused by, 352- 353 Radiofrequency, for punctal occlusion, 62 Radius of curvature, corneal, 6, 39 in cornea plana, 254 instantaneous (meridional/ tangential power), 40, 41f keratometry in measurement of, 38- 39 RANTES,I 77! Raynaud phenomenon, cold induced anterior segment trauma and, 351 - 352 RB. See Reticulate body RBCD. See Reis -Biicklers corneal dystrophy Reactive arthritis (Reiter syndrome), 209 Reactive hyperplasia/ reactive lymphoid hyperplasia. See Lymphoid hyperplasia Rebleeding, after traumatic hyphema, 365- 367, 367f Recipient eye preparation for Descemet stripping automated endothelial keratoplasty, 439- 44 1, 440f for penetrating keratoplasty, 418 Recurrent corneal erosion, 83- 85, 85f pain caused by, 83 posttraumatic, 372 Red reflex, in keratoconus, 297

Reflection, specular, for slit -lamp biomicroscopy, 12-14,

14f Reflex secretory block, dry ere and, 50-51 Reflex tear arc non - Sjogren syndrome disorders of, 65 in Sjogren syndrome, 63 Reflex tear secretion, tests of, 54, 54t Refracting power, 39. See also Refractive power Refraction clinical corneal abnormalities affecting, 11 manifest, after penetrating keratoplasty, 426, 427f law of (Snell's law), 38 Refractive errors in cornea plana, 255 after penetrating keratoplasty, management of, 426- 427,427f Refractive index ofcornea,6,38 of tear (fluid) lens, 38 Refractive power, of cornea, 37-38 keratometry in measurement of, 38-39 Refractive surgery astigmatism and, corneal topography in detection! management of, 44 corneal topography and, 43-44, 44/ iron lines associated with, 336 Refsum syndrome (phytanic acid storage disease), ichthyosis and, 74 Regulatory (suppressor) T lymphocytes. See also T cells in atopy, 179- 180 in external eye defense, 96, 174t Reis-Biicklers corneal dystrophy, 2681, 270t, 275-277, 276f genetics of, 269t, 276 Reiter syndrome (reactive arthritis), 209 Rejection (graft), 407, 408, 427-430, 428f, 429f, 436 corneal allograft, 407, 408, 427- 430, 428f, 429f, 436 after lamellar keratoplasty, 436 after penetrating keratoplasty, 427- 430, 428j, 429f HLA/transplantation antigens and, 407 Relaxing incisions, for corneal astigmatism after penetrating keratoplasty, 427 Remicade. See lnfliximab Rendu-Osler-Weber disease (hereditary hemorrhagic telangiectasia), 76 Replication, microbial, as virulence factor, 99 RET oncogene, amyloidosis and, 31 7t Reticulate body, ClJlamydia, 137 Retinal detachment after anterior segment trauma repair, 382 in sarcoidosis, 74 Retinoids, for xerophthalmia/ dry-eye syndrome, 79 Retinopathy, diabetic, neurotrophic keratopathy/ persistent corneal epithelial defect and, 87 Retinoscopy, 45 Retrocorneal fibrous membrane (posterior collagenous layer),29 Retroillumination, for slit-lamp biomicroscopy, 14-15, 16f Retroviruses, 130 Reverse transcriptase, 130 RF. See Rheumatoid factor

506 • Index Rheumatoid arthritis peripheral ulcerative keratitis and, 211, 212, 212/ scleritis/scleromalacia perforans and, 220, 220/, 222 Rheumatoid facto r in aqueous tear deficiency, 57 in Sjogren syndrome, 57 testing for, 182t Rhinophyma, in rosacea, 69 Rhinosporidium seeberi (rhinosporidiosis), 139 Rhinoviruses, 129 RllizopuslRhizopus infection, 140 Richner-Hanhart syndrome, 314 Rieger anomaly/syndrome. See Axenfeld-Rieger syndrome Rifabutin, endothelial pigmentation caused by, 349 Rigid gas-permeable contact lenses, in giant papillary conjunctivitis patients, 195 Riley-Day syndrome (familial dysautonomia) congenital corneal anesthesia and, 264 neurotrophic keratopathy in, 87 River blindness (onchocerciasis), 141 Rizzutti sign, in keratoconus, 297- 298, 298/ RNA viruses, 129- 130 Rosacea, 69-71 , 70I, 71/ blepharitis and, 69, 144t meibomian gland dysfunction and, 67-68, 69, 1441 Rose bengal stain, 17 in tear-film evaluation, 17, 56, 56/ Rotational corneal autograft, 432 Rotational flap, for wound closure after pterygium excision, 392I, 393 Rothmund-Thomson syndrome, 324t Rubella, congenital, 130 Rubeola (measles) virus, 129 Rud syndrome, ichthyosis in, 74 Running sutures, for penetrating keratoplasty, 419, 420/ Rust ring, iron foreign body causing, 371, 371/ Salivary gland biopsy/histology, in Sjogren syndrome, 57, 59f, 63 SALK. See Superficial anterior lamellar keratoplasty Salmon patches, in syphilitic keratitis, 208, 208/ Salmonella, 135 Salzmann nodular degeneration, 340- 341, 34lj Sanfilippo syndrome, 305- 307, 306t Sarcoid granuloma, 73 - 74 Sarcoidosis, 73-74 retina affected in, 74 Sattler veil (central epithelial edema), 91 Scanning-slit confocal microscope, 36. See also Confocal microscopy Scanning-slit systems/topography for anterior segment imaging, 34, 35/ for pachometry, 28 Scattering, light, fo r slit-lamp biomicroscopy, 14, 15/ SCCD (Schnyder crystalline corneal dyst rophy) . See Schnyder corneal d ystrophy SCD. See Schnyder corneal dystrophy Scheie syndrome, 305 , 306t congenital/infantile corneal opacities and, 263 Scheimpflug camera for anterior segment imaging, 34, 34.f for pachometry, 28, 29f

Schirmer tests, 53, 54, 54I, 54t type I, 54, 54t type II, 54, 54! Schlichting dystrophy. See Posterior polymorphous corneal dystrophy Schnyder corneal dystrophy, 268t, 270t, 284- 285, 285J, 309 genetics of, 269t, 284 Schwalbe line/ring in Axenfeld-Rieger syndrome, 256 in posterior embryotoxon, 255, 256f Schwannoma, conjunctival, 240 Sclera, 9 aging of, 9, 345- 346, 346f anatomy of, 9 bare, wound closure after pterygium excision and, 391,392f blue, 252- 253 in Ehlers-Danlos syndrome, 252, 325 in keratoglobus, 302 in Marfan syndrome, 325 in osteogenesis imperfecta, 252 congenital anomalies of, 249-253 degenerations of, 345- 346, 346f development of, 4 disorders of, 21 t degenerations, 345- 346, 3461 immune-mediated, 217- 223, 218J, 218t, 219J, 220J, 22 If ionizing radiation causing, 352- 353 infection/inflammation of, 21t, 28. See also Episc1eritis; Scleritis innervation of, 9 perforation o f, repair of, 377-378, 379f See also Corneosc1erallaceration, repair of pigment spot of, 233 Scleral contact lenses in dry-eye patients, 61 for graft-vs-host disease, 204, 204f Scleral dellen, 91 Scleral plaques, senile, 9, 345- 346, 346f Scleritis, 21t, 117- 223, 218J, 218t, 219I, 220J, 221f anterior, 28, 218, 218J, 218 t, 219f complications of, 220-222, 22 If corticosteroids for, 222, 223 diffuse, 218, 218f in herpes zoster, 120 immune-mediated, 181,2 17-223, 218J, 218t, 219f, 2'0f, 22lf laboratory evaluation of, 222 management of, 222 - 223 microbial, 171, 171/ necrotizing, 21 t, 28, 218-220, 218t, 219I, 220I, 222, 223 with inflammation, 2181, 219, 219f without inflammation (scleromalacia perforans), 2181,220,220/ nodular, 218, 219/ nonnecrotizing, 2It, 28 posterior, 218t, 220, 22 1/ subtypes and prevalence of, 2181 Sclerocornea, 258, 260J, 2621 cornea plana and, 254, 255, 258

Index . 507 Sclerokeratitis, 22 1-222,221[,223 Scleromalacia, 28 perforans, 218t, 220, 220f Sclerotic scatter, for silt-lamp biom icroscopy, 14, 15/ Scraping, for specimen collection, 47, 102-103 Scurvy (vitamin C deficiency). 79 Seasonal allergic conju nctivitis, 185-187 Sebaceous carcinoma, 233. 234f Sebaceous glands of eyelid, 4 . tumo rs arising in, 233, 234f Seborrheic blepharitis, 71-72, 143, 144t Secretory IgA, 173 in external eye defense, 95 Seidel test, 17, 19f Semilunar fold. 4 Senile furrow degeneration, 339 Senile scieraUcalcific plaques, 9, 345-346, 346/ Sensation, in cornea. 6 esthesiometry in evaluation of, 30-31 reduction of in diabetes mellitus, 308 in herpes simplex epithelial keratitis, 110 in neurotrophic keratopathy, 87 Septata, keratoconjunctivitis caused by, 170 Septate filamen tous fungi , 138, 138[, 138t, 139 Serratia, 135 Serum drops fo r dry eye. 60 fo r neurotrophic keratopathy, 88 Shagreen, crocodile, 337 Sha rps containers, in infection control, 46 Shield ulcer, 187, 189f Shigella, 135 Shingles. See Herpes zoster Sialic acid, in microbial adherence, 98 Sialidoses, dysmorphic. 312 Sickle cell disease. traumatic hyphema and, 369 Siderosis, corneal pigmentation in. 337t Silkone plugs, for dry eye, 61-62, 621 Silver compounds. corneal pigmentation caused by. 337t, 349 Simple (diffuse) episcieritis. 28, 2 16 Single-pedicle (racquet) flaps, 400 Single-sided disk confocal microscope, 36 Sipple-Gorlin syndrome, enlarged corneal nerves in, 328-329,3291 Sjogren-Larsson syndrome, ichthyosis in, 74 Sjogren syndrome, 63-65, 64/ aqueous tear deficiency/ dry eye and, 50, 5 1J, 52 classification of, 63, 64t laboratory evaluation in diagnosis of, 57, 59/. 59t Sjogren Syndrome Foundation, 61 Skeletal disorders. See also Connective tissue disorders corneal changes in, 322-324 t Skill desquamating disorde rs of, ocular surface involved in.74 eyelid,4 Ski n grafts. See Grafts SLC4A /1 gene, in congenital hereditary endothelial dystrophy, 2691, 296 Sliding flap, for wound closure after pterygium excision, 39 1.392f

Slit illumination, for slit-lamp biomicroscopy, 12, 13/ Slit -lamp biomicroscopy/examination, 12- 16 clinical procedure for, 15- 16 illumination system of direct illumination methods and, 12- 14, 13[, 14/ indirect illumination methods and, 14-15, ISj, 16f in recurrent corneal erosions, 83 Slit-lamp photography, 3 1 SLK. See Superior limbic keratoconjunctivitis Slow-reacting substance of anaphylaxis, 1791 Smallpox vaccination, ocular complications of, 128 SMAS (Specular Microscopy Ancillary Study), 411 Smooth muscle tumors, 240 Snell's law (law of refraction), 38 Snow blindness, 352 Sodium borate transporter. member II (SLC4A 11) gene, in congenital hereditary endothelial dystrophy, 2691.296 Sodium citrate, for chemical injuries, 358 Soft (flexible) contact lenses conjunctivitis caused by, 193-195 neovascularization associated with, 92 Soil contamination, in ocular inju ry, Bacillus endophthalmitis and, 375 SP. See Swelling pressure Specimen collection/ hand ling for ocular cytology. 47-48 for ocular microbiology, 100-103, 101t, 102/ Spectacle lenses (spectacles), for dry eye, 61 Spectinomycin, for gonococcal conjunctivitis, 152 Specular Microscopy Ancillary Study (SMAS), 411 Specular microscopy/photomicroscopy, 14, 31-33,32/ Specular reflection, for slit -lamp biomicroscopy, 12 - 14,

I'f

Spherocytosis, corneal deposits and, 328 Spheroidal degeneration (Labrador keratopalhy), 334-335,335/ Sphingolipidoses, 310-311 corneal changes in, 310-311, 311/ Spindle cell carcinoma, 233 Spirochetes, 137 SPK. See Thygeson superficial punctate keratitis Spon taneous hyphema. 365 Squamous cell carcinoma, of conj unctiva, 226t, 231-232,232/ Squamous dysplasia, of conjunctiva, 228 SS. See Sjogren syndrome SS antibodies in aqueous tear deficienc)" 57 in Sjogren syndrome. 57, 64t SSCM . See Scanning-slit confocal microscope SSPE. See Subacute sclerosing panencephalitis Stains/staining techniques, 17, 18f, 19/ for microbial keratitis. 103t Stamler lid splint, 39 1 Staphylococcus, 132-133

aureus blepharitis/blepharoconjunctivitis caused by, 143-148, 144J, 144t, 146J, 150 hordeolum caused by, 148 keratitis caused by, 145- 146, 146f as normal ocular fl ora, 96, 97/

508 • Index blepharitis/ blepnaroconjunclivilis caused by, 1011, 143 - 148, 144f, l.t4r, 145, 146f, 150 kcralilisand, 1-l5-146, 146/ marginal infLItrates in, 145, 146f, 147,210 epidermidis, as normal ocular nora, 96, 97t hordeolum caused by. 148 as normal ocular flora, 96, 971 Staphylomas congenital, 258-260, 262t. 263/ in scleromalacia perforans, 220 "'Stare test;' 56 Stem cell transplantation. See Limbal transplantation Stem cells, 5, 6, 9, 92- 93 . See also Limbal stem cells conjunctival,92 corneal, 5, 6, 9, 92- 93, 389 in corneal and conjunctival wound healing/repair. 388 Stevens-Johnson syndrome (erythema muhiforme major), 195-198, 1961, 197/, 198! mucous membrane grafting for, 198,401 Stiles-Crawford effect, 37 Stocker-Holt variant .Meesmann corneal d ystrophy, 272 . See also Meesmann corneal Uuvenile hereditary epithelial) dystrophy Stocker lines, 332, 3371 Strabismus, nanophthalmos and, 251 StrepIOCOcwS, 133, 133f conjunctivitis caused by, IOlt, 149-150 keratitis caused by, 159, 160/ after penetrating keratoplasty, 425 as normal ocular flora, 96, 971 persistence and, 99 pllelllnolliae (pneumococcus), 133, 133f conjunctivitis caused by, 149-\50 as normal ocular flora, 96 pyogenes (group A p-hemolytic), l33, 149 Streptolysin, 133 Striate keratopathy. intraocular surgery causing, 383 Striate melanokeratosis, 234 Stroma conjunctival. See Substantia propria corneal, 7-8, 7f, 8f anatomy of, 7-8, 7f, 8f development of, 4 inflammation of, 25, 17f, 271 in systemic infections, 169-170 neovascularization of, contact lenses caUSing, 92 pigmentation of, 348-349 drug-induced,3471 refractive index of, 38 Stromal corneal dystrophies, 2681, 278-290, 278t Avellino (granular type 2), 2681, 2691, 2701, 278t, 282,

282/ central doudy of Franlfois. 2681, 270t, 289-290, 289f genetics of, 2691, 289 congenital/congenital hereditary, 260, 2681, 2701,

286-287,286/ genetics of, 2691, 286 Fleck, 2681, 2701, 287, 287f genetics of, 2691, 287 granular, 2681, 278t. See also Granular corneal dyslropb}' type I (dassic/CeD!), 268t, 2701, 480-281, 28 1/ type 2 (granular-lattice/ Avellino), 2681, 2691, 2701, 278t, 282, 282f

lattice, 2681, 278t. See a/so Lattice corneal drstrophy macular. 2681, 2701, 2781, 283-284, 28'if genelics of, 269t, 283 non-TGFB I-associated, 268t. 283-290 posterior amorphous, 2681, 2701, 288- 289, 288/ genelics of, 269t, 288 pre-Descernet, 268f, 269t, 270t, 290, 290/ genetics of, 269(, 290 Schnyder, 268t, 270t, 284-285, 28Sj, 309 genetics of, 269r, 284 TGFBI -associated, 268t. 278-282. 278r Stromal degenerations, 336-344 age-relatedlinvolutional changes and, 336-338, 338f,

339/ peripheral, 339- 340, 340/ poslinOammatory changes and, 340- 344, 34 If, 342f,

343/ Stromal edema, 29 Stroma! graft rejection, 429. See also Rejection Stromal keratitis, 21 t, 25, 27f, 271 in Cogan syndrome, 209, 210 Epstein -Barr virus causing. 122-123, 123f herpes Simplex virus caUSing, 108t, 113-116, 114f,

115/ penetrating keratoplast» for, 11 7 in herpes zoster ophlhalmicus, 120 microsporidial, 170 necrotizing, 25 non necrotizing, 27f nonsuppurative, 2It, 25, 27f, 271 systemic infections and, 169-170 scleritis and, 221 suppurative, 21 t, 25, 27[, 27t syphilitic, 207, 208 Stromal micropuncture, for recurrent corneal erosions,

84,85/ Slurge-Weber syndrome, port-wine stain in, 241 Slye (external hordeolum), 148 Subacute sclerOSing panencephalitis, 129 Subconjunctival fibrosi s, medications causing.

360-361 Subconjunctival hemorrhage, 75, 76, 761, 362-363 Subepithelial corneal degenerations, 334-336, 335f Subepithelial corneal dystrophies. See Epithelial/ subepithelial dystrophies Subepithelial corneal infiltrate, 21 t Subepithelial graft rejection , 428-429, 428f See a/50 Rejection Substance P, 177t Substantia propria, conjunctival (conjunctival stroma), 5-6 age-relatedlin\,olutional changes in, 331 in external eye defense, 96 immune and inflammatory cells in, 173, 1741 Sulfatase deficiency, multiple. 3 LO Sunflower cataract, in Wilson disease, 327 Superficial anterior lamellar keratoplasty (SALK), 413, 415-416/, 435 advantages of, 4161 complications of intraoperative, 415t postoperative, 41St disadvantages of, 4161 indications for, 4151

Index . 509 penetrating/selective keratoplasty compared with, 415- 4161 surgica l technique for, 435 Superficial granular corneal dystrophy. See ReisBUcklers corneal dystrophy Superficial keratectomy, 402-403 Superficial punctate keratitis ofThygeson, 204-207, 206/ Su perior limbic keratoconjunctivit is, 81-82, 821 Supp r~ssor (regulatory) T cells. See ITlso T cells in atopy, 179-180 in external eye, 96, 1741 Supratarsa l corticosteroid injec tions, for vernal keratoconjunctivitis, 189 Sutures (surgical) for penetrating keratoplasty. 418-419, 419j, 4201 postoperative problems and, 423-425, 4241 removal of in children, 431, 4311 removal of after corneosd eral laceration repai r, 382 after pediatric corneal transplantation, 431, 431t Swabbi ng, for specimen collection, 47, 100- 102 Sweat gla nds of eyelid, 'I Swelling pressure, 8 Symblepharon in cicat ricial pemphigoid, 200, 202, 2JOj in Stevens-Johnson syndrome, 197, 198! Sympathetic ophthalmia, en ucleation in prevention of, 376 Syncchiolysis, with penetrating keratoplasty, 419-420 Syphilis. 13i congenital/intrauterine, corneal manifestations of, 207-209, 20Sf, 264 interstitia l keratitis caused by, 207-209, 208j, 264 T cells (T lymphocytes) in anaphylactic/atopic (type I) rellctions, 179-180 in cel1·mediated immunit)" 180 in externlll eye, 96, 174t in herpetic stromal kerati tis, 114 in HJV infection/AIDS, 130 ki11er, 180 in Sjogren syndrome, 63 T helper cells in anaphylactic/atopic (type I) rea ctions, 179 in delayed hypersen sitivity (type JV) reactions, 180 in ex ternal eye, 174t T helper-I cells, 177 in delayed hypersensi tivity (type JV) reactions, 180 T helper-2 ceils, in anaphylactic/atopic (type 1) reactions, 179 Tacrolimus for allergic conjunctivitis, 187 for atopic dermatitis, 185 for corn eal graft rejection, 430 for graft-vs -host disease. 203 for Thygeson superficial punctllte keratitis, 206 TACSTD2 gene, in gelatinous droplike corneal dystrophy, 269(, 274 Taellia solil/m (pork tapeworm), 142 Tandem sca nning confocal microscopy, 36. See also Confoca l microscopy T;lngential power (instantan eolls mdius of curvature), 40,4 1/

T:mgier d isease, 310 Tapeworm, pork ('{(leni(l SOUl/III), 142 Tarantula hairs. ocular inflammation c all~ed by, 362 TarSlI l conjunctiva, 4. See (I/so Conj unctiva in superior limbic keratoconjunctivitis, 81, 82 Tarsal plates/tllrslls, 4, 51 Tarsoconju nctival grafts. for chemical injuries, 358 Tarsorrhaph)'.390-391 for chemical injuries. 358 for dry eye, 6Ot, 62 for exposure keratopathy, 80 for neurotrophic kerlltopathy, 88 for persistent corneal epit heli al defects, 87 Tarsotomy, for trichiasis, 89 Tattoo, corneal, 337r, 405 Tay-Sachs disease (GM! gangliosidOSiS type 1), 310 TBCD. See 'J·hid·Behnke corneal dystrophy TBU'I: See Tear breakup lime TCF8, in posterior polymorphous corneal dystrophy, 293 Tear breakup, 52 Tear breakup time, 52-53 nuorescein in evaluation of. 17,52-53 Tear defiCiency states. See a/so specific lype and Dry-eye syndrome aqueous tear deficiency, 49-50, 50f, 51, 51j, 52, 55-65 evaporative tear dysfunction, 51, 51f, 52, 65-75 rose bengal in evaluation of, 17 tests of, 53-54, 54j, 541 Tea r film (tears), 175- 177, 1771 bloody, 76 composition of, assays of, 54-55 evaluation of, 52-55, 53j, 54[. 541 nuorescein for, 17 in external eye defense, ), 95 immune response/immunol ogic feiltures of, 175-1 77, 1771 in ~pec tion in eVllluation of, 52-53, 53! instability of, 48-49, 49-50, 50! osmolarity of, 54 refractive index of, 38 secretion of, tests of, 53-54. 54f, 541 Tea r hyperosmolarity, dry eye